8
Y. Ikuma et al. / Bioorg. Med. Chem. xxx (2015) xxx–xxx
158.5, 155.1, 155.0, 142.3, 140.5, 134.9, 132.0, 129.6, 129.2, 128.6,
127.2, 126.5, 124.8, 123.9, 119.6, 116.8, 114.8, 79.3, 62.2, 59.6,
56.7, 55.3, 51.5, 46.4, 46.0, 31.5, 29.2, 28.4, 22.6, 22.2, 19.1; HRMS
(ESI) [M+H]+ calcd for C37H48O6N6Cl 707.3318, found 707.3308; IR
(ATR): 1716, 1654, 1569, 1558, 1506, 1457, 1363, 1309, 1272,
678.2325, found 678.2325; IR (ATR): 1824, 1716, 1652, 1558,
1508, 1473, 1307, 1216, 1166, 1097, 1049, 1033 cmꢀ1
.
5.1.13. (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-{(3R)-3-[(tert-
butoxycarbonyl)amino]piperidin-1-yl}-3-(2-chloro-5-
fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-
c]quinoline-7-carboxylate (9l)
1236, 1220, 1166, 1114, 1066 cmꢀ1
.
5.1.10. (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-{(3R)-3-[(tert-
butoxycarbonyl)amino]piperidin-1-yl}-3-(2-chlorobenzyl)-5-
methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinoline-8-
carboxylate (9h)
Compound 9l was prepared from 8 in a manner similar to that
described for compound 9b with a quantitative yield as a white
amorphous. 1H NMR (400 MHz, CDCl3) d 8.38 (d, J = 8.2 Hz, 1H),
8.14 (d, J = 1.2 Hz, 1H), 7.99 (dd, J = 1.2, 8.2 Hz, 1H), 7.40–7.36 (m,
1H), 6.95–6.90 (m, 1H), 6.45–6.42 (m, 1H), 5.90 (s, 1H), 5.71 (d,
J = 17.0 Hz, 1H), 5.62 (d, J = 17.0 Hz, 1H), 5.15 (s, 2H), 3.82 (br s,
1H), 3.81 (s, 3H), 3.47 (dd, J = 3.2, 12.4 Hz, 1H), 3.21–3.10 (m,
3H), 2.28 (s, 3H), 1.84–1.56 (m, 4H), 1.46 (s, 9H); 13C NMR
(100 MHz, DMSO-d6) d 166.5, 162.3 (d, 1J(C, F) = 245 Hz), 159.0,
155.8, 155.6, 152.7, 141.9, 141.1, 137.9, 137.9 (d, 3J(C,
F) = 6.8 Hz), 134.1, 131.6 (d, 3J(C, F) = 8.2 Hz), 129.0, 127.4 (d,
4J(C, F) = 2.7 Hz), 123.8, 123.7, 121.6, 121.2, 117.3, 116.4 (d, 2J(C,
F) = 22.8 Hz), 114.5 (d, 2J(C, F) = 24.6 Hz), 79.8, 55.7, 55.2, 52.2,
47.0, 46.6, 32.2, 29.9, 29.1, 23.3, 10.1; HRMS (ESI) [M+H]+ calcd
for C34H36O8N5ClF 696.2231, found 696.2238; IR (ATR): 1824,
1716, 1652, 1558, 1540, 1508, 1473, 1457, 1363, 1307, 1216,
Compound 9h was prepared from 5 in a manner similar to that
described for compound 9b with a yield of 96% as a white amor-
phous. 1H NMR (400 MHz, CDCl3) d 8.96 (br s, 1H), 8.15 (dd, J = 2.1,
8.9 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.41 (dd, J = 1.0, 7.9 Hz, 1H),
7.22–7.18 (m, 1H), 7.15–7.11 (m, 1H), 6.69 (d, J = 7.5 Hz, 1H), 5.77
(d, J = 17.2 Hz, 1H), 5.64 (d, J = 17.2 Hz, 1H), 5.14 (s, 2H), 5.11 (br s,
1H), 3.82 (br s, 1H), 3.75 (s, 3H), 3.47 (dd, J = 3.3, 12.3 Hz, 1H),
3.16–3.09 (m, 3H), 2.28 (s, 3H), 1.81–1.72 (m, 2H), 1.61–1.60 (m,
2H), 1.43 (s, 9H); 13C NMR (100 MHz, DMSO-d6) d 165.1, 158.1,
154.9, 154.0, 152.1, 141.3, 140.6, 140.5, 135.2, 133.7, 131.2, 129.4,
128.9, 128.8, 127.7, 126.9, 123.5, 122.3, 119.0, 116.2, 116.0, 77.9,
55.1, 54.7, 50.6, 46.7, 46.2, 29.9, 29.0, 28.4, 23.5, 9.1; HRMS (ESI)
[M+H]+ calcd for C34H37O8N5Cl 678.2325, found 678.2325; IR
(ATR): 1822, 1716, 1673, 1654, 1506, 1434, 1394, 1315, 1270,
1164, 1103, 1049, 1033 cmꢀ1
.
1216, 1160, 1105, 1093, 1066, 1049 cmꢀ1
.
5.1.14. [(2,2-Dimethylpropanoyl)oxy]methyl 2-[(3R)-3-
aminopiperidin-1-yl]-3-(2-chlorobenzyl)-5-methyl-4-oxo-4,5-
dihydro-3H-imidazo[4,5-c]quinoline-8-carboxylate
5.1.11. (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-{(3R)-3-[(tert-
butoxycarbonyl)amino]piperidin-1-yl}-3-(2-chloro-5-
hydrochloride (10b)
fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-
c]quinoline-8-carboxylate (9i)
To a solution of 9b (80.0 mg, 0.118 mmol) in 1,4-dioxane (2 mL)
was added 4N HCl-1,4-dioxane (2 mL). The reaction mixture was
stirred at room temperature for 2 h and concentrated under reduced
pressure to give 10b (76.3 mg, quantitative yield) as a white amor-
phous. 1H NMR (400 MHz, DMSO-d6) d 8.68 (d, J = 2.1 Hz, 1H), 8.41
(br s, 3H), 8.07 (dd, J = 2.1, 8.9 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.50
(d, J = 7.9 Hz, 1H), 7.32–7.28 (m, 1H), 7.23–7.19 (m, 1H), 6.69 (d,
J = 7.3 Hz, 1H), 6.01 (s, 2H), 5.61 (d, J = 17.2 Hz, 1H), 5.55 (d,
J = 17.2 Hz, 1H), 3.73–3.65 (m, 1H), 3.63 (s, 3H), 3.49–3.45 (m, 1H),
3.33–3.23 (m, 1H), 3.10–3.07 (m, 1H), 2.89–2.82 (m, 1H), 1.97–
1.96 (m, 1H), 1.78–1.76 (m, 1H), 1.62–1.48 (m, 2H), 1.16 (s, 9H);
13C NMR (75 MHz, DMSO-d6) d 176.5, 164.1, 157.6, 154.0, 140.7,
140.6, 134.9, 130.9, 129.4, 129.0, 128.9, 127.6, 126.9, 123.7, 121.8,
119.1, 116.3, 115.8, 80.0, 59.2, 52.1, 50.9, 46.3, 46.1, 29.1, 27.2,
26.5, 22.0; HRMS (ESI) [M+H]+ calcd for C30H35O5N5Cl 580.2319,
found 580.2312; IR (ATR): 1704, 1672, 1616, 1594, 1508, 1442,
Compound 9i was prepared from 6 in a manner similar to that
described for compound 9b with a yield of 87% as a white amor-
phous. 1H NMR (300 MHz, CDCl3) d 8.95 (d, J = 2.2 Hz, 1H), 8.16
(dd, J = 2.2, 9.0 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.40–7.36 (m, 1H),
6.95–6.88 (m, 1H), 6.44–6.42 (m, 1H), 5.70 (d, J = 17.2 Hz, 1H),
5.60 (d, J = 17.2 Hz, 1H), 5.14 (s, 2H), 5.10 (br s, 1H), 3.81 (br s,
1H), 3.76 (s, 3H), 3.48 (dd, J = 2.9, 12.1 Hz, 1H), 3.12–3.06 (m,
3H), 2.28 (s, 3H), 1.85–1.75 (m, 3H), 1.42 (s, 9H), 1.27–1.15 (m,
1H); 13C NMR (100 MHz, CDCl3)
d
166.2, 162.3 (d, 1J(C,
F) = 245 Hz), 159.2, 155.7, 155.7, 152.9, 143.0, 141.6, 141.0, 138.0
(d, 3J(C, F) = 7.1 Hz), 134.4, 131.6 (d, 3J(C, F) = 8.2 Hz), 130.1,
127.5 (d, 4J(C, F) = 3.2 Hz), 125.9, 123.5, 120.1, 117.5, 116.4 (d,
2J(C, F) = 22.8 Hz), 115.6, 114.6 (d, 2J(C, F) = 24.5 Hz), 80.3, 56.2,
54.9, 52.1, 47.1, 46.9, 30.3, 30.0, 29.0, 23.2, 10.2; HRMS (ESI)
[M+H]+ calcd for C34H36O8N5ClF 696.2231, found 696.2231; IR
(ATR): 1818, 1716, 1652, 1569, 1506, 1473, 1386, 1305, 1272,
1375, 1317, 1245, 1218, 1114, 1049 cmꢀ1
.
1218, 1166, 1091, 1049 cmꢀ1
.
5.1.15. 2-(Dimethylamino)ethyl 2-[(3R)-3-aminopiperidin-1-
yl]-3-(2-chlorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-
5.1.12. (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-{(3R)-3-[(tert-
butoxycarbonyl)amino]piperidin-1-yl}-3-(2-chlorobenzyl)-5-
methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinoline-7-
carboxylate (9k)
imidazo[4,5-c]quinoline-8-carboxylate dihydrochloride (10c)
Compound 10c was prepared from 9c in a manner similar to
that described for compound 10b with a yield of 98% as a white
amorphous. 1H NMR (400 MHz, DMSO-d6) d 10.98 (s, 1H), 8.78
(d, J = 1.8 Hz, 1H), 8.51 (br s, 3H), 8.23 (dd, J = 1.8, 8.8 Hz, 1H),
7.69 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.32–7.28 (m,1H),
7.24–7.20 (m, 1H), 6.73 (d, J = 7.5 Hz, 1H), 5.64 (d, J = 17.2 Hz,
1H), 5.58 (d, J = 17.2 Hz, 1H), 4.63 (br s, 2H), 3.75–3.72 (m, 1H),
3.64 (s, 3H), 3.61–3.50 (m, 3H), 3.37–3.27 (m, 2H), 3.12–3.09 (m,
1H), 2.88 (s, 6H), 1.97 (m, 1H), 1.75 (m, 1H), 1.64–1.62 (m, 1H),
1.51–1.48 (m, 1H); 13C NMR (75 MHz, DMSO-d6) d 165.0, 157.1,
153.9, 140.4, 140.1, 134.8, 130.9, 129.4, 129.4, 129.0, 127.7,
127.0, 123.9, 122.7, 118.9, 116.0, 115.3, 59.4, 54.8, 52.1, 50.8,
46.5, 46.0, 42.5, 29.1, 27.1, 21.9; HRMS (ESI) [M+H]+ calcd for
Compound 9k was prepared from 7 in a manner similar to that
described for compound 9b with a yield of 73% as a white amor-
phous. 1H NMR (400 MHz, CDCl3) d 8.35 (d, J = 8.2 Hz, 1H), 8.13 (d,
J = 1.1 Hz, 1H), 7.96 (dd, J = 1.1, 8.2 Hz, 1H), 7.41 (dd, J = 1.0,
7.9 Hz, 1H), 7.22–7.19 (m, 1H), 7.15–7.11 (m, 1H), 6.69 (br d,
J = 7.5 Hz, 1H), 6.00 (br s, 1H), 5.78 (d, J = 17.2 Hz, 1H), 5.65 (d,
J = 17.4 Hz, 1H), 5.15 (s, 2H), 3.81 (br s, 1H), 3.80 (s, 3H), 3.44 (dd,
J = 3.3, 12.6 Hz, 1H), 3.25–3.21 (m, 1H), 3.08 (m, 2H), 2.28 (s, 3H),
1.77–1.72 (m, 3H), 1.56–1.51 (m, 1H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 166.4, 159.0, 155.8, 155.5, 152.7, 141.6, 141.0,
137.8, 135.4, 134.1, 132.5, 130.2, 129.2, 128.7, 127.8, 127.1, 123.6,
123.5, 121.6, 121.4, 117.2, 79.7, 55.4, 55.1, 52.1, 47.0, 46.4, 30.1,
29.8, 29.1, 22.2, 10.1; HRMS (ESI) [M+H]+ calcd for C34H37O8N5Cl
C
28H34O3N6Cl 537.2375, found 537.2372; IR (ATR): 1718, 1670,
1627, 1608, 1592, 1558, 1515, 1457, 1446, 1371, 1321, 1276,
1261, 1241, 1218, 1126, 1114, 1066, 1051, 1039 cmꢀ1
.