2954 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 14
max: 3650-2000, 2906, 2804, 1606, 1506, 1490, 1240, 1227,
Renaud et al.
ν
2.5 Hz, 1H), 6.47 (dd, J ) 2.5, 8.5 Hz, 1H), 4.03 (t, J ) 6.0 Hz,
2H), 3.48-3.38 (m, 1H), 3.28-3.18 (m, 1H), 3.11-3.00 (m, 1H),
2.85-2.74 (m, 3H), 2.58-2.46 (m, 4H), 1.77-1.64 (m, 4H), 1.56
(s, 3H). 13C NMR (125.8 MHz, DMSO) δ: 158.3 (d, J C-F ) 239
Hz), 157.0, 155.0, 146.8, 141.2, 135.1, 135.0, 130.0, 129.4, 127.1
(d, J C-F ) 8 Hz), 114.35 (d, J C-F ) 22 Hz), 113.9, 113.8, 113.5,
66.7, 63.95, 54.6, 54.25, 46.2, 30.5, 23.3, 22.95. HRMS (ESI,
M + H+) calcd for C28H31FN2O2: 447.2448; found: 447.2446.
HPLC Purity: 100%; tR 3.49 min.
1183, 847, 839, 765 cm-1. 1H NMR (500 MHz, DMSO) δ: 9.22
(s, 1H), 7.14 (d, J ) 8.8 Hz, 2H), 7.04 (t, J ) 7.5 Hz, 2H), 6.87
(t, J ) 7.5 Hz, 1H), 6.80 (d, J ) 8.8 Hz, 2H), 6.60 (d, J ) 7.5
Hz, 2H), 6.57 (d, J ) 8.5 Hz, 1H), 6.53 (d, J ) 2.5 Hz, 1H),
6.47 (dd, J ) 2.5, 8.5 Hz, 1H), 4.04 (t, J ) 6.0 Hz, 2H), 3.50-
3.30 (m, 2H), 3.13-3.03 (m, 1H), 2.86-2.76 (m, 3H), 2.61-
2.50 (m, 4H), 1.76-1.67 (m, 4H), 1.60 (s, 3H). 13C NMR (125.8
MHz, DMSO) δ: 156.9, 154.9, 150.5, 141.8, 135.3, 135.1, 129.9,
129.1, 127.9, 124.6, 122.3, 113.9, 113.8, 113.6, 66.5, 64.0, 54.5,
54.2, 45.9, 30.6, 23.3, 23.1. HRMS (ESI, M + H+) calcd for
C28H32N2O2: 429.2542; found: 429.2538. HPLC Purity: 98%;
tR 3.37 min.
2-(4-F lu or op h e n yl)-1-m e t h yl-1-[4-(2-p ip e r id in -1-yl-
eth oxy)p h en yl-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (20c).
IR (KBr) νmax: 3650-2300, 2936, 1610, 1501, 1240, 1229, 1206,
1195, 1183, 839 cm-1. H NMR (500 MHz, DMSO) δ: 9.19 (s,
1
1-Meth yl-2-ph en yl-1-[4-(2-piper idin -1-yl-eth oxy)ph en yl]-
1H), 7.06 (d, J ) 8.5 Hz, 2H), 6.87 (t, J ) 8.7 Hz, 2H), 6.77 (d,
J ) 8.5 Hz, 2H), 6.59-6.54 (m, 2H), 6.52 (d, J ) 8.5 Hz, 1H),
6.50 (d, J ) 2.0 Hz, 1H), 6.44 (dd, J ) 2.0, 8.5 Hz, 1H), 3.99 (t,
J ) 6.0 Hz, 2H), 3.45-3.37 (m, 1H), 3.25-3.17 (m, 1H), 3.08-
3.00 (m, 1H), 2.77 (dm, J for d ) 16.0 Hz, 1H), 2.62 (t, J ) 6.0
Hz, 2H), 2.41 (br s, 4H), 1.54 (s, 3H), 1.53-1.45 (m, 4H), 1.42-
1.33 (m, 2H). 13C NMR (125.8 MHz, DMSO) δ: 158.1 (d, J C-F
) 239 Hz), 156.9, 154.8, 146.7, 141.0, 134.9, 134.8, 129.8, 129.2,
127.0 (d, J C-F ) 8 Hz), 114.2 (d, J C-F ) 22 Hz), 113.7, 113.6,
113.4, 65.4, 63.8, 57.5, 54.5, 46.0, 30.3, 25.6, 24.0, 22.8. HRMS
(ESI, M + H+) calcd for C29H33FN2O2: 461.2604; found:
461.2606. HPLC Purity: 99%; tR 3.72 min.
1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (20a ). IR (KBr) νmax
3650-2300, 2937, 1609, 1593, 1508, 1491, 1238, 1228, 1183,
837, 767 cm-1 1H NMR (500 MHz, DMSO) δ: 8.78 (s, 1H),
:
.
7.13 (d, J ) 8.8 Hz, 2H), 7.04 (t, J ) 7.5 Hz, 2H), 6.87 (t, J )
7.5 Hz, 1H), 6.79 (d, J ) 8.8 Hz, 2H), 6.68 (d, J ) 7.5 Hz, 2H),
6.64 (d, J ) 8.5 Hz, 1H), 6.55 (d, J ) 2.5 Hz, 1H), 6.50 (dd, J
) 2.5, 8.5 Hz, 1H), 4.10 (t, J ) 5.5 Hz, 2H), 3.48-3.38 (m,
2H), 3.07-2.93 (m, 1H), 2.90-2.75 (m, 3H), 2.68-2.54 (m, 4H),
1.67 (s, 3H), 1.64-1.53 (m, 4H), 1.50-1.42 (m, 2H). 13C NMR
(125.8 MHz, DMSO, 80 °C) δ: 157.3, 155.3, 150.8, 142.1,
135.63, 135.56, 129.7, 129.3, 128.0, 125.1, 122.4, 114.5, 114.3,
114.2, 66.0, 64.1, 57.5, 54.6, 46.6, 30.6, 25.5, 24.4, 23.9. HRMS
(ESI, M + H+) calcd for C29H34N2O2: 443.2699; found: 443.2698.
HPLC Purity: 100%; tR 3.52 min.
2-(4-Ch lor op h en yl)-1-m et h yl-1-[4-(2-p yr r olid in -1-yl-
eth oxy)p h en yl]-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (19d ).
IR (KBr) νmax: 3650-2100, 2968, 2921, 2826, 1606, 1585, 1505,
1
1-[4-(2-Azep a n -1-yl-eth oxy)p h en yl]-1-m eth yl-2-p h en yl-
1489, 1476, 1308, 1238, 1226, 1179, 1044, 836 cm-1. H NMR
1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (26a ). IR (KBr) νmax
:
(500 MHz, DMSO) δ: 9.20 (s, 1H), 7.11 (d, J ) 8.5 Hz, 2H),
7.05 (d, J ) 8.8 Hz, 2H), 6.78 (d, J ) 8.5 Hz, 2H), 6.60-6.50
(m, 3H), 6.49 (d, J ) 2.0 Hz, 1H), 6.44 (dd, J ) 2.0, 8.5 Hz,
1H), 4.00 (t, J ) 6.0 Hz, 2H), 3.48-3.22 (m, 2H), 3.12-3.00
(m, 1H), 2.81-2.71 (m, 3H), 2.57-2.43 (m, 4H), 1.73-1.63 (m,
4H), 1.58 (s, 3H). 13C NMR (125.8 MHz, DMSO) δ: 156.9,
154.8, 149.2, 141.1, 135.0, 134.8, 129.8, 129.0, 127.6, 125.9,
125.7, 113.75, 113.55, 66.5, 63.9, 54.4, 54.1, 45.7, 30.3, 23.2,
22.8. HRMS (ESI, M + H+) calcd for C28H31ClN2O2: 463.2152;
found: 463.2150. HPLC Purity: 96%; tR 3.97 min.
2924, 2853, 1609, 1509, 1490, 1361, 1331, 1249, 1227, 1185,
1
831, 703 cm-1. H NMR (500 MHz, DMSO) δ: 10.22 (br s, 1
H), 9.22 (s, 1H), 7.19 (d, J ) 8.8 Hz, 2H), 7.05 (t, J ) 8.0 Hz,
2H), 6.92-6.84 (m, 3H), 6.61 (d, J ) 8.0 Hz, 2H), 6.58 (d, J )
8.5 Hz, 1H), 6.53 (d, J ) 2.5 Hz, 1H), 6.48 (dd, J ) 2.5, 8.5 Hz,
1H), 4.43-4.26 (br s, 2H), 3.60-3.17 (m, 8H), 3.14-3.02 (m,
1H), 2.90-2.77 (m, 2H), 1.93-1.77 (m, 4H), 1.74-1.53 (m, 7H).
13C NMR (125.8 MHz, DMSO) δ: 156.3, 155.2, 150.7, 142.9,
135.4, 135.3, 130.1, 129.4, 128.1, 124.8, 122.5, 114.2, 114.1,
114.1, 65.3, 64.2, 55.4, 54.8, 46.2, 30.7, 26.5, 23.5, 23.2. HRMS
(ESI, M + H+) calcd for C30H36N2O2: 457.2850; found: 457.2850.
HPLC Purity: 98%; tR 3.36 min.
2-(4-Ch lor op h e n yl)-1-m e t h yl-1-[4-(2-p ip e r id in -1-yl-
eth oxy)p h en yl]-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (20d ).
IR (KBr) νmax: 3650-2100, 2941, 1606, 1585, 1503, 1488, 1477,
1
1-Met h yl-1-[4-(2-p yr r olid in -1-yl-et h oxy)p h en yl]-2-p -
tolyl-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (19b). IR (KBr)
1302, 1238, 1226, 1179, 1049, 1039, 836 cm-1. H NMR (500
MHz, DMSO) δ: 9.21 (s, 1H), 7.11 (d, J ) 8.8 Hz, 2H), 7.06
(d, J ) 8.8 Hz, 2H), 6.79 (d, J ) 8.8 Hz, 2H), 6.60-6.50 (m,
3H), 6.50 (d, J ) 2.5 Hz, 1H), 6.44 (dd, J ) 2.5, 8.5 Hz, 1H),
4.00 (t, J ) 6.0 Hz, 2H), 3.46-3.22 (m, 2H), 3.12-3.00 (m, 1H),
2.78 (dm, J ) 16.0 Hz, 1H), 2.64 (br s, 2H), 2.43 (s, 4H), 1.59
(s, 3H), 1.53-1.43 (m, 4H), 1.40-1.30 (m, 2H). 13C NMR (125.8
MHz, DMSO) δ: 156.9, 154.8, 149.2, 141.1, 135.0, 134.7, 129.7,
128.9, 127.6, 125.9, 125.7, 113.7, 113.6, 65.3, 63.9, 57.45, 54.45,
45.7, 30.3, 25.5, 23.9, 22.8. HRMS (ESI, M + H+) calcd for
C29H33ClN2O2: 477.2309; found: 477.2305. HPLC Purity: 99%;
tR 4.11 min.
νmax: 3650-2200, 2958, 2929, 2825, 1511, 1499, 1478, 1295,
1247, 1199, 1181, 1034, 850, 822, 804 cm-1. 1H NMR (300 MHz,
CD3OD) δ: 7.06 (d, J ) 8.8 Hz, 2H), 6.82 (d, J ) 8.0 Hz, 2H),
6.79 (d, J ) 8.8 Hz, 2H), 6.63-6.43 (m, 5H), 4.10 (t, J ) 5.5
Hz, 2H), 3.46-3.36 (m, 1H), 3.33-3.26 (m, 1H), 3.13-3.00 (m,
1H), 2.97 (t, J ) 5.5 Hz, 2H), 2.85 (ddd, J ) 4.5, 4.5, 16.0 Hz,
1H), 2.80-2.67 (m, 4H), 2.19 (s, 3H), 1.93-1.77 (m, 4H), 1.62
(s, 3H). HRMS (ESI, M + H+) calcd for C29H34N2O2: 443.2699;
found: 443.2699. HPLC Purity: 98%; tR 3.47 min.
1-Meth yl-1-[4-(2-piper idin -1-yl-eth oxy)ph en yl]-2-p-tolyl-
1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (20b). IR (KBr) νmax
3650-2200, 2969, 2938, 2817, 1610, 1507, 1465, 1302, 1238,
1225, 1185, 1134, 839 cm-1 1H NMR (400 MHz, DMSO) δ:
:
2-(4-Isop r op ylp h en yl)-1-m eth yl-1-[4-(2-p yr r olid in -1-yl-
eth oxy)p h en yl]-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (19e).
IR (KBr) νmax: 3650-2200, 2957, 2934, 2825, 1499, 1478, 1370,
.
1
9.18 (s, 1H), 7.07 (d, J ) 8.8 Hz, 2H), 6.82 (d, J ) 8.0 Hz, 2H),
6.76 (d, J ) 8.8 Hz, 2H), 6.55-6.40 (m, 5H), 4.00 (t, J ) 6.0
Hz, 2H), 3.43-3.25 (m, 1H), 3.25-3.17 (m, 1H), 3.08-2.95 (m,
1H), 2.76 (dm, J for d ) 16.0 Hz, 1H), 2.62 (t, J ) 6.0 Hz, 2H),
2.47-2.34 (m, 4H), 2.14 (s, 3H), 1.53 (s, 3H), 1.53-1.43 (m,
4H), 1.40-1.30 (m, 2H). 13C NMR (125.8 MHz, DMSO) δ:
156.8, 154.7, 147.8, 141.5, 135.2, 134.9, 131.4, 129.8, 129.2,
128.2, 125.1, 113.7, 113.6, 113.3, 65.3, 63.7, 57.5, 54.5, 45.9,
30.4, 25.6, 23.9, 22.8, 20.3. HRMS (ESI, M + H+) calcd for
1331, 1296, 1244, 1180, 1119, 1031, 851, 836 cm-1. H NMR
(400 MHz, CDCl3) δ: 7.05 (d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 8.5
Hz, 2H), 6.69 (d, J ) 8.5 Hz, 1H), 6.63 (d, J ) 8.8 Hz, 2H),
6.60-6.48 (m, 4H), 4.12 (t, J ) 5.5 Hz, 2H), 3.43-3.28 (m, 2H),
3.10-2.70 (m, 9H), 1.90 (br s, 4H), 1.67 (s, 3H), 1.205 (d, J )
7.0 Hz, 3H), 1.20 (d, J ) 7.0 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3) δ: 157.0, 154.3, 148.1, 143.5, 141.5, 136.0, 135.9, 130.0,
129.5, 126.1, 125.6, 114.5, 113.8, 113.2, 66.0, 64.0, 55.2, 54.6,
46.4, 33.4, 30.5, 24.1, 24.0, 23.4. HRMS (ESI, M + H+) calcd
for C31H38N2O2: 471.3012; found: 471.3016. HPLC Purity:
99%; tR 3.96 min.
C
30H36N2O2: 457.2855; found: 457.2855. HPLC Purity: 100%;
tR 3.59 min.
2-(4-F lu or op h en yl)-1-m et h yl-1-[4-(2-p yr r olid in -1-yl-
eth oxy)p h en yl-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (19c).
IR (KBr) νmax: 3650-2000, 2920, 2837, 1607, 1505, 1237, 1220,
841 cm-1. 1H NMR (500 MHz, DMSO) δ: 9.23 (s, 1H), 7.09 (d,
J ) 8.8 Hz, 2H), 6.89 (t, J ) 9.0 Hz, 2H), 6.80 (d, J ) 8.8 Hz,
2H), 6.65-6.56 (m, 2H), 6.55 (d, J ) 8.5 Hz, 1H), 6.53 (d, J )
2-(4-Isop r op ylp h en yl)-1-m eth yl-1-[4-(2-p ip er id in -1-yl-
eth oxy)p h en yl]-1,2,3,4-tetr a h yd r oisoqu in olin -6-ol (20e).
IR (KBr) νmax: 3700-2400, 2955, 2930, 1592, 1500, 1480, 1370,
1361, 1296, 1248, 1179, 1025, 851, 838 cm-1 1H NMR (400
.
MHz, CDCl3) δ: 7.06 (d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 8.5 Hz,
2H), 6.70 (d, J ) 8.5 Hz, 1H), 6.62 (d, J ) 8.8 Hz, 2H), 6.60-