Journal of Medicinal Chemistry
Article
organic extracts were washed with brine (10 mL), dried over Na2SO4,
and concentrated under vacuum. The crude product was purified by
flash chromatography (0−20% EtOAc/hexane) to afford 16c as an
4H). 13C NMR (CDCl3) δ 166.9, 155.3, 143.7, 134.2, 134.0, 131.3,
130.0 (2C), 129.4, 127.7 (2C), 120.0, 117.2, 102.6, 57.7, 53.1, 52.2,
34.1, 28.2, 24.9.
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off-white solid (300 mg, 65%). H NMR (CDCl3) δ 7.22 (d, J = 2.2
4-((7-Chloro-2-oxo-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)-
methyl)-N-hydroxybenz-amide (18a). 18a was synthesized from 17a
(200 mg, 0.58 mmol) following General Procedure A, Step (ii) and was
Hz, 1H), 7.11 (dd, J = 8.3, 2.3 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 3.75
(br s, 1H), 3.02 (dd, J = 7.0, 3.8 Hz, 2H), 2.81−2.65 (m, 2H), 1.81−
1.75 (m, 2H), 1.70−1.55 (m, 2H). 13C NMR (CDCl3) δ 149.7, 135.9,
133.3, 129.3, 121.0, 112.9, 48.9, 35.9, 31.8, 26.8.
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obtained as a white powder (140 mg, 70%). H NMR (DMSO-d6) δ
11.12 (br s, 1H), 8.98 (br s, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.34 (dd, J
= 8.3, 2.5 Hz, 1H; d, J = 2.5 Hz, 1H, overlapping), 7.26 (d, J = 8.2 Hz,
2H), 5.02 (s, 2H), 2.52−2.50 (m, 2H, overlapping with solvent peak),
2.23 (t, J = 7.1 Hz, 2H), 2.09−2.07 (m, 2H). 13C NMR (DMSO-d6) δ
171.9, 163.9, 141.0, 140.7, 137.5, 131.7, 129.8, 129.0, 127.7 (2C),
127.3, 127.0 (2C), 124.3, 49.4, 32.7, 29.1, 28.1. ESI HRMS calcd for
C18H17ClN2O3: [M + H]+, m/z 344.1000; found: 344.0098.
N-Hydroxy-4-((2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)-
methyl)benzamide (18b). 18b was synthesized from 17b (120 mg,
0.41 mmol) following General Procedure A, Step (ii) and was obtained
as a white powder (110 mg, 90%). 1H NMR (DMSO-d6) δ 11.14 (br
s, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (d, J =
7.4 Hz, 1H), 7.09−7.02 (m, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.82 (t, J =
7.1 Hz, 1H), 4.36 (s, 2H), 2.95−2.77 (m, 4H), 1.60−1.56 (m, 4H).
13C NMR (126 MHz, DMSO-d6) δ 164.1, 151.6, 142.9, 135.5, 131.5,
2,3,4,5-Tetrahydro-1H-benz[b]azepine-7-carbonitrile (16d). To a
solution of 16c (100 mg, 0.44 mmol) in DMF/water (99:1, 2 mL)
were added Zn(CN)2 (112 mg, 0.48 mmol), S-Phos (18 mg, 0.04
mmol), and Pd2(dba)3 (20 mg, 0.02 mmol) in a microwave reaction
tube. Then, the resulting mixture was heated at 170 °C for 30 min in a
microwave reactor. After completion, the reaction was quenched with
water (10 mL), and the mixture was extracted with EtOAc (10 × 3
mL). The combined organic extracts were washed with water and
brine, dried over Na2SO4, and concentrated under a vacuum. The
crude product was purified by flash chromatography (0−50% EtOAc/
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hexane) to afford 16d as a colorless oil (70 mg, 93%). H NMR
(CDCl3) δ 7.33 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 8.2, 1.8 Hz, 1H),
6.66 (d, J = 8.2 Hz, 1H), 4.16 (br s, 1H), 3.25−3.07 (m, 2H), 2.78−
2.75 (m, 2H), 1.87−1.77 (m, 2H), 1.77−1.67 (m, 2H). 13C NMR
(CDCl3) δ 154.5, 135.0, 132.3, 130.9, 120.2, 119.0, 102.3, 47.8, 35.3,
30.7, 26.3.
129.9, 128.0, 126.9 (2C), 126.6 (2C), 121.12, 117.70, 57.3, 54.1, 34.3,
25.4. ESI HRMS calcd for C18H19N2O2: [M − H]−, m/z 295.1452;
found: 295.1446.
Methyl 4-((7-Chloro-2-oxo-2,3,4,5-tetrahydro-1H-benz[b]azepin-
1-yl)methyl)benzoate (17a). 17a was synthesized from 15b (140 mg,
0.72 mmol) and 3d (196 mg, 0.86 mmol) following the procedure for
4-((7-Chloro-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)methyl)-
N-hydroxybenzamide (18c). 18c was synthesized from 17c (70 mg,
0.21 mmol) following General Procedure A, Step (ii) and was obtained
as a white powder (55 mg, 79%). 1H NMR (500 MHz, DMSO-d6) δ
11.14 (s, 1H), 8.98 (br s, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.44 (d, J =
7.9 Hz, 2H), 7.17 (d, J = 2.6 Hz, 1H), 7.08 (dd, J = 8.5, 2.6 Hz, 1H),
6.92 (d, J = 8.6 Hz, 1H), 4.35 (s, 2H), 2.87 (t, J = 5.0 Hz, 2H), 2.83−
2.76 (m, 2H), 1.60−1.55 (m, 4H). 13C NMR (126 MHz, DMSO-d6)
δ 164.1, 150.4, 142.6, 137.5, 131.5, 129.2, 127.8 (2C), 126.9 (2C),
126.0, 124.5, 119.2, 57.3, 53.9, 33.8, 29.3, 25.0. ESI HRMS calcd for
C18H18ClNO2: [M − H]−, m/z 329.1062; found: 329.1068.
4-((7-Bromo-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)methyl)-
N-hydroxybenzamide (18d). 18d was synthesized from 17d (50 mg,
0.13 mmol) following General Procedure A, Step (ii) and was obtained
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13a and was obtained as a colorless oil (200 mg, 81%). H NMR
(CDCl3) δ 7.88 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.16
(dd, J = 8.5, 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.5 Hz,
1H), 4.99 (s, 2H), 3.83 (s, 3H), 2.44 (t, J = 7.1 Hz, 2H), 2.31 (t, J =
7.1 Hz, 2H), 2.16−2.06 (m, 2H). 13C NMR (CDCl3) δ 172.9, 166.7,
142.6, 140.7, 137.6, 131.6, 129.8 (2C), 129.3, 129.3, 128.0 (2C),
127.5, 123.9, 52.0, 50.9, 32.9, 29.8, 28.6.
Methyl 4-((2,3,4,5-Tetrahydro-1H-benz[b]azepin-1-yl)methyl)-
benzoate (17b). 17b was synthesized from 16a (70 mg, 0.48
mmol) and 3d (163 mg, 0.71 mmol) following General Procedure A,
Step (i) and was obtained as a colorless oil (120 mg, 85%). 1H NMR
(CDCl3) δ 8.02 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.15−
7.12 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.90 (td, J = 7.4, 0.9 Hz, 1H),
4.38 (s, 2H), 3.92 (s, 3H), 2.90 (s, 4H), 1.64 (s, 4H). 13C NMR
(CDCl3) δ 167.2, 152.3, 145.5, 136.4, 130.2, 129.8 (2C), 129.1,
128.4(2C), 126.8, 121.7, 117.8, 58.5, 54.0, 52.1, 35.1, 30.1, 25.9.
Methyl 4-((7-Chloro-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)-
methyl)benzoate (17c). 17c was synthesized from 16b (70 mg,
0.36 mmol) and 3d (125 mg, 0.55 mmol) following General Procedure
A, Step (i) and was obtained as a colorless oil (70 mg, 85%). 1H NMR
(CDCl3) δ 8.01 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.11 (d,
J = 2.4 Hz, 1H), 7.06 (dd, J = 8.5, 2.5 Hz, 1H), 6.83 (d, J = 8.5 Hz,
1H), 4.33 (s, 2H), 3.91 (s, 3H), 2.96−2.79 (m, 4H), 1.62 (s, 4H). 13C
NMR (CDCl3) δ 167.1, 150.7, 144.9, 138.0, 129.84 (2 C), 129.82,
129.2, 128.2 (2 C), 126.4, 126.3, 119.0, 58.5, 54.1, 52.2, 34.8, 29.8,
25.5.
Methyl 4-((7-Bromo-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)-
methyl)benzoate (17d). 17d was synthesized from 16c (190 mg,
0.84 mmol) and 3d (287 mg, 1.26 mmol) following General Procedure
A, Step (i) and was obtained as an off-white solid (100 mg, 31%). 1H
NMR (CDCl3) δ 8.02 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H),
7.27 (d, J = 2.4 Hz, 1H), 7.21 (dd, J = 8.5, 2.4 Hz, 1H), 6.79 (d, J =
8.5 Hz, 1H), 4.34 (s, 2H), 3.93 (s, 3H), 2.87 (d, J = 14.3 Hz, 4H),
1.63 (s, 4H). 13C NMR (CDCl3) δ 167.1, 151.2, 144.9, 138.4, 132.7,
129.9 (2C), 129.4, 129.2, 128.2 (2C), 119.4, 113.9, 58.43, 54.0, 52.2,
34.8, 29.8, 25.5.
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as an off-white powder (45 mg, 92%). H NMR (500 MHz, DMSO-
d6) δ 11.14 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H),
7.29 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 6.86 (d, J =
8.6 Hz, 1H), 4.35 (s, 2H), 2.88 (t, J = 5.1 Hz, 2H), 2.83−2.76 (m,
2H), 1.61−1.53(m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 164.1,
150.8, 142.6, 137.9, 132.0, 131.5, 128.9, 127.8 (2C), 126.9 (2C),
119.7, 112.5, 57.2, 53.8, 33.8, 29.2, 25.0. ESI HRMS calcd for
C18H18BrN2O2: [M − H]−, m/z 373.0557; found: 373.0547.
4-((7-(1H-Pyrazol-4-yl)-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-
yl)methyl)-N-hydroxy-benzamide (18e). 18e was synthesized from
17d (50 mg, 0.13 mmol) following the procedure for 1q and was
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obtained as a gray powder (5.2 mg, 11% over two steps). H NMR
(DMSO-d6) δ 11.14 (s, 1H), 7.92 (s, 2H), 7.69 (d, J = 8.1 Hz, 2H),
7.47 (d, J = 8.1 Hz, 2H), 7.36 (s, 1H), 7.27 (dd, J = 8.2, 1.9 Hz, 1H),
6.91 (d, J = 8.3 Hz, 1H), 4.38 (s, 2H), 2.86 (br s, 4H), 1.60 (br s,
4H). ESI HRMS calcd for C21H21N4O2: [M − H]−, m/z 361.1670;
found: 361.1666.
4-((7-Cyano-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)methyl)-
N-hydroxybenzamide (18f). 18f was synthesized from 17e (30 mg,
0.094 mmol) following General Procedure A, Step (ii) and was
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obtained as a white powder (28 mg, 93%). H NMR (DMSO-d6) δ
11.16 (s, 1H), 9.01 (br s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.47 (d, J =
1.8 Hz, 1H), 7.43−7.40 (m, 1H), 7.38 (d, J = 8.0 Hz, 2H), 6.82 (d, J
= 8.4 Hz, 1H), 4.51 (s, 2H), 3.20 (s, 2H), 2.86 (s, 2H), 1.69 (s, 4H).
ESI HRMS calcd for C19H18N3O2: [M − H]−, m/z 320.1405; found:
320.1392.
1-(4-(Hydroxycarbamoyl)benzyl)-2,3,4,5-tetrahydro-1H-benz[b]-
azepine-7-carboxamide (18g). (i) To a stirred solution of 17e (30
mg, 0.094 mmol) and K2CO3 (1.3 mg, 0.0094 mmol) in DMSO (1
mL) was added aqueous H2O2 solution (30%, 0.5 mL) at 0 °C. The
resulting mixture was slowly warmed to room temperature and stirred
Methyl 4-((7-Cyano-2,3,4,5-tetrahydro-1H-benz[b]azepin-1-yl)-
methyl)benzoate (17e). 17e was synthesized from 16d (70 mg,
0.41 mmol) and 3d (139 mg, 0.61 mmol) following General Procedure
A, Step (i) and was obtained as a colorless oil (60 mg, 46%). 1H NMR
(CDCl3) δ 8.01 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.35−
7.29 (m, 2H), 6.78 (d, J = 8.3 Hz, 1H), 4.45 (s, 2H), 3.90 (s, 3H),
3.14 (d, J = 4.9 Hz, 2H), 2.87 (d, J = 5.4 Hz, 2H), 1.81−1.67 (m,
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J. Med. Chem. 2021, 64, 4810−4840