CN1179155A - Heterocyclic compound - Google Patents

Abstract

The present invention relates to N1-(Halogenocyclopropyl)-substituted pyridonecarboxylic acid derivatives represented by general formula (I), heterocyclic compounds useful as antibacterial agents, wherein X<1> represents halo or hydrogen; X<2> represents halo; R<1> represents hydrogen, hydroxy, thiol, halomethyl, amino, alkyl or alkoxy; R<2> represents a group of general formula (II) (wherein R<3> and R<4> represent each hydrogen or alkyl; and n represents an integer of 1 or 2); A represents nitrogen or a group of general formula (III), (wherein X<3> represents halo, cyano, amino, alkyl, halomethyl, alkoxy or halomethoxy); and R represents hydrogen, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2-oxo-1, 3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, alkyl, alkoxymethyl or phenylalkyl.

Description

Heterocyclic compound

technical field

The present invention relates to an antibacterial compound used as medicine, veterinary medicine, aquaculture medicine or antibacterial preservative and antibacterial medicine or antibacterial preparation containing them.

Background technique

Although quinolone derivatives containing 1-amino-3-azabicyclo[3.2.0]hept-3-yl substituents have been disclosed in JP-A-64-56673 and JP-A-3-86875 (the term "used herein" JP-A" means "Unexamined Published Japanese Patent Application"), but it is considered that the amino-substituted fused-bicyclic heterocyclic compound contains a substituent derived from the amino-substituted fused-bicyclic heterocyclic compound and also contains a halocyclopropyl group at the 1-position However, nothing is known about the quinolone derivatives of the present invention.

In recent years, it has been found that synthetic quinolone antibacterial agents not only have antibacterial activity, but also have excellent biodistribution properties such as oral absorption, organ distribution, urinary excretion rate, etc., and many of these compounds have now been used as effective drugs against various infectious diseases. Chemotherapeutics are used clinically. However, in recent years, the number of clinically less sensitive strains to this drug has gradually increased, and, just like Staphylococcus aureus (MRSA) has lower sensitivity to β-lactam antibiotics, it has a higher sensitivity to synthetic quinolone antibacterial agents. Less susceptible strains are also on the rise, some of which have developed resistance not only to other drugs but also to synthetic quinolone antimicrobials. Therefore, there is a need to develop drugs with higher efficacy clinically.

Detailed description of the invention

The inventor of the present invention thinks, the structure that 7-and 1-position replaces can generally affect the antibacterial activity, efficacy and safety of synthetic quinolone antibacterial agent, therefore, the inventor of the present invention has carried out painstaking research, in order to obtain to broad-spectrum bacteria comprising Quinolone-resistant strains have a compound with higher antibacterial activity. It was found that quinolone derivatives containing substituents derived from amino-substituted condensed bicyclic heterocyclic compounds at the 7-position are effective against Gram-positive and Gram-positive strains. Negative bacteria, especially quinolone-resistant bacteria, including MRSA, have strong antibacterial activity, and wherein the quinolone derivatives substituted by halocyclopropyl, especially fluorocyclopropyl, at the 1-position not only have antibacterial activity, but also Get great efficacy and safety.

In the quinolone derivatives of the present invention, in the absence of isomerization in other substituents, a pair of enantiomers will be produced only because of the 1-position halocyclopropane group, which is caused by the cyclopropane ring Formed by the stereochemical relationship between the pyridone carboxylic acid group and the halogen atom. When the isomers formed are racemates, these derivatives are mixtures of enantiomers which are useful as medicines.

In addition, in addition to the isomerization of the halogenated cyclopropene ring, when there is isomerization at other positions, especially at the 7-position substituent, the quinolone derivative is composed of diastereomers , that is to say there are 4 or more stereoisomers. Since a diastereomeric mixture is a mixture of compounds with different physical properties, it is difficult to use the mixture as a medicine.

The inventors of the present invention have conducted intensive research and obtained quinolone derivatives composed of a single stereoisomer, even in 1-(1,2-cis-2-halocyclopropane composed of diastereomers) group)-substituted quinolone derivatives.

As a result, the inventors of the present invention succeeded in obtaining each enantiomer of cis-2-fluorocyclopropylamine as a pure compound. The inventors of the present invention also successfully obtained each enantiomer of the quinolone derivative formed from the fluorocyclopropane ring in the form of a compound composed of a single isomer of the pure cis-fluorocyclopropylamine. The inventors of the present invention have also successfully obtained each isomer of amino-substituted fused-bicyclic heterocyclic compounds containing asymmetric carbon atoms and nitrogen heteroatoms in the form of pure compounds.

Owing to successfully obtaining the quinolone derivatives that can be used as synthetic intermediates and the amino-substituted condensed-bicyclic heterocyclic compounds containing nitrogen heteroatoms, the synthesis of quinolone derivatives with a single stereochemistry consisting of single diastereomers things become possible.

Thereafter, the inventors of the present invention found that a group derived from an amino-substituted condensed-bicyclic heterocyclic compound at the 7-position and a halocyclopropyl group at the 1-position were found on the basis of the above findings. The novel quinolone derivative of the present invention is a compound with high safety and significant activity against broad-spectrum bacterial species including quinolone-resistant bacterial strains.

Therefore, the present invention relates to an N ₁ -(halocyclopropyl)-substituted pyridonecarboxylic acid derivative or a salt thereof represented by the following formula (I): Wherein X ¹ represents a halogen atom or a hydrogen atom;

X ² represents a halogen atom;

R ¹ represents a hydrogen atom, a hydroxyl group, a mercapto group, a halomethyl group, an amino group, an alkyl group containing 1-6 carbon atoms or an alkoxy group containing 1-6 carbon atoms, wherein the amino group may contain , a substituent of an alkyl group containing 1-6 carbon atoms and an acyl group containing 2-5 carbon atoms, provided that when the substituent is an alkyl group, wherein the alkyl groups may be the same or different from each other, then the amino group may be dialkyl-substituted;

^R represents a group derived from an amino-substituted condensed-bicyclic heterocycle represented by the following formula (II): Wherein R ^{and R} independently represent a hydrogen atom or an alkyl group containing 1-6 carbon atoms and n is an integer of 1 or 2; A represents a nitrogen atom or a partial structure of the following formula (III):

Wherein X ³ represents a hydrogen atom, a halogen atom, a cyano group, an amino group, a compound containing 1-6 carbon atoms

Alkyl, halomethyl, alkoxy containing 1-6 carbon atoms, halomethoxy, its

The amino group described in can contain formyl, alkyl containing 1-6 carbon atoms and containing

A substituent for an acyl group of 2-5 carbon atoms, provided that when said substituent is an alkyl group,

wherein the alkyl groups can be the same or different from each other, then the amino groups can be replaced by dialkyl-

and R represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-dihydroindenyl, 2-benzene And[c]furanone alkynyl (phthalidynyl), 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, 3-acetoxy-2-oxo A butyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group consisting of an alkylene group having 1 to 6 carbon atoms and a phenyl group.

The present invention also relates to the above compound or a salt thereof, wherein the halocyclopropyl group in formula (I) is 1,2-cis-2-halocyclopropyl.

The present invention also relates to the above compound or a salt thereof, wherein R ² in formula (I) is a stereochemically pure substituent.

The present invention also relates to the above compound or a salt thereof, wherein the halocyclopropyl group in formula (I) is a stereochemically pure substituent.

The present invention also relates to the above compound or a salt thereof, wherein the halocyclopropyl is (1R,2S)-2-halocyclopropyl.

The present invention also relates to the above compound or a salt thereof, wherein X ² is a fluorine atom.

The present invention also relates to an antibacterial drug, wherein the drug contains the above-mentioned compound of formula (I) or a salt thereof as an active ingredient.

The substituents in the compound of formula (I) of the present invention are as described below.

When X ¹ , X ² and X ³ are halogen atoms respectively, X ¹ and X ² are most preferably fluorine atoms and X ³ is preferably a fluorine atom or a chlorine atom.

^R is a hydrogen atom, a hydroxyl group, a mercapto group, a halomethyl group, an amino group, an alkyl group containing 1-6 carbon atoms or an alkoxy group containing 1-6 carbon atoms, wherein the amino group may contain , a substituent of an alkyl group containing 1-6 carbon atoms and an acyl group containing 2-5 carbon atoms, provided that when the substituent is an alkyl group, wherein the alkyl groups may be the same or different from each other, then the amino group Can be dialkyl-substituted.

For R ¹ , the alkyl group may be a straight or branched chain alkyl group having 1 to 6 carbon atoms, but is preferably methyl, ethyl, n-propyl or isopropyl.

As the halogen atom in the halomethyl group, a fluorine atom is particularly preferred and the number of atoms may be 1-3. Preferable examples of halomethyl include fluoromethyl and difluoromethyl.

When R ¹ is amino, hydroxyl or mercapto, these groups can be protected by commonly used protecting groups.

Examples of such protecting groups include alkoxycarbonyl such as tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc., aralkoxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyl Oxycarbonyl, etc., acyl such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, butyryl, etc., alkyl or aralkyl such as tert-butyl, benzyl, p- Nitrobenzyl, p-methoxybenzyl, trityl, etc., ethers such as methoxymethyl, tert-butoxymethyl, tetrahydropyran, 2,2,2-trichloroethoxymethyl groups, etc., and silyl groups such as trimethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl, tert-butyldiphenylsilyl Base etc.

Among these protecting groups, ether and silyl groups are preferably used as protecting groups for hydroxy and mercapto, and other protecting groups are used as protecting groups for any of amino, hydroxy and mercapto.

^X3 is a hydrogen atom, a halogen atom, a cyano group, an amino group, an alkyl group containing 1-6 carbon atoms, a halomethyl group, an alkoxy group or a halomethoxy group containing 1-6 carbon atoms, wherein The amino group may contain a substituent selected from formyl, an alkyl group containing 1-6 carbon atoms, and an acyl group containing 2-5 carbon atoms, provided that when the substituent is an alkyl group, wherein the alkyl group can be mutually The same or different, the amino group may be dialkyl-substituted.

For X ³ , the alkyl group may be a straight or branched chain alkyl group having 1 to 6 carbon atoms, but is preferably methyl, ethyl, n-propyl or isopropyl.

As the halogen atom in the halomethyl group, a fluorine atom is particularly preferred and the number of atoms may be 1-3. Preferable examples of halomethyl include fluoromethyl and difluoromethyl.

The alkoxy group may contain 1 to 6 carbon atoms and is preferably methoxy.

As the halogen atom in the halomethyl group, a fluorine atom is particularly preferred and the number of atoms may be 1-3.

When A is a partial structure shown in the following formula (III), A preferred combination between ^R1 and ^X3 is that ^R1 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group containing 1-6 carbon atoms, while ^X3 is an alkyl group containing 1-6 carbon atoms, containing 1 - an alkoxy group of 6 carbon atoms, a halogen atom, a halomethoxy group or a hydrogen atom.

A more preferred combination is that R ¹ is amino, hydrogen atom, hydroxyl or methyl, and X ³ is methyl, methoxy, fluorine atom, chlorine atom, difluoromethoxy or hydrogen atom.

The most preferred combination is that R ¹ is amino, hydrogen atom, hydroxyl or methyl, and X ³ is methyl or methoxy.

For these R ¹ and X ³ groups, it is preferred that X ¹ and X ² are fluorine atoms.

其衍生于下式所示的氨基-取代的稠合-双环杂环化合物：(尽管这里用是5-元环的氮原子是被氢取代的这种情况来说明，其实其可以被其他取代基例如氮原子保护基取代)。此基团在桥头碳原子上含有氨基取代基，因此，此基团似乎具有小的脂环族环胺结构，因而，本发明发明人认为，此结构在本发明化合物所表现出的出色特性中起着重要的作用。R ² is a group shown in the following formula (II):

It is derived from amino-substituted fused-bicyclic heterocycles of the formula: (Although it is illustrated here that the nitrogen atom of the 5-membered ring is substituted by hydrogen, it may be substituted by other substituents such as nitrogen atom protecting groups). This group contains an amino substituent on the bridgehead carbon atom, therefore, this group seems to have a small cycloaliphatic cyclic amine structure, and therefore, the inventors of the present invention believe that this structure is responsible for the excellent properties exhibited by the compounds of the present invention It plays an important role.

The term "fused-bicyclic heterocyclic compound" used herein refers to a compound having a structure formed by replacing a ring-forming carbon atom of a fused-bicyclic hydrocarbon compound with a heteroatom such as a nitrogen atom or the like.

In the above formula, ^R3 and ^R4 independently represent a hydrogen atom or an alkyl group containing 1-6 carbon atoms and n is an integer of 1 or 2. The alkyl group may be a linear or branched chain alkyl group having 1 to 6 carbon atoms, and is preferably a methyl group.

In addition, ^R3 and ^R4 can combine to form a methylene chain containing 2-6 carbon atoms and a ring structure containing a nitrogen atom bonded to ^R3 and ^R4 .

In a preferred combination of ^R3 and ^R4 , one of ^R3 and ^R4 is a hydrogen atom, and the other is an alkyl group containing 1-6 carbon atoms.

In a more preferred combination, one of ^R3 and ^R4 is a hydrogen atom and the other is methyl or ethyl.

In addition, n is an integer of 1 or 2.

The inventors of the present invention have found that the following groups are also preferred substituents for R ² .

It is known that quinolone derivatives containing 3-aminomethylpyrrolidine substituents have strong antibacterial activity against Gram-positive bacteria. For example, 7-(3-aminomethylpyrrolidinyl) quinolone carboxylic acid derivatives are disclosed in Journal of Medicinal Chemistry (Journal of Medicinal Chemistry) vol.29, p.445 (1986), and in Journal of Medicinal Chemistry vol.37 , p.733 (1994) discloses 7-[3-(1-amino-1-methylethyl)pyrrolidinyl]quinolonecarboxylic acid derivatives.

In addition, although quinolone derivatives with 3-aminoalkylpyrrolidinyl at the 7-position exhibit strong antibacterial activity against Gram-negative and Gram-positive bacteria, many of them not only act bacteria, but also eukaryotic cells, where their use as pharmaceuticals or veterinary drugs is difficult due to their low selective toxicity.

The inventor of the present invention has carried out intensive research on the quinolone derivatives with 3-aminoalkylpyrrolidinyl on the 7-position, and found that, when the 5- and 8-positions of the quinolone skeleton are all non-hydrogen atom substituents, it can To obtain quinolone derivatives with high antibacterial activity, excellent safety and high selective toxicity.

(尽管这里用吡咯烷氮原子是被氢取代的这种情况来说明，其实其可以被其他取代基例如氮原子保护基取代)。That is, the 3-aminoalkylpyrrolidinyl group is preferably a pyrrolidinyl group containing an aminoalkyl group at the 3-position shown in the following formula (IV): It is derived from a 3-aminoalkylpyrrolidine compound of the formula:

(Although the case where the pyrrolidine nitrogen atom is substituted by hydrogen is illustrated here, it may be substituted by other substituents such as nitrogen atom protecting groups).

In the above formula, ^R5 and ^R6 independently represent a hydrogen atom or an alkyl group containing 1-3 carbon atoms. The alkyl group may be straight or branched, and is preferably methyl or ethyl.

In addition, ^R5 and ^R6 may combine to form a methylene chain containing 2-6 carbon atoms and a ring structure containing a nitrogen atom bonded to ^R5 and ^R6 .

R ⁷ represents an alkyl group containing 1-6 carbon atoms and R ⁸ represents a hydrogen atom or an alkyl group containing 1-6 carbon atoms.

In a preferred combination of ^R5 and ^R6 , one of ^R5 and ^R6 is a hydrogen atom, and the other is an alkyl group containing 1-3 carbon atoms.

A more preferred combination is that one of ^R5 and ^R6 is a hydrogen atom and the other is methyl or ethyl.

Pyrrolidine derivatives having an aminoalkyl group at the 3-position can be produced as described in, for example, JP-A-63-166876 or JP-A-3-72476.

In addition, the inventors of the present invention have also found that quinolone derivatives containing aminocycloalkyl group-substituted saturated nitrogen-containing heterocyclic substituents exhibit strong antibacterial activity against Gram-positive bacteria, particularly MRSA.

That is, the case where R ² is a saturated nitrogen-containing heterocyclic substituent having a structure represented by the following formula (V).

In this formula, R ⁹ is a hydrogen atom or an alkyl group containing 1-6 carbon atoms. The alkyl group may be a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and is preferably methyl, ethyl, n-propyl or isopropyl.

R ¹⁰ is a hydrogen atom, an alkyl group containing 1-6 carbon atoms, a hydroxyl-containing alkyl group containing 1-6 carbon atoms, or a halogen-containing alkyl group containing 1-6 carbon atoms.

The alkyl group may be a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and is preferably methyl, ethyl, n-propyl or isopropyl.

For hydroxyalkyl groups having 1 to 6 carbon atoms, 2-hydroxyethyl or 3-hydroxypropyl is preferred.

For the halogen atom in the halogen atom-containing alkyl group of 1 to 6 carbon atoms, 1 to 3 fluorine atoms are particularly preferred. Particularly preferred for halogen-substituted alkyl groups having 1 to 6 carbon atoms are 2-fluoroethyl, 2,2-difluoroethyl or 2,2,2-trifluoroethyl.

In addition, ^R9 and ^R10 can combine to form a methylene chain containing 2-6 carbon atoms and a ring structure containing nitrogen atoms bonded to ^R9 and ^R10 .

In the preferred combination of ^R9 and ^R10 , one of ^R9 and ^R10 is a hydrogen atom, and the other is an alkyl group containing 1-6 carbon atoms, or ^R9 is a hydrogen atom and ^R10 is an alkyl group containing 1-6 hydroxyalkyl groups of carbon atoms.

A more preferred combination is that one of ^R5 and ^R6 is a hydrogen atom and the other is a methyl or ethyl group, or ^R9 is a hydrogen atom and ^R10 is a 2-hydroxyethyl group.

Also, p is an integer of 1-3, preferably 2, and q is an integer of 1-3, preferably 1 or 2.

The bonding to ^R2 at the 7-position of the core nucleus of the quinolone compound is most preferably on the nitrogen atom forming the ring structure of ^R2 , and may also be carried out on the carbon atom on ^R2 .

When there is stereoisomerism on R ² , the quinolone core compound can directly react with the stereoisomer mixture of the compound shown in the formula R ² -H of R ² substituent source, because 1,2-cis In the presence of -2-halocyclopropyl, the resulting quinolone derivative becomes a mixture of diastereomers. When there is stereoisomerism on R ² , it is ideal that only the R ² -H compound One of the isomers reacts with the quinolone parent core compound.

When R ² is introduced at the 7-position of the quinolone and the R ² -H compound contains an amino group, the amino group can be reacted with a compound that can be converted into a conventional protecting group.

Examples of such protecting groups include alkoxycarbonyl such as tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc., aralkoxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro Benzyloxycarbonyl, etc., acyl such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl, etc., alkyl or aralkyl such as tert-butyl, benzyl group, p-nitrobenzyl, p-methoxybenzyl, trityl, etc., alkylsulfonyl or haloalkylsulfonyl such as methylsulfonyl, trifluoromethanesulfonyl, etc., and arylsulfonyl such as benzenesulfonyl Acyl, tosyl, etc.

In addition, the halocyclopropyl group at the N ₁ -position is as described below.

Examples of the halogen atom as the substituent include a fluorine atom and a chlorine atom, among which a fluorine atom is particularly preferred.

Considering the stereochemical environment of this group, it is particularly desirable that the halogen atom and the pyridonecarboxylic acid group are in cis configuration with respect to the cyclopropane ring.

Said enantiomer is formed only from this 1-cis-2-halocyclopropyl group, with

Stereoisomerism of the substituents at other positions, especially the R ² at the 7-position is irrelevant, and we found that these isomers have stronger antibacterial activity and higher safety.

When the compound (I) of the present invention has a structure in which diastereomers exist and such compounds of the present invention are administered to humans and animals, it is desirable to administer the compound consisting of the pure diastereomers. The term "consisting of pure diastereomers" refers not only to the complete absence of other diastereomers, but also to the degree of chemical purity. In other words, other diastereomers may be present to this extent without affecting physical constants and biological activity.

In addition, the term "stereochemically pure" means that when a compound contains multiple isomeric forms due to the presence of its asymmetric carbon atom, the compound consists of only one of these isomeric forms. At this time, the term "pure" can also be considered to have the same meaning as above.

The pyridonecarboxylic acid derivatives of the present invention can be used in their free form or in the form of acid addition salts or carboxyl salts thereof. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, etc., organic acid salts such as acetate, methanesulfonate, Benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate, etc.

Described carboxyl salt can be any in inorganic and organic salt, such as alkali metal salts such as lithium salt, sodium salt, potassium salt, alkaline earth metal salts such as magnesium salt, calcium salt, ammonium salt, triethylamine salt, N- Methylglutamate, tris-(hydroxymethyl)aminomethane salt, etc.

In addition, the free form, acid addition salt, and carboxylate salt of the pyridonecarboxylic acid derivative may also exist in the form of a hydrate.

Furthermore, quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters can be used as synthetic intermediates.

Examples of esters useful as prodrugs are esters that are readily hydrolyzed in vivo to the free carboxylic acid, such as acetoxymethyl esters, pivaloyloxymethyl esters, ethoxycarbonyl esters, choline esters, dimethyl Aminoethyl esters, 5-2,3-indanyl esters, 2-benzo[c]furanonyl esters and oxoalkyl esters such as 5-alkyl-2-oxo-1,3-m Dioxol-4-ylmethyl ester, 3-acetoxy-2-oxobutyl ester, and the like.

其中X是可用作离去基团的取代基，例如氟原子、氯原子、含有1-3个碳原子的烷基磺酰基或者芳基磺酰基例如苯磺酰基、甲苯磺酰基等，R与式(I)中所定义的R相同或者是式(VII)表示的基团：其中R¹¹和R¹²分别是氟原子或低级烷羰氧基，并且X¹、X²、R¹和A如式(I)中定义。The compound of the present invention represented by formula (I) can be prepared by various methods. A preferred example is that the compound can be prepared by the following method, that is, the compound of the formula R ² -H (wherein R ² can be protected by the protecting group Rx of the nitrogen atom, such as the above formula (I )) or its acid addition salt reacts with the compound (quinolone parent nucleus compound) shown in formula (VI):

Wherein X is a substituent that can be used as a leaving group, such as a fluorine atom, a chlorine atom, an alkylsulfonyl group or an arylsulfonyl group containing 1-3 carbon atoms such as a benzenesulfonyl group, a toluenesulfonyl group, etc., R and R defined in formula (I) is the same or a group represented by formula (VII): wherein R ¹¹ and R ¹² are respectively a fluorine atom or a lower alkylcarbonyloxy group, and X ¹ , X ² , R ¹ and A are as defined in formula (I).

The nitrogen atom protecting group Rx can be any group commonly used in the art and examples of such protecting groups include alkoxycarbonyl such as tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc., arane Oxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc. Acyl such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl , benzoyl, etc., alkyl or aralkyl such as tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trityl, etc., alkylsulfonyl or haloalkylsulfonyl such as methyl Sulfonyl, trifluoromethanesulfonyl, etc., and arylsulfonyl such as benzenesulfonyl, toluenesulfonyl, etc.

When R is a carboxylic acid derived from an aralkyl group, the aralkyl group contains an alkyl group of 1-6 carbon atoms, an alkoxymethyl group of 2-7 carbon atoms, or an alkoxymethyl group containing 1-6 carbon atoms The group formed by the alkylene group and phenyl group, the compound shown in the interesting formula (I) can be obtained by conversion into the corresponding carboxylic acid under acidic or basic conditions commonly used in the hydrolysis of carboxyl esters , and, if desired, other substituents may be protected at this point and then deprotected under correspondingly suitable conditions.

When R in the compound of formula (VI) is a group represented by the above ^formula (VII), it can be converted into the corresponding of carboxylic acids.

The substitution reaction of the compound of formula (VI) with the compound of R ² -H can be carried out with or without the presence of solvent. When a solvent is used, it may be one that is inert under the reaction conditions. Examples of suitable solvents include dimethylsulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, 3-methoxybutanol, and mixtures thereof .

The reaction is usually carried out at room temperature to 200°C, preferably at 25-150°C. The reaction time is 30 minutes to 48 hours, and the reaction is usually completed within 30 minutes to 2 hours.

Advantageously, the reaction is carried out in the presence of acid acceptors, including inorganic bases such as alkali metal or alkaline earth metal carbonates or bicarbonates and organic base compounds such as triethylamine, pyridine and the like.

Synthetic examples of amino-substituted fused-bicyclic heterocycles are described below. For example, 1-tert-butoxycarbonylamino-3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexyl, consisting of stereochemically pure isomers, can be prepared by alkyl.

That is, first use ethanol as a solvent to react (S)-(-)-phenethylamine with glycidol, and then react with acrylonitrile to obtain N-(2-cyanoethyl)-N-[(1S) -Phenylethyl]-3-amino-1,2-propanediol. Reaction of this compound with triphenylphosphine and carbon tetrabromide gives N-(2-cyanoethyl)-N-[(1S)-phenethyl]-3-amino-1,2-dibromo propane. Reaction of this compound in the presence of a strong base affords 1-cyano-3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane. Since this compound contains a phenethyl group at the 3-position and an asymmetric carbon atom at the 1-position, a mixture of diastereomers is obtained. These isomers can be separated from each other by silica gel column chromatography or high performance liquid chromatography. Each of the isomers thus obtained is reacted with a base in a conventional manner to give 3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid. When this compound is subjected to a Curtius reaction in the presence of tert-butanol, it can be converted immediately into the protected 3-[(1S)-phenethyl]-3-azabicyclo[3.1.0] Hexane-1-carboxylic acid. This reaction can be easily carried out when diphenylphosphoryl azide is used, but the synthesis of the intermediate azide is not in any way limited here and any conventional synthetic method can be used. When the phenethyl group is removed from this compound by catalytic hydrogenation in a conventional manner, 1-tert-butoxycarbonylamino-3-azabicyclo[3.1.0 composed of pure optical isomers can be obtained ] Hexane.

For example, 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane consisting of stereochemically single isomers can be obtained by the following method.

That is, ethyl 1-bromocyclobutenecarboxylate is reacted with a base to obtain 1-cyclobutenecarboxylic acid. Reaction of this compound with ethyl iodide by using a base gives ethyl 1-cyclobutenecarboxylate. Using an acid as a catalyst, this compound is reacted with n-butoxymethyltrimethylsilylmethyl[(S)-phenethyl]amine to give 3-[(S)-phenethyl]-3- Ethyl azabicyclo[3.2.0]heptane-1-carboxylate, in this reaction eg trifluoroacetic acid can be used as the acid. Since this compound contains a phenethyl group at the 3-position and an asymmetric carbon atom at the 1-position, a mixture of diastereomers is obtained. These isomers can be separated from each other by silica gel column chromatography or high performance liquid chromatography. Each isomer thus obtained was reacted with benzyl chloroformate to give ethyl 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylate. This compound is subjected to ester hydrolysis in a conventional manner to give 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid. When this compound is subjected to a Curtis reaction in the presence of tert-butanol, it can be converted immediately to the protected 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane . This reaction can be easily carried out when diphenylphosphoryl azide is used, but the synthesis of the intermediate azide is not in any way limited here and any conventional synthetic method can be used. When the benzyloxycarbonyl group is removed from this compound by catalytic hydrogenation in a conventional manner, 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0] consisting of pure optical isomers can be obtained heptane.

A synthesis example of an aminocycloalkyl-substituted saturated nitrogen-containing heterocyclic compound, which is necessary for introducing the aminocycloalkyl-substituted saturated nitrogen-containing heterocyclic group, is described below. In the following reaction formulas or illustrations, Me is methyl, Et is ethyl, Ph is phenyl, Z is benzyloxycarbonyl, Boc is tert-butoxycarbonyl, TFA is trifluoroacetic acid and Ts is p-toluenesulfonyl . In some cases, arrows indicate that there are multiple options for the reaction step.

1. Preparation of (3R)-3-(1-aminocyclopropyl)pyrrolidine:

Reaction of (3R)-ethyl 1-[(R)-phenethyl]pyrrolidine-3-acetate disclosed in U.S. Patent 621,101 with benzyl chloroformate affords (3R)-ethyl 1- Benzyloxycarbonyl-pyrrolidine-3-acetate.

This compound is then reacted first with a strong base and then with ethyl chlorocarbonate to give 1-benzyloxycarbonyl-3-(R)-pyrrolidinylmalonate. Reaction of this compound with a base gives ethyl 1-benzyloxycarbonyl-3-(R)-pyrrolidinylmalonate hydrogen.

This compound was then reacted with Eschenmoser's salt to give ethyl 2-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)acrylate. This compound was reacted with diazomethane using palladium acetate as a catalyst to give ethyl 1-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropanecarboxylate.

This compound is then converted into 1-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropanecarboxylic acid by hydrolysis with a base in a conventional manner.

When this compound is subjected to a Curtis reaction in the presence of tert-butanol, it can be immediately converted into the protected (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropane base) pyrrolidine. This reaction can be easily carried out when diphenylphosphoryl azide is used, but the synthesis of the intermediate azide is not in any way limited here and any conventional synthetic method can be used.

When Z is removed from the obtained (3R)-1-benzyloxycarbonyl-3--(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine by conventional catalytic hydrogenation or similar methods, (3R )-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine.

In addition, when (3S)-ethyl[1-(S)-phenylethyl]pyrrolidine-3-acetate was used instead of (3R)-ethyl[1-(R)-phenethyl]pyrrolidine- In the case of 3-acetate, (3S)-3-(1-aminocyclopropyl)pyrrolidine derivatives can be obtained.

Furthermore, (3R)-1-benzyloxycarbonyl-(1-ethoxycarbonylcyclopropyl)pyrrolidine can also be obtained by the following method.

2. Another synthetic method of (3R)-3-(1-aminocyclopropyl)pyrrolidine:

Reaction of ethyl acetoacetate with 1,2-dibromoethane gives ethyl 1-acetylcyclopropanecarboxylate. Ethyl 1-acetylcyclopropanecarboxylate is then reacted with zinc powder and ethyl bromoacetate to give ethyl 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropanecarboxylate.

This compound is then reacted with thionyl chloride using pyridine as a solvent to give 1-ethoxycarbonyl-β-chloro-β-methylcyclopropanepropionate, which is then reacted with a base to give (E)-ethyl 3- (1-Ethoxycarbonylcyclopropyl)-2-butenoate, examples of organic bases used include pyridine, 2,6-lutidine and similar aromatic heterocyclic compounds, and 1,8-diazepine Organic bases such as heterobicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, etc.

Reaction of (E)-ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-butenoate thus obtained with N-bromosuccinimide affords (E)-ethyl 4-bromo -3-(1-ethoxycarbonylcyclopropyl)-2-butenoate, which is then reacted with (S)-phenyl-ethylamine to give 4-(1-ethoxycarbonylcyclopropyl) -1-[(S)-1-phenethyl]-3-pyrrolidin-2-one. Conventional catalytic hydrogenation of this compound affords 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-phenethyl]-2-pyrrolidinone. Due to the presence of the (S)-phenethyl group at the 1-position, this compound is a mixture of diastereomers. The mixture can be separated by fractional recrystallization or silica gel column chromatography.

Reaction of (4R)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-phenethyl]-2-pyrrolidone thus isolated with Lawesson's reagent affords (4S)-4-( 1-ethoxycarbonylcyclopropyl)-1-[(S)-phenethyl]-2-pyrrolidinhione. This reaction can also be carried out with phosphorus pentasulfide.

The (4S)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-phenethyl]-2-pyrrolidinhione thus obtained was reacted with Raney nickel followed by benzyl chloroformate Base ester reaction to give (3R)-1-benzyloxycarbonyl-(1-ethoxycarbonylcyclopropyl)pyrrolidine.

Thereafter, (3R)-3-(1-aminocyclopropyl)pyrrolidine was obtained through the above reaction.

The following method can be used to synthesize (3R)-3-(1-alkylaminocyclopropyl)pyrrolidine or (3R)-1-[1-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl) )amino)cyclopropyl]pyrrolidine.

3. Preparation of (3R)-3-(1-substituted aminocyclopropyl)pyrrolidine:

In order to obtain (3R)-3-(1-methylaminocyclopropyl)pyrrolidine, first in N,N-dimethylformamide, (3R)-1-benzyloxycarbonyl-3-(1-tert Reaction of butoxycarbonylaminocyclopropyl)pyrrolidine with iodomethane and silver oxide to give (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-methyl)aminocyclopropyl Base] pyrrolidine.

When ethyl iodide is used instead of methyl iodide, (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-ethyl)aminocyclopropyl]pyrrolidine can be obtained.

Thereafter, removal of Z from this compound by conventional catalytic hydrogenation affords (3R)-3-(1-alkylaminocyclopropyl)pyrrolidines.

In order to obtain (3R)-1-[1-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino)cyclopropyl]pyrrolidine, first under acidic conditions, use trifluoroacetic acid, hydrochloric acid, etc. Allow to react to remove Boc from (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine, then in the presence of triethylamine or similar acid remover The product was reacted with benzyloxyacetyl chloride to give (3R)-3-{1-(benzyloxyacetyl)aminocyclopropyl]-1-benzyloxycarbonylpyrrolidine.

By reducing this compound with borane-tetrahydrofuran complex and then adding Boc to it, (3R)-1-benzyloxycarbonyl-3-[1-(N-2-benzyloxyethyl-N- tert-butoxycarbonyl)aminocyclopropyl]pyrrolidine.

Thereafter, removal of the benzyl group and Z from this compound by conventional catalytic hydrogenation affords the (3R)-1-[1-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino) ring Propyl]pyrrolidine.

For example, 3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine can be prepared by the following method.

4. Preparation of 3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine:

Reaction of ethyl 1,1-cyclobutanedicarboxylate with diphenylphosphoric azide and triethylamine or a similar acid remover in tert-butanol as solvent gives 1-tert-butoxycarbonyl Ethyl aminocyclobutanecarboxylate.

Under basic conditions, the ester of this compound is hydrolyzed to give 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid. This compound is reacted with 1,1'-carbonyldiimidazole, dicyclohexylcarbodiimide, chlorocarbonate, etc. to give a mixture of active esters or anhydrides, which is then reacted with the magnesium salt of ethyl hydrogen malonate to give 1- tert-Butoxycarbonylamino-β-oxocyclobutane propionate ethyl ester.

Reduction of this compound with sodium borohydride gave ethyl 1-tert-butoxycarbonylamino-β-hydroxycyclobutanepropionate.

Using triethylamine, pyridine or a similar base as an acid scavenger, this compound is converted into a sulfonate by reacting it with methanesulfonyl chloride or p-toluenesulfonyl chloride, and then reacting the resulting compound with pyridine, 2,6-di picoline or similar aromatic heterocyclic compound or 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene Or a similar organic base reaction to obtain ethyl 1-tert-butoxycarbonylaminocyclobutane acrylate.

This compound can also be obtained synthetically by converting the alcohol into an acid halide with thionyl chloride or bromide and then reacting the product with the above-mentioned base.

Reaction of this compound with nitromethane in the presence of a base affords ethyl 3-(1-tert-butoxycarbonylaminocyclobutyl)-4-nitrobutyrate. Examples of the base used in this reaction include 1,1,3,3-tetramethyl-guanidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and similar organic bases.

This reaction can be carried out with a solvent or with nitromethane as a solvent. Examples of solvents used in this reaction are those solvents which are inert under the stated reaction conditions, such as benzene, toluene and similar aromatic compounds, chloroform, dichloromethane and similar chlorine-substituted compounds or diethyl ether, tetrahydrofuran and similar Ether compounds.

When the ethyl 3-(1-tert-butoxycarbonylaminocyclobutyl)-4-nitrobutanoate thus obtained is subjected to conventional catalytic hydrogenation, immediately after the nitro group has been reduced to the amino group, cyclization affords 4-(1 - tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone.

When non-cyclized 4-amino-3-(1-tert-butoxycarbonylaminocyclobutyl)butyrate is present, it can be converted to Conversion to 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone.

In this cyclization reaction, sodium ethoxide, potassium butoxide or similar bases can be used.

Then, 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone was reacted with benzyl bromide or benzyl chloride as base to give 1-benzyl-4-(1-tert-butoxycarbonyl aminocyclobutyl)-2-pyrrolidone.

Treatment of this compound under acidic conditions removes the Boc, followed by 4-(1-aminocyclobutyl)-1-benzyl-2-pyrrolidinone. This reaction can be carried out by any method commonly used for removing Boc.

In the following reaction, 4-(1-aminocyclobutyl)-1-benzyl- 2-Pyrrolidone trifluoroacetate.

4-(1-Aminocyclobutyl)-1-benzyl-2-pyrrolidone trifluoroacetate was mixed with D-(R)-p-toluenesulfonyl-proline in the presence of pyridine or similar acid scavenger Aminoacyl chloride reaction to give 1-benzyl-4-[1-[N'-p-toluenesulfonyl-2-(R)-pyrrolidinecarbonyl]aminocyclobutyl]-2-pyrrolidone, which is then separated into 2 stereoisomers.

Separation of the isomers can be performed by silica gel column chromatography or high performance liquid chromatography.

Each isomer thus obtained is hydrolyzed with acid to give optically active 1-benzyl-4-(1-aminocyclobutyl)-2-pyrrolidone. Reaction of each optically active isomer with lithium aluminum hydride gave 1-benzyl-3-(1-aminocyclobutyl)pyrrolidine, which was subsequently reacted with di-tert-butyl dicarbonate to give 1- Benzyl-3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine.

When this compound is subjected to catalytic hydrogenation by a conventional method, optically active 3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine is obtained.

For example, 3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine can be prepared by the following method.

5. Preparation of 3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine:

Reaction of 1-benzhydryl-3-hydroxyazetidine with p-toluenesulfonyl chloride using an acid scavenger gives 1-benzhydryl-3-(p-toluenesulfonyloxy)azetidine butane. This compound is reacted with diethyl malonate in the presence of a base to give diethyl (1-benzhydryl-3-azetidinyl)malonate.

Reaction of this compound with benzyl chloroformate gave diethyl (1-benzyloxycarbonyl-3-azetidinyl)malonate, which was then subjected to partial ester hydrolysis to give (1-benzyloxy Carbonyl-3-azetidinyl) ethyl hydrogen malonate.

Reaction of this compound with Eschenmoser's salt affords ethyl 2-(1-benzyloxycarbonyl-3-azetidinyl)acrylate. Using a base, this compound is reacted with trimethylsulfoxonium iodide to give ethyl 1-(1-benzyloxycarbonyl-3-azetidinyl)cyclopropane-carboxylate.

This compound is hydrolyzed to give 1-(1-benzyloxycarbonyl-3-azetidinyl)cyclopropanecarboxylic acid, which is reacted with diphenylphosphoric acid in the presence of a base and using tert-butanol as a solvent. The azide reaction affords 1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine. Catalytic hydrogenation of this compound by a conventional method affords 3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine.

The substituted quinolone compound represented by formula (IV) or (V) can be prepared by the same method as the substituted quinolone compound represented by formula (II).

Alternatively, the compound of formula (VIII) consisting of a single isomer can also be synthesized from an optically active cis-2-fluorocyclopropylamine derivative according to the method described in, for example, JP-A-2-231475.

As a compound in formula (VIII), 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-5-hydroxyl-4- Oxoquinoline-3-carboxylate can be produced by the following method.

Reaction of ethyl 2,3,4,5,6-pentafluorobenzoylacetate with N,N-dimethylformamide dimethyl acetal, then in the presence of triethylamine or similar acid remover , reaction with (1R,2S)-2-fluorocyclopropylamine, followed by 5,6,7,8-tetrafluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1, 4-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester.

Reaction of this compound with benzyl alcohol in the presence of a base affords 5-benzyloxy-6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4- Ethyl dihydro-4-oxoquinoline-3-carboxylate. This reaction can be carried out according to any method known in the art, and examples of the base used in the reaction include sodium hydride, potassium carbonate, sodium hydroxide and potassium hydroxide.

Treatment of this compound under acidic conditions affords 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-5-hydroxy-4-oxo Quinoline-3-carboxylate.

Using the same method as above, using 2,4,5-trifluoro-6-nitrobenzoic acid containing a lower alkyl group at the 3-position as a starting material, a compound wherein R ¹ is amino and X ³ is lower alkyl can be obtained. A compound of formula (VIII), wherein the starting material can be prepared by nitrating 2,4,5-trifluorobenzoic acid containing a lower alkyl group at the 3-position by a conventional method.

Although 3-methyl-2,4,5-trifluorobenzoic acid can be prepared according to the method described in JP-A-61-205240 or JP-A-3-95176, it can also be more easily prepared by the following method synthesized.

That is, for example, reacting 3,4,5,6-tetrafluorophthalic acid diester with malonic acid diester using a base to give 4-diethoxycarbonylmethyl-3,5,6-tri Diethyl fluorophthalate.

The base that can be used in this reaction can be an inorganic base or an organic base, and examples of the inorganic base include alkali metal hydroxides, carbonates, bicarbonates, etc., such as lithium hydroxide, sodium hydroxide , potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. Phase-transfer catalysts such as quaternary ammonium salts and the like can also be used in this reaction.

Examples of organic bases include trialkylamines such as triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, etc., dialkylanilines such as diethylaniline, dimethylaniline, Aniline, etc., and saturated or aromatic heterocyclic compounds such as N-methylmorpholine, pyridine, N,N-dimethylaminopyridine, etc.

When a solvent is used, it may be one that is inert under the reaction conditions. Examples of suitable solvents include dimethylsulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, benzene, toluene, water, and mixtures thereof.

The reaction can usually be carried out at 0-150°C, preferably at 25-100°C.

Then, under acidic or basic conditions, hydrolyze 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalic acid diethyl ester to obtain 4-carboxymethyl-3,5,6- Trifluorophthalic acid.

Examples of the acid used in this reaction include concentrated sulfuric acid and concentrated hydrochloric acid. Examples of the base include inorganic bases such as alkali metal hydroxides, carbonates, bicarbonates, etc., including lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, Potassium bicarbonate, etc.

The 4-carboxymethyl-3,5,6-trifluorophthalic acid thus obtained is heated in dimethylsulfoxide in the presence of a base to give 3-methyl-2,4,5-trifluorobenzene formic acid.

Examples of organic bases used in this reaction include trialkylamines such as triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, etc., dialkylanilines such as diethylaniline , dimethylaniline, etc., and saturated or aromatic heterocyclic compounds such as N-methylpyrrolidone, pyridine, N,N-dimethylaminopyridine, etc.

The reaction can be carried out at 100-200°C, preferably at 100-150°C. The reaction can be carried out for 1-96 hours, but generally it can be completed within 5-48 hours.

When 3,4,5,6-tetrafluorophthalonitrile is used instead of 3,4,5,6-tetrafluorophthalic acid diester as a starting material, the preparation process can be carried out in the same manner. In addition, malononitrile is used instead of malonate diester, and 3-alkyl-2,4,5-trifluoro-6-nitrobenzoic acid can be prepared from alkylmalonate diester and alkylmalononitrile , which contain non-methyl alkyl groups.

Since the compound of the present invention exhibits strong antibacterial activity, it can be used as a medicine suitable for humans, animals and fish or as a preservative for agricultural chemicals and feed.

When the compound of the present invention is used as a medicament suitable for human use, the dose for an adult may range from 50 mg to 1 g, preferably 100 mg to 300 mg per day.

When applied to animals, the dosage will depend on the purpose of the administration (therapeutic or prophylactic), the type and size of each animal to be treated, the type of pathogenic bacteria infecting and the degree of infection, but is usually given at 1 kg per day The body weight of the animal is in the range of 1-200 mg, preferably 5-100 mg.

The daily dosage may be once a day or divided into 2-4 times a day. The daily dose may exceed the above range if necessary.

Since the compounds of the present invention are active against a broad spectrum of microorganisms that can cause various infectious diseases, they can cure, prevent or alleviate diseases caused by these pathogenic microorganisms.

Examples of bacteria and bacteria-like microorganisms susceptible to the compounds of the present invention include Staphylococcus, Streptococcus pyogenes, Streptococcus hemolyticus, Enterococcus, Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, Citrobacter, Shigella Bacillus, Friedlander, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, Chlamydia trachomatis, etc.

Examples of diseases caused by these pathogenic microorganisms include folliculitis, furuncle, carbuncle, erysipelas, cellulitis, lymphangitis, whitlow, subcutaneous abscess, hidradenitis, acne, atheroma contagiosum, perirectal abscess, Mastitis, superficial secondary infection such as injury, burn, surgical wound, etc., pharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infection of chronic respiratory disease, Pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonorrhea urethritis, nongonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterine annex inflammation, intrauterine infection, Bartholinitis, Blepharitis, hordeolum, dacryocystitis, meibomianitis, corneal ulcer, otitis media, sinusitis, periodontitis, crownitis, jawitis, peritonitis, endocarditis, sepsis, meningitis, dermatitis wait.

The compounds of the present invention are also effective against various microorganisms that cause infectious diseases in animals, such as microorganisms belonging to the following genera: Escherichia coli, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus , Mycoplasma, etc. Illustrative examples of such diseases include for poultry, including colibacillosis, pullorum, chicken paratyphoid, fowl cholera, infectious rhinitis, staphylococcal infection, mycoplasma infection, etc., and for pigs, including colibacillosis, Salmonella disease, Pasteurellosis, Haemophilus disease, atopic rhinitis, exudative epidermatitis, mycoplasma infection, etc. For cattle, including colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma Infections, bovine pleuropneumonia, bovine mastitis, etc., in dogs including enteric sepsis, salmonellosis, hemorrhagic sepsis, pyometra, cystitis, etc., and in cats including exudative pleurisy, cystitis, chronic Rhinitis, haemophilus infection, kitten diarrhea, mycoplasma infection, etc.

The antibacterial agent containing the compound of the present invention can be prepared by using various commonly used methods for the preparation of pharmaceutical preparations by selecting an appropriate dosage for each administration method. Examples of antibacterial dosage forms containing the compound of the present invention as an active ingredient include oral preparations such as tablets, powders, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like.

When used as an injection, the preparation may contain stabilizers, preservatives and solubilizers. The solution, which may contain auxiliary substances, may be filled into a container and made into a redissolvable solid preparation before use by freeze-drying or other methods as needed. Additionally, the container may contain a single dose or multiple doses.

The antibacterial agent of the present invention can also be prepared into preparations suitable for external use such as solutions, suspensions, emulsions, ointments, gels, emulsions, lotions, sprays and the like.

Solid preparations may contain pharmaceutically acceptable additives and active compounds and may be prepared by mixing additives arbitrarily selected from, for example, fillers, swelling agents, binders, disintegrants, solubilizers, wetting agents, lubricants, etc. .

Liquid preparations include solutions, suspensions, emulsions and the like which may contain additives such as suspending agents and emulsifying agents.

When the compound of the present invention is administered to animals, it can be done, for example, by directly orally administering the compound or adding it to a feed, or by making a solution of the compound and then directly orally Oral administration or injection after administration or addition to drinking water or feed.

When the compound of the present invention is administered to animals, it can be optionally prepared into powder, subtilae, soluble powder, syrup or injection by conventional methods in the art.

Formulation examples of pharmaceutical preparations are described below. Preparation Example 1 (capsule)

Compound of Invention Example 2 100.0mg

Corn starch 23.0mg

CMC Calcium 22.5mg

Hydroxymethylcellulose 3.0mg

Magnesium stearate 1.5mg

A total of 150.0mg formulation example 2 (solution)

Invention Example 2 Compound 1-10g

Acetic acid or sodium hydroxide 0.5-2g

Ethyl p-hydroxybenzoate 0.1g

Purified water 88.9-98.4g

A total of 100g formulation embodiment 3 (powder suitable for mixed feeding)

Invention Example 2 Compound 1-10g

Corn starch 98.5-89.5g

Soft silicic anhydride 0.5g

Total 100g

Best Embodiment of the Invention

The following inventive examples and reference examples further illustrate the present invention, but do not serve any limiting purpose. For the antibacterial activity of the optically active compound of interest, the test was carried out according to the conventional method described in Japan Society of Chemotherapy, and the results are expressed in MIC (μg/ml), as shown in Table 1. Reference Example A-1: N-(2-cyanoethyl)-N-[(1S)-phenethyl]-3-amino-1,2-propanediol

Under ice cooling, glycidol (37g, 0.5mol) was added to a solution of (S)-(-)phenethylamine (75ml, 0.58mol) in ethanol (500ml), and the mixture was stirred at room temperature for 20 minutes, and then heated at reflux for 62 hours. After adding acrylonitrile (40 ml) thereto, the reaction mixture was heated under reflux for 45 hours and then concentrated. Thereafter, the obtained residue was purified by silica gel column chromatography and eluted with 5% methanol-chloroform to obtain 121 g (84%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.41-1.48(3H, m), 2.39-2.50(2H, m), 2.60-3.25

(4H, m), 3.41-3.46 (IH, m), 3.68-3.78 (2H, m), 3.93

-4.02(1H, m), 7.27-7.40(5H, m). Reference Example A-2: N-(2-cyanoethyl)-N-[(1S)-phenethyl]-3-amino -1,2-Dibromopropane

Add triphenyl Phosphine (57.71 g, 0.22 mol) and carbon tetrabromide (73 g, 0.22 mol). Under stirring, the resulting mixture was heated to 90 ° C, after the supernatant was separated, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography, and eluted with n-hexane-ethyl acetate (4:1) to obtain 38 g ( 100%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.43-1.46(3H, m), 2.35-2.44(2H, m), 2.82-2.96

(3H, m), 3.14-3.27 (1H, m), 3.67-4.15 (4H, m), 7.27

-7.40(5H, m). Reference Example A-31-cyano-3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane

Under ice-cooling, N-(2-cyanoethyl)-N-[(1S)-phenethyl]-3-amino-1,2-dibromopropane (37.4g, 0.1mol) in toluene (700ml) solution was added dropwise with 1M tetrahydrofuran solution of sodium (bistrimethylsilyl)amide (220ml, 0.22mol), followed by stirring for 20 minutes. After the reaction was completed, saturated ammonium chloride aqueous solution (100 ml) was added dropwise to the reaction solution, followed by warming to room temperature. The organic layer was separated, washed with saturated brine, and dried over sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography and eluted with n-hexane-ethyl acetate (9:1) to obtain 7.93 g (37%) of a low polar fraction of the title compound (fraction 1) followed by 7.85 g (36%) of a highly polar fraction of the title compound (fraction 2). Fraction 1; ¹ H-NMR (CDCl ₃ ) δ:

1.09(1H,dd,J=4.5,8.3Hz), 1.29(3H,d,J=6.4

Hz), 1.57(1H, t, J=4.5Hz), 1.95-1.99(1H, m),

2.27(1H,dd,J=3.9,9.8Hz), 2.61(1H,d,J=8.8

Hz), 2.68(1H, d, J=9.8Hz), 3.33-3.38(2H, m),

7.21-7.31 (5H, m). Fraction 2; ¹ H-NMR (CDCl ₃ ) δ:

1.09(1H,dd,J=4.9,8.3Hz), 1.29(3H,d,J=6.4

Hz), 1.55-1.58 (1H, m), 2.04-2.09 (1H, m), 2.35

(1H, d, J = 8.8Hz), 2.53 (1H, dd, J = 3.9, 9.3Hz),

2.86(1H, d, J=9.3Hz), 3.18(1H, d, J=9.3Hz),

3.32-3.37 (1H, m), 7.21-7.32 (5H, m). Reference Example A-4: 3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane- 1-Carboxylic acid (fraction 1 )

To a solution of 1-cyano-3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane (fraction 1, 5.6 g, 26.4 mmol) in methanol (500 mL) was added 2N hydrogen Aqueous sodium oxide solution (50ml) was then heated at reflux for 30 hours. After methanol was distilled off, the resulting residue was washed with chloroform (30ml x 2), adjusted to pH 3 with concentrated hydrochloric acid, and extracted with n-butanol (80ml x 3). The extract was dried over sodium sulfate, and the solvent was distilled off to obtain 6.11 g (100%) of a crude product of the title compound. It was used directly in the following reaction. Reference Example A-5: 3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid

Fraction 2 was also subjected to the same reaction. Reference Example A-6: 1-tert-butoxycarbonylamino-3-[(1S)-phenethyl]-3-azabicyclo[310]hexane (fraction 1)

To a solution of 3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane-1-carboxylic acid (fraction 1, 6.11g, 266.4mmol) in tert-butanol (200ml) was added Diphenylphosphoric azide (9.99 g, 34.3 mmol) and triethylamine (4.23 g, 36.9 mmol) were then heated at reflux for 4 hours. After the reaction solution was cooled, the solvent was distilled off and the resulting residue was mixed with 200 ml of ethyl acetate, washed with saturated brine (50 ml×2), and then dried over sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography and eluted with n-hexane-ethyl acetate (4:1) to obtain 3.19 g (40%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

0.67-0.71(1H, m), 1.25-1.31(4H, m), 1.45(9H, s),

1.60(1H, brs.), 2.30-2.38(1H, m), 2.51-2.58(2H,

m), 3.20-3.35 (2H, m), 4.96 (1H, brs.), 7.20-7.29

(5H, m). Reference Example A-7: 1-tert-butoxycarbonylamino-3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane (fraction 2) ¹ H-NMR(CDCl ₃ )δ:

0.69-0.71 (1H, m), 1.25 (3H, d, J=6.4Hz), 1.39

(9H, s), 1.50-1.72 (2H, m), 2.29 (1H, d, J=8.3Hz),

2.58-2.82(2H, m), 3.08-3.15(1H, m), 3.30-3.38

(1H, m), 4.82 (1H, brs.), 7.19-7.37 (5H, m). Reference Example A-8: 1-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (fraction 1)

Add 1-tert-butoxycarbonylamino-3-[(1S)-phenethyl]-3-azabicyclo[3.1.0]hexane (fraction 1, 3.1g, 10.26mmol) in ethanol (50ml) solution 10% palladium on carbon (3 g) was added, followed by catalytic hydrogenation for 3 hours under 4 atmospheres of warming under a tungsten lamp. After filtering off the catalyst, the solvent was evaporated to give 2.04 g (100%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

0.85-1.14(2H, m), 1.44(9H, s), 1.44-1.70(1H, m),

2.95-3.34 (4H, m), 5.0 8 (1H, brs.). Reference example B-1: 1-cyclobutene carboxylic acid

After the 85% potassium hydroxide solution and 125 ml of toluene were refluxed and heated together, 10 g (48.31 mmol) of ethyl 1-bromocyclobutenecarboxylate was added dropwise to the solution at a speed of maintaining reflux. After the dropwise addition was complete, the resulting mixture was heated at reflux for an additional 1 hour. After cooling to room temperature, water was added thereto and the formed aqueous layer was separated. It was washed with hexane, acidified with 1N hydrochloric acid, and extracted with ether. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 4.1047 g (41.88 mmol, 86.7%) of a crude product of the title compound. Reference Example B-2: Ethyl 1-cyclobutenecarboxylate

To a solution of 3.2425 g (33.09 mmol) of 1-cyclobutenecarboxylic acid in 60 ml of dimethylformamide was added 12 ml (150 mmol) of iodoethane and 5.53 g (40 mmol) of potassium carbonate, followed by stirring at room temperature for 20 hours. The reaction solution was poured into water and extracted with ether. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 4.5267 g of the title compound as a mixture containing ethyl iodide and ether. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.29(3H, t, J=7.5Hz), 2.47(1H, dt, J=1.0, 3.0

Hz), 2.73 (1H, t, J=3.0Hz), 4.19 (2H, q, J=7.5

Hz), 6.77 (1H, t, J=1.0Hz). Reference Example B-3: 3-[(S)-phenethyl]-3-azabicyclo[3.2.0]heptane-1-carboxy ethyl acetate

Under cooling in an ice bath, add 0.116ml (1.5mmol) trifluoroacetic acid dropwise to 4.5267g (33.09mmol) of the above-mentioned ethyl 1-cyclobutenecarboxylate, ethyl iodide and ether mixture and 14.65g (50mmol) of azo azomethinylide in dichloromethane (100ml), followed by stirring at room temperature for 64 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain 4.1832 g (14.58 mmol, 44.1% of the 2-step reaction from Reference Example B-2) of The title compound as a mixture of enantiomers. This mixture was separated by high-performance liquid chromatography to obtain 1.9203g (6.69mmol, 20.2% from the 2-step reaction of reference example B-2) low polarity product (fraction 1) and 990.5mg (3.45mmol, 10.4% from 2-step reaction starting with reference example B-2) highly polar product (fraction 2). Low polarity product (fraction 1) ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.21(3H, t, J=7.0Hz), 1.40(3H, d, J=6.5Hz),

1.77-1.84(1H, m), 1.97-2.05(1H, m), 2.11-2.20

(1H, m), 2.29 (1H, dd, J=6.0, 9.0Hz), 2.38 (1H, dt,

J=6.5, 11.0Hz), 2.69(1H, d, J=9.0Hz), 2.96(1H,

dt, J=5.0, 9.5Hz), 3.07 (1H, d, J=9.0Hz), 3.29

(1H, q, J=6.5Hz), 4.10 (2H, q, J=7.0Hz), 7.21-

7.33 (3H, m), 7.39-7.41 (2H, m). Highly polar product (fraction 2) ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.28(3H, t, J=7.5Hz), 1.40(3H, d, J=6.5Hz),

1.68-1.72(1H, m), 2.02-2.18(3H, m), 2.41(1H, d,

J=9.0Hz), 2.45-2.50(1H, m), 2.55(1H, d, J=9.0

Hz), 2.82-2.87 (1H, m), 3.19 (1H, d, J=9.0Hz),

3.29 (1H, q, J = 6.5Hz), 4.10 (2H, q, J = 7.5Hz),

7.21-7.41 (5H, m). Reference Example B-4: Ethyl 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylate (fraction 1)

Under ice cooling, drop 980mg (3.41mmol) of 3-[(S)-phenethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid ethyl ester in dichloromethane (20ml) solution 0.714 ml (5.0 mmol) of benzyl chloroformate was added, followed by stirring at room temperature for 40 hours. After distilling off the solvent, the resulting residue was purified by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 921.5 mg (2.91 mmol, 85.3%) of the title compound. Reference Example B-5: Ethyl 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylate (fraction 2)

Under ice-cooling, add 863.8mg (3.01mmol) 3-[(S)-phenethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid ethyl ester in dichloromethane (15ml) 0.642 ml (4.5 mmol) of benzyl chloroformate was added dropwise to the solution, followed by stirring at room temperature for 45 hours. After distilling off the solvent, the resulting residue was purified by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 829 mg (2.62 mmol, 87.0%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.27(3H,t,J=7.0Hz), 1.72(1H,br), 1.97(1H,br),

2.22(1H, br), 2.56(1H, dt, J=8.0, 11.5Hz), 3.10

(1H, dd, J=6.5, 14.5Hz), 3.38-3.42 (1H, m), 3.66-

3.84(3H, m), 4.18(2H, q, J=7.0Hz), 5.18(2H, s),

7.27-7.40 (5H, m). Reference Example B-6: 3-Benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid (fraction 1)

Under ice cooling, to 920 mg (2.90 mmol) of 1-ethoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in ethanol (10 ml) was added 6 ml of 1N aqueous sodium hydroxide solution, followed by Stir at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid aqueous solution, ethanol was distilled off. The obtained residue was mixed with 1N aqueous hydrochloric acid solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 847.2 mg (quantitative) of a crude product of the title compound. Reference Example B-7: 3-Benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid (fraction 2)

Under cooling in an ice bath, 5 ml of 1N aqueous sodium hydroxide solution was added to a solution of 825 mg (2.60 mmol) of 1-ethoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in ethanol (10 ml), followed by Stir at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid aqueous solution, ethanol was distilled off. The obtained residue was mixed with 1N aqueous hydrochloric acid solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 776.6 mg (quantitative) of a crude product of the title compound. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.75(1H,br), 2.00(1H,br), 2.25(1H,br), 2.59-

2.66(1H, m), 3.14-3.19(1H, m), 3.39-3.44(1H, m),

3.66-3.81(2H, m), 3.84-3.91(1H, m), 5.18(2H, s),

7.29-7.39 (5H, m). Reference Example B-8: 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane (fraction 1)

To a solution of 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid (2.90mmol) in tert-butanol (15ml) was added 0.53ml (3.8mmol) of triethylamine and 0.819ml (3.8 mmol) diphenylphosphoryl azide, followed by stirring at 70°C for 9 hours. After cooling to room temperature, the reaction solution was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 817.8 mg (2.27 mmol, 78.3% of the 2-step reaction from Reference Example B-2) the title compound. Reference Example B-9: 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane (fraction 2)

To a solution of 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid (2.60mmol) in tert-butanol (15ml) was added 0.474ml (3.4mmol) of triethylamine and 0.733ml (3.4 mmol) diphenylphosphoryl azide, followed by stirring at 70°C for 9 hours. After cooling to room temperature, the reaction solution was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 642.2 mg (1.78 mmol, 68.4% of the 2-step reaction from Reference Example B-7) the title compound. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.43(9H, s), 2.18(3H, br), 2.85(1H, br), 3.45-3.65

(3H, m), 3.87 (1H, br), 4.80 (1H, br), 5.16 (2H, s),

7.310-7.37 (5H, m). Reference Example B-10: 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane (fraction 1)

To a solution of 368 mg (1.02 mmol) of 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in methanol (20 ml) was added 400 mg of 20% palladium hydroxide on carbon, followed by Stir vigorously under a hydrogen atmosphere. After removing insoluble matter by filtration through celite, the resulting filtrate was concentrated to obtain 274.6 mg of a crude product of the title compound. Reference Example B-11: 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane (fraction 2)

To a solution of 360 mg (1.02 mmol) of 1-tert-butoxycarbonyl-3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane in methanol (20 ml) was added 400 mg of 20% palladium hydroxide on carbon, followed by Stir vigorously under a hydrogen atmosphere. After removing insoluble matter by filtration through celite, the resulting filtrate was concentrated to obtain 243.8 mg of a crude product of the title compound. ¹ H-NMR (400MHz, CD ₃ OD) δ:

1.54(9H, s), 1.76-1.83(1H, m), 2.31-2.45(3H, m),

3.07-3.22(1H, m), 3.40-3.48(1H, m), 3.51-3.67

(2H, m), 3.68-3.71 (1H, m). Inventive Example 1: 5-amino-7-(1-amino-3-azabicyclo[3.1.0]hexane-3-yl)-6 , 8-Difluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fraction 1)

To 5-amino-6,7,8-trifluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (316mg, 1mmol) in acetonitrile (15ml) was added 1-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane (fraction 1) (396mg, 2mmol) and triethylamine (5ml), followed by Heated at reflux for 2 hours. After distilling off the solvent, the resulting residue was mixed with chloroform (20 ml), washed with 10% citric acid (10 ml×2), and then dried over sodium sulfate, followed by distilling off the solvent. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes. The reaction solution was washed with chloroform (5ml x 2), adjusted to pH 7.3 with 20% aqueous sodium hydroxide solution, and then extracted with chloroform (30ml x 3). After drying over sodium sulfate, the solvent was distilled off to obtain 190 mg (48%) of a crude product of the title compound. Thereafter, the crude product was recrystallized from chloroform-methanol-ethanol to obtain 111 mg of the title compound. ¹ H-NMR (0.1N-NaOD) δ:

0.61-0.64 (1H, m), 0.80-0.83 (1H, m), 1.21-1.83

(3H, m), 3.23-3.79 (5H, m), 4.87-4.98 (0.5H, m),

8.21(1H, s).

Elemental analysis C ₁₈ H ₁₈ F ₃ N ₄ O ₃ ·0.25H ₂ O:

Calculated: C, 54.07; H, 4.66; N, 14.01

Measured values: C, 53.98; H, 4.54; N, 13.82 Melting point (°C): 191-203 (decomposition) [α] _D +72.37° (T=22.4°C, c=0.665, 0.1N-NaOH) Invention examples 2: 7-(1-Amino-3-azabicyclo[3.1.0]hexane-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8 -Methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fraction 1)

To 6,7-difluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF2 Add 1-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane (fraction 1) (298mg, 1.5mmol) and three Ethylamine (0.2ml), followed by stirring at room temperature for 200 hours. After triethylamine was distilled off, the resulting residue was mixed with water (10 ml) and stirred at room temperature for 30 minutes. The precipitated crystals were washed with water, collected by filtration and dissolved in a mixed solvent of ethanol:water=4:1 (50ml), and the resulting solution was mixed with triethylamine (5ml) and heated under reflux for 3 hours. After distilling off the solvent, the resulting residue was mixed with chloroform (50 ml), washed with 10% citric acid (20 ml x 2), and then dried over magnesium sulfate, followed by distilling off the solvent. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes. The reaction solution was washed with chloroform (5ml x 2), adjusted to pH 7.3 with 20% aqueous sodium hydroxide solution, and then extracted with chloroform (30ml x 3). After drying over sodium sulfate, the solvent was distilled off. The resulting residue was separated and purified by preparative TLC (low layer development with chloroform:methanol:water=7:3:1) to obtain 35 mg of the crude product of the title compound. Thereafter, the crude product was recrystallized from chloroform-ethanol to obtain 18 mg of the title compound. ¹ H-NMR (0.1N-NaOD) δ:

0.78-0.83 (2H, m), 1.12-1.21 (1H, m), 1.38-1.39

(1H, m), 1.51-1.62 (1H, m), 2.36 (3H, s), 3.03 (1H,

d, J = 9.3Hz), 3.31 (1H, d, J = 9.3Hz), 3.56 (1H, d,

J=9.3Hz), 3.72-3.74 (1H, m), 3.99-4.04 (1H, m),

5.00-5.08 (0.5H, m), 7.60 (1H, d, J=13.67Hz), 8.44

(1H, d, J=2.4Hz).

Elemental analysis C ₁₉ H ₁₉ F ₂ N ₃ O ₃ ·0.75H ₂ O:

Calculated: C, 58.68; H, 5.31; N, 10.81

Measured value: C, 59.01; H, 5.15; N, 10.65 Melting point (°C): 189-210 (decomposition) Inventive Example 3: 7-(1-Amino-3-azabicyclo[3.1.0]hexane- 3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fraction 2)

Using Fraction 2, the title compound was also synthesized in the same manner as described in Inventive Example 2. ¹ H-NMR (0.1N-NaOD) δ:

0.75-0.83 (2H, m), 1.13-1.17 (1H, m), 1.39-1.41

(1H, m), 1.55-1.61 (1H, m), 2.39 (3H, s), 3.26 (1H,

d, J=9.3Hz), 3.35 (1H, d, J=9.3Hz), 3.47-3.49

(1H, m), 3.55-3.60 (1H, m), 3.98-4.04 (1H, m), 5.01

-5.08(0.5H, m), 7.62(1H, d, J=13.67Hz), 8.45(1H,

d, J=1.9Hz).

Elemental analysis C ₁₉ H ₁₉ F ₂ N ₃ O ₃ ·0.25H ₂ O:

Calculated: C, 60.07; H, 5.17; N, 11.06

Measured value: C, 59.87; H, 5.33; N, 10.46 Melting point (°C): 200-217 (decomposition) Invention Example 4: 7-(1-Amino-3-azabicyclo[3.1.0]hexane- 3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxy Acid (fraction 1)

To 6,7-difluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Add 1-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane (fraction 1) (170mg, 0.86mmol) to a solution of BF2 chelate (217mg, 0.6mmol) in dimethylsulfoxide (2.5ml) ) and triethylamine (0.2ml), followed by stirring at room temperature for 150 hours. After triethylamine was distilled off, the resulting residue was mixed with water (10 ml) and stirred at room temperature for 30 minutes. The precipitated crystals were washed with water, collected by filtration and dissolved in a mixture of ethanol:water=4:1 (20ml), and the resulting solution was mixed with triethylamine (3ml) and heated under reflux for 2 hours. After distilling off the solvent, the resulting residue was mixed with chloroform (30 ml), washed with 10% citric acid (10 ml×2), and then dried over magnesium sulfate, followed by distilling off the solvent. The resulting residue was mixed with concentrated hydrochloric acid (5 ml) and stirred at room temperature for 5 minutes. The reaction solution was washed with chloroform (5ml x 2), adjusted to pH 7.3 with 20% aqueous sodium hydroxide solution, and then extracted with chloroform (30ml x 3). After drying over sodium sulfate, the solvent was distilled off to obtain 175 mg (74%) of a crude product of the title compound. Thereafter, the crude product was recrystallized from chloroform-ethanol-ether to obtain 80 mg of the title compound. ¹ H-NMR (0.1N-NaOD) δ:

0.67-0.69 (1H, m), 0.82-0.85 (1H, m), 1.40-1.66

(3H, m), 3.42-3.61 (4H, m), 3.54 (3H, s), 3.98-4.03

(1H, m), 4.98-5.05 (0.5H, m), 7.64 (1H, d, J=13.67

Hz), 8.47(1H, s).

Elemental analysis C ₁₉ H ₁₉ F ₂ N ₃ O ₄ ·0.25H ₂ O:

Calculated: C, 57.65; H, 4.96; N, 10.61

Measured value: C, 57.53; H, 5.03; N, 10.57 Melting point (°C): 188-185 (decomposition) [α] _D +138.73° (c=0.395, 0.1N-NaOH) Inventive Example 5: 7-( 1-Amino-3-azabicyclo[3.1.0]hexane-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methoxy- 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid (fraction 2)

Using Fraction 2, the title compound was synthesized in the same manner as described in Inventive Example 4.

¹ H-NMR (0.1N-NaOD) δ:

0.72-0.74 (1H, m), 0.86-0.89 (1H, m), 1.44-1.67

(3H, m), 3.39-3.44 (2H, m), 3.58 (3H, s), 3.72 (1H,

d, J=7.8Hz), 3.83 (1H, d, J=9.8Hz), 4.01-4.06

(1H, m), 5.03-5.06 (0.5H, m), 7.66 (1H, d, J=14.16,

Hz), 8.48(1H, s).

Elemental analysis C ₁₉ H ₁₉ F ₂ N ₃ O ₃ ·0.25H ₂ O:

Calculated: C, 57.65; H, 4.96; N, 10.61

Measured value: C, 57.61; H, 4.93; N, 10.72 Melting point (°C): 189-188 (decomposition) [α] _D +45.53° (c=0.303, 0.1N-NaOH) Invention Example 6: 7-( 1-Amino-3-azabicyclo[3.2.0]heptane-3-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8- Methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fraction 1)

To a solution of 1-tert-butoxycarbonyl-3-azabicyclo[3.2.0]heptane (1.02 mmol) in dimethylsulfoxide (1.5 ml) was added 180 mg (0.5 mmol) of 1-[2-(S) -Difluoroboronic acid of -fluoro-1-(R)-cyclopropyl]-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ester and 0.5 mL of triethylamine, followed by stirring at room temperature for 110 hours. After triethylamine was distilled off, the resulting residue was mixed with water, and the precipitated crystals were collected by filtration. To the collected crystals were added 15 ml of 90% methanol and 3 ml of triethylamine, followed by reflux for 4 hours. It was cooled to room temperature, then concentrated. The resulting residue was mixed with 10% citric acid and extracted with chloroform. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was dissolved in dichloromethane (5 ml), trifluoroacetic acid (5 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. After concentration, the resulting residue was mixed with concentrated hydrochloric acid and washed with chloroform. The resulting solution was adjusted to pH 7.5 with concentrated aqueous sodium hydroxide solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resulting residue was recrystallized from ethanol to obtain 75.9 mg of the title compound. ¹ H-NMR (400MHz, 0.1N NaOD) δ:

1.48-1.70 (3H, m), 2.03-2.24 (3H, m), 2.60 (1H, dd,

J=5.5, 13.0Hz), 3.22(1H, d, J=10.5Hz), 3.53(1H,

dd, J=5.5, 9.5Hz), 3.65-3.71 (2H, m), 3.72 (3H,

s), 4.07-4.12(1H, m), 4.90-5.10(1H, m), 7.74(1H,

d, J=13.5Hz), 8.50(1H, s).

Elemental analysis C ₂₀ H ₂₁ N ₃ O ₄ F ₂ 1/4H ₂ O:

Calculated: C, 58.604; H, 5.286; N, 10.251

Measured values: C, 58.51; H, 5.38; N, 9.94 Melting point (°C): 233-236 Inventive Example 7: 7-(1-amino-3-azabicyclo[3.2.0]heptane-3-yl )-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3- Carboxylic acid (fraction 2)

180 mg (0.5 mmol) of 1-[2-(S)- Difluoroborate ester of fluoro-1-(R)-cyclopropyl]-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (BF2 chelate) and 0.5 ml of triethylamine, followed by stirring at room temperature for 115 hours. After triethylamine was distilled off, the resulting residue was mixed with water, and the precipitated crystals were collected by filtration. To the collected crystals were added 15 ml of 90% methanol and 3 ml of triethylamine, followed by reflux for 4 hours. It was cooled to room temperature, then concentrated. The resulting residue was mixed with 10% citric acid and extracted with chloroform. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The obtained residue was dissolved in dichloromethane (5 ml), trifluoroacetic acid (5 ml) was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. After concentration, the resulting residue was mixed with concentrated hydrochloric acid and washed with chloroform. The resulting solution was adjusted to pH 7.5 with concentrated aqueous sodium hydroxide solution, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resulting residue was recrystallized from ethanol to obtain 101.6 mg of the title compound. ¹ H-NMR (400MHz, 0.1N NaOD) δ:

1.34-1.54 (3H, m), 1.89-2.02 (2H, m), 2.04-2.14

(2H, m), 2.44-2.47 (1H, m), 2.92 (1H, d, J=10.5

Hz), 3.35(1H, d, J=10.5Hz), 3.51-3.56(4H, m),

3.74(1H, d, J=10.5Hz), 3.90-3.95(1H, m), 4.70-

4.91(1H, m), 7.57(1H, d, J=13.5Hz), 8.34(1H, s).

Elemental Analysis C ₂₀ H ₂₁ N ₃ O ₄ F ₂ :

Calculated: C, 59.236; H, 5.224; N, 10.369

Measured values: C, 59.28; H, 5.32; N, 10.17 Melting point (°C): 238-240 Inventive Example 8: 5-amino-7-[(3R, 1′S)-3-(1-aminoethyl )-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

626mg (2.92mmol) (3R, 1'S)-3-(1-tert-butoxycarbonylaminoethyl) pyrrolidine was suspended in 10ml of dimethyl sulfoxide, and 437mg (1.46mmol) of 5-amino -1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2.80ml triethylamine, then at 150-160°C Heat under nitrogen atmosphere for 21 hours. After distilling off the solvent, the resulting residue was mixed with chloroform, washed successively with water, 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained tert-butyl carbamate compound was mixed with 4 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 20 minutes, washed with chloroform (50 ml×3), and adjusted to pH 7.4 with aqueous sodium hydroxide solution , and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was recrystallized from ethanol-diethyl ether to obtain 369 mg (65%) of the title compound. Melting point: 106-107°C [α] _D ²⁵ = -15.48 (c = 0.394, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.63(1H, brs), 0.75(1H, brs), 1.02-1.18(5H, m),

1.54-1.58(1H, m), 1.99-2.10(2H, m), 2.29(3H, s),

2.79 (1H, brs), 3.31-3.44 (3H, m), 3.58-3.60 (1H,

m), 3.91(1H, brs), 8.37(1H, s).

Elemental analysis C ₂₀ H ₂₅ N ₄ O ₃ F·1/2H ₂ O:

Calculated: C, 60.44; H, 6.59; N, 14.10

Found: C, 60.35; H, 6.55; N, 14.30 Inventive Example 9: 5-amino-7-[(3R, 1′S)-3-(1-aminoethyl)-1-pyrrolidinyl] -6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

394 mg (1.84 mmol) (3R, 1'S)-3-(1-tert-butoxycarbonylaminoethyl) pyrrolidine was suspended in 10 ml of dimethyl sulfoxide, and 317 mg (1.00 mmol) of 5-amino -6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2.00 ml of triethylamine, and then heated at 150-160°C under a nitrogen atmosphere for 18 hours. After distilling off the solvent, the resulting residue was mixed with chloroform, washed successively with water, 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained tert-butyl carbamate compound was mixed with 3 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 10 minutes, washed with chloroform (50 ml×3), and adjusted to pH 7.4 with aqueous sodium hydroxide solution , and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was purified by preparative TLC (chloroform:methanol:water=7:3:1), and the obtained crude product was recrystallized from ethanol to obtain 118 mg (29%) of the title compound. Melting point: 225-226°C [α] _D ²⁵ = -305.07 (c = 0.276, 0.1 N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1 N NaOD) δ:

1.11-1.19 (4H, m), 1.48-1.59 (2H, m), 2.09-2.13

(2H, m), 2.29 (3H, s), 2.84 (1H, brs), 3.30 (1H, br

s), 3.41(1H, brs), 3.52(1H, brs), 3.78(1H, brs),

3.94(1H, brs), 8.26(1H, 2s).

Elemental analysis C ₂₀ H ₂₂ N ₄ O ₃ F ₂ ·9/4H ₂ O:

Calculated: C, 53.74; H, 6.43; N, 12.54

Found: C, 53.80; H, 6.02; N, 12.48 Reference Example C-1: (3R)-Ethyl 1-benzyloxycarbonylpyrrolidine-3-acetate

12g (45.9mmol) (3R)-ethyl 1-[(R)-1-phenylethyl]pyrrolidine-3-acetate known in the literature was dissolved in 100ml of dichloromethane, then at room temperature to 7.87 ml (55.1 mmol) of benzyl chloroformate was added dropwise thereto. After the dropwise addition was completed, the mixture was stirred at the same temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated. Thereafter, the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=5:1, to obtain 10.1 g (76%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.26(3H, t, J=7.32Hz), 1.53-1.64(1H, m), 2.07-

2.15(1H, m), 2.36-2.42(2H, m), 2.55-2.67(1H, m),

3.01-3.07(1H, m), 3.36-3.42(1H, m), 3.49-3.62

(1H, m), 3.67-3.73 (1H, m), 4.14 (2H, q, J=7.32

Hz), 5.13 (2H, s), 7.29-7.38 (5H, m). Reference example C-2: 1-benzyloxycarbonyl-3-(R)-pyrrolidinylmalonate diethyl ester

Dissolve 146 mg (0.5 mmol) of (3R)-ethyl 1-benzyloxycarbonylpyrrolidine-3-acetate in 3 ml of tetrahydrofuran (THF), and then add 1 ml (1 mmol) (bistris Methylsilyl) sodium amide solution in 1 mol tetrahydrofuran. After stirring at the same temperature for 30 minutes, a solution of 0.12 ml (1 mmol) of ethyl chloroformate in 2 ml of tetrahydrofuran was added dropwise to the reaction solution at -78°C and stirred at the same temperature for 2 hours. After the reaction was completed, 5 ml of 1N hydrochloric acid was added dropwise to the reaction solution, followed by warming to room temperature. The reaction solution was mixed with 40 ml of ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution (50 ml×1) and saturated brine (50 ml×1), and then dried over magnesium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=4:1, to obtain 150 mg (83%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.24-1.29 (6H, m), 1.60-1.75 (1H, m), 2.03-2.19

(1H, m), 2.79-2.91 (1H, m), 3.09-3.17 (1H, m), 3.28

(1H, d, J=9.76Hz), 3.32-3.41 (1H, m), 3.55-3.65

(1H, m), 3.72-3.77 (1H, m), 4.17-4.24 (4H, m), 5.13

(2H, s), 7.28-7.59 (5H, m). Reference example C-3: 1-benzyloxycarbonyl-3-(R)-pyrrolidinyl hydrogen malonate ethyl ester

177 mg (0.49 mmol) of diethyl 1-benzyloxycarbonyl-3-(R)-pyrrolidinylmalonate was dissolved in 10 ml of ethanol. Under ice-cooling, a solution of 32 mg (0.49 mmol) of potassium hydroxide (85%) in 10 ml of ethanol was added dropwise to the solution. After the dropwise addition, the reaction solution was stirred at room temperature for 18 hours. After the reaction was completed, 20 ml of water was added to the reaction solution, and then ethanol was distilled off. The remaining aqueous layer was washed with dichloromethane (50ml×2), and the obtained aqueous layer was acidified with concentrated hydrochloric acid, then extracted with diethyl ether (50ml×3). The organic layers were combined and dried over magnesium sulfate, then the solvent was evaporated to give 160 mg (97%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.23-1.30(3H, m), 1.63-1.71(1H, m), 2.09-2.20

(1H, m), 2.79-2.90 (1H, m), 3.10-3.20 (1H, m), 3.28

-3.43(2H, m), 3.51-3.65(1H, m), 3.71-3.84(1H,

m), 4.19-4.25 (2H, m), 5.13 (2H, s), 7.28-7.55 (5H,

m). Reference example C-4: ethyl 2-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)acrylate

1.94g (5.78mmol) of 1-benzyloxycarbonyl-3-(R)-pyrrolidinyl hydrogen malonate ethyl ester and 2.18g (11.56mmol) of Eschenmoser salt were dissolved in 200ml of acetonitrile, and the solution was mixed with a catalytically effective amount of The potassium acetate was mixed and heated at reflux for 12 hours. After the reaction was complete, acetonitrile was distilled off, and the resulting residue was mixed with 200ml ethyl acetate, washed successively with 10% citric acid (50ml×1), 10% aqueous sodium sulfite (50ml×1) and saturated brine (50ml×1). After the organic layer was dried over sodium sulfate, the solvent was distilled off. Thereafter, the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=5:1, to obtain 1.12 g (64%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.31(3H, t, J=7.33Hz), 1.53-1.62(1H, m), 1.79-

1.89(1H, m), 2.11-2.21(1H, m), 3.18-3.31(2H, m),

3.38-3.48(1H, m), 3.51-3.63(1H, m), 4.22(2H, q,

J=7.33Hz), 5.14(2H, s), 5.58(1H, s), 6.26(1H, d,

J=1.96Hz), 7.29-7.38 (5H, m). Reference example C-5: ethyl 1-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropylcarboxylate

To a mixture of 852 mg (2.8 mmol) 2-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl) acrylate and 5 mg (0.02 mmol) palladium acetate, 100 ml of ether was added, followed by dropwise addition of excess (10 equivalents) of diazomethane in ether. After the dropwise addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography eluting with n-hexane:ethyl acetate=3:1 to obtain 890 mg (quantitative) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.71-0.82 (2H, m), 1.19-1.28 (5H, m), 1.43-1.59

(1H, m), 1.84-1.95 (1H, m), 2.73-2.85 (1H, m), 2.93

(1H, dd, J=10.25Hz, 18.55Hz), 3.28-3.39(1H, m),

3.55-3.75(2H, m), 4.09-4.15(2H, m), 5.13(2H, s),

7.28-7.36 (5H, m). Reference Example C-6: 1-(1-Benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropanecarboxylic acid

Dissolve 5.26g (16.6mm0l) of ethyl 1-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropylcarboxylate in 300ml of ethanol and cool the solution in an ice bath, and 16.6ml of 10N Aqueous sodium hydroxide solution was mixed and then stirred at room temperature for 5 days. After the reaction was completed, ethanol was distilled off, and the remaining aqueous layer was acidified with hydrochloric acid and extracted with diethyl ether (50ml×4). The organic layers were combined and dried over magnesium sulfate, and then the solvent was evaporated to obtain 4.95 g of the title compound quantitatively as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.75-0.85 (2H, m), 1.22-1.33 (2H, m), 1.45-1.61

(1H, m), 1.82-1.98 (1H, m), 2.69-2.78 (1H, m), 2.93

-3.01(1H, m), 3.25-3.36(1H, m), 3.55-3.75(2H,

m), 5.12 (2H, s), 7.28-7.35 (5H, m), 11.09 (1H, br

s). Reference Example C-7: (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine

289 mg (1 mmol) of 1-(1-benzyloxycarbonyl-3-(R)-pyrrolidinyl)cyclopropanecarboxylic acid were dissolved in 10 ml of tert-butanol. To this solution, 0.28 ml (1.3 mmol) of diphenylphosphoric azide and 0.24 ml (1.6 mmol) of triethylamine were successively added dropwise at room temperature, followed by stirring at the same temperature for 2 hours. After the formation of the acid azide was confirmed, the reaction temperature was increased to reflux for 18 hours. After completion of the reaction, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography eluting with n-hexane:ethyl acetate=4:1 to obtain 263 mg (73%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.65-0.85(4H, m), 1.41(9H, s), 1.59-1.75(1H, m),

1.95-2.00(1H, m), 2.20-2.35(1H, m), 3.07-3.15

(1H, m), 3.27-3.35 (1H, m), 3.51-3.65 (2H, m), 4.87

(1H, d, J=10.3Hz), 5.13(2H, s), 7.29-7.37(5H,

m).

[α] _D ²⁵ =6.83, (c=0.731, CHCl ₃ )

The product was found to be a 4:1 mixture of enantiomers (60% ee) as determined by HPLC analysis on a chiral column.

The conditions for this analysis are described below.

Column: DAICEL CHIRALCEL OD, 25cm×0.46cm

Mobile phase: n-hexane:isopropanol=95:5

Flow rate: 1.5ml/min

Temperature: room temperature

Detection: UV (254nm)

The retention times of optical isomers are as follows.

(3R) isomer: 13.06 minutes

(3S) isomer: 15.65 minutes

4 g of the 4:1 mixture were recrystallized from acetonitrile to give 2.65 g of the (3R) isomer. [α] _D ²⁵ =10.00, (c=0.660, CHCl ₃ ) Reference Example D-1: Ethyl 1-acetylcyclopropanecarboxylate

204ml (1.6mol) of ethyl acetoacetate and 138ml (1.6mol) of 1,2-dibromoethane were dissolved in 3 liters of N,N-dimethylformamide, and at room temperature the solution was mixed with 460g (3.3mol) Potassium carbonate was mixed and stirred at the same temperature for 2 days. After the reaction was completed, the insoluble matter was filtered off, and then N,N-dimethylformamide was distilled off under a reduced pressure of 50 mmHg. The obtained residue was mixed with 1.5 L of ether, washed with water (500 ml×3), and then dried over anhydrous sodium sulfate. Diethyl ether was distilled off to give 113.43 g (45%) of the title compound as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.29(3H, t, J=6.84Hz), 1.47(4H, s), 2.47(3H, s),

4.21 (2H, q, J=6.84Hz). Reference Example D-2: 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropane propionate ethyl ester

61.7 g (0.39 mol) of ethyl 1-acetylcyclopropanecarboxylate were dissolved in 500 ml of benzene, and then 13 g of zinc powder and a catalytically effective amount of iodine were added thereto. While heating under reflux, add 56.2ml (0.51mol) of ethyl bromoacetate in 100ml of benzene solution dropwise to the above mixture, when the reaction starts to be violent, suspend the dropwise addition, add 39g of zinc powder in small portions, and then dropwise add the remaining Ethyl bromoacetate solution in benzene. After the addition was complete, the reaction solution was heated at reflux for an additional 2 hours. The reaction solution was allowed to cool naturally, mixed with 500 ml of 1N hydrochloric acid, and filtered through celite. The organic layer was separated, washed with saturated brine (500ml×2), and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 90.31 g (95%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.08-1.18 (4H, m), 1.23 (3H, t, J=6.84Hz), 1.27

(3H, t, J=7.33Hz), 1.43(3H, s), 2.91(1H, d, J=

15.14Hz), 2.98(1H, d, J=15.14Hz), 4.09(2H, q, J

=6.84Hz), 4.19 (2H, dq, J=1.95Hz, J=6.84Hz). Reference Example D-3: (E)-ethyl 3-(1-ethoxycarbonylcyclopropyl)-2- crotonate

90.31 g (0.37 mol) of ethyl 1-ethoxycarbonyl-β-hydroxy-β-methyl-cyclopropanepropionate were dissolved in 182 ml of pyridine, and thionyl chloride was then added dropwise thereto at -10°C to -5°C. After the dropwise addition was completed, it was stirred at the same temperature for 3 hours. After the reaction was completed, the reaction solution was poured into 1 liter of ice water and extracted with dichloromethane (300ml×3). The organic layers were combined, washed successively with 1N hydrochloric acid (1 L×1) and saturated brine (1 L×1), and dried over anhydrous sodium sulfate. To the obtained dichloromethane solution was added dropwise 58 ml of 1,8-diazabicyclo[5,4,0]-7-undecene at 0°C, followed by stirring at room temperature for 18 hours. After the reaction was completed, the reaction solution was washed successively with 1N hydrochloric acid (1 L×1) and saturated brine (1 L×1), and then dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=9:1, to obtain 56.57 g (68%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.01(2H, dd, J=3.91Hz, J=6.84Hz), 1.24(3H, t,

J=7.32Hz), 1.28(3H, t, J=7.32Hz), 1.40(2H, dd,

J=3.91Hz, J=6.84Hz), 2.29(3H, d, J=1.46Hz),

4.13 (2H, q, J = 7.32Hz), 4.16 (2H, q, J = 7.32Hz),

5.78 (1H, d, J=0.98Hz). Reference Example D-4: 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-3-pyrroline -2-one

25.37g (0.11mol) (E)-ethyl 3-(1-ethoxycarbonylcyclopropyl)-2-butenoate was dissolved in 300ml of carbon tetrachloride, and 23.9g (0.13mol) was added thereto N-bromosuccinimide and a catalytically effective amount of azobisisobutyronitrile were then refluxed for 5 hours under sunlight. After the reaction was completed, the reaction solution was filtered and the resulting filtrate was concentrated. The residue thus obtained was dissolved in 250 ml of ethanol and mixed with 18.83 g (0.22 mol) of sodium bicarbonate. At room temperature, 15.84 ml (0.12 mol) of (S)-phenethylamine was added dropwise thereto. After the dropwise addition, it was stirred at room temperature for 30 minutes, and then heated under reflux for 4 hours. After the reaction was complete, the solvent was distilled off and the resulting residue was mixed with 500ml ethyl acetate, washed with water (500ml×1), 1N hydrochloric acid (500ml×2) and saturated brine (500ml×2) successively, and then washed with anhydrous sodium sulfate dry. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=1:1, to obtain 13.1 g (39%) of the title compound as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.13-1.15 (2H, m), 1.18 (3H, t, J=6.83Hz), 1.60

(3H, d, J=7.32Hz), 1.61-1.64 (2H, m), 3.80 (1H, d,

J = 19.53Hz), 4.09 (2H, q, J = 6.83Hz), 4.13 (1H, d,

J=19.53Hz), 5.56(1H, q, J=7.32Hz), 5.85(1H, t,

J=1.47Hz), 7.25-7.37 (5H, m). Reference example D-5: 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenylethyl]-2 -pyrrolidone

Dissolve 13.1g (43.8mmol) of 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenethyl]-3-pyrroline-2-one in 300ml of methanol, and oxidize with 400mg Platinum was mixed, then stirred under hydrogen atmosphere for 18 hours. After completion of the reaction, the reaction solution was filtered and concentrated to obtain 13.0 g (99%) of the title compound as an oil.

The product was found to be a mixture of (4S):(4R)=3.5:1 by NMR analysis. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.63-0.65and0.71-0.73(2H, m), 1.11-1.28(5H,

m), 1.51-1.60 (3H, m), 2.14-2.31 (1H, m), 2.43-

2.52[(S)-2Hand(R)-1H, m], 2.64-2.76[(S)-2H, m],

3.14 [(R)-2H, d, J=7.81Hz], 3.48[(S)-1H, t, J=

8.79Hz], 3.97-4.15(2H, m), 5.49and5.52(1H, each

q, J=5.86Hz and 6.84Hz), 7.14-7.36 (5H, m). Reference example D-6: (4S)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S) -1-Phenylethyl]-2-pyrrolidinhione

13.04g (43.3mmol) 4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenethyl]-2-pyrrolidone was dissolved in 500ml benzene, and 19.26g (47.6mmol) Lawesson The reagents were mixed, then heated at reflux for 1 hour. After the reaction was completed, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography, eluting with n-hexane: ethyl acetate = 3:1, to obtain a mixture of diastereomers. Fractional recrystallization was performed using n-hexane:isopropyl ether = 1:1 to obtain 6.81 g (62% (4S) content) of the title compound as needle crystals. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.63(2H, d, J=2.44Hz), 1.11-1.23(2H, m), 1.14

(3H, t, J=7.32Hz), 1.59 (3H, d, J=6.83Hz), 2.68

(1H, dd, J=8.79Hz, J=17.48Hz), 2.79(1H, dq, J=

8.30Hz), 3.02(1H, dd, J=7.32Hz, J=11.23Hz),

3.09(1H, dd, J=8.79Hz, J=17.48Hz), 3.76(1H,dd,

J=8.30Hz, J=11.23Hz), 4.01(2H, q, J=7.32Hz),

6.39 (1H, q, J=6.83Hz), 7.30-7.36 (5H, m). Reference example D-7: (3R)-1-benzyloxycarbonyl-(1-ethoxycarbonylcyclopropyl)pyrrolidine

Dissolve 6.81g (21mmol) (4S)-4-(1-ethoxycarbonylcyclopropyl)-1-[(S)-1-phenethyl]-2-pyrrolidinhione in 40ml ethanol, and 21ml Raney nickel mixed, then heated at reflux for 6 hours. After the reaction was completed, the reaction solution was filtered, and then ethanol was distilled off. The obtained residue was dissolved in 400ml of chloroform, washed successively with 10% ammonia water (500ml×2), 0.5N hydrochloric acid (500ml×2) and saturated brine (500ml×2), and then dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was dissolved in 200 ml of dichloromethane, and then 4.57 ml (32 mmol) of benzyl chloroformate was added dropwise thereto. After the dropwise addition, the reaction solution was heated under reflux for 20 hours. After the reaction was completed, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=4:1, to obtain 3.62 g (54%) of the title compound as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

0.71-0.82 (2H, m), 1.19-1.28 (2H, m), 1.43-1.59

(1H, m), 1.84-1.95 (1H, m), 2.73-2.85 (1H, m), 2.93

(1H, dd, J=10.25Hz, J=18.55Hz), 3.28-3.39 (1H,

m), 3.55-3.75 (2H, m), 4.09-4.15 (2H, m), 5.13 (2H,

s), 7.28-7.36 (5H, m). Reference Example E-1: (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-methyl)aminocyclopropane base]pyrrolidine

1.27g (3.52mmol) (3R)-1-benzyloxycarbonyl-(1-ethoxycarbonylcyclopropyl)pyrrolidine was dissolved in a mixed solvent consisting of 22ml iodomethane and 2ml N,N-dimethylformamide , mixed with 8.2g (35.2mmol) of silver oxide, and then heated at 80°C for 7 hours in a closed test tube. After the reaction was completed, the reaction solution was filtered and the obtained filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=3:1, to obtain 1.22 g (93%) of the title compound as an oil . ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

0.55-1.00(4H, m), 1.42, 1.44 and 1.47(9H, eachs),

1.50-1.69 (1H, m), 1.80-1.95 (1H, m), 2.25-2.55

(1H, m), 2.81 and 2.84 (3H, eachs), 2.98-3.12 (1H,

m), 3.24-3.34 (1H, m), 3.51-3.65 (2H, m), 5.12 (2H,

s), 7.30-7.36 (5H, m). Reference Example E-2: (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-ethyl)aminocyclopropane base]pyrrolidine

1.04g (2.89mmol) (3R)-1-benzyloxycarbonyl-3-(1-ethoxycarbonylcyclopropyl)pyrrolidine was dissolved in 11.6ml iodoethane and 1ml N,N-dimethylformamide 6.7 g (28.9 mmol) of silver oxide was mixed with the mixed solvent of the composition, and then heated at 80° C. for 4 hours in a closed test tube. After the reaction was completed, the reaction solution was mixed with diethyl ether and filtered through celite, the resulting filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=4:1 to obtain 831 mg (74 %) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.5-0.98(4H, m), 1.05-1.18(3H, brs), 1.43and

1.46 (9H, eachs), 1.47-1.61 (1H, m), 1.78-1.93

(1H, m), 2.34-2.53 (1H, m), 2.83-3.43 (4H, m), 3.48

-3.62(2H, m), 5.12(2H, s), 7.32-7.36(5H, m). Reference Example E-3: (3R)-3-[1-(benzyloxyacetyl)aminocyclopropane Base]-1-benzyloxycarbonylpyrrolidine

Under cooling in an ice bath, 10 ml of trifluoroacetic acid was added dropwise to 1.8 g (5.0 mmol) of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine, and then the mixture was placed in Stir at room temperature for 1 hour. After trifluoroacetic acid was distilled off, the resulting residue was mixed with 80 ml of tetrahydrofuran and 3.48 ml (25 mmol) of triethylamine, and 0.86 ml (5.5 mmol) of benzyloxyacetyl chloride dissolved in 20 ml of tetrahydrofuran was added dropwise thereto under ice-cooling. After stirring at the same temperature for 1 hour, the reaction solution was washed successively with water (100ml×1), 10% citric acid (100ml×1), saturated aqueous sodium bicarbonate (100ml×1) and saturated brine (100ml×1). The layer was dried over magnesium sulfate, and the solvent was distilled off. The obtained product was immediately used in the next reaction. Reference Example E-4: (3R)-1-benzyloxycarbonyl-3-[1-(N-2-benzyloxyethyl-N-tert-butoxycarbonyl)aminocyclopropyl]pyrrolidine

Dissolve 5mmol (3R)-3-[1-(benzyloxyacetyl)aminocyclopropyl]-1-benzyloxycarbonylpyrrolidine in 10ml tetrahydrofuran, and add 30ml (30mmol) borane dropwise under ice-cooling - 1 mol tetrahydrofuran solution of the tetrahydrofuran complex. After the dropwise addition, a saturated aqueous sodium bicarbonate solution was added dropwise to the reaction solution to hydrolyze the excess borane-tetrahydrofuran complex. When foaming stopped, 100 ml of saturated aqueous sodium bicarbonate solution and 50 ml of water were added thereto, and the mixture was stirred for 4 days. The tetrahydrofuran layer of the reaction solution was separated, and the aqueous layer was extracted with ether (100ml×3). The organic layers were combined, dried over magnesium sulfate and the solvent was distilled off. The resulting residue was dissolved in 50 ml of acetonitrile, mixed with 1.6 g (7.5 mmol) of di-tert-butyl carbonate, and then stirred at room temperature for 18 hours. After the reaction was completed, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography, eluting with n-hexane:ethyl acetate=5:1, to obtain 1.31 g (53%) of the title compound as an oil. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.48-1.11(4H, m), 1.21-1.35(1H, m), 1.39 and 1.47

(9H, each s), 1.79-1.89 (1H, m), 2.24-2.69 (1H, m),

2.83-3.69 (8H, m), 4.47 (2H, s), 5.12 (2H, s), 7.29-

7.36 (5H, m). Reference Example E-5: (3R)-1-[1-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino)cyclopropyl]pyrrolidine

Dissolve 772mg (1.56mmol) of (3R)-1-benzyloxycarbonyl-3-[1-(N-2-benzyloxyethyl-N-tert-butoxycarbonyl)aminocyclopropyl]pyrrolidine in 20ml of methanol , mixed with 200 mg of 5% palladium on carbon, and then hydrogenated at 10 kg/cm ² for 36 hours under the warmth of an infrared lamp. After the reaction was complete, 5% palladium on carbon was filtered off, and then methanol was distilled off to obtain 413 mg (98%) of the title compound. This product was used immediately in the substitution reaction. Reference Example F-1: Ethyl 1-tert-butoxycarbonylaminocyclobutanecarboxylate

Dissolve 1.72g (10.0mmol) of ethyl 1,1-cyclobutanedicarboxylate in 20ml of tert-butanol, with 3.30g (1.2mmol) of diphenylphosphoric acid azide and 1.67ml (1.2mmol) of triethyl The amines were mixed and then heated at reflux overnight. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (SiO ₂ 120 ml, hexane:ethyl acetate=20:1→4:1) to obtain 2.11 g (87%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.28(3H, t), 1.43(9H, s), 2.00-2.04(2H, m), 2.31

(2H, brs), 4.22 (2H, dd). Reference Example F-2: 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid

64.28 g (264 mmol) of ethyl 1-tert-butoxycarbonylaminocyclobutanecarboxylate were dissolved in 400 ml of methanol, mixed with 400 ml of 1N aqueous sodium hydroxide solution, and stirred overnight at room temperature. After distilling off the solvent, the resulting residue was mixed with 20% aqueous citric acid-chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 55.2 g (97%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.45(9H, s), 2.02-2.08(2H, m), 2.26(2H, brs), 2.67

(2H, brs), 5.20 (1H, brs). Reference example F-3: ethyl 1-tert-butoxycarbonylamino-β-oxocyclobutane propionate

To 100.0 ml of ethanol were sequentially added 5.0 g (0.21 mmol) of magnesium and 15.0 ml of carbon tetrachloride, followed by stirring at room temperature for 1 hour. Ethyl hydrogen malonate was added dropwise thereto, and after stirring at room temperature for 1 hour, the solvent was distilled off to obtain magnesium malonate as a colorless foam. In addition, 55.29g (0.26mmol) of 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid was dissolved in 450.0ml of THF, and 45.81g (0.28mmol) of 1,1'-carbonyldiimidazole was stirred at room temperature for 1.5 hours . Thereto, 450.0 ml of a THF solution of the above-mentioned magnesium salt was added dropwise over 30 minutes, followed by stirring at room temperature for 2 days. The solvent was distilled off, the resulting residue was partitioned between 10% aqueous citric acid and ethyl acetate, and the resulting organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound quantitatively. ¹ H-NMR (CDCl ₃ ) δ:

1.26-1.30(2H, m), 1.43(9H, s), 1.87-2.08(4H, m),

2.66-2.70 (2H, m), 3.54 (2H, s), 4.20 (2H, q), 5.22

(1H, brs). Reference Example F-4: ethyl 1-tert-butoxycarbonylamino-β-hydroxycyclobutane propionate

70.21 g (257 mmol) of ethyl 1-tert-butoxycarbonylamino-β-oxocyclobutanepropionate was dissolved in 500.0 ml of ethanol, and 4.86 g (514 mmol) of sodium borohydride was added thereto in batches under ice cooling. After stirring at the same temperature for 2 hours, water was added and the solvent was distilled off. The resulting residue was extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 65.25 g (93%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.28(3H,t), 1.44(9H,s), 1.84-2.57(8H,m), 4.17

(2H, q). Reference Example F-5: 1-tert-butoxycarbonylaminocyclobutane ethyl acrylate

65.25 g (238 mmol) of ethyl 1-tert-butoxycarbonylamino-β-hydroxycyclobutanepropionate were dissolved in 1,000 ml of dichloromethane and mixed with 66.30 g (476 mmol) of triethylamine. Under ice-water-brine cooling, 23.93 ml (7.04 mmol) of methanesulfonyl chloride was added dropwise thereto, followed by stirring at the same temperature for 1 hour. To this solution, 78.25 ml (523.6 mmol) of 1,8-diazabicyclo[5,4,0]undec-7-ene was added dropwise, then the temperature was gradually raised, and then stirred at room temperature for 5 hours. It was washed with 10% citric acid aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 40.95 g (64%) of the title compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ:

1.28(3H, t), 1.43(9H, s), 1.91-2.05(2H, m), 2.27

(4H, brs), 4.20 (2H, q), 5.88 (1H, d, J=15.6Hz),

7.16 (1H, d, J=15.6Hz). Reference Example F-6: 3-(1-tert-butoxycarbonylaminocyclobutyl) ethyl 4-nitrobutyrate

Dissolve 40.95g (152mmol) of ethyl 1-tert-butoxycarbonylaminocyclobutane acrylate in 210.0ml of nitromethane, with 57.2ml (456mol) of diphenylphosphoric azide and 1.67ml (1.2mmol) of tetramethyl - Guanidine was mixed and then stirred at room temperature for 2 days. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (silica gel 1,500 ml, hexane:ethyl acetate=20:1→3:1) to obtain 26.60 g (41%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.26(3H, t), 1.43(9H, s), 1.75-2.22(6H, m), 2.42

(1H, dd, J=15.6, 7.8Hz), 2.56 (1H, dd, J=15.6, 4.8

Hz), 4.12(2H, q), 4.21(1H, dd, J=14.1, 7.3Hz),

4.45 (1H, dd, J=13.1, 8.3Hz), 4.70 (1H, brs). Reference Example F-7: 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone

Dissolve 20.6g (62.5mmol) of ethyl 3-(1-tert-butoxycarbonylaminocyclobutyl)-4-nitrobutyrate in 500.0ml of ethanol, and with 40.0ml of Raney nickel (R-100, water and ethanol after washing) and then stirred overnight at room temperature under hydrogen. After filtering off the catalyst, the solvent was distilled off. The resulting residue was dissolved in 200.0 ml of toluene and heated at reflux overnight. After natural cooling, the solvent was distilled off to obtain 15.13 g (95%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.43(9H, s), 1.7-2.6(8H, m), 3.1-3.5(3H, m),

4.84 (1H, brs), 6.20 (1H, brs). Reference example F-8: 1-benzyl-4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone

Under ice cooling, 15.13g (59.5mmol) 4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone was dissolved in 30.0ml N, N-dimethylformamide, and 2.62g (65.44mmol ) sodium hydride (60% suspension in oil), then stirred at room temperature for 30 minutes. This was mixed with 7.78 ml (65.44 mmol) benzyl bromide and stirred overnight at room temperature. Since some raw materials still remained, 1.19 g (29.74 mmol) of sodium hydride and 3.54 ml (29.74 mmol) of benzyl bromide were further added and stirred at room temperature for another 5 hours. After distilling off the solvent, the resulting residue was mixed with water, extracted with ethyl acetate and washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. Thereafter, the resulting residue was purified by silica gel column chromatography (silica gel 800 ml, ethyl acetate:hexane=10:1→1:1→2:1) to obtain 5.65 g (28%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.41(9H, s), 1.69-1.71(1H, m), 1.95-2.19(5H, m),

2.36(1H,dd,J=17.0,7.8Hz), 2.52(1H,dd,J=

17.0, 9.2Hz), 2.95-3.29 (3H, m), 4.43 (2H, AB-q, J

=14.6Hz), 4.77 (1H, brs), 7.22-7.34 (5H, m). Reference example F-9: 4-(1-aminocyclobutyl)-1-benzyl-2-pyrrolidone trifluoroethyl salt

Under cooling in an ice bath, 50.0 ml of trifluoroacetic acid was added dropwise to 5.65 g (16.40 mmol) of 1-benzyl-4-(1-tert-butoxycarbonylaminocyclobutyl)-2-pyrrolidone, followed by stirring at room temperature for 1 Hour. The excess reagent was distilled off, and the resulting residue was mixed with toluene and heated azeotropically to obtain the title compound quantitatively as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ:

1.73-2.35 (6H, m), 2.55 (1H, dd, J=17.5, 7.3Hz),

2.72(1H, dd, J=17.5, 9.7Hz), 2.83-2.92(1H, m),

3.33(1H, dd, J=10.7, 6.3Hz), 3.44-3.49(1H, m),

4.43 (2H, AB-q, J=14.6Hz), 7.14-7.35 (5H, m). Reference example F-10: 1-benzyl-4-[1-[N′-p-toluenesulfonyl-2 -(R)-pyrrolidinecarbonyl]aminocyclobutyl]-2-pyrrolidone (fraction 1) (fraction 2)

5.87 g (16.40 mmol) of 4-(1-aminocyclobutyl)-1-benzyl-2-pyrrolidone trifluoroacetate were dissolved in 30.0 ml of dichloromethane (no stabilizer) and mixed with 13.26 ml of pyridine. Under ice cooling, a solution of 7.07 g (24.6 mol) of D-(R)-N-p-toluenesulfonyl pyrophosphoryl chloride in 30.0 ml of dichloromethane was added dropwise thereto. After stirring overnight at room temperature, the solvent and excess pyridine were distilled off, and the resulting residue was mixed with 1N hydrochloric acid and extracted with chloroform. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (1 kg of silica gel, ethyl acetate → ethyl acetate: isopropyl ether = 50: 1) to obtain 3.16 g (39%) (fraction 1) and 3.33 g ( 41%) (fraction 2). Low polarity product (fraction 1) ¹ H-NMR (CDCl ₃ ) δ:

1.55-2.37(12H, m), 2.45(3H, s), 2.57(1H, dd, J=

17.0, 9.2Hz), 2.90-2.98 (1H, m), 3.10-3.17 (1H,

m), 3.25(1H, t, J=9.7Hz), 3.36(1H, dd, J=9.7,

5.8Hz), 3.51-3.56(1H, m), 3.85(1H, dd, J=8.3,

2.9Hz), 4.41(2H, AB-q, J=14.6Hz), 7.22-7.36(7H,

m), 7.72 (2H, d, J=8.3Hz). Highly polar product (fraction 2) ¹ H-NMR (CDCl ₃ ) δ:

1.50-2.44(12H, m), 2.45(3H, s), 2.52(1H, dd, J=

17.0, 9.2Hz), 3.03-3.18 (3H, m), 3.36 (1H, dd, J=

9.7, 8.3Hz), 3.51-3.56 (1H, m), 3.88 (1H, dd, J =

8.7, 2.9Hz), 4.48 (2H, AB-q, J=14.6Hz), 7.22-7.36

(7H, m), 7.71 (2H, d, J=8.3Hz). Reference example F-11: 1-benzyl-4-(1-hydrogencyclobutyl)-2-pyrrolidone (fraction 1)

2.40g (4.84mmol) 1-benzyl-4-[1-[N'-p-toluenesulfonyl-2-(R)-pyrrolidinecarbonyl]aminocyclobutyl]-2-pyrrolidone (fraction 1) and 15ml of water and 15ml of concentrated hydrochloric acid were mixed, then heated under reflux for 2 days. After cooling, the reaction solution was mixed with 100 ml of water, washed with chloroform, and then basified with aqueous sodium hydroxide. It was extracted with chloroform (150ml×4), washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 1.01 g (85%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.44(2H, brs), 1.58-1.99(6H, m), 2.30-2.38(1H,

m), 2.49-2.56 (2H, m), 3.03-3.07 (1H, m), 3.28-

3.32(1H, m), 4.45(2H, AB-q, J=14.6Hz), 7.22-7.35

(5H, m). Reference Example F-12: 1-Benzyl-4-(1-aminocyclobutyl)-2-pyrrolidone (fraction 2)

2.84 g (5.73 mmol) of 1-benzyl-4-[1-[N'-p-toluenesulfonyl-2-(R)-pyrrolidinecarbonyl]aminocyclobutyl]-2-pyrrolidone (fraction 2) was mixed with 20ml of water and 20ml of concentrated hydrochloric acid were mixed, then heated under reflux for 2 days. After cooling, the reaction solution was mixed with 100 ml of water, washed with chloroform, and then basified with aqueous sodium hydroxide. It was extracted with chloroform (150ml×4), washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound quantitatively. ¹ H-NMR (CDCl ₃ ) δ:

1.25(2H, brs), 1.59-1.99(6H, m), 2.30-2.37(1H,

m), 2.48-2.58 (2H, m), 3.03-3.07 (1H, m), 3.26-

3.32(1H, m), 4.45(2H, AB-q, J=14.6Hz), 7.22-7.35

(5H, m, Ar-H). Reference Example F-13: 1-benzyl-3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine (fraction 1)

1.01g (4.13mmol) of 1-benzyl-4-(1-aminocyclobutyl)-2-pyrrolidone (fraction 1) was dissolved in 150.0ml of tetrahydrofuran, and then, under ice cooling, 627mg (16.52 mmol) lithium aluminum hydride. After heating under reflux with stirring for 12 hours, the reaction solution was cooled in an ice bath and mixed successively with 627 μl of water, 627 μl of 15% aqueous sodium hydroxide solution and 627 μl of water. After stirring at room temperature for 30 minutes, the insoluble matter was filtered off and the solvent was distilled off. To the resulting slurry was added 50.0 ml of acetonitrile and then 1.14 ml (4.96 mmol) of di-tert-butyl carbonate at room temperature, followed by stirring overnight. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (100 ml of 230-400 mesh silica gel, 5% methanol-chloroform) to obtain 212 mg (16%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.45-1.98(15H, m), 2.06-2.20(2H, m), 2.47-2.52

(1H, m), 2.75-3.01 (4H, m), 3.57 (2H, s), 5.15 (1H,

brs), 7.22-7.37 (5H, m). Reference Example F-14: 1-benzyl-3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine (fraction 2)

Dissolve 1.50 g (6.14 mmol) of 1-benzyl-4-(1-aminocyclobutyl)-2-pyrrolidone (fraction 2) in 200.0 ml of tetrahydrofuran, and then add 932 mg of (24.56 mmol) lithium aluminum hydride. After heating under reflux with stirring for 12 hours, the reaction solution was cooled in an ice bath and mixed successively with 932 µl of water, 932 µl of 15% aqueous sodium hydroxide solution and 932 µl of water. After stirring at room temperature for 30 minutes, the insoluble matter was filtered off and the solvent was distilled off. To the resulting slurry was added 70.0 ml of acetonitrile and then 1.69 ml (7.37 mmol) of di-tert-butyl carbonate at room temperature, followed by stirring overnight. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (150 ml of 230-400 mesh silica gel, 5% methanol-chloroform) to obtain 525 mg (26%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.45-1.96(15H, m), 2.06-2.20(2H, m), 2.47-2.52

(1H, m), 2.75-3.01 (4H, m), 3.57 (2H, s), 4.21 (1H,

brs), 7.25-7.37 (5H, m). Reference Example F-15: 3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine (fraction 1)

Dissolve 212mg (0.65mmol) of 1-benzyl-3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine (fraction 1) in 20.0ml of ethanol, mix with 200mg of 10% palladium on carbon and heat Stir under 4 atmospheres of hydrogen for 3 hours under heat. After filtering off the catalyst, the solvent was evaporated to give 136 mg (88%) of the title compound. Reference Example F-16: 3-(1-tert-butoxycarboxyaminocyclobutyl)pyrrolidine (fraction 2)

525 mg (1.59 mmol) of 1-benzyl-3-(1-tert-butoxycarbonylaminocyclobutyl) pyrrolidine (fraction 2) was dissolved in 50.0 ml of ethanol, mixed with 500 mg of 10% palladium on carbon and heated under infrared lamp temperature Stir under 4 atmospheres of hydrogen for 3 hours under heat. After filtering off the catalyst, the solvent was distilled off to obtain the title compound quantitatively. Reference Example G-1: 1-Benzhydryl-3-(p-toluenesulfonyloxy)azetidine

To 2.39 g (10 mmol) of 1-benzhydryl-3-hydroxyazetidine dissolved in 20 ml of pyridine was added 1.46 g (12 mmol) of dimethylaminopyridine. At -40°C, 12.10 g (11 mmol) of p-toluenesulfonyl chloride was added thereto, followed by gradually raising the temperature and stirring at room temperature for 1 day. It was mixed with 150ml of water, extracted with chloroform (100ml×3), and then dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (250 ml of ethyl acetate:hexane=1:2) to obtain 2.88 g (73%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

2.42(3H, s), 3.02-3.06(2H, m), 3.43-3.47(2H, m),

4.32(1H, s), 4.86-4.89(1H, m), 7.15-7.76(14H,

m). Reference example G-2: (1-benzhydryl-3-azetidinyl) diethyl malonate

To 17.90 g (111.80 mmol) of diethyl malonate dissolved in 250 ml of tetrahydrofuran was added 4.07 g (101.75 mmol) of 60% sodium hydride at room temperature, followed by stirring for 2 hours. Thereafter, 20 g (50.82 mmol) of 1-benzhydryl-3-(p-toluenesulfonyloxy)azetidine dissolved in 90 ml of tetrahydrofuran was added thereto, followed by heating under reflux for 1 week. The reaction solution was mixed with 10% citric acid aqueous solution, and tetrahydrofuran was distilled off. The resulting residue was mixed with saturated aqueous sodium bicarbonate, extracted with chloroform (200ml×3) and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (230-400 mesh silica gel 450 ml, ethyl acetate:hexane=1:3) to obtain the title compound quantitatively. ¹ H-NMR (CDCl ₃ ) δ:

1.21(6H, t, J=7.3Hz), 2.89-2.92(2H, m), 2.97-

3.05(1H, m), 3.35-3.39(2H, m), 3.64(1H, d, J=

10.2Hz), 4.14(4H, dd), 4.32(1H, s), 7.14-7.38

(10H, m). Reference Example G-3: (1-benzyloxycarbonyl-3-azetidinyl)diethyl malonate

Add 1.91ml (13.36mmol) benzyl chloroformate to 3.40g (8.91mmol) of (1-benzhydryl-3-azetidinyl) diethyl malonate dissolved in 30ml of dichloromethane ester, followed by stirring overnight at room temperature. After distilling off the solvent, the residue was purified by silica gel column chromatography (250 ml, 3-5% methanol-dichloromethane) to obtain 2.64 g (84%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.25(6H, t), 3.16-3.19(1H, m), 3.62(1H, d, J=

11.7Hz), 3.79-3.83(2H, m), 4.16-4.22(4H, m),

5.08 (2H, s), 7.31-7.35 (5H, m). Reference example G-4: (1-benzyloxycarbonyl-3-azetidinyl) ethyl hydrogen malonate

To 13.43 g (38.33 mmol) of (1-benzyloxycarbonyl-3-azetidinyl) diethyl malonate dissolved in 130 ml of ethanol was added 38.44 ml of 1N potassium hydroxide ethanol solution, followed by stirring at room temperature overnight. After distilling off the solvent, the resulting residue was mixed with 10% aqueous citric acid, extracted with chloroform (200ml×3), and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound quantitatively. ¹ H-NMR (CDCl ₃ ) δ:

1.27(3H, t), 3.17-3.22(1H, m), 3.66(1H, d, J=

10.7Hz), 3.83 (2H, dd, J=5.8, 8.7Hz), 4.17-4.24

(4H, m), 5.09 (2H, s), 7.33-7.34 (5H, m). Reference example G-5: 2-(1-benzyloxycarbonyl-3-azetidinyl) ethyl acrylate

To 732 mg (2.28 mmol) of ethyl (1-benzyloxycarbonyl-3-azetidinyl) hydrogen malonate dissolved in 70 ml of acetonitrile was added 1.05 g (5.67 mmol) of Eshenmoser's salt and a catalytically effective amount of acetic acid Potassium, followed by heating at reflux for 4.5 hours. After distilling off the solvent, the resulting residue was mixed with 100 ml of ethyl acetate, washed successively with 10% aqueous citric acid solution, 10% aqueous sodium sulfite solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 569 mg (86%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

1.29(3H, t), 3.60-3.64(1H, m), 3.91-3.95(2H, m),

4.18-4.25 (4H, m), 5.09 (2H, s), 5.66 (1H, d, J=1.9

Hz), 6.36 (1H, d, J=1.4Hz), 7.29-7.36 (5H, m). Reference Example G-6: 1-(1-benzyloxycarbonyl-3-azetidinyl) ring Ethyl propanecarboxylate

To 1.27 g (5.76 mmol) of trimethylsulfoxonium iodide dissolved in 10 ml of dimethylsulfoxide was added 192 mg (4.80 mmol) of 60% sodium hydride, followed by stirring at room temperature for 15 minutes, and then 1.39 g ( 4.80 mmol) ethyl 2-(1-benzyloxycarbonyl-3-azetidinyl)acrylate dissolved in 10 ml dimethylsulfoxide. The resulting mixture was stirred at room temperature for 4 hours and then at 100°C for 1 hour. The reaction solution was mixed with 200ml of saturated brine and extracted with ethyl acetate (100ml×3), and the organic layer was washed with saturated brine (100ml×2) and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (100 ml, ethyl acetate:hexane=1:2) to obtain 536 mg (37%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

0.84(2H, s), 1.20-1.25(5H, m), 3.26-3.28(1H, m),

3.54(2H, brs), 4.0 5-4.13(4H, m), 5.08(2H, s), 7.32

-7.35(5H, m). Reference Example G-7: 1-(1-benzyloxycarbonyl-3-azetidinyl)cyclopropanecarboxylic acid

To 2.68 g (8.83 mmol) of ethyl 1-(1-benzyloxycarbonyl-3-azetidinyl) cyclopropanecarboxylate dissolved in 27 ml of ethanol was added 27 ml of 1N aqueous sodium hydroxide solution, followed by Stir overnight. After distilling off the solvent, the resulting residue was mixed with 10% citric acid, extracted with chloroform (50ml×3), and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.35 g (97%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

0.93(2H, s), 1.31(2H, d, J=2.4Hz), 3.24-3.28

(1H, m), 3.54 (2H, brs), 4.06 (2H, brs), 5.08 (2H, s),

7.30-7.37 (5H, m). Reference Example G-8: 1-Benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine

2.35g (8.54mmol) of 1-(1-benzyloxycarbonyl-3-azetidinyl)cyclopropanecarboxylic acid was dissolved in 40ml of tert-butanol and mixed with 3.52g (12.7mmol) of diphenylphosphoric azide It was mixed with 2.38 ml (17.07 mmol) of triethylamine, and the mixture was heated at reflux overnight. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography (600 ml of silica gel, hexane:ethyl acetate=2:3) to obtain 1.84 g (62%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ:

0.75(2H, s), 0.83(2H, s), 1.41(9H, s), 2.82-2.89

(1H, m), 3.71 (2H, brs), 4.22 (2H, t, J=8.7Hz), 5.06

(1H, brs), 5.08 (2H, s), 7.2 8-7.34 (5H, m). Reference example G-9: 3-(1-tert-butoxycarbonylaminocyclopropyl) azetidine

Add 1.5 g of 10% palladium/carbon to 1.84 g (5.31 mmol) of 1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl) azetidine dissolved in 100 ml of ethanol, followed by Catalytic hydrogenation was carried out overnight at atmospheric pressure and room temperature. After filtering off the catalyst, the solvent was distilled off to obtain the title compound quantitatively. ¹ H-NMR (CDCl ₃ ) δ:

0.79 (2H, brs), 0.87 (2H, s), 1.44 (9H, s), 1.78 (1H,

brs), 3.00 (1H, brs), 4.01 (4H, d, J=7.8Hz), 5.29

(1H, brs). Reference Example H-1: dimethyl 3,4,5,6-tetrafluorophthalate

Under cooling in an ice bath, 300 ml of sulfuric acid was added to 300 g (1.26 mol) of 3,4,5,6-tetrafluorophthalic acid dissolved in methanol, followed by reflux for 3 days. After cooling to room temperature, the precipitated crystals were collected by filtration. After methanol was distilled off from the filtrate, the resulting residue was mixed with 2 liters of ice water, and the precipitated crystals were collected. The combined crystals were washed with water and dried to give 294.86 g of a partially purified product of the title compound. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

0.95(6H, s). Reference Example H-2: Dimethyl 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalate

Add 164ml (1.08mol) diethyl malonate and 414.63g (3 mol) potassium carbonate, followed by stirring at room temperature for 26 hours. The reaction mixture was filtered, and the filtrate was poured into 1,200 ml of 4N hydrochloric acid and extracted with diethyl ether (1 L×2). The obtained organic layer was washed with water (1 L×2) and saturated brine (1 L), and then dried over anhydrous sodium sulfate. The solvent was evaporated to give 433.61 g (1.068 mol, 99.2%) of a partially purified product of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.29(6H, t, J=7.5Hz), 3.92(3H, s), 3.96(3H, s),

4.28 (4H, q, J=7.5Hz), 4.98 (1H, s). Reference Example H-3: 4-carboxymethyl-3,5,6-trifluorophthalic acid

2 liters of 60% sulfuric acid were added to 433.6 g (1.068 mol) of dimethyl 4-diethoxycarbonylmethyl-3,5,6-trifluorophthalate, followed by stirring at 110° C. for 40 hours. After cooling to room temperature, it was poured into 1 L of water and extracted with ethyl acetate (1 L×3). The organic layer was washed with 1 L of water and 1 L of saturated brine, and then dried over sodium sulfate. After distilling off the solvent, 304.35 g of a partially purified product of the title compound were obtained. ¹ H-NMR (400MHz, D ₂ O) δ:

3.77(2H,s). Reference Example H-4: 2,4,5-Trifluoro-3-methylbenzoic acid

To 304.35 g of 4-carboxymethyl-3,5,6-trifluorophthalic acid dissolved in 1.5 liters of dimethylsulfoxide was added 0.5 liters of triethylamine, followed by stirring at 140°C for 64 hours. After cooling to room temperature, dimethyl sulfoxide was distilled off. The resulting residue was mixed with 1 L of 1N hydrochloric acid and extracted with diethyl ether (1 L x 3). The organic layer was washed with 1 L of water and 1 L of saturated brine, and then dried over sodium sulfate. The solvent was evaporated to give 177.94 g (0.64 mol, 60%) of a partially purified product of the title compound. ¹ H-NMR (4 00 MHz, CDCl ₃ ) δ:

2.29(3H, t, J=1.5Hz), 7.70(1H, dt, J=6.5, 9.5

Hz). Reference Example H-5: 2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid

Under ice-cooling, 43.4g (0.21mol) of 2,4,5-trifluoro-3-methylbenzoic acid was added to 120ml of concentrated sulfuric acid, and fuming nitric acid was added dropwise at a speed not exceeding 30°C (d1 .52). After the dropwise addition, it was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 1.5 liters of ice water, and the resulting crystals were collected by filtration. The obtained crystals were washed with water (100ml×3) and dissolved in 500ml of ethyl acetate, and the solution was dried over anhydrous sodium sulfate. The filtrate obtained above was extracted with chloroform (300ml×4) and dried over anhydrous sodium sulfate. After this time, the organic layers were combined and concentrated to afford 50.3 g (quantitative) of the title compound. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

2.36 (3H, t, J=2.44Hz). Reference Example H-6: 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl ethyl acetate

2,4,5-Trifluoro-3-methyl-6-nitrobenzoic acid was suspended in 490 ml of benzene, and then 30.4 ml (0.42 mol) of thionyl chloride was added dropwise thereto at room temperature. After the dropwise addition, the reaction solution was heated under reflux for 22 hours. After distilling off benzene, the resulting residue was subjected to azeotropic treatment twice with 200 ml of benzene to obtain crude 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. 6.13 g (0.25 mol) of magnesium and 200 ml of ethanol were mixed, and 10 ml of carbon tetrachloride was added dropwise thereto at room temperature, followed by stirring at the same temperature for 6 hours. When the magnesium was dissolved, 44 ml (0.29 mol) of diethyl malonate dissolved in 150 ml of tetrahydrofuran was added thereto for 1 hour. After the dropwise addition was completed, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off and the resulting residue was dried under reduced pressure. The resulting solid was mixed with 300 ml of tetrahydrofuran, and then a solution of the acid chloride obtained above in 150 ml of tetrahydrofuran was added dropwise thereto over 1.5 hours. After the dropwise addition, the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was mixed with 400ml ethyl acetate and washed successively with 10% citric acid (500ml×1), water (500ml×1) and saturated brine (500ml×1), and the organic layer was dried with anhydrous sodium sulfate and distill off the solvent. The resulting residue was mixed with 1.5 liters of water and 1.5 liters of p-toluenesulfonic acid and heated at reflux for 1.5 hours. After the reaction was completed, the reaction solution was allowed to cool naturally and extracted with benzene (500ml×5). The organic layers were combined, washed with 500 ml of saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the resulting residue was purified by silica gel column chromatography, eluting with hexane:ethyl acetate=95:5, to obtain 37.65 g (44%) of the title compound. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.26 and 1.34 (3H, each t, J=7.33Hz), 2.33 and 2.35

(3H, each t, J=2.44Hz), 3.90(1.35H, s), 4.20 and

4.28(2H, each q, J=7.33Hz), 5.48(0.325H, s), 12.34

(0.325H, s). Reference Example H-7: 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl- 5-nitro-4-oxoquinoline-3-carboxylic acid ethyl ester

Add 17.9ml (107.6mmol) of ethyl orthoformate and 29ml of acetic anhydride to 16.4g (53.8mmol) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl ethyl acetate, followed by Stir at 100°C for 2 hours. The solvent was distilled off, the residue obtained was dissolved in 200 ml of toluene and mixed with 16 g (64.7 mmol) of the p-toluenesulfonate salt of (1R,2S)-2-fluorocyclopropylamine. Under cooling in an ice bath, 10.87 ml (78 mmol) of triethylamine dissolved in 30 ml of toluene was added dropwise thereto. After the dropwise addition was completed, it was stirred at the same temperature for 2 hours. The reaction solution was mixed with 200ml of ethyl acetate and washed successively with water (500ml×1) and saturated brine (500ml×2), the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The obtained residue was dissolved in 150 ml of 1,4-dioxane, and then 3.23 g (80.7 mmol) of sodium hydride was added thereto in portions under ice-cooling. After stirring at room temperature for 1 hour, the reaction solution was poured into 0.5N hydrochloric acid cooled in an ice bath. The resulting crystals were collected by filtration, washed with water (100ml×3), and then recrystallized from chloroform-ethanol to obtain 13.9g (70%) of the title compound. Melting point: 230-231°C ¹ H-NMR (400MHz, CDCl ₃ ) δ:

1.38(3H, t, J=7.33Hz), 1.35-1.45(1H, m), 1.58-

1.70(1H, m), 2.75(3H, d, J=3.42Hz), 3.85-3.93

(1H, m), 4.37 (2H, q, J=7.33Hz), 4, 80-4.83and

4.95-4.99 (1H, m), 8.57 (1H, d, J=2.93Hz). Reference example H-8: 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclo Propyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester

3.91g (37.6mmol) of 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4- Ethyl oxoquinoline-3-carboxylate was suspended in 1 liter of a 1:1 mixture of methanol and 1,4-dioxane, which was mixed with 200 ml of Raney nickel and stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was filtered and the resulting filtrate was concentrated. The resulting residue was dissolved in 300 ml of chloroform and filtered through celite, and the filtrate was concentrated to give 12.5 g (98%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.25-1.38 (1H, m), 1.39 (3H, t, J=7.33Hz), 1.45-

1.59(1H, m), 2.46(3H, d, J=2.44Hz), 3.73-3.79

(1H, m), 4.38 (2H, q, J=7.33Hz), 4.73-4.75and

4.88-4.92 (1H, m), 6.99 (2H, brs), 8.40 (1H, d, J =

3.42Hz).

Elemental analysis C ₁₆ H ₁₃ F ₃ N ₂ O ₅ 1/4H ₂ O:

Calculated value: C51.28 H3.63 N7.47

Measured value: C51.51 H3.58 N7.43 Reference example H-9: 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-di Hydrogen-8-methyl-4-oxoquinoline-3-carboxylic acid

10.43g (30.6mmol) of 5-amino-6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquin The ethyl phenoline-3-carboxylate was mixed with 150 ml of acetic acid and 150 ml of conc. hydrochloric acid, then heated at reflux for 1 hour. After the reaction was completed, the reaction solution was allowed to cool naturally and mixed with 700ml of water, and the resulting crystals were collected by filtration, washed with water (100ml×2), ethanol (300ml×1) and ether (300ml×1) successively, and then dried to obtain 7.52g (79%) of the title compound. Melting point: 293-297°C (decomposition) ¹ H-NMR (400MHz, 0.1N NaOD) δ:

1.31-1.42(1H, m), 1.53-1.68(1H, m), 2.52(3H, s),

4.03-4.10 (1H, m), 4.85-4.93 and 5.05-5.10 (1H,

m), 8.32(1H, s). Reference Example I-1: 2,3,4,5,6-ethyl pentafluorobenzoyl acetate

A mixture of 100 g (0.47 mol) of pentafluorobenzoic acid, 900 ml of benzene and 350 ml (4.80 mol) of thionyl chloride was heated under reflux for 40 hours. After the reaction was completed, the solution was concentrated under reduced pressure, and after repeated evaporation with benzene (900ml×2), the resulting residue was dissolved in 500ml of ether. A mixture of 11.5g (0.47mol) of magnesium, 450ml of ethanol and 20ml of carbon tetrachloride was stirred at room temperature for 1 hour, and 71.6ml (0.47mol) of diethyl malonate dissolved in 900ml of ether was added dropwise thereto . After stirring at the same temperature for 17 hours, the reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in 1,500 ml of ether, and the above acid chloride was added dropwise thereto at room temperature, followed by stirring at the same temperature for 63 hours. After the reaction was completed, the reaction solution was washed successively with 10% citric acid and water, then dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was mixed with 300 ml of water and 1.00 g (5.81 mol) of p-toluenesulfonic acid, heated at reflux for 6 hours, mixed with 2,500 ml of benzene, and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was purified by distillation under reduced pressure (10 mmHg, 118-120°C) to obtain 89.7 g (67%) of the title compound. Reference Example I-2: 5,6,7,8-tetrafluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3 - ethyl carboxylate

Dissolve 14.4g (51.0mmol) ethyl 2,3,4,5,6-pentafluorobenzoylacetate in 150ml benzene, and 28.8ml (204mmol) N,N-dimethylformamide dimethyl acetal Mix and then heat at reflux for 3 hours. After the reaction was completed, the solvent was distilled off. The resulting residue was mixed with 120ml toluene and 12.6g (51.0mmol) (1R, 2S)-2-fluoropropylamine p-toluenesulfonate and cooled in an ice bath, then 8.54mll (61.2mmol ) triethylamine in toluene (39ml). After the dropwise addition, it was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered with suction, the filtrate was washed with water (50ml×3), and the aqueous layer was extracted with ethyl acetate (100ml×3). The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off. Under cooling in an ice bath, the residue was mixed with 100 ml of 1,4-dioxane and mixed with 2.04 g (51.0 mmol) of 60% sodium hydride, followed by stirring at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into 10% citric acid and extracted with dichloromethane (200ml×2). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The resulting residue was crystallized from dichloromethane-isopropyl ether. The resulting crystals were collected by filtration, washed well with ether, and then dried under reduced pressure to obtain 12.6 g (71%) of the title compound. ¹ H-NMR (400MHz, CDCl ₃ ) δ:

8.46(1H, s), 5.02-4.80(1H, m), 4.37(2H, q, J=

7.32Hz), 3.83-3.75(1H, m), 1.75-1.55(2H, m),

1.40 (3H, t, J=7.32Hz). Reference Example I-3: 5-benzyloxy-6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl] -1,4-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester

2.35g (6.77mmol) of 5,6,7,8-tetrafluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3 - Ethyl carboxylate was dissolved in 20 ml toluene and mixed with 0.70 ml (6.77 mmol) benzyl alcohol. After cooling to 0°C, it was further mixed with 280 mg (6.99 mmol) of 60% sodium hydride suspended in 10 ml of toluene, and the mixture was stirred at the same temperature for 2 hours and then at room temperature for 2 hours. After the reaction was completed, the reaction solution was mixed with 10% citric acid and extracted with chloroform (100ml×2). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 1.68 g (57%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

8.41(1H, s), 7.62-7.28(5H, m), 5.25and5.19(2H,

ABd, J=10.25Hz), 5.00-4.77 (1H, m), 4.39 (2H, q,

J=7.33Hz), 3.82-3.72 (1H, m), 1.70-1.53 (2H, m),

1.39 (3H, t, J=7.33Hz). Reference Example I-4: 6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-bis Hydrogen-5-hydroxy-4-oxoquinoline-3-carboxylate

1.68g (3.86mmol) of 5-benzyloxy-6,7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo Ethyl quinoline-3-carboxylate was mixed with 15 ml of an acetic acid-water-sulfuric acid mixture (8:6:1) and heated at 100°C for 1 hour. The reaction solution was cooled to room temperature and mixed with 20 ml of water, and the resulting crystals were collected by filtration, washed well with water, and then dried under reduced pressure to obtain 1.04 g (85%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

13.11(1H, s), 13.10-12.75(1H, br), 8.82(1H, s),

5.09-4.83(1H, m), 3.99-3.88(1H, m), 1.86-1.69

(2H, m). Inventive Example 10: 5-amino-7-[(3R)-3-(1-aminocyclopropyl)-1-pyrrolidinyl]-6,8-difluoro-1-[ (1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate hydrochloride

278.8 mg (1.25 mmol) of 1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl) pyrrolidine was suspended in 10 ml of acetonitrile, and 194.8 mg (0.62 mmol) of 5-amino-6 , 7,8-trifluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.60ml (4.30mmol) triethylamine, then heated at reflux for 11 hours. After distilling off the solvent, the resulting residue was mixed with chloroform, washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The resulting residue was developed twice by silica gel thin-layer chromatography (chloroform:methanol:water = 7:3:1 for the lower layer) to obtain a yellow oil and a solid mixture. The tert-butylcarbamate compound thus obtained was cooled in a sodium chloride-ice bath, and 8.0 ml of trifluoroacetic acid was added dropwise thereto. After stirring at the same temperature for 20 minutes, trifluoroacetic acid was distilled off, and the resulting residue was washed three times by decantation after addition of diethyl ether. The pale yellow-brown powder thus obtained was dissolved in 1N aqueous sodium hydroxide solution, the solution was adjusted to pH 7.4 with hydrochloric acid, extracted with chloroform-methanol (10:1), and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The obtained residue was mixed with diethyl ether, and the resulting powder was dissolved in ethanol, mixed with hydrochloric acid-diethyl ether, and then stirred at room temperature. After distilling off the solvent, the resulting residue was washed three times by decantation after adding diethyl ether, and the resulting yellow solid was recrystallized from ethanol to obtain 55.7 mg (26.2) of the title compound as a yellow powder. Melting point: 240.0-260.0°C ¹ H-NMR(D ₂ O)δ:

0.75-0.95 (4H, m), 1.22-1.60 (3H, m), 1.86-2.02

(1H, m), 2.40-2.62 (1H, m), 3.18-3.40 (1H, m), 3.40

-3.82(4H, m), 4.65-4.98(1H, m), 8.20(1H, s). Inventive Example 11: 7-[(3R)-3-(1-aminocyclopropyl)-1-pyrrole Alkyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

Dissolve 433mg (1.2mmol) (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine in 10ml methanol, then add 100mg 5% palladium/carbon to it, and infra-red The hydrogenation was carried out under lamp warming and atmospheric pressure for 2 hours. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 10 ml of dimethyl sulfoxide (DMSO), and 0.174 ml (1.25 mmol) of triethylamine and 217 mg (0.6 mmol) of triethylamine were added thereto. 6,7-Difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid BF2 chelate , and then stirred at room temperature for 25 hours. After the reaction was completed, DMSO was distilled off, the resulting residue was mixed with water, and the resulting crystals were collected by filtration and washed with water (10ml×4). The obtained crystals were dissolved in 20 ml of methanol and 5 ml of water, and the solution was mixed with 0.3 ml of triethylamine, and heated under reflux for 4.5 hours. After the reaction was completed, the reaction solution was mixed with 50 ml of water, methanol was distilled off, and the resulting residue was extracted with chloroform (50 ml×2). The organic layers were combined and dried over sodium sulfate, and the solvent was evaporated. Under ice-cooling, 10 ml of concentrated hydrochloric acid was added dropwise to the obtained residue, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, the solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 ml×5). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from methanol-2-propanol to obtain 181 mg (72%) of the title compound. Melting point: 195-197°C [α] _D ²⁵ = -123.10, (c = 0.515, 1N aqueous sodium hydroxide solution) ¹ H-NMR (400MHz, 0.1N NaOD) δ:

0.60(4H, s), 1.34-1.60(2H, m), 1.71-1.82(1H, m),

1.99-2.07(1H, m), 2.20-2.29(1H, m), 3.46-3.65

(2H, m), 3.60 (3H, s), 3.69-3.78 (1H, m), 3.98-4.07

(1H, m), 4.93-4.96 and 5.12-5.15 (1H, m), 7.60 (1H,

d, J=13.67Hz), 8.43 (1H, d, J=2.93Hz).

Elemental Analysis C ₂₁ H ₂₃ F ₂ N ₃ O ₄

Calculated value: C60.14 H5.53 N 10.02

Measured value: C60.02 H5.45 N 9.92 Inventive Example 12: 7-[(3R)-3-(1-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

Dissolve 322mg (0.89mmol) (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine in 10ml methanol, then add 100mg 5% palladium/carbon to it, and infra-red The hydrogenation was carried out under lamp warming and atmospheric pressure for 2 hours. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 3 ml of sulfolane, and 0.124 ml (0.89 mmol) of triethylamine and 172 mg (0.5 mmol) of 6,7 were added thereto -Difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid BF2 chelate, then at room temperature Under stirring for 6 days. After the reaction was completed, the reaction solution was mixed with 100 ml of ethyl acetate:ether=1:1 solution, washed with 10% citric acid (100 ml×2), and then dried over sodium sulfate. After distilling off the solvent, the resulting residue was dissolved in a mixed solvent of 50 ml of methanol and 10 ml of water, the solution was mixed with 1 ml of triethylamine, and heated under reflux for 4 hours. After the reaction was completed, methanol was distilled off and the resulting residue was mixed with 100 ml of ether and washed with 10% citric acid (100 ml×2). The organic layer was dried over magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel thin-layer chromatography (methanol:chloroform=1:9), and the silica gel was collected and extracted with a solvent of methanol:chloroform=1:9. Under ice-cooling, 10 ml of concentrated hydrochloric acid was added dropwise to the resulting compound, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off. Thereafter, the obtained residue was recrystallized from 2-propanol to obtain 81 mg (40%) of the title compound. Melting point: 195-197°C [α] _D ²⁵ = -320.00, (c = 0.270, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.58(4H, s), 1.21-1.38(1H, m), 1.60-1.82(2H, m),

2.01-2.07(1H, m), 2.22-2.32(1H, m), 2.53(3H, s),

3.38-3.43(2H, m), 3.52-3.59(1H, m), 3.75-3.83

(1H, m), 4.10-4.14 (1H, m), 4.93-4.96 and 5.09-

5.14(1H, m), 7.71(1H, d, J=14.16Hz), 8.45(1H, d,

J=2.44Hz).

Elemental Analysis C ₂₁ H ₂₃ F ₂ N ₃ O ₃

Calculated value: C62.52 H5.75 N10.42

Measured value: C62.48 H5.78 N10.25 Inventive Example 13: 7-[(3R)-3-(1-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[( R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Dissolve 322mg (0.89mmol) (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine in 10ml methanol, then add 100mg 5% palladium/carbon to it, and infra-red The hydrogenation was carried out under lamp warming and atmospheric pressure for 2 hours. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 5 ml of acetonitrile, and 0.5 ml of triethylamine and 113 mg (0.4 mmol) of 6,7-difluoro-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, then heated under reflux for 18 hours. After the reaction was completed, the reaction solution was allowed to cool naturally, and the resulting crystals were collected by filtration. Under cooling in an ice bath, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained crystals, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from ammonia-ethanol to obtain 120 mg (77%) of the title compound. Melting point: 240-242°C [α] _D ²⁵ = -32.30, (c = 0.260, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.57(4H, s), 1.68-1.83(3H, m), 2.01-2.10(1H, m),

2.19-2.25(1H, m), 3.29-3.35(1H, m), 3.48-3.65

(4H, m), 5.12-5.17 and 5.28-5.33 (1H, m), 6.80 (1H,

d, J = 7.32Hz), 7.76 (1H, d, J = 15.13Hz), 8.39 (1H,

s).

Elemental Analysis C ₂₀ H ₂₁ F ₂ N ₃ O ₃

Calculated value: C61.69 H5.44 N10.79

Measured value: C60.64 H5.27 N10.59 Invention Example 147-[(3R)-3-(1-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthalene-3-carboxylic acid

Dissolve 180mg (0.5mmol) (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine in 10ml methanol, then add 100mg 5% palladium/carbon to it, and infra-red The hydrogenation was carried out under lamp warming and atmospheric pressure for 2 hours. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 5 ml of acetonitrile, and 0.5 ml of triethylamine and 144 mg (0.48 mmol) of 7-chloro-6-fluoro-[( 1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthalene-3-carboxylic acid, then heated at reflux for 1 hour, then stirred at room temperature 18 hours. After the reaction was completed, the reaction solution was allowed to cool naturally, and the resulting crystals were collected by filtration. Under cooling in an ice bath, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained crystals, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the obtained residue was recrystallized from liquid ammonia-ethanol to obtain 79 mg (42%) of the title compound. Melting point: 232-234°C [α] _D ²⁵ =58.33, (c=0.120, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.58(4H, s), 1.60-1.87(3H, m), 2.05-2.15(1H, m),

2.20-2.31 (1H, m), 3.48-3.79 (3H, m), 3.95-4.07

(2H, m), 5.02-5.09 and 5.19-5.23 (1H, m), 7.85 (1H,

d,J=13.19Hz), 8.37(1H,s).

Elemental Analysis C ₁₉ H ₂₀ F ₂ N ₄ O ₃

Calculated value: C58.46 H5.16 N14.35

Measured value: C59.39 H4.97 N14.27 Inventive Example 15: 7-[3-(1-aminocyclobutyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S) -2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (fraction 2)

To 446 mg (1.30 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4 dissolved in 6 ml of sulfolane -Oxoquinoline-3-carboxylic acid BF ₂ chelate was added 530mg (2.20mmol) 3-(1-tert-butoxycarbonylaminocyclobutyl)pyrrolidine (fraction 2) and 0.54ml triethylamine, followed by Stir at room temperature for 12 days. After distilling off triethylamine, the resulting residue was mixed with 10 ml of water and stirred at room temperature for 30 minutes. The resulting crystals were washed with water, collected by filtration, and then dissolved in 20 ml of a mixed solvent of methanol:water=9:1, and the solution was mixed with 4 ml of triethylamine and heated under reflux for 3 hours. After distilling off the solvent, the resulting residue was mixed with 50 ml of chloroform, washed with 10% citric acid (20 ml×2) and dried over magnesium sulfate, and then the solvent was distilled off. To the obtained residue was added 5 ml of concentrated hydrochloric acid and stirred at room temperature for 2 hours, and then the reaction solution was washed with chloroform (5 ml×2). The reaction solution was adjusted to pH 7.3 with 20% aqueous sodium hydroxide solution and extracted with chloroform (30ml x 3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. The residue was separated and purified by preparative TLC (the lower layer was developed with chloroform:methanol:water=7:3:1) and recrystallized from ethanol to obtain 220 mg (41%) of the title compound. Melting point: 140-143°C ¹ H-NMR (400MHz, 0.1N NaOD) δ:

1.06-1.21(1H, m), 1.55-1.71(3H, m), 1.81-1.85

(3H, m), 1.91-2.08 (3H, m), 2.33-2.48 (4H, m), 3.17

-3.24(2H, m), 3.44-3.48(1H, m), 3.67-3.68(1H,

m), 4.02-4.05 (1H, m), 7.64 (1H, d, J=14.16Hz),

8.44 (1H, s).[α] _D ²³ = -318.47, (c = 0.184, methanol/chloroform = 2/1)

Elemental Analysis C ₁₉ H ₁₉ N ₄ O ₃ F ₃ 1/4H ₂ O

Calculated value: C60.68 H6.25 N9.65

Measured value: C60.41 H6.20 N9.58 Inventive Example 16: 5-amino-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-di Hydrogen-7-[(3R)-(1-methylaminocyclopropyl)-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid

Dissolve 310 mg (0.83 mmol) of (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-methyl)aminocyclopropyl]pyrrolidine in 10 ml of methanol, and then add 200 mg of 5% palladium on carbon was hydrogenated under infrared lamp warming and normal pressure for 1 hour. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 10 ml of acetonitrile, and 1.24 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene ( DBU) and 190 mg (0.6 mmol) of 5-amino-6,7,8-trifluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline- 3-carboxylic acid, then heated at reflux for 18 hours. After the reaction was completed, acetonitrile was distilled off and the resulting residue was mixed with 200ml of chloroform and washed with 10% citric acid (100ml×1). The organic layer was dried over sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel thin layer chromatography (methanol:chloroform=5:95) twice, and the silica gel was collected and extracted with a solvent system of methanol:chloroform=1:9. Under cooling in an ice bath, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained compound, followed by stirring for 10 minutes. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the obtained residue was recrystallized from liquid ammonia-2-propanol to obtain 96 mg (37%) of the title compound. Melting point: 180-181°C [α] _D ²⁵ = -242.26, (c = 0.265, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.54-0.65 (4H, m), 1.37-1.64 (3H, m), 1.88-1.98

(1H, m), 2.33 (3H, s), 2.75-2.87 (1H, m), 3.29-3.48

(1H, m), 3.51-3.64 (2H, m), 3.71-3.83 (2H, m), 4.80

-4.91and5.03-5.07(1H, m), 8.18(1H, s).

Elemental Analysis C ₂₁ H ₂₃ F ₂ N ₄ O ₃

Calculated value: C56.63 H5.43 N12.58

Found value: C56.57 H5.31 N12.44 Inventive Example 17: 6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy -7-[(3R)-3-(1-methylaminocyclopropyl)-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid

Dissolve 449 mg (1.2 mmol) of (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-methyl)aminocyclopropyl]pyrrolidine in 10 ml of methanol, and then add 100mg of 5% palladium on carbon was hydrogenated under infrared lamp warming and normal pressure for 1 hour. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 10 ml of dimethyl sulfoxide, and 0.174 ml (1.25 mmol) of triethylamine and 217 mg (0.6 mmol) of 6,7 were added thereto -difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid BF ₂ chelate, then Stir at room temperature for 5 hours. After the reaction was completed, dimethylsulfoxide was distilled off, the resulting residue was mixed with water, and the resulting crystals were collected by filtration and washed with water (10ml×3). The resulting crystals were dissolved in a mixed solvent of 20 ml of methanol and 5 ml of water, and the solution was mixed with 0.3 ml of triethylamine and heated under reflux for 15.5 hours. After the reaction was completed, methanol was distilled off, and the reaction solution was mixed with 50 ml of water and extracted with chloroform (20 ml×2). The organic layers were combined, extracted with 10% citric acid (100ml×2) and dried over sodium sulfate, and the solvent was evaporated. Under ice-cooling, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained residue, followed by stirring at the same temperature for 10 minutes. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50 ml×5). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from methanol-ethanol to obtain 215 mg (83%) of the title compound. Melting point: 208-209°C [α] _D ²⁵ = -123.42, (c = 0.525, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.53-0.69 (4H, m), 1.32-1.59 (3H, m), 1.91-2.02

(1H, m), 2.34 (3H, s), 2.85-2.95 (1H, m), 3.29-3.38

(1H, m), 3.51-3.62 (2H, m), 3.57 (3H, s), 3.70-3.79

(1H, m), 3.98-4.07 (1H, m), 4.95-4.98 and 5.09-

5.13(1H, m), 7.66(1H, d, J=14.23Hz), 8.39(1H, d,

J=2.93).

Elemental Analysis C ₂₂ H ₂₅ F ₂ N ₃ O ₄

Calculated value: C60.96 H5.81 N9.69

Found value: C60.79 H5.73 N9.55 Inventive Example 18: 6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl- 7-[(3R)-3-(1-methylaminocyclopropyl)-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid

Dissolve 749 mg (2.0 mmol) of (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-methyl)aminocyclopropyl]pyrrolidine in 10 ml of methanol, and then add 200 mg of 5% palladium on carbon was hydrogenated under infrared lamp warming and normal pressure for 1 hour. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 5 ml of sulfolane, and 0.279 ml (2.0 mmol) of triethylamine and 345 mg (1.0 mmol) of 6,7 were then added thereto. -Difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid BF2 chelate, then at room temperature Under stirring for 11 days. After the reaction was completed, the reaction solution was mixed with 50 ml of water, and the resulting crystals were collected by filtration and washed with water (10 ml×2). The resulting crystals were dissolved in 32 ml of methanol and 8 ml of water, and the solution was mixed with 0.5 ml of triethylamine and heated under reflux for 18 hours. After the reaction was completed, methanol was distilled off, and the resulting residue was mixed with 200 ml of chloroform and washed with 10% citric acid (100 ml×1). The organic layer was dried over sodium sulfate and the solvent was distilled off. The resulting residue was subjected to silica gel thin-layer chromatography (methanol:chloroform-1:9), and the silica gel was collected and extracted with a mixed solvent of methanol:chloroform=1:9. Under ice-cooling, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained compound, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100 ml×3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from methanol-ethanol to obtain 124 mg (30%) of the title compound. Melting point: 211-212°C [α] _D ²⁵ = -330.18, (c = 0.275, methanol) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.51-0.67 (4H, m), 1.20-1.35 (1H, m), 1.43-1.68

(2H, m), 1.94-2.02 (1H, m), 2.32 (3H, s), 2.46 (3H,

s), 2.89-2.98 (1H, m), 3.30-3.42 (3H, m), 3.75-

3.83(1H, m), 4.05-4.13(1H, m), 4.90-4.93 and 5.03

-5.10(1H, m), 7.66(1H, d, J=14.65Hz), 8.41(1H,

d, J=3.42Hz).

Elemental Analysis C ₂₂ H ₂₅ F ₂ N ₃ O ₃

Calculated value: C63.30 H6.04 N10.07

Measured value: C62.97 H6.25 N9.91 Inventive Example 19: 5-amino-7-[(3R)-3-(1-ethylaminocyclopropyl)-1-pyrrolidinyl]-6,8 -Difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

Dissolve 414 mg (1.07 mmol) of (3R)-1-benzyloxycarbonyl-3-[1-(N-tert-butoxycarbonyl-N-ethyl)aminocyclopropyl]pyrrolidine in 15 ml of methanol, and then add 200 mg of 5% palladium on carbon was hydrogenated under infrared light for 1.5 hours under normal pressure. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 10 ml of acetonitrile, and 1 ml of triethylamine and 225 mg (0.71 mmol) of 5-amino-6,7,8-tri Fluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, then heated at reflux for 18 hours. After the reaction was completed, acetonitrile was distilled off, and the resulting residue was mixed with 100 ml of chloroform and washed with 10% citric acid (100 ml×1). The organic layer was dried over sodium sulfate, and the solvent was distilled off. Under ice-cooling, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained residue, followed by stirring for 1 hour. After the reaction was completed, the reaction solution was mixed with 10 ml of water and washed with dichloromethane (15 ml×1). The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50ml x 3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from liquid ammonia-2-propanol to obtain 243 mg (76%) of the title compound. Melting point: 151-152°C [α] _D ²⁵ = -116.82, (c = 0.315, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.51-0.69 (4H, m), 1.04 (3H, t, J=7.32Hz), 1.37-

1.62(3H, m), 1.92-1.99(1H, m), 2.71(2H, q, J=

7.32Hz), 2.78-2.88(1H, m), 3.30-3.39(1H, m),

3.53-3.64 (2H, m), 3.72-3.85 (2H, m), 4.85-4.92

and 5.03-5.07(1H, m), 8.19(1H, s).

Elemental analysis C ₂₂ H ₂₅ F ₃ N ₄ O ₃ 1/4H ₂ O

Calculated value: C58.08 H5.65 N12.31

Measured value: C58.23 H5.89 N11.98 Inventive Example 20: 5-amino-6,8-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-di Hydrogen-7-[(3R)-3-[1-(2-hydroxyethyl)aminocyclopropyl]-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid

Dissolve 332 mg (0.67 mmol) (3R)-1-benzyloxycarbonyl-3-[1-[N-(2-benzyloxyethyl)-N-tert-butoxycarbonyl]aminocyclopropyl]pyrrolidine in 20ml methanol, then add 100mg 5% palladium/carbon therein, and carry out hydrogenation under 7kg/cm ² pressure for 24 hours under infrared lamp warming. After the reaction was completed, 5% palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 10 ml of acetonitrile, and 1 ml of triethylamine and 177 mg (0.56 mmol) of 5-amino-6,7,8-tri Fluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro 4-oxoquinoline-3-carboxylic acid, then heated at reflux for 23 hours. After the reaction was completed, acetonitrile was distilled off, and the resulting residue was mixed with 100 ml of chloroform and washed with 10% citric acid (100 ml×1). The organic layer was dried over sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel thin-layer chromatography (methanol:chloroform=1:9), and the silica gel was collected and extracted with a solvent system of methanol:chloroform=1:9. Under ice-cooling, 10 ml of concentrated hydrochloric acid was added dropwise to the resulting compound, followed by stirring for 30 minutes. After the reaction was completed, the reaction solution was washed with dichloromethane (10ml×2). The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100ml x 3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the obtained residue was recrystallized from liquid ammonia-ethanol to obtain 97 mg (36%) of the title compound. Melting point: 198-200°C [α] _D ^22.5 = -141.49, (c = 0.335, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.58-0.66 (4H, m), 1.45-1.60 (3H, m), 1.92-1.97

(1H, m), 2.82-2.88 (3H, m), 3.31-3.38 (1H, m), 3.55

-3.69(4H, m), 3.75-3.83(2H, m), 4.85-4.92and

5.03-5.08(1H, m), 8.19(1H, s).

Elemental analysis C ₂₂ H ₂₅ F ₃ N ₄ O ₄ 1/4H ₂ O

Calculated value: C56.11 H5.46 N11.90

Found value: C56.38 H5.37 N11.75 Inventive Example 21: 6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-7-[(3R )-3-[1-(2-Hydroxyethyl)aminocyclopropyl]-1-pyrrolidinyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid

Dissolve 210mg (0.78mmol) of (3R)-3-[1-(2-hydroxyethyl)aminocyclopropyl]pyrrolidine in 10ml of dimethyl sulfoxide, then add 0.109ml (0.78mmol) of triethylamine and 231 mg (0.64 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3- The carboxylic acid BF ₂ chelate was then stirred at room temperature for 20 hours. After the reaction was completed, dimethyl sulfoxide was distilled off, the resulting residue was mixed with water, and the resulting crystals were collected by filtration and washed with water (10ml×2). The resulting crystals were dissolved in 16 ml of methanol and 4 ml of water, and the solution was mixed with 1 ml of triethylamine and heated under reflux for 3 hours. After the reaction was completed, methanol was distilled off and the resulting residue was mixed with 100 ml of chloroform and washed with 10% citric acid (100 ml×2). The organic layer was dried over sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel thin-layer chromatography (methanol:chloroform=1:9), and the silica gel was collected and extracted with a solvent system of methanol:chloroform=1:9. Under ice-cooling, 5 ml of concentrated hydrochloric acid was added dropwise to the obtained compound, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was washed with dichloromethane (20ml×1). The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50ml x 3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from liquid ammonia-2-propanol to obtain 120 mg (40%) of the title compound. Melting point: 153-155°C [α] _D ^25.4 = -106.66, (c = 0.270, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400MHz, 0.1N NaOD) δ:

0.55-0.67 (4H, m), 1.33-1.43 (1H, m), 1.48-1.62

(2H, m), 1.94-2.04 (1H, m), 2.82-2.94 (3H, m), 3.29

-3.36(1H, m), 3.51-3.61(2H, m), 3.57(3H, s), 3.66

(2H, t, J=5.86Hz), 3.66-3.78 (1H, m), 3.98-4.05

(1H, m), 4.91-4.95 and 5.07-5.11 (1H, m), 7.65 (1H,

d, J=14.16Hz), 8.39 (1H, d, J=2.93Hz).

Elemental Analysis C ₂₃ H ₂₇ F ₂ N ₃ O ₅

Calculated value: C59.60 H5.87 N9.07

Found value: C59.34 H6.03 N8.84 Inventive Example 22: 6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-7-[(3R )-3-[1-(2-Hydroxyethyl)aminocyclopropyl]-1-pyrrolidinyl]-8-methyl-4-oxoquinoline-3-carboxylic acid

203mg (0.74mmol) of (3R)-3-[1-(2-hydroxyethyl)aminocyclopropyl]pyrrolidine was dissolved in 2ml of sulfolane, and 0.082ml (0.6mmol) of triethylamine was added thereto and 206 mg (0.6 mmol) of 6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxy Acid BF2 chelate, then stirred at room temperature for 7 days. After the reaction was completed, the reaction mixture was mixed with 100 ml of chloroform and washed with 10% citric acid (100 ml×1). The organic layer was dried over sodium sulfate, and the solvent was distilled off. The resulting residue was dissolved in 16 ml of methanol and 4 ml of water, and the solution was mixed with 1 ml of triethylamine and heated under reflux for 3 hours. After the reaction was completed, methanol was distilled off and the resulting residue was mixed with 100 ml of chloroform, washed with 10% citric acid (100 ml×1). The organic layer was dried over sodium sulfate and the solvent was distilled off. The resulting residue was subjected to silica gel thin-layer chromatography (methanol:chloroform=1:9), and the silica gel was collected and extracted with a solvent system of methanol:chloroform=1:9. Under ice-cooling, 2 ml of concentrated hydrochloric acid was added dropwise to the resulting compound, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was washed with dichloromethane (20ml×1). The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (50ml x 3). The organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Thereafter, the resulting residue was recrystallized from liquid ammonia-ethanol to obtain 63 mg (23%) of the title compound. Melting point: 168-170°C [α] _D ^25.2 = -236.47, (c = 0.170, 0.1N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.55-0.67 (4H, m), 1.18-1.25 (1H, m), 1.42-1.69

(2H, m), 1.92-1.99 (1H, m), 2.43 (3H, s), 2.82-2.94

(3H, m), 3.22-3.34 (3H, m), 3.65 (2H, t, J=5.86

Hz), 3.69-3.79(1H, m), 4.03-4.09(1H, m), 4.90-

4.95 and 5.07-5.11 (1H, m), 7.65 (1H, d, J = 14.16

Hz), 8.43 (1H, d, J=2.93Hz).

Elemental Analysis C ₂₃ H ₂₇ F ₂ N ₃ O ₄

Calculated value: C61.74 H6.08 N9.39

Measured value: C61.68 H6.19 N9.31 Inventive Example 23: 5-amino-7-[3-(1-aminocyclobutyl)-1-pyrrolidinyl]-6,8-difluoro-1 -[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fraction 1)

136 mg (0.57 mmol) of 3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine (fraction 1) was suspended in 10.0 ml of acetonitrile, to which was subsequently added 120 mg (0.38 mmol) of 5-amino-6,7, 8-trifluoro-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.79ml (3.79mmol) triethylamine, then Heated at reflux overnight. After distilling off the solvent, the resulting residue was mixed with chloroform, washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. 2 ml of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was mixed with 10 ml of water, washed with chloroform, and then neutralized with an aqueous sodium hydroxide solution. This was extracted with chloroform and dried over sodium sulfate, and then the solvent was distilled off. After this time, the resulting residue was recrystallized from 2-propanol to afford 29 mg (15%) of the title compound as a yellow solid. Melting point: 181-183°C (decomposition) ¹ H-NMR (0.1N-NaOD) δ:

1.53-1.72 (4H, m), 1.81-1.91 (3H, m), 1.98-2.13

(3H, m), 2.25-2.33 (1H, m), 3.42-3.60 (3H, m), 3.68

-3.80(2H, m), 4.81-5.03(1H, m), 8.25(1H, s).

Elemental Analysis C ₂₁ H ₂₃ F ₃ N ₄ O ₃ 1/4H ₂ O

Calculated value: C57.20 H5.37 N12.71

Measured value: C57.09 H5.34 N12.38 Inventive Example 24: 5-amino-7-[3-(1-aminocyclobutyl)-1-pyrrolidinyl]-6,8-difluoro-1 -[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (fraction 2)

242 mg (1.00 mmol) of 3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine (fraction 2) was suspended in 10.0 ml of acetonitrile, to which was subsequently added 212 mg (0.67 mmol) of 5-amino-6,7, 8-trifluoro-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1.40ml (6.70mmol) triethylamine, then Heated at reflux overnight. After distilling off the solvent, the resulting residue was mixed with chloroform, washed successively with water, 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. 2 ml of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was mixed with 10 ml of water, washed with chloroform, and then neutralized with an aqueous sodium hydroxide solution. This was extracted with chloroform and dried over sodium sulfate, and then the solvent was distilled off. After this time, the resulting residue was recrystallized from ethanol-isopropyl ether to afford 292 mg (37%) of the title compound as a yellow solid. Melting point: 133-139°C ¹ H-NMR (0.1N-NaOD) δ:

1.46-1.68 (4H, m), 1.81-1.86 (3H, m), 1.94-1.99

(1H, m), 2.05-2.10 (2H, m), 2.27-2.31 (1H, m), 3.47

-3.54(3H, m), 3.67-3.71(2H, m), 3.86-5.02(1H,

m), 8.19(1H, s).

Elemental Analysis C ₂₁ H ₂₃ F ₃ N ₄ O ₃ ·H ₂ O

Calculated value: C55.50 H5.54 N12.33

Found value: C55.76 H5.33 N11.85 Inventive Example 25: 7-[3-(1-aminocyclobutyl)-1-pyrrolidinyl]-6,8-difluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (fraction 2)

215mg (0.89mmol) of 3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine (fraction 2) was suspended in 2.0ml of dimethyl sulfoxide, to which was subsequently added 215mg (0.60mmol) of 6,7,8 -Trifluoro-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 249 μl (1.80mmol) triethylamine, then at room temperature Stir overnight. After distilling off triethylamine, the resulting residue was mixed with water, and the resulting precipitate was collected by filtration. It was dissolved in 10 ml of 90% aqueous methanol, and the solution was mixed with 2 ml of triethylamine and heated under reflux for 2 hours. After distilling off the solvent, the resulting residue was mixed with chloroform, washed successively with 10% aqueous citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent. 2 ml of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was mixed with 10 ml of water, washed with chloroform, and then neutralized with an aqueous sodium hydroxide solution. This was extracted with chloroform and dried over sodium sulfate, and then the solvent was distilled off. After this time, the resulting residue was recrystallized from ethanol-isopropyl ether to afford 71 mg (27%) of the title compound as a yellow solid. Melting point: 123-139°C ¹ H-NMR (0.1N-NaOD) δ:

1.33-1.40(1H, m), 1.50-1.60(1H, m), 1.68-1.79

(2H, m), 1.86-1.88 (3H, m), 2.03-2.07 (1H, m), 2.14

(2H, brs), 2.40-2.49 (1H, m), 3.50-3.52 (3H, m),

3.56(3H, s), 3.67-3.71(1H, m), 3.98-4.03(1H, m),

7.66(1H, d, J=14.6Hz), 8.42(1H, 2s).

Elemental Analysis C ₂₂ H ₂₅ F ₂ N ₃ O ₄ 3/4H ₂ O

Calculated value: C50.12 H5.98 N9.40

Measured value: C58.94 H5.70 N9.13 Inventive Example 26: 5-amino-7-[3-(1-aminocyclopropyl)-1-azetidinyl]-6,8-di Fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

212 mg (1.00 mmol) of 3-(1-tert-butoxycarbonylaminocyclopropyl)azetidine was suspended in 10.0 ml of acetonitrile, to which 210 mg (0.66 mmol) of 5-amino-6,7 were subsequently added, 8-trifluoro-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.92ml (6.60mmol) triethylamine, then Heated at reflux for 22 hours. After distilling off the solvent, the resulting residue was mixed with chloroform, washed with water, 10% aqueous citric acid solution, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. 2 ml of concentrated hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with aqueous sodium hydroxide solution and extracted with chloroform. The extract was dried over sodium sulfate and the solvent was distilled off. Thereafter, the resulting residue was purified by preparative TLC (the lower layer was developed with chloroform:methanol:water=7:3:1), recrystallized in concentrated ammonia-ethanol, and then washed with water and ether successively to obtain 108 mg (40%) of yellow The title compound was obtained as a solid. Melting point: 188-191°C (decomposition) [α] _D ²⁵ = 36.44, (c = 0.225, 1N aqueous sodium hydroxide solution) ¹ H-NMR (0.1 N-NaOD) δ:

0.58(4H, 2s), 1.54-1.61(2H, m), 2.84-2.87(1H,

m), 3.78(1H, m), 3.99(2H, m), 4.32(2H, m), 8.1(1H,

s).

Elemental Analysis C ₁₉ H ₁₉ F ₃ N ₄ O ₃ 1/2H ₂ O

Calculated value: C54.68 H4.83 N13.42

Found value: C54.39 H4.74 N13.22 Inventive Example 27: 5-Amino-7-[(3R)-3-(1-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro- 1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

649 mg (1.8 mmol) of (3R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine was dissolved in 20 ml of methanol, and 200 mg of 5% (v/v) palladium was added thereto / carbon, hydrogenation was carried out under infrared lamp warming and normal pressure for 2 hours. After the reaction was completed, 5% (v/v) palladium/carbon was filtered off and methanol was distilled off, and the resulting residue was dissolved in 20 ml of dimethyl sulfoxide, and 2 ml of triethylamine and 312 mg (1 mmol) of 5-amino -6,7-difluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, then at 150 Stir at °C for 18 hours. After the reaction was completed, dimethylsulfoxide was distilled off, and the resulting residue was mixed with 100ml of chloroform, washed with 10% citric acid (100ml×1) and saturated brine (100ml×1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. Under ice-cooling, 10 ml of concentrated hydrochloric acid was added dropwise to the obtained residue, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction solution was washed with dichloromethane (20ml×1), and the aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (100ml×4). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel thin-layer chromatography, and the lower layer was developed with a mixed solvent system of chloroform:methanol:water=7:3:1, and then extracted with the same solvent. Thereafter, the resulting crude product was recrystallized from chloroform-isopropyl ether to obtain 101.5 mg (24%) of the title compound. Melting point: 215-216°C [α] _D ²⁵ = -406.96, (c = 0.115, 0.1 N aqueous sodium hydroxide solution) ¹ H-NMR (400 MHz, 0.1N-NaOD) δ:

0.55(4H, s), 1.09-1.18(1H, m), 1.45-1.57(1H, m),

1.61-1.74 (1H, m), 1.95-2.05 (1H, m), 2.16-2.25

(1H, m), 2.27 (3H, s), 3.24-3.37 (2H, m), 3.45-3.57

(1H, m), 3.68-3.80 (1H, m), 3.89-3.98 (1H, m), 4.85

-4.91 and 5.02-5.07 (1H, m), 8.26 (1H, d, J=2.93

Hz).

Elemental analysis C ₂₁ H ₂₄ F ₂ N ₄ O ₃ 1/2H ₂ O

Calculated value: C59.01 H5.89 N13.39

Measured value: C59.35 H5.85 N12.83 Inventive Example 28: 7-[(3R)-3-(1-aminocyclopropyl)-1-pyrrolidinyl]-6,8-difluoro-1 -[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-5-hydroxyl-4-oxoquinoline-3-carboxylic acid

360mg (1.00mmol) of (R)-1-benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminomethylcyclopropyl)pyrrolidine was dissolved in 10ml of methanol, and 125mg of 5% (v/v ) palladium/carbon, stirred at room temperature under hydrogen flow for 3.5 hours. After filtration through celite, methanol was distilled off. The resulting residue was mixed with 1 ml of triethylamine and 159 mg (0.50 mmol) of 6,7,8-trifluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-bis in 10 ml of acetonitrile Hydrogen-5-hydroxy-4-oxoquinoline-3-carboxylic acid were mixed and the prepared mixture was heated at reflux for 1 hour. After the reaction was completed, the reaction solution was mixed with 10% citric acid and extracted with chloroform (50ml×3). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. To the obtained residue was added dropwise 5 ml of concentrated hydrochloric acid, followed by stirring at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, and the precipitated crystals were collected by filtration. The resulting filtrate was extracted with chloroform (100ml×3), the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Thereafter, the resulting residue and the collected crystals were combined and recrystallized from ethanol-liquid ammonia to obtain 227 mg (82%) of the title compound. Melting point: 199-201°C

¹ H-NMR (400 MHz, 0.1N NaOD) δ:

0.55(4H, s), 1.76-0.64(3H, m), 2.05-1.94(1H, m),

2.27-2.14(1H, m), 3.58-3.38(3H, m), 3.76-3.65

(1H, m), 3.87-3.76 (1H, m), 5.07-4.81 (1H, m), 8.12

(1H, s).[α] _D ²¹ =-159.33, (c=0.625, 0.1 N aqueous sodium hydroxide solution)

Elemental analysis C ₂₀ H ₂₀ F ₃ N ₃ O ₄ 1/3C ₂ H ₅ OH 3/4H ₂ O

Calculated value: C54.89 H5.24 N9.29

Measured value: C54.94 H5.35 N9.32 Inventive Example 29: 5-amino-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methanol yl-7-[3-(R)-(1-methylaminocyclopropyl)-1-pyrrolidinyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate hydrochloride

5% palladium/ Activated carbon catalyst (moisture content 55.6%, 1.0 g). The mixture was stirred at room temperature at an initial hydrogen pressure of 4.5 kg/ ^cm2 for 3 hours, then filtered through celite with ethanol to remove the catalyst. The filtrate was concentrated in vacuo and to a solution of the resulting amorphous residue in dimethylsulfoxide (7.5ml) were added triethylamine (3.8ml) and 5-amino-6,8-difluoro-1-[2-(S) -Fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (351.1mg, 1.124mmol), the mixture was stirred at 150°C under nitrogen atmosphere 15 hours. After cooling, the resulting mixture was concentrated in vacuo to remove dimethylsulfoxide and dissolved in chloroform (100ml). The solution was washed with 10% citric acid (100ml) and saturated aqueous sodium chloride solution (100ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo. To the obtained residue was added dropwise 35% hydrochloric acid (10ml) at 0°C, and the mixture was stirred at room temperature for 1 hour, and then washed with dichloromethane (50ml×2). The aqueous layer was adjusted to pH 7.4 with 1N sodium hydroxide solution, followed by extraction with chloroform (100ml x 4). The combined organic layers were dried over anhydrous magnesium sulfate, then concentrated in vacuo. The resulting residue was purified by recrystallization from 2-propanol-isopropyl ether. To a solution of the resulting precipitate in ethanol (20ml) was added 1N hydrochloric acid (2.0ml) at 0°C, and the mixture was stirred at 0°C for 5 minutes, then concentrated to dryness in vacuo. After adding diethyl ether to the residue, the resulting precipitate was purified by recrystallization from 2-propanol-ethanol, and then dried under vacuum at 80°C for 37 hours to give the desired product (288.3 mg, 54.7%) as a pale yellow powder. Melting point: 196.3-198.6°C (decomposition) [α] _D ^22.8 = -620.95° (c = 0.422, H ₂ O) ¹ H-NMR (400 MHz, D ₂ O) δ:

8.51 (1H, d, J = 3.51Hz), 5.02 and 4.91 (1H, m), 4.03

-3.83(1H, m), 3.60-3.41(2H, m), 3.39-3.21(1H,

m), 2.93-2.83(1H, m), 2.81(3H, s), 2.21(3H, s),

2.17-2.11 (1H, m), 1.83-1.61 (3H, m), 1.59-1.39

(1H, m), 1.19-1.09 (1H, m), 0.64-0.59 (4H, m).

Elemental analysis C ₂₂ H ₂₆ F ₂ N ₄ O ₃ ·HCl

Calculated value: C53.27; H6.08; N11.30

Found values: C53.19; N6.11; N11.21 Reference Example J-1: dimethyl 4-(1,1-diethoxycarbonylethyl)-3,5,6-trifluorophthalate ester

Under ice cooling, dimethyl malonate (34.84 g, 0.20 mol) was added to a suspension of 80% NaH (8.0 g, 0.20 mol) in DMF (300 ml). Dimethyl tetrafluorophthalate (53.23 g, 0.20 mol) was added to the mixture and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (1000ml) and the solution was washed with water (3 x 500ml), dried over anhydrous sodium sulfate and evaporated to give 83.7g of the title compound as a pale yellow oil. ¹ H-NMR (400 MHz, D ₂ O) δ:

1.27(6H, t, J=7Hz), 1.85(3H, s), 3.91(3H, s),

3.97(3H, s), 4.26(2H, q, J=7Hz), 4.27(2H, q, J=

7Hz). Reference Example J-2: 4-(1-carboxyethyl)-3,5,6-trifluorophthalic acid

A mixture of 4-(1,1-diethoxycarbonylethyl)-3,5,6-trifluorophthalic acid dimethyl ester (12.9g, 30.7mmol), hydrochloric acid (120ml) and acetic acid (120ml) Reflux for 24 hours. The reaction mixture was concentrated to dryness to obtain 9.0 g of the title compound as colorless crystals. ¹ H-NMR (400 Mhz, D ₂ O) δ:

1.45 (3H, d, J=7.4Hz), 4.25-4.32 (2H, m). Reference Example J-3: 3-Ethyl-2,4,5-trifluorobenzoic acid

A mixture of 4-(1-carboxyethyl)-3,5,6-trifluorophthalic acid (14.9g, 47.9mmol), dimethyl sulfoxide (100ml) and triethylamine (30ml) was heated at 140°C It was heated for 4 days and the reaction mixture was concentrated to dryness. 1N HCl (100ml) was added to the residue, and the solution was extracted with ether. The extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to give 9.27 g of the title compound as pale yellow crystals. ¹ H-NMR (400 MHz, CDCl ₃ ) δ:

1.24(3H, 7, J=7Hz), 2.78(2H, q, J=7Hz), 7.67-

7.73 (1H, m), 8.5-9.3 (1H, broad). Reference example K-1: 5-amino-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-tri Hydrogen-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester

1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylic acid ethyl ester (1.72g, 4.45mmol) was dissolved in a mixed solvent of THF (40ml) and EtOH (40ml), Raney nickel (1ml) was added to the solution and the mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. After the Raney nickel was filtered off and the solvent was evaporated, the residue was purified by column chromatography on silica gel with 3% MeOH- _CHCl3 to afford 1.33 g (84%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ): δ

1.39(3H, t, J=6.84Hz), 1.40-1.60(2H, m), 3.76-

3.82(1H, m), 3.86(3H, s), 4.38(2H, q, J=6.84Hz),

4.72-4.76(0.5H, m), 4.88-4.92(0.5H, m), 8.40(1H,

s) Reference Example K-25-amino-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3 -carboxylic acid

5-Amino-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid ethyl ester ( 1.33g, 3.73mmol) was suspended in a mixed solvent of EtOH (10ml) and MeOH (5ml), 1N NaOH (8ml) was added to the suspension and the mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated, concentrated hydrochloric acid was added to the residue under ice cooling, and the precipitated crystals were washed with water and EtOH to obtain 1.0 g (82%) of the title compound. Invention Example 30: 5-amino-7-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R) -cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

1-tert-butoxycarbonylamino-3-azabicyclo[3.1.0]hexane (fraction 1) (350 mg, 1.77 mmol) and triethylamine (2 ml) were added to 5-amino-6,7-difluoro -1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (335mg, 1.02mmol) DMSO (8ml) solution. The mixture was heated at 100°C for 24 hours and the solvent was distilled off. CHCl ₃ (20 ml) was added to the residue and insoluble material was filtered off. The filtrate was washed with 10% citric acid solution (10ml×2), dried over anhydrous sodium sulfate, and then the solvent was distilled off. Concentrated hydrochloric acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was washed with CHCl ₃ (10 ml×2), the aqueous layer was neutralized to pH 7.3 with 20% aqueous NaOH, and extracted with CHCl ₃ (30 ml×3). The extract was dried over anhydrous MgSO ₄ and the solvent was evaporated to give 240 mg (58%) of crude product. The crude product was recrystallized from EtOH-28% _NH3 solution to obtain 120 mg of the title compound. Melting point: 219-230°C (decomposition) ¹ H-NMR (400 MHz, 0.1N-NaOD): δ

0.62-0.65 (1H, m), 0.78-0.82 (1H, m), 1.21-1.52

(3H, m), 3.37 (3H, s), 3.42 (1H, d, J=9.28Hz), 3.52

(2H, brs), 3.63-3.69 (1H, m), 3.83-3.90 (1H, m),

4.75-4.81(0.5H, m), 4.90-4.95(0.5H, m), 8.26(1H,

s). Inventive Example 31: 5-Amino-7-[(3R, 1′S)-3-(1-methylaminoethyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R , 2S)-2-fluorocyclopropyl]-1.4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

(3R, 1'S)-3-[1-(N-methyl)-tert-butoxycarbonylaminoethyl]pyrrolidine (369 mg), 5-amino-1-[(1R, 2S)-(2 -fluorocyclopropyl]-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (312mg), DMSO (5ml) and triethylamine ( 5ml) were mixed. The mixture was stirred for 3 days at 120°C under a nitrogen atmosphere, and the solvent was evaporated. Concentrated hydrochloric acid (5ml) was added to the residue, and the mixture was stirred for 30 minutes. The aqueous layer was adjusted to pH 11 with NaOH solution, and then adjusted with 1N HCl to pH 7.40 and extracted with CHCl ₃ (500ml×3). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized in isopropanol to obtain 125mg of the title compound.

Elemental analysis C ₂₁ H ₂₆ F ₂ N ₄ O ₃ 1/4H ₂ O

Calculated value: C59.35 H6.29 N13.18

Measured value: C59.41 H6.21 N12.95

Industrial Applicability

The heterocyclic compound of the present invention has antibacterial activity against various types of bacteria, and thus can be used as an antibacterial drug.

Table 1 Bacteria/Compound (Example No.) 1 1 2 2 3 3 8 Escherichia coli, NIHJ ≤0.003 ≤0.003 ≤0.003 ≤0.003 Shigella flexneri, 2A 5503 ≤0.003 0 ≤0.003, 0 ≤0.003 Proteus 08601 0.013 ≤0.003 ≤0.003 0.025 Strange Transformers, IFO-3849 0.025 0.013 0.013 0.05 viscosity Sandal bacteria, 10100 0.05 0.025 0.10 copper green monolobacteria, 32104 0.05 0.10 0.10 copper solid bacteria, 32 copper 32, 32 copper. 0.025 0.05 Matsylobe, IID-1275 0.025 0.05 0.05 0.10 Staphylococcus aureus, 209P ≤ 0.003 ≤0.003 0.006 ≤0.003 Epitrobal Staphylococcus, 56500 0.013 0.025 0.006 Perisia, G-36 0.013 0.05 ≤05 ≤05 ≤05 ≤ 00 Streptococcus faecalis, ATCC-19433 0.05 0.05 0.10 0.025 Staphylococcus aureus, 87037 0.10 0.10 0.20 0.05

Table 1 (continued) bacterial/compound (Example No. 9 10 16 23 E. coli, NIHJ 0.006 ≤0.003 ≤0.003 ≤0.003 Fahrenham, 2A 5503 0.006 ≤0.003 ≤0.003 ≤0.003 normal deformation bacteria, 08601 0.013 0.006 ≤0.003 0.013 Strange Transformers, IFO-3849 0.10 0.006 0.013 0.025 sticky Sandachi, 10100 0.025 0.05 0.05 copper green monolithic bacteria, 32104 0.0505 0.10 copper green bacteria, 3.21211111 0.025 Malt-pseudo-bacteria, IID-1275 0.20 0.006 0.05 0.10 Golden Bacillus, 209P ≤ 0.003 ≤ 0.003 ≤0.003 Epigary Poilis, 56500 ≤ 0.003 ≤0.003 ≤0.003 olsine, G-36 ≤ 0.003 ≤0.003 ≤0.003 ≤0.003 Streptococcus faecalis, ATCC-19433 0.025 0.013 0.025 0.013 Staphylococcus aureus, 87037 0.025 0.006 0 0.025

Table 1 (Continued) Bacteria/Compound (Example No.) 28 Ofloxacin Escherichia coli, NIHJ ≤0.003 0.025 Shigella flexneri, 2A 5503 ≤0.003 0.05 Proteus vulgaris, 08601 0 2 0 5 0 , IFO-3849 0.013 0.10 sticky Sandrobacteria, 10100 0.025 0.10 copper green fake monolm, 32104 0.10 0.39 copper green single bacteria, 32121 0.025 0.20 malt pseudolytic bacteria, IID-1275 0.006 0.39 golden pornis bacteria , 209p ≤0.003 0.20 Epidermiococcus, 56500 ≤0.003 0.78 pus, germ, G-36 ≤0.003 1.56 dung link bacteria, ATCC-19433 0.013 1.56 Staphylococcus aureus, 87037 0.006> 6.25

Claims (7)

1. An N ₁ -(halocyclopropyl)-substituted pyridonecarboxylic acid derivative or a salt thereof represented by the following formula (I):

Wherein X ¹ represents a halogen atom or a hydrogen atom; X ² represents a halogen atom; R ¹ represents a hydrogen atom, a hydroxyl group, a mercapto group, a halomethyl group, an amino group, an alkyl group containing 1-6 carbon atoms or an alkoxy group containing 1-6 carbon atoms, wherein the amino group may contain , a substituent of an alkyl group containing 1-6 carbon atoms and an acyl group containing 2-5 carbon atoms, provided that when the substituent is an alkyl group, wherein the alkyl groups may be the same or different from each other, then the amino group may be dialkyl-substituted; R ² is a group shown in the following formula (II): Wherein R ^{and R} independently represent a hydrogen atom or an alkyl group containing 1-6 carbon atoms, and n is an integer of 1 or 2; A represents a nitrogen atom or a partial structure of the following formula (III): Wherein ^X represents a hydrogen atom, a halogen atom, a cyano group, an amino group, an alkyl group containing 1-6 carbon atoms, a halomethyl group, an alkoxy group or a halomethoxy group containing 1-6 carbon atoms, wherein The amino group may contain a substituent selected from formyl, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms, provided that when the substituent is an alkyl group, the alkyl group may the same or different from each other, the amino groups may be dialkyl-substituted; and R represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-dihydroindenyl, 2-benzo[c ] furanone alkynyl (phthalidynyl), 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, An alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group consisting of an alkylene group having 1 to 6 carbon atoms and a phenyl group. 2. The compound or salt thereof according to claim 1, wherein said halocyclopropyl group in formula (I) is 1,2-cis-2-halocyclopropyl group. 3. The compound or salt thereof according to claim 2, wherein ^R2 in formula (I) is a stereochemically pure substituent. 4. The compound or salt thereof according to claim 1, 2 or 3, wherein said halocyclopropyl group in formula (I) is a stereochemically pure substituent. 5. The compound or salt thereof according to claim 4, wherein the halocyclopropyl is (1R,2S)-2-halocyclopropyl. 6. The compound or salt thereof according to claim 5, wherein ^X2 is a fluorine atom. 7. An antibacterial composition, wherein said composition comprises the above-mentioned compound of formula (I) or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier.