4556 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 14
Harper et al.
6H), 1.60-1.97 (m, 7H), 1.97-2.13 (m, 2H), 2.57-2.73 (m, 2H),
2.95-3.22 (m, 5H), 3.50-3.67 (m, 1H), 3.85 (s, 3H), 3.91-4.05
(m, 1H), 4.35-4.49 (m, 1H), 4.81-5.04 (m, 2H), 7.12 (d, J )
8.8 Hz, 2H), 7.25 (d, J ) 8.8 Hz, 2H), 7.66 (d, J ) 8.3 Hz, 1H),
7.83 (d, J ) 8.3 Hz, 1H), 7.94 (s, 1H), 9.80 (br s, 1H), 12.52 (br
58.0, 112.2, 118.7, 119.6, 119.7, 123.3, 128.6, 129.3, 130.1,
132.2, 133.6, 136.7, 138.5, 165.8, 168.2; MS (ES+) m/z 550 (M
+ H)+; RP-HPLC method 1, tR ) 7.5 min (>99%); method 2, tR
) 6.5 (>99%); HRMS calculated for C32H41N3O3Cl (M + H)+
550.2831, found 550.2819.
s, 1H); MS (ES+) m/z 546 (M + H)+; RP-HPLC method 1, tR
)
1-(1-{[6-Carboxy-3-cyclohexyl-2-(3-furyl)-1H-indol-1-yl]-
acetyl}piperidin-4-yl)azetidinium Trifluoroacetate (56).
Step 1. Following the general procedure described for 55,
treatment of 60 (0.50 g, 1.49 mmol) with 3-furylboronic acid
afforded methyl 3-cyclohexyl-2-(3-furyl)-1H-indole-6-carboxy-
7.1 min (>99%); method 2, tR ) 6.0 (>99%); HRMS calculated
for C33H44N3O4 (M + H)+ 546.3326, found 546.3324.
1-{[6-Carboxy-2-(4-chlorophenyl)-3-cyclohexyl-1H-in-
dol-1-yl]acetyl}-N,N-diethylpiperidin-4-aminium Chlo-
ride (55). Step 1: General Procedure for Suzuki Cross-
Couplings. A solution of 60 (5.0 g, 15.9 mmol) in DME/EtOH
(5:2) was treated with aqueous Na2CO3 (2 N, 8.5 equiv) and
4-chlorophenylboronic acid (2.8 g, 17.8 mmol) and then de-
gassed. Pd(PPh3)4 (1.7 g, 1.48 mmol) was added, and the
mixture was stirred at 80 °C for 6 h. The cooled solution was
diluted with EtOAc and filtered through Celite. The filtrate
was washed with brine, dried, and concentrated to afford a
residue that was purified by flash chromatography (1:9 to 4:6
EtOAc/petroleum ether) to give methyl 2-(4-chlorophenyl)-3-
cyclohexyl-1H-indole-6-carboxylate (4.40 g, 80%) as a white
solid. 1H NMR (400 MHz, DMSO-d6) δ 1.22-1.45 (m, 3H),
1.67-1.85 (m, 5H), 1.90-2.06 (m, 2H), 2.78-2.90 (m, 1H), 3.86
(s, 3H), 7.55 (d, J ) 8.3 Hz, 2H), 7.60 (d, J ) 8.8 Hz, 1H), 7.62
(d, J ) 8.3 Hz, 2H), 7.85 (d, J ) 8.8 Hz, 1H), 7.99 (s, 1H),
11.56 (s, 1H); MS (ES+) m/z 368 (M + H)+.
Step 2. A solution of the material from above (3.2 g, 8.9
mmol) in DMF (100 mL) was cooled to 0 °C and treated with
NaH (60% suspension in mineral oil, 0.30 g, 12.4 mmol). The
mixture was stirred for 1 h and then treated with tert-butyl
bromoacetate (3.50 g, 17.7 mmol). The resulting solution was
stirred at 20 °C for 12 h and then diluted with EtOAc and
aqueous HCl (1 N). The organic phase was separated, washed
with brine, and dried. Removal of the solvent in vacuo afforded
a residue that was purified by flash chromatography (1:99 to
1:9 EtOAc/petroleum ether) to give methyl 1-(2-tert-butoxy-2-
oxoethyl)-2-(4-chlorophenyl)-3-cyclohexyl-1H-indole-6-carboxy-
late (4.0 g, 94%). 1H NMR (DMSO-d6) δ 1.11-1.34 (m, 3H),
1.29 (s, 9H), 1.60-1.94 (m, 7H), 2.52-2.63 (m, 1H), 3.87 (s,
3H), 4.76 (s, 2H), 7.36 (d, J ) 8.4 Hz, 2H), 7.61 (d, J ) 8.4 Hz,
2H), 7.69 (dd, J ) 8.4 Hz, J ) 1.0 Hz, 1H), 7.87 (d, J ) 8.4 Hz,
1H), 8.09 (d, J ) 1.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ
26.4, 27.4, 28.4, 33.6, 37.0, 47.0, 52.7, 82.5, 112.8, 120.3, 120.7,
120.9, 123.4, 129.6, 130.5, 130.6, 133.1, 134.7, 137.3, 139.6,
168.0, 168.8; MS (ES+) m/z 482 (M + H)+.
Step 3. A solution of the material from above (3.80 g, 7.8
mmol) in CH2Cl2 (20 mL) was cooled to 0 °C and treated with
TFA (20 mL). The resulting solution was allowed to warm to
room temperature and was then stirred for 6 h. The volatiles
were removed under reduced pressure, and the residue was
taken up in toluene. The mixture was concentrated in vacuo
to afford [2-(4-chlorophenyl)-3-cyclohexyl-6-(methoxycarbonyl)-
1H-indol-1-yl]acetic acid (3.30 g, 99%) as a pale-yellow solid.
1H NMR (DMSO-d6) δ 1.11-1.37 (m, 3H), 1.58-1.94 (m, 7H),
2.52-2.63 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 7.36 (d, J ) 8.2
Hz, 2H), 7.62 (d, J ) 8.2 Hz, 2H), 7.69 (d, J ) 8.6 Hz, 1H),
7.87 (d, J ) 8.6 Hz, 1H), 8.05 (s, 1H), 12.99 (br s,1H); 13C NMR
(75 MHz, DMSO-d6) δ 26.4, 27.4, 33.7, 37.0, 46.2, 52.7, 112.9,
120.1, 120.6, 120.9, 123.4, 129.7, 130.5, 130.6, 133.0, 134.7,
137.2, 139.7, 168.0, 171.1; MS (ES+) m/z 426 (M + H)+.
1
late (0.39 g, 81%). H NMR (DMSO-d6) δ 1.34-1.52 (m, 3H),
1.66-1.88 (m, 5H), 1.88-2.06 (m, 2H), 2.86-3.01 (m, 1H), 3.87
(s, 3H), 6.87 (d, J ) 1.1 Hz, 1H), 7.59 (dd, J ) 8.5 Hz, 1.4 Hz,
1H), 7.82 (d, J ) 8.5 Hz, 1H), 7.86-7.90 (m, 1H), 7.98 (d, J )
1.1 Hz, 1H), 8.06 (s, 1H), 11.40 (s, 1H).
Step 2. A solution of the compound from above (0.39 g, 1.21
mmol) in DMF (20 mL) was cooled to 0 °C and treated with
NaH (60% suspension in mineral oil, 41 mg, 1.69 mmol). The
t
mixture was stirred for 0.5 h and then treated with BuO2-
CCH2Br (0.28 g, 1.45 mmol) and then warmed to 20 °C. The
solution was stirred for 1 h, then diluted with EtOAc and
aqueous HCl (1 N). The organic layer was separated, washed
with brine, and dried. Removal of the solvent afforded a
residue that was diluted with CH2Cl2 (4 mL) and then cooled
to 0 °C. TFA (4 mL) was added, and the mixture was stirred
for 4 h at 20 °C. The volatiles were removed and the residue
was triturated with Et2O to afford [3-cyclohexyl-2-(3-furyl)-6-
1
(methoxycarbonyl)-1H-indol-1-yl]acetic acid (0.34 g, 76%). H
NMR (DMSO-d6) δ 1.20-1.43 (m, 3H), 1.62-2.01 (m, 7H),
2.62-2.78 (m, 1H), 3.88 (s, 3H), 4.89 (s, 2H), 6.58 (d, J ) 1. 1
Hz, 1H), 7.68 (dd, J ) 8.5 Hz, 1.3 Hz, 1H), 7.80-7.94 (m, 3H),
8.06 (d, J ) 1.1 Hz, 1H), 12.93 (br s, 1H).
Step 3. Following the general amide coupling procedure
described for 53, treatment of the compound from above (40
mg, 0.10 mmol) with 4-azetidin-1-ylpiperidine bis(trifluoroac-
etate) gave a residue that was hydrolyzed as described for 41.
Purification by RP-HPLC (method 4) afforded the title com-
1
pound (30 mg, 48%) as a white solid. H NMR (DMSO-d6) δ
1.00-1.45 (m, 5H), 1.60-2.09 (m, 9H), 2.17-2.34 (m, 1H),
2.37-2.57 (m, 2H), 2.58-2.79 (m, 2H), 2.98-3.14 (m, 1H),
3.95-4.25 (m, 5H), 4.27-4.45 (m, 1H), 5.07 (s, 2H), 6.52 (s,
1H), 7.65 (d, J ) 8.4 Hz, 1H), 7.79 (s, 1H), 7.82 (d, J ) 8.4 Hz,
1H), 7.87 (s, 1H), 7.96 (s, 1H), 9.91 (br s, 1H), 12.31-12.88
(m, 1H); MS (ES+) m/z 490 (M + H)+; RP-HPLC method 1, tR
) 6.7 min (96%); method 2, tR ) 5.5 (95%); HRMS calculated
for C29H36N3O4 (M + H)+ 490.2700, found 490.2687.
N-[(4-{[6-Carboxy-3-cyclohexyl-2-(4-methoxyphenyl)-
1H-indol-1-yl]acetyl}morpholin-2-yl)methyl]-N-ethyl-
ethanaminium Trifluoroacetate (57). Following the gen-
eral amide coupling procedure described for 53, treatment of
[3-cyclohexyl-6-(methoxycarbonyl)-2-(4-methoxyphenyl)-1H-in-
dol-1-yl]acetic acid (70 mg, 0.17 mmol) with N-ethyl-N-(mor-
pholin-2-ylmethyl)ethanamine gave a residue that was hydro-
lyzed as described for 41. Purification by RP-HPLC (method
5) afforded the title compound (27 mg, 29%) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 1.10-1.35 (m, 9H), 1.60-
1.78 (m, 5H), 1.80-1.92 (m, 2H), 2.53-2.63 (m, 1H), 2.72-
2.95 (m, 1H), 3.10-3.21 (m, 6H), 3.22-3.35 (m, 1H), 3.38-
3.52 (m, 1H), 3.60-3.95 (m, 6H), 4.09-4.27 (m, 1H), 4.78-
5.05 (m, 2H), 7.02-7.14 (m, 2H), 7.24 (d, J ) 8.3 Hz, 2H), 7.67
(d, J ) 8.3 Hz, 1H), 7.81 (d, J ) 8.3 Hz, 1H), 7.97 (s, 1H), 9.20
(br s, 1H); MS (ES+) m/z 562 (M + H)+; RP-HPLC method 1,
tR ) 7.1 min (>99%); method 2, tR ) 6.1 (>99%); HRMS
calculated for C33H44N3O5 (M + H)+ 562.3275, found 562.3290.
Step 4. Following the general amide coupling procedure
described for 53, treatment of the material from above (50 mg,
0.12 mmol) with N,N-diethylpiperidin-4-amine afforded a
residue that was hydrolyzed as described for 41. Purification
by RP-HPLC (method 1) gave the title compound (54 mg, 70%)
1-tert-Butyl 6-Methyl-3-cyclohexyl-2-(tributylstannyl)-
1H-indole-1,6-dicarboxylate (61). Step 1. To a solution of
60 (0.50 g, 1.49 mmol) in CH2Cl2 (15 mL) were added
4-dimethylaminopyridine (0.19 g, 1.56 mmol) and di-tert-butyl
dicarbonate (0.34 g, 1.56 mmol). The mixture was stirred at
room temperature for 1.5 h and then diluted with CH2Cl2 and
washed with aqueous HCl (1 N) and brine. The organic phase
was dried and concentrated to give 1-tert-butyl 6-methyl-2-
bromo-3-cyclohexyl-1H-indole-1,6-dicarboxylate (0.60 g, 93%)
1
as a white solid. H NMR (400 MHz, DMSO-d6) δ 1.12-1.47
(m, 5H), 1.28 (t, J ) 7.2 Hz, 6H), 1.57-1.79 (m, 5H), 1.79-
1.93 (m, 2H), 1.95-2.06 (m, 2H), 2.51-2.59 (m, 1H), 2.59-
2.71 (m, 1H), 2.98-3.20 (m, 5H), 3.50-3.63 (m, 1H), 3.91-
4.02 (m, 1H), 4.32-4.44 (m, 1H), 4.85-5.06 (m, 2H), 7.34 (d,
J ) 8.5 Hz, 2H), 7.63 (d, J ) 8.5 Hz, 2H), 7.66 (dd, J ) 8.3 Hz,
J ) 1.3 Hz, 1H), 7.83 (d, J ) 8.3 Hz, 1H), 7.97 (d, J ) 1.3 Hz,
1H), 9.68 (br s, 1H), 12.56 (br s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 9.8, 25.5, 26.5, 32.8, 36.1, 39.9, 42.7, 43.9, 44.9,
1
as a solid. H NMR (DMSO-d6) δ 1.33-1.50 (m, 3H), 1.67 (s,