Journal of Medicinal Chemistry
Article
HPLC [0−100% Solvent B, 20 min]: Rt = 13.2 min. HRMS:
calculated 556.3135 [C29H41N5O6 + H]+, found 556.3229 [M + H]+.
1H NMR (599 MHz, CDCl3) δ 7.30 (sbr, 1H), 7.06 (d, J = 8.4 Hz,
(S)-N-(1-Carbamoylcyclopentyl)-1-((S)-2-cyclohexyl-2-(3,4,5-
trimethoxyphenyl)acetyl)piperidine-2-carboxamide (29). The gen-
eral procedure was used with Fmoc-1-amino-cyclopentane carboxylic
acid, and 29 was obtained as colorless oil (32 mg, 60 μmol, 75.0%).
HPLC [0−100% Solvent B, 20 min]: Rt = 18.1 min. HRMS:
calculated 530.3230 [C29H43N3O6 + H]+, found 530.3266 [M + H]+.
1H NMR (300 MHz, CDCl3) δ 6.52 (s, 2H), 5.94 (s, 1H), 5.19 (sbr,
1H), 5.10−5.03 (m, 1H), 4.06 (dd, J = 13.2, 4.2 Hz, 1H), 3.88−3.73
(m, 9H), 3.39 (d, J = 10.2 Hz, 1H), 2.95−2.82 (m, 1H), 2.26 (d, J =
13.4 Hz, 1H), 2.17−1.98 (m, 3H), 1.88−1.75 (m, 2H), 1.74−1.44 (m,
10H), 1.41−1.24 (m, 4H), 1.23−1.06 (m, 3H), 0.96−0.84 (m, 1H),
0.83−0.68 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 175.86, 173.91,
171.21, 153.49, 137.33, 133.37, 105.24, 66.96, 60.73, 56.28, 55.10,
52.98, 43.82, 41.28, 37.23, 36.25, 32.54, 30.40, 26.42, 26.01, 25.96,
25.44, 24.88, 23.87, 23.67, 20.23.
(S)-N-(1-Carbamoylcyclohexyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trime-
thoxyphenyl) acetyl)piperidine-2-carboxamide (30). The general
procedure was used with Fmoc-1-amino-cyclohexane carboxylic acid,
and 30 was obtained after purification by flash chromatography (0−
100% [EtOAc + 2% MeOH + 0.1% TEA] in cyclohexane) as colorless
oil (21 mg, 38 μmol, 47.8%).
HPLC [0−100% Solvent B, 20 min]: Rt = 18.9 min. HRMS:
calculated 544.3387 [C30H45N3O6 + H]+, found 544.3438 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 6.55 (s, 3H), 5.95 (s, 1H), 5.28 (sbr,
1H), 5.20−5.12 (m, 1H), 4.19−4.14 (m, 1H), 3.88−3.77 (m, 9H),
3.63 (ddt, J = 24.9, 12.1, 4.0 Hz, 2H), 3.45 (d, J = 10.3 Hz, 1H), 3.24
(td, J = 11.6, 2.6 Hz, 1H), 3.14−2.95 (m, 2H), 2.37−2.25 (m, 1H),
2.22−2.12 (m, 1H), 2.10−2.06 (m, 1H), 2.05−1.96 (m, 2H), 1.86−
1.73 (m, 4H), 1.73−1.63 (m, 4H), 1.62−1.55 (m, 2H), 1.55−1.41 (m,
2H), 1.39−1.29 (m, 2H), 1.17 (qd, J = 12.3, 2.9 Hz, 2H), 0.93 (qd, J =
12.3, 3.4 Hz, 1H), 0.77 (qd, J = 12.0, 3.5 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 175.06, 174.24, 171.35, 153.51, 137.37, 133.30,
105.29, 62.96, 62.70, 60.74, 57.22, 56.33, 54.99, 53.23, 44.04, 41.30,
32.79, 32.51, 31.83, 30.43, 26.43, 26.01, 25.98, 25.45, 24.89, 20.27.
(S)-N-(1-Carbamoylcyclohexyl)-1-((S)-2-cyclohexyl-2-(3,4,5-trime-
thoxyphenyl) acetyl)piperidine-2-carboxamide (31). The general
procedure was used with Fmoc-4-amino-tetrahydropyran-4-carboxylic
acid, and 31 was obtained after purification by flash chromatography
(0−100% [EtOAc + 2% MeOH + 0.1% TEA] in cyclohexane) as
colorless oil (19 mg, 35 μmol, 43.5%).
1H), 6.57 (s, 2H), 6.33 (s, 1H), 6.18 (sbr, 1H), 5.10−5.04 (m, 1H),
4.71−4.64 (m, 1H), 4.02−3.93 (m, 1H), 3.79 (d, J = 57.4 Hz, 9H),
3.41 (d, J = 10.0 Hz, 1H), 2.98 (dd, J = 15.1, 4.9 Hz, 1H), 2.75−2.66
(m, 1H), 2.54−2.46 (m, 1H), 2.17−2.08 (m, 1H), 2.03 (d, J = 12.8
Hz, 1H), 1.82 (d, J = 12.1 Hz, 1H), 1.74−1.59 (m, 4H), 1.59−1.52
(m, 2H), 1.48−1.41 (m, 2H), 1.34−1.25 (m, 3H), 1.15 (q, J = 12.7
Hz, 2H), 0.95−0.86 (m, 1H), 0.82−0.73 (m, 1H). 13C NMR (151
MHz, CDCl3) δ 173.85, 172.04, 171.54, 153.30, 136.71, 133.81,
133.30, 129.38, 116.83, 105.45, 60.78, 56.21, 55.11, 52.62, 51.50,
43.74, 41.19, 40.92, 32.50, 30.46, 28.08, 26.41, 26.03, 25.98, 25.12,
25.05, 19.94.
(S)-N-((R)-1-Amino-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-1-
((S)-2-cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-car-
boxamide (26b). The general procedure was used with Fmoc-D-
His(Trt)-OH. The trityl protection group was cleaved with 1% TFA
and 1% TIS in DCM at RT for 5 h. The crude product was loaded on
silica and purified by flash chromatography (50% [EtOAc + 2%
MeOH + 0.1% TEA] − 100% [EtOAc + 10% MeOH + 0.1% TEA] in
cyclohexane) to obtain 26b as colorless oil (13 mg, 23 μmol, 28.8%).
HPLC [0−100% Solvent B, 20 min]: Rt = 13.7 min. HRMS:
calculated 556.3135 [C29H41N5O6 + H]+, found 556.3217 [M + H]+.
1H NMR (599 MHz, CDCl3) δ 7.61 (s, 1H), 7.10−7.01 (m, 2H),
6.77−6.70 (m, 1H), 6.47 (s, 2H), 5.61 (s, 1H), 5.02−4.95 (m, 1H),
4.59−4.52 (m, 1H), 3.99−3.92 (m, 0H), 3.84−3.72 (m, 9H), 3.66−
3.60 (m, 1H), 3.43 (d, J = 10.0 Hz, 1H), 3.23−3.12 (m, 1H), 2.94−
2.81 (m, 2H), 2.18−2.03 (m, 2H), 1.80 (d, J = 12.4 Hz, 1H), 1.70−
1.58 (m, 5H), 1.48 (tdd, J = 13.0, 8.2, 4.6 Hz, 2H), 1.34−1.28 (m,
3H), 1.17−1.07 (m, 2H), 0.98−0.86 (m, 1H), 0.79−0.70 (m, 1H). 13C
NMR (151 MHz, CDCl3) δ 174.15, 173.14, 171.19, 153.17, 136.88,
134.53, 133.44, 105.60, 60.80, 56.28, 56.20, 55.14, 53.82, 52.48, 44.01,
41.07, 40.96, 32.67, 30.57, 28.73, 26.44, 26.10, 25.84, 25.19, 20.11.
(S)-N-(1-Carbamoylcyclopropyl)-1-((S)-2-cyclohexyl-2-(3,4,5-
trimethoxyphenyl)acetyl)piperidine-2-carboxamide (27). The gen-
eral procedure was used with Fmoc-1-amino-cyclopropane carboxylic
acid, and 27 was obtained after purification by flash chromatography
(0−100% [EtOAc + 2% MeOH + 0.1% TEA] in cyclohexane) as
colorless oil (18 mg, 36 μmol, 45.0%). HPLC [0−100% Solvent B, 20
min]: Rt = 16.8 min. HRMS: calculated 502.2917 [C27H39N3O6 + H]+,
HPLC [0−100% Solvent B, 20 min]: Rt = 18.9 min. HRMS:
calculated 546.3179 [C29H44N3O7 + H]+, found 546.3201 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 6.55 (s, 3H), 5.95 (s, 1H), 5.28 (s,
1
found 502.2950 [M + H]+. H NMR (400 MHz, CDCl3) δ 6.39 (s,
2H), 6.21 (s, 1H), 5.33 (s, 1H), 4.94−4.83 (m, 1H), 3.89 (d, J = 13.8
Hz, 1H), 3.75 (d, J = 5.1 Hz, 9H), 3.30 (d, J = 10.1 Hz, 1H), 2.70
(ddd, J = 14.5, 11.6, 3.2 Hz, 1H), 2.21−2.10 (m, 1H), 2.04 (qt, J =
11.0, 3.3 Hz, 1H), 1.67−1.40 (m, 9H), 1.36−1.16 (m, 5H), 1.14−0.99
(m, 2H), 0.83 (qd, J = 12.3, 3.3 Hz, 1H), 0.76−0.62 (m, 2H), 0.42
(ddd, J = 10.3, 7.6, 4.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ
174.08, 173.91, 172.17, 153.63, 137.31, 132.96, 105.12, 60.85, 56.26,
55.62, 53.44, 43.83, 40.95, 34.33, 32.77, 30.42, 26.46, 26.08, 26.03,
25.05, 24.79, 19.98, 17.37, 16.87.
(S)-N-(1-Carbamoylcyclobutyl)-1-((S)-2-cyclohexyl-2-(3,4,5-
trimethoxyphenyl)acetyl)piperidine-2-carboxamide (28). The gen-
eral procedure was used with Fmoc-1-amino-cyclobutane carboxylic
acid, and 28 was obtained after purification by flash chromatography
(0−100% [EtOAc + 2% MeOH + 0.1% TEA] in cyclohexane) as
colorless oil (17 mg, 33 μmol, 41.3%).
1H), 5.20−5.12 (m, 1H), 4.19−4.14 (m, 1H), 3.88−3.77 (m, 9H),
3.63 (ddt, J = 24.9, 12.1, 4.0 Hz, 2H), 3.45 (d, J = 10.3 Hz, 1H), 3.24
(td, J = 11.6, 2.6 Hz, 1H), 3.14−2.95 (m, 2H), 2.37−2.25 (m, 1H),
2.22−2.12 (m, 1H), 2.10−2.06 (m, 1H), 2.05−1.96 (m, 2H), 1.86−
1.73 (m, 4H), 1.73−1.63 (m, 4H), 1.62−1.55 (m, 2H), 1.55−1.41 (m,
2H), 1.39−1.29 (m, 2H), 1.17 (qd, J = 12.3, 2.9 Hz, 2H), 0.93 (qd, J =
12.3, 3.4 Hz, 1H), 0.77 (qd, J = 12.0, 3.5 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 175.06, 174.24, 171.35, 153.51, 137.37, 133.30,
105.29, 62.96, 62.70, 60.74, 60.40, 57.22, 56.33, 54.99, 53.23, 44.04,
41.30, 32.79, 32.51, 31.83, 30.43, 26.43, 26.01, 25.98, 25.45, 24.89,
20.27, 14.20.
(S)-N-(1-((2-Amino-2-oxoethyl)carbamoyl)cyclopentyl)-1-((S)-2-
cyclohexyl-2-(3,4,5-trimethoxyphenyl)acetyl)piperidine-2-carboxa-
mide (32). The general procedure was used with Fmoc-Gly-OH and
Fmoc-1-amino-cyclopentane carboxylic acid (first coupling step
repeated). Compound 32 was obtained after purification by flash
chromatography (0−100% [EtOAc + 2% MeOH + 0.1% TEA] in
cyclohexane) as colorless oil (14 mg, 24 μmol, 30.2%).
HPLC [0−100% Solvent B, 20 min]: Rt = 18.9 min. HRMS:
calculated 516.3074 [C28H41N3O6 + H]+, found 516.3069 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 6.44 (s, 2H), 6.11 (s,
1H), 5.13−5.03 (m, 2H), 4.02−3.96 (m, 1H), 3.76−3.67 (m, 9H),
3.33 (d, J = 10.2 Hz, 1H), 2.80 (ddd, J = 13.9, 12.3, 2.8 Hz, 1H), 2.54−
2.42 (m, 2H), 2.21 (dd, J = 13.5, 3.5 Hz, 1H), 2.13−2.03 (m, 1H),
1.83−1.70 (m, 2H), 1.69−1.52 (m, 8H), 1.52−1.39 (m, 3H), 1.31−
1.21 (m, 2H), 1.13−1.00 (m, 2H), 0.88−0.75 (m, 1H), 0.68 (qd, J =
12.0, 3.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 175.20, 173.73,
171.13, 153.55, 137.28, 133.33, 105.14, 60.76, 59.06, 56.28, 55.27,
52.59, 43.87, 41.10, 32.66, 31.42, 31.02, 30.42, 26.91, 26.47, 26.06,
26.00, 25.47, 24.84, 20.29, 15.53.
HPLC [0−100% Solvent B, 20 min]: Rt = 19.1 min. HRMS:
calculated 587.3445 [C31H46N4O7 + H]+, found 587.3530 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 6.81 (t, 1H), 6.47 (s,
2H), 6.11 (s, 1H), 5.34 (s, 1H), 4.97 (t, 1H), 4.00 (d, 1H), 3.86 (dd,
1H), 3.76 (s, 6H), 3.72 (s, 3H), 3.62 (dd, 1H), 3.34 (d, 1H), 2.86 (m,
1H), 2.19−2.02 (m, 3H), 1.90−1.84 (m, 3H), 1.74 (d, 2H), 1.65−1.52
(m, 8H), 1.32−1.16 (m, 5H), 1.11−1.01 (m, 2H), 0.82 (qd, 1H),
0.75−0.57 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.27, 173.39,
172.17, 172.03, 153.56, 137.39, 133.37, 105.23, 66.78, 60.77, 56.32,
K
J. Med. Chem. XXXX, XXX, XXX−XXX