Journal of Medicinal Chemistry
Article
(CDCl3) δ 2.69 (3H, s), 3.91 (3H, s), 7.27−7.38 (2H, m), 7.45−7.53
(1H, m), 7.65 (1H, td, J = 7.9, 1.5 Hz), 7.77 (1H, d, J = 2.3 Hz).
3-Acetyl-1-(2-fluoro-4-iodophenyl)-5-methoxypyridazin-4(1H)-
one (25b). Compound 25b was obtained (23%) as a pale-yellow solid in
a manner similar to that described for the synthesis of 18. H NMR
(CDCl3) δ 2.67 (3H, s), 3.90 (3H, s), 7.36−7.41 (1H, m), 7.66−7.71
(2H, m), 7.73 (1H, d, J = 2.6 Hz).
3.83−3.87 (4H, m), 3.89 (3H, s), 6.31 (1H, t, J = 9.0 Hz), 6.45 (1H, dd,
J = 9.0, 2.6 Hz), 6.58 (1H, dd, J = 14.7, 2.6 Hz), 7.26 (1H, d, J = 1.9 Hz),
7.33−7.45 (5H, m), 7.74 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J = 1.9 Hz).
LC-MS (ESI) m/z 448 [M + H]+. Anal. Calcd for C24H22FN5O3: C,
64.42; H, 4.96; N, 15.65. Found: C, 64.33; H, 4.98; N, 15.59.
1
4-{3-Fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)-
pyridazin-1(4H)-yl]phenyl}morpholin-3-one (27e). A suspension of
26 (244 mg, 0.5 mmol), 3-morpholinone (60.7 mg, 0.6 mmol), CuI
(9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL,
0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL)
was refluxed for 6 h under Ar atmosphere. The mixture was poured into
water and extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by column chromatography (basic silica gel,
EtOAc) followed by recrystallization from MeOH/water to give 27e
(136 mg, 59%) as a white solid; mp 193−195 °C. 1H NMR (CDCl3) δ
3.75−3.79 (2H, m), 3.90 (3H, s), 4.04−4.07 (2H, m), 4.35 (2H, s), 6.41
(1H, t, J = 9.0 Hz), 7.00 (1H, ddd, J = 9.0, 2.3, 1.1 Hz), 7.31 (1H, d, J =
2.3 Hz), 7.33−7.46 (6H, m), 7.78−7.80 (2H, m). LC-MS (ESI) m/z 462
[M + H]+. Anal. Calcd for C24H20FN5O4: C, 62.47; H, 4.37; N, 15.18.
Found: C, 62.31; H, 4.33; N, 15.25.
1-[2-Fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-5-methoxy-3-
(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27f). Compound 27f
was obtained (71%) as a pale-yellow solid in a manner similar to that
described for the synthesis of 27e; mp 218−220 °C. 1H NMR (CDCl3)
δ 3.90 (3H, s), 4.03−4.08 (2H, m), 4.51−4.56 (2H, m), 6.42 (1H, t, J =
9.0 Hz), 7.01 (1H, ddd, J = 9.0, 2.3, 1.1 Hz), 7.30 (1H, d, J = 1.9 Hz),
7.35−7.45 (5H, m), 7.66 (1H, dd, J = 13.6, 2.3 Hz), 7.78 (2H, d, J = 1.9
Hz). LC-MS (ESI) m/z 448 [M + H]+. Anal. Calcd for C23H18FN5O4: C,
61.74; H, 4.06; N, 15.65. Found: C, 61.48; H, 4.07; N, 15.54
3-Acetyl-1-[2-fluoro-4-(trifluoromethoxy)phenyl]-5-methoxypyri-
dazin-4(1H)-one (25c). Compound 25c was obtained (79%) as a pale-
yellow solid in a manner similar to that described for the synthesis of 18.
1H NMR (CDCl3) δ 2.68 (3H, s), 3.91 (3H, s), 7.19−7.25 (2H, m),
7.69−7.75 (2H, m).
1-(2-Fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-
pyridazin-4(1H)-one (26). A solution of 25b (2.02 g, 5.2 mmol) in
DMFDMA (30 mL) was refluxed for 6 h. After cooling to room
temperature, the reaction mixture was concentrated under reduced
pressure.
A solution of the residue and phenylhydrazine (1.54 mL, 15.6 mmol)
in AcOH (20 mL) was refluxed for 2 h. After cooling to room tem-
perature, the reaction mixture was concentrated under reduced pressure.
The residue was diluted with EtOAc, washed successively with 1 M HCl
aq, 1 M NaOH aq, and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, EtOAc) followed by recrystallization from
EtOAc to give 26 (1.14 g, 45%) as a pale-yellow solid. 1H NMR (CDCl3)
δ 3.90 (3H, s), 6.04 (1H, t, J = 8.5 Hz), 7.30−7.47 (7H, m), 7.54 (1H, dd,
J = 10.6, 1.9 Hz), 7.76 (1H, d, J = 2.3 Hz), 7.78 (1H, d, J = 2.3 Hz).
1-(2-Fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-
pyridazin-4(1H)-one (27a). Compound 27a was obtained (59%) as a
white solid in a manner similar to that described for the synthesis of
26; mp 163−165 °C. 1H NMR (CDCl3) δ 3.90 (3H, s), 6.43 (1H, td, J =
7.9, 1.5 Hz), 6.98−7.04 (1H, m), 7.18 (1H, ddd, J = 11.3, 8.3, 1.1 Hz),
7.28−7.46 (7H, m), 7.78 (1H, d, J = 1.9 Hz), 7.81 (1H, d, J = 2.3 Hz).
LC-MS (ESI) m/z 363 [M + H]+. Anal. Calcd for C20H15FN4O2: C,
66.29; H, 4.17; N, 15.46. Found: C, 66.09; H, 4.22; N, 15.42.
1-[2-Fluoro-4-(trifluoromethyl)phenyl]-5-methoxy-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin-4(1H)-one (27b). A suspension of 26
(244 mg, 0.5 mmol), methyl 2,2-fluoro-2-(fluorosulfonyl)acetate
(0.318 mL, 2.5 mmol), CuI (114 mg, 0.6 mmol), and HMPA (0.435 mL,
2.5 mmol) in DMF (2.5 mL) was stirred at 90 °C for 24 h under Ar
atmosphere. The mixture was poured into water and extracted with
EtOAc. The organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography (basic silica gel, 50:50 hexane/EtOAc)
followed by recrystallization from EtOAc/hexane to give 27b (71.7
mg, 33%) as an off-white solid; mp 169−171 °C. 1H NMR (CDCl3) δ
3.92 (3H, s), 6.42−6.47 (1H, m), 7.22−7.26 (1H, m), 7.37−7.49
(7H, m), 7.80 (1H, d, J = 1.9 Hz), 7.84 (1H, d, J = 2.3 Hz). LC-MS (ESI)
m/z 431 [M + H]+. Anal. Calcd for C21H14F4N4O2: C, 58.61; H, 3.28; N,
13.02. Found: C, 58.50; H, 3.36; N, 12.93.
1-[2-Fluoro-4-(1H-imidazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin-4(1H)-one (27g). Compound 27g was
obtained (8%) as a white solid in a manner similar to that described
1
for the synthesis of 27e; mp 235−236 °C. H NMR (CDCl3) δ 3.93
(3H, s), 6.49 (1H, t, J = 8.7 Hz), 7.03 (1H, ddd, J = 8.7, 2.3, 1.1 Hz),
7.22−7.27 (3H, m), 7.35 (1H, d, J = 1.9 Hz), 7.38−7.49 (5H, m), 7.80
(1H, d, J = 1.9 Hz), 7.82 (1H, d, J = 2.6 Hz), 7.86 (1H, t, J = 1.1 Hz). LC-
MS (ESI) m/z 429 [M + H]+. Anal. Calcd for C23H17FN6O2: C, 64.48;
H, 4.00; N, 19.62. Found: C, 64.35; H, 3.90; N, 19.43.
1-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). A suspension of 26
(4.88 g, 10 mmol), pyrazole (0.681 g, 10 mmol), Cu2O (0.143 g, 1 mmol),
salicylaldoxime (0.549 g, 4 mmol), and Cs2CO3 (6.52 g, 20 mmol) in
CH3CN (100 mL) was refluxed for 5 h under Ar atmosphere. The
mixture was poured into water and extracted with EtOAc. The organic
layer was washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatography
(basic silica gel, 33:67 hexane/THF) followed by recrystallization from
EtOH/water to give 27h (1.90 g, 44%) as a pale-yellow solid; mp 214−
216 °C. 1H NMR (CDCl3) δ 3.92 (3H, s), 6.44 (1H, t, J = 9.0 Hz), 6.53
(1H, dd, J = 2.3, 1.9 Hz), 7.30 (1H, ddd, J = 9.0, 2.3, 1.1 Hz), 7.34 (1H, d,
J = 1.9 Hz), 7.37−7.48 (5H, m), 7.61 (1H, dd, J = 12.4, 2.3 Hz), 7.76
(1H, d, J = 1.9 Hz), 7.79 (1H, d, J = 1.9 Hz), 7.82 (1H, d, J = 2.3 Hz),
7.92 (1H, d, J = 2.3 Hz). LC-MS (ESI) m/z 429 [M + H]+. Anal. Calcd
for C23H17FN6O2: C, 64.48; H, 4.00; N, 19.62. Found: C, 64.41; H, 4.00;
N, 19.54.
1-[2-Fluoro-4-(trifluoromethoxy)phenyl]-5-methoxy-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin-4(1H)-one (27c). Compound 27c was
obtained (66%) as a white solid in a manner similar to that described
1
for the synthesis of 26; mp 117−118 °C. H NMR (CDCl3) δ 3.90
(3H, s), 6.43 (1H, t, J = 8.7 Hz), 6.85−6.90 (1H, m), 7.09 (1H, dd, J =
11.5, 1.7 Hz), 7.34 (1H, d, J = 1.9 Hz), 7.35−7.47 (5H, m), 7.77 (1H, d,
J = 2.3 Hz), 7.78 (1H, d, J = 1.9 Hz). LC-MS (ESI) m/z 447 [M + H]+.
Anal. Calcd for C21H14F4N4O3: C, 56.51; H, 3.16; N, 12.55. Found: C,
56.51; H, 3.14; N, 12.61.
Methyl 2-[(4-Iodophenyl)hydrazono]-4-methoxy-3-oxobuta-
noate (29). Compound 29 was obtained (78%) as a yellow−brown
1
solid in a manner similar to that described for the synthesis of 15. H
1-[2-Fluoro-4-(morpholin-4-yl)phenyl]-5-methoxy-3-(1-phenyl-
1H-pyrazol-5-yl)pyridazin-4(1H)-one (27d). A suspension of 26
(244 mg, 0.5 mmol), morpholine (0.053 mL, 0.6 mmol), Pd2(dba)3
(18.3 mg, 0.02 mmol), Xantphos (46.3 mg, 0.08 mmol), and NaOt-Bu
(67.3 mg, 0.7 mmol) in 1,4-dioxane (2.5 mL) was stirred at 90 °C for 2 h
under Ar atmosphere. The mixture was poured into water and extracted
with EtOAc. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography (basic silica gel, EtOAc) followed
by recrystallization from MeOH/water to give 27d (148 mg, 66%) as an
off-white solid; mp 226−228 °C. 1H NMR (CDCl3) δ 3.16−3.19 (4H, m),
NMR (CDCl3) δ 3.50 (3H, s), 3.92 (3H, s), 4.64 (2H, s), 7.05−7.10
(2H, m), 7.68−7.73 (2H, m), 12.91 (1H, s).
Methyl 1-(4-Iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyrida-
zine-3-carboxylate (30). A mixture of 29 (10.0 g, 26.6 mmol),
DMFDMA (50 mL), and CH3CN (50 mL) was refluxed for 2 h. The
mixture was concentrated to half its volume under reduced pressure.
The precipitate was collected by filtration and washed with EtOAc. The
filtrate was concentrated under reduced pressure, and the residue was
washed with EtOAc/MeOH (9/1). The combined solid was dried at
60 °C under reduced pressure to give 30 (7.2 g, 70%) as a beige solid. 1H
M
dx.doi.org/10.1021/jm5013648 | J. Med. Chem. XXXX, XXX, XXX−XXX