K. Kinoshita et al. / Bioorg. Med. Chem. 20 (2012) 1271–1280
1277
0.35–0.41 (2H, m); HRMS (ESI), m/z Calcd for C27H25N3O+H:
408.2070, Found: 408.2067.
5.1.10. 9-(4-Cyclopropyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (10a)
Compound 10a was prepared from 9 following the same proce-
dure as described for 7a (42%, a yellow solid). 1H NMR (400 MHz,
DMSO-d6) d: 12.74 (1H, s), 8.33 (1H, d, J = 8.8 Hz), 8.01 (1H, s),
7.60–7.71 (3H, m), 7.32 (1H, d, J = 8.6 Hz), 3.15–3.22 (4H, m),
2.68–2.75 (4H, m), 1.72 (6H, s), 1.63–1.71 (1H, m), 0.43–0.49
(2H, m), 0.33–0.38 (2H, m); HRMS (ESI), m/z Calcd for
5.1.6. 6,6-Dimethyl-9-(1-oxetan-3-yl-1,2,3,6-tetrahydro-pyridin
-4-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-
carbonitrile (7b)
To a solution of 6 (100 mg, 0.27 mmol) in THF/THF/AcOH
(2.0 mL/2.0 mL/0.5 mL) were added 3-oxetanone (55 lL, 1.08
mmol) and sodium cyanoborohydride (33.9 mg, 0.54 mmol) at
room temperature. After stirring for 3 h at room temperature,
the reaction mixture was dissolved with water, and extracted
with AcOEt. The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatog-
C26H26N4O+H: 411.2179, Found: 411.2176.
5.1.11. 6,6-Dimethyl-9-(4-oxetan-3-yl-piperazin-1-yl)-11-oxo-6,
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (10b)
Compound 10b was prepared from 9 following the same proce-
dure as described for 7b (41%, a white solid). 1H NMR (400 MHz,
DMSO-d6) d: 12.74 (1H, s), 8.33 (1H, d, J = 8.4 Hz), 8.01 (1H, s),
7.59–7.73 (3H, m), 7.34 (1H, d, J = 6.6 Hz), 4.58 (2H, t, J = 6.6 Hz),
4.49 (2H, t, J = 6.0 Hz), 3.43–3.50 (1H, m), 3.22–3.28 (4H, m),
2.41–2.47 (4H, m), 1.72 (6H, s); HRMS (ESI), m/z Calcd for
raphy (CH2Cl2/AcOEt) to give 7b as
a light-yellow solid
(79.6 mg, 69%). 1H NMR (400 MHz, DMSO-d6) d: 12.81 (1H,
bs), 8.34 (1H, d, J = 8.2 Hz), 8.22 (1H, d, J = 1.8 Hz), 8.03 (1H,
s), 7.76–7.90 (2H, m), 7.64 (1H, dd, J = 8.2, 1.8 Hz), 6.25–6.34
(1H, m), 4.60 (2H, dd, J = 6.6, 6.0 Hz), 4.52 (2H, dd, J = 6.6,
6.0 Hz), 3.57 (1H, t, J = 6.0 Hz), 3.03 (2H, m), 2.55 (4H, m),
C26H26N4O2+H: 427.2129, Found: 427.2122.
1.77 (6H, s); HRMS (ESI), m/z Calcd for
424.2020, Found: 424.2016.
C
27H25N3O2+H:
5.1.12. 9-Bromo-6,6-dimethyl-11-oxo-8-piperazin-1-yl-6,11-
dihydro-5H-benzo[b]carbazole-3-carbonitrile (12)
To a solution of 11 (6.0 g, 11.7 mmol) in NMP (75 mL) was
added piperazine (10.1 g, 117 mmol). After stirring for 30 min at
120 °C, the reaction mixture was cooled and poured into water to
afford precipitation. The precipitate was filtered off and dried un-
der reduced pressure to yield 12 as a white solid (3.9 g, 74%). 1H
NMR (400 MHz, DMSO-d6) d: 8.30 (1H, d, J = 7.9 Hz), 8.28 (1H, s),
8.00 (1H, s), 7.61 (1H, d, J = 7.9 Hz), 7.41 (1H, s), 3.32 (2H, bs),
3.01–3.10 (4H, m), 2.85–2.91 (4H, m), 1.76 (6H, s); HRMS (ESI),
m/z Calcd for C23H21BrN4O+H: 449.0972, Found 449.0973.
5.1.7. 9-(1-Cyclopropyl-piperidin-4-yl)-6,6-dimethyl-11-oxo- 6,
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (8a)
To a solution of 7a (34.0 mg, 0.08 mmol) in MeOH (2.0 mL), 10%
palladium on carbon (20 mg, 60% w/w) was added at room temper-
ature. After being stirred vigorously under hydrogen gas for 4.5 h at
room temperature, the reaction mixture was filtered through Cel-
ite. The filtrate was concentrated under reduced pressure. The res-
idue was purified by flash column chromatography (AcOEt/MeOH)
to yield 8a as a white solid (14.2 mg, 41%). 1H NMR (400 MHz,
DMSO-d6) d: 12.77 (1H, s), 8.33 (1H, d, J = 7.9 Hz), 8.05 (1H, s),
8.01 (1H, s), 7.80 (1H, d, J = 8.4 Hz), 7.62 (1H, d, J = 8.4 Hz), 7.59
(1H, d, J = 8.4 Hz), 3.02–3.10 (2H, m), 2.60–2.70 (1H, m), 2.24–
2.36 (3H, m), 1.70–1.84 (7H, m), 1.55–1.69 (3H, m), 0.40–0.47
(2H, m), 0.29–0.36 (2H, m); HRMS (ESI), m/z Calcd for
5.1.13. 9-Bromo-8-(4-cyclopropyl-piperazin-1-yl)-6,6-dimethyl-
11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
(13a)
Compound 13a was prepared from 12 following the same pro-
cedure as described for 7a (25%, a light-yellow solid). 1H NMR
(400 MHz, DMSO-d6) d: 8.22–8.30 (2H, m), 8.00 (1H, s), 7.56 (1H,
d, J = 7.9 Hz), 7.43 (1H, s), 3.30(1H, d, J = 5.8 Hz), 3.11 (4H, s), 2.75
(4H, s), 1.75 (6H, s), 0.47 (2H, d, J = 5.8 Hz), 0.34 (2H, d,
J = 5.8 Hz); HRMS (ESI), m/z Calcd for C26H25BrN4O+H: 489.1285,
Found: 489.1285.
C27H27N3O+H: 410.2227, Found: 410.2226.
5.1.8. 6,6-Dimethyl-9-(1-oxetan-3-yl-piperidin-4-yl)-11-oxo-6,
11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (8b)
Compound 8b was prepared from 7b following the same proce-
dure as described for 8a (56%, a white solid). 1H NMR (400 MHz,
DMSO-d6) d: 12.78 (1H, s), 8.34 (1H, d, J = 8.4 Hz), 8.08 (1H, s),
8.02 (1H, s), 7.82 (1H, d, J = 8.4 Hz), 7.59–7.65 (2H, m), 4.56 (2H,
t, J = 6.2 Hz), 4.47 (2H, t, J = 6.2 Hz), 3.59–3.62 (1H, m), 3.39–3.46
(1H, m), 2.79–2.86 (2H, m), 2.69–2.63 (1H, m), 1.79–1.94 (4H,
m), 1.65–1.79 (7H, m); HRMS (ESI), m/z Calcd for C27H27N3O2+H:
426.2176, Found: 426.2178.
5.1.14. 9-Bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-
11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
(13b)
To a solution of 12 (25 mg, 0.06 mmol) in THF (1.0 mL) were
added cyclobutanone (14.2 lL, 0.19 mmol) and sodium triacetoxy-
borohydride (53.6 mg, 0.25 mmol) at room temperature. After stir-
ring for 2.5 h at room temperature, the resulting mixture was
filtered, and concentrated under reduced pressure. The residue
was purified by preparative HPLC to yield 13b as a white solid
(10.9 mg, 34%).1H NMR (400 MHz, DMSO-d6) d: 8.23–8.29 (2H,
m), 8.00 (1H, s),7.55 (1H, d, J = 7.9 Hz), 7.45 (1H, s), 4.04–4.15
(1H, m), 3.10–3.20 (4H, m), 2.39–2.48 (4H, m), 1.97–2.06 (2H,
m), 1.78–1.88 (2H, m), 1.77 (6H, s), 1.61–1.72 (2H, m); HRMS
(ESI), m/z Calcd for C27H27BrN4O+H: 503.1441, Found: 503.1436.
5.1.9. 6,6-Dimethyl-11-oxo-9-piperazin-1-yl-6,11-dihydro-5H-
benzo[b]carbazole-3-carbonitrile (9)
A mixture of 4 (100 mg, 0.23 mmol), piperazine (59.4 mg,
0.69 mmol), K3PO4 (132 mg, 0.46 mmol), Pd2(dba)3 (10.5 mg,
0.01 mmol), JohnPhos (7.1 mg, 0.02 mmol), and DMA (2.0 mL)
was stirred for 2.5 h at 80 °C under nitrogen atmosphere. The reac-
tion mixture was then cooled, diluted with AcOEt and water,
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by preparative
5.1.15. 9-Bromo-6,6-dimethyl-8-(4-oxetan-3-yl-piperazin-1-yl)-
11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (13c)
Compound 13c was prepared from 12 following the same pro-
cedure as described for 7b (73%, an off-white solid). 1H NMR
(400 MHz, DMSO-d6) d: 12.83 (1H, s), 8.30 (1H, d, J = 7.9 Hz), 8.28
(1H, s), 8.02 (1H, s), 7.62 (1H, d, J = 7.9 Hz), 7.48 (1H, s), 4.56–
4.61 (2H, m), 4.46–4.51 (2H, m), 3.47–3.56 (1H, m), 3.15–3.24
HPLC to give 9 as
a
yellow solid (22.9 mg, 27%). 1H NMR
(400 MHz, DMSO-d6) d: 13.06 (1H, bs), 8.33 (1H, d, J = 8.4 Hz),
8.01 (1H, s), 7.74 (1H, d, J = 8.8 Hz), 7.69 (1H, s), 7.36 (1H, d,
J = 8.8 Hz), 3.28–3.36 (4H, m), 3.03–3.11 (4H, m), 1.74 (6H, s);
HRMS (ESI), m/z Calcd for
C23H22N4O+H: 371.1866, Found:
371.1865.