Journal of Medicinal Chemistry
Article
300 (m, each 2H, cycloheptane CH2), 7.05 (ddd, J = 0.9, 5.0, and 7.0
Hz, 1H, pyridine CH), 7.20 (dd, J = 8.3 and 12.0 Hz, 1H, aromatic
CH), 7.30 (dt, J = 0.9 and 7.6 Hz, 1H, aromatic CH), 7.50 (dq, J = 1.4
and 7.3 Hz, 1H, aromatic CH), 7.70 (dt, J = 1.4 and 7.0 Hz, 1H,
pyridine CH), 8.10−8.20 (m, 2H, aromatic CH and NH), 8.20 (d, J =
4.4 Hz, 1H, pyridine CH), 8.30 (d, 1H, J = 8.4 Hz, pyridine CH),
13.00 (d, J = 11.0 Hz, 1H, NH); 13C NMR (CDCl3) δ 27.3, 27.6, 28.6,
29.0, 31.7, 114.3, 116.3 (d, JC−F = 23 Hz), 118.8, 119.8, 119.9, 124.9,
132.1, 133.0, 133.2, 134.1 (d, JC−F = 9 Hz), 138.4, 141.4, 147.9, 151.2,
159.8, 160.6 (d, JC−F = 248 Hz), 164.6. Anal. (C22H20FN3O2S) C, H,
N.
eluting with EtOAc/cyclohexane (15%) and then crystallized by EtOH
to give 5 in 31% yield: mp 160−161 °C; H NMR (CDCl3) δ 1.65−
1
1.75 (m, 4H, cycloheptane CH2), 1.85−1.90, 2.75−2.80, and 2.90−
2.95 (m, each 2H, cycloheptane CH2), 7.05 (ddd, J = 0.9 and 5.0 and
7.0 Hz, 1H, pyridine CH), 7.30−7.45 (m, 3H, aromatic CH), 7.70 (dt,
J = 1.4 and 7.0 Hz, 1H, pyridine CH), 7.75 (dd, J = 1.6 and 7.5 Hz,
1H, aromatic CH), 8.15 (d, J = 4.4 Hz, 1H, pyridine CH), 8.25 (d, J =
8.3 Hz, 1H, pyridine CH), 8.40 (bs, 1H, NH), 11.40 (s, 1H, NH); 13C
NMR (CDCl3) δ 27.3, 27.5, 28.6, 29.0, 31.7, 114.2, 118.8, 120.0,
127.1, 130.6, 130.7, 131.4, 132.0, 133.0, 133.1, 133.3, 138.3, 141.4,
148.0, 151.1, 162.8, 164.6. Anal. (C22H20ClN3O2S) C, H, N.
The physical−chemical properties are comparable to those of the
commercial compound (STK063428) purchased from Vitas-M
(Moscow, Russia) including the purity that is 100% for both the
compounds, as assessed by UV chromatogram at 280 nm.
2-(4-Chlorobenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-
4H-cyclohepta[b]thiophene-3-carboxamide (6). The title com-
pound was prepared starting from 19 by method B, using 4-
chlorobenzoyl chloride. The reaction mixture was poured into ice/
water obtaining a precipitate which was filtered and purified by flash
chromatography, eluting with EtOAc/cyclohexane (20%) to give 6 in
29% yield: mp 222−223 °C; 1H NMR (CDCl3) δ 1.70−1.80 (m, 4H,
cycloheptane CH2), 1.85−1.90, 2.75−2.80, and 3.00−3.05 (m, each
2H, cycloheptane CH2), 7.10 (ddd, J = 0.9 and 5.0 and 7.0 Hz, 1H,
pyridine CH), 7.45 (d, J = 8.4 Hz, 2H, aromatic CH), 7.75 (dt, J = 1.4
and 7.0 Hz, 1H, pyridine CH), 7.90 (d, J = 8.4 Hz, 2H, aromatic CH),
8.10 (bs, 1H, NH), 8.25−8.30 (m, 2H, pyridine CH), 12.00 (s, 1H,
NH). Anal. (C22H20ClN3O2S) C, H, N.
2-(Benzoylamino)-N-pyridin-2-yl-5,6,7,8-tetrahydro-4H-
cyclohepta[b]thiophene-3-carboxamide (2). The title compound
was prepared starting from 19 by method B, using benzoyl chloride.
The reaction mixture was poured into ice/water. A precipitate was
obtained, which was filtered and purified by flash chromatography,
eluting with EtOAc/petroleum ether (15%), and then washed with
cyclohexane to give 2 in 34% yield: mp 208−210 °C; 1H NMR
(DMSO d6) δ 1.45−1.70 (m, 6H, cycloheptane CH2), 1.70−1.85 and
2.65−2.80 (m, each 2H, cycloheptane CH2), 7.05−7.10 (m, 1H,
pyridine CH), 7.40−7.60 (m, 3H, aromatic CH), 7.65−7.85 (m, 3H,
aromatic CH and pyridine CH), 8.15 (d, J = 8.2 Hz, 1H, pyridine
CH), 8.30 (d, J = 4.0 Hz, 1H, pyridine CH), 10.40 and 11.00 (s, each
1H, NH). Anal. (C22H21N3O2S) C, H, N.
2-[(2-Chloro-4-fluorobenzoyl)amino]-N-pyridin-2-yl-5,6,7,8-
tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (7).
The title compound was prepared starting from 19 by method B,
using 2-chloro-4-fluorobenzoyl chloride. The reaction mixture was
poured into ice/water, obtaining a precipitate which was filtered and
purified by flash chromatography, eluting with EtOAc/cyclohexane
2-[(3-Fluorobenzoyl)amino]-N-(2-pyridinyl)-5,6,7,8-tetrahy-
dro-4H-cyclohepta[b]thiophene-3-carboxamide (3). The title
compound was prepared starting from 19 by method B, using 3-
fluorobenzoyl chloride. The reaction mixture was poured into ice/
water and extracted with EtOAc. The organic layer was evaporated to
dryness, obtaining a solid which was purified by flash chromatography,
eluting with EtOAc/cyclohexane (15%) and then crystallized by EtOH
1
(15%) to give 7 in 25% yield: mp 162−163 °C; H NMR (CDCl3) δ
1.70−1.80 (m, 4H, cycloheptane CH2), 1.85−1.90, 2.75−2.80, and
3.00−3.05 (m, each 2H, cycloheptane CH2), 7.05−7.15 (m, 2H,
aromatic CH and pyridine CH), 7.20 (dd, J = 2.4 and 8.4 Hz, 1H,
aromatic CH), 7.70 (dt, J = 1.4 and 7.0 Hz, 1H, pyridine CH), 7.80
(dd, J = 6.0 and 8.4 Hz, 1H, aromatic CH), 8.00 (bs, 1H, NH), 8.20
(d, J = 8.4 Hz, 1H, pyridine CH), 8.30 (d, J = 4.6 Hz, 1H, pyridine
CH), 11.50 (s, 1H, NH). Anal. (C22H19ClFN3O2S) C, H, N.
1
to give 3 in 39% yield: mp 215−216 °C; H NMR (CDCl3) δ 1.75−
1.80 (m, 6H, cycloheptane CH2), 1.85−1.90, 2.80−2.85 and 3.00−
3.05 (m, each 2H, cycloheptane CH2), 7.10 (ddd, J = 0.9, 5.0, and 7.0
Hz, 1H, pyridine CH), 7.30 (dt, J = 2.5 and 8.9 Hz, 1H, aromatic CH),
7.50 (dq, J = 2.5 and 5.5 Hz, 1H, aromatic CH), 7.70−7.80 (m, 3H,
pyridine CH and aromatic CH), 8.25 (d, J = 4.4 Hz, 1H, pyridine
CH), 8.30 (bs, 1H, NH), 8.35 (d, J = 8.3 Hz, 1H, pyridine CH), 12.00
(s, 1H, NH); 13C NMR (CDCl3) δ 27.2, 27.5, 28.6, 29.1, 31.5, 114.3,
114.8 (d, JC−F = 28 Hz), 117.9, 119.3 (d, JC−F = 21 Hz), 120.0, 122.7
2-[(2,4-Dichlorobenzoyl)amino]-N-pyridin-2-yl-5,6,7,8-tetra-
hydro-4H-cyclohepta[b]thiophene-3-carboxamide (8). The title
compound was prepared starting from 19 by method B, using 2,4-
dichlorobenzoyl chloride. The reaction mixture was poured into ice/
water, obtaining a precipitate which was filtered and crystallized by
1
EtOH to give 8 in 30% yield: mp 190−191 °C; H NMR (CDCl3) δ
1.70−1.80 (m, 4H, cycloheptane CH2), 1.85−1.90, 2.75−2.80, and
3.00−3.05 (m, each 2H, cycloheptane CH2), 7.05 (ddd, J = 0.9 and 5.0
and 7.0 Hz, 1H, pyridine CH), 7.35 (dd, J = 1.8 and 8.4 Hz, 1H,
aromatic CH), 7.45 (d, J = 1.8 Hz, 1H, aromatic CH), 7.65−7.75 (m,
2H, aromatic CH and pyridine CH), 8.10 (bs, 1H, NH), 8.20−8.25
(m, 2H, pyridine CH), 11.50 (s, 1H, NH). Anal. (C22H19Cl2N3O2S)
C, H, N.
(d, JC−F = 3 Hz), 130.5 (d, JC−F = 8 Hz), 132.8, 132.9, 134.9 (d, JC−F
=
7 Hz), 138.3, 142.8, 148.1, 151.0, 162.1, 162.9 (d, JC−F = 248 Hz),
164.9. Anal. (C22H20FN3O2S) C, H, N.
2-[(4-Fluorobenzoyl)amino]-N-(2-pyridinyl)-5,6,7,8-tetrahy-
dro-4H-cyclohepta[b]thiophene-3-carboxamide (4). The title
compound was prepared starting from 19 by method B, using 4-
fluorobenzoyl chloride. The reaction mixture was poured into ice/
water and extracted with EtOAc. The organic layer was evaporated to
dryness, obtaining a solid which was purified by flash chromatography,
eluting with EtOAc/cyclohexane (15%) to give 4 in 44% yield: mp
2-[(Cyclohexylcarbonyl)amino]-N-pyridin-2-yl-5,6,7,8-tetra-
hydro-4H-cyclohepta[b]thiophene-3-carboxamide (9). The title
compound was prepared starting from 19 by method B, using
cyclohexanecarbonyl chloride. The reaction mixture was poured into
ice/water, obtaining a precipitate which was filtered and purified by
flash chromatography, eluting with EtOAc/petroleum ether (15%) to
give 9 in 20% yield: mp 201−204 °C; 1H NMR (DMSO d6) δ 1.00−
1.80 (m, 17H, cyclohexane CH2, cyclohexane CH, and cycloheptane
CH2), 2.50−2.65 (m, 4H, cycloheptane CH2), 7.05 (dd, J = 5.0 and
7.3 Hz, 1H, pyridine CH), 7.75 (dt, J = 2.0 and 9.2 Hz, 1H, pyridine
CH), 8.10 (d, J = 8.1 Hz, 1H, pyridine CH), 8.25 (d, J = 3.6 Hz, 1H,
pyridine CH), 10.20 and 10.30 (s, each 1H, NH). Anal.
(C22H27N3O2S) C, H, N.
1
192−193 °C; H NMR (CDCl3) δ 1.70−1.80 (m, 4H, cycloheptane
CH2), 1.85−1.90, 2.75−2.80 and 3.00−3.05 (m, each 2H, cyclo-
heptane CH2), 7.10 (ddd, J = 0.9 and 5.0 and 7.0 Hz, 1H, pyridine
CH), 7.15−7.20 (m, 2H, aromatic CH), 7.75 (dt, J = 1.4 and 7.0 Hz,
1H, pyridine CH), 7.95−8.05 (m, 2H, aromatic CH), 8.15−8.20 (m,
2H, pyridine CH and NH), 8.30 (d, J = 8.3 Hz, 1H, pyridine CH),
12.00 (s, 1H, NH); 13C NMR (CDCl3) δ 27.2, 27.5, 28.5, 29.1, 31.5,
114.3, 115.9 (d, JC−F = 22 Hz), 117.6, 120.0, 128.8, 129.9 (d, JC−F = 9
Hz), 132.6, 132.8, 138.3, 143.2, 148.1, 151.0, 162.3, 163.9, 165.2 (d,
JC−F = 252 Hz), 166.5. Anal. (C22H20FN3O2S) C, H, N.
2-[(2-Chlorobenzoyl)amino]-N-(2-pyridinyl)-5,6,7,8-tetrahy-
dro-4H-cyclohepta[b]thiophene-3-carboxamide (5). The title
compound was prepared starting from 19 by method B, using 2-
chlorobenzoyl chloride. The reaction mixture was poured into ice/
water and extracted with EtOAc. The organic layer was evaporated to
dryness, obtaining a solid which was purified by flash chromatography,
2-{[(4-Fluorophenyl)acetyl]amino}-N-pyridin-2-yl-5,6,7,8-tet-
rahydro-4H-cyclohepta[b]thiophene-3-carboxamide (10). The
title compound was prepared starting from 19 by method B, using (4-
fluorophenyl)acetyl chloride. The reaction mixture was poured into
ice/water, obtaining a precipitate which was filtered and purified by
flash chromatography, eluting with EtOAc/cyclohexane (15%) to give
10126
dx.doi.org/10.1021/jm401560v | J. Med. Chem. 2013, 56, 10118−10131