Journal of Medicinal Chemistry
Article
dichloromethane (4 mL), the appropriate 2-amino-thiophene-3-
carboxamide (1.0 mmol) and pyridine (2.0 mmol) were added, and
the mixture was made to react at room temperature for 16 h. The
solvent was evaporated at reduced pressure, and the residue was
washed in sequence with diethyl ether (2 × 5 mL), 2 M sodium
hydroxide, 2 M hydrochloric acid, and water. Finally, the residue was
dried under a vacuum and chromatographed on silica gel (eluent, 9:1
dichloromethane/methanol mixture).
NMR (DMSO-d6)
δ
−67.42 (s, 3F); HRMS: calcd for
C24H20F3N5O3S 516.1312 (M + H+), found 516.1318 (M + H+).
2-({[5-Phenyl-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-
2-yl]carbonyl}amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-car-
1
boxamide (7). Yield, 75%. Yellow crystals, mp >270 °C; H NMR
(DMSO-d6) δ 13.3 (s, 1H), 8.6 (s, 1H), 8.5−8.4 (m, 2H), 7.7 (m,
4H), 7.0 (s, 1H), 2.7 (dt, J = 32 and 6.0 Hz, 4H), 2.0−1.5 (m, 4H);
13C NMR (DMSO-d6) δ 167.7, 163.1, 158.9, 156.3, 155.1, 141.7,
135.3, 135.3 (q, J = 38 Hz), 133.1, 129.9, 129.8 (2C), 128.8 (2C),
128.0, 119.5 (q, J = 250 Hz), 118.0, 109.1, 25.7, 24.4, 22.9, 22.8; 19F
NMR (DMSO-d6): δ −67.48 (s, 3F). HRMS: calcd for
C22H17F3N6O2S 487.1164 (M + H+), found 487.1161 (M + H+).
2-(3-Pyridinecarbonylamino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxamide (8). Yield, 71%. Yellow crystals, mp 233−
235 °C; 1H NMR (DMSO-d6) δ 13.06 (s, 1H), 9.05 (s, 1H), 8.81 (d, J
= 3.9 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.75 (bs, 1H), 7.63 (dd, J =
7.5 and 5.0 Hz, 1H), 7.15 (bs, 1H), 2.74 (bs, 2H), 2.66 (bs, 2H), 1.75
(bs, 4H); 13C NMR (DMSO-d6) δ 168.2, 161.5, 153.4, 148.6, 142.9,
135.4, 129.8, 128.7, 127.3, 124.6, 117.2, 25.6, 24.4, 22.9, 22.8; HRMS:
calcd for C15H15N3O2S 302.0963 (M + H+), found 302.0965 (M +
H+).
2-(3-Bromobenzamido)-N-(sec-butyl)benzamide (17a). A mixture
of 3-bromobenzoyl chloride (700 mg, 3.1 mmol), 2-amino-N-(sec-
butyl)benzamide (16a) (600 mg, 3.1 mmol), and triethylamine (0.56
mL, 4.0 mmol) in toluene (40 mL) was kept at 110 °C for 14 h. After
solvent evaporation at reduced pressure, the crude product was
crystallized from methanol to obtain a white solid (81% yield)
exhibiting the following properties: mp 133−134 °C; 1H NMR
(CDCl3) δ 12.16 (s, 1H), 8.71 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.90
(d, J = 8.3 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.59−7.45 (m, 2H), 7.38
(t, J = 7.9 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.30 (bd, J = 8.5 Hz, 1H),
4.13 (hept, J = 6.9 Hz, 1H), 1.61 (q, J = 7.2 Hz, 2H), 1.27 (d, J = 6.6
Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3) δ 168.6, 164.1,
139.4, 136.9, 134.8, 132.6, 131.1, 130.3, 126.6, 125.4, 123.2, 123.1,
121.6, 121.0, 47.3, 29.7, 20.4, 10.5; HRMS calcd for C18H1979BrN2O2
375.0703 (M + H+), found 375.0715 (M + H+).
N-(3-Carbamoyl-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-7-
(difluoromethyl)-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxa-
mide (1). Yield, 69%. Yellow crystals, mp >270 °C; 1H NMR (DMSO-
d6) δ 12.82 (s, 1H), 8.95−8.67 (m, 3H), 8.17 (s, 1H), 7.67 (t, J = 53
Hz, 1H), 7.87−7.42 (m, 3H), 7.54 (bs, 1H), 6.77 (s, 1H), 2.97 (t, J =
7.2 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.39 (p, J = 7.5 Hz, 2H); 13C
NMR (DMSO-d6) δ 167.2, 159.6, 158.2, 148.3, 148.2, 145.8, 140.4 (t,
J = 27 Hz), 139.6, 135.4, 132.8, 132.3, 129.6 (2C), 129.4 (2C), 112.3,
109.6 (t, J = 253 Hz), 105.2, 104.7 (t, J = 5.0 Hz), 29.7, 28.8, 28.2; 19F
NMR (DMSO-d6) δ −124.47 (d, J = 52 Hz, 2F); HRMS: calcd for
C22H17F2N5O2S 454.1149 (M + H+), found 454.11496 (M + H+).
N-(3-Carbamoyl-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-5-
phenyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide (2). Yield, 49%. Yellow crystals, mp >270 °C; 1H NMR (DMSO-
d6) δ 12.84 (s, 1H), 9.00−8.78 (m, 3H), 8.38 (s, 1H), 7.96−7.40 (m,
4H), 6.79 (bs, 1H), 2.97 (t, J = 7.0 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H),
2.44−2.27 (m, 2H); 13C NMR (DMSO-d6) δ 167.4, 159.4, 158.0,
148.5, 148.3, 146.4, 139.0, 135.1, 134.6 (q, J = 37 Hz), 132.8, 132.5,
129.7 (2C), 129.6 (2C), 119.8 (q, J = 273 Hz), 112.6, 106.9, 105.7,
29.6, 28.2, 28.0; 19F NMR (DMSO-d6) δ −67.50 (3F); HRMS: calcd
for C22H16F3N5O2S 472.1055 (M + H+), found 472.1051 (M + H+).
2-({[5-Phenyl-7-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-
carbonyl}amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxa-
mide (3). Yield, 59% Yellow crystals, mp >270 °C; 1H NMR (DMSO-
d6) δ 12.37 (s, 1H), 8.84−8.77 (m, 3H), 8.18 (s, 1H), 7.68 (t, J = 52
Hz, 1H), 7.74−7.58 (m, 3H), 7.54 (s, 1H), 7.04 (s, 1H), 3.02−2.70
(m, 2H), 2.70−2.61 (m, 2H), 1.94−1.64 (m, 4H); 13C NMR (DMSO-
d6) δ 167.4, 159.5, 158.1, 148.2, 145.8, 142.0, 140.5 (t, J = 27 Hz),
135.4, 132.3, 129.7 (2C), 129.4 (2C), 129.3, 126.9, 117.6, 108.9 (t, J =
257 Hz), 105.3, 104.7 (t, J = 4.9 Hz), 25.6, 24.2, 23.0, 22.9; 19F NMR
(DMSO-d6) δ −124.95 (d, J = 52 Hz, 2F); HRMS: calcd for
C23H19F2N5O2S 468.1306 (M + H+), found 468.1309 (M + H+).
2-({[5-Phenyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-
carbonyl}amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxa-
mide (4). Yield, 59%. Orange crystals, mp >270 °C; 1H NMR
(DMSO-d6) δ 12.42 (s, 1H), 8.85 (s, 3H), 8.40 (s, 1H), 7.67 (m, 4H),
7.08 (bs, 1H), 2.78 (bs, 2H), 2.68 (bs, 2H), 1.77 (s, 4H). 13C NMR
(DMSO-d6) δ 167.4, 159.4, 158.0, 148.5, 146.4, 142.0, 135.1, 134.6 (q,
J = 37 Hz), 132.5, 129.7 (2C), 129.6 (2C), 129.4, 127.0, 119.8 (q, J =
273 Hz), 117.6, 106.9, 105.7, 25.7, 24.2, 23.0, 22.9; 19F NMR (DMSO-
d6) δ −67.48 (s, 3F). HRMS: calcd for C23H18F3N5O2S 486.1206 (M
+ H+), found 486.1215 (M + H+).
2-(3-Bromo-4-methylbenzamido)-N-(sec-butyl)benzamide (17b).
The title compound was prepared from 3-bromo-4-methylbenzoyl
chloride and 2-amino-N-(sec-butyl)benzamide (16a), analogously to
1
17a, to give a white solid in 80% yield; mp 136−137 °C. H NMR
(CDCl3) δ 12.07 (s, 1H), 8.72 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 2.0 Hz,
1H), 7.81 (dd, J = 7.8 and 2.1 Hz, 1H), 7.57−7.29 (m, 3H), 7.08 (t, J
= 6.5 and 5.5 Hz, 1H), 6.15 (bd, J = 9.5 Hz, 1H), 4.13 (hept, J = 7.0
Hz, 1H), 2.46 (d, J = 4.0 Hz, 3H), 1.60 (p, J = 7.3 Hz, 2H), 1.25 (d, J
= 6.6 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (CDCl3) δ 168.6,
164.1, 142.0, 139.6, 134.2, 132.6, 132.0, 131.0, 126.4, 125.6, 125.4,
123.0, 121.6, 121.0, 47.3, 29.7, 23.1, 20.4, 10.5; HRMS calcd for
C19H2179BrN2O2 389.0859 (M + H+), found 389.0854 (M + H+).
2-(3-Bromo-4-methylbenzamido)-N-(phenyl)benzamide (17c).
The title compound was prepared according to the procedure used
for 17b, from 3-bromo-4-methylbenzoyl chloride and 2-amino-N-
(phenyl)benzamide (16b), to give a pale pink solid product in 88%
yield; mp 215 °C (dec.); 1H NMR (DMSO-d6) δ 11.55 (s, 1H), 10.53
(s, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J = 7.9, 1H),
7.79 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.61 (t, J = 7.9 Hz,
1H), 7.55 (d, J = 7.8 Hz, 1H), 7.44−7.27 (m, 3H), 7.20−7.05 (m,
1H), 2.41 (s, 3H); 13C NMR (DMSO-d6) δ 167.7, 163.6, 142.1, 139.1,
138.6, 134.5, 132.5, 131.9, 131.4, 129.5, 129.1 (2C), 126.5, 124.9,
124.6, 124.4, 124.1, 122.3, 121.4 (2C), 23.0; HRMS: calcd for
C21H1779BrN2O2 409.0546 (M + H+), found 409.0550 (M + H+).
General Procedure To Prepare Polyamido Products 10, 18−
22.47,48 Butyllithium (20.3 mL, 1.48 M in hexanes, 30 mmol) was
added dropwise at −75 °C to a solution of the appropriate bromo
derivative (17a−c) (10 mmol) in tetrahydrofuran (100 mL), and the
mixture was made to react for 10 min, under stirring, before the bath
temperature was allowed to rise to −60 °C. Sulfur dioxide was bubbled
into the mixture until its pH value reached 6−7. The cold bath was
removed, and the temperature was allowed to rise to 25 °C. Hexane
(20 mL) was added and the formed white precipitate was filtered,
washed with hexane, and dried at 50 °C. The dry solid was suspended
2-({[5-(p-Tolyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-
carbonyl}amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxa-
mide (5). Yield, 47%. Yellow crystals, mp >270 °C; 1H NMR (DMSO-
d6) δ 12.36 (s, 1H), 8.81 (s, 1H), 8.75 (d, J = 8.2 Hz, 2H), 8.36 (s,
1H), 7.59 (bs, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.07 (bs, 1H), 2.72 (bs,
2H), 2.67 (bs, 2H), 2.42 (s, 3H), 1.73 (bs, 4H); 13C NMR (DMSO-
d6) δ 167.4, 159.3, 158.0, 148.4, 146.4, 142.9, 142.0, 134.5 (q, J = 38
Hz), 132.4, 130.3 (2C), 129.6 (2C), 129.3, 126.9, 119.8 (q, J = 275
Hz), 117.6, 106.7, 105.5, 25.6, 24.2, 23.1, 23.0, 21.6; 19F NMR
(DMSO-d6) δ −67.46 (s, 3F). HRMS: calcd for C24H20F3N5O2S
500.1363 (M + H+), found 500.1371 (M + H+).
2-({[5-(4-Methoxyphenyl)-7-(trifluoromethyl)pyrazolo-[1,5-a]-
pyrimidin-3-yl]carbonyl}amino)-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxamide (6). Yield, 85%. Orange crystals, mp >270
1
°C; H NMR (DMSO-d6) δ 12.37 (s, 1H), 8.58 (d, J = 9.0 Hz, 2H),
8.79 (s, 1H), 8.32 (s, 1H), 7.62 (bs, 1H), 7.25 (d, J = 9.0 Hz, 2H), 7.07
(bs, 1H), 3.92 (s, 3H), 2.78 (bs, 2H), 2.68 (bs, 2H), 1.78 (bs, 4H). 13C
NMR (DMSO-d6) δ 167.4, 163.3, 159.0, 158.0, 148.3, 146.4, 142.1,
134.3 (q, J = 37 Hz), 131.7 (2C), 129.3, 127.6, 126.9, 119.8 (q, J = 369
Hz), 117.5, 115.1 (2C), 106.4, 105.2, 56.1, 25.6, 24.2, 23.1, 23.0; 19F
4346
dx.doi.org/10.1021/jm500300r | J. Med. Chem. 2014, 57, 4337−4350