7
996
X. Zhang et al. / Bioorg. Med. Chem. 21 (2013) 7988–7998
7
1
.02–7.06 (m, 1H), 7.52–7.54 (m, 1H), 7.81–7.82 (m, 1H), 8.55 (s,
H), 8.64 (s, 1H), 8.68 (s, 1H). ESI-MS m/z 520 [M+H] .
2H), 3.12 (s, 3H), 3.50–3.54 (m, 2H), 3.85–4.08 (m, 4H), 5.21 (m,
1H), 7.06 (s, 1H), 7.16–7.22 (m, 1H), 7.60–7.66 (m, 1H), 7.96–7.99
+
+
(
m, 1H), 8.40 (s, 1H), 8.50 (s,1H). ESI-MS m/z 517 [M+H] .
6
.1.11. (S)-1-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-3-(3-
6.1.16. (S)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-3-hydroxyazetidine-1-carboxa-
mide (8p)
Compound 8p was synthesized by following the procedure de-
scribed for 8a using azetidin-3-ol instead of 2-aminoethanol. The
(
dimethylamino)propyl)urea (8k)
Compound 8k was synthesized by following the procedure de-
1
1
scribed for 8a using N ,N -dimethylpropane-1,3-diamine instead of
-aminoethanol. The crude was purified by flash chromatography
2
1
on silica gel to provide the desired product 8k in 83% yield.
NMR (400 MHz, CDCl ) d 2.12–2.21 (m, 2H), 2.33–2.40 (m, 2H),
H
crude was purified by flash chromatography on silica gel to provide
1
3
the desired product 8p in 81% yield. H NMR (300 MHz, CD
3
OD) d
2
1
6
8
.77 (s, 6H), 3.04–3.15 (m, 2H), 3.31–3.35 (m, 1H), 3.44–3.48 (m,
H), 3.90–3.95 (m, 2H), 4.17–4.22 (m, 2H), 5.11 (s, 1H), 6.95–
.99 (m, 2H), 7.38–7.40 (m, 1H), 7.54–7.57 (m, 1H), 8.21 (s, 1H),
2.15–2.22 (m, 1H), 2.36–2.40 (m, 1H), 2.78 (br s, 1H), 3.88–4.07 (m,
4H), 4.39–4.47 (m, 4H), 5.08 (m, 1H), 6.96–7.07 (m, 3H), 7.43–7.47
(m, 1H), 7.72–7.75 (m, 1H), 8.15 (s, 1H), 8.55 (s, 1H), 8.64 (s, 1H).
+
+
.44 (s, 1H), 8.53 (s, 1H), 8.75 (s, 1H). ESI-MS m/z 503[M+H] .
ESI-MS m/z 474 [M+H] .
6
.1.12. (S)-1-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
6.1.17. (S)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-3-fluoroazetidine-1-carboxami-
de (8q)
furan-3-yloxy)quinazolin-6-yl)-3-(3-(diethylamino)propyl)urea
8l)
Compound 8l was synthesized by following the procedure de-
(
Compound 8q was synthesized by following the procedure de-
scribed for 8a using 3-fluoroazetidine instead of 2-aminoethanol.
The crude was purified by flash chromatography on silica gel to
1
1
scribed for 8a using N ,N -diethylpropane-1,3-diamine instead of
-aminoethanol. The crude was purified by flash chromatography
2
1
1
on silica gel to provide the desired product 8l in 73% yield.
NMR (400 MHz, CDCl ) d 1.27 (t, J = 7.2 Hz, 6H), 1.33–2.26 (m,
H
provide the desired product 8q in 83% yield. H NMR (400 MHz,
3
3
CDCl ) d 2.18–2.40 (m, 2H), 3.92–4.04 (m, 4H), 4.14–4.36 (m,
2
3
2
8
5
H), 2.26–2.39 (m, 2H), 2.94–3.12 (m, 6H), 3.19–3.39 (m, 2H),
.86–3.95 (m, 2H), 4.11–4.17 (m, 2H), 5.02 (s, 1H), 6.85–6.89 (m,
H), 7.29–7.33 (m, 1H), 7.42–7.44 (s, 1H), 7.77–7.80 (m, 1H),
.29 (s, 1H), 8.46 (s, 1H), 8.73 (s, 1H), 8.77 (s, 1H). ESI-MS m/z
4H), 5.08 (s, 1H), 5.28 (d, J = 57.2 Hz, 1H), 6.83 (s, 1H), 6.98–7.08
(m, 2H), 7.45 (s, 1H), 7.73–7.74 (m, 1H), 8.36 (s, 1H), 8.53 (s, 1H),
+
8.65 (s, 1H). ESI-MS m/z 476 [M+H] .
+
31 [M+H] .
6.1.18. (S)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-3,3-difluoropyrrolidine-1-car-
boxamide (8r)
6
.1.13. (S)-3-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-1-(2-(dimethylamino)ethyl)-1-
methylurea (8m)
Compound 8r was synthesized by following the procedure de-
scribed for 8a using 3,3-difluoropyrrolidine instead of 2-aminoeth-
anol. The crude was purified by flash chromatography on silica gel
Compound 8m was synthesized by following the procedure de-
1
1
2
1
scribed for 8a using N ,N ,N -trimethylethane-1,2-diamine instead
to provide the desired product 8r in 87% yield. H NMR (400 MHz,
of 2-aminoethanol. The crude was purified by flash chromatogra-
3
CDCl ) d 2.13–2.20 (m, 1H), 2.33–2.40 (m, 1H), 2.42–3.52 (m, 2H),
phy on silica gel to provide the desired product 8m in 81% yield.
H NMR (400 MHz, CDCl ) d 2.05–2.11 (m, 1H), 2.28–2.34 (m,
3
3.64–3.68 (m, 2H), 3.77–3.83 (m, 2H), 3.89–4.06 (m, 4H), 5.05 (m,
1H), 6.92–6.96 (m, 1H), 7.00–7.01 (m, 2H), 7.43–7.47 (m, 1H),
7.68–7.71 (m, 1H), 8.37 (s, 1H), 8.49 (s, 1H), 8.63 (s, 1H). ESI-MS
1
1
2
7
H), 2.37 (s, 6H), 2.54–2.64 (m, 2H), 3.04 (s, 3H), 3.40–3.59 (m,
H), 3.82–4.05 (m, 4H), 4.88 (s, 1H), 6.88–6.95 (m, 2H), 7.33–
+
m/z 508 [M+H] .
.35 (m, 1H), 7.58 (s, 1H), 8.44 (s, H), 8.59 (s, 1H), 8.73 (s, 1H).
+
ESI-MS m/z 503 [M+H] .
6.1.19. (S)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-4-methylpiperazine-1-carboxa-
mide (8s)
6
.1.14. (S)-3-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-1-(2-(diethylamino)ethyl)-1-
methylurea (8n)
Compound 8s was synthesized by following the procedure de-
scribed for 8a using 1-methylpiperazine instead of 2-aminoetha-
Compound 8n was synthesized by following the procedure de-
scribed for 8a using N ,N -diethyl-N -methylethane-1,2-diamine
instead of 2-aminoethanol. The crude was purified by flash chro-
nol. The crude was purified by flash chromatography on silica gel
1
1
2
1
to provide the desired product 8s in 76% yield.
(400 MHz, CDCl
H NMR
3
) d 2.33 (s, 6H), 2.36–2.46 (m, 4H), 3.53 (s, 3H),
matography on silica gel to provide the desired product 8n in
3.88–4.07 (m, 4H), 5.05 (s, 1H), 6.93–6.98 (m, 1H), 7.02 (s, 1H),
7.30 (s, 1H), 7.42–7.46 (m, 1H), 8.48–8.51 (m, 2H), 8.69 (s, 1H).
ESI-MS m/z 501 [M+H] .
1
7
2
3
1
8
7% yield. H NMR (400 MHz, CDCl
3
) d 1.08 (t, J = 6.8 Hz, 6H),
+
.07–2.10 (m, 1H), 2.35–2.40 (m, 1H), 2.63–2.76 (m, 6H), 3.09 (s,
H), 3.39–3.64 (m, 2H), 3.83–4.08 (m, 4H), 4.87 (s, 1H), 6.90 (s,
H), 6.95–6.99 (m, 1H), 7.34–7.35 (m, 1H), 7.56–7.57 (m, 1H),
6.1.20. (S)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
furan-3-yloxy)quinazolin-6-yl)-4-fluoropiperidine-1-carboxa-
mide (8t)
+
.48 (s, 1H), 8.57 (s, 1H), 8.68 (s, 1H). ESI-MS m/z 531 [M+H] .
6
.1.15. (S)-3-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydro-
Compound 8t was synthesized by following the procedure
described for 8a using 4-fluoropiperidine instead of 2-aminoeth-
anol. The crude was purified by flash chromatography on silica
gel to provide the desired product 8t in 88% yield. 1H NMR
furan-3-yloxy)quinazolin-6-yl)-1-(3-(dimethylamino)propyl)-
1
-methylurea (8o)
Compound 8o was synthesized by following the procedure de-
1
1
3
scribed for 8a using N ,N ,N -trimethylpropane-1,3-diamine in-
3
(400 MHz, CDCl ) d 1.86–1.95 (m, 4H), 2.15–2.36 (m, 2H),
stead of 2-aminoethanol. The crude was purified by flash
3.58–3.62 (m, 4H), 3.89–4.05 (m, 4H), 5.00 (s, 1H), 6.89–6.93
(m, 1H), 6.97 (s, 1H), 7.29 (s, 1H), 7.38–7.39 (m, 1H), 7.57–
7.58 (m, 1H), 8.48 (s, 1H), 8.58 (s, 1H), 8.65 (s, 1H). ESI-MS m/
chromatography on silica gel to provide the desired product 8o
1
in 71% yield. H NMR (300 MHz, CD
3
OD) d 1.94–2.04 (m, 2H),
+
2
.15–2.23 (m, 1H), 2.36–2.54 (m, 1H), 2.69 (s, 6H), 2.90–2.95 (m,
z 504 [M+H] .