N,N-dimethylazetidin-3-amine;dihydrochloride

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 87 mg of the title compound as a colorless powder. to cool the precipitate was collected by filtration washed with ethanol and diisopropylether successively

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30.0 mg, 0.058 mmol) and 3-(dimethylamino)azetidine dihydrochloride (30.2 mg. 0.174 mmol) in 1,4-dioxane (1 mL) was added triethylamine (58.8 mg, 81.0 μL, 0.581 mmol). The reaction mixture was heated at 50° C. for 1 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C30H35ClN5O3S (M+H+): 580.2; Found: 580.1 (M+H+). Upon completion of the reaction the reaction mixture was filtered through Celite (ethyl acetate eluent) concentrated used without further purification

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 4, but starting with 1.4 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.04 g of 3-(dimethylamino)azetidine dihydrochloride. After concentration of the combined organic extracts to dryness, the solid obtained is recrystallized in 40 cm3 of ethanol. 1.2 g of 1-cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 225° C. 1-Cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions After concentration of the combined organic extracts to dryness, the solid obtained is recrystallized in 40 cm3 of ethanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 4, but starting with 1.4 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.04 g of 3-(dimethylamino)azetidine dihydrochloride. After concentration of the combined organic extracts to dryness, the solid obtained is recrystallized in 40 cm3 of ethanol. 1.2 g of 1-cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 225° C. 1-Cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions After concentration of the combined organic extracts to dryness, the solid obtained is recrystallized in 40 cm3 of ethanol

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8-(3-Dimethylamino-1-azetidinyl)-3-ethoxy-carbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 2, but starting with 1.7 g of 3-ethoxy-carbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, and 1.3 g of 3-(dimethyl- amino)azetidine dihydrochloride. After reaction, the reaction mixture, cooled to approximately 20° C., is poured into 50 cm3 of water and extracted with 3 times 100 cm3 of dichloromethane. The combined organic extracts are washed with 3 times 150 cm3 of water and dried over magnesium sulphate. After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C. the residue is taken up with 50 cm3 of ethyl ether, filtered off and washed with twice 50 cm3 of the same solvent. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 232° C., which is used without further purification for the subsequent steps. After reaction extracted with 3 times 100 cm3 of dichloromethane The combined organic extracts are washed with 3 times 150 cm3 of water dried over magnesium sulphate After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C. the residue filtered off washed with twice 50 cm3 of the same solvent

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 8-(3-Dimethylamino-1-azetidinyl)-3-ethoxy-carbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 2, but starting with 1.7 g of 3-ethoxy-carbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, and 1.3 g of 3-(dimethyl- amino)azetidine dihydrochloride. After reaction, the reaction mixture, cooled to approximately 20° C., is poured into 50 cm3 of water and extracted with 3 times 100 cm3 of dichloromethane. The combined organic extracts are washed with 3 times 150 cm3 of water and dried over magnesium sulphate. After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C. the residue is taken up with 50 cm3 of ethyl ether, filtered off and washed with twice 50 cm3 of the same solvent. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 232° C., which is used without further purification for the subsequent steps. After reaction extracted with 3 times 100 cm3 of dichloromethane The combined organic extracts are washed with 3 times 150 cm3 of water dried over magnesium sulphate After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C. the residue filtered off washed with twice 50 cm3 of the same solvent

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 2 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine, 1.2 g of 3-(dimethylamino)azetidine dihydrochloride and 1.5 g of sodium carbonate in 30 cm3 of dimethyl sulphoxide is heated with stirring to a temperature in the region of 95° C. for 5 hours. After cooling to approximately 20° C., the reaction mixture is treated with 60 cm3 of water. The insoluble matter is drained and washed with 3 times 20 cm3 of water. 2 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine are obtained in the form of a yellow solid, melting point 224° C., which is used without further purification for the subsequent steps. is heated After cooling to approximately 20° C. washed with 3 times 20 cm3 of water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of Example C2 (0.42 g, 1.02 mmol), N,N-dimethyl-3-azetidinamine dihydrochloride (0.176 g, 1.02 mmol) and N-methylpyrrolidine (0.182 g, 2.13 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resultant material was dissolved in MeCN/H2O, frozen and lyophilized to afford 3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide as a yellowish-white solid (59 mg, 11%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.45 (s, 1H), 9.51 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.38 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 4.17-4.03 (m, 4H), 3.95-3.82 (br s, 1H), 2.62 (s, 6H), 1.21 (s, 9H); MS (ESI) m/z: 456.2 (M+H+). concentrated to dryness purified via silica gel chromatography (MeOH/DCM) The resultant material was dissolved in MeCN/H2O frozen

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of Example C2 (0.42 g, 1.02 mmol), N,N-dimethyl-3-azetidinamine dihydrochloride (0.176 g, 1.02 mmol) and N-methylpyrrolidine (0.182 g, 2.13 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The resultant material was dissolved in MeCN/H2O, frozen and lyophilized to afford 3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)azetidine-1-carboxamide as a yellowish-white solid (59 mg, 11%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.45 (s, 1H), 9.51 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.38 Hz, 1H), 6.63 (dd, J=5.7, 2.4 Hz, 1H), 4.17-4.03 (m, 4H), 3.95-3.82 (br s, 1H), 2.62 (s, 6H), 1.21 (s, 9H); MS (ESI) m/z: 456.2 (M+H+). concentrated to dryness purified via silica gel chromatography (MeOH/DCM) The resultant material was dissolved in MeCN/H2O frozen

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 310 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(dimethylamino)azetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 87 mg of the title compound as a colorless powder. to cool the precipitate was collected by filtration washed with ethanol and diisopropylether successively

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-dimethylazetidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3 H) 2.77 (br. s., 6 H) 4.07-4.18 (m, 1 H) 4.26 (br. s., 2 H) 4.52 (br. s., 1 H) 4.63 (br. s., 1 H) 7.70 (d, J=6.82 Hz, 1 H) 7.79 (d, J=11.37 Hz, 1 H) 8.19-8.26 (m, 2 H) 8.43 (d, J=8.84 Hz, 1 H) 8.69 (d, J=2.27 Hz, 1 H); ESI-MS m/z [M+H]+ 421.3.

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 271 mg (1.5 mmol) of N,N-dimethylazetidine-3-amine dihydrochloride, 400 mg (1.5 mmol) of the compound from Example 12A and 847 mg (6.1 mmol) of potassium carbonate are suspended in 8 ml of N,N-dimethylformamide and stirred at 100° C. for 16 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength trifluoroacetic acid). Further purification is carried out by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength formic acid). 2 ml of 1 N hydrochloric acid is added to the product-containing fractions, and the mixture is stirred at RT for 1 h. The solid is filtered off and dried under high vacuum. Yield: 62 mg (17% of theory) The reaction mixture is concentrated under reduced pressure purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength trifluoroacetic acid) Further purification is carried out by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength formic acid) 2 ml of 1 N hydrochloric acid is added to the product-containing fractions the mixture is stirred at RT for 1 h The solid is filtered off dried under high vacuum