3096 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 13
Liu et al.
aqueous TFA (43%); 1H NMR (300 MHz, DMSO-d6) δ 8.65 (t, J
) 5.9 Hz, 1H), 7.85 (d, J ) 9.5 Hz, 1H), 7.48-7.38 (m, 2H), 7.32-
7.27 (m, 2H), 7.03-6.94 (m, 1H), 4.85-4.78 (m, 1H), 4.08-3.96
(m, 3H), 3.81-3.58 (m, 4H), 3.36 (t, J ) 5.9 Hz, 2H), 2.09-1.96
(m, 2H), 1.91-1.69 (m, 5H), 1.67-1.54 (m, 1H); MS (ESI) m/z
417 (M + H)+. Anal. (C21H25ClN4O3‚1.2CF3COOH) C, H, N.
6-(4-(2-Chlorophenoxy)piperidin-1-yl)-N-(2-(thiophen-2-yl)-
ethyl)pyridazine-3-carboxamide (15l). White solid (61%); 1H
NMR (300 MHz, DMSO-d6) δ 8.93 (t, J ) 5.9 Hz, 1H), 7.84 (d,
J ) 9.5 Hz, 1H), 7.49-7.36 (m, 2H), 7.35-7.24 (m, 3H), 7.05-
6.88 (m, 3H), 4.88-4.75 (m, 1H), 4.06-3.92 (m, 2H), 3.77-3.66
(m, 2H), 3.61-3.49 (m, 2H), 3.13-3.04 (m, 2H), 2.12-1.95 (m,
2H), 1.81-1.67 (m, 2H); MS (ESI) m/z (M + H)+. Anal. (C22H23-
ClN4O2S) C, H, N.
N-(2-(1H-Imidazol-4-yl)ethyl)-6-(4-(2-chlorophenoxy)piperi-
din-1-yl)pyridazine-3-carboxamide (15m). White solid (68%)
purified by reverse phase HPLC eluting with 5-100% CH3CN in
1% aqueous TFA; 1H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H),
7.84 (d, J ) 9.5 Hz, 1H), 7.56 (s, 1H), 7.46-7.36 (m, 2H), 7.33-
7.26 (m, 3H), 7.02-6.94 (m, 1H), 6.91 (s, 1H), 4.86-4.75 (m,
1H), 4.08-3.92 (m, 2H), 3.77-3.66 (m, 2H), 3.60-3.52 (m, 2H),
2.87-2.69 (m, 2H), 2.07-1.95 (m, 2H), 1.81-1.76 (m, 2H); MS
(ESI) m/z (M + H)+. Anal. (C21H26Cl2N4O2‚0.3CF3COOH) C, H,
N.
6-(4-(2-Chlorophenoxy)piperidin-1-yl)-N-(pyridin-3-ylmeth-
yl)pyridazine-3-carboxamide (15n). White solid (56%); 1H NMR
(300 MHz, DMSO-d6) δ 9.49 (t, J ) 6.1 Hz, 1H), 8.57 (s, 1H),
8.46 (s, 1H), 7.84 (d, J ) 9.5 Hz, 1H), 7.77 (d, J ) 7.7 Hz, 1H),
7.46-7.36 (m, 3H), 7.32-7.26 (m, 2H), 7.02-6.94 (m, 1H), 4.86-
4.77 (m, 1H), 4.52 (d, J ) 6.4 Hz, 2H), 4.08-3.97 (m, 2H), 3.77-
3.66 (m, 2H), 2.07-1.95 (m, 2H), 1.81-1.69 (m, 2H); MS (ESI)
m/z (M + H)+. FAB-HRMS calcd for C22H22ClN5O2 (M + H)+,
424.1535; found, 424.1547.
6-(4-(2-Chlorophenoxy)piperidin-1-yl)-N-((3-methylisoxazol-
5-yl)methyl)pyridazine-3-carboxamide (15o). White solid (52%);
1H NMR (300 MHz, DMSO-d6) δ 9.46 (t, J ) 5.9 Hz, 1H), 7.85
(d, J ) 9.5 Hz, 1H), 7.48-7.38 (m, 2H), 7.36-7.24 (m, 2H), 7.01-
6.94 (m, 1H), 6.16 (s, 1H), 4.83 (d, J ) 3.4 Hz, 1H), 4.56 (d, J )
6.1 Hz, 2H), 4.02 (s, 2H), 3.80-3.66 (m, 2 H), 2.18 (s, 3H), 2.10-
1.95 (m, 2H), 1.77 (d, J ) 3.4 Hz, 2H); MS (ESI) m/z (M + H)+.
FAB-HRMS calcd for C21H22ClN5O3 (M + H)+, 377.1375; found,
377.1377.
4-phenoxypiperidine hydrochloride (155 mg, 0.72 mmol) according
to the procedure described for 15a as a white solid (151 mg, 74%).
1H NMR (300 MHz, DMSO-d6) δ 7.86 (d, J ) 9.5 Hz, 1H), 7.40
(d, J ) 9.8 Hz, 1H), 7.33-7.27 (m, 2H), 7.01 (d, J ) 7.5 Hz, 2H),
6.94 (t, J ) 7.3 Hz, 1H), 4.72 (tt, J ) 7.7, 3.9 Hz, 1H), 4.18-4.08
(m, 2H), 3.72-3.59 (m, 2H), 2.09-1.99 (m, 2H), 1.74-1.62 (m,
2H); MS (ESI) m/z 281 (M + H)+.
N′-Hydroxy-6-(4-phenoxypiperidin-1-yl)pyridazine-3-carbox-
imidamide (19a). To a stirring mixture of 18a (145 mg, 0.52 mmol)
in ethanol (6 mL) and CH2Cl2 (0.5 mL) were added hydroxylamine
hydrochloride (55 mg, 0.78 mmol) and triethylamine (123 µL, 0.88
mmol). The heterogeneous mixture was stirred at room temperature
for 14 h. The mixture was diluted with EtOAc (30 mL), washed
with saturated aq NaHCO3 (15 mL) and brine (10 mL), and filtered
1
and concentrated to give 19a as a white solid (114 mg, 70%). H
NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.70 (d, J ) 9.8 Hz,
1H), 7.35-7.26 (m, 3H), 7.00 (d, J ) 7.8 Hz, 2H), 6.93 (t, J )
7.29 Hz, 1H), 5.86 (s, 2H), 4.72-4.64 (m, 1H), 4.11-4.02 (m,
2H), 3.55-3.46 (m, 2H), 2.03 (ddd, J ) 13.1, 6.5, 3.7 Hz, 2H),
1.72-1.60 (m, 2H); MS (ESI) m/z 314 (M + H)+.
3-(5-Methyl-1,2,4-oxadiazol-3-yl)-6-(4-phenoxypiperidin-1-yl)-
pyridazine (20a). To a mixture of 19a (31.3 mg, 0.1 mmol) with
CH3CN (1.0 mL) in a microwave vial were added acetyl chloride
(15.7 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.29
mmol). The mixture was heated in a microwave reactor at 150 °C
for 15 min and then diluted with EtOAc (10 mL), washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel flash column
chromatography, eluting with a gradient of 0-60% EtOAc in
1
hexanes to provide 20a as an off-white solid (16.8 mg, 50%). H
NMR (300 MHz, DMSO-d6) δ 7.85 (d, J ) 9.8 Hz, 1H), 7.40 (d,
J ) 9.8 Hz, 1H), 7.33-7.26 (m, 2H), 7.01 (d, J ) 7.8 Hz, 2H),
6.94 (t, J ) 7.5 Hz, 1H), 4.72 (dt, J ) 7.7, 3.8 Hz, 1H), 4.17-4.08
(m, 2H), 3.70-3.60 (m, 2H), 2.09-1.99 (m, 3H), 1.74-1.61 (m,
2H), 1.20 (s, 3 H); MS (ESI) m/z 338 (M + H)+. FAB-HRMS
calcd for C18H19N5O2 (M + H)+, 338.1547; found, 338.1552.
Compounds 20b-20d. The general procedure described for 20a
was followed for the preparation of these compounds starting from
19a, using the appropriate acyl chlorides for the cyclization.
3-(4-Phenoxypiperidin-1-yl)-6-[5-(trifluoromethyl)-1,2,4-oxa-
1
diazol-3-yl]pyridazine (20b). White solid (38%); H NMR (300
MHz, DMSO-d6) δ 7.96 (d, J ) 9.8 Hz, 1H), 7.47 (d, J ) 9.5 Hz,
1H), 7.33-7.27 (m, 2H), 7.02 (d, J ) 7.8 Hz, 2H), 6.94 (t, J ) 7.3
Hz, 1H), 4.73 (dt, J ) 7.9, 4.0 Hz, 1H), 4.21-4.12 (m, 2H), 3.69-
3.60 (m, 2H), 2.12-2.02 (m, 2H), 1.64-1.76 (m, 2H); MS (ESI)
m/z 392 (M + H)+. FAB-HRMS calcd for C18H16F3N5O2 (M +
H)+, 392.1264; found, 392.1260.
6-(4-(2-Chlorophenoxy)piperidin-1-yl)-N-((3-methyl-1H-pyra-
zol-5-yl)methyl)pyridazine-3-carboxamide (15p). White solid
purified by reverse phase HPLC eluting with 5-100% CH3CN in
1
1% aqueous TFA (50%); H NMR (300 MHz, DMSO-d6) δ 8.98
(s, 1H), 7.85 (d, J ) 9.5 Hz, 1H), 7.47-7.38 (m, 2H), 7.35-7.26
(m, 2H), 7.02-6.93 (m, 1H), 5.90 (s, 1H), 4.89-4.74 (m, 1H),
4.41 (d, J ) 5.8 Hz, 2H), 4.09-3.93 (m, 2H), 3.79-3.65 (m, 2H),
2.16 (s, 3H), 2.05 (d, J ) 16.3 Hz, 2H), 1.76 (s, 2H); MS (ESI)
m/z (M + H)+. Anal. (C21H23ClN6O2‚0.35CF3COOH) C, H, N.
N-((1H-Imidazol-2-yl)methyl)-6-(4-(2-chlorophenoxy)piperi-
din-1-yl)pyridazine-3-carboxamide (15q). White solid purified by
reverse phase HPLC eluting with 5-100% CH3CN in 1% aqueous
TFA (55%); 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 9.09
(t, J ) 5.9 Hz, 1H), 7.90-7.83 (m, 1H), 7.46-7.38 (m, 2H), 7.32-
7.21 (m, 2H), 7.07-6.92 (m, 2H), 6.80 (s, 1H), 4.91-4.71 (m,
1H), 4.52 (d, J ) 6.1 Hz, 2H), 4.08-3.93 (m, 2H), 3.82-3.64 (m,
2H), 2.09-1.96 (m, 2H), 1.81-1.63 (m, 2H); MS (ESI) m/z (M +
H)+. Anal. (C20H21ClN6O2‚0.3CF3COOH) C, H, N.
3-(6-(4-Phenoxypiperidin-1-yl)pyridazin-3-yl)-5-propyl-1,2,4-
1
oxadiazole (20c). Pale yellow solid (42%). H NMR (300 MHz,
DMSO-d6) δ 7.88 (d, J ) 9.5 Hz, 1H), 7.44 (d, J ) 9.8 Hz, 1H),
7.36-7.26 (m, 2H), 7.02 (d, J ) 7.8 Hz, 2H), 6.94 (t, J ) 7.3 Hz,
1H), 4.78-4.64 (m, 1H), 4.21-4.08 (m, 2H), 3.66-3.53 (m, 2H),
3.00 (t, J ) 7.5 Hz, 2H), 2.12-2.00 (m, 2H), 1.88-1.77 (m, 2H),
1.75-1.60 (m, 2H), 0.99 (t, J ) 7.5 Hz, 3H); MS (ESI) m/z 366
(M + H)+. Anal. (C20H23N5O2‚0.25 H2O) C, H, N.
3-(5-Benzyl-1,2,4-oxadiazol-3-yl)-6-(4-phenoxypiperidin-1-yl)-
pyridazine (20d). White solid (42%); 1H NMR (300 MHz, DMSO-
d6) δ 7.86 (d, J ) 9.83 Hz, 1H), 7.44-7.38 (m, 4H), 7.36-7.27
(m, 4H), 7.01 (d, J ) 7.8 Hz, 2H), 6.94 (t, J ) 7.3 Hz, 1H), 4.75-
4.68 (m, 1H), 4.46 (s, 2H), 4.10 (d, J ) 3.1 Hz, 2H), 3.64-3.55
(m, 2H), 2.04 (s, 2H), 1.72-1.65 (m, 2H); MS (ESI) m/z 414 (M
+ H)+. Anal. (C24H23N5O2‚0.5H2O) C, H, N.
3-[4-(2-Chlorophenoxy)piperidin-1-yl]-6-(5-methyl-1,2,4-oxa-
diazol-3-yl)pyridazine (20e). The title compound was prepared
according to the procedures described for 20a, substituting 4-(2-
chlorophenoxy)-piperidine hydrochloride for 4-(phenoxy)-piperidine
hydrochloride used in 18a to provide 20e as a white solid (19.3
mg, 52%); 1H NMR (300 MHz, DMSO-d6) δ 7.88 (d, J ) 9.8 Hz,
1H), 7.49-7.39 (m, 2H), 7.33-7.26 (m, 2H), 7.03-6.94 (m, 1H),
4.89-4.76 (m, 1H), 4.11-3.96 (m, 2H), 3.80-3.67 (m, 2H), 2.68
6-Chloropyridazine-3-carbonitrile (17). To a stirring mixture
of 6c (200 mg, 1.27 mmol) in pyridine (5 mL) was added
trifluoroacetic anhydride (720 µL, 5.08 mmol) at -14 °C. After
stirring for 1 h, the mixture was quenched with ice and diluted
with EtOAc (20 mL). The organic layer was washed with saturated
aq NaHCO3 (40 mL) and brine (40 mL), dried over Na2SO4, and
then filtered and concentrated to give a white solid (101 mg, 57%).
1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J ) 8.8 Hz, 1 H), 8.47
(d, J ) 8.8 Hz, 1 H); MS (ESI) m/z (M + H)+.
6-(4-Phenoxypiperidin-1-yl)pyridazine-3-carbonitrile (18a).
The title compound was made from 17 (101 mg, 0.72 mmol) and