GW788388: A TGF-â Type I Receptor Inhibitor
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2217
A in 6.8% yield , after recrystallization from EtOAc: mp 149-
according to general method A: 1H NMR (300 MHz, CDCl3) δ
8.84 (d, J ) 5 Hz, 2H), 8.10 (d, J ) 8.9 Hz, 2H), 7.94 (s, 1H),
7.92 (s, 1H), 7.80 (ddd, J ) 7.7, 7.7, and 1.9 Hz, 1H), 7.66 (br d,
J ) 7.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.17 (d, J ) 8.9 Hz, 2H),
4.04 (s, 3H), NH (pyrazole) not observed; MS (API) 329 (M +
H)+; HR-MS calcd for C20H16N4O 329.1402 (M + H), found
329.1392; analytical HPLC tR ) 2.57 min (A), tR ) 2.35 min (B).
2-[4-Fluorophenyl]-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyri-
dine (1k). Compound 1k was prepared in 17% yield, after
recrystallization from iPrOH, from 2k according to general method
A: mp 117 °C; 1H NMR (300 MHz, CDCl3) δ 8.62 (br d, J ) 4.9
Hz, 1H), 8.59 (d, J ) 5.5 Hz, 1H), 7.91-7.82 (m, 2H), 7.71 (s,
1H), 7.68 (br s, 1H), 7.57 (ddd, J ) 7.8, 7.8, and 1.7 Hz, 1H), 7.42
(d, J ) 7.5 Hz, 1H), 7.25-7.16 (m, 2H), 7.06 (dd, J ) 8.6 Hz,
2H), NH (pyrazole) not observed; MS (API) 317 (M + H)+; HR-
MS calcd for C19H13FN4 (M + H) 317.1202, found 317.1210;
analytical HPLC tR ) 2.66 min (A), tR ) 2.44 min (B).
2-[4-Isopropylphenyl]-4-[3-(pyridin-2-yl)-1H-pyrazol-4-yl]py-
ridine (1l). Compound 1l was prepared in 16.5% yield from 2l
according to general method A: 1H NMR (300 MHz, CDCl3) δ
8.63 (br d, J ) 4.9 Hz, 2H), 7.84 (d, J ) 8.3 Hz, 2H), 7.74 (s, 1H),
7.72 (s, 1H), 7.58 (ddd, J ) 7.7, 7.7, and 1.5 Hz, 1H), 7.43 (d, J
) 7.9 Hz, 1H), 7.27 (d, J ) 8.3 Hz, 2H), 7.22 (dd, J ) 5.3 and 1.5
Hz, 1H), 7.19 (s, 1H), 2.99-2.81 (m, 1H), 1.21 (d, J ) 6.7 Hz,
6H), NH (pyrazole) not observed; MS (ES) 341 (M + H)+; HR-
MS calcd for C22H20N4 (M + H) 341.1766, found 341.1790;
analytical HPLC tR ) 3.09 min (A), tR ) 2.84 min (B).
1
151 °C; H NMR (300 MHz, CDCl3) δ 8.63 (d, J ) 5.1 Hz, 1H),
8.59 (d, J ) 4.5 Hz, 1H), 7.67 (s, 1H), 7.59 (ddd, J ) 7.9, 7.7, and
1.7 Hz, 1H), 7.46 (d, J ) 7.9 Hz, 1H), 7.39 (br s, 1H), 7.35-7.30
(m, 1H), 7.26 (dd, J ) 5.1 and 1.7 Hz, 1H), 7.24-7.17 (m, 4H),
2.30 (s, 3H), NH (pyrazole) not observed; MS (API) m/z 313 (M
+ H)+; HR-MS calcd for C20H16N4 (M + H) 313.1453, found
313.1479; analytical HPLC tR )2.56 min, 100% pure (A), tR
2.35 min, 100% pure (B).
)
2-[2-(Trifluoromethyl)phenyl]-4-(3-pyridin-2-yl-1H-pyrazol-
4-yl)pyridine (1d). Compound 1d was prepared in 12.4% yield,
after recrystallization from EtOAc, from 2d according to general
method A: mp 173-175 °C, 1H NMR (300 MHz, CDCl3) δ 8.70
(d, J ) 5.1 Hz, 1H), 8.67 (br d, J ) 4 Hz, 1H), 7.79-7.73 (m,
2H), 7.70-7.58 (m, 2H), 7.56-7.44 (m, 4H), 7.40 (dd, J ) 5.1
and 1.7 Hz, 1H), 7.32-7.26 (m, 1H), NH (pyrazole) not observed;
MS (API) 367(M + H)+; HR-MS calcd for C20H13F3N4 (M + H)
367.1170, found 367.1152; analytical HPLC tR ) 2.66 min (A), tR
) 2.42 min (B).
2-[3-Methylphenyl]-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyri-
dine (1e). Compound 1e was prepared in 11% yield, after
recrystallization from EtOAc, from 2e according to general method
1
A: mp 133-135 °C; H NMR (300 MHz, CDCl3) δ 8.57 (d, J )
4.7 Hz, 1H), 8.46 (d, J ) 4.9 Hz, 1H), 7.92 (d, J ) 7.9 Hz, 1H),
7.70 (ddd, J ) 7.7, 7.5, and 1.7 Hz, 1H), 7.65 (br s, 1H), 7.57 (br
d, J ) 7.9 Hz, 1H), 7.54 (br s, 1H), 7.35 (ddd, J ) 7.5, 7.5, and
1.1 Hz, 1H), 7.18 (dd, J ) 7.7 and 7.8 Hz, 1H), 7.09-7.03 (m,
3H), 2.26 (s, 3H), NH (pyrazole) not observed; MS (API) 313 (M
+ H)+; HR-MS calcd for C20H16N4 313.1453 (M + H), found
313.1448; analytical HPLC tR ) 2.73 min (A), tR ) 2.50 min (B).
2-[3-(Trifluoromethyl)phenyl]-4-(3-pyridin-2-yl-1H-pyrazol-
4-yl)pyridine (1f). Compound 1f was prepared in 14% yield from
2f according to general method A: 1H NMR (300 MHz, CDCl3) δ
8.36 (d, J ) 5 Hz, 2H), 8.12 (d, J ) 8.9 Hz, 2H), 7.95 (s, 1H),
7.71(ddd, J ) 7.7, 7.7, and 1.9 Hz, 1H), 7.67-7.52 (m, 3H), 7.22
(br d, J ) 5.1 Hz, 2H), NH (pyrazole) not observed; MS (API)
367 (M + H)+; HR-MS calcd for C20H13F3N4 367.1170 (M + H),
found 367.1128; analytical HPLC tR ) 3.01 min, (A), tR ) 2.73
min (B).
2-[4-Chlorophenyl]-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyri-
dine (1m). Compound 1m was prepared in 5% from 2m according
to general method A: 1H NMR (300 MHz, CDCl3) δ 8.54-8.46
(m, 2H), 7.70 (d, J ) 8.5 Hz, 2H), 7.58 (br s, 1H), 7.56 (br s, 1H),
7.44 (dd, J ) 7.4 and 7.4 Hz, 1H), 7.28 (d, J ) 7.5 Hz, 1H), 7.22
(d, J ) 8.5 Hz, 2H), 7.14-7.04 (m, 2H), NH (pyrazole) not
observed; MS (API) 333 (M + H)+; HR-MS calcd for C19H13ClN4
333.0907 (M + H), found 333.0906; analytical HPLC tR ) 2.87
min (A), tR ) 2.65 min (B).
General Method B: 2-(4-Hydroxyphenyl)-4-(3-pyridin-2-yl-
1-trityl-1H-pyrazol-4-yl)pyridine (7). A solution of 6 (4.6 g, 8.47
mmol) in toluene (100 mL) was treated with tetrakis(triphenylphos-
phine)palladium (0.83 g) and stirred at room temperature for 30
min. An aqueous solution of Na2CO3 (2 M, 22.58 mL) was added
to the reaction mixture, followed by 4-hydroxyphenylboronic acid,
pinacol ester (2.67equiv, 4.9 g, 22.31 mmol) in EtOH (30 mL).
The resulting mixture was heated under reflux for 2 h. The cooled
mixture was poured into ice and extracted with toluene. The organic
layer was washed with water, dried over Na2SO4, and filtered.
Evaporation of the solvent in vacuo gave a crude oil, which was
purified by chromatography on silica gel (CH2Cl2/MeOH 98:2) to
give 7 as a white solid (4.3 g, 91%), which contains the 2-trityl
2-[3-Methoxyphenyl]-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyri-
dine (1g). Compound 1g was prepared in 12% yield, after
recrystallization from EtOAc, from 2g according to general method
1
A: mp 143-145 °C; H NMR (300 MHz, CDCl3) δ 8.87-8.83
(m, 2H), 7.96 (br s, 1H), 7.95 (s, 1H), 7.80 (ddd, J ) 7.9, 7.7, and
1.7 Hz, 1H), 7.72 (br s, 1H), 7.66 (br d, J ) 7.4 Hz, 2H), 7.56-
7.39 (m, 3H), 7.13 (dd, J ) 8 and 2.6 Hz, 1H), 4.40 (s, 3H), NH
(pyrazole) not observed; MS (API) 329(M + H)+; HR-MS : calcd
for C20H16N4O 329.1402 (M + H), found 329.1395; analytical
HPLC tR ) 2.58 min (A), tR ) 2.36 min (B).
1
2-[4-Methylphenyl]-4-(3-pyridin-2-yl-1H-pyrazol-4-yl pyri-
dine (1h). Compound 1h was prepared in 40% yield from 2h
according to general method A: 1H NMR (300 MHz, CDCl3) δ
8.62 (br d, J ) 4.9 Hz, 2H), 7.80 (br d, J ) 8.3 Hz, 2H), 7.72 (br
s, 2H), 7.57 (ddd, J ) 7.9, 7.9, and 1.7 Hz, 1H), 7.43 (br d, J )
7.9 Hz, 1H), 7.25-7.20 (m, 4H), 2.34 (s, 3H), NH (pyrazole) not
observed; NH (pyrazole) not observed; MS (ES) 313 (M + H)+;
HR-MS calcd for C20H16N4 313.1453 (M + H), found 313.1404;
analytical HPLC tR ) 2.43 min (A), tR ) 2.48 min (B).
isomer as a minor component: mp 175°C; H NMR (300 MHz,
CDCl3) δ 8.38 (d, J ) 4.7 Hz, 1H), 8.31 (d, J ) 5.5 Hz, 1H),
7.61-7.43 (m, 5H), 7.23-7.15 (m, 7H), 7.14-7.08 (m, 8H); 7.05-
7.00 (m, 3H), 6.94 (dd, J ) 5.3 and 1.5 Hz,1H), 6.59 (br d, J )
8.3 Hz, 2H); MS (API) 557 (M + H)+.
4-[4-(3-Pyridin-2-yl-1-trityl-1H-pyrazol-4-yl)pyridin-2-yl]ben-
zaldehyde (8). Compound 8 was prepared in 85% yield from 6
and 4-formylphenylboronic acid as described in general method
1
B: H NMR (300 MHz, CDCl3) δ 10.08 (s, 1H), 8.61 (d, J ) 5
2-[4-(Trifluoromethyl)phenyl]-4-(3-pyridin-2-yl-1H-pyrazol-
4-yl)pyridine (1i). Compound 1i was prepared in 27% yield, after
Hz, 1H), 8.56 (d, J ) 4 Hz, 1H), 8.18 (d, J ) 8 Hz, 2H), 7.97 (d,
J ) 8 Hz, 2H), 7.95 (br s, 1H), 7.82 (d, J ) 7.6 Hz, 1H), 7.74
(ddd, J ) 7.6, 7.6, and 1.5 Hz, 1H), 7.66 (s, 1H), 7.42-7.34 (m,
8H), 7.33-7.23 (m, 10H); MS (API) 569 (M + H)+.
i
recrystallization from Pr2O/iPrOH, from 2i according to general
1
method A: mp 155 °C; H NMR (300 MHz, CDCl3) δ 8.68 (d, J
) 5 Hz, 1H), 8.63 (br d, J ) 4.9 Hz, 1H), 8.02 (d, J ) 8 Hz, 2H),
7.79 (br s, 1H), 7.74 (s, 1H), 7.67 (d, J ) 8 Hz, 2H), 7.60 (ddd, J
) 7.7, 7.7, and 1.7 Hz, 1H), 7.43 (d, J ) 8 Hz, 1H), 7.31 (dd, J )
5.1 and 1.5 Hz, 1H), 7.24 (ddd, J ) 4.9, 4.9, and 1.7 Hz, 1H), NH
(pyrazole) not observed; MS (API) 367(M + H)+; HR-MS calcd
for C20H13F3N4 (M + H) 367.1170, found 367.1183; analytical
HPLC tR ) 3.03 min (A), tR ) 2.76 min (B).
4-[4-(3-Pyridin-2-yl-1-trityl-1H-pyrazol-4-yl)pyridin-2-yl]ben-
zoic Acid Methyl Ester (9). Compound 9 was prepared in 83.6%
yield from 6 and 4-(methoxycarbonylphenyl)boronic acid as
described in general method B: 1H NMR (300 MHz, CDCl3) δ
8.50 (d, J ) 5.1 Hz, 1H), 8.46 (d, J ) 4.9 Hz, 1H), 8.02 (d, J )
8.5 Hz, 2H), 7.89 (d, J ) 8.5 Hz, 2H), 7.80 (br s, 1H), 7.70 (d, J
) 7.7 Hz, 1H), 7.63 (ddd, J ) 7.9, 7.4, and 1.7 Hz, 1H), 7.56 (s,
1H), 7.32-7.25 (m, 7H), 7.05-7.00 (m, 10H), 3.86 (s, 3H); MS
(API) 599 (M + H)+.
2-[4-Methoxyphenyl]-4-(3-pyridin-2-yl-1H-pyrazol-4-yl)pyri-
dine (1j). Compound 1j was prepared in 25% yield from 2j