6064 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Tian et al.
2-{4-[2-Amino-3-(4-fluoro-phenyl)-propionyl]-3-methyl-2-oxo-
NMR (300 MHz, CDCl3, δ): 8.85-8.90 (m, 1H), 8.15-8.35 (m,
1H), 7.13-7.79 (m, 10H), 6.83-6.94 (m, 2H), 5.44-5.58 (m, 1H),
5.01-5.19 (m, 1H), 4.61-4.66 (m, 2H), 3.62-4.22 (m, 1H),
2.70-3.46 (m, 11H), 0.85-1.03 (m, 2H), 0.27-0.49 (m, 4H). MS
(ESI) m/z: 630 [M + 1]. Anal. Calcd for (C34H36FN5O4S·0.05-
CF3CO2H): C, H, N.
N-((R)-3-(4-Fluorophenyl)-1-((S)-4-((S)-1-(methylamino)-3-(naph-
thalen-2-yl)-1-oxopropan-2-yl)-3-oxo-2-propylpiperazin-1-yl)-1-
oxopropan-2-yl)isonicotinamide (32). Compound 32 was synthe-
sized from 23 and isonicotinic acid, as described for 27, and was
purified by the use of reversed-phase HPLC. 1H NMR (300 MHz,
CD3OD, δ): 8.64-8.91 (m, 1H), 7.65-7.90 (m, 2H), 7.36-7.79
(m, 8H), 7.15-7.27 (m, 2H), 6.93-7.01 (m, 2H), 5.85 (dd, J )
11.3, 4.9 Hz, 1H), 5.04-5.26 (m, 1H), 4.64 (t, J ) 6.2 Hz, 1H),
3.78-4.22 (m, 1H), 2.69-3.51 (m, 11H), 0.91-1.02 (m, 2H),
0.21-0.45 (m, 4H). MS (ESI) m/z: 624 [M + 1]. Anal. Calcd for
(C36H38FN5O4 ·0.1 CF3CO2H): C, H, N.
N-((R)-3-(4-Fluorophenyl)-1-((S)-4-((S)-1-(methylamino)-3-(naph-
thalen-2-yl)-1-oxopropan-2-yl)-3-oxo-2-propylpiperazin-1-yl)-1-
oxopropan-2-yl)nicotinamide (33). was synthesized from 23 and
nicotinic acid as described for 27 and purified by the use of
reversed-phase HPLC. 1H NMR (300 MHz, CD3OD, δ): 8.64-8.96
(m, 1H), 7.70-7.90 (m, 2H), 7.40-7.79 (m, 8H), 7.15-7.27 (m,
2H), 6.93-7.01 (m, 2H), 5.85 (dd, J ) 11.3, 4.9 Hz, 1H), 5.04-5.26
(m, 1H), 4.64 (t, J ) 6.2 Hz, 1H), 3.80-4.22 (m, 1H), 2.72-3.51
(m, 11H), 0.91-1.02 (m, 2H), 0.21-0.45 (m, 4H). MS (ESI) m/z:
624 [M + 1]. Anal. Calcd for (C36H38FN5O4 ·0.1CF3CO2H): C, H,
N.
N-((R)-3-(4-Fluorophenyl)-1-((S)-4-((S)-1-(methylamino)-3-(naph-
thalen-2-yl)-1-oxopropan-2-yl)-3-oxo-2-propylpiperazin-1-yl)-1-
oxopropan-2-yl)picolinamide (34). Compound 34 was synthesized
from 23 and picolinic acid, as described for 27, and was purified
by the use of reversed-phase HPLC. 1H NMR (300 MHz, CD3OD,
δ): 8.61-8.63 (m, 1H), 7.92-8.06 (m, 2H), 7.36-7.79 (m, 8H),
7.15-7.27 (m, 2H), 6.92-6.97 (m, 2H), 5.85 (dd, J ) 11.3, 4.9
Hz, 1H), 5.04-5.26 (m, 1H), 4.64 (t, J ) 6.2 Hz, 1H), 3.78-4.22
(m, 1H), 2.69-3.51 (m, 11H), 0.91-1.02 (m, 2H), 0.21-0.45 (m,
4H). MS (ESI) m/z: 624 [M + 1]. Anal. Calcd for (C36H38FN5-
O4 ·0.15CF3CO2H): C, H, N.
(S)-2-((S)-4-((R)-2-Acetamido-3-amino propan-(4-fluorophenyl)-
propanoyl)-2-oxo-3-propylpiperazin-1-yl)-N-methyl-3-(naphthalen-
2-yl)propanamide (35). To a solution of 23 (300 mg, 0.47 mmol)
in DMF (3.0 mL) were added N-methylmorpholine (258 µL, 2.35
mmol), 2-(tert-butoxycarbonyl)-2-methylpropanoic acid (165 mg,
0.57 mmol), 1-hydroxybenzotriazole hydrate (141 mg, 1.03 mmol),
and EDCI (117 mg, 0.61 mmol), and the reaction mixture was
stirred for 3 h. The reaction was quenched with saturated ammonium
chloride solution (7 mL) and was extracted with ethyl acetate (3 ×
10 mL). The extracts were combined, were washed with brine, were
dried over Na2SO4, and were concentrated. The residue was purified
by flash column chromatography (silica gel, 8:2 hexane/ethyl
acetate, followed by 1:1 hexane/ethyl acetate and then 100% ethyl
acetate) to afford tert-butyl (R)-3-(4-fluorophenyl)-1-((S)-4-((S)-1-
(methylamino)-3-(naphthalen-2-yl)-1-oxopropan-2-yl)-3-oxo-2-pro-
pylpiperazin-1-yl)-1-oxopropan-2-ylcarbamate (250 mg, 75% yield).
1H NMR (300 MHz, CDCl3, δ): 7.70-7.81 (m, 4H), 7.39-7.48
(m, 3H), 7.25 (m, 2H), 6.98 (m, 2H), 5.56-5.67 (m, 1H), 4.57-5.06
(m, 2H), 3.96-4.23 (m, 1H), 3.63-3.82 (m, 1H), 3.16-3.44 (m,
4H), 2.76-3.00 (m, 6 H), 1.54 (s, 3H), 1.5 (s, 9H), 1.47 (s, 3H),
0.92-1.35 (m, 2H), 0.27-0.41 (m, 5H). MS (ESI) m/z: 704 [M +
1].
The Boc intermediate (302 mg, 0.43 mmol) that was obtained
above was dissolved in 1:1 TFA/dichloromethane (2.0 mL). The
reaction mixture was stirred for 20 min, was diluted with 1,2-
dichloroethane, and was concentrated under reduced pressure. The
residue was purified by the use of reversed-phase HPLC to afford
35 (238 mg) as a TFA salt. 1H NMR (300 MHz, CDCl3, δ):
7.70-7.81 (m, 4H), 7.39-7.48 (m, 3H), 7.25 (bs, 2H), 6.98 (m,
2H), 5.56-5.67 (m, 1H), 4.57-5.06 (m, 2H), 3.96-4.23 (m, 1H),
3.63-3.82 (m, 1H), 3.16-3.44 (m, 4H), 2.76-3.00 (m, 6H), 1.54
(s, 3H), 1.47 (s, 3H), 0.92-1.35 (m, 2H), 0.27-0.41 (m, 5H). MS
piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (25). Com-
1
pound 25 was synthesized from alanine, as described for 23. H
NMR (300 MHz, CD3OD, δ): 7.75-7.85 (m, 3H), 7.64 (m, 1H),
7.30-7.52 (m, 3H), 7.18 (m, 2H), 6.98 (m, 2H), 5.43-5.59 (m,
1H), 4.25-4.65 (m, 1H), 2.40-3.50 (m, 12H), 0.55-0.76 (m, 3H).
MS (ESI) m/z: 491 [M + H]. Anal. Calcd for (C28H31FN4-
O3 ·1.2CF3CO2H): C, H, N.
2-{4-[2-Amino-3-(4-fluoro-phenyl)-propionyl]-3-isopropyl-2-oxo-
piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (26). Com-
pound 26 was synthesized from valine, as described for 23. 1H
NMR (300 MHz, CD3OD, δ): 7.69-7.81 (m, 4H), 7.33-7.51 (m,
5H), 6.97-7.21 (m, 2H), 5.50-5.66 (m, 1H), 4.64 (t, J ) 7.3 Hz,
1H), 4.50 (d, J ) 6.9 Hz, 1H), 4.10-4.19 (m, 1H), 3.56-3.83 (m,
2H), 3.00-3.52 (m, 6H), 2.77-2.84 (m, 3H), 1.29-1.47 (m, 1H),
0.43-0.59 (m, 3H), 0.12-0.16 (m, 3H). MS (ESI) m/z: 519 [M +
1]. Anal. Calcd for (C30H35FN4O3 ·1.7CF3CO2H): C, H, N.
2-{4-[2-Acetylamino-3-(4-fluoro-phenyl)-propionyl]-2-oxo-3-pro-
pyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide (27).
To a solution of 23 (386 mg, 0.75 mmol) in DMF (6.0 mL) were
added N-methylmorpholine (490 µL), EDCI (181 mg, 0.95 mmol),
acetic acid (58 mg, 0.97 mmol), and 1-hydroxybenzotriazole hydrate
(224 mg, 1.65 mmol), and the reaction mixture was stirred at 0 °C
for 3 h. The reaction was then quenched with saturated ammonium
chloride solution (10 mL) and was extracted with ethyl acetate (3
× 10 mL). The extracts were combined and washed with brine,
were dried over Na2SO4, and were concentrated. Purification of
the residue by flash chromatography (silica gel, eluting with 8:2
hexane/ethyl acetate, followed by 1:1 hexane/ethyl acetate and then
1
100% ethyl acetate) afforded 27 (210 mg, 50% yield). H NMR
(300 MHz, CD3OD, δ): 7.63-7.90 (m, 4H), 7.35-7.48 (m, 3H),
7.20 (m, 2H), 6.94 (m, 2H), 5.58 (m, 1H), 4.56 (m, 1H), 2.70-4.00
(m, 12H), 1.88 (m, 3H), 0.85 (m, 2H), 0.15-0.35 (m, 5H). MS
(ESI) m/z: 561 [M + 1]. Anal. Calcd for (C32H37FN4O4): C, H, N.
N-((1R)-1-[(4-Fluorophenyl)methyl]-2-{(2S)-4-[(1S)-2-(methyl-
amino)-1-(2-naphthalenylmethyl)-2-oxoethyl]-3-oxo-2-propyl-1-pip-
erazinyl}-2-oxoethyl)-2,2-dimethylpropanamide (28). Compound 28
was synthesized from 23 and 2,2-dimethylpropanoic acid, as
described for 27, and was purified by the use of reversed-phase
HPLC. 1H NMR (300 MHz, CD3OD, δ): 7.60-7.85 (m, 4H),
7.35-7.50 (m, 3H), 7.20 (m, 2H), 6.95 (m, 2H), 5.50-5.65 (m,
1H), 4.80-5.05 (m, 1H), 3.90 (m, 1H), 2.65-3.60 (m, 12H),
1.00-1.15 (m, 9H), 0.87 (m, 2H), 0.20-0.40 (m, 5H). MS (ESI)
m/z: 572 [M + 1]. Anal. Calcd for (C35H43FN4O4 ·0.7CF3CO2H):
C, H, N.
(2S)-2-((3S)-4-{4-Fluoro-N-[(methyloxy)acetyl]-D-phenylalanyl}-
2-oxo-3-propyl-1-piperazinyl)-N-methyl-3-(2-naphthalenyl)pro-
panamide (29). Compound 29 was synthesized from 23 and
(methyloxy) acetic acid, as described for 27, and was purified by
1
the use of reversed-phase HPLC. H NMR (300 MHz, CD3OD,
δ): 7.60-7.90 (m, 4H), 7.35-7.55 (m, 3H), 7.10-7.25 (m, 2H),
6.95 (m, 2H), 5.50-5.65 (m, 1H), 5.05 (m, 1H), 4.57 (m, 1H),
2.85-4.15 (m, 17H), 0.80-1.00 (m, 2H), 0.20-0.40 (m, 5H). MS
(ESI) m/z: 591 [M + 1]. Anal. Calcd for (C33H39FN4O5 · 0.3C-
F3CO2H): C, H, N.
N-((R)-3-(4-Fluorophenyl)-1-((S)-4-((S)-1-(methylamino)-3-(naph-
thalen-2-yl)-1-oxopropan-2-yl)-3-oxo-2-propylpiperazin-1-yl)-1-
oxopropan-2-yl)-5-oxopyrrolidine-2-carboxamide (30). Compound
30 was synthesized from 23 and pyroglutamic acid, as described
1
for 27, and was purified by the use of reversed-phase HPLC. H
NMR (300 MHz, CDCl3, δ): 7.42-7.81 (m, 6H), 7.30-7.32 (m,
2H), 7.10-7.12 (m, 2H), 6.90-6.94 (m, 2H), 5.42-5.67 (m, 1H),
4.58-5.05 (m, 3H), 4.09-4.12 (m, 1H), 3.08-3.82 (m, 4H),
2.71-2.95 (m, 4H), 2.04-2.44 (m, 3H), 0.30-1.05 (m, 9H). MS
(ESI) m/z: 630 [M + 1]. Anal. Calcd for (C35H40FN5O5 · 0.5C-
F3CO2H): C, H, N.
N-((R)-3-(4-Fluorophenyl)-1-((S)-4-((S)-1-(methylamino)-3-(naph-
thalen-2-yl)-1-oxopropan-2-yl)-3-oxo-2-propylpiperazin-1-yl)-1-
oxopropan-2-yl)thiazole-4-carboxamide (31). Compound 31 was
synthesized from 23 and 2-carboxylic acid thiazole, as described
1
for 27, and was purified by the use of reversed-phase HPLC. H