7-(3-aminomethyl-4-substituted-benzyloxyimino-1-pyrrolidinyl)naphthyridinone carboxylic acid compounds

[0051] Example 11-[(1R,2S)-2-fluorocyclopropyl]-6-fluoro-7-[3-aminomethyl-4-(4-fluorobenzyloxyimino)-pyrrolidine-1- base]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

[0052] 1-[(1R,2S)-2-fluorocyclopropyl]-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (180mg , 0.6mmol), a mixture of 3-aminomethyl-4-(chlorobenzyloxyimino)-pyrrolidine dihydrochloride (345mg, 1mmol), triethylamine (0.42ml) and anhydrous acetonitrile (30ml) The reaction was stirred at room temperature for 10 h. Concentrate under reduced pressure, add 5% NaOH (5mL) to the residue, stir for 0.5h, filter with suction, adjust the pH of the filtrate to 6.5-7.0 with 20% acetic acid, and wash with CHCl 3 Extract and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, the residue was slurried with ether-dichloromethane, and 230 mg of light yellow solid was filtered by suction, the yield (44.2%). (c 0.040, CH 3 OH), 1 H NMR (600MHz...

[0059] Example 21-[(1R,2S)-2-fluorocyclopropyl]-6-fluoro-7-[3-aminomethyl-4-(4-chlorobenzyloxyimino)-pyrrolidine-1- base]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

[0060] Same as the preparation method of the compound in Example 1, 1-[(1R,2S)-2-fluorocyclopropyl]-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8- Condensation reaction of naphthyridine-3-carboxylic acid with 3-aminomethyl-4-(4-chlorobenzyloxyimino)-pyrrolidine dihydrochloride, followed by alkaline hydrolysis to give a light white solid (53.9%) . (c 0.049, CH 3 OH), 1 H NMR(600MHz,dmso)δ8.67(s,1H),8.02(d,J=12.6Hz,1H),7.58–7.23(m,4H),5.25–4.99(m,3H),4.63(s, 2H),4.28–4.08(m,1H),3.92-3.89(m,1H),3.75-3.71(m,1H),3.02(s,1H),2.76-2.47(m,2H),1.91–1.79( m,1H),1.65-1.58(m,1H).MS-ESI(m / z):518.20(M+H) + .HRMS-ESI(m / z): Calcd.for C 18 h 20 o 4 N 5 f 2 (M+H) + :518.14011; Found: 518.14048.

[0061] Example 31-[(1R,2S)-2-fluorocyclopropyl]-6-fluoro-7-[3-aminomethyl-4-(4-bromobenzyloxyimino)-pyrrolidine-1- base]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

[0062] Same as the preparation method of the compound in Example 1, 1-[(1R,2S)-2-fluorocyclopropyl]-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8- Naphthyridine-3-carboxylic acid is condensed with 3-aminomethyl-4-(4-bromobenzyloxyimino)-pyrrolidine dihydrochloride, and then alkaline hydrolyzed to obtain a light white solid yield (33.7 %). (c 0.023, CH 3 OH), 1 H NMR (600MHz, dmso) δ8.67 (s, 1H), 8.01 (d, J = 12.6Hz, 1H), 7.60–7.50 (m, 2H), 7.33-7.29 (m, 2H), 5.26–5.01 ( m,3H),4.63(s,2H),4.29–4.05(m,1H),4.03–3.86(m,1H),3.75-3.71(dt,m,1H),3.01(s,1H),2.85– 2.67(m,2H),1.93–1.79(m,1H),1.71–1.56(m,1H).MS-ESI(m / z):562.12(M+H) + .HRMS-ESI(m / z): Calcd.for C 18 h 20 o 4 N 5 f 2 (M+H) + :562.09278; Found: 562.09326.