Journal of Medicinal Chemistry
Article
purifying by reverse phase HPLC using a gradient of 30−100%
acetonitrile in water containing 0.1% formic acid.
2H), 7.14−7.22 (m, 1H), 6.66−6.72 (m, 2H), 5.27 (s, 2H). MS: m/z
= 472.1 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-
5-(4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-
quinazolin-6-yl)pyrimidine-2,4(1H,3H)-dione (10j). Yielded 2.6
mg (7.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.76−
9.82 (brs, 1H), 8.47−8.59 (m, 2H), 8.30 (s, 1H), 8.04 (m, 2H), 7.81−
7.88 (m, 1H), 7,71−7.80 (m. 2H), 7.59−7.67 (m, 1H), 7.43−7.50 (m,
1H), 7.31−7.36 (m, 1H), (m, 7.23−7.31 (m, 2H), 7.18 (t, J = 8.4 Hz,
1H), 5.26 (s, 2H). MS: m/z = 490.0 (M + H)+.
(morpholinosulfonyl)phenyl)quinazolin-4-amine (10a). Yield:
1
48.1%. H NMR (500 MHz, DMSO-d6) δ: 10.00 (s, 1H), 8.92 (d, J
= 1.46 Hz, 1H), 8.64 (s, 1H), 8.28 (dd, J = 1.95, 8.79 Hz, 1H), 8.17 (d,
J = 8.79 Hz, 2H), 8.04 (d, J = 2.44 Hz, 1H), 7.92 (d, J = 8.79 Hz, 3H),
7.76 (dd, J = 2.45, 8.80 Hz, 1H), 7.46−7.50 (m, 1H), 7.30−7.36 (m,
3H), 7.19−7.23 (m, 1H), 5.28 (s, 2H), 3.66−3.68 (m, 4H), 2.93−2.95
(m, 4H). MS: m/z = 605.2 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-methyl-
naphthalen-1-yl)quinazolin-4-amine (10b). Yielded 1 mg (2.6%)
as a yellow film. 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 8.65
(s, 2H), 8.15 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.87−7.96
(m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.71−7.76 (m, 1H), 7.63 (t, J = 8.0
Hz, 1H), 7.49−7.57 (m, 2H), 7.42−7.49 (m, 2H), 7.31 (t, J = 6.0 Hz,
2H), 7.25 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 7.3 Hz, 1H), 5.24 (s, 2H),
2.74 (s, 3H). MS: m/z = 520.1 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(3-
(morpholinosulfonyl)phenyl)quinazolin-4-amine (10k). Yield:
1
30.4%. H NMR (500 MHz, DMSO-d6) δ: 10.01 (s, 1H), 8.85 (d, J
= 1.95 Hz, 1H), 8.63 (s, 1H), 8.24−8.27 (m, 2H), 8.12 (t, J = 1.71 Hz,
1H), 8.03 (d, J = 2.93 Hz, 1H), 7.86−7.92 (m, 2H), 7.80−7.85 (m,
1H), 7.73 (dd, J = 2.44, 8.79 Hz, 1H), 7.46−7.52 (m, 1H), 7.30−7.35
(m, 3H), 7.17−7.22 (m, 1H), 5.28 (s, 2H), 3.66 (t, J = 4.90 Hz, 4H),
2.95 (t, J = 4.40 Hz, 4H). MS: m/z = 605.1 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-(piperidin-
1-ylsulfonyl)phenyl)quinazolin-4-amine (10l). Yield: 14.6%. 1H
NMR (500 MHz, DMSO-d6) δ: 10.00 (s, 1H), 8.91 (d, J = 1.46 Hz,
1H), 8.64 (s, 1H), 8.27 (dd, J = 1.95, 8.30 Hz, 1H), 8.14 (d, J = 8.30
Hz, 2H), 8.04 (d, J = 2.93 Hz, 1H), 7.89−7.92 (m, 3H), 7.76 (dd, J =
2.69, 9.03 Hz, 1H), 7.46−7.51 (m, 1H), 7.31−7.36 (m, 3H), 7.20 (dt,
J = 2.44, 8.55 Hz, 1H), 5.28 (s, 2H), 2.95−2.98 (m, 4H), 1.55−1.60
(m, 4H), 1.39−1.40 (m, 2H). MS: m/z = 603.2 (M + H)+.
4-(4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-
quinazolin-6-yl)-N-ethyl-2-fluorobenzamide (10c). Yielded 1 mg
1
(2.4%) as a yellow film. H NMR (400 MHz, DMSO-d6) δ: 9.98 (s,
1H), 8.87 (s, 1H), 8.58−8.61 (s, 1H), 8.35−8.42 (m, 1H), 8.26−8.34
(m, 1H), 8.01 (s, 1H), 7.87 (d, J = 4.4 Hz, 1H), 7.84 (m, 2H), 7.79 (d,
J = 8.1 Hz, 1H), 7.70−7.76 (m, 1H), 7.47 (q, J = 7.3 Hz, 1H), 7.32
(dd, JA = 13.2 Hz, JB = 7.3 Hz, 3H), 7.18 (t, J = 8.8 Hz, 1H), 5.27 (s,
2H), 3.29 (q, J = 8.0 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H). MS: m/z =
545.2 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(3-(piperidin-
1
1-ylsulfonyl)phenyl)quinazolin-4-amine (10m). Yield: 24.8%. H
NMR (500 MHz, DMSO-d6) δ: 10.01 (s, 1H), 8.84 (d, J = 1.95 Hz,
1H), 8.62 (s, 1H), 8.24 (dd, J = 1.95, 8.79 Hz, 1H), 8.21 (d, J = 7.35
Hz, 1H), 8.11 (t, J = 1.71 Hz, 1H), 8.02 (d, J = 2.44 Hz, 1H), 7.90 (d, J
= 8.30 Hz, 1H), 7.82−7.86 (m, 1H), 7.79−7.81 (m, 1H), 7.72 (dd, J =
2.69, 9.03 Hz, 1H), 7.45−7.51 (m, 1H), 7.29−7.36 (m, 3H), 7.19 (dt,
J = 2.44, 8.55 Hz, 1H), 5.27 (s, 2H), 2.96 (t, J = 5.4 Hz, 4Hm, 4H),
1.52−1.60 (m, 4H), 1.33−1.40 (m, 2H). MS: m/z = 603.2 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-(pyrrolidin-
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(3-(5-methyl-
1,3,4-oxadiazol-2-yl)phenyl)quinazolin-4-amine (10d). Ob-
tained 1 mg (2.5% yield) as a yellow oil. 1H NMR (400 MHz,
DMSO-d6) δ: 9.09−10.04 (brs, 1H), 8.88 (s, 1H), 8.61 (s, 1H), 8.42
(s, 1H), 8.37 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.1 Hz,
1H), 8.0 (m, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.72−7.81 (m, 2H), 7.43−
7.51 (m, 1H), 7.28−7.36 (m, 2H), 7.14−7.22 (m, 1H) 5.26 (s, 2H),
2.65 (s, 3H). MS: m/z = 538.1 (M + H)+.
1
1-ylsulfonyl)phenyl)quinazolin-4-amine (10n). Yield: 19.6%. H
3-(4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-
quinazolin-6-yl)-N-cyclopropylbenzamide (10e). Yielded 0.8 mg
NMR (500 MHz, DMSO-d6) δ: 10.00 (s, 1H), 8.91 (d, J = 1.95 Hz,
1H), 8.63 (s, 1H), 8.27 (dd, J = 1.95, 8.79 Hz, 1H), 8.13 (d, J = 8.30
Hz, 2H), 8.03 (d, J = 2.44 Hz, 1H), 7.98 (d, J = 8.79 Hz, 2H), 7.90 (d,
J = 8.79 Hz, 1H), 7.76 (dd, J = 2.44, 8.79 Hz, 1H), 7.45−7.52 (m, 1H),
7.29−7.36 (m, 3H), 7.20 (dt, J = 2.44, 8.55 Hz, 1H), 5.28 (s, 2H), 3.22
(t, J = 6.84 Hz, 4H), 1.66−1.72 (m, 4H). MS: m/z = 589.1 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(3-(pyrrolidin-
1
(2.0%) as a yellow film. H NMR (400 MHz, DMSO-d6) δ: 10.00 (s,
1H), 8.83 (s, 1H), 8.63 (d, J = 3.7 Hz, 1H), 8.59 (s, 1H), 8.35 (s, 1H),
8.26 (d, J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.97−8.05 (m, 1H), 7.87 (t, J =
8.1 Hz, 2H), 7.74 (dd, JA = 8.8 Hz, JB = 2.0 Hz, 1H), 7.63 (t, J = 7.7
Hz, 1H), 7.43−7.52 (m, 1H), 7.25−7.35 (m, 2H), 7.17 (t, J = 8.0 Hz,
1H), 5.27 (s, 2H), 2.85−2.92 (m, 1H), 0.69−0.76 (m, 2H), 0.58−0.65
(m, 2H). MS: m/z = 539.2 (M + H)+.
1
1-ylsulfonyl)phenyl)quinazolin-4-amine (10o). Yield: 28.2%. H
NMR (500 MHz, DMSO-d6) δ: 10.03 (s, 1H), 8.85 (d, J = 1.46 Hz,
1H), 8.62 (s, 1H), 8.26 (dd, J = 1.95, 8.79 Hz, 1H), 8.18−8.23 (m,
2H), 8.03 (d, J = 2.44 Hz, 1H), 7.88−7.93 (m, 2H), 7.81−7.87 (m,
1H), 7.73 (dd, J = 2.44, 8.79 Hz, 1H), 7.45−7.52 (m, 1H), 7.30−7.37
(m, 3H), 7.20 (dt, J = 2.44, 8.55 Hz, 1H), 5.28 (s, 2H), 3.23 (t, J =
6.84 Hz, 4H), 1.68 (td, J = 3.54, 6.59 Hz, 4H). MS: m/z = 589.2 (M +
H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(quinolin-5-
yl)quinazolin-4-amine (10f). Yielded 3.2 mg (8.4%) as a yellow
solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.81 (s, 1H), 8.98 (d, J = 2.9
Hz, 1H), 8.70 (s, 1H), 8.68 (s, 1H), 8.21−8.27 (m, 1H), 8.14 (d, J =
8.1 Hz, 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.95−8.00 (m, 1H), 7.88−7.95
(m, 2H),7.68−7.96 (m, 2H), 7.53−7.59 (dd, JA = 8.4 Hz, JB = 4.0 Hz,
1H), 7.46 (q, J = 8.0 Hz, 1H), 7.22−7.33 (m, 3H), 7.17 (t, J = 8.8 Hz,
1H), 5.23 (s, 2H). MS: m/z = 507.2 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methyl-
piperazin-1-yl)sulfonyl)phenyl)quinazolin-4-amine (10p). Yield:
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(2-
1
phenoxyphenyl)quinazolin-4-amine (10g). Yielded 1.4 mg
30.6%. H NMR (500 MHz, DMSO-d6) δ: 9.95 (s, 1H), 8.87 (d, J =
1
(2.4%) as an orange oil. H NMR (400 MHz, DMSO-d6) δ: 9.85 (s,
1.46 Hz, 1H), 8.59 (s, 1H), 8.23 (dd, J = 1.95, 8.79 Hz, 1H), 8.11 (d, J
= 8.30 Hz, 2H), 7.99 (d, J = 2.44 Hz, 1H), 7.83−7.90 (m, 3H), 7.71
(dd, J = 2.69, 9.03 Hz, 1H), 7.40−7.47 (m, 1H), 7.25−7.32 (m, 3H),
7.15 (dt, J = 2.44, 8.55 Hz, 1H), 5.23 (s, 2H), 2.91 (br s, 4H), 2.34 (br
s, 4H), 2.11 (s, 3H). MS: m/z = 618.2 (M + H)+.
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-((4-methyl-
1,4-diazepan-1-yl)sulfonyl)phenyl)quinazolin-4-amine (10q).
Yield: 42.8%. 1H NMR (500 MHz, DMSO-d6) δ: 10.00 (s, 1H),
8.91 (d, J = 1.95 Hz, 1H), 8.63 (s, 1H), 8.27 (dd, J = 1.95, 8.79 Hz,
1H), 8.12 (d, J = 8.80 Hz, 2H), 8.03 (d, J = 2.44 Hz, 1H), 7.96 (d, J =
8.30 Hz, 2H), 7.90 (d, J = 8.79 Hz, 1H), 7.76 (dd, J = 2.69, 9.03 Hz,
1H), 7.45−7.50 (m, 1H), 7.30−7.36 (m, 3H), 7.20 (dt, J = 2.44, 8.55
Hz, 1H), 5.28 (s, 2H), 3.37−3.39 (m, 2H), 3.34 (t, J = 6.10 Hz, 2H),
2.61−2.64 (m, 2H), 2.54−2.58 (m, 2H), 2.28 (s, 3H), 1.74−1.80 (m,
2H). MS: m/z = 632.2 (M + H)+.
1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.01−8.06 (m, 2H), 7.72−7.78 (m,
2H), 7.67 (d, J = 6.6 Hz, 1H), 7.42−7.51 (m, 2H), 7.24−7.39 (m,
6H), 7.19 (t, J = 7.3 Hz, 1H), 7.00−7.09 (m, 2H), 6.94 (d, J = 8.1 Hz,
2H), 5.27 (s, 2H). MS: m/z = 548.1 (M + H)+.
6-(Benzo[b]thiopen-2-yl)-N-(3-chloro-4-((3-fluorobenzyl)-
oxy)phenyl)quinazolin-4-amine (10h). Obtained 5.4 mg (14%
1
yield) as a yellow solid. H NMR (400 MHz, DMSO-d6) δ: 8.75 (s,
1H), 8.15 (t, J = 8.8 Hz, 1H), 8.03 (m, 1H), 7.96 (d, J = 8.8 Hz, 1H),
7.87 (d, J = 2.1 Hz, 2H), 7.82 (d, J = 7.3 Hz, 1H), 7.68 (s, 1H), 7.51−
7.59 (m, 1H), 7.49 (s, 1H), 7.32−7.44 (m, 3H), 7.19−7.25 (m, 1H),
6.91−7.09 (m, 2H), 5.27 (s, 2H). MS: m/z = 512.0 (M + H)+.
4-(4-((3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-
quinazolin-6-yl)phenol (10i). Yielded 1 mg (2.4%) as a yellow film.
1H NMR (400 MHz, DMSO-d6) δ: 10.09 (s, 1H), 8.98 (s, 1H), 8.63
(s, 2H), 8.45 (s, 1H), 8.42 (s, 1H), 8.05 (s, 1H), 7.96 (d, J = 8.8 Hz,
1H), 7.82 (d, J = 9.5 Hz, 1H), 7.43−7.51 (m, 2H), 7.27−7.36 (m,
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(4-
(thiomorpholinosulfonyl)phenyl)quinazolin-4-amine (10r).
H
dx.doi.org/10.1021/jm400349k | J. Med. Chem. XXXX, XXX, XXX−XXX