Journal of Medicinal Chemistry
Article
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(2.00 g, 5.26 mmol) to afford 65 (1.30 g, 36%) as white foam: H
NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 7.90 (s, 1H), 7.06 (m, 4H),
6.97 (br s, 2H, NH2), 6.05 (d, J = 1.6 Hz, 1H), 5.48 (dd, J = 1.6, 6.3
Hz, 1H), 5.01 (m, 1H), 4.74−4.14 (m, 4H), 2.98−2.73 (m, 2H), 2.70
(m, 2H), 2.57−2.46 (m, 4H), 2.39−2.34 (m, 2H), 1.58 (m, 2H), 1.54
(s, 3H), 1.42 (s, 9H), 1.33 (s, 3H); 13C NMR (125.7 MHz, CDCl3):
δ 156.1, 155.2, 153.0, 148.9, 139.7, 132.8, 129.0, 128.8, 126.4, 126.0,
120.1, 114.1, 90.7, 86.7, 83.9, 83.7, 79.7, 50.4, (49.6, 48.4), 48.0,
(43.1, 42.4), 34.2, 30.9, 30.1, 29.8, 28.4, 27.0, 25.2; MS (ESI+) m/z
(relative intensity): 626 (MH+, 100), 526 (75), 391 (20), 313 (50);
HRMS (ESI+) m/z: calcd for C31H44N7O5S (MH+), 626.3125; obsd,
626.3122.
5′-Deoxy-5′-{3-{[7-chloro-3,4-dihydro-2(1H)-(1,1-
dimethylethoxy)carbonyl-isoquinolin-3-yl]methyl}amino-
propyl}thio-2′,3′-O-(1-methylethylidene)-adenosine (66). This
compound was prepared in a similar manner as 48 using the
procedure outlined previously, but using aldehyde 46 (450 mg, 1.52
mmol) and amine 61 (600 mg, 1.58 mmol) as the starting materials to
afford 66 (0.68 g, 68%) as white foam: 1H NMR (500 MHz, CDCl3):
δ 8.28 (s, 1H), 7.91 (s, 1H), 7.06−6.97 (m, 3H), 6.63 (br s, 2H,
NH2), 6.06 (d, J = 1.6 Hz, 1H), 5.50 (d, J = 6.2 Hz, 1H), 5.02 (dd, J =
2.9, 6.2 Hz, 1H), 4.72 (m, 1H), 4.54−4.13 (m, 2H), 4.34 (m, 1H),
2.93−2.76 (m, 2H), 2.70 (m, 2H), 2.57−2.36 (m, 6H), 1.56 (m, 5H),
1.44 (s, 9H), 1.35 (s, 3H); 13C NMR (125.7 MHz, CDCl3): δ 155.9,
155.1, 153.0, 149.0, 139.8, 134.7, 131.6, 131.3, 130.3, 126.6, 125.9,
120.1, 114.2, 90.8, 86.7, 83.9, 83.7, 80.0, 50.3, 49.5, 48.1, (42.8, 42.1),
34.3, 30.4, 30.2, 29.8, 28.4, 27.0, 25.2; MS (FAB−) m/z (relative
intensity): 660 (MH+, 68), 560 (20), 307 (90), 289 (55), 154 (100),
136 (70); HRMS (ESI+) m/z: calcd for C31H43ClN7O5S (MH+),
660.2735; obsd, 660.2759.
43%) as white foam: H NMR (500 MHz, CDCl3): δ 8.33 (s, 1H),
7.94 (s, 1H), 7.16 (m, 4H), 6.13 (br s, 2H, NH2), 6.09 (s, 1H), 5.54
(m, 1H), 5.06 (dd, J = 3.0, 6.3 Hz, 1H), 4.82 (m, 1H), 4.70−4.24 (m,
2H), 4.40 (m, 1H), 3.07−2.83 (m, 2H), 2.77 (m, 2H), 2.59−2.49 (m,
6H), 1.62 (s, 3H), 1.49 (s, 9H), 1.45 (m, 4H), 1.40 (s, 3H), 1.36 (m,
2H); 13C NMR (125.7 MHz, CDCl3): δ 155.7, 155.5, 153.2, 149.2,
140.0, 132.9, 129.2, 129.1, 126.6, 126.2, 126.1, 120.2, 114.3, 90.9,
87.1, 84.0, 83.9, 80.0, 50.8, (49.6, 48.6), 49.4, (43.4, 42.5), 34.3, 32.5,
31.2, 29.6, 29.4, 28.5, 27.1, 26.4, 25.3; MS (ESI+) m/z (relative
intensity): 654 (MH+, 45), 554 (20), 327 (100); HRMS (ESI+) m/z:
calcd for C33H48N7O5S (MH+), 654.3438; obsd, 654.3446.
5′-Deoxy-5′-{6-{[3,4-dihydro-2(1H)-(1,1-dimethylethoxy)-
carbonyl-isoquinolin-3-yl]methyl}amino-hexyl}thio-2′,3′-O-
(1-methylethylidene)-adenosine (70). This compound was
prepared in a similar manner as 48 using the procedures outlined
previously, but using aldehyde 45 (0.60 g, 2.3 mmol) and amine 64
(0.97 g, 2.3 mmol) as the starting materials to afford 70 (0.90 g, 59%)
as white foam: 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.94 (s,
1H), 7.14 (m, 4H), 6.35 (br s, 2H, NH2), 6.09 (d, J = 2.0 Hz, 1H),
5.54 (dd, J = 2.0, 6.3 Hz, 1H), 5.07 (dd, J = 3.0, 6.3 Hz, 1H), 4.90−
4.45 (m, 2H), 4.40 (m, 1H), 4.23 (m, 1H), 3.10−2.85 (m, 2H), 2.79
(m, 2H), 2.64−2.44 (m, 6H), 1.62 (s, 3H), 1.50 (s, 9H), 1.45 (m,
2H), 1.40 (s, 3H), 1.34 (m, 2H), 1.25 (m, 4H); 13C NMR (100 MHz,
CDCl3): δ 156.3, 155.7, 153.5, 149.6, 140.4, 133.4, 133.3, 129.6,
129.5, 127.0, 126.5, 120.7, 114.8, 91.3, 87.4, 84.4, 84.3, 80.3, 51.1,
49.9, 48.6, (43.7, 42.9), 34.7, 33.0, 31.6, 30.4, 29.9, 29.1, 28.9, 27.5,
27.2, 25.7; MS (ESI+) m/z (relative intensity): 668 (MH+, 100), 568
(30); HRMS (ESI+) m/z: calcd for C34H50N7O5S (MH+), 668.3594;
obsd, 668.3593.
5′-Deoxy-5′-{2-[3,4-dihydro-2(1H)-(1,1-dimethylethoxy)-
carbonyl-isoquinoline-3-carboxamido]ethyl}thio-2′,3′-O-(1-
methylethylidene)-adenosine (71). To a stirred mixture of acid
41 (2.50 g, 9.02 mmol), amine 34 (3.30 g, 9.02 mmol), and HOBt·
H2O (1.22 g, 9.02 mmol) in DMF (25 mL) was added EDCI·HCl
(1.73 g, 9.02 mmol) and then N-methylmorpholine (1.0 mL, 9.0
mmol) under argon at 0 °C. The reaction mixture was warmed to
room temperature and stirred for 12 h. The solvent was removed
under reduced pressure and the residue was purified by flash
chromatography (silica gel) eluting with CHCl3/MeOH (40:1) to
yield 71 (5.50 g, 98%) as white foam: 1H NMR (500 MHz, CD3OD):
δ 8.26 (s, 1H), 8.23 (s, 1H), 7.15 (m, 4H), 6.17 (s, 1H), 5.49 (m,
1H), 5.03 (br s, 1H), 4.60−4.46 (m, 3H), 4.30 (br s, 1H), 3.21−3.08
(m, 4H), 2.76 (m, 2H), 2.46−2.40 (m, 2H), 1.58 (s, 3H), 1.51, 1.42
(two peaks, 9H), 1.38 (s, 3H); 13C NMR (100 MHz, CD3OD): δ
(173.8, 173.1), 156.3, (156.1, 156.4), 152.9, 149.2, 140.9, (134.9,
134.2), (133.9, 133.5), (128.0, 127.5), (127.4, 127.2), 126.9, 126.2,
119.6, 114.5, 90.6, 86.9, 84.2, 84.1, 81.1, (56.9, 55.3), (45.4, 44.5),
(38.9, 38.8), 33.9, (32.5, 31.9), 31.5, 27.8, 26.5, 24.7; MS (FAB+) m/z
(relative intensity): 626 (MH+, 50), 524 (15), 136 (100); HRMS
(FAB+) m/z: calcd for C30H40N7O6S (MH+), 626.2761; obsd,
626.2763.
5′-Deoxy-5′-{3-{[3,4-dihydro-2(1H)-(1,1-dimethylethoxy)-
carbonyl-7-nitro-isoquinolin-3-yl]methyl}amino-propyl}thio-
2′,3′-O-(1-methylethylidene)-adenosine (67). This compound
was prepared in a similar manner as 48 using the procedure outlined
previously, but using aldehyde 47 (500 mg, 1.63 mmol) and amine 61
(500 mg, 1.32 mmol) as the starting materials to afford 67 (420 mg,
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48%) as yellow foam: H NMR (500 MHz, CDCl3): δ 8.36 (s, 1H),
8.03 (m, 2H), 7.94 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.09 (d, J = 1.4
Hz, 1H), 5.72 (br s, 2H, NH2), 5.55 (dd, J = 1.7, 6.3 Hz, 1H), 5.06
(dd, J = 3.0, 6.3 Hz, 1H), 4.88 (m, 1H), 4.56−4.28 (m, 2H), 4.39 (m,
1H), 3.07−2.96 (m, 2H), 2.77 (m, 2H), 2.62−2.44 (m, 6H), 1.64 (m,
2H), 1.63 (s, 3H), 1.51 (s, 9H), 1.41 (s, 3H); 13C NMR (125.7 MHz,
CDCl3): δ 155.5, 155.0, 153.0, 149.2, 146.5, 140.9, 140.0, 134.7,
130.0, 121.6, 121.3, 120.3, 114.3, 90.9, 86.9, 83.9, 83.8, 80.4, 50.5,
49.4, 48.1, 42.5, 34.4, 31.2, 30.3, 29.8, 28.4, 27.0, 25.3; MS (CI) m/z
(relative intensity): 671 (MH+, 75), 571 (30), 240 (75); HRMS
(ESI+) m/z: calcd for C31H43N8O7S (MH+), 671.2975; obsd,
671.2987.
5′-Deoxy-5′-{4-{[3,4-dihydro-2(1H)-(1,1-dimethylethoxy)-
carbonyl-isoquinolin-3-yl]methyl}amino-butyl}thio-2′,3′-O-(1-
methylethylidene)-adenosine (68). This compound was prepared
in a similar manner as 48 using the procedure outlined previously, but
using aldehyde 45 (440 mg, 1.69 mmol) and amine 62 (0.670 g, 1.69
mmol) as the starting materials to afford 68 (0.52 g, 48%) as white
5′-{2-[7-Chloro-3,4-dihydro-2(1H)-(1,1-dimethylethoxy)-
carbonyl-isoquinoline-3-carboxamido]ethyl}thio-5′-deoxy-
2′,3′-O-(1-methylethylidene)-adenosine (72). This compound
was prepared in a similar manner as 71 using the procedures outlined
previously but using 39 (170 mg, 0.550 mmol) as the starting material
to afford 72 (300 mg, 83%) as white foam: IR (KBr): 3334, 3191,
2981, 2930, 1660, 1593, 1486, 1383, 1209, 1163, 1096, 871, 738
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foam: H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.94 (s, 1H),
7.13 (m, 4H), 6.09 (d, J = 2.0 Hz, 1H), 5.96 (br s, 2H, NH2), 5.53
(dd, J = 2.0, 6.3 Hz, 1H), 5.06 (dd, J = 3.0, 6.3 Hz, 1H), 4.82 (m,
1H), 4.71−4.23 (m, 2H), 4.40 (m, 1H), 3.07−2.83 (m, 2H), 2.77 (m,
2H), 2.57 (m, 6H), 1.62 (s, 3H), 1.50 (s, 9H), 1.45 (m, 4H), 1.41 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 155.7, 155.4, 153.0, 149.1,
139.9, 132.9, 130.8, 129.0, 128.8, 126.5, 126.1, 120.2, 114.3, 90.8,
86.8, 83.9, 83.8, 79.9, 50.6, (49.6, 48.5), 48.9, (43.3, 42.4), 34.2, 32.4,
31.1, 29.0, 28.4, 27.1, 27.0, 25.3; MS (CI) m/z (relative intensity):
640 (MH+, 30), 407 (20), 292 (15), 136 (60); HRMS (ESI+) m/z:
calcd for C32H46N7O5S (MH+), 640.3281; obsd, 640.3292.
5′-Deoxy-5′-{5-{[3,4-dihydro-2(1H)-(1,1-dimethylethoxy)-
carbonyl-isoquinolin-3-yl]methyl}amino-pentyl}thio-2′,3′-O-
(1-methylethylidene)-adenosine (69). This compound was
prepared in a similar manner as 48 using the procedure outlined
previously, but using aldehyde 45 (0.760 g, 2.91 mmol) and amine 63
(1.18 g, 2.91 mmol) as the starting materials to afford 69 (0.81 g,
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cm−1; H NMR (500 MHz, CD3OD): δ 8.26 (s, 1H), 8.23 (s, 1H),
7.16−7.09 (m, 3H), 6.17 (s, 1H), 5.49 (m, 1H), 5.03 (br s, 1H),
4.58−4.46 (m, 3H), 4.30 (br s, 1H), 3.21−3.05 (m, 4H), 2.77 (m,
2H), 2.49 (m, 2H), 1.58 (s, 3H), 1.50, 1.42 (two peaks, 9H), 1.37 (s,
3H); 13C NMR (125.7 MHz, CD3OD): δ (172.9, 172.3), 155.9,
(155.4, 155.0), 152.6, 148.7, 140.3, (136.4, 135.7), (132.2, 131.9),
(129.1, 128.6), (128.5, 127.8), (126.9, 126.7), 125.7, 119.1, 114.0,
90.2, 86.5, 83.7, 83.6, 80.7, (56.0, 54.4), (44.6, 43.7), (38.4, 38.3),
33.4, (31.4, 30.9), 31.1, 27.3, 26.0, 24.2; MS (CI) m/z (relative
intensity): 660 (M+, 25), 560 (20), 324 (25), 292 (60), 136 (80), 120
(90); HRMS (FAB+) m/z: calcd for C30H39ClN7O6S (MH+),
660.2371; obsd, 660.2366.
P
J. Med. Chem. XXXX, XXX, XXX−XXX