KR100219327B1 - Quinolone carboxylic acid derivatives - Google Patents

Abstract

Provided are compounds of Formula 1 and pharmaceutically acceptable salts thereof.

In the formula,

R ₁ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 4 carbon atoms substituted with halogen, or a phenyl group substituted with halogen,

X is N, CH or CY,

Y is halogen or lower alkoxy of 1 to 4 carbon atoms, or

R ₁ and X together form —COCH ₂ CH (CH ₃ ) —,

R ₅ is H or an amino group,

R ₂ and R ₃ are each H, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group substituted with halogen,

n is 0 or 1;

Description

Quinolone Carboxylic Acid Derivatives

The present invention relates to novel quinolone carboxylic acid derivatives, methods for their preparation, and their use as antibacterial agents.

The quinolone derivatives reported so far and the quinolone antibacterial agents used in the clinic are known to express excellent antibacterial activity (EP 78,362, EP 270904-A, etc.). However, conventional quinolone-based antimicrobial agents have low antibacterial activity against gram positive bacteria or gram positive bacteria and gram negative bacteria, but have poor solubility in water or poor cytotoxicity and phototoxicity.

An object of the present invention is to provide an antibacterial compound having excellent antibacterial activity, broad antibacterial spectrum, improved solubility in water, and low cytotoxicity. In particular, it is to provide an antimicrobial compound that is excellent in antimicrobial activity against Gram-positive bacteria and methicillin-resistant bacteria and is less selective.

The inventors have found that compounds having 3-azabicyclo [2.1.1] amine derivatives at position 7 of the quinolone parent nucleus have excellent antimicrobial activity, broad antimicrobial spectrum and low selectivity.

The present invention provides a compound of Formula 1 below, and a pharmaceutically acceptable salt thereof.

Formula 1

In the formula,

R ₁ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 4 carbon atoms substituted with halogen, or a phenyl group substituted with halogen,

X is N, CH or CY,

Y is halogen or lower alkoxy of 1 to 4 carbon atoms, or

R ₁ and X together form —COCH ₂ CH (CH ₃ ) —,

R ₅ is H or an amino group,

R ₂ and R ₃ are each H, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group substituted with halogen,

n is 0 or 1;

Among the compounds represented by the formula (1),

R ₁ is ethyl, halogen substituted ethyl, cyclopropyl or phenyl substituted with halogen,

X is N, CH or CY,

Y is F, Cl, or CH ₃ O, or

R ₁ and X together form —COCH ₂ CH (CH ₃ ) —,

R ₅ is H or an amino group,

R ₂ and R ₃ are each ethyl substituted with H, CH ₃ or halogen,

n is 0 or 1, or a pharmaceutically acceptable salt thereof.

Particularly preferred compounds of the formula (1) are

1-cyclopropyl-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3 Carboxylic acids,

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acid,

9-fluoro-2,3-dihydro-3-methyl-10- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -7-oxo-7H-pyrido [1.2 .3-d, e] -1,4-benzooxazine-6-carboxylic acid,

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro -4-oxoquinoline-3-carboxylic acid,

1- (2,4-difluorophenyl) -6-fluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid,

1-cyclopropyl-6-fluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid,

1- (2-fluoroethyl) -6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4 Oxoquinoline-3-carboxylic acid,

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-amino-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxo Quinoline-3-carboxylic acid,

1-cyclopropyl-6-fluoro-8-methoxy-7- (1-N- (2-fluoroethyl) aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid,

1-cyclopropyl-6-fluoro-7- (1-N-methylamino-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3- Carboxylic acid, and

1-cyclopropyl-6-fluoro-8-chloro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acids, and pharmaceutically acceptable salts thereof.

The present invention also provides a process for preparing the compound of formula (1). The compound of formula 1 is prepared by condensation reaction of a compound of formula 2 with a compound of formula 3 in a solvent in the presence of a base.

In formula, R <_1> , R <_2> , R <_3> , R <_5> , X and n are the same as the above definition.

The condensation reaction is carried out at a temperature of 20 to 120 ℃.

Solvents that can be used in the process of the invention are water or organic solvents. Suitable organic solvents include, for example, acetonitrile, dimethylformamide, dimethyl sulfoxide, pyridine and the like.

Bases that can be used in the process of the invention are inorganic bases or organic bases. Suitable organic bases include, for example, tertiary amines such as triethylamine, pyridine, diazabicyclo [5.4.0] undes-7-ene, diisopropylethylamine.

Compounds of formula 2 are described, for example, in Chem. Pharm. Bull., 1986, 34, 4098; J. Hetero. Chem., 1987, 24, 181; J. Med. Chem., 1988, 31, 503; EP 115,841; And JP 62-252772 and the like.

The compound of formula 3 is a novel compound. Accordingly, the present invention also provides a compound of formula 3 and a process for preparing the same.

The compound of formula 3 may be prepared according to the following Schemes 1 to 4, for example.

Hereinafter, the present invention is illustrated in Examples. This embodiment does not limit the invention.

Example 1

Preparation of 1-aminomethyl-3-azabicyclo [2.1.1] hexane dihydrochloride

1) Preparation of 2-t-butyldimethylsilyloxy-1,3-dibromopropane

500 ml of anhydrous methylene chloride, 50 g (0.32 ml) of 1,3-dibromo-2-propanol, 43 g of t-butyldimethylchlorosilane, and 16 g of imidazole were mixed, followed by stirring at room temperature for 10 hours. 300 ml of water was added to the mixture, extracted twice with 200 ml of methylene chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was column chromatographed on silica gel (hexane: ethyl acetate = 5: 1) to give 68 g of the target compound as an oil.

¹ H NMR (CDCl ₃ ): δ 0.10 (s, 6H), 0.58 (s, 9H), 3.43 (d, 4H), 4.04-3.92 (m, 1H)

2) Preparation of Diisoamyl 3-t-butyldimethylsilyloxy-1,1-cyclobutanedicarboxylic acid ester

12 g of sodium was dissolved in 500 ml of isoamyl alcohol, 90 ml of diethyl malonate was added, and ethanol was fractionally distilled off. 68 g of 2-t-butyldimethylsilyloxy-1,3-dibromopropane was slowly added dropwise under ice bath, followed by heating to reflux for 18 hours. Isoamyl alcohol was removed under reduced pressure, the residue was cooled, water was added and extracted twice with ethyl ether. Then it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionally distilled (175-179 ° C., 0.4 mmHg) under reduced pressure to give 68 g of the target compound as a colorless oil.

¹ H NMR (CDCl ₃ ): δ 0.002 (s, 6H), 0.84 (s, 9H), 0.86-0.90 (d, 12H), 1.43-1.47 (m, 4H), 1.50-1.70 (m, 2H), 2.37-2.48 (m, 2H), 2.81 (m, 2H), 4.09-4.17 (m, 4H), 4.26-4.34 (m, 1H)

3) Preparation of 1,1-dihydroxymethyl-3-t-butyldimethylsilyloxycyclobutane

After filling the 1 L round flask with nitrogen, 9.84 g of lithium aluminum and 500 ml of ethyl ether were added, and diisoamyl 3-t-butyldimethylsilyloxy-1,1-cyclobutanedicarboxylic acid ester was stirred at room temperature. 68 g was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour, and a small amount of water was added under an ice bath. Extracted with ethyl ether, dried over anhydrous magnesium sulfate and distilled under reduced pressure. Column chromatography on silica gel (hexane: ethyl acetate = 2: 1) gave 30 g of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ -0.01 (s, 6H), 0.83 (s, 9H), 1.66-1.75 (m, 2H), 2.13-2.23 (m, 2H), 3.65 (s, 2H), 3.68 (s, 2H), 4.18-4.32 (m, 1H)

4) Preparation of 1,1-di-p-toluenesulfonyloxymethyl-3-t-butyldimethylsilyloxycyclobutane

37 g of p-toluenesulfonylchloride, 2.35 g of dimethylaminopyridine and 27 ml of triethylamine were mixed in 300 ml of anhydrous methylene chloride, and then 1,1-dihydroxymethyl-3-t-butyldimethylsilyloxycyclobutane 19 g was added slowly. After reacting at room temperature overnight, 300 ml of water was added, extracted twice with 200 ml of methylene chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Column chromatography on silica gel (hexane: ethyl acetate = 3: 1) gave 35 g of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ -0.01 (s, 6H), 0.80 (s, 9H), 1.63-1.73 (m, 2H), 2.07-2.18 (m, 2H), 2.44 (s, 6H), 3.90 (s, 2H), 3.92 (s, 2H), 4.05-4.16 (s, 1H), 7.25-7.77 (m, 8H)

5) Preparation of 1,1-diazidomethyl-3-t-butyldimethylsilyloxycyclobutane

20 g of sodium azide was suspended in 200 ml of dimethylformamide, followed by addition of 35 g of 1,1-di-p-toluenesulfonyloxymethyl-3-t-butyldimethylsilyloxycyclobutane and 2 hours at 100 ° C. Was stirred. The reaction mixture was cooled to room temperature, extracted three times with 300 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was column chromatographed with silica gel (hexane: ethyl acetate = 7: 1) to obtain 18 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 0.006 (s, 6H), 0.84 (s, 9H), 1.72-1.83 (m, 2H), 2.13-2.24 (m, 2H), 3.36 (s, 2H), 3.39 ( s, 2H), 4.21-4.31 (m, 2H)

6) Preparation of 1,1-diazidomethyl-3-hydroxycyclobutane

18 g of 1,1-diazidomethyl-3-t-butyldimethylsilyloxycyclobutane and 77 ml of tetrabutylammonium chloride were mixed and then stirred at room temperature for 30 minutes. THF was removed, and column chromatography (hexane: ethyl acetate = 3: 1) using silica gel gave 10 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.75-1.85 (m, 2H), 2.18-2.24 (m, 2H), 2.26 (br, 1H), 3.36 (s, 2H), 3.39 (s, 2H), 4.21- 4.31 (m, 1 H), 7.25-7.77 (m, 8 H)

7) Preparation of 1,1-diazidomethyl-3-methanesulfonyloxycyclobutane

100 g of 1,1-diazidomethyl-3-hydroxycyclobutane and 10 ml of triethylamine were added to 200 ml of anhydrous methylene chloride, and 5.64 ml of methylsulfonyl chloride was slowly added at -10 ° C, and then under ice bath. Stir for 40 minutes. 200 ml of water was added to the reaction mixture, and extracted twice with 100 ml of methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) to obtain 14 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 2.14-2.25 (m, 2H), 2.34-2.44 (m, 2H), 2.96 (s, 3H), 3.40 (s, 2H), 3.41 (s, 2H), 4.91- 5.05 (m, 1 H)

8) Preparation of 3-N- (t-butoxycarbonyl) -1- (N-t-butoxycarbonyl) aminomethyl-3-azabicyclo [2.1.1] hexane

14 g of 1,1-diazidomethyl-3-methanesulfonyloxycyclobutane was dissolved in 400 ml of anhydrous methanol, and 2.8 g of 10% Pd-C was added, followed by stirring in 60 Psi of hydrogen gas for 20 hours. Pd-C was filtered through celite, 27 g of ditetrabutyldicarbonate and 10 ml of triethylamine were added to the filtrate, and the mixture was stirred at room temperature for 5 hours. After concentration under reduced pressure to remove the solvent, column chromatography on silica gel (hexane: ethyl acetate = 3: 1) to give 10.4 g of the target compound in the form of white crystals.

¹ H NMR (CDCl ₃ ): δ 1.41 (m, 20H), 1.67-1.69 (m, 2H), 3.15 (s, 2H), 3.33-3.34 (d, 2H), 4.24-4.30 (m, 1H), 4.68 (m, 1 H)

9) Preparation of 1-aminomethyl-3-azabicyclo [2.1.1] hexane dihydrochloride

1 g of 3-N- (t-butoxycarbonyl) -1- (Nt-butoxycarbonyl) aminomethyl-3-azabicyclo [2.1.1] hexane is added to 10 ml of a 16% methanol solution of hydrogen chloride, and room temperature Stir overnight at. The resulting precipitate was filtered under reduced pressure, washed with methanol and dried to give 0.37 g of the target compound as a white solid.

¹ H NMR (D ₂ O): δ 1.57-1.63 (m, 2H), 2.10 (m, 2H), 3.30 (s, 2H), 3.32 (s, 2H), 4.18-4.19 (m, 1H)

Example 2

Preparation of 1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane dihydrochloride

1) Preparation of 2- (t-butyldimethylsilyloxy) -7,7-dimethyl-6,8-dioxaspiro [3.5] nonane

26 g of 1-dihydroxymethyl-3- (t-butyldimethylsilyloxy) cyclobutane was dissolved in 1 L of THF, followed by addition of 2.4 g of p-TsOH.H ₂ O and 13.46 g of 2,2-dimethoxypropane. And stirred for 150 minutes at room temperature. The solvent was removed under reduced pressure, water was added, followed by extraction with ether, dried over anhydrous magnesium sulfate and concentrated to give a colorless oily material. The obtained material was column chromatographed with silica gel (hexane: ethyl acetate 3: 1) to obtain 25 g of pure target compounds.

¹ H NMR (CDCl ₃ ): δ 0.003 (s, 6H), 0.848 (s, 9H), 1.362 (s, 6H), 1.65-1.74 (m, 2H), 2.17-2.27 (m, 2H), 3.36 ( s, 2H), 3.68 (s, 2H), 4.14-4.25 (m, 1H)

2) Preparation of 2-hydroxy-7,7-dimethyl-6,8-dioxaspiro [3.5] nonane

To 25 g of 2- (t-butyldimethylsilyloxy) -7,7-dimethyl-6,8-dioxaspiro [3.5] nonane was added 200 ml of THF, and then 165 ml of tetrabutylammonium chloride was added thereto. Stir for 40 minutes. After removing the solvent, column chromatography with silica gel (hexane: ethyl acetate = 2: 1) gave 13 g of the target compound as a colorless oil.

¹ H NMR (CDCl ₃ ): δ 1.34 (s, 6H), 1.61-1.71 (m, 2H), 2.20-2.30 (m, 2H), 2.54 (br, 1H), 3.65 (s, 2H), 3.66 ( s, 2H), 4.20-4.30 (m, 1H)

3) Preparation of 2-p-toluenesulfonyloxy-7,7-dimethyl-6,8-dioxaspiro [3.5] nonane

After 500 ml of methylene chloride was added to 23 g of 2-hydroxy-7,7-dimethyl-6,8-dioxaspiro [3.5] nonane, 45 g of p-toluenesulfonylchloride, 2.47 g of dimethylaminopyridine and trityl 37 ml of amine were mixed and then stirred at room temperature for 4 hours. After adding water, the mixture was extracted with CH ₂ Cl ₂ , dried over anhydrous magnesium sulfate, and distilled under reduced pressure. The residue was column chromatographed with silica gel (hexane: ethyl acetate = 3: 1) to obtain 39 g of the target compound in the form of white crystals.

¹ H NMR (CDCl ₃ ): δ 1.32 (s, 6H), 1.85-1.95 (m, 2H), 2.16-2.27 (m, 2H), 2.42 (s, 3H), 3.61 (s, 2H), 3.63 ( s, 2H), 4.70-4.84 (m, 1H), 7.28-7.32 (d, J = 8.4, 2H), 7.72-7.76 (d, J = 8.4, 2H)

4) Preparation of 2-azido-7,7-dimethyl-6,8-dioxaspiro [3.5] nonane

After dissolving 39 g of 2-p-toluenesulfonyloxy-7,7-dimethyl-6,8-dioxaspiro [3.5] nonane in 500 ml of dimethylformamide, 37 g of sodium azide was added thereto at 100 ° C. Stir for 1 hour. Water was added, extraction was performed with ethyl acetate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 5: 1) to obtain 23 g of a target compound as a colorless oil.

¹ H NMR (CDCl ₃ ): δ 1.34 (s, 6H), 1.77-1.88 (m, 2H), 2.18-2.29 (m, 2H), 3.66 (s, 2H), 3.68 (s, 2H), 3.77- 3.92 (m, 1 H)

5) Preparation of 1-azido-3,3-dihydroxymethylcyclobutane

To 250 g of methanol was added to 16 g of 2-azido-7,7-dimethyl-6,8-dioxaspiro [3.5] nonane, 4.8 g of p-TsOH.H ₂ O was added and stirred at room temperature for 4 hours. It was. The solvent was removed, 200 ml of water was added, extracted with ether, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) to give 12 g of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 1.86-1.97 (m, 2H), 2.22-2.30 (m, 2H), 3.71 (s, 4H), 3.84-3.96 (m, 1H)

6) Preparation of 1-azido-3,3- (dimethanesulfonyloxymethyl) cyclobutane

1.1 g of 1-azido-3,3-dihydroxymethylcyclobutane was dissolved in 20 ml of anhydrous methylene chloride, 24 ml of tritylamine were added thereto, and methylsulfonyl chloride was slowly added dropwise at -10 ° C. After stirring for 1 hour in an ice bath, water was added, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was column chromatographed with silica gel (hexane: ethyl acetate = 1: 1) to give 1.97 g of the pure target compound as a yellow oil.

¹ H NMR (CDCl ₃ ): δ 2.07-2.09 (m, 2H), 2.30-2.27 (m, 2H), 3.00 (s, 6H), 3.93-4.03 (m, 2H), 4.16 (s, 2H), 4.17 (s, 2H)

7) Preparation of 1-methanesulfonyloxymethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

After dissolving 200 ml of methanol in 1.97 g of 1-azido-3,3- (dimethanesulfonyloxymethyl) cyclobutane, 0.2 g of Pd-C was added and stirred overnight in 60 Psi of hydrogen gas. Pd-C was filtered through celite, the solvent was removed, the residue was dissolved in a small amount of methanol, then 120 ml of toluene was added and heated to reflux for 20 hours. After cooling to room temperature, 1.67 g of ditetrabutyldicarbonate and 1 ml of tritylamine were added and stirred at room temperature for 1 hour. The solvent was removed, water and ethyl acetate were added, the organic layer was extracted, and column chromatography (hexane: ethyl acetate = 3: 1) with silica gel gave 0.66 g of the target compound as a white crystal.

¹ H NMR (CDCl ₃ ): δ 1.45 (s, 9H), 1.52-1.54 (m, 2H), 1.86-1.87 (m, 2H), 3.01 (s, 3H), 3.27 (s, 2H), 4.38 ( s, 2H), 4.38 (m, 1H)

8) Preparation of 1- (N-methyl) aminomethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

To 660 mg of 1-methanesulfonyloxymethyl-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane, add 5 ml of 40% aqueous methylamine solution and 5 ml of methanol, and then stir at room temperature for one day. It was. The solvent was removed, water and ethyl acetate were added, the organic layer was extracted, and column chromatography (CH ₂ Cl ₂ : MeOH = 6: 1) with silica gel gave 250 mg of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.19 (m, 11H), 1.50 (m, 2H), 2.20 (s, 3H), 2.57 (s, 2H), 2.96 (s, 2H), 4.05 (br, 1H)

9) Preparation of 1- (N-methyl) aminomethyl-3-azabicyclo [2.1.1] hexanedihydrochloride

250 mg of 1- (N-methyl) aminomethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane was added to 10 ml of a 16% methanol solution of hydrogen chloride and stirred at room temperature for 10 hours. The solvent was removed under reduced pressure to give 198 mg of the target compound.

¹ H NMR (D ₂ O): δ 1.31 (m, 2H), 2.00 (m, 2H), 2.41 (s, 3H), 2.80 (s, 2H), 3.25 (s, 2H), 4.05 (br, 1H )

Example 3

Preparation of 1-amino-3-azabicyclo [2.1.1] hexane dihydrochloride

1) Preparation of 1-acetoxymethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

4.8 g of 1- (methanesulfonyloxy) methyl-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane of Example 2 7) was dissolved in dimethylformamide, and then potassium acetate 4.85 g was added, stirred at 70 ° C. for 1 h and then cooled. Water and ethyl acetate were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was column chromatographed (hexane: ethyl acetate = 1: 1) to give 4.4 g of pure target compound as yellow oil.

¹ H NMR (CDCl ₃ ): δ 1.39 (s, 9H), 1.45 (m, 2H), 1.74 (m, 2H), 2.00 (s, 3H), 3.17 (s, 2H), 4.19 (m, 1H)

2) Preparation of 1-hydroxymethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

4.4 g of 1-acetoxymethyl-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane was dissolved in 20 ml of ethanol, and then 3 g of potassium hydroxide was dissolved in a minimum amount of water with stirring in ice water. The mixture was diluted with ethanol, added slowly, and neutralized with 10% sulfuric acid. The ethanol was removed, then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was column chromatographed (hexane: ethyl acetate = 1: 1) to obtain 3.7 g of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 1.40 (m, 2H), 1.42 (s, 9H), 1.76 (m, 2H), 2.45 (s, 1H, OH), 3.20 (S, 2H), 3.76 (s, 2H), 4.30 (m, 1H)

3) Preparation of 3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexyl-1-carboxylic acid

3.4 g of 1-hydroxymethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane and 21.6 g of pyridinium dichromate were added to 45 ml of dimethylformamide and stirred at room temperature for 5 hours. The reaction mixture was filtered, then water and ethyl acetate were added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (chloroform: methanol = 6: 1) to obtain 2.24 g of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 1.44 (s, 9H), 1.73 (m, 2H), 2.18 (m, 2H), 3.50 (s, 2H), 4.32 (m, 1H)

4) Preparation of 1-azidocarbonyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

1 g of 3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexyl-1-carboxylic acid is dissolved in 15 ml of dichloromethane, followed by 1.14 g of diphenylphosphoroazide and 0.68 of triethylamine. After adding ml, the mixture was stirred at room temperature for 3 hours. Water was added, extracted twice with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 3: 1) to obtain 647 mg of the target compound.

¹ H NMR (CD ₃ OD): δ 1.46 (s, 9H), 1.69 (m, 1H), 1.73 (m, 1H), 2.10-2.23 (m, 2H), 3.30 (m, 1H), 3.45 (m , 1H), 4.20-4.37 (m, 1H)

5) Preparation of 1- (N-trifluoromethylcarbonyl) amino-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

647 mg of 1-azidocarbonyl-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane was dissolved in 10 ml of dichloromethane, and then 0.24 ml of trifluoroacetate was added for 24 hours. Heated to reflux. After cooling the reaction mixture, the solvent was removed, 3 ml of triethylamine and 2.0 g of di-t-butyldicarbonate in methanol were added thereto, and the mixture was stirred at room temperature for 5 hours. After removing methanol, water and ethyl acetate were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate = 3: 1) to give 281 mg of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 1.40 (s, 9H), 1.88 (m, 2H), 2.10 (m, 2H), 3.43 (s, 2H), 4.30 (m, 1H), 6.73 (s, 1H, NH)

6) Preparation of 1- (N-t-butoxycarbonyl) amino-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

407 mg of 1- (N-trifluoromethylcarbonyl) amino-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane were dissolved in a mixture of water and methanol (2: 8) , 320 mg of potassium carbonate was added, and stirred at room temperature overnight. When the starting material disappeared, 450 mg (2.07 mmol) of di-t-butyldicarbonate was added and stirred at room temperature for 8 hours. After methanol was removed, water and ethyl acetate were added, the organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was column chromatographed (hexane: ethyl acetate = 2: 1) to give 388 mg of the target compound as a white solid.

¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H), 1.43 (s, 9H), 1.75 (m, 2H), 2.02 (m, 2H), 3.32 (s, 2H), 4,25 (m, 1H), 5.00 (br, 1H, NH)

7) Preparation of 1-amino-3-azabicyclo [2.1.1] hexane dihydrochloride

368 mg of 1- (Nt-butoxycarbonyl) amino-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane was added to 5 ml of 37% hydrogen chloride ethanol solution, stirred overnight, and then The obtained salt was filtered to give 188 mg of white target compound.

¹ H NMR (D ₂ O): δ 1.86 (m, 1H), 1.88 (m, 1H), 2.26 (m, 2H), 3.37 (s, 2H), 4.20 (m, 1H)

Example 4

Preparation of 1- (N-methyl) amino-3-azabicyclo [2.1.1] hexane dihydrochloride

1) Preparation of 1- (N-methyl-N-t-butoxycarbonyl) amino-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

3 g of 1- (Nt-butoxycarbonyl) amino-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane prepared in the same manner as in Example 6) was dimethylformamide 30 It was dissolved in ml, 0.7 g of 60% sodium hydride was added and stirred for 3 hours, then 1.1 g of methyl iodide was added dropwise and stirred at room temperature for 5 hours. 100 ml of water was added to the reaction mixture, which was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography (hexane: ethyl acetate = 5: 1) gave 3.5 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H), 1.43 (s, 9H), 1.75 (m, 2H), 2.02 (m, 2H), 2.70 (s, 3H), 3.32 (s, 2H) , 4.25 (m, 1 H)

2) Preparation of 1- (N-methyl) amino-3-azabicyclo [2.1.1] hexane dihydrochloride

1.5 g of 1- (N-methyl-Nt-butoxycarbonyl) amino-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane was added to 5 ml of 37% hydrogen chloride ethanol solution and stirred overnight Then, the resulting salt was filtered to obtain 1.8 g of a white target compound.

¹ H NMR (D ₂ O): δ 1.86 (m, 1H), 1.88 (m, 1H), 2.26 (m, 2H), 2.36 (s, 3H), 3.37 (s, 2H)

Example 5

Preparation of 1- (N-2-fluoroethyl) aminomethyl-3-azabicyclo [2.1.1] hexane dihydrochloride

1) Preparation of 1- (N-2-fluoroethyl-N-t-butoxycarbonyl) aminomethyl-3-N-t-butoxycarbonyl-3-azabicyclo [2.1.1] hexane

1.6 g of 1- (Nt-butoxycarbonyl) aminomethyl-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane prepared in the same manner as in Example 8) was dimethylformamide. Dissolve in 15 ml, add 0.4 g of 60% sodium hydride and stir for 3 hours. Then 0.9 g of 1-fluoro-2-chloroethane was added dropwise and stirred at room temperature for 14 hours. The reaction mixture was added to 60 ml of water, mixed and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was column chromatographed (hexane: ethyl acetate = 5: 1) to give 1.78 g of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H), 1.43 (s, 9H), 1.75 (m, 2H), 2.02 (m, 2H), 2.70 (s, 3H), 3.32 (s, 2H) ,

2) Preparation of 1- (N-2-fluoroethyl) aminomethyl-3-azabicyclo [2.1.1] hexanedihydrochloride

1.0 g of 1- (N-2-fluoroethyl-Nt-butoxycarbonyl) aminomethyl-3-Nt-butoxycarbonyl-3-azabicyclo [2.1.1] hexane 5 ml of 37% hydrogen chloride ethanol solution It was added to the mixture, stirred overnight, and the resulting salt was filtered to give 0.6 g of a white target compound.

¹ H NMR (D ₂ O): δ 1.86 (m, 1H), 1.88 (m, 1H), 2.26 (m, 2H), 2.36 (s, 3H), 3.37 (s, 2H)

Example 6

1-cyclopropyl-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3 Preparation of Carboxylic Acids

280 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-aminomethyl-3-azabicyclo [2.1.1] hexane 220 mg of dihydrochloride was placed in 5 ml of acetonitrile, and 417 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added and then heated to reflux for 6 hours. The resulting crystals were filtered off, washed with acetonitrile and dried to give 280 mg of the desired compound in off-white crystal form.

¹ H NMR (CF ₃ COOD): δ 1.55-1.59 (m, 2H), 1.71-1.76 (m, 2H), 2.06-2.15 (m, 2H), 2.46-2.53 (m, 2H), 3.94 (s, 2H), 4.25 (s, 2H), 4.63-4.68 (m, 1H), 5.43 (m, 1H), 8.24-8.26 (d, 1H), 9.41 (s, 1H)

Example 7

1-cyclopropyl-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3 Preparation of Carboxylic Acid Hydrochloride

1-cyclopropyl-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3 200 mg of carboxylic acid was added to 10 ml of a 16% methanol solution of hydrogen chloride and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and crystallized by addition of ethyl ether. After filtration and washing with ethyl ether sufficiently, it was dried under reduced pressure to give 160 mg of yellow target compound.

¹ H NMR (D ₂ O): δ 1.04-1.23 (m, 4H), 1.26-1.69 (m, 2H), 1.96-2.05 (m, 2H), 3.32 (s, 2H), 3.59 (s, 2H) , 3.93-4.01 (m, 1H), 4.54 (m, 1H), 7.23-7.42 (m, 1H), 8.52-8.61 (m, 1H)

Example 8

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- Preparation of oxoquinoline-3-carboxylic acid

100 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-aminomethyl-3-azabicyclo [2.1 .1] 79 mg of hexane dihydrochloride was added to 2 ml of acetonitrile, and 166 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added, followed by treatment in the same manner as in Example 6. 110 mg of compound was obtained.

¹ H NMR (CF ₃ COOD): δ 1.38-1.41 (m, 2H), 1.53-1.61 (m, 2H), 2.01-2.10 (m, 2H), 2.38-2.42 (m, 2H), 3.82 (s, 2H), 4.10 (m, 2H), 4.40 (m, 1H), 5.20 (m, 1H), 9.20 (s, 1H)

Example 9

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- Preparation of oxoquinoline-3-carboxylic acid hydrochloride

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- 110 mg of oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 7 to obtain 80 mg of the target compound in yellow color.

¹ H NMR (D ₂ O): δ 0.81-0.89 (m, 2H), 0.93-1.00 (m, 2H), 1.49-1.51 (m, 2H), 1.86-1.88 (m, 2H), 3.18 (s, 2H), 3.34 (s, 2H), 3.69 (m, 1H), 4.39-4.33 (m, 1H), 5.32 (m, 1H)

Example 10

9-fluoro-2,3-dihydro-3-methyl-10- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -7-oxo-7H-pyrido [1 Preparation of 2,3-d, e] -1,4-benzoxazine-6-carboxylic acid

9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-d, e] -1,4-benzooxazine-6-carr 100 mg of acid and 79 mg of 1-aminomethyl-3-azabicyclo [2.1.1] hexane dihydrochloride were added to 2 ml of acetonitrile and 1,8-diazabicyclo [5.4.0] undes-7-ene After adding 166 mg, it was treated in the same manner as in Example 6 to obtain 78 mg of the target compound.

¹ H NMR (CF ₃ COOD): δ 1.82-1.84 (m, 5H), 2.10-2.25 (m, 2H), 3.57-3.36 (m, 2H), 3.74-3.82 (m, 2H), 4.47-4.58 ( m, 2H), 4.93 (m, 1H), 5.28-5.35 (m, 1H), 8.13-8.17 (d, 1H), 9.45 (s, 1H)

Example 11

9-fluoro-2,3-dihydro-3-methyl-10- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -7-oxo-7H-pyrido [1 , 2,3-d, e] -1,4-benzoxazine-6-carboxylic acid hydrochloride

9-fluoro-2,3-dihydro-3-methyl-10- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -7-oxo-7H-pyrido [1 70 mg of 2,3-d, e] -1,4-benzoxazine-6-carboxylic acid was treated in the same manner as in Example 7 to obtain 50 mg of the target compound in yellow color.

¹ H MNR (D ₂ O): δ 1.37-1.40 (m, 2H), 1.50 (m, 2H), 1.87 (m, 2H), 3.18 (s, 2H), 3.37 (m, 2H), 4.21 (m , 1H), 4.76-4.81 (m, 1H), 7.39 (d, 1H), 8.65 (s, 1H)

Example 12

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro Preparation of 4-oxoquinoline-3-carboxylic acid

160 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-N-methylaminomethyl-3-azabi 128 mg of cyclo [2.1.1] hexane dihydrochloride were added to 2 ml of acetonitrile, and 206 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added, followed by the same method as in Example 6. Treatment gave 136 mg of the target compound.

¹ H NMR (CF ₃ COOD): δ 1.29-1.34 (m, 2H), 1.43-1.47 (m, 2H), 1.91 (m, 2H), 2.29 (m, 2H), 3.05 (s, 3H), 3.68 (s, 2H), 3.97 (s, 2H), 4.30 (m, 1H), 5.01 (m, 1H), 9.10 (s, 1H)

Example 13

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro Preparation of 4-oxoquinoline-3-carboxylic acid hydrochloride

1-cyclopropyl-5-amino-6,8-difluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro 136 mg of 4-oxoquinoline-3-carboxylic acid was treated in the same manner as in Example 7 to obtain 100 mg of the yellow target compound.

¹ H NMR (D ₂ O): δ 0.79-0.82 (m, 2H), 1.01-1.12 (m, 2H), 1.36 (m, 2H), 1.69 (m, 2H), 2.72 (s, 3H), 3.13 (s, 2H), 3.25 (s, 2H), 3.70 (m, 1H), 4.48 (m, 1H), 8.68 (s, 1H)

Example 14

1- (2,4-difluorophenyl) -6-fluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4 Preparation of -oxo-1,8-naphthyridine-3-carboxylic acid

120 mg of 1- (2,4-difluorophenyl) -6,7-difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 1-amino 79 mg of methyl-3-azabicyclo [2.1.1] hexane dihydrochloride was added to 5 ml of acetonitrile and 166 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added. 110 mg of the target compound was obtained in the same manner as in the same method.

¹ H NMR (CDCl ₃ ): δ 2.06-2.15 (m, 2H), 2.46-2.53 (m, 4H), 3.94 (s, 2H), 4.25 (m, 1H), 7.26 (m, 2H), 7.62 ( m, 1H), 8.28 (d, 1H), 9.2 (d, 1H), 11.6 (s, 1H)

Example 15

1-cyclopropyl-6-fluoro-7-[(1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane) -3-yl] -1,4-dihydro-4-oxo- Preparation of 1,8-naphthyridine-3-carboxylic acid

95 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid and 1-N-methylaminomethyl-3-azabi 79 mg of cyclo [2.1.1] hexane dihydrochloride was added to 5 ml of acetonitrile, and 166 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added and treated in the same manner as in Example 6. 101 mg of the target compound were obtained.

¹ H NMR (CDCl ₃ ): δ 1.35 (m, 2H), 1.56 (m, 2H), 2.07-2.18 (m, 2H), 2.46-2.53 (m, 7H), 3.94 (s, 2H), 4.18 ( m, 1H), 4.21 (m, 1H), 8.20 (d, 1H), 9.19 (s, 1H), 11.5 (s, 1H)

Example 16

1- (2-fluoroethyl) -6,8-difluoro-7-{(1-aminomethyl-3-azabicyclo [2.1.1] hexane) -3-yl} -1,4-dihydro Preparation of 4-oxoquinoline-3-carboxylic acid

100 mg of 1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-aminomethyl-3-azabicyclo [ 2.1.1] 79 mg of hexane dihydrochloride was added to 3 ml of acetonitrile, and 130 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added, followed by treatment in the same manner as in Example 6. 92 mg of the target compound were obtained.

¹ H NMR (CDCl ₃ ): δ 2.03-2.11 (m, 2H), 2.40-2.51 (m, 4H), 3.94 (s, 2H), 4.22 (m, 2H), 4.61 (m, 2H), 5.20 ( m, 1H), 8.05 (d, 1H), 9.38 (s, 1H), 11.51 (s, 1H)

Example 17

1-cyclopropyl-5-amino-6,8-difluoro-7-{(1-amino-3-azabicyclo [2.1.1] hexane) -3-yl} -1,4-dihydro-4 Preparation of oxoquinoline-3-carboxylic acid

100 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-amino-3-azabicyclo [2.1. 1] 79 mg of hexane dihydrochloride was added to 5 ml of acetonitrile, and 126 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added and treated in the same manner as in Example 6 to obtain the target compound. 113 mg was obtained.

¹ H NMR (CF ₃ COOD): δ 1.38 (m, 2H), 1.54-1.60 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 4.10 (m, 2H), 4.40 (m , 1H), 5.21 (m, 1H), 9.21 (s, 1H), 11.61 (s, 1H)

Example 18

1-cyclopropyl-6-fluoro-8-methoxy-7- {1- (N-2-fluoroethyl) aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl} -1, Preparation of 4-dihydro-4-oxoquinoline-3-carboxylic acid

100 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (N-2-fluoroethyl) amino 120 mg of methyl-3-azabicyclo [2.1.1] hexane dihydrochloride were added to 5 ml of acetonitrile, and 160 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added. Treatment in the same manner as 6 afforded 123 mg of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.19 (m, 1H), 1.30 (m, 1H), 1.48 (m, 1H), 1.56 (m, 1H), 2.06-2.14 (m, 2H), 2.43-2.61 ( m, 4H), 3.36 (m, 2H), 3.74 (s, 3H), 3.94 (s, 2H), 4.10 (m, 1H), 4.56 (m, 2H), 5.01 (m, 1H), 8.05 (d , 1H), 9.32 (s, 1H), 11.52 (s, 1H)

Example 19

1-cyclopropyl-6-fluoro-7-{(1-N-methylamino-3-azabicyclo [2.1.1] hexane) -3-yl} -1,4-dihydro-4-oxoquinoline- Preparation of 3-carboxylic Acid

100 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-N-methylamino-3-azabicyclo [2.1.1] hexane 79 mg of dihydrochloride was added to 5 ml of acetonitrile, 152 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added, and the same procedure as in Example 6 was carried out to obtain 103 mg of the target compound. Got it.

¹ H NMR (CDCl ₃ ): δ 1.40-1.60 (m, 4H), 2.03-2.10 (m, 2H), 2.40-2.61 (m, 5H), 3.91 (m, 2H), 4.21 (m, 1H), 5.10 (m, 1H), 8.14 (d, 1H), 8.21 (d, 1H), 9.01 (s, 1H), 11.42 (s, 1H)

Example 20

1-cyclopropyl-6-fluoro-8-chloro-7- (1- (N-methyl) aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro- Preparation of 4-oxoquinoline-3-carboxylic acid

100 mg of 1-cyclopropyl-6,7-difluoro-8-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1- (N-methyl) aminomethyl-3-azabi 129 mg of cyclo [2.1.1] hexane dihydrochloride were added to 5 ml of acetonitrile, 170 mg of 1,8-diazabicyclo [5.4.0] undes-7-ene was added, and the same procedure as in Example 6 was performed. Treatment gave 133 mg of the target compound.

¹ H NMR (CDCl ₃ ): δ 1.60 (m, 2H), 1.81 (m, 2H), 2.07-2.2 (m, 2H), 2.41-2.51 (m, 5H), 3.94 (s, 2H), 4.24 ( m, 2H), 4.28 (m, 1H), 5.31 (m, 1H), 8.28 (d, 1H), 9.45 (s, 1H), 11.57 (s, 1H)

In vitro antibacterial activity test

To test the antimicrobial activity of the compounds of the present invention, the minimum inhibitory concentrations (MIC, μg / ml) of several compounds synthesized in the above examples were measured by two-fold dilution using agar medium. Hoechst standard strains were used as strains, and 10 ⁷ CFU / ml of bacteria were inoculated into the medium. After incubation for about 18 hours at 37 ℃ growth of the bacteria was observed. At this time, cyprofloxacin and spafloxacin were used as controls. The MIC test results are shown in Table 1 below.

In vitro antimicrobial activity (minimum inhibitory concentration, μg / ml) Strain Example 16 Compound Example 17 Compound Cyprofloxacin Spafloxacin One Purulent Streptococcus 308a 0.049 0.049 3.125 0.391 2 Purulent Streptococcus 77A 0.025 0.025 0.781 0.195 3 Streptococcus paesium MD 8b (Steptococcus faecium) 0.025 0.049 0.391 0.391 4 Staphylococcus aureus SG 511 0.007 0.007 0.195 0.098 5 Staphylococcus aureus 285 0.013 0.013 0.781 0.049 6 Staphylococcus aureus 503 0.007 0.013 0.391 0.049 Method: Agar Dilution (Cheist 345) Solvent: H ₂ O or 1N-NaOH Inoculation Size: 10 ⁷ CFU / ml (Medium): Muller Hinton Agar Temperature: 37 ℃ Incubation time: 18 hours

Select toxicity test

Selectivity Index is Inhibitory Concentration of Compounds of the Invention to Topoisomerase II _Against Inhibitory Concentration of Compounds of the Invention (IC _{100, Gyrase} (μg / ml)) to _{DNA Gyrase} of _Coli (IC _{100, Topo II} (Μg / ml)).

Select toxicity IC _{100, Topo II} (µg / ml) IC _{100, Gyrase II} (μg / ml) Select toxicity Compound of Example 16 Compound of Example 17 Cypropoxycinspafloxacin 1,0001,000 500 300 0.50.40.51.0 2,0002,5001,000500

The compound of the present invention has excellent antibacterial activity, broad antibacterial spectrum and low cytotoxicity.

Claims (5)

A compound of Formula 1 and a pharmaceutically acceptable salt thereof. Formula 1

In the formula, R ₁ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 4 carbon atoms substituted with halogen, or a phenyl group substituted with halogen, X is N, CH or CY, Y is halogen or lower alkoxy of 1 to 4 carbon atoms, or R ₁ and X together form —COCH ₂ CH (CH ₃ ) —, R ₅ is H or an amino group, R ₂ and R ₃ are each H, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group substituted with halogen, n is 0 or 1; The method of claim 1, R ₁ is ethyl, halogen substituted ethyl, cyclopropyl or phenyl substituted with halogen, X is N, CH or CY, Y is F, Cl, or CH ₃ O, or R ₁ and X together form —COCH ₂ CH (CH ₃ ) —, R ₅ is H or an amino group, R ₂ and R ₃ are each ethyl substituted with H, CH ₃ or halogen, n is 0 or 1; The method of claim 1, 1-cyclopropyl-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3 Carboxylic acids, 1-cyclopropyl-5-amino-6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -7-oxo-7H-pyrido [1 , 2,3-d, e] -1,4-benzooxazine-6-carboxylic acid, 1-cyclopropyl-5-amino-6,8-difluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro -4-oxoquinoline-3-carboxylic acid, 1- (2,4-difluorophenyl) -6-fluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, 1- (2-fluoroethyl) -6,8-difluoro-7- (1-aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4 Oxoquinoline-3-carboxylic acid, 1-cyclopropyl-5-amino-6,8-difluoro-7- (1-amino-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxo Quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-8-methoxy-7- (1-N- (2-fluoroethyl) aminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-7- (1-N-methylamino-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4-oxoquinoline-3- Carboxylic acid, and 1-cyclopropyl-6-fluoro-8-chloro-7- (1-N-methylaminomethyl-3-azabicyclo [2.1.1] hexane-3-yl) -1,4-dihydro-4- Oxoquinoline-3-carboxylic acid, and pharmaceutically acceptable salts thereof. A method for preparing a compound of formula 1 comprising condensation reaction of a compound of formula 2 with a compound of formula 3 in a solvent in the presence of a base: Formula 1

Formula 2

Formula 3

In the formula, R ₁ is a lower alkyl group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 4 carbon atoms substituted with halogen, or a phenyl group substituted with halogen, X is N, CH or CY, Y is halogen or lower alkoxy of 1 to 4 carbon atoms, or R ₁ and X together form —COCH ₂ CH (CH ₃ ) —, R ₅ is H or an amino group, R ₂ and R ₃ are each H, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group substituted with halogen, n is 0 or 1; A compound of formula Formula 3

In the formula, R ₂ and R ₃ are each H, a lower alkyl group having 1 to 4 carbon atoms, or a lower alkyl group substituted with halogen, n is 0 or 1;