Journal of Medicinal Chemistry
Article
3.6 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.33 (s,
1H), 8.39 (d, J = 4.3 Hz, 1H).
compound 24d in a manner similar to that described for the preparation
of 28a: 1H NMR (500 MHz, CDCl3) δ 3.03 (t, J = 8.5 Hz, 2H), 4.01 (t, J
= 8.0 Hz, 2H), 6.81(dd, J = 5.5, 7.5 Hz, 1H), 7.35 (dd, J = 1.5, 8.0 Hz,
1H), 7.57−7.60 (m, 2H), 7.95−7.98 (m, 2H), 8.12 (d, J = 5.0 Hz, 1H).
(E)-tert-Butyl 3-(4-(1H-Pyrazolo[3,4-b]pyridin-1-ylsulfonyl)-
phenyl)acrylate (29a). A mixture of 28a (1270 mg, 3.78 mmol),
tert-butyl acrylate (0.60 mL, 4.54 mmol), triethylamine (0.75 mL, 6.45
mmol), triphenylphosphine (490 mg, 1.90 mmol), palladium acetate
(420 mg, 1.90 mmol), and sodium bicarbonate (320 mg, 3.78 mmol)
was heated to 80 °C in DMF (2 mL) for 5 h. The mixture was then
filtered, and the filtrate was extracted with H2O (30 mL) and CH2Cl2 (3
× 30 mL). The organic layer was collected and dried over anhydrous
MgSO4. After the removal of MgSO4 by filtration, the filtrate was
concentrated in vacuo to yield an oily product which was purified by
flash chromatography over silica gel (1:10 EtOAc/n-hexane) to give 680
mg (47%) of 29a as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.57
(s, 9H), 6.38 (d, J = 16.0 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.50−7.59 (m,
3H), 7.70 (dd, J = 3.5, 8.5 Hz, 1H), 7.98 (dd, J = 9.0, 17.0 Hz, 2H), 8.19−
8.23 (m, 2H).
(E)-tert-Butyl 3-(4-(1H-Pyrrolo[2,3-c]pyridin-1-ylsulfonyl)-
phenyl)acrylate (29b). The title compound was obtained in 83%
overall yield from compound 28b in a manner similar to that described
for the preparation of 29a: 1H NMR (500 MHz, CDCl3) δ 1.51 (s, 9H),
6.37 (d, J = 16.0 Hz, 1H), 6.69 (d, J = 3.5 Hz, 1H), 7.46−7.49 (m, 2H),
7.55 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 4.0 Hz, 1H), 7.91 (d, J = 8.5 Hz,
1H), 8.42 (d, J = 5.0 Hz, 1H), 9.32 (s, 1H).
(E)-tert-Butyl 3-(4-(1H-Pyrrolo[2,3-b]pyridin-1-ylsulfonyl)-
phenyl)acrylate (29c). The title compound was obtained in 35%
overall yield from compound 28c in a manner similar to that described
for the preparation of 29a: 1H NMR (500 MHz, CDCl3) δ 1.39 (s, 9H),
6.30 (d, J = 16.0 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 7.08 (dd, J = 4.5, 7.5
Hz, 1H), 7.38 (d, J = 16.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.59 (d, J =
4.0 Hz, 1H), 7.75 (dd, J = 1.5, 8.0 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 8.26
(dd, J = 1.5, 5.0 Hz, 1H).
(E)-tert-Butyl 3-(3-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine-1-
ylsulfonyl)phenyl)acrylate (26d). Compound 26d was prepared in
72% overall yield from compound 25d in a manner similar to that
1
described for the preparation of 26a: H NMR (500 MHz, CDCl3) δ
1.53 (s, 9H), 3.05 (t, J = 8.5 Hz, 2H), 4.06 (t, J = 8.5 Hz, 2H), 6.44 (d, J =
16.0 Hz, 1H), 6.82 (dd, J = 5.0, 7.0 Hz, 1H), 7.35 (dd, J = 1.0, 7.5 Hz,
1H), 7.48 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 16.0 Hz, 1H), 7.65 (d, J = 8.0
Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 4.5 Hz, 1H), 8.27 (s, 1H).
(E)-3-(3-(1H-Indazol-1-ylsulfonyl)phenyl)acrylic Acid (27a).
Trifluoroacetic acid (8.60 mL, 0.13 mmol) was added to compound
26a (1030 mg, 2.60 mmol) and stirred for 30 min. Then H2O (20 mL)
was added to afford a white solid. The resulting solid was collected by
filtration and purified by recrystallization with EtOH to give 450 mg
(53%) of 27a as a pink solid: 1H NMR (500 MHz, CD3OD and CDCl3)
δ 6.07 (d, J = 16.0 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 8.0 Hz,
1H), 7.19 (d, J = 7.0 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.36 (dd, J = 8.0,
13.5 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.78 (d, J = 8.5 Hz,
1H), 7.89 (s, 1H).
(E)-3-(3-(1H-Pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)acrylic
Acid (27b). The title compound was obtained in 94% overall yield from
compound 26b in a manner similar to that described for the preparation
of 27a: 1H NMR (500 MHz, CD3OD) δ 6.64 (d, J = 16.0 Hz, 1H), 7.16
(d, J = 3.5 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 16.0 Hz, 1H),
7.98 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 6.0 Hz, 1H), 8.15 (d, J = 8.0 Hz,
1H), 8.37 (d, J = 1.5 Hz, 1H), 8.48 (d, J = 6.5 Hz, 1H), 8.54 (d, J = 3.5
Hz, 1H), 9.57 (s, 1H).
(E)-3-(3-(1H-Pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)-
acrylic Acid (27c). This compound was obtained in 97% overall yield
from compound 26c in a manner similar to that described for the
preparation of 27a: 1H NMR (500 MHz, CD3OD) δ 6.05 (d, J = 12.9
Hz, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.75 (m, 1H), 7.06−7.15 (m, 2H),
7.27 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 3.0 Hz, 1H), 7.43 (s, 1H), 7.66 (s,
1H), 7.89 (s, 1H), 7.94 (s, 1H).
(E)-3-(3-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)-
phenyl)acrylic Acid (27d). The title compound was obtained in 92%
overall yield from compound 26d in a manner similar to that described
for the preparation of 27a: 1H NMR (500 MHz, CD3OD and CDCl3) δ
3.08 (t, J = 8.0 Hz, 2H), 4.07 (t, J = 8.0 Hz, 2H), 6.51 (d, J = 16.0 Hz,
1H), 6.90 (dd, J = 5.0, 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.63−7.67
(m, 3H), 8.06−8.10 (m, 3H).
(E)-tert-Butyl 3-(4-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-
ylsulfonyl)phenyl)acrylate (29d). This compound was obtained in
72% overall yield from compound 28d in a manner similar to that
1
described for the preparation of 29a: H NMR (500 MHz, CDCl3) δ
1.91 (s, 9H), 3.04 (t, J = 8.0 Hz, 2H), 4.05 (t, J = 8.0 Hz, 2H), 6.54 (d, J =
16.0 Hz, 1H), 6.91 (dd, J = 5.0, 8.0 Hz, 1H), 7.50 (dd, J = 1.5, 8.0 Hz,
1H), 7.57 (d, J = 16.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 8.5
Hz, 3H).
1-(4-Bromophenylsulfonyl)-1H-indazole (28a). 4-Bromobenze-
nesulfonyl chloride (1300 mg, 5.10 mmol) was added to a mixture of
indazole (500 mg, 4.23 mmol), KOH (470 mg, 8.46 mmol), and
tetrabutylammonium hydrogen sulfate (220 mg, 0.63 mmol) in dry
CH2Cl2 (30 mL), and the mixture was stirred overnight. The mixture
was then filtered, and water was added followed by extraction with
CH2Cl2 (3 × 30 mL). The organic layer was collected and dried over
anhydrous MgSO4 and concentrated in vacuo to yield an oily product.
The residue was purified by flash column chromatography over silica gel
(EtOAc/n-hexane = 3: 1; Rf = 0.30) to give 1250 mg (88%) of 28a as a
solid: 1H NMR (500 MHz, CDCl3) δ 7.11 (td, J = 2.5, 8.5 Hz, 1H), 7.31
(dd, J = 2.0, 7.5 Hz, 1H), 7.64 (dd, J = 9.0, 16.0 Hz, 2H), 7.68 (d, J = 9.0
Hz, 2H), 7.96 (dd, J = 1.5, 7.0 Hz, 2H), 8.62 (s, 1H).
1-(4-Bromophenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (28b).
The title compound was obtained in 67% overall yield from compound
24b in a manner similar to that described for the preparation of 28a: 1H
NMR (500 MHz, CDCl3) δ 6.69 (d, J = 3.5 Hz, 1H), 7.46 (dd, J = 1.0,
5.5 Hz, 1H), 7.59 (m, 2H), 7.64 (dd, J = 1.0, 3.5 Hz, 1H), 7.76 (dd, J =
2.0, 4.0 Hz, 2H), 8.42 (dd, J = 2.0, 5.0 Hz, 1H), 9.29 (s, 1H).
1-(4-Bromophenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (28c).
The title compound was obtained in 79% overall yield from compound
24c in a manner similar to that described for the preparation of 28a: 1H
NMR (500 MHz, CDCl3) δ 6.61 (d, J = 4.5 Hz, 1H), 7.19 (dd, J = 5.0,
8.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 4.0 Hz, 1H), 7.85 (dd, J
= 1.5, 8.0 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 8.42 (dd, J = 1.5, 4.5 Hz,
1H).
(E)-3-(4-(1H-Indazol-1-ylsulfonyl)phenyl)acrylic Acid (30a).
Trifluoroacetic acid (4.80 mL, 0.07 mmol) was added to compound
29a (560 mg, 1.46 mmol), and the mixture was stirred for 30 min. Then
H2O (20 mL) was added, affording a white solid. This solid was
collected by filtration and purified by recrystallization from MeOH to
1
give 410 mg (86%) of 30a as a white solid: H NMR (500 MHz,
CD3OD) δ 6.44 (d, J = 16.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.53−7.62
(m, 4H), 7.71 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 8.16 (d, J =
8.5 Hz, 1H), 8.23 (s, 1H).
(E)-3-(4-(1H-Pyrrolo[2,3-c]pyridin-1-ylsulfonyl)phenyl)acrylic
Acid (30b). The title compound was obtained in 94% overall yield from
compound 29b in a manner similar to that described for the preparation
of 30a: 1H NMR (500 MHz, CD3OD) δ 6.61 (d, J = 16.0 Hz, 1H), 7.15
(d, J = 3.5 Hz, 1H), 7.64 (d, J = 16.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 2H),
8.12 (d, J = 6.5 Hz, 1H), 8.15 (d, J = 8.5 Hz, 2H), 8.46−8.48 (m, 2H),
9.52 (s, 1H).
(E)-3-(4-(1H-Pyrrolo[2,3-b]pyridin-1-ylsulfonyl)phenyl)-
acrylic Acid (30c). This compound was obtained in 97% overall yield
from compound 29c in a manner similar to that described for the
preparation of 30a: 1H NMR (500 MHz, CDCl3 and CD3OD) δ 6.24 (d,
J = 16.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.37
(d, J = 5.7 Hz, 1H), 7.40 (d, J = 6.6 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H),
7.72 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 8.04 (s,
1H).
(E)-3-(4-(2,3-Dihydro-1H-pyrrolo[2,3-b]pyridin-1-ylsulfonyl)-
phenyl)acrylic Acid (30d). The title compound was obtained in 88%
overall yield from compound 29d in a manner similar to that described
for the preparation of 30a: 1H NMR (500 MHz, CD3OD and DMSO) δ
1-(4-Bromophenylsulfonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]-
pyridine (28d). This compound was obtained in 93% overall yield from
4019
dx.doi.org/10.1021/jm401899x | J. Med. Chem. 2014, 57, 4009−4022