Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 7 2981
5-Bromo-1-(2-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-
X-Phos (7 mg) and tris(dibenzylideneacetone)dipalladium (0)
(6.7 mg) in 2.0 mL of dioxane and 1.0 mL of water in a sealed
glass tube was heated in a microwave at 135 ꢀC for 30 min. The
reaction mixture was partitioned between 10 mL of EtOAc and
1 mL of 1 N NaOH. The organic layer was washed with 1 mL of
brine, dried over MgSO4, filtered, and concentrated. Purification
on a silica gel column (eluted with 40-90% EtOAc in hexanes)
afforded the title compound (76.3 mg, 72% yield) as a white fluffy
one (9n). 1H NMR(DMSO-d6):δ12.62 (br, 1 H), 8.48 (s, 1 H), 8.15
(s, 1 H), 7.66 (t, J = 8.8 Hz, 1 H), 7.49 (m, 2 H), 7.40 (t, J = 7.6 Hz,
1 H). MS (ESI, pos.ion) m/z: 307.9/309.9 (Mþ1). HPLC (Method
A): retention time 1.56 min.
5-Bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]-
pyridin-6(7H)-one (10f). At 0 ꢀC, a solution of 5-bromo-1-(2,
6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (9f)
(11.3 g, 34.7 mmol) in DME (78 mL) and DMF (7.7 mL) was
treated with sodium hydride (1.24 g of 95% wt., 49 mmol) in small
portions and the solution was allowed to stir at 0 ꢀC for 10 min.
Finely ground lithium bromide (8.83 g, 102 mmol) was then added
and the solution stirred at RT for 20 min at which point iodo-
methane (4.37 mL, 68.9 mmol) was added. The suspension was
heated at 40 ꢀC for 16 h then cooled to RT. The reaction mixture
was quenched with ice cold water (25 mL) slowly and extracted
with EtOAc (3 ꢀ 100 mL). The combined organic solution was
washed with 2 ꢀ 20 mL of brine, dried over MgSO4, filtered, and
concentrated. The resulting crude solid was then suspended in
300 mL of 1:1 solution of EtOAc/hexanes with stirring over
30 min. The solution was allowed to precipitate in the freezer for
2 h. The resulting solid was collected by filtration washing with 2 ꢀ
30 mL of methyl t-butyl ether to afford the title compound (5.27 g)
in >95% purity as a beige solid. The mother liquor was and
concentrated to ca. 15 mL in vacuo and treated with 50 mL of
MTBE and again chilled in the freezer overnight. The resulting
solid was collected by filtration followed by washing with 2 ꢀ
10 mL of methyl t-butyl ether to afford a second crop (2.54 g) in
>95% purity. 1H NMR (CDCl3): δ 8.09 (s, 1 H), 7.91 (s, 1 H),
7.56 (m, 1 H), 7.15 (m, 2 H), 3.39 (s, 3 H). MS (ESI, pos.ion) m/z:
340.0/342.0 (Mþ1). HPLC (Method B): retention time 5.37 min.
A similar procedure was used to prepare compounds 10a-e
and 10n.
5-Bromo-7-methyl-1-o-tolyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-
one (10a). 1H NMR (CDCl3): δ (s, 1 H), 7.83 (s, 1 H), 7.43-7.50
(m, 1 H), 7.34-7.40 (m, 3 H), 3.21 (s, 3 H), 2.05 (s, 3 H). MS (ESI,
pos.ion) m/z: 317.9/320.0 (Mþ1). HPLC (Method A): retention
time 1.83 min.
5-Bromo-1-(2-chlorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-
6(7H)-one (10b). 1H NMR (CDCl3): δ 8.09 (s, 1 H), 7.85 (s, 1 H),
7.62-7.46 (m, 4 H), 3.29 (s, 3 H). MS (ESI, pos.ion) m/z: 337.9/
339.9 (Mþ1). HPLC (Method B): retention time 5.49 min.
5-Bromo-7-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1H-
pyrazolo[3,4-b]pyridin-6(7H)-one (10c). 1H NMR (CDCl3): δ
8.81 (d, J = 4.7 Hz, 1 H), 8.26-8.34 (m, 1 H), 8.11 (s, 1 H),
7.88 (s, 1 H), 7.71 (dd, J = 7.7, 5.0 Hz, 1 H), 3.24 (s, 3 H). MS
(ESI, pos.ion) m/z: 372.8/374.9 (Mþ1). HPLC (Method A):
retention time 1.71 min.
1
amorphous solid. H NMR (CDCl3): δ 7.97 (s, 1 H), 7.66 (m,
2 H), 7.56 (m, 2 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 8.0 Hz,
2 H), 6.20 (br, 1 H), 3.49 (s, 3 H), 2.88 (m, 1 H), 2.29 (s, 3 H), 0.85
(m, 2 H), 0.59 (m, 2 H). MS (ESI, pos.ion) m/z: 435.1 (Mþ1).
HPLC (Method A): retention time 1.84 min. HPLC (Method B):
retention time 5.67 min.
A similar procedure was used to prepare compounds 3a-e
and 3n.
N-Cyclopropyl-4-methyl-3-(7-methyl-6-oxo-1-o-tolyl-6,7-dihydro-
1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (3a).1H NMR (methanol-
d4): δ 8.07 (s, 1 H), 7.89 (s, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.66 (s,
1 H), 7.53-7.61 (m, 2 H), 7.42-7.53 (m, 2 H), 7.38 (d, J = 8.0 Hz,
1 H), 3.24 (s, 3 H), 2.86 (m, 1 H), 2.28 (s, 3 H), 2.13 (s, 3 H),
0.78-0.85 (m, 2 H), 0.60-0.67 (m, 2 H). MS (ESI, pos.ion) m/z:
413.1 (Mþ1). HPLC (Method A): retention time 1.90 min. HPLC
(Method B): retention time 5.31 min.
3-(1-(2-Chlorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo-
[3,4-b]pyridin-5-yl)-N-cyclopropyl-4-methylbenzamide (3b).1HNMR
(CDCl3): δ 7.91 (s, 1 H), 7.67 (m, 3 H), 7.60 (m, 1 H), 7.57-7.44 (m,
3 H), 7.31 (d, J = 8.0 Hz, 1 H), 6.25 (br, 1 H), 3.28 (s, 3 H), 2.89 (m,
1 H), 2.28 (s, 3 H), 0.85 (m, 2 H), 0.59 (m, 2 H). MS (ESI, pos.ion)
m/z: 433.2 (Mþ1). HPLC (Method A): retention time 1.88 min.
HPLC (Method B): retention time 5.55 min.
N-Cyclopropyl-4-methyl-3-(7-methyl-6-oxo-1-(3-(trifluoromethyl)-
pyridin-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide
(3c). 1H NMR (CDCl3): δ 8.83 (dd, J = 4.8, 1.5 Hz, 1 H), 8.32 (dd,
J = 8.0, 1.6 Hz, 1 H), 7.92-7.96 (m, 1 H), 7.64-7.74 (m, 3 H), 7.55
(d,J= 1.8 Hz, 1 H), 7.32 (d, J= 8.0 Hz, 1 H), 6.21 (br, 1 H), 3.23 (s,
3 H), 2.89 (td, J = 7.0, 3.3 Hz, 1 H), 2.29 (s, 3 H), 0.81-0.89 (m,
2 H), 0.55-0.63 (m, 2 H). MS (ESI, pos.ion) m/z: 468.0 (Mþ1).
HPLC (Method A): retention time 1.80 min.
N-Cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-
dihydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide (3d).
1H NMR (methanol-d4): δ 8.09 (s, 1 H), 7.88 (s, 1 H), 7.84 (td,
J = 8.7, 5.8 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.66 (s, 1 H),
7.34-7.41 (m, 2 H), 7.28 (t, J = 8.3 Hz, 1 H), 3.38 (s, 3 H), 2.86
(dt, J = 7.0, 3.5 Hz, 1 H), 2.27 (s, 3 H), 0.77-0.85 (m, 2 H),
0.61-0.67 (m, 2 H). MS (ESI, pos.ion) m/z: 435.1 (Mþ1). HPLC
(Method A): retention time 1.86 min. HPLC (Method C): reten-
tion time 2.84 min.
5-Bromo-1-(2,4-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]-
pyridin-6(7H)-one (10d). 1H NMR (CDCl3): δ 8.08 (s, 1 H), 7.84
(s, 1 H), 7.58 (td, J = 8.5, 6.0 Hz, 1 H), 7.02-7.14 (m, 2 H), 3.36
(s, 3 H). MS (ESI, pos.ion) m/z: 339.9/341.9 (Mþ1). HPLC
(Method B): retention time 5.31 min.
5-Bromo-1-(2,5-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]-
pyridin-6(7H)-one (10e). 1H NMR (DMSO-d6): δ 8.43 (s, 1 H),
8.08 (s, 1 H), 7.81 (m, 1 H), 7.60 (m, 2 H), 3.24 (s, 3 H). MS (ESI,
pos.ion) m/z: 340.0/342.0 (Mþ1). HPLC (Method C): retention
time 2.78 min.
5-Bromo-1-(2-fluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]-
pyridin-6(7H)-one (10n). 1H NMR (DMSO-d6): δ 8.43 (s, 1 H),
8.06 (s, 1 H), 7.78 (t, J = 7.8 Hz, 1 H), 7.67 (m, 1 H), 7.53 (t, J =
9.0 Hz, 1 H), 7.44 (t, J = 7.7 Hz, 1 H), 3.19 (s, 3 H). MS (ESI, pos.
ion) m/z: 321.9/323.9 (Mþ1). HPLC (Method A): retention time
1.73 min.
N-Cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-di-
hydro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide (3f). A
mixture of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo-
[3,4-b]pyridin-6(7H)-one (10f) (83.0 mg, 0.24 mmol), potassium
phosphate (155 mg, 0.73 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,
5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (88 mg, 0.29 mmol),
N-Cyclopropyl-3-(1-(2,5-difluorophenyl)-7-methyl-6-oxo-6,7-dihy-
dro-1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide (3e). H
1
NMR (DMSO-d6): δ 8.35 (d, J = 3.9 Hz, 1 H), 8.13 (s, 1 H), 7.86
(s, 1 H), 7.73 (d, J = 7.9 Hz, 1 H), 7.65-7.59 (m, 4 H), 7.32 (d,
J = 7.8 Hz, 1 H), 3.32 (s, 3 H), 2.84 (m, 1 H), 2.19 (s, 3 H), 0.68
(m, 2 H), 0.59 (m, 2 H). MS (ESI, pos.ion) m/z: 435.0 (Mþ1).
HPLC (Method A): retention time 1.86 min.
N-Cyclopropyl-3-(1-(2-fluorophenyl)-7-methyl-6-oxo-6,7-dihydro-
1H-pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzamide (3n). H NMR
1
(DMSO-d6): δ 8.34 (d, J = 4.1 Hz, 1 H), 8.10 (s, 1 H), 7.96 (s, 1 H),
7.84 (t, J = 7.9 Hz, 1 H), 7.74-7.65 (m, 3 H), 7.54 (t, J = 9.5 Hz, 1
H), 7.46 (t, J = 7.7 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 3.20 (s, 3 H),
2.85 (m, 1 H), 2.19 (s, 3 H), 0.67 (m, 2 H), 0.56 (m, 2 H). MS (ESI,
pos.ion) m/z: 417.0 (Mþ1). HPLC (Method A): retention time 1.80
min. HPLC (Method C): retention time 1.81 min.
3-(1-(2,6-Difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-
pyrazolo[3,4-b]pyridin-5-yl)-4-methylbenzoic acid (16). A mixture
of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]-
pyridin-6(7H)-one (10f) (717 mg, 2.10 mmol), 3-borono-4-methyl-
benzoic acid (14) (455 mg, 2.53 mmol), and tetrakis(triphenyl-
phosphine)palladium (0) (73 mg, 0.06 mmol) in dioxane (10 mL)
and sodium carbonate (5.2 mL of 1 N solution) in a sealed glass