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4.1.5.15. N-(3-(2-Oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-
yl)phenyl)pyrazine-2-carboxamide (9f). The title compound was
isolated as a yellow solid (99%); 1H NMR (400 MHz, DMSO d6) d
10.97 (1H, s), 10.53 (1H, s), 9.33 (1H, d, J = 1.5 Hz), 8.95 (1H, d, J
= 2.5 Hz), 8.84 (1H, dd, J = 2.5, 1.5 Hz), 8.63 (1H, s), 8.07 (1H, dd,
J = 8.1, 1.3 Hz), 7.80 (1H, d, J = 8.5 Hz), 7.57–0.50 (2H, m), 7.03
(1H, d, J = 3.7 Hz), 3.62 (2H, s); 13C NMR (100 MHz, DMSO d6)
d165.5, 162.4, 158.3, 148.3, 145.4, 144.6, 143.8, 142.1, 139.1,
138.6, 131.8, 129.6, 123.8, 123.4, 120.1, 119.4, 110.2; HRMS (ESI)
calcd. for C18H14N5O2S [M+H]+: 364.0863, found: 364.0863.
isolated as a brown solid (66%); 1H NMR (400 MHz, DMSO d6) d
10.98 (1H, s), 10.55 (1H, s), 8.64 (1H, t, J = 8.3 Hz), 8.55 (1H, s),
8.48 (1H, d, J = 8.5 Hz), 8.27 (1H, dd, J = 11.3, 2.8 Hz), 8.14 (1H,
dd, J = 15.4, 6.7 Hz), 8.04 (1H, d, J = 8.4 Hz), 7.97–7.91 (1H, m),
7.85–7.74 (1H, m), 7.71–7.65 (1H, m), 7.63 (1H, d, J = 8.5 Hz),
7.60–7.53 (1H, m), 7.04 (1H, d, J = 3.7 Hz), 3.66 (2H, s); 13C NMR
(100 MHz, DMSO d6) d 170.4, 165.0, 150.0, 149.9, 146.0, 145.9,
138.3, 137.3, 130.7, 130.3, 129.4, 129.0, 128.5, 128.2, 128.0,
127.5, 127.4, 121.2, 120.0, 119.5, 118.8, 42.7; HRMS (ESI) calcd.
for C23H17N4O2S [M+H]+: 413.1067, found: 413.1087.
4.1.5.16.
3-(4-Methylpiperazin-1-yl)-N-(3-(2-oxo-2,3-dihydro-1H-
benza-
4.1.5.21. N-(3-(2-Oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-
yl)phenyl)quinoline-3-carboxamide (9l). The title compound was
isolated as a yellow solid (88%); 1H NMR (400 MHz, DMSO d6) d
10.85 (1H, s), 10.56 (1H, s), 9.39 (1H, dd, J = 6.2, 2.2 Hz), 9.02 (1H,
d, J = 2.0 Hz), 8.87 (1H, d, J = 2.2 Hz), 8.48 (1H, t, J = 2.0 Hz), 8.43
(1H, d, J = 2.1 Hz), 8.19–8.05 (1H, m), 7.96–7.89 (1H, m), 7.84
(1H, ddd, J = 8.5, 6.9, 1.4 Hz), 7.77–7.72 (1H, m), 7.71–7.66 (1H,
m), 7.57–7.55 (1H, m), 7.04 (1H, d, J = 3.7 Hz), 3.63 (2H, s); 13C
NMR (100 MHz, DMSO d6) d 164.6, 162.3, 149.0, 148.1, 147.3,
141.8, 134.6, 133.4, 131.6, 130.5, 130.2, 129.2, 128.8, 128.8,
128.6, 127.6, 127.3, 126.7, 126.4, 119.0, 109.8, 38.2; HRMS (ESI)
calcd. for C23H17N4O2S [M+H]+: 413.1067, found: 413.1091.
thieno[3,4-b][1,4]diazepin-4-yl)phenyl)-5-(trifluoromethyl)
mide (9g). The title compound was isolated as a brown solid
(63%); 1H NMR (400 MHz, DMSO d6) d 10.55 (s, 1H), 10.53 (s,
1H), 8.40 (t, J = 3.6 Hz, 1H), 8.00 (d, d, J = 1.2, 1.2 Hz, 1H), 7.73 (d,
J = 2.4 Hz, 2H), 7.65 (s, 1H), 7.54–7.50 (t, s, J = 7.6 Hz, 2H), 7.38 (s,
1H), 7.01 (d, J = 4 Hz, 1H), 3.61 (s, 2H), 2.55–2.45 (m, 8H), 2.23 (s,
3H); 13C NMR (100 MHz, DMSO d6) d165.0, 164.6, 157.9, 151.3,
141.6, 139.3, 138.1, 136.4, 133.9, 131.4, 130.8, 130.3, 130.0,
129.1, 125.5, 123.2, 123.1, 119.4, 118.8, 117.4, 113.6, 109.7, 54.2,
47.3, 45.5; HRMS (ESI) calcd. for
528.1676, found: 528.1685; IR (ATR)
1545, 1113, 998, 787.
C
26H25F3N5O2S [M+H]+:
max/cmꢀ1: 2805, 1666,
m
4.1.5.22.
(R)-6-Hydroxy-2,5,7,8-tetramethyl-N-(3-(2-oxo-2,3-dihy-
4.1.5.17. 2-(1H-Indol-3-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-
b][1,4]diazepin-4-yl)phenyl)acetamide (9h). The title compound
was isolated as a yellow solid (93%); 1H NMR (400 MHz, DMSO d6)
d 10.93 (1H, s), 10.51 (1H, s), 10.33 (1H, s), 8.25 (1H, t, J = 1.8 Hz),
7.88–0.82 (1H, m), 7.63 (1H, dd, J = 16.6, 8.1 Hz), 7.52 (1H, d, J =
3.7 Hz), 7.43 (1H, t, J = 8.0 Hz), 7.35 (1H, dt, J = 8.1, 0.9 Hz), 7.27
(1H, d, J = 2.3 Hz), 7.07 (1H,ddd,J = 8.1, 7.0, 1.2 Hz), 7.01 (1H, dd,
J = 5.1, 2.4 Hz), 6.99–0.96 (1H, m), 3.75 (2H,s), 3.56 (2H,s); 13C
NMR (100 MHz, DMSO d6) d 170.5, 165.4, 158.4, 142.1, 140.3,
138.6, 136.6, 131.8, 129.6, 127.7, 124.4, 122.7, 121.9, 121.5,
119.3, 119.1, 118.9, 118.2, 111.9, 110.1, 108.9; HRMS (ESI) calcd.
for C23H19N4O2S [M+H]+: 415.1223, found: 415.1224.
dro-1H-thieno[3,4-b][1,4]diazepin-4-yl)phenyl)chroman-2-carbox-
amide (9m). The title compound was isolated as a brown solid
(90%); 1H NMR (400 MHz, DMSO d6) d 10.51 (1H, s), 9.50 (1H, s),
8.31 (1H, t, J = 1.9 Hz), 7.77 (1H, ddd, J = 8.2, 2.0, 0.8 Hz), 7.69 (1H,
ddd, J = 7.8, 1.6, 1.0 Hz), 7.56–7.50 (3H, m), 7.43 (1H, t, J = 8.0 Hz),
7.03 (1H, dd, J = 9.0, 3.5 Hz), 3.57 (2H, s), 2.19 (3H, d, J = 3.0 Hz),
2.09–2.04 (7H, m), 1.54–1.49 (5H, m); 13C NMR (100 MHz,
DMSO d6) d 172.5, 165.0, 158.0, 146.1, 144.0, 142.0, 138.8, 138.1,
131.4, 129.0, 122.8, 122.6, 121.5, 120.4, 119.0, 118.9, 117.1, 109.7,
77.5, 38.3, 29.4, 24.7, 23.7, 20.8, 12.8, 12.2, 11.8; HRMS (ESI) calcd.
for C27H28N3O4S [M+H]+: 490.1795, found: 490.1814.
4.1.6. General syntheses of N-(3 or 4-(2-oxo-2,3-dihydro-1H-thieno
4.1.5.18. 2-(Biphenyl-4-yl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-b]
[1,4]diazepin-4-yl)phenyl)acetamide (9i). The title compound was
isolated as a brown solid (89%); 1H NMR (400 MHz, DMSO d6) d
10.52 (1H, s), 10.44 (1H, s), 8.26 (1H, t, J = 1.8 Hz), 7.85 (1H, dd, J
= 8.1, 1.2 Hz), 7.66 (1H, d, J = 1.4 Hz), 7.64 (2H,s), 7.62 (1H, d, J =
1.8 Hz), 7.52 (1H, d, J = 3.7 Hz), 7.47 (1H, d, J = 1.7 Hz), 7.46 (2H,
d, J = 1.3 Hz), 7.43 (2H, d, J = 2.0 Hz), 7.36–7.38 (1H, m), 7.35 (1H,
d, J = 1.8 Hz), 7.02 (1H, d, J = 3.7 Hz), 3.71 (2H, d, J = 4.4 Hz), 3.57
(2H, s); 13C NMR (100 MHz, DMSO d6) d169.4, 165.0, 157.9, 141.6,
140.00, 139.6, 138.6, 138.2, 135.2, 131.4, 129.8, 129.2, 128.9,
127.3, 126.7, 126.6, 122.4, 121.5, 118.8, 117.8, 109.7, 43.0, 38.3;
HRMS (ESI) calcd. for C27H22N3O2S [M+H]+: 452.1427, found:
452.1439.
[3,4-b][1,4]diazepin-4-yl)phenyl)urea (10a–10d), (11a–11d)
Aminophenyl-1H-thieno[3,4-b][1,4]diazepin-2(3H)-one
(7a–
7b) (25.7 mg, 0.1 mmol) and substituted isocyanate (0.12 mmol)
in THF were stirred at room temperature overnight. The reaction
mixture was diluted with ethyl acetate and washed with brine.
The organic layer was dried over Na2SO4. The concentrated crude
product was purified by flash column chromatography with hex-
ane/ethyl acetate = (1:1) as the eluent to give the indicated product.
4.1.6.1. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihy-
dro-1H-thieno[3,4-b][1,4]diazepin-4-yl)-phenyl)urea (10a). The title
compound was isolated as a yellow solid (93%); 1H NMR (400
MHz, DMSO d6) d10.46 (1H, s), 9.25 (1H, s), 9.19 (1H, s), 8.13 (1H,
d, J = 2.0 Hz), 7.98 (2H, d, J = 8.8 Hz), 7.68–7.60 (4H, m), 7.47 (1H,
d, J = 3.6 Hz), 7.00 (1H, d, J = 3.6 Hz), 3.57 (2H, s); 13C NMR (100
MHz, DMSO d6) d165.0, 157.5, 152.2, 141.9, 139.1, 132.0, 131.4,
131.1, 128.5, 123.3, 122.6, 118.1, 118.0, 109.5; HRMS (ESI) calcd.
for C21H15ClF3N4O2S [M+H]+: 479.0551, found: 479.0538.
4.1.5.19. 2-(2-Fluorophenyl)-N-(3-(2-oxo-2,3-dihydro-1H-thieno[3,4-
b][1,4]diazepin-4-yl)phenyl)acetamide (9j). The title compound was
isolated as a brown solid (79%); 1H NMR (400 MHz, DMSO d6) d
10.52 (1H, s), 10.45 (1H, s), 8.29–8.26 (1H, m), 7.81 (1H, ddd, J =
7.8, 1.8, 0.7 Hz), 7.68 (1H, ddd, J = 7.9, 1.8, 1.1 Hz), 7.52 (1H, d, J
= 3.7 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.41–7.39 (1H, m), 7.32–7.29
(1H, m), 7.19–7.17 (2H, m), 7.02 (1H, d, J = 3.7 Hz), 3.76 (2H, s),
3.57 (2H, s); 13C NMR (100 MHz, DMSO d6) d 168.4, 168.1, 165.0,
159.5, 157.9, 141.6, 139.6, 132.1, 131.9, 131.4, 128.9, 128.5,
124.3, 124.1, 118.8, 115.2, 115.0, 114.8, 109.7, 38.3, 36.4; HRMS
(ESI) calcd. for C21H17FN3O2S [M+H]+: 394.1020, found: 394.1028.
4.1.6.2. 1-(4-Chlorophenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno[3,4-
b][1,4]diazepin-4-yl)phenyl)urea (10b). The title compound was
isolated as a yellow solid (51%); 1H NMR (400 MHz, DMSO d6)
d10.45 (1H, s), 9.05 (1H, s), 8.91 (1H, s), 7.97 (2H, d, J = 8.8 Hz),
7.59 (2H, d, J = 8.8 Hz), 7.51–7.49 (2H, m), 7.46 (1H, d, J = 3.6 Hz),
7.35–7.33 (2H, m), 7.00 (1H, d, J = 3.6 Hz), 3.57 (2H, s); 13C NMR
(100 MHz, DMSO d6) d165.1, 157.5, 152.2, 142.3, 142.0, 138.4,
131.4, 130.8, 128.7, 128.5, 125.6, 119.9, 118.0, 117.7, 109.5; HRMS
(ESI) calcd. for C20H16ClN4O2S [M+H]+: 411.0677, found: 411.0660.
4.1.5.20. N-(3-(2-Oxo-2,3-dihydro-1H-thieno[3,4-b][1,4]diazepin-4-
yl)phenyl)quinoline-2-carboxamide (9k). The title compound was