High Performance Liquid Chromatography:Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 14 mg 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 12 mg 3-(4-chlorophenyl)-N-[(1S,2R)-2-hydroxycyclohexyl]-6-oxo-6H-1,4′-bipyridazine-5-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 3 mg 6-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 66 mg rac-6-(4-Chlorophenyl)-N-[(trans)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then water was added and the precipitate subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 55 mg 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 85%/B 15%→A 45%/B 55%; flow: 150 mL/min; UV-detection: 254 nm) to yield 15 mg 6-(4-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: A solution of 125 mg intermediate 3-(4-chlorophenyl)-6-oxo-6H-1,4′-bipyridazine-5-carboxylic acid, 106 mg cis-4-aminotetrahydro-3-furanol hydochloride, 289 mg HATU, 0.19 mL ethyldiisopropylamine and 3 mg 4-dimethylaminopyridine in 3 mL of DMF was stirred at room temperature for 14 hours and at 50° C. for 1 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85%/B 15%→A 45%/B 55%; flow: 150 mL/min; UV-detection: 254 nm) to yield 17 mg 3-(4-chlorophenyl)-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-6-oxo-6H-1,4′-bipyridazine-5-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 63 mg 3-oxo-2-(pyridin-3-yl)-N-[1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide.
Purification:Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 14 mg 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 12 mg 3-(4-chlorophenyl)-N-[(1S,2R)-2-hydroxycyclohexyl]-6-oxo-6H-1,4′-bipyridazine-5-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 3 mg 6-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 66 mg rac-6-(4-Chlorophenyl)-N-[(trans)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then water was added and the precipitate subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 55 mg 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 85%/B 15%→A 45%/B 55%; flow: 150 mL/min; UV-detection: 254 nm) to yield 15 mg 6-(4-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: A solution of 125 mg intermediate 3-(4-chlorophenyl)-6-oxo-6H-1,4′-bipyridazine-5-carboxylic acid, 106 mg cis-4-aminotetrahydro-3-furanol hydochloride, 289 mg HATU, 0.19 mL ethyldiisopropylamine and 3 mg 4-dimethylaminopyridine in 3 mL of DMF was stirred at room temperature for 14 hours and at 50° C. for 1 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85%/B 15%→A 45%/B 55%; flow: 150 mL/min; UV-detection: 254 nm) to yield 17 mg 3-(4-chlorophenyl)-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-6-oxo-6H-1,4′-bipyridazine-5-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 63 mg 3-oxo-2-(pyridin-3-yl)-N-[1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide.
Residue:Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 14 mg 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 12 mg 3-(4-chlorophenyl)-N-[(1S,2R)-2-hydroxycyclohexyl]-6-oxo-6H-1,4′-bipyridazine-5-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 3 mg 6-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 66 mg rac-6-(4-Chlorophenyl)-N-[(trans)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then water was added and the precipitate subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 55 mg 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1 vol % formic acid in water, eluent B: acetonitrile; gradient: A 85%/B 15%→A 45%/B 55%; flow: 150 mL/min; UV-detection: 254 nm) to yield 15 mg 6-(4-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: A solution of 125 mg intermediate 3-(4-chlorophenyl)-6-oxo-6H-1,4′-bipyridazine-5-carboxylic acid, 106 mg cis-4-aminotetrahydro-3-furanol hydochloride, 289 mg HATU, 0.19 mL ethyldiisopropylamine and 3 mg 4-dimethylaminopyridine in 3 mL of DMF was stirred at room temperature for 14 hours and at 50° C. for 1 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85%/B 15%→A 45%/B 55%; flow: 150 mL/min; UV-detection: 254 nm) to yield 17 mg 3-(4-chlorophenyl)-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-6-oxo-6H-1,4′-bipyridazine-5-carboxamide.
Article Title: 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer
Article Snippet: Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm×30 mm, eluent A: water+0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70%/B 30%→A 30%/B 70%; flow: 150 mL/min; UV-detection: 254 nm) to yield 63 mg 3-oxo-2-(pyridin-3-yl)-N-[1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide.
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