W. Wei et al. / European Journal of Medicinal Chemistry 133 (2017) 62e68
65
2
.1.15. N-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-
3.43e3.53 (m, 2H); 3.72 (s, 3H); 3.79 (s, 3H); 3.92e3.98 (m, 1H);
4.06e4.13 (m, 1H); 4.62 (s, 2H); 4.65e4.72 (m, 1H); 5.00 (s, 2H);
5.29e5.36 (m, 1H); 5.47e5.55 (m, 1H); 5.86 (d, J ¼ 5.9 Hz, 1H); 6.89
dimethyltetrahydrofuro [3,4-d]- [1,3]dioxol-4-yl)methyl)-2-(4-(4-
bromophenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (c6)
ꢀ
1
White powder, 39.8%, mp 170e171 C; H NMR (DMSO-d
6
): 1.32
(s, 1H); 7.05 (s, 1H); 7.33 (s, 2H); 8.15 (s, 1H); 8.34 (s, 1H); 8.41 (t,
þ
(
s, 3H); 1.55 (s, 3H); 3.45 (qt, J ¼ 13.9 Hz, J ¼ 6.2 Hz, 2H); 4.23 (td,
J ¼ 6.0 Hz, 1H); EIMS m/z 542 (M ). Anal. Calcd for C24
H
26
N
6
O
9
: C,
J ¼ 6.1 Hz, J ¼ 3.3 Hz, 1H); 4.85 (s, 2H); 4.97 (dd, J ¼ 6.4 Hz,
53.14; H, 4.83; N, 15.49; Found: C, 53.17; H, 4.83; N, 15.48.
J ¼ 3.4 Hz, 1H); 5.04 (s, 2H); 5.45 (dd, J ¼ 6.4 Hz, J ¼ 2.8 Hz, 1H); 6.17
(
d, J ¼ 2.8 Hz, 1H); 7.38 (s, 2H); 7.60 (d, J ¼ 8.7 Hz, 2H); 7.84 (d,
2.1.21. N-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-
dimethyltetrahydrofuro [3,4-d]- [1,3]dioxol-4-yl)methyl)-2-(4-(3-
J ¼ 8.7 Hz, 2H); 8.20 (s, 1H); 8.35 (s, 1H); 8.53 (t, J ¼ 5.8 Hz, 1H);
þ
EIMS m/z 600 (M ). Anal. Calcd for C25
H25BrN
6
7
O : C, 49.93; H, 4.19;
fluorophenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (c9)
ꢀ
1
Br, 13.29; N, 13.97; Found: C, 49.89; H, 4.19; Br, 13.30; N, 13.98.
White powder, 34.9%, mp 148e150 C; H NMR (DMSO-d
6
): 1.32
(
s, 3H); 1.54 (s, 3H); 3.46 (tq, J ¼ 14.5 Hz, J ¼ 6.5 Hz, 2H); 4.19e4.27
2.1.16. N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
(m, 1H); 4.87 (s, 2H); 4.97 (dd, J ¼ 6.3 Hz, J ¼ 3.4 Hz, 1H); 5.05 (s,
2H); 5.44 (dd, J ¼ 6.3 Hz, J ¼ 2.9 Hz, 1H); 6.17 (s, 1H); 7.12 (td,
J ¼ 8.6 Hz, J ¼ 2.7 Hz, 1H); 7.38 (s, 2H); 7.44 (dd, J ¼ 14.5 Hz,
J ¼ 8.0 Hz, 1H); 7.71 (dd, J ¼ 11.2 Hz, J ¼ 1.7 Hz, 1H); 7.76 (dd,
dihydroxytetrahydrofuran-2-yl)meth-yl)-2-(4-(4-bromophenyl)-5-
oxo-2,5-dihydrofuran-3-yloxy)acetamide (d6)
White powder, 49.8%, mp 197e199 C; 1H NMR (DMSO-d
ꢀ
):
6
3
.45e3.55 (m, 2H); 4.01 (q, J ¼ 5.3 Hz, 1H); 4.12 (td, J ¼ 5.0 Hz,
J ¼ 7.9 Hz, J ¼ 1.3 Hz,1H); 8.20 (s,1H); 8.34 (s,1H); 8.55 (t, J ¼ 5.7 Hz,
þ
J ¼ 3.3 Hz, 1H); 4.71 (q, J ¼ 5.9 Hz, 1H); 4.88 (s, 2H); 5.04 (s, 2H);
1H); EIMS m/z 540 (M ). Anal. Calcd for C25
H25FN
6
7
O : C, 55.55; H,
5
1
.38 (d, J ¼ 4.9 Hz, 1H); 5.55 (d, J ¼ 6.1 Hz, 1H); 5.88 (d, J ¼ 6.0 Hz,
4.66; F, 3.51; N, 15.55; Found: C, 55.60; H, 4.65; F, 3.51; N, 15.54.
H); 7.33 (s, 2H); 7.58 (d, J ¼ 8.7 Hz, 2H); 7.83 (d, J ¼ 8.7 Hz, 2H); 8.19
þ
(
s,1H); 8.36 (s,1H); 8.65 (t, J ¼ 5.8 Hz,1H); EIMS m/z 560 (M ). Anal.
2.1.22. N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)meth-yl)-2-(4-(3-fluorophenyl)-5-
oxo-2,5-dihydrofuran-3-yloxy)acetamide (d9)
Calcd for C22
6 7
H21BrN O : C, 47.07; H, 3.77; Br, 14.23; N, 14.97; Found:
C, 47.13; H, 3.77; Br, 14.22; N, 14.95.
White powder, 63.2%, mp 161e163 C; 1H NMR (DMSO-d
ꢀ
):
6
2
.1.17. N-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-
3.44e3.56 (m, 2H); 4.01 (q, J ¼ 4.9 Hz, 1H); 4.12 (q, J ¼ 4.6 Hz, 1H);
4.71 (q, J ¼ 5.7 Hz, 1H); 4.90 (s, 2H); 5.05 (s, 2H); 5.34 (d, J ¼ 4.7 Hz,
1H); 5.50 (d, J ¼ 6.2 Hz, 1H); 5.88 (d, J ¼ 5.9 Hz, 1H); 7.11 (td,
J ¼ 8.6 Hz, J ¼ 2.8 Hz, 1H); 7.33 (s, 2H); 7.43 (dd, J ¼ 14.6 Hz,
J ¼ 8.1 Hz, 1H); 7.71 (dt, J ¼ 11.2 Hz, J ¼ 2.2 Hz, 1H); 7.75 (d,
dimethyltetrahydrofuro [3,4-d]- [1,3]dioxol-4-yl)methyl)-2-(4-(3,4-
dichlorophenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (c7)
ꢀ
1
White powder, 38.4%, mp 134e136 C; H NMR (DMSO-d
s, 3H); 1.54 (s, 3H); 3.37e3.52 (m, 2H); 4.22 (td, J ¼ 6.0 Hz,
J ¼ 3.3 Hz, 1H); 4.89 (s, 2H); 4.97 (dd, J ¼ 6.3 Hz, J ¼ 3.4 Hz,1H); 5.06
s, 2H); 5.44 (dd, J ¼ 6.3 Hz, J ¼ 2.9 Hz, 1H); 6.17 (d, J ¼ 2.8 Hz, 1H);
6
): 1.32
(
J ¼ 8.0 Hz,1H); 8.19 (s,1H); 8.36 (s,1H); 8.62 (t, J ¼ 5.8 Hz,1H); EIMS
þ
(
m/z 500 (M ). Anal. Calcd for C22
H21FN
6
7
O : C, 52.80; H, 4.23; F, 3.80;
7
1
.37 (s, 2H); 7.67 (d, J ¼ 8.6 Hz, 1H); 7.90 (dd, J ¼ 8.6 Hz, J ¼ 2.1 Hz,
N, 16.79; Found: C, 52.77; H, 4.25; F, 3.82; N, 16.82.
H); 8.13 (d, J ¼ 2.1 Hz, 1H); 8.20 (s, 1H); 8.34 (s, 1H); 8.56 (t,
þ
J ¼ 5.9 Hz, 1H); EIMS m/z 590 (M ). Anal. Calcd for C25
H24Cl
2
N
6
O
7
:
2.1.23. N-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-
dimethyltetrahydrofuro [3,4-d]- [1,3]dioxol-4-yl)methyl)-2-(4-(4-
fluorophenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (c10)
C, 50.77; H, 4.09; Cl, 11.99; N, 14.21; Found: C, 50.82; H, 4.10; Cl,
1.97; N, 14.19.
1
ꢀ
1
6
White powder, 55.6%, mp 166e168 C; H NMR (DMSO-d ): 1.32
2
.1.18. N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
(s, 3H); 1.55 (s, 3H); 3.36e3.56 (m, 2H); 4.23 (td, J ¼ 5.9 Hz,
J ¼ 3.3 Hz,1H); 4.84 (s, 2H); 4.97 (dd, J ¼ 6.3 Hz, J ¼ 3.4 Hz, 1H); 5.04
(s, 2H); 5.44 (dd, J ¼ 6.4 Hz, J ¼ 2.9 Hz, 1H); 6.17 (d, J ¼ 2.8 Hz, 1H);
7.23 (t, J ¼ 9.0 Hz, 2H); 7.38 (s, 2H); 7.91 (dd, J ¼ 8.8 Hz, J ¼ 5.7 Hz,
dihydroxytetrahydrofuran-2-yl)meth-yl)-2-(4-(3,4-
dichlorophenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (d7)
ꢀ
1
6
White powder, 54.7%, mp 210e212 C; H NMR (DMSO-d ):
3
4
5
.47e3.60 (m, 2H); 3.98e4.06 (m, 1H); 4.10e4.20 (m, 1H);
.67e4.75 (m, 1H); 4.92 (s, 2H); 5.07 (s, 2H); 5.32e5.40 (m, 1H);
.48e5.55 (m, 1H); 5.88 (d, J ¼ 6.1 Hz, 1H); 7.33 (s, 2H); 7.65 (d,
2H); 8.20 (s, 1H); 8.35 (s, 1H); 8.53 (t, J ¼ 5.8 Hz, 1H); EIMS m/z 540
þ
(M ). Anal. Calcd for C25
H
25FN
6
O
7
: C, 55.55; H, 4.66; F, 3.51; N,
15.55; Found: C, 55.50; H, 4.67; F, 3.51; N, 15.57.
J ¼ 8.5 Hz,1H); 7.89 (dd, J ¼ 8.5 Hz, J ¼ 2.1 Hz,1H); 8.13 (d, J ¼ 2.0 Hz,
1
H); 8.19 (s, 1H); 8.35 (s, 1H); 8.62e8.71 (m, 1H); EIMS m/z 550
2.1.24. N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
dihydroxytetrahydrofuran-2-yl)meth-yl)-2-(4-(4-fluorophenyl)-5-
oxo-2,5-dihydrofuran-3-yloxy)acetamide (d10)
þ
(
M ). Anal. Calcd for C22
H20Cl
2
N
6
O
7
: C, 47.93; H, 3.66; Cl, 12.86; N,
15.24; Found: C, 47.88; H, 3.66; Cl, 12.88; N, 15.25.
ꢀ
1
6
White powder, 47.9%, mp 184e186 C; H NMR (DMSO-d ): 3.52
2
.1.19. N-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-
(t, J ¼ 5.8 Hz, 2H); 4.03 (q, J ¼ 5.3 Hz, 1H); 4.13 (q, J ¼ 4.5 Hz, 1H);
4.72 (q, J ¼ 5.8 Hz, 1H); 4.87 (s, 2H); 5.04 (s, 2H); 5.35 (d, J ¼ 4.9 Hz,
1H); 5.51 (d, J ¼ 6.2 Hz, 1H); 5.90 (d, J ¼ 6.0 Hz, 1H); 7.22 (t,
J ¼ 9.0 Hz, 2H); 7.34 (s, 2H); 7.90 (dd, J ¼ 8.8 Hz, J ¼ 5.8 Hz, 2H); 8.20
dimethyltetrahydrofuro [3,4-d] [1,3]- dioxol-4-yl)methyl)-2-(4-(3,4-
dimethoxyphenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (c8)
ꢀ
1
White powder, 40.5%, mp 133e136 C; H NMR (DMSO-d
6
): 1.32
13
(
s, 3H); 1.54 (s, 3H); 3.36e3.43 (m, 2H); 3.71 (s, 3H); 3.78 (s, 3H);
(s, 1H); 8.36 (s, 1H); 8.62 (t, J ¼ 5.8 Hz, 1H); C NMR (DMSO-d
6
,
4
.18 (td, J ¼ 5.9 Hz, J ¼ 3.3 Hz, 1H); 4.61 (d, J ¼ 3.0 Hz, 2H); 4.93 (dd,
100 MHz): d 41.50; 65.52; 69.20; 71.75; 73.15; 83.54; 88.42; 100.27;
J ¼ 6.3 Hz, J ¼ 3.3 Hz, 1H); 5.01 (s, 2H); 5.40 (dd, J ¼ 6.3 Hz,
115.33 (d, J ¼ 21.1 Hz); 119.92; 126.27 (d, J ¼ 3.2 Hz); 129.43 (d,
J ¼ 2.9 Hz, 1H); 6.14 (d, J ¼ 2.9 Hz, 1H); 6.86 (s, 1H); 7.04 (s, 1H); 7.38
J ¼ 7.9 Hz); 140.77; 149.62; 153.04; 156.62; 161.38 (d, J ¼ 245.0 Hz);
þ
(
5
s, 2H); 8.16 (s, 1H); 8.32 (s, 1H); 8.36 (t, J ¼ 5.8 Hz, 1H); EIMS m/z
166.92; 172.47; 175.00; EIMS m/z 500 (M ). Anal. Calcd for
þ
82 (M ). Anal. Calcd for C27
H
30
N
6
O
9
: C, 55.67; H, 5.19; N, 14.43;
22 6 7
C H21FN O : C, 52.80; H, 4.23; F, 3.80; N, 16.79; Found: C, 52.84; H,
Found: C, 55.70; H, 5.18; N, 14.42.
4.21; F, 3.76; N, 16.78.
2
.1.20. N-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-
2.1.25. N-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-
dimethyltetrahydrofuro [3,4-d]- [1,3]dioxol-4-yl)methyl)-3-
bromobenzamide (c11)
dihydroxytetrahydrofuran-2-yl)meth-yl)-2-(4-(3,4-
dimethoxyphenyl)-5-oxo-2,5-dihydrofuran-3-yloxy)acetamide (d8)
ꢀ
1
ꢀ
1
White powder, 62.9%, mp 157e160 C; H NMR (DMSO-d
6
):
White powder, 63.2%, mp 181e182 C; H NMR (DMSO-d ): 1.32
6