2894 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11
Wu et al.
method A); 99% (3.78 min, method F); HRMS calcd for
C
(S)-3-(2-Meth oxy-p h en yl)-N-[1-(3-m or p h olin -4-yl-p h en -
(1H, d, J ) 15.5 Hz), 6.62 (1H, dd, J ) 1.5, 8.0 Hz), 6.69 (1H,
brd s), 7.20 (1H, t, J ) 8.0 Hz), 7.25 (1H, brd s), 7.34 (3H, m),
7.47 (2H, dd, J ) 2.0, 8.0 Hz), 7.61 (1H, d, J ) 15.5 Hz); 13C
NMR (100 MHz, CDCl3) δ 21.6, 29.3, 43.5, 47.6, 49.6, 52.1,
70.0, 110.4, 111.1, 113.6, 120.9, 127.8, 128.8, 129.6, 129.9,
134.9, 141.1, 144.3, 148.7, 164.9; HPLC purity (retention
time): 95% (1.50 min, method C); 91% (3.81 min, method F);
HRMS calcd for C22H27N2O2 351.2073 (MH+), found 351.2076.
21H23F2N2O2 373.1728 (MH+), found 373.1731.
yl)-eth yl]-a cr yla m id e (7): 1H NMR (400 MHz, CDCl3) δ 1.53
(3H, d, J ) 6.9 Hz), 3.14 (4H, m), 3.83 (7H, m), 5.22 (1H, m),
6.08 (1H, d, J ) 8.1 Hz), 6.53 (1H, d, J ) 15.7 Hz), 6.87 (5H,
m), 7.26 (2H, m), 7.42 (1H, dd, J ) 7.70, 1.34 Hz), 7.86 (1H, d,
J ) 15.7 Hz); 13C NMR (100 MHz, CDCl3) δ 21.8, 49.3, 49.6
(2C), 55.5, 66.9 (2C), 111.2, 114.5, 114.8, 118.1, 120.8, 121.8,
124.0, 129.2, 129.7, 130.8, 136.7, 144.6, 151.4, 158.4, 165.7;
HPLC purity (retention time): 99% (1.18 min, method B); 99%
(S)-N-{1-[3-(2,6-cis-Dim eth yl-m or p h olin -4-yl)-p h en yl]-
eth yl}-3-(2-flu or o-p h en yl)-a cr yla m id e (18): 1H NMR (400
MHz, CDCl3) δ 1.24 (6H, d, J ) 6.4 Hz), 1.54 (3H, d, J ) 6.8
Hz), 2.41 (2H, t, J ) 10.8 Hz), 3.44 (2H, d, J ) 1.2 Hz), 3.78
(2H, m), 5.24 (1H, quintet, J ) 7.2 Hz), 5.88 (1H, brd d, J )
6.8 Hz), 6.50 (1H, d, J ) 16.0 Hz), 6.81 (1H, dd, J ) 1.0, 6.4
Hz), 6.85 (1H, d, J ) 7.6 Hz), 6.90 (1H, brd s), 7.06 (dd, J )
8.8, 1.0 Hz), 7.12 (1H, t, J ) 7.6 Hz), 7.25 (3H, m), 7.45 (1H,
dt, J ) 1.2, 7.6 Hz), 7.67 (1H, d, J ) 16.0 Hz); 13C NMR (125
MHz, CDCl3) δ 19.1, 21.6, 49.5, 54.8, 71.7, 114.3, 114.8, 116.2
(d, J ) 22 Hz), 117.3, 122.9 (d, J ) 11.0 Hz), 123.7 (d, J ) 6.0
Hz), 124.4 (d, J ) 4.0 Hz), 129.6, 129.8, 130.9 (d, J ) 9.0 Hz),
134.3, 144.1, 151.3, 161.4 (d, J ) 252.0 Hz), 164.8; HPLC
purity (retention time): 100% (1.65 min, method C); 99% (4.09
min, method F); HRMS calcd for C23H28FN2O2 383.2135 (MH+),
found 383.2132.
(3.71 min, method F); HRMS m/z calcd for
C22H26N2O2
367.2022 (MH+), found 367.2035.
(S)-3-(3-Meth oxy-p h en yl)-N-[1-(3-m or p h olin -4-yl-p h en -
yl)-eth yl]-a cr yla m id e (8): 1H NMR (400 MHz, CDCl3) δ 1.52
(3H, d, J ) 6.8 Hz), 3.13 (4H, t, J ) 5.2 Hz), 3.78 (3H, s), 3.82
(4H, t, J ) 5.2 Hz), 5.21 (1H, quintet, J ) 7.2 Hz), 6.09 (1H,
brd d, J ) 8.0 Hz), 6.38 (1H, d, J ) 15.6 Hz), 6.88 (1H, dd, J
) 1.6, 8.4 Hz), 6.90 (1H, brd s), 6.97 (1H, brd s), 7.05 (1H, d,
J ) 7.6 Hz), 7.24 (2H, dt, J ) 2.4, 8.0 Hz), 7.57 (1H, d, J )
15.6 Hz); 13C NMR (125 MHz, CDCl3) δ 21.7, 49.3, 49.4, 55.3,
67.0, 113.0, 114.2, 114.7, 115.4, 117.6, 120.4, 121.2, 129.6,
129.9, 136.3, 141.1, 144.2, 151.7, 159.9, 165.0; HPLC purity
(retention time): 94% (1.46 min, method A); 98% (3.67 min,
method F); HRMS calcd for C22H27N2O3 367.2022 (MH+), found
367.2014.
(S)-N-[1-(4-Met h oxy-5-m or p h olin -4-yl-p h en yl)-et h yl]-
3-p h en yl-a cr yla m id e (9): 1H NMR (400 MHz, CDCl3) δ 1.54
(3H, d, J ) 6.8 Hz), 3.16 (4H, t, J ) 4.8 Hz), 3.82 (3H, s), 3.85
(4H, t, J ) 4.8 Hz), 5.22 (1H, quintet, J ) 7.2 Hz), 5.78 (1H,
brd d, J ) 8.0 Hz), 6.23 (1H, d, J ) 15.6 Hz), 6.88 (5H, m),
7.25 (1H, t, J ) 8.8 Hz), 7.41 (2H, d, J ) 8.4 Hz), 7.58 (1H, d,
J ) 15.6 Hz); 13C NMR (125 MHz, CDCl3) δ 21.7, 49.3, 49.4,
55.4, 66.9, 114.3, 114.8, 115.4, 117.7, 118.3, 127.6, 129.4, 129.7,
140.9, 144.4, 151.6, 161.0, and 165.3; HPLC purity (retention
time): 92% (1.42 min, method A); 98% (3.62 min, method F);
HRMS calcd for C22H27N2O3 367.2022 (MH+), found 367.2016.
(S)-N-[1-(2-Met h oxy-5-m or p h olin -4-yl-p h en yl)-et h yl]-
3-p h en yl-a cr yla m id e (10): 1H NMR (500 MHz, CDCl3) δ
1.50 (3H, d, J ) 7.0 Hz), 3.05 (4H, m), 3.83 (4H, m), 3.87 (3H,
s), 5.32 (1H, quintet, J ) 7.5 Hz), 6.35 (1H, d, J ) 15.5 Hz),
6.64 (1H, brd d, J ) 9.0 Hz), 6.78 (1H, dd, J ) 2.5, 9.0 Hz),
6.85 (1H, d, J ) 8.5 Hz), 6.89 (1H, brd s), 7.33 (3H, m), 7.48
(2H, m), 7.59 (1H, d, J ) 15.5 Hz); 13C NMR (125 MHz, CDCl3)
δ 21.6, 48.4, 50.7, 55.8, 66.9, 112.1, 115.8, 117.8, 121.3, 127.8,
128.8, 129.5, 131.5, 135.0, 140.8, 145.4, 151.7, 164.6; HPLC
purity (retention time): 100% (1.71 min, method E); 100%
(3.69 min, method F); HRMS calcd for C22H27N2O3 367.2022
(MH+), found 367.2015.
(S)-N-[1-(4-Met h oxy-3-m or p h olin -4-yl-p h en yl)-et h yl]-
3-p h en yl-a cr yla m id e (11): 1H NMR (500 MHz, CDCl3) δ
1.55 (3H, d, J ) 7.2 Hz), 3.08 (4H, m), 3.86 (3H, s), 3.88 (4H,
m), 5.21 (1H, quintet, J ) 7.2 Hz), 5.76 (1H, brd s), 6.36 (1H,
d, J ) 16.0 Hz), 6.8-7.1 (3H, m), 7.36 (3H, m), 7.48 (2H, m),
7.61 (1H, d, J ) 16.0 Hz); HPLC purity (retention time): 95%
(1.63 min, method E); 100% (3.53 min, method F); HRMS calcd
for C22H27N2O3 367.2022 (MH+), found 367.2025.
(S)-N-{1-[3-(2,6-cis-Dim eth yl-m or p h olin -4-yl)-p h en yl]-
eth yl}-3-(4-flu or o-p h en yl)-a cr yla m id e (19): 1H NMR (500
MHz, CDCl3) δ 1.25 (6H, d, J ) 6.0 Hz), 1.54 (3H, d, J ) 7.0
Hz), 1.42 (2H, t, J ) 11.0 Hz), 3.44 (2H, d, J ) 11.0 Hz), 3.79
(2H, brd s), 5.21 (1H, quintet, J ) 7.5 Hz), 5.77 (1H, brd s),
6.27 (1H, d, J ) 15.5 Hz), 6.82 (1H, d, J ) 7.5 Hz), 6.86 (1H,
d, J ) 7.0 Hz), 6.91 (1H, brd s), 7.04 (2H, t, J ) 8.5 Hz), 7.23
(1H, t, J ) 7.5 Hz), 7.46 (2H, dd, J ) 5.5, 8.5 Hz), 7.57 (1H, d,
J ) 15.5 Hz); 13C NMR (125 MHz, CDCl3) δ 19.1, 21.7, 49.5,
54.9, 71.7, 114.4, 114.9, 115.9, 116.1, 120.5, 129.5 (d, J ) 10.0
Hz), 129.6, 140.0, 144.1, 163.6 (d, J ) 248.8 Hz), 164.8; HPLC
purity (retention time): 100% (1.66 min, method C); 100%
(4.05 min, method F); HRMS calcd for C23H28FN2O2 383.2135
(MH+), found 338.2137.
(S)-3-(2-F lu or o-p h en yl)-N-{1-[3-(4-m eth yl-p ip er a zin -1-
yl)-p h en yl]-eth yl}-a cr yla m id e (20): 1H NMR (500 MHz,
CDCl3) δ 1.55 (3H, d, J ) 7.0 Hz), 2.35 (3H, s), 2.57 (4H,
apparent t), 3.22 (4H, apparent t), 5.22 (1H, quintet, J ) 7.0
Hz), 5.82 (1H, brd d, J ) 8.0 Hz, 1H), 6.49 (1H, d, J ) 16.0
Hz, 1H), 6.84 (2H, t, J ) 8.0 Hz), 6.93 (1H, brd s), 7.07 (1H, t,
J ) 9.0 Hz), 7.12 (1H, t, J ) 7.5 Hz), 7.22 (1H, m), 7.29 (1H,
m), 7.46 (1H, apparent t, J ) 15.0 Hz), 7.68 (1H, d, J ) 16.0
Hz). 13C NMR (125 MHz, CDCl3) δ 21.6, 46.0, 48.9, 49.5, 55.1,
114.7, 115.1, 116.1, 116.3, 117.4, 123.0 (d, J ) 11.3 Hz), 123.9
(d, J ) 7.5 Hz), 124.4, 129.6, 129.8, 131.0 (d, J ) 8.8 Hz), 134.3,
144.1, 151.6, 161.5 (d, J ) 251.3 Hz), 164.8; HPLC purity
(retention time): 97% (1.26 min, method A); 98% (4.22 min,
method F).
(S)-N-[1-(3-Mor ph olin -4-yl-ph en yl)-eth yl]-3-ph en yl-pr o-
p ion a m id e (23): 1H NMR (500 MHz, CDCl3) δ 1.39 (3H, d, J
) 7.0 Hz), 2.45 (2H, t, J ) 7.0 Hz), 2.96 (2H, t, J ) 7.0 Hz),
3.13 (4H, t, J ) 4.5 Hz), 3.84 (4H, t, J ) 5.0 Hz), 5.04 (1H,
quintet, J ) 7.0 Hz), 5.46 (1H, brd d, J ) 7.0 Hz), 6.70 (1H, d,
J ) 7.5 Hz), 6.79 (2H, m), 7.20-7.30 (6H, m); 13C NMR (125
MHz, CDCl3) δ 21.5, 31.7, 38.6, 49.0, 49.3, 66.9, 114.1, 114.6,
117.4, 126.2, 128.4, 128.5, 129.5, 140.8, 144.1, 151.6, and 171.0;
HPLC purity (retention time): 90% (1.18 min, method D);
100% (3.54 min, method F); HRMS calcd for C21H27N2O2
339.2073 (MH+), found 339.2087.
(S)-N-[1-(4-F lu or o-3-m or p h olin -4-yl-p h en yl)-et h yl]-3-
p h en yl-a cr yla m id e (12): 1H NMR (400 MHz, CDCl3) δ 1.53
(3H, d, J ) 6.9 Hz), 3.08 (4H, t, J ) 4.4 Hz), 3.85 (4H, t, J )
4.4 Hz), 5.20 (1H, m), 5.86 (1H, d, J ) 7.6 Hz), 6.38 (1H, d, J
) 15.7 Hz), 6.95 (3H, m), 7.35 (3H, m), 7.47 (2H, m), 7.62 (1H,
d, J ) 15.7 Hz); 13C NMR (75 MHz, CDCl3) δ 21.9, 48.8, 50.9
(2C), 67.1 (2C), 116.3 (d, J ) 22.5 Hz), 117.2, 119.9 (d, J ) 7.5
Hz), 120.7, 127.9 (2C), 128.9 (2C), 129.8, 134.9, 139.7, 140.1
(d, J ) 7.5 Hz), 141.5, 154.9 (d, J ) 247.0 Hz), 165.1; HPLC
purity (retention time): 95% (1.54 min, method B); 99% (3.74
min, method F); HRMS calcd for C21H23FN2O2 355.1822 (MH+),
found 355.1831.
(S)-N-[1-(3-[1,4]Oxa zep a n -4-yl-p h en yl)-eth yl]-3-p h en yl-
a cr yla m id e (15): 1H NMR (500 MHz, CDCl3) δ 1.54 (3H, d,
J ) 6.8 Hz), 2.01 (2H, quintet, J ) 6.0 Hz), 3.61 (4H, q, J )
6.5 Hz), 3.69 (2H, t, J ) 5.5 Hz), 3.82 (2H, t, J ) 4.5 Hz), 5.19
(1H, quintet, J ) 7.5 Hz), 5.78 (1H, brd d, J ) 7.5 Hz), 6.35
(S)-3-Meth yl-1H-in d en e-2-ca r boxylic a cid [1-(3-m or -
p h olin -4-yl-p h en yl)-eth yl]-a m id e (25): 1H NMR (400 MHz,
CDCl3) δ 1.56 (3H, d, J ) 7.0 Hz), 2.52 (3H, s), 3.17 (4H, m),
3.58 (2H, s), 3.85 (4H, m), 5.26 (1H, quintet, J ) 7.0 Hz), 5.87
(1H, brd d, J ) 7.5 Hz), 6.84 (1H, dd, J ) 2.0, 7.5 Hz), 6.90
(1H, d, J ) 7.5 Hz), 6.94 (1H, brd s), 7.31 (3H, m), 7.44 (2H, t,
J ) 7.0 Hz); 13C NMR (125 MHz, CDCl3) δ 12.3, 22.0, 38.5,
49.1, 49.4, 67.0, 114.2, 114.7, 117.6, 120.8, 123.8, 126.9, 127.2,
129.7, 132.3, 142.0, 144.6, 145.8, 147.0, 151.7 and 165.3; HPLC
purity (retention time): 99% (1.34 min, method B); 98% (3.96