Pyridine DeriVatiVes as CRF-1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 22 7283
1-[2-Chloro-4-(methylsulfonyl)phenyl]-6-methyl-4-[3-(1,3-thia-
zol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
(19). 1H NMR (300 MHz, CDC13): δ 8.06 (m, 2H), 7.93 (d, 1H),
7.86 (m, 2H), 7.40 (d, 1H), 7.12 (d, 1H), 6.88 (s, 1H), 4.21 (t, 2H),
3.66 (t, 2H), 3.12 (s, 3H), 2.47 (s, 3H). MS (m/z): 472.9 [MH]+.
4-(6-Methyl-4-[3-(1,3-thiazol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-1-yl)-3-(2-thienyl)benzonitrile (20). 1H
NMR (300 MHz, CDC13): δ 7.93 (d, 1H), 7.85 (d, 1H), 7.78 (d,
1H), 7.67 (d, 1H), 7.55 (dd, 1H), 7.31 (d, 1H), 7.27 (d, 1H), 7.22
(d, 1H), 7.03 (d, 1H), 6.99 (dd, 1H), 6.71 (s, 1H), 3.67 (t, 2H),
3.40 (t, 2H), 2.38 (s, 3H). MS (m/z): 467.5 [MH]+.
4-(6-Methyl-4-[3-(1,3-thiazol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-1-yl)-1,3-benzenedicarbonitrile (21). 1H
NMR (400 MHz, CDC13): δ 8.03 (m, 2H), 7.95 (m, 2H), 7.88 (dd,
1H), 7.39 (d, 1H), 7.09 (d, 1H), 6.95 (s, 1H), 4.40 (t, 2H), 3.42 (t,
2H), 2.51 (s, 3H). MS (m/z): 410.4 [MH]+.
6-Methyl-1-[6-(methyloxy)-2-(trifluoromethyl)-3-pyridinyl]-4-[3-
(1,3-thiazol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]py-
1
ridine (32). H NMR (400 MHz, CDC13): δ 7.9 (d, 1H), 7.8 (d,
1H), 7.6 (d, 1H), 7.3 (d, 1H), 7.0 (d, 1H), 6.9 (d, 1H), 6.7 (s, 1H),
3.9 (s, 3H), 3.8 (t, 2H), 3.5 (t, 2H), 2.33 (s, 3H). MS (m/z): 459
[MH]+.
N,N,4-Trimethy1-5-(6-methvl-4-[3-(1,3-thiazol-2-yl)-1H-pyrazol-
1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-pyridinamine (33).
1H NMR (400 MHz, CDC13): δ 8.57 (d, 1H), 7.95 (s, 1H), 7.92
(d, 1H), 7.78 (d, 1H), 7.04 (d, 1H), 6.86 (s, 1H), 6.55 (s, 1H), 3.88
(t, 2H), 3.49 (t, 2H), 3.16 (s, 3H), 3.14 (s, 3H), 3.01 (s, 6H). MS
(m/z): 418 [MH]+.
3-Chloro-4-(6-methyl-4-[3-(2-pyridinyl)-1H-pyrazol-1-yl]-2,3-di-
1
hydro-1H-pyrrolo[2.3-b]pyridin-1-yl)benzonitrile (34). H NMR
(300 MHz, CDC13): δ 8.67 (d, 1H), 8.11 (d, 1H), 8.03 (d, 1H),
7.75 (m, 2H), 7.75 (m, 1H), 7.55 (dd, 1H), 7.26 (m, 1H), 7.2 (d,
1H), 6.88 (s, 1H), 4.16 (t, 2H), 3.65 (t, 2H), 2.43 (s, 3H). MS (m/
z): 413 [MH]+.
1-(4-Fluoro-2-nitrophenyl)-6-methyl-4-[3-(1,3-thiazol-2-yl)-1H-
pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (22). 1H NMR
(300 MHz, CD3OD): δ 9.35 (d, 1H), 8.77 (d, 1H), 7.98 (d, 1H),
7.80-7.71 (m, 2H), 7.49 (m, 2H), 7.11 (s, 1H), 5.44 (t, 2H), 3.12
(t, 2H), 2.25 (s, 3H). MS (m/z): 423.4 [MH]+.
3-Methyl-4-(6-methyl-4-[3-(2-pyridinyl)-1H-pyrazol-1-yl]-2,3-di-
1
hydro-1H-pyrrolo[2.3-b]pyridin-1-yl)benzonitrile (35). H NMR
(300 MHz, CDC13): δ 8.65 (dd, 1H), 8.10 (d, 1H), 8.00 (d, 1H),
7.75 (dt, 1H), 7.55-7.48 (m, 2H), 7.39 (d, 1H), 7.26 (m, 1H), 7.15
(d, 1H), 6.78 (s, 1H), 4.00 (t, 2H), 3.60 (t, 2H), 2.37 (s, 3H), 2.31
(s, 3H). MS (m/z): 393 [MH]+.
4-(6-Methyl-4-[3-(2-pyridinyl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-
pyrrolo[2.3-b]pyridin-1-yl)-3-(trifluoromethyl)benzonitrile (36). 1H
NMR (300 MHz, CDC13): δ 8.66 (dd, 1H), 8.10 (d, 1H), 8.02 (d,
1H), 8.00 (d, 1H), 7.84 (dd, 1H), 7.76 (t, 1H), 7.69 (d, 1H), 7.27
(t, 1H), 7.18 (d, 1H), 6.87 (s, 1H), 4.02 (t, 2H), 3.64 (t, 2H), 2.38
(s, 3H). MS (m/z): 447 [MH]+.
4-[4-(1′H-1,3′-Bipyrazol-1′-yl)-6-methyl-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-1-yl]-3-methylbenzonitrile (37). 1H NMR (400
MHz, CDC13): δ 8.2 (d, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.6 (d, 1H),
7.5 (dd, 1H), 7.4 (dd, 1H), 6.8 (d, 1H), 6.7 (d, 1H), 6.4 (t, 1H), 4.0
(t, 2H), 4.0 (t, 2H), 3.6 (t, 2H), 2.41,2.35 (s + s, 6H). MS (m/z):
382 [MH]+.
4-[4-(1′H-1,3′-Bipyrazol-1′-yl)-6-methyl-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-1-yl]-3-chlorobenzonitrile (38). 1H NMR (400
MHz, CDC13): δ 8.2 (d, 1H), 8.0 (d, 1H), 7.8 (m, 3H), 7.6 (d,
1H), 6.8 (m, 2H), 6.4 (d, 1H), 4.2 (t, 2H), 3.6 (t, 2H), 2.40 (s, 3H).
MS (m/z): 402 [MH]+.
1-(4-Chloro-2-nitrophenyl)-6-methyl-4-[3-(1,3-thiazol-2-yl)-1H-
pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (23). 1H NMR
(300 MHz, CD3OD): δ 9.27 (d, 1H), 8.59 (d, 1H), 8.27 (d, 1H),
8.21 (d, 1H), 8.14 (d, 1H), 7.72 (d, 1H), 7.68 (dd, 1H), 7.47 (s,
1H), 5.47 (t, 2H), 3.37 (t, 2H), 2.55 (s, 3H). MS (m/z): 439.9 [MH]+.
4-(6-Methyl-4-[3-(1,3-thiazol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-
1
1H-pyrrolo[2,3-b]pyridin-1-yl)-3-nitrobenzonitrile (24). H NMR
(400 MHz, DMSO): δ 10.07 (s, 1H), 9.52 (d, 1H), 8.55 (d, 1H),
8.36 (s, 2H), 8.07 (dd, 1H), 8.02-7.99 (m, 2H), 7.68 (s, 1H), 5.31
(t, 2H), 3.37 (t, 2H), 2.57 (s, 3H). MS (m/z): 430.4 [MH]+.
6-Methyl-1-[4-(methyloxy)-2-nitrophenyl]-4-[3-(1,3-thiazol-2-yl)-
1
1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (25). H
NMR (300 MHz, CD3OD): δ 9.22 (d, 1H), 8.29 (d, 1H), 8.12 (d,
1H), 8.00 (d, 1H), 7.61 (m, 2H), 7.20-7.13 (m, 2H), 5.37 (t, 2H),
3.79 (s, 3H), 3.42 (t, 2H), 2.56 (s, 3H). MS (m/z): 435.4 [MH]+.
1-[2,4-Bis(methylsulfonyl)phenyl]-6-methyl-4-[3-(1,3-thiazol-2-
yl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (26). 1H
NMR (300 MHz, CDCl3): δ 8.75 (d, 1H), 8.25 (dd, 1H), 8.05 (d,
1H), 7.90 (d, 1H), 7.65 (d, 1H), 7.40 (d, 1H), 7.10 (d, 1H), 6.85 (s,
1H), 4.10 (t, 2H), 3.65 (t, 2H), 3.25 (s, 3H), 3.10 (s, 3H), 2.35 (s,
3H). MS (m/z): 516.6 [MH]+.
4-[4-(1′H-1,3′-Bipyrazol-1′-y1)-6-methyl-2,3-dihydro-1H-pyrro-
lo[2,3-b]pyridin-1-yl]-3-(trifluoromethyl)benzonitrile (39). 1H NMR
(300 MHz, CDC13): δ 8.2 (d, 1H), 8.0 (dd, 2H), 7.8 (dd, 1H), 7.7
(d, 1H), 7.6 (dd, 1H), 6.8 (m, 2H), 6.4 (d, 1H), 4.0 (t, 2H), 3.6 (t,
2H), 2.41 (s, 3H). MS (m/z): 436 [MH]+.
1-(2-Difluoromethyl-4-methoxyphenyl)-6-methyl-4-[3-(1,3-thia-
zol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
1
(27). H NMR (400 MHz, CDC13): δ 8.00 (d, 1H), 7.89 (d, 1H),
7.36 (d, 1H), 7.24 (m, 2H), 7.08 (m, 2H), 6.88 (t, 1H, J(H-F)
)
6-Methyl-N-[2-methyl-4-(methyloxy)phenyl]-3-[(E)-2-(methy-
loxy)ethenyl]-4-[3-(1,3-thiazol-2-yl)-1H-pyrazol-1-yl]-2-pyridi-
namine (56). To a solution of (methoxymethyl)triphenylphospho-
nium chloride (4.24 g, 12.3 mmol) in dry THF (20 mL) at 0 °C
under N2 was added n-BuLi (1.6 M) in cyclohexane (7.73 mL, 12.37
mmol), and the reaction mixture was brought to room temperature
and then stirred for 15 min. A solution of intermediate 50 (1.25 g,
4.1 mmol) in dry THF (15 mL) was then added, and the mixture
was stirred at room temperature for 1.5 h. The reaction was then
quenched with water, and the layer was extracted with EtOAc,
washed with brine, dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
(silica gel, cyclohexane/ethyl acetate 4:l) to give 961 mg of the
enol ether intermediate as a white solid (E/Z ) 3:2 mixture, used
as such in the next step). To a solution of this intermediate (180
mg, 0.542 mmol) in dry DME (2 mL) were added Pd2(dba)3 (50
mg, 0.054 mmol), K3PO4 (270 mg, 1.35 mmol), and 2-methyl-4-
(methyloxy)aniline (145 µL, 1.08 mmol), and the resulting mixture
was submitted to microwave irradiation at 100 °C for 10 min. The
reaction mixture was then poured into water and extracted with
ethyl acetate. The organic extracts were dried (Na2SO4), filtrated,
and concentrated in vacuo. The crude material was then purified
by flash chromatography (cyclohexane/ethyl acetate from 8:2 to
55.8 Hz), 6.71 (s, 1H), 3.95 (t, 2H), 3.87 (s, 3H), 3.56 (t, 2H), 2.36
(s, 3H). MS (m/z): 440 [MH]+.
6-Methyl-1-[4-(methyloxy)phenyl]-4-[3-(1,3-thiazol-2-yl)-1H-
pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (28). 1H NMR
(400 MHz, DMSO): δ 8.57 (d, 1H), 7.90 (d, 1H), 7.77 (d, 2H),
7.75 (d, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.91 (d, 2H), 4.03 (t, 2H),
3.70 (s, 3H), 3.46 (t, 2H), 2.36 (s, 3H). MS (m/z): 390.4 [MH]+.
3-Fluoro-4-(6-methyl-4-[3-(1,3-thiazol-2-yl)-1H-pyrazol-1-yl]-2,3-
dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (29). 1H NMR
(300 MHz, CDCl3): δ 8.19 (dd, 1H), 8.00 (d, 1H), 7.86 (d, 1H),
7.42 (d, 1H), 7.35 (m, 2H), 7.12 (d, 1H), 6.85 (s, 1H), 4.18 (t, 2H),
3.62 (t, 2H), 2.35 (s, 3H). MS (m/z): 403.4 [MH]+.
6-Methyl-1-[2-methyl-6-(methyloxy)-3-pyridinyl]-4-[3-(1,3-thia-
zol-2-yl)-1H-pyrazol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
1
(30). H NMR (300 MHz, CDC13): δ 7.98 (d, 1H), 7.88 (d, 1H),
6.98 (d, 1H), 6.83 (d, 1H), 7.03 (d, 1H), 6.62 (d, 1H), 6.60 (s, 1H),
3.92 (s, 3H), 3.90 (d, 2H), 3.56 (d, 2H), 2.39 (s, 3H), 2.35 (s, 3H).
MS (m/z): 405 [MH]+.
1-[2,6-Bis(methyloxy)-3-pyridinyl]-6-methyl-4-[3-(1,3-thiazol-2-
yl)-1H-pyrazol-1-yl]- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (31).
1H NMR (300 MHz, CDC13): δ 7.98 (d, 1H), 7.87 (d, 1H), 7.72
(d, 1H), 7.34 (d, 1H), 7.06 (d, 1H), 6.67 (s, 1H), 6.36 (d, 1H), 3.96
(t, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.51 (t, 2H), 2.37 (s, 3H). MS
(m/z): 421 [MH]+.
1
1:1) to give the target compound (90 mg, 40%). H NMR (300
MHz, CDC13): δ 7.79-7.85 (m, 2H), 7.27 (d, 2H), 7.00 (m, 1H),