K. Yokoyama et al. / Bioorg. Med. Chem. 16 (2008) 7021–7032
7027
3.27–3.35 (2H, m), 3.806 (3H, s), 3.813 (3H, s), 4.12–4.24 (1H, m),
4.74–4.84 (2H, m), 6.71 (1H, s), 7.24 (1H, d, J = 7.6 Hz), 7.45 (1H,
s). Anal. Calcd for C26H39N5O2.0.5H2O: C, 68.04; H, 8.88; N, 14.69.
Found: C, 68.27; H, 9.13; N, 14.68.
Mp (dec) 203–204 °C (Et2O); MS (FAB+) m/z 468 [M+H]+. 1H NMR
(400 MHz, DMSO-d6) d 1.04–1.17 (1H, m), 1.20–1.33 (2H, m), 1.37–
1.69 (10H, m), 1.70–1.88 (6H, m), 1.90–2.00 (2H, m), 2.07–2.19
(2H, m), 3.52–3.65 (4H, m), 3.72–3.84 (2H, m), 3.87 (3H, s), 3.90
(3H, s), 4.26–4.38 (1H, m), 4.82–4.94 (2H, m), 7.70 (1H, s), 7.97
(1H, s), 9.21 (1H, d, J = 6.8 Hz), 11.53 (1H, s), 12.90 (1H, s). Anal. Calcd
for C27H41N5O2ꢁ2HClꢁ1.6H2O: C, 56.95; H, 8.18; N, 12.30; Cl, 12.45.
Found: C, 56.81; H, 8.30; N, 12.21; Cl, 12.80.
6.1.14. N-Cycloheptyl-2-(4-fluoro-1,40-bipiperidine-10-yl)-6,7-
dimethoxyquinazolin-4-amine (14b)
14b (682 mg, 94%) was obtained as a white solid from 2-chloro-
N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 13a (504 mg,
1.5 mmol), Hunig’s base (233 mg), and crude 4-fluoro-1,40-bipiper-
idine 8 (279 mg). 14b (682 mg) was treated with 4 M-HCl-dioxane,
and the mixture was concentrated. The residue was recrystallized
from isopropanol to yield the hydrochloride salt (440 mg, 0.79
mmol, 56%) as a white solid.
6.1.18. N-Cycloheptyl-6-methoxy-2-(4-pyrrolidin-1-
ylpiperidine-1-yl)quinazolin-4-amine-N-cycloheptyl-6-
methoxy-2-(4-pyrrolidin-1-ylpiperidine-1-yl)quinazolin-4-
amine (14f)
14f (480 mg, 57%) was obtained as a colorless solid from 2-
chloro-N-cycloheptyl-6-methoxyquinazolin-4-amine 13b (610 mg,
2 mmol) and 4-pyrrolidin-1-ylpiperidine (620 mg). 14f (450 mg)
was treated with 4 M-HCl-ethylacetate and the mixture was con-
centrated. The resulting residue was washed with Et2O to yield
the hydrochloride salt (500 mg, 95%) as a colorless solid.
Mp (dec) 198–199 °C (Et2O); MS (ESI+) m/z 424 [M+H]+. 1H NMR
(400 MHz, DMSO-d6) d 1.46–1.69 (6H, m), 1.70–2.02 (13H, m),
2.18–2.28 (2H, m), 3.02–3.22 (4H, m), 3.42–3.52 (2H, m), 3.88
(3H, s), 4.26–4.38 (1H, m), 4.78–4.88 (2H, m), 7.41–7.48 (1H, m),
7.92–8.01 (2H, br), 9.25 (1H, s), 11.39 (1H, s), 12.49 (1H, s). Anal.
Calcd for C25H37N5Oꢁ2HCl H2O: C, 58.36; H, 8.03; N, 13.61; Cl,
13.78. Found: C, 58.52; H, 8.30; N, 13.72; Cl, 13.43.
Mp (dec) 225–226 °C (i-PrOH); MS (FAB+) m/z 486 [M+H]+. 1H
NMR (400 MHz, DMSO-d6) d 1.44–1.68 (6H, m), 1.71–1.90 (6H,
m), 1.92–2.02 (2H, m), 2.03–2.40 (6H, m), 3.04–3.20 (4H,
m), 3.35–3.50 (2H, m), 3.52–3.62 (1H, m), 3.87 (3H, s), 3.89 (3H,
s), 4.26–4.32 (1H, m), 4.82–4.90 (2H, m), 4.93–5.10 (1H, m),
7.62–7.70 (1H, m), 7.90 (1H, s), 8.99–9.10 (1H, m), 11.28 (1H, m),
12.42–12.56 (1H, m). Anal. Calcd for C27H40FN5O2ꢁ2HClꢁ1.7H2Oꢁ
0.1C3H8O: C, 55.09; H, 7.82; N, 11.77; Cl, 11.91; F, 3.19. Found: C,
54.99; H, 7.88; N, 11.75; Cl, 12.05; F, 3.19.
6.1.15. N-Cycloheptyl-2-[4-(cyclopentylamino)piperidine-1-yl]-
6,7-dimethoxyquinazolin-4-amine (14c)
14c (660 mg, 87%) was obtained from 2-chloro-N-cycloheptyl-
6,7-dimethoxyquinazolin-4-amine 13a (548 mg, 1.63 mmol), Hu-
nig’s base (253 mg), and crude N-cyclopentylpiperidine-4-amine
10a (275 mg). 14c (660 mg) was treated with 4 M-HCl-dioxane,
and the mixture was concentrated. The resulting residue was
washed with Et2O to yield the hydrochloride salt (660 mg, 87%)
as a white solid.
6.1.19. N-Cycloheptyl-7-methoxy-2-(4-pyrrolidin-1-
ylpiperidine-1-yl)quinazolin-4-amine (14g)
14g(470 mg, 94%) wasobtainedas a colorlessamorphousfrom2-
chloro-N-cycloheptyl-7-methoxyquinazolin-4-amine 13c (360 mg,
1.18 mmol) and 4-pyrrolidin-1-ylpiperidine (360 mg). 14g
(470 mg) was treated with 4 M-HCl-ethylacetate and the mixture
was concentrated. The resulting residue was washed with Et2O to
yield the hydrochloride salt (370 mg, 67%) as a yellowish solid.
Mp (dec) 164–166 °C (Et2O); MS (ESI+) m/z 424 [M+H]+. 1H NMR
(400 MHz, DMSO-d6) d 1.42–1.76 (13H, m), 1.78–2.04 (6H, m),
2.06–2.20 (2H, m), 2.85–3.12 (4H, m), 3.40–3.55 (2H, m), 3.83
(3H, s), 4.14–4.28 (1H, m), 4.78–4.92 (2H, m), 6.65–7.10 (2H, br),
8.00–8.20 (1H, s), 10.86 (1H, br), 12.35 (1H, br). Anal. Calcd for
Mp (dec) 248 °C (Et2O); MS (FAB+) m/z 468 [M+H]+. 1H NMR
(400 MHz, DMSO-d6) d 1.40–1.80 (18H, m), 1.95–2.05 (4H, m),
2.20–2.28 (2H, m), 3.15–3.24 (2H, m), 3.58–3.62 (1H, m), 3.88
(6H, s), 4.24–4.36 (1H, m), 4.66–4.76 (2H, m), 7.52 (1H, s),
7.84 (1H, s), 8.96 (1H, br), 9.16 (2H, s), 12.30 (1H, s). Anal.
Calcd for
C
27H41N5O2ꢁ2HClꢁ1.4H2Oꢁ0.4C4H8O2: C, 57.15; H,
8.22; N, 11.65; Cl, 11.80. Found: C, 57.05; H, 8.18; N, 11.65;
Cl, 11.96.
C
25H37N5Oꢁ1.4HClꢁ2H2O: C, 58.80; H, 8.37; N, 13.71; Cl, 9.72.
Found: C, 59.04; H, 8.72; N, 13.79; Cl, 9.48.
6.1.16. N-Cycloheptyl-2-{4-[cyclopentyl(methyl)amino]piper-
idine-1-yl}-6,7-dimethoxyquinazolin-4-amine (14d)
6.1.20. N-Cycloheptyl-2-(4-pyrrolidin-1-ylpiperidine-1-
yl)quinazolin-4-amine (14h)
14d (185 mg, 37%) was obtained from 2-chloro-N-cycloheptyl-
6,7-dimethoxyquinazolin-4-amine 13a (344 mg, 1.03 mmol),
Hunig’s base (160 mg), and crude N-cyclopentyl-N-methylpiperi-
dine-4-amine 10b (187 mg). 14d (185 mg) was treated with
4 M-HCl-dioxane, and the mixture was concentrated. The resulting
residue was washed with Et2O and EtOH to yield the hydrochloride
salt (229 mg) as a white solid.
14h (2.20 g) was obtained from crude 2-chloro-N-cyclohep-
tylquinazolin-4-amine13d, Hunig’s base (1.3 mL), and 4-pyrroli-
din-1-ylpiperidine (1.16 g). 14h (2.20 g) was treated with
4 M-HCl-dioxane, and the mixture was concentrated. The result-
ing residue was recrystallized from Et2O/MeCN to yield the
hydrochloride salt (1.51 g, 3.2 mmol, 43% from 2, 4-dichloroqui-
nazoline) as a slightly orange solid.
Mp (dec) 265–266 °C (EtOH); MS (FAB+) m/z 482 [M+H]+. 1H
NMR (400 MHz, CD3OD) d 1.55–1.94 (17H), 1.95–2.32 (7H, m),
2.79 (3H, s), 3.29–3.31 (1H, m), 3.83–3.87 (2H, m), 3.88 (6H, s),
4.35–4.44 (1H, m), 4.84–4.86 (2H, m), 7.25 (1H, s), 7.70 (1H, s).
Anal. Calcd for C28H43N5O2ꢁ2HClꢁ0.8 H2O: C, 59.10; H, 8.25; N,
12.31; Cl, 12.46. Found: C, 58.71; H, 8.28; N, 12.22; Cl, 12.85.
MS (FAB+) m/z 394 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d
1.44–2.03 (19H, m), 2.18–2.28 (2H, m), 2.98–3.25 (4H, m), 3.44–
3.52 (2H, m), 4.25–4.36 (1H, m), 4.87–4.98 (2H, m), 7.38–7.45
(1H, m), 7.76–7.82 (1H, m), 8.10 (1H, d, J = 8.3 Hz), 8.50 (1H, d,
J = 8.3 Hz), 9.32 (1H, d, J = 7.3 Hz), 11.55 (1H, s), 12.71 (1H, s). Anal.
Calcd for C24H35N5ꢁ2.1ꢁHClꢁ1.8H2O: C, 57.36; H, 8.16; N, 13.94; Cl,
14.81. Found: C, 57.58; H, 8.41; N, 13.96; Cl, 14.57.
6.1.17. N-Cycloheptyl-2-(4-cyclohexylpiperazine-1-yl)-6,7-
dimethoxyquinazolin-4-amine (14e)
14e (780 mg, 67%) was obtained as a colorless solid from
6.1.21. Benzyl 4-[4-(cycloheptylamino)-6,7-
2-chloro-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine
13a
dimethoxyquinazolin-2-yl]piperidine-1-carboxylate (17)
DMF (3 drops) and oxalyl chloride (1.54 mL, 17.68 mmol) were
added to a solution of 1-[(benzyloxy)carbonyl]piperidine-4-car-
boxylic acid 15 (4.43 g, 16.84 mmol) in CH2Cl2 (50 mL), and the
(840 mg, 5 mmol) and 1-cyclohexylpiperazine (860 mg). 14e
(700 mg) was treated with 4 M-HCl-dioxane, and the mixture
was concentrated. The resulting residue was washed with Et2O to
yield the hydrochloride salt (760 mg, 94%) as a colorless solid.