Journal of Medicinal Chemistry
Article
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procedure A (1.53 g, 63%). H NMR (400 MHz, CDCl3): δ 7.40 (s,
Methyl 4-((2,7,9-Trimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
5(2H)-yl)methyl)benzoate (2d). The title compound was synthesized
from 2,7,9-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1d
(0.30 g, 1.4 mmol) according to general procedure B (0.40 g,
78%).1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.3 Hz, 2H), 7.16
(d, J = 8.3 Hz, 2H), 6.92 (s, 1H), 6.75 (s, 1H), 5.24 (s, 2H), 4.26 (s,
2H), 3.91 (s, 3H), 3.57 (t, J = 5.8 Hz, 2H), 3.19 (t, J = 6.4 Hz, 2H),
3.02 (s, 3H), 2.43 (s, 3H), 2.38 (s, 3H). 13C NMR (100 MHz, DMSO-
d6): δ 166.6, 148.9, 135.7, 131.4, 129.7, 129.6, 128.8, 128.5, 127.5,
124.4, 123.0, 107.4, 107.2, 65.9, 52.4, 50.0, 41.2, 30.5, 21.6, 20.0, 19.9.
ESI-HRMS: calc. for C23H26N2O2: [M+H]+ = 363.2067 m/z, found:
[M+H]+ = 363.2065 m/z.
1H), 7.20 (m, 2H), 3.75 (s, 2H), 2.83 (m, 4H), 2.60 (s, 3H), 1.39 (s,
9H). 13C NMR (100 MHz, MeOD): δ 139.6, 133.2, 129.9, 124.0,
117.0, 110.9, 108.3, 105.0, 50.6, 49.9, 42.8, 32.4, 29.6, 21.4. ESI-
HRMS: calc. for C16H22N2: [M+H]+ = 243.1856 m/z, found: [M+H]+
= 243.1855 m/z.
8-Methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(1f). The title compound was synthesized from (4-methoxyphenyl)-
hydrazine hydrochloride (2.00 g, 11.5 mmol) according to general
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procedure A (1.71 g, 69%). H NMR (400 MHz, CDCl3): δ 7.05 (d,
J = 8.7 Hz, 1H), 6.77 (s, 1H), 6.66 (dd, J = 2.5 Hz, 8.7 Hz, 1H), 3.75
(s, 3H), 3.55 (s, 2H), 2.72 (m, 4H), 2.46 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 153.8, 132.8, 131.3, 126.4, 111.2, 110.6, 108.4, 100.0,
55.9, 52.5, 51.8, 45.8, 23.9. ESI-HRMS: calc. for C13H16N2O: [M+H]+
= 217.1335 m/z, found: [M+H]+ = 217.1340 m/z.
Methyl 4-((8-tert-Butyl-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]-
indol-5(2H)-yl)methyl)benzoate (2e). The title compound was
synthesized from 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido-
[4,3-b]indole 1e (0.50 g, 2.1 mmol) according to general procedure B
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(1g). The title compound was synthesized from (4-chlorophenyl)-
hydrazine hydrochloride (2.00 g, 11.2 mmol) according to general
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(0.64 g, 79%). H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz,
2H), 7.45 (s, 1H), 7.20 (m, 1H), 7.09 (m, 3H), 5.38 (s, 2H), 3.92 (s,
3H), 3.78 (s, 2H), 2.85 (m, 2H), 2.78 (m, 2H), 2.61 (br, 3H), 1.39 (s,
9H). 13C NMR (100 MHz, MeOD): δ 166.7, 144.0, 141.9, 135.1,
132.7, 129.5, 128.9, 126.1, 125.4, 119.1, 113.1, 108.5, 107.5, 52.0, 51.3,
51.2, 45.5, 44.2, 34.0, 31.1, 22.0. ESI-HRMS: calc. for C25H30N2O2:
[M+H]+ = 391.2380 m/z, found: [M+H]+ = 391.2397 m/z.
Methyl 4-((8-Methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]-
indol-5(2H)-yl)methyl)benzoate (2f). The title compound was
synthesized from 8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido-
[4,3-b]indole 1f (0.50 g, 2.3 mmol) according to general procedure
B (0.40 g, 48%). 1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.0 Hz,
2H), 7.04 (m, 3H), 6.93 (d, J = 8.7 Hz, 1H), 6.77 (dd, J = 2.4 Hz, 8.6
Hz, 1H), 5.27 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.71 (s, 2H), 2.83
(m, 2H), 2.77 (m, 2H), 2.58 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
166.7, 154.0, 143.2, 134.0, 131.9, 130.1, 129.3, 126.2, 126.1, 110.7,
109.7, 108.5, 100.3, 55.9, 52.5, 52.1, 51.9, 46.3, 45.8, 23.0. ESI-HRMS:
calc. for C22H24N2O3: [M+H]+ = 365.1860 m/z, found: [M+H]+ =
365.1859 m/z.
Methyl 4-((8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
5(2H)-yl)methyl)benzoate (2g). The title compound was synthesized
from 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1g
(0.15 g, 0.7 mmol) according to general procedure B (0.18 g, 72%).
1H NMR (400 MHz, CDCl3): δ 7.87 (d, J = 8.1 Hz, 2H), 7.35 (s, 1H),
7.05 (m, 2H), 7.02 (d, J = 8.0, 2H), 5.27 (s, 2H), 3.89 (s, 3H), 3.67 (s,
2H), 2.82 (br, 2H), 2.62 (br, 2H), 2.57 (s, 3H). 13C NMR (100 MHz,
MeOD): δ 166.8, 144.0, 142.0, 135.2, 132.7, 129.5, 128.9, 126.1, 125.3,
119.1, 113.0, 108.4, 107.4, 51.1, 45.5, 44.1, 34.0, 30.9, 22.0. ESI-
HRMS: calc. for C21H21ClN2O2: [M+H]+ = 369.1364 m/z, found:
[M+H]+ = 369.1373 m/z.
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procedure A (1.08 g, 44%). H NMR (400 MHz, MeOD): δ 7.33 (s,
1H), 7.23 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H),
2.92 (m, 4H), 2.61 (s, 3H). 13C NMR (100 MHz, MeOD): δ 133.4,
131.9, 125.2, 122.5, 118.8, 114.6, 109.9, 104.9, 50.4, 49.5, 42.7, 21.3.
ESI-HRMS: calc. for C12H13ClN2: [M+H]+ = 221.0840 m/z, found:
[M+H]+ = 221.0838 m/z.
8-Bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(1h). The title compound was synthesized from (4-bromophenyl)-
hydrazine (3.00 g, 16.0 mmol) according to general procedure A
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(2.82 g, 94%). H NMR (400 MHz, MeOD): δ 7.47 (d, J = 1.6 Hz,
1H), 7.18 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 1.8 Hz, 6.7 Hz, 1H), 3.62
(s, 2H), 2.90 (t, J = 5.3 Hz, 2H), 2.84 (t, J = 5.2 Hz, 2H), 2.52 (s, 3H).
13C NMR (100 MHz, MeOD): δ 134.8, 132.9, 127.1, 122.6, 118.9,
111.5, 111.0, 106.0, 51.6, 50.6, 43.9, 22.4. ESI-HRMS: calc. for
C12H13BrN2: [M+H]+ = 265.0335 m/z, found: [M+H]+ = 265.0348
m/z.
Methyl 4-((2,6-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
5(2H)-yl)methyl)benzoate (2a). The title compound was synthesized
from 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1a (0.40 g,
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2.0 mmol) according to general procedure B (0.07 g, 9%). H NMR
(400 MHz, CDCl3): δ 7.93 (d, J = 8.3 Hz, 2H), 7.03 (m, 2H), 6.93
(d, J = 8.3 Hz, 2H), 6.86 (d, J = 7.2 Hz, 1H), 5.54 (s, 2H), 3.89
(s, 3H), 3.84 (s, 2H), 2.95 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 5.7 Hz, 2H),
2.64 (s, 3H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7,
144.7, 135.4, 133.3, 130.2, 129.6, 129.0, 126.5, 125.1, 124.6, 120.5,
119.5, 115.8, 63.7, 52.1, 51.3, 47.9, 45.2, 22.2, 19.5. ESI-HRMS:
calc. for C22H24N2O2: [M+H]+ = 349.1911 m/z, found: [M+H]+ =
349.1898 m/z.
Methyl 4-((8-Bromo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
5(2H)-yl)methyl)benzoate (2h). The title compound was synthesized
from 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1h
(0.50 g, 1.9 mmol) according to general procedure B (0.37 g, 47%).
1H NMR (400 MHz, MeOD): δ 7.87 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H),
Methyl-4-((2,7-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
5(2H)-yl)methyl)benzoate (2b). The title compound was synthesized
from 2,7-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1b (0.35
g, 1.7 mmol) according to general procedure B (0.36 g, 59%).
1H NMR (400 MHz, CDCl3): δ 7.95 (d, J = 8.3 Hz, 2H), 7.36 (d,
J = 7.9 Hz, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.96 (m, 2H), 5.27 (s, 2H),
3.90 (s, 3H), 3.73 (s, 2H), 2.83 (t, J = 5.6 Hz, 2H), 2.76 (br, 2H),
2.58 (s, 3H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7,
143.2, 134.2, 132.3, 131.0, 130.1, 129.3, 126.1, 123.7, 121.0, 117.5,
109.2, 108.2, 52.3, 52.1, 51.7, 46.1, 45.4, 22.6, 21.9. ESI-HRMS:
calc. for C22H24N2O2: [M+H]+ = 349.1911 m/z, found: [M+H]+ =
349.1904 m/z.
Methyl 4-((2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-
5(2H)-yl)methyl)benzoate (2c). The title compound was synthesized
from 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 1c
(0.30 g, 1.5 mmol) according to general procedure B (0.35 g, 56%).
1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.1 Hz, 2H), 7.26 (m,
7.14 (br, 2H), 7.04 (d, J = 8.4 Hz, 2H), 5.33 (s, 2H), 3.84 (s, 3H), 3.74
(s, 2H), 2.93 (t, J = 5.9 Hz, 2H), 2.82 (t, J = 5.5 Hz, 2H), 2.58 (s, 3H).
13C NMR (100 MHz, MeOD): δ 166.3, 142.9, 135.2, 134.0, 129.2,
128.7, 126.7, 125.7, 123.3, 119.5, 111.9, 110.3, 106.3, 51.3, 50.8, 50.4,
45.2, 43.5, 21.4. ESI-HRMS: calc. for C21H21BrN2O2: [M+H]+
=
413.0859 m/z, found: [M+H]+ = 413.0859 m/z.
4-((2,6-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-
methyl)-N-hydroxybenzamide·TFA (3a). The title compound was
synthesized from methyl 4-((2,6-dimethyl-3,4-dihydro-1H-pyrido[4,3-
b]indol-5(2H)-yl)methyl)benzoate 2a (0.07 g, 0.2 mmol) according to
general procedure C and the TFA salt was isolated as a white solid (12
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mg, 18%). H NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 10.22
2H), 7.12 (d, J = 8.1 Hz, 1H), 7.08 (d, J = 8.2 Hz, 2H), 5.26 (s, 2H),
4.09 (s, 2H), 3.91 (s, 3H), 3.57 (t, J = 5.9 Hz, 2H), 3.18 (t, J = 6.3 Hz,
2H), 3.01 (s, 3H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 166.5, 141.9, 135.6, 130.3, 130.0, 129.8, 129.7, 125.9, 125.0, 124.4,
117.6, 109.4, 101.5, 52.2, 50.7, 50.6, 46.5, 41.6, 21.4, 19.2. ESI-HRMS:
calc. for C22H24N2O2: [M+H]+ = 349.1911 m/z, found: [M+H]+ =
349.1910 m/z.
(br, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 6.93 (m,
4H), 5.62 (m, 2H), 4.67 (br, 1H), 4.35 (br, 1H), 3.78 (br, 1H), 3.60
(br, 1H), 3.01 (br, 5H), 2.44 (s, 3H). 13C NMR (100 MHz, DMSO-
d6): δ 164.2, 143.2, 135.5, 132.3, 132.2, 127.9, 125.8, 125.5, 125.4,
121.2, 120.4, 116.3, 103.1, 51.0, 50.4, 47.8, 42.2, 20.0, 19.4. ESI-
HRMS: calc. for C21H23N3O2: [M+H]+ = 350.1863 m/z, found: [M
+H]+ = 350.1863 m/z.
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dx.doi.org/10.1021/jm200773h | J. Med. Chem. 2012, 55, 639−651