NoVel Druglike CRF1 Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 23 7377
filtered, and after removal of the solvent in vacuo, the residue was
filtered over a silica gel pad (CH2Cl2) to give the title compound
(148 mg, 84% yield) as pale-yellow oil. 1H NMR (400 MHz,
DMSO-d6) δ: 7.17 (d, 1H), 6.85 (d, 1H), 6.77 (dd, 1H), 6.40 (s,
1H), 3.89 (t, 2H), 3.73 (s, 3H), 3.16 (t, 2H), 2.17-2.11 (bs, 6H).
MS: m/z 403 [M + H]+.
4-Iodo-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihy-
dro-1H-pyrrolo[2,3-b]pyridine (29). To a solution of intermediate
28 (913 mg, 2.27 mmol) in anhydrous NMP (7 mL) was added KI
(1.13 g,) and the reaction mixture was stirred at 150 °C for 18 h.
It was then cooled down to room temperature and poured in water.
The aqueous phase was extracted with EtOAc (3 × 30 mL), and
the combined organic extracts were dried over anhydrous Na2SO4.
The solid was filtered, and the solvent evaporated in vacuo. The
crude residue was then purified by flash chromatography (cyclo-
hexanes/EtOAc 9:l) to give the title compound as a clear oil, which
solidified upon standing (681 mg, 79% yield). 1H NMR (400 MHz,
CDCl3) δ: 7.14 (d, 1H), 6.81-6.74 (m, 2H), 6.70 (s, 1H), 3.84 (t,
2H), 3.81 (s,3H), 3.03 (t, 2H), 2.22 (s, 6H). MS: m/z 381 [M +
H]+.
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidi-
none (3). In a sealed vial, at room temperature, under nitrogen
atmosphere, compound 29 (60 mg, 0.158 mmol), CuI (6 mg, 0.032
mmol), and K2CO3 (4.5 mg, 0.4 mmol) were added to a solution
of dodecane (14.3 µL, 0.063), (1R,2R)-1,2-cyclohexanediamine (14
µL, 0.095), and 1-(1H-pyrazol-3-yl)-2-imidazolidinone (intermediate
8, 48 mg, 0.316) in anhydrous NMP (N-methylpyrrolidinone) (5
mL) and the reaction mixture was stirred at 130 °C for 3.5 h. It
was then cooled down to room temperature and poured in EtOAc/
H2O. The organic phase was separated, and the aqueous layer was
extracted with EtOAc (2 × 10 mL). The combined organic extracts
were dried over anhydrous Na2SO4, the solids were filtered, and
the solvent evaporated in vacuo. The crude compound was purified
by flash chromatography (EtOAc/cyclohexanes 6:4, then 1:1, then
3:7) followed by a SCX cartridge (100% MeOH, then 2 M NH3/
MeOH), to give the title compound as a white solid (34 mg, 53%).
1H NMR (600 MHz, DMSO-d6) δ8.31 (d, J ) 2.75 Hz, 1H), 7.17
(d, J ) 8.79 Hz, 1H), 7.06 (s, 1H), 6.86 (d, J ) 2.75 Hz, 1H),
6.68-6.83 (m, 2H), 3.87-4.06 (m, 1H), 3.83 (t, J ) 8.38 Hz, 1H),
3.76 (s, 2H), 3.46 (t, J ) 8.24 Hz, 2H), 3.31 (s, 3H), 2.16 (d, J )
12.36 Hz, 3H). MS: m/z 405 [M + H]+. 13C NMR (150.81 MHz,
DMSO-d6): 163.64, 158.06, 157.34, 155.81, 150.28, 141.51, 137.27,
133.84, 129.65, 127.36, 115.69, 111.87, 106.64, 101.25, 97.28,
55.15, 51.54, 43.33, 37.21, 26.66, 23.93, 18.34.
1-(1-{6-Ethyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-pyrrolidino-
ne (4). Compound obtained as a pale-yellow solid. 1H NMR (400
MHz, DMSO-d6) δ: 8.35 (d, 1H), 7.20 (d, IH), 6.95 (d, 1H), 6.85
(d, 1H), 6.75 (m, 2H), 3.90 (m, 4H), 3.70 (s, 3H), 3.45 (t, 2H),
2.50 (m, 2H), 2.15 (s, 3H), 2.10 (m, 2H), 2.10 (s, 3H). MS: m/z
404 [M + H]+.
1-Methyl-3-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-
imidazolidinone (5). Compound obtained as a pale-yellow solid.
1H NMR (300 MHz, CDCl3): δ 7.76 (d, 1H), 7.15 (d, 1H), 6.93
(d, 1H), 6.80-6.75 (m, 3H), 6.52 (s, 1H), 3.96 (t, 2H), 3.84 (t,
2H), 3.77 (s, 2H), 3.50 (t, 2H), 3.42 (t, 2H), 3.89 (s, 3H), 2.28 (s,
3H), 2.20 (s, 3H). MS: (m/z) 419 [MH]+.
3-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-oxazolidin-
2-one (6). Compound obtained as a white solid. 1H NMR (300
MHz, CDCl3) δ: 7.85 (d, 1H), 7.16 (d, 1H), 6.93 (d, 1H), 6.81 (d,
1H), 6.77 (dd, 1H), 6.55 (s, 1H), 4.54 (t, 2H), 4.2 (t, 2H), 3.87 (t,
2H), 3.8 (s, 3H), 3.44 (t, 2H), 2.32 (s, 3H), 2.24 (s, 3H). MS: m/z
406 [M + H]+.
1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)tetrahydro-2(1H)-
pyrimidinone (8). Compound as a white solid. 1H NMR (400 MHz,
CDCl3) δ: 7.80 (d, 1H), 7.2 (d, 1H), 7.0 (d, 1H), 6.80 (d, 1H), 6.75
(dd, 1H), 6.60 (s, 1H), 4.95 (bs, 1H), 4.05 (dd, 2H), 3.90 (t,2H),
3.80 (s, 3H), 3.45 (t, 2H), 3.40 (bm, 2H), 2.45 (s, 3H), 2.25 (s,
3H), 2.05 (m, 2H). MS: m/z 419 [M + H]+.
1-(1-{1-[4-(Ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-
1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidi-
none] (11). 1H NMR (300 MHz, DMSO-d6) δ: 7.82 (d, 1H), 7.15
(d, lH), 6.90 (d, 1H), 6.78 (d, 1H), 6.75 (dd, 1H), 6.70 (dd, 1H),
4.70 (bs, 1H), 4.2-4.0 (m, 4H), 3.80 (t, 2H), 3.60 (t, 2H), 3.40 (t,
2H), 2.30 (s, 3H), 2.25 (s, 2H), 1.45 (t, 3H). MS: m/z 419 [M +
H]+.
1-[1-(6-Methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-
imidazolidinone (12). 1H NMR (400 MHz, DMSO-d6) δ: 7.90 (d,
1H), 7.10 (d, lH), 6.90 (d, 1H), 6.8-6.7 (m, 2H), 6.55 (s, 1H),
4.60 (bs, 1H), 4.50 (m, 1H), 4.10 (t, 2H), 3.90 (t, 2H), 3.60 (t,
2H), 3.45 (t, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 1.26 (d, 6H). MS: m/z
475 [M + H]+.
1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-
imidazolidinone (13). 1H NMR (400 MHz, CDCl3) δ: 7.84 (d,
1H), 7.30 (d, 1H), 7.12 (s, 1H), 7.09 (d, 1H), 6.98 (d, 1H), 6.63 (s,
1H), 4.68 (s, 1H), 4.10 (t, 2H), 3.91 (t, 2H), 3.63 (t, 2H), 3.50 (t,
2H), 2.36 (s, 3H), 2.29 (s, 3H). MS: m/z 459 [M + H]+.
3-Methyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyra-
zol-1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-
yl}benzonitrile (14). 1H NMR (400 MHz, CDCl3) δ: 7.82 (d, 1H),
7.6 (bs, 1H), 7.49 (m, 1H), 7.34 (m, 1H), 6.96 (d, 1H), 6.65 (s,
1H), 4.7 (bs, 1H), 4.11 (t, 2H), 3.92 (t, 2H), 3.62 (t, 2H), 3.49 (t,
2H), 2.41 (s, 3H), 1.22 (t, 3H).). MS: m/z 414 [M + H]+.
1-(1-{6-Methyl-1-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-2,3-di-
hydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imida-
zolidinone (15). 1H NMR (400 MHz, CDCl3) δ: 7.90 (d, 1H), 7.84
(d, 1H), 7.72 (d, 1H), 7.68 (m, 1H), 7.64 (m, 1H), 7.37 (d, 1H),
6.97 (d, 1H), 6.62 (s, 1H), 6.45 (t, 1H), 4.77 (s, 1H), 4.11 (t, 2H),
3.94 (t, 2H), 3.63 (t, 2H), 3.50 (t, 2H), 2.34 (s, 6H). MS: m/z 441
[M + H]+.
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}-3-(trifluoromethyl)-
1
benzonitrile (16). H NMR (400 MHz, CDCl3) δ: 8.01 (d, 1H),
7.85 (d, 1H), 7.84 (dd, 1H), 7.69 (d, 1H), 7.00 (d, 1H), 6.75 (s,
1H), 4.65 (s, 1H), 4.10 (t, 2H), 3.98 (t, 2H), 3.64 (t, 2H), 3.51 (t,
2H), 2.36 (s, 3H). MS: m/z 454 [M + H]+.
1-(1-{1-[2-(Difluoromethyl)-4-(methyloxy)phenyl]-6-methyl-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-
imidazolidinone (17). 1H NMR (300 MHz, CDCl3) δ: 7.84 (d,
1H), 7.21 (m, 2H), 7.02 (dd, 1H), 6.87 (t, 1H), 6.97 (d, 1H), 6.64
(s, 1H), 4.84 (bs, 1H), 4.13 (t, 2H), 3.93 (t, 2H), 3.9 (s, 3H), 3.66
(t, 2H), 3.53 (t, 2H), 2.33 (s, 3H). MS: m/z 441 [M + H]+.
4-{6-Methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-1-yl]-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}-3-[(trifluoromethyl)-
oxy]benzonitrile (18). 1H NMR (300 MHz, CDCl3) δ: 8.05 (d,
1H), 7.84 (m, 1H), 7.54 (bs, 1H), 7.5 (m, 1H), 6.98 (m, 1H), 6.78(s,
1H), 4.63 (bs, 1H), 4.11 (m, 4H), 3.62 (t, 2H), 3.48 (t, 2H), 2.41
(s, 3H). MS: m/z 470 [M + H]+.
3-Ethyl-4-{6-methyl-4-[3-(2-oxo-1-imidazolidinyl)-1H-pyrazol-
1-yl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile (19).
1H NMR (400 MHz, CDCl3) δ: 7.82 (d, 1H), 7.6 (bs, 1H), 7.49
(m, 1H), 7.34 (m, 1H), 6.96 (d, 1H), 6.65 (s, 1H), 4.7 (bs, 1H),
4.11 (t, 2H), 3.92 (t, 2H), 3.62 (t, 2H), 3.49 (t, 2H), 2.66 (m, 2H),
2.41 (s, 3H), 1.22 (t, 3H). MS: m/z 414 [M + H]+.
1-(1-{6-Methyl-1-[2-(methyloxy)-4-(1H-pyrazol-1-yl)phenyl]-
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-
imidazolidinone (20). 1H NMR (400 MHz, CDCl3) δ: 7.89 (d,
1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.58 (d, 1H), 7.42 (d, 1H), 7.16
(dd, 1H), 6.94 (d, 1H), 6.62 (s, 1H), 6.44 (t, 1H), 4.68 (bs, 1H),
4.13-3.66 (t, 4H), 3.89 (s, 3H), 3.93-3.53 (t, 4H), 2.34 (s, 3H).
MS: m/z 457 [M + H]+.
1-{1-[1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyr-
rolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-2-imidazolidinone (21).
1H NMR (300 MHz, CDCl3) δ: 7.82 (s, lH), 7.78 (s, lH), 7.44 (s,
lH), 7.42 (s, lH), 7.26 (s, lH), 6.95 (s, lH), 6.66 (s, lH), 4,57 (b s,