A. Brunschweiger et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
13
+
5
.1.2.20. 8-(3-Methoxyphenethyl)-1,3-dimethyl-6,7,8,9-tetrahy-
dropyrazino[2,1-f]purine-2,4-(1H,3H)-dione (25). Yield:
) d 7.25–7.23 (m, 1H, C5-H,
3
CH ). ESI-MS: positive mode 408.3 [M+H] . HPLC: 99.2% (A) and
99.1% (B).
1
4
1%; mp: 212 °C; H NMR (CDCl
phe), 6.84–6.81 (m, 3H, C2-/C4-/C6-H, phe), 4.46 (t, J = 5.4 Hz,
H, C6-H ), 3.79 (s, 3H, OCH ), 3.51 (s, 3H, N1-CH ), 3.42 (s, 2H,
C9-H ), 3.37 (s, 3H, N3-CH ), 3.08 (br s, 6H, C7-H , N8-CH , N8-
CH -CH ) d 160.8 (C3, phe), 159.0 (C9a), 157.1
C4), 151.7 (C2), 148.4 (C10a), 139.9 (C1, phe), 130.4 (C5, phe),
3
3
5.1.2.25. 8-(2,4-Dichlorophenethyl)-1,3-dimethyl-6,7,8,9-tetra-
2
2
3
3
hydropyrazino[2,1-f]purine-2,4-(1H,3H)-dione (30).
Yield:
7.36 (d, J = 1.1 Hz,
J = 1.1 Hz, 1H, C3-H, phe), 7.17–7.16 (m, 2H, C5-/C6-H, phe),
4.34 (br s, 2H, C6-H ), 3.87 (s, 2H, C9-H ), 3.53 (s, 3H, N1-CH ),
3.37 (s, 3H, N3-CH ), 3.02 (br s, 2H, C7-H ), 2.97 (t, J = 6.9 Hz,
1
4
2
3
2
2
70%; mp: 185 °C;
3
H NMR (CDCl ) d
1
3
4
2
2 3
). C NMR (CDCl
(
2
2
3
3
1
5
20.8 (C6, phe), 114.2 (C4, phe), 113.2 (C2, phe), 106.2 (C4a),
8.6 (N8-CH ), 55.4 (OCH ), 48.0 (C7), 45.9 (C9), 43.9 (C6), 33.2
-CH ), 29.9 (N1-CH ), 27.9 (N3-CH ). ESI-MS: positive
mode 370.4 [M+H] . HPLC: 96.6% (A) and 96.8% (B).
3
2
3
13
2
3
2H, N8-CH
2
), 2.84 (t, J = 7.3 Hz, 2H, N8-CH
2 2 3
-CH ). C NMR (CDCl )
(
N8-CH
2
2
3
3
d 155.0 (C9a), 151.7 (C4), 148.5 (C2), 147.6 (C10a), 135.3 (C1,
phe), 134.6 (C2, phe), 133.0 (C4, phe), 131.5 (C6, phe), 129.4 (C3,
+
phe), 127.3 (C5, phe), 106.5 (C4a), 56.9 (N8-CH
(C9), 44.1 (C6), 30.6 (N8-CH -CH ), 29.7 (N1-CH
ESI-MS: positive mode 408.3 [M+H] . HPLC: 98.9% (A) and 99.0%
(B).
2
), 51.1 (C7), 49.0
), 27.8 (N3-CH ).
5
.1.2.21. 8-(3,4-Difluorophenyl)ethyl)-1,3-dimethyl-6,7,8,9-tetrahy-
2
2
3
3
+
dropyrazino[2,1-f]purine-2,4-(1H,3H)-dione (26).
mp: 178 °C; H NMR (CDCl
Yield: 75%;
) d 7.02–6.94 (m, 3H, C -/C5-/C6-H, phe),
), 3.82 (s, 2H, C9-H ), 3.54 (s, 3H, N1-
), 2.97 (t, J = 5.4 Hz, 2H, C7-H ), 2.91 (t,
1
2
3
3
4.32 (t, J = 5.1 Hz, 2H, C6-H
2
2
3
CH
3
), 3.37 (s, 3H, N3-CH
J = 7.9 Hz, 2H, N8-CH ), 2.83 (t, J = 7.6 Hz, 2H, N8-CH
NMR (CDCl ) d 155.0 (C9a), 151.7 (C4), 150.6 (dd, JC,F = 248.1 Hz, JC,
= 13.0 Hz, C3, phe), 148.9 (dd,
phe), 148.5 (C2), 147.8 (C10a), 128.7 (d, JC,F = 12.7 Hz, C1, phe), 125.4
dd, JC,F = 6.4 Hz, JC,F = 3.2 Hz, C2, phe), 124.0 (dd, JC,F = 6.7 Hz, JC,
= 4.7 Hz, C3, phe), 115.5 (d, JC,F = 17.2 Hz, C6, phe), 106.6 (C4a), 57.3
N8-CH ), 50.9 (C7), 48.6 (C9), 44.2 (C6), 29.7 (N1-CH ), 27.8 (N3-
CH ), 26.8 (N8-CH -CH ). ESI-MS: positive mode 376.0 [M+H] . HPLC:
7.8% (A) and 96.2% (B).
3
2
5.1.2.26.
dimethyl-6,7,8,9-tetrahydropyr-azino[2,1-f]purine-2,4(1H,3H)-
dione (31). Purification by column chromatography. Yield:
60%; mp: 195 °C; H NMR (CDCl
8-(4-Chloro-2-(trifluoromethyl)phenethyl)-1,3-
3
3
13
2
2 2
-CH ).
C
1
2
3
1
C,F = 245.8 Hz, 2
1
4
F
J
JC,F = 12.0 Hz, C4,
3
) d 7.61 (d, J = 2.2 Hz, 1H, C3-
H, phe), 7.44 (dd, J = 8.2 Hz, J = 1.9 Hz, 1H, C5-H, phe), 7.29 (d,
3
4
3
3
(
J = 8.2 Hz, 1H, C6-H, phe), 4.34 (t, J = 5.4 Hz, 2H, C6-H
(s, 2H, C9-H ), 3.54 (s, 3H, N1-CH ), 3.38 (s, 3H, N3-CH ), 3.02–
2.97 (m, 4H, C7-H , N8-CH ), 2.83–2.80 (m, 2H, N8-CH -CH ).
C NMR (125 MHz, CDCl ) d 155.0 (C-9a), 151.7 (C-4), 148.5 (C-
2), 147.6 (C-10a), 134.4 (C-4, phenyl), 133.7 (C-5, phenyl), 130.7
C-6, phenyl), 130.5 (C-1, phenyl), 130.2 (C-2, phenyl), 126.4 (C-
2
), 3.84
F
2
3
3
(
2
3
2
2
2
2
+
13
3
2
2
3
9
(
1
5
.1.2.22.
8-(2-Fluoro-5-(trifluoromethyl)phenethyl)-1,3-
3, phenyl), 126.3 (q,
CH
CH
J
C,F = 272.6 Hz, CF
3
), 106.5 (C-4a), 56.9 (N8-
), 27.9 (N3-
). ESI-MS: positive mode 442.0 [M+H] . HPLC: 99.9% (A) and
dimethyl-6,7,8,9-tetrahydropyra-zino[2,1-f]purine-2,4(1H,3H)-
dione (27).
2
), 51.4 (C-7), 49.0 (C-9), 44.4 (C-6), 29.8 (N1-CH
3
1
+
3
Yield: 61%; mp: 226 °C; H NMR (CDCl ) d 7.72–
3
7
.70 (m, 1H, C6-H, phe), 7.59–7.56 (m, 1H, C4-H, phe), 7.19–7.17
99.1% (B).
3
(
m, 1H, C5-H, phe), 4.38 (t, J = 5.4 Hz, 2H, C6-H
), 3.52 (s, 3H, N1-CH ), 3.37 (s, 3H, N3-CH ), 3.02 (t, J = 5.4 Hz,
H, C7-H ), 2.83 (br s, 4H, N8-CH
CDCl ) d 163.0 (d,
51.7 (C-4), 148.5 (C-2), 147.6 (C-10a), 128.7 (C-6, phenyl),
2
), 3.81 (s, 2H, C9-
3
H
2
2
3
3
1
5.1.2.27.
8-(2-(5-Bromo-2-methoxyphenyl)ethyl)-1,3-
3
2
2
-CH
2
). C NMR (125 MHz,
C,F = 251.3 Hz, C-6, phenyl), 155.0 (C-9a),
dimethyl-6,7,8,9-tetrahydropyrazi-no[2,1-f]purine-2,4(1H,3H)-
dione (32).
36%; mp: 198 °C; H NMR (CDCl
H, phe), 7.26 (s, 1H, C6-H, phe), 6.72 (d, J = 8.5 Hz, 1H, C3-H,
1
3
J
Purification by column chromatography. Yield:
1
3
1
1
3
) d 7.29 (d, J = 8.9 Hz, 1H, C4-
1
3
27.3 (C-5, phenyl), 126.8 (C-1, phenyl), 126.2 (q,
= 270.4 Hz, CF ), 124.4 (C-1, phenyl), 116.4 (C-3, phenyl), 106.5
C-4a), 53.9 (N8-CH ), 50.9 (C-7), 48.6 (C-9), 44.2 (C-6), 29.7
N1-CH ), 27.8 (N3-CH
J
C,
F
3
phe), 4.36 (br s, 2H, C6-H
OCH ), 3.53 (s, 3H, N1-CH ), 3.37 (s, 3H, N3-CH
C7-H ), 2.84–2.81 (m, 4H, N8-CH
156.5 (C2, phe), 155.0 (C9a), 151.7 (C4), 148.5 (C2), 147.6
C10a), 132.8 (C6, phe), 130.2 (C5, phe), 129.9 (C4, phe), 112.6
(C1, phe), 112.0 (C3, phe), 106.5 (C4a), 58.7 (N8-CH ), 55.5
(OCH ), 51.3 (C7), 48.9 (C9), 44.2 (C6), 29.7 (N1-CH ), 27.8 (N3-
CH ), 27.7 (N8-CH -CH ). ESI-MS: positive mode 450.1 and 452.1
2
), 3.86 (s, 2H, C9-H
), 3.00 (br s, 2H,
C NMR (CDCl ) d
2
), 3.82 (s, 3H,
(
(
2
3
3
3
+
13
3
3
). ESI-MS: positive mode 426.0 [M+H] .
2
2
-CH
2
).
3
HPLC: 99.6% (A) and 98.3% (B).
(
5.1.2.23. 8-(2,6-Dichlorophenethyl)-1,3-dimethyl-6,7,8,9-tetrahy-
2
dropyrazino[2,1-f]purine-2,4-(1H,3H)-dione (28).
mp: 221 °C; H NMR (CDCl
Yield: 74%;
3
3
1
) d 7.33 (d, 3J = 7.9 Hz, 2H, C3-/C5-H,
3
3
2
2
3
+
phe), 7.09–7.08 (m, 1H, C4-H, phe), 4.40 (t, J = 5.4 Hz, 2H, C6-H
2
),
), 3.24
), 2.84 (t,
) d 155.0 (C9a), 151.7
C4), 148.5 (C2), 147.6 (C10a), 143.1 (C1, phe), 135.5 (C2/C6, phe),
[M+H] . HPLC: 99.2% (A) and 99.3% (B).
3
.95 (s, 2H, C9-H
2
), 3.53 (s, 3H, N1-CH
3
), 3.37 (s, 3H, N3-CH
3
3
3
(
t, J = 7.3 Hz, 2H, N8-CH
J = 7.3 Hz, 2H, N8-CH
2
), 3.09 (t, J = 5.4 Hz, 2H, C7-H
2
5.1.2.28. 8-(2-(2,3-Dimethoxyphenyl)ethyl)-1,3-dimethyl-6,7,8,9-
3
13
2
-CH
2
). C NMR (CDCl
3
tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (33).
cation by column chromatography. Yield: 39%; mp: 180 °C; H NMR
(CDCl ) d 7.00–6.97 (m, 1H, C5-H, phe), 6.81–6.78 (m, 2H, C4-/C6-H,
phe), 4.40 (br s, 2H, C6-H
(s, 3H, N1-CH ), 3.37 (s, 3H, N3-CH
). C NMR (CDCl ) d 155.0 (C9a), 152.8 (C3, phe), 151.7
Purifi-
1
(
3
4
1
28.3 (C /C /C5, phe), 106.5 (C4a), 55.0 (N8-CH
), 28.6 (N8-CH -CH
ESI-MS: positive mode 408.3 [M+H] . HPLC: 99.2% (A) and 99.1% (B).
2
), 51.1 (C7), 49.0
3
9
(
C9), 44.1 (C6), 29.7 (N1-CH
3
2
2
), 27.8 (N3-CH ).
3
2
), 3.85–3.84 (s, 8H, C -H
2
, 2 ꢁ OCH
3
), 3.53
, N8-
+
3
3
), 3.06–2.87 (m, 6H, C7-H
2
13
CH
2
-CH
2
3
5
.1.2.24. 8-(3,4-Dichlorophenethyl)-1,3-dimethyl-6,7,8,9-tetra-
(C4), 150.0 (C, phe), 148.5 (C2), 147.6 (C10a), 147.1 (C2, phe), 124.2
(C1, phe), 124.1 (C6, phe), 123.6 (C5, phe), 111.8 (C4, phe), 106.5
hydropyrazino[2,1-f]purine-2,4-(1H,3H)-dione (29).
Yield:
1
) d 7.33 (d, 3J = 8.2 Hz, 1H, C5-H,
8
1%; mp: 177 °C; H NMR (CDCl
3
(C4a), 60.7 (N8-CH
29.7 (N1-CH ), 28.0 (N8-CH
mode 400.5 [M+H] . HPLC: 97.5% (A) and 99.6% (B).
2
), 55.7 (2 ꢁ OCH
3
), 51.4 (C7), 49.0 (C9), 44.2 (C6),
4
3
phe), 7.29 (d, J = 2.0 Hz, 1H, C2-H, phe), 7.02 (dd, J = 8.2 Hz,
3
2
-CH ), 27.9 (N3-CH
2
3
). ESI-MS: positive
4
J = 2.0 Hz, 1H, C6-H, phe), 4.34 (t, 3J = 5.1 Hz, 2H, C6-H
H, C9-H ), 3.54 (s, 3H, N1-CH ), 3.38 (s, 3H, N3-CH
J = 5.1 Hz, 2H, C7-H ), 2.82 (br s, 4H, N8-CH
CDCl ) d 155.0 (C9a), 151.7 (C4), 148.4 (C2), 147.6 (C10a), 139.4
C1, phe), 132.5 (C3, phe), 130.6 (C5, phe), 130.5 (C4, phe), 130.5
C2, phe), 128.1 (C6, phe), 106.6 (C4a), 58.4 (N8-CH ), 51.2 (C7),
9.2 (C9), 44.1 (C6), 32.6 (N8-CH -CH ), 29.8 (N1-CH ), 27.9 (N3-
+
2
), 3.81 (s,
3
), 2.97 (t,
). C NMR
2
2
3
3
13
2
2
-CH
2
5.1.2.29.
8-(2-(3,4-Dimethoxyphenyl)ethyl)-1,3-dimethyl-6,7,8,9-
Yield:
) d 6.89–6.83 (m, 3H, C -/C5-/C6-H,
), 3.95 (s, 2H, C9-H ), 3.86 (s, 3H, OCH ),
), 3.53 (s, 3H, N1-CH ), 3.37 (s, 3H, N3-CH ),
(
(
(
3
tetrahydropyrazino[2,1-f]purine-2,4-(1H,3H)-dione (34).
1
2
48%; mp: 219 °C; H NMR (CDCl
phe), 4.46 (br s, 2H, C6-H
3.84 (s, 3H, OCH
3
2
2
2
3
4
2
2
3
3
3
3