Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 24 7983
4H), 1.86-2.02 (m, 4H), 2.10-2.27 (m, 3H), 3.17-3.30 (m, 2H),
3.42-3.52 (m, 1H), 3.61-3.95 (m, 4H), 4.14-4.39 (m, 1H),
5.25-5.49 (m, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.48-7.53 (m, 2H),
7.72 (d, J = 8.3 Hz, 1H), 8.12 (dd, J = 11.5, 4.9 Hz, 1H), 8.22 (d,
J = 8.3 Hz, 1H), 9.79 (s, 1H), 12.04 (broad s, 1H). MS (ESI), m/z
575 [M þ H]þ. HRMS (ESI), m/z Calcd for C28H29ClF2-
N4O5þH: 575.1873. Found: 575.1908. Anal. Calcd for C28H29-
ClF2N4O5: C, 58.49; H, 5.08; Cl, 6.17; F, 6.61; N, 9.74. Found:
C, 58.29; H, 5.13; Cl, 6.08; F, 6.51; N, 9.55.
trans-4-[1-[[4-(3-Benzo[d]isothiazolylcarboxamido)-5-chloro-
2-fluorophenyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cy-
clohexanecarboxylic Acid (13j). Yield 64% (two steps). Colorless
solid. IR (ATR) 2935, 1691, 1637, 1622, 1525, 1406, 1196, 1093,
741 cm-1 1H NMR (DMSO-d6) δ 1.17-1.38 (m, 4H),
.
1.82-2.23 (m, 7H), 3.20-4.02 (m, 7H), 4.13-4.38 (m, 1H),
5.35-5.49 (m, 1H), 7.50-7.55 (m, 1H), 7.64-7.74 (m, 2H),
7.93-7.97 (m, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.81 (d, J = 8.3 Hz,
1H), 10.30 (s, 1H), 12.05 (broad s, 1H). MS (ESI), m/z 592 [M þ
trans-4-[1-[[3-Chloro-4-(1-methyl-3-indolylcarboxamido)phenyl]-
acetyl-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic
Acid (13e). Yield 72% (two steps). Colorless solid. IR (ATR) 2938,
2863, 1647, 1512, 1465, 1101, 744 cm-1. 1H NMR (DMSO-d6) δ
1.19-1.39 (m, 4H), 1.90-2.11 (m, 4H), 2.14-2.27 (m, 3H),
3.17-3.22 (m, 1H), 3.43-3.87 (m, 6H), 3.89 (s, 3H), 4.16-4.35
(m, 1H), 5.25-5.45 (m, 1H), 7.18-7.28 (m, 3H), 7.37-7.39 (m,
1H), 7.52 (d, J = 8.1 Hz, 1H), 7.69-7.73 (m, 1H), 8.15 (d, J = 7.8
Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 9.23 (s, 1H), 11.95 (broad s, 1H).
MS (ESI), m/z 570 [M þ H]þ. Anal. Calcd for C30H33Cl-
H]þ. Anal. Calcd for C28H28ClF2N3O5S 0.5H2O: C, 55.95; H,
3
4.86; N, 6.99. Found: C, 56.01; H, 4.84; N, 6.88.
trans-4-[1-[[4-(3-Benzo[d]isoxazolecarboxamido)-5-chloro-2-
fluorophenyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclo-
hexanecarboxylic Acid (13k). Yield 61% (two steps). Colorless
solid. IR (ATR) 2937, 1736, 1697, 1622, 1533, 1097, 756 cm-1
.
1H NMR (DMSO-d6) δ 1.19-1.40 (m, 4H), 1.88-2.23 (m, 7H),
3.19-4.00 (m, 7H), 4.13-4.38 (m, 1H), 5.36-5.49 (m, 1H),
7.50-7.58 (m, 2H), 7.66-7.68 (m, 1H), 7.77-7.81 (m, 1H),
7.94 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 10.65
(broad s, 1H), 12.05 (broad s, 1H). MS (ESI), m/z 576 [M þ H]þ.
Anal. Calcd for C28H28ClF2N3O6: C, 58.39; H, 4.90; N, 7.30.
Found: C, 58.19; H, 4.87; N, 7.18.
FN3O5 0.75 H2O: C, 61.75; H, 5.96; N, 7.20. Found: C, 61.85;
3
H, 5.92; N, 6.83.
trans-4-[1-[[5-Chloro-2-fluoro-4-(1-methyl-3-indolylcarboxamido)-
phenyl]acetyl-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic Acid (13f). Yield 86% (two steps). Colorless solid. IR
(ATR) 2940, 2863, 1652, 1521, 1404, 1227, 1099, 744 cm-1. 1H
NMR (DMSO-d6) δ 1.16-1.41 (m, 4H), 1.86-2.32 (m, 7H),
3.17-3.84 (m, 6H), 3.89 (s, 3H), 4.13-4.38 (m, 1H), 5.25-5.47
(m, 1H), 7.19-7.29 (m, 2H), 7.41-7.46 (m, 1H), 7.54 (d, J = 8.4
Hz, 1H), 7.70-7.72 (m, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.29-8.30
(m, 1H), 9.28 (s, 1H), 12.01 (broad s, 1H). MS (ESI), m/z 588 [M
þ H]þ. Anal. Calcd for C30H32ClF2N3O5: C, 61.27; H, 5.48; N,
7.15. Found: C, 61.41; H, 5.48; N, 7.11.
trans-4-[1-[[3-Chloro-4-(1-isoquinolinylcarboxamido)phenyl]-
acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarbo-
xylic Acid (13l). Yield 84% (two steps). Yellow solid. IR (ATR)
2935, 2861, 1716, 1596, 1527, 1442, 1093, 754 cm-1. 1H NMR
(DMSO-d6) δ 1.13-1.41 (m, 4H), 1.85-2.25 (m, 7H), 3.17-3.89
(m, 7H), 4.14-4.36 (m, 1H), 5.25-5.46 (m, 1H), 7.26-7.30 (m,
1H), 7.43-7.45 (m, 1H), 7.81 (t, J = 7.1 Hz, 1H), 7.88 (t, J = 7.1
Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 5.6 Hz, 1H),
8.20-8.24 (m, 1H), 8.67 (d, J = 5.6 Hz, 1H), 9.31 (d, J = 8.5 Hz,
1H), 10.84 (s, 1H), 12.02 (broad s, 1H). MS (ESI), m/z 568 [M þ
H]þ. Anal. Calcd for C30H31ClFN3O5: C, 63.43; H, 5.50; N,
7.40. Found: C, 63.40; H, 5.62; N, 7.13.
trans-4-[1-[[3-Chloro-4-(1-ethyl-3-indolylcarboxamido)phenyl]-
acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecarbox-
ylic Acid (13g). Yield 77% (two steps). Colorless amorphous
trans-4-[1-[[5-Chloro-2-fluoro-4-(1-isoquinolinylcarboxamido)-
phenyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclozhexa-
necarboxylic Acid (13m). Yield 87% (two steps). Yellow solid.
IR (ATR) 3282, 2940, 2863, 1722, 1693, 1650, 1619, 1581, 1517
1
solid. IR (ATR) 2937, 1647, 1512, 1209, 1093, 746 cm-1. H
NMR (DMSO-d6) δ 1.10-1.40 (m, 4H), 1.45 (t, J = 7.2 Hz, 3H),
1.80-2.04 (m, 4H), 2.04-2.36 (m, 3H), 3.10-3.97 (m, 7H),
4.07-4.39 (m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 5.32-5.39 (m,
1H), 7.10-7.30 (m, 3H), 7.38 (d, J = 6.8Hz, 1H), 7.59(d, J = 8.0
Hz, 1H), 7.65 (m, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 9.31
(s, 1H), 12.05 (broad s, 1H). MS (ESI), m/z 584 [M þ H]þ. Anal.
1
cm-1. H NMR (DMSO-d6) δ 1.15-1.41 (m, 4H), 1.86-2.33
(m, 7H), 3.17-4.00 (m, 7H), 4.14-4.37 (m, 1H), 5.26-5.48 (m,
1H), 7.49-7.54 (m, 1H), 7.82 (t, J = 7.3 Hz, 1H), 7.88 (t, J = 7.3
Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.18-8.23 (m, 2H), 8.67 (d,
J = 5.6 Hz, 1H), 9.38 (d, J = 8.8 Hz, 1H), 10.95-10.96 (m, 1H),
12.02 (broad s, 1H). MS (ESI), m/z 586 [M þ H]þ. Anal. Calcd
Calcd for C31H35ClFN3O5 0.25H2O: C, 63.26; H, 6.08; Cl, 6.02;
3
F, 3.23; N, 7.14. Found: C, 63.20; H, 6.08; Cl, 5.86; F, 3.18;
N, 6.96.
for C30H30ClF2N3O5 0.25H2O: C, 61.02; H, 5.21; N, 7.12.
3
trans-4-[1-[[3-Chloro-4-(1-isopropyl-3-indolylcarboxamido)phe-
nyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohexanecar-
boxylic Acid (13h). Yield 76% (two steps). Colorless amorphous
Found: C, 61.01; H, 5.17; N, 7.00.
trans-4-[1-[[5-Chloro-2-fluoro-4-(1-methyl-3-indolylcarboxamido)-
phenyl]acetyl]-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic Acid
(14a). Yield 74% (two steps). [R]D25 -49.9 (c 1.0, CHCl3). Colorless
amorphous solid. IR (ATR) 2933, 1724, 1612, 1514, 1404, 1219,
1
solid. IR (ATR) 2933, 1643, 1511, 1203, 1095, 746 cm-1. H
NMR (DMSO-d6) δ 1.08-1.44 (m, 4H), 1.53 (d, J = 6.8 Hz,
6H), 1.80-2.05 (m, 4H), 2.05-2.34 (m, 3H), 3.12-3.90 (m,
7H), 4.14-4.40 (m, 1H), 4.83-4.86 (m, 1H), 5.32-5.46 (m,
1H), 7.12-7.28 (m, 3H), 7.39 (d, J = 6.8 Hz, 1H), 7.59-7.63 (m,
2H), 8.17 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 9.35 (s, 1H),
12.04 (broad s, 1H). MS (ESI), m/z 598 [M þ H]þ. Anal. Calcd
1182, 1099, 744 cm-1 1H NMR (CDCl3) δ 1.13-1.28 (m,
.
2H), 1.40-1.53 (m, 2H), 1.88-2.06 (m, 8H), 2.23-2.34 (m, 1H),
3.16-3.25 (m, 1H), 3.37-3.80 (m, 6H), 3.88 (s, 3H), 4.13-4.25
(m, 1H), 7.32-7.37 (m, 2H), 7.39-7.44 (m, 2H), 7.81 (s,
1H), 8.11-8.14 (m, 1H), 8.29 (s, 1H), 8.46-8.51 (m, 1H). MS
(FAB), m/z 570 [M þ H]þ. Anal. Calcd for C30H33ClFN3-
for C31H37ClFN3O5 0.25H2O: C, 63.78; H, 6.27; Cl, 5.88;
3
F, 3.15; N, 6.97. Found: C, 63.62; H, 6.32; Cl, 5.72; F, 3.13;
N, 6.77.
O5 0.25H2O: C, 62.71; H, 5.88; N, 7.31. Found: C, 62.55; H, 5.99;
3
N, 6.96.
trans-4-[1-[[4-(3-Benzo[d]isothiazolylcarboxamido)-3-chloro-
phenyl]acetyl]-(4S)-fluoro-(2S)-pyrrolidinylmethoxy]cyclohex-
anecarboxylic Acid (13i). Yield 64% (two steps). Colorless solid.
IR (ATR) 2935, 2862, 1691, 1604, 1579, 1520, 1191, 1090, 742
trans-4-[1-[[5-Chloro-2-fluoro-4-(1-methyl-3-indolylcarbox-
amido)phenyl]acetyl]-(4S)-hydroxy-(2S)-pyrrolidinylmethoxy]-
cyclohexanecarboxylic Acid (14b). Yield 75% (two steps). Pale
yellow solid. IR (ATR) 2935, 1633, 1520, 1400, 1227, 1099, 742
1
1
cm-1. H NMR (DMSO-d6) δ 1.11-1.38 (m, 4H), 1.86-1.99
cm-1. H NMR (DMSO-d6) δ 1.14-1.37 (m, 4H), 1.75-2.17
(m, 4H), 2.12-2.33 (m, 3H), 3.17-3.89 (m, 7H), 4.14-4.36 (m,
1H), 5.25-5.46 (m, 1H), 7.26 (t, J = 6.4 Hz, 1H), 7.44 (dd, J =
7.7, 1.6 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.69-7.73 (m, 1H),
7.93-7.96 (m, 1H), 8.37 (d, J = 8.3 Hz, 1H), 8.80 (d, J = 8.1 Hz,
1H), 10.27 (s, 1H), 12.05 (broad s, 1H). MS (ESI), m/z 575 [M þ
H]þ. Anal. Calcd for C28H29ClFN3O5S: C, 58.58; H, 5.09; N,
7.32. Found: C, 58.41; H, 5.13; N, 7.02.
(m, 7H), 3.10-3.93 (m, 7H), 3.88 (s, 3H), 4.01-4.31 (m, 2H),
5.04-5.09 (m, 1H), 7.19-7.29 (m, 2H), 7.40-7.45 (m, 1H), 7.55
(d, J = 8.3 Hz, 1H), 7.67-7.71 (m, 1H), 8.14 (d, J = 7.8 Hz, 1H),
8.30 (s, 1H), 9.29 (s, 1H), 12.03 (broad s, 1H). MS (ESI), m/z 586
[M þ H]þ. Anal. Calcd for C30H33ClFN3O6 0.25H2O: C, 61.01;
3
H, 5.72; Cl, 6.00; F, 3.22; N, 7.12. Found: C, 61.04; H, 5.75; Cl,
6.06; F, 3.15; N, 6.95.