Pyridone and pyridazone analogues as gpr119 modulators
a technology which is applied in the field of pyridone and pyridazone compounds and analogues, can solve the problems of serious health problems, inability to move glucose into the cells of patients, and failure of kidneys,
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example 1
Step E. Example 1
[0296]A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridine-2(1H)-one (173 mg, 0.652 mmol), cis-tert-butyl 2-methyl-4-(methylsulfonyloxy)piperidine-1-carboxylate (191 mg, 0.652 mmol) and potassium carbonate (180 mg, 1.304 mmol) in DMF (3.0 mL) was heated at 140° C. for 6 hrs and 100° C. overnight. To the above mixture additional potassium carbonate (90 mg, 1 equiv.) was added and the reaction was heated at 120° C. for 3 hrs and then cooled to room temperature. The mixture was diluted with EtOAc and water and the aqueous layer was extracted further with EtOAc (4×). The combined organic layers were washed with brine / water (1:1, 2×), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc / hexane) to yield trans-isomer of tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (31.4 mg, 10.4%) as an off-white solid. 1H NMR (500 MHz, CDCl...
example 2
cis-tert-Butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate
[0298]
[0299]A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (125 mg, 0.471 mmol), trans-tert-butyl 2-methyl-4-(methylsulfonyloxy)piperidine-1-carboxylate (138.2 mg, 0.471 mmol, Example 1) and potassium carbonate (163 mg, 1.178 mmol) in DMF (4.0 mL) was heated at 110° C. for 20 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic layers were washed with brine / water (1:1, 2×), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexane) to yield cis isomer of tert-butyl 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (114.6 mg, 52% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3). δ 8.07 (d, J=8.80 Hz, 2H...
example 3
Step B. Example 3
[0302]A mixture of cis-4-(2-methylpiperidin-4-yloxy)-1-(4-(methylsulfonyl)-phenyl)pyridin-2(1H)-one hydrochloric acid salt (45 mg, 0.124 mmol), 2-chloro-5-propylpyrimidine (38.9 mg, 0.248 mmol, Wako) and cesium carbonate (162 mg, 0.497 mmol, Aldrich) in DMF (0.8 mL) was heated under microwave conditions
[0303](180° C., 2 hrs). The resulting mixture was diluted with EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined extracts were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by preparative HPLC(C18 column; 0-100% methanol in water containing 0.05% trifluoroacetic acid) to yield Example 3 (12.7 mg, off-white solid, 20%) upon lyophilization. 1H NMR (500 MHz, CDCl3). δ 8.40 (s, 2H), 8.09 (d, J=8.80 Hz, 2H), 7.63 (d, J=8.80 Hz, 2H), 7.30 (d, J=7.70 Hz, 1H), 6.15 (dd, J=7.70, 2.20 Hz, 1H), 6.12 (d, J=2.75 Hz, 1H), 4.99-5.07 (m, 1H), 4.79 (app brs, 1H), 4.51-4.58 (m, 1H), 3.51-3.63 (m, 1...
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