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W.T. Jorgensen et al. / European Journal of Medicinal Chemistry 108 (2016) 730e740
5.2.22. 5-(4-(3,5-Bis(benzyloxy)benzyl)piperazin-1-yl)-1-(1-
methyl-4,10-dihydrobenzo[b]pyrazolo[3,4-e][1,4]diazepin-5(1H)-yl)
pentan-1-one (24)
5.2.25. 8-(4-(3,5-Bis(benzyloxy)benzyl)piperazin-1-yl)-1-(1-
methyl-4,10-dihydrobenzo[b]pyrazolo[3,4-e][1,4]diazepin-5(1H)-yl)
octan-1-one (27)
Treating 20 (170 mg, 0.47 mmol) with piperazine 15c according
to the above general procedure gave the title compound as a col-
Treating 23 (150 mg, 0.38 mmol) with piperazine 15c according
to the above general procedure gave the title compound as a col-
ourless oil (110 mg, 35%) (Rf
dichloromethane).
¼
0.52, 1:9 v/v methanol/
ourless oil (141 mg, 52%) (Rf
¼
0.38, 1:9 v/v methanol/
dichloromethane).
1H NMR (Chloroform-d, 500 MHz)
d
7.41 (dd, J ¼ 8.2, 1.6 Hz, 4H),
1H NMR (MeOD-d4, 400 MHz)
d 7.49e7.21 (m, 10H), 7.21e7.10
7.39e7.34 (m, 4H), 7.33e7.28 (m, 2H), 7.24 (dd, J ¼ 7.5, 1.5 Hz, 1H),
7.18 (s, 1H), 7.14 (dd, J ¼ 7.8, 1.5 Hz, 1H), 7.06e6.99 (m, 2H), 6.58 (d,
J ¼ 2.3 Hz, 2H), 6.54e6.48 (m, 2H), 5.64 (d, J ¼ 14.5 Hz, 1H), 5.02 (s,
4H), 3.82 (d, J ¼ 14.4 Hz, 1H), 3.69 (s, 3H), 3.41 (s, 2H), 2.61e2.30 (m,
8H), 2.12e2.14 (m, 3H), 1.99e1.93 (m, 1H), 1.62e1.42 (m, 2H),
(m, 3H), 7.02 (dt, J ¼ 7.4, 3.8 Hz, 2H), 6.74e6.12 (m, 3H), 5.49 (d,
J ¼ 14.0 Hz, 1H), 5.02 (s, 4H), 3.70 (s, 3H), 3.79 (d, J ¼ 14.4 Hz, 1H),
3.41 (d, J ¼ 2.5 Hz, 2H), 2.42 (br s, 8H), 2.25 (dt, J ¼ 7.7, 3.7 Hz, 2H),
2.13e2.01 (m, 2H), 1.57e1.33 (m, 4H), 1.13 (br s, 6H) ppm. NH peak
not observed. 13C NMR (MeOD-d4, 101 MHz)
d 175.0, 161.3, 141.5,
1.41e1.17 (m, 2H) ppm. 13C NMR (Chloroform-d, 126 MHz)
d
172.4,
140.7,140.7,138.7,137.4,132.9,131.1,130.4,129.5,128.8,128.6,123.3,
121.3, 109.7, 102.6, 102.4, 71.0, 63.9, 59.6, 53.9, 53.5, 44.5, 35.2, 34.7,
30.0, 30.0, 28.4, 27.3, 26.3 ppm. IR (diamond cell, thin film) nmax
159.9, 140.7, 139.2, 139.1, 137.0, 136.5, 132.2, 130.4, 129.1, 128.6,
128.0, 127.6, 122.7, 120.1, 108.2, 101.6, 100.8, 70.1, 63.0, 58.2, 53.2,
52.9, 43.1, 34.9, 33.6, 26.1, 23.3 ppm. IR (diamond cell, thin film)
nmax: 3339, 2943, 1648, 1564, 1559, 1503, 1448, 1397, 1156, 1209,
835, 740, 698 cmꢁ1. LRMS (þESI) m/z: 671 [(M þ H)þ, 100%].
:
3292, 2930, 1593, 1558, 1503, 1448, 1317, 1153, 1056, 950, 835, 736,
696 cmꢁ1. LRMS (þESI) m/z: 713 [(M þ H)þ, 100%].
5.2.26. General procedure for the synthesis of 4a-7a
A magnetically stirred suspension of the appropriate benzyl
protected resorcinol 24e27 (0.1 mmol) and Pd/C (20 mg of 10% w/
w) in methanol (25 mL) was placed under an atmosphere of H2
(1 atm) for 8 h. The resulting mixture was filtered through Celite™
and the solids thus retained were washed with methanol
(3 ꢂ 20 mL). The combined filtrates were concentrated under
reduced pressure and purified by flash column chromatography
5.2.23. 6-(4-(3,5-Bis(benzyloxy)benzyl)piperazin-1-yl)-1-(1-
methyl-4,10-dihydrobenzo[b]pyrazolo[3,4-e][1,4]diazepin-5(1H)-yl)
hexan-1-one (25)
Treating 21 (180 mg, 0.45 mmol) with piperazine 15c according
to the above general procedure gave the title compound as a col-
ourless oil (104 mg, 33%) (Rf
dichloromethane).
¼
0.38, 1:9 v/v methanol/
(0.1:0.9:9
v/v/v
28%
aqueous
ammonia/methanol/
1H NMR (Chloroform-d, 500 MHz)
d
7.46e7.39 (m, 4H),
dichloromethane):
7.39e7.35 (m, 4H), 7.34e7.29 (m, 2H), 7.27e7.23 (m,1H), 7.19 (s,1H),
7.14 (dd, J ¼ 7.8, 1.5 Hz, 1H), 7.06 (dd, J ¼ 8.1, 1.3 Hz, 1H), 7.02 (td,
J ¼ 7.6, 1.4 Hz, 1H), 6.57 (d, J ¼ 2.3 Hz, 2H), 6.52 (t, J ¼ 2.3 Hz, 1H),
6.41 (br s, 1H), 5.64 (d, J ¼ 14.6 Hz, 1H), 5.02 (s, 4H), 3.81 (d,
J ¼ 14.6 Hz, 1H), 3.73 (s, 3H), 3.43 (s, 2H), 2.46 (br s, 8H), 2.27 (dt,
J ¼ 10.7, 5.9 Hz, 2H), 2.13 (ddd, J ¼ 15.1, 8.1, 6.7 Hz, 1H), 1.94 (ddd,
J ¼ 15.3, 8.3, 6.7 Hz, 1H), 1.57e1.46 (m, 2H), 1.38e1.34 (m, 2H),
5.2.27. 5-(4-(3,5-Dihydroxybenzyl)piperazin-1-yl)-1-(1-methyl-
4,10-dihydrobenzo[b]pyrazolo[3,4-e][1,4]diazepin-5(1H)-yl)pentan-
1-one (4a)
Subjecting 24 (120 mg, 0.16 mmol) to the above general pro-
cedure produced the title compound (4a) as a white powder, mp
147e149 ꢀC (77 mg, 95%) (Rf ¼ 0.08, 0.1:0.9:9 v/v/v 28% aqueous
ammonia/methanol/dichloromethane).
1.21e1.02 (m, 2H) ppm. 13C NMR (Chloroform-d, 126 MHz)
d 172.5,
160.0,140.6,139.2,139.1, 137.1, 136.5,132.3,130.5,129.2,128.7, 128.1,
127.7,122.7,120.1,108.2,101.6,100.9, 70.2, 63.0, 58.5, 53.2, 52.7, 43.1,
35.0, 33.7, 27.0, 26.2, 25.1 ppm. IR (diamond cell, thin film) nmax
3290, 2945, 2812, 1637, 1594, 1558, 1503, 1447, 1395, 1348, 1313,
1290, 1156, 1506, 835, 737, 697 cmꢁ1. LRMS (þESI) m/z: 685
[(M þ H)þ, 100%].
1H NMR (MeOD-d4, 400 MHz)
d 7.29e7.27 (m, 2H), 7.22e7.18 (m,
1H), 7.16 (s, 1H), 7.04 (dt, J ¼ 8.0, 1.6 Hz, 1H), 6.26 (s, 2H), 6.17 (s, 1H),
5.51 (d, J ¼ 14.5 Hz,1H), 3.82 (d, J ¼ 14.5 Hz,1H), 3.72 (s, 3H), 3.35 (s,
2H), 2.43 (br s, 8H), 2.20e2.15 (m, 3H), 2.11e2.00 (m, 1H), 1.45 (t,
J ¼ 8.1 Hz, 2H), 1.30 (q, J ¼ 8.0, 7.5 Hz, 2H) ppm. NH and 2 OH peaks
:
not observed. 13C NMR (MeOD-d4, 101 MHz)
d 174.6, 159.5, 141.5,
140.6, 140.4, 137.3, 132.9, 131.1, 130.5, 123.4, 121.6, 109.0, 102.6,
102.5, 63.9, 59.1, 53.7, 53.5, 44.5, 35.2, 34.5, 26.6, 24.3 ppm. IR
(diamond cell, thin film) nmax: 3150, 2815, 1594, 1556, 1502, 1444,
1390,1287,1147, 997, 832, 760, 571, 450 cmꢁ1. LRMS (þESI) m/z: 491
[(M þ H)þ, 100%]. HRMS (þESI) Found: (M þ H)þ, 491.2761.
5.2.24. 7-(4-(3,5-Bis(benzyloxy)benzyl)piperazin-1-yl)-1-(1-
methyl-4,10-dihydrobenzo[b]pyrazolo[3,4-e][1,4]diazepin-5(1H)-yl)
heptan-1-one (26)
Treating 22 (200 mg, 0.51 mmol) with piperazine 15c according
to the above general procedure gave the title compound as a col-
C
27H34N6O3 requires (M þ H)þ, 491.2765. HPLC purity: 97.06%, RT:
ourless oil (127 mg, 36%) (Rf
dichloromethane).
¼
0.35, 1:9 v/v methanol/
13.02 min.
1H NMR (Chloroform-d, 500 MHz)
d
7.44e7.39 (m, 4H),
5.2.28. 6-(4-(3,5-Dihydroxybenzyl)piperazin-1-yl)-1-(1-methyl-
4,10-dihydrobenzo[b]pyrazolo[3,4-e][1,4]diazepin-5(1H)-yl)hexan-
1-one (5a)
7.39e7.34 (m, 4H), 7.33e7.28 (m, 2H), 7.23 (td, J ¼ 7.7, 7.2, 1.5 Hz,
1H), 7.19e7.16 (m, 2H), 7.13 (dd, J ¼ 7.8, 1.5 Hz, 1H), 7.00 (td, J ¼ 7.5,
1.5 Hz, 1H), 6.93e6.77 (br s, 1H), 6.58 (d, J ¼ 2.3 Hz, 2H), 6.52 (t,
J ¼ 2.3 Hz, 1H), 5.63 (d, J ¼ 14.5 Hz, 1H), 5.02 (s, 4H), 3.81 (d,
J ¼ 14.5 Hz, 1H), 3.73 (d, J ¼ 1.1 Hz, 3H), 3.44 (s, 3H), 2.53 (br m, 8H),
2.33e2.30 (m, 2H), 2.06 (dq, J ¼ 40.0, 7.5 Hz, 2H), 1.72e1.34 (m, 4H),
Subjecting 25 (90 mg, 0.13 mmol) to the above general proce-
dure produced the title compound (5a) as a white powder, mp
153e155 ꢀC (60 mg, 90%) (Rf ¼ 0.08, 0.1:0.9:9 v/v/v 28% aqueous
ammonia/methanol/dichloromethane).
1.21e0.99 (m, 4H) ppm. 13C NMR (Chloroform-d, 126 MHz)
d
172.68,
1H NMR (MeOD-d4, 500 MHz)
d 7.32e7.27 (m, 2H), 7.22 (d,
156.0, 140.5, 139.4, 139.3, 137.0, 136.5, 132.1, 130.4, 129.0, 128.6,
128.0, 127.6, 122.4, 120.1, 108.2, 101.5, 100.9, 70.1, 62.9, 58.5, 53.1,
52.3, 43.1, 35.2, 33.7, 28.9, 27.0, 26.1, 25.2 ppm. IR (diamond cell,
thin film) nmax: 3288, 2933, 2813, 1594, 1559, 1503, 1447, 1395, 1347,
1290, 1154, 1057, 952, 835, 738, 697 cmꢁ1. LRMS (þESI) m/z: 699
[(M þ H)þ, 100%].
J ¼ 7.7 Hz,1H), 7.16 (s,1H), 7.05 (t, J ¼ 7.5 Hz,1H), 6.27 (s, 2H), 6.18 (s,
1H), 5.50 (d, J ¼ 14.4 Hz, 1H), 3.83 (d, J ¼ 14.5 Hz, 1H), 3.73 (s, 3H),
3.38 (s, 2H), 2.51 (br s, 8H), 2.30 (br s, 2H), 2.09 (dq, J ¼ 49.4, 7.5 Hz,
2H), 1.46 (br s, 2H), 1.35 (br s, 2H), 1.24e0.98 (m, 2H) ppm. 1 NH and
2 OH peaks not observed. 13C NMR (MeOD-d4, 126 MHz)
d
174.8,
159.6, 141.5, 140.7, 140.2, 137.4, 132.9, 131.1, 130.5, 123.4, 121.3, 109.0,