Journal of Medicinal Chemistry
Article
35 °C in an oil bath for 5 h. The reaction mixture was
concentrated, dissolved in CHCl3, washed with H2O, dried over
Na2SO4, filtered, and concentrated. The crude product was
purified by chromatography on silica gel eluting with MeOH/
CHCl3 (0 to 2%) to give (S)-benzyl 1-(2-hydroxypropyl)-5-
methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate
(8.7 g, 79% yield) as a solid.
(S)-N-(3-Fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-
hydroxybutyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxamide (58c). The general procedure for amide
coupling between 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxylic acid and anilines was followed to prepare the title
compound. MS (ESI pos ion) m/z: calcd for C31H29FN4O5, 556.2;
found, 556.6 (M + H). 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J = 7.3
Hz, 3 H), 1.27−1.43 (m, 2 H), 1.60−1.82 (m, 1 H), 2.85 (s, 3 H),
3.56−3.66 (m, 1 H), 3.70 (dd, J = 1.6 Hz, 1 H), 3.79−3.90 (m, 1 H),
3.95 (s, 3 H),6.42 (d, J = 5.3 Hz, 3 H), 7.11−7.31 (m, 6 H), 7.36 (d,
J = 2.2 Hz, 1 H), 7.39−7.53 (m, 3 H), 7.95 (dd, J = 12.5, 2.0 Hz, 1 H),
8.30 (d, J = 9.2 Hz, 1 H), 8.50 (d, J = 5.3 Hz, 1 H), 10.90 (s, 1 H).
N-(3-Fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hy-
droxy-3-methylbutyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-
1H-pyrazole-4-carboxamide (58d). The general procedure for
amide coupling between 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carboxylic acid and anilines was followed to prepare the
title compound. MS (ESI pos ion) m/z: calcd for C32H31FN4O5,
570.2; found, 571.6 (M + H). 1H NMR (400 MHz, CDCl3) δ 0.73 (d,
J = 6.8 Hz, 3 H), 0.79 (d, J = 6.8 Hz, 3 H), 1.45−1.70 (m, 3H), 2.85
(s, 3 H), 3.39−3.48 (m, 1 H), 3.72−3.80 (m, 1 H), 3.83−3.92 (m,
1 H), 3.96 (s, 3 H), 6.38−6.44 (m, 1 H), 7.13−7.24 (m, 2 H), 7.28−
7.33 (m, 2 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.42−7.49 (m, 1 H), 7.49−
7.58 (m, 2 H), 7.92 (dd, J = 12.4, 2.4 Hz, 1 H), 8.28 (d, J = 9.0 Hz,
1 H), 8.56 (d, J = 5.3 Hz, 1 H), 10.89 (s, 1 H).
(B) The Next Two Steps Were Carried Out Similar to That for the
Preparation of (R)-58a. MS (ESI pos ion) m/z: calcd for
1
C30H27FN4O5, 542.5; found, 543.2 (M + H). H NMR (400 MHz,
DMSO-d6) δ 0.90 (d, J = 6.1 Hz, 3 H), 2.76 (s, 3 H), 3.55−3.70 (m, 2
H), 3.88 (dd, J = 15.1, 8.6 Hz, 1 H), 3.94 (s, 3 H), 5.07 (d, J = 5.3 Hz,
1 H), 6.49 (d, J = 5.1 Hz, 1 H), 7.26−7.38 (m, 2 H), 7.38−7.47 (m, 3
H), 7.47−7.54 (m, 1 H), 7.54−7.64 (m, 2 H), 7.98 (dd, J = 13.1,
2.4 Hz, 1 H), 8.23 (d, J = 9.2 Hz, 1 H), 8.62 (d, J = 5.3 Hz, 1 H), 10.99
(s, 1 H). Anal. Calcd for: C, 66.41; H, 5.02; N, 10.33. Found: C, 65.39;
H, 5.03; N, 10.21.
1-(2-Hydroxypropyl)-N-(5-(7-methoxyquinolin-4-yloxy)-
pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxamide (59a). Prepared from racemic 57a and aniline
9d through amide coupling. MS (ESI pos ion) m/z: calcd for
1
C29H27N5O5, 525.2; found, 526.2 (M + H). H NMR (400 MHz,
DMSO-d6) δ 0.86−0.93 (m, 3 H), 2.77 (s, 3 H), 3.56−3.69 (m, 2 H),
3.88 (dd, J = 15.2, 8.9 Hz, 1 H), 3.94 (s, 3 H), 5.08 (d, J = 5.3 Hz,
1 H), 6.54 (d, J = 5.3 Hz, 1 H), 7.30 (dd, J = 9.1, 2.4 Hz, 1 H), 7.39−
7.45 (m, 3 H), 7.47−7.55 (m, 1 H), 7.55−7.64 (m, 2 H), 7.80 (dd, J =
9.0, 2.9 Hz, 1 H), 8.22 (d, J = 9.0 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H),
8.36 (d, J = 9.0 Hz, 1 H), 8.62 (d, J = 5.3 Hz, 1 H), 11.27 (s, 1 H).
N-(3-Fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hy-
droxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxamide (58b). (A) 1-(2-Hydroxyethyl)-5-methyl-3-
Synthesis of 58e and 59e were described previously.9
1-(2-Aminoethyl)-N-(3-fluoro-4-(7-methoxyquinolin-4-
yloxy)phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxamide (61). (A) 1-(2-(1,3-Dioxoisoindolin-2-yl)-
ethyl)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-5-methyl-
3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (60). To a
solution of N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-
1-(2-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazole-4-carboxamide (0.20 g, 0.38 mmol) and phthalimide
(0.11 g, 0.76 mmol) in DCM (10 mL) was added Ph3P (0.15 g,
0.57 mmol), followed by diethyl azodicarboxylate (0.089 mL,
0.57 mmol) via a syringe. The mixture was stirred at rt for 16 h.
The solution was concentrated in vacuo, and the residue was
purified by chromatography on silica gel with MeOH/EtOAc
(0 to 10%) to give the desired product as light-yellow solid
(0.22 g, 88%). MS (ESI pos ion) m/z calcd for C37H28FN5O6,
657.2; found, 658.2 (M + H). 1H NMR (300 MHz, CD3OD) δ
2.61 (s, 3 H), 3.67 (t, J = 5.5 Hz, 2 H), 3.89 (s, 3 H), 4.20 (t,
J = 5.5 Hz, 2 H), 6.41 (dd, J = 5.4, 1.0 Hz, 1 H), 7.15−7.31 (m,
6 H), 7.35−7.46 (m, 3 H), 7.70−7.85 (m, 5 H), 8.20 (d, J = 9.0
Hz, 1 H), 8.45 (d, J = 5.5 Hz, 1 H).
oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic Acid (57b).
A
mixture of benzyl 1-(2-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazole-4-carboxylate (56b, 0.73 g, 2.1 mmol)
and Pd/C (10%, 0.22 g) in EtOAc (40 mL) was stirred under
H2 (balloon) for 3 h. The mixture was filtered though a pad of
Celite, and the filtrate was concentrated in vacuo. The residue
was washed with MeOH to give the desired product as white
solid (0.45 g, 83%). MS (ESI pos ion) m/z calcd for
1
C13H14N2O4, 262.1; found, 263.1 (M + H). H NMR (300
MHz, CD3OD) δ 2.72 (s, 3 H), 3.48 (t, J = 5.1 Hz, 2 H), 4.01
(t, J = 5.2 Hz, 2 H), 7.37−7.49 (m, 2 H), 7.52−7.67 (m, 3 H).
(B) N-(3-Fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hy-
droxyethyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-
carboxamide (58b). The general procedure for amide coupling
between 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-car-
boxylic acid and anilines was followed to prepare the title compound,
starting with 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine-
HCl salt (0.26 g, 0.92 mmol) and 1-(2-hydroxyethyl)-5-methyl-3-
oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.40 g, 1.5
mmol), as white solid (0.43 g, 89%). MS (ESI pos ion) m/z calcd for
(B) 1-(2-Aminoethyl)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-
phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-car-
boxamide (61). To a solution of 1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-
N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-5-methyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.20 g, 0.30 mmol) in
EtOH/H2O (1:1, 20 mL) was added H2N2 (0.049 g, 1.5 mmol). The
mixture was heated at 50 °C for 8 h and allowed to cool to rt. The
mixture was diluted with NaHCO3 (saturated, 20 mL) and EtOAc (60
mL). The organic phase was separated and washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
washed with hexanes/EtOAc (20%) to give desired product as light-
yellow solid (0.13 g, 81%). MS (ESI pos ion) m/z calcd for
1
C29H25FN4O5, 528.2; found, 529.2 (M + H). H NMR (300 MHz,
CD3OD) δ 2.84 (s, 3 H), 3.52 (t, J = 5.1 Hz, 2 H), 3.99 (s, 3 H), 4.03
(t, J = 5.2 Hz, 2 H), 6.51 (dd, J = 5.37, 1.0 Hz, 1 H), 7.24−7.41 (m,
4 H), 7.43−7.51 (m, 2 H), 7.51−7.68 (m, 3 H), 7.89−8.00 (m, 1 H),
8.30 (d, J = 9.2 Hz, 1 H), 8.55 (d, J = 5.3 Hz, 1 H).
1-(2-Hydroxyethyl)-N-(5-(7-methoxyquinolin-4-yloxy)-
pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxamide (59b). The general procedure for amide
coupling between 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxylic acid and anilines was followed to prepare the title
compound, starting with 1-(2-hydroxyethyl)-5-methyl-3-oxo-2-phenyl-
2,3-dihydro-1H-pyrazole-4-carboxylic acid (0.30 g, 1.1 mmol) and
5-(7-methoxyquinolin-4-yloxy)pyridin-2-amine (0.31 g, 1.1 mmol), as
white solid (TFA salt) (0.20 g, 34%). MS (ESI pos ion) m/z calcd for
1
C29H26FN5O4, 527.1; found, 528.1 (M + H). H NMR (300 MHz,
CD3OD) δ 2.67 (t, J = 6.7 Hz, 3 H), 2.82 (s, 3 H), 3.86−4.04 (m, 6
H), 6.49 (dd, J = 5.5, 0.94 Hz, 1 H), 7.21−7.40 (m, 4 H), 7.40−7.50
(m, 2 H), 7.52−7.69 (m, 3 H), 7.89−8.00 (m, 1 H), 8.29 (d, J = 9.2
Hz, 1 H), 8.53 (d, J = 5.5 Hz, 1 H).
1-(2-Methoxyethyl)-N-(5-(7-methoxyquinolin-4-yloxy)-
pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-
zole-4-carboxamide (63). (A) Benzyl 1-(2-Methoxyethyl)-5-
methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate
(62a). To a solution of benzyl 1-(2-hydroxyethyl)-5-methyl-3-
oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (5.0 g, 14
mmol) in DCM (50 mL) was added a solution of fluoroboric
acid (50%, 14 mL, 284 mmol). A solution of trimethylsilyl
1
C28H25N5O5, 511.2.2; found, 512.2 (M + H). H NMR (300 MHz,
CD3OD) δ 2.84 (s, 3 H), 3.43−3.58 (m, 2 H), 4.03 (t, J = 4.4 Hz,
2 H), 4.08 (s, 3 H), 7.00 (d, J = 6.6 Hz, 1 H), 7.38−7.68 (m, 8 H),
7.83 (d, J = 9.0 Hz, 1 H), 8.33 (bs, 1 H), 8.47 (d, J = 9.0 Hz, 1 H),
8.55 (d, J = 9.4 Hz, 1 H), 8.81 (d, J = 6.8 Hz, 1 H).
1893
dx.doi.org/10.1021/jm201331s | J. Med. Chem. 2012, 55, 1868−1897