WO1999033835A1 - Fused-ring quinolinecarboxylic acid derivatives - Google Patents

Abstract

Novel fused-ring quinolinecarboxylic acid derivatives exhibiting an inhibitory activity against the propagation of viruses, which are compounds represented by general formula (I) or pharmacologically acceptable salts thereof or esters of both, wherein R1 is optionally substituted aryl, an optionally substituted heteroaromatic ring group or the like; R?2 and R3¿ are each hydrogen or lower alkyl; X is O or S; and m is 2 or 3.

Description

 TECHNICAL FIELD The present invention relates to a novel quinoline carboxylic acid derivative, which inhibits the growth of viruses, particularly human immunodeficiency virus (hereinafter referred to as HIV) and human cytomegalovirus (hereinafter referred to as HCMV). The present invention relates to a novel fused quinoline carboxylic acid derivative, or a pharmaceutically acceptable salt or ester thereof. Background art

HIV infects the CD _4-positive lymphocytes (helper / b Ndeyusa I) was primarily gradually reduce the number of cells in vivo and eventually severe acquired immunodeficiency syndrome (hereinafter AIDS ). To date, many efforts have been made to treat AIDS, but the development of pectin is extremely difficult and antiviral agents are expected to be developed.

 However, currently approved antiviral drugs that inhibit the virus-specific reverse transcriptase can prolong life in AIDS patients but cannot cure them completely. In addition, these inhibitors have many problems such as strong side effects such as bone marrow disorders and gastrointestinal disorders, and the fact that drug-resistant viruses are frequently separated from long-term patients, and the development of new drugs is urgent. Is peeling.

As a compound having a condensed quinoline carboxylic acid skeleton and having anti-H1V activity, DR-335, an optically active form of the synthetic antibacterial agent ofloxacin, is known ( J. Nozaki, Renard et al., AIDS 4, 1283 (1990)). On the other hand, HCMV is a virus that infects humans indigenously and is known to hide in various organs and frequently reactivate to cause fl opportunistic infections. In general, HCMV is weakly pathogenic and has only subclinical infections, but is immunocompromised, for example, after organ transplantation on immunosuppressive therapy, receiving radiation and chemotherapy. In cancer patients, as well as in AIDS patients, CMV is the primary factor in opportunistic infections and is known to cause severe symptoms.

 Ganciclovir and fosca-net are commercially available for the treatment of HCMV infection. However, all of these drugs have strong side effects and the emergence of resistant viruses after long-term use. It has been reported that a fused quinoline carboxylic acid compound having the following formula has an antibacterial activity, but there is no report on an antiviral activity (Japanese Patent Laid-Open No. 59-14989, J. Heterocyclic Chem. 28, 1061 (1991)).

X: 0 or S

本発明者等は、 各種キノ リ ンカルボン酸誘導体について、 抗 H I V活性を 検討してきたところ、 上記化合物とは、 化学構造の異なる、 上記式の 1 0位 が置換されていてもよいァリール基もしく は複素芳香環等で置換されたピぺ ラジニルまたはホモピぺラジェル基である縮環キノ リ ンカルボン酸誘導体

The present inventors have studied the anti-HIV activity of various quinoline carboxylic acid derivatives.As a result, they are different from the above-mentioned compounds in the chemical structure and the aryl group which may be substituted at the 10-position of the above formula. Is a condensed quinoline carboxylic acid derivative which is a pyrazinyl or homopiragel group substituted with a heteroaromatic ring, etc.

(I) Mosquito virus (especially HIV and HCMV) Infected cells were found to specifically suppress the growth of the virus, and the present invention was completed. Disclosure of the invention

(1) The fused quinoline carboxylic acid derivative of the present invention is represented by the general formula (I)

上記式 （ I ) 中、 R ¹は蹬換基 R。で置換されていてもよい炭素数 6乃至 1 0個のァリール基、 又は、 置換基 R。で置換されていてもよく、 ベンゼン又 は リ ジン還と縮合してもよい N， O及び Sから選ばれるヘテロ原子を 1 も しく は 2個含む 5員もしく は 6員の複素芳香環基を示し、 該置換基 R。はハ ロゲン原子、 ヒ ドロキシ基、 炭素数 1乃至 6個のアルキル基、 ハロゲン原子 で置換された炭素数 1 乃至 6個のアルキル基、 炭素数 1乃至 6個のアルコキ シ甚'、 炭素数 1 乃至 6個のアルキルチオ基又は、 ハロゲン原子、 炭素数 1 乃 至 6個のアルキル、 炭素数 1 乃至 6個のアルコキシ、 ニ トロ、 ヒ ドロキシも しくはシァノで置換されていてもよいァリ一ル基から選ばれる基を示し、 R ²及び R ³は同一又は異なって水素原子又は炭素数 1 乃至 6個のアルキル基を 示し、 Xは O又は Sを示し、 mは 2又は 3の整数を示す。 また、 本発明は、 上記式 （ I ) の化合物の薬理上許容される塩及び上記式 ( I ) の化合物のエステルに関する。 さらに、 本発明は、 上記式 （〖） の化合物あるいはその薬理上許容される 塩又はそのエステルを有効成分とする、 医薬組成物、 特に、 エイズ疾患の治 ^又は予防のための組成物及びサイ 卜メガロ ウィルス感染症の治療又は予防 のための組成物に f¾]する。 さらにまた、 本 明は、 医薬、 特に、 エイズ疾患の治療又は予防のための 組成物又はサイ トメガロウイルス感染症の治療又は予防のための組成物を製 造するための上記化合物あるいはその薬现上許容される塩又はそのエステル の使用に関する。 またさらに、 本発明は、 上記式 （ I ) の化合物あるいはその薬理上許容さ れる塩又はそのエステルの、 薬理的な有効量を温血動物に投与するエイズ疾 患又はサイ 卜メガロウイルス感染症の治療方法又は予防方法に関する。 前記一般式 （ 1 ) における R ¹の 「ァリ ール基」 としては、 例えば、 フエ ニル、 1 —ナフチル及び 2—ナフチル基を挙げることができ、 好適には、 フ ェニル基である。 (I)

In the above formula (I), R ¹ is a substituent R. And an aryl group having 6 to 10 carbon atoms which may be substituted with, or a substituent R. 5 or 6 membered heteroaromatic group containing 1 or 2 heteroatoms selected from N, O and S which may be substituted with benzene or lysine And the substituent R. Is a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and 1 carbon atom. 6 to 6 alkylthio groups or halogen atoms, alkyl having 1 to 6 carbons, aryl having 1 to 6 carbons, optionally substituted with alkoxy, nitro, hydroxy or cyano R ² and R ³ are the same or different and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; X represents O or S; m represents an integer of 2 or 3 . The present invention also relates to a pharmacologically acceptable salt of the compound of the formula (I) and an ester of the compound of the formula (I). Furthermore, the present invention provides a pharmaceutical composition, particularly a composition for treating or preventing AIDS disease, comprising a compound of the above formula (II) or a pharmacologically acceptable salt thereof or an ester thereof as an active ingredient. A composition for the treatment or prevention of a submegalovirus infection is used. Furthermore, the present invention relates to a medicament, in particular, the above compound or a medicament thereof for producing a composition for treating or preventing AIDS disease or a composition for treating or preventing cytomegalovirus infection. The use of the above acceptable salts or esters thereof. Still further, the present invention provides a method for treating AIDS disease or cytomegalovirus infection, which comprises administering to a warm-blooded animal a pharmacologically effective amount of the compound of the formula (I) or a pharmacologically acceptable salt or ester thereof. It relates to a method of treatment or prevention. Examples of the “aryl group” for R ¹ in the general formula (1) include a phenyl, 1-naphthyl and 2-naphthyl group, and a phenyl group is preferable.

As a 5-membered or 6-membered heteroaromatic group j containing 1 or 2 heteroatoms selected from N, O and S which may be condensed with a benzene or pyridine ring for R ¹ , for example, Chenyl, furyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazul, pyridazinyl, benzoxazolyl, benzothiazolyl, benzimidazolinole, benzoisoxazolinole, benzoisothiazolyl, benzoxazolo [5,4- Pyridyl, thiazolo [5, 4-b] pyridyl, imidazo [5, 4-b] pyridyl, oxazolo [4, 51-b] pyridyl, thiazolo [4, 5-b] pyridyl, thiazolo [ 5,4—c] pyridyl and thiazolo [4,5-c] pyridyl groups, preferably 2-Chenyl, 2-furyl, 2-oxazolyl, 2-thiazolinole, 2-i-midazolinole, 2-pyridyl, 3-pyridinole, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidyl, 5-pyrimidinyl, 2-pyrazul, 3-pyridazinyl, 2-b Nzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 3-benzoisoxazolyl, 3-benzoisothiazolinole, oxazolo [5,4-b] pyridine-12-yl, thiazolo [5,4-] b] Lysine-1—yl, imidazo [5,4-b] pyridine—2—yl, oxazo Mouth [4,5-b] pyridin-1-2—yl, thiazolo [4,5-b] pyridin 1-yl, thiazolo [5,4-c] pyridin-12-yl or thiazolo [4,5-c] pyridin-12-yl group, more preferably 2-oxazolyl, 2 —Thiazolyl, 2-imidazolyl, 2-pyridyl, 2-pyrimidyl, 4-pyrimidinyl, 2 —pyrazul, 3 —pyridazinyl, 2-benzothiazolyl, 2 —benzobenzoxazolyl or thiazolo [5,4– b] a pyridine-12-yl group, particularly preferably 2-thiazolyl, 2-pyridyl, 2-pyrimidinyl, 2-benzothiazolyl, 2-benzoxazolyl or thiazolo [5,

4 b] is a pyridine-12-yl group.

Conversion of R ¹ SR. Examples of the “halogen atom” in the above include, for example, a fluorine, chlorine, bromine, and iodine atom, and a fluorine or chlorine atom is preferable. Substituent R. Examples of the "alkyl group having 1 to 6 carbon atoms" include, for example, methylol, ethyl, propyl, isopropyl, butynole, s-butyl, isobutylinole, t-butyl, pentyl and hexyl groups. It is preferably an alkyl group having 1 to 4 carbon atoms, more preferably a methyl or ethyl group, and particularly preferably a methyl group. Substituent R. Examples of the “alkyl group having 1 to 6 carbon atoms substituted with a halogen atom” in the above include, for example, monofluoromethyl, difluoromethyl, trifluoromethinole; 2-fluorenetinole; 2-phenylene propyl, 3— Fluorop mouth pill; 2—Fluorobtinole, 3—Fluorobtinole, 4—Funoleolobutinole;

5-Fluoropentinole; 6-Fluorohexinole; Monochloromethinole, Dichromethinole; 2—Chlorochinole; 2—Chloropropinole, 3—Chloropropinole; 2—Chlorobutinole, 3—Chlorobutinole, 4—Chlorobutinole; 5—Black mouth pen 6-methyl hexinole; monobromomethinole, jib mouth; 2-bromopropynole; 2-bromopropinole, 3-bromopropyl; 2-bromobutynole, 3-bromobutynole, 4-bromobutynole; 5-bromopentynole; Examples thereof include a 6-bromohexyl group and the like, preferably an alkyl group having 1 to 4 carbon atoms substituted with a fluorine atom, and more preferably a trifluoromethyl group.蹬 交 基 R. Examples of the “alkoxy group having 1 to 6 carbon atoms” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentyloxy and hexyloxy groups. It is preferably an alkoxy group having 1 to 4 carbon atoms, more preferably a methoxy or ethoxy group, particularly preferably a methoxy group. Examples of the “alkylthio group having 1 to 6 carbon atoms” for the substituent R ° include a methylthio, ethinorethio, propylthio, isopropylthio, butinorethio, isobutylthio, s-butylthio, t-butylthio, pentylthio, and hexylthio group. It is preferably an alkylthio group having 1 to 4 carbon atoms, more preferably a methylthio or ethylthio group, and particularly preferably a methylthio group. Substituent R. The “optionally substituted aryl group” has the same meaning as described above, and is preferably a phenyl group. Substituent R. The "halogen atom", the "alkyl group having 1 to 6 carbon atoms" and the "alkoxy group having 1 to 6 carbon atoms" of the substituents of the "optionally substituted aryl group" Is equivalent to Si substituent R. The substituent of the "optionally substituted aryl group" is preferably a fluorine, chlorine, methyl, methoxy, nitro, hydroxy or cyano group. Substituent R. Examples of the optionally substituted aryl group J include, for example, pheninole, 2 — fenole, fenole, 3 — fenole, 4 — fenole, 2 — Black mouth feninole, 3 — black mouth feninole, 4 single mouth pheninole; 2 — bromopheninole, 3 — bromophenyl, 4 — bromopheninole; 2 — methinolephenyl, 3 — methylphenyl, 4 — methinolepheninole; 2—Echinoref フ ninore,

3—Ethynolephenine, 4—Ethynolephene; 2—Methoxyphenine, 3—Methoxyphenine, 4-methoxyphenyle; 2—Ethoxyphenyl, 3—Ethoxyphenine, 4-Ethoxyphenine 2—Nitro fenore, 3—Nitro fenore, 412 trophenyl; 2—Hydroxypheninole, 3—Hydroxyfenore, 4—Hydroxyfenore; 2—Cyanofeniole, 3— 1-naphthyl, 2-naphthyl and the like, preferably substituted with fluorine, chlorine, methyl, methoxy, nitro, hydroxy or a cyano group. And more preferably phenyl, 4-phenylenophenylene, 4-cyclopheninole, 4-methinole Feninore,

4- methoxyphenyl, 4-nitrophenyl, 4-hydroxyphenyl and 4-cyanophenyl. Replacement ¾ R. Is preferably a halogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted by a fluorine atom, an alkoxy group having 1 to 4 carbon atoms, An alkylthio group having 1 to 4 carbon atoms, or a phenyl group which may be replaced by fluorine, chlorine, methyl, methoxy, nitro, hydroxy or cyano group, more preferably Nitrogen, chlorine, hydroxy, methyl, ethyl, trifluoromethylinole, methoxy, ethoxy, methinorecho, etinorecho. Fuenore, 4-funoroleolopheninole, 4-chlorof. Heninole, 4-methinorefue-nore, 4-methoxyphene, 4-212trophenine, 4-hydroxyphenyl or 4-cyanophenyl group, particularly preferably fluorine, salt, hydroxy, methyl, A trifluoromethyl, methoxy or methylthio group.

Overall R ¹ group,

 Preferably, a phenyl group which may have a substituent, or a heteroatom selected from N, O and S which may have a substituent and may be condensed with a benzene or pyridine ring, Or a 5- or 6-membered heteroaromatic group containing two, and the substituent is a halogen atom, a hydroxy group, an alkyl having 1 to 4 carbon atoms, or a substituted carbon atom substituted by a fluorine atom. Replace with an alkyl group of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 carbon atoms, an alkylthio group of 1 to 4 carbon atoms, or a fluorine, chlorine, methyl, methoxy, nitro, hydroxy, or cyano group A phenyl group which may be

More preferably, phenyl, 2-chyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, which may have a substituent, 1-pyridyl, 2-pyrimidyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyragel, 3-pyridaziel, 2-benzoxazolinole, 2-benzothiazolyl, 2-benzimidazolyl, 3-benzoisoxazolyl, 3-Benzoi sothiazolyl, oxazolo [5,4-b] pyridine-2-yl, thiazolo [5,4-b] pyridine-1 2-yl, imidazo [5,4-b] pyridine-1 2— Yl, oxazolo [4,5—b] pyridin-12-yl, thiazolo [4,5-b] pyridine-12-yl, thiazolo [5,4-c] pyridine-12-yl or thiazolo [4, 5— c] pyridine-1 And the substituent is fluorine, chlorine, hydroxy, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methinolethio, ethylthio, feninole, 4-phenylenophenylene, 4-chloropheninole. , 4-Methynolefe-Norme, 4-Methoxy phenol, 412-Trophenyl, 4-Hydroxyphene or 4—Cyanophenyl group,

 Particularly preferred is a phenyl group which may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl; fluorine, tfi 尜, hydroxy, methynole, phenyl, 4-fluorophenyl, 4 2-thiazolyl group optionally substituted with monophenyl, 4-methylphenyl, 4-methoxyphenyl or 4- 12-trophenyl; fluorine, chlorine, hydroxy, methyl or methoxy. Optionally substituted 2-pyridyl group; fluorine, chlorine, hydroxy, methyl or methoxy optionally substituted 2-pyrimidyl group; fluorine, chlorine, hydroxy, methyl, methoxy or methinorethio Optionally substituted 2-benzothiazolyl group; fluorine, chlorine, hydroxy, methyl, meth 2-benzoxazolyl group optionally substituted by xy or methylthio; thiazolo [5,4-b] pyridine-1-2-optionally substituted by fluorine, chlorine, hydroxy, methyl, methoxy or methylthio Group

Most preferably, feninole, 4-funolenophenyl, 2-methoxyphenine, 4-methoxyphene, 3—cloth feninole, 2-thiazolinole, 4-methinole, 1,2-thiazolyl , 3,4—Dimethyl-2-thiazolyl, 2-pyridyl, 2-pyrimidinyl, 5-funoleolol 2-pyridimigenole, 5—hydroxy-2—pyrimidyl, 5-methoxy-2-pyrimidinyl, 2-benzothiazolinole, 6-Methoxy 2-benzothiazolyl, 2-benzoxazolyl or thiazo [5,4-b] pyridine-12-yl group. The “alkyl groups having 1 to 6 carbon atoms” of 2 and 1 to ³ include, for example, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, t-butyl, pentyl and hexyl groups. And preferably a methyl, ethyl, propyl or isopropyl group, more preferably a methyl, ethyl or propyl group, particularly preferably a methyl or ethyl group, most preferably Preferably, it is a methyl group. R ² and R ³ are preferably a hydrogen atom, a methyl, an ethyl or a propyl group, more preferably a hydrogen atom, a methyl or an ethyl group, particularly preferably a hydrogen atom or a methyl group. Most preferably, it is a hydrogen atom.

X is preferably an oxygen atom. m is preferably 2. The “ester” of the compound represented by the general formula (I) indicates an ester as a prodrug formed by a carboxyl group and / or a hydroxy group present in the compound, and the pharmacological property of the compound The ester is not particularly limited as long as it does not inhibit the action and does not show significant toxicity. Examples of the ester residue as a prodrug formed by the carboxyl group include an alkyl group having 1 to 4 carbon atoms such as a methyl, ethyl, ^, propyl, isopropyl, butyl, and isobutyl group. Is an aralkyl group having 7 to 10 carbon atoms such as benzyl and phenylethyl groups; and 11 (alkanoyloxy having 2 to 5 carbon atoms) such as acetoxmethyl and bivaloyloxymethyl groups—1 carbon atom 1 to 4 alkyl groups; 1— (ethoxycarbonyloxy) ethyl and 1— (isopropoxy propylonyloxy) ethyl group, etc.—1 to 4 carbon atoms (alkoxycarbonyloxy) 1 to 4 carbon atoms Alkyl groups; mono- or di- (alkyl having 1 to 4 carbon atoms) such as Ν-methylcarbamoinolemethyl group, ,, Ν-dimethylcarbamoylmethyl group, etc. Substitution power rubamoyl-alkyl group having 1 to 4 carbon atoms; —, Ν-di (alkyl having 1 to 4 carbon atoms) such as 2- (Ν, Ν-dimethylamino) ethyl group, substituted amino group having 1 to 4 carbon atoms 4-alkyl group; 2-trimethylammonioethyl group and other tri- (C1-4 alkyl) ammonium mono-C1-4 alkyl group; 2-morpholinoethyl, 2- Select from Ν, Ο and S such as piperidinoethyl and 2- (4-methylbiperidino) ethyl groups Or a 5- or 6-membered, saturated, monocyclic, K-substituted, alkyl group having 1 to 4 carbon atoms containing 2 hetero atoms or (5-methyl (or 5-phenyl) 1-2-oxo 1,3-Dioxolen-14-yl) a group forming a prodrug, such as a methinole group,

 Preferably, an alkyl group having 1 to 4 carbon atoms, 1 (alkanoyloxy having 2 to 5 carbon atoms), an alkyl group having 1 to 2 carbon atoms, 1 — (alkoxycarbonyl having 1 to 4 carbon atoms) Oxy) —alkyl group having 1 to 2 carbon atoms, mono or di (alkyl group having 1 to 2 carbon atoms), substitution ability rubamoylmethyl group, N, N-di (alkyl having 1 to 2 carbon atoms), substituted amino group C 2 -C 3 alkyl group, tri (C 1 -C 2 alkyl) ammonium-C 1 -C 2 alkyl group, one or two selected from N, O and S A 5- or 6-membered heterosaturated monocyclic group-substituted alkyl group having 2 to 3 carbon atoms, including a hetero atom, or (5-methynole (or 5-phenyl) -12-oxo-1 1 , 3-dioxolene 4-methyl) is a methyl group. Examples of the acyl residue of the ester as a prodrug formed by the hydroxy group include alkanoyl groups having 2 to 5 carbon atoms such as acetyl, propanoyl, butanol, isobutanoyl, and vivaloil groups. Preferably, it is an acetyl or bivaloyl group. The “pharmacologically acceptable salt” of the compound represented by the above general formula (I) and its ester is also encompassed in the present description,

Examples of such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodic acid, sulfate and phosphate; methanesulfonate, ethanesulfonate Acid addition of organic acids such as salts, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumaric acid ^, acetates, tartrates and citrates; or sodium salts, potassium And metal salts of carboxylic acids such as calcium salts, calcium salts, magnesium salts, manganese salts, iron salts and aluminum salts. The active ingredient of the present invention, compound (I), an ester thereof and a pharmaceutically acceptable salt thereof may exist as a hydrate or a solvate. The compound represented by the above general formula (I) may have two or four optical isomers based on the configuration of the carbon atom to which the substituents R ² and R ³ are bonded. However, the present invention also encompasses individual optical isomers and mixtures of these optical isomers in any proportion. The contraction represented by the general formula (1) of the above (1)! Among the quinolinecarboxylic acid derivatives, preferred are the following derivatives (2) to (10).

(2) In (1), R ¹ ; a phenyl group which may have a substituent 、 or a ^ -substituent, which may be condensed with a benzene or pyridine ring N A 5- or 6-membered aromatic ring containing 1 or 2 heteroatoms selected from, O and S, wherein the substituent is a halogen atom, a hydroxy group, or a carbon atom. ¾ 4 alkyl groups, alkyl groups having 1 to 4 carbon atoms, substituted by fluorine atoms, 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, alkylthio S having 1 to 4 carbon atoms, or fluorine A fused quinoline carboxylic acid derived from a phenyl group which may be substituted with chlorine, methyl, methoxy, nitro, hydroxy or cyano ffi; a derivative thereof or a pharmaceutically acceptable salt thereof and an ester thereof;

(3) In (1), R ¹ may have a substituent, phenyl, 2-phenyl, 2-furinole, 2-oxazolyl, 2-thiazolyl, 2-imidazolinole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidininole, 5-pyrimidinyl, 2-pyrazul, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl , 2-Benzomidazolinole, monobenzoisoxazolyl, 3-benzoisothiazolinole, oxazo [5, 4-b] Pyridine-12-yl, thiazolo [5, 4-b] Pyridine-12-inole, imidazo [5, 4-b] Pyridine-12-yl, oxazolo [4, 5-b] Pyridin-2-yl, thiazolo [4, 5-b] pyridine-1-yl, thiazolo [5, 4-c] pyridine-2-yl or thiazolo [4, 5-c] pyridine-1-yl S, and the substituent is fluorine, chlorine, hydroxy, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, methylthio, ethylthio, feninole, 4-phenylenophenylene, Black mouth phenyl, 4-methinophenyl, 4—methoxyphenyl, 4-nitrophenol, 4-hydroxyphenyl or 4-cyanophenol fused to quinoline carboxylic acid Derivatives are salts that are acceptable on the drug and their esters,

(4) In (1), R ¹ may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl; a phenyl group; fluorine, chlorine, hydroxy, methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methynolephen, 4-methoxyphenyl or 4-nitrophenyl 2-thiazolyl group which may be substituted; fluor, chlorine, phenyl 2-pyridyl group optionally substituted with hydroxy, methyl or methoxyl; 2-pyrimidinyl group optionally substituted with fluorine, salt, hydroxy, methyl or methoxy; fluorine, chlorine 2-benzothioazolyl group which may be substituted with, hydroxy, methyl, methoxy or methylthio; fluorine, chlorine, hydroxy 2-benzoxazolyl group which may be substituted by cis, methyl, methoxy or methylthio; or thiazolo which may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy or methylthio [5 , 4-b] pyridin-2-yl-condensed quinoline carboxylic acid derivatives or pharmaceutically acceptable salts and esters thereof,

(5) In (1), R ¹ force; phenyl, 4-fluorophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3—cloth, 2-phenyl Azolyl, 4-methyl-2-thiazolyl, 3,4-dimethyl-2-thiazolinole, 2-pyridyl, 2-pyrimidinyl, 5-fluoro-2-pyrimidinole, 5-hydroxy-1-pyrimidinyl, 5 .—Methoxy-1-pyrimidinyl, 2-benzothiazolyl, 6-methoxy-2-benzothiazolinole, 2-benzobenzoxazolyl or thiazolo [5,4-b] pyridine-Fused ring that is a pyridine-2-yl group Phosphorus carboxylic acid derivatives or pharmacologically acceptable salts thereof and esters thereof,

(6) In the above (1) to (5), R ² and R ³ are the same or different and each is a hydrogen, methyl, ethyl or propyl group, or a pharmaceutically acceptable derivative thereof. Salts and esters thereof,

(7) (1) to (5), 1 ² and 1 ^3, same or different, MizusakuHara - Ryo - or is condensed Kino Li Nkarubon acid derivative or a drug现上allowed a methyl group Salts and esters thereof,

(8) (1) to (5), 1 ² and 1 ³ are condensed keno Li Nkarubon acid derivative or a pharmacologically acceptable salt and ester le is hydrogen atom,

(9) In (1) to (8), the fused quinoline carboxylic acid derivative wherein X is O (oxygen atom) or a pharmaceutically acceptable derivative thereof; ^ and its ester,

(10) The fused quinoline carboxylic acid derivative according to any one of (1) to (2), wherein m is 2, a pharmaceutically acceptable salt thereof, and an ester thereof. The above substituents RR ^2, R atoms X and the variable m in the preferred compounds} ^gamma Il.糾viewed together}. Rarero compound is more preferable, for example, the following (1 1) The compound of 乃 ^ (1 3) can be mentioned.

(11) In the above (1), R ¹ force; optionally substituted phenyl, 2-phenyl, 2-furinole, 2-oxazolyl, 2-thiazolinole, 2-imidazolyl , 2 —pyridyl, 3 —pyridyl, 4-pyridyl, 2 —pyrimigenole, 4 —pyrimidinyl, 5 —pyrimidinyl, 2 —pyrazul, 3 —pyridazinole, 2-benzoxoxazolyl, 2-benzothiazolyl , 2-Benzomidazolinole, 3 Benzosozoxazolyl, 3-Benzoisothiazolinole, Oxazolo [5,4-b] pyridine-12-yl, thiazolo [5,4-b] Pyridine-12-inole, Imidazo [5,4-b] Pyridine-1-2-yl, oxazolo [4,5-b] pyridin-2-yl, thiazolo [4,5-b] Pyridine-1-2-yl, thiazolo

[5,4-c] pyridine-12-yl or thiazolo [4,5-c] pyridine-12-yl group, wherein the substituent is fluorine, chlorine, hydroxy, methyl, ethyl, Trifluorome Λ ^, methoxy, ethoxy, methinorecho, echinorecho, fueinore, 4 — fenoleo fuenore, 4 one-clope fuenore, 4 — methinolefénore, 4-metroxie , 4-nitrophenyl, 4-hydroxyphenyl or 4-cyanophenyl, R ² and R ³ are the same or different and are a hydrogen atom, methyl, butyl or propyl group, and X is Ο (Oxygen atom), wherein m is 2 and a fused quinoline carboxylic acid derivative or a pharmaceutically acceptable salt and an ester thereof;

(12) In (1), R ¹ is a phenyl group which may be substituted with fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl-; fluorine, chlorine, hydroxy, methyl, Phenyl, 4-fluorophenyl, 4-cyclophenyl, 4-methynolephenyl, 4-methoxyphenyl or 4-dithiophenyl optionally substituted 2-thiazolyl group; fluorine, 2-pyridyl which may be substituted with hydrogen, hydroxy, methyl or methoxy; substituted with fluorine, salt, hydroxy, methyl or methoxy 2-pyrimidinyl group which may be substituted; 2-benzothiazolyl group which may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy or methylthio; fluorinated, chlorine, hydroxy, methyl, methoxy or methylthio A 2-benzoxazolyl group which may be substituted with a thiazolo [5,4-1b] pyridine which may be substituted by fluorine, chlorine, hydroxy, methyl, methoxy or methylthio A fused quinoline carboxylic acid derivative wherein R ² and R ³ are the same or different and are a hydrogen atom or a methyl group, X is O (oxygen atom) and m is 2, or Its pharmacologically acceptable salts and their esters,

(1 3) In (1), R ¹ force S, feninole, 4 — phenyolofeninole, 2- methoxypheninole, 4 — methoxyfeninole, 3 — clofeninole, 2 — thiazolinole , 4 —Methyl-2 —thiazolyl, 3,4 —Dimethyl-2-thiazolinole, 2 —pyridyl, 2 —pyrimidinyl, 5 —fluoro-2-pyrimidyl, 5-hydroxy-2 —pyrimidinyl, 5-methoxy 2 — Pyrimidinyl, 2-benzothiazolinole, 6-methoxy-2-benzothiazolyl, 2-benzoxazolyl or thiazolo [5,4-b] pyridin-12-yl group, wherein R ² and R ³ are the same or -A condensed quinoline carboxylic acid derivative having a hydrogen atom or a methyl group, X being O (oxygen atom) and m being 2, or a pharmaceutically acceptable ^ and an ester thereof. Preferred compounds represented by the general formula (1) are shown in Tables 1 to 5, but the compounds of the present invention are not limited thereto.

N o. R ¹

 1 1 1 Phenyl

 1 ― 2 9 ―

 1 1 3 1 Funore Lofeninore

 1 1 4 4 1 Funoreo mouth

 1 1 5 2 1 Black mouth Feninore

 1-6 3

 1 1 7 4-Kuro Ro Fenore

 1-8 methoxyphenyl

 1 1 9 3 ―Methoxyphenyl

 1 1 1 0 4 1 Methoxyphenyl

 丄 丄 1 Lie: ^, Nof: Ninnore

 2 2-Trifluoromethinolephenyl

1 — 1 3 3 — Trifluorometinolefenir

1-1 4 4-Uri Fluorometinorefeniru

1 1 1 5 2, 4 —Gifnore

1 1 1 6 1 Methyl phenyl

 1 1 1 7 3 ― Methylpheninole

 1 1 1 8 2 ― -Methylthiophene

 1 1 1 9 3--Methylthiophene

 1 — 0 4 ― -Methylthiophene

1 ― 1 ') I-Echinoret r Feninore 1-2 2 3 —ethylthiophenyl

 1 to 2 3 4 —Echinoretoffeninore

 1 — 2 4 2 — Oxazoli Nore

 1-2 5 2—thiazolinole

 1 — 2 6 2—I Midazolinore

 ] 1 2 7 2 — pyridyl

 1-2 8 6 —Methoxy 2- 2-pyridyl

 1-2 9 3 -Fluoro-2-pyridyl

 1-3 0 3 —pyridyl

 1 — 3 1 4 — pyridyl

 1 — 3 2 2 — Benzoxazolinole

 1-3 3 5—Black mouth 1 2—Benzoxazolinole

 -3 4 2—Benzothiazolinole

 1 — 3 5 5 —Methyl-1 2 —Benzothiazolinole

 1 — 3 6 2—Benzoi Mi Dazolinore

 -3 7 2—Pyrimidinyl

 1-3 8 5—Black mouth 1 2—Pirimi gel

 1-3 9 4 -Methoxyxy 2-pyrimidinyl

 1-4 4, 6-Dimethoxy 2-Pyrimidininole

1-1 4 —pyrimidinyl

 1—4 2 6—Ethyl 1 4—Pyrimidinyl

 1 1 4 3 6—Black mouth 1 4—Pili Migenore

 1-4 4 5 —Black mouth 1 6 —Methyl-4 1 pyrimidininole

1-4 5 3 —pyridazinil

 1-4 6 6 — Black mouth 3 — Pyridazininole

 1-4 7 2—Pyrazidinore

 1-4 8 Ί Ί Benzoi Soxazolinore

1-4 9 3 —Benzoisothiazolyl 5 —Methoxy 1 2 —Benzothiazolinole

6-Methoxy 2-benzothiazolinole

5 — methoxy 2 — benzoxazolyl

4 —methyl-2 —thiazolyl

4,5—Dimethyl-2-thiazolyl

4 — feninole 2 — thiazolinole

4- (4-Funoleolopheninole) 1 2 —Thiazolinole 4 —Phenyl 1 5 —Black mouth 1 2 —Thiazolinole 4-(4 —Cro mouth Hue-Nore) 1 2—Thiazolinole 4-1- (4-Methinolephenyl) 1 2—Thiazolinole 4 — (4 —Methoxyphenole) 1 2—Thiazolinole 4 — (4112 phenyl) 1 2 —Thiazolinole 4 1Feninole 1 2 —Oxazolinole

4-(4-Funoleolofenisle) 1 2-Oxazolinole 5-Funoleo mouth 1 2-Pyrimidinole

5—Metkin 1 2—Pili Migenore

 5 — Hydroxy 1 2 — Piri Migenore

Oxazolo [5,4—b] pyridin-1 2—yl thiazolo [5,4—b] pyridine-2—yl imidazo [5,4—b] pyridine-2-yloxazolo [4,5— b] pyridin-1 2 -yl thiazolo [4,5-b] pyridine-1 2 -yl thiazolo [5,4-c] pyridine-1 2 -yl thiazolo [4,5-c] pyridine-2- Le

N o. R ¹

 2-1 Fe Ninore

 2 1 2 — Hunole mouth Hue-Nore

 2 1 3 3 1 Funofore Lofeninore

Li 1 4 4 1

 9 ― 5 2 1

 9 1 6 3 1 Black mouth

 2 1 7 1 Black mouth

 2 1 8 2 1

 2-9 3 1 methoxy phenol

 9-104

Li-1 1 1

 9 1 1 2 2-Trifluoromethylinophenyl 1 1 3 1 Trifluoromethylphenyl

2 1 1 4 4 1 Trifluoromethisolefernil

2 1 1 5 2, 4-Gifolo Feninole

2 1 1 6 2 1-Methylpheninole

 One 1 7 3 One methyl phenyl

 2 1 1 8 9 ― Methylthiophene

 ') 1 1 9 3 -Methylthiophene

9 1 2 0 4 1 1 1 2 1! ： Chinolechiofeninore 2 2 3—ethylthiophenyl

 2 3 4—Etilchi

 2 4 2-oxazolyl

 2 52 2-thiazolyl

 2 6 2—Midazolyl

 2 7 2-pyridyl

 2 8 6—Methoxy 2-pyridyl

 2 9 3—Fluoro 2-pyridyl

 3 0 3 One pyridyl

3 1 4 One pyridyl

3 2 2—Venzo-aged Kisazolinore

3 3 5—Black mouth 1 2—Benzoxazolinole

3 4 2 —Venzothiazolinole

3 5 5—Methinole 1—Venzothiazolinole

3 6 2—Benzy midazoli paste

3 7 2—Pyrimidinyl

3 8 5 — Black mouth 1 2 — Pyrimidinyl

 3 9 4-Methoxy-1 2-pyrimidinyl

 4 0 4, 6 —Dimethoxy 2 —Pyrimidinyl 4 1 4 —Pyrimidinyl

4 2 6—Ethyl—4 Pyridimidinyl

4 3 6—Black mouth 1 4 Pyridimidinyl

4 4 5—Black mouth 1 6—Methinole 4 1 Pyridimidininole 4 5 3—Pyridazinyl

4 6 6—Black mouth 1 3—Pyridazinyl

4 7 2 1 pyrajur

4 8 5 —Fluoro-2-pyrimidinyl

4 9 5 —Methoxy 2—Pyrimidinyl 2-500-Hydroxy 2-pyrimidinyl

 2-5 1 Oxazolo [5, 4-b] pyridin-1-yl

 2-5 2 Thiazolo [5, 4-b] pyridin-1-yl

2-5 3 Thiazolo [4, 5-b] pyridin-2-inole

 (Table 3)

No. R R R

3-1 phenyl hydrogen methyl

3-2 2—Henoleolopheninole Hydrogen Methyl

3-3 3—Funoleolopheninole Hydrogen Methyl

3-4 4-fuenore rofeninore hydrogen methyl

3—5 2—Cross mouth feninole Hydrogen Methyl

3-6 3—Black mouth hydrogen methyl

3-7 4 1-mouth feninole Hydrogen methyl

3-8 2—Methoxyethoxy Hydrogen Methyl

3-9 3-Methoxyphenyl hydrogen methyl

3-104-methoxyphenyl hydrogen methyl

3-1 1 2—Ethoxyphenyl Hydrogen Methyl

3— 1 2 2— Trifluoromethylphenyl hydrogen Methyl

3-1 3 3— Trifluoromethylphenyl Hydrogen Methyl

3-1 4 4— Tri-Finoleolomethinolefeninole Hydrogen Methyl 3 1 1 6 2—Methinolefeninole Ice, 袠 ■ ^

3 1 1 7 3 1 Mech / Refeninole

3-1 8 2 6-Mechinorechiofeninore k, table ΤΓ ^

3−1 9−

0 —— ノ 7 7 7 ノ ノ ノ 1 1 1 1 J 1 J J

 / ΝThread Funore-9 o o one ~ j, shi — -T ^ * ^ ノ _- / Reno * ノ "7: ―ichino'shi

 Ν Thread

— ノ レ ゾ ・ ノ ・ エ--"Normal thread-ο Λ ― -J-J] ~ / 1 1,

 "^ No.

 Nanore]

 Sonore Nanore / 1 1

 Λ Sonore Mizubon Nanore

9 7 ~ J f-

 Δone sonore 71 ^ thread

9 D 7 ^ Ν Ν 7 Ν ^

9 - "7 γη one - Les ⁰ 11, and click

 Δ Δ ソ ソ レ レ 7Ν thread

Q-Q-. 1] /

 Sono hydrogen

* 1 —— V ³ 1

^ — ——Be, '; ϊ ¹ · 4, /, U Nore I Kino Nonorele

3−3 3 π π− 9 £ —B, No, Zo: ^ Notosono, Reno Norele Small vffi Hando Nonorele

3 1 3 4 9 —Benso z, Chinoa / Zo ^ 1 No)

3 1 3 5 5 —— Metinole 2 ——Benzo, thiazo, linole

3 3 6 2 one base Nzoi, ^ヽda z Reno raised to the power of small, Tenofovir Nonore ¹ ^

3− 3 7 2 —Pi 11> Ginore Water 袠 Hand ― ― 8 3 8 ¾j —No r V "* r π—Q —No. 1 1 ^ ヽ, ——Nonore Thread /" Nonore

3 1 3 9 4 —Methoxy 2-pyrimidinyl Hydrogen Methyl

3 1 4 4, 6-Dimethoxy-2-pyrimidinyl Hydrogen Methyl

3 1 4 1 4 1 Pyrimidinyl Hydrogen Methyl

3 1 4 2 6 —Ethyl 1 4 —Pyrimidinole Hydrogen Methyl

3-4 3 6 1 mouth 1 4 1 pyrimidininole Hydrogen methyl 3-4 4 5 Black mouth 6-Mechinore-4-Pyri "

* A ~ t 'ri f ζf ,,--ί 7k

^ —— A a no no — p and no no H 7, no, ——- 'Nore Hand, Nore ^f —— A 7 "-No, no No * * Ku, Kino / Nore

Q-A Q Fune-

A Δ Funo / Shi ~ y * No "D ~ τ · * — // Shi τ No NoShi-c

 O U 4 No / Reno :! _ ― / レ 寧 Γ Γ Γ Γ Γ Γ Γ O Γ 5 5 5 Γ Γ 5 5 5

 D no? 1 レ Water rate

― O

O ο Bok emissions Roh X - Norre N tea to Norre c Les ^u 11 S, tooth

 O ― O 4 Δ ,,

 Rf ジ 系>

Q c

a O 0 Δ 匕 V

O Ό ο

 J Ginore

Q-c

 O * 7

 f ο Henonona, Nori Nore q-Q

 O O ο water

 Five

 ― O Q y ―

 No / / No

Q ― a Ό A \ J ノ,,,--マ マ 7 Γ

/ ;1レ ζ キノ ノクしレ キ / ノクしレ 手

ノ /ノレReno / ―

/; 1 ζ ζ ノ

No / Nore

Q ― u Q -J ¾: ¾ = ·, z, nohno // レ ^ キ キ キ o o t t t "" "" — — — r r r r r r

^ One u c:

 o V 1)

It was ^0-Soviet / Norre key to Norre Chome

Q-Do. 1 to 1, ^--Nore * ¹

3 6 7 2 Thiazolyl methyl methyl

3 6 8 2 Benzothiazolinole methyl methyl

3 6 9 2 Benzoxazolinole methyl methyl

3-70 Phenyl methyl ethynole

3 7 1 'Finore: ^ Mouth methyl -7 2 4-Monofluorophenyl methyl ethynole-732 -Cross phenyl methyl ethynole-7 4 2 -Methoxy phenyl methyl ethynole-7 52 -Ethoxy phenyl methyl ethynole-7 62 -Pyridyl methyl ethynole- 7 7 2-Pyrimidinyl methyl ethynole-7 8 2 -Thiazolinole methyl ethynole-7 92 -Benzothiazolyl methyl ethynol-80 2 -Benzoxazolinole methyl ethynole-8] Phenyl ethynole ethyl-8 2 2- Fluoro-Phennole-Echinole- 8 3 4-Fnenole-Ro-Pennole-Echinole- 8 4 2—Clo mouth Feninole-Echinole-Echinole — 85 2—Methoxyphenine-Echinole-Echinole-86 2—Etoxene 8 7 2—Pyridyl ethyl echinolle-8 8 2—Pyrimidinyl ethyl echinolle-8 92 Linole echinole echinole — 9 0 2—Venzothiazolinole echinole echinole- 9 1 2—benzozoxazolinole ethyl echinole-9 25 —fluoro-2-pyrimidinyl hydrogen Methinole-933 5—Methoxy-1-2-pyrimidinyl hydrogen Methyl-945-hydroxy-2-pyrimidinyl hydrogen Methyl-95oxazolo [5,4-b] pyridin-1 2-inole Hydrogen methyl-96 6 thiazolo [5,4-b] pyridin-1 2- Le Hydrogen Methinole-97 7 Thiazolo [4, 5—b] Pyridin-1-yl Hydrogen Methyl (¾ 4)

N o R ¹

 4-1-1 phenyl

 One 22-Funore

4 1 3 1 Funore

4 1 4 4-Fenore

4 1 5 2 1 Black mouth Hue Ninore

4 1 6 3 1

4 1 7 4 1 Black mouth

4 1 8 2 1 Methoxyphenyl

4-9 3 1 methoxy phenol

4 1 1 0 1 Methoxy phenyl

4 1 1 1 2 1

4 1 1 2 2-

4-1 3 3 1 Horioleno Mechinorev

4 1 1 4 4 ― Trifluoromethyl

4-1 5 2, 4—Diphnoleolofeni

4-1 6 2

4-1 7 3 -Methylpheninole

 1 1 8 2-Methinolethiopheninole

4-1 9 3 1 .Metinolethiopheninole

4-1 2 0 4-Mechinoretiofeninore

4 ― 2 1 2--Ethylthiopheninole -2 2 3—Echiruchiofeninore

-2 3 4 -ethylthiophenyl

-2 4 2 —Oxazolyl

-2 5 2 —thiazolyl

-2 6 2 — I Midazolyl

-2 7 2 —pyridyl

-2 8 6 —Methoxy 1 2 —Pyridyl

-2 9 3 —Fluoro-2-pyridyl

-303-pyridyl

-3 1 4—pyridyl

-3 2 2 — Benzoxazolyl

-3 3 5 — Black mouth 1 2 — Benzoxazolinole

-3 4 2 —Benzothiazolinole

-3 5 5 —Methinole 2 —Benzothiazolinole

-3 6 2 — Benzoi Midazolyl

-3 7 2 — Piri Migel

-3 8 5 — Black mouth 2 — Pyrimidinyl

-3 9 4—Methoxy 2—Pyrimidgel

1 4 4, 6 —Dimethoxy-1 2 —Pyrimigel-4 1 4 1Pyrimidinyl

-4 2 6 —Ethyl— 4—Pyrimidinyl

-4 3 6—Black mouth 1 4

-4 4 5-Chloro-6-Methynole 4-1 Pyridimidininole-4 53-Pyridazinyl

-4 6 6—Chloro-3-pyridazinyl

-4 7 2 —Pyrajur

-4 8 3 — Benzoi soxazolinole

-4 9 3—Benzoi Sothiazolinole -505-Methoxy-2-benzothiazolyl-5 16-Methoxy-2-benzothiazolyl

-5 2 5 -Methoxy 2- 2-benzoxazolyl

-5 3 4—Methyl-2-thiazolyl

-5 4 4, 5-Dimethyl-2-thiazolyl

-5 5 4 1 2 1 2-Thiazolyl

-5 6 4 1 (4-Fluorophenyl) 1-2-thiazolinole 1 5 7 4-Fennole 1-5-Chloro 1-Thiazolinole 1 5 8 4-(4-Chlorofern) 1-2-Thiazolinole -5 9 4-(4-Methynolephenyl) 1 2-Thiazolinole-6 0 4-1 (4-Methoxyphenyl) 1-2-Thiazolyl-6 14-(4-12 Trophenyl) 1-2-Thiazolinole-6 2 4 One feninole 2-Oxazolinole

-6 3 4-(4-Fluorophenyl) 1-2-oxazolyl-6 4 5-Fluoro-2- pyrimigel

-6 5 5-Methoxy-1 2-pyrimidinyl

-6 6 5—Hydroxy-1-2-pyrimidinyl

— 6 7 oxazolo [5,4-b] pyridine-1-2-inole-68 thiazolo [5,4-b] pyridine-1 2-inole — 69 thiazolo [4,5-b] pyridine-1 2-yl

(Table 5)

N o R ¹ RR

5-1 phenyl hydrogen methyl

5-2 2—

5— 3 4—Fluoropheninole Aqueous methyl

5-4 2—Hydrogen methyl

5-52 2-Methoxyphenyl Hydrogen Methyl

5-6 2—Ethoxyphenyl hydrogen methyl

5-7 2-pyridyl hydrogen methyl

5-8 2-Pyrimidinyl hydrogen methyl

5-92 2-thiazolyl hydrogen methyl

5-10 2-Benzothiazolyl hydrogen methyl 5- 1 1 2-Benzoxazolyl hydrogen methyl

5-1 2 Phenyl methyl methyl

5—1 3 2—Funoleolopheninole Methinole Methyl

5-1 4 4-Funole

5—1 5 2—Cross mouth feninole methyl methyl

5-1 6 2—Methoxy methoxy methyl methyl

5-7 2-Ethoxyphenyl methyl methyl

5-1 82 2-pyridylmethyl methyl

5-1 92 2-pyrimidinole methyl methyl

5-202-thiazolyl methyl methyl 5 2 1 2 -Benzothiazolyl methinole Methynole 5 2 2 2 -Benzoxazolinole methinole Methynole 5 2 3 5 -Fluoro-2-pyrimidyl Hydrogen Methyl 5 5-Hydroxy 2-pyrimidinole hydrogen methyl 5 26 oxazolo [5,4-b] pyridin-1-yl hydrogen methyl 5 2 7 thiazolo [5,4-b] pyridin-2-yl hydrogen Methyl 528 thiazolo [4,5-b] pyridin-12-ylhydrogen methyl In the above table, suitable compounds are exemplified compound numbers 111, 114, 166, 118, 1 — 1 0, 1 — 2 5, 1 — 2 7, 1 — 3 2, 1 1 3 4, 1 1 3 7, 1 1 5 1, 1 — 5 3, 1 — 5 4, 1-6, 1 1 6 5, 1 1 6 6, 1 — 6 8,

2-1, 2-4, 2-25, 2-27, 2-3 2, 2-3 4, 2-3 7, 2 1 4 8, 2-49, 3-1, 3-4 , 3-2 5 3-2 7, 3-3 2, 3-3 4, 3-37, 3-92, 3-93, 4-1 4 1-4, 4-1 2, 5, 4-2 7, 4-32, 4-34, 4-37, 4-64, 4-65, 5-1-1, 5--3, 5--7, 5--8, 5--9, 5--1 0, 5—1 1 5—2 3 and 5—24

 Further preferred compounds are exemplified compound numbers 1 1 1 1 1 4, 1 — 6, 1 1 8, 1 1 1 0, 1 1 2 5, 1 — 2 7, 1 1 3 2, 1-3 4, 1 1 3 7, 1-51, 1 1 53, 1 54, 1 1 64, 1 — 65, 1-66, 1 — 68, 3-25 and 3-37 compounds Yes,

 Particularly preferred compounds are

 9-funoleo mouth 1-3-methylene-1 7-oxo-1 10- (4 pheninolepiperazine-1-11-yl) 1,2,3-dihydro 7 H-pyrido [12,3-de] [1,4] Benzoxazine-6-carboxylic acid (Exemplified Compound 1-1),

9-Funoleolo 1 0— [4- (4-Funoleolophenyl) piperazine-1 1-yl] -13-Methylene-1 7-oxo-1 2,3—Dihydro 7 H-pyrido [ 2,3-de] [1,4] benzoxazine-16-carboxylic acid (Exemplified compound 1-4),

 9-Funoleolose 1 0 — [4-1- (4-methoxyphenyl) piperazine-1 1-yl] — 3 —Methylene-1 7-oxo-1 2,3 —Dihidro 7 H—Pyrido [1,2, 3 — de] [1, 4] Benzoxazine-6-carboxylic acid (Exemplified compound 1-10),

 9-Funoleolone 3 —Methylene-1 7-oxo-1 10 — [4-1 (2 —Thiazolyl) piperazine-1 1 —yl] 1,2,3-Dihydro-1 7 H—Pyrido [1,2,

3-de] [1 _; 4] Benzoxazine-6-carboxylic acid (Exemplified compound 1 — 25),

9 1 FUNOREI 3 — Methylene 1 7 — Oxo 1 1 0 — [4 — (2 — pyridyl) pyrazine 1 — yl] — 2, 3 — Jihi draw 7 H— pyrido [1, 2 , 3-de] [1 _: 4] Benzoxazine-6-carboxylic acid (Exemplified Compound 11

2 7),

 1 0-[4 — (2 — benzoxazolinole) piperazine-1 1 -inole] 1 9 — fluoro-3 — methylene 1 7 — oxo-1 2, 3 — dihydro 1 7 H— pyrido [1, 2,3—de] [1,4] benzoxazine-16-carboxylic acid (example compound 1—32),

 1 0 — [4-(2-benzothiazolyl) piperazine 1 1-yl] 1 9-fluoro 3-methylene 1 7-oxo 1, 2, 3-dihydro 7 H-pyrido [1, 2, 3 — de] [1, 4] Benzoxazine-6-carboxylic acid (Exemplified compound 1-34),

 9 —Hunoleo mouth 1 3 —Methylene 1 7 —Oxo 1 1 0— [4— (2—Pyrimidinyl) pyrazine-1 1—yl] —2,3—Dihidro 7 H—Pyrido [1, 2,

3 — d e] [1, 4] Benzoxazine-6-capillonic acid (Exemplary compound 13 7),

9-Funoleollow 1 0 — [4 — (6 —Methoxy-1 2 —benzothiazolinole) piperazine-1 1 —yl] -1 3 —Methylene-1 7 —Oxo-1 2,3-Dihydro-1 7 H-pyrido [1,2,3-de] [1,4] benzoxazine-16-carboxylic acid (exemplified compound 151),

 9 —Fluoro-1 0— [4- (6-Methoxy-1 2 —benzothiazolyl) piperazine-1 1-yl] -1 3 —Methylene-1 7 —oxo-1 2,3 —Dihydro-1 7 H—pyrid [ [1,2,3-de] [1,4] benzoxazine-16-carboxylate ethyl ester (exemplified compound 151-ethyl ester),

 9 Monofluoro 1 0— [4— (4-Methyl-1-2-thiazolyl) piperazine — 1-yl] — 3 —Methylene-17 —Oxo-1,2,3-dihidro 7-Pyrido [1 , 2,3-de] [1,4] Benzoxazine-16-carboxylic acid (example compound: 153),

 9 monofluoro-10— [4— (3,4-dimethyl-1-2-thiazolinole) pirazin-1—yl] —3—methylene-17—oxo-1 2,3—dihidro 7 H [1,2,3-de] [1,4] benzoxazine-16-carboxylic acid (exemplified compound 1-54),

 9 1 Fluoro 1 0— [4 — (5 —Fluoro 2 —pyrimidel) Piperazine 1 1 1 yl] 1 3 —Methylene 1 7 —Oxo 1 2,3 —Dihydro 1 7 H—Pyrido [1 , 2,3-de] [1,4] Benzoxazine-16-carboxylic acid (Exemplified compound 164-1),

 9 Monofluoro 1 0— [4— (5 —Methoxy 2 —Pyrimigel) Piperazine 1 1 1yl] 1 3 —Methylene 1 7 —Oxo 1 2,3 —Dihydro 1 7 Pyrido [1 , 2,3-de] [1,4] Benzoxazine- 1-6—Rubon

(Exemplified Compound 1 1 6 5),

 9-1 Fluoro 1 1—— 4— (5—Hydroxy-1—Pyrimigenole) Pyrazine—1—1yl—1—3—Methylene—7—Oxo—1,2—3-Hydrogen 7 H—Pyrido [1,2,3-de] [1,4] benzoxazine-16-carboxylic acid (exemplified compound 1-66),

9-Funoleol 3—Methylene 1 10— [3—Methinole 4— (2—Thiazolyl) pyrazine] 1-yl] 1 7—oxo-1 2,3—Dihydro 1 7H—pyri De [1,2,3—de] [1,4] benzoxazine-16-carboxylic acid (example compound 3-25),

 9-Fluoro-3-methylene-1 10— [3-Methyl-1- (2-pyrimidinyl) piperazine-11-yl] — 7-oxo-1 2,3-Dihydro-1 7H—pi Lid [1,2,3—de] [1,4] Benzoxazine—6—Capric acid

(Exemplified compound 3-3 7),

 1 0— [4 — (2 —benzothiazolyl) piperazine-1 1-yl] — 9-fluoro-1 3-methylene-1 7-oxo-1 2,3 —dihidro 7 H—pyrid [1,2, 3 — de] [1, 4] Benzoxazine-16-carboxylate (ethyl ester of Exemplified Compound 1-34) and

1 0 — [4 — (2 —benzothiazolyl) piperazine-1 1-yl] — 9-fluoro-1 3-methylene-1 7-oxo-1 2,3 —dihidro 7 H—pyrid [1, 2,3—de] [1,4] Benzoxazine-16-sodium sodium rubonate (sodium salt of Exemplified compound 1-34).

The compound represented by the general formula (1), which is the active ingredient of the present invention, can be produced by the following methods Λ, Β or C.

 Law

m)

B method

(m)

 (I)

C method

 (vm)

(I) In the above formula, R ′, RR ³ , X and m have the same meanings as described above, L represents a fluorine atom or an acetyl group, and Ha 1 represents a halogen atom (preferably a fluorine or chlorine atom. ).

In Method A, a quinoline carboxylic acid compound (II) is subjected to force-blowing of a cyclic diamine (II) in the presence or absence of a deoxidizing agent, in the presence or absence of a solvent, to give the desired compound (1). ). Examples of the solvent used in this reaction include sulfoxides such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, and hexamethylphosphoric acid triamide. Nonprotonic polar solvents such as amides (especially dimethyl sulfoxide or N, N-dimethylformamide) are suitable, but other ketones such as acetone and methylethylketone; Use ethers such as getyl ether, tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols such as methanol, ethanol, propanol, isopropanol and butanol; and nitriles such as acetate tritol. You can also. Examples of the deoxidizing agent include 1,8-diazabicyclo [5.4-0] -17-indene, 1,5-diazabicyclo [4.3.0] —5-nonene, triethylamine, N Tertiary amines such as N, N-diisopropylethylamine, tributylamine, pyridine, picolin, lutidine and collidine; sodium methoxide, sodium methoxide and potassium t— Metal alkoxides such as butoxide; inorganic bases such as sodium carbonate and carbonated lime can be used, and tertiary amines (particularly triethylamine) are preferred. The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (II). In the case of the tertiary amines described in flii, it can be used in a large excess as a solvent. Also Excessive diamines (110 also acts as a deoxidizing agent, so the reaction proceeds smoothly without adding any other deoxidizing agent. The reaction is carried out at 0 "C to 200 ° C. C (preferably 80 ° C. to 150 ° C.), and is usually carried out for 0.5 to 24 hours (preferably 2 to 12 hours).

In the method B, the cyclic diamines (III) are added to the boron carboxylate compound (IV) of a carboxyquinoline in the presence or absence of a deoxidizing agent and a solvent in the same manner as in the method A. Or absence: a method in which compound (V) is obtained by force-pulling down and then reacted in a hydroalcoholic alcohol in the presence of a base to dechelate to produce the desired compound (I).

In the coupling reaction in the method B, the same deoxidizing agent and solvent as described in the method A are used, and the reaction temperature is 0 ° C to 150 ° C (preferably 0 ° C to 80 ° C). ) In the range of 0.5 o'clock to 24 o'clock (preferably) hours to 10 o'clock. Examples of the base used for the de-chelation in the above-mentioned Method B include sodium hydroxide and alkali metal hydroxides such as sodium hydroxide, sodium carbonate and the like. Alkali metal carbonates such as potassium carbonate; 1,8-diazabicyclo [5.4.0] — 7-ndecene, 1,5-diazabicyclo [4.3.0] — 5—nonene, triethylamine, N Tertiary amines such as N, N-diisopropylethylamine and 4-dimethylaminopyridine; or metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. And tertiary amines (particularly, triethylamine or 1,8-diazabicyclo [5.4.0] —7-indene). The use efficiency of the salt is preferably equimolar to 10-fold molar amount to compound (V), but a large excess of 1: can also be used. As a water-containing alcohol used as a solvent, for example, can be used methanol containing from 5 to 9 0 wt ° / ₀ of water, ethanol, propanol, isopropanoyl no Honoré及Binomatawa butanol Preferably, it is methanol or ethanol containing 5 to 30% by weight of water. The reaction is carried out at a temperature ranging from 0 ° C to 150 ° C (preferably 50 ° C to 120 ° C), from 0. hour fill to 24 hours (preferably 1 to 10 hours). Q) This is done over time.

In the method C, the compound (VIII) is used in place of the starting compound (IV) in the method B, and the reaction is carried out in the same manner as in the method B to obtain a compound (VIII). Then, the compound is removed in the presence of a base. This is a method for producing the target compound (I) by a hydrogen halide reaction.

Examples of the base used in the dehydrohalogenation reaction in Method C include the same bases as those used in the above-described dechelation. Preferably, tertiary amines (particularly, 8-diazabicyclo [5.4.0] — 7-indene or triethylamine). The amount of the base to be used is 1 to 30 moles (preferably 1 to 20 moles) relative to compound (VIII). Examples of the solvent include non-profit compounds such as sulphoxides such as dimethylsulfoxide, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphate triamide. Polar solvents; phenols such as methanol, ethanol, butanol and butanol; etc .; acetonitrile Nitrils such as toluene; water and their mixed solvents can be used, and preferred are alcohols (particularly methanol and ethanol) or hydrous alcohols (particularly hydrous methanol and hydrous ethanol). . The reaction is 0. C. to 150.degree. C. (preferably 50.degree. C. to 120.degree. C.) for 0.5 to 24 hours (preferably 1 to 10 hours). . In addition, when the compound (VII) is de-cleaved, the reaction is carried out using a large excess of a base, so that the de-chelation and the dehydrohalogenation reaction are carried out simultaneously, so that the target compound (1) can be obtained at once. You can also get. The compound (1 ′) in which the substituent R ¹ of the general formula (I) is a heteroaromatic ring group can also be produced by the following Method D.

D method

上記式屮、 R²、 R \ X及び mは前記と同意義であり、 R ¹' は複素芳香環 基であり、 H a 1 はハロゲン原子を示す。 D法の反応は、 A法で述べたものと同様に行われる。 即ち、 キノ リ ンカルボン酸化合物（IX) と等モル乃至 5倍モルの化合物 ( X ) とを、 脱酸剤の存在下、 溶媒の存在下又は不存在下にカップリングさ せることにより、 化合物 （ 1 ' ) が製造される。

The above formulas, R ² , R \ X and m have the same meaning as described above, R ¹ ′ is a heteroaromatic group, and Ha 1 represents a halogen atom. The reaction in Method D is performed in the same manner as described in Method A. That is, by coupling the quinoline carboxylic acid compound (IX) with an equimolar to 5-fold molar amount of the compound (X) in the presence of a deoxidizing agent, in the presence or absence of a solvent, the compound ( 1 ') is manufactured.

Examples of the solvent used in the method D include sulfoxides such as dimethyl sulfoxide, amides such as N, N-dimethylformamide, N, N-dimethylinoleacetamide, and hexamethylphosphoric acid triamide. Such non-protonic polar solvents (particularly, N, N-dimethylformamide) are suitable, but other ketones such as acetone, methylethylketone, etc .; getyl ether, tetrahydrofuran, dioxane, etc. Ethers; esters such as ethyl acetate; methanol, ethanol, propanol, and isoprono. It is also possible to use alcohols such as ethanol and butanol; and butyryls such as acetonitrile. Examples of the deoxidizing agent include 1,8-diazabicyclo [5.4.0] -7-indene, 1,5-diazabicyclo [4.3.0] -15-nonene, triethylamine, tributyla Tertiary amines such as amine, pyridine, picoline, lutidine and collidine; or inorganic bases such as sodium carbonate and carbonated carbonate can be used. In particular, potassium carbonate. The amount of the deoxidizing agent to be used is preferably equimolar to 10-fold molar with respect to the compound (X), but when the tertiary amines are used, they should be used in large excess as a solvent. Can also. This reaction is carried out at a temperature of 0 ° C. to 200 ° C. (preferably 80 ° C. to 150 ° C.), usually for 1 hour to 24 hours (preferably 2 to 10 hours). Q) It is done over. In the compound represented by the general formula (1), a substituent R is used. In the case of producing a compound having a hydroxyl group, it is preferable to protect the hydroxy group contained in the starting compound (III) or (X) with an appropriate protecting group. That is, as a raw material compound, a hydroxy group is protected with a protected S (preferably a benzyl group) such as a benzyl group, a methyl group, a t-butyl group, a methoxymethyl group, a methoxymethyloxy group or a t-butyldimethylsilyl group. The compound (I) in which the corresponding hydroxy group is protected is obtained by any one of the above methods A to D using the obtained compound, and the protecting group is then removed to obtain the substituent R. As a result, a compound having a hydroxy group-can be easily produced.

 The introduction and removal of the protecting group for the hydroxy group can be appropriately selected from known methods (see TWGreene and Pi) and H. Wuts Protective Groups in Organic Synthesis 2nd Ed. John Wiley and Sons.). For example, the removal of the benzyl group can be carried out by a method using a thioazirnotritrifluoroacetic acid, a thiol compound (especially ethyl mercaptan), a boron trifluoride etherate complex, or trimethylsilyl iodide (preferably thiol thiol). The method can be easily carried out by dissolving Z-trifluoroacetic acid). In the above reaction, after completion of the reaction, the target compound of this reaction can be obtained by treating the reaction mixture according to a conventional method, and, if necessary, using a usual purification method such as a recrystallization method or column chromatography. And can be purified.

The compound (1) thus obtained can be converted into a desired pharmacologically acceptable salt or ester derivative according to a conventional method, if necessary. Compound (II) used as a starting material in the above-mentioned Method A is disclosed, for example, in JP-A-59-14889 or J. Heterocyc 1 icchem., 28, 1061 (1992). 1) or a method similar thereto The starting compound (IV) in the method B can be obtained from the compound (II) or its ester by a known method, for example, a method using borofluoric acid, a boron fluoride ether complex or triacetoxyboric acid. It is easily manufactured. The compound (III) used in the above method (1) can be easily prepared, for example, by the method described in JP-A-6-116241 or JP-A-8-187375 or a method analogous thereto. It is manufactured in. The starting compound (VO can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. Sho 62-155,282 or a method similar thereto. In the method D, it is used as a starting material. The compound (IX) is produced by reacting the compound (II) or (IV) as a starting material with a cyclic diamine (III) wherein R ¹ is a hydrogen atom in the same manner as in the method A or the method B. The compound represented by the above general formula (I) produced as described above may have an optically active substance, in which case, the compound is optically resolved at an appropriate stage. By carrying out the above reaction using the starting compounds, the corresponding optical isomer of the target compound (I) can be obtained. Each optical isomer is processed according to the optical resolution method of As described above, the carboxyl group of the compound represented by the general formula (I) may form an ester acceptable on the drug 1 as described above. Conventional methods (for example, in the former case, a dehydration condensation method using an acid catalyst, a method via an acid halide, and a dehydration condensation method using a carbodiimide) in the latter case. Basic conditions G exchange reaction below). The compounds of the general formula (I) of the present invention, their pharmaceutically acceptable esters and their pharmaceutically acceptable salts have excellent antiviral activity (in particular, anti-HIV and anti-HCMV activity). It is useful as a therapeutic agent for infectious diseases caused by viruses. Dosage forms for that purpose include, for example, oral administration by tablets, capsules, granules, powders, syrups, etc., or parenteral administration by intravenous injections, intramuscular injections, suppositories, etc. No. These drugs are manufactured by a known method using additives such as a shaping agent, a binder, a disintegrant, a lubricant, a stabilizer, and a flavoring agent, if necessary. The dosage varies depending on age, body weight, symptoms, dosage form and number of administrations.For example, in the case of oral administration to adults, the lower limit is 1 mg (preferably 10 mg) per 13 doses. As an upper limit, 100 mg (preferably 500 mg) is administered once or in several divided doses. Further, the compound of the general formula (I) did not show toxicity even when orally administered to a rat a dose several times the above-mentioned administration fi (converted to body weight).

 Next, the present invention will be described more specifically with reference to Examples, Formulation Examples and Test Examples. BEST MODE FOR CARRYING OUT THE INVENTION (Example 1)

 9-Funoleol 3-Methylene-1 7-oxo-1 10— [4- (2-Pyrimidinyl) pyrazine-1 1-yl] —2,3-Dihydro-1 7H—Pyrido [1,2 , 3-de] [1, 4] Benzoxazine-16-carboxylic acid

9,7-Difluoro-3-fluoromethinole 7-oxo-1,2,3-dihydro 1-7 H-pyrido [1,2,3-de] [1,4] benzoxazine-6- 4δ Carboxylic acid boron trifluoride adduct 1. O g (2.9 mmo 1) was dissolved in 5.7 m 1 of dimethyl sulfoxide, and 0.95 g of 1- (2-pyrimidyl) pidazine was dissolved. 5.8 mmo1) and 0.8 lml of triethylamine were added, and the mixture was left overnight at room temperature. 300 ml of dimethyl ether containing a small amount of ethanol was added to the reaction mixture, and the precipitated yellow crystals of the chelate compound were collected by filtration. The obtained crystal was suspended in 200 ml of 90% methanol, and 1,8-diazabicyclo [5.

4.0] —7-Pendecene (10 ml) was added, and the mixture was heated under reflux with stirring for 10 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, neutralized with a dilute acetic acid aqueous solution, and the crystals were collected by filtration. The dried product was dried and subjected to silica gel gel chromatography (eluent: chloroform: methanol = 9:〗) to give 0.61 g of the title compound as a yellow powder.

 Melting point: 287-289. C

Mass storage (CI): / z 4 2 4 (M ⁺ + 1)

NR spectrum Bok Honoré _{(DMS0- d 6, δ) 3.37-3.40} (411, m), 3.86-3.89 (4Η, m),

 5.01 (2Η, s), 5.53 (111, d, J = 3Hz), 6.01 (111, d, J = 3Hz), 6.67 (1H, t, J = 5.1 Hz), 7.63 (111, d, J = ll. 7Hz), 8.39 (211, d, J = 5.1Hz), 8.91 (1H, s), 14.81 (1H, s).

(Example 2)

 1 0 — [4-(2-benzothiazolyl) piperazine-1 1 -yl] — 9-fluoro 3-methylene-1 7 -oxo-1, 2,3-dihydro-1 7 H-pyrido [1, 2, 3-de] [1, 4] Synthesis of Benzoxazine-1-6-Rubonic Acid

 The title compound was obtained as a yellow powder in the same manner as in Example 1 except that 1- (2-pyrimidyl) pidazine was used instead of 1- (2-benzodiazolyl) pidazine.

 Melting point: 263-265. C

Mass spectrum (CI): mZ z 4 7 9 (M + + 1)

NMR spectrum Bok Honoré _{(CDC1 3, δ) 3.49-3.51 (} H, m), 3.78- 3.81 (4H, m),

4.85 (211, s), 5.32 (1H, d, J = 2.9Hz), 5.67 (1H, d, J = 2.9Hz), 7.11 (111, t, J = 7.3Hz), 7.29-7.35 (111, m), 7.57-7.65 (211, m),

7.77 (lll, d, J = 11.7Hz), 8.91 (111, s), 14.55 (111, s) ₀

(Example 3)

 9-Fluoro-1 0— [4- (6-Methoxy-2-benzothiazolyl) piperazine-1 1-yl] — 3—Methylene-1 7 —oxo-1 2,3-Dihidro 7 H—Pyrido [1 , 2,3-de] [1,4] Synthesis of benzoxazine-16-carboxylic acid

 1 In place of 1- (2-pyrimidyl) pidazine, 1- (6-Methoxy-1-2-benzothiazolyl) pidazine was used to convert the title compound to a yellow powder in the same manner as in Example 1. I got it.

 Melting point: 246-248 ° C

 Mass spectrum (C I): m / z 509 (M ++ 1)

NMR spectrum Honoré _{(CDC1 3, 6) 3.48-3.51 (} 4Η, m), 3.73-3.76 (4Η, m),

3.83 (3Η, s), 4.85 (2Η, s), 5.32 (1H, d, J = 2.9Hz), 5.67 (111, d, J = 2.9Hz),

6.93 (1H, dd, J = 8.8Hz, J = 2.9Hz), 7.18 (111, d, J = 2.911z), 7.49 (1H, d, J = 8.8Hz),

7.76 (111, d, J-ll. 7Ilz), 8.90 (1H, s), 14.57 (1H, s). In the same manner as in Example 1, the compounds of Examples 4 to 18 described in Table 6 were obtained.

(Table 6)

実施例 R ² R 性状 融点 (°C)

Example R ² R Properties Melting point (° C)

4 Water 4 Funole Sai Loff Einore Light yellow powder 2-6—248 5 Hydrogen 2-pyridyl yellow powder 229-230

 6 Hydrogen 2-Methoxyphenyl pale yellow powder 223-225

 7 Hydrogen 3-black Mouth orange yellow powder 225 to 227

 8 Hydrogen 2-benzoxazolyl pale yellow powder 259 ~ 260

 Hydrogen phenyl yellow powder 215-218

 10 Hydrogen 4-Methoxyphenyl Yellow powder 254-257

 11 Hydrogen 51-Funoleo 2-Pyrimidinole

 Yellow powder 295 (decomposition)

 12 Hydrogen 5-Methoxy 2-Pyrimidgel

 Light yellow powder 283-286

 13 Methinole 2-pyrimidinyl yellow powder 270-272

 14 Methyl 2-thiazolyl blue powder 238 ~ 20

 15 Hydrogen thiazolo [5,4-b] pyridin-2-yl

 Yellow powder 285 ~ 286

 16 Hydrogen 2-thiazolyl yellow powder 236-238

 1 Hydrogen 4-methinole-2-thiazolinole

 Yellow powder 260-262

 18 Hydrogen 4,5-dimethyl-2-thiazolinole

 Yellow powder 258.5-259.5

(Example 19)

 9-Flu mouth-:! 0- [4— (5-Hydroxy-2-pyrimidinyl) pidazine-1 1-inole] -3-3-methylene-1 7-oxo-2,3-dihydro-7H-pyrido [1,2, Synthesis of 3-de] [1, 4] benzoxazine-6-carboxylic acid

9-Funoleo mouth—10- [4- (5-benzyloxy-2-pyrimidinyl) piperazin-1-yl] -3-3-methylene-7-oxo-1 2,3-dihydro-7H- 1.30 g (25 mmol) of pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid are added to 38 ml of trifluoroacetic acid, followed by 11 ml of thioanisone monol. Plus 40. Stirred at C for 9 hours. After cooling, 15 Oml of ether was added, and the precipitated solid was collected by filtration. The obtained solid was subjected to silica gel column chromatography (a mixed solution of eluent black form: methanol: aqueous ammonia = 9: 1: 0.1) to give 0.11 g of the title compound. Obtained as a yellow powder.

 Melting point: 300 ° C or more

NMR spectra (DMS0-d6,6)

 3.32-3.34 (411, m), 3.71-3.73 (4H, m), 5.00 (2Η, s), 5.52 (1Η, d, J = 2.4Hz), 6.00 (111, d, J = 2, 4Ilz), 7.62 (111, d,] = 12.2Hz), 8.06 (2H, s), 8.91 (1H, s), 9.30 (1H, brs), 14.82 (111, brs).

(Example 20)

 1 0— [4— (2-benzothiazolinole) piperazine— 1—inole] — 9—funoleo mouth _ 3 -methylene-7-oxo-1, 3,3-dihydro-7 H-pyrido [1 , 2,3-de] [1,4] Synthesis of sodium benzoxazine-6-carboxylate

 10- [4- (2-Benzothiazolyl) pidazine—1-inole] —9-fluoro-3-methylene-17-oxo-1,2,3-dihydro 7H—pyrid [1,2,3-de [1,4] To 0.96 g (2.0 mmol) of benzoxazine-16-carboxylic acid, 20 m 1 of 1N sodium hydroxide aqueous solution and 100 ml of ethanol were added. After heating to a homogeneous solution, the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the mixture was again concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with ethanol, and dried to obtain 0.66 g of the title compound as a pale yellowish white powder.

 Melting point: 232-253. C (decomposition)

(Example 2) (Ethyl ester of Example 2)

1 0-[4-(2-benzothiazolyl) piperazine-1-yl] 1-9-fluoro-1-methylene-1 7-oxo-1, 3-dihydro 2 H-pyrido [1, 2, 3-de] [], 4] Benzoxazine-1 6-force norebon g etinoreeste Ί9 synthesis

 1 0 — [4 — (2-Benzothiazolyl) pidazine-1 1-yl] -1 9-phenololeol 3 —Methylene-1 7-oxo-1, 2,3-dihydro-7 H-pyrido [1,2, 3 — de] [1, 4] Benzoxazine-16-carboxylic acid 6.36 g (13 mmol) and 3.1 g (67 mmol) of ethinoleanoloneco and 41 N, N-dimethylaminopyridine 6. 5 g (53 mmol) and 10.2 g (53 mmol) of 1-ethyl-3 hydrochloride- (3-dimethylaminopropyl) carbodiimide were added to 50 Om1 of methylene chloride, and the mixture was cooled to room temperature. After stirring for 7 days, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel gel chromatography (eluent: chloroform: ethanol = 9: 1 mixture) to give 0.777 g of the title compound as a white powder.

 Melting point: 250-252 ° C

Masusu Bae click Honoré (CI): m / z 5 0 7 (M + + l). (Example 22)

 1 0 — [4- (2-benzothiazolinol) piperazine-1 1-inole] — 9 —funoleol 3 —Medelene 7 7-oxo-1 2,3-dihidroh 7 H-pyrido [1,2,3-de] [1, 4] Benzoxazine-synthesis of 6-potassium trimethylammonionethinolestenole

 The title compound was obtained as a white powder in the same manner as in Example 21 except that a link mouth was used instead of ethanol.

 Melting point: 225-240 ° C (decomposition)

(Example 23)

1 0 — [4- (2-benzothiazolyl) piperazine-1 1-yl] -1-9-fluoro 3-methylene-1 7-oxo-1,2,3-dihydro 7H-pyrido [1,2, 3 — de] [1, 4] Benzoxazine-6-potassium N, N-dimethyl benzoate 1 0-[4-(2-Benzothiazolyl) pyridine 1-1-inole]-9-fluoro 3-methylene 1 7-oxo 1, 2, 3-dihydro 7 H-pyrido [1, 2, 3-] de] [1,4] Benzoxazine-16-potassic acid 0.60 g (1.3 mmol) was added to 10 ml of dimethylformamide, followed by 0.21 g (1. 5 mmol) and 0.17 g (0.15 mmol) of 2-chloro-N, N-dimethylacetamide are added. With C, the mixture was stirred for 4 hours. After cooling, the mixture was added to ice water, and the precipitated solid was collected by filtration. After washing with water and drying, the residue was dissolved in a cross-linked form, ethanol was added, and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with ethanol, and dried to obtain 0.65 g of the title compound. Obtained as a white powder.

 Melting point: 24 6 ~ 2 4 7 ° C

(¾Example 2 4)

 1 0-[4-(2-benzothiazolyl) piperazine-1-inole]-9-phenololeol 3-methylene-1 7-oxo-1,3-dihydro 7 H-pyrido [1, 2, 3-de ] [1, 4] Benzoxazine-6-potassium N-methinolate Syntheses of enolen methinooleestenole

 The title compound was obtained as a pale yellowish white powder in the same manner as in Example 23.

 Melting point: 24 7 ~ 2 49 ° C

(Formulation Example 1)

 Capsule

 50 mg of the compound of Example 1

 Lactose 1 2 8 mg

 Corn starch 70 0 mg

 Magnesium stearate 2 mg

 250 mg

Mix the powder of the above formula, pass through a 60 mesh sieve, Put 50 mg in a No. 3 gelatin capsule to make a capsule.

(Formulation Example 2)

 Tablets

 50 mg of the compound of Example 1

 Lactose 1 2 6 mg

 Corn starch 23 mg

 Magnesium stearate l mg

 2 0 0 mg

 The powder of the above formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 200 mg per tablet. These tablets can be sugar-coated if necessary.

(Test Example 1) Anti-HIV activity

The anti-HIV activity of the compound of the present invention is measured according to the method of R. Pauwe 1 and the like (J. Viro 1 ogica 1 Mehods 20, 309-32 1 (1 988)). went. That is, MT-4 cells are centrifuged, and the cell suspension in which the obtained cell sediment is suspended is infected with HIV by inoculation, followed by addition of 10% fetal calf serum RPM I-164 0 medium (hereinafter referred to as serum medium) was added, washed, and centrifuged. The thus II IV infected cells及Pi HIV uninfected cells obtained were suspended in serum medium so that each becomes 4 X 1 0 ⁵ or Zm 1. Compounds that had been serially diluted in serum medium were added in 100 μl portions to each well of a 96-well plastic microplate for tissue culture, and then added in the presence of 5% carbon dioxide. C for 5 days. Similarly, H1V-infected cells and non-infected cells without compound addition were cultured. After completion of the culture, the number of viable cells is measured using MTT (3 — (4, 5 — dimethylthiazoyl 2-yl) — 2,5 — diphenyltrazolamide bromide), and the cytotoxicity inhibitory activity by adding the compound is measured. I asked. It was confirmed that mycoplasma was not contained in the cell solution and the inoculated virus solution. The cytotoxicity-suppressing activity of non-compound-free HIV-infected cells was set at 100%, and that of compound-free H1V-infected cells was set at 0%. The concentration (EC ₅ ) of the compound showing% cytotoxicity-inhibiting activity was determined. Further, as the cytotoxic activity of the compounds, the growth of HIV uninfected cells sought 5 0% inhibition concentration (CC _50), Jiji _5. / £ 〇 _5. The value was taken as the selection coefficient (SI) of the anti-141 V activity, and Table 7 shows the test results.

 The compound used as a comparative compound in Test Example 1 and Test Example 2 described later was represented by the formula

X: 0.

で表される化合物であって、 特開昭 5 9— 1 4 8 9号及び J . H e t e r o e y e 1 i c C h e m. 2 8卷、 1 0 6 1 頁 （ 1 9 9 1年） に記載された ものである。

Which is described in JP-A-59-14889 and J. Heteroeye 1ic Chem. 28, Vol. 16, page 61 (1991). It is something.

(Table 7)

 Compound E C 50 0 50 S I

 (t g / m 1) (μ g / m 1)

 Example 1 0.15 2.6 17.3 Example 2 0 0 0 8 0 .1 6 2 0

 Example 3 0 0 4 3 0 .3 7 9

 Example 4 0 1 7 2. 5 1 4.7 Example 5 0 1 5 2. 7 1 8

 Male 6 2 3 5

Example 7 0 4 4 2 1 0 5 -Example 8 0 2 1 .2 6 Example 9 0 2 5. 4 2 7

 Example 1 0 0 7 7 7.5 2 2.7 Example 1 1 0 3 7 4.2

 Example 1 2 0 6 2 5.69

 Example 1 3 0 6 7 2 8.3 Example 1 4 0 1 .8 1 1.8 Example 1 5 0 5. 7.6

 Example 1 6 0 4 6 3.99 9

 Example 1 7 0 3 8 2. 4 6

 Example 1 8 0 1 9 1 .3 7

 Example 1 9 0 2 8 8 6

 Comparative compounds> 25.0 The compounds of the present invention exhibited excellent anti-HIV activity and low cytotoxicity. In particular, the compounds of Zang Examples 2, 9, 10 and 13 exhibited excellent anti-HIV activity with a selectivity factor (SI) of 20 or more.

(Test Example 2) Anti-H CMV activity

The anti-HCMV activity of the compounds of the invention can be determined according to the method reported by Tims et al. (J. Antimi crobial and Chemotherapy Vol. 8, pp. 62-75, 1989), according to the general method. The plaque reduction method was used. That is, human embryonic fibroblasts (MR C - 5) HCMV strain (AD 1 6 9) in monolayer culture 1 00 plaque forming units (pf _U) Bruno 1 0 ⁵ cells equivalent to infected, the test compounds The cells were cultured at 37 ° C for 8 minutes in the presence of the microorganism. 0.5 ° / for culture after infection. The cell phase was overlaid with Eagle's MEM medium (supplemented with 2% fetal calf serum) containing agar, fixed 10 days after infection, and stained with methylene blue. A drug concentration-dependent curve of the plaque formation reduction rate compared to the drug-untreated control was plotted. 0% P11 concentration: (IC ₅₀ ) was determined.

 The test results are shown in Table 8 together with the results of Test Example 3.

(Test Example 3) Cytotoxicity

 The cytotoxicity of the compound was measured using MT-4 cells according to the method of R. Pauwe 1 et al. (J. Virological Methods 20, 309-321, 1988). went. That is, 10% fetal calf serum added R PM I-164 0 medium

MT-4 cells were suspended in a serum medium (hereinafter referred to as serum medium) at a concentration of 4 x 10 ⁵ Zm1, and the compound, which had been serially diluted in serum medium, was placed in a 96-well plate for tissue culture. 4. Add 100 μl to the wells. 3/7 in the presence of carbon dioxide. 5 Ptiij cells were cultured. After completion of the culture, the number of viable cells was measured using MMT (3- (45-dimethylthiazol-1-yl) -125-diphenyltetrazolamide bromide). The percentage of the number of viable cells to which the compound was added when the concentration was 0% was determined, and the concentration of the compound at which ₅₀ % of the cells survived (CC ₅₀ ) was determined. Among the compound which is the active ingredient of the present invention (I), illustrating the anti-HCMV activity of the compound of Example 2 5 and 9 (IC _5. Values) and cytotoxicity (CC _5. Value) in Table 8. Incidentally, in the table SI value (selectivity coefficient) is, CC _5. IC ₅ values. The value is divided by the value and is an indicator of the safety of the compound.

(Table 8)

Compound IC _so C so SI

(g X m 1) (μ g / m \) Example 2 0. 0 1 6 0. 1 6 1 0 Example 3 0. 0 1 6 0. 3 7 2 3 Example 5 0.3 3 8.0 24.2 Example 9 0.47 1 2.0 25.5 Comparative Compound> 4.0 The compound (I) of the present invention has excellent anti-HCMV activity. And low cytotoxicity. Compounds of实施Example 2 IC _5. The value was 0.016 μg / m 1, indicating extremely strong anti-HCMV activity. Further, the compounds of Examples 3, 5 and 9 exhibited excellent anti-HCMV activity having a selectivity factor (S1 value) of 20 or more.

(Reference example)

 1. Cell lines and media used

 Human 14-week-old fetal lung-derived cell line MR C-5 was purchased from Dainippon Pharmaceutical and supplied with 10% immobilized fetal serum (FBS) and 5% Penicillin-Streptomycin Solution (Sigma) II After incubation in Minimum Essential Medium, Hank's salts (MEM-H), apply 10% immobilized fetal blood (FBS) and 0.2% Penicill in-Streptomycin Solution (Sigma). [I 7] The medium was exchanged for Minimum Essential Medium, Earle's salts (MEM-E), and the cells were cultured. The medium was changed every 3 to 4 days.

2. H CMV strain and culture method

Human Cytomegalovirus (HCMV) AD169 strain was purchased from ATCC. Winores cultivated as follows. First, 4 ml of a virus solution diluted to 0.1 virion per cell was added to MRC-5 cells, which form a nearly monolayer in a medium-angle flask, and 37. Cells were infected by incubation for 90 minutes at C. Then remove the virus solution and add 8 ml of MEM-E containing 2% FBS. The cells were cultured for 7 to 10 days in a carbon dioxide gas incubator C. After confirming that viral damage (CPE) has appeared in most cells, After peeling the cells from the flask with a Rusker, the lid was closed and the cells were sonicated for 2 minutes to disrupt the cells and release virus particles. Transfer the lysate to a 50 ml centrifuge tube, centrifuge at 800 rpm for 5 minutes to precipitate cell fragments, dispense the upper part into a vial as a virus stock solution, and store at -80 ° C. did.

3. Measurement of HCMV titer by plaque assay

1 2 -well plate to MR C-5 cells monolayer culture, 1 0 to 1 0 ⁵ diluted virus solution 0. 4 ml Dzukkuwae, 3 7 ° C, 9 0 minutes kept to infected to cells I let it. Thereafter, except for the virus solution, and 2 m 1 Dzu' overlaid with those of 2-fold concentration of MEM one E 1% Agaro Ichisu was equivalent mixture containing 4% FBS, 3 7 ^D C of carbonated moth Thin particulate beta one From 10th to 10th, the cells were cultured until the cell damage (CPE) due to the virus appeared. Then, 3.7% formaldehyde was added to fix the cells, agarose was peeled off, stained with 0.3% methylene blue for 20 minutes, washed with running water, and the number of plaques (CPE) was counted. When virus 1 0 ⁿ dilution 0. 4 ml inoculated k number of plaques were detected, the virus titer of the stock solution (plaque foming unite, PFU) was calculated from the following equation.

PFU / ml = k X l O r * X 2. condensed keno Li Nkarubon acid derivatives represented by the general formula (1) of the availability of the present invention on 5 industries, esters and their acceptable thereof蔡理Pharmaceutically acceptable salts exhibit excellent antiviral activity, especially anti-HIV and anti-HCMV activity, are superior in oral absorption, and are less toxic, and are therefore suitable for viruses (especially, It is useful as a proliferative inhibitor for 111 ¥) and as a prophylactic or therapeutic agent for viral (especially 141 1 and 111 ^) infectious diseases.

Claims

 The scope of the claims -General formula (1)

[In the formula (I), R ¹ is a substituent R. And aryl and / or substituent R having 6 to 10 carbon atoms which may be substituted with Or a 5- or 6-membered heteroaromatic group containing one or two heteroatoms selected from N, O and S which may be condensed with benzene or pyridine. And the substituent R. Represents a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms replaced by a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and a carbon atom having 1 to 6 carbon atoms. 6 alkylthio groups or a group selected from a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a nitryl group, an aryl group which may be substituted with hydroxy or cyano. Wherein R ² and R ³ are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, X represents O or S, and m represents an integer of 2 or 3. And a pharmacologically acceptable salt or ester thereof. 2. In claim 1, R ¹ may be a phenyl group which may have a substituent or may have a substituent, and may be condensed with a benzene or pyridine ring. And a 5- or 6-membered heteroaromatic group containing one or two heteroatoms selected from S and S, wherein the substituent is a halogen atom, a hydroxy group, an alkyl group having 1 to 4 carbon atoms, a fluorine atom An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms A fused quinoline carboxylic acid derivative or a pharmacologically acceptable salt thereof, which is a phenyl group optionally substituted by a fluorine, chlorine, methyl, methoxy, nitro, hydroxy, or cyano group; Or an ester thereof. 3. The method according to claim 1, wherein R ¹ may have a substituent, phenyl, 2-phenyl, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2 — pyridyl, 3 — pyridyl, 4 — pyridyl, 2 — pyrimidinole, 4 — pyrimidinyl, 5 — pyrimidinyl, 2 — pyrazur, 3 — pyridajunole, 2—benzoxazolinole, 2-benzothiazolinole, 2—benzimidazolinole, 3—Benzoisoxazolyl, 3—Benzoisothiazolyl, Oxazolo [5, 4-b] Pyridine-1 2-yl, thiazolo [5, 4-b] Pyridine-12-inole, imidazo [5, 4-b] Pyridine-12-yl, oxazolo [4, 5-b] Lysine-1 2-yl, thiazolo [4, 5-b] Pyridine-2-yl, thiazolo [5,4-c] pyridine-12-yl or thiazolo [4,5-c] pyridine-12-yl group, and the substituent is fluorine, chlorine, hydroxy, methyl, ethylene, Trifluoromethyl, methoxy, ethoxy, methylthio, ethinolechio, feninole, 4—funenole, feninole, 4-cloth feninole, 4-methinolefeninole, 4-methinofeninole, 4-methoxy A condensed quinoline carboxylic acid derivative which is tropofinole, 4-hydroxypheninole or 4-cyanophenyl group, or a pharmaceutically acceptable salt or ester thereof. 4. In claim 1,! ¾ 'phenyl which may be substituted with fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl | £; fluorine, chlorine, hydroxy, methyl, phenyl, 4-fluorophenyl Phenyl, 4-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, or 4-methoxyphenyl 2-thiazolyl; fluorine, chlorine, hydroxy, methyl Or 2-pyridyl group optionally substituted with methoxy; substituted with fluorine, chlorine, hydroxy, methyl or methoxy 2-pyrimidinyl group; 2-benzothiazolyl group optionally substituted with fluorine, chlorine, hydroxy, methyl, methoxy or methylthio; fluorine, chlorine, hydroxy, methyl, methoxy or 2-Benzoxazolyl group optionally substituted with methylthio; or thiazolo [5,4-1b] pyridine-12-yl optionally substituted with fluorine, chlorine, hydroxy, methyl, methoxy or methylthio A fused quinoline carboxylic acid derivative or a pharmaceutically acceptable salt or ester thereof. 5. The method according to claim 1, wherein: R ¹ ; phenyl, 4-phenylphenol, 2-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 2-thiazolinole, 4-thiazole. Methyl-1-2-thiazolyl, 3,4-Dimethyl-2-thiazolyl, 2-pyridyl, 2-pyrimidinyl, 5-fluoro-2-pyrimidyl, 5-hydroxy1-2-pyrimidyl, 5-methoxy-1-2 —Pyrimidinyl, 2—Benzothiazolyl, 6—Methoxy-12-benzothiazolyl, 2—Benzoxazolyl or thiazolo [5,4-1b] Pyridine-12-A fused quinoline carboxylic acid derivative or a pharmacologically An acceptable salt or ester thereof. 6. In Claims 1 to 5, R ² and R ³ are the same or different and are a hydrogen atom, a methyl, ethyl or propyl group, or a fused quinoline carboxylic acid derivative or a pharmacologically acceptable salt thereof. ester. 7. In claims 1 to 5, 1¾ ² and 1¾ ^3, same or different, condensed Keno Li Nkarubon acid derivative or a salt or ester thereof pharmacologically acceptable is hydrogen atom or a methyl group. 8. The fused quinoline carboxylic acid derivative according to any one of claims 1 to 5, wherein R ² and R ³ are a hydrogen atom, or a pharmaceutically acceptable salt or ester thereof. 9. The fused quinoline carboxylic acid derivative or a pharmacologically acceptable salt or ester thereof according to any one of claims 1 to 8, wherein X is O (oxygen atom). 10. The fused quinoline carboxylic acid derivative according to any one of claims 1 to 9, wherein m is 2, or a pharmacologically acceptable salt or ester thereof. 11. The method according to claim 1, wherein R ¹ may have a substituent, 2-Cheninole, 2-furyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyridyl, 4-pyridyl Midinyl, 5-pyridimidinyl, 2-pyragel, 3-pyridazinyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzothimidazolinole, 3—Benzoisoxazolinole, 3—Benzoisothiazoli7, Oxazolo [5, 4-b] pyridin-1-yl, thiazolo [5, 4-b] pyridin-12-yl, imidazo [5, 4 — b] pyridine-12-yl, oxazolo [4, 5-] b] Pyridine—2—yl, thiazolo [4, 5-b] Pyridine—2—yl, thiazolo [5,4-1c] pyridin-2-yl or thiazolo [4,5-c] pyridin-2-yl group (the substituents are fluorine, chlorine, hydroxy, methyl, ethyl, triethyl) Funoleolomethinole, Methoxy, Ethoxy, Mechinorecho, Etinorecho, Feninore, 4-Funoleolofeninole, 4—Clo-mouth Feninore, 4—Methinolefeninole, 4-Methoxyfeninole, 4 R ² and R ³ are the same or different and are a hydrogen atom, a methyl, ethyl or propyl group, and X is an O—N-nitrophenyl, 4—Hydroxyphenyl or 4-Cyanophenyl group. A fused quinoline carboxylic acid derivative wherein m is 2 or a pharmacologically acceptable salt or ester thereof. 12. The method according to claim 1, wherein R ¹ is a phenyl group which may be substituted with fluorine, chlorine, hydroxy, methyl, methoxy, methylthio or trifluoromethyl; fluorine, chlorine, hydroxy, methyl, Phenyl, 4-fluorofluoro Nyl, 4-chloro mouth phenyl, 4-methinophenol, 4-methoxyphenyl or 412 2-thiazolyl group optionally substituted with trophenyl; fluorine, chlorine, hydroxy, methyl or 2-pyridyl group optionally substituted with methoxy; fluorine, chlorine, hydroxy, methyl or 2-pyrimidinyl group optionally substituted with methoxy; fluorine, chlorine, hydroxy, methyl, methoxy 2-benzothiazolyl group optionally substituted with thio or methylthio; 2-benzobenzoazolyl group optionally substituted with fluorine, chlorine, hydroxy, methyl, methoxy or methylthio; or fluorine, chlorine, hydroxy, Thiazolo [5, 4—b] pyridine—2 optionally substituted with methyl, methoxy or methylthio An I le group, R ² and R ³ are the same or different, a hydrogen atom or a methyl group, X is O (oxygen atom), or a condensed onboard phosphoric acid derivatives where m is 2 A pharmacologically acceptable salt or ester thereof. 13. The claim 1, wherein R ¹ phenyl, 4-fluorophenol, 2-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenol, 2-thiazolinole, 4-methylinole 2. Thiazolyl, 3,4-dimethyl-2-thiazolinole, 2-pyridyl, 2-pyrimidyl, 5-fluoro-2-pyrimidyl, 5-hydroxy-1-2-pyrimidinyl, 5-methoxy-1--2-pyrimidinyl, 2— Benzothiazolyl, 6-methoxy-12-benzothiazolyl, 2-benzoxazolyl or thiazolo [5,4-b] pyridin-12-yl group, wherein R ² and R ³ are the same or different and are hydrogen A condensed quinoline carboxylic acid derivative, which is an atom or a methyl group, X is O (oxygen atom) and m is 2, or a pharmaceutically acceptable salt or ester thereof. 1 4.9 —Funolero 3 —Methylene 1 7 —Oxo 1 10— (4 —Feninole pyrazine 1 1-yl) 1, 2,3 —Jihi draw 7 H—Pyrido [1,2, 3-de] [1, 4] Benzoxazine-1-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 1 5. 9—Phenolone 1 0— [4- (4-fluorophenylene) piperazin-1 1-yl] — 3-methylene-1 7-oxo-2,3-dihydro 7 H—Pyrido [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 1 6.9-Fluoro-1 0— [4- (4-Methoxyphenyl) pirazine — 1 —yl] — 3-methylene-17-oxo-1,2,3-dihydro-7 H-pyrido [1 , 2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmacologically acceptable salt thereof or an ester thereof. 1 7.9-Fluoro-3-methylene-1 7-oxo1 10— [4- (2-thiazolyl) piperazine-11-yl] —2,3-dihydro-1-7-pyrido [1 , 2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 1 8.9-Fluoro-3-methylene-1 7-oxo-1 10— [4- (2-pyridyl) piperazine-1—yl] -1,2,3-dihydro-1 7H—pyridone [1 , 2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 19.1 0-[4- (2-Benzoxazolyl) pidazine-1 1-inole] — 9-fluoro-3-methylene-17-oxo-1,2,3-dihydro-1 7H-pyri [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 20. 10- [4- (2-benzothiazolyl) piperazine-1 1-yl] -1-9-fluoro-3-methylene-1 7-oxo-1,2,3-dihydro 7 H-pyri De [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 2 1 .9 —Fluoro 3—methylene 1 7—oxo 1 1 0 — [4— (2—pyrimidinyl) piperazine-1 1] 1 2,3—dihydro 7 H— Pyrid [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 2 2. 9 —Fluoro 1 0 — [4- (6—Methoxy-1—benzothiazolyl) pyrazine-1-yl] — 3—Methylene-1 7 —Oxo-1 2,3 —Dihydro 7 H —Pyrido [1,2,3—de] [1,4] Benzoxazine-16—carboxylic acid or a pharmacologically acceptable salt or ester thereof. 23.9—Fluoro-10— [4- (4-Methyl-1-thiazolinole) pyrazine-1—yl] — 3—Methylene-17-oxo-2,3—Dihidro 7 H—Pyrido [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 2 4.9 —Fluoro-10 — [4— (3,4—Dimethyl-2-thiazolyl) pyrazine-1-yl] —3-Methylene-17—Oxo-1,2,3-dihydro 7 H —Pyrido [1,2,3—de] [1,4] Benzoxazine-16—carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 2 5 · 9 —Hunoleo mouth 1 0 — [4— (5 —Hunoleo mouth 1 2 —pyridininole) Pirazine 1 1 —yl] — 3 —Methylene 1 7 —Oxo 1 2,3 —Dihydro 7 H-pyrido [1,2,3-de] [1,4] benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 26. 9-Fluoro 1 0— [4-1 (5-Methoxy-1—Pyrimidininole) pyrazine-1 1—yl] — 3-Methylene-1 7-oxo-2,3-Dihidro 7 H— Pyrid [1,2,3-de] [1,4] Benzoxazine-16-force oleonic acid or a pharmaceutically acceptable salt or ester thereof. 2 7. 9—Fluoro 1 0— [4— (5-hydroxy 2-pyrimidyl) piperazine—11-yl] —3-methylene—7—oxo-1,2,3-dihydro 7 —Pyrido [1,2,3-de] [1,4] benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 28. 9-Fluoro-3-methylene-1 10— [3-Methyl-4-1- (2-thiazolyl) piperazine-1 1-yl] -7-oxo-1 2,3-Dihydro-1 7-—pyrid [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 29. 9—Henoreo 1—3—Methylene 1 10— [3-Methinole 4— (2-pyrimidinyl) pyrazine—1—yl] — 7—oxo 2,3—dihydro 7 II —Pyrido [1,2,3-de] [1,4] Benzoxazine-16-carboxylic acid or a pharmaceutically acceptable salt or ester thereof. 30. 1 0-[4-(2-benzothiazolyl) piperazine 1-yl] 1-9-fluo-1-3-methylene-1 7-oxo-1, 2-3-dihydro 7-pyrido [1, 2,3-de] [1,4] Benzoxazine-1 6-carboxylate. 3 1.10— [4— (2-benzothiazolyl) piperazine-1 1-yl] -1-9-funoleolor 3-methylene-1 7-oxo-1,2,3-dihydro-1 7H—pyridone [1,, 2,3-de] [1, 4] Benzoxazine-16-carboxylate Realm.  32. A pharmaceutical composition comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 33. A composition for treating or preventing AIDS disease, comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 34. A composition for treating or preventing cytomegalovirus infection, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 35. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for producing a medicament. 36. Use of the compound according to claim 1 or a pharmacologically acceptable salt thereof for producing a method for treating or preventing AIDS disease. 37. Use of the compound according to claim 1 or a pharmacologically acceptable salt thereof for producing a composition for treating or preventing cytomegalovirus infection. 38. A method for treating or preventing AIDS disease in which a pharmacologically effective Ik of the compound according to claim 1 or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal.