MXPA00002143A - Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient - Google Patents

Abstract

Pyridonecarboxylic acid derivatives represented by general formula (1) or their salts, wherein R1 represents hydrogen or a carboxyl protecting group;R2 represents hydroxy, lower alkoxy or optionally substituted amino;R3 represents hydrogen or halogeno;R4 represents hydrogen or halogeno;R5 represents optionally halogenated or substituted saturated cyclic amino;R6 represents hydrogen, halogeno, nitro or optionally protected amino;X, Y and Z may be the same or different and each represents nitrogen, -CH=or -CR7=wherein R7 represents lower alkyl, halogeno or cyano, provided that at least one of X, Y and Z represents nitrogen;and W represents nitrogen or -CR8=wherein R8 represents hydrogen, halogeno or lower alkyl.

Description

COMPOUNDS AMINO INTERMEDIARY OF PYRIDONACARBOXILIC ACID.

TECHNICAL FIELD The present invention relates to novel derivatives of pyridonecarboxylic acid or its salts having excellent antibacterial properties and oral absorption, and with antibacterial agents containing them. BACKGROUND OF THE ART Many compounds having a basic basic structure of priridonacarboxylic acid are known as synthetic antibacterials useful for their excellent antibacterial properties and a broad antibacterial spectrum. Among such compounds, norfloxacin (Japanese Patent Application Laid Open to the public 53-141286), Enoxacin (Japanese Patent Application Laid-Open No. 55-31042), Ofloxacin (Japanese Patent Application Laid-open No. 57-46986), Ciprofloxacin (Japanese Patent Application Open) to the public number 58-76667), tosofloxacin (Japanese Patent Application Laid-Open No. 60-228479 and the like.

However, these compounds need further improvement in terms of antibacterial activities, intestinal absorption, metabolic stability and side effects and, in particular, in phototoxicity and cytotoxicity. Accordingly, an object of the present invention is to provide novel compounds which are suitable in such aspects. DESCRIPTION OF THE INVENTION In view of such a situation, the inventors of the present invention have made an intensive study to find compounds which would be excellent synthetic antibacterial agents in clinical practice, and found that the novel compounds represented by the following general formula ( 1) have good antibacterial properties against gram-negative and gram-positive bacteria as well as extremely low toxicity and, therefore, would be very useful synthetic antibacterials. The present invention has been carried out based on such a finding.

(I) [In the formula, R 1 represents a hydrogen atom or a carboxyl protecting group; R 2 represents a hydroxyl group, a lower alkoxy group or a substituted or unsubstituted amino group; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom or a halogen atom; R 5 represents a halogen atom or an optionally substituted saturated cyclic amino group; R6 represents a hydrogen atom, a halogen atom, a nitro group or an optionally protected amino group; X, Y and Z may be the same or different and represent respectively a nitrogen atom, -CH = or CR7 = (in which R7 represents a lower alkyl group, a halogen atom or a cyano group) (with the proviso that at least one of X, Y and Z represents the nitrogen atom), and represents a nitrogen atom or -CR8 = (in which R8 represents a hydrogen atom, a halogen atom or a lower alkyl group)]. Accordingly, the present invention provides pyridonecarboxylic acid derivatives represented by the general formula (1), above, or their salts and antibacterial agents containing the pyridonecarboxylic acid derivatives or their pharmaceutically acceptable salts as their effective components.

The novel pyridonecarboxylic acid derivatives of the present invention are represented by the general formula (1) as shown above, and the term "lower" used for the substituents of the pyridonecarboxylic acid derivatives represented by the general formula (1) designate that the substituents' comprise 1 to 7 carbon atoms, and preferably 1 to 5 carbon atoms in the case of a linear substituent, and the substituent comprises 3 to 7 carbon atoms in the case of a cyclic substituent. In the general formula (1), R1 represents a hydrogen atom or. a carboxyl protecting group and the term "carboxyl protecting group" herein denotes an ester residue of a carboxylate ester, and the carboxyl protecting group can be any carboxylate ester residue which is relatively easy to generate to generate the corresponding free carboxyl group. Exemplary carboxyl protecting groups include those in which they can be removed by hydrolysis, catalytic reduction and other treatments under moderate conditions such as lower alkyl groups such as the methyl group, the ethyl group, the n-propyl group, the i-group propyl, the n-butyl group, the 1-butyl group, the t-butyl group, the pentyl group, the hexyl group and the heptyl group; lower alkenyl groups such as the vinyl group, the allyl group, the 1-propenyl group, the butenyl group, the pentenyl group, the hexenyl group and the hepetin group; aralkyl groups such as the benzyl group; and aryl groups such as the phenyl group and the naphthyl group; and those which can be easily removed in the body such as the lower (lower) alkanoyloxy groups such as the acetoxymethyl group and the pivaloyloxymethyl group; the lower alkoxycarbonyloxy lower alkyl group such as the methoxycarbonyloxymethyl group and the 1-ethoxycarbonyloxyethyl group; the lower alkoxymethyl group such as the methoxymethyl group; the lactonyl group such as phthalidyl; the lower dialkylamino-lower alkyl group such as the l-dimethylaminoethyl group, and the group (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl. It should be noted that R1 is most preferably a hydrogen atom. In the general formula (1), R 2 represents a hydroxyl group, a lower alkoxy group or a substituted or unsubstituted amino group. Exemplary substituents for the substituted amino group include lower alkyl groups such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group and heptyl group; lower alkenyl groups such as vinyl group, allyl group, 1-propenyl group, butenyl group, pentenyl group, hexenyl group and heptenyl group; aralkyl groups such as the benzyl group and 1-phenylethyl group; aryl groups such as the phenyl group and the naphthyl group; lower alkanoyl groups such as the formyl group, acetyl group, propionyl group, butyl group and isobutyl group; lower alkoxycarbonyl groups such as the methoxycarbonyl group and the ethoxycarbonyl group; aroyl groups such as the benzoyl group and the naphthoyl group; amino acid residues or oligopeptide residues such as glycyl, leucyl, valyl, alanyl, phenylalanyl, alanyl-analyl, glycyl-valyl, and glycyl-glycyl-valyl, and amino acid residues or oligopeptide residues wherein the functional group thereof is protected with an acyl, a lower aralkyl or other protecting groups which are commonly used in the chemistry of peptides; and a cyclic amino group. One or two substituents which may be the same or different may be selected from the substituents as described above. The compounds protected with the amino acid residue or the oligopeptide residue are expected to have an improved solubility in water. Preferably, R 2 is an amino group, a lower alkylamino group, a lower dialkylamino group, a lower alkanoylamino group, an amino group substituted with an amino acid, or an amino group substituted with an oligopeptide. More preferably, examples of R 2 include an amino group, a methylamino group, an ethylamino group and a dimethylamino group, among which the amino group is further preferred. It should be noted that exemplary preferred lower alkoxy groups used for R 2 include lower alkoxy groups having 1 to 4 carbon atoms such as methoxy group, ethoxy group, propoxy group and butoxy group, among these, the use of the methoxy group is preferable. Then, in the general formula (1), R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom or a halogen atom; R 5 represents a halogen atom or an optionally substituted saturated cyclic amino group; Rs represents a hydrogen atom, a halogen atom, a nitro group or an optionally protected amino group; X, Y and Z may be the same or different and represent respectively a nitrogen atom, -CH = or -CR7 = (in which R7 represents a lower alkyl group, a halogen atom or a cyano group) and W represents an atom of nitrogen or -CR8 = (in which R6 represents a hydrogen atom or a halogen atom). The halogen atoms represented by R3, R4, R5, R6, R7 and R8 include the fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, they are preferred in the fluorine atom and the chlorine atom, and in particular, R3 to R7 are preferably a fluorine atom and R8 is preferably a chlorine atom or a bromine atom. The lower alkyl groups represented by R7 and R8 include those containing 1 to 7 carbon atoms such as the methyl group, the ethyl group, propyl group, butyl group, pentyl group, hexyl group and heptyl group, among which is preferred methyl group.

With respect to X, Y and Z, two or three of X, Y and Z may be the same or, alternatively, may be different from each other. However, it is required that at least one of X, Y and Z be a nitrogen atom. Exemplary preferable combinations of X, Y and Z are nitrogen for X and -CH = or -CR7 = (wherein R7 represents a lower alkyl group, a halogen atom or a cyano group) for Y and Z; nitrogen for Y and -CH = or -CR7 = (in which R7 represents a lower alkyl group or a halogen atom) for X and Z; and nitrogen for X and Y, and -CH = or -CR7 = (in which R7 represents a lower alkyl group or a halogen atom) for Z. It should also be noted that the compound of formula (1) has a main structure of naphthylidine when it represents nitrogen, and a quinoline skeleton when it represents -CR8 =, and it is more preferable that it represents -CR6 = where R6 represents a hydrogen atom or a lower alkyl group). Then, the optionally substituted saturated cyclic amino group represented by Rs may additionally contain one or more heteroatoms such as nitrogen atom, oxygen atom and sulfur atom as well as carbonyl carbon in its ring, and may be monocyclic or di- or tricyclic. The saturated cyclic amino group is preferably a 4- to 7-membered ring when it is monocyclic, a 7 to 11 membered ring when it is bicyclic and a 9 to 15 membered ring when it is tricyclic. Such exemplary cyclic amino groups include saturated monocyclic amino groups, 3- to 7-membered rings containing a nitrogen atom such as aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl; saturated monocyclic amino groups of a 3 to 7 membered ring containing 2 nitrogen atoms such as piprazrazin-1-yl and homopiperazin-1-yl; saturated monocyclic amino groups of a 3 to 7 membered ring containing a heteroatom which is selected from an oxygen atom or a sulfur atom in addition to a nitrogen atom such as oxazolidin-3-yl, morpholin-4-yl, thiazolidin -1-yl and thiomorpholin-4-yl; saturated bicyclic or tricyclic amino groups such as tetrahydroquinolin-1-yl; and 5 to 12-membered spiro or amino-cross-linked ring group such as 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-diazabicyclo [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- ilo and 3, 8-diazabicyclo [3.2.1] octan-3-yl. The atom constituting the ring of such a saturated cyclic amino group may be substituted with an appropriate substituent, and such exemplary substituents include a hydroxyl group, lower alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted lower aminoalkyl groups, alkoxy groups lower and halogen atoms. Exemplary lower alkyl groups for the substituent of the saturated cyclic amino group include those containing 1 to 7 carbon atoms such as the methyl group, the ethyl group, propyl group, butyl group, pentyl group, hexyl group and heptyl group; and exemplary lower alkoxy groups include those containing 1 to 7 carbon atoms such as the methoxy group, ethoxy group and n-propoxy group; and exemplary halogen groups include fluorine atom, chlorine atom and bromine atom. Of the substituents of saturated cyclic amino groups, the substituted amino groups and the substituted lower aminoalkyl groups may have a substituent which may be the same as described for R2, and preferable examples of the substituted amino groups and substituted and unsubstituted lower aminoalkyl groups include the methylamino group, ethylamino, dimethylamino group, aminoethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-amino-1-ethyl group, methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group, leucyl-amino group, valil-amino group , alanyl-amino group and alanyl-alanyl-amino group. Of the saturated cyclic amino groups as described above, the most preferable group for R6 includes those represented by the following formulas (a) and (b): - li ten the A represents an oxygen atom, a sulfur atom or NR9 (where R9 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, g represents a number from 0 to 2, J1, J2 and J3, which may be the same or different, represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower aminoalkyl group, an amino group, a lower alkylamino group, a lower alkoxy group or a halogen atom]. Examples of the lower alkyl group, the lower aminoalkyl group, the lower alkylamino group, the lower alkoxy group and the halogen atom and the formulas (a) and (b) as described above are the same as those shown for R2 to Rs. Exemplary cyclic amino groups represented by the formula (a) include azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, and the exemplary cyclic amino groups represented by the formula (b) include piperazin-1-yl , morpholin-4-yl, thiomorpholin-4-yl, homopiperazin-1-yl, N-thiazalidinyl and N-oxazolidinyl. When R 5 is an aminocyclic group, R 5 is preferably a cyclic amino group represented by the formula (a), and R 6 is more preferably azetidin-1-yl or pyrrolidin-1-yl. The most preferable examples of the groups represented by the formulas (a) and (b) are as described below, group 3-aminoazetidin-1-yl, 3-methylaminoazetidin-1-yl group, 3-dimethylaminoazetidin-1-group ilo, 3-aminomethylazetidin-1-yl group, 3-amino-2-methylazetidin-1-yl group, 3-amino-3-methylazetidin-1-yl group, 3-alanyl-aminoazetidin-1-yl group, 3-alanyl group -valon-aminoazetidin-1-yl, 3-valyl-aminoazetidin-1-yl group, 3-pyrrolidin-1-yl group, 3-hydroxypyrrolidin-1-yl group, 3, 4-dihydroxypyrrolidin-1-yl group 3-methoxypyrrolidin-1-yl, 3-methylpyrrolidin-1-yl group, 3-hydroxy-4-methylpyrrolidin-1-yl group, 3-am i nop irro 1 idin-1-i 1 or group 3 - . 3 - . 3-methylaminopyrrolidin-1-yl, 3-dimethylaminopyrrolidin-1-yl group, 3-ethylaminopyrrolidin-1-yl, 3-diethylaminopyrrolidin-1-yl group, 3-aminomethylpyrrolidin-1-yl group, 3-amino-3-group methylpyrrolidin-1-yl, 3-amino-4-methylpyrrolidin-1-yl group, 3-amino-5-methylpyrrolidin-1-yl group, 3-methylamino-4-me ti -pyrrolidinyl group 3 -dimethylamino-4-methylpyrrolidin-1-yl, group 3-ethylamino-methylpyrrolidin-1-yl, group 3-diethylamino-3-methylpyrrolidin-1-yl, 3-diethylamino-4-methyl-1-pyrrolidinyl group, 3-aminomethyl-4-methylpyrrolidin-1-yl group, 3-methylaminomethyl-4-methylpyrrolidin-1 group - ilo, group 3-dimethylaminomethyl-4-methylpyrrolidin-1-yl, 3-ethylaminomethyl-4-methylpyrrolidin-1-yl group, 3- (1-aminoethyl) -4-methylpyrrolidin-1-yl group, 3- (2-aminoethyl) group -4-methylpyrrolidin-1-yl, 3-amino-4-ethylpyrrolidin-1-yl group, 3-methylamino-4-ethylpyrrolidin-1-yl group, 3-dimethylamino-ethylpyrrolidin-1-yl group 3 -dimethylamino-4-ethylpyrrolidin-1-yl, 3-diethylamino-4-ethylpyrrolidin-1-yl group, 3-aminomethyl-4-ethylpyrrolidin-1-yl group, 3-methylaminomethyl-4-ethylpyrrolidin-1-yl group, group 3-dimethylaminomethyl-4-ethylpyrrolidin-1-yl, 3-amino-3-methylpyrrolidin-1-yl group, 3-methylamino-3-methylpyrrolidin-1-yl group, 3-dimethylamino-3-methylpyrrolidin-1-yl group , group 3-amino-3,4-dime ti 1 aminop irrol idin-1-i lo, group 3-amino-4,4-dime i 1 amino i rro 1 idin- 1 - i lo, group 3-amino- 4, 5-dime ti laminop ir rol idin-1-i lo, 3-amino-2,4-dimethylaminopyrrolidin-1-yl group, 3-methylamino-3,4 -dimet-ilpyrrolidin-yl group, group 2 -methylamino- 3, 4-dimethylpyrrolidin-1-yl, 2-methyl-3-aminopyrrolidin-1-yl group, 2-methyl-3-dimethylaminopyrrole-idin-yl group, 3-amino-4-methoxypyrrole group idin - 1-yl, 3-alanyl-aminopyrrolidin-1-yl group, 3-valyl-aminopyrrolidin-1-yl group, piperazin-1-yl group, 4-methylpiperazin-1-yl group, 3-methylpiperazin-1-group ilo, 2-methylpiperazin-1-yl group, 3, 4-dimethylpiperazin-1-yl group, 3,5-dimethylpiperazin-1-yl group, 3, 3-dimethylpiperazin-1-yl group, 3, 4, 5-trimethylpiperazin-1-yl group, piperidin-1-yl group, 4-aminopiperidinyl group ilo, 4-dimethylaminopiperidin-1-yl group, 4-hydroxypiperidin-1-yl group, morpholin-4-yl group, 2-aminomethylmorpholin-4-yl group, 2-methylaminomorpholin-4-yl group 2 dimethylaminomorph olin-4-yl, thiomorpholin-4-yl group, homopiperazin-1-yl group, 4-methylhomopiperazin-1-yl group, N-thiazolidinyl group and N-oxazolidinyl group. The optionally protected amino group represented by R6 includes an amino group as well as an amino group protected by an appropriate protecting group. Such exemplary protected amino groups include the amino group protected with a lower alkanoyl group such as formyl, acetyl, propionyl, pivaloyl, hexaloyl or the like; a lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl or the like; an aroyl such as benzoyl, toluoyl, naphthoyl or the like; a lower arylalkanoyl group such as phenylacetyl, phenylpropionyl or the like; an aryloxycarbonyl group such as phenoxycarbonyl, naphthyloxycarbonyl or the like; a lower aryloxyalkanoyl group such as phenoxyacetyl, phenoxypropionyl or the like; an aralkyloxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl or the like; or an aralkyl group such as benzyl, phenethyl, benzhydryl, trifly or the like. The preferable combination of R 1, R 2, R 3, R 4, R 5, R s, X, Y, Z and is such that R 1 is a hydrogen atom, R 2 is an amino group, a lower alkylamino group or a lower dialkylamino group, R 3 is a halogen atom, R4 is a halogen atom, X is a nitrogen atom, Y and Z are -CH = or -CR7 = (where R7 is a lower alkyl group or a halogen atom), is -CR8 (R8 is a halogen atom or a lower alkyl group), Rs is a group represented by the formula (a) (e = 3 or 4), and Rs is a hydrogen atom, the most preferable combination of R1, R2, R3, R6, Rs, R5, X, Y, Z and is such that R1 is a hydrogen atom, R2 is an amino group, R3 is a fluorine atom, R4 is a fluorine atom, X is a nitrogen atom , Y is -CF =, Z is -CH =, W is -CCl, -CBr = or -CCH3 =, R5 is a group represented by the formula (a) (e = 3) and Rs is a hydrogen atom. The salts of the pyridonecarboxylic acid derivatives of the formula (1) as described above can be acid adduct salts or base adduct salts. The term "salts", as used herein, also includes salts of a chelate with a boron compound. Exemplary acid adduct salts include: (i) salts with a mineral acid such as hydrochloric acid or sulfuric acid; (ii) salts with an organic carboxylic acid such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid; and (iii) salts with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid; and exemplary base adduct salts include: (i ') salts with an alkali metal such as sodium or potassium; (ii ') salts with an alkaline earth metal such as calcium or magnesium; (iii1) ammonium salts; (iv1) salts with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine , 1-efenamine or N, N'-dibenzylethylenediamine. Exemplary boron compounds include boron halides such as boron fluoride, and lower acyloxyboros such as acetoxyboron. The pyridonecarboxylic acid derivatives and the salts thereof of the present invention may also be in the form of a hydrate or a solvate in addition to the unsolvated form.

Accordingly, the compound of the present invention includes all of the crystalline form, the hydrate form and the solvate form. In addition, the pyridonecarboxylic acid derivatives and salts thereof may be present in the form of an optically active substance and such optically active substance is also within the scope of the compounds of the present invention. In addition, the pyridonecarboxylic acid derivatives and salts thereof may be present in the form of a stereoisomer (cis or trans) and such a stereoisomer is also within the scope of the compounds of the present invention. The pyridonecarboxylic acid derivatives and the salts thereof of the present invention represented by the formula (1) as described above can be produced by any method appropriately selected in accordance with factors such as the type of the substituents, and an exemplary process It is as described below. (Process 1) Of the compounds represented by the general formula (1), the compounds (la) wherein R 1 is a hydrogen atom or a lower alkyl group, and R 5 is a halogen atom can be produced, for example, by Procedure 1 represented by the reaction scheme as described below.

(The A) (The A) [wherein Rla represents a lower alkyl group; R10 represents a lower alkyl group; L1 represents a halogen atom; R5a represents a halogen atom; R2A represents a hydroxyl group, a lower alkoxy group or a substituted or unsubstituted amino group, or a protected amino group; R6a represents a hydrogen atom, a halogen atom or a nitro group; R6b represents an optionally substituted amino group; R2, R3, R4, R6, X, Y, Z and W are as defined above]. More illustratively, the compound of the present invention is produced by reacting the compound (A) with an orthopharmamate such as methyl orthoformate or ethyl orthoformate to produce the acrylate derivative (B); reacting the acrylate derivative (B) with an amino compound (C) to produce the compound (D); cyclize the compound (D) to produce the compound (E) and hydrolyze the compound (E) to obtain the compound (la). The reaction between the compound (A) and the orthoformate is generally carried out at 0 to 160 ° C, and preferably 50, at 150 ° C, usually during a reaction period of 10 minutes to 48 hours, and preferably from 1 to 10 hours. The orthoformate is used in an equimolar amount or more for the compound (A) and, preferably, in 1 to 10 times the molar amount relative to the compound (A). The reaction with the compound (C) can be carried out without solvent or in a solvent. The solvent used in this reaction can be any solvent to the extent that the reaction is not affected by the solvent, and exemplary solvents include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diglyme; aliphatic hydrocarbons such as pentane, hexane, heptane and ligroin; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; non-protic polar solvents such as dimethylformamide and dimethyl sulfoxide; and alcohols such as methanol, ethanol and propanol. This reaction is generally carried out from 0 to 150 ° C, and preferably from 0 to 100 ° C, usually during a reaction period of 10 minutes to 48 hours. The compound is used (O in a molar quantity or more with respect to the compound (A) and preferably, in one to two times the molar amount with respect to the compound (A). Alternatively, the compound (A) can be reacted with an acetal such as N, N-dimethylformamide dimethylacetal or N-dimethylformamide diethylacetal and then, with the compound (C) to produce the compound (D) The solvent used in the reaction with the acetal can be any solvent insofar as the reaction is not altered by the solvent, and exemplary solvents are those described in the foregoing. That reaction is generally carried out at 0 to 150 ° C, and preferably at room temperature up to 100 ° C, generally during a reaction period of 10 minutes to 48 hours, and preferably from 1 to 10 hours. Subsequently, the cyclization of the compound (D) in the compound (E) is carried out in a suitable solvent either in the presence or absence of a basic compound. The solvent used in this reaction can be any solvent to the extent that the reaction is not affected by the solvent, and exemplary solvents include aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as diethyl ether, tetrahydrofuran, dioxane and monoglyme; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; alcohols such as methanol, ethanol, propanol and butanol; non-protic polar solvents such as dimethylformamide and dimethyl sulfoxide. The basic exemplary compounds used are alkali metals such as metallic sodium and metallic potassium; metal hydrides such as sodium hydride and calcium hydride; inorganic salts such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide; metal fluorides such as sodium fluoride and potassium fluoride; organic salts such as triethylamine and 1,8-diazabicyclo [5.4.0] undendane (DBU). This reaction is carried out at a reaction temperature of 0 to 200 ° C and preferably from room temperature to 180 ° C, and the reaction is generally completed in 5 minutes to 24 hours. The basic compound is used in an equimolar or greater amount relative to the compound (D), and preferably in 1 to 2 times the molar amount relative to the compound (D). The compound (E) is subjected to hydrolysis to remove the carboxyl protecting group Rla and / or the amino protecting group R2a to obtain the compound (la). The hydrolysis can be carried out under any of the conditions commonly used in hydrolysis; for example, in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, a mineral acid such as hydrochloric acid, sulfuric acid and hydrobromic acid, or an organic acid such as p-acid. toluene sulfonic acid in a solvent such as water, an alcohol such as methanol, ethanol or propanol or an ether such as tetrahydrofuran or dioxane, a ketone such as acetone or methyl ethyl ketone, acetic acid or a mixture of such solvents. The reaction is generally carried out from room temperature to 180 ° C and preferably from room temperature to 140 ° C usually during a reaction period of 1 to 24 hours. It should be noted that in the case of production of a compound in which Rs in the formula (1) is an optionally protected amino group, the compound (E) is first produced through the reactions as described above by using of a compound (A) in which R6a is a halogen atom or a nitro group for the starting material, and the compound (Ela) is subsequently produced by aminating the halogen atom or by reduction of the nitro group and compound (la) is derived from the compound (Ela) by removing the amino protecting group if necessary and removing the carboxyl protecting group.

(Procedure 2) Of the compounds represented by the general formula (1) Compounds wherein R5 is an optionally substituted saturated cyclic amino group can be produced, for example, by process 2 represented by the reaction scheme as described below: [wherein R5b represents an optionally substituted saturated cyclic amino group; and R1, R2, R3, R4, R5a, Rs, X, Y, Z and are as defined above]. More illustratively, compound (G) is obtained by aminating compound (F) using the compound represented by the formula: RSb-H. This reaction can be carried out in a solvent which does not affect the reaction such as an aromatic hydrocarbon such as benzene, toluene or xylene; an alcohol such as methanol or ethanol; an ether such as tetrahydrofuran, dioxane or monoglyme; a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride; a non-protic polar solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone; acetonitrile or pyridine, and in the optional presence of a neutralizer such as sodium carbonate, calcium carbonate, sodium acid carbonate, triethylamine,} 1, 8-diazabicyclo [5.4.0] undecene (DBU) from room temperature to 160 ° C. The reaction period is from several minutes to 48 hours and, preferably, from 10 minutes to 24 hours. The compound Rsb-H is used in an equimolar amount or greater with respect to the compound (F) and preferably, in 1 to 5 times the molar amount with respect to the compound (F). It should be noted that compound (F) can be obtained as in process 1 as described above and that when R1 is a carboxyl protecting group, it can be substituted with a hydrogen atom by hydrolysis.

(Procedure 3) Of the compounds represented by the general formula (1) compounds in which R1 is a carbaxyl protecting group can be prepared, for example, by the process 3 represented by the reaction scheme as described below: [wherein R 1b represents a carboxyl protecting group; L2 represents a halogen atom and R2, R3, R4, R5, Rs, X, Y, Z and W are as defined above]. More illustratively, the compound (I) is obtained by reacting the compound (H) with a halogen compound: Rlb-L2. The solvents which may be used in this reaction include aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; non-protic polar solvents such as dimethylformamide and dimethyl sulfoxide; and inert solvents such as acetonitrile. The reaction temperature is usually from room temperature to 100 ° C. Preferably the reaction is conducted in the presence of a basic compound such as triethylamine, diisopropylethylamine, dicyclohexylamine, DBU, sodium carbonate, potassium carbonate and sodium hydroxide. It should be noted that compound (H) can be obtained by Process 1 and Process 2 as described above. When the amino group, the imino group, the hydroxy group, the mercapto group, the carboxyl group or the like which are not involved in the reaction are present in the initial materials of procedure 1, 2 or 3, as described above, such Groups must be protected during the reaction and the protecting group can be removed after completion of the reaction by a conventional method. The protecting group used in such a case can be any group insofar as the compound of the present invention produced by the reaction can be deprotected without decomposition of its structure, and any group commonly used in the field of peptide chemistry, Aminosugars and nucleic acid can preferably be used ("Protective Groups in Organic Synthesis", Second Edition, T. Green and PGM Wuts, John Wiley &Sons Inc., 1991). 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 1) Japanese Patent Application Laid-Open No. 63-145268 J. Med. Chem. 29, 2363 (1986) 9) J. Fluorin Chem. 28, 361 (1985) 10) Japanese Patent Application Laid-Open No. 63-198664 11) Japanese Patent Application Open to the Public No. 63-264461 12) Japanese Patent Application Laid-Open No. 63-104974 13) European Patent Application No. 230948 i4: Japanese Patent Application Laid-Open No. 2- 282384 ís: Published Japanese Translation of the Publication International PCT for Patent Application Number 3-502452 i 6: J. Het. Chem. 27, 1609 (1990) The starting compound (C) can be produced by any process, and an exemplary production process is as described below. The starting compound (C) can be obtained by replacing the halogen atom attached to the carbon atom constituting the 6-membered ring with an amine such as ammonia, an alkylamine, benzylamine or the like by a known substitution reaction of halogen-amine . It should be noted that when the substituted amine such as an alkylamine or benzylamine is used for the amine, the substituent of the substituted amino group can be suitably removed by a conventional method as shown in the following reaction scheme. When R2a is a substituted or unsubstituted amino group or an amino group substituted with a protecting group, a similar halogen-amine substitution reaction can be carried out.

[In the formula, Hal represents a halogen atom such as F or Cl; Hc-NH and He '. NH are respectively a substituted amino group or an amino group substituted with a protecting group; Hc.NH2 and He '. NH2 are respectively an amine thereof. R2b represents a hydroxyl group or a lower alkoxy group. R3, X, Y and Z are as defined above]. When there is no readily available candidate starting material, specifically, the ring compound of nitrogen containing members substituted with dihalogen having the substituents corresponding to the substituents (R3, and when X, Y and Z are -CR7 = or -CH =, R7 or hydrogen) in the nitrogen-containing six-membered ring of the target substance, the target substance can be produced by using a six-membered ring compound containing halogen-disubstituted nitrogen more readily available for the starting material. More illustratively, a suitable substituent substitution reaction can be carried out simultaneously with the halogen-amine substitution reaction by the substituted amino group. Exemplary substitution reactions useful substituent are processes in which the halogen atom is substituted with an amino group, and the amino group is further substituted with another halogen atom or a cyano group by a reaction such as the Sandmeyer reaction or Schiemann's reaction; the process in which the halogen atom is substituted with a hydroxyl group, and the hydroxyl group is additionally substituted with another halogen atom by the use of a phosphorus halide or a phosphorus oxyhalide; the process in which a bromine atom or a chlorine atom is substituted with a fluorine atom by the use of a reagent such as potassium fluoride; the process in which the halogen atom is replaced with a hydrogen atom by hydrogenation; the process in which the alkoxycarbonyl group or the acyl group is reduced to a lower alkyl group by the use of a hydride compound; the process in which the carbonyl group is substituted with a hydrogen atom by decarboxylation; and the combination of the processes mentioned above. It should be noted that, when the compound having the amino group introduced in this way or the hydroxyl group is subjected to a substitution reaction of additional substituent, sometimes the protection of the amino group or the hydroxyl group is necessary. In such a case, the protection can be carried out by phthalimidation in the case of an amino group, and benzyloxidation in the case of the hydroxyl group. The protected group can be checked out at a later appropriate stage. The halogen atom involved in the halogen-amine substitution reaction which is represented by Hal in the reaction scheme shown above is not limited to any particular type. However, the halogen atom is preferably a fluorine atom with high reactivity. In such a case, if the fluorine atom is present as a substituent at any of the highly reactive sites or at another site, such a site can be protected by replacing the fluorine atom with another halogen atom such as a bromine atom or a Chlorine atom by the reactions as described above. Alternatively, the starting compound (C) can be produced by reducing the nitro group to an amino group by a normal process as shown in the following reaction scheme. - reduction reduction [In the formula, R 2b, R 3, X, Y and Z are as defined above] The compound thus obtained of the present invention is isolated and purified according to a standard method. The compound is obtained in the form of a salt, a free carboxylic acid or a free amine based on the conditions of isolation and separation. However, the form of the compound can be mutually converted, and the compounds of the present invention can be prepared in the desired form. The compound represented by the above general formula (1) or the salt thereof can be formulated in an antibacterial composition with a pharmaceutically acceptable carrier adapted for parenteral administration such as injection, trans-rectal administration or eye drops, or oral administration in solid form or liquid. When the antibacterial composition of the present invention is in the form of an injection, it may be in the form of a solution, a suspension or an emulsion in a pharmaceutically acceptable sterilized aqueous or non-aqueous medium. Examples of suitable carriers, diluents and non-aqueous vehicles include propylene glycol, polyethylene glycol, vegetable oils and olive oils and organic esters suitable for injection such as ethyl oleate. Such a composition may also contain additives such as a condom, a wetting agent, an emulsifier and a dispersant. The composition can be sterilized, for example, by filtering through a filter to eliminate bacteria or by incorporating it in a sterilizer in the form of a sterilizer or a sterile solid composition soluble in a sterilizable medium for injection just before use. A preparation for administration as drops in the eyes may preferably contain a solubilizer, a preservative, an isotonicity agent, a thickening agent and the like, in addition to the compound of the present invention. Solid preparations for oral administration include capsules, tablets, pills, powders and granules. In preparing such solid preparations, the compounds of the present invention are typically mixed with at least one inert diluent such as sucrose, lactose or starch. The preparation may also contain substances other than inert diluents such as lubricants (e.g., magnesium stearate, etc.). In the case of capsules, tablets or pills, the preparation may also include a buffer. The tablets and pills may have an enteric coating. Liquid preparations for oral administration include emulsions, solutions, suspensions, syrups and aromatically acceptable elixirs containing an inert diluent commonly used in the art such as water. In addition to such an inert diluent, the composition may also contain additives such as a wetting agent, an emulsifying agent, an agent for improving the suspension as well as a sweetener, an enhancer and a flavoring.

Preparations for intermediate administrations preferably contain an excipient such as cocoa butter or suppository wax in addition to the compound of the present invention. The dosage of the compound of the present invention varies based on the nature of the compound administered, the route of administration, the desired treatment period and other factors. However, the compounds of the present invention are typically administered at about 0.1 to 1000 mg / kg per day, in particular at about 0.5 to 100 mg / kg per day. If desired, such a dose can be administered in 2 to 4 portions. The novel pyridonecarboxylic acid derivatives and salts of the present invention show very strong antibacterial actions as well as low phototoxicity and cytotoxicity and therefore, would be widely applicable as pharmaceutical substances for humans and other animals as well as pharmaceutical substances for fish, insecticides, condoms for food and the like. The compound of the present invention is also expected to show antiviral properties, and especially actions against HIV (human immunodeficiency virus) and to be effective in preventing and treating AIDS. In the following, the present invention is described in further detail with reference to the examples and reference examples, which in no way limit the scope of the present invention.

[Reference Example 1] Synthesis of 2- (t-butylamino) -3,5,6-trifluoropyridine To 40 ml of acetonitrile are added 11.0 g of 2,3,5,6-tetrafluoropyridine and 18.5 g of t-butylamine, and the mixture is stirred at 60 ° C for 3 days, and the solvent and the like are distilled off. To the residue, 100 ml of chloroform are added and the mixture is washed with 50 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.7 g of the title compound as a light yellow oil. HRMN (CDC13) d: 1.45 (s, 9H), 4.40 (s broad, ÍH), 7.16 (ddd, J = 7Hz, 8Hz, 9Hz, ÍH) [Reference Example 2] Synthesis of 2-benzylamino-6- (t-butylamino) -3,5-difluoropyridine To 20 ml of N-methylpyrrolidone is added 9.7 g of 2- (t-butylamino) -3,5,6-trifluoropyridine together with 15.5 g of benzylamine, and the mixture is stirred at 160 ° C for 1 day and allowed to cool After adding 50 ml of chloroform, the mixture is washed three times with 500 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain approximately 16.5 g of the title compound as a dark green oil.

[Reference Example 3] Synthesis of 2-amino-6- (t-butylamino) -3,5-difluoropyridine To 60 ml of methanol are added 10.7 g of unreacted 2-benzylamino-6- (t-butylamino) -3,5-difluoropyridine as described above, together with 1.10 g of 10% palladium and carbon, and 3.8 g of Concentrated hydrochloric acid, and the mixture is hydrogenated for 1 day. The catalyst is separated by filtration and the solvent and the like are removed by distillation, under reduced pressure, to the residue is added 150 ml of chloroform and the mixture is washed with 80 ml of a 10% aqueous solution of sodium carbonate and the The washings are extracted again with 50 ml of chloroform. The chloroform layers are combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to chromatography (silica gel, 100 g, eluent: chloroform: n-hexane, 2: 1 and then chloroform) to obtain 3.3 g of the title compound as a light brown oil. XHRMN (CDC13) d: 1.43 (s, 9H), 4.11 (broad s, 2H), 6.94 (t, J = 10Hz, ÍH) [Example 1] Synthesis of 1- \ 6- (t-butylamino) -3,5-difluoropyridin-2-ill-8-chloro-6,7-difluoro-4-1,4-dihydroquinoline-3-carboxylate ethyl To 15 ml of chloroform solution of 3-ethoxy'-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 4.20 g of 3-chloro-2,4,5-trifluorobenzoylacetate from ethyl per normal process, 3.30 g of 2-amino-6- (t-butylamino) -3,5-difluoropyridine are added. The solution is concentrated under reduced pressure to obtain orange solid residue. To this residue is added 4.0 g of anhydrous potassium carbonate and 8 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 10 minutes and allowed to cool. The solution is prepared by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer is washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to rest. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 4.67 g of the title compound as a colorless powder. Melting point; 203 at 205 ° C 1HRMN (CDC13) d 1.39 (S, 9H), 1.40 (t, J = 7Hz, 3H), 4.40 (c, J = 7Hz, 2H), 4.70 (s broad, ÍH), 7.21 (dd) , J = 8Hz, 10Hz, ÍH), 8.31 (dd, J = 8Hz, 10H, 1H), 8.50 (s, ÍH) [Example 2] Synthesis of 8-bromo-l- ÍS- (t-butylamino) -3,5-difluoropyridin-2-yl-6,7-difluoro-4-oxo-l, 4-dihydrosuinoline-3-carboxylate ß ati a To 5 ml of a Chloroform solution of ethyl 3-ethoxy-2- (3-bromo-2,, 5-trifluorobenzoyl) acrylate prepared • from 1.32 g of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process, 2-amino-6- (t-butylamino) -3 is added., 5-difluoropyridine to complete the conversion to the aminoacrylate form which is verified by examining the reaction by CCD. The solution is concentrated under reduced pressure to obtain a yellow solid residue. To this residue is added 1.2 g of anhydrous potassium carbonate and 2 ml of N, N-dimethylforma ida, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over magnesium sulfate, concentrated under reduced pressure and allowed to settle . The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 1.41 g of the title compound as a colorless powder: Melting point: 198 to 203 ° C: HRMN (CDC1-.): 1.38 (S, 9H ), 1.40 (t, J = 7Hz, 3H), 4.40 (c, J = 7Hz, 2H), 4.71 (s broad, 1H), 7.20 (dd, J = 8Hz, 10Hz, ÍH), 8.36 (dd, J) = 9 Hz, 10H, ÍH), 8.54 (s, ÍH).

[Example 3] Synthesis of 1- ÍS- (t-butylamino) -3.5. { difluoropyridin-2-ill-6,7, 8-trifluoro-4-oxo-l.4-dihydroquinoline-3-ethylcarboxylate To 1 ml of chloroform solution of 3-ethoxy-2- (2, 3, 4, 5-tetrafluorobenzoyl) ethyl acrylate prepared from 0.27 g of ethyl 2, 3, 4, 5-etrafluorobenzoylacetate by a normal process is added 2-amino-6- (t-butylamino) -3,5-difluoropyridine until complete the conversion into the aminoacrylate form which is confirmed by verification of the reaction by CCD. The solution is concentrated under reduced pressure. To the residue is added 0.6 g of anhydrous potassium carbonate and 1 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed let it rest. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 0.15 g of the title compound as a colorless powder. Melting point: 174 to 178 ° C: HRMN (CDC1,): 1.40 (t, J = 7Hz, 3H), 1.42 (a, 9H), 4.40 (C, J = 7Hz, 2H), 4.71 (s broad, ÍH), 7.25 (dd, J = 8Hz, 19Hz, ÍH), 8.16 (ddd, J = 2Hz, 8Hz, 10H, ÍH), 8.48 (s, ÍH).

[Example 4] Synthesis of 1- \ 6 - (t-butylamino) -3,5-difluoropyridin-2-ill-7-chloro-6-fluoro-4-oxo-1,4-dihydro-l.8-narftilidene-3-ethylcarboxylate A 1 ml of solution in chloroform of ethyl 3-ethoxy-2- (2,6-dichloro-5-fluoronicotinoyl) acrylate prepared from 0.27 g of ethyl 2,6-dichloro-5-fluoronicotionyl acrylate by normal processes is added 2 -amino-6- (t-butyl) amino-3,5-difluoropyridine until the conversion to the aminoacrylate form is completed and confirmed by verification of the reaction by CCD. The solution is concentrated under reduced pressure. To the residue is added 0.5 g of anhydrous potassium carbonate and 1 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to rest. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 0.19 g of the title compound as yellow crystals. Melting point: 158 to 160 ° C '-HRMN (CDC1,): 1.39 (t, J = 7Hz, 3H), 1.45 (s, 9H), 4.40 (c, J = 7Hz, 2H), 4.68 (s broad) , HH), 7.27 (t, J = Hz, HH), 8.48 (D, J = 7Hz, HH), 8.75 (s, HH).

[Example 5] Synthesis of O-O 1- (6-atninQ-3, 5-difl orQpyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To a mixed solution of 10 ml of 4N hydrochloric acid and 10 ml of acetic acid are added 4.10 g of 1- [6- (t-buylamino) -3,5-difluoropyridin-2-yl] -8-chloro-6,7-difluoro-4 -oxo-l, ethyl 4-dihydroquinoline-3-carboxylate, and the mixture is stirred under reflux conditions for 5 hours. After adding 20 ml of distilled water, the solution is allowed to cool. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 3.32 g of the title compound as a colorless powder. Melting point; 280 ° C or higher "? NMR (ds-DMSO) d; 6.80 (s, 2H), 7.99 (t, J = 9Hz, ÍH), 8.38 (t, J = 9Hz, ÍH), 8.93 (s, ÍH) [Rence Example 4] Synthesis of 2-benzylamino-3, 5,6-trifluoropyridine To 50 ml of acetonitrile is added 12.0 g of 2,3,5,6-tetrafluoropyridine and 18.0 g of benzylamide, and the mixture is stirred under reflux conditions for 2 hours, and the solvent and the like are removed by distillation. To the residue is added 150 ml of ethyl acetate and the mixture is washed twice with 150 ml of distilled water and 150 ml of 10% aqueous solution of citric acid. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 16.0 g of the title compound as a light yellow compound. XHRMN (CDC13) d 4.58 (d, J = 6Hz, 2H), 4.81 (s broad, ÍH), 7.23 (m, ÍH), 7.35 (m, 5H).

[Reference Example 5] Synthesis of 2-amino-3,5,6-trifluoropyridine To 40 ml of methanol 7.60 g of crude 2-benzylamino-3,5,6-trifluoropyridine are added as described above along with 0.55 g of 10% palladium on carbon and 2 ml of acetic acid and the mixture is hydrogenated. at 50 ° C for one day. The catalyst is removed by filtration and the solvent and the like are removed by distillation under reduced pressure. The precipitate is dispersed in n-hexane and collected by filtration to obtain 3.85 g of the title compound as a colorless solid.

XHRMN (CDC13) d 4.53 (broad s, 2H), 7.27 (m, ÍH) [Reference Example 6] Synthesis of 2-amino-3,5-difluoro-6- (p-methoxybenzylamino) -pyridine To 10 ml of N-methylpyrrolidone 3.90 g of 2 - . 2-amino-3,5,6,6-trifluoropyridine and 7.60 g of p-methoxybenzylamine and the mixture is stirred under a nitrogen atmosphere at 140 ° C for one day and allowed to cool. To the solution 50 ml of chloroform are added and the solution is washed three times with 500 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is subjected to chromatography (silica gel, 32 g, eluent: chloroform) to obtain 4.50 g of the title compound as an untreated oil. of 'light yellow color. XHRMN (CDC13) d; 3.80 (s, 3H), 4.18 (s broad, ÍH), 4.49 (broad s, 3H), 6.87 (d, J = 9Hz, 2H), 6.99 (t, J = 10Hz, ÍH), 7.28 (t, J = 10Hz, 2H).

[Example 6] Synthesis of 8-chloro-1-? 3 .5-difluoro-6- (p-methoxybenzylamino) -pyridin-2-ill-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-ethylcarboxylate To 18 ml of a chloroform solution of ethyl 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) acrylate prepared from 2.52 g of 3-chloro-2,4,5-trifluorobenzoylacetate ethyl ester by normal process, 2.65 g of 2-amino-3,5-difluoro-6- (p-methoxybenzylamino) iridine are added. The solution is concentrated under reduced pressure and to the residue 2.5 g of anhydrous potassium carbonate and 6 ml of N, N-dimethylformamide are added, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool. The solution is separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer is washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to rest. The precipitate is dispersed in ethanol, collected by filtration and washed with ethanol to obtain 3.20 g of the title compound as a yellow powder. Melting point: 197-200 ° C XHRMN (CDC13) d; 1.40 (t, J = 7Hz, 3H), 3.80 (s, 3H), 4.41 (c, J = 7Hz, 2H), 4.48 (m, 2H), 5.10 (s broad, ÍH), 6.83 (d, J = 7Hz, 2H), 7.20 (d, J = 7Hz, 2H), 7.25 (dd, J = 8Hz, 9Hz, ÍH), 8.31 (dd, J = 8Hz, 10Hz, ÍH), 8.47 (s, ÍH) [Example 7] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To a mixed solution of 6 ml of 4N hydrochloric acid and 6 ml of acetic acid is added 3.00 g of 8-chloro-l- [3,5-difluoro-6- (p-methoxybenzylamino) pyridin-2-yl] -6 Ethyl 7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture is heated under reflux with stirring for 6 hours. The solution is allowed to cool and settle, and the precipitate is collected by decanting, and washed by adding a small amount of distilled water, shaking, allowing it to settle and decant. To the precipitate is added 10 ml of ethanol and the mixture is heated under reflux with stirring for 1 hour and allowed to cool and settle, and the precipitate is collected by decantation. To this precipitate, 10 ml of chloroform are again added and the mixture is stirred under reflux conditions for 1 hour and allowed to cool, then the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1.25 g of the compound of the title as a light brown powder.

[Example 8] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -7- r (3S) -3-aminopyrrolidin-1-ill-8-chloro-6-fluoro-4-oxo-l .4- dihydroquinoline-3-carboxylic acid To 250 mg of N.N-dimethylformamide add 60 mg of acid 1-. { 6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 60 mg of (3S) -3-aminopyrrolidine, and the mixture is heated under reflux with stirring at 90 ° C for 1 hour. After adding 1 ml of methanol, the mixture is allowed to cool and the precipitate is collected by filtration, and washed successively with ethanol and diisopropyl ether to obtain 41 mg of the title compound as a light brown powder.

Melting point: 248 at 250 ° C (decomposition) 1HRMN (ds-DMSO) d; 1.73 (m, ÍH), 2.03 (m, ÍH), 4.67 (m, 2H), 6.75 (broad s, 2H), 7.95 (t, J = 9Hz, ÍH), 7.98 (d, J = 14Hz, 1H) , 8.73 (s, ÍH) (Part of the signals are superimposed with the, proton of the water, and were not differentiable).

[Example 9] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline -3-carboxyl To 350 mg of N, N-dimethylformamide is added 100 mg of the 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4 acid. -dihydroquinoline-3-carboxylic acid, 80 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 1 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 86 mg of the title compound as a colorless powder. Melting point: 260 to 263 (decomposition) XHRMN (d6-DMSO) d; 3.73 (m, ÍH), 4.09 (m, 2H), 4.67 (m, 2H), 6.74 (broad s, 2H), 7.86 (d, J = 14Hz, ÍH), 7.94 (t, J = 9Hz, 1H), 8.68 (s, ÍH).

[Example 10] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-methylaminoazetidin-1-yl) -4-oxo-l, 4-dihydroquinolidin-3 -carbQXÍlÍCF.

To 400 mg of N, N-dimethylformamide are added 90 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1, 4 -dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride and 160 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 92 mg of the title compound as a colorless powder. Melting point: 259 to 265 ° C (decomposition) '-HRMN d6-DMSO) d: 2.20 (s, 3H), 3.48 (m, ÍH), 4.14 (m, 2H), 4.64 (m, 2H), 6.75 (s broad, 2H), 7.86 (d, J = 14Hz, ÍH), 7.94 (t, J = 9Hz, ÍH), 8.68 (s, ÍH) [Example 11] Synthesis of 1- (6-amino-3,5-di luoropyridin-2-yl) -7- (3-amino-3-methylazetidin-1-yl) -8-chloro-6-fluoro-4-oxo- 1.4-dihydroquinoline-3-carboxylic acid To 350 mg of N, N-dimethylformide is added 80 mg of the acid 1-. { 6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-amino-3-dihydrochloride methylazetidine and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 40 minutes. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed with ethanol to obtain 64 mg of the title compound as a light yellow powder. Melting point: 280 ° C or higher 1HRMN (d6-DMS0) d; 1.35 (s, 3H), 4.19 (m, 2H), 4.30 (m, 2H), 6.75 (s broad, 2H), 7.86 (d, J = 14Hz, ÍH), 7.94 (t, J = 9Hz, ÍH) , 8.68 (s, ÍH) [Example 12] Synthesis of the 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-hydroxyazetidin-l-yl) -4 -oxo- acid 3-hydroxyzetidine salt 1,4-dihydroquinoline-3-carboxylic acid To 800 mg of acetonitrile are added 100 mg of the acid 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difiuoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is heated under reflux for 1 hour. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 56 mg of the title compound as a colorless powder. Melting point: 185 to 190 ° C (decomposition) XHRMN (d6-DMSO) d; 3.45 (m, 2H), 3.65 (m, 2H), 4.14 (m, 2H), 4.39 (m, 2H), 4. 46 (m, ÍH), 4.68 (m, 2H), 6.70 (s broad, 2H), 7.80 (d, J = 14Hz, ÍH), 7.91 (t, J = 9Hz, ÍH), 8.52 (s, ÍH) [Example 13] Synthesis of the N- methylpyrrolidine salt of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-hydroxyzetidin-1-yl) -4 - oxo-l. 4-dihydroquinoline-3-carboxylic acid.

To 200 mg of N, N-dimethylformamide is added 300 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-acid. -dihydroquinoline-3-carboxylic acid, 110 mg of 3-hydroxyzetidine dihydrochloride and 300 mg of N-methylpyrrolidine, and the mixture is stirred at 80 ° C for 10 hours. After adding 2 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 22 mg of the title compound as a colorless powder. Melting point: 234 At 238 ° C (decomposition) XHRMN (ds-DMS0) d; 1.67 (m, 4H), 2.24 (s, ÍH), 2.38 (m, 4H), 4.18 (m, 2H), 4.47 (m, ÍH), 4.71 (, 2H), 5.73 (m, ÍH), 6.75 ( s broad, 2H), 7.86 (d, J = 14Hz, ÍH), 7.94 (t, J = 9Hz, ÍH), 8.67 (s, 1H).

[Example 14] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-7-piperazino-1,4-dihydroquinoline-3-carboxylic acid To 170 mg of N, N-dimethylformamide is added 50 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-acid. -dihydroquinoline-3-carboxylic acid, 50 mg of piperazine and the mixture is stirred at 90 ° C for 1 hour. After adding approximately 0.3 ml of methanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 33 mg of the title compound as a colorless powder. 'Melting point: 273 to 277 ° C (decomposition) 1HRMN (d6-DMS0) d; 2.82 (m, 4H), 3.16 (m, 4H), 6.76 (broad s, 2H), 7.95 (t, J = 9Hz, ÍH), 8.05 (d, J = 12Hz, ÍH), 8.79 (s, ÍH) [Reference Example 7] Synthesis of 3.5.6-trifluoro-2- (methylamino) pyridine To 10 ml of acetonitrile is added 4.5 g of 2,3,5,6-tetrafluoropyridine and 10 ml of methylamine (10% aqueous solution), and the mixture is stirred at 50 ° C for 2 hours. To the solution is added 50 ml of chloroform and the mixture is washed four times with 250 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a light brown untreated oil. XHRMN (CDC13) d; 2.99 (d, J = 5Hz, 3H), 4.53 (s broad, ÍH), 7.20 (ddd, J = 7Hz, 8Hz, 9Hz, ÍH) [Reference Example 8] Synthesis of 2-benzylamino-3, 5-difluoro-6- (methylamino) pyridine To 20 ml of N-methylpyrrolidone is added the complete amount of 3,5,6-trifluoro-2- (methylamino) -pyridine described above together with 10 g of benzylamine, and the mixture is stirred at 140 ° C for 19 hours and it is allowed to cool. To the solution 50 ml of chloroform are added and the mixture is washed six times with 200 ml of distilled water. Dry the chloroform layer over anhydrous magnesium sulfate and concentrate under reduced pressure to obtain the title compound as an untreated oil.

[Reference Example 9] Synthesis of 2-amino-3,5-difluoro-6- (methylamino) pyridine To a mixed solution of 10 ml of methanol and 1 ml of concentrated hydrochloric acid is added the entire amount of the 2-benzylamino-3,5-difluoro-6- (methylamino) pyridine described above together with 0.55 g of 10% palladium in charcoal, and the mixture is hydrogenated at 50 ° C overnight. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. To the residue is added 50 ml of chloroform, and the mixture is washed with 50 ml of 5% aqueous sodium carbonate solution. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid precipitate is collected by filtration to obtain 840 mg of the title compound as a light gray solid. XHRMN (CDC13) d; 2.95 (d, J = 5Hz, 3H), 4.19 (broad s, 3H), 6.98 (t, J = 10Hz, ÍH) [Example 15] Synthesis s 8-chloro-6,7-difluoro-l- (3,5-difluoro-S-metilaminopiridin-2-yl) -4 -oxo-1,4-dihydroquinolin-3-ethylcarboxylate To 5 ml of a chloroform solution of ethyl 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) acrylate prepared from 0.70 g of 3-chloro-2,4,5-trifluorobenzoylacetate ethyl per normal process, 430 mg of 2-amino-3, 5-difluoro-6- (melamine) pyridine are added. The solution is concentrated under reduced pressure. To the residue 0.3 g of anhydrous potassium carbonate and 2 ml of N, N-dimethylformamide are added, and the mixture is stirred at 90 ° C for 10 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to rest. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 184 mg of the title compound as a colorless powder. Melting point: 207 at 209 ° C 1HRMN (CDC13) d; 1.41 (t, J = 7Hz, 3H), 2.98 (d, J = 5Hz, 3H), 4.41 (c, J = 7Hz, 2H), 4.85 (s broad, ÍH), 7.23 (dd, J = 8Hz, 9Hz , ÍH), 8.32 (dd, J = 8Hz, 10Hz, ÍH), 8.50 (s, ÍH) [Example 16] Synthesis of 8-chloro-6,7-difluoro-1- (3,5-difluoro-6-methylaminopyridin-2-yl) -4 -oxo-1,4-dihydroquinoline-3-carboxylic acid To 3 ml of a mixed solution (1: 1, v / v) of 4 ml of 4N hydrochloric acid and 1 ml of acetic acid is added 510 mg of 8-chloro-6,7-difluoro-1- (3, 5 ethyl difluoro-6-methylamino-pyridin-2-yl) -4-oxo-1,4-hydroquinoline-3-carboxylate and the mixture is heated under reflux with stirring for 2.5 hours. After adding 2 ml of distilled water, the mixture is allowed to cool / and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 454 mg of the title compound as a gray powder. Melting point: 236 to 242 ° C XHRMN (d6-DMSO) d; 2.67 (d, J = 5Hz, 3H), 5.94 (broad s, ÍH), 7.06 (t, J = 8Hz, ÍH), 7.45 (dd, J = 10Hz, 12Hz, ÍH), 8.41 (dd, J = 9Hz , 10Hz, ÍH), 8.72 (s, ÍH) [Example 17] Synthesis of 7- (3-amino-azetidin-1-yl) -8-chloro-6-fluoro-1- (3,5-difluoro-6-methylaminopyridin-2-yl) -4-oxo-l, 4-dihydroquinoline-3 -carboxylic To 400 mg of N, N-dimethylformamide is added 100 mg of the acid 8-c paroro-6,7-di f luoro-1 - (3,5-di f luoro-6-methylaminopyridin-2-yl) -4- oxo-l, 4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride and 120 mg of N-methylpyrrolidine, and the mixture is stirred at 100 ° C for 1 hour. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 102 mg of the title compound as a colorless powder. Melting point: 222 to 227 ° C (decomposition) XHRMN (ds-DMSO) d; 2.77 (d, J = 5Hz, 3H), 3.75 (m, ÍH), 4.07 (m, 2H), 4.67 (m, 2H), 7.19 (s broad, ÍH), 7.88 (d, J = 14Hz, ÍH) , 7.95 (t, J = 7Hz, ÍH), 8.70 (s, 1H).

[Reference Example 10] Synthesis of 2-benzylamino-3,5,6-trifluoro-4-methylpyridine ? 2 ml of N-methylpyrrolidone are added 1.65 g of 2, 3, 5, 6-tetrafluoro-4-methylpyridine and 2.30 g of benzylamine, and the mixture is stirred at 80 ° C for 2 hours and allowed to cool. After adding 25 ml of chloroform, the mixture is washed three times with 300 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound in an untreated form.

[Reference Example 11] Synthesis of 2-amino-3,5,6-trifluoro-4-methylpyridine To 4 ml of methanol the full amount of the 2-benzylamino-3, 5,6-trifluoro-4-methylpyridine untreated as described above, together with 0.18 g of 10% palladium on carbon and 2 ml of acetic acid, and the mixture is hydrogenated at 50 ° C for one day. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure to obtain: 1.35 g of the title compound as a colorless solid. NMR (CDC13) d; 2.26 (t, J = 2Hz, 3H), 4.40 (s broad, 2H) [Reference Example 12] Synthesis of 2-amino-3,5-difluoro-6- (p-methoxybenzylamino) -4-ethylpyridine To 3 ml of methylpyrrolidone is added 1.35 g of 2-amino-3,5,6-trifluoro-4-methylpyridine together with 3.0 g of p-methoxybenzylamine, and the mixture is stirred under a nitrogen atmosphere at 140 ° C for 18 hours. hours and it is allowed to cool. After adding 30 ml of chloroform, the mixture is washed three times with 300 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to chromatography (silica gel, 20 g, eluent: chloroform: n-hexane, 1: 1, and then chloroform) to obtain 0.90 g of the title compound as an untreated light yellow oil. XHRMN (CDC13) d; 2.15 (t, J = 2Hz, 3H), 3.80 (s, 3H), 4.11 (broad s, 2H), 4.41 (s broad, ÍH), 4.48 (m, 2H), 6.87 (d, J = 8Hz, 2H ), 7.27 (d, J = 8Hz, 2H) [Example 18] Synthesis S 8-chloro-l- [3,5-difluoro-6 - (p-methoxybenzylamino) -4-me ilpyridin-2-ill-6,7-difluoro-4 -oxo-1,4-hydroxyquinoline-3-ethylcarboxylate To 3 ml of a chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 0.78 g of 3-chloro-2,4,5-trifluorobenzoylacetate from ethyl per normal process 0.90 g of 2-amino-3,5-difluoro-6- (p-methoxybenzylamino) -4-methylpyridine are added. The solution is concentrated under reduced pressure and to the residue are added 1.3 g of anhydrous potassium carbonate and 3 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the compound of the title as an untreated brown oil.

[Example 19] Synthesis of 1- (6-amino-3,5-difluoro-4-methylpyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To a mixed solution of 2.5 ml of 4N hydrochloric acid and 2.5 ml of acetic acid is added the complete amount of 8-chloro-L- [3, 5-difluoro-6- (p-methoxybenzylamino) -4-methylpyridin-2. ethyl] -6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylate described above, and the mixture is heated under reflux with stirring for three hours and allowed to cool and settle. To the residue is added 10 ml of distilled water, and the solution is concentrated under reduced pressure. The procedure of adding 10 ml of ethanol and concentrating the solution under reduced pressure is repeated three times, and 6 ml of chloroform are added to the residue, and the mixture is heated under reflux with stirring for 1 hour and allowed to cool. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 128 mg of the title compound as a colorless powder. Melting point: 253 to 257 ° C '-HRMN (d6-DMS0) d; 2.24 (s, 3H), 6.67 (s broad, 2H), 8.38 (t, J = 9Hz, ÍH), 8.89 (s, 1H).

[Example 20] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3,5-difluoro-4-met ilpyridin-2-yl) -8-chloro-6-fluoro-4 -oxo- 1.4 -dihydroquinoline-3-carboxylic acid To 280 mg of N, N-dimethylformamide is added 50 mg of 1- (6-amino-3,5-difluoro-4-methylpyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo acid 1, 4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride and 120 mg of N-methylpyrrolidone and the mixture is stirred at 90 ° C for 1 hour. After adding 0.4 ml of ethanol, the mixture is allowed to cool. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 45 mg of the title compound as a colorless powder. Melting point: 243 to 245 ° C (decomposition) ^ NMR (d6-DMSO) d; 2.23 (s, 3H), 3.71 (m, ÍH), 4.05 (m, 2H), 4.67 (m, 2H), 6. 60 (s broad, 2H), 7.85 (d, J = 14Hz, ÍH), 8.64 (s, ÍH) [Reference Example 13] Synthesis of 4- (t-butylamino) -2, 3, 5, 6-tetrafluoropyridine To 100 ml of acetonitrile, 24.5 g of pentaflnoropyridine are added, and the mixture is stirred in an ice bath simultaneously by the dropwise addition of 30 g of t-butylamine. When the mixture is warmed to room temperature, 150 ml of chloroform are added and the mixture is washed twice with 800 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 23 g of the title compound as a light yellow oil.

[Reference Example 14] Synthesis of 2-benzylamino-4- (t-butylamino) -3,5,6-trifluoropyridine To 10 ml of N-methylpyrrolidone is added 6.8 g of 4- (t-butylamino) -2, 3, 5, 6-tetrafluoropyridine together with 7.2 g of benzylamine and the mixture is stirred at 115 ° C for 1 day and Allow it to cool. After adding 40 ml of chloroform, the mixture is washed three times with 400 ml of distilled water. Dry the chloroform layer over anhydrous magnesium sulfate and concentrate under reduced pressure to obtain approximately 8.0 g of the title compound as an untreated dark green oil. XHRMN (CDC13) d: 1.39 (s, 9H), 4.16 (s broad, ÍH), 4.35 (s broad, 2H), 4.48 (m, 2H), 7.35 (m, 5H) [Reference Example 15] Synthesis of 2-amino-4- (t-butylamino) -3.5.6-trifluoropyridine To 13 ml of acetic acid 4.0 g of the untreated 2-benzylamino-4- (t-butyl) amino-3,5,6-trifluoropyridine are added as described above together with 0.43 g of 10% palladium on carbon , and the mixture is hydrogenated at 60 ° C for 6 hours. The catalysts are removed by filtration and the solvent and the like are distilled off under reduced pressure to obtain the title compound as an untreated brown oil.

[Reference example 161 Synthesis s 3- r r4-t-butylamino-3,5,6-trifluoro-pyridin-2-iDaminol -2-r 3 -chloro-2,4,5-trifluorobenzonyl) ethyl acrylate To 1.4 g of ethyl 3-chloro-2, 4-5-trifluorobenzoylacetate is added 1.5 g of acetic anhydride and 1.5 g of triethyl orthoformate, and the mixture is heated under reflux for 2 hours. The solvent is distilled off and toluene is added to the residue for azeotropic distillation. 3 ml of chloroform is added to half the residue and 5 ml of a chloroform solution of 1 g of 2-amino-3,5,6-trifluoro-4- (t-butylamino) pyridine is added dropwise and cooled with ice, the mixture is subsequently stirred at room temperature for 2 hours. The solvent is distilled off, and the solid precipitate is collected by filtration and washed with diethyl ether to obtain 1.14 of the title compound.

[Example 21] Synthesis of 1- (4-t-butylamino.no-3,5,6-trifluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate-ethyl To 6 ml of a N, N-dimethylformamide solution of 1.14 g of 3- [4- (4-t-butylamino-3,5,6,6-trifluoro-pyridin-2-yl) amino] -2- (3-chloro) -2,4,5-trifluorobenzoyl) ethyl acrylate is added 700 mg of potassium carbonate and the mixture is stirred at room temperature for 3.5 hours. The reaction solution is poured into ice water and ethyl acetate is added for extraction. The organic layer is separated and dried over magnesium sulfate, and the solvent is distilled off. The solid content is collected by filtration to obtain 1.25 g of the title compound as a colorless powder. Melting point: 145 to 146 ° C '"HRMN (CDC1 1.40 (t, j = 7Hz, 3H), 1.48 (s, 9H), 4.41 (c, J = 7Hz, 2H =, 4.78 (ÍH, S broad) , 8.31 (t, J = 9Hz, ÍH), 8.44 (ÍH, S) [Example 22] Synthesis of i- (4-amino-3,5,6-tri luoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-4-dihydro-quinoline-3-carboxylic acid To 300 ml of 1- ( 4-t-Butylamino-3,5,6-trifluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-ethylcarboxylate is added with 3 ml of 12N hydrochloric acid and 0.5 ml of acetic acid, and the mixture is heated under reflux for 1.5 hours. The reaction solution is allowed to cool and the solid precipitate is collected by filtration and washed successively with ethanol and diethyl ether to obtain 168 mg of the title compound as a colorless powder. Melting point: 280 to 283 ° C XHRMN (ds-DMS0) d; 7.54 (s, ÍH), 8.38 (dd, J = 9Hz, 10Hz, ÍH), 8.98 (s, ÍH) [Example 23] Synthesis of a-acid 7- (3-aminoazetidin-l-yl) -1- (4-amino-3, 5,6-trifluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l .4 -dihydroquinoline-3-carboxylic acid To the ml of a solution in dimethyl sulfoxide of 70 mg of 3-aminoazetidine dihydrochloride and 250 mg of triethylamine at 80 ° C is added 150 mg of 1- (4-amino-3,5,6,6-trifluoro-iridinyl) acid. 2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with stirring, and the mixture is stirred at 80 ° C for 1 hour. The reaction solution is allowed to cool and decant with diethyl ether. Ethanol is added to the residue and the solid content is dispersed, and the solid content is collected by filtration, washed with ethanol and dried to obtain 85 mg of the title compound as a light yellow powder. Melting point: decomposition at 230 ° C or higher XHRMN (d6-DMSO + TFA) d: 4.05 (m, 1H), 4.45 (m, 2H), 4.77 (m, 2H), 7.50 (2H, broad s) 7.93 (d, J = 14Hz, ÍH), 8.32 (s broad, 2H), 8.80 (s, ÍH) [Reference Example 17] Synthesis of 3,5-diamino-2-chloropyridine To the mixture of 2.19 g of iron powder, 5 ml of water and 10 ml of ethanol is stirred at 80 ° C for 2 minutes. After the addition in 1 ml increments of concentrated hydrochloric acid, the mixture is stirred at the same temperature until the solution becomes neutral. To the reaction solution is added in suspension a suspension of 1 g of 2-chloro-3,5-dinitropyridine in 5 ml of ethanol, and the mixture is stirred at 80 ° C for 40 minutes. The reaction solution is allowed to cool and the iron is removed by filtration with celite and the solvent and the filtrate are distilled off. Ethanol is added to the residue to disperse the solid content and the solid content is collected by filtration to obtain 360 mg of the title compound.

[Reference example 18] Synthesis of 3- r r5-amino-6-chloropyridin-3-yl) aminol -2- C -r.l nm-2.4.5 -trifluorobenzinyl) ethyl acrylate To 1.4 g of 3-chloro-2,4,5-trifluorobenzoyl-ethyl acetate is added 1.5 g of acetic anhydride and 1.5 g of triethyl orthoformate, and the mixture is refluxed for 2 hours. The solvent is distilled off and toluene is added to the residue for azeotropic distillation. 3 ml of chloroform are added to half the residue and a solution of 360 mg of 3,5-diamino-2-chloropyridine in 3 ml of ethanol is added dropwise to the mixture at room temperature and the mixture is stirred at room temperature. environment for 30 minutes.

The solvent is distilled off and the residue is purified by column chromatography to obtain 200 mg of the title compound.

[Example 24] Synthesis of 1- (5-amino-6-chloropyridin-3-yl) -8-chloro-6,1-difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate? of ethyl To a solution of 180 mg of 3- [[5-amino-6-chloropyridin-3-yl) amino] -2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate, in 3 ml of N, N-dimethylformamide are added 57 mg of potassium carbonate and the mixture is stirred at room temperature for 2 hours. The reaction solution is poured into ice water and extracted by adding ethyl acetate. The organic layer is separated and dried over magnesium sulfate, and the solvent is distilled off. The solid content is collected by filtration to obtain 125 mg of the compound as a light yellow powder. Melting point: 233 to 236 ° c XHRMN (CDC1 1.39 (t, J = 7Hz, 3H), 4.40 (c, J = 7Hz, 2H), 4.46 (broad s, 2H), 7.04 (s, ÍH), 7.26 (s, ÍH), 7.86 (s, ÍH), 8.32 (t, J = 9Hz, ÍH), 8.37 (s, ÍH). [Example 25] Synthesis of 1- (5-amino-6-chloropyridin-3) acid -il) -8-chloro-6.7-difluoro-4-QXQ-l, 4-dihiflro (mipQlin-3-carpQxilicQ To 100 g of 1- (5-amino-6-chloropyridin-3-yl) -8-chloro-6,7-difluoro-4-oxoyl, 4-dihydroquinoline-3-ethylcarboxylate is added 3 ml of concentrated hydrochloric acid and the mixture is heated under reflux for 2 hours. The reaction solution is allowed to cool and the precipitated solid is collected by filtration. The solid is washed with ethanol to obtain 86 mg of the title compound as a light yellow powder Melting point: 277 to 281 ° C XHRMN (d6-DMSO) d; 7.37 (s, 1H), 7.86 (s, 1H) ),. 8.41 (t, J = 9Hz, 1 H), 8. 69 (s, ÍH) [Example 26] Synthesis of 7- (3-aminoazetidin-l-yl) -1- (5-amino-6-chloropyridin-3-yl) -8-chloro-6-fluoro-4-oxo-l, 4-dihydroquinoline-3 -carboxylic To 1 ml of dimethylsulfoxide solution of 53 mg of 3-aminoazetidine dihydrochloride and 146 mg of triethylamine at 80 ° C is added 80 mg of 1- (5-amino-S-chloropyridin-3-yl) -8-chloro 6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylic acid with stirring, and the mixture is stirred at 80 ° C for 1 hour. The reaction solution is allowed to cool and decanted with diethyl ether. Ethanol is added to the residue to disperse the solid content, and the solid content is collected by filtration, washed with ethanol and dried to obtain 45 mg of the title compound as a light yellow powder. Melting point: 280 ° C or higher XHRMN (ds-DMS0) d; 3. 78 (m, ÍH), 4.14 (m, 2H), 4.64 (m, 2H), 6.04 (broad, 2H), 7.30 (s, ÍH), 7.75 (s, 1H), 7.89 (d, J = 14Hz, ÍH), 8.49 (s, ÍH) [Reference Example 19] Synthesis of 2,4-dichloro-5-fluoropyrimidine .3 g of 5-fluorouracil are mixed thoroughly with 72.9 of phosphorus pentachloride, and the mixture is gradually heated to 130 ° C and reacted for 4 hours. (The reaction mixture becomes liquid in about 1 hour, and the reaction proceeds at high speed). After adding 300 ml of ice water and 200 ml of chloroform, the mixture is stirred for 20 minutes. The insoluble content is separated by filtration with celite and the filtrate is separated. The chloroform layer is washed with a 5% aqueous solution of sodium carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 30.6 g of the title compound as a brown oil (which crystallizes at a temperature minor). ^ RM (CDC13) d; 8.49 (s, ÍH) [Reference Example 20] Synthesis of 4- (t-butylamino) -2-chloro-5-fluoropyrimidine To 20 ml of acetonitrile is added 6.4 g of 2,4-dichloro-5-fluoropyrimidine and 7.0 g of t-butylamine, and then the mixture is stirred at 50 ° C for 20 minutes. The solution is concentrated under reduced pressure and separated by adding 40 ml of distilled water and 70 ml of chloroform. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated light yellow crystals are dispersed in diisopropyl ether and collected by filtration to obtain 4.1 g of the title compound. XHRMN (CDC13) d; 1.51 (s, 9H), 5.07 (s broad, ÍH), 7.83 (d, J = 3Hz, 1H) [Reference Example 21] Synthesis of 2-benzylamino-4- (t-butylamino) -5-fluoropyrimidine To 5 ml of N-methylpyrrolidone is added 1.8 g of 4- (t-butylamino) -2-chloro-5-fluoropyrimidine and 4.0 g of benzylamine, and the mixture is stirred at 140 ° C for 17 hours and separated upon addition. 300 ml of distilled water and 40 ml of chloroform. The chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated light yellow crystals are dispersed in diisopropyl ether and collected by filtration to obtain 1.9 g of the title compound. 1 HNMR (CDCl 3) d; 1.40 (s, 9H), 4.54 (d, J = 6Hz, 2H), 4.71 (s broad, 'ÍH), 5.06 (s broad, ÍH), 7.33 (m, 5H), 7.65 (d, J = 3Hz, ÍH) [Reference Example 22] Synthesis of 2-amino-4- (t-butylamino) -5-fluoropyrimidine To 8 ml of acetic acid is added 1.00 g of 2-benzylamino-4- (t-butylamino) -5-fluoropyrimidine together with 215 mg of 10% palladium on carbon, and the mixture is hydrogenated at 60 ° C for 10 days . The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. The procedure of adding 10 ml of ethanol and concentrating under reduced pressure is repeated three times, and the residue is separated by column chromatography (silica gel, 25 g, eluent: chloroform, and then chloroform: methanol, 200: 1) and the corresponding fractions are collected and concentrated under reduced pressure to obtain 360 mg of the title compound as a light gray solid. XHRMN (CDCI3) d; 1. 47 (s, 9H), 4.92 (s broad, ÍH), 5.57 (s broad, 2H), 7.51 (d, J = 3Hz, ÍH) [Example 27] Synthesis of 1- T4- (t-butylamino) -5-fluoropyrimidin-2-yl-8-chloro-6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylate ethyl To 3 ml of a chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 210 mg of 3-chloro-2,4,5-trifluorobenzoylacetate ethyl per normal process are added 340 mg of 2-amino-4- (t-butylamino) -5-fluoropyrimidine. The solution is concentrated under reduced pressure. To the residue are added 550 mg of anhydrous potassium carbonate and 2 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 1 hour and 10 minutes, and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated by column chromatography (silica gel, 16 g, eluent: chloroform: methanol, 200: 1) and the corresponding fractions are collected and concentrated under reduced pressure. To the residue is added 0.5 ml of ethanol and the precipitate is collected by filtration and washed successively with ethanol and ether [Example 29] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (4-amino-5-fluoropyrimidin-2-yl) -8-chloro-6-fluoro-4 -oxo-1,4-dihydroquinoline-3-carboxylic acid To 100 mg of N, N-dimethylformamide are added 25 mg of 1- (4-amino-5-fluoropyrimidin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline. 3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride and 50 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 0.2 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 10 mg of the title compound as a colorless powder. Melting point: 269 to 271 ° C (decomposition) 1HRMN (d6-DMS0) d; 3.73 (m, ÍH), 4.07 (m, 2H), 4.67 (m, 2H), 7.81 (d, J = 15Hz, ÍH), 7.95 (s broad, ÍH), 8.29 (d, J = 3Hz, ÍH) , 8.83 (s, ÍH) [Reference Example 23] Synthesis of 2-amino-3,5-difluoro-6-methoxypyridine [Example 29] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (4-amino-5-fluoropyrimidin-2-yl) -8-chloro-6-fluoro-4-oxo-l, 4-dihydroquinoline-3 -carboxylic To 100 mg of N, -dimethylformamide are added 25 mg of 1- (4-amino-5-fluoropyrimidin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline- 3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride and 50 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 0.2 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 10 mg of the title compound as a colorless powder. Melting point: 269 to 271 ° C (decomposition) XHRMN (d6-DMS0) d; 3.73 (m, ÍH), 4.07 (m, 2H), 4.67 (m, 2H), 7.81 (d, J = 15Hz, ÍH), 7.95 (s broad, ÍH), 8.29 (d, J = 3Hz, ÍH) , 8.83 (s, ÍH) [Reference Example 23] Synthesis of 2-amino-3,5-difluoro-6-methoxypyridine To 1 ml of methanol are added 500 mg of 2-amino-3,5,6-trifluoropyridine together with 800 mg of a 28% solution of sodium methoxide / methanol, and the mixture is stirred at 70 ° G for 3 and a half hours, and allowed to cool. After adding 25 ml of chloroform, the mixture is washed with 5 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound.

[Example 30] Synthesis of ethyl 8-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) -6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylate To 3 ml of chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 0.78 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process 2-amino-3 is added, 5-difluoro-6-methoxypyridine until the conversion to the amino acrylate form is completed, which is confirmed by checking the reaction by CCD. The reaction is concentrated under reduced pressure and 0.80 g of anhydrous potassium carbonate and 2 ml of N, N-dimethylformamide are added to the residue, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool- The solution it is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to settle. The precipitate is collected by filtration, washed with ethanol to obtain 615 mg of the title compound as a light brown powder. Melting point: 140 to 143 ° C XHRMN (CDC13) d; 1.41 (t, J = 7Hz, 3H), 3.99 (s, 3H), 4.41 (c, J = 7Hz, 2H), 7.44 (t, J = 8Hz, ÍH), 8.33 (dd, J = 8Hz, 10Hz) , 8.45 (s, ÍH).

[Example 31] Synthesis of 8-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) -6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylic acid 385 mg of 8-chloro-1- (3,5-difluoro-6-methylpyridin-2-yl) -6,7-difluoro- 4-Oxo-l, 4-dihydroquinoline-3-ethylcarboxylate and the mixture is heated under reflux with stirring for 30 minutes. After adding 2 ml of distilled water, allow the solution to cool and settle. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 297 mg of the title compound as a colorless powder.

Melting point: 205 to 210 ° C XHRMN (d6-DMSO) d; 3.92 (s, 3H), 8.39 (t, J = 9Hz, ÍH), 40 (t, J = 9Hz, ÍH), 9.03 (s, ÍH) [Example 32] Synthesis of 7- (3-aminoazetidin-1-yl) -8-chloro-1- (3,5-difluoro-6-methoxypyridin-2-yl) -6-fluoro-4-oxo-l, 4-dihydroquinoline-3 -carboxylic To 500 mg of acetonitrile is added 75 mg of 8-chloro-1- (3,5-difluoro-6-methoxypyridin-2-yl) -6,7-difluoro-4-oxo-1,4-hydroquinoline-3 acid. -carboxylic acid, 65 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is heated under reflux for 1 hour. The precipitate is collected by filtration and successively washed with ethanol and diisopropyl ether to obtain 28 mg of the title compound as a colorless powder. Melting point: 171 to 175 ° C XHRMN (ds-DMSO) d; 3.70 (m, 1H), 3.91 (s, 3H), 4.05 (M, 2h), 4.66 (m, 2H), 7. 88 (d, J = 14Hz, ÍH), 8.34 (t, J = 9hz, ÍH), 8.79 (s, ÍH) [Example 33] Synthesis of 7-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-l, 8-naphthylidin-3-ethylcarboxylate To 10 ml of a chloroform solution of ethyl 3-ethoxy-2- (2,6-dichloro-5-fluoronicotinyl) acrylate prepared from 1.25 g of ethyl 2,6-dichloro-5-fluoronicotinoylacetate by normal process the unreacted 2-amino-3, 5-difluoro-6-methoxypyridine is added until complete conversion into the amino acrylate form is confirmed by verification of the reaction by CCD. The solution is concentrated under reduced pressure and to the residue are added 2.0 g of anhydrous potassium carbonate and 4 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 20 minutes and allowed to cool. The solution is separated by adding 50 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate is dispersed in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1010 mg of the title compound as a light brown powder. Melting point: 208 to 212 ° C XHRMN (CDC13) d; 1. 42 (t, J = 7Hz, 3h), 4.04 (s, 3H), 4.40 (c, J = 7Hz, 2H), 7.50 (t, J = 8Hz, ÍH), 8.48 (d, J = 7Hz, ÍH) , 8.69 (S, ÍH) [Example 34] Synthesis of 7-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidine-3-carboxylic acid To 1.5 ml of a mixed solution (1: 1, v / v) of 3N hydrochloric acid and acetic acid is added 300 mg of 7-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) - 6-Fluoro-4-oxo-l, 4-dihydro-1, 8-naphthylidin-3-ethylcarboxylate and the mixture is heated under reflux with stirring for 1 hour. After adding 2 ml of distilled water, the mixture is heated under reflux for 10 minutes and allowed to cool, and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 248 mg of the title compound as a light brown powder.

Melting point: 220 to 225 ° C: HRMN (ds-DMS0) 3. 97 (s, 3H), 8. 41 (t, J = 9Hz, ÍH), 8. 76 (d, - J = 7Hz, 1H), 9. 21 (S, ÍH) [Example 35] Synthesis of 7- f (3S) -3-aminopyrrolidin-1-ill -1- (3,5-difluoro--methoxypyridin-2-yl) -6-fluoro-4-oxo-1,4-dihydro-1,8-naphthylidin 3 -carboxylic To 400 mg of N. N-dime ilformamide 82 mg of 7-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) -6-fluoro-4-oxo-1, 4- are added. dihydro-l, 8-naphthylidine-3-carboxylic acid, 70 mg of (3S) -3-aminopyrrolidine and 60 mg of triethylamine, and the mixture is heated under reflux at 80 ° C for 30 minutes. After adding 2.5 ml of ethanol, the mixture is heated under reflux for 5 minutes and allowed to cool, and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 102 mg of the title compound as a powder light brown. Melting point: 231 to 233 ° C XHRMN (d6-DMSO) d; 1.65 (m, ÍH), 1.93 (m, ÍH), 3.95 (s, 3H), 8.02 (d, J = 13Hz, ÍH), 8.35 (t, J = 9Hz, ÍH), 8.94 (s, 1H) ( Part of the signals overlapped with the water proton and were not differentiable) [Example 36] Synthesis of 7- (3S. 4S) -3-amino-4-methrrolidin-1-ill -1- (3,5-difluoro-6-methoxypyridin-2-yl) -6-fluoro-4 - acid oxo-1, 4-dihydro-1, 8-naphthylidene-3-carboxylic acid To 500 mg of N, N-dimethylformamide is added 85 mg of 7-chloro-l- (3,5-difluoro-6-methoxypyridin-2-yl) -6-fluoro-4-oxo-1, 4- dihydro-l, 8-naphthylidin-3-carboxylic acid, 70 mg of (3S, 4S) -3-amino-4-methrrolidine dihydrochloride and 150 mg of triethylamine, and the mixture is heated under reflux at 80 ° C for 30 minutes . After adding 2.5 ml of ethanol, the mixture is heated under reflux for 5 minutes and allowed to cool, and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 105 mg of the title compound as a powder colorless. Melting point: 226 to 229 ° C 1HRM (d6-DMSO) d; 0.94 (broad d, J = 8Hz, 3H), 2.16 (m, ÍH), 3.95 (s, 3H), 8.02 (d, J = 13Hz, ÍH), 8.35 (m, ÍH), 8.95 (s, ÍH) (Part of the signals overlapped with the water proton, and were not differentiable).

[Example 37] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6-r-7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylic acid To a mixed solution of 3.5 ml of 4N hydrochloric acid and 3.5 ml of acetic acid are added 1.38 g of 8-bromo-1- [6- (t-butylamino) -3,5-difluoropyridin-2-yl] -6,7-difluoro-4- Ethyl oxo-1,4-dihydroquinoline-3-carboxylate and the mixture is refluxed with stirring for 5 hours. After adding 5 ml of distilled water, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1.10 g of the title compound as a colorless powder. Melting point: 272 to 278 ° C ^? NMR (ds-DMSO) d; 6.80 (s, 2H), 7.99 (t, J = 9Hz, ÍH), 8.38 (t, J = 9Hz, ÍH), 8.93 (s, ÍH) [Example 38] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To a mixed solution of 0.5 ml of hydrochloric acid 4N and 0.5 ml of acetic acid are added 235 mg of 1- [6- (t-butylamino) -3,5-difluoropyridin-2-yl] -6,7,8-trifluoro-4-oxo-1, 4- ethyl dihydroquinoline-3-carboxylate and the mixture is heated under reflux with stirring for 7 hours. After adding 1 ml of distilled water, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 182 mg of the title compound as a colorless powder. Melting point: 280 ° C or higher 1HRMN (d6-DMSO) d; 6.81 (broad s, 2H), 8.04 (t, J = 9Hz, ÍH), 8.23 (m, 1H), 8.98 (s, ÍH) [Example 39] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6-fluoro-4-oxo-l, 4-dihydroquinoline -3-carboxyl To 300 mg of N, N-dimethylformamide are added 105 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4-acid. -dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 79 mg of the title compound as a colorless powder. Melting point: 258 to 264 ° C (decomposition) XHRMN (d6-DMSO) d; 3. 73 (m, ÍH), 4.06 (m, 2H), 4.69 (m, 2H). , 6.75 (s broad, 2H), 7.89 (d, J = 14Hz, ÍH), 7.94 (t, J = 9Hz, ÍH), 8.70 (s, ÍH).

[Example 40] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -6,8-difluoro-4-oxo-1,4-dihydroquinoline-3 acid -carboxylic 270 mg of N, N-dimethylformamide are added with 90 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline. -3-carboxylic acid, 50 mg of 3-aminoazetidine dihydrochloride and 110 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 0.3 ml of ethanol, the mixture is allowed to cool, and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 70 mg of the title compound as a colorless powder. Melting point: 256 to 260 ° C (decomposition) ^ NMR (d6-DMSO) d; 3.76 (m, ÍH), 3.94 (m, 2H), 4.44 (m, 2H), 6.74 (broad s, 2H), 7.78 (d, J = 13Hz, ÍH), 7.99 (t, J = 9Hz, ÍH), 8.73 (s, ÍH).

[Example 41] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6-fluoro-7- (3-methylaminoazetidin-1-yl) -4-oxo-1,4-dihydroquinoline -3-carboxylic? To 800 mg of N, N-dimethylformamide are added 260 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4 acid. -dihydroquinoline-3-carboxylic acid, 130 mg of 3-methylaminoazetidine dihydrochloride and 300 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected, by filtration and washed successively with ethanol and diisopropyl ether to obtain 247 mg of the title compound as a light yellow powder. Melting point: 238 to 245 ° C (decomposition) 1HRMN (d5-DMS0) d; 2.21 (s, 3H), 3.46 (m, ÍH), 4.12 (m, 2H), 4.63 (m, 2H), 6.75 (s broad, 2H), 7.88 (d, J = 14Hz, ÍH), 7.94 (t , J = 9Hz, ÍH), 8.70 (s, ÍH).

[Example 42] Synthesis of 7-? 3 - (ethylamino) azetidin-l-ill -1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-4 -oxo-1,4-dih.idroguinolin -3-carboxyl To 310 mg of N, N-dimethylformamide is added 100 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4 acid. -dihydroquinoline-3-carboxylic acid, 70 mg of 3- (ethylamino) azetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 15 minutes. After adding 1 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 107 mg of the title compound as a colorless powder. Melting point: 241 to 245 ° C (decomposition) XHRMN (d6-DMSO) d; 0.98 (t, J = 7Hz, 3H), 2.49 (c, J = 7Hz, 2H), 3.55 (m, ÍH), 4.14 (m, 2H), 4.66 (m, 2H), 6.76 (s broad, 2H) , 7.86 (d, J = 14Hz, ÍH), 7.95 (t, J = 9Hz, ÍH), 8.69 (s, ÍH).

[Example 43] Synthesis of 7- [3 - (dimethylamino) azetidin-1-ill -1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l, 4-dihydroquinoline -3-carboxylic acid To 310 mg of N, N-dimethylformamide are added 100 mg of 1- acid. { 6-amino-3, 5-difluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3- (dimethylamino) azetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 15 minutes. After adding 1 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 87 mg of the title compound as a colorless powder. Melting point: 283 to 287 ° C (decomposition) ^ NMR (d6-DMSO) d; 2.07 (s, 6H), 3.03 (m, ÍH), 4.24 (m, 2H), 4.55 (m, 2H), 6.77 (s broad, 2H), 7.86 (d, J = 14Hz, ÍH), 7.95 (t , J = 9Hz, ÍH), 8.70 (S, ÍH).

[Example 44] Synthesis of 7- [3- (aminomethyl) azetidin-1-ill -1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l, 4 -dihydroquinoline-3-carboxylic acid To 280 mg of N, N-dimethylformamide are added 80 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1, - dihydroquinoline-3-carboxylic acid, 100 mg of 3- (aminomethyl) azetidine dihydrochloride and 200 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 25 minutes. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 42 mg of the title compound as a colorless powder. Melting point: 249 to 254 ° C (decomposition) XHRMN (d6-DMSO) d; 2.67 (m, ÍH), 2.80 (m, 2H), 4.21 (m, 2H), 4.49 (m, 2H), 6.73 (s broad, 2H), 7.80 (d, J = 14Hz, ÍH), 7.93 (t , J = 10Hz, ÍH), 8.56 (s, ÍH) [Reference Example 24] Synthesis of 4-amino-3-chloro-2,5,6-trifluoropyridine To 100 ml of acetonitrile 20.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine are dissolved and 30 ml of a 25% aqueous solution of ammonia is added in three portions while the mixture is stirred and cooled with water , and the agitation continues for another 30 minutes. The solution is concentrated under reduced pressure. After adding 200 ml of chloroform to the solid residue, the solution is washed with 50 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure and the precipitate is collected by filtration to obtain 16.6 g of the title compound as colorless flake crystals.

[Reference Example 25] Synthesis of 4-bromo-3-chloro-2,5,6-trifluoropyridine To 45 ml of acetonitrile, 9.4 g of 4-amino-3-chloro-2,5,6-trifluoropyridine are dissolved and 7.5 g of t-butyl nitrile are added dropwise during 25 minutes with stirring at 45 ° C, and The mixture is heated under reflux for 40 minutes and concentrated under reduced pressure. The residue is separated by adding 150 ml of chloroform and 100 ml of 2N hydrochloric acid, and the chloroform layer is washed with 20 ml of distilled water. The chlorofoxm layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 10.2 g of the title compound as a light yellow oil.

[Reference Example 26] Synthesis of 4-bromo-2- (t-butylamino) -5-chloro-3,6-difluoropyridine To 40 ml of acetonitrile 10.2 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 10.5 g of t-butylamine are dissolved, and the mixture is heated under reflux for 1 hour and the solvent and the like are separated by distillation under reduced pressure. 80 ml of chloroform is added to the residue and the mixture is washed with 50 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 12.8 g of the title compound as a reddish orange oil.

[Reference Example 27] Synthesis of 2- (t-butylamino) -5-chloro-3.6-difluoropyridine To 30 ml of methanol are added 12.8 g of 4-bromo-2- (t-butylamino) -5-chloro-3,6-difluoropyridine and 2.5 g of triethylamine together with 0.57 g of 10% palladium in charcoal, and the The mixture is hydrogenated at 50 ° C for 5 days. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. To the residue is added 80 ml of chloroform and the mixture is washed with 70 ml of distilled water, and the chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 9.3 g of the title compound as an oil. coffee.

[Reference Example 28] Synthesis d = _ 2-benzylamino-6- (t-butylamino) -3-chloro-5-fluoroplridine To 10 ml of N-methylpyrrolidine are added 6.8 g of 2- (t-butylamino) -5-chloro-3,6-difluoropyridine together with 8.0 g of benzylamine and the mixture is stirred at 150 ° C for 1 day, and Allow it to cool. After 80 ml of chloroform, the mixture is washed three times with 300 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography (silica gel, 100 g, eluent; chloroform: n-hexane, 1: 1) to obtain about 7.0 g of the title compound as an untreated light brown oil.

[Reference Example 29] Synthesis of 2-amino-6- (t-butylamino) -3-chloro-5-fluoropyridine and 2-amino-6- (t-butylamino) -5-fluoropyridine To a mixed solution of 18 ml of methanol and 1.4 g of concentrated hydrochloric acid is added 3.1 g of 2-benzylamino-6- (t-butylamino) -3-chloro-5-fluoropyridine together with 0. 33 g of 10% palladium in charcoal, and the mixture is hydrogenated at 30 ° C for 1 hour. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. To the residue is added 50 ml of chloroform and the mixture is washed with 10 ml of a 6% aqueous solution of sodium hydroxide, and the chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography (silica gel, 40 g, eluent: chloroform: n-hexane, 3: 1 and then 1: 1) to obtain 1.35 g of 2-amino-6- (t-butylamino) - 3-chloro-5-fluoropyridine as a light brown oil, and 0.32 g of 2-amino-6- (t-butylamino) -5-fluoropyridine as a brown oil. 2-amino-6- (t-butylamino) -3-chloro-5-fluoropyridine XHRMN (CDC13) d; 1.44 (s, 9H), 4.32 (s broad, ÍH), 4.37 (s broad, ÍH), 7. 02 (d, J = 10Hz, ÍH) 2-amino-6- (t-butylamino) -5-fluoropyridine XHRMN (CDC13) d; 1.46 (s, 9H), 3.99 (s broad, ÍH), 4.30 (s broad, ÍH), . 61 (dd, J = 2Hz, 8Hz, ÍH), 6.91 (dd, J = 8Hz, 11Hz, ÍH) [Example 45] Synthesis of 1- [6- (t-butylamino) -3-chloro-5-fluoropyridin-1-ethyl-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate To 3 ml of chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl crilate prepared from 0.84 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process 0.65 g of 2-amino-6- (t-butylamino) -3-chloro-5-fluoropyridine are added. The solution is concentrated under reduced pressure to obtain a yellow solid residue. To this residue is added 0.7 g of anhydrous potassium carbonate and 3 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 25 minutes and allowed to cool. The solution is separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to rest. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 1.6 g of the title compound as a light yellow powder. _ Melting point: 210 to 213 ° C XHRMN (CDC13) d; 1.38 (s, 9H), 1.41 (t, J = 7Hz, 3H), 4,431 (c, J = 7Hz, 2H), 4.84 (s broad, ÍH), 7.32 (d, J = 10Hz, ÍH), 8.32 ( dd, J = 8Hz, 10Hz, ÍH), 8.45 (s, ÍH) [Example 46] Synthesis d = I 1- (6-amino-3-chloro-5-fluoropyridin-2-yl) -8-chloro-6-7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylic acid To a mixed solution (1: 1) of 2.5 ml of 4N hydrochloric acid and acetic acid is added 600 mg of 1- [6- (t-butylamino) -3-chloro-5-fluoropyridin-2-yl] -8- ethyl chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture is heated under reflux with stirring for 4.5 hours. After adding 2 ml of distilled water, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 458 mg of the title compound as a light yellow powder. Melting point: 280 ° C or higher XHRMN (d6-DMSO) d; 7.10 (s broad, 2H), 7.99 (d, J = 10Hz, ÍH), 8.40 (s, J = 10Hz, ÍH), 8.89 (s, ÍH) [Example 47] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3-chloro-5-fluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l .4 -dihydroquinolin-3-carboxylic acid To 300 mg of N, N-dimethylformamide are added 100 mg of 1- (6-amino-3-chloro-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro acid 4-oxo-l, 4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidone, and the mixture is stirred at 90 ° C for 30 minutes. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 95 mg of the title compound as a colorless powder. Melting point: 268 at 270 ° C (decomposition) NMR (ds-DMS0) d; 3.71 (m, ÍH), 4.08 (m, H), 4.67 (m, 2H), 7.04 (broad s, 2H), 7.87 (d, J = 14Hz, ÍH), 7.94 (d, J = 10Hz, ÍH), 8.62 (s, ÍH) [Example 48] Synthesis of 1- ÍS-amino-3-chloro-5-fluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-methylaminoazetidin-1-yl) -4 -oxo-1,4-dihydroquinoline- 3 -carboxylic To 300 mg of N, N-dimethylformamide is added 103 mg of 1- (6-amino-3-chloro-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo- 1, 4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoacetidine dihydrochloride and 150 mg of N-methylpyrrolidone, and the mixture is stirred at 85 ° C for 30 minutes. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 98 mg of the title compound as a colorless powder. Melting point: 277 to 280 ° C (decomposition) XHRMN (d6-DMSO) d; 2.20 (s, 3H), 3.45 (m, ÍH), 4.13 (m, 2H), 4.64 (m, 2H), 7.04 (s broad, 2H), 7.87 (d, J = 14Hz, ÍH), 7.94 (d , J = 10Hz, ÍH), 8.62 (s, ÍH) [Example 49] Synthesis of 1- T6- (t-butylamino) -5-fluoropyridin-2-ip-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate ethyl To 2 ml of chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 0.56 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process, 0.42 g of 2-amino-6- (t-butylamino) -5-fluoropyridine are added. The solution is concentrated under reduced pressure to obtain a yellow solid residue. To this residue is added 0.6 g of anhydrous potassium carbonate and 1.5 ml of N, N-dimethylformamide and the mixture is stirred at 90 ° C for 20 minutes and allowed to cool. The solution is separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, supplemented with 2 ml of ethanol and allow it to sit. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 0.48 g of the title compound as a light yellow powder. Melting point: 207 at 210 ° C XHRMN (CDC13) d; 1.37 (s, 9H), 1.40 (t, J = 7Hz, 3H), 4.40 (c, J = 7hz, 2H), 4.82 (s broad, ÍH), 6.52 (dd, J = 3Hz, 8Hz, ÍH), 7.25 (dd, J = 8Hz, 10Hz, ÍH), 8.31 (dd, J = 8Hz, 10Hz, ÍH), 8.61 (s, ÍH) [Example 50] Synthesis of 1- (6-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 2 ml of a mixed solution (1: 1) of 4N hydrochloric acid and acetic acid are added 450 mg of 1- [6- (t-butylamino) -5-fluoropyridin-2-yl) -8-chloro-6, 7-difluoro-4-oxo-1, -dihydroquinolin-3-ethylcarboxylate, and the mixture is heated under reflux with stirring for 3 hours. After adding 1 ml of distilled water, the mixture is allowed to cool, and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 342 mg of the title compound as a colorless powder. Melting point: 232 to 235 ° C XHRMN (dg-DMSO) d; 6.87 (s broad, 2H), 6.91 (dd, J = 3Hz, 8Hz, ÍH), 7.64 (dd, J = 8Hz, 11Hz, ÍH), 8.36 (t, J = 9Hz, ÍH), 8.77 (s, ÍH) ) [Example 51] Synthesis of 7- (3-amino-azetidin-1-yl) -1- (6-amino-5-fluoro-pyridin-2-yl) -8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3 -carboxylic To 270 mg of N, N-dimethylformamide are added 55 mg of 1- (6-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline. -3-carboxylic acid, 70 mg of 3-aminoacetidine dihydrochloride and 80 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 15 minutes. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 62 mg of the title compound as a colorless powder.

Melting point: 250 to 254 ° C (decomposition) XHRMN (d6-DMSO) d; 3.71 (m, ÍH), 4.05 (m, 2H), 4.67 (m, 2H), 6.78 (dd, J = 3Hz, 8Hz, ÍH), 6.80 (s broad, 2H), 7.60 (dd, J = 8Hz, 10Hz, ÍH), 7.85 (d, J = 14Hz, ÍH), 8.60 (s, ÍH) [Example 52] Synthesis of 1- (6-amino-5-fluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-methylaminoazetidin-1-yl) -4-oxo-l, 4-dihydroquinoline-3 -carboxylic To 300 mg of N, N-dimethylformamide are added 101 mg of 1- (6-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-acid. dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoacetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 85 ° C for 30 minutes. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 82 mg of the title compound as a colorless powder. Melting point: 252 to 255 ° C (decomposition) XHRMN (d6-DMSO) d; 2. 21 (s, 3H), 3.46 (m, ÍH), 4.13 (m, 2H), 4.62 (m, 2H), 6.78 (m, 1H), 6.81 (s broad, 2H), 7.60 (dd, J = 8Hz , 10Hz, ÍH), 7.84 (d, J = 14Hz, ÍH), 8.60 (s, ÍH).

[Example of Reference 30] Synthesis of N- (3-chloro-2,5,6-trifluoropyridin-4-yl) phthalimide To a mixed solution of 40 ml of dichloromethane and 20 ml of N, N-dimethylformamide are added 18.5 g of 3-chloro-2,4,5,6-tetrafluoropyridine and 20.5 g of potassium phthalimide, and the mixture is stirred at room temperature. 40 ° C for one day. After adding 40 ml of chloroform, the mixture is washed twice with 500 ml of distilled water and once with 500 ml of a 0.5% aqueous solution of sodium hydroxide. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate is dispersed in diisopropyl ether and collected by filtration to obtain 32.0 g of the title compound as a colorless powder.

[Reference Example 31] Synthesis of N- \ 2 - (t-butylamino) -5-chloro-3.6-difluoropyridin-4-ill phthalimide To 150 ml of acetonitrile are added 30.0 g of N- (3-chloro-2,5,6-trifluoropyridin- 4-yl) phthalimide together with 42.2 g of t-butylamine and the mixture is heated under reflux with stirring for 30 minutes. The solution is concentrated under reduced pressure, then 200 ml of chloroform are added and washed with 100 ml of distilled water. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain approximately the title compound as a colorless solid residue.

[Reference Example 32] Synthesis of N- (2-amino-5-chloro-3,6-difluoropyridin-4-yl) phthalimide To 80 ml of trifluoroacetic acid the whole amount of N- [2- (t-butylamino) -5-chloro-3,6-difluoropyridin-4-yl] phthalimide is added and the mixture is stirred at 70 ° C for 5 hours and a half. The solution is concentrated under reduced pressure. The precipitate is dispersed in chloroform and collected by filtration to obtain 19.5 g of the title compound as a colorless powder.

[Reference Example 33] Synthesis of N- (2,5-dichloro-3,6-difluoropyridin-4-yl) phthalimide To 80 ml of acetonitrile is added 21.3 g of N (2-amino-5-chloro-3,6-difluoropyridin-4-yl) phthalimide together with 14.0 g of cupric chloride and the mixture is stirred at room temperature simultaneously with the dropwise addition of 15.8 g of t-butyl nitrite dissolved in 30 ml of acetonitrile for 10 minutes. The mixture is stirred at 60 ° C for 1 hour and concentrated under reduced pressure. The residue is separated by adding 500 ml of chloroform and 250 ml of 2N hydrochloric acid and the chloroform layer is washed with 50 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The precipitate is dissolved and collected by filtration to obtain -16.2 g of the title compound as a colorless powder.

[Reference Example 34] Synthesis of 4-amino-2,5-dichloro-3,6-difluoropyridine To a mixed solution of 100 ml of chloroform and 40 ml of methanol are added 16.2 g of N- (2,5-dichloro-3,6-difluoropyridin-4-yl) phthalimide together with 20 ml of a 25% aqueous solution. of ammonia, and the mixture is stirred at room temperature for 30 minutes. The solution is concentrated under reduced pressure and after adding 150 ml of chloroform to the residue, the mixture is washed with 20 ml of a 15% aqueous solution of ammonia and then with 10 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4.55 g of the title compound as a colorless powder.

[Reference Example 35] Synthesis of 4-amino-2, 5-difluoropyridine To 40 ml of methanol is added 4.5 g of 4-amino-2,5-dichloro-3,6-difluoropyridine and 4.5 g of triethylamine together with 0.40 g of 10% palladium in carbon and the mixture is hydrogenated at 50 ° C. for 12 days. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. To the residue is added 100 ml of chloroform and the mixture is washed with 10 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue are added 1.5 g of triethylamine, 0.35 g of 10% palladium in carbon and 30 ml of methanol, and the mixture is hydrogenated at 50 ° C for 41 hours. The catalyst is removed by filtration and the solvent and the like are removed by distillation under reduced pressure. To the residue is added 100 ml of chloroform and the mixture is washed with 10 ml of distilled water. Dry the chloroform layer over anhydrous magnesium sulfate and concentrate under reduced pressure to obtain 2.67 g of the title compound as a precipitate, as a colorless solid.

[Reference Example 36] Synthesis of 2-benzylamino-4-amino-5-fluoropyridine To 1 ml of N-methylpyrrolidone is added 410 mg of 4 - . 4-amino-2, 5-difluoropyridine together with 930 mg of benzylamine and the mixture is allowed to react under a nitrogen atmosphere 150 ° C for 3 days and allowed to cool. After adding ml of chloroform, the mixture is washed twice with 300 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography (silica gel, 15 g, eluent: chloroform: methanol, 1: 0 and then 50: 1) to obtain 400 mg of the title compound as a colorless solid. XHRMN (CDC13) d; 4.06 (broad s, 2H), 4.40 (d, J = 6Hz, 2H), 4.60 (broad s, ÍH), 5.69 (d, J = 6Hz, ÍH), 7.33 (m, 5H), 7.75 (d, J = 3Hz, ÍH) [Reference Example 37] Synthesis of 2,4-diamino-5-fluoropyridine hydrochloride To 4 ml of methanol, 400 mg of concentrated hydrochloric acid have been added, 350 mg of 2-benzylamino-4-amino-5-fluoropyridine together with 50 mg of 10% palladium in charcoal, and the mixture is hydrogenated at 40 ° C for 2 days. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. The procedure of adding 10 ml of distilled water to the residue and concentrating under reduced pressure is repeated four times, and the procedure of adding 10 ml of ethanol and concentrating under reduced pressure is repeated twice. 260 mg of the title compound are obtained as a residue in the form of a yellowish orange paste.

[Reference Example 38] Synthesis of 3- (4-amino-5-fluoropyridin-2-yl) amino-2 - (3-chloro-2,4,5-trifluorobenzoyl) acrylate. ethyl and 3- (2-amino-5-fluoropyridin-4-yl) amino-2 - (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate To 1.2 ml of chloroform solution of ethyl 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) acrylate prepared from 0.34-g of 3-chloro-2,4,5-trifluorobenzoylacetate ethyl per normal process 0.25 g of 2,4-diamino-5-fluoropyridine hydrochloride together with 0.28 g of N-methylpyrrolidine are added. The solution is concentrated under reduced pressure and to the residue 0.52 g of anhydrous potassium carbonate and 0.8 ml of N, N-dimethylformamide are added, and the mixture is stirred at 90 ° C for 15 minutes and allowed to cool. The solution is separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer is washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography (silica gel, 14 g), eluent: chloroform: methanol, 1: 0 and then 100: 1), and the fraction containing the main product is concentrated under reduced pressure. The precipitate is dispersed in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 1.06 g of the title mixture (1: 1 in NMR) as a light brown powder.

[Example 53] Synthesis of ethyl 1- (4-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylate To 150 mg of the mixture of 3 - (4-amino-5-fluoropyridin-2-yl) amino-2- (3-chloro-2,, 5-trifluorobenzoyl) ethyl acrylate and 3- (2-amino-5) -f luoropyridin-4-yl) amino-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate are added 230 mg of anhydrous potassium carbonate and 50 mg of N, N-dimethylformamide and the mixture Stir at 100 ° C for 20 minutes and allow it to cool. The solution is separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer is washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography (silica gel, 3.2 g, eluent: chloroform: methanol, 100: 1), and the fraction containing the main product is concentrated under reduced pressure to obtain 35 mg of the title compound as a Solid waste. Melting point: 140 to 148 ° C XHRMN (CDC13) d; 1.38 (t, J = 7Hz, 3H), 4.37 (c, J = 7Hz, 2H), 4.78 (s broad, 2H), 6.78 (d, J = 6Hz, ÍH), 8.11 (d, J = 3Hz, ÍH) ), 8.27 (dd, J = 8Hz, 10Hz, ÍH), 8.55 (s, ÍH) [Example 54] Synthesis of 1- (4-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 400 mg of the mixed solution (1: 1) of 4N hydrochloric acid and acetic acid is added 35 mg of 1- (4-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-dif luoro-4-oxo-l, ethyl 4-dihydroquinoline-3-carboxylate, and the mixture is heated under reflux with stirring for 3 hours and allowed to cool. The precipitate is collected by filtration and washed successively with distilled water, ethanol and diisopropyl ether to obtain 31 mg of the title compound as a light yellow powder. Melting point: 280 ° C or higher XHRMN (d6-DMS0) d; 6.86 (broad s, 2H), 7.00 (d, J = 7Hz, ÍH), 8.12 (d, J = 3Hz, ÍH), 8.39 (t, J = 9Hz, ÍH), 8.74 (s, ÍH).

[Example 55] Synthesis of 7- (3-amino-azetidin-1-yl) -1- (4-amino-5-fluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l, 4-dihydroquinoline-3 -carboxylic "To 110 mg of N, N-dimethylformamide are added 23 mg of 1- (4-amino-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-acid. dihydroquinoline-3-carboxylic acid, 20 mg of 3-aminoazetidine dihydrochloride and 50 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C. for 20 minutes, after adding 500 mg of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 23 mg of the title compound as a colorless powder Melting point: 280 ° C or higher XHRMN (d6-DMSO) d; 3. 75 (m, ÍH), 4.10 (m, 2H), 4.66 (m, 2H), 6.77 (s broad, 2H), 6.92 (d, J = 7Hz, ÍH), 7.86 (d, J = 14Hz, ÍH) , 8.08 (d, J = 3Hz, ÍH), 8.57 (s, ÍH).

[Reference Example 39] Synthesis of methyl 2,6-dichloro-5-fluoronicotinate To 60 ml of dichloromethane are added 21.0 g of 2,6-dichloro-5-fluoronicotinic acid, 10 ml of oxalyl chloride and 10 drops of N, N-dimethylformamide, and the mixture is stirred at room temperature for one day. The solvent and excess reagents are removed by distillation under reduced pressure and the residue is dissolved in 50 ml of chloroform. 10 ml of methanol are added dropwise to the solution and the solution is stirred at room temperature for 60_ minutes, and 15 g of anhydrous potassium carbonate are added to the solution and the solution is stirred for another 30 minutes. The solution is separated by adding 150 ml of chloroform and 150 ml of distilled water, and the chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 26.6 g of the title compound as an untreated and colorless oily residue.

[Reference Example 40] Synthesis of methyl 6-t-butylamino-2,5-difluoronicotinate To 300 ml of dimethyl sulfoxide is added three quarts (19.95 g) of methyl 2,6-dichloro-5-fluoronicotinate synthesized as described above, 14.5 g of potassium fluoride (spray drying) and 1.6 g of tetramethylammonium chloride, and the mixture is stirred at 110 ° C for 2 and a half hours and allowed to cool. After adding 100 ml of chloroform, the mixture is washed twice with 1 liter of distilled water and once with 1 liter of a 1% aqueous solution of potassium carbonate. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude methyl 2,5,6-trifluoronicotinate is obtained in the form of a brown oily residue, and this residue is dissolved in 60 ml of acetonitrile and 12.0 g of t-butylamine and added to this solution. The solution is concentrated under reduced pressure and the residue is separated by adding 100 ml of chloroform and 60 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate is dispersed in n-hexane and collected by filtration to obtain 6.85 g of the title compound as colorless crystals. XHRMN (CDC13) d; 1.50 (s, 9H), 3.86 (s, 3H), 5.04 (s broad, ÍH), 7.71 (dd, J = 7Hz, 11Hz, ÍH) [Reference Example 41] Synthesis of methyl 6-t-butylamino-5-fluoro-2- (1, 1, 3,3-tetramethylbutyl-amino) nicotinate To 7 ml of N-methylpyrrolidone, 2.44 g of methyl 6-t-butylamino-2,5-difluoronicotinate and 4.0 g of 1,1,3,3-tetramethylbutylamine are added and the mixture is stirred at 140 ° C for 16 hours. and it is allowed to cool. After adding 50 ml of chloroform, the mixture is washed three times with 300 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue is subjected to column chromatography (silica gel, 40 g, eluent: chloroform: n-hexane, 1: 1) to obtain 2.90 g of the title compound as a colorless oily residue. XHRMN (CDC13) d; 0.96 (s, 9H), 1.51 (s, 9H), 1.53 (s, 6H), 3.76 (s, 3H), 4.87 (s broad, ÍH), 7.52 (d, J = 12Hz, ÍH), 8.38 (s) broad, ÍH) [Reference Example 42] Synthesis of 2-t-butylamino-3-fluoro-5-methyl-6 - (1.1.3.3-tetramethylbutylamino) pyridine To 20 ml of tetrahydrofuran is dispersed 850 mg of lithium aluminum hydride. The dispersion is cooled with water and stirred simultaneously with the dropwise addition of 2.80 g of methyl 6-t-butylamino-5-fluoro-2- (1,1,3, 3-tetramethylbutylamino) nicotinate dissolved in 30 ml tetrahydrofuran. . The reactor is placed in an oil bath of 50 ° C and the mixture is stirred for two and a half hours. The reactor is cooled with water and added dropwise 8 ml of ethyl acetate and the mixture is stirred for 1 hour. 8 ml of ethanol are added dropwise and the mixture is stirred for 1 hour, then 8 ml of distilled water is added dropwise and the mixture is stirred overnight. The precipitate is separated by filtration and the filtrate is presented under reduced pressure. The residue is subjected to column chromatography (silica gel, 40 g, eluent: chlorofoxam: n-hexane, 1: 1) to obtain 1.67 g of the title compound as a colorless oily residue. XHRMN (CDC13) d; 0.99 (s, 9H), 1.47 (s, 9H), 1.52 (s, 6H), 1.91 (s, 3H), 3.73 (s broad, ÍH), 4.11 (s broad, 1H), 6.81 (d, J = 12Hz, ÍH) [Reference Example 43] Synthesis of 2,6-diamino-3-fluoro-5-methylpyridine To 800 mg of trifluoroacetic acid are added 340 mg of 2-t-butylamino-3-fluoro-5-methyl-6- (1,1,3,3-tetramethyl) -butylamino) -pyridine and the mixture is allowed to stand at room temperature for 30 minutes. The solution is concentrated under reduced pressure to obtain the 2, 6-diamino-3-fluoro-5-methylpyridine untreated as a light brown solid residue.

[Example 56] Synthesis of 1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-l.4-dihydroquinoline-3-ethylcarboxylate To 1 ml of chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 280 ml of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process the whole of 2 is added, 6-diamino-3-fluoro-5-methylpyridine as described above together with 2 ml of methanol and 4 ml of chloroform. After allowing to stand at room temperature for 40 minutes, the solution is concentrated under reduced pressure. To the residue is added 600 mg of anhydrous potassium carbonate and 1 ml of N, N-dimethylformamide, and the mixture is stirred at 85 ° C for 15 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added 0.5 ml of ethanol and the mixture is allowed to sit overnight. The precipitate is dispersed in ethanol, collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 171 mg of the title compound as a colorless powder. Melting point: 198 to 202 ° C XHRMN (CDC13) d; 1.40 (t, J = 7Hz, 3H), 2.02 (s, 3H), 4.39 (c, J = 7Hz, 2H), 4.71 (s broad, 2H), 7.25 (d, J = 10Hz, ÍH), 8.34 (t, J = 10Hz, ÍH), 8.34 (s, ÍH) [Example 57] Synthesis of 1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 800 g of the mixed solution (1: 1) of 4N hydrochloric acid and acetic acid is added 160 mg of 1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6. , Ethyl 7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylate and the mixture is heated under reflux with stirring for 30 minutes. After adding 0.5 ml of distilled water, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 145 mg of the title compound as a light brown powder. Melting point: 279 to 284 ° C (decomposition) XHRMN (d6-DMSO) d; i.94 (s, 3H), 6.62 (s broad, 2H), 7.57 (d, J = 11Hz, 1H), 8.40 (t, J = 9Hz, ÍH), 8.72 (s, ÍH) [Example 58] Synthesis of 7- (3-aminoazetidin-l-yl) -1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6-fluoro-oxo-l .4- dihydroquinoline-3-carboxylic acid To 250 mg of N, N-dimethylformamide are added 80 mg of 1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-l acid. , 4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-aminoazetidine dihydrochloride and 120 mg of N-methylpyrrolidine and the mixture is stirred at 85 ° C for 45 minutes. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 72 mg of the title compound as a colorless powder. Melting point: 256 to 258 ° C (decomposition) ^ NMR (d6-DMSO) d; 1. 90 (s, 3H), 3.69 (m, ÍH), 4.03 (m, 2H), 4.66 (m, 2H), 6.57 (s broad, 2H), 7.52 (d, J = 11Hz, ÍH), 7.87 (d , J = 14Hz, ÍH), 8.47 (s, ÍH).

[Example 59] Synthesis of 7- [3- (methylamino) azetidin-1-ill -1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6-fluoro-4-oxo-lr4 -dihydroquinoline-3-carboxylic acid To 90 mg of N, N-dimethylformamide are added 25 mg of 1- (6-amino-5-fluoro-3-methylpyridin-2-yl) -8-chloro-6,1-difluoro-4-oxo-l acid. , 4-dihydroquinoline-3-carboxylic acid, 25 mg of 3- (methylamino) azetidine dichloride and 70 mg of N-methylpyrrolidine and the mixture is stirred at 85 ° C for 45 minutes. After adding 0.2 ml of ethanol, the mixture is allowed to cool and the precipitate is washed successively with ethanol and diisopropyl ether to obtain 20 mg of the title compound as a colorless powder. Melting point: 251 to 253 ° C (decomposition) XHRMN (d6-DMS0) d; 1.90 (s, 3H), 2.20 (s, ÍH), 3.44 (m, ÍH), 4.12 (m, 2H), 4.63 (m, 2H), 6.57 (s broad, 2H), 7.52 (d, J = 11Hz , ÍH), 7.86 (d, J = 14Hz, ÍH), 8.47 (s, 1H) [Reference Example 44] Synthesis of 6-t-butylamino-2-chloro-3-cyano-5-fluoropyridine To a solution of 7.6 g of 2,6-dichloro-3-cyano-5-fluoropyridine in 40 ml of acetonitrile is added 8.8 g of t-butylamine and the mixture is stirred overnight at room temperature. The solvent is distilled off from the reaction solution: The residue is separated by adding methylene chloride and water. The organic layer is dried over magnesium sulfate, and the solvent is distilled off to obtain 6 g of the title compound as a light yellow powder. Melting point: 84 to 85 ° C XHRMN (CDC13) d; 1.50 (s, 9H), 5.15 (s broad, ÍH), 7.25 (d, J = 11Hz, ÍH) [Reference Example 45] Synthesis of 2-benzylamino-6-t-butylamino-3-cyano-5-fluoropyridine To 40 ml of a solution of N-methylpyrrolidine of 6 g of 6-t-Butylamino-2-chloro-3-cyano-5-fluoropyridine 6.3 g of benzylamine are added and the mixture is stirred under a nitrogen atmosphere at 160 ° C for 3 hours and allowed to cool. The reaction solution is separated by adding chloroform and water, and the organic layer is dried over magnesium sulfate and the solvent is distilled off. The precipitated crystals are collected from the residue by filtration to obtain 2 g of the title compound as a light yellow powder. Melting point: 138 at 140 ° C 1HRMN (CDC13) d; 1.38 (s, 9H), 4.63 (d, J = 6Hz, 2H), 4.87 (s broad, 1Hz, 5.25 (s broad, ÍH), 7.31 (s, 5H) [Reference Example 46] Synthesis of 2-amino-6-t-butylamino-3-cyano-5-fluoropyridine To 500 mg of 2-benzylamino-6-t-butylamino-3-cyano-5-fluoropyridine are added 3 ml of acetic acid and 0.5 ml of ethanol, and then 10 microspheres of palladium black, and the mixture is stirred under an atmosphere of hydrogen at 60 ° C for 2 days. The crystals are removed with a membrane filter and the solvent of the filtrate is distilled off. Chloroform is added to the residue and the mixture is washed with an aqueous solution of sodium hydrogen carbonate. The organic layer is collected and dried over magnesium sulfate. The solvent is distilled off to obtain 300 mg of the title compound.

[Example 60] Synthesis ds 1- (6-t-butylamino-3-cyano-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-1,4-dihydro-4-oxochionolone-3-ethylcarboxylate A solution of 300 mg of unpurified 2-amino-6-t-butylamino-3-cyano-5-fluoropyridine in 2 ml of ethanol is added dropwise to a solution of 420 mg of 3-methoxy-2- (3. chloro-2,4,6-trifluorobenzoyl) ethyl acrylate in 2 ml of ethanol at room temperature, and the mixture is stirred overnight. The solvent is distilled off from the reaction solution, and 3 ml of N, N-dimethylformamide and 200 mg of potassium carbonate are added to the residue, and the mixture is stirred at room temperature for 90 minutes and at 80 ° C for 2 hours. hours. The reaction solution is extracted by adding water and ethyl acetate, and the organic layer is collected and dried over magnesium sulfate. The solvent is distilled off and the residue is collected by filtration using ethanol and washed with diethyl ether to obtain 280 mg of the title compound as a light yellow powder. Melting point: 245 ° C or higher (decomposition) 1HRMN (CDC13) d; 1.39 (s, 9H), 1.41 (t, J = 7Hz, 3H), 4.41 (c, J = 7HZ, 2H), 5.39 (s broad, ÍH), 7.43 (d, J = 10Hz, ÍH), 8.32 (t, J = 9Hz, ÍH), 8.53 (s, ÍH) [Example 61] Synthesis of 1- (6-amino-3-cyano-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylic acid A 280 mg of 1- (6-t-butylamino-3-cyano-5-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinolone-3-carboxylate Ethyl is added 3 ml of 12N hydrochloric acid and the mixture is heated under reflux for 6 hours and allowed to cool. The solid precipitate is collected by filtration and washed successively with ethanol and diethyl ether to obtain 120 mg of the title compound as a light yellow powder. Melting point: 277 ° C or higher (decomposition) 1HRMN (d6-DMSO) d; 8.00 (s broad, 2H), 8.21 (d, J = 11Hz, ÍH), 8.40 (t, J = 9Hz, ÍH), 9.05 (s, ÍH).

[Example 62] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3-cyano-5-fluoropyridin-2-yl) -8-chloro-6-fluoro-1,4-dihydro-4-oxoquinolone -3-carboxylic acid To a solution in 300 mg of N, N-dimethylformamide of 40 mg of 3-aminoazetidine dihydrochloride and 80 mg of triethylamine are stirred at 90 ° C and 50 mg of 1- (6-amino-3-cyano-5-fluoropyridin-2-yl) -8-chloro- 6,7-difluoro-l, 4-dihydro-4-oxoquinolone-3-carboxylic acid to the solution, and stirred at 90 ° C for 10 minutes. To the reaction solution is added 1 ml of ethanol and the solid precipitate is collected and dried to obtain 36 mg of the title compound as a light yellow powder. Melting point: 290 ° C or higher XHRMN (d6-DMS0) d; 4.09 (m, ÍH), 4.48 (m, 2H), 4.79 (m, 2H), 7.90-8.06 (m, 3H), 8.16 (d, J = 11Hz, ÍH), 8.33 (s broad, 2H), 8.85 (Yes H) [Example 63] Synthesis of 1- [6- (t-butylamino) -3,5-difluoropyridin-2-yl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinolin-3-ethylcarboxylate To 3.4 g of ethyl 2,4-trifluoro-3-methylbenzoylacetate 3.2 g of acetic anhydride and 2.3 g of triethyl orthoformate are added, and the mixture is heated under reflux for 4 hours and the solvent is distilled off. Toluene is added to the residue and the solution is distilled azeotropically. After adding 5 ml of ethanol to the residuea solution of 2.7 g of 2-amino-6- (t-butylamine) -3,5-difluoropyridine in 20 ml of ethanol is added dropwise at 0 ° C and the mixture is stirred at room temperature for 20 minutes. The solvent is distilled off from the reaction solution and the residue is subjected to silica gel column chromatography and from the eluent of ethyl acetate: hexane, 1: 8 4.6 g of 2- (2,4, 5-trifluoro-3-methylbenzoyl) -3- [6- (t-butylamino) -3,5-difluoropyridin-2-yl] ethyl methacrylate as an oil. To the solution of 4.6 g of ethyl 2- (2,4-, 5-trifluoro-3-methylbenzoyl) -3- [6- (t-butylamino) -3,5-difluoropyridin-2-yl) aminoacrylate obtained from this 10 ml of dimethylformamide are added with 1.35 g of potassium carbonate and the mixture is stirred at 100 ° C for 50 minutes. The reaction solution is extracted by adding water and acetic acid, and the organic layer is collected and dried over magnesium sulfate. The solvent is distilled off and the residue is collected by filtration with ethanol and washed with diethyl ether to obtain 2.6 g of the title compound as a light yellow powder. Melting point: 207 to 211 ° C XHRMN (CDC13) d; 1.34-1.48 (m, 12H), 1.82 (d, J = 3Hz, 3H), 4.40 (c, J = 7Hz, 2H), 4.75 (s broad, ÍH), 7.23 (t, J = 9Hz, ÍH), 8.22 (t, J = 10Hz, ÍH), 8.50 (s, ÍH) [Example 64] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -6,7-di inor - -me-1, 4-dihydro-oxo-uinoline-3-carboxylic acid A 2.5 g of 1- [ 6- (t-Butylamino) -3,5-difluoropyridin-2-yl] -6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-ethylcarboxylate - 10 ml of acid are added 12 N hydrochloric acid and the mixture is heated overnight under reflux. The reaction solution is allowed to stand and the solid precipitate is collected by filtration and washed with ethanol and then with diethyl ether to obtain 1.7 g of the title compound as a light yellow powder. Melting point: 274 to 277 ° C XHRMN (d6-DMSO) d; 1.84 (s, 3H), 6.91 (s broad, 2H), 8.03 (t, J = 9Hz, ÍH), 8.25 (t, J = 9Hz, ÍH), 8.93 (s, ÍH).

[Example 65] Synthesis of 7- (3-amino-azetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -6-fluoro-8-methyl-1,4-dihydro-oxoquinoline-3-carboxylic acid To a solution of 70 mg dichloride 3-aminoazetidine, 200 mg of 1,8-diazabicyclo [5.4.0] undecene and 300 mg of pyridine is stirred at 100 ° C and 110 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) - 6, 7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid to the solution and the solution is stirred at 100 ° C for 6 minutes. The solvent is distilled off from the reaction solution and 1 residue of acetic acid and 3 ml of ethanol are added to the residue with heating, and the solution is allowed to settle. The solid precipitate is collected and dried to obtain 13 mg of the title compound as a light yellow powder. Melting point: 280 ° C or higher 1HRMN (d6-DMS0) d; 1.60 (s, 3H), 3.77 (m, 2H), 3.93 (m, ÍH), 4.46 (m, 2H), 6.86 (s broad, 2H), 7.75 (d, J = 13Hz, ÍH), 7.95 (t , J = 9Hz, ÍH), 8.70 (s, ÍH) [Example 66] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -6-fluoro-8-methyl-7- (3-methylaminoazetidin-1-yl) -1,4-dihydro-4-oxoquinolone-3 -carboxylic The title compound (20 mg) is obtained as a light yellow powder in a manner similar to Example 65 except that 180 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -6 acid was used, 7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 110 mg of 3-aminoazetidine dihydrochloride. Melting point: 229 ° C or higher XHRMN (d6-DMSO) d; 1. 63 (s, 3H), 2.21 (s, 3H), 3.87 (m, ÍH), 4.02 (m, ÍH), 4.43 (m, 2H), 6.86 (s broad, 2H), 7.75 (d, J = 14Hz , ÍH), 7.97 (t, J = 10Hz, ÍH), 8.71 (s, ÍH) [Example 67] Synthesis of 7- (3-amino-3-methylazetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -6-fluoro-8-methyl-1,4-dihydro-4-oxoquinolone - 3-carboxylic The title compound (60 mg) is obtained as a light yellow powder in a manner similar to Example 65, except that 180 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -6 acid is used. , 7-difluoro-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylic acid and 110 mg of 3-amino-3-methylazetidine dihydrochloride. Melting point: 235 ° C or higher XHRMN (d6-DMS0) d; 1.37 (s, 3H), 1.62 (s, 3H), 3.87 (mIH), 4.08 (m, 3H), 6.85 (s broad, 2H), 7.74 (d, J = 14Hz, ÍH), 7.96 (t, J = 10Hz, ÍH), 8.70 (s, ÍH) [Example 68] Synthesis of dsl 1- (6-amino-3,5-difluoropyridin-2-yl) -6,8-difluoro-7- (3-methylaminoazetidin-1-yl) -4-oxo-l, 4-hydroquinoline-3-carboxylic acid To 200 mg of N, N-dimethylformamide are added 65 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -6,7,8-trifluoro-4-oxo-1,4-acid. dihydroquinoline-3-carboxylic acid, 45 mg of 3-methylaminoazetidine dihydrochloride and 100 mg of N-methylpyrrolidine together with 3 drops of ethanol and the mixture is stirred at 85 ° C for 30 minutes. After adding 0.2 ml of ethanol, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 52 mg of the title compound as a colorless powder. Melting point: 262 to 268 ° C (decomposition) 1HR N (d6-DMSO) d; 2.19 (s, 3H), 3.52 (m, ÍH), 4.01 (m, 2H), 4.44 (m, 2H), 6.75 (s broad, 2H), 7.77 (d, J = 13Hz, ÍH), 7.99 (t , J = 9Hz, ÍH), 8.74 (s, ÍH) [Example 69] Synthesis of 1- (6-amino-3,5-dif luoropyridin-2-yl) -8-bromo-6-fluoro- "7- ((3-hydroxyzetidin-l-yl) -4 -oxo-l, 4-dihydroquinoline-3-carbohydrate To 270 mg of N, -dimethylformamide are added 110 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-bromo-6,7-difluoro-4 acid -oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyzetidine hydrochloride and 100 mg of N-methylpyrrolidine together with 3 drops of ethanol and the mixture is stirred at 85 ° C for 25 minutes. 0.5 ml of ethanol, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 101 mg of the title compound as a light yellow powder Melting point: 215 to 220 ° C XHRMN (d6-DMSO) d; 4.06 (m, 2H), 4.51 (m, 3H), 5.75 (s broad, ÍH), 6.76 (s broad, 2H), 7.79 (d, J = 13Hz, ÍH), 7.99 (t, J = 9Hz, ÍH), 8.75 (s, ÍH).

[Example 70] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-hydroxyazetidin-1-yl) -4-oxo-1,4-dihydroquinoline-3 -carboxylic To 3.5 g of N, N-dimethylformamide is added 2.00 g of 1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4 acid. -hydroquinoline-3-carboxylic acid, 1.00 g of 3-hydroxyazetidine hydrochloride and 2.00 g of N-methylpyrrolidine together with 0.2 ml of ethanol and the mixture is stirred at 85 ° C for 10 minutes. The solvent and the like are removed by distillation under reduced pressure. After adding 10 ml of ethanol to the residue, the mixture is refluxed for 10 minutes and allowed to cool, and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 2.10 g of the title compound as a light yellow powder. Melting point: 235 to 238 ° C XHRMN (d6-DMSO) d; 4.18 (m, 2H), 4.48 (m, ÍH), 4.72 (m, 2H), 5.74 (d, J = 6Hz, ÍH), 6.76 (broad s, 2H), 7.86 (d, J = 14Hz, ÍH), 7.95 (t, J = 9Hz, ÍH), 8.70 (s, ÍH) [Example 71] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -6,8-difluoro-7- (3-hydroxyzetidin-1-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 280 mg of N, N-dimethylformamide are added 125 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, 60 mg of 3-hydroxyazetidine hydrochloride and 120 mg of N-methylpyrrolidine together with 3 drops of ethanal and the mixture is stirred at 85 ° C for 10 minutes. After adding 0.8 ml of ethanol, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 90 mg of the title compound as a light yellow powder. Melting point: 269 to 272 ° C XHRMN (ds-DMS0) d; 4.06 (m, 2H), 4.51 (m, 3H), 5.75 (s broad, ÍH), 6.76 (s broad, 2H), 7.79 (d, J = 13Hz, ÍH), 7.99 (t, J = 9Hz, ÍH) ), 8.75 (s, ÍH).

[Example 72] Synthesis of 8-bromo-l- 16- (t-butylamino) -5-fluoropyridin-2-ill-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate ethyl To 1 ml of a chloroform solution of ethyl 3-ethoxy-2- (3-bromo-2,, 5-trifluorobenzoyl) acrylate prepared from 0.65 g of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate by normal process, 0.3 g of 2-amino-6- (t-butylamino) -5-fluoropyridine are added. The solution is concentrated under reduced pressure to obtain a yellowish orange solid residue. To this residue is added 0.4 g of anhydrous potassium carbonate and 2 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 25 minutes and allowed to cool. The solution is separated by adding 25 ml of chloroform and 400 ml of distilled water, and the chloroform layer is washed with 400 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After adding 2 ml of ethanol, the solution is allowed to settle. The precipitate is dispersed in ethanol and collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0.53 mg of the title compound as a light yellow powder. Melting point: 192 to 195 ° C XHRMN (CDC13) d; 1.37 (s, 9H), 1.40 (t, J = 7Hz, 3H), 4.40"(c, J = 7Hz, 2H), 4.83 (s broad, ÍH), 6.50 (dd, J = 3Hz, 8Hz, ÍH) , 7. 24 (dd, J = 8Hz, 10Hz, ÍH), 8.35 (t, J = 9Hz, ÍH), 8.65 (s, ÍH) [Example 73] Synthesis of 1- (6-amino-5-fluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 4 ml of a mixed solution (1: 1) of 4N hydrochloric acid and acetic acid is added 480 mg of 8-bromo-1- [6- (t-butylamino) -5-fluoropyridin-2-yl] -6, Ethyl 7-difluoro-4-yloxy-l, 4-dihydroquinoline-3-carboxylate and the mixture is heated under reflux with stirring for 2 hours. After adding 4 ml of distilled water, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 345 mg of the title compound as a colorless powder. Melting point: 245 to 251 ° C (decomposition) XHRMN (d6-DMSO) d; '6.84-6.92 (m, 3H), 7.64 (dd, J = 8Hz, 11Hz, ÍH), 8.40 (t, J = 9Hz, ÍH), 8.79 (s, ÍH) [Example 74] Synthesis of 7- (3-aminoazetidin-l-yl) -1- (6-amino-5-fluoropyridin-2-yl) -8-bromo-6-fluoro-4-oxo-l, 4-dihydroquinoline-3 -carboxylic To 250 mg of N, N-dimethylformamide are added 80 mg of 1- (6-amino-5-fluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline -3-carboxylic acid, 55 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 10 minutes. After adding 0.3 ml of ethanol, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 68 mg of the title compound as a colorless powder. Melting point: 245 at 250 ° C (decomposition) XHRMN (d6-DMS0) d; 3. 72 (m, ÍH), 4.02 (m, 2H), 4.67 (m, 2H), 6.73 (dd, J = 2Hz, 8Hz, ÍH), 6.82 (s broad, 2H), 7.59 (dd, J = 8Hz, 10Hz, ÍH), 7.87 (d, J = 14Hz, ÍH), 8.69 (s, ÍH) [Example 75] Synthesis of 1- (6-amino-5-fluoropyridin-2-yl) -8-bromo-6-fluoro-7- (3-methylaminoazetidin-1-yl) -4 -oxo-l, 4-dihydroquinoline-3 -carboxylic To 250 mg of N, N-dimethylformamide are added 80 mg of 1- (6-amino-5-fluoropyridin-2-yl) -8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline. -3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride and 200 mg of N-methylpyrrolidine and the mixture is stirred at 85 ° C for 10 minutes. After adding 0.5 ml of ethanol, the solution is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 66 mg of the title compound as a colorless powder. Melting point: 210 to 218 ° C (decomposition) XHRMN (d6-DMS0) d; 2.22 (s, 3H), 3.48 (m, ÍH), 4.12 (m, 2H), 4.61 (m, 2H), 6.74 (d, J = 10Hz, 2H), 6.81 (s broad, 2H), 7.59 (t , J = 10Hz, ÍH), 7.87 (d, J = 14Hz, ÍH), 8.68 (s, ÍH) [Reference Example 47] Synthesis of 2-amino-5-chloro-3,6-difluoropyridine To 25 ml of methanol are added 2.7 g of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 1.15 g of triethylamine together with 0.145 g of 10% palladium in charcoal, and the mixture is hydrogenated at room temperature for 1.5 hours. The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. To the residue, 50 ml of chloroform are added and the mixture is washed with 30 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting uncolous flake crystals are dispersed in a mixed solution of diisopropyl ether and n-hexane (1: 2), and collected by filtration to obtain 1.62 g of the title compound.

[Reference Example 48] Synthesis of 2-amino-5-chloro-3-fluoro-6- (p-methoxybenzylamino) -pyridine To 2 ml of N-methylpyrrolidone are added 510 mg of 2-amino-5-chloro-3,6-difluoropyridine and 910 mg of p-methoxybenzylamine, and the mixture is stirred at 150 ° C for one day, and the cool. After adding a mixed solution of 60 ml of benzene and n-. hexane (1: 1 v / v), the solution is washed twice with 400 ml of distilled water. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 960 mg of the title compound as a brown untreated oil. XHRMN (CDC13) d; 3.80 (s, 3H), 4.35 (broad s, 2H), 4.50 (m, 2H), 4.86 (s broad, ÍH), 6.87 (d, J = 8Hz, 2H), 7.15 (d, J = 10Hz, ), 7.27 (d, J = 8Hz, 2H).

[Example 76] Synthesis of 8-chloro-l-r5-chloro-3-fluoro-6- (p-methoxybenzylamino) -pyridin-2-ill-6,7-difluoro-4-oxo-l.4-dihydroquinoline-3-carboxylic acid ethyl ester To 2 ml of a chloroform solution of 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) ethyl acrylate prepared from 0.56 g of 3-chloro-2,4,5-trifluorobenzoylacetate from ethyl per normal process 0.66 g of 2-amino-5-chloro-3-fluoro-6- (p-methoxybenzylamino) pyridine are added. The solution is concentrated under reduced pressure. To the residue is added 0.5 g of anhydrous potassium carbonate and 1.5 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 20 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solution is allowed to settle after adding 4 ml of ethanol. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 0.56 g of the title compound as a light yellow powder. Melting point: 168 to 171 ° C XHRMN (CDC13) d; 1.40 (t, J = 7Hz, 3H), 3.80 (s, 3H), 4.40 (d, J = 7Hz, 2H), 4.42 (c, J = 7Hz, 2H), 5.46 (s broad, ÍH), 6.83 (d, J = 9hz, 2H), 7.18 (d, J = 9Hz, 2H), 7.53 (d, J = 8Hz, ÍH), 8.29 (t, J = 9Hz, ÍH), 8.48 (s, ÍH) [Example 77] Synthesis of 1- (6-amino-5-chloro-3-fluoro-pyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-lf-4-dihydroquinoline-3-ethylcarboxylate To 530 mg of 8-chloro-l- [5-chloro-3-fluoro-6- (p-methoxybenzoylamino) pyridin-2-yl] -6,7-difluoro-4-oxo-l, 4-dihydroquinolin-3 ethyl carboxylate 2 ml of trifluoroacetate are added and the solution is allowed to stand for 30 minutes at room temperature. The solution is concentrated under reduced pressure and 4 ml of ethanol are added to the residue, and the solution is concentrated under reduced pressure. The precipitate is dispersed in ethanol, collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 462 mg of the title compound as a light yellow powder. -Fusion point: 186 to 189 ° C XHRMN (CDC13) d; 1.40 (t, J = 7Hz, 3H), 4.40 (c, J = 7Hz, 2H), 5.02 (broad s, 2H), 7.57 (d, J = 8Hz, 2H), 8.30 (t, J = 9Hz, ÍH) ), 8.48 (s, ÍH) [Example 78] Synthesis of 1- (6-amino-5-chloro-3-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 2 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1: 1) is added 430 mg of 1- (6-amino-5-chloro-3-fluoro-pyridin-2-yl) -8-chloro-6, 7-difluoro-4-oxo-l, 4-dihydroquinoline-3-ethyl carboxylate, and the mixture is heated under reflux for 6 hours with stirring and allowed to cool. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 375 mg of the title compound as a colorless powder. Melting point: 280 ° C or higher XHRMN (d6-DMS0) d; 6. 86 (s broad, 2H), 8.15 (d, J = 9Hz, ÍH), 8.38 (t, J = 9Hz, ÍH), 8.95 (s, ÍH) [Example 79] Synthesis of 7- (3-amino-azetidin-1-yl) -1- (6-amino-5-chloro-3-fluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l .4 -dihydroquinoline-3-carboxylic acid To 280 mg of N, N-dimethylformamide is added 90 mg of 1- (6-amino-5-chloro-3-fluoro-iridin-2-yl) -8-chloro-6,7-difluard-4-oxo- 1, 4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride and 160 mg of N-methylpyrrolidine, and the mixture is stirred at 85 ° C for 20 minutes. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 50 mg of the title compound as a colorless powder. Melting point: 240 to 245 ° C (decomposition XHRMN (d6-DMSO) d; 3.71 (m, ÍH), 4.06 (m, 2H), 4.66 (m, 2H), 6.79 (broad s, 2H), 7.85 ( d, J = 14Hz, 1H), 8.08 (d, J = 9Hz, ÍH), 8.70 (s, ÍH) [Reference Example 49] Synthesis of 2.3.5-trifluoro-6-isopropylaminopyridine To 20 ml of acetonitrile, 6.0 g of 2,3,5,6-tetrafluoropyridine and 6.0 g of isopropylamine are added and the mixture is stirred at room temperature for 2 hours and concentrated under reduced pressure. After adding 40 ml of chloroform, the solution is washed with 50 ml of a 3% aqueous solution of potassium carbonate. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.9 g of the title compound as a colorless oil.

[Reference Example 50] Synthesis of 3.5 - d i f 1 uor o - 2 - i s op r op i 1 am no - 6 - (p -methoxybenzylamino) pyridine To 4.1 g of N-methylpyrrolidone is added the complete amount of 2,3,5-trifluoro-6-isopropylaminopyridine as described above, together with 3.1 g of p-methoxybenzylamine and the mixture is stirred at 150 ° C for 15 hours and it is allowed to cool. After adding 50 ml of the mixed solution of benzene and n-hexane (1: 1, v / v), the solution is washed twice with 400 ml of distilled water. Dry the organic layer over anhydrous magnesium sulfate and concentrate under reduced pressure to obtain 3.9 g of the title compound as an untreated brown oil.

[Reference Example 51] Synthesis of 2-amino-3,5-difluoro-6-isopropylaminopyridine To 1.9 g of 3,5-difluoro-2-isopropylamino-6- (p-methoxybenzylamino) pyridine, add 4 ml of trifluoroacetate and allow the mixture to stand at room temperature for 15 minutes. The solution is concentrated under reduced pressure and 25 ml of chloroform are added to the residue, and the solution is washed with 25 ml of a 5% aqueous solution in sodium carbonate. The cloxoform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue is subjected to column chromatography (silica gel, 40 g, eluent: chloroform) to obtain 0.6 g of the title compound as an oil. coffee.

[Example 80] Synthesis of ethyl 8-chloro-6,7-difluoro-1- (3,5-difluoro-6-isopropylamino-pyridin-2-yl) -4-oxo-l. 4-dihydroquinoline-3-carboxylate To 2.5 ml of a solution of Chloroform of ethyl 3-ethoxy-2- (3-chloro-2,4,5,5-trifluorobenzoyl) acrylate prepared from 0.70 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by the normal process are added 600 mg of 2-amino-3,5-difluoro-6-isopropylaminopyridine. The solution is concentrated under reduced pressure. To the residue is added 600 mg of anhydrous potassium carbonate and 2 ml of N, N-dimethylformamide, and the mixture is stirred at 90 ° C for 20 minutes and allowed to cool. The solution is separated by adding 30 ml of chloroform and 400 ml of distilled water, and the chloroform layer is washed twice with 400 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and allowed to rest. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 620 mg of the title compound as a light yellow powder. Melting point: 206 to 209 ° C 1HRMN (CDC13) d; 1.20 (d, J = 7Hz, 3H), 1.24 (d, J = 7Hz, 3H), 1.40 (t, J = 7Hz, 3H), 4.11 (m, 1H), 4.40 (c, J = 7Hz, 2H) , 4.60 (broad s, 1H9, 7.22 (dd, J = 8Hz, 9Hz, ÍH), 8.32 (dd, J = 8Hz, 10Hz, ÍH), 8.49 (s, ÍH).

[Example 81] Synthesis d = I 8-chloro-6,7-difluoro-1- (3,5-difluoro-6-isopi o 1 aminop ir idin -2 -il) -4 -oxo-l .4-dihi acid Lino-3-carboxylic droquinol ? 3 ml of the mixed solution of 4N hydrochloric acid and acetic acid (1: 1, v / v) are added 300 mg of 8-chloro-6,7-dif luoro- 1- (3, 5-dif luoro-6) ethyl isopropylaminopyridin-2-yl) -4-oxo-l, 4-dihydroquinoline-3-carboxylate, and the mixture is heated under reflux for 19 hours with stirring. The precipitate is collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 625 mg of the title compound as a yellow powder. Melting point: 226 to 230 ° C XHRMN (d6-DMSO) d; 1.10 (d, J = 7Hz, H), 1.16 (d, J = 7Hz, 3H), 3.94 (m, ÍH), 7.02 (broad d, J = 8Hz, 2H), 7.97 (t, J = 9Hz, ÍH), 8.39 (t, J = 9Hz, ÍH), 8.92 (s, ÍH) [Example 82] Synthesis of 7- (3-aminoazetidin-1-yl) -8-chloro-6-f luoro-1- (3,5-difluoro-6-isopropylamino-iridin-2-yl) -4 -oxo-4-dihydroquinoline- 3-carboxylic acid To 160 mg of N, N-dimethylformamide are added 55 mg of 8-chloro-6,7-difluoro-1- (3,5-difluoro-6-isopropylamino-pyridin) -2-yl) -4 acid -oxo-l, 4-dihydroquinoline-3-carboxylic acid, 35 mg of 3-aminoazetidine dihydrochloride and 120 mg of N-methylpyrrolidine, and the mixture is stirred at 80 ° C for 30 minutes. After adding 0.5 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 51 mg of the title compound as a colorless powder. Melting point: 220 to 223 ° C XHRMN (d6-DMSO) d; 1.13 (, J = 7Hz, 3H), 1.16 (d, J = 7Hz, 3H), 3.70 (m, ÍH) [Example 84] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -5.6.7.8-tetrafluoro-4-oxo-l. -dihydroquinoline-3-ethyl carboxylate A 1080 mg of 1- [3,5-difluoro-6- (p-methoxybenzylamino) -pyridin-2-yl] -5,6,7,8-tetrafluoro-4-oxo-l, 4-dihydroquinoline-3 - ethyl carboxylate 4 ml of trifluoroacetic acid are added, and the mixture is allowed to stand at room temperature for 30 minutes. The solution is concentrated under reduced pressure and 4 ml of ethanol are added to the residue, and the solution is again concentrated under reduced pressure. The precipitate is dispersed in ethanol, collected by filtration and washed with ethanol to obtain 960 mg of the title compound as a gray powder. Melting point: 223 to 230 ° C XHRMN (CDC13) d; 1.39 (t, J = 7Hz, 3H), 4.38 (d, J = 7Hz, 2H), 4.83 (broad s, 2H), 6.83 (d, J = 9Hz, 2H), 7.35 (t, J = 9Hz, ÍH), 8.32 (s, ÍH) [Example 85] Synthesis of 1- (6-amino-3,5-difluoropyridin-2-yl) -5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 2 ml of the mixed solution (1: 1) of 4N hydrochloric acid and acetic acid is added 320 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -5, 6, 7, 8- ethyl tetraf luoro-4 -oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture is heated under reflux for 3 hours with stirring, and allowed to cool. The precipitate is collected by filtration and washed with ethanol to obtain 280 mg of the title compound as a colorless powder. Melting point: 236 to 242 ° C XHRMN (d6-DMSO) d; 6. 82 (broad s, 2H), 8.03 (t, J = 9Hz, ÍH), 8.92 (s, ÍH) [Example 86] Synthesis of 7- (3-amino-azetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -5,6,8-trifluoro-4-oxo-1,4-dihydroquinoline-3 -carboxylic To 300 mg of N, N-dimethylformamide are added 100 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -5,6,7,8-tetrafluoro-4-oxo-1,4 acid. -dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 30 minutes. After adding 0.3 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 50 mg of the title compound as a light yellow powder. Melting point: 264 to 271 ° C (decomposition) XHRMN (d6-DMSO) d; 3.77 (m, ÍH), 3.96 (m, 2H), 4.46 (m, 2H), 6.75 (broad s, 2H), 7.97 (t, J = 9Hz, ÍH), 8.66 (s, ÍH) [Example 87] Synthesis of 5-benzylamino-l- 3,6-difluoro-6- (p-methoxybenzylamino) pyridin-2-yl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3 ethyl carboxylate To 8 ml of toluene is added 1.58 g of 1- [3,5-difluoro-6- (p-methoxybenzylamino) pyridin-2-yl] -5,6,7,8-tetrafluoro-4-oxo-1, 4 Ethyl dihydroquinoline-3-carboxylate together with 0.68 g of benzylamine, and the mixture is stirred at 110 ° C for 20 minutes and allowed to cool. After adding 15 ml of toluene and 15 ml of n-hexane, the mixture is washed twice with 300 ml of distilled water. The organic layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue is added 4 ml of ethanol and the solution is allowed to settle, and the precipitate is collected by filtration and washed with ethanol to obtain 1.20 g of the title compound as a yellow powder. Melting point: 146 to 148 ° C XHRMN (CDC13) d; 1.37 (t, J = 7Hz, 3H), 3.79 (s, 3H), 4.37 (c, J = 7Hz, 2H), 4.47 (s broad, ÍH), 4.68 (m, 2H), 5.01 (s broad, ÍH) ), 6.84 (d, J = 9Hz, 2H), 7.16-7.40 (m, 10H), 8.22 (Yes H) [Example 88] Synthesis of ethyl 1- (6-amino-3,5-difluoropyridin-2-yl) -5-benzylamino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate To 600 mg of 5-benzylamino-l- [3, 5-difluoro-6- (p-methoxybenzylamino) pyridin-2-yl] -6,7,8-trifluoro-4-oxo-l, -dihydroquinoline-3 - ethyl carboxylate 2 ml of trifluoroacetic acid are added and the mixture is allowed to stand at room temperature for 20 minutes. The solution is concentrated under reduced pressure - and 3 ml of ethanol is added to the residue, and the solution is again concentrated under reduced pressure. The precipitate is dispersed in ethanol, collected by filtration and washed with ethanol to obtain 530 mg of the title compound as a yellow powder. Melting point: 176 to 180 ° C XHRMN (CDC13) d; 1.36 (t, J = 7Hz, 3H), 4.36 (c, J = 7Hz, 2H), 4.47 (s broad, ÍH), 4.68 (d, J = 4Hz, 2H), 4.74 (s broad, ÍH), 6.84 (d, J = 9Hz, 2H), 7.24-7.40 (m, 6H), 8.21 (s, 1H) [Example 89] Synthesis of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -6,7, 8-trifluoro-4-oxo-1,4-dihydroquinoline-3-ethylcarboxylate To 5 ml of acetic acid are added 260 mg of 1- (6-amino-3,5-difluoropyridin-2-yl) -5-benzylamino-6,7,8-trifluoro-4-oxo-l, 4-dihydroquinoline-3-ethylcarboxylate together with 10% palladium on charcoal, and the mixture is hydrogenated at room temperature for 4 hours. The catalyst is removed by filtration, and the solvent and the like are distilled off under reduced pressure. The process of adding 10 ml of ethanol to the residue is repeated twice and concentrated under reduced pressure. The precipitate is concentrated in ethanol, collected by filtration, and washed successively with ethanol and diisopropyl ether to obtain 160 mg of the title compound as a light yellow powder. Melting point: 225 to 230 ° C XHRMN (CDC13) 5; 1.38 (t, J = 7Hz, 3H), 4.38 (c, J = 7Hz, 2H), 4.73 (s broad, 2H), 4.68 (d, J = 4Hz, 2H), 6.8 (s broad, 2H), 6.84 (d, J = 9Hz, 2H), 7.32 (t, J = 9Hz, ÍH), 8.25 (s.

[Example 90] Synthesis of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 1.5 ml of the mixed solution (1: 1) 4N hydrochloric acid and acetic acid are added 145 mg of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -6,7,8-trifluoro-4 -oxo ethyl l, 4-dihydroquinoline-3-carboxylate, and the mixture is heated under reflux for 17 hours with stirring and allowed to cool. The precipitate is collected by filtration and washed with ethanol to obtain 129 mg of the title compound as a yellow powder. XHRMN (d6-DMSO) d; 6.78 (s broad, 2H), 7.75 (s broad, ÍH), 7.99 (t, J = 9Hz, ÍH), 8.77 (s, ÍH).

[Example 91] Synthesis of 5-amino-7- (3-amino-azetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -6,8-difluoro-4-oxo-1,4-hydroquinoline-3-carboxylic acid To 210 mg of N, N-dimethylformamide is added 50 mg of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -6,7,8-trifluoxo-4-oxo- acid, 4-dihydroquinoline-3-carboxylic acid, 40 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 1 hour, and concentrated under reduced pressure. The procedure of adding 2 ml of diisopropyl ether to the residue twice, stirring and decanting are repeated twice. 2 ml of ethanol and 40 mg of N-methylpyrrolidine are added to the residue, and the mixture is allowed to stand overnight and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 26 mg of the title compound. like a light yellow powder. Melting point: 205 to 210 ° C (decomposition) XHRMN (ds-DMSO) d; 3.72 (m, ÍH), 3.88 (m, 2H), 4.37 (m, 2H), 6.71 (s broad, 2H), 7.23 (broad s, 2H), 7.94 (t, J = 9Hz, ÍH), 8.50 ( Yes H) [Example 92] Synthesis of 1- (6-t-butylamino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-5-nitro-4-oxo-l, 4-dihydroquinolin-3-ethylcarboxylate To 10 ml of a chloroform solution of 3-ethoxy-2- (3-chloro-2", 4, 5-trifluoro-6-nitrobenzoyl) ethyl acrylate prepared from 3.25 g of ethyl 3-chloro-2,4,5-trifluoro-6-nitrobenzoylacetate with a normal process, 2.14 g of 2-amino- 3,5-difluoro-6-t-butylaminopyridine. The solution is concentrated under reduced pressure and to the residue 2.7 g of anhydrous potassium carbonate and 10 ml of N, N-dimethylformamide are added, and the mixture is stirred at 90 ° C for 5 minutes and allowed to cool. The solution is separated by adding 100 ml of chloroform and 500 ml of a solution. water at 2% citric acid, and the chloroform layer is washed twice with 500 ml of a 2% aqueous solution of citric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate is dispersed in ethanol, collected by filtration, washed successively with ethanol and diisopropyl ether to obtain 3.13 g of the title compound as a light yellow powder. Melting point: 215 to 217 ° C XHRMN (CDC13) d; 1.37 (t, J = 7Hz, 3H), 1.39 (s, 9H), 4.39 (c, J = 7Hz, 2H), 4.77 (s broad, ÍH), 7.24 (t, J = 8Hz, ÍH), 8.35 ( t, J = 9Hz, ÍH), 8.52 (s, ÍH) [Example 93] Synthesis of 5-amino-l- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-l, 4-dihydroquinoline-3-carboxylic acid To 10 ml of formic acid are added 960 mg of 1- (6-t-butylamino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-5-nitro-oxo-1, 4-ethyl-dihydroquinoline-3-carboxylate together with 1.0 g of iron powder and the mixture is stirred at 80 to 90 ° C for 5 hours and 40 minutes. The insoluble content is filtered off through celite, and the contents are separated by celite and the celite is washed with formic acid and chloroform. The filtrate and the washings are concentrated under reduced pressure. To the residue is added 6 ml of a mixed solution of 4N hydrochloric acid and acetic acid (1: 1) and the mixture is heated under reflux for 2 hours with stirring and allowed to cool. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 625 mg of the title compound as a yellow powder. Melting point: 280 ° C or higher 1HRMN (d6-DMSO) d; 6.77 (s broad, 2H), 7.94 (y.J = 9Hz, ÍH), 8.20 (s broad, 2H), 8.70 (s, 1H).

[Example 94] Synthesis of 5-amino-7- (3-aminoazetidin-1-yl) -1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-4-oxo-l acid , 4-dihydroquinoline-3-carboxylic acid To 550 mg of pyridine there are added 185 mg of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4 acid. -dihydroquinoline-3-carboxylic acid, 110 mg of 3-aminoazetidine dihydrochloride and 200 mg of N-methylpyrrolidine, and the mixture is stirred at 100 ° C for 30 minutes and concentrated under reduced pressure. After adding 2 ml of ethanol, the mixture is stirred and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 48 mg of the title compound as a yellow powder. XHRMN (dg-DMSO) d; 3.83 (m, ÍH), 4.14 (m, 2H), 4.61 (m, 2H), 6.71 (s broad, 2H), 7.52 (s broad, 2H), 7.89 (t, J = 9Hz, ÍH), 8.51 (m, Yes H) [Example 95] Synthesis of 6,7-difluoro-1- (3,5-difluoro-6-p-methoxybenzylamino-pyridin-2-yl) -8-methyl-5-nitro-1,4-dihydro-oxoquinol-3-carboxylate from ethyl To 5.0 g of ethyl 3,4, 6-trifluoro-5-methyl-2-nitrobenzoylacetate, 11.5 g of acetic anhydride and 4.7 g of ethyl orthoformate are added, and the mixture is heated under reflux for 1.5 hours. The reaction solution is allowed to cool and the reagent and the like are removed by distillation, and toluene is added to the residue for azeotropic distillation. The residue is added to 10 ml of ethanol and a solution of 5.0 g of 2-amino-3,5-difluoro-6- (p-methoxybenzylamino) pyridine in 15 ml of ethanol is added dropwise in an ice bath and The mixture is stirred at room temperature for 10 minutes. The solvent is distilled off from the reaction solution and the residue is subjected to silica gel column chromatography to obtain 7.1 g of an oil of the fractions eluted by ethyl acetate: hexane, 1.10. To 7.0 g of this oil were added 10 ml of N, N-dimethylformamide and 2.0 g of potassium carbonate, and the mixture was stirred at 70 ° C for 30 minutes. To the reaction solution is added ethyl acetate and water, and the organic layer is separated and dried over magnesium sulfate. The solvent is distilled off and ethanol is added to the residue to disperse the solids content for collection by filtration and thereby obtain 1.5 g of the title compound as a light yellow powder. Melting point: 225 to 227 ° C '-HRMN (CDC13) d; 1.37 (t, J = 7Hz, 3H), 1.68 (d, J = 3Hz, 3H), 3.81 (s, 3H), 4.39 (c, J = 7Hz, 2H), 4.45 (s, 2H), 5.29 (s) broad, ÍH), 6.83 (d, J = 8Hz, 2H), 7.17 (d, J = 8Hz, 2H), 7.31 (t, J = 9Hz, ÍH), 8.45 (s, ÍH) [Example 96] Synthesis _d = _ 5 -amino -6, 7-difl uoro -1- (3,5-difluoro-6-p-methoxybenzylaminopyridin-2-yl) -8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate of ethyl To 10 ml of a solution in acetic acid of 1.7 g of 6, 7-dif luoro-1- (4,6-difluoro- - methoxybenzylaminopyridin-2-yl) -8-methyl-5-nitro-1,4-dihydro-4-oxoquinolin-3-ethylcarboxylate 1.4 g of iron powder are added, and the mixture is heated and stirred at 90 ° C for 4 hours and 40 minutes. The catalyst in the reaction solution is removed by filtration, and the solvent is distilled off in the filtrate. The residue is subjected to column chromatography on silica gel. The fraction eluted by chloroform: methanol, 10: 1 is concentrated, and ethanol is added to the residue. The powder precipitate is collected by filtration to obtain 1.3 g of the title compound as a light brown powder. Melting point: 150 to 153 ° C HlRMN (d6-DMSO) d; 1.24 (t, J = 7Hz, 3H), 1.30 (s, 3H), 3.71 (s, 3H), 4.20 (c, J = 7Hz, 2H), 4.33 (dd, J = 5Hz, 12Hz, 2H), 6.76 (d, J = 8Hz, 2H), 7.14 (d, J = 8Hz, 2H), 7.85 (s broad, ÍH), 7.93 (t, J = 10Hz, ÍH), 8.27 (s, ÍH) [Example 97] Synthesis of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid To 0.99 g of 5-amino-6,7-difluoro-1- (3,5-difluoro-6-p-methoxy-benzylaminopyridin-2-yl) -8-methyl-1,4-dihydro-4-oxoquinolin- 3 - ethyl carboxylate 10 ml of 12N hydrochloric acid are added and the mixture is heated under reflux for 10 hours. The reaction solution is allowed to cool, and the solid content is collected by filtration. The solid content is washed with ethanol and then with diethyl ether to obtain 880 mg of the title compound as a yellow powder. Melting point: 250 ° C or higher (decomposition) XHRMN (d6-DMSO) d; 1.60 (s, 3H), 6.80 (s broad, 2H), 7.96 (t, J = 9Hz, ÍH), 8.69 (s, ÍH) [Reference Example 52] Synthesis of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine To 20 ml of acetonitrile is added 4.9 g of 4-bromo-3-chloro-2,5,6-trifluoropyridine and 4 ml of a 25% aqueous solution of ammonia, and the mixture is stirred at 55 ° C for 2 hours. . The solvent and the like are removed by distillation under reduced pressure. 50 ml of chloroform are added to the residue and the solution is washed with 50 ml of distilled water. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure.

The residue is dispersed in a mixed solution of diisopropyl ether and n-hexane, and collected by filtration to obtain 3.8 g of the title compound as light yellow needle crystals.

[Reference Example 53] Synthesis d = 2-amino-4-bromo-5-chloro-3-fluoro-6 - (1,1 -3,3-tetra-methylbutylamino) pyridine.

To 6 ml of N-methylpyrrolidone, 2-4 g of 2-amino-4-bromo-5-chloro-3,6-difluoropyridine and 3.5 g of 1,1,3,3-tetramethylbutylamine are added and the mixture is stirred at room temperature. 140 ° C for 82 hours and allowed to cool. 50 ml of the mixed solution of benzene and n-hexane (1: 1, v / v) are added, and the solution is washed twice with 400 ml of distilled water. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The brown oily residue is subjected to column chromatography (silica gel, 30 g, eluent: chloroform: n-hexane, 1: 1) to obtain 1.6 g of the title compound as an insoluble oily residue.

[Reference Example 54] Synthesis of 2-amino-3-fluoro-6- (1.1.3, 3-tetramethyl-butylamino) -pyridine To 10 ml of methanol is added 1.6 g of 2-amino-4-bromo-5-chloro-3-fluoro-6- (1,1,3,3-tetramethylbutylamino) pyridine together with 0.47 g of triethylamine and 0.09 g of 10% palladium on charcoal, and the mixture is hydrogenated at room temperature for 39 hours.

The catalyst is removed by filtration and the solvent and the like are distilled off under reduced pressure. To the residue, 50 ml of chloroform are added and the mixture is washed with 50 ml of distilled water. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is subjected to chromatography (silica gel, 25 g, eluent: chloroform) to obtain 0.75 g of 2-amino-3-fluoro-6- (1,1,3,3-tetramethylbutylamino) pyridine as a light brown oil. , and 0.2 g of 2-amino-4-bromo-3-fluoro-6- (1,1,3, 3-tetramethylbutylamino) -pyridine as a brown oil.

[Example 98] Synthesis of 1- [3-fluoro-6- (1,1,3,3-tetramethylbutylamino) pyridin-2-ill-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate of ethyl To 3 ml of a chloroform solution of ethyl 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) acrylate prepared from 0.84 g of 3-chloro-2,4,5-trifluorobenzoylacetate ethyl per normal process 0.75 g of 2-amino-3-fluoro-6- (1,1,3,3-tetramethylbutylamino) pyridine are added. The solution is concentrated under reduced pressure and to the residue 0.65 g of anhydrous potassium carbonate and 1.5 ml of N, N-dimethylformamide are added, and the mixture is stirred at 90 ° C for 1 hour and allowed to cool. The solution is separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer is washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 0.45 g of the title compound as a light yellow powder. Melting point: 178-180 ° C XHRMN (CDC13) d; 0.96 (s, 9H), 1.41 (m, 9H), 1.77 (dd, J = 15Hz, 22Hz, 2H), 4.42 (c, J = 7Hz, 2H), 4.53 (s broad, ÍH), 6.44 (dd, J = 3Hz, ÍH), 7.30 (t, J = 9Hz, ÍH), 8.30 (t, J = 9Hz, ÍH), 8.56 (s, ÍH) [Example 99] Synthesis of 1- (6-amino-3-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid To 1.2 ml of the mixed solution of hydrochloric acid 4N and acetate (1: 1) are added 235 mg of 1- [3-fluoro-6- (1, 1,3,3 -te-ramethylbutylamino) pyridin-2-yl] -8-chloro-6,7-difluoro Ethyl 4-oxo-l, 4-dihydroquinoline-3-carboxylate and the mixture is heated under reflux for 6 hours with stirring and allowed to cool. The precipitate is collected by filtration and washed with ethanol to obtain 145 mg of the title compound as a gray powder. Melting point: 228 to 230 ° C NMR (ds-DMSO) d; 6.70 (dd, J = 3Hz, 9Hz, 1H9, 7.66 (t, J = 9Hz, ÍH), 8. 38 (t, J = 9Hz, ÍH), 8.87 (s, ÍH) [Example 100] Synthesis of 7- (3-aminoazetidin-1-yl) -1- (6-amino-3-fluoropyridin-2-yl) -8-chloro-β-fluoro-4-oxo-1,4-dihydroquinoline-3 acid -carboxylic To 190 mg of N, N-dimethylformamide are added 57 mg of 1- (6-amino-3-fluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline. 3-carboxylic acid, 37 mg of 3-aminoazetidine dihydrochloride and 100 mg of N-methylpyrrolidine, and the mixture is stirred at 90 ° C for 30 minutes. After adding 0.2 ml of ethanol, the mixture is allowed to cool and the precipitate is collected by filtration and washed successively with ethanol and diisopropyl ether to obtain 40 mg of the title compound as a colorless powder. Melting point: 250 to 255 ° C (decomposition) XHRMN (d6-DMSO) d; 3. 71 (m, ÍH), 4.04 (m, 2H), 4.67 (m, 2H), 6.44 (broad s, 2H), 6.62 (dd, J = 3Hz, 9Hz, ÍH), 7.61 (d, J = 9Hz, ÍH), 7.85 (t, J = 14Hz, ÍH), 8.63 (s, ÍH).

[Example 101] Synthesis of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-methylaminoazetidin-1-yl) -4 -oxo-l acid. 4-dihydroquinoline-3-carboxylic acid To 300 mg of pyridine is added 120 mg of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1, 4 acid. -dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine diacetate and 250 mg of N-methylpyrrolidine, and the mixture is stirred at 100 ° C for 10 minutes. After adding 5 ml of diethyl ether, the mixture is stirred and allowed to stand for 1 hour, and decanted. 2 ml of ethanol are added and the mixture is stirred. The precipitate is collected by filtration and washed successively with ethanol and diethyl ether to obtain 72 mg of the title compound as a yellow powder. Melting point: 204 to 213 ° C XHRMN (d6-DMS0) d; 2.02 (s, 3H), 4.05 (m, 2H), 4.57 (m, 2H), 6.70 (broad s, 2H), 7.48 (s broad, ÍH), 7.89 (t, J = 10Hz, ÍH), 8.49 (s) s, ÍH) [Example 102] Synthesis of 5-amino-l- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6-fluoro-7- (3-hydroxy-aminoazet idin-1-yl) -4-oxo-1,4- dihydroquinoline-3-carboxylic acid To 300 mg of pyridine are added 120 mg of 5-amino-1- (6-amino-3,5-difluoropyridin-2-yl) -8-chloro-6,7-difluoro-4-oxo-1,4 acid. -dihydroquinoline-3-carboxylic acid, 80 mg of 3-hydroxyaminoazetidine hydrochloride and 250 mg of N-methylpyrrolidine, and the mixture is stirred at 100 ° C for 3 minutes. After adding 5 ml of diethyl ether, the mixture is allowed to stand for 1 hour, and decanted. 2 ml of ethanol are added and the mixture is stirred. The precipitate is collected by filtration and washed successively with ethanol and diethyl ether to obtain 64 mg of the title compound as a yellow powder. Melting point: 267 to 290 ° C (decomposition) XHRMN (d6-DMS0) d; 4.09 (m, 2H), 4.45 (m, ÍH), 4.63 (m, 2H), 5.69 (d, J = 6Hz, ÍH), 6.71 (s broad, 2H), 7.48 (s broad, ÍH), 7. 89 (t, J = 10Hz, 1H9, 8.51 (s, ÍH) (1) Antibacterial action The compounds of examples 9, 10, 12 and 39 as described above, were evaluated for their minimum growth inhibitory concentration (MIC, μg / ml) according to the standard method of the Japan Chemotherapy Society (Chemoteraphy 29 (1), 76, 1981) using the standard strains (S. aureus 209P, S. epidermidis IF012293 and P. aeroginosa IFO 3445). The results are shown in table 1. It should be noted that ciprofloxacin, levofloxacin, esparfloxacin and tosufloxacin, which are conventional antibacterials, were also evaluated for their minimum growth inhibitory concentration (MIC, μg / ml) for comparison purposes. The results are also shown in table 1.

Table 1 The results shown in Table 1 reveal that the compounds of the present invention have excellent antibacterial activities superior to that of conventional antibacterials. (2) Phototoxicity test The compounds of examples 9, 10, 12 and 39 as described above were subjected to phototoxicity tests by the procedure described below. ICR female mice were administered intravenously (5 to 6 weeks of age) with the test compound (40 mg / kg / 10 ml), and irradiated with UV (320 to 400 nm, 1. 8 mW / cm2 / sec) for 4 hours. The abnormality in the ears is monitored at hour 0 (immediately after irradiation) and after 24 and 48 hours. The abnormality in the ears was evaluated by the following criteria: no abnormality (0 points), very light erythema (1 point), well-defined erythema (2 points), moderate to severe erythema and edema formation (3 points). The results are shown in Table 2. Tosufloxacin, which is a conventional known antibacterial agent, was also tested in a similar manner for comparison purposes. The results are also shown in table 2.

Table 2 The results shown in Table 2 demonstrate that the compounds of the present invention have very little toxicity. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (5)

1. R E I V I N D I C A C I O N S 1. An amino compound represented by the following general formula (c): [wherein, X represents a nitrogen atom, Y represents -CH = or - CR7 =, where R7 represents a lower alkyl group or a halogen atom, Z represents -CH =, R2a represents a substituted or unsubstituted amino group or an amino group substituted with a protected group, and R3 represents a hydrogen atom or a halogen atom].
2. 2. The amino compound according to claim 1, wherein R3 represents a fluorine atom or a chlorine atom.
3. 3. An amino compound according to claim 1 or 2, wherein Y represents -CH = or CR7 =, wherein R7 represents a methyl group, a fluorine atom or a chlorine atom.
4. 4. The amino compound according to any one of claims 1 to 3, wherein the substituted amino group or the amino group substituted with a protected group R V a p-methoxybenzylamino group or a 1,3,3-tetramethyl butylamino group.
5. 5. The amino compound according to any one of claims 1 to 3, wherein R2a represents an unsubstituted amino group. SUMMARY. INVENTION A pyridonecarboxylic acid derivative represented by the following general formula (1): [wherein R 1 represents a hydrogen atom or a carboxyl protecting group; R 2 represents a hydroxyl group, a lower alkoxy group or a substituted or unsubstituted amino group; R3 represents a hydrogen atom or a halogen atom; R4 represents a hydrogen atom or a halogen atom; R 5 represents a halogen atom or an optionally substituted saturated cyclic amino group; Rs represents a hydrogen atom, a halogen atom, a nitro group or an optionally protected amino group; X, Y and Z may be the same or different and represent respectively a nitrogen atom, -CH = or CR7 = (in which R7 represents a lower alkyl group, a halogen atom or a cyano group) (with the proviso that at least one of X, Y and Z represents the nitrogen atom), and W represents a nitrogen atom or -CR8 = (in which R8 represents a hydrogen atom, a halogen atom or a lower alkyl group)] or its salt, as well as an antibacterial agent containing such compound.