MXPA99011056A

MXPA99011056A - Substituted cyclobutylamine derivatives

Info

Publication number: MXPA99011056A
Application number: MXPA/A/1999/011056A
Authority: MX
Inventors: Takemura Makoto; Takahashi Hisashi; Sugita Kazuyuki; Miyauchi Rie
Original assignee: Daiichi Pharmaceutical Co Ltd
Priority date: 1997-05-30
Filing date: 1999-11-30
Publication date: 2000-09-04

Abstract

Substituted cyclobutylamine derivatives with novel structures represented by general formula (I), wherein R1 to R4 and Q represent each a specific substituent and, in particular, Q represents a quinolone derivative of a specific structure. These derivatives are useful as antibacterial compounds which have excellent antibacterial actions over a wide scope of bacteria including gram-negative and gram-positive ones, exert potent antibacterial activities particularly on methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and quinolone-resistant bacteria and are excellent in the in vivo dynamics and safety.

Description

DERIVATIVE OF CICLOBUTI LAMI NA SU BSTITU I DA FIELD I NDUSTRIAL This invention relates to an antibacterial compound useful for a medicament, a veterinary medicament, a medicament for fisheries or an antibacterial preservative, and an antibacterial agent and an antibacterial preparation, which contains the compound.

BACKGROUND Due to the discovery of norfloxacin, the antibacterial and pharmacokinetic activity have been improved after the administration of quinolone antibacterial agents, and many compounds are now used in the clinical field as chemotherapeutic agents, which are effective in most infectious diseases. systemic In recent years, the generation of bacteria has been increasing, having low sensitivity to synthetic quinolone antibacterial agents in the clinical field. For example, similar to the case of Staphylococcus aureus (MRSA), which is not sensitive to ß-lactam antibiotics, there has been an increase in a case in which bacteria originally resistant to drugs other than quinolone antibacterial agents are It is also not very sensitive to quinolone antibacterial agents. Consequently, the development of a drug having greater efficacy in the clinical field. On the other hand, it has been revealed that quinolone synthetic antibacterial agents cause a side effect, in which a severe seizure is induced, when a non-steroidal anti-inflammatory drug is used simultaneously, as well as other side effects, such as phototoxicity and the like, so that the development of a synthetic quinolone antibacterial agent is also required, having greater safety.

DESCRIPTION OF THE INVENTION In view of the foregoing, the inventors of the present invention have conducted intensive studies in order to provide an excellent compound, which can satisfy the aforementioned requirements. As a result of the efforts, it was found that a substituted cyclobutylamine derivative represented by the formula (I) described below, a salt thereof and a hydrate thereof, possess an excellent antibacterial action on a wide range of Gram-negative bacteria and Gram-positive, can show particularly strong antibacterial activity on the quinolone-resistant bacteria, including MRSA, and have excellent pharmacokinetics and safety, resulting in the achievement of the present invention. According to this, the present invention relates to a compound represented by the following formula (I), its salts or hydrates: (I) { wherein R1 and R2, each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms (excluding a case in which, R1 and R2 are both hydrogen atoms), wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an halogen atom and an alkoxy group having 1 to 6 carbon atoms, R3 and R4, each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, n is an integer of 1 or 2, Q is a partial structure represented by the following formula: [wherein R5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms or an alkylamino group, having 1 to 6 carbon atoms, R6 represents a hydrogen atom or a alkylthio group having 1 to 6 carbon atoms, wherein R6 and the aforementioned R5 can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed can contain a sulfur atom as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 atoms of carbon, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have or one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, X1 represents a halogen atom or a hydrogen atom, A1 represents a nitrogen atom or a partial structure represented by the following formula (II): (wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 at 5 carbon atoms, and X2 and the aforementioned R5 can together form a cyclic structure including a part of the parent core, and the ring thus formed can contain an oxygen atom, a nitrogen atom or a sulfur atom such as an atom ring constituent, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), A2 and A3, each representing a nitrogen atom or a carbon atom, wherein A2 and A3 j Together with carbon atoms to which they are linked, they form a partial structure: or a partial structure: Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a ftalidinyl group, a 5-alkyl-2-oxo group -1,3-dioxol-4-ylmethyl, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of alkylene group having 1 to 6 carbon atoms and phenyl group]} . The present invention also relates to: the aforementioned compound, its salt or hydrates thereof, in which a partial structure resulting from the exclusion of Q of formula (I) is a stereochemically pure compound; the aforementioned compound, its salt or hydrates thereof, wherein Q in the formula (I) is a compound having a structure represented by the following formula: . { wherein R 5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, wherein R6 and the aforementioned R5 can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed can contain a sulfur atom as a ring constituent atom, and the ring also can have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, a group or alkyl having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, X1 represents a halogen atom or a hydrogen atom, A1 represents a nitrogen atom or a partial structure represented by the following formula (II): (wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 atoms of carbon, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and X2 and R5 mentioned above can together form a cyclic structure including a part of the parent core, and the ring thus formed can contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), and Y represents a hydrogen atom , a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a ftalidyl group, a 5-alkyl-2-oxo-1 group, dioxol-4-ylmethyl, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group}; the aforementioned compound, its salt or hydrates thereof, wherein Q in the formula (I) is a compound having a structure represented by the following formula: . { wherein R 5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms or an alkylamine group having 1 to 6 carbon atoms , R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, wherein R6 and the aforementioned R5 can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed can contain a carbon atom. sulfur as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a group hydroxyl, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, X1 represents a halogen atom or a hydrogen atom, A1 represents a nitrogen atom or a partial structure represented by the following formula (II): (wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and X2 and R5 mentioned above can together form a cyclic structure including a part of the parent core, and the ring thus formed can contain an oxygen atom , a nitrogen atom or a sulfur atom as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), and Y represents a hydrogen atom; phenogen, a phenyl group, an acetoxymethyl group, a pyruvaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthaiidinyl group, a 5-alkyl-2-oxo-1, 3- group dioxol-4-ylmethyl, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group}; the above-mentioned compound, its salt or hydrates thereof, wherein Q in the formula (I) is a 6-carboxy-9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo group -7H-pyrido [1, 2, 3-de] [1,4] benzoxazin-10-yl the above-mentioned compound, its salt or hydrates thereof, wherein Q in the formula (I) is a 5-amino-3-carboxy-6-fluoro-1 - [2- (S) -fluoro-1 - group (R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinolin-7-yl the above-mentioned compound, its salt or hydrates thereof, wherein Q in the formula (I) is a 3-carboxy-6-fluoro-1 - [2- (S) -fluoro-1 - (R) - cyclopropyl] -1,4-di-idro-8-methoxy-4-oxoquinolin-7-yl the above-mentioned compound, its salt or hydrates thereof, wherein Q in the formula (I) is a 5-amino-3-carboxy-6,8-difluoro-1 - [2- (S) -fluoro- 1 - (R) -cyclopropyl] -1,4-dihydro-4-oxoquinolin-7-yl the above-mentioned compound, its salt or hydrates thereof, wherein R5 is a halogenocyclopropyl group; the aforementioned compound, its salt or hydrates thereof, wherein the halogenocyclopropyl group is a 1,2-cis-halogenocyclopropyl group; the above-mentioned compound, its salt or hydrates thereof, in which the halogenocyclopropyl group is a stereochemically pure substituent; the above-mentioned compound, its salt or hydrates thereof, in which the halogenocyclopropyl group is a group (1 R, 2S) -2-halogenocyclopropyl; the above-mentioned compound, its salt or hydrates thereof, in which the halogen atom of the halogenocyclopropyl group is a fluorine atom; the above-mentioned compound, its salt or hydrates thereof, wherein the compound of formula (I) is a stereochemically pure compound; 5-amino-7- [3- (3-amino-1-fluorocyclobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof; 7- [3- (3-am ino- 1 -fluorocyclobutan-3-yl) pyrrolidin-1-yl] -6-f-loro [1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] ] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof; 5-am ino-7- [3- (3-am] -no-1-f-1-chlorobutan-3-yl) pyrrolidin-1-yl] -6,8-difluoro-1 - [2- (S) - fluoro-1 - (R) -cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof; 7- [3- (3-amino-1,1-difluorocyclobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro-1 - (R) - acid cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof; 5-amino-7- [3- (3-am ino-1, 1 -dif luorocobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro-1 acid - (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof; a pharmaceutical composition, which comprises the above-mentioned compound, its salt or hydrates thereof as an active ingredient; and an antibacterial agent, which comprises the aforementioned compound, its salt or hydrates thereof as an active ingredient. The other objects and advantages of the present invention will become apparent as the description progresses.

MODALITIES FOR CARRYING OUT I NVENTION Each of the substituent groups of the compound of the present invention represented by the formula (I) is described below. The substituents R1 and R2, each independently, are a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms (excluding a case in which R1 and R2 are both hydrogen atoms), wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an atom of halogen and an alkoxy group having 1 to 6 carbon atoms. As the halogen atom, fluorine or chlorine atom are preferred, the fluorine atom being particularly preferred. The alkyl group can be either a straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group.

The alkoxy group can be either a straight or branched group, having 1 to 6 carbon atoms, and its preferred examples include methoxy group and ethoxy group. The alkylthio group can be either a straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methylthio group and ethylthio group. When an alkoyl group having 1 to 6 carbon atoms has a hydroxyl group as a substituent, the alkyl group can be either linear or branched, and the hydroxyl group substituting position can be preferably at the terminal carbon atom of the alkyl group. Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include hydroxymethyl group, 2-hydroxyethyl group and 3-hydroxypropyl group. When an alkyl group having 1 to 6 carbon atoms has a halogen atom as a substituent, the alkyl group can be either linear or branched, and a fluorine atom such as the halogen atom is preferable. With respect to the number of fluorine atoms, it can be anything from mono-substitution to perfluoro substitution. Their examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and similar groups. When an alkyl group having 1 to 6 carbon atoms has an alkoxy group as a substituent, each of the alkyl portions can be either linear or branched, and an alkoxymethyl or alkoxyethyl group is preferable. Their most preferred examples include methoxymethyl group, ethoxymethyl group and 2-methoxyethyl group.

A feature of the present invention is that one or two fluorine atoms are present in the cyclobutyl ring of the formula (I). Particularly preferred examples of the combination of R1 and R2 include a case in which one of R1 and R2 is a hydrogen atom and the other is a fluorine atom, and a case in which both R1 and R2 are fluorine atoms . In this connection, when the substituent group R1 and the substituent group R2 are different from one another, the carbon atoms to which R1 and R2 are linked become asymmetric carbons to form isomers, and all such isomers are included in the present invention . Substituent groups R3 and R4, each independently, is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an atom of halogen, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms. The alkyl group can be either a straight or branched group having 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group. When an alkyl group has a hydroxyl group as a substituent, the alkyl group can be either a straight or branched group having 1 to 6 carbon atoms, and the hydroxyl group can be placed, preferably, on the carbon atom. of the alkyl group. As the alkyl group having a hydroxyl group, a group having up to 3 carbon atoms is preferred, and a hydroxymethyl group, a 2-hydroxyethyl group and a 3-hydroxypropyl group and the like are more preferable. When an alkyl group has a halogen atom as a substituent, the alkyl group can be either a straight or branched group having 1 to 6 carbon atoms, and a fluorine atom is preferable as the halogen atom. With respect to the number of fluorine atoms, it can be anything from mono-substitution to perfluoro substitution. Their examples include monofluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like group. When an alkyl group has an alkyl group as a substituent, the alkyl group can be either straight or branched having 1 to 6 carbon atoms and the alkylthio group can also be straight or branched having 1 to 6 carbon atoms. carbon. As the alkyl group having an alkylthio group, an alkylthiomethyl group, an alkylthioethyl group or an alkylthioproyl group is preferable, and the alkylthio group may preferably have 1 to 3 carbon atoms. Their most preferred examples include methylthiomethyl group, ethylthiomethyl group and methylthioethyl group. When an alkyl group has an alkoxy group as a substituent, the alkyl group can be either straight or branched having 1 to 6 carbon atoms and the alkoxy group can also be either linear or branched having 1 to 6 atoms of carbon. As the alkyl group having an alkoxy group, an alkoxymethyl group, an alkoxyethyl group and an alkoxypropyl group are preferred, and the alkoxy group may preferably have up to 3 carbon atoms. Their most preferred examples include methoxymethyl group, ethoxymethyl group and methoxyethyl group. The symbol n is an integer of 1 or 2. Q is a partial structure represented by the following formula: In the above formula, A2 and A3, each represents a nitrogen atom or a carbon atom, where A2 and A3 together with carbon atoms to which they are bound, form a partial structure: or a partial structure: A condensed heterocyclic partial structure represented by the following formula: _ is preferred as the structure of Q. The substituent R5 is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an akoxyl group having 1 to 6 atoms of carbon or an alkylamino group having 1 to 6 carbon atoms. In this case, the ethyl group is preferable as the alkyl group having 1 to 6 carbon atoms, and the vinyl group or 1-isopropenyl group is preferable as the alkenyl group having 2 to 6 carbon atoms. The 2-fluoroethyl group is preferable as the halogenoalkyl group having 1 to 6 carbon atoms.

The cyclopropyl group is particularly preferable as the cyclic alkyl group, and a halogen atom, particularly a fluorine atom, is preferable as its substituent. Examples of the aryl group, which may have a substituent include phenyl or similar group, which may have 1 to 3 substituents selected from the group consisting, for example, of fluorine, chlorine, bromine or the like halogen atom, hydroxyl group, amino group, nitro group, an alkyl group having 1 to 6 carbon atoms, and their preferred illustrative examples include phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4 group -hydroxyphenyl, 3-amino-4,6-difluorophenyl group and 4,6-difluoro-3-methylaminophenyl group. The heteroaryl group is a substituent derived from a five or six membered aromatic heterocyclic compound, which contains one or more hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. Their examples include pyridyl, pyrimidyl and similar groups. As a substituent in these rings, an alkyl group, a halogen atom or the like is preferred. The methoxyl group is preferable as the alkoxy group having 1 to 6 carbon atoms. Glympomethylamino is preferable as the alkylamido group having 1 to 6 carbon atoms. As the substituent R5, a cyclic alkyl group, which may have a substituent, is preferable, and a cyclopropyl group or a 2-halogenocyclopropyl group is particularly preferable. The halogenocyclopropyl group mentioned as a preferred example of the substituent R5 is described in detail.

As the substituent halogen atom, fluorine atom and chlorine atom can be exemplified, and fluorine atom is particularly preferable. As the stereochemical environment in its portion, it is particularly preferable that the halogen atom and the pyridonecarboxylic acid moiety are in cis configuration, with respect to the cyclopropane ring. The so-called antipodal isomers exist solely by the cis-2-halogencyclopropyl portion of R5, and a strong antibacterial activity and high safety have been observed in all these isomers. The substituent R6 is a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R5 and R6 can together form a cyclic hydrocarbon structure including a part of the parent core (ie, by including A2 to which R5 is linked) and the carbon atom to which R6 is linked). The ring thus formed may contain a sulfur atom as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent. The ring to be formed in the present may have a size from a four-membered ring to a six-membered ring, and the ring may be saturated, partially saturated or unsaturated. Your examples are shown below.

(In the above formulas, R56 means a hydrogen atom or an alkyl group, and A1, Y, X1 and R7 are as defined in formula (I).) The substituent R7 is a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 6 carbon atoms. The alkyl group can be either a straight or branched group having 1 to 6 carbon atoms and its preferred examples include methyl group, ethyl group, normal proyl group and isopropyl group. The alkenyl group can be either a straight or branched group having 2 to 6 carbon atoms and preferably is a vinyl group. The alkynyl group can be either a straight or branched group having 2 to 6 carbon atoms and is preferably an ethynyl group. The fluorine atom is particularly preferable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxy group may have 1 to 6 carbon atoms and is preferably methoxyl group.

The substituent R7 is preferably a hydrogen atom, an alkyl group or amino group, of which an unsubstituted methyl group or amino group is more preferred. When the substituent R7 is an amino group, hydroxyl group or thiol group, these groups can be protected with normally used protecting groups. Examples of such protecting groups include tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and similar alkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and similar aralkyloxycarbonyl groups, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pyruvaloyl, formyl, benzoyl and groups. similar acyl, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and similar alkyl or aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl and similar ethers and trimethylsilyl, isopropyldimethylsilyl, ter -butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl and similar syryl groups. Compounds whose substituents are protected with these protecting groups are particularly useful as production intermediates. The substituent X1 is a halogen atom or hydrogen atom, and the fluorine atom is preferred as the halogen atom. Among these atoms, fluorine or hydrogen is preferred as the substituent. When A1 is a partial structure represented by the following formula (I I), X2 is a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having 1 to 6 atoms of carbon and an acyl group having 2 to 5 carbon atoms. The alkyl group can be either a straight or branched group having 1 to 6 carbon atoms and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group. The alkenyl group can be either a straight or branched group having 2 to 6 carbon atoms and is preferably a vinyl group. The alkynyl group can be either a straight or branched group, having 2 to 6 carbon atoms and is preferably an ethynyl group. The fluorine atom is particularly preferable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxy group may have 1 to 6 carbon atoms and is preferably a methoxyl group. The fluorine atom is particularly preferable as the halogen of the halogenomethoxy group, and its number can be from 1 to 3.

Among these substituents, a halogen atom, an alkyl group or an alkoxy group is preferable, and is more preferably a fluorine atom, methyl group or methoxyl group. In addition, X2 and the aforementioned R5 can together form a cyclic hydrocarbon structure (the size of the ring can be from a four-membered ring to a seven-membered ring, and the ring can be saturated, partially saturated or unsaturated) including a part of the parent nucleus (namely, including the carbon atom to which X2 is bound and A2 to which R5 is linked), and the ring thus formed may contain an oxygen atom, nitrogen atom or sulfur atom as an atom ring constituent, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent. Your examples are shown below.

(In the above formulas, G is an oxygen atom, a sulfur atom or C = O and Y, X1, R6 and R7 are as defined in formula (I).) A structure of the following formula: is preferable as Q. When Q is partial structure just described and A1 is a partial structure of the formula (I I), a preferred combination of R7 and X2 is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms and X2 is a halogen atom, a group alkyl having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenomethoxy group or a hydrogen atom. A more preferred combination is a case, in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X2 is a fluorine atom, a methyl group, a methoxyl group, a difluoromethoxyl group or a hydrogen atom. A most preferred combination is a case, in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group or a methoxyl group. For these groups R7 and X2, a fluorine atom such as X1 is preferable.

When the substituents X1 and X2 are halogen atoms, X1 is particularly a fluorine atom and X2 is preferably a fluorine atom or chlorine atom. When Q is a structure represented by the following formula: and A1 is a partial structure of formula (II), a preferred combination of R7 and X2 is a case in which R7 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms. carbon and X2 is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenomethoxy group or hydrogen atom. A more preferred combination is a case, in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group, a methoxyl group, a difluoromethoxy group or a hydrogen atom. A most preferred combination is a case, in which R7 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group and X2 is a fluorine atom, a methyl group or a methoxyl group. When the substituents X1 and X2 are halogen atoms, X1 is particularly preferable a fluorine atom, and X2 is preferably a fluorine atom or a chlorine atom. When the diastereomers are present in a compound of formula (I) of the present invention, and when such an inventive compound is administered to humans and animals, it is preferable to administer a compound comprising a single diastereomer. As used herein, the term "simple" of "comprised by a simple diastereomer" means not only a case in which it is completely free of another diastereomer, but also a case in which it is in a chemically pure degree. In other words, it is interpretable that the other diastereomer may be present to such an extent that it does not exert any influence on the physical constants and physiological activities of the compound. In addition, the term "stereochemically pure", as used herein, means that when a compound or the like exists in a plurality of isomeric forms due to the presence of asymmetric carbon atoms, the compound is comprised of only one of them. The term "pure" in this case can also be considered in the same way as the term "simple" described above. The pyridonecarboxylic acid derivative of the present invention can be used either in its simple form or as an acid addition salt or a salt of its carboxyl group. Examples of the acid addition salt include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and salts of similar inorganic acids, or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate and salts of similar organic acids . The carboxyl group salt can be either an inorganic or organic salt, and its illustrative examples include lithium salt, sodium salt, potassium salt and similar alkali metal salts, magnesium salt, calcium salt and alkaline earth metal salts similar, ammonium salt or triethylamine salt, N-methylglucamine salt, tris- (hydroxylmethyl) aminomethane salt and the like.

In addition, these free forms, acid addition salts and carboxyl group salts of the pyridonecarboxylic acid derivative can be present as hydrates. On the other hand, a quinolone derivative, whose carboxylic acid moiety is an ester, is useful as a synthetic intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates. In addition, the ester to be used as a prodrug is an ester, which is easily cut into the living body for a free form of carboxylic acid, and its illustrative examples include acetoxymethyl ester, pyruvaloyloxymethyl ester, ethoxycarbonyl ester, ester of choline, dimethylaminoethyl ester, 5-iandanyl ester, phthalimidyl ester, and 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, 3-acetoxy-2-oxobutyl ester or the ester of oxoalkyl similar. The compound of the present invention represented by the formula (I) can be produced by various methods, and in a preferred example of these methods, it can be produced, for example, by allowing a compound represented by the following formula (I I I): (III) [wherein X3 is a substituent which serves as a leaving group, such as fluorine atom, chlorine atom, bromine atom, substituted phenylsulfonyl group or unsubstituted, or a substituted alkylsulfonyl group or substituted having 1 to 3 carbon atoms, Y1 is the Y defined in the formula (I) or a boron-containing substituent represented by the following formula (IV): (wherein each of Y1 1 and Y12 is a fluorine atom or a group alkylcarbonyloxy having 2 to 4 carbon atoms), and R5, R6, R7, A1 and X1 are as defined in formula (I)], or a compound represented by the following formula (V): [wherein R5, R6, R7, A1 and X1, X3 and Y1 are as defined in the formula (I I I)], to react with a compound represented by the following formula (VI): (VI) [wherein R31 is identical to R3 defined in formula (I) or an amino group protecting group, and R1, R2, R4 and n are as defined in formula (I)], or an addition salt of the same. The newly described compound (VI) can be obtained by deprotecting the following compound, in which the cyclic nitrogen atom is protected by a protecting group.

[In the above formula, Q 'is a group protecting group am ino, and R31, R1, R2, R4 and n are as defined in formula (I).] The reaction can be carried out with or without using a solvent. The solvent to be used in the reaction may be any solvent which is inert under the reaction conditions, and its illustrative examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran , water, 3-methoxybutanol and the like, or a mixture thereof. Preferably, the reaction may be performed in the presence of an acid receptor such as an inorganic base or an organic base, which includes a carbonate or alkali metal or alkaline earth metal bicarbonate or basic inorganic compound like or triethylamine , pyridine, 1,8-diazabicycloundecene or the similar organic basic compound.

The reaction can be carried out at a temperature from room temperature to 200 ° C, preferably from 25 to 150 ° C.

The reaction is carried out for a period from 30 minutes to 48 hours and is completed generally after about 30 minutes to 2 hours. Examples of protecting groups of amino group include those generally used in this field, such as tert-butoxycarbonyl, 2,2,2, -trichloroethoxycarbonyl and the like alkoxycarbonyl groups, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl and the like aralkyloxycarbonyl groups, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl and the like acyl groups, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, triphenylmethyl and the like alkyl or aralkyl groups, methoxymethyl, tert-butoxymethyl, tetrahydropyranyl, 2,2,2 trichloroethoxymethyl and similar ethers and trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl and similar silyl groups. When Y and Y1 are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, the compound of interest it can be converted into its corresponding carboxylic acid by treating it under an acidic or basic condition, which is generally employed for the hydrolysis of carboxylic acid esters. When Y1 is a structure of the formula (IV), its conversion to the corresponding carboxylic acid can be effected by allowing the compound (VI) to react with the compound (III) or (V), and then treating it under an acid or basic In addition, when deprotection is required, the compound of interest represented by formula (I) can be obtained by removing the protecting group under the appropriate procedure known in this field., corresponding to the protective groups. The compound of formula (VI) can be produced by several methods, and, although not particularly limited, it can be synthesized by a method shown in the reference examples, according to a preferred example. The cis-2-fluorocyclopropylamine comprised of a simple isomer, which is preferable for the synthesis of the compound of formula (I) comprised of a simple isomer, can be synthesized for example, by the method described in J PA-2-231475 ( the term "JP-A", as used herein, means a Japanese patent application published without examination). The synthesis of the compound of formula (I) comprised of a simple isomer can be carried out using the optically active cis-2-fluorocyclopropylamine derivative obtained in this manner as the material, according to the method described, for example, in JP-A -2-231475. Because the compound of the present invention has strong antibacterial actions, it can be used as a medicament for use in human, animal and fish bodies, or as food preservatives and agricultural chemicals.

. When the compound of the present invention is used as a medicament for human bodies, its dosage is within the range of generally 50 mg to 1 g, preferably from 1000 mg to 300 mg, per day per adult. Its dosage as an animal drug varies depending on the purpose of its administration (cure or prevention), class and size of each animal to be treated and class and degree of each pathogenic bacterium infected, but the dosage may be within the range generally from 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kg of body weight per day. The daily dose can be used once a day or by dividing it in 2 to 4 doses per day. As the occasion demands, the daily dose may exceed the aforementioned range. Because the compound of the present invention has activity against a wide range of microorganisms, which cause various infectious diseases, it can treat, prevent or alleviate diseases induced by these pathogens. Illustrative examples of bacteria and bacterioid microorganisms on which is effective compound of the present invention include those belonging to the genus Staphylococcus, Streptococcus pyogenes, hemolytic streptococci, enterococci, pneumococci, those belonging to Peptostreptococcus genus, Neisseria gonorrhoeae, Escherichia coli, those which belong to the genus Citrobacter, those which belong to the genus Shigella, Klebsiella pneumoniae, those which belong to the genus Enterobacter, those which belong to the Serratia genus, those who belong to the genus Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, those which belong to the genus Acinetobacter, those that belong to the genus Campylobacter, Chlamydia trachomatis and the like. Illustrative examples of diseases which are induced by these pathogens include folliculitis, boils, carbuncles, erysipelas, phlegmon, lymphangitis, felon, subcutaneous abscess, hidrandenitis, acne conglobata, infectious atheroma, perirectal abscess, mastitis, superficial secondary infections after injury, burn injury, operative wounds and the like, pharyngitis, acute bronchitis, tonsillitis, chronic uitis bronq, bronchiectasis, diffuse bronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nonspecific urethritis, cholecystitis , cholangitis, bacillary dysentery, enteritis, uterine adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, half octitis, sinusitis, periodentitis, pericoronitis, jaw infection, peritonitis, endocarditis, sepsis, meningitis, infection l to skin and the like. The inventive compound is also effective against several microorganisms, which cause infectious diseases in animals, such as, those belonging to the genus Escherichia, Salmonella, pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and the like. Illustrative examples of such diseases include colibacillosis, pullorum, paratyphoid of birds, cholera of birds, infectious coryza, staphylococcosis, mycoplasma infection and the like in the case of birds; colibacillosis, salmonellosis, pasteurellosis, hemos infection, atrophic rhinitis, exudative epidermis, mycoplasma infection and the like in the case of pigs; colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine pleuropneumonia, bovine mastitis and the like in the case of cattle; colisepsis, salmonella infection, hemorrhagic sepsis, uterine empyema, cystitis, and similes in the case of dogs; Exudative pleurisy, cystitis, chronic rhinitis, hemophilic infection, cat diarrhea, mycoplasma infection and the like in the case of cats. The antibacterial preparation, which comprises the compound of the present invention, can be prepared by selecting the appropriate preparation depending on each method of administration and generally employing various methods of preparation. With respect to the dosage forms of the antibacterial preparation, which uses the compound of the present invention as its principal agent, tablets, powders, granules, capsules, solutions, syrups, the oil, aqueous or similar suspensions, and the like, can be exemplified as oral preparations.

With respect to the injections, a stabilizing agent, an antiseptic agent, a solubilizing agent and the like can be used in the preparation, and a solution which can contain these auxiliary agents can be contained in a container and made into a solid preparation by lyophilization or similar medium, to be re-dissolved when used. In addition, a single dose may be contained in a single container or multiple doses may be contained in the same container.

In addition, solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like can be exemplified as preparations for external use. The solid preparations may contain pharmaceutically acceptable additives together with the active compound and may be prepared, for example, by mixing the compound with optionally selected additives from fillers, extenders, binders, disintegrators, solubilizing enhancing agents, wetting agents, lubricating agents and the like. As the liquid preparation, solutions, suspensions, emulsions and the like, which may contain a suspending agent, an emulsifying agent and the like as additives, can be exemplified. Examples of the method for administering the compound of the present invention to animals include a method in which it is administered orally directly or when mixed with food, a method in which it is converted to solution and then administered orally directly, or when mixed with water for drinking or food, and a method in which it is administered by injection. With respect to the pharmaceutical preparations for use in administering the compound of the present invention to animals, it can optionally be made into powders, fine "subtilaes", soluble powders, syrups, solutions or injections making use of the techniques generally used in this field. . Formulation examples of the pharmaceutical preparations are shown below.

Formulation Example 1 (Capsules): Compound of Inventive Example 2 100.0 mg Corn starch 23.0 mg CMC calcium 22.5 mg Hydroxymethyl cellulose 3.0 mg Magnesium stearate 1.5 mg Total 1 50.0 mg Formulation Example 2 (Solutions): Compound of Inventive Example 2 1 -1 0 g Acetic acid or sodium hydroxide 0.5-2 g ethyl para-hydroxybenzoate 0.1 g Purified water 87.9-98.4 g Total 100 g Formulation Example 3 (Powders for mixing with the feed): Compound of Inventive Example 2 1 -10 g Corn Compound 98.5-89-5 g Light anhydrous silicic acid 0.5 g Total 100 g MODALI D M ANTERS TO MAKE THE I NVENTION Examples of the present invention are given below by way of illustration and not by way of limitation.

Reference Example 1: 1-benzyloxy-3- (tert-butoxycarbonylamino) -3-isoamyloxycarbonylcyclobutane A portion of 46.70 g (145.8 mmol) of 1-benzyloxy-3-isoamyloxycarbonylcyclobutane-3-carboxylic acid was dissolved in 750 ml of tertiary butanol to which, while cooling in an ice bath with stirring, 34.55 ml (1 60.3 mmol) of diphenyl phosphorus azide and 44.70 ml (320.7 mmol) of triethylamine were subsequently added in that order. After 10 minutes of stirring at the same temperature, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. After 8 hours of heating under reflux, the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by silica gel column chromatography to give 45.28 g (79.4%) of the title compound. 1 H-NMR (CDCl 3) d: 0.91 (3 H, d, J = 6.8 Hz), 0.92 (3 H, d, J = 6.8 Hz), 1.43 (9 H, s), 1 .48 - 1 .57 (2 H, m), 1 .63 - 1 .71 (1 H, m), 2.23 - 2.38 (1 H, m), 2.39 - 2.52 (1 Jl, m), 2.55 - 2.69 (1 H, m), 2.82 - 2.93 (1 H, m), 4.09 -4.28 (3 H, m), 4.44 (2 H, s), 4.92 (0.5 H, brs), 5.1 2 (0.5 H, brs), 7.28 - 7.36 (5 H, m).

Reference Example 2: 1-Benzyloxy-3- (tert-butoxycarbonylamine) -cyclobutane-3-carboxylic acid A portion of 45.28 (1 15.7 mmol) of 1-benzyloxy-3- (tert-butoxycarbonylamino) -3 -isoamyloxycarbonylcyclobutane was dissolved in 300 ml of methanol which, while cooling in an ice bath with stirring, was subsequently added dropwise with 127 ml (127.2 mmol) of 1 N sodium hydroxide in 10 minutes. After 10 minutes of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 5 hours. This was mixed with 200 ml of water, and methanol was evaporated under reduced pressure. The residue thus obtained was mixed with ether to effect the separation of layers, the resulting aqueous layer was extracted with diethyl ether, and the ether layer was extracted with water. The aqueous layers were combined, acidified with 10% citric acid while cooling in an ice bath with stirring, and then mixed with ethyl acetate to effect layer separation. The resulting organic layer was washed with saturated brine, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to give 37.24 g (quantitative) of the title compound. This compound was used in the next reaction without purification.

Reference example 3: 3- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-yn-3-oxopropionate ethyl A portion of 37.24 g (1-1.5 mmol) of 1-benzyloxy-3- ( tert-butoxycarbonylamino) cyclobutane-3-carboxylic acid was dissolved in 300 ml of tetrahydrofuran, which, while cooling in an ice bath with stirring, was added 20.63 g (127.2 mmol) of N, N-carbonyldiimidazole. After 10 minutes of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. To the reaction solution, which was cooled in an ice bath with stirring, 200 ml of tetrahydrofuran solution containing 36.45 g (1 27.2 mmol) of magnesium ethylmalonate was added dropwise. After 1 hour of stirring, the ice bath was removed, and the reaction mixture was stirred at room temperature for 10 hours. While cooling in an ice bath with stirring, the reaction mixture was mixed with 10% aqueous citric acid solution, and then with ethyl acetate to effect the separation of layers, and the resulting organic layer was washed with water. aqueous solution of saturated sodium bicarbonate. The organic layer was further washed with saturated brine. After extraction of the aqueous layer with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 38.84 g (85.8% >) of the title compound.

Reference Example 4: 3- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-ip-3-hydroxypropionate ethyl A portion of 38.84 g (99.22 mmol) of 3- [1-benzyloxy-3- ( ethyl tert-butoxycarbonylamino) cyclobutan-3-yl] -3-oxopropionate was dissolved in 300 ml of methanol which, while cooling in an ice bath with stirring, was subsequently added 1.617 g (42.75 mmol). of sodium tetrahydroborate in five portions. After stirring for 10 minutes at the same temperature, saturated aqueous ammonium chloride solution was gradually added thereto. After evaporation of methanol under a reduced pressure, ethyl acetate was added to the residue thus obtained to effect the separation of layers. The resulting organic layer was washed with saturated brine, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 35.61 g (91.2%) of the title compound.

Reference Example 5: (E) -3- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-ethyl acrylate A portion of 35.61 g (90.50 mmol) of 3- [1-benzyloxy-3- ( ethyl tert-butoxycarbonylamino) cyclobutan-3-yl] -3-hydroxypropionate was dissolved in 200 ml of dichloromethane, to which, while cooling in an ice bath with stirring, 9,050 ml (16.9 mmol) were subsequently added. ) of methanesulfonyl chloride and 37.24 ml (267.2 mmol) of triethylamine in that order. After 2 hours of stirring, 30.60 ml (204.6 mmol) of diazabicycloundecene was added thereto. After 1 hour of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. While cooling in an ice bath with stirring, this was mixed with saturated aqueous ammonium chloride solution and then with ethyl acetate to effect layer separation. The resulting organic layer was washed with 10% aqueous citric acid solution and then with saturated brine. After extraction of the aqueous layer with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 31.07 g (91.4%) of the title compound. 1 H-NMR (CDCl 3) d: 1-25-1.30 (3 H, m), 1.42 (4.5 H, s), 1.43 (4.5 H, s), 2.22 - 2.35 (2 H, m), 2.57 - 2.72 ( 2 H, m), 4.01 - 4.05 (0.5 H, m), 4.07 - 4.27 (2.5 H, m), 4.48 (2 H, s), 4.81 (0.5 H, s), 4.94 (0.5 H, brs), 5.79 (0.5 H, d, J = 15.5 Hz), 5.86 (0.5 H, d, J = 15.5 Hz), 6.98 (0.5 H, d, J = 15.5 Hz), 7.02 (0.5 H, d, J = 15.5 Hz ), 7.27 - 7.36 (5 H, m).

Reference Example 6: 3- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-yl-4-nitrobutanoate ethyl A portion of 31.07 g (82.75 mmol) of (E) -3- [1 -benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-yl] ethyl acrylate was dissolved in 300 ml of nitromethane which, while cooling in an ice bath with stirring, was subsequently added in the form of drops 13.37 ml. (82.75 mmol) of diazabicycloundecene. After 10 minutes of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, the reaction solution was acidified by gradually adding 10% citric acid aqueous solution and then mixed with ethyl acetate to effect layer separation. The resulting organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 35.12 g (97.2% of the title compound) This compound was used in the next reaction without purification.

Reference Example 7: 4- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-yl-2-pyrrolidone A portion of 35.12 g (80.46 mmol) of 3- [1-benzyloxy-3- (ter -butoxycarbonylamino) cyclobutan-3-yl] -4-nitrobutanoate was dissolved in 700 ml of ethanol to which, under a nitrogen atmosphere, 50 ml of Raney nickel was subsequently added. After replacing the atmosphere with hydrogen, this was stirred at 50 ° C for 5 hours. After cooling in an ice bath, the reaction solution was filtered through celite and then the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by silica gel column chromatography to give 20.53 g (70.8% o) of the title compound.

Reference example 8: 1 -be ncyl-4- [1-benzyl oxy-3- (tert-butoxycarbon or lamellar) butan-3-yl cycle} -2-pyrrolidone A portion of 20.53 g (56.96 mmol) of 4- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-yl] -2-pyrrolidone was dissolved in a mixed solvent consisting of 200 ml of dimethylformamide and 60 ml of tetrahydrofuran, and to the resulting solution, which was cooled in an ice bath and stirred, 2.51 g (62.7 mmol) of 60% sodium hydride was gradually added gradually. After 10 minutes of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. While cooling in an ice bath with stirring, 7.21 ml (62.7 mmol) of benzyl chloride were added dropwise therein, and the resulting reaction solution was stirred for 1 hour at the same temperature, and then for 12 hours. hours at room temperature. Water was added to the reaction solution, which was cooled in an ice bath and stirred, and then layer separation was effected upon addition of ethyl acetate. The organic layer thus separated was washed with saturated brine, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1 8.00 g (70.1%) of the title compound as a mixture of diastereomers 1: 1. Subsequently, the title compound thus obtained was subjected again to a silica gel column chromatography to separate it into the diastereomers A and B, and the following reaction was performed using Isomer B. Isomer A 1 HN MR (CDCl 3) d: 1 .41 (9 H, s), 1 .93 - 2.04 (2 H, m), 2.30 - 2.52 (4 H, m), 2.92 - 3.08 (1 H, m), 3.1 0 - 3.1 8 (1 H , m), 3.1 8 - 3.27 (1 H, m), 4.1 0 - 4.08 (1 H, m), 4.34 (1 H, d, J = 14.6 Hz), 4.36 (2 H, s), 4.52 (1 H, d, J = 14. 6 Hz), 4.63 (1 H, s), 7.21 - 7.36 (1 0 H, m). Isomer B 1 H-NM R (CDCl 3) d: 1.40 (9 H, s), 2.10 - 2.17 (1 H, m), 2.21 - 2.37 (2 H, m), 2.41 - 2.54 (3 H, m ), 2.70 - 2.80 (1 H, m), 3.08 - 3.20 (1 H, m), 3.20 - 3.28 (1 H, m), 3.74 - 3.83 (1 H, m), 4.33 (1 H, d, J = 14.6 Hz), 4.37 (2 H, s), 4.52 (1 H, d, J = 14.6 Hz), 4.78 (1 H, s), 7.21 - 7.35 (10 H, m).

Reference Example 9: 1 -benzyl-4-f3- (tert-butoxycarbonylamino) -1-hydroxycyclobutan-3-n-2-pyrrolidone (Isomer B) A portion of 4.86 g (1 0.8 mmol) of 1-benzyl -4- [1-benzyloxy-3- (tert-butoxycarbonylamino) cyclobutan-3-yl] -2-pyrrolidone (Isomer B) was dissolved in 140 ml of ethanol, and the solution was mixed with 1 g of palladium hydroxide in carbon catalyst and subjected to 1 hour of catalytic reduction under a hydrogen pressure of 3 atmospheres and under light irradiation. After removal of the catalyst by filtration, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give 4.01 g (quantitative) of the title compound. Subsequently, the optical resolution of Isomers B 1 and B2 as enantiomers originated from the asymmetric carbon atom of position 4 of pyrrolidine of the compound thus obtained, was carried out under HPLC under the following conditions. HPLC conditions Column: DIACEL CHIRALPACK AD 20 x 250 mm Mobile phase: hexane: ethanol = 1: 1 Flow rate: 1 5 ml / min Temperature: room temperature Detection: UV (254 nm) 1 H-NMR (CDCI3) d : 1.42 (9 H, s), 2.23 - 2.42 (3 H, m), 4.45 - 4.68 (4 H, m), 3.03 - 3.06 (1 H, m), 3.23 - 3.33 (1 H, m), 3.97 - 40.97 (1 H, m), 4.38 (1 H, d, J = 14.7 Hz), 4.49 (1 H, d, J = 14.7 Hz), 4.72 (1 H, s), 7.21 - 7.36 (5 H, m).

Reference Example 1 0: 1 -benzyl-4- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yn-2-pyrrolidone (Isomer B 1) A portion of 1.79 g (4.96 mmol) of 1-benzyl-4- [3- (tert-butoxycarbonylamino) -1-hydroxycyclobutan-3-yl] -2-pyrrolidone (Isomer B1) was dissolved in a mixed solvent consisting of 50 ml of toluene and 20 ml of dichloromethane a which, while cooling in an ice bath with stirring, was then added 1.31 ml (9.92 mmol) of diethylaminosulfur trifluoride, subsequently carrying out 12 hours of stirring at room temperature. While cooling in an ice bath with stirring, the reaction solution was alkalified by slowly adding saturated aqueous sodium bicarbonate solution and then mixed with chloroform, to perform the separation of layers, and the resulting organic layer was washed with saturated brine The aqueous layer was extracted again with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 541 mg (30.0%) of the title compound. 1 H-NM R (CDCIs) d: 1.41 (9 H, m), 2.12-2.24 (2 H, m), 2.30 - 2.37 (1 H, m), 2.48 - 2.72 (3 H, m), 2.93 - 3.05 (1 H, m), 3.16 - 3.1 8 (1 H, m), 3.25 -3.33 (1 H, m), 4.34 (1 H, d, J = 14.7 Hz), 4.53 (1 H, d , J = 14.7 Hz), 4.73 (1 H, s), 5.04 - 5.1 1 (0.5 H, m), 5.1 8 - 5.25 (0.5 H, m), 7.22 - 7.36 (5 H, m).

Reference Example 1 1: 1-benzyl-4-, 3- (tert-butoxycarbonyl) -l-1-fluorocyclobutan-3-yl-2-pyrrolidone (Isomer B2) A portion of 1.79 g (4.96 mmol) of 1-benzyl-4- [3- (tert-butoxycarbonylamino) -1-hydroxycyclobutan-3-yl] -2-pyrrolidone (Isomer B2) was dissolved in a mixed solvent consisting of 50 ml of toluene and 20 ml of dichloromethane to which, while cooling in an ice bath with stirring, then 1.31 ml (9.92 mmol) of diethylaminosulfur trifluoride was added, subsequently carrying out 12 hours of stirring at 50 ° C. While cooling in an ice bath with stirring, the reaction solution was made alkaline by slowly adding saturated aqueous sodium bicarbonate solution, and then mixed with chloroform to perform the separation of layers, and the resulting organic layer was washed with saturated brine. The aqueous layer was extracted again with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 964 mg (53.6%) of the title compound. The 1H-NMR data of the compound thus obtained coincided with the aforementioned data of its enantiomer, Isomer B1.

Reference Example 12: 1-benzyl-4-y3- (tert-butoxycarbonylamino) -1-fluoro-cyclobutan-3-ip-2-pyrrolidinationa (Isomer B1) A portion of 517 mg (1.43 mmol) of 1- Benzyl-4- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] -2-pyrrolidone (Isomer B1) was dissolved in 20 ml of toluene, and the solution was mixed with 635 mg (1.57 mmol) of Lawesson's reagent and stirred at 50 ° C for 3 hours.

After evaporation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to give 485 mg (89.5%) of the title compound. 1 H-NMR (CDCl 3) d: 1.41 (9 H, s), 2.04-2.22 (2 H, m), 2.44 - 2.60 (1 H, < 'm), 2.60 - 2.73 (1 H, m), 2.80 - 3.07 (2 H, m), 3.13 - 3.20 (1 H, m), 3.56 - 3.63 (2 H, m), 4.59 (1 H, s ), 4.76 (1 H, d, J = 14.2 Hz), 5.02 -5.11 (0.5 H, m), 5.11 - 5.23 (1.5 H, m), 7.27 - 7.38 (5 H, m).

Reference Example 13: 1-benzyl-4- [3- (tert-butoxycarbonyl-lamino) -1-f luorocyclobutan-3-in-2-pyrrolidinationa (Isomer B2) A portion of 896 mg (2.47 mmol) of 1- Benzyl-4- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] -2-pyrrolidone (Isomer B2) was dissolved in 20 ml of toluene, and the solution was mixed with 1.10 g (2.72 mmol) of Lawesson's reagent and stirred at 50 ° C for 3 hours. After evaporation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography to give 833 mg (89.1%) of the title compound. The 1 H-NM R data of the compound thus obtained coincided with the aforementioned data of its enantiomer, Isomer B1.

Reference Example 14: 1 -benzyl-3-y3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-y-pyrrolidine (Isomer B1) A portion of 485 mg (1.28 mmol) of 1-benzyl-4- [3 - (tert-butoxycarbonyllamino-1-fluoro) cyclobutan-3-yl] -2-pyrrolidinationa (Isomer B 1) was dissolved in 20 ml of ethanol and, under a nitrogen atmosphere, 2.0 ml of Raney nickel was added to the solution thus prepared, which was stirred and cooled in an ice bath. After 10 minutes of stirring at the same temperature, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, the solvent was evaporated under reduced pressure and then the resulting residue was purified by column chromatography on silica gel to give 310 mg (69.5%) of the title compound. 1 H-NMR (CDCl 3) d: 1.49 (9 H, s), 1.57 - 1.70 (2 H, m), 1.94 - 2.28 (6 H, m), 2.58 - 2.63 (1 H, m), 2.70 - 2.82 (1 H, m), 2.93 - 3.21 (3 H, m), 3.59 (2 H, s), 5.1 9 - 5.22 (0.5 H, m), 5.32 - 5.41 (0.5 H , m), 7.25 - 7.33 (5 H, m).

Reference Example 15 1 -benzyl-3-f3- (tert-butoxycarbonyllamino) -1-fluorocyclobutan-3-inpyrrolidine (Isomer B2) A portion of 833 mg (2.20 mmol) of 1-benzyl-4- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] -2-pyrrolidinationa (Isomer B2) was dissolved in 30 ml of ethanol and, under a nitrogen atmosphere, 1.5 ml of Raney nickel was added to the solution thus prepared, which was stirred and cooled in an ice bath. After 10 minutes of stirring at the same temperature, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, the solvent was evaporated under reduced pressure and then the resulting residue was purified by silica gel column chromatography to give 677 mg (88.2%) of the title compound. The H-NMR data of the compound thus obtained coincided with the aforementioned data of its enantiomer, Isomer B 1.

Reference Example 16: 3- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl. pyrro I id i na (Isomer B11 A 31.0 mg portion (0.89 mmol) of 1-benzyl-3- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer B1) was dissolved in 20 ml of ethanol, which was subsequently added 310 mg of 10% Palladium on carbon catalyst. The mixture thus prepared was stirred for 2 hours under irradiation of light and under a hydrogen pressure of 4 atmospheres. After removal of the catalyst by filtration, the solvent was evaporated under reduced pressure to give 233 mg (quantitative) of the title compound. The compound thus obtained was used in the next reaction without purification.

Reference Example 17: 3- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-illpyrrolidine (Isomer B2) A portion of 677 mg (1.92 mmol) of 1-benzyl-3- [3- (ter -butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer B2) was dissolved in 20 ml of ethanol to which 670 mg of catalyst of 1.0% palladium on carbon were subsequently added. The mixture thus prepared was stirred for 2 hours under irradiation of light and under a hydrogen pressure of 4 atmospheres. After removal of the catalyst by filtration, the solvent was evaporated under reduced pressure to give 51 7 mg (quantitative) of the title compound. The compound thus obtained was used in the next reaction without purification.

Inventive Example 1: 5-am ino-7-r3- (3-amin or-1-fluoro-cyclobutan-3-yl) pyrrolidin-1-l-6-f luoro-1-r2- (S) -fluoro- acid 1- (R) -cyclopropin-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Isomer B 1) A portion of 281 mg (0.90 mmol) of 5-amino-6,7-difluoro acid -1- [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 233 mg (0.89 mmol) of 3- [3 - (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer B1) were suspended in 3 ml of dimethyl sulfoxide, and the suspension was mixed with 5 ml of triethylamine and stirred at 110 ° C for 72 hours under a nitrogen atmosphere. After evaporation of the solvent under a reduced pressure, concentrated hydrochloric acid was added to the residue thus obtained, which was stirred in an ice bath. After 10 minutes of stirring, this was mixed with water, and the resulting aqueous layer was washed with chloroform. After extraction of the chloroform layer with 1N hydrochloric acid, the aqueous layers were combined and, while stirring in an ice bath, was adjusted to pH 12 with saturated aqueous sodium hydroxide solution. This was then adjusted to pH 7.4 with hydrochloric acid and extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography and then subjected to purification by recrystallization by 2-propanol, thereby giving 142 mg (36.0%) of the title compound. 1 H-NMR (NaOD 0.1 N) d: 1.01 - 1.08 (0.5 H, m), 1.08 - 1.17 (0.5 H, m), 1.42 - 1.54 (1 H, m), 1.58 - 1.74 (1 H, m), 1.93 - 2.05 (1 H, m), 2.19 -2.38 (4 H, m), 2.25 (3 H, s), 2.38 - 2.52 (1 H, m), 3.19 - 3.34 (2 H, m), 3.42 - 3.49 (1 H, m), 3.64 - 3.77 (1 H, m), 3.83 - 3.92 (1 H, m), 4.70 - 4.90 (0.5 H, m), 4.98 - 5.03 (0.5 H, m), 5.20 - 5.27 (0.5 H, m), 5.36 - 5.41 (0.5 H, m), 8.26 (1 H, d, J = 1.9 Hz). Elements analysis data for C22H25F3N4? 3 »2H2O Caled. : c, 50.53; H, 5.78; N, 1 0.71. Found: C, 50.15; H, 5.30; N, 10.69.

Inventive Example 2: 5-am ino-7-f3- (3-am-no-1-fluoro-cyclobutan-3-yl) pyrrolidin-1-yl-6-f-1-f2- (S) -fluoro- 1- (R) -cyclopropyl-H-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Isomer B2) A portion of 281 mg (0.90 mmol) of 5-amino-6 acid, 7-difluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 51 7 mg (1.94 mmol ) of 3- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer B 1) were suspended in 3.5 ml of dimethyl sulfoxide, and the suspension was mixed with 5 ml of triethylamine and stirred at 11 ° C for 72 hours under a nitrogen atmosphere. After evaporation of the solvent under reduced pressure, concentrated hydrochloric acid was added to the residue thus obtained, which was stirred in an ice bath. After 10 minutes of stirring, this was mixed with water, and the resulting aqueous layer was washed with chloroform. After extraction of the chloroform layer with 1N hydrochloric acid, the aqueous layers were combined and, while stirring in an ice bath, was adjusted to pH 1 2 with saturated aqueous sodium hydroxide solution. It was then adjusted to pH 7.4 with hydrochloric acid and extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography and then subjected to recrystallization purification by 2-propanol, thereby giving 194 mg (22.2%) of the title compound. 1 H-NMR (NaOD 0.1 N) d: 1.10-1.22 (1 H, m), 1.44 - 1.55 (1 H, m), 1.67 - 1.78 (1 H, m), 1.96 - 2.04 (1 H, m), 2.20 - 2.37 (4 H, m), 2.31 (3 H, s), 2. 44 - 2.56 (1 H, m), 3.15 - 3.22 (1 H, m), 3.33 - 3.41 (1 H, m), 3.44 - 3.57 (2 H, m), 2.89 - 3.94 (1 H, m), 4.75 - 4.85 (0.5 H, m), 4.95 - 5.00 (0.5 H, m), 5.18 - 5.22 (0.5 H, m), 5.31 - 5.38 (0.5 H, m), 8.29 (1 H, d, J = 1.6 Hz). Element analysis data for C22H25F3N4O3 »0.5H2O Caled .: C, 57.51; H, 5.70; N, 12.19. Found: C, 57.30; H, 5.67; N, 12.14.

Reference Example 18: 1-benzyl-4-r3- (tert-butoxycarbonylamino) -1-oxocyclobutan-3-in-2-pyrrolidone A portion of 4.89 g (13.6 mmol) of 1-benzyl-4- [3- (tert-butoxycarbonylamino) -1-hydroxycyclobutan-3-yl] -2-pyrrolidone was dissolved in 100 ml of dimethyl sulfoxide which, while cooling in an ice bath with stirring, was then added 6.24 ml ( 44.8 mmol) of triethylamine and 6.47 g 810.7 mmol) of the sulfur trioxide-pyridine complex in that order, subsequently carrying out 14 hours of stirring at room temperature. While cooling in an ice bath with stirring, the reaction solution was mixed with water and then with ethyl acetate to effect layer separation. The organic layer was washed with saturated brine, the aqueous layer was extracted with ethyl acetate and then the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give 4.69 g (96.3%) of the title compound.

Subsequently, the optical resolution of the F1 and F2 isomers as enantiomers originated from the asymmetric carbon atom of position 4 of pyrrolidine of the compound thus obtained was carried out by HPLC under the following conditions. HPLC conditions Column: DAICEL CHIRALPACK AD 20 x 250 mm Mobile phase: hexane: ethanol: methanol = 2: 1: 1 Flow rate: 15 ml / min Temperature: room temperature Detection: UV (254 nm) H-NMR (CDCI3 ) d: 1.43 (9 H, s), 2.35 (1 H, dd, J = 17.1, 7.3 Hz), 2.62 (1 H, dd, J = 17.1, 9.3 Hz), 2.95 - 3.05 (3 H, m), 3.13 - 3.18 (1 H, m), 3.22 - 3.39 (4 H, m), 4.36 (1 H, d, J = 14.2 Hz), 4.53 (1 H, d, J = 14.2 Hz), 4.98 (1 H, s), 7.22-7.37 (5 H, m).

Reference Example 19: 1-benzyl-4- [3- (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-yl1-2-pyrrolidone (F1 Isomer) A portion of 2.30 g (6.42 mmol) of 1-benzyl -4- [3- (tert-butoxycarbonylamino) -1-oxocyclobutan-3-yl] -2-pyrrolidine (F1 isomer) was dissolved in 30 ml of tetrahydrofuran, 3.40 ml (25.7 mmol) of diethylamine sulfur trifluoride was added to the solution thus prepared, which was stirred and cooled in an ice bath, and then the mixture was stirred for 48 hours while heating to 60 ° C. While stirring and cooling in an ice bath, the reaction solution was alkalized by gradually adding saturated aqueous sodium bicarbonate solution. This was mixed with chloroform to effect the separation of layers, and the resulting organic layer was washed with saturated salt. The aqueous layer was extracted again with chloroform and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 927 mg (38.0%) of the title compound. 1 H-NMR (CDCl 3) d: 1.42 (9 H, s), 2.32 (1 H, d, J = 17.6, 7.3 Hz), 2.53 -2.64 (3 H, m), 2.64 - 2.90 (2 H , m), 2.92 - 3.03 (1 H, m), 3.08 - 3. 1 8 (1 H, m), 3.27 - 3.35 (1 H, m), 4.35 (1 H, d, J = 15.7 Hz), 4.53 (1 H, d, J = 15.7 Hz), 4.73 (1 H, s), 7.22 - 7.36 (5 H, m).

Reference Example 20: 1 -benzyl-4-y3- (tert-butoxycarbonylamino) -1, 1-difluorocyclobutan-3-ill-2-pyrrolidone (Isomer F2) A 2.16 g portion 86.01 mmol) of 1-benzyl-4 - [3- (tert-butoxycarbonylamino) -1-oxocyclobutan-3-yl] -2-pyrrolidone (Isomer F2) was dissolved in 30 ml of tetrahydrofuran, 3.1 ml (24.1 mmol) of diethylamine sulfur trifluoride were added to the solution thus prepared, which was stirred and cooled in an ice bath, and then the mixture was stirred for 48 hours while heating to 60 ° C. . While stirring and cooling in an ice bath, the reaction solution was made alkaline by gradually adding saturated aqueous sodium bicarbonate solution. This was mixed with chloroform to effect the separation of layers, and the resulting organic layer was washed with saturated brine. The aqueous layer was extracted again with chloroform and the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 825 mg (36.1%) of the title compound. The data of 1 H-NM R of the compound thus obtained coincided with the aforementioned data of its enantiomer, Isomer F1.

Reference Example 21: 1 -benzyl-3- [3- (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-illpyrrolidine (F1 Isomer) Under a nitrogen atmosphere, 927 mg (2.44 mmol) of 1-benzyl- 4- [3- (tert-butoxycarbonyl-lamino) -1,1-di-uo-cyclobutan-3-yl] -2-pyrrolidone (F1 isomer) were dissolved in 20 ml of tetrahydrofuran, which, while cooling in a bath of ice with stirring, 7.31 ml of tetrahydrofuran solution of 1 N borane-tetrahydrofuran complex was subsequently added. Ten minutes later, the ice bath was separated and the reaction mixture was stirred at room temperature for 1 8 hours. After evaporation of the solvent under reduced pressure, the residue thus obtained was mixed with 30 ml of 80% ethanol and 3 ml of triethylamine, and heated to reflux for 2 hours. After evaporation of the solvent under reduced pressure, the residue thus obtained was mixed with ethyl acetate and saturated aqueous sodium bicarbonate solution to effect layer separation. The organic layer was washed with saturated brine, the aqueous layer was extracted with ethyl acetate and then the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 501 mg (56.1%) of the title compound. H-NMR (CDC) d: 1.50 (9 H, s), 1.60 - 1.73 (1 H, m), 1.97 - 2.07 (1 H, m), 2.07 - 2.17 (1 H, m), 2.17 - 2.24 ( 1 H, m), 2.24 - 2.36 (2 H, m), 2.44 -2.50 (1 H, m), 2.75 - 2.79 (1 H, m), 2.99 - 3.09 (1 H, m), 3.35 - 3.60 ( 4 H, m), 7.25-7.33 (5 H, m).

Reference Example 22: 1-benzyl-3- [3- (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-illpyrrolidine (Isomer F2) Under a nitrogen atmosphere, 825 mg (2.17 mmol) of 1-benzyl 4- [3- (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-yl] -2-pyrrolidone (Isomer F2) were dissolved in 20 ml of tetrahydrofuran, which, while cooling in an ice bath with stirring , 6.51 ml of tetrahydrofuran solution of borane-tetrahydrofuran 1N complex were subsequently added. Ten minutes later, the ice bath was separated and the reaction mixture was stirred at room temperature for 18 hours. After evaporation of the solvent under reduced pressure, the residue thus obtained was mixed with 30 ml of 80% ethanol and 3 ml of triethylamine and heated under reflux for 2 hours. After evaporation of the solvent under reduced pressure, the residue thus obtained was mixed with ethyl acetate and saturated aqueous sodium bicarbonate solution to effect layer separation. The organic layer was washed with saturated brine, the aqueous layer was extracted with ethyl acetate and then the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 494 mg (62.2%) of the title compound. The 1 H-NMR data of the compound thus obtained coincided with the aforementioned data of its enantiomer, Isomer F1.

Reference Example 23: 3- [3- (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-illpyrrolidine (F 1 isomer) A portion of 317 mg (0.87 mmol) of 1 -benzyl-3- [3 - (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-yl] pyrrolidine (F1 isomer) was dissolved in 20 ml of ethanol to which 350 mg of catalyst of 1.0% palladium on carbon were subsequently added. The mixture thus prepared was stirred for 2 hours under irradiation of light and under a hydrogen pressure of 4 atmospheres. After removal of the catalyst by filtration, the solvent was evaporated under reduced pressure to give 239 mg (quantitative) of the title compound. The compound thus obtained was used in the next reaction without purification.

Reference example 24: 3-y3- (tert-butoxycarbonylamino) -1, 1-difluorocyclobutan-3-pyrrolidine (Isomer F2) A portion of 1 83 mg (0.50 mmol) of 1 -benzyl-3- [3- (tert-butoxycarbonylamino) -1, 1-difluorocyclobutan-3-yl] pyrrolidine (Isomer F2) was dissolved in 20 ml of ethanol to which, subsequently, 183 mg of 10% palladium carbon catalyst was added. The mixture thus prepared was stirred for 2 hours under irradiation of light and under a hydrogen pressure of 4 atmospheres. After removal of the catalyst by filtration, the solvent was evaporated under reduced pressure to give 533 mg (quantitative) of the title compound. The compound thus obtained was used in the next reaction without purification.

Inventive Example 3: 7- [3- (3-Am-ino-1,1 -difluorocyclobutan-3-yl) pyrrolidin-1-in-6-fluoro-1 - [2- (S) -fluoro-1-acid (R) -cyclopropyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (F1 isomer) A portion of 1 81 mg (0.50 mmol) of BF2 chelate of 6,7-difluoro- 1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1 38 mg (0.50 mmol) of 3- [3 - (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-yl] pyrrolidine (F1 isomer), were suspended in 1.5 ml of dimethyl sulfoxide, and the suspension was mixed with 0.21 ml of triethylamine and stirred at 45.degree. ° C for 48 hours under a nitrogen atmosphere. After evaporation of the solvent under a reduced pressure, water was added to the residue thus obtained, which was stirred and cooled in an ice bath, the crystals thus formed were collected by filtration and dissolved in 30 ml of 80% ethanol , and then the solution was mixed with 3 ml of triethylamine and heated under reflux for 2 hours. The solvent was evaporated under reduced pressure, and concentrated hydrochloric acid was added to the residue thus obtained, which was stirred in an ice bath. After 10 minutes, stirring, this was mixed with water, and the resulting aqueous layer was washed with chloroform. After extraction of the chloroform layer with 1N hydrochloric acid, the aqueous layers were combined and, while stirring and cooling in an ice bath, was adjusted to pH 1 2 with saturated aqueous sodium hydroxide solution. This was then adjusted to 7.4 with hydrochloric acid and extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography and then subjected to recrystallization purification by 2-propanol, thereby giving 1 65 mg (70.4%) of the title compound. H-NMR (NaOD 0.1 N) d: 1.32-1.46 (1 H, m), 1.46-1.58 (1 H, m), 1.70-1.82 (1 H, m ), 2.04 - 2.1 3 (1 H, m), 2.43 - 2.64 (3 H, m), 2.73 - 2.84 (2 H, m), 3.43 - 3.53 (1 H, m), 3.53 - 3.65 (2 H, m), 3.57 (3 H, s), 3.65 - 3.73 (1 H, m), 3.95 - 4.04 (1 H, m), 4.88 - 4.93 (0.5 H, m), 5.07 - 5.1 1 (0.5 H, m ), 7.65 (1 H, d, J = 14.2 Hz), 8.40 (1 H, s).

Elements analysis data for C2_H23F4N3O4 »0.25H2O Caled. : C, 55.75; H, 5.00; N, 8.87. Found: C, 55.62; H, 4.86; N, 8.70.

Inventive Example 4: 7- [3- (3-Amino-1,1 -difluorocyclobutan-3-yl) pyrrolidin-1-yl-6-fluoro-1,2- (S) -fluoro-1 - ( R) -cyclopropyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Isomer F2) A portion of 1 81 mg (0.50 mmol) of BF2 chelate of 6,7-difluoro-1-acid [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methoxy-1,4-dhydro-4-oxoquinoline-3-carboxylic acid and 1 38 mg (0.50 mmol) of 3- [3 - (tert-butoxycarbonylamino) -1,1-difluorocyclobutan-3-yl] pyridine (Isomer F2) were suspended in 1.5 ml of dimethyl sulfoxide, and the suspension was mixed with 0.21 ml of triethylamine and stirred at 45 ° C. ° C for 48 hours under a nitrogen atmosphere. After evaporation of the solvent under a reduced pressure, water was added to the residue thus obtained, which was stirred and cooled in an ice bath, the crystals thus formed were collected by filtration and dissolved in 30 ml of 80% ethanol , then the solution was mixed with 3 ml of triethylamine and heated under reflux for 2 hours. The solvent was evaporated under reduced pressure, and concentrated hydrochloric acid was added to the residue thus obtained, which was stirred in an ice bath. After 10 minutes of stirring, this was mixed with water and the resulting aqueous layer was washed with chloroform. After extraction of the chloroform layer with 1N hydrochloric acid, the aqueous layers were combined and, while stirring and cooling in an ice bath, was adjusted to pH 12 with saturated aqueous sodium hydroxide solution. This was then adjusted to pH 7.4 with hydrochloric acid and extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography and then subjected to recrystallization purification by 2-propanol, thereby giving 149 mg (63.2%) of the title compound. 1 HN MR (NaOD 0.1 N) d: 1 .50 - 1 .78 (3 H, m), 2.02 - 2.1 2 (1 H, m), 2.41 -2.62 (3 H, m), 2.73 - 2.86 (2 H, m), 3.40 - 3.63 (3 H, m), 3.57 (3 H, s), 3.72 - 3.83 (1 H, m), 3.99 - 4.08 (1 H, m), 4.82 - 4.90 (0.5 H, m), 4.93 -5.00 (0.5 H, m), 7.65 (1 H, d, J = 14.3 Hz), 8.47 (1 H, s). Elements analysis data for C22H23F4N3O4 <; »0.25H2O Caled. : C, 55.75; H, 5.00; N, 8.87. Found: C, 55.55; H, 4.82; N, 8.67.

Inventive Example 5: 5-amino-7- [3- (3-amino-1,1-difluorocyclobutan-3-yl) pyrrolidin-1-yl-6-fluoro-1 - [2- (S) -fluoro acid -1- (R) -cyclopropyl-1-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (F-Isomer 1) A portion of 312 mg (1 .00 mmol) of 5-amino-6 acid, 7-difluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 239 mg (0.87 mmol) of 3 - [3- (tert-butoxycarbonylamino) -1,1-diffuorocyclobutan-3-yl] pyrrolidine (F1 isomer) were suspended in 2 ml of dimethyl sulfoxide, and the suspension was mixed with 5 ml of triethylamine and stirred at 110 ° C. ° C for 96 hours under a nitrogen atmosphere. After evaporation of the solvent under a reduced pressure, concentrated hydrochloric acid was added to the residue thus obtained, which was stirred in an ice bath. After 10 minutes of stirring, this was mixed with water, and the resulting aqueous layer was washed with chloroform. After extraction of the chloroform layer with 1 N hydrochloric acid, the aqueous layers were combined and, while stirring and cooling in an ice bath, was adjusted to pH 12 with saturated aqueous sodium hydroxide solution. This was then adjusted to pH 7.4 with hydrochloric acid and extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography and then subjected to recrystallization purification by 2-propanol, thereby giving 191 mg (46.0%) of the title compound. 1 H-NMR (NaOD 0.1 N) d: 1.03-1.17 (1 H, m), 1.43 - 1.54 (1 H, m), 1.64 - 1.75 (1 H, m), 2.00 - 2.12 (1, H, m ), 2.27 (3 H, s), 2.41 - 2.63 (3 H, m), 2.70 - 2.83 (2 H, m), 3.28 - 3.36 (2 H, m), 3.41 - 3.50 (1 H, m), 3.69 -3.79 (1 H, m), 3.89 - 3.95 (1 H, m), 4.70 - 4.90 (0.5 H, m), 4.96 - 5.05 (0.5 H, m), 8.25 (1 H, s). Elements analysis data for C22H24F4N O3 »0.5H2O Caled .: C, 55.34; H, 5.28; N, 11.73. Found: C, 55.06;: H, 5.16; N, 11.34.

Inventive example 6: 7- [3- (3-amino-1-fluoro-cyclobutan-3-yl) -pyrrolidinyl-1-in-6-fluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Isomer B 1) A portion of 361 mg (1 .00 mmol) of BF2 chelate of 6,7-difluoro-1 - [2] - (S) -fluoro-1 - (R) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 274 mg (1 .00 mmol) of 3- [3- (ter -butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer B1) were suspended in 3 ml of dimethyl sulfoxide, and the suspension was mixed with 0.42 ml of triethylamine and stirred at 40 ° C for 48 hours. After evaporation of the solvent under reduced pressure, water was added to the residue thus obtained, which was stirred and cooled in an ice bath. The crystals thus formed were collected by filtration and dissolved in 50 ml of 80% ethanol, and the solution was mixed with 10 ml of triethylamine and heated under reflux for 2 hours. After evaporation of the solvent under a reduced pressure, concentrated hydrochloric acid was added to the residue thus obtained, which was stirred in an ice bath. After 10 minutes of stirring, this was mixed with water and chloroform to effect the separation of the layers. The aqueous layer was extracted twice with chloroform, and the chloroform layers were combined and extracted with 1N hydrochloric acid. The aqueous layers were combined and, while stirring and cooled in an ice bath, were adjusted to pH 12 with saturated aqueous sodium hydroxide solution and then to pH 7.4 with 1 N hydrochloric acid, subsequently extracted twice with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was then evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography (developed by the lower layer of chloroform: methanol: water = 7: 3: 1) and the crude crystals thus obtained were recrystallized from 2-propanol, thereby giving 290 mg (0.635 mmol) of the title compound. 1 H-NMR (0.1 N NaOH) d: 1.30 - 1.45 (1 H, m), 1.45 - 1.61 (1 H, m), 1.68 - 1.82 (1 H, m), 2.00 - 2.09 (1 H, m), 2.25 - 2.43 (4 H, m), 2.44 - 2.56 (1 H, m), 3.45 - 3.63 (3 H, m), 3.58 (3 H, s), 3.63 - 3.74 (1 H, m), 3.92 - 4.03 (1 H, m), 4.90 - 4.96 (0.5.H, m), 5.05 - 5.11 (0.5 H, m), 5.22 - 5.30 (0.5 H, m), 5.37 - 5.43 (0.5 H, m), 7.65 (1 H, d, J = 14.2 Hz), 8.40 (1 H, m). Elements analysis data for C22H2 F3N3O4 «0.25H2O Caled .: C, 57.95; H, 5.42; N, 9.22. Found: C, 58.02; H, 5.40; N, 9.07.

Inventive Example 7: 5-amino-7- [3- (3-amino-1-fluoro-cyclobutan-3-yl) pyrrolidin-1-n-6,8-difluoro-1- [2- (S) acid] -fluoro-1- (R) -cyclopropin-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (Isomer B1) A portion of 183 mg (0.574 mmol) of 5-amino-1- [2- (S ) -fluoro-1- (R) -cyclypropyl] -8-methyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-quinoline-3-carboxylic acid and 148 mg (0.574 mmol) of 3- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer B1) were suspended in 10 ml of acetonitrile, and the suspension was mixed with 5 ml of triethylamine and heated under reflux for 48 hours. After evaporation of the solvent under reduced pressure, concentrated hydrochloric acid was added to the residue thus obtained, which was stirred and cooled in an ice bath. After 10 minutes of stirring, this was mixed with water and chloroform to effect layer separation. The aqueous layer was extracted twice with chloroform, and the chloroform layers were cmbined and extracted with 1N hydrochloric acid. The aqueous layers were combined and, while stirring and cooling in an ice bath, they were adjusted to pH 12 with solution water of saturated sodium hydroxide, and then to pH 7.4 with 1N hydrochloric acid, subsequently extracting twice with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was then evaporated under reduced pressure. Subsequently, the resulting residue was purified by preparative thin layer chromatography (developed by the lower layer of chloroform: methanol: water = 7: 3: 1) and the crude crystals thus obtained were recrystallized from 2-propanol to give 121 mg (0.266 mmol) of the title compound. 1 H-NMR (NaOD 0.1 N) d: 1.42-1.67 (3 H, m), 1.93-2.02 (1 H, m), 2.17 -2.43 (5 H, m), 3.40 - 3.60 (3 H, m), 3.65 - 3.76 (2 H, m), 4.80 - 5.02 (1 H, m), 5.18 - 5.25 (0.5 H, m), 5.30 - 5.40 (0.5 H, m), 8.15 (1 H, s). Elements analysis data for C2iH22F4N4? 3 »0.5H2O Caled .: C, 54.43; H, 5.00; N, 12.09. Found: C, 54.54; H, 5.00; N, 11.79.

Reference Example 25: ethyl 3-f1-benzyloxy-3- (isoamyloxycarbonyl) cyclobutan-3-ill-3-oxo-propionate A portion of 21.49 g (67.08 mmol) of 1-benzyloxy-3- (isoamyloxycarbonyl) cyclobutane acid -3-carboxylic acid was dissolved in 200 ml of tetrahydrofuran, which, while cooling in an ice bath with stirring, was added 13.05 g (80.49 mmol) of N, N-carbonyldiimidazole. After 10 minutes of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. To the reaction solution, which was cooled in an ice bath and stirred, 100 ml of tetrahydrofuran solution containing 23.06 g (80.49 mmol) of magnesium ethylmalonate was added dropwise. After 1 hour of stirring, the ice bath was removed and the reaction mixture was stirred at room temperature for 10 hours. While cooling in an ice bath and stirring, the reaction mixture was mixed with aqueous 10% citric acid solution, and then with ethyl acetate to effect layer separation, and the resulting organic layer was washed with aqueous solution of saturated sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure and then the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 ) to give 11.37 g (29.12 mmol) of the title compound. 1 H-NMR (CDCl 3) d: 0.86 - 0.95 (6 H, m), 1.21 - 1.36 (4 H, m), 1.48 - 1.56 (2 H, m), 1.61 - 1.70 (1 H, m), 2.48 - 2.56 (2 H, m), 2.70 - 2.86 (2 H, m), 3.49 - 3.53 (1 H, m), 4.12 - 4.29 (5 H, m), 4.41 (2 H, s), 7.26 - 7.36 ( 5 H, m).

Reference Example 26: Ethyl 3-H -benzylloxy-3- (isoamloxycarbonyl) cyclobutan-3-ip-3-hydroxypropionate A portion of 1 1 .37 g (29.12 mmol) of 3- [1 - ethyl benzyloxy-3- (isoamyloxycarbonyl) cyclobutan-3-yl] -3-oxopropionate was dissolved in 100 ml of methanol to which, while cooling in an ice bath and stirring, 441 mg (1 1 .65 mmol) of sodium tetrahydroborate was subsequently added. After stirring for 10 minutes at the same temperature, saturated aqueous ammonium chloride solution was gradually added thereto. After evaporation of methanol under a reduced pressure, ethyl acetate was added to the residue thus obtained to effect the separation of layers. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 1 1 .41 g (29.07 mmol) of the title compound. The compound thus obtained was used in the next reaction without purification.

Reference Example 27: (E) -3-f-1-benzyloxy-3- (isoamyloxycarbonyl) ethyl cyclobutan-3-ylacrylate A portion of 1 1 .41 g (29.07 mmol) of 3- [ Crude ethyl-1-benzyloxy-3- (isoamyloxycarbonyl) cyclobutan-3-yl] -3-hydroxypropionate was dissolved in 100 ml of dichloromethane which, while cooling in an ice bath and stirring, was subsequently added 2.70 mi (34.9 mmol) of methanesulfonyl chloride and 10.1 3 mL (72.68 mmol) of triethylamine in that order. After 2 hours of stirring, 9.56 ml (72.7 mmol) of diazabicycloundecene was added thereto. After 1 hour of stirring, the reaction mixture was further stirred at room temperature for 2 hours. While cooling in an ice bath and stirring, this was mixed with saturated aqueous ammonium chloride solution, and then with ethyl acetate to effect the separation of layers. The resulting organic layer was washed with 10% aqueous citric acid solution and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure and then the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1 ) to give 9.46 g (25.26 mmol) of the title compound. 1 H-NMR (CDCl 3) d: 0.89-0.92 (6 H, m), 1 .24 - 1 .36 (4 H, m), 1 .48 - 1 .56 (2 H, m), 1 .61 - 1 .70 (1 H, m), 2.1 9 - 2.25 (1 H, m), 2.23 - 2.38 (1 H, m), 2.48 - 2.54 (1 H, m), 2.58 - 2.63 (1 H, m ), 2.78 - 2.86 (1 H, m), 4.12 -4.29 (5 H, m), 4.41 (2 H, s), 5.83 - 5.93 (1 H, m), 7.1 1 - 7.1 8 (1 H, m ), 7.26 - 7.39 (5 H, m).

Reference example 28: Ethyl 3-ri-benzyloxy-3- (isoamyloxycarbonyl) cyclobutan-3-yl-4-n-butobutanoate A portion of 9.46 g (25.3 mmol) of (E) -3- [1-benzyloxy] -3- (isoamyloxycarbonyl) cyclobutan-3-yl] ethyl acrylate was dissolved in 50 ml of nitromethane which, while cooling in an ice bath and stirring, was subsequently added in the form of drops 3.78 ml (25.3 mmol ) of diazabicycloundecene. After 10 minutes of stirring, the reaction mixture was further stirred at room temperature for 1 hour. While cooling in an ice bath and stirring, the reaction solution was acidified by gradually adding 10% aqueous citric acid solution, and then mixed with ethyl acetate to effect layer separation. The resulting organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 1 1 .45 g 825.26 mmol) of the title compound. The compound thus obtained was used in the next reaction without purification.

Reference Example 29: 4- [1-benzyloxy-3- (isoamyloxycarbonyl) cyclobutan-3-in-2-pyrrolidone A portion of 1 1 .45 g 825.26 mmol) of 3- [1-benzyloxy-3- (isoamyloxycarbonyl ) crude ethyl cyclobutan-3-yl] -4-nitrobutanoate was dissolved in 200 ml of ethanol, to which 10 ml of Raney nickel was subsequently added under a nitrogen atmosphere. After replacing nitrogen with hydrogen, this was stirred at 50 ° C for 5 hours under a hydrogen atmosphere. After cooling in an ice bath, the reaction solution was filtered through celite, and then the solvent was evaporated under reduced pressure to give 6.51 g (1 9.5 mmol) of the title compound. The compound thus obtained was used in the next reaction without purification.

Reference Example 30: 1-benzyl-4-ri-benzyloxy-3- (ethoxycarbonyl) cyclobutan-3-ill-2-pyrrolidone A portion of 6.51 g 81 0.5 mmol) of 4- [1-benzyloxy-3- (isoam iloxycarbonyl) cyclobutan-3-yl] -2-pyrrolidone was dissolved in a mixed solvent consisting of 45 ml of dimethylformamide and 45 ml of tetrahydrofuran, and to the resulting solution, which was cooled in an ice bath and stirred, Subsequently, 935 mg (23.4 mmol) of 60% oily sodium hydride were gradually added. After 1 0 minutes of stirring, the reaction mixture was further stirred at room temperature for 1 hour and then, while cooling in an ice bath with stirring, 2.80 ml (23.4 mmol) of benzyl chloride were added thereto in the form of drops. After 1 hour of stirring, the resulting reaction solution was subjected to layer separation at room temperature. The organic layer thus separated was washed with saturated saline and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give an oily material. The oily material was dissolved in 100 ml of ethanol, 20 ml of aqueous sodium hydroxide solution 10 0 N were added dropwise to the resulting solution, which was cooled and stirred in an ice bath, and then dried. They performed 14 hours of agitation at room temperature. After the evaporation of ethanol under a reduced pressure, the residue thus obtained was mixed with 20 ml of water and then, while cooling in an ice bath, it was acidified with concentrated hydrochloric acid. After filtration, this was extracted with diethyl ether (1000 ml x 3) and then dried over anhydrous sodium sulfate.

After filtration, this was concentrated under reduced pressure, the residue thus obtained was dissolved in 180 ml of ethanol and the resulting solution was gradually mixed with 4.55 g (23.9 mmol) of p-toluenesulfonic acid monohydrate and heated under reflux during 3 hours. The reaction solution was concentrated, mixed with saturated aqueous sodium bicarbonate solution and then extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 2.20 g of the title compound as a mixture of diastereomers. Subsequently, the title compound thus obtained was again subjected to silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to separate the diastereoisomers in 0.76 g of Isomer A and 1.44 g of Isomer B, and the following reaction was performed using Isomer A. Isomer A 1 H-NMR (400 MHz, CDCl 3) d: 1.21 (3 H, d, J = 7.13 Hz), 1.97-2.23 (2 H, m), 2.16 (1 H, dd, J = 10.75, 16.12 Hz), 2.40 - 2.67 (4 H, m), 2.85 (1 H, dd, J = 5.86, 9.76 Hz), 3.39 (1 H, dd, J = 7.33, 10.25 Hz), 4.09 (1 H, q, J = 3.13 Hz), 4.39 - 4.49 (5 H, m), 7.19 - 7.52 (10 H, m). Isomer B 1 H-NMR (400 MHz, CDCl 3) d: 1.21 (3 H, d, J = 7.33 Hz), 2.17 - 2.26 (3 H, m), 2.39 - 2.62 (4 H, m), 2.81 (1 H , dd, J = 5.13, 9.77 Hz), 3.35 (1 H, dd, J = 6.84, 9.77 Hz), 4.00 - 4.11 (3 H, m), 4.38 - 4.49 (4 H, m), 7.17 - 7.35 ( 10 H, m).

Reference Example 31: 1-benzyl-4-r3- (ethoxycarbonyl) -1-hydroxycyclobutan-3-in-2-pyrrolidone (Isomer A portion of 524 mg (1.29 mmol) of 1-benzyl-4- [1-benzyloxy-3- (ethoxycarbonyl) cyclobutan-3-yl] -2-pyrrolidone (Isomer A) was dissolved in 20 ml of ethanol, and the solution was mixed with 530 mg of palladium hydroxide catalyst on carbon and subjected to 1.5 hours of catalytic reduction under a hydrogen pressure of 5 atmospheres and under light irradiation. After removal of the catalyst by filtration, the solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform: methane! = 95: 5) to give 454 mg (quantitative) of the title compound. 1 H-NMR (400 MHz, CDCl 3) d: 1.23 (3 H, d, J = 7.32 Hz), 1.93 - 2.05 (3 H, m), 2.19 (1 H, dd, J = 9.77, 15.62 Hz), 2.46 - 2.60 (3 H, m), 2.67 - 2.73 (1 H, m), 2.84 (1 H, dd, J = 5.86, 10.26 Hz), 3.39 (1 H, dd, J = 7.32, 9.77 Hz), 4.08 - 4.14 (2 H, m), 4.41, 4.46 (every 1 H, ABq, J = 14.65 Hz), 4.69 - 4.77 (1 H, m), 7.19 - 7.35 (5 H, m).

Reference Example 32: 1-benzyl-4-r3- (ethoxycarbonyl) -1-fluorocyclobutan-3-yl1-2-pyrrolidone (Isomer Ai A portion of 495 mg (1.56 mmol) of 1-benzyl-4- [3- (ethoxycarbonyl) -1-hydroxycyclobutan-3-yl] -2-pyrrolidone (Isomer A) was dissolved in a mixed solvent consisting of 12 ml. of toluene and 6 ml of dichloromethane to which, while cooling in an ice bath with stirring, were then added 839 μl (6.24 mmol) of diethylaminosulfur trifluoride, subsequently carrying out 20 hours of stirring at 40 ° C. While cooling in an ice bath with stirring, the reaction solution was made alkaline by slowly adding saturated aqueous sodium bicarbonate solution and then mixed with chloroform to perform layer separation, and the resulting organic layer was washed with saturated brine. . The aqueous layer was extracted again with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give 400 mg (80.0%) of the composed of the title. 1 H-NMR (400 MHz, CDCl 3) d: 1.24 (3 H, t, J = 7.08 Hz), 2.1 6 - 2.27 (3 H, m), 2.52 - 2.61 (3 H, m), 2.85 - 2.89 (1 H, m), 2.87 (1 H, dd, J = 6.1 1, 1 0.01 Hz), 3.42 (1 H, dd, J = 7.08, 1 0.01 Hz), 4.08 - 4.1 6 (2 H, m ), 4.40, 4.46 (every 1 H, ABq, J = 14.65 Hz), 5.38 (1 H, br.d, J = 56.6 Hz), 7.28 -7.35 (5 H, m).

Reference Example 33: 1-benzl-4- [3- (carboxyl) -1-fluorocyclobutan-3-n-2-pyrrolidone (Isomer A) A 400 mg portion (1.25 mmol) of 1 - benzyl-4- [3- (ethoxycarbonyl) -1-fluorocyclobutan-3-yl] -2-pyrrolidone (Isomer A) was dissolved in 10 ml of ethanol which, while cooling in an ice bath, was added Subsequently in the form of droplets 625 μ of aqueous solution of sodium hydroxide 1 0 N. After 1 6 hours of stirring at room temperature, ethanol was evaporated under reduced pressure. The residue thus obtained was acidified by adding aqueous concentrated hydrochloric acid solution in the form of drops and extracted with chloroform (50 ml x 2) and 30 ml of diethyl ether in that order, and the organic layers were combined and dried over sodium sulfate. anhydrous sodium After filtration, the resulting filtrate was concentrated under reduced pressure to give 398 mg (quantitative) of the title compound as white crystals. 1 H-NMR (400 MHz, CDCl 3) d: 2.10-2.27 (3 H, m), 2.43-2.59 (3 H, m), 2.64-2.72 (1 H, m), 2.82 (1 H, dd, J = 5.86, 1 0.25 Hz), 3.37 (1 H, dd, J = 7.82, 10.01 Hz), 4.32 - 4.40 (2 H, m), 5.29 (1 H, br.d, J = 56.64 Hz), 7.10 - 7.27 (5 H, m).

Reference Example 34: 1 -benzyl-4- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yn-2-pyrrolidone (Isomer A) A portion of 263 mg (1.63 mmol) of 1, 1'-carbonyldiimidazole to a solution of acetonitrile (20 ml) containing 298 mg (1.25 mmol) of 1-benzyl-4- [3- (carboxyl) -1-fluorocyclobutan-3-yl] -2-pyrrolidone (Isomer) A), and the mixture was stirred at room temperature for 30 minutes. Subsequently, the ammonia gas was bubbled into the reaction solution for 45 minutes. After evaporation of the solvent under reduced pressure, the residue thus obtained was mixed with 500 ml of chloroform and washed with water, and the resulting organic layer was dried over sodium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure, and the residue thus obtained was dissolved in 20 ml of tertiary butyl alcohol, mixed with 831 g (1.88 mmol) of lead tetraacetate (90% or more in purity) and then stirred at 80 ° C for 30 minutes. After cooling, this was mixed with sodium bicarbonate and diluted with 30 ml of diethyl ether, and then the insoluble matter was removed by filtration. The resulting filtrate was washed with saturated aqueous sodium bicarbonate solution, the organic layer was dried over sodium sulfate and then the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give 467 mg (quantitative) of the title compound. 1 HN MR (400 MHz, CDCI3) d: 1.35 (9 H, s), 2.1 3 - 2.24 (3 H, m), 2.46 -2.53 (1 H, m), 2.63 - 2.71 (1 H, m ), 2.85 (1 H, dd, J = 5.38, 10.26 Hz), 2.95 - 2.98 (1 H, m), 3.22 (1 H, dd, J = 7.33, 1 0.26 Hz), 3.27 - 3.33 (1 H, m), 4.30, 4.41 (every 1 H, ABq, J = 14.89 Hz), 1.35 (1 H, s), 5.32 (1 H, br.d, J = 56.64 Hz), 7.1 1 - 7.28 (5 H, m).

Reference Example 35: 1 -benzyl-4-r3- (tert-butoxycarbonylamino-1-fluoro) cyclobutan-3-ill-2-pyrrolidinationa (Isomer A) A portion of 1 70 mg (0.468 mmol) of 1-benzyl- 4- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] -2-pyrrolidone (Isomer A) was dissolved in 5 ml of toluene, and the solution was mixed with 208 mg (0.515 mmol) of reagent Lawesson and stirred at 80 ° C for 12 hours. Subsequently, the reaction solution was purified by column chromatography on silica gel (chloroform: methanol = 95.5) to give 111 mg (62.6%) of the title compound. 1 H-NMR (400 MHz, CDCl 3) d: 1.54 (9 H, s), 2.40 - 2.61 (3 H, m), 2.94 -2.98 (2 H, m), 3.09 - 3.13 (1 H, m), 3.40 - 3.48 (2 H, m), 3.66 (1 H, dd, J = 7.09, 11.40 Hz), 4.56 - 4.58 (1 H, m), 4.96, 5.19 (every 1 H, ABq, J = 14.16 Hz), 5.68 (1 H, br.d, J = 56.64 Hz), 7.39-7.46 (5 H, m).

Reference Example 36: 1-benzyl-3- [3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-n-pyrrolidine (Isomer A) A portion of 108 mg (0.285 mmol) of 1-benzyl-4- [3 - (tert-butoxycarbonylamino-1-fluoro) cyclobutan-3-yl] -2-pyrrolidinationa (Isomer B1) was dissolved in 1 ml of tetrahydrofuran, and 1.5 ml of Raney nickel was added to the solution thus prepared. After 15 minutes of stirring at room temperature, the reaction solution was filtered through celite and the solvent was evaporated under reduced pressure. Subsequently, the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give 91.8 mg (92.3%) of the title compound. 1 H-NMR (400 MHz, CDCl 3) d: 1.47 (9 H, s), 2.16 - 2.49 (6 H, m), 2.51, 2.62 (every 1 H, ABq, J = 9.03 Hz), 2.76 (1 H, t, J = 8.30 Hz), 3.13 - 3.20 (1 H, m), 3.33 - 3.37 (1 H, m), 3.61 (2 H, s), 4.90 (1 H, br.d, J = 55.67 Hz) , 5.14 (1 H, s), 7.30 - 7.40 (5 H, m).

Reference Example 37: 3-r3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-ippyrrolidine (Isomer Ai A 145 mg portion (0.41 6 mmol) of 1-benzyl-3- [3- (ter- butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer A) was dissolved in 10 ml of ethanol, to which 1 50 mg of 1 0% palladium catalyst on carbon was subsequently added. stirred for 1.5 hours under light irradiation and under a hydrogen pressure of 3.5 atmospheres.After removal of the catalyst by filtration, the solvent was evaporated under reduced pressure to give 17 mg (quantitative) of the title compound. The compound thus obtained was used in the next reaction without purification.1 H-NMR (400 MHz, CDCl 3) d: 1.37 (9 H, s), 2.08-2.20 (3 H, m), 2.29 -2.37 (2 H, m), 2.74 - 2.77 (1 H, m), 2.88 - 2.94 (3 H, m), 3.05 - 3.1 0 (1 H, m), 3.24 - 3.30 (1 H, m), 3.62 - 3.74 ( 1 H, m), 4.70 (1 H, s), 4.91 (1 H, br.d, J = 55. 17 Hz).

Inventive Example 8: 7- [3- (3-Am ino-1-fluoro-cyclobutan-3-yl) pyrrolidin-1-yl-1-6-f-1-f2- (S) -fluro-1 - (R) acid ) -cyclopropyl-1, 4-hydroxy-8-methoxy-4-oxoq-quinoline-3-carboxylic acid (Isomer A) 3- was dissolved. { 3- (tert-butoxycarbonylamino) -1-fluorocyclobutan-3-yl] pyrrolidine (Isomer A) in 750 μl of dimethyl sulfoxide, the solution was mixed with 137 mg (0.378 mmol) of BF2 chelate of 6,7- difluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid and 1 1 6 μl ( 0.832 mmol) of triethylamine, and the mixture was stirred at room temperature, for 1 1 hours and then at 40 ° C for 26 hours. After concentration of the reaction solution under reduced pressure, water was added to the residue thus obtained, and the solid material thus formed was collected by filtration and washed with water. The solid material thus obtained was suspended in 50 ml of a solution of ethanol: water = 10: 1, and the suspension was mixed with 1 ml of triethylamine and heated under reflux for 2 hours. The reaction solution was cooled spontaneously and then concentrated under reduced pressure, and the residue thus obtained was dissolved in 100 ml of chloroform. The resulting solution was washed with 50 ml of 10% aqueous citric acid solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the resulting filtrate was concentrated under reduced pressure, 3 ml of concentrated hydrochloric acid was added dropwise to the residue thus obtained, which was cooled in an ice bath, and the mixture was then stirred at room temperature. environment for 30 minutes. The reaction solution was mixed with 3 ml of 1N hydrochloric acid, washed with chloroform (50 ml x 5), adjusted to pH 2.0 with aqueous sodium hydroxide solution and then to pH 7.4 with 1 N hydrochloric acid. and finally it was extracted with chloroform (100 ml x 5). The organic layers were combined, dried over anhydrous sodium sulfate and filtered, and the resulting filtrate was concentrated under reduced pressure. Subsequently, the resulting residue was purified by recrystallization from a 28% aqueous ethanol-ammonia system and then dried under reduced pressure, thereby giving 93.1 mg (53%) of the title compound as a mixture of diastereomers in The shape of crystals pale yellow. 1 H-NMR (400 MHz, 0.1 N NaOD) d: 1.31-1.50 (3 H, m), 1.98 - 2.03 (1 H, m), 2.13 - 2.27 (3 H, m), 2.36 - 2.48 (1 H, m), 2.74 - 2.82 (1 H, m), 3.26 - 3.73 (4 H, m), 3.39 (3 H, s), 3.85 - 3.90 (1 H, m), 4.80 (1 H, brd, J = 65.43 Hz), 7.50 (1 H, d, J = 13.66 Hz), 8.30, 8.29 (every 0.5 H, s). Elements analysis data for C22H24F3N3? 4 »0.5H2? Caled .: C, 57.39; H, 5.47; N, 9.13 Found: C, 57.14; H, 5.48; N, 8.92 The antibacterial activity of each compound of the present invention was measured according to the standard method specified by the Japanese Chemotherapy Society, with the results shown in the table below as MIC values (μg / ml).

APPLICABI LI DAD I NDUSTRIAL In this way, as described above, the compound of the present invention possesses an excellent antibacterial action against a wide range of Gram-negative and Gram-positive bacteria, showing a strong antibacterial activity particularly against strains of methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant pneumococcal strains and quinolone-resistant bacteria, and also possesses both excellent pharmacokinetics and high safety, so that it is useful as an antibacterial compound.

Claims

REIVI NDICATIONS

1 . A compound represented by the following formula (I), its salt or hydrates thereof: . { wherein R1 and R2, each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms (excluding a case in which, R1 and R2 are both hydrogen atoms), wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an halogen atom and an alkoxy group having 1 to 6 carbon atoms, R3 and R4, each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, n is an integer of 1 or 2, Q is a partial structure represented by the following formula: [wherein R5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, an alkyl group cyclic having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms or a alkylamino group, having 1 to 6 carbon atoms, R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, wherein R6 and the aforementioned R5 can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed may contain a sulfur atom as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substitute R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, X1 represents a halogen atom or a hydrogen atom, A1 represents a nitrogen atom or a partial structure represented by the following formula (II): (wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 at 5 carbon atoms, and X2 and the aforementioned R5 can together form a cyclic structure including a part of the parent core, and the ring thus formed can contain an oxygen atom, a nitrogen atom or a sulfur atom such as an atom ring constituent, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), A2 and A3, each representing a nitrogen atom or a carbon atom, wherein A2 and A3 ju With carbon atoms to which they are linked, they form a partial structure: or a partial structure:

Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy group- 2-oxobutyl, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and phenyl group]} . 2. A compound, its salts or hydrates thereof according to claim 1, wherein a partial structure resulting from the exclusion of Q from formula (I) is a stereochemically pure compound.

3. A compound, its salts or hydrates thereof according to claim 1 or 2, wherein Q in the formula (I) is a compound having a structure represented by the following formula: OR . { wherein R 5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms, R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, wherein R6 and the aforementioned R5 can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed can contain a sulfur atom as a ring constituent atom, and the ring also may have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, a group alkyl having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group I having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, X1 represents a halogen atom or a hydrogen atom, A1 represents a nitrogen atom or a partial structure represented by the following formula (II): (wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 atoms of carbon, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and X2 and R5 mentioned above can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed can contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring constituent atom, and the ring can also have an alkyl group having 1 to 6 carbon atoms as a substituent), and Y represents a hydrogen atom. a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a ftalidinyl group, a 5-alkyl-2-oxo-1, 3 group dioxol-4-ylmethyl, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group} .

4. A compound, its salts or hydrates thereof, according to claim 1 or 2, wherein Q in the formula (I) is a compound having a structure represented by the following formula: . { wherein R 5 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a cyclic alkyl group having 3 to 6 carbon atoms, which may have a substituent, an aryl group, which may have a substituent, a heteroaryl group, which may have a substituent, an alkoxy group having 1 to 6 carbon atoms or an alkylamine group having 1 to 6 carbon atoms , R6 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, wherein R6 and the aforementioned R5 can together form a cyclic structure including a part of the parent nucleus, and the ring thus formed can contain a sulfur atom as a ring constituent atom, and the ring can also have an alkyl group having 1 to 6 carbon atoms as a substituent, R7 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, a group alkyl having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, X1 represents a halogen atom or a hydrogen atom, A1 represents a nitrogen atom or a structure partial heading represented by the following formula (I I): (wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxy group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, wherein the amino group may have one or more substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms, and X2 and R5 mentioned above can together form a cyclic structure including a part of the parent core, and the ring thus formed can contain an oxygen atom , a nitrogen atom or a sulfur atom as a ring constituent atom, and the ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent), and Y represents an atom of an ester, a phenyl group, an acetoxymethyl group, a pyruvaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1, 3- group dioxol-4-iimethyl, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group} .

5. A compound, its salt or hydrates thereof according to claim 1 or 2, wherein Q in the formula (I) is a 6-carboxy-9-fluoro-2,3-dihydro-3- (S) group ) -methyl-7-oxo-7H-pyrido [1, 2,3-de] [1,4] benzoxazin-10-yl.

6. A compound, its salt or hydrates thereof according to claim 1 or 2, wherein Q in the formula (I) is a 5-amino-3-carboxy-6-fluoro-1 - [2- ( S) -fluoro-1 - (R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinolin-7-yl. A compound, its salt or hydrates thereof according to claim 1 or 2, wherein Q in the formula (I) is a 3-carboxy-6-fluoro- 1 - [2- (S) -fluoro group -1 - (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinolin-7-yl. 8. A compound, its salt or hydrates thereof according to claim 1 or 2, wherein Q in the formula (I) is a 5-amino-3-carboxy-6,8-difluoro-1 - [2] group - (S) -fluoro-1 - (R) -cyclopropyl] -1,4-dihydro-4-oxoquinolin-7-yl. 9. A compound, its salt or hydrates thereof according to any of claims 1 to 4, wherein R5 is a halogenocyclopropyl group. 1. A compound, its salt or hydrates thereof according to claim 9, wherein the halogenocyclopropyl group is a 1,2-cis-halogenocyclopropyl group. eleven . A compound, its salt or hydrates thereof according to claim 9 or 10, wherein the halogeocyclopropyl group is a stereochemically pure substituent. 12. A compound, its salt or hydrates thereof according to claim 1, wherein the halogenocyclopropyl group is a group (1 R, 2S) -2-h to logen propyl. 3. A compound, its salt or hydrates thereof according to any of claims 9 to 12, wherein the halogen atom of the halogenocyclopropyl group is a fluorine atom. 14. A compound, its salt or hydrates thereof according to any of claims 1 to 13, wherein the compound of formula (I) is a stereochemically pure compound. 1 5. 5-amino-7- [3- (3-amino-1-fluoro-cyclobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro-1-acid (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof. 16. 7- [3- (3-Amino-1-fluorocyclobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl acid. ] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof. 1

7. Acid 5-am ino-7- [3- (3-amino-1-fluoro-cyclobutan-3-yl) pyrrolidin-1-yl] -6,8-difluoro-1 - [2- (S) -fluoro-1 - (R) -cyclopropyl] -1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof. 1

8. 7- [3- (3-Amino-1,1-difluorocyclobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro-1 - (R) acid ) -cyclopropyl] -8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof. 1

9. 5-amino-7- [3- (3-amino-1,1-difluorocyclobutan-3-yl) pyrrolidin-1-yl] -6-fluoro-1 - [2- (S) -fluoro- acid 1- (R) -cyclopropyl] -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, its salt or hydrates thereof. 20. A pharmaceutical composition, which comprises a compound, its salt thereof or hydrates thereof, described in any of claims 1 to 1 9 as an active ingredient. twenty-one . An antibacterial agent, which comprises a compound, its salt thereof or hydrates thereof, described in any of claims 1 to 1 9 as an active ingredient.