Journal of Medicinal Chemistry
Article
tert-Butyl (3S)-3-[({3-[(Aminocarbonyl)amino]-5-bromo-2-
thienyl}carbonyl)-amino]piperidine-1-carboxylate (9). To a
solution of 8 (1.6 g, 5.7 mmol) in dry THF (30 mL) was added a
solution of Me3Al/tert-butyl (3S)-3-aminopiperidine-1-carboxylate in
THF (18 mL) (preformed by the addition of Me3Al (17.2 mL, 34.4
mmol) to a solution of tert-butyl (3S)-3-aminopiperidine-1-carboxylate
(3.7 g, 17.2 mmol) in THF at −78 °C, and the resulting yellow
solution was stirred at this temperature for 15 min), and the resulting
deep yellow solution was warmed to room temperature and stirred
overnight. The reaction mixture was cooled with ice, and a saturated
solution of sodium potassium tartrate was added to quench the
reaction. The mixture was partitioned between EtOAc and H2O (3:1
ratio). The aqueous layer was extracted with EtOAc (3×), and the
combined organic extracts were washed with H2O, brine and dried
over MgSO4. Evaporation gave a pale orange solid. Purification by
reverse phase HPLC using a gradient of 5−95% MeCN in 0.1% TFA
containing water gave the desired product as an off-white solid (1.0 g,
2 H), 1.92 (d, 2 H), 2.92 (m, 2 H), 3.17 (d, 1 H), 3.30 (d, 1 H), 4.21
(s, 1 H), 7.03 (s, 2 H) 7.25 (t, 2 H) 7.59 (t, 2 H), 7.92 (s, 1 H), 8.31
(d, 1 H), 9.07 (d, 2 H), 10.90 (s, 1 H). LC/MS (APCI, ES): (M + H)+
363.
5-(3-Chlorophenyl)-2-ureidothiophene-3-carboxylic Acid
1
(S)-Piperidin-3-ylamide (11d). H NMR (DMSO-d6): δ 10.94 (s,
1H), 9.10 (s, 1H), 8.30 (d, 1H), 8.06 (s, 1H), 7.61 (s, 1H), 7.49 (d,
1H), 7.42 (t, 1H), 7.30 (d, 1H), 7.09 (s, 2H), 4.21 (s, 1H), 3.32 (d,
1H), 3.17 (d, 1H), 2.92 (t, 2H), 1.93 (d, 2H), 1.68 (m, 2H). LC/MS
(APCI, ES): (M + H)+ 379.
5-(3,5-Difluorophenyl)-2-ureidothiophene-3-carboxylic Acid
1
(S)-Piperidin-3-ylamide (11e). H NMR (DMSO-d6): δ 10.95 (s,
1H), 9.10 (s, 1H), 8.98 (s, 1H), 8.32 (d, 1H), 8.16 (s, 1H), 7.26 (d,
2H), 7.12 (t, 2H), 4.22 (s, 1H), 3.28 (d, 1H), 3.17 (d, 1H), 2.95 (m,
2H), 1.91 (d, 2H), 1.65 (m, 2H). LC/MS (APCI, ES): (M + H)+ 381.
5-(2,3-Difluorophenyl)-2-ureidothiophene-3-carboxylic Acid
1
(S)-Piperidin-3-ylamide (11f). H NMR (DMSO-d6): δ 11.01 (s,
1
1H), 9.22 (s, 1H), 9.14 (s, 1H), 8.46 (d, 1H), 8.10 (s, 1H), 7.81 (t,
1H), 7.29 (m, 2H), 7.11 (br, 2H), 4.20 (s, 1H), 3.30 (d, 1H), 3.14 (d,
1H), 2.92 (m, 2H), 1.90 (d, 2H), 1.69 (m, 2H). LC/MS (APCI, ES):
(M + H)+ 381.
40%). H NMR (DMSO-d6): δ 10.06 (s, 1H), 8.02 (s, 1H), 7.89 (d,
1H), 6.71 (br s, 2H), 4.04 (m, 1H), 3.72 (m, 2H), 2.74 (m, 2H), 1.81
(m, 1H), 1.68 (m, 1H), 1.52 (m, 1H), 1.37 (s, 9H), 1.34 (m, 1H). LC/
MS (APCI, ES): (M + H)+ 448.
5-(2,4-Difluorophenyl)-2-ureidothiophene-3-carboxylic Acid
tert-Butyl (3S)-3-({[3-[(Aminocarbonyl)amino]-5-(3-fluoro-
phenyl)-2-thienyl]carbonyl}amino)piperidine-1-carboxylate
(10). In a round bottomed flask, 9 (1 g, 2.24 mmol), 3-
fluorobenzeneboronic acid (0.5 g, 3.36 mmol), and cesium carbonate
(2.9 g, 8.96 mmol) were dissolved in a mixture of water (3 mL) and
1,4-dioxane (20 mL). The solution was degassed under low vacuum
and nitrogen. Palladium(0) tetrakistriphenylphosphine was added
(0.26 g, 0.22 mmol) to the solution, and the colorless reaction mixture
was heated at 75 °C with stirring for 1 h. The aqueous layer was
separated. Ethyl acetate was added (20 mL), and the resulting solution
was dried over MgSO4 (anhydrous). After solvent evaporation the
residual solid was subjected to flash chromatography on silica gel (40
g) with 2−5% methanol in DCM over a 30 min gradient. The main
fraction contained traces of triphenylphosphine oxide and was
resubjected to flash chromatography under the same conditions to
afford a light yellow solid (0.92 mg, 88%). 1H NMR (CDCl3): δ 10.35
(s, 1H), 8.30 (s, 1H), 7.43−7.28 (m, 3H), 7.05 (m, 1H), 5.91 (br s,
1H), 4.79 (br s, 2H), 4.05 (m, 1H), 3.53−3.55 (m, 2H), 3.36−3.29(m,
2H), 1.89−1.49 (m, 13H). LC/MS (APCI, ES): (M + H)+ 463.
5-(2-Fluorophenyl)-2-ureidothiophene-3-carboxylic Acid
(S)-Piperidin-3-ylamide Hydrochloride (4). Intermediate 10
(0.92 g, 1.98 mmol) was dissolved in methanol (7 mL), and 4 M
HCl in dioxane (10 mL, 40 mmol) was added while cooling at 0 °C.
The solution was stirred for 3 h. The solvent was evaporated under
reduced pressure, and the residue was taken in methanol (20 mL) and
evaporated to dryness. This procedure was repeated 5 times to yield a
white powder. The solid was dissolved in water (10 mL) and filtered,
and solvent was evaporated by lyophilization over 48 h to obtain a
1
(S)-Piperidin-3-ylamide (11g). H NMR (DMSO-d6): δ 10.97 (s,
1H), 9.30 (s, 1H), 9.18 (s, 1H), 8.45 (d, 1H), 8.02 (s, 1H), 7.78 (q,
1H), 7.38 (t, 1H), 7.18 (t, 1H), 7.06 (br, 2H), 4.23 (s, 1H), 3.29 (d,
1H), 3.14 (d, 1H), 2.92 (m, 2H), 1.90 (d, 2H), 1.69 (m, 2H). LC/MS
(APCI, ES): (M + H)+ 381.
5-(3,4-Dichlorophenyl)-2-ureidothiophene-3-carboxylic
Acid (S)-Piperidin-3-ylamide (11h). 1H NMR (DMSO-d6): δ 10.96
(s, 1H), 9.30 (s, 1H), 9.19 (s, 1H), 8.43 (d, 1H), 8.18 (s, 1H), 7.79 (s,
1H), 7.63 (d, 1H), 7.51 (d, 1H), 7.10 (br, 2H), 4.24 (s, 1H), 3.29 (d,
1H), 3.13 (d, 1H), 2.94 (m, 2H), 1.92 (d, 2H), 1.70 (m, 2H). LC/MS
(APCI, ES): (M + H)+ 413.
5-(4-Cyanophenyl)-2-ureidothiophene-3-carboxylic Acid (S)-
1
Piperidin-3-ylamide (11i). H NMR (DMSO-d6): δ 10.98 (s, 1 H),
9.03 (s, 2 H), 8.37 (d, 1 H), 8.22 (s, 1 H), 7.84 (d, 2 H), 7.72 (d, 2 H),
7.14 (s, 2 H), 4.20 (s, 1 H), 3.31 (d, 1 H), 3.17 (d, 1 H), 2.93 (t, 2 H),
1.93 (d, 2 H), 1.67 (m, 2 H). LC/MS (APCI, ES): (M + H)+ 370.
5-(3-Cyanophenyl)-2-ureidothiophene-3-carboxylic Acid (S)-
Piperidin-3-ylamide (11j). 1H NMR (DMSO-d6): δ 10.94 (s, 1 H),
9.01 (s, 2 H), 8.28 (d, 1 H), 8.11 (s, 1 H), 7.98 (s, 1 H), 7.83 (d, 2 H),
7.71 (d, 1 H), 7.61 (t, 1 H), 7.12 (s, 2 H), 4.18 (s, 1 H), 3.18 (d, 2 H),
2.91 (m, 2 H), 1.93 (d, 2 H), 1.68 (m, 2 H). LC/MS (APCI, ES): (M
+ H)+ 370.
5-Phenyl-3-ureidothiophene-2-carboxylic Acid (S)-Piperi-
1
din-3-ylamide (12a). H NMR (DMSO-d6): δ 10.02 (s, 1H), 9.39
(brs, 2H), 8.25 (s, 1H), 8.18(d, 1H), 7.6 (d, 2H), 7.58−7.31 (m, 3H),
4.19 (m, 1H), 3.34−3.12 (m, 2H), 2.83 (m, 2H), 1.90−1.51 (m, 4H).
LC/MS (APCI, ES): (M + H)+ 345.
1
5-(2-Fluorophenyl)-3-ureidothiophene-2-carboxylic Acid
light yellow solid (0.67 g, 84%). H NMR (DMSO-d6): δ 10.98 (s,
1
(S)-Piperidin-3-ylamide (12b). H NMR (DMSO-d6): δ 9.95 (s, 1
1H), 9.29 (s, 1H), 9.20 (s, 1H), 8.43 (d, 1H), 8.06 (s, 1H), 7.77 (m,
2H), 7.29 (m, 3H), 7.08 (br, 2H), 4.25 (s, 1H), 3.29 (d, 1H), 3.14 (d,
1H), 2.92 (m, 2H), 1.93 (d, 2H), 1.67 (m, 2H). LC/MS (APCI, ES):
(M + H)+ 363.
H), 8.66 (s, 2 H), 7.84−8.02 (m, 1 H) 8.15 (d, 1 H), 7.70−7.86 (m, 1
H), 7.22−7.57 (m, 3 H), 7.10 (s, 1 H), 6.69 (s, 1 H), 3.79−4.58 (m, 2
H), 3.11−3.36 (m, 2 H), 2.77−3.05 (m, 1 H), 1.74−2.21 (m, 3 H),
1.47−1.75 (m, 1 H). LC/MS (APCI, ES): (M + H)+ 363.
Application of this two-step procedure described above for
synthesizing 4 from 10 enabled generation of compounds 11a−j
and 12a−j as hydrochloride salts.
5-(4-Fluorophenyl)-3-ureidothiophene-2-carboxylic Acid
1
(S)-Piperidin-3-ylamide (12c). H NMR (DMSO-d6): δ 9.94 (s, 1
H), 8.73 (s, 2 H), 8.22 (s, 1 H), 8.08 (d, J = 7.54 Hz, 1 H), 7.56−7.76
(m, 2 H), 7.19−7.44 (m, 2 H), 6.68 (s, 2 H), 4.05−4.28 (m, 1 H),
3.07−3.48 (m, 2 H), 2.67−3.00 (m, 2 H), 1.88 (s, 2 H), 1.53−1.68
(m,, 2 H). LC/MS (APCI, ES): (M + H)+ 363.
5-(2-Fluorophenyl)-2-ureidothiophene-3-carboxylic Acid
1
(S)-Piperidin-3-ylamide (11a). H NMR (DMSO-d6): δ 10.98 (s,
1H), 9.29 (s, 1H), 9.20 (s, 1H), 8.43 (d, 1H), 8.06 (s, 1H), 7.77 (m,
2H), 7.29 (m, 3H), 7.08 (br, 2H), 4.25 (s, 1H), 3.29 (d, 1H), 3.14 (d,
1H), 2.92 (m, 2H), 1.93 (d, 2H), 1.67 (m, 2H). LC/MS (APCI, ES):
(M + H)+ 363
5-(3-Chlorophenyl)-3-ureidothiophene-2-carboxylic Acid
1
(S)-Piperidin-3-ylamide (12d). H NMR (DMSO-d6): δ 9.85 (s, 1
H), 8.58 (s, 2 H), 8.30 (s, 1 H), 8.07−8.14 (m, 1 H), 8.05 (s, 1 H),
7.88 (d, 1 H), 7.81 (d, 1 H), 7.62 (t,1 H), 6.65 (s, 1 H), 3.92−4.29 (m,
1 H), 3.08−3.28 (m, 2 H), 2.70−2.87 (m, 2 H), 1.72−1.91 (m, 2 H),
1.44−1.71 (m, 2 H). LC/MS (APCI, ES): (M + H)+ 379.
5-(3,5-Difluorophenyl)-3-ureidothiophene-2-carboxylic Acid
(S)-Piperidin-3-ylamide (12e). 1H NMR (DMSO-d6): δ 9.89 (s,
1H), 9.19 (br s, 2H), 8.32 (s, 1H), 8.30 (d, 1H), 7.28 (m, 3H), 6.62
5-(3-Fluorophenyl)-2-ureidothiophene-3-carboxylic Acid
1
(S)-Piperidin-3-ylamide (11b). H NMR (DMSO-d6): δ 10.94 (s,
1 H), 8.98 (d, 2 H), 8.27 (d, 2 H), 8.03 (s, 1 H), 7.40 (m, 3 H), 7.08
(t, 2 H), 4.19 (s, 1H), 3.30 (m, 1H), 3.18 (d, 1H), 2.93 (m, 2H), 1.93
(d, 2H), 1.67 (m, 2H). LC/MS (APCI, ES): (M + H)+ 363.
5-(4-Fluorophenyl)-2-ureidothiophene-3-carboxylic Acid
1
(S)-Piperidin-3-ylamide (11c). H NMR (DMSO-d6): δ 1.68 (m,
5138
dx.doi.org/10.1021/jm300025r | J. Med. Chem. 2012, 55, 5130−5142