KR100499366B1 - Novel pyridonecarboxylic acid derivatives or salts thereof and antibacterial agents comprising the same as active ingredient - Google Patents

Abstract

Formula 1

[Wherein, R ¹ represents a hydrogen atom or a carboxy protecting group, R ² represents a nitro group or a substituted or unsubstituted amino group, R ³ represents a halogen atom, and R ⁴ and R ⁵ may be the same or different hydrogen; An atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁶ represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or an amino group, R ⁷ represents a hydrogen atom or a halogen atom, and A represents a nitrogen atom or -CX = (Wherein X represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group), and Z represents a saturated cyclic amino group which may have a halogen atom or a substituent. Or an antimicrobial agent containing the same.

Description

Novel pyridonecarboxylic acid derivative or its salt and an antimicrobial agent containing the substance as an active ingredient {NOVEL PYRIDONECARBOXYLIC ACID DERIVATIVES OR SALTS THEREOF AND ANTIBACTERIAL AGENTS COMPRISING THE SAME AS ACTIVE INGREDIENT}

The present invention relates to a novel pyridonecarboxylic acid derivative or salt thereof having excellent antibacterial action and oral absorption and an antimicrobial agent containing the same.

Among the compounds having a pyridonecarboxylic acid as a basic skeleton, since they have excellent antimicrobial activity and broad antimicrobial spectrum, they are known to be useful as synthetic antimicrobial agents. Among them, norfloxacin (Japanese Patent Application Laid-Open No. 53-141286), Enoxashin (Japanese Patent Application Laid-Open No. 55-31042), Ofloxacin (Japanese Patent Application Laid-Open No. 57-46986), and Ciprofloxacin (Japanese Patent Application Laid-Open No. 58-76667) , Tosfloxacin (Japanese Patent Application Laid-Open No. 60-228479) and the like are widely used in the clinical treatment of infectious diseases.

However, these compounds are still insufficient in terms of antibacterial activity, intestinal absorption, metabolic stability and side effects, in particular, phototoxicity and cytotoxicity.

(Initiation of invention)

The present invention has been made in view of the above circumstances, and a novel pyridonecarboxylic acid derivative or salt thereof which satisfies antimicrobial activity, intestinal absorption, metabolic stability and side effects, in particular, phototoxicity and cytotoxicity, and an antimicrobial agent containing the same For the purpose of providing it.

In view of the above situation, the present inventors earnestly examined to obtain a compound that can be a clinically excellent synthetic antimicrobial agent, and as a result, the compound represented by the following Chemical Formula 1 has excellent antimicrobial activity against Gram-negative bacteria and Gram-positive bacteria and is very low toxicity. The present invention has been found to be useful as a synthetic antimicrobial agent.

That is, the present invention is represented by the following formula 1

(Wherein R ¹ represents a hydrogen atom or a carboxy protecting group, R ² represents a nitro group or a substituted or unsubstituted amino group, R ³ represents a halogen atom, and R ⁴ and R ⁵ may be the same or different hydrogen). An atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁶ represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group or an amino group, R ⁷ represents a hydrogen atom or a halogen atom, and A represents a nitrogen atom or -CX = A pyridonecarboxylic acid derivative or its salt represented by (wherein X represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) and Z represents a saturated cyclic amino group which may have a halogen atom or a substituent. To provide.

Moreover, this invention provides the antibacterial agent which uses the said pyridonecarboxylic acid derivative or its salt as an active ingredient.

(The best form to carry out invention)

Hereinafter, the present invention will be described in more detail. In addition, in the substituent of the pyridonecarboxylic acid derivative represented by the said Formula (1) of this invention, when the substituent is linear, it shows C1-C7, Especially C1-C 5 is preferable and when it is cyclic, it means a C3-C7 thing.

The carboxy protective group represented by R ¹ in the general formula (1) refers to an ester moiety of a carboxylic acid ester, and includes any of those that dissociate relatively easily and give rise to a corresponding free carboxyl group. Lower alkyl groups such as ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl and heptyl groups; Lower alkenyl groups such as vinyl group, allyl group, 1-propenyl group, butenyl group, pentenyl group, hexenyl group and heptenyl group; Aralkyl groups having 7 to 11 carbon atoms such as benzyl group; Desorption by treatment under mild conditions such as hydrolysis or catalytic reduction such as aryl groups having 6 to 14 carbon atoms such as phenyl group and naphthyl group, or lower alkanoyloxy lower alkyl groups such as acetoxymethyl group and pivaloyloxymethyl group; Lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl group and 1-ethoxycarbonyloxyethyl group; Lower alkoxy lower alkyl groups such as methoxymethyl; Lactonyl groups such as phthalidyl group; Di lower alkylamino lower alkyl groups such as 1-dimethylaminoethyl group; And easily detaching in vivo, such as (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl group. R ¹ is particularly preferably a hydrogen atom.

The substituent in the substituted amino group represented by R ² is, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group Lower alkyl groups such as these; Lower alkenyl groups such as vinyl group, allyl group, 1-propenyl group, butenyl group, pentenyl group, hexenyl group and heptenyl group; Aralkyl groups having 7 to 11 carbon atoms such as benzyl and 1-phenylethyl; C6-C14 aryl groups, such as a phenyl group and a naphthyl group; Lower alkanoyl groups such as formyl group, acetyl group, propionyl group, butyryl group and isobutyryl group; Lower alkoxy carbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group; Aroyl groups having 7 to 15 carbon atoms such as a benzoyl group and naphthoyl; Amino acid residues or oligopeptide residues such as glycyl, leucil, valelyl, alanyl, phenylalanyl, alanyl-alanyl, glycyl-valyl, glycyl-glysil-valyl, and their functional groups are acyl or lower aralkyl And amino acid residues or oligopeptide residues protected by conventional protecting groups in peptide chemistry such as cyclic amino groups. These substituents can be arbitrarily selected from 1 to 2 homogeneous or heterogeneous ones. The compound protected by such an amino acid residue or a peptide residue is expected to improve water solubility.

More preferred R ² includes an amino group, a lower alkylamino group, a lower alkylamino group, a lower alkanoylamino group, an amino acid substituted amino group and an oligopeptide substituted amino group. More preferable examples of R ² include an amino group, a methylamino group, an ethylamino group, a dimethylamino group, a formylamino group, a glycyl-amino group, a leusil-amino group, a valeryl-amino group, an alanyl-amino group, an alanyl-alanyl-amino group, and the like. And double amino groups are particularly preferred.

The halogen atom represented by R ³ , R ⁴ , R ⁵ , R ⁶ or R ⁷ may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, but a double fluorine atom or a chlorine atom is preferable, and a fluorine atom is particularly preferable.

Lower alkyl groups represented by R ⁴ , R ⁵ , R ⁶ and X are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexyl groups , Heptyl group and the like, and a double methyl group is preferable. As a lower alkoxy group represented by R <^4> , R <^5> and X, a methoxy group, an ethoxy group, n-propoxy group, n-butoxy group, t-butoxy group, etc. are mentioned, for example.

Preferred combinations of R ⁴ and R ⁵ are halogen and hydrogen atoms, more preferably R ⁴ is fluorine or chlorine atom, R ⁵ is hydrogen atom, R ⁴ is fluorine atom and R ⁵ is hydrogen atom The case is particularly preferred. In addition, R ⁴ is particularly preferably substituted with a para position of R ² .

Halogen atoms represented by X and Z include fluorine atom, chlorine atom, bromine atom and iodine atom, but fluorine atom and chlorine atom are particularly preferable.

In addition, the compound of Formula 1 has a naphthyridine bone grain when A represents a nitrogen atom, and a quinoline skeleton when A represents -CX =, but when A represents a nitrogen atom and -CCl = Particularly preferred.

The saturated cyclic amino group which may have a substituent represented by Z may further contain one or two or more heteroatoms such as nitrogen atoms, oxygen atoms, sulfur atoms, and carbonyl carbon in the ring, and may be monocyclic or 2-3 tricyclic. good. In the case of monocyclic, a 4-7 membered ring, a 7-11 membered ring in the case of a bicyclic ring, and a 9-15 membered ring in the case of a tricycle are preferable. Such a cyclic amino group is a saturated monocyclic 3 to 7 membered member having one nitrogen atom such as adiridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, or piperazin-1-yl. Cyclic amino groups; For example, Saturated monocyclic 3-7 membered cyclic amino group which has two nitrogen atoms, such as piperazin-1-yl and homopiperazin-1-yl; For example, saturation having a hetero atom selected from an oxygen atom and a sulfur atom in addition to nitrogen atoms such as oxazolidin-3-yl, morpholin-4-yl, thiazolidin-1-yl and thiomorpholin-4-yl Monocyclic 3- to 7-membered cyclic amino group; For example, saturated 2-3-cyclic cyclic amino groups, such as tetrahydroquinolin-1-yl; Eg 2,8-diazaspiro [4.4] nonan-2-yl, 5-azaspiro [2.4] heptan-5-yl, 7-azabicyclo [2.2.1] heptan-7-yl, 2,8-dia Xavicyclo [4.3.0] nonan-8-yl, 5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl, 2, 5-diazabicyclo [2.2.1] heptan-2 5-12 membered cyclic amino groups, such as spiro and crosslinking | saturation, such as -yl, 3, and 8- diazabicyclo [3.2.1.] Octan-3-yl, etc. are mentioned.

The atoms constituting the ring of these saturated cyclic amino groups may be substituted with an appropriate substituent, and examples of such substitutable groups include a hydroxyl group, a lower alkyl group, a substituted or unsubstituted amino group, and a substituted or unsubstituted amino lower group. Alkyl group, lower alkoxy group, a halogen atom, etc. are mentioned.

Here, as the lower alkyl group which can be substituted with a saturated cyclic amino group, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, or the like, and a lower alkoxy group, for example, a methoxy group or an ethoxy group Examples of the carbon atom having 1 to 7 carbon atoms such as a time period and an n-propoxy group include a fluorine atom, a chlorine atom and a bromine atom. Moreover, as a substituent in a substituted amino group and a substituted amino lower alkyl group, the thing similar to what was represented by R <^2> is mentioned among the substituents on the said saturated cyclic amino group, Especially preferable examples of these substituted amino group and substituted or unsubstituted amino lower alkyl group are mentioned. Is methylamino group, ethylamino group, dimethylamino group, aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-amino-1-ethyl group, methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group, leucil- And an amino group, a valeryl-amino group, an alanyl-amino group, an alanyl-alanyl-amino group, and the like.

Among these saturated cyclic amino groups, those represented by the following formulas (a) and (b) are mentioned as preferable groups.

[Wherein Y represents an oxygen atom, a sulfur atom or NR ⁸ (where R ⁸ represents a hydrogen atom or a lower alkyl group), e represents a number from 3 to 5, f represents a number from 1 to 3, and g is The number of 0-2 is represented, J <^1> , J <^2> and J <^3> may be same or different, and a hydrogen atom, a hydroxyl group, a lower alkyl group, an amino lower alkyl group, an amino group, a lower alkylamino group, a lower alkoxy group, and a halogen atom Is displayed.]

Examples of the lower alkyl group, the amino lower alkyl group, the lower alkylamino group, the lower alkoxy group and the halogen atom in the formulas (a) and (b) can be the same as the groups represented by the above R ² to R ⁵ .

Examples of the cyclic amino group represented by the formula (a) include an azetidin-1-yl group, a pyrrolidin-1-yl group, and a piperidin-1-yl group. Examples of the cyclic amino group represented by the formula (b) include Piperazin-1-yl group, morpholin-4-yl group, thiomorpholin-4-yl group, homopiperazin-1-yl group, N-thiazolidinyl group, N-oxazolidinyl group, etc. are mentioned. Among these, the cyclic amino group represented by the formula (a) is more preferable, and the azetidin-1-yl group or the pyrrolidin-1-yl group is particularly preferable.

Particularly preferred specific examples of the groups represented by the formulas (a) and (b) are as follows.

3-aminoazetidin-1-yl group, 3-methylaminoazetidin-1-yl group, 3-dimethylaminoazetidin-1-yl group, 3-aminomethylazetidin-1-yl group, 3-amino-2-methyl Azetidin-1-yl group, 3-amino-3-methylazetidin-1-yl group, 3-alanyl-aminoazetidin-1-yl group, 3-valyl-aminoazetidin-1-yl group, pyrrolidine- 1-yl group, 3-hydroxypyrrolidin-1-yl group, 3, 4-dihydroxypyrrolidin-1-yl group, 3-methoxypyrrolidin-1-yl group, 3-methylpyrrolidin-1 -Yl group, 3-hydroxy-4-methylpyrrolidin-1-yl group, 3-aminopyrrolidin-1-yl group, 3-methylaminopyrrolidin-1-yl group, 3-dimethylaminopyrrolidine- 1-yl group, 3-ethylaminopyrrolidin-1-yl group, 3-diethylaminopyrrolidin-1-yl group, 3-aminomethylpyrrolidin-1-yl group, 3-amino-3-methylpyrroli Din-1-yl group, 3-amino-4-methylpyrrolidin-1-yl group, 3-amino-5-methylpyrrolidin-1-yl group, 3-methylamino-4-methylpyrrolidin-1- Diary, 3-dimethylamino-4-methylpyrroli -1-yl group, 3-ethylamino-4-methylpyrrolidin-1-yl group, 3-diethylamino-3-methylpyrrolidin-1-yl group, 3-diethylamino-4-methylpyrrolidine -1-yl group, 3-aminomethyl-4-methylpyrrolidin-1-yl group, 3-methylaminomethyl-4-methylpyrrolidin-1-yl group, 3-dimethylaminomethyl-4-methylpyrrolidine -1-yl group, 3-ethylaminomethyl-4-methylpyrrolidin-1-yl group, 3- (1-aminoethyl) -4-methylpyrrolidin-1-yl group, 3- (2-aminoethyl) -4-methylpyrrolidin-1-yl group, 3-amino-4-ethylpyrrolidin-1-yl group, 3-methylamino-4-ethylpyrrolidin-1-yl group, 3-dimethylamino-4- Ethylpyrrolidin-1-yl group, 3-ethylamino-4-ethylpyrrolidin-1-yl group, 3-diethylamino-4-ethylpyrrolidin-1-yl group, 3-aminomethyl-4-ethyl Pyrrolidin-1-yl group, 3-methylaminomethyl-4-ethylpyrrolidin-1-yl group, 3-dimethylaminomethyl-4-ethylpyrrolidin-1-yl group, 3-amino-3-methylpyrrole Rollidin-1-yl group, 3-methylamino-3-methylpyrrolidin-1-yl group, 3-dimethyl Mino-3-methylpyrrolidin-1-yl group, 3-amino-3, 4-dimethylpyrrolidin-1-yl group, 3-amino-4, 4-dimethylpyrrolidin-1-yl group, 3-amino -4, 5-dimethylpyrrolidin-1-yl group, 3-amino-2, 4-dimethylpyrrolidin-1-yl group, 3-methylamino-3, 4-dimethylamino-1-yl group, 2-methyl -3-aminopyrrolidin-1-yl group, 2-methyl-3-dimethylaminopyrrolidin-1-yl group, 3-amino-4-methoxypyrrolidin-1-yl group, 3-alanyl-aminopyrrole Rollidin-1-yl group, 3-valyl-aminopyrrolidin-1-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl group, 3-methylpiperazin-1-yl group, 2-methyl Piperazin-1-yl, 3, 4-dimethylpiperazin-1-yl, 3, 5-dimethylpiperazin-1-yl, 3, 3-dimethylpiperazin-1-yl, 3, 4, 5-trimethyl Piperazin-1-yl group, piperazin-1-yl group, 4-aminopiperazin-1-yl group, 4-dimethylaminopiperidin-1-yl group, 4-hydroxypiperidin-1-yl group, morpholine -4-yl group, 2-aminomethylmorpholin-4-yl group, 2-methylamino Morpholin-4-yl group, 2-dimethylaminomorpholin-4-yl group, thiomorpholin-4-yl group, homopiperazin-1-yl group, 4-methyl homopiperazin-1-yl group, N-thiazolidine Diary, N-oxazolidine Diary.

More preferred combinations of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A and Z in formula (1) include R ¹ being a hydrogen atom; R ² is an amino group, a lower alkylamino group, a lower alkylamino group, a lower alkanoylamino group, an amino acid substituted amino group or an oligopeptide substituted amino group; R ³ is a halogen atom; R ⁴ is a halogen atom; R ⁵ is a hydrogen atom; R ⁶ is a hydrogen atom; R ⁷ is a fluorine atom; A is a nitrogen atom, -CH = or -CCl =; Z is the case of group represented by Formula (a). More preferred combinations of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A and Z are those in which R ¹ is a hydrogen atom; R ² is an amino group; R ³ is a fluorine atom or a chlorine atom; R ⁴ is a fluorine atom or a chlorine atom (substituted in the para position of R ² ); R ⁵ is a hydrogen atom; R ⁶ is a hydrogen atom; R ⁷ is a fluorine atom; A is a nitrogen atom or -CCl =; It is the case of group (e = 3 or 4) in which Z is represented by Formula (a).

The pyridonecarboxylic acid derivative or its salt (1) can form both acid addition salts or base addition salts. In addition, this salt includes the thing which formed the chelate salt with a boron compound. Acid addition salts are salts with mineral acids such as (A) hydrochloric acid and sulfuric acid, and (B) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid. And (C) salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and as base addition salts, salts with alkali metals such as (A ') sodium and potassium. , (B ') salts with alkaline earth metals such as calcium and magnesium, (C') ammonium salts, (D ') trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methyl Piperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine, etc. Salts with a nitrogen-containing organic base. Moreover, as a boron compound, lower acyloxy boron, such as boron halides, such as a boron fluoride, and an acetoxy boron, is mentioned.

The pyridone carboxylic acid derivative or its salt (1) may exist as a hydrate or a solvate as well as an unsolvated type. Thus, the compounds of the present invention include all of their crystalline forms and hydration or solvates.

The pyridone carboxylic acid derivative or its salt (1) may exist as an optically active agent. These optically active agents are also included in the compound of the present invention. Compound 1 may also exist as different stereoisomers (cis, trans). These stereoisomers are also included in the compound of the present invention.

A pyridone carboxylic acid derivative or its salt (1) is manufactured by arbitrary methods suited to it according to a substituent type etc., but one example thereof is as follows.

(Step 1) Of the compounds represented by the general formula (1), R ¹ is a hydrogen atom or a lower alkyl group, and Z is a halogen atom is produced by a series of step 1 represented by the following scheme.

(Wherein R ^1a represents a lower alkyl group, R ⁹ represents a lower alkoxy group or group —NR ¹² R ¹³ (wherein R ¹² and R ¹³ each represents a lower alkyl group), and R ¹⁰ and R ¹¹ are each A lower alkyl group, L ¹ represents a halogen atom, Z ¹ represents a halogen atom, R ^2a represents a substituted amino group, and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and A are Has the same meaning.)

That is, compounds (1a) to (1d) of the present invention react compound (A) with orthoformate esters (H) such as ethyl orthoformate or methyl orthoformate, and then react with compound (J), followed by cyclization reaction. The resulting compound (C) is nitrated to compound (1a), and this is reduced to give compound (1b). When this is alkylated or acylated, compound (1c) is obtained. ) Is obtained. Compound (1d) can also be obtained by hydrolyzing compound (1b).

The reaction of the compound (A) and ortho formic acid esters (H) is usually carried out at 0 to 160 ° C, preferably 50 to 150 ° C, and the reaction time is usually 10 minutes to 48 hours, preferably 1 to 10 hours. The amount of ortho formic acid ester used is preferably at least equimolar to the compound (A), particularly about 1 to 10-fold molar.

The reaction with the compound (J) is carried out in a solvent-free or suitable solvent. Moreover, it is desired to add carboxylic anhydrides, such as acetic anhydride, as a reaction adjuvant. The solvent used herein may be any solvent that does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; Aliphatic hydrocarbons such as pentane, hexane, heptane, ligroin and the like; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like; Aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like; Alcohols such as methanol, ethanol, propanol and the like. This reaction is usually performed at 0-150 degreeC, Preferably it is 0-100 degreeC, and reaction time is 10 minutes-48 hours normally. The usage-amount of compound (J) is equimolar or more with respect to compound (A), Preferably it is equimolar-2 times mole.

Another method is to react compound (A) with acetals such as N, N-dimethylformamide dimethylacetal and N-dimethylformamide diethyl acetal, and then react with compound (J) to induce compound (B). You may. As long as the solvent used for reaction with acetals does not affect this reaction, any may be used, for example, the above may be mentioned. The present reaction is usually carried out at 0 to 150 ° C, preferably at room temperature to 100 ° C, and the reaction time is usually 10 minutes to 48 hours, preferably 1 to 10 hours.

Compound (B) is referred to a cyclization reaction to obtain compound (C). This reaction is carried out in a suitable solvent in the presence or absence of a basic compound. The solvent used in this reaction can be used as long as it does not affect the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and the like; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like; Alcohols such as methanol, ethanol, propanol, butanol and the like; And aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide. Moreover, the basic compound used is alkali metals, such as metal sodium and metal potassium; Metal hydrides such as sodium hydride, calcium hydride and the like; Inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; Alkoxides such as sodium methoxide, sodium ethoxide, potassium-t-butoxide and the like; Metal fluorides such as sodium fluoride, potassium fluoride and the like; And organic salts such as triethylamine and 1,8-diazabicyclo [5.4.0] undecene (DBU). The reaction temperature of the present reaction is usually 0 to 200 ° C, preferably room temperature to 180 ° C, and the reaction is usually completed in 5 minutes to 24 hours. The amount of the basic compound used is equal to or greater than the compound (B), preferably equal to 2 moles.

Compound (C) of the present invention can be produced by referencing compound (C) to a nitration reaction. As the nitration, a general method used for nitration of an aromatic compound is applied. Examples of the nitration agent include nitric acid or mixed acid combining nitrate and sulfuric acid, acetyl nitrate, and the like. The amount of mixed acid provided for the reaction is 1 equivalent to 1 equivalent of sulfuric acid relative to 1 equivalent of compound (C), 1 excess equivalent to nitric acid, and the reaction is carried out by adding compound (C) to the mixed acid, for example. The reaction temperature is -10 ° C to 80 ° C and the reaction time is preferably 5 minutes to 5 hours.

Compound (1b) can be obtained by reducing compound (1a).

Reduction is generally carried out using a commonly used method, and for example, a reduced metal reduction using zinc, iron, tin, tin (II) chloride, etc. in an acid solution, sulfides such as sodium sulfide, sodium hydrosulfide, and sodium itionate. And reduction using platinum, a catalytic reduction method using platinum, graphite-graphite (Pt-C), palladium-carbon (Pd-C) and the like.

Compound (1d) in which R ¹ is a hydrogen atom can be obtained by hydrolyzing compound (1b) or by hydrolyzing compound (1b) after alkylation or acylation as desired.

The hydrolysis is applicable to any of the reaction conditions used in the normal hydrolysis reaction, and includes, for example, basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; Mineral acids such as hydrochloric acid, sulfuric acid and hydrobromic acid; Or in the presence of organic acids such as p-toluenesulfonic acid, alcohols such as water, methanol, ethanol and propanol, ethers such as tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone, solvents such as acetic acid, or It is performed in these mixed solvents. This reaction is usually carried out at room temperature to 180 ° C, preferably at room temperature to 140 ° C, and the reaction time is usually 1 to 24 hours.

In the alkylation reaction for obtaining the compound (1c) of the present invention, alkylating agents such as dialkylsulfuric acid, alkyl iodide, and alkyl bromide corresponding to a desired alkyl group, preferably in the presence of a base such as sodium carbonate and potassium carbonate, N, N It can carry out by making it react with compound (1b) at the temperature of about room temperature-about 150 degreeC in solutions, such as -dimethylformamide and N-methylpyrrolidone. Moreover, this alkylation reaction coexists the carbonyl compound corresponding to a desired alkyl group, and can also be performed by the catalytic reduction method using platinum, a nickel, platinum-graphite, and palladium carbon. The acylation reaction can be carried out by any reaction used for acylation of a common amino group. For example, the acyl chloride or acid anhydride and the compound (1b) corresponding to the desired acyl group may be reacted with methylene chloride, chloroform, carbon tetrachloride, chlorobenzene, or the like. Halogenated hydrocarbons; Aromatic hydrocarbons such as benzene and toluene; Pyridine, picoline, N, N-dimethylaniline, N- at 0 ° C to room temperature in ethers such as tetrahydrofuran and dioxane or aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and the like. Reaction at -70 to 100 캜 in the presence or absence of a base such as methyl morpholine, dimethylamine, triethylamine, sodium carbonate or potassium carbonate, or an acid such as formic acid or acetic acid or an acid anhydride thereof at room temperature to 150 캜. It can also be performed by making it react.

In addition, in the formula (1), the compound in which R ⁶ is an amino group is reacted with compound (1a), (1b), (1c) or (1d) by performing the above reaction using compound (A) in which R ⁶ is halogen atom as starting material. After that, it is preferable to obtain by amination of the halogen atom.

In addition, compound (1b) can be synthesized by the following method.

[Wherein, R ¹⁴ represents an amino protecting group, and R ^1a , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ , L ¹ , Z ¹ and A have the same meanings as above.]

That is, by condensing and reducing the acrylic esters (D) and phenylene amines (K) obtained by reacting ortho formic acid esters (H) with the compound (A), the compound (L) is obtained. Compound (1b) can be obtained.

The reaction for obtaining the compound (L) from the compound (A) can be carried out under the same conditions as the reaction for obtaining the compound (C) from the compound (A).

Desorption of amino protecting groups (mainly acyl groups and carbamoyl groups) is performed by hydrolysis with an acid or an alkali. These conditions are the same as those described in the hydrolysis of the compounds (1b) and (1c).

(Step 2) Among compounds represented by the general formula (1), a compound in which Z is a saturated cyclic amino group which may have a substituent is produced by, for example, Step 2 shown in the following scheme.

[Wherein, Z ² represents a saturated cyclic amino group which may have a substituent, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Z ¹ and A have the same meaning as described above. ]

That is, compound (O) is obtained by amination of compound (N) using a compound represented by the formula Z ² -H.

This reaction can be carried out by aromatic hydrocarbons such as benzene, toluene, xylene and the like; Alcohols such as methanol and ethanol; Ethers such as tetrahydrofuran, dioxane, monoglyme and the like; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like; Aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like; Among the solvents which do not affect the reaction of acetonitrile and pyridine, deoxidizers such as sodium carbonate, calcium carbonate, sodium hydrogen carbonate, triethylamine, 1,8-diazabicyclo [5.4.0] undecene (DBU), if necessary ) At room temperature to 160 ° C. The reaction time is several minutes to 48 hours, preferably 10 minutes to 24 hours. The amount of the compound Z ² -H used is preferably at least equimolar to the compound (N), preferably at equimolar to 5-fold molar. When R ¹ is a carboxy protecting group, it can be converted into a hydrogen atom by hydrolysis if desired.

(Step 3) Among the compounds represented by the general formula (1), a compound in which R ¹ is a carboxy protecting group is produced by, for example, Step 3 represented by the following scheme.

[Wherein, R ^1b represents a carboxy protecting group, L ² represents a halogen atom and R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A and Z have the same meaning as above.]

That is, the compound (Q) is obtained by reacting a halogen compound R ^1b -L ² in the compound (P). Solvents used herein include aromatic hydrocarbons such as benzene, toluene and the like; Halogenated hydrocarbons such as methylene chloride, chloroform and the like; Aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like; Inert solvents, such as acetonitrile, are mentioned. The reaction temperature is usually around room temperature to 100 ° C. This reaction is preferably carried out in the presence of a basic compound such as triethylamine, diisopropylethylamine, dicyclohexylamine, DBU, sodium carbonate, potassium carbonate, sodium hydroxide and the like.

If amino, imino, hydroxy, mercapto or carboxyl groups, etc., which are not involved in the present reaction, are present among the starting compounds used in the above steps 1 to 3, then these groups are used in a protected form, and after completion of the reaction, according to the conventional method. The protecting group may be removed. The protecting group may be any one that can be removed without destroying the structure of the compound of the present invention formed by the reaction, and groups commonly used in the chemical field of peptides, amino sugars, and nucleic acids are used.

The raw material compound (A) can be produced by the method described in the following literature or a method equivalent thereto.

1) J. Heterocyclic Chem. 22, 1033 (1985)

2) Liebigs Ann. Chem. 29 (1987)

3) J. Med. Chem. 31, 991 (1988)

4) J. Org. Chem. 35, 930 (1970)

5) Japanese Patent Application Laid-Open No. 62-246541

6) Japanese Patent Application Laid-Open No. 62-26272

7) JP-A 63-145268

8) J. Med. Chem. 29, 2363 (1986)

9) J. Fluorin Chem. 28, 361 (1985)

10) JP 63-198664

11) Japanese Patent Application Laid-Open No. 63-264461

12) JP-A 63-104974

13) European Patent Application No. 230948

14) JP-A 2-282384

15) Publication No. 3-502452

16) J. Het. Chem. 27, 1609 (1990)

The compound of the present invention thus obtained is usually isolated and purified according to the law. Depending on the isolation and purification conditions, it is obtained in the form of a salt, in the form of a free carboxylic acid or a free amine, but these are mutually converted as desired to produce a compound of the present invention of a desired form.

Compound (1) of the present invention or a salt thereof is an antimicrobial agent, and the composition is formulated with a pharmaceutically acceptable carrier for parenteral administration such as injection, stiff rectum, eye drop, oral administration in solid or liquid form, and the like. can do.

Forms of the antimicrobial compositions of the invention for injection may include pharmaceutically acceptable sterile water or non-aqueous solutions, suspensions or emulsions. Examples of suitable non-carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Such compositions may be contained as adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. These compositions can be sterilized, for example, by filtration with a bacterial retention filter or by incorporation of the sterilizing agent in the form of a sterile solid composition which can be dissolved in a sterilizing agent or some other sterile injectable medium immediately before use.

Formulations for topical administration may preferably be added to the compounds of the present invention to add dissolution aids, preservatives, isotonic and thickening agents and the like.

Solid preparations for oral administration include capsules, tablets, pills, powders, and granules. In the preparation of this solid preparation, the compound of the present invention is generally mixed with at least one inert diluent such as sucrose, lactose or starch. This formulation may also use additional substances other than inert diluents such as glidants (such as magnesium stearate) in conventional formulations. In the case of capsules, tablets and pills, a buffer may be used again. An enteric coating may be given to tablets and pills.

Liquid preparations for oral administration include inert diluents commonly used by those skilled in the art, such as pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, including water. In addition to such inert diluents, the composition may be formulated with auxiliaries such as wetting agents, emulsifying agents, suspending agents and sweetening, flavoring and flavoring agents. Formulations for transrectal administration may preferably contain excipients, such as cacao butter or suppository waxes, in addition to the compounds of the present invention.

The dosage of the compound (1) of the present invention depends on the nature of the compound to be administered, the route of administration, the desired treatment time and other factors, but generally about 0.1 to 1000 mg / kg, especially about 0.5 to 100 mg / day, per adult Kg is preferred. Moreover, this daily amount can also be divided | segmented and administered 2-4 times as needed.

Since compound (1) of the present invention and its salt have very high antibacterial effect, low phototoxicity and low cytotoxicity, it can be widely used as a medicine for humans and animals, and as a fish disease drug, pesticide, food preservative, etc. . In addition, the compound of the present invention is expected to have antiviral action, in particular anti-HIV (human immunodeficiency virus) action, and is thought to have an effect on preventing or treating AIDS.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

(Reference Example 1)

Ethyl 7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1- (2, 4, 6-trifluorophenyl) -1, 8-naphthyridine-3-carboxylate:

1.39 ml of 2,4,6-trifluoroaniline 1.39 ml of toluene under ice-cooling in 10 ml of a toluene solution of 6.40 g of ethyl 2- (2, 6-dichloro-5-fluoronicotinoyl) -3-ethoxyacrylate 5 ml of the solution was added dropwise and stirred overnight at room temperature. The solvent is distilled off, ethanol is added, the crystals are filtered off, washed with diethyl ether, and ethyl 2, 6-dichloro-5-fluoronicotinoyl-3-trifluorophenylaminoacrylate is obtained. Carbonic acid in a solution of N, N-dimethylformamide (9 ml) in 2.0 g of ethyl 2,6-dichloro-5-fluoronicotinoyl-3- (2, 4, 6-trifluorophenylamino) acrylate 0.63 g of potassium was added and stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, and the precipitated solid was filtered, washed with ethanol and diethyl ether to obtain 1.38 g of the title compound.

Appearance: Colorless powder

Melting point: 158-160 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.42 (q, J = 7 Hz, 2H), 6.92-7.06 (m, 2H), 8.48 (d, J = 11 Hz, 1H), 8.49 (s, 1H)

(Reference Example 2)

Ethyl 7-chloro-1- (2-chloro-4-fluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 1 except that 2-chloro-4-fluoroaniline was used.

Appearance: Colorless powder

Melting Point: 177-178 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.41 (q, J = 7 Hz, 2H), 7.23 (dd, J = 3 Hz, 8 Hz, 1H), 7.36-7.51 (m, 2H), 8.49 (d, J = 7 Hz, 1H), 8.49 (s, 1H)

(Reference Example 3)

Ethyl 1- (2-chloro-4-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

13 ml of chloroform solution of 2.46 g of ethyl 2- (2,4,5-trifluorobenzoyl) -3-ethoxyacrylate was cooled on ice and 5 ml of chloroform solution of 1.2 ml of 2-chloro-4-fluoroaniline was added. It was dripped and stirred overnight at room temperature. The solvent was distilled off, ethanol was added, the crystals were filtered off, washed with diethyl ether, ethyl 2- (2, 4, 5-trifluorobenzoyl) -3- (2-chloro-4-fluorophenylamino) acrylic The rate was obtained. Potassium carbonate 1.03 in 15 ml of N, N-dimethylformamide solution of 3.00 g of this ethyl 2- (2,4,5-trifluorobenzoyl) -3- (2-chloro-4-fluorophenylamino) acrylate g was added and stirred for 90 minutes at room temperature. The reaction solution was poured into ice water, and the precipitated solid was filtered off, washed with ethanol and diethyl ether to obtain 2.74 g of the title compound.

Appearance: colorless crystals

Melting Point: 220 ℃ (Decomposition)

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.39 (q, J = 7 Hz, 2H), 6.54 (dd, J = 6 Hz, 11 Hz, 1H), 7.46 (dd, J = 3 Hz, 7 Hz, 1H), 7.56 ( dd, J = 5 Hz, 9 Hz, 1H), 7.50-7.64 (m, 2H), 8.25-8.38 (m, 1H), 8.34 (s, 1H)

(Reference Example 4)

Ethyl 7-chloro-1- (4-chloro-2-fluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 1 except that 4-chloro-2-fluoroaniline was used.

Appearance: Colorless powder

Melting Point: 216-218 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.34-7.45 (m, 3H), 8.47 (d, J = 9 Hz, 1H), 8.55 (s, 1H)

(Reference Example 5)

Ethyl 7-chloro-6-fluoro-1- (4-fluoro-2-methylphenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 1 except that 4-fluoro-2-methylaniline was used.

Appearance: Colorless powder

Melting point: 199-200 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 2.06 (s, 3H), 4.41 (q, J = 7 Hz, 2H), 7.05-7.17 (m, 2H), 7.23 (d, J = 5 Hz, 1H), 8.48 (d, J = 7 Hz, 1H), 8.51 (s, 1H)

(Example 1)

Ethyl 7-chloro-1- (2, 4-difluoro-5-nitrophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate :

2.00 g of ethyl 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate To the concentrated sulfuric acid was added, 600 mg of potassium nitrate was added in small portions while stirring under ice cooling. After stirring at room temperature for 30 minutes to complete the nitration, the reaction solution was poured while stirring 150 ml of chloroform and 100 ml of ice water, and after stirring for 15 minutes at room temperature, the chloroform layer was dried over anhydrous magnesium sulfate. Concentrated under reduced pressure. The precipitated crystals were dispersed in ethanol, filtered and washed with ethanol and diisopropyl ether in order to obtain 2.08 g of the title compound.

Appearance: Colorless needle crystal

Melting point: 256-257 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.42 (d, J = 7 Hz, 1H), 7.37 (t, J = 9 Hz, 1H), 8.35 (t, J = 7 Hz, 1H), 8.49 (d, J = 7 Hz, 1H), 8.54 (s, 1H)

(Example 2)

7-chloro-6-fluoro-1- (2, 4-difluoro-5-nitrophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

25 ml of 6.0 g of 7-chloro-1- (2, 4-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid Was added to concentrated sulfuric acid, and 5.0g of potassium nitrate was added in small portions while stirring under ice-cooling. The temperature was gradually raised and stirred at 80 ° C. for 2 hours. After allowing to cool, it was added to 200 g of ice water and left overnight. The precipitate was filtered off, washed with distilled water, ethanol and diisopropyl ether, and air dried to obtain 6.4 g of the title compound.

Appearance: Colorless powder

Melting Point: 262-265 ℃ (Decomposition)

¹ HNMR (CDCl ₃ ) δ;

8.15 (t, J = 11 Hz, 1H), 8.79 (d, J = 7 Hz, 1H), 8.86 (t, J = 8 Hz, 1H), 9.17 (s, 1H)

(Example 3)

1- (2,4-Difluoro-5-nitrophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid:

4 g of 1- (2,4-difluorophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was added to 40 ml of concentrated sulfuric acid, and calcium nitrate 3.6. A small amount of mg was added and stirred at room temperature for 1 hour. The reaction solution was poured into ice water and stirred overnight. The precipitated solid was filtered off and washed with water, ethanol and diethyl ether. 42 g of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (CDCl ₃ ) δ;

7.70 (dd, J = 6 Hz, 12 Hz, 1H), 8.21 (t, J = 11 Hz, 1H), 8.36 (t, J = 9 Hz, 1H), 8.93 (t, J = 8 Hz, 1H), 9.10 (s, 1H)

(Example 4)

Ethyl 1- (2, 4-difluoro-5-nitrophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

40 ml of dichloroethane in 4.2 g of 1- (2,4-difluoro-5-nitrophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 7 g of oxalyl chloride was dripped under ice cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. 15 ml of ethanol was added dropwise to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, ethanol was added to the residue, the solid was filtered off, and the solid was washed with diethyl ether. 3.7 g of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point: 165-173 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.74 (t, J = 7 Hz, 3H), 4.37 (q, J = 7 Hz, 2H), 7.47 (dd, J = 10 Hz, 11 Hz, 1H), 8.11-8.24 (m, 2H), 8.72 (s, 1H) , 8.93 (t, J = 9 Hz, 1 H)

(Example 5)

1- (2, 4-Difluoro-5-nitrophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

1.7 g of 1- (2,4-difluorophenyl) -6, 7, 8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was added to 10 ml of concentrated sulfuric acid, 1.5 g of potassium nitrate was added little by little and the mixture was stirred overnight at 60 ° C. After cooling, it was poured into iced water and stirred overnight. The precipitated solid was filtered off and washed with water, ethanol and diethyl ether. 1.7 g of the title compound were obtained.

Appearance: Pale yellow powder

Melting point: 245-255 ℃

¹ HNMR (d ₆ -DMSO) δ;

8.17 (t, J = 10Hz, 1H), 8.26 (t, J = 9Hz, 1H), 8.97 (s, 1H), 9.00 (t, J = 8Hz, 1H)

(Example 6)

Ethyl 1- (2, 4-difluoro-5-nitrophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

Except for using 1- (2,4-difluoro-5-nitrophenyl) -6, 7, 8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 4.

Appearance: Colorless Powder

Melting point: 210-217 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.27 (t, J = 7 Hz, 3H), 4.26 (q, J = 7 Hz, 2H), 8.07 (t, J = 11 Hz, 1H), 8.16 (t, J = 10 Hz, 1H), 8.64 (s, 1H) , 9.00 (t, J = 8 Hz, 1H)

(Example 7)

7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -1, 8-naphthyridine-3-carboxyl mountain:

890 mg of 7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1- (2, 3, 4-trifluorophenyl) -1, 8-naphthyridine-3-carboxylic acid 10 mL of concentrated sulfuric acid was added, 730 mg of potassium nitrate was added little by little, and the mixture was stirred at room temperature for 2 days. After cooling, it was poured into iced water and stirred overnight. The precipitated solid was filtered off and washed with water, ethanol and diethyl ether. 860 mg of the title compound were obtained.

Appearance: Yellow Powder

Melting Point: 216-221 ℃

¹ HNMR (d ₆ -DMSO) δ;

8.72-8.84 (m, 2H), 9.11 (s, 1H)

(Example 8)

Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -1,8-naphthyridine-3-car Compound Rate:

7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 4 except for using the acid.

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.42 (q, J = 7 Hz, 2H), 8.18-8.26 (m, 1H), 8.59 (d, J = 8 Hz, 1H), 8.54 (s, 1H)

(Example 9)

6,7-Difluoro-1,4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -quinoline-3-carboxylic acid:

830 mg of 6, 7-difluoro-1, 4-dihydro-4-oxo-1- (2, 3, 4-trifluorophenyl) -quinoline-3-carboxylic acid was added to 10 ml of concentrated sulfuric acid, 710 mg of potassium nitrate was added little by little and stirred at 100 ° C for 3 days. After cooling, it was poured into iced water and stirred overnight. The precipitated solid was filtered off and washed with water, ethanol and diethyl ether. 700 mg of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point:> 215 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

7.76 (dd, J = 6 Hz, 11 Hz, 1H), 8.37 (t, J = 9 Hz, 1H), 8.85 (t, J = 6 Hz, 1H), 9.07 (s, 1H)

(Example 10)

Ethyl 6, 7-difluoro-1, 4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -quinoline-3-carboxylate:

Except for using 6, 7-difluoro-1, 4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 4.

Appearance: Colorless Powder

Melting point: 106-115 ℃

¹ HNMR (CDCl ₃ ) δ;

1.27 (t, J = 7 Hz, 3H), 4.24 (q, J = 7 Hz, 2H), 7.53 (dd, J = 6 Hz, 11 Hz, 1H), 8.16 (t, J = 10 Hz, 1H), 8.69 (s, 1H), 8.83 (t, J = 8 Hz, 1H)

(Example 11)

Ethyl 7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1- (2, 4, 6-trifluoro-3-nitrophenyl) -1, 8-naphthyridine-3-car Compound Rate:

Using ethyl 7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1- (2, 4, 6-trifluorophenyl) -1, 8-naphthyridine-3-carboxylate A title compound was obtained in the same manner as in Example 1 except for the following.

Appearance: Yellow Powder

Melting Point: 177-184 ℃

¹ HNMR (CDCl ₃ ) δ;

1.42 (t, J = 7 Hz, 3H), 4.43 (q, J = 7 Hz, 2H), 7.24 (t, J = 11 Hz, 2H), 8.49 (s, 1H), 8.50 (d, J = 10 Hz, 1H)

(Example 12)

Ethyl 7-chloro-1- (2-chloro-4-fluoro-5-nitrophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Using ethyl 7-chloro-1- (2-chloro-4-fluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate A title compound was obtained in the same manner as in Example 1 except for the following.

Appearance: Colorless needle crystal

Melting Point: 237-242 ℃ (Decomposition)

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.62 (d, J = 10 Hz, 1H), 8.19 (d, J = 8 Hz, 1H), 8.50 (d, J = 8 Hz, 1H), 8.55 (s, 1H)

(Example 13)

Ethyl 1- (2-chloro-4-fluoro-5-nitrophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

As in Example 1, except that ethyl 1- (2-chloro-4-fluorophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was used The title compound was obtained.

Appearance: Pale yellow needle crystal

Melting Point: 216-219 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 6.53 (dd, J = 6 Hz, 12 Hz, 1H), 7.77 (d, J = 11 Hz, 1H), 8.32 (s. 1H), 8.26-8.35 (m, 1H), 8.40 (d, J = 7 Hz, 1H)

(Example 14)

Ethyl 7-chloro-1- (4-chloro-2-fluoro-5-nitrophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Using ethyl 7-chloro-1- (4-chloro-2-fluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate A title compound was obtained in the same manner as in Example 1 except for the following.

Appearance: Colorless needle crystal

Melting Point: 219-221 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.62 (d, J = 10 Hz, 1H), 8.19 (d, J = 8 Hz, 1H), 8.50 (d, J = 8 Hz, 1H), 8.55 (s, 1H)

(Example 15)

Ethyl 7-chloro-6-fluoro-1- (4-fluoro-2-methyl-5-nitrophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Other than using ethyl 7-chloro-6-fluoro-1- (4-fluoro-2-methylphenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate The title compound was obtained in the same manner as in Example 1.

Appearance: Colorless Powder

Melting Point: 215-216 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 2.19 (s, 1H), 4.43 (q, J = 7 Hz, 2H), 7.41 (d, J = 8 Hz, 1H), 8.11 (d, J = 7 Hz, 1H) , 8.50 (s, 1 H), 8.52 (d, J = 8 Hz, 1 H)

(Example 16)

Ethyl 1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate :

Ethyl 7-chloro-6-fluoro-1- (2, 4-difluoro-5-nitrophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate 3.0 g was added to 50 ml of dichloromethane, 30 ml of ethanol, and 2 ml of concentrated hydrochloric acid solution together with 280 mg of 10% palladium carbon and hydrogenated overnight at room temperature. 2 ml of pyridine was added and concentrated under reduced pressure. 80 ml of chloroform and 10 ml of distilled water were added to the residue, and the chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, 8 ml of ethanol was added to the residue, and the mixture was left at room temperature. The precipitate was filtered off, ethanol, diiso It washed with propyl ether in order to obtain 1.95 g of the title compound.

Appearance: Colorless Powder

Melting Point: 208-210 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.27 (t, J = 7 Hz, 3H), 4.24 (q, J = 7 Hz, 2H), 7.11 (t, J = 8 Hz, 1H), 7.47 (t, J = 10 Hz, 1H), 8.53 (d, J = 8 Hz, 1H), 8.71 (s, 1H)

(Example 17)

1- (3-Amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

Ethyl 1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate 4 ml of 3N hydrochloric acid-acetic acid mixture was added to 0.6 g, and the mixture was heated to reflux for 2 hours. After 3 ml of distilled water was added to reflux for 5 minutes, the precipitate was filtered off and washed with ethanol to obtain 0.54 g of the title compound.

Appearance: Yellow Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

5.46 (s, 2H), 7.00 (t, J = 8 Hz, 1H), 7.43 (t, J = 10 Hz, 1H), 8.76 (d, J = 8 Hz, 1H), 8.97 (s, 1H)

(Example 18)

Ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

60 ml of acetic acid 3.7 g of ethyl 1- (2,4-difluoro-5-nitrophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate It dissolved in and 400 mg of 10% palladium carbon was added. It stirred for 2 days at room temperature under hydrogen atmosphere. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was filtered and washed with diethyl ether. 2.9 g of the title compound were obtained.

Appearance: Yellow Powder

Melting point: 198-205 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.28 (t, J = 7 Hz, 3H), 4.23 (q, J = 7 Hz, 2H), 5.52 (s, 2H), 7.01 (t, J = 9 Hz, 1H), 7.19 (dd, J = 6 Hz, 10 Hz, 1H), 8.14 (t, J = 9 Hz, 1H), 8.54 (s, 1H)

(Example 19)

1- (3-Amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

1 g of ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate was added to 8 ml of acetic acid, It was added to 2 ml of hydrochloric acid and heated to reflux overnight. After cooling, the reaction solution was concentrated under reduced pressure, ethanol was added to the residue, and the solid was filtered and washed with diethyl ether. 830 mg of the title compound were obtained.

Appearance: Colorless Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.14 (t, J = 9 Hz, 1H), 7.47 (dd, J = 6 Hz, 10 Hz, 1H), 7.54 (t, J = 10 Hz, 1H), 8.34 (t, J = 10 Hz, 1H), 8.89 (s, 1H)

(Example 20)

Ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

Methanol 2.2 g of ethyl 1- (2,4-difluoro-5-nitrophenyl) -6, 7, 8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate 20 mL, 50 mL of acetic acid and 10 mL of dichloroethane were dissolved, and 200 mg of 10% palladium carbon was added thereto. Stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was filtered off and washed with diethyl ether. 1.12 g of the title compound were obtained.

Appearance: Yellow Powder

Melting Point: 187-196 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.28 (t, J = 7 Hz, 3H), 4.22 (q, J = 7 Hz, 2H), 5.49 (s, 2H), 7.11 (t, J = 8 Hz, 1H), 7.42 (t, J = 10 Hz, 1H) , 8.05 (t, J = 10 Hz, 1H), 8.46 (s, 1H)

(Example 21)

1- (3-Amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

Other than using ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate In the same manner as in Example 19, the title compound was obtained.

Appearance: Colorless Powder

Melting Point: 256-261 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.15-7.30 (m, 1H), 7.49 (t, J = 10 Hz, 1H), 8.25 (t, J = 8 Hz, 1H), 8.77 (s, 1H)

(Example 22)

Ethyl 1- (3-amino-4, 5, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car Compound Rate:

Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- (2, 3, 4-trifluoro-5-nitrophenyl) -1,8-naphthyridine-3-car 780 mg of the carboxylate was dissolved in 5 ml of methanol and 10 ml of acetic acid, and 80 mg of 10% palladium carbon was added. Stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was filtered off and washed with diethyl ether. 200 mg of the title compound were obtained.

Appearance: Brown Powder

Melting Point: 165-174 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.29 (t, J = 7 Hz, 3H), 4.26 (q, J = 7 Hz, 2H), 5.82 (s, 2H), 8.55 (d, J = 8 Hz, 1H), 8.75 (s, 1H)

(Example 23)

1- (3-amino-4, 5, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl mountain:

Ethyl 1- (3-amino-4, 5, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car 600 mg of the carboxylate was dissolved in 30 ml of methanol, 10 ml of acetic acid and 30 ml of dichloroethane, and 100 mg of 10% palladium carbon was added. Stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. 4 ml of acetic acid and 1 ml of hydrochloric acid were added to the residue, and the mixture was heated and stirred overnight at 100 ° C. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was filtered off and washed with diethyl ether. 160 mg of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point:> 242 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

6.87 (t, J = 5 Hz, 1H), 7.76 (d, J = 8 Hz, 1H), 9.02 (s, 1H)

(Example 24)

Ethyl 1- (3-amino-4, 5, 6-trifluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

280 mg of ethyl 6,7-difluoro-1,4-dihydro-4-oxo-1- (2, 3,4-trifluoro-5-nitrophenyl) -quinoline-3-carboxylate 10 ml, 5 ml of acetic acid and 5 ml of dichloroethane were dissolved, and 30 mg of 10% palladium carbon was added. Stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. Ethanol was added to the residue, and the solid was filtered off and washed with diethyl ether. 200 mg of the title compound were obtained.

Appearance: Yellow Powder

Melting point: 116-124 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.27 (t, J = 7 Hz, 3H), 4.22 (q, J = 7 Hz, 2H), 5.85 (s, 2H), 6.83 (t, J = 8 Hz, 1H), 7.42 (dd, J = 6 Hz, 12 Hz, 1H), 8.13 (t, J = 10 Hz, 1H), 8.60 (s, 1H)

(Example 25)

1- (3-Amino-4, 5, 6-trifluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

Other than using ethyl 1- (3-amino-4, 5, 6-trifluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate In the same manner as in Example 23, the title compound was obtained.

Appearance: Pale yellow powder

Melting Point:> 211 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

5.91 (brs, 2H), 6.86 (t, J = 7 Hz, 1H), 7.68 (dd, J = 7 Hz, 11 Hz, 1H), 8.34 (t, J = 9 Hz, 1H), 8.94 (s, 1H)

(Example 26)

Ethyl 1- (3-amino-2, 4, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car Compound Rate:

Ethyl 1- (2, 4, 6-trifluoro-3-nitrophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car The title compound was obtained in the same manner as in Example 16 except for using a carboxylate.

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 6.83-7.04 (br, 2H), 7.22-7.35 (m, 1H), 8.48 (d, J = 8 Hz, 1H) , 8.50 (s, 1H)

(Example 27)

1- (3-amino-2, 4, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl mountain:

Ethyl 1- (3-amino-2, 4, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car The title compound was obtained in the same manner as in Example 17 except for using a carboxylate.

Appearance: Pale yellow powder

Melting Point: 222-228 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.44 (t, J = 11 Hz, 1H), 8.77 (d, J = 8 Hz, 1H), 9.21 (s, 1H)

(Example 28)

Ethyl 1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Ethyl 1- (6-chloro-4-fluoro-3-nitrophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 16 except that the rate was used.

Appearance: Yellow Powder

Melting point: 206-208 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 6.86 (d, J = 8 Hz, 1H), 7.26 (d, J = 11 Hz, 1H), 8.48 (d, J = 8 Hz, 1H), 8.49 (s, 1H)

(Example 29)

1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid :

Ethyl 1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 17 except that the rate was used.

Appearance: Pale yellow powder

Melting Point: 265-267 ℃

¹ HNMR (d ₆ -DMSO) δ;

5.81 (s, 2H), 7.07 (d, J = 8Hz, 1H), 7.52 (d, J = 11Hz, 1H), 8.76 (d, J = 7Hz, 1H), 8.93 (s, 1H)

(Example 30)

Ethyl 1- (3-amino-6-chloro-4-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

Except for using ethyl 1- (6-chloro-4-fluoro-3-nitrophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate The title compound was obtained in the same manner as in Example 16.

¹ HNMR (CDCl ₃ ) δ;

1.39 (t, J = 7 Hz, 3H), 4.38 (q, J = 7 Hz, 2H), 6.65 (dd, J = 5 Hz, 12 Hz, 1H), 6.91 (d, J = 9 Hz, 1H), 7.31 (d, J = 11Hz, 1H), 8.28 (q, J = 9Hz, 16Hz, 1H), 8.35 (s, 1H)

(Example 31)

1- (3-Amino-6-chloro-4-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

Except for using ethyl 1- (3-amino-6-chloro-4-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate The title compound was obtained in the same manner as in Example 19.

Appearance: Colorless Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

5.91 (brs, 1H), 7.08 (d, J = 8 Hz, 1H), 7.34 (dd, J = 7 Hz, 11 Hz, 1H), 7.59 (d, J = 12 Hz, 1H), 8.35 (t, J = 11 Hz, 1H), 8.83 (s, 1H)

(Example 32)

Ethyl 1- (3-amino-4-chloro-6-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Ethyl 1- (4-chloro-6-fluoro-3-nitrophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 16 except that the rate was used.

Appearance: Pale yellow powder

Melting point: 200-202 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 6.82 (d, J = 7 Hz, 1H), 7.29 (d, J = 11 Hz, 1H), 8.47 (d, J = 8 Hz, 1H), 8.55 (s, 1H)

(Example 33)

1- (3-amino-4-chloro-6-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid :

Ethyl 1- (3-amino-4-chloro-6-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl 1.00 g of the rate was dissolved in 10 ml of acetic acid, 10 ml of methanol, and 20 ml of dichloroethane, and 132 mg of 10% palladium carbon suspended in 20 ml of acetic acid was added, followed by stirring overnight under hydrogen stream. Palladium carbon was filtered through a membrane filter and 10% sodium hydroxide was added to the filtrate and extracted from chloroform. After drying the organic layer, the solvent was distilled off and the solid was filtered off to obtain 0.380 g of the title compound.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

5.76 (br, 2H), 7.03 (d, J = 9 Hz, 1H), 7.57 (d, J = 10 Hz, 1H), 8.78 (d, J = 8 Hz, 1H). 9.00 (s, 1H)

(Example 34)

Ethyl 1- (3-amino-4-fluoro-2-methylphenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate :

Ethyl 1- (4-fluoro-2-methyl-3-nitrophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 16 except that the rate was used.

Appearance: Pale yellow powder

Melting Point: 212-213 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 1.91 (s, 3H), 3.79-3.96 (br, 2H), 4.40 (q, J = 7 Hz, 2H), 6.70 (d, J = 8 Hz, 1H), 7.02 (d, J = 11 Hz, 1H), 8.50 (d, J = 11 Hz, 1H), 8.50 (s, 1H)

(Example 35)

1- (3-Amino-4-fluoro-2-methylphenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

Ethyl 1- (3-amino-4-fluoro-2-methylphenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate A title compound was obtained in the same manner as in Example 17 except for using.

Appearance: Colorless Powder

Melting Point: 274-279 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.84 (s, 3H), 6.95 (d, J = 8Hz, 1H), 7.19 (d, J = 12Hz, 1H), 8.75 (d, J = 8Hz, 1H), 8.79 (s, 1H)

(Example 36)

Ethyl 7-chloro-1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car Compound Rate:

Ethyl 7-chloro-6-fluoro-1- (2, 4-difluoro-5-nitrophenyl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate 3.5 g was added to 20 ml of dichloromethane, 10 ml of formic acid, and 0.3 ml of concentrated hydrochloric acid with 280 mg of 10% palladium carbon and hydrogenated at room temperature for 5 hours. 1.2 ml of acetic anhydride was added thereto, and the mixture was left at room temperature for 1 hour. The catalyst was filtered off, concentrated under reduced pressure, and the precipitate was dispersed in ethanol, washed with ethanol and diisopropyl ether in order to obtain 2.65 g of the title compound.

Appearance: Colorless Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.28 (t, J = 7 Hz, 3H), 4.25 (q, J = 7 Hz, 2H), 7.77 (dd, J = 10 Hz, 11 Hz, 1H), 8.35 (s, 1H), 8.45 (t, J = 8 Hz, 1H), 8.54 (d, J = 8 Hz, 1H), 8.77 (s, 1H)

(Example 37)

7-chloro-1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl mountain:

1- (3-Amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid 465 The mg was dissolved in 1 ml of formic acid, 0.2 g of acetic anhydride was added, and the mixture was stirred at 60 ° C for 1 hour. Concentrated under reduced pressure, 2 ml of ethanol was added to the residue, and the mixture was stirred at 60 ° C for 2 hours. The precipitate was washed with filtration, ethanol and diisopropyl ether in order to obtain 450 mg of the title compound.

Appearance: Colorless Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.46 (brs, 1H), 7.78 (dd, J = 10 Hz, 11 Hz, 1H), 8.35 (s, 1H), 8.50 (t, J = 8 Hz, 1H), 8.76 (d, J = 8 Hz, 1H), 9.08 (s, 1H)

(Example 38)

Ethyl 7-chloro-1- (2, 4-difluoro-5-formylmethylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3- Carboxylate:

Ethyl 7-chloro-1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car 500 mg of carboxylate was added to 2.5 ml of N and N-dimethylformamide together with 500 mg of calcium carbonate and 1.5 g of methyl iodide, followed by stirring at 50 ° C for 1 hour. 40 ml of chloroform and 150 ml of distilled water were added and the mixture was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was dispersed in ethanol, filtered, washed with ethanol and diisopropyl ether, and then labeled with 455 mg. The compound was obtained.

Appearance: Colorless Crystal

Melting Point: 264-267 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 3.34 (s, 3H), 4.42 (q, J = 7 Hz, 2H), 7.27 (t, J = 10 Hz, 1H), 7.39 (t, J = 7 Hz, 1H) , 8.35 (s, 1H), 8.49 (d, J = 7Hz, 1H), 8.56 (s, 1H)

(Example 39)

Ethyl 1- (3-t-butoxycarbonylamino-2, 4-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine -3-carboxylate:

2.0 g of N- (t-butoxycarbonyl) -2 and 6-difluoro-3-nitroaniline were hydrogenated in 20 ml of methanol using 0.2 g of 10% palladium carbon for 3 days at room temperature. After filtration of the catalyst, the filtrate was left as it was. Solution 20 of dichloromethane dissolved in 0.5 mmol / ml ethyl 2- (2 ', 6'-dichloro-5-fluoronicotinoyl) -3-ethoxy-acrylate To ml. The solution was concentrated under reduced pressure, 2.5 g of anhydrous potassium carbonate and 10 ml of N, N-dimethylformamide were added to the residue, followed by stirring at 90 ° C for 30 minutes. After cooling, 100 ml of chloroform and 400 ml of distilled water were added thereto, followed by separating an aliquot, and then the chloroform layer was washed twice with 400 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and left to add 1 ml of ethanol. The residue was subjected to chromatography using 150 g of silica gel (eluent, chloroform-chloroform: methanol = 7.5: 1), and the precipitate from the fraction corresponding to the main product was dispersed in ethanol, filtered, and 575 mg of the title compound was collected. Got it.

Appearance: Colorless Crystal

Melting point: 128-131 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 1.51 (s, 9H), 4.40 (q, J = 7 Hz, 2H), 6.11 (s, 1H), 7.16 (t, J = 11 Hz, 1H), 7.30 (t , J = 7Hz, 1H), 8.48 (d, J = 7Hz, 1H), 8.54 (s, 1H)

(Example 40)

1- (3-Amino-2, 4-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

Ethyl 1- (3-t-butoxycarbonylamino-2, 4-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine 500 mg of -3-carboxylate was added to a mixture of 8 ml of 3N hydrochloric acid and acetic acid, and the mixture was heated under reflux for 3.5 hours. 16 ml of distilled water was added thereto, and the mixture was heated to reflux for 10 minutes and then allowed to cool. 80 ml of chloroform and 10 ml of distilled water were added and the mixture was separated, and the chloroform layer was concentrated under reduced pressure. The precipitate was dispersed in ethanol, filtered, and washed with ethanol and diisopropyl ether in order to obtain 295 mg of the title compound.

Appearance: Yellow Powder

Melting Point: 244-248 ° C (Decomposition)

¹ HNMR (CDCl ₃ ) δ;

4.04 (s, 1H), 6.64 (dt, J = 5Hz, 8Hz, 1H), 7.02 (ddd, J = 2Hz, 8Hz, 10Hz, 1H), 8.52 (d, J = 7Hz, 1H), 8.87 (s, 1H)

(Example 41)

1- (3-benzoylamino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid :

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid 310 MG was added to 920 mg of N and N-dimethylformamide together with 220 mg of benzoic anhydride, followed by stirring at 70 ° C. for 2 hours and 100 ° C. for 2 and a half hours. 50 ml of chloroform and 150 ml of distilled water were added and the mixture was separated. The chloroform layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, 6 ml of ethanol was added to the residue, and the precipitate was filtered, followed by ethanol and diisopropyl ether. The residue was washed to obtain 184 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 260-263 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.53-7.68 (m, 3H), 7.80 (t, J = 10 Hz, 1H), 7.98 (d, J = 8 Hz, 2H), 8.11 (t, J = 7 Hz, 1H), 9.09 (s, 1H), 10.40 (s, 1H)

(Example 42)

Ethyl 7-chloro-1- (2, 4-difluoro-5-methylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Ethyl 1- (5-amino-2, 4-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate 500 mg was added to 10 ml of 1, 2-dichloroethane, 5 ml of methanol, 0.5 ml of acetic acid mixture together with 100 mg of 37% formalin and hydrogenated using 0.08 g of 10% palladium carbon (16 hours). ). After filtration of the catalyst, the filtrate was concentrated under reduced pressure, the residue was dissolved in 50 ml of chloroform, washed with 50% aqueous sodium carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography using 20 g of silica gel (eluent, chloroform) to obtain 150 mg of the title compound.

Appearance: Pale yellow needle

Melting Point: 226-231 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 2.89 (s, 3H), 4.41 (q, J = 7 Hz, 2H), 6.64 (t, J = 7 Hz, 1H), 7.02 (dd, J = 9 Hz, 11 Hz, 1H), 8.47 (d, J = 7 Hz, 1H), 8.59 (s, 1H)

(Example 43)

7-chloro-1- (2, 4-difluoro-5-methylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid :

Ethyl 7-chloro-1- (2, 4-difluoro-5-methylaminophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxyl 150 mg of rate was added to a mixture of 1 ml of 3N hydrochloric acid and acetic acid (1: 1, V / V), and the mixture was refluxed under stirring for 2 hours. 5 ml of distilled water was added thereto, and the mixture was further heated to reflux for 10 minutes, and then allowed to stand. The precipitate was dispersed in ethanol, filtered off, washed with ethanol and diisopropyl ether in order to obtain 70 mg of the title compound.

Appearance: Yellow Crystal

Melting point: 250-252 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.69 (d, J = 5 Hz, 3H), 5.90 (brs, 1H), 7.01 (t, J = 8 Hz, 1H), 7.46 (t, J = 11 Hz, 1H), 8.76 (d, J = 8 Hz, 1H) , 8.99 (s, 1H)

(Example 44)

Ethyl 1- (2, 4-difluoro-5-methylaminophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate:

Except using ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylate The title compound was obtained in the same manner as in Example 42.

Appearance: Yellow Powder

Melting point: 208-216 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.28 (t, J = 7 Hz, 3H), 2.72 (d, J = 4 Hz, 3H), 4.23 (q, J = 7 Hz, 2H), 5.94-6.04 (m, 1H), 7.04 (t, J = 8 Hz, 1H), 7.19 (dd, J = 4 Hz, 10 Hz, 1H), 7.52 (t, J = 10 Hz, 1H), 8.14 (t, J = 10 Hz, 1H), 8.55 (s, 1H)

(Example 45)

1- (2,4-Difluoro-5-methylaminophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid:

Except for using ethyl 1- (2,4-difluoro-5-methylaminophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate The title compound was obtained in the same manner as in Example 43.

Appearance: Brown Powder

Melting Point:> 164 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.71 (s, 3H), 6.01 (brs, 1H), 7.05 (t, J = 8Hz, 1H), 7.39-7.51 (m, 1H), 7.53 (t, J = 10Hz, 1H), 8.34 (t, J = 9 Hz, 1H), 8.90 (s, 1H)

(Example 46)

Ethyl 7-chloro-1- (3-dimethylamino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl Rate:

Ethyl 1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate 500 mg was added to 10 ml of 1, 2-dichloroethane, 5 ml of methanol, 0.5 ml of acetic acid mixture together with 500 mg of 37% formalin and hydrogenated using 0.08 g of 10% palladium carbon (64 hours). ). After filtration of the catalyst, the filtrate was concentrated under reduced pressure to obtain the title compound.

Appearance: Yellow Powder

Melting Point: 158-163 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 2.88 (s, 6H), 4.41 (q, J = 7 Hz, 2H), 6.85 (t, J = 7 Hz, 1H), 7.04 (dd, J = 9 Hz, 12 Hz, 1H), 8.47 (d, J = 7 Hz, 1H), 8.57 (s, 1H)

(Example 47)

7-chloro-1- (3-dimethylamino-4, 6-difluoro-phenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl mountain:

Ethyl 7-chloro-1- (3-dimethylamino-4, 6-difluoro-phenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphth obtained in Example 46 The total amount of lidine-3-carboxylate was added to 4 ml of 3N hydrochloric acid and acetic acid mixture (1: 1, V / V), and the mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated under reduced pressure, and the precipitate was dispersed in ethanol, filtered off, washed with ethanol and diisopropyl ether in order to obtain 295 mg of the title compound.

Appearance: Pale yellow powder

Melting Point: 244-2470 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.79 (s, 6H), 7.41 (t, J = 8 Hz, 1H), 7.57 (dd, J = 10 Hz, 13 Hz, 1H), 8.77 (d, J = 8 Hz, 1H), 9.04 (s, 1H)

(Example 48)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- Oxo, 1,8-naphthyridine-3-carboxylic acid:

1- (3-Amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid 1300 600 mg of (3S) -3-aminopyrrolidine and 1000 mg of triethylamine were added to 6500 mg of N, N-dimethylformamide and stirred at 90 ° C for 1 hour. After cooling, 25 ml of ethanol was added and heated to reflux for 5 minutes. After cooling, the precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 1410 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 260-266 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.81 (m, 1H), 2.06 (m, 1H), 5.36 (brs, 2H), 6.97 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.06 (d, J = 13 Hz , 1H), 8.69 (s, 1H)

(Example 49)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid triethylamine salt:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-niphthyridine-3-carboxylic acid 220 mg, 210 mg of (3S) -3-aminopyrrolidine dihydrochloride and 400 mg of triethylamine were added with 1000 mg of N and N-dimethylformamide, and it stirred at 90 degreeC for 1 hour 30 minutes. After cooling, 10 ml of ethanol was added and heated to reflux for 5 minutes. After cooling by cold, the precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 220 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 245-249 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.06 (t, J = 7 Hz, 9H), 1.66 (m, 1H), 1.92 (m, 1H), 3.44 (q, J = 7 Hz, 6H), 5.35 (s, 2H), 6.96 (t, J = 8 Hz , 1H), 7.35 (t, J = 10 Hz, 1H), 8.02 (d, J = 13 Hz, 1H), 8.66 (s, 1H)

(Example 50)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid dihydrochloride:

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- 100 mg of oxo-1,8-naphthyridine-3-carboxylic acid was dissolved in 2.5 ml of 6N hydrochloric acid, and then concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was triturated and washed with ethanol and diisopropyl ether in order to obtain 97 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 246-250 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.09 (m, 1H), 2.22 (m, 1H), 7.03 (brt. 1H), 7.39 (t, J = 10 Hz, 1H), 8.12 (d, J = 12 Hz, 1H), 8.30 (brs, 2H), 8.72 (s, 1 H)

(Example 51)

1- (3-amino-2, 4-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-4-oxo-1, 4-di Hydro-1,8-naphthyridine-3-carboxylic acid formate:

1- (3-amino-2, 4-difluorophenyl) -7 [(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-4-oxo-1, 4-dihydro After 200 mg of -1,8-naphthyridine-3-carboxylic acid and 200 mg of formic acid were stirred for about 1 minute, ethanol 200 mg was added, and the mixture was stirred at 90 ° C for one minute. 2 ml of ethanol was added, the mixture was stirred at the same temperature for 2 minutes and left to stand. The precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 154 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 223-226 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.75 (m, 1H), 2.00 (m, 1H), 5.36 (s, 2H), 6.96 (t, J = 8 Hz, 1H), 7.35 (t, J = 11 Hz, 1H), 8.04 (d, J = 12 Hz , 1H), 8.26 (s, 1H), 9.68 (s, 1H)

(Example 52)

1- (3-amino-2, 4-difluorophenyl) -7-[(3S) -3-amino pyrrolidin-1-yl] -6-fluoro-4-oxo-1, 4-di Hydro-1,8-naphthyridine-3-carboxylic acid p-toluene sulfonate:

1- (3-amino-2, 4-difluorophenyl) -7 [(3S) -3-amino pyrrolidin-1-yl] -6-fluoro-4-oxo-1, 4-dihydro 100 mg of -1,8-naphthyridine-3-carboxylic acid and 55 mg of p-toluenesulfonic acid hydrate were added to 300 mg of N, N-dimethylformamide and stirred for about 5 minutes. 8 ml of diisopropyl ether was added to the homogenized solution, stirred and left to stand, and the supernatant was removed by decantation. Here, 1 ml of ethanol was added thereto, the mixture was heated to reflux for 2 minutes, and then allowed to cool. The precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 120 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.02 (m, 1H), 2.24 (m, 1H), 2.28 (s, 3H), 3.89 (m, 1H), 5.37 (brs, 2H), 6.96 (t, J = 7 Hz, 1H), 7.11 (d, J = 8Hz, 2H), 7.35 (dt, J = 2Hz, 12Hz, 1H), 7.47 (d, J = 8Hz, 2H), 7.95 (brs, 2H), 8.13 (d, J = 12Hz, 1H), 8.72 (s, 1H)

(Example 53)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-7- (3-hydroxypyrrolidin-1-yl) -4-oxo-1 , 8-naphthyridine-3-carboxylic acid:

150 mg of 1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro 1,8-naphthyridine-3-carboxylic acid , 100 mg of 3-hydroxypyridine and 100 mg of triethylamine were added to 550 mg of N and N-dimethylformamide, followed by stirring at 70 ° C. for 30 minutes. 8 ml of diisopropyl ether was added and left to stand after stirring. The supernatant was removed by decantation.

Then, 2 ml of ethanol was added, and the precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 156 mg of the title compound.

Appearance: Colorless Powder

Melting point: 251-253 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.56 (m, 1H), 1.70-1.95 (m, 3H), 2.58-2.96 (m, 4H), 4.16 (m, 1H), 4.30 (brs, 1H), 5.35 (s, 2H), 6.95 (t, J = 8Hz, 1H), 7.36 (t, J = 10Hz, 1H), 8.01 (d, J = 13Hz, 1H), 8.59 (s, 1H)

(Example 54)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S, 4S) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4 -Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that (3S, 4S) -3-amino-4-methylpyrrolidine dihydrochloride was used.

Appearance: Dark Brown Powder

¹ HNMR (d ₆ -DMSO) δ;

0.93 (d, J = 7 Hz, 3H), 2.17 (m, 1H), 5.35 (s, 2H), 6.97 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 7.99 (d , J = 12 Hz, 1H), 8.65 (s, 1H)

(Example 55)

1- (3-amino-4, 6-difluorophenyl) -7-[(3R, 4R) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4 -Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that (3R, 4R) -3-amino-4-methylpyrrolidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 214-217 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.93 (d, J = 7 Hz, 3H), 2.17 (m, 1H), 5.36 (s, 2H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 7.99 (d , J = 12 Hz, 1H), 8.65 (s, 1H)

(Example 56)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S, 4R) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4 -Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that (3R, 4R) -3-amino-4-methylpyrrolidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 234-240 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.98 (d, J = 7 Hz, 3H), 1.93 (m, 1H), 3.03 (m, 1H), 5.36 (s, 2H), 6.97 (t, J = 8 Hz, 1H), 7.37 (t, J = 10 Hz , 1H), 8.04 (d, J = 12 Hz, 1H), 8.68 (s, 1H)

(Example 57)

1- (3-amino-4, 6-difluorophenyl) -7-[(3R, 4S) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4 -Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that (3R, 4S) -3-amino-4-methylpyrrolidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 237-241 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.98 (d, J = 6 Hz, 3H), 1.93 (m, 1H), 3.02 (m, 1H), 5.37 (s, 2H), 6.97 (t, J = 8 Hz, 1H), 7.37 (t, J = 10 Hz , 1H), 8.03 (d, J = 13 Hz, 1H), 8.67 (s, 1H)

(Example 58)

1- (3-amino-4, 6-difluorophenyl) -7- (3-amino-4, 4-dimethylpyrrolidin-1-yl) -6-fluoro-1, 4-dihydro- 4-Oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3-amino-4 and 4-dimethylpyrrolidine dihydrochloride were used.

Appearance: Light Brown Powder

Melting Point: 267-269 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

0.86 (s, 3H), 0.95 (s, 3H), 2.88-3.05 (m, 1H), 5.36 (s, 2H), 6.97 (t, J = 8 Hz, 1H), 7.38 (t, J = 10 Hz, 1H ), 8.02 (d, J = 13 Hz, 1H), 8.66 (s, 1H)

(Example 59)

1- (3-amino-4, 6-difluorophenyl) -7- [3- (N-ethylaminomethyl) phyllolidin-1-yl] -6-fluoro-1, 4-dihydro- 4-Oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3- (N-ethylaminomethyl) pyrrolidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 235-244 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.01 (t, J = 7 Hz, 3H), 1.61 (m, 1H), 1.98 (m, 1H), 2.32 (m, 1H), 2.54 (q, J = 7 Hz, 2H), 5.34 (s, 2H), 6.96 (t, J = 8Hz, 1H), 7.35 (t, J = 10Hz, 1H), 8.02 (d, J = 12Hz, 1H), 8.67 (s, 1H)

(Example 60)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- Oxo-quinoline-3-carboxylic acid:

29 mg of 3S-(-)-aminopyrrolidine and 68 mg of triethylamine were added to 1 ml of dimethyl sulfoxide, followed by stirring for 10 minutes, to obtain 1- (3-amino-4, 6-difluorophenyl) -6. , 80-mg of 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid was added, and it stirred at 100 degreeC for 2 hours. After cooling, diethyl ether was added to the reaction solution to remove the supernatant. Ethanol was added to the residue, and the solid was filtered and washed with diethyl ether. 76 mg of the title compound were obtained.

Appearance: Colorless Powder

Melting Point: 213-221 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.62-1.76 (m, 1H), 1.88-2.06 (m, 1H), 3.08 (brs, 1H), 5.53 (s, 2H), 5.92 (d, J = 8 Hz, 1H), 7.03 (t, J = 8 Hz , 1H), 7.50 (t, J = 11 Hz, 1H), 7.85 (d, J = 14 Hz, 1H), 8.61 (s, 1H)

(Example 61)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S, 4S) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4 -Dihydro-4-oxo-quinoline-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 60 except that (3S, 4S) -3-amino-4-methylpyrrolidine was used.

Appearance: Brown Powder

Melting Point: 196-202 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.95 (d, J = 7 Hz, 3H), 2.20 (brs, 1H), 5.53 (s, 2H), 5.88 (d, J = 5 Hz, 1H), 7.02 (m, 1H), 7.50 (t, J = 9 Hz , 1H), 7.85 (d, J = 14 Hz, 1H), 8.60 (s, 1H)

(Example 62)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-7- (pyrrolidin-1-yl) -quinoline-3-carr Acid:

The title compound was obtained in the same manner as in Example 60 except that pyrrolidinine was used.

Appearance: Colorless Powder

Melting Point: 264-268 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.89 (brs, 4H), 5.52 (s, 2H), 5.97 (d, J = 8 Hz, 1H), 7.03 (t, J = 8 Hz, 1H), 7.49 (t, J = 10 Hz, 1H), 7.85 (d , J = 14 Hz, 1H), 8.62 (s, 1H)

(Example 63)

1- (3-amino-4, 6-difluorophenyl) -7-[(1S, 6S) -2, 8-diazabicyclo [4.3.0] nona-8-yl] -6-fluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 60 except that (1S, 6S) -2 and 8-diazabicyclo [4.3.0] nonane were used.

Appearance: Colorless Powder

Melting Point: 226-233 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.53-1.81 (m, 4H), 2.63 (brs, 1H), 2.88 (brs, 1H), 3.51 (m, 2H), 3.83 (brs, 2H), 5.57 (s, 2H), 5.97 (d, J = 8 Hz, 1H), 7.05 (t, J = 9 Hz, 1H), 7.51 (t, J = 10 Hz, 1H), 7.92 (d, J = 14 Hz, 1H), 8.65 (s, 1H)

(Example 64)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6, 8-difluoro-1, 4-dihydro 4-oxo-quinoline-3-carboxylic acid:

Except for using 1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 60.

Appearance: Brown Powder

Melting Point: 204-210 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.67 (m, 1H), 1.95 (m, 1H), 5.42 (s, 2H), 7.08 (m, 1H), 7.37 (t, J = 10 Hz, 1H), 7.78 (d, J = 14 Hz, 1H), 8.45 (s, 1 H)

(Example 65)

1- (3-amino-4, 6-difluorophenyl) -7- (3-hydropyrrolidin-1-yl) -6, 8-difluoro-1, 4-dihydro-4-oxo -Quinoline-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 60 except that 3-hydroxypyrrolidine was used.

Appearance: Pale yellow powder

Melting Point: 144-152 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.81 (m, 2H), 3.79 (m, 1H), 4.29 (brs, 1H), 5.00 (s, 1H), 5.44 (s, 2H), 7.09 (t, J = 8 Hz, 1H), 7.39 (t, J = 10Hz, 1H), 7.80 (d, J = 14Hz, 1H), 8.47 (s, 1H)

(Example 66)

1- [3-amino-2, 4-difluorophenyl] -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid:

1- [3-amino-2, 4-difluorophenyl] -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid The title compound was obtained in the same manner as in Example 48 except for the use.

Appearance: Light Brown Powder

Melting Point: 268-272 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.79 (m, 1H), 2.05 (m, 1H), 5.58 (s, 2H), 6.84 (m, 1H), 7.11 (t, J = 10 Hz, 1H), 8.07 (d, J = 13 Hz, 1H), 8.69 (s, 1 H)

(Example 67)

1- [3-amino-2,4-difluorophenyl] -7-[(3S, 4S) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4 -Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- [3-amino-2, 4-difluorophenyl] -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid The title compound was obtained in the same manner as in Example 48 except for the use.

Appearance: Light Brown Powder

¹ HNMR (d ₆ -DMSO) δ;

0.91 (brd, 1H), 2.14 (m, 1H), 5.58 (s, 2H), 6.83 (m, 1H), 7.10 (t, J = 10 Hz, 1H), 8.02 (d, J = 12 Hz, 1H), 8.65 (s, 1 H)

(Example 68)

1- (3-amino-4, 5, 6-trifluorophenyl) -7- (3S) -3-amino pyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 5, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 60 except for using an acid.

Appearance: Brown Powder

Melting Point:> 256 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.58-1.84 (m, 1H), 1.84-2.23 (m, 1H), 5.74 (s, 2H), 6.81 (t, J = 5 Hz, 1H), 8.03 (d, J = 12 Hz, 1H), 8.73 (s , 1H)

(Example 69)

1- (3-amino-4, 5, 6-trifluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro- 4-oxo-quinoline-3-carboxylic acid:

Except for using 1- (3-amino-4, 5, 6-trifluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid The title compound was obtained in the same manner as in Example 60.

Appearance: Brown Powder

Melting Point: 270 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.61-1.81 (m, 1H), 1.89-2.15 (m, 1H), 5.88 (s, 2H), 6.88 (brs, 1H), 7.85 (d, J = 15 Hz, 1H), 8.69 (s, 1H)

(Example 70)

1- (3-amino-2, 4, 6-trifluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro- 4-Oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-2, 4, 6-trifluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl 70 mg of acid was dissolved in 1 ml of dimethyl sulfoxide, 0.04 ml of 3 (S) -3-aminopyrrolidine 0.018 ml triethylamine was added, and the mixture was stirred at 80 ° C. for 1 hour. Diethyl ether was added to the reaction solution, and the decantation was repeated twice. A small amount of ethanol was added to the residue, and the mixture was refluxed for 10 minutes. The precipitated solid was filtered off, washed with diethyl ether to obtain 51 mg of the title compound.

Appearance: Light color powder

Melting Point: 273-277 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.75-1.78 (m, 1H), 2.00-2.18 (m, 1H), 5.46 (brs, 1H), 7.39 (t, J = 10 Hz, 1H), 8.08 (d, J = 13 Hz, 1H), 8.97 (s , 1H)

(Example 71)

1- (3-amino-6-chloro-4-fluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid The title compound was obtained in the same manner as in Example 70 except for using.

Appearance: Pale yellow powder

Melting point: 249-252 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.74-1.95 (m, 1H), 2.00-2.16 (m, 1H), 5.69 (brs, 2H), 7.00 (d, J = 9 Hz, 1H), 7.47 (d, J = 11 Hz, 1H), 8.02 (d , J = 12 Hz, 1H), 8.61 (s, 1H)

(Example 72)

1- (3-amino-6-chloro-4-fluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4 Oxo-quinoline-3-carboxylic acid:

Except for using 1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1 and 4-dihydro-4-oxo-quinoline-3-carboxylic acid In the same manner as in Example 70, the title compound was obtained.

Appearance: Light Red Powder

Melting Point: 177-182 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.59-1.75 (m, 1H), 1.86-2.07 (m, 1H), 5.78 (d, J = 7 Hz, 1H), 5.89 (brs, 2H), 7.06 (d, J = 9 Hz, 1H), 7.60 (d , J = 11 Hz, 1H), 7.86 (d, J = 14 Hz, 1H), 8.56 (s, 1H)

(Example 73)

1- (3-amino-4-chloro-6-fluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4-chloro-6-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 70 to obtain the title compound.

Appearance: Multicolored Powder

Melting Point:> 258 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.53-1.80 (m, 1H), 1.83-2.06 (m, 1H), 5.56 (brs, 2H), 6.99 (d, J = 7 Hz, 1H), 7.48 (d, J = 10 Hz, 1H), 8.02 (d , J = 13 Hz, 1H), 8.68 (s, 1H)

(Example 74)

1- (3-amino-4-fluoro-2-methylphenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4-fluoro-2-methylphenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid The title compound was obtained in the same manner as in Example 70 except for using.

Appearance: Light color powder

Melting Point:> 165 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.53-1.73 (m, 1H), 1.74-1.98 (m, 1H), 1.83 (s, 3H), 5.25 (br, 2H), 6.75 (d, J = 9 Hz, 1H), 7.09 (d, J = 13 Hz , 1H), 8.02 (d, J = 13 Hz, 1H), 8.48 (s, 1H)

(Example 75)

7-[(3S) -3-Aminopyrrolidin-1-yl] -1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro- 4-Oxo-1, 8-naphthyridine-3-carboxylic acid:

7-chloro-1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 48 except for using the acid.

Appearance: Light Brown Powder

Melting Point: 218-225 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.62 (m, 1H), 1.90 (m, 1H), 7.72 (t, J = 10 Hz, 1H), 8.01 (d, J = 13 Hz, 1H), 8.34 (s, 1H), 8.38 (t, J = 8 Hz , 1H), 8.71 (s, 1H)

(Example 76)

7-[(3S, 4S) -3-amino-4-methylpyrrolidin-1-yl] -1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1 , 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

7-chloro-1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl The title compound was obtained in the same manner as in Example 54 except for using the acid.

Appearance: Colorless Powder

Melting Point: 215-216 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.92 (brd, 3H), 2.15 (m, 1H), 7.71 (t, J = 10 Hz, 1H), 8.01 (d, J = 12 Hz, 1H), 8.34 (s, 1H), 8.38 (t, J = 8 Hz , 1H), 8.78 (s, 1H)

(Example 77)

7-[(3S) -3-aminopyrrolidin-1-yl] -1- (3-benzoylamino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-benzoylamino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 48 to obtain the title compound.

Appearance: Light Brown Powder

Melting point: 197-200 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.65 (m, 3H), 1.92 (m, 1H), 7.51-7.63 (m, 3H), 7.72 (t, J = 10 Hz, 1H), 7.94-8.07 (m, 4H), 8.78 (s, 1H)

(Example 78)

7-[(3S) -3-aminopyrrolidin-1-yl] -1- (2, 4-difluoro-5-methylaminophenyl) -6-fluoro-1, 4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid:

7-chloro-1- (2, 4-difluoro-5-methylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 48 to obtain the title compound.

Appearance: Light Brown Powder

Melting Point: 256-258 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.63 (m, 1H), 1.91 (m, 1H), 2.70 (d, J = 5 Hz, 3H), 5.79 (brs, 1H), 6.96 (t, J = 8 Hz, 1H), 7.39 (t, J = 10 Hz , 1H), 8.02 (d, J = 12 Hz, 1H), 8.68 (s, 1H)

(Example 79)

7-[(3S) -3-aminopyrrolidin-1-yl] -1- (2, 4-difluoro-5-methylaminophenyl) -6-fluoro-1, 4-dihydro-4 Oxo-quinoline-3-carboxylic acid:

The procedure was carried out except that 1- (2,4-difluoro-5-methylaminophenyl) -6, 7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was used. The title compound was obtained in the same manner as in Example 60.

Appearance: Brown Powder

Melting Point: 219-226 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.59-1.78 (m, 1H), 1.91-2.07 (m, 1H), 2.70 (d, J = 5 Hz, 3H), 5.91-6.04 (m, 1H), 7.04 (t, J = 8 Hz, 1H), 7.54 (t, J = 11 Hz, 1H), 7.86 (d, J = 14 Hz, 1H), 8.63 (s, 1H)

(Example 80)

7-[(3S) -3-aminopyrrolidin-1-yl] -1- (3-dimethylamino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4 Oxo-1,8-naphthyridine-3-carboxylic acid:

7-chloro-1- (3-dimethylamino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 48 to obtain the title compound.

Appearance: Light Brown Powder

Melting Point: 248-251 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.63 (m, 1H), 1.91 (m, 1H), 2.77 (s, 6H), 7.36 (t, J = 8 Hz, 1H), 7.49 (t, J = 10 Hz, 1H), 8.02 (d, J = 13 Hz , 1H), 8.74 (s, 1H)

(Example 81)

7-[(3S) -3-aminopyrrolidin-1-yl] -1- [2, 4-difluoro-5- (L-gylsilamino) -phenyl] -6-fluoro-1, 4-Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid 700 MG, (3S) -3- (t-butoxycarbonylamino) pyrrolidine 450 mg, and triethylamine 400 mg were added to 2 mL of N, N-dimethylformamide and stirred at 70 ° C for 30 minutes. 30 ml of diisopropyl ether was added, the mixture was left to stir, and the supernatant was removed by decantation. This was used for the next reaction as it was.

350 mg of N-Boc-glycine and 210 mg of N-methylmorpholine were added to 10 ml of dichloromethane, and 270 µl of isobutyl chloroformate was added thereto and stirred at -20 ° C for 20 minutes. The solution was cooled to -60 占 폚 and 1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3- (t-butoxycarbonylamino) pyrrolidinyl as described above. ] -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid whole quantity was dissolved and added in 10 ml of dichloromethane. The mixture was slowly returned to room temperature and then heated to reflux for 2 hours. After standing at room temperature overnight, 50 ml of chloroform and 10 ml of distilled water were added, the mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. One third of the foamed solid residue was dissolved in 6 ml of acetonitrile, 1.5 ml of 4N hydrogen chloride dioxane solution was added, and the mixture was stirred at room temperature. A precipitate formed in about 1 minute. After stirring overnight, the precipitate was filtered off, dissolved in about 4 ml of distilled water, and a small amount of 10% aqueous sodium hydroxide solution was added thereto to neutralize to pH 8 to form a precipitate. The mixture was heated to reflux for 1 hour, allowed to cool, and the precipitate was filtered off, washed with distilled water, ethanol and diisopropyl ether in the order of 193 mg as a colorless powder to obtain a display compound.

Appearance: Colorless Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.65 (m, 1H), 1.92 (m, 1H), 7.73 (t, J = 11 Hz, 1H), 8.04 (d, J = 13 Hz, 1H), 8.38 (m, 1H), 8.78 (s, 1H)

(Example 82)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3- (L-valylamino) pyrrolidin-1-yl] -1, 4- Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

220 mg of N-Boc-L-valine and 106 mg of N-methylmorpholine were added to 5 ml of dichloromethane, and 140 µl of isobutyl chloroformate was added thereto and stirred at 20 ° C for 20 minutes. The solution was cooled to -60 deg. C, and ethyl-7-[(3S) -3-aminopyrrolidin-1-yl] -1- (2, 4-difluoro-5-formylaminophenyl)- 475 mg of 6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate was added dispersed in 10 ml of dichloromethane. The mixture was slowly returned to room temperature and then stirred at 40 ° C. for 30 minutes. 20 ml of chloroform and 10 ml of distilled water were added, the mixture was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Half the residue solidified into a foam was added to an ethanol mixture of 3 ml of N hydrochloric acid and stirred at 100 ° C for 1 and a half hours. It concentrated under reduced pressure, 3 ml of 1N hydrochloric acid was added to the residue, and it stirred at 100 degreeC for 40 minutes. Concentrated under reduced pressure, and the residue was dissolved in 2 ml of distilled water. A small amount of 10% aqueous sodium hydroxide solution was added to neutralize to pH 8 to form a precipitate. 2 ml of ethanol was added thereto, and the mixture was heated to reflux for 30 minutes.

Appearance: Colorless Powder

Melting Point: 162-167 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.78 (d, J = 7 Hz, 3H), 0.80 (d, J = 7 Hz, 3H), 1.71-1.92 (m, 2H), 1.95-2.10 (m, 1H), 2.88 (d, J = 6 Hz, 1H) , 4.32 (brs, 1H), 5.35 (s, 2H), 6.95 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.06 (d, J = 12 Hz, 1H), 8.69 ( s, 1 H)

(Example 83)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3- (L-valylamino) pyrrolidin-1-yl] -1, 4- Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid monomethane sulfonate:

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3- (L-valylamino) pyrrolidin-1-yl] -1, 4- 215 mg of dihydro-4-oxo-1 and 8-naphthyridine-3-carboxylic acid were added to 4 ml of ethanol together with 24 mg of methanesulfonic acid, followed by stirring under reflux for 30 minutes. After cooling, the precipitate was filtered off, washed with ethanol and diisopropyl ether in order to air dry to obtain 211 mg of the title compound.

Appearance: Colorless Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.87 (d, J = 7 Hz, 6H), 1.84-2.18 (m, 3H), 2.31 (s, 3H), 3.45 (brs, 1H), 4.36 (brs, 1H), 5.36 (s, 2H), 6.96 ( t, J = 8Hz, 1H), 7.32 (m, 1H), 8.06 (brs, 2H), 8.09 (d, J = 12Hz, 1H), 8.64 (d, J = 7Hz, 1H), 8.71 (s, 1H )

(Example 84)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3- (L-leucamino) pyrrolidin-1-yl] -1, 4- Dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 82 except for using N-Boc-L-leucine.

Appearance: Light Brown Powder

Melting Point: 149-154 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.7 (d, J = 7Hz, 3H), 0.82 (d, J = 7Hz, 3H), 1.14-1.37 (m, 2H), 1.54-1.65 (m, 1H), 1.79-1.94 (m, 1H), 1.95 -2.10 (m, 2H), 3.10 (t, J = 7 Hz, 1H), 4.28 (brd, 1H), 5.35 (s, 2H), 6.96 (t, J = 8 Hz, 1H), 7.34 (t, J = 10 Hz, 1H), 8.05 (d, J = 12 Hz, 1H), 8.69 (s, 1H)

(Example 85)

1- (3-amino-4, 6-difluorophenyl) -7- (3-methylaminopiperidino) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthy Lidine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3-methylaminopiperidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 240-242 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.23-1.46 (m, 2H), 1.62-1.87 (m, 2H), 2.11 (d, J = 9 Hz, 3H), 3.82-4.18 (m, 2H), 5.36 (s, 2H), 6.98 (t, J = 7 Hz, 1 H), 7.39 (m, 1 H), 8.09 (d, J = 14 Hz, 1 H), 8.71 (s, 1 H)

(Example 86)

1- (3-amino-4, 6-difluorophenyl) -7- (3-methylaminopiperidin-1-yl) -6-fluoro-1, 4-dihydro-4-oxo-quinoline 3-carboxylic acid:

The title compound was obtained in the same manner as in Example 60 except that 3-methylaminopiperidine dihydrochloride was used.

Appearance: Colorless Powder

Melting Point: 254-258 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.62 (m, 2H), 1.85 (m, 1H), 1.99 (m, 1H), 2.55 (s, 3H), 2.91 (m, 1H), 5.58 (s, 2H), 6.52 (d, J = 7 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.52 (t, J = 10 Hz, 1H), 8.02 (d, J = 13 Hz, 1H), 8.76 (s, 1H)

(Example 87)

1- (3-amino-4, 6-difluorophenyl) -7-piperazino-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl mountain:

The title compound was obtained in the same manner as in Example 48 except for using piperazine.

Appearance: Light Brown Powder

Melting Point: 174-184 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.69 (m, 4H), 3.56 (m, 4h), 5.37 (s, 2H), 6.98 (t, J = 7 Hz, 1H), 7.37 (t, J = 10 Hz, 1H), 8.11 (d, J = 13 Hz , 1H), 8.73 (s, 1H)

(Example 88)

1- (3-amino-4, 6-difluorophenyl) -7- (3, 5-dimethylpiperadino) -6-fluoro-1, 4-dihydro-4-oxo-1, 8- Naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except for using piperazine.

Appearance: Light Brown Powder

Melting Point: 251-256 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

0.96 (brs, 6H), 2.57-2.90 (m, 4H), 4.08 (m, 2H), 5.39 (brs, 2H), 6.98 (t, J = 8 Hz, 1H), 7.41 (t, J = 11 Hz, 1H ), 8.16 (d, J = 13 Hz, 1H), 8.78 (s, 1H)

(Example 89)

1- (3-Amino-4, 6-difluorophenyl) -7-piperazino-6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 60 except that piperazine was used.

Appearance: Pale yellow powder

Melting Point: 192-200 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.14 (m, 4H), 3.25 (m, 4h), 5.58 (brs, 2H), 6.48 (d, J = 7 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.51 (t, J = 10 Hz , 1H), 8.02 (d, J = 13 Hz, 1H), 8.75 (s, 1H)

(Example 90)

1- (3-amino-4, 6-difluorophenyl) -7- (3-methylpiperazino) -6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-carboxyl Acid Dihydrochloride:

35 mg of 3-methylpiperazine and 120 mg of triethylamine were added to 1 ml of dimethyl sulfoxide, followed by stirring for 10 minutes. 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro 80 mg of -1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid was added, and it stirred with 100 degreeC for 2 hours. After cooling, diethyl ether was added to the reaction solution, and the supernatant was removed. Ethanol and hydrochloric acid were added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was filtered off and washed with diethyl ether. 30 mg of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point: 206-213 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.26 (d, J = 7 Hz, 3H), 2.85-3.02 (m, 1H), 6.51 (d, J = 7 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.52 (t, J = 10 Hz, 1H), 8.04 (d, J = 13 Hz, 1H), 8.76 (s, 1H)

(Example 91)

1- (3-amino-4, 6-difluorophenyl) -7- (3, 5-dimethylpiperazine) -6-fluoro-1, 4-dihydro-4-oxo-quinoline-3-car Acid:

The title compound was obtained in the same manner as in Example 60 except that 3, 5-dimethylpiperazine was used.

Appearance: Colorless Powder

Melting Point: 202-210 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.17 (brs, 6H), 2.74 (m, 1H), 3.54 (m, 2H), 5.57 (s, 2H), 6.50 (d, J = 7 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.52 (t, J = 10 Hz, 1H), 8.02 (d, J = 13 Hz, 1H), 8.75 (s, 1H)

(Example 92)

1- (3-amino-6-chloro-4-fluorophenyl) -6-fluoro-7-piperazino-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car Acid:

1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid 100 mg was dissolved in 8 ml of dimethyl sulfoxide, 120 mg of piperazine was added, and the mixture was stirred at 80 ° C. for 1 hour 30 minutes. Diethyl ether was added to the reaction solution, and the decantation was repeated twice. A small amount of ethanol was added to the residue, and the mixture was refluxed for 10 minutes, and then the precipitated solid was filtered off and washed with diethyl ether to obtain 19 mg of the title compound.

Appearance: Dark Brown Powder

Melting Point: 190 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.88 (s, 4H), 3.65 (s, 4H), 5.72 (s, 2H), 7.01 (d, J = 5Hz, 1H), 7.46 (d, J = 11Hz, 1H), 8.17 (d, J = 13Hz , 1H), 8.71 (s, 1H)

(Example 93)

1- (3-Amino-6-chloro-4-fluorophenyl) -6-fluoro-7-piperadino-1, 4-dihydro-4-oxo-quinoline-3-carboxylic acid:

Except for using 1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1 and 4-dihydro-4-oxo-quinoline-3-carboxylic acid In the same manner as in Example 92, the title compound was obtained.

Appearance: Pale yellow powder

Melting point: 228-237 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.81 (s, 4H), 5.91 (brs, 2H), 6.30 (d, J = 7Hz, 1H), 7.10 (d, J = 10Hz, 1H), 7.61 (d, J = 11Hz, 1H), 7.97 (d , J = 12 Hz, 1H), 8.69 (s, 1H)

(Example 94)

1- (3-amino-4-chloro-6-fluorophenyl) -6-fluoro-7-piperazino-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car Acid:

1- (3-amino-4-chloro-6-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 92 to obtain the title compound.

Appearance: Tan powder

Melting Point: 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.87 (brs, 4H), 5.59 (brs, 2H), 7.00 (d, J = 7 Hz, 1H), 7.55 (d, J = 10 Hz, 1H), 8.12 (d, J = 13 Hz, 1H), 8.75 (s , 1H)

(Example 95)

1- (3-amino-4-fluoro-6-methylphenyl) -6-fluoro-7-piperazino-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxyl mountain:

1- (3-amino-4-fluoro-6-methylphenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid The title compound was obtained in the same manner as in Example 92 except for using.

Appearance: Tan powder

Melting Point: 239 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.08 (s, 3H), 2.68 (brs, 4H), 3.48 (brs, 4H), 5.28 (brs, 2H), 6.77 (d, J = 8 Hz, 1H), 7.09 (d, J = 12 Hz, 1H), 8.11 (d, J = 14 Hz, 1H), 8.55 (s, 1H)

(Example 96)

1- (3-amino-2,4-difluorophenyl) -7-[(3S) -3- (formylamino) pyrrolidin-1-yl] -6-fluoro-4-oxo-1 , 4-dihydro-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-2, 4-difluorophenyl) -7 [(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-4-oxo-1, 4-dihydro 210 mg of -1,8-naphthyridine-3-carboxylic acid and 40 mg of formic acid were added to 600 mg of N and N-dimethylformamide, followed by stirring at 120 ° C for 1 hour. 8 ml of diisopropyl ether was added and left to stand after stirring. The supernatant was removed by decantation. Subsequently, 2 ml of ethanol was added thereto, the mixture was heated to reflux for 20 minutes, and then allowed to cool. The precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 180 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 214-216 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.83 (m, 1H), 2.09 (m, 1H), 4.36 (m, 1H), 5.36 (s, 1H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 7.96 (d, J = 4 Hz, 1H), 8.07 (d, J = 13 Hz, 1H), 8.38 (m, 1H), 8.70 (s, 1H)

(Reference Example 6)

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

5 g of ethyl 3-chloro-2, 4, 5-trifluorobenzoyl acetate were added to 3.9 g of ethyl orthoformate and 5.5 of acetic anhydride, and the mixture was heated to reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, 20 ml of chloroform was added to the residue, 2.3 ml of 2,4-difluoroaniline was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, hexane was added to the residue, and the solid was filtered off, ethyl 2- (3-chloro-2, 4, 5, 6-tetrafluorobenzoyl) -3- (2, 4-difluoroamino ) Acrylate was obtained. 2.5 g of calcium carbonate, N, N-dimethyl in 6.3 g of ethyl 2- (3-chloro-2, 4, 5, 6-tetrafluorobenzoyl) -3- (2,4-difluoroamino) acrylate 20 ml of formamide was added, and it stirred at 90 degreeC for 1 hour. After allowing to cool, the reaction solution was poured into ice water to precipitate the precipitate, and washed with water. The precipitate was dissolved in chloroform and washed with water. After drying over magnesium sulfate, the residue was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was filtered off, washed with ethanol and diethyl ether to obtain 5.1 g of the title compound.

Appearance: Colorless Powder

Melting Point: 211-212 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.02-7.12 (m, 2H), 7.44 (m, 1H), 8.31-8.37 (m, 1H), 8.33 (s , 1H)

(Reference Example 7)

Ethyl 5, 6, 7, 8-tetrafluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that ethyl 2, 3, 4, 5, 6-pentafluorobenzoyl acetate was used.

Appearance: Colorless Powder

Melting Point: 172-173 ℃

¹ HNMR (CDCl ₃ ) δ;

1.38 (t, J = 7 Hz, 3H), 4.37 (q, J = 7 Hz, 2H), 7.08 (m, 2H), 7.50 (m, 1H), 8.18 (s, 1H)

(Reference Example 8)

N-ethoxycarbonyl-2, 4-difluoro-m-phenylenediamine methanesulfonic acid salts:

151 g of 2, 4-difluorobenzoic acid was added to 500 ml of concentrated sulfuric acid, and 114 g of potassium nitrate powder was added in small portions over 30 minutes while ice-cooling stirring. The stirring was continued for 1 hour to produce a precipitate on the sherbet. This was added to a water-resistant of 1.51 and stirred for 30 minutes. The precipitate was filtered off, washed with distilled water of 11, air-dried, and then dried under reduced pressure over phosphorus pentoxide to give 164.5 g of 2,4-difluoro-5-nitrobenzoic acid as colorless crystals. Got as.

6.1 g of 2,4-difluoro-5-nitrobenzoic acid was added to 2.0 ml of dichloromethane, and 3 ml of oxalyl chloride, 4 drops of N and N-dimethylformamide were added, the mixture was stirred for 2 hours, and then a solvent and excess The reagent was distilled off under reduced pressure. The residue was dissolved in 6 ml of dichloromethane, and 2.1 g of sodium azide was added to 5 ml of N, N-dimethylformamide and added dropwise while stirring under ice-cooling. After 10 minutes, the mixture was returned to room temperature and stirred for 5 minutes. Then, 45 mL of ethyl ether, 15 mL of n-hexane, and 100 mL of distilled water were added thereto, followed by separation. The organic layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Two-thirds of the residue was aliquoted, and 6 ml of ethanol was added thereto, followed by heating in a hot water bath at 80 DEG C for 2 hours to prepare an ethanol solution of the prepared N-ethoxycarbonyl-2 and 4-difluoro-5-nitroaniline. Got.

14 ml of ethanol was added to the solution, and 2.0 g of methanesulfonic acid and 0.2 g of 10% palladium carbon were added and hydrogenated overnight at room temperature (15 hours). Since there was a precipitate, 20 ml of methanol was added to dissolve and the catalyst was filtered off. The filtrate was concentrated under reduced pressure, and the precipitated scale crystals were filtered off, washed with a mixture of ethanol and diisopropyl ether to obtain the title compound as 4.0 g of non-red crystals.

(Reference Example 9)

N-benzyloxycarbonyl-2, 4-difluoro-m-phenylenediamine:

20.3 g of 2,4-difluoro-5-nitrobenzoic acid was added to 60 ml of dichloromethane, and 10 ml of oxalyl chloride, 15 drops of N, N-dimethylformamide were added, and the mixture was stirred overnight, followed by a solvent and excess reagent. Was distilled off under reduced pressure. The residue was dissolved in 30 ml of dichloromethane, added to 15 ml of N and N-dimethylformamide, and stirred with ice cooling, and 7.5 g of sodium azide was added in small portions. After returning to room temperature for 10 minutes as it was, and stirring for 10 minutes, 100 mL of ethyl ether, 50 mL of n-hexane, and 400 mL of distilled water were added to the solution after shaking. The organic layer was washed twice with 400 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 12.0 g of benzyl alcohol was added, concentrated under reduced pressure, 150 ml of toluene was added thereto, heated for 2 hours in a 40 ° C. hot water bath, heated for 25 hours in a 60 ° C. hot water bath, heated for 1 hour in a 100 ° C. hot water bath, and then concentrated under reduced pressure. Prepared N-benzyloxycarbonyl-2 and 4-difluoro-5-nitroaniline were obtained as a residue to solidify.

84 g of iron powder was added to 300 ml of distilled water and 200 ml of ethanol mixture, and 7 ml of concentrated hydrochloric acid was added little by little while stirring at 80 ° C, followed by stirring for 5 minutes. Subsequently, the entire amount of N-benzyloxycarbonyl-2 and 4-difluoro-5-nitroaniline was dissolved in 100 ml of ethanol and added in small portions to a mild reflux, followed by stirring at 80 ° C. for 15 minutes. 500 ml of benzyl was added and stirred for 5 minutes. The iron powder was filtered off, washed with ethanol, and 200 ml of distilled water was added to shake the liquid. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure through a layer of short silica gel powder. The colorless precipitated crystals were dispersed in diisopropyl ether and filtered off to obtain 18.2 g of the title compound.

(Example 97)

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluoro-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluoro-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

2.5 g of ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate in 15 ml of sulfuric acid Under ice-cooling, 950 mg of potassium nitrate was added in small portions, followed by stirring overnight at room temperature. The reaction solution was poured into ice water and stirred overnight at room temperature. The precipitate was filtered off and washed with water, ethanol and diethyl ether. 2.4 g of the title compound were obtained.

Appearance: Colorless Powder

Melting Point: 209-210 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.43 (t, J = 9 Hz, 1H), 8.30 (s, 1H), 8.36 (m, 2H)

(Example 98)

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluoro-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate 2 g, 10 200 mg of palladium carbon was added to 20 ml of dichloroethane and 10 ml of formic acid, and the mixture was stirred for 3 hours at room temperature under a hydrogen stream, followed by addition of acetic anhydride and stirring overnight. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, the solid was filtered off, and the residue was washed with ethanol and diethyl ether to obtain 1.9 g of the title compound.

Appearance: Colorless Powder

Melting Point: 223-229 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.27 (t, J = 7 Hz, 3H), 4.23 (q, J = 7 Hz, 2H), 7.76 (t, J = 10 Hz, 1H), 8.23 (t, J = 10 Hz, 1H), 8.33 (s, 1H) , 8.47-8.60 (m, 1 H), 8.51 (S, 1 H)

(Example 99)

1- (3-Amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro 1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate 1.8 g was added to 5 ml of hydrochloric acid and 20 ml of acetic acid, and the mixture was heated to reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, ethanol was added to the residue, and the solid was filtered off and washed with diethyl ether. 1.4 g of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point: 225-226.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.09 (t, J = 8Hz, 1H), 7.43 (t, J = 11Hz, 1H), 8.40 (t, J = 9Hz, 1H), 8.69 (s, 1H)

(Example 100)

Ethyl 5-benzyloxy-1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-car Compound Rate:

1.35 g of ethyl 2-benzyloxy-3, 4, 6-trifluorobenzoyl acetate was added to 860 mg of ethyl ortho formate and 1.2 g of acetic anhydride, followed by heat stirring for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure. 20 ml of chloroform was added to the residue, followed by ice cooling. A solution of 20 ml of methanol of 1.2 g of N-ethoxycarbonyl-2, 4-difluoro-m-phenylenediamine methanesulfonate of Reference Example 8 and 0.5 ml of triethylamine Was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 630 mg of potassium carbonate, 5 ml of N and N-dimethylformamide were added to the residue, and the mixture was heated and stirred at 90 ° C for 1 hour. After cooling, the reaction solution was dissolved in chloroform and the organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off. Ethanol and diethyl ether were added to the residue, and the solid was filtered off and washed with diethyl ether. 1.2 g of the title compound were obtained.

Appearance: Yellow Powder

Melting point: 130-134 ℃

¹ HNMR (CDCl ₃ ) δ;

1.33 (t, J = 7 Hz, 3H), 1.38 (t, J = 7 Hz, 3H), 4.26 (q, J = 7 Hz, 2H), 4.38 (q, J = 7 Hz, 2H), 5.32 (s, 2H) , 6.41 (m, 1H), 6.97 (d, J = 3 Hz, 1H), 7.19 (dd, J = 9 Hz, 10 Hz, 1H), 7.26-7.42 (m, 3H), 7.64 (m, 2H), 8.25 ( s, 1H), 8.38 (t, J = 8 Hz, 1H)

(Example 101)

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-5-hydroxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 5-benzyloxy-1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-car 500 mg of carboxylate was added to 5 ml of 48% hydrobromic acid and 5 ml of acetic acid, and the mixture was heated to reflux overnight. After cooling, the mixture was concentrated under reduced pressure, ethanol was added to the residue, and the solid was filtered off and washed with diethyl ether. 130 mg of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₃ -DMSO) δ;

6.64 (dd, J = 6 Hz, 12 Hz, 1H), 6.99 (dd, 8 Hz, 9 Hz, 1H), 7.49 (dd, 10 Hz, 11 Hz, 1H), 8.77 (s, 1H)

(Example 102)

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -6, 7-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxyl Rate:

2.6 g of ethyl 2-methyl-3, 4, 6-trifluorobenzoyl acetate were added to 2.2 mg of ethyl ortho formate and 3.1 g of acetic anhydride, and the mixture was heated and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure. 20 ml of chloroform was added to the residue, and a 10 ml solution of 2.78 g of N-benzyloxycarbonyl-2 and 4-difluoro-m-phenylenediamine of Reference Example 9 was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 1.65 g of potassium carbonate, 10 ml of N and N-dimethylformamide were added to the residue, and the mixture was heated and stirred at 90 ° C for 1 hour. After cooling, the reaction solution was added to ice water, and the precipitated solid was filtered out. The solid was dissolved in chloroform, and the organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off. Ethanol and diethyl ether were added to the residue, and the solid was filtered off and washed with diethyl ether to obtain 2.4 g of the title compound.

Appearance: Colorless Powder

Melting point: 202-204 ℃

¹ HNMR (CDCl ₃ ) δ;

1.38 (t, J = 7 Hz, 3H), 2.92 (d, J = 3 Hz, 3H), 4.38 (q, J = 7 Hz, 2H), 5.21 (s, 2H), 6.50 (t, J = 9 Hz, 1H) , 7.08 (brs, 1H), 7.19 (t, J = 10 Hz, 1H), 7.39 (brs, 5H), 8.27 (s, 1H), 8.38 (t, J = 8 Hz, 1H)

(Example 103)

1- (3-Amino-4, 6-difluorophenyl) -6, 7-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- [3- (benzyloxycarbonylamino-4, 6-difluorophenyl)]-6, 7-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3- 2 g of carboxylate was added to 10 ml of hydrochloric acid and 20 ml of acetic acid and heated to reflux for 3 hours. After cooling, the mixture was concentrated under reduced pressure, ethanol was added to the residue, the solid was filtered off, and washed with diethyl ether to obtain 940 mg of the title compound.

Appearance: Colorless powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.86 (brs, 3H), 7.07 (t, J = 8 Hz, 1H), 7.20 (m, 1H), 7.52 (t, J = 11 Hz, 1H), 8.81 (s, 1H)

(Example 104)

Ethyl 5, 6, 7, 8-tetrafluoro-1- (2, 4-difluoro-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Example except using ethyl 5, 6, 7, 8-tetrafluoro-1- (2, 4-difluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate The title compound was obtained in the same manner as 97.

Appearance: Colorless powder

Melting Point: 235-238 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.26 (t, J = 7 Hz, 3H), 4.23 (q, J = 7 Hz, 2H), 8.15 (t, J = 10 Hz, 1H), 8.54 (s, 1H), 8.95 (t, J = 8 Hz, 1H)

(Example 105)

Ethyl 5, 6, 7, 8-tetrafluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Using ethyl 5, 6, 7, 8-tetrafluoro-1- (2, 4-difluoro-5-nitrophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 98 except for the above.

Appearance: Light brown powder

Melting Point: 179-182 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.25 (t, J = 7 Hz, 3H), 4.22 (q, J = 7 Hz, 2H), 7.78 (t, J = 10 Hz, 1H), 8.34 (s, 1H), 8.44 (s, 1H), 8.55 (t , J = 8Hz, 1H)

(Example 106)

Ethyl 5-benzylamino-6, 7, 8-trifluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-car Compound Rate:

Ethyl 5, 6, 7, 8-tetrafluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate 800 Mg, 0.21 ml of benzylamine, and 240 mg of anhydrous potassium carbonate were added to 30 ml of toluene, and the mixture was heated to reflux overnight. After cooling, the mixture was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was washed with water. After drying over magnesium sulfate, the solvent was distilled off, diethyl ether was added to the residue, the solid was filtered off, and washed with diethyl ether. 600 mg of the title compound were obtained.

Appearance: Colorless powder

Melting Point: 151-156 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.24 (t, J = 7 Hz, 3H), 4.19 (q, J = 7 Hz, 2H), 4.66 (m, 2H), 7.29 (m, 2H), 7.36 (s, 3H), 7.73 (t, J = 11 Hz , 1H), 8.33 (s, 2H), 8.50 (t, J = 8 Hz, 1H)

(Example 107)

Ethyl 5-amino-6, 7, 8-trifluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxyl Rate:

Ethyl 5-benzylamino-6, 7, 8-trifluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-car 600 mg of carboxylate and 100 mg of 10% palladium carbon were added to 20 ml of ethanol and 10 ml of acetic acid, followed by stirring at room temperature under hydrogen stream for 2 days. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid was filtered off and washed with diethyl ether. 420 mg of the title compound were obtained.

Appearance: Colorless powder

Melting Point:> 230 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.25 (t, J = 7 Hz, 3H), 4.20 (q, J = 7 Hz, 2H), 7.73 (t, J = 11 Hz, 1H), 7.88 (brs, 2H), 8.30 (s, 1H), 8.34 (s , 1H), 8.49 (t, J = 8 Hz, 1H)

(Example 108)

5-Amino-1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 5-amino-6, 7, 8-trifluoro-1- (2, 4-difluoro-5-formylaminophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxyl The title compound was obtained in the same manner as in Example 99 except for using the rate.

Appearance: Colorless powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.14 (t, J = 8Hz, 1H), 7.42 (t, J = 10Hz, 1H), 8.50 (s, 1H)

(Example 109)

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate:

11.8 g of ethyl 2,6-dichloronicotinoyl acetate was added to 8.8 ml of ethyl orthoformate and 13 ml of acetic anhydride, and the mixture was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure. 20 ml of toluene was added to 3.2 g of this compound, and 10 ml of toluene and 10 ml of ethanol of 3.1 g of N-benzyloxycarbonyl-2 and 4-difluoro-m-phenylenediamine of Reference Example 9 were added dropwise, After completion of the dropwise addition, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain ethyl 2- (2, 6-dichloronicotinoyl) -3- (3-benzyloxycarbonylamino-4, 6-difluorophenylamino) acrylate. The whole amount was dissolved in 10 ml of N and N-dimethylformamide, 1.39 g of potassium carbonate was added, and it stirred at room temperature overnight. The reaction solution was poured into ice water, and the solid was filtered off, washed with ethanol and diethyl ether in order to obtain 3.4 g of the title compound.

Appearance: Colorless powder

Melting Point: 242-243 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.41 (q, J = 7 Hz, 2H), 5.22 (s, 2H), 7.01 (brs, 1H), 7.13 (t, J = 9 Hz, 1H), 7.37 (s , 2H), 7.40 (s, 3H), 7.50 (m, 1H), 8.35 (m, 1H), 8.54 (s, 1H), 8.72 (d, J = 8Hz, 1H)

(Example 110)

1- (3-Amino-4, 6-difluorophenyl) -7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -7-chloro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate 1.0 4 ml of 12N hydrochloric acid and 8 ml of acetic acid were added thereto, and the mixture was heated to reflux for 3 hours, and stirred at room temperature overnight. The solid precipitated in the reaction solution was filtered and washed with ethanol, chloroform and diethyl ether in this order to obtain 550 mg of the title compound.

Appearance: Colorless powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.07 (t, J = 8 Hz, 1H), 7.44 (t, J = 10 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 8.78 (d, J = 8 Hz, 1H), 8.96 (s, 1H)

(Example 111)

7-Chloro-6-fluoro-1- (4-fluoro-3-nitrophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1.5 g of 7-chloro-6-fluoro-1- (4-fluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid was added to 10 ml of concentrated sulfuric acid. 1.4 g of potassium nitrate was added little by little, and it stirred at 80 degreeC for 2 hours. After cooling, the mixture was poured into ice water and stirred overnight. The precipitated solid was filtered off and washed with water, ethanol and diethyl ether. 1.1 g of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.89 (t, J = 10 Hz, 1H), 8.09-8.17 (m, 1H), 8.59-8.66 (m, 1H), 8.80 (d, J = 7 Hz, 1H), 9.08 (s, 1H)

(Example 112)

Methyl 7-chloro-6-fluoro-1- (4-fluoro-3-nitrophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate:

1 g of thionyl chloride was added dropwise to 25 ml of methanol, and 7-chloro-6-fluoro-1- (4-fluoro-3-nitrophenyl) -1 and 4-dihydro-4-oxo-1 were added to this solution. , 1.1 g of 8-naphthyridine-3-carboxylic acid was added and heated to reflux overnight. After cooling, the mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was filtered off. 1.4 g of the title compound were obtained.

Appearance: Yellow Powder

Melting point: 207-212 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.78 (s, 3H), 7.87 (d, J = 9Hz, 1H), 8.10-8.17 (m, 1H), 8.54-8.62 (m, 2H), 8.78 (s, 1H)

(Example 113)

1- (3-Amino-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

600 mg of methyl 7-chloro-6-fluoro-1- (4-fluoro-3-nitrophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate It dissolved in 30 ml of methanol, 10 ml of acetic acid, and 30 ml of dichloroethane, and added 100 mg of 10% palladium carbon. Stirred overnight at room temperature under hydrogen atmosphere. The catalyst was filtered off with a membrane filter, and the filtrate was concentrated under reduced pressure. 4 ml of acetic acid was added to the residue, followed by stirring at 100 ° C. overnight. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was filtered off and washed with diethyl ether. 160 mg of the title compound were obtained.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

6.74-6.83 (m, 1H), 6.96 (dd, J = 3 Hz, 8 Hz, 1H), 7.23 (dd, J = 9 Hz, 11 Hz, 1H), 8.76 (d, J = 8 Hz, 1H) 8.79 (s, 1H )

(Example 114)

Ethyl 7-chloro-1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3 Carboxylate:

Ethyl 3-ethoxy-2- (2'6'-dichloro-5'-fluoronicotinoyl) acrylic acid prepared according to a conventional method in 1.25 g of 2, 6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester To 10 ml of methanol solution in which ester was dissolved, 1.30 g of N-ethoxycarbonyl-2 and 4-difluoro-m-phenylenediamine methanesulfonate of Reference Example 8 were added together with 500 mg of triethylamine. . This solution was concentrated under reduced pressure. 50 ml of chloroform and 50 ml of distilled water were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2.1 g of anhydrous potassium carbonate and 4 ml of N, N-dimethylformamide were added to the residue, which was stirred for 15 minutes at 90 ° C. After cooling, 50 ml of chloroform and 300 ml of distilled water were added thereto, followed by separating an aliquot, and then the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol and washed with filtration, ethanol and diisopropyl ether in order to obtain 647 mg of the title compound.

Appearance: Light Brown Powder

Melting Point: 209-212 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.24 (t, J = 7 Hz, 3H), 1.28 (t, J = 7 Hz, 3H), 4.13 (q, J = 7 Hz, 2H), 4.24 (q, J = 7 Hz, 2H), 7.70 (t, J = 10 Hz, 1H), 8.03 (t, J = 8 Hz, 1H), 8.54 (d, J = 8 Hz, 1H), 8.76 (s, 1H)

(Example 115)

7-chloro-1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3- Carboxylic acid:

Ethyl 7-chloro-1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3 200 mg of carboxylate was added to a mixture of 1.5 ml of 3N hydrochloric acid and 1 ml of acetic acid, followed by stirring under reflux for 3 hours and 40 minutes. After cooling, the precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 149 mg of the title compound.

Appearance: Pale yellow powder

Melting Point: 233-235 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.24 (t, J = 7 Hz, 3H), 4.13 (q, J = 7 Hz, 2H), 7.71 (t, J = 10 Hz, 1H), 8.08 (t, J = 8 Hz, 1H), 8.77 (d, J = 7 Hz, 1H), 9.06 (s, 1H), 9.65 (s, 1H)

(Example 116)

Of 1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid Separate Synthesis:

Ethyl 7-chloro-1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3 200 mg of carboxylate was added to a mixture of 2 ml of 6N hydrochloric acid and 2 ml of acetic acid, followed by stirring and refluxing for 4 days. After cooling, the precipitate was filtered off, the filtrate was concentrated under reduced pressure, and 6 ml of 6N hydrochloric acid was added to the residue, followed by stirring and refluxing for 18 hours. The precipitate was concentrated under reduced pressure, 1 ml of ethanol was added thereto, and the precipitate formed was filtered off, washed with ethanol and diisopropyl ether in that order to obtain the title compound as a 29 mg pale yellow powder.

(Example 117)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8- Naphthyridine-3-carboxylic acid:

1- (3-Amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid 3.7 g, 2.18 g of 3-aminoazetidine dihydrochloride and 6.06 g of triethylamine were added to 200 ml of acetonitrile. It stirred at 80 degreeC for 15 hours. The solid which formed after cold was filtered. It washed with ethanol and isopropyl ether, and obtained the title compound of 3.7g.

Appearance: Pale yellow powder

Melting Point: 168.5-170.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.60-4.60 (m, 5H), 5.35 (brs, 2H), 6.95 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.03 (d, J = 11.5 Hz, 1H), 8.68 (s, 1 H)

(Example 118)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7- (3-hydroxyazetidin-1-yl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except that hydroxyazetidine hydrochloride and triethylamine were used.

Appearance: Pale yellow powder

Melting Point:> 253 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.60-4.65 (m, 5H), 5.35 (brs, 2H), 5.82 (brs, 1H), 6.95 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.03 (d, J = 11.5 Hz, 1H), 8.68 (s, 1H)

(Example 119)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7- (3-methylaminoazetidin-1-yl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except that methylaminoazetidine dihydrochloride and triethylamine were used.

Appearance: Colorless powder

Melting Point: 135.5-140.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.53 (s, 3H), 3.80-4.90 (m, 5H), 5.38 (brs, 2H), 6.97 (t, J = 8Hz, 1H), 7.36 (t, J = 10Hz, 1H), 8.11 (d, J = 10.7 Hz, 1H), 8.70 (s, 1H)

(Example 120)

1- (3-amino-4, 6-difluorophenyl) -7- (3-ethylaminoazetidin-1-yl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except that ethylaminoazetidine dihydrochloride and triethylamine were used.

Appearance: Colorless powder

Melting point: 122.5-124 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.98 (t, J = 7 Hz, 3H), 2.45 (q, J = 7 Hz, 2H), 3.20-4.80 (m, 5H), 5.34 (brs, 2H), 6.94 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.01 (d, J = 10.7 Hz, 1H), 8.67 (s, 1H)

(Example 121)

1- (3-amino-4, 6-difluorophenyl) -7- (3-dimethylaminoazetidin-1-yl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid hydrochloride:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 A free form of the title compound was obtained in the same manner as in Example 117 except that dimethylaminoazetidine dihydrochloride and triethylamine were used. 110 mg of this solid was dissolved in 5 ml of chloroform and 2 ml of tetrahydrochloric acid / 1.4-dioxane was added. The solvent was distilled off and 2 ml of ethanol was added to the residue. The resulting solid was filtered off to obtain 60 mg of the title compound.

Appearance: Pale yellow powder

Melting Point:> 242 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.72 (s, 6H), 3.90-4.80 (m, 5H), 5.20-6.70 (br, 2H), 7.18 (t, J = 8Hz, 1H), 7.45 (t, J = 10Hz, 1H), 8.13 (d , J = 11.1 Hz, 1H), 8.73 (s, 1H)

(Example 122)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-trans-2-methyl-3-aminoazetidin-1-yl) -1, 4-dihydro-4- Oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and trans The title compound was obtained in the same manner as in Example 117 except for using 2-methyl-3-aminoazetidine dihydrochloride and triethylamine.

Appearance: Pale yellow powder

Melting Point:> 237 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

0.90-1.35 (m, 3H), 3.20-3.55 (m, 2H), 3.80-4.60 (m, 2H), 5.37 (brs, 2H), 6.85-7.05 (m, 1H), 7.25-7.50 (m, 1H ), 8.09 (d, J = 9 Hz, 1 H), 8.72 (s, 1 H)

(Example 123)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8 Naphthyridine-3-carboxylic acid p-toluenesulfonate:

The title compound was obtained in the same manner as in Example 52, except that the compound 117 was used.

Appearance: Light Red Powder

Melting Point: 179-184 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.28 (s, 3H), 3.50-4.80 (m, 5H), 6.96 (t, J = 8Hz, 1H), 7.11 (d, J = 8Hz, 1H), 7.37 (t, J = 10Hz, 1H), 7.48 (d, J = 8 Hz, 1H), 8.12 (d, J = 11.1 Hz, 1H), 8.30 (brs, 3H), 8.74 (s, 1H)

(Example 124)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8 Naphthyridine-3-carboxylic acid methanesulfonate:

The title compound was obtained in the same manner as in Example 52 except for using the compound 117 and methanesulfonic acid.

Appearance: Light Red Powder

Melting Point:> 214 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.34 (s, 3H), 3.80-4.80 (m, 5H), 6.96 (t, J = 8 Hz, 1H), 7.37 (t, J = 10 Hz, 1H), 8.14 (d, J = 11.2 Hz, 1H), 8.31 (brs, 3H), 8.74 (s, 1H)

(Example 125)

7- (3-amino-3-methylazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except for using -amino-3-methylazetidine dihydrochloride and triethylamine.

Appearance: Colorless powder

Melting Point: 244-246.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.42 (s, 3H), 3.20-4.55 (m, 4H), 5.37 (brs, 2H), 6.95 (t, J = 8Hz, 1H), 7.36 (t, J = 10Hz, 1H), 8.07 (d, J = 11.1 Hz, 1H), 8.71 (s, 1H)

(Example 126)

7- (3-L-alanylamino azetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except for using -L-alanylaminoazetidine dihydrochloride and triethylamine.

Appearance: Pale yellow powder

Melting Point: 208.5-214 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.28 (d, J = 6.8 Hz, 3H), 3.55-3.75 (m, 1H), 3.70-4.80 (m, 5H), 5.38 (brs, 2H), 6.97 (t, J = 8 Hz, 1H), 7.36 ( t, J = 10 Hz, 1H), 8.07 (d, J = 11.1 Hz, 1H), 8.70 (s, 1H), 9.07 (brs, 1H)

(Example 127)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7- (3-L-valylaminoazetidin-1-yl) -1, 4-dihydro-4-oxo- 1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except for using -L-valylaminoazetidine dihydrochloride and triethylamine.

Appearance: Colorless powder

Melting Point: 262.5-264.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.78 (d, J = 7 Hz, 3H), 0.85 (d, J = 7 Hz, 3H), 1.70-1.95 (m, 1H), 2.91 (d, J = 5.5 Hz, 1H), 3.70-4.80 (m, 5H ), 5.35 (brs, 2H), 6.95 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.06 (d, J = 11.1 Hz, 1H), 8.52 (brs, 1H), 8.69 (s, 1 H)

(Example 128)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7- (3-methylaminopyrrolidin-1-yl) -4-oxo-1, 4-dihydro-1 , 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3-methylaminopyrrolidine dihydrochloride was used.

Appearance: Colorless powder

Melting Point: 273-276 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.79 (m, 1H), 1.93 (m, 1H), 2.24 (s, 3H), 5.35 (brs, 2H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 8.03 (d, J = 12 Hz, 1H), 8.68 (s, 1H)

(Example 129)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3- (methylamino) pyrrolidin-1-yl-4-oxo-1, 4 -Dihydro-1,8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that (3S) -3- (methylamino) pyrrolidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 246-248 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.79 (m, 1H), 1.92 (m, 1H), 2.23 (s, 3H), 3.18 (m, 2H), 5.35 (brs, 2H), 6.97 (t, J = 8 Hz, 1H), 7.36 (t, J = 10Hz, 1H), 8.02 (d, J = 13Hz, 1H), 8.68 (s, 1H)

(Example 130)

1- (30-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3- (ethylamino) pyrrolidin-1-yl] -4-oxo-1, 4-dihydro-1,8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that (3S) -3- (ethylamino) pyrrolidine dihydrochloride was used.

Appearance: Light Brown Powder

Melting Point: 248-251 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

0.98 (t, J = 7 Hz, 3H), 1.75 (m, 1H), 1.95 (m, 1H), 5.35 (brs, 2H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 11 Hz , 1H), 8.01 (d, J = 12 Hz, 1H), 8.67 (s, 1H)

(Example 131)

1- (3-amino-4, 6-difluorophenyl) -7- (3-amino-3-methylpyrrolidin-1-yl) -6-fluoro-4-oxo-1, 4-di Hydro-1,8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3-amino-3-methylpyrrolidine dihydrochloride was used.

Appearance: Colorless powder

Melting Point: 223-225 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.20 (d, J = 3 Hz, 3H), 1.60 (m, 1H), 1.71 (m, 1H), 5.35 (brs, 2H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz , 1H), 7.99 (d, J = 13 Hz, 1H), 8.63 (s, 1H)

(Example 132)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminomethylpyrrolidin-1-yl) -6-fluoro-4-oxo-1, 4-dihydro-1 , 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3-aminomethylpyrrolidine dihydrochloride was used.

Appearance: Colorless powder

Melting point: 205-210 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.42-1.98 (m, 2H), 2.60 (d, J = 7 Hz, 2H), 5.34 (s, 2H), 6.96 (t, J = 8 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.01 (d, J = 12 Hz, 1H), 8.66 (s, 1H)

(Example 133)

1- (3-amino-4, 6-difluorophenyl) -7- (4-aminopiperidin-1-yl) -6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 4-aminopiperidine dihydrochloride was used.

Appearance: Colorless powder

Melting Point: 212-215 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.28 (m, 2H), 1.74 (m, 2H), 2.95 (m, 1H), 3.10 (m, 2H), 4.06 (m, 2H), 5.39 (s, 2H), 6.97 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 8.06 (d, J = 12 Hz, 1H), 8.67 (s, 1H)

(Example 134)

1- (3-amino-4, 6-difluorophenyl) -7- (cis-3-amino-4-methoxypyrrolidin-1-yl) -6-fluoro-1, 4-dihydro- 4-Oxo-1, 8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that cis-3-amino-4-methoxypyrrolidine was used.

Appearance: Pale yellow powder

Melting Point:> 164 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.13 (s, 3H), 3.73 (m, 2H), 3.93 (m, 1H), 5.38 (brs, 2H), 6.97 (m, 1H), 7.37 (m, 1H), 8.10 (d, J = 12 Hz, 1H), 8.71 (s, 1H)

(Example 135)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7- [3- (2-hydroxyethylamino) pyrrolidine] -1, 4-dihydro-4-oxo -1,8-naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 48 except that 3- (2-hydroxyethylamino) pyrrolidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting Point:> 235 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.65-2.13 (m, 2H), 2.52-2.70 (m, 2H), 3.42-3.58 (m, 2H), 3.55-4.73 (m, 1H), 5.36 (brs, 2H), 6.97 (t, J = 8 Hz , 1H), 7.36 (t, J = 11 Hz, 1H), 8.04 (d, J = 13 Hz, 1H), 8.69 (s, 1H)

(Example 136)

1- (3-amino-4, 6-difluorophenyl) -7- (7-amino-5-azaspiro [2.4] heptan-5-yl) -6-fluoro-1, 4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride:

173 mg of 7-tert-butyloxycarbonylamino-5-azaspiro [2.4] heptane B and 164 mg of triethylamine were added to 2 ml of dimethylsulfoxide, and the mixture was heated and stirred at 80 ° C for 1- (3-amino- 4 mg of 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid was added and stirred overnight. It was. After cooling, diethyl ether was added to the reaction solution, and the diethyl ether layer was concentrated under reduced pressure. Chloroform was added to the residue, washed with water, dried over magnesium sulfate, and the solvent was distilled off. Diethyl ether was added to the residue, and the solid was filtered off. 30 mL of chloroform and 5 mL of 4N hydrochloric acid-dioxane were added to this solid, and it stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the solid was filtered off and washed with diethyl ether. 120 mg of the title compound were obtained.

Appearance: Yellow powder

Melting Point: 222 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

0.78 (m, 4H), 3.26-4.44 (m, 6H), 7.09 (m, 1H), 7.41 (m, 1H), 8.12 (d, J = 13 Hz, 1H), 8.35 (brs, 3H), 8.73 ( s, 1 H)

(Example 137)

7- (3-aminoazetidin-1-yl) -6-fluoro-1- (2, 4-difluoro-5-methylaminophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

With 7-chloro-6-fluoro-1- (2,4-difluoro-5-methylaminophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid The title compound was obtained in the same manner as in Example 117 except that 3-aminoazetidine dihydrochloride and triethylamine were used.

Appearance: Pale yellow powder

Melting Point:> 231 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.69 (d, J = 4.3 Hz, 3H), 3.80-4.80 (m, 5H), 5.83 (brs, 1H), 6.96 (t, J = 8 Hz, 1H), 7.41 (t, J = 11 Hz, 1H), 8.14 (d, J = 12 Hz, 1H), 8.20-8.60 (br, 2H), 8.76 (s, 1H)

(Example 138)

7-[(3S) -3-aminopyrrolidin-1-yl] -1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -6-fluoro-4-oxo-1 , 4-dihydro-1, 8-naphthyridine-3-carboxylic acid:

1- (3-ethoxycarbonylamino-4, 6-difluorophenyl) -7-chloro-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3- 68 mg of carboxylic acid and 70 mg of (3S) -3-aminopyrrolidine were added to 350 µl of N, N-dimethylformamide and stirred at 80 ° C for 20 minutes. Subsequently, 0.5 ml of ethanol was added and allowed to cool. The precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 73 mg of the title compound.

Appearance: Colorless powder

Melting Point:> 280 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.23 (t, J = 7 Hz, 3H), 1.34 (m, 1H), 1.53-1.95 (m, 3H), 2.42 (m), 2.74 (m), 4.12 (q, J = 7 Hz, 2H), 7.63 ( t, J = 10Hz, 1H), 7.95 (t, J = 8Hz, 1H), 7.99 (d, J = 7Hz, 1H), 8.63 (s, 1H)

(Example 139)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -1, 4-dihydro-4-oxo-1, 8-naphthyridine-3 -Carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7 while acetonitrile 3 ml solution of 61 mg of 3-aminoazetidine dihydrochloride and 119 mg of N-methylpyrrolidine was stirred at 80 ° C 100 mg of -chloro-1, 4-dihydro-4-oxo-1 and 8-naphthyridine-3-carboxylic acid were added, and the mixture was stirred at 80 ° C for 2 hours and 50 minutes. After the reaction solution was allowed to cool, decantation was performed with diethyl ether, and a small amount of ethanol was added to disperse the solid and filtered. The solid was washed with ethanol and diethyl ether in order to obtain 63 mg of the title compound.

Appearance: Pale yellow powder

Melting Point:> 240 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.50-4.48 (br, 5H), 5.35 (brs, 2H), 6.73 (d, J = 9 Hz, 1H), 6.96 (t, J = 9 Hz, 1H), 7.35 (t, J = 10 Hz, 1H), 8.32 (d, J = 9 Hz, 1H), 8.69 (s, 1H)

(Example 140)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -1, 4-dihydro-4-oxo-1, 8 Naphthyridine-3-carboxylic acid:

The title compound was obtained in the same manner as in Example 139 except for using (3S) -3-aminopyrrolidine.

Appearance: Light brown powder

Melting Point:> 261 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.53-1.84 (m, 1H), 1.84-2.15 (m, 1H), 5.33 (brs, 2H), 6.82 (t, J = 10 Hz, 1H), 6.97 (t, J = 8 Hz, 1H), 7.35 (t , J = 10Hz, 1H), 8.28 (d, J = 10Hz, 1H), 8.65 (s, 1H)

(Example 141)

1- (3-amino-6-chloro-4-fluorophenyl) -7- (3-aminoazetidin-1-yl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-6-chloro-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 139 to obtain the title compound.

Appearance: Pale yellow powder

Melting point: 200-203 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.70-4.48 (br, 3H), 5.69 (brs, 2H), 6.96 (d, J = 8 Hz, 1H), 7.46 (d, J = 12 Hz, 1H), 8.04 (d, J = 12 Hz, 1H), 8.62 (s, 1H)

(Example 142)

1- (3-amino-6-methyl-4-fluorophenyl) -7- (3-aminoazetidin-1-yl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-6-methyl-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid Except for using the same as in Example 117 to obtain the title compound.

Appearance: Pale yellow powder

Melting Point:> 238 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.82 (s, 3H), 2.94-4.28 (br, 5H), 5.27 (brs, 3H), 6.74 (d, J = 9Hz, 1H), 7.09 (d, J = 12Hz, 1H), 8.09 (d, J = 10 Hz, 1H), 8.52 (s, 1H)

(Example 143)

1- (3-amino-4-fluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-1, 4-dihydro-4-oxo-1 , 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4-fluorophenyl) -7-chloro--6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, (3S The title compound was obtained in the same manner as in Example 60 except for using) -3-aminopyrrolidine.

Appearance: Brown Powder

Melting point: 262-265 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.56-1.83 (m, 1H), 1.86-2.09 (m, 1H), 5.50 (brs, 2H), 6.67-6.78 (m, 1H), 6.92 (d, J = 9 Hz, 1H), 7.17 (t, J = 12 Hz, 1 H), 8.03 (d, J = 13 Hz, 1 H), 8.53 (s, 1 H)

(Example 144)

1- (3-amino-4-fluorophenyl) -7-[(3S, 4S) -3-amino-4-methylpyrrolidin-1-yl] -6-fluoro-1, 4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid:

1- (3-amino-4-fluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, (3S, The title compound was obtained in the same manner as in Example 60 except that 4S) -3-amino-4-methylpyrrolidine was used.

Appearance: Brown Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.96 (d, J = 7 Hz, 3H), 2.12 (brs, 1H), 5.50 (s, 2H), 6.68-6.76 (m, 1H), 6.89-7.01 (m, 1H), 7.19 (t, J = 11 Hz , 1H), 8.03 (d, J = 13Hz, 1H), 8.53 (s, 1H)

(Example 145)

1- (3-amino-4, 6-difluorophenyl) -7- (cis-3-hydroxy-4-methylpyrrolidin-1-yl) -6-fluoro-1, 4-dihydro 4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-3-hydroxy- The title compound was obtained in the same manner as in Example 60 except that 4-methylpyrrolidine was used.

Appearance: Brown Powder

Melting point: 174-180 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.94 (d, J = 7 Hz, 3H), 2.11 (m, 1H), 2.86-3.81 (m, 4H), 3.86 (m, 1H), 5.18 (brs, 2H), 5.93 (d, J = 6 Hz, 1H ), 7.04 (t, J = 8 Hz, 1H), 7.50 (t, J = 10 Hz, 1H), 7.86 (d, J = 13 Hz, 1H), 8.62 (s1H)

(Example 146)

1- (3-amino-4, 6-difluorophenyl) -7- (trans-3-amino-4-methylpyrrolidin-1-yl) -6-fluoro-1, 4-dihydro- 4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-amino-4 The title compound was obtained in the same manner as 60 except that -methylpyrrolidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting Point:> 164 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.09 (d, J = 7Hz, 3H), 2.28 (m, 1H), 2.97-3.91 (m, 5H), 5.58 (brs, 2H), 5.96 (d, J = 7Hz, 1H), 7.05 (t, J = 8 Hz, 1H), 7.52 (t, J = 10 Hz, 1H), 7.92 (d, J = 14 Hz, 1H), 8.66 (s1H)

(Example 147)

1- (3-amino-4, 6-difluorophenyl) -6-fluoro-7-[(3S) -3-methylaminopyrrolidin-1-yl] -1, 4-dihydro-4 Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1,4-dihiro-4-oxoquinoline-3-carboxylic acid, (3S) -3-methyl The title compound was obtained in the same manner as in Example 60 except that aminopyrrolidine was used.

Appearance: Pale yellow powder

Melting point: 188-199 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.86 (brs, 1H), 2.00 (brs, 1H), 2.30 (s, 3H), 3.11-3.66 (m, 5H), 5.54 (brs, 2H), 5.95 (d, J = 7 Hz, 1H), 7.04 ( t, J = 8Hz, 1H), 7.50 (t, J = 11Hz, 1H), 7.86 (d, J = 14.1H), 8.63 (s, 1H)

(Example 148)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo quinoline-3- Carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxo quinoline-3-carboxylic acid, 3-aminoazetidine dihydrochloride Except for using the same as in Example 60 to obtain the title compound.

Appearance: Colorless powder

Melting Point:> 183 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.76 (brs, 2H), 3.91 (m, 1H), 4.24 (brs, 2H), 5.55 (brs, 2H), 5.77 (d, J = 7 Hz, 1H), 7.02 (t, J = 8 Hz, 1H), 7.50 (t, J = 10.1H), 7.88 (d, J = 12Hz, 1H), 8.64 (s, 1H)

(Example 149)

1- (3-amino-4, 6-difluorophenyl) -7- (trans-3-amino-4-hydroxypyrrolidin-1-yl) -6, 8-difluoro-1, 4 -Dihydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3-amino The title compound was obtained in the same manner as in Example 60 except that 4-hydroxypyrrolidine dihydrochloride was used.

Appearance: Brown powder

Melting Point:> 145 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.92-4.26 (m, 4H), 5.46 (brs, 2H), 7.10 (t, J = 9 Hz, 1H), 7.40 (t, J = 11 Hz, 1H), 7.86 (d, J = 14 Hz, 1H), 8.52 (s, 1H)

(Example 150)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6, 8-difluoro-1, 4-dihydro-oxoquinoline-3 -Carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-aminoazetidine The title compound was obtained in the same manner as in Example 60 except that dihydrochloride was used.

Appearance: Colorless powder

Melting Point:> 203 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.90 (m, 1H), 4.10 (m, 1H), 4.49 (m, 2H), 5.46 (brs, 2H), 7.08 (t, J = 9 Hz, 1H), 7.39 (t, J = 10 Hz, 1H), 7.81 (d, J = 13 Hz, 1H), 8.48 (s, 1H)

(Example 151)

1- (3-amino-4, 6-difluorophenyl) -6, 8-difluoro-7- (3-hydroxyazetidin-1-yl) -1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-hydroxyase The title compound was obtained in the same manner as in Example 60 except that thiidine hydrochloride was used.

Appearance: Colorless powder

Melting Point: 218-225 ℃

¹ HNMR (d ₆ -DMSO) δ;

4.13 (brs, 2H), 4.50 (brs, 3H), 5.33 (brs, 2H), 5.72 (brs, 1H), 7.08 (t, J = 8 Hz, 1H), 7.39 (t, J = 10 Hz, 1H), 7.79 (d, J = 13 Hz, 1H), 8.46 (s, 1H)

(Example 152)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-amino The title compound was obtained in the same manner as in Example 60 except that the azetidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.75 (m, 1H), 4.10 (m, 2H), 4.66 (m, 2H), 5.43 (brs, 2H), 6.97 (t, J = 8 Hz, 1H), 7.36 (t, J = 11 Hz, 1H), 7.87 (d, J = 14 Hz, 1H), 8.44 (s, 1H)

(Example 153)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -8-chloro-6-fluoro-1, 4-di Hydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, (3S) The title compound was obtained in the same manner as in Example 60 except that 3-aminopyrrolidine was used.

Appearance: Pale yellow powder

Melting Point:> 205 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.17 (m, 1H), 2.09 (m, 1H), 3.02-3.81 (m, 5H), 5.41 (brs, 2H), 6.97 (m, 1H), 7.38 (t, J = 11 Hz, 1H), 7.94 ( d, J = 14 Hz, 1H), 8.50 (s, 1H)

(Example 154)

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6-fluoro-7- (3-hydroxyazetidin-1-yl) -1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-hydrate The title compound was obtained in the same manner as in Example 60 except that the hydroxy azetidine hydrochloride was used.

Appearance: Pale yellow powder

Melting Point: 145-150 ℃

¹ HNMR (d ₆ -DMSO) δ;

4.18 (brs, 2H), 4.47 (brs, 1H), 4.71 (brs, 2H), 5.41 (brs, 2H), 5.71 (d, J = 5 Hz, 1H), 6.96 (t, J = 8 Hz, 1H), 7.37 (t, J = 10 Hz, 1H), 7.88 (d, J = 14 Hz, 1H), 8.44 (s, 1H)

(Example 155)

1- (3-Amino-4, 6-difluorophenyl) -8-chloro-6-fluoro-7-piperazino-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, piperazine The title compound was obtained in the same manner as in Example 60 except for using.

Appearance: Pale yellow powder

Melting Point:> 232 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.87 (brs, 4H), 3.19 (brs, 4H), 5.43 (brs, 2H), 6.97 (t, J = 8 Hz, 1H), 7.37 (t, J = 11 Hz, 1H), 8.07 (d, J = 12 Hz , 1H), 8.54 (s, 1H)

(Example 156)

1- (3-amino-4, 6-difluorophenyl) -7- (3-amino-3-methylazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro 4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-amino The title compound was obtained in the same manner as in Example 117 except for using 3-methylazetidine.

Appearance: Yellow Powder

Melting Point: 252-257 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.35 (s, 3H), 4.17 (brs, 2H), 4.30 (brs, 2H), 5.42 (brs, 2H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 7.87 (d, J = 14 Hz, 1H), 8.43 (s, 1H)

(Example 157)

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6-fluoro-7- (3-methylaminoazetidin-1-yl) -1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-methyl The title compound was obtained in the same manner as in Example 117 except for using aminoazetidine.

Appearance: Pale yellow powder

Melting point: 220-224 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.20 (s, 3H), 3.45 (brs, 1H), 4.12 (brs, 2H), 4.63 (brs, 2H), 5.42 (brs, 2H), 6.96 (t, J = 8 Hz, 1H), 7.36 (t, J = 10 Hz, 1H), 7.86 (d, J = 14 Hz, 1H), 8.43 (s, 1H).

(Example 158)

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6-fluoro-7- (3, 5-dimethylpiperazino) -1, 4-dihydro-4-oxoquinoline 3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 2, 6 The title compound was obtained in the same manner as in Example 117 except that dimethylpiperazine was used.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

0.96 (d, J = 6 Hz, 6H), 2.80 (m, 2H), 2.91 (m, 2H), 3.08 (m, 2H), 5.43 (brs, 2H), 6.97 (t, J = 8 Hz, 1H), 7.38 (t, J = 11 Hz, 1H), 8.07 (d, J = 12 Hz, 1H), 8.56 (s, 1H)

(Example 159)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-5-hydroxy-1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-5-hydroxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3- The title compound was obtained in the same manner as in Example 60 except that the aminoazetidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting Point:> 262 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.75-4.02 (m, 3H), 4.24 (brs, 2H), 5.25 (d, J = 7 Hz, 1H), 5.54 (brs, 2H), 6.98 (t, J = 8 Hz, 1H), 7.49 (t, J = 10 Hz, 1H), 8.48 (s, 1H)

(Example 160)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-5-hydroxy-1, 4- Dihydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-5-hydroxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, (3S The title compound was obtained in the same manner as in Example 60 except for using) -3-aminopyrrolidine.

Appearance: Pale yellow powder

Melting Point:> 237 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.01 (m, 1H), 2.21 (m, 1H), 3.34-4.97 (m, 5H), 5.46 (d, J = 7Hz, 1H), 6.98 (t, J = 8Hz, 1H), 7.50 (t, J = 10 Hz, 1H), 8.64 (s, 1H)

(Example 161)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-5-methyl-1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-amino The title compound was obtained in the same manner as in Example 60 except that the azetidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.75 (brs, 3H), 3.90 (brs, 2H), 4.01 (brs, 1H), 4.26 (brs, 2H), 5.55 (brs, 2H), 5.65 (d, J = 7 Hz, 1H), 6.99 (t, J = 8Hz, 1H), 7.49 (t, J = 11Hz, 1H), 8.59 (s, 1H)

(Example 162)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-fluoro-5-methyl-1, 4-di Hydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, (3S) The title compound was obtained in the same manner as in Example 60 except that 3-aminopyrrolidine was used.

Appearance: Light Brown Powder

Melting Point:> 197 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.68 (m, 1H), 1.96 (m, 1H), 3.01-3.65 (m, 5H), 5.53 (brs, 2H), 5.81 (d, J = 7 Hz, 1H), 6.99 (t, J = 8 Hz, 1H ), 7.49 (t, J = 11 Hz, 1H), 8.55 (s, 1H)

(Example 163)

5-amino-1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

5-amino-1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, ( The title compound was obtained in the same manner as in Example 60 except that 3S) -3-aminopyrrolidine was used.

Appearance: Pale yellow powder

Melting Point:> 247 ℃ (decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.62 (m, 1H), 1.89 (m, 1H), 3.22 (m, 1H), 3.39-3.78 (m, 4H), 5.38 (brs, 2H), 7.02 (t, J = 8 Hz, 1H), 7.23 ( brs, 2H), 7.34 (t, J = 10 Hz, 1H), 8.23 (s, 1H)

(Example 164)

5-amino-7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6, 8-difluoro-1, 4-dihydro- 4-oxoquinoline-3-carboxylic acid:

5-Amino-1- (3-amino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3 The title compound was obtained in the same manner as in Example 60 except that the aminoazetidine dihydrochloride was used.

Appearance: Yellow Powder

Melting Point:> 237 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

4.04 (brs, 1H), 4.28 (brs, 2H), 4.48 (brs, 2H), 5.41 (brs, 2H), 7.05 (t, J = 8 Hz, 1H), 7.30 (m, 1H), 8.25 (s, 1H)

(Example 165)

7- (3-aminoazetidin-1-yl) -1- (3-amino-6-chloro-4-fluorophenyl) -6-fluoro-1, 4-dihydro-4-oxoquinoline-3 -Carboxylic acid:

Example except using 1- (3-amino-6-chloro-4-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid The title compound was obtained in the same manner as 139.

Appearance: Pale yellow powder

Melting Point:> 208 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.88-4.58 (br, 5H), 5.69 (d, J = 8 Hz, 1H), 5.92 (brs, 2H), 7.08 (d, J = 8 Hz, 1H), 7.59 (d, J = 10 Hz, 1H), 7.93 (d, J = 13 Hz, 1H), 8.61 (s, 1H)

(Example 166)

Ethyl 7-chloro-1- (2, 4-difluoro-5-formylaminophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-car Separate synthesis of carboxylates:

Ethyl 7-chloro-6-fluoro-1- (2, 4-difluoro-5-nitrophenyl) -4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate 305 mg of iron and 400 mg of iron were added to 1.5 ml of formic acid, followed by stirring at 80 ° C. for 3 hours. The insolubles were filtered through celite, concentrated under reduced pressure, and the precipitates were dispersed in ethanol and washed with filtration, ethanol and diisopropyl ether in order to obtain 295 mg of the title compound as a pale yellow powder.

(Reference Example 10)

N- (t-butoxycarbonyl) -2, 4-difluoro-m-phenylenediamine:

N- (t-butoxycarbonyl) -2 and 4-difluoro-5-nitroaniline were obtained as colorless crystals in the same manner as in Reference Example 8 except that t-butanol was used instead of ethanol.

This 3.8g was added to 50 ml of methanol with 360 mg of 10% palladium carbon, and hydrogenated at room temperature for 4 days. The catalyst was filtered off, the solvent and the like were distilled off under reduced pressure, and the precipitate was dispersed and filtered through diisopropyl ether to obtain 3.2 g of the titled compound as light brown crystals.

(Reference Example 11)

Ethyl 8-chloro-1- (2-chloro-4-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 2-chloro-4-fluoroaniline was used.

Appearance: Colorless powder

Melting Point: 208-212 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.16-7.23 (m, 1H), 7.34 (dd, J = 3 Hz, J = 8 Hz, 1H), 7.48 (dd, J = 5Hz, J = 9Hz, 1H), 8.27 (s, 1H), 8.35 (t, J = 9Hz, 1H)

(Reference Example 12)

Ethyl 8-chloro-6, 7-difluoro-1- (4-fluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 4-fluoroaniline was used.

Appearance: Colorless powder

Melting Point: 226-231 ℃

¹ HNMR (CDCl ₃ ) δ;

1.39 (t, J = 7Hz, 3H), 4.39 (q, J = 7Hz, 2H), 7.20-7.24 (m, 2H), 7.34-7.35 (m, 2H), 8.34 (t, J = 9Hz, 1H) , 8.42 (s, 1H)

(Reference Example 13)

Ethyl 8-chloro-6, 7-difluoro-1- (4-fluoro-2-methylphenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 2-methyl-4-fluoroaniline was used.

Appearance: Pale yellow powder

Melting Point: 180-182 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 2.10 (s, 3H), 4.40 (q, J = 7 Hz, 2H), 7.02-7.10 (m, 2H), 7.22-7.36 (m, 1H), 8.31 (s , 1H), 8.37 (t, J = 9 Hz, 1H)

(Reference Example 14)

Ethyl 1- (2-bromo-4-fluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 2-bromo-4-fluoroaniline was used.

Appearance: Pale yellow powder

Melting Point: 183-188 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.18-7.32 (m, 1H), 7.48-7.55 (m, 2H), 8.27 (s, 1H), 8.36 (t , J = 9Hz, 1H)

(Reference Example 15)

Ethyl 1- (2-methoxy-4-fluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 2-methoxy-4-fluoroaniline was used.

Appearance: Colorless powder

Melting Point: 240-246 ℃ (Decomposition)

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 3.77 (s, 3H), 4.39 (q, J = 7 Hz, 2H), 6.72-6.89 (m, 2H), 7.31 (dd, J = 6 Hz, J = 9 Hz, 1H), 8.30 (s, 1H), 8.34 (t, J = 10 Hz, 1H)

(Reference Example 16)

Ethyl 8-chloro-1- (4-chloro-2-fluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 4-chloro-2-fluoroaniline was used.

Appearance: Colorless powder

Melting point: 159-160 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.39 (q, J = 7 Hz, 2H), 7.31-7.47 (m, 2H), 8.32-8.40 (m, 2H)

(Reference Example 17)

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Reference Example 6 except that 2, 4, 6-trifluoroaniline was used.

Appearance: Pale yellow powder

Melting Point: 135-149 ℃ (Decomposition)

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 6.93 (t, J = 7 Hz, 1H), 8.25 (s, 1H), 8.34 (t, J = 10 Hz, 1H)

(Reference Example 18)

8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Concentrated hydrochloric acid to 1.2 g of ethyl 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate 5 ml and acetic acid 1 ml were added, and the mixture was heated to reflux for 3 hours. After cooling, the precipitated solid was filtered off and washed with ethanol and diethyl ether. 750 mg of the title compound was obtained.

Appearance: Light Red Powder

Melting Point:> 158 ℃ (decomposition)

¹ HNMR (d ₆ -DMSO) δ;

7.60-7.72 (m, 2H), 8.41 (t, J = 9 Hz, 1H), 9.01 (s, 1H)

(Example 167)

1- (3-amino-4, 6-difluorophenyl) -7- (trans-3-amino-2-methylazetidin-1-yl) -8-chloro-6-fluoro-1, 4- Dihydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, trans-3 The title compound was obtained in the same manner as in Example 117 except for using -amino-2-methylazetidine.

Appearance: Brown powder

Melting Point:> 211 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.38 (brs, 3H), 3.73-3.90 (m, 1H), 4.69-4.82 (m, 1H), 4.82-4.97 (m, 1H), 5.32-5.48 (m, 1H), 5.49 (s, 1H), 6.70-7.59 (m, 2H), 7.94 (d, J = 14 Hz, 1H), 8.48 (s, 1H)

(Example 168)

1- (3-amino-4, 6-difluorophenyl) -7- (4-methylpiperazin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 4-methyl The title compound was obtained in the same manner as in Example 117 except for using piperazine.

Appearance: Yellow Powder

Melting Point: 198-205 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.54 (s, 3H), 2.81 (brs, 4H), 3.42 (brs, 4H), 7.01 (t, J = 7 Hz, 1H), 7.40 (t, J = 11 Hz, 1H), 8.15 (d, J = 12 Hz , 1H), 8.62 (s, 1H)

(Example 169)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S, 4R) 3-amino-4-methylpyrrolidin-1-yl] -8-chloro-6-fluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, (3S, 4R) The title compound was obtained in the same manner as in Example 117 except that 3-amino-4-methylpyrrolidine was used.

Appearance: Yellow Powder

Melting Point: 170-179 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

0.95-1.11 (m, 3H), 1.88-2.09 (m, 1H), 2.60-3.72 (m, 5H), 5.38 (s, 1H), 5.46 (s, 1H), 6.82-7.52 (m, 2H), 7.96 (d, J = 14 Hz, 1H), 8.40 (brs, 1H)

(Example 170)

1- (3-amino-4, 6-difluorophenyl) -7-[(3R) -3-aminopyrrolidin-1-yl] -8-chloro-6-fluoro-1, 4-di Hydro-4-oxo-quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, (3R) The title compound was obtained in the same manner as in Example 117 except for using 3-aminopyrrolidine.

Appearance: Brown Powder

Melting Point: 169-179 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.52-1.80 (m, 1H), 1.84-2.07 (m, 1H), 2.71-3.82 (m, 5H), 5.40 (brs, 2H), 6.93 (m, 1H), 7.36 (t, J = 10 Hz, 1H ), 7.88 (d, J = 14 Hz, 1H), 8.40 (s, 1H)

(Example 171)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminoazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo -Quinoline-3-carboxylic acid p-toluenesulfonate:

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminoazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo 440 mg of -quinoline-3-carboxylic acid was added to 0.5 ml of N and N-dimethylformamide, and 191 mg of p-toluenesulfonic acid monohydrate was added and stirred at room temperature. Diethyl ether was added to the reaction solution to remove the supernatant. Ethanol was added to the residue, and the solid was filtered off and washed with diethyl ether to obtain 340 mg of the title compound.

Appearance: Yellow Powder

Melting Point: 211-220 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.28 (s, 3H), 4.04 (brs, 1H), 4.42 (brs, 2H), 4.76 (brs, 2H), 6.99 (t, J = 8Hz, 1H), 7.11 (d, J = 7Hz, 2H), 7.37 (t, J = 11 Hz, 1H), 7.48 (d, J = 8 Hz, 2H), 7.94 (d, J = 15 Hz, 1H), 8.33 (brs, 3H), 8.44 (s, 1H)

(Example 172)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminoazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid methanesulfonate:

The title compound was obtained in the same manner as in Example 171 except for using methanesulfonic acid.

Appearance: Pale yellow powder

Melting Point: 180-190 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.35 (s, 3H), 4.04 (brs, 1H), 4.43 (brs, 2H), 4.75 (brs, 2H), 6.99 (t, J = 8Hz, 1H), 7.37 (t, J = 11Hz, 1H), 7.95 (d, J = 14 Hz, 1H), 8.36 (brs, 3H), 8.48 (s, 1H)

(Example 173)

Ethyl 8-chloro-6, 7-difluoro-1- (2-chloro-4-fluoro-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Except that ethyl 8-chloro-6, 7-difluoro-1- (2-chloro-4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate was used The title compound was obtained in the same manner as in Example 97.

Appearance: Brown Powder

Melting point: 197-201 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.27 (t, J = 7 Hz, 3H), 4.25 (q, J = 7 Hz, 2H), 8.23-8.32 (m, 2H), 8.55 (s, 1H), 8.94 (d, J = 7 Hz, 1H)

(Example 174)

1- (3-Amino-6-chloro-4-fluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

1.5 g of ethyl 8-chloro-6, 7-difluoro-1- (2-chloro-4-fluoro-5-nitrophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate And 2 g of iron were added to 5 ml of formic acid, and the mixture was heated and stirred at 60 ° C for 2 hours. The insolubles were filtered off with celite and washed with formic acid and chloroform. The filtrate was concentrated under reduced pressure, ethanol was added to the residue, the solid was filtered off and washed with diethyl ether. 4 ml of concentrated hydrochloric acid and 4 ml of acetic acid were added to the solid, and the mixture was heated and refluxed for 1 hour. After cooling, the precipitate was filtered off and washed with ethanol and diethyl ether to obtain the title compound (970 mg).

Appearance: Pale yellow powder

Melting Point: 237-242 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.12 (d, J = 8 Hz, 1H), 7.50 (d, J = 12 Hz, 1H), 8.41 (t, J = 9 Hz, 1H), 8.60 (s, 1H)

(Example 175)

7- (3-aminoazetidin-1-yl) -1- (3-amino-6-chloro-4-difluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4 Oxoquinoline-3-carboxylic acid:

Using 8-chloro-6, 7-difluoro-1- (3-amino-6-chloro-4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid A title compound was obtained in the same manner as in Example 117 except for the above.

Appearance: Colorless Powder

Melting Point:> 265 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.70 (brs, 1H), 4.06 (brs, 2H), 4.67 (brs, 2H), 5.76 (s, 2H), 6.99 (d, J = 8 Hz, 1H), 7.46 (d, J = 11 Hz, 1H), 7.88 (d, J = 14 Hz, 1H), 8.48 (s, 1H)

(Example 176)

1- (3-amino-6-chloro-4-fluorophenyl) -7 [(3S) -3-aminopyrrolidin-1-yl] -8-chloro-6-fluoro-1, 4-di Hydro-4-oxoquinoline-3-carboxylic acid:

8-chloro-6, 7-difluoro-1- (3-amino-6-chloro-4-fluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, (3S The title compound was obtained in the same manner as in Example 117 except for using) -3-aminopyrrolidine.

Appearance: Pale yellow powder

Melting Point:> 195 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.52-1.74 (m, 1H), 1.91-2.15 (m, 1H), 2.71-3.80 (m, 5H), 5.75 (brs, 2H), 6.99 (t, J = 8 Hz, 1H), 7.46 (t, J = 11 Hz, 1H), 7.92 (d, J = 14 Hz, 1H), 8.35 (s, 1H)

(Example 177)

Ethyl 8-chloro-6, 7-difluoro-1- (4-fluoro-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

As in Example 97, except that ethyl 8-chloro-6, 7-difluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate was used The title compound was obtained.

Appearance: Colorless Powder

Melting point: 249-256 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.26 (t, J = 7 Hz, 3H), 4.23 (q, J = 7 Hz, 2H), 7.84 (t, J = 10 Hz, 1H), 8.14-8.19 (m, 1H), 8.23 (t, J = 9 Hz, 1H), 8.50 (s, 1H), 8.65-8.68 (m, 1H)

(Example 178)

8-chloro-6, 7-difluoro-1- (3-amino-4-fluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Other than using ethyl 8-chloro-5, 6, 7-trifluoro-1- (4-fluoro-5-nitrophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate In the same manner as in Example 174, the title compound was obtained.

Appearance: Colorless Powder

Melting Point: 238-243 ℃

¹ HNMR (d ₆ -DMSO) δ;

6.74-6.89 (m, 1H), 6.95-7.07 (m, 1H), 7.21 (t, J = 8 Hz, 1H), 8.40 (t, J = 9 Hz, 1H), 8.56 (s, 1H)

(Example 179)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4-fluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo-quinoline- 3-carboxylic acid:

Example except using 8-chloro-6, 7-difluoro-1- (3-amino-4-fluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid The title compound was obtained in the same manner as 117.

Appearance: Yellow Powder

Melting Point: 236-246 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.77 (brs, 1H), 4.12 (brs, 2H), 4.66 (brs, 2H), 5.58 (s, 2H), 6.60-6.72 (m, 1H), 6.87 (d, J = 8 Hz, 1H), 7.16 ( t, J = 10Hz, 1H), 7.87 (d, J = 14Hz, 1H), 8.39 (s, 1H)

(Example 180)

Ethyl 8-chloro-6, 7-difluoro-1- (4-fluoro-2-methyl-5-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Except that ethyl 8-chloro-6, 7-difluoro-1- (2-methyl-4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate was used The title compound was obtained in the same manner as in Example 97.

Appearance: Red Powder

Melting Point: 187-191 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 2.25 (s, 3H), 4.20 (q, J = 7 Hz, 2H), 7.36 (d, J = 11 Hz, 1H), 8.11 (d, J = 7 Hz, 1H) , 8.26 (s, 1 H), 8.38 (t, J = 9 Hz, 1 H)

(Example 181)

8-Chloro-6, 7-difluoro-1- (3-amino-4-fluoro-6-methylphenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Using ethyl 8-chloro-6, 7-difluoro-1- (4-fluoro-2-methyl-5-nitrophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 174 except for the following.

Appearance: Colorless Powder

Melting point: 225-230 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.89 (s, 3H), 7.00 (d, J = 8Hz, 1H), 7.16 (d, J = 12Hz, 1H), 8.42 (t, J = 9Hz, 1H), 8.51 (s, 1H)

(Example 182)

1- (3-amino-4-fluoro-6-methylphenyl) -7- (3-aminoazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4-oxo -Quinoline-3-carboxylic acid:

Other than 8-chloro-6, 7-difluoro-1- (3-amino-4-fluoro-6-methylphenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid Was obtained in the same manner as in Example 117 to obtain the title compound.

Appearance: Brown Powder

Melting Point:> 251 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.88 (s, 3H), 3.71 (brs, 1H), 4.06 (brs, 2H), 4.65 (brs, 2H), 5.38 (s, 2H), 6.79 (d, J = 7 Hz, 1H), 7.06 (d, J = 11Hz, 1H), 7.91 (d, J = 13Hz, 1H), 8.29 (s, 1H)

(Example 183)

Ethyl 1- (2-bromo-4-fluoro-5-nitrophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Except for using ethyl 1- (2-bromo-4-fluorophenyl) -8-chloro-6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate In the same manner as in Example 97, the title compound was obtained.

Appearance: Brown Powder

Melting point: 205-214 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.27 (t, J = 7 Hz, 3H), 4.25 (q, J = 7 Hz, 2H), 8.27 (t, J = 9 Hz, 1H), 8.41 (d, J = 11 Hz, 1H), 8.53 (s, 1H) , 8.91 (d, J = 8 Hz, 1H)

(Example 184)

8-chloro-6, 7-difluoro-1- (3-amino-6-bromo-4-fluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- (2-bromo-4-fluoro-5-nitrophenyl) -8-chloro-6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 117 except for the use.

Appearance: Pale yellow powder

Melting Point: 231-239 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.14 (d, J = 9 Hz, 1H), 7.58 (d, J = 11 Hz, 1H), 8.43 (t, J = 9 Hz, 1H), 8.58 (s, 1H)

(Example 185)

7- (3-aminoazetidin-1-yl) -1- (3-amino-6-bromo-4-fluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4 Oxoquinoline-3-carboxylic acid:

8-chloro-6, 7-difluoro-1- (3-amino-6-bromo-4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid A title compound was obtained in the same manner as in Example 117 except for the above.

Appearance: Pale yellow powder

Melting Point:> 200 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.89 (brs, 1H), 4.27 (brs, 2H), 4.71 (brs, 2H), 5.81 (s, 2H), 7.03 (d, J = 8 Hz, 1H), 7.55 (d, J = 11 Hz, 1H), 7.93 (d, J = 14 Hz, 1H), 8.33 (s, 1H)

(Example 186)

Ethyl 1- (2-methoxy-4-fluoro-5-nitrophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Except for using ethyl 1- (2-methoxy-4-fluorophenyl) -8-chloro-6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate In the same manner as in Example 97, the title compound was obtained.

Appearance: Pale yellow powder

Melting Point: 220-225 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 3.92 (s, 3H), 4.40 (q, J = 7 Hz, 2H), 6.94 (d, J = 12 Hz, 1H), 8.21-8.30 (m, 1H), 8.26 (s, 1H), 8.34 (t, J = 9 Hz, 1H)

(Example 187)

8-chloro-6, 7-difluoro-1- (3-amino-6-methoxy-4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- (2-methoxy-4-fluoro-5-nitrophenyl) -8-chloro-6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 174 except for using.

Appearance: Pale yellow powder

Melting Point: 143-151 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.70 (s, 3H), 7.19-7.37 (m, 2H), 8.40 (t, J = 9 Hz, 1H), 8.56 (s, 1H)

(Example 188)

1- (3-amino-6-methoxy-4-fluorophenyl) -7- (3-aminoazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4 Oxo-quinoline-3-carboxylic acid:

8-chloro-6, 7-difluoro-1- (3-amino-6-methoxy-4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid A title compound was obtained in the same manner as in Example 117 except for the above.

Appearance: Pale yellow powder

Melting Point:> 244 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.68 (brs, 4H), 4.05 (brs, 2H), 4.65 (brs, 2H), 5.01 (s, 2H), 6.87 (brs, 1H), 7.09 (d, J = 12 Hz, 1H), 7.86 (d, J = 14 Hz, 1H), 8.29 (s, 1H)

(Example 189)

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-5-nitro-1, 4-dihydro-4-oxoquinoline- 3-carboxylate:

The title compound was obtained in the same manner as in Example 102 except that ethyl 3-chloro-2, 4, 5-trifluoro-6-nitrobenzoyl acetate was used.

Appearance: Brown Powder

Melting Point: 233-241 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.38 (t, J = 7 Hz, 3H), 4.38 (q, J = 7 Hz, 2H), 5.21 (s, 2H), 7.01-7.15 (m, 2H), 7.40 (s, 5H), 8.32-8.40 (m , 1H), 8.36 (s, 1H)

(Example 190)

5-Amino-1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid :

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-5-nitro-1, 4-dihydro-4-oxoquinoline- The title compound was obtained in the same manner as in Example 174 except for using 3-carboxylate.

Appearance: Yellow Powder

Melting Point:> 270 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.02 (t, J = 8 Hz, 1H), 7.39 (t, J = 10 Hz, 1H), 8.46 (s, 1H)

(Example 191)

5-amino-1- (3-amino-4, 6-difluorophenyl) -7- (3-aminoazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro 4-oxoquinoline-3-carboxylic acid:

5-Amino-1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid Except for using the same as in Example 117 to obtain the title compound.

Appearance: Brown Powder

Melting Point:> 229 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.98 (brs, 1H), 4.38 (brs, 2H), 4.67 (brs, 2H), 5.39 (s, 2H), 6.90 (t, J = 8 Hz, 1H), 7.34 (t, J = 11 Hz, 1H), 8.29 (s, 1 H)

(Example 192)

Ethyl 1- (3-benzyloxycarbonylamino-4, 5, 6-trifluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3- Carboxylate:

As in Example 102, except that ethyl 3-chloro-2, 4, 5-trifluorobenzoyl acetate, N-benzyloxycarbonyl-4, 5, 6-trifluoro-m-phenylenediamine were used The title compound was obtained.

¹ HNMR (d ₆ -DMSO) δ;

1.42 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 5.21 (s, 2H), 7.05 (brs, 1H), 7.39 (s, 5H), 8.19 (brs, 1H), 8.31 (s, 1H), 8.34 (t, J = 8Hz, 1H)

(Example 193)

1- (3-Amino-4, 5, 6-trifluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- (3-benzyloxycarbonylamino-4, 5, 6-trifluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3- The title compound was obtained in the same manner as in Example 103 except that the carboxylate was used.

Appearance: Colorless Powder

Melting Point: 232-238 ℃

¹ HNMR (d ₆ -DMSO) δ;

6.88 (dd, J = 4 Hz, J = 9 Hz, 1H), 8.40 (t, J = 9 Hz, 1H), 8.79 (s, 1H)

(Example 194)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 5, 6-trifluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4 Oxoquinoline-3-carboxylic acid:

Using 1- (3-amino-4, 5, 6-trifluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid A title compound was obtained in the same manner as in Example 117 except for the above.

Appearance: Pale yellow powder

Melting Point:> 224 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.73 (brs, 1H), 4.08 (brs, 2H), 4.68 (brs, 2H), 5.78 (s, 2H), 6.78 (t, J = 6 Hz, 1H), 7.87 (d, J = 14 Hz, 1H), 8.55 (s, 1 H)

(Example 195)

Ethyl 1- (3-tert-butyloxycarbonylamino-4, 6-difluorophenyl) -8-bromo-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3 Carboxylate:

Ethyl 3-bromo-2, 4, 5-trifluorobenzoyl acetate, except that N- (t-butoxycarbonyl) -2 and 4-difluoro-m-phenylenediamine of Reference Example 10 were used. In the same manner as in Example 102, the title compound was obtained.

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 1.54 (s, 9H), 4.40 (q, J = 7 Hz, 2H), 6.81 (brs, 1H), 7.07 (t, J = 10 Hz, 1H), 8.25-8.48 (m, 2 H), 8.38 (s, 1 H)

(Example 196)

1- (3-Amino-4, 6-difluorophenyl) -8-bromo-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- (3-tert-butyloxycarbonylamino-4, 6-difluorophenyl) -8-bromo-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3 The title compound was obtained in the same manner as in Example 103 except that carboxylate was used.

Appearance: Yellow Powder

Melting point: 228-232 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.05 (t, J = 8Hz, 1H), 7.43 (t, J = 11Hz, 1H), 8.43 (t, J = 9Hz, 1H), 8.69 (s, 1H)

(Example 197)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -8-bromo-6-fluoro-1, 4-dihydro-4- Oxo-quinoline-3-carboxylic acid:

Using 1- (3-amino-4, 6-difluorophenyl) -8-bromo-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid A title compound was obtained in the same manner as in Example 117 except for the above.

Appearance: Pale yellow powder

Melting Point:> 206 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.76 (brs, 1H), 4.07 (brs, 2H), 4.68 (brs, 2H), 5.41 (s, 2H), 6.92 (t, J = 8 Hz, 1H), 7.38 (t, J = 11 Hz, 1H), 7.90 (d, J = 14 Hz, 1H), 8.46 (s, 1H)

(Example 198)

Ethyl 1- [3- (Nt-butoxycarbonyl-N-methylamino) -4, 6-difluorophenyl] -8-chloro-6, 7-difluoro-4-oxo-1, 4- Dihydro-quinoline-3-carboxylate:

3-ethoxy-2- (3'-chloro-2 ', 4', 5'-trifluorobenzoyl, prepared according to a conventional method with 1.40 g of 3-chloro-2, 4, 5-trifluorobenzoyl acetate ethyl ester ) N- (t-butoxycarbonyl) -4 and 6-difluoro-m-phenylenediamine were added to 10 ml of chloroform solutions in which ethyl ester of acrylic acid was dissolved while the reaction end point was measured by TLC. This solution was concentrated under reduced pressure. 1.4 g of anhydrous potassium carbonate and 6 ml of N, N-dimethylformamide were added thereto, followed by stirring at 90 ° C for 10 minutes. After allowing to cool, 1.4 g of anhydrous potassium carbonate and 5.0 g of methyl iodide were added, followed by stirring at 60 ° C. for 2 hours. 50 mL of chloroform and 500 mL of distilled water were added thereto, followed by separating the chloroform layer with 500 mL of distilled water twice, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and left to stand by adding 3 mL of ethanol. The precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 1.38 g of the title compound.

Appearance: Pale yellow powder

Melting Point: 192-194 ℃

¹ HNMR (CDCl ₃ ) δ;

1.43 (t, J = 7 Hz, 3H), 1.44 (s, 9H), 3.22 (s, 3H), 4.41 (q, J = 7 Hz, 2H), 7.10 (t, J = 9 Hz, 1H), 7.38 (t , J = 8 Hz, 1H), 8.34 (dd, J = 8 Hz, 10 Hz, 1H), 8.58 (s, 1H)

(Example 199)

1- (3-Methylamino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid:

Ethyl 1- [3- (Nt-butoxycarbonyl-N-methylamino) -4, 6-difluorophenyl] -8-chloro-6, 7-difluoro-4-oxo-1, 4- 1.26 g of dihydro-quinoline-3-carboxylate was added to a mixture of 4 mL of 4N hydrochloric acid and acetic acid (1: 1, V / V), and the mixture was heated under reflux for 1 hour and a half. 5 ml of distilled water was added, followed by cooling. The precipitate was filtered off and washed with ethanol and diisopropyl ether in order to obtain 890 mg of the title compound.

Appearance: Pale yellow powder

Melting Point: 217-220 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.67 (d, J = 5 Hz, 3H), 5.95 (brs, 1H), 7.06 (t, J = 8 Hz, 1H), 7.45 (dd, J = 10 Hz, 12 Hz, 1H), 8.41 (dd, J = 9 Hz, 10 Hz, 1H), 8.72 (S, 1H)

(Example 200)

7- (3-aminoazetidinyl) -1- (3-methylamino-4, 6-difluorophenyl) -8-chloro-6-fluoro-4-oxo-1, 4-dihydro-quinoline 3-carboxylic acid:

150 mg of 1- (3-methylamino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid , 110 mg of 3-aminoazetidine dihydrochloride and 250 mg of N-methylpyrrolidine were added to 650 mg of N and N-dimethylformamide, followed by stirring at 90 ° C for 1 hour. 0.5 ml of ethanol was added, followed by cooling. The precipitate was filtered off, washed with ethanol and diisopropyl ether in order to obtain 130 mg of the title compound.

Appearance: Colorless Powder

Melting Point: 209-212 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.68 (d, J = 5 Hz, 3H), 3.69 (m, 1H), 4.02 (m, 2H), 4.65 (m, 2H), 5.89 (brs, 1H), 6.96 (t, J = 8 Hz, 1H), 7.40 (t, J = 10 Hz, 1H), 7.88 (d, J = 14 Hz, 1H), 8.48 (S, 1H)

(Example 201)

Ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

To 4.1 g of ethyl 2,4,5-trifluoro-3-methoxybenzoyl acetate, 8.6 ml of acetic anhydride and 3.2 ml of triethyl ortho formate were added and refluxed for 2 hours, the solvent was distilled off, and toluene was added to the residue to azeotrope. I was. 10 ml of chloroform was added to the residue, and a 10 ml solution of 1.81 g of N-benzyloxycarbonyl-2 and 4-difluoro-m-phenylenediamine was added dropwise at 0 ° C, followed by stirring at room temperature for 3 days. A solvent of 4 ml of 580 mg of N, N-dimethylformamide in 2.4 g of an oily product obtained by distilling off the solvent of the reaction solution, and refining by silica gel column chromatography (elution solvent; ethyl acetate: hexane = 1: 8) 138 mg of potassium carbonate was added to the mixture, and the mixture was stirred at 100 ° C for 25 minutes. The reaction solution was poured into ice water, ice water and ethyl acetate were added to the reaction solution, the organic layer was separated, washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; chloroform: Methanol = 10: 1), and the obtained solid was filtered and washed with diethyl ether to obtain 250 mg of the title compound.

Appearance: Pale yellow powder

Melting point: 159-162 ℃

¹ HNMR (CDCl ₃ ) δ;

1.39 (t, J = 7 Hz, 3H), 3.57 (s, 3H), 4.37 (q, J = 7 Hz, 2H), 6.84 (t, J = 8 Hz, 1H), 7.00 (t, J = 9 Hz, 1H) , 8.08 (t, J = 9 Hz, 1 H), 8.26 (s, 1 H)

(Example 202)

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Using ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 103 except for the above.

Appearance: Colorless Powder

Melting Point:> 277 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.12 (s, 3H), 6.71 (t, J = 9Hz, 1H), 7.00 (t, J = 10Hz, 1H), 7.73 (t, J = 9Hz, 1H), 8.20 (s, 1H)

(Example 203)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-8-methoxy-1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

170 mg of 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid It was suspended in 4 ml of diethyl ether, 9 ml of boron trifluoride diethyl ether complex was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Diethyl ether was added to the reaction solution, and the precipitated solid was filtered off, washed with ethanol and diethyl ether in order to obtain a pale yellow powder.

70 mg of 3-aminoazetidine-dihydrochloride and 1 ml of dimethylsulfoxide solution of 0.17 ml of triethylamine were stirred at 70 ° C, and 100 mg of the compound was added and stirred at the same temperature for 2 hours. Diethyl ether was added to the reaction solution, followed by decantation. To the residue, 5 ml of 80% methanol and 5 ml of triethylamine were added and refluxed overnight. Ethanol was added to the reaction solution, and a solid was filtered to obtain 34 mg of the title compound as a tan powder.

Appearance: Yellow Powder

Melting Point:> 290 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.11 (s, 3H), 3.74-3.89 (m, 2H), 3.90-4.02 (m, 1H), 4.38-4.48 (m, 2H), 5.36 (brs, 2H), 7.14 (t, J = 9 Hz, 1H ), 7.30 (t, J = 10 Hz, 1H), 7.76 (d, J = 12 Hz, 1H), 8.39 (s, 1H)

(Example 204)

8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluoro-3-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

The procedure was carried out except that 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid was used. The title compound was obtained in the same manner as in Example 9.

Appearance: Pale yellow powder

Melting Point: 157-159 ℃

¹ HNMR (d ₆ -DMSO) δ;

8.16 (t, J = 11 Hz, 1H), 8.40 (t, J = 9 Hz, 1H), 9.06 (s, 1H)

(Example 205)

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluoro-3-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluoro-3-nitrophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (830 2 ml of thionyl chloride was added to the solution, and the mixture was stirred overnight at 80 ° C. 4 ml of ethanol under ice-cooling was slowly added dropwise to the reaction solution, and then the solvent of the reaction solution was distilled off and the precipitated solid was filtered to give 310 mg of the titled compound.

Appearance: Pale yellow powder

Melting Point: 167-169 ℃

¹ HNMR (CDCl ₃ ) δ;

1.41 (t, J = 7 Hz, 3H), 4.41 (q, J = 7 Hz, 2H), 7.19 (t, J = 9 Hz, 1H), 8.22 (s, 1H), 8.35 (t, J = 9 Hz, 1H)

(Example 206)

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluoro-3-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxyl Rate:

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluoro-3-nitrophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 166 except for using.

Appearance: Light Brown Powder

Melting point: 197-199 ℃

(Example 207)

1- (3-Amino-2, 4, 6-trifluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 8-chloro-6, 7-difluoro-1- (2, 4, 6-trifluoro-3-formylaminophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxyl The title compound was obtained in the same manner as in Example 19 except that the rate was used.

Appearance: Pale yellow powder

¹ HNMR (d ₆ -DMSO) δ;

5.57 (brs, 2H), 7.42 (t, J = 11 Hz, 1H), 8.40 (t, J = 9 Hz, 1H), 8.91 (s, 1H)

(Example 208)

7- (3-aminoazetidin-1-yl) -1- (3-amino-2, 4, 6-trifluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4 Oxoquinoline-3-carboxylic acid:

Using 1- (3-amino-2, 4, 6-trifluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid A title compound was obtained in the same manner as in Example 117 except for the above.

Appearance: Light Brown Powder

Melting Point:> 290 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.77-3.86 (m, 1H), 4.15-4.27 (m, 2H), 4.64-4.75 (m, 1H), 5.52 (brs, 2H), 7.38 (t, J = 10 Hz, 1H), 7.91 (d, J) = 13 Hz, 1H), 8.66 (s, 1H)

(Example 209)

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -6-chloro-7, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxyl Rate:

Except for using ethyl 5-chloro-2, 3, 4-trifluorobenzoyl acetate, 3-benzyloxycarbonyl-2, 4-difluoro-m-phenylenediamine, the title compound was used in the same manner as in Example 102. Got.

Appearance: Pale yellow powder

Melting point: 204-205 ℃

¹ HNMR (CDCl ₃ ) δ;

1.39 (t, J = 7 Hz, 3H), 4.38 (q, J = 7 Hz, 2H), 7.02 (brs, 1H), 7.11 (t, J = 10 Hz, 1H), 7.39 (s, 5H), 8.28 (s , 1H), 8.35-8.50 (m, 2H)

(Example 210)

1- (3-Amino-4, 6-difluorophenyl) -6-chloro-7, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -6-chloro-7, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxyl The title compound was obtained in the same manner as in Example 103 except that the rate was used.

Appearance: Colorless Powder

Melting Point: 276-278 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.15 (t, J = 9 Hz, 1H), 7.45 (t, J = 11 Hz, 1H), 8.38 (d, J = 8 Hz, 1H), 8.73 (s, 1H)

(Example 211)

1- (3-amino-4, 6-difluorophenyl) -7-[(3S) -3-aminopyrrolidin-1-yl] -6-chloro-8-fluoro-1, 4-di Hydro-4-oxoquinoline-3-carboxylic acid:

Other than using 1- (3-amino-4, 6-difluorophenyl) -6-chloro-7, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid In the same manner as in Example 60, the title compound was obtained.

Appearance: Pale yellow powder

Melting Point:> 240 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

1.51-1.68 (m, 1H), 1.88-2.04 (m, 1H), 5.44 (brs, 2H), 7.09 (t, J = 8 Hz, 1H), 7.39 (t, J = 11 Hz, 1H), 8.05 (s , 1H), 8.48 (s, 1H)

(Example 212)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-chloro-8-fluoro-1, 4-dihydro-4-oxo Quinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -6-chloro-7, 8-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-amino The title compound was obtained in the same manner as in Example 60 except that the azetidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting point: 190-193 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.65-3.77 (m, 1H), 3.97-4.10 (m, 2H), 4.52-4.68 (m, 2H), 5.44 (brs, 2H), 7.07 (t, J = 8 Hz, 1H), 7.38 (t, J = 11 Hz, 1H), 7.96 (s, 1H), 8.45 (s, 1H)

(Example 213)

Ethyl 8-chloro-1- (4-chloro-2-fluoro-5-nitrophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

Except that ethyl 8-chloro-1- (4-chloro-2-fluorophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was used The title compound was obtained in the same manner as in Example 97.

Appearance: Colorless Powder

Melting point: 206-208 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.57 (d, J = 9 Hz, 1H), 8.16 (d, J = 7 Hz, 1H), 8.30 (s, 1H) , 8.34 (t, J = 10 Hz, 1H)

(Example 214)

Ethyl 8-chloro-1- (4-chloro-6-fluoro-3-formylaminophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate :

Using ethyl 8-chloro-1- (4-chloro-2-fluoro-5-nitrophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 166 except for the following.

Appearance: Light Brown Powder

Melting Point: 241-244 ℃

(Example 215)

1- (3-Amino-4-chloro-6-fluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 8-chloro-1- (4-chloro-6-fluoro-3-formylaminophenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate Except for using the same as in Example 19 to obtain the title compound.

Appearance: Pale yellow powder

Melting Point: 255-258 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.08 (d, J = 7 Hz, 1H), 7.55 (d, J = 10 Hz, 1H), 8.40 (t, J = 9 Hz, 1H), 8.70 (s, 1H)

(Example 216)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4-chloro-6-fluorophenyl) -8-chloro-6-fluoro-1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

1- (3-amino-4-chloro-6-fluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3- The title compound was obtained in the same manner as in Example 60 except that the aminoazetidine dihydrochloride was used.

Appearance: Pale yellow powder

Melting Point:> 290 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.66-3.79 (m, 1H), 4.00-4.15 (m, 2H), 4.60-4.74 (m, 2H), 5.61 (brs, 2H), 7.00 (d, J = 10 Hz, 1H), 7.50 (d, J = 10 Hz, 1 H), 7.87 (d, J = 14 Hz, 1 H)

(Example 217)

Ethyl 1- (3-t-butoxycarbonylamino-4-fluoro-2-methoxyphenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxyl Rate:

Except for using ethyl 3-chloro-2, 4, 5-trifluorobenzoyl acetate, 3-t-butoxycarbonylamino-4-fluoro-2-methoxyaniline, and the like. Got.

Appearance: Pale yellow powder

Melting Point: 184-189 ℃

¹ HNMR (CDCl ₃ ) δ;

1.39 (t, J = 7 Hz, 3H), 3.64 (s, 3H), 4.39 (q, J = 7 Hz, 2H), 6.05 (brs, 1H), 7.06 (t, J = 8 Hz, 1H), 7.21-7.29 (m, 1 H), 8.31-8.40 (m, 2 H)

(Example 218)

1- (3-Amino-4-fluoro-2-methoxyphenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 1- (3-t-butoxycarbonylamino-4-fluoro-2-methoxyphenyl) -6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxyl The title compound was obtained in the same manner as in Example 103 except that the rate was used.

Appearance: Pale yellow powder

Melting Point: 203-215 ° C (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.43 (s, 3H), 6.78-6.90 (m, 1H), 7.08 (t, J = 8 Hz, 1H), 8.42 (t, J = 7 Hz, 1H), 8.61 (s, 1H)

(Example 219)

7- (3-aminoazetidin-1-yl) -1- (3-amino-4-fluoro-2-methoxyphenyl) -6-fluoro-1, 4-dihydro-4-oxoquinoline- 3-carboxylic acid:

1- (3-amino-4-fluoro-2-methoxyphenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, 3-aminoazetidine The title compound was obtained in the same manner as in Example 117 except that dihydrochloride and N-methylpyrrolidine were used.

Appearance: Colorless Powder

Melting Point:> 179 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

3.42 (s, 3H), 3.96-4.13 (m, 2H), 4.55-4.72 (m, 2H), 5.40 (brs, 2H), 6.71-6.83 (m, 1H), 7.03 (t, J = 7Hz, 1H ), 7.88 (d, J = 14 Hz, 1H), 8.39 (s, 1H)

(Example 220)

Ethyl 6, 7, 8-trichloro-1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Example 102 except that ethyl 2, 3, 4, 5-tetrachlorobenzoyl acetate, 3-benzyloxycarbonyl-2, and 4-difluoro-m-phenylenediamine were used.

Appearance: Pale yellow powder

Melting point: 128-129 ℃

¹ HNMR (CDCl ₃ ) δ;

1.40 (t, J = 7 Hz, 3H), 4.40 (q, J = 7 Hz, 2H), 7.03-7.14 (m, 2H), 7.40 (s, 5H), 8.27 (s, 1H), 8.60 (s, 1H )

(Example 221)

1- (3-Amino-4, 6-difluorophenyl) -6, 7, 8-trichloro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Ethyl 6, 7, 8-trichloro-1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -1, 4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 103 except for the above.

Appearance: Colorless Powder

Melting point: 251-252 ℃

¹ HNMR (d ₆ -DMSO) δ;

7.01 (t, J = 8Hz, 1H), 7.41 (t, J = 10Hz, 1H), 8.52 (s, 1H), 8.66 (s, 1H)

(Example 222)

Ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylate:

The title compound was obtained in the same manner as in Example 201 except that ethyl 2, 4, 5-trifluoro-3-methylbenzoyl acetate was used.

Appearance: Pale yellow powder

Melting Point: 221-223 ℃

¹ HNMR (CDCl ₃ ) δ;

1.38 (t, J = 7 Hz, 3H), 1.85 (s, 3H), 3.98 (brs, 2H), 4.37 (q, J = 7 Hz, 2H), 6.81 (t, J = 8 Hz, 1H), 7.02 (t , J = 10Hz, 1H), 8.19 (t, J = 10Hz, 1H), 8.32 (s, 1H)

(Example 223)

1- (3-Amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

Using ethyl 1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-8-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylate A title compound was obtained in the same manner as in Example 103 except for the above.

Appearance: Pale yellow powder

Melting Point: 264-267 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.86 (d, J = 3 Hz, 1H), 7.12 (t, J = 8 Hz, 1H), 7, 47 (t, J = 11 Hz, 1H), 8.25 (t, J = 9 Hz, 1H), 8.69 (s, 1H)

(Example 224)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminomethyl-3-hydroxyazetidin-1-yl) -8-chloro-6-fluoro-1, 4- Dihydro-4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-aminomethyl The title compound was obtained in the same manner as in Example 117 except for using 3-hydroxyazetidine dihydrochloride and triethylamine.

Appearance: Pale yellow powder

Melting Point:> 209 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.83 (brs, 2H), 4.21 (brs, 2H), 4.52 (brs, 2H), 5.42 (brs, 2H), 6.90-7.10 (m, 1H), 7.36 (t, 1H), 7.85 (d, J = 14.5 Hz, 1H), 8.39 (s, 1H)

(Example 225)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminomethylazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-aminomethyl The title compound was obtained in the same manner as in Example 117 except for using azetidine dihydrochloride and triethylamine.

Appearance: Pale yellow powder

Melting Point:> 217 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO + d-TFA) δ;

2.89 (brs, 1H), 3.11 (brs, 2H), 4.29 (brs, 2H), 4.58 (brs, 2H), 6.90-7.05 (m, 1H), 7.36 (t, 1H), 7.90 (d, J = 13 Hz, 1H), 8.46 (s, 1H)

(Example 226)

1- (3-amino-4, 6-difluorophenyl) -8-chloro-7- (3-dimethylaminoazetidin-1-yl) -6-fluoro-1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-dimethylamino The title compound was obtained in the same manner as in Example 117 except that the azetidine dihydrochloride and triethylamine were used.

Appearance: Yellow Powder

Melting Point:> 256 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

2.07 (s, 6H), 3.03 (brs, 1H), 4.23 (brs, 2H), 4.54 (brs, 2H), 5.41 (brs, 2H), 6.98 (t, J = 8 Hz, 1H), 7.37 (t, J = 11 Hz, 1H), 7.87 (d, J = 13 Hz, 1H), 8.45 (s, 1H)

(Example 227)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminomethylpyrrolidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4 Oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-aminomethyl The title compound was obtained in the same manner as in Example 117 except for using pyrrolidine dihydrochloride and triethylamine.

Appearance: Yellow Powder

Melting Point: 183.0-185.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.50-1.80 (br, 1H), 1.85-2.10 (br, 1H), 2.35-2.60 (m, 1H), 2.80 (brs, 2H), 3.00-3.65 (m, 4H), 5.45 (brs, 2H), 6.90-7.05 (m, 1H), 7.35 (t, 1H), 7.96d (d, J = 12 Hz, 1H), 8.55 (s, 1H)

(Example 228)

1- (3-amino-4, 6-difluorophenyl) -8-chloro-7- (3-hydroxycarbonylazetidin-1-yl) -6-fluoro-1, 4-dihydro- 4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and azetidine-3 The title compound was obtained in the same manner as in Example 117 except that carboxylic acid hydrochloride and triethylamine were used.

Appearance: Pale yellow powder

Melting Point: 227.0-231.0 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.25-3.60 (m, 1H), 4.50 (brs, 2H), 4.66 (brs, 2H), 5.42 (brs, 2H), 6.96 (t, J = 8 Hz, 1H), 7.37 (t, J = 10 Hz, 1H ), 7.89 (d, J = 13.7 Hz, 1H), 8.46 (s, 1H)

(Example 229)

7- (3-acetylaminoazetidin-1-yl) -1- (3-amino-4, 6-difluorophenyl) -6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except that acetylaminoazetidine hydrochloride and triethylamine were used.

Appearance: Light Brown Powder

Melting Point: 289.0-295.0 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.81 (s, 3H), 3.60-4.90 (m, 5H), 5.35 (brs, 2H), 6.94 (t, 1H), 7.35 (t, J = 10Hz, 1H), 8.06 (d, J = 10Hz, 1H ), 8.54 (brs, 1H), 8.69 (s, 1H)

(Example 230)

1- (3-amino-4, 6-difluorophenyl) -7-((1R, 4R) -2, 5-diazabicyclo [2.2.1] heptan-2-yl) -6-fluoro- 1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid ( The title compound was obtained in the same manner as in Example 117 except that 1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane dihydrochloride and triethylamine were used.

Appearance: Pale yellow powder

Melting Point:> 284 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO + d-TFA) δ;

1.90 (d, J = 11 Hz, 1H), 2.11 (d, J = 11 Hz, 1H), 3.15-3.90 (m, 5H), 4.45 (s, 1H), 5.20-6.10 (br, 2H), 6.98 (t , 1H), 7.36 (t, J = 10 Hz, 1H), 8.18 (d, J = 12 Hz, 1H), 8.76 (s, 1H), 9.15-9.30 (br, 2H)

(Example 231)

1- (3-amino-4, 6-difluorophenyl) -8-chloro-7- (3, 7-diazabicyclo [3.3.0] octan-3-yl) -6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride:

100 mg of 1- (4-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 3 104 mg of -t-butoxycarbonyl-3 and 7-diazabicyclo [3.3.0] octane and 150 mg of triethylamine were dissolved in 3 ml of acetonitrile and stirred at 80 ° C for 3 hours. The solvent was distilled off under reduced pressure. Extracted in 30 ml of chloroform. The organic layer was washed with 20 ml of 3% citric acid aqueous solution. It was distilled off after drying. This was dissolved in 20 ml of dichloromethane. 5 ml of 4N hydrochloric acid / dioxane was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was solidified with isopropyl ether and filtered off. 120 mg of the title compound as a pale yellow powder was obtained.

Appearance: Pale yellow powder

Melting Point: 199.5-204.0 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.85-3.10 (m, 4H), 3.30-3.70 (m, 6H), 7.02 (t, J = 8 Hz, 1H), 7.41 (t, J = 10 Hz, 1H), 8.08 (d, J = 12.5 Hz, 1H ), 8.59 (s, 1 H), 9.13 (brs, 1 H), 9.26 (brs, 1 H)

(Example 232)

1- (3-amino-4, 6-difluorophenyl) -7- (3, 7-diazabicyclo [3.3.0] octan-3-yl) -6-fluoro-1, 4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride:

1- (3-amino-4, 6-difluorophenyl) -7-chloro-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 231 except for using -t-butoxycarbonyl-3 and 7-diazabicyclo [3.3.0] octane.

Appearance: Pale yellow powder

Melting Point: 203.0-208.0 ℃

¹ HNMR (d ₆ -DMSO) δ;

3.06 (brs, 4H), 3.36 (brs, 2H), 3.40-3.90 (m, 4H), 7.12 (t, 1H), 7.42 (t, J = 11z, 1H), 8.09 (d, J = 13 Hz, 1H ), 8.72 (s, 1 H), 9.46 (brs, 2 H)

(Example 233)

1- (3-amino-4, 6-difluorophenyl) -7- (3, 7-diazabicyclo [3, .3.0] octan-3-yl) -6-fluoro-1, 4-di Hydro-4-oxoquinoline-3-carboxylic acid hydrochloride:

1- (3-amino-4, 6-difluorophenyl) -6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-t-butoxycarbonyl The title compound was obtained in the same manner as in Example 231 except for using -3,7-diazabicyclo [3.3.0] octane.

Appearance: Yellow Powder

Melting Point: 221-224.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

2.95-3.20 (m, 4H), 3.25-3.65 (m, 6H), 6.06 (d, 1H), 7.12 (t, 1H), 7.53 (t, 1H), 7.91 (d, J = 14 Hz, 1H), 8.67 (s, 1 H), 9.30-9.70 (br, 2 H)

(Example 234)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminoethylazetidin-1-yl) -8-chloro-6-fluoro-1, 4-dihydro-4- Oxoquinoline-3-carboxylic acid trifluoroacetate:

1- (3-amino-4, 6-difluorophenyl) -8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3-t- It reacted like Example 231 except having used butoxycarbonylaminoethylazetidine and triethylamine. Deprotection yielded the title compound using trifluoro acetic acid rather than 4N hydrochloric acid / dioxane.

Appearance: Yellow Powder

Melting Point: 140.0-141.5 ℃

¹ HNMR (d ₆ -DMSO) δ;

1.80-1.95 (m, 2H), 2.60-2.85 (m, 3H), 4.14 (brs, 2H), 4.57 (brs, 2H), 6.95 (dd, J = 7 Hz, J = 9 Hz, 1H), 7.36 (t , J = 11 Hz, 1H), 7.70 (brs, 3H), 7.87 (d, J = 13.5 Hz, 1H), 8.45 (s, 1H)

(Example 235)

5-benzyloxy-1- (3-benzyloxycarbonylamino-4, 6-difluorophenyl) -6, 7, 8-trifluoro-1, 4-dihydro4-oxoquinoline-3-car Ethyl Acid Ester:

1.11 g of ethyl 6-benzyloxy-2, 3, 4, 5-tetrafluorobenzoyl acetate, 0.75 ml of ethyl ortho formate, and 0.85 ml of acetic anhydride were stirred at 130 ° C. for 1 hour. It was distilled off under reduced pressure. 10 ml of dichloromethane was added to the residue. 0.8 g of N-benzyloxycarbonyl-2 and 4-difluoro-m-phenylenediamine were added thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. This was dissolved in 3 ml of N and N-dimethylformamide. 0.41 g of potassium carbonate was added and stirred at 100 ° C for 10 minutes. 50 ml of 5% citric acid was added to the reaction solution. Extracted with 50 ml of chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. It was distilled off under reduced pressure. The residue was referred to column chromatography (silica gel, chloroform / ethyl acetate = 20/1). 1.4 g of the compound was obtained as a red oil.

Appearance: Red Oil

¹ HNMR (CDCl ₃ ) δ;

1.37 (t, J = 7Hz, 3H), 4.38 (t, J = 7Hz, 2H), 5.21 (s, 1H), 5.26 (s, 1H), 7.01 (s, 1H), 7.08 (t, J = 10Hz , 1H), 7.25-7.55 (brs, 8H), 7.55-7.65 (m, 2H), 8.14 (s, 1H), 8.40 (brs, 1H)

(Example 236)

1- (3-Amino-4, 6-difluorophenyl) -5-hydroxy-6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid:

1.3 g of the compound synthesized in Example 235 was added to 8 ml of acetic acid and 10 ml of 6N hydrochloric acid, followed by stirring at 100 ° C for 4 hours. The solvent was distilled off under reduced pressure. Water was added to the residue. The solid was filtered off. It washed with water, ethanol, and isopropyl ether. 0.55 g of the compound as a yellow solid was obtained.

Appearance: Yellow Powder

Melting Point:> 278.0 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO) δ;

5.47 (brs, 2H), 7.08 (dd, J = 8 Hz, J = 9 Hz, 1H), 7.41 (dd, J = 10 Hz, J = 11 Hz, 1H), 8.59 (s, 1H)

(Example 237)

1- (3-amino-4, 6-difluorophenyl) -7- (3-aminoazetidin-1-yl) -6, 8-difluoro-5-hydroxy-1, 4-dihydro 4-oxoquinoline-3-carboxylic acid:

1- (3-amino-4, 6-difluorophenyl) -5-hydroxy-6, 7, 8-trifluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid and 3 The title compound was obtained in the same manner as in Example 117 except that the aminoazetidine dihydrochloride and triethylamine were used.

Appearance: Yellow Powder

Melting Point:> 261 ℃ (Decomposition)

¹ HNMR (d ₆ -DMSO + d-TFA) δ;

3.93 (brs, 1H), 4.14 (brs, 2H), 4.48 (brs, 2H), 5.43 (brs, 2H), 7.04 (t, 1H), 7.36 (t, J = 10 Hz, 1H), 8.36 (s, 1H)

(Test Example 1)

Antimicrobial activity:

According to the Japanese Society for Chemotherapeutic Standards (CHEMOTHERAPY, 29 (1), 76.1981), the minimum growth inhibition concentration (MIC: µg / ml) was measured. The results are shown in Table 1.

   Compound   S.aureus 209P   P.aeruginosa IFO3445 Compound of Example 48       0.025           0.1 Compound of Example 56       0.025           0.1 Compound of Example 60       0.013           0.1 Compound of Example 117       0.05           0.1 Compound of Example 150       0.025           0.2 Compound of Example 152      <0.013           0.05 Compound of Example 156      <0.013           0.1 Compound of Example 157      <0.013           0.1 Compound of Example 160       0.025           0.2 Compound of Example 162       0.013           0.2 Tosfloxacin       0.05           0.39

(Test Example 2)

Cytotoxicity Test:

HelaS3 cells and IMR 32 cells (5 × 10 ³ cells / well, 4 ×, respectively) suspended in Eagle MEM medium supplemented with 10% fetal bovine serum, 0.1 mM non-essential amino acid in each well of a 96 well tissue culture plate. 10 ⁴ pcs / well). Various concentrations of the drug were added, incubated for 6 hours at 37 ° C in the presence of 5% CO ₂ , and stained with 5% glutaraldehyde and 0.05% methylene blue after the incubation. The dye was further extracted with 0.3 N HCl, absorbance was measured at a wavelength of 650 nm, and the IC ₅₀ value was calculated. The results are shown in Table 2.

    Compound   HeLa cell   IMR32 cell Compound of Example 48     39.0      38.4 Compound of Example 117     36.8     > 50.0 Compound of Example 160    > 25.0     > 25.0 Tosfloxacin      7.7       9.6

(Test Example 3)

Phototoxicity test:

Cancer ICR mice (5-6 weeks old) were administered intravenously (40 mg / kg / 10 ml) of the test compound, and then irradiated with ultraviolet (320-400 nm, 1.8 mW / cm 2 / sec) for 4 hours. Immediately after irradiation, 0 hours were observed, and ear abnormalities were observed after 24 and 48 hours. Ear abnormalities were evaluated as no abnormality (0 point), mild erythema (1 point), moderate erythema (2 points), moderate erythema or edema (3 points). The results are shown in Table 3.

    Compound 0 hours (rating, frequency)   24 hours   48 hours Compound of Example 48       0, 0/3    0, 0/3    0, 0/3 Compound of Example 117       0, 0/3    0, 0/3    0, 0/3 Compound of Example 150       0, 0/3    0, 0/3    0, 0/3 Compound of Example 152       0, 0/3    0, 0/3    0, 0/3 Compound of Example 160       0, 0/3    0, 0/3    0, 0/3 Tosfloxacin     1.8, 4/5  0.8, 4/5  0.2, 1/5

(Test Example 4)

Chromosome Aberration Test:

CHL cells (0.2-2 × 10 ⁵ cells / well) suspended in Eagle MEM medium to which 10% fetal bovine serum was added to a 60 mm chalet were inoculated. Incubated at 37 ° C. 4 to 72 hours in the presence of 5% CO ₂ , exchanged with a medium containing various concentrations of drugs, and then cultured under the same conditions. In the case of the metabolic activation method (S9-added medium), after 6 hours of culture, the cells were replaced with a drug and no S9-free medium, and cultured for 18 hours. In the direct method, two cultures, 24 hours and 48 hours, were performed. After incubation, chromosomal specimens were prepared according to the Japanese Society of Environmental Mutagens, followed by a speculum, and 100 mitotic phases were observed. It was.

As a result, the compounds of Examples 48 and 117 were negative from 0 to 200 µg / ml.

Claims (2)

Formula 1

[Wherein, R ¹ represents a hydrogen atom or a carboxy protecting group, R ² is a nitro group or C _1-7 alkyl group, C _7-11 aralkyl group, C _6-14 aryl group, C _1-7 alkanoyl group, C _1-7 alkoxycarbonyl group, C _7-15 aroyl group, amino acid residue An amino group or an unsubstituted amino group substituted with a substituent selected from the group consisting of R ³ represents a halogen atom, R ⁴ and R ⁵ represent a hydrogen atom, a halogen atom, a C _1-7 alkyl group or a C _1-7 alkoxy group, which may be the same or different, and R ⁶ represents a hydrogen atom, a halogen atom, a hydroxy group, a C _1-7 alkyl group or an amino group, R ⁷ represents a hydrogen atom or a halogen atom, A represents a nitrogen atom or -CX = (where X represents a halogen atom, a C _1-7 alkyl group or a C _1-7 alkoxy group), Z represents a saturated cyclic amino group which may have a halogen atom or a substituent, The saturated cyclic amino group is a saturated monocyclic 3 to 7 membered cyclic amino group having 1 nitrogen atom, a saturated monocyclic 3 to 7 membered cyclic amino group having 2 nitrogen atoms, a saturated 2 to 3 ring cyclic amino group and spiro A saturated cyclic amino group selected from the group consisting of 5- to 12-membered cyclic amino groups of the formula and crosslinking saturation; The substituent of the saturated cyclic amino group may be a hydroxyl group, a C _1-7 alkyl group, a substituted or unsubstituted amino group, a substituted amino C _1-7 alkyl group or an unsubstituted amino C _1-7 alkyl group, C _1-7 alkoxy A group, a halogen atom; The substituted amino group represents an amino group substituted with a substituent selected from the group consisting of a C _1-7 alkyl group, a C _1-7 alkanoyl group, a C _1-7 alkoxycarbonyl group, and an amino acid residue]. Or salts thereof. An antimicrobial agent comprising the pyridonecarboxylic acid derivative according to claim 1 or a salt thereof as an active ingredient.