Journal of Medicinal Chemistry
Article
was purified by flash column chromatography (EtOAc) to give pale
(203 mg, 957 μmol). Flash column chromatography (EtOAc) gave the
title compound as a pale yellow oil (110 mg, 29%). H NMR δ 7.23
yellow needles (675 mg, 61%, lit.31 52%). H NMR δ 7.71 (dd, J =
1
1
7.5/1.4 Hz, 1H), 7.51 (s, 1H), 7.40 (td, J = 7.4/1.6 Hz, 1H), 7.34 (td,
J = 7.5/1.4 Hz, 1H), 7.19 (dd, J = 7.4/0.8 Hz, 1H), 3.13 (q, J = 6.5 Hz,
2H), 2.87 (t, J = 7.1 Hz, 2H), 2.02 (p, J = 6.8 Hz, 2H). 13C NMR δ
174.4 (C), 138.5 (C), 135.2 (C), 131.3 (CH), 128.74 (CH), 128.70
(CH), 127.0 (CH), 39.6 (CH2), 30.7 (CH2), 30.4 (CH2).
(dd, J = 8.1/2.0 Hz, 1H), 7.17−7.14 (m, 1H), 6.96 (d, J = 8.2 Hz, 1H),
4.37 (s, 1H), 3.56 (s, 2H), 3.37 (s, 1H), 2.82 (t, J = 5.9 Hz, 2H), 2.69
(t, J = 5.9 Hz, 2H), 2.56−2.44 (m, 2H), 2.04−1.95 (m, 2H), 1.84−
1.73 (m, 2H), 1.53−1.42 (m, 11H), 1.29−1.22 (m, 1H), 1.12−0.97
(m, 4H). 13C NMR δ 155.4 (C), 137.3 (C), 133.6 (C), 130.4 (CH),
129.5 (CH), 129.3 (CH), 119.2 (C), 79.1 (C), 56.2 (CH2), 55.9
(CH2), 50.8 (CH2), 50.0 (CH), 35.4 (CH), 34.3 (CH2), 33.6 (CH2),
32.1 (CH2), 28.7 (CH2), 28.6 (CH3). HRMS (m/z): [MH]+ calcd for
C22H33BrN2O2, 437.1798; found 437.1803.
2,3,4,5-Tetrahydro-1H-benzo[c]azepine (4).56 Lithium alumi-
num hydride (177 mg, 4.65 mmol) was taken up in dry THF (10 mL),
and to the stirred solution under N2 at 0 °C was slowly added a
solution of 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (3) (250 mg,
1.55 mmol) in dry THF (5 mL). The solution was stirred at room
temperature for 30 min, then heated to reflux. After 16 h, the mixture
was cooled on ice, and water (15 mL) was slowly added. The solids
were filtered through a plug of Celite and then washed with Et2O
(30 mL). The product was then further extracted with Et2O (2 ×
20 mL), and the combined extracts were dried and concentrated in
vacuo to reveal the title compound as a clear oil (197 mg, 86%, lit.56
tert-Butyl (trans-4-(2-(7-(Trifluoromethyl)-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)cyclohexyl)carbamate (10f). General procedure A was
followed using 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydro-
chloride (9f) (227 mg, 957 μmol) and DIPEA (333 μL, 1.91 mmol).
Flash column chromatography (EtOAc/petroleum spirits, 1:1, v/v)
1
gave the title compound as a pale yellow solid (125 mg, 34%). H
NMR δ 7.36 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 8.0 Hz,
1H), 4.37 (s, 1H), 3.64 (s, 2H), 3.38 (s, 1H), 2.94 (t, J = 5.7 Hz, 2H),
2.73 (t, J = 5.9 Hz, 2H), 2.59−2.48 (m, 2H), 1.98 (s, 2H), 1.85−1.75
(m, 2H), 1.54−1.42 (m, 11H), 1.33−1.26 (m, 1H), 1.14−0.96 (m,
4H). 13C NMR δ 155.4 (C), 138.8 (C), 135.8 (C), 129.2 (CH), 128.1
(C, q, JCF = 32.2 Hz), 124.4 (C, q, JCF = 271.8 Hz), 123.6 (CH, q,
JCF = 3.8 Hz), 122.9 (CH, q, JCF = 3.7 Hz), 79.1 (C), 56.3 (CH2), 56.1
(CH2), 50.7 (CH2), 50.0 (CH), 35.4 (CH), 34.2 (CH2), 33.5 (CH2),
32.1 (CH2), 29.3 (CH2), 28.6 (CH3). HRMS (m/z): [MH]+ calcd for
C23H33F3N2O2, 427.2567; found 427.2586.
1
60%) which required no further purification. H NMR δ 7.17−7.07
(m, 4H), 3.92 (s, 2H), 3.24−3.15 (m, 2H), 2.98−2.89 (m, 2H), 1.76−
1.66 (m, 2H), 1.41 (s, 1H). 13C NMR δ 143.1 (C), 143.0 (C), 129.3
(CH), 128.4 (CH), 127.1 (CH), 126.1 (CH), 55.3 (CH2), 53.8
(CH2), 36.3 (CH2), 31.1 (CH2).
tert-Butyl ((trans)-4-(2-(3,4-Dihydroisoquinolin-2(1H)-yl)-
ethyl)cyclohexyl)carbamate (10b). General procedure A was fol-
lowed using 1,2,3,4-tetrahydroisoquinoline (9b) (82.8 mg, 622 μmol).
Flash column chromatography (EtOAc) gave the title compound as a
1
white solid (190 mg, 85% yield). H NMR δ 7.16−7.05 (m, 3H),
tert-Butyl (trans-4-(2-(4,5-Dihydro-1H-benzo[c]azepin-2(3H)-yl)-
ethyl)cyclohexyl)carbamate (10g). General procedure A was
followed using 2,3,4,5-tetrahydro-1H-benzo[c]azepine (9g) (121 mg,
820 μmol). Purification by flash column chromatography (EtOAc/
MeOH, 90:10, v/v) gave the title compound as a pale yellow oil
7.04−6.97 (m, 1H), 4.39 (br s, 1H), 3.60 (s, 2H), 3.38 (br s, 1H), 2.89
(t, J = 5.9 Hz, 2H), 2.71 (t, J = 5.9 Hz, 2H), 2.53−2.50 (m, 2H), 2.02−
1.94 (m, 2H), 1.84−1.72 (m, 2H), 1.55−1.45 (m, 2H), 1.44 (s, 9H),
1.33−1.20 (m, 1H), 1.13−0.97 (m, 4H). 13C NMR δ 155.4 (C), 134.9
(C), 134.4 (C), 128.7 (CH), 126.7 (CH), 126.2 (CH), 125.7 (CH),
79.1 (C), 56.4 (CH2), 56.3 (CH2), 51.1 (CH2), 50.0 (CH), 35.4
(CH), 34.3 (CH2), 33.6 (CH2), 32.1 (CH2), 29.2 (CH2), 28.6 (CH3).
HRMS (m/z): [MH]+ calcd for C22H34N2O2, 359.2693; found 359.2711.
tert-Butyl (trans-4-(2-(7-Fluoro-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)cyclohexyl)carbamate (10c). General procedure A
was followed using 7-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride
(9c) (231 mg, 1.23 mmol) and DIPEA (429 μL, 2.46 mmol). Flash
column chromatography (EtOAc/petroleum spirits, 4:1, v/v) gave the
title compound as a pale yellow solid (195 mg, 46%). 1H NMR δ 7.03
(dd, J = 8.4/5.8 Hz, 1H), 6.81 (td, J = 8.5/2.6 Hz, 1H), 6.71 (dd, J =
9.4/2.5 Hz, 1H), 4.46 (s, 1H), 3.56 (s, 2H), 3.43−3.30 (m, 1H), 2.84
(t, J = 5.7 Hz, 2H), 2.69 (t, J = 5.9 Hz, 2H), 2.53−2.46 (m, 2H), 2.05−
1.93 (m, 2H), 1.84−1.75 (m, 2H), 1.54−1.41 (m, 11H), 1.33−1.21
(m, 1H), 1.14−0.98 (m, 4H). 13C NMR δ 162.2 (C), 159.8 (C), 155.3
(C), 136.8 (C, d, JCF = 7.1 Hz), 130.0 (CH, d, JCF = 7.9 Hz), 129.9 (C,
1
(62 mg, 22%). H NMR δ 7.21−7.06 (m, 4H), 4.35 (s, 1H), 3.90 (s,
2H), 3.34 (s, 1H), 3.17−3.06 (m, 2H), 2.95−2.84 (m, 2H), 2.40−2.31
(m, 2H), 1.99−1.91 (m, 2H), 1.75−1.65 (m, 4H), 1.47−1.35 (m,
11H), 1.22−1.11 (m, 1H), 1.09−0.90 (m, 4H). 13C NMR δ 155.4 (C),
143.0 (C), 138.9 (C), 130.0 (CH), 129.0 (CH), 127.4 (CH), 126.1
(CH), 79.2 (C), 59.3 (CH2), 59.0 (CH2), 50.8 (CH2), 50.0 (CH),
36.2 (CH2), 35.2 (CH), 34.3 (CH2), 33.5 (CH2), 32.1 (CH2), 28.6
(CH3), 24.9 (CH2). HRMS (m/z): [MH]+ calcd for C23H36N2O2,
373.2850; found 373.2853.
tert-Butyl ((trans)-4-(2-(6,7-Dihydrothieno[3,2-c]pyridin-
5(4H)-yl)ethyl)cyclohexyl)carbamate (10h). General procedure
A was followed using 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydro-
chloride (9h) (160 mg, 912 μmol) and DIPEA (289 μL, 1.66 mmol).
Purification by flash column chromatography (EtOAc/petroleum
spirits, 1:1, v/v) gave the title compound as a white solid (42 mg,
1
14%). H NMR δ 7.06 (d, J = 5.1 Hz, 1H), 6.71 (d, J = 5.1 Hz, 1H),
4.38 (s, 1H), 3.53 (s, 2H), 3.36 (s, 1H), 2.88 (t, J = 5.5 Hz, 2H), 2.77
(t, J = 5.7 Hz, 2H), 2.57−2.50 (m, 2H), 2.04−1.94 (m, 2H), 1.82−
1.73 (m, 2H), 1.52−1.42 (m, 11H), 1.30−1.24 (m, 1H), 1.15−0.99
(m, 4H). 13C NMR δ 155.4 (C), 134.0 (C), 133.6 (C), 125.4 (CH),
122.7 (CH), 79.1 (C), 55.9 (CH2), 53.3 (CH2), 51.1 (CH2), 50.0
(CH), 35.4 (CH), 34.5 (CH2), 33.6 (CH2), 32.1 (CH2), 28.6 (CH3),
25.6 (CH2). HRMS (m/z): [MH]+ calcd for C20H32N2O2S, 365.2257;
found 365.2274.
d, JCF = 2.8 Hz), 113.2 (CH, d, JCF = 21.3 Hz), 112.9 (CH, d, JCF
=
21.2 Hz), 79.0 (C), 56.17 (CH2), 56.15 (CH2), 51.0 (CH2), 49.9
(CH), 35.3 (CH), 34.2 (CH2), 33.5 (CH2), 32.0 (CH2), 28.5 (CH3),
28.4 (CH2). HRMS (m/z): [MH]+ calcd for C22H33FN2O2, 377.2599;
found 377.2604.
tert-Butyl (trans-4-(2-(7-Chloro-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)cyclohexyl)carbamate (10d). General procedure
A was followed using 7-chloro-1,2,3,4-tetrahydroisoquinoline (9d) (160 mg,
957 μmol). Purification by flash column chromatography (EtOAc/
petroleum spirits, 2:1, v/v) gave the title compound as a pale yellow oil
(104 mg, 30%). 1H NMR δ 7.11 (dd, J = 8.2/2.1 Hz, 1H), 7.06−7.00
(m, 2H), 4.37 (s, 1H), 3.67 (s, 2H), 3.39 (d, J = 13.4 Hz, 1H), 2.91−
2.76 (m, 4H), 2.66−2.55 (m, 2H), 2.03−1.95 (m, 2H), 1.83−1.75 (m,
2H), 1.52 (dd, J = 15.4/6.9 Hz, 2H), 1.44 (s, 9H), 1.31−1.26 (m, 1H),
1.10−1.01 (m, 4H). 13C NMR δ 155.3 (C), 136.8 (C), 132.9 (C),
131.1 (C), 130.0 (CH), 126.5 (CH), 126.3 (CH), 79.1 (C), 56.2
(CH2), 55.9 (CH2), 50.8 (CH2), 50.0 (CH), 35.3 (CH), 34.2 (CH2),
33.5 (CH2), 32.1 (CH2), 28.6 (CH2), 28.5 (CH3). HRMS (m/z):
[MH]+ calcd for C22H33ClN2O2, 393.2303; found 393.2306.
tert-Butyl (trans-4-(2-(7-Bromo-3,4-dihydroisoquinolin-
2(1H)-yl)ethyl)cyclohexyl)carbamate (10e). General procedure
A was followed using 7-bromo-1,2,3,4-tetrahydroisoquinoline (9e)
tert-Butyl (trans-4-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)-
ethyl)cyclohexyl)carbamate (10i). General procedure A was fol-
lowed using 1-(2-methoxyphenyl)piperazine hydrochloride (9i)
(284 mg, 1.24 mmol, 2 equiv) and DIPEA (0.237 mL, 1.36 mmol,
2.2 equiv). Purification by flash column chromatography (MeOH/
DCM 0:100 to 5:95) gave the title compound as a white solid
1
(235 mg, 91%). H NMR δ 7.00 (ddd, J = 7.9/7.1/2.2 Hz, 1H), 6.95
(dd, J = 7.9/2.2 Hz, 1H), 6.93−6.90 (m, 1H), 6.86 (dd, J = 8.0/1.1 Hz,
1H), 4.48−4.20 (m, 1H), 3.86 (s, 3H), 3.50−2.95 (m, 5H), 2.94−2.25
(m, 6H), 2.11−1.89 (m, 2H), 1.88−1.68 (m, 2H), 1.67−1.34 (m,
11H), 1.33−1.16 (m, 1H), 1.16−0.94 (m, 4H). 13C NMR δ 159.1 (C),
152.4 (C), 139.7 (C), 123.3 (CH), 121.2 (CH), 118.5 (CH), 111.3
(CH), 79.2 (C), 56.8 (CH2), 55.5 (CH3), 53.5 (CH2), 53.5 (CH2),
50.0 (CH), 35.6 (CH), 34.1 (CH2), 33.5 (CH2), 32.1 (CH2), 28.6
L
J. Med. Chem. XXXX, XXX, XXX−XXX