Journal of Medicinal Chemistry
Drug Annotation
6H), 1.92−2.00 (m, 2H). MS (ESI) m/e [M + 1]+ 297.0. HPLC
purity: 99.9% (254 nm).
Compound 61 was prepared from 6,6-dimethyl-5,6,7,9-tetrahydro-
[1,2]diazepino[3,4,5,6-def ]carbazol-10(4H)-one (compound 37) ac-
cording to the procedures for compound 59. 1H NMR (DMSO-d6) δ
9.89 (s, 1H), 7.56 (d, 1H, J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.15
(t, 1H, J = 7.8 Hz), 4.15−4.17 (m, 2H), 2.76 (s, 2H), 2.62−2.64 (m,
2H), 2.43−2.46 (m, 4H), 2.25 (s, 2H), 1.07 (s, 6H), 0.81 (t, 6H, J =
7.2 Hz). MS (ESI) m/e [M + 1]+ 353.0. HPLC purity: 99.92% (254
nm).
10-(2-(Dibenzylamino)ethyl)-2,2-dimethyl-2,3,5,10-
tetrahydro[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (62).
Compound 62 was prepared from 6,6-dimethyl-5,6,7,9-tetrahydro-
[1,2]diazepino[3,4,5,6-def ]carbazol-10(4H)-one (compound 37) ac-
cording to the procedures for compound 59. 1H NMR (DMSO-d6) δ
9.87 (s, 1H), 7.40 (d, 1H, J = 7.2 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.13−
7.22 (m, 10 H), 7.00 (dd, 1H, J = 7.2, 7.6 Hz), 4.15−4.18 (m, 2H),
3.61 (br s, 4H), 2.56−2.59 (m, 2H), 2.24 (s, 2H), 2.11 (s, 2H), 0.87
(s, 6H). MS (ESI) m/e [M + 1]+ 477.0. HPLC purity: 98.80% (254
nm).
10-(2-(Diethylamino)ethyl)-2,3,5,10-tetrahydro[1,2]-
diazepino[3,4,5,6-def]carbazol-6(1H)-one (54). Compound 54
was prepared from 5,6,7,9-tetrahydro[1,2]diazepino[3,4,5,6-def ]-
carbazol-10(4H)-one (compound 33) according to the procedures
for compound 59. 1H NMR (DMSO-d6) δ 9.88 (s, 1H), 7.56 (d, 1H,
J = 7.2 Hz), 7.45 (d, 1H, J = 7.2 Hz), 7.15 (t, 1H, J = 7.2 Hz), 4.16−
4.18 (m, 2H), 2.89−2.91 (m 2H), 2.63−2.65 (m, 2H), 2.40−2.45 (m,
6H), 1.98−2.00 (m, 2H), 0.82 (t, 6H, J = 7.2 Hz). MS (ESI) m/e [M
+ 1]+ 325.0. HPLC purity: 99.55% (254 nm).
4-(2-(Dibenzylamino)ethyl)-5,6,7,9-tetrahydro[1,2]-
diazepino[3,4,5,6-def]carbazol-10(4H)-one (55). Compound 55
was prepared from 33 according to the procedures for compound 59.
1H NMR (DMSO-d6) δ 9.89 (s, 1H), 7.40 (d, 1H, J = 7.6 Hz), 7.29
(d, 1H, J = 7.6 Hz), 7.06−7.19 (m, 10H), 6.98 (t, 1H, J = 7.6 Hz),
4.18−4.21 (m, 2H), 3.55 (br s, 4H), 2.61−2.64 (m, 2H), 2.46−2.48
(m, 2H), 2.27−2.31 (m, 2H), 1.78−1.81 (m, 2H). MS (ESI) m/e [M
+ 1]+ 449.0. HPLC purity: 99.18% (254 nm).
2,2-Dimethyl-10-(2-(pyrrolidin-1-yl)ethyl)-2,3,5,10-
tetrahydro[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (63).
Compound 63 was prepared from 6,6-dimethyl-5,6,7,9-tetrahydro-
[1,2]diazepino[3,4,5,6-def ]carbazol-10(4H)-one (compound 37) ac-
cording to the procedures for compound 59. 1H NMR (DMSO-d6) δ
9.91 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz), 7.47 (d, 1H, J = 7.2 Hz), 7.17
(dd, 1H, J = 7.2, 7.8 Hz), 4.23−4.26 (m, 2H), 2.69−2.74 (m 4H),
2.45 (br s, 4H), 2.25 (br s, 2H), 1.64−1.65 (m, 4H), 1.07 (s, 6H). MS
(ESI) m/e [M + 1]+ 351.0. HPLC purity: 100% (254 nm).
2,2-Dimethyl-10-(2-(piperidin-1-yl)ethyl)-2,3,5,10-
tetrahydro[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (64).
Compound 64 was prepared from 6,6-dimethyl-5,6,7,9-tetrahydro-
[1,2]diazepino[3,4,5,6-def ]carbazol-10(4H)-one (compound 37) ac-
cording to the procedures for compound 59. 1H NMR (DMSO-d6) δ
9.89 (s, 1H), 7.57 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.17
(dd, 1H, J = 8.4, 7.8 Hz), 4.20−4.22 (m, 2H), 2.89 (br s, 2H), 2.50
(br s, 2H), 2.35 (br s, 4H), 2.25 (br s, 2H), 1.35−1.46 (m, 6H), 1.07
(s, 6H). MS (ESI) m/e [M + 1]+ 365.0. HPLC purity: 100% (254
nm).
10-(2-(Pyrrolidin-1-yl)ethyl)-2,3,5,10-tetrahydro[1,2]-
diazepino[3,4,5,6-def]carbazol-6(1H)-one (56). Compound 56
was prepared from 5,6,7,9-tetrahydro[1,2]diazepino[3,4,5,6-def ]-
carbazol-10(4H)-one (compound 33) according to the procedures
for compound 59. 1H NMR (DMSO-d6) δ 9.91 (s, 1H), 7.57 (d, 1H,
J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.25−
4.27 (m, 2H), 2.87−2.89 (m 2H), 2.72 (br s, 2H), 2.41−2.47 (m,
6H), 1.98−2.00 (m, 2H), 1.66 (br s, 4H). MS (ESI) m/e [M + 1]+
323.0.
10-(2-(Piperidin-1-yl)ethyl)-2,3,5,10-tetrahydro[1,2]-
diazepino[3,4,5,6-def]carbazol-6(1H)-one (57). Compound 57
was prepared from 5,6,7,9-tetrahydro[1,2]diazepino[3,4,5,6-def ]-
carbazol-10(4H)-one (compound 33) according to the procedures
for compound 59. 1H NMR (DMSO-d6) δ 9.89 (s, 1H), 7.57 (d, 1H,
J = 7.8 Hz), 7.46 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.23−
4.25 (m, 2H), 2.89−2.91 (m 2H), 2.51−2.55 (m, 2H), 2.36−2.43 (m,
6H), 1.98−2.00 (m, 2H), 1.36−1.45 (m, 6H). MS (ESI) m/e [M +
1]+ 337.0.
10-(2-Morpholinoethyl)-2,3,5,10-tetrahydro[1,2]diazepino-
[3,4,5,6-def]carbazol-6(1H)-one (58). Compound 58 was pre-
pared from 5,6,7,9-tetrahydro[1,2]diazepino[3,4,5,6-def ]carbazol-
10(4H)-one (compound 33) according to the procedures for
2,2-Dimethyl-10-(2-morpholinoethyl)-2,3,5,10-tetrahydro-
[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (65). Compound
65 was prepared from 6,6-dimethyl-5,6,7,9-tetrahydro[1,2]diazepino-
[3,4,5,6-def ]carbazol-10(4H)-one (compound 37) according to the
1
compound 59. H NMR (DMSO-d6) δ 9.90 (s, 1H), 7.59 (d, 1H, J
1
procedures for compound 59. H NMR (DMSO-d6) δ 9.91(s, 1H),
= 7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.25−
4.27 (m, 2H), 3.52−3.54 (m, 4H), 2.89−2.91 (m, 2H), 2.58−2.60
(m, 2H), 2.41−2.43 (m, 6H), 1.99−2.01 (m, 2H). MS (ESI) m/e [M
+ 1]+ 339.0.
7.59 (d, 1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (dd, 1H, J =
8.4, 7.8 Hz), 4.24−4.26 (m, 2H), 3.53−3.54 (m, 4H), 2.77 (br s, 2H),
2.57−2.59 (m, 2H), 2.42 (br s, 4H), 2.25 (br s, 2H), 1.08 (s, 6H). MS
(ESI) m/e [M + 1]+ 367.0. HPLC purity: 100% (254 nm).
10-(2-(Dimethylamino)ethyl)-2,2-dimethyl-2,3,5,10-
tetrahydro[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (59).
To a cooled solution (0 °C) of 37 (94 mg, 0.37 mmol) and DMF (10
mL) were slowly added K2CO3 (205 mg, 1.48 mmol) and then N,N-
dimethylamino-2-chloroethane (53 mg, 0.37 mmol). The resulting
solution was stirred at 70 °C for 4 h. The solution was allowed to
cool, and water was added (10 mL). The mixture was extracted with
ethyl acetate (2 × 20 mL). The organic layers were combined, dried
over Na2SO4, and filtered. The filtrate was concentrated, and the
residue was chromatographed to give the product (90 mg, 75%) as a
10-(2-Hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro[1,2]-
diazepino[3,4,5,6-def]carbazol-6(1H)-one (66). To a solution of
37 (100 mg, 0.39 mmol) in dry DMF (8 mL) was added 2-(2-
bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol). K2CO3
(215 mg, 1.6 mmol) was added, and the mixture was heated at 70
°C for 12 h. Then water (100 mL) was added to the mixture, which
was then extracted with EtOAc (50 mL × 3). The organic layers were
combined, washed with brine, dried over Na2SO4, and concentrated
to provide a crude yellow oil. Then MeOH (15 mL) was added to the
residue, followed by the addition of PTSA·H2O (100 mg, 0.52 mmol),
and the mixture was stirred at room temperature for 1 h. Water (100
mL) was added to the mixture, and the mixture was extracted with
EtOAc (50 mL × 3). The organic layers were combined, washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4, and
concentrated. The residue was purified by chromatography on silica
gel (elution with hexane/ethyl acetate) to give 80 mg (69% yield) of
1
yellow solid. H NMR (DMSO-d6) δ 9.91 (s, 1H), 7.58 (d, 1H, J =
7.8 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.16 (t, 1H, J = 7.8 Hz), 4.23 (m,
2H), 2.74 (s, 2H), 2.51 (m, 2H), 2.25 (s, 2H), 2.18 (s, 6H), 1.07 (s,
6H). MS (ESI) m/e [M + 1]+ 325.0. HPLC purity: 95.42% (254 nm).
10-(2-(Dimethylamino)ethyl)-8-fluoro-2,2-dimethyl-
2,3,5,10-tetrahydro[1,2]diazepino[3,4,5,6-def ]carbazol-6(1H)-
one (60). Compound 60 was prepared from 2-fluoro-6,6-dimethyl-
5,6,7,9-tetrahydro[1,2]diazepino[3,4,5,6-def ]carbazol-10(4H)-one
1
66 as a yellow solid. H NMR (DMSO-d6) δ 9.89 (s, 1H), 7.58 (d,
1
1H, J = 8.4 Hz), 7.47 (d, 1H, J = 7.2 Hz), 7.15 (dd, 1H, J = 7.2, 8.4
Hz), 4.88 (t, 1H, J = 5.4 Hz), 4.21 (t, 2H, J = 5.4 Hz), 3.65−3.68 (m,
1H), 2.76 (s, 2H), 2.25 (s, 2H), 1.07 (s, 6H). MS (ESI) m/e [M + 1]+
298.1. HPLC purity: 96.68% (254 nm).
2,2-Dimethyl-10-(oxiran-2-ylmethyl)-2,3,5,10-tetrahydro-
[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (67). Compound
67 was prepared from 6,6-dimethyl-5,6,7,9-tetrahydro[1,2]diazepino-
(compound 38) according to the procedures for compound 59. H
NMR (DMSO-d6) δ 10.1 (s, 1H), 7.56 (dd, 1H, J = 9.6, 1.8 Hz), 7.21
(dd, 1H, J = 10.2, 1.8 Hz), 4.22 (m, 2H), 2.74 (s, 2H), 2.51 (m, 2H),
2.26 (s, 2H), 2.17 (s, 6H), 1.06 (s, 6H). MS (ESI) m/e [M + 1]+
343.0. HPLC purity: 95.61% (254 nm).
10-(2-(Diethylamino)ethyl)-2,2-dimethyl-2,3,5,10-
tetrahydro[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one (61).
O
J. Med. Chem. XXXX, XXX, XXX−XXX