JPH0696578B2 - Trivalent compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel tricyclic compounds, especially pyrido [3,2,1-i
The present invention relates to a j] -1,3,4-benzooxadiazine derivative, a process for producing them, a pharmaceutical composition containing these compounds and an intermediate useful for the process.

More specifically, the present invention relates to general formula (I), In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group; R ²
Represents a hydrogen atom or a lower alkyl group which may be substituted with a halogen atom; R ³ and R ⁴ may each independently be substituted with a hydrogen atom, a hydroxyl group, or a substituted or unsubstituted amino group. Represents a lower alkyl group; X represents a halogen atom; and R ⁵ and R ⁶ are each independently a hydrogen atom, or a lower alkyl which may be substituted with a hydroxyl group, a lower alkoxy group or a substituted or unsubstituted amino group. Or R ⁵ and R ⁶ together with the adjacent nitrogen atom may form a 5- to 7-membered heterocycle, wherein the heterocycle has one or more substituents at its carbon atom. in may be substituted, further heterocycle ^{-NR 7 -, - O -,} - S -, - SO -, - SO 2 - or -NR ⁷ -CO- [where, R ⁷ is a hydrogen atom , Lower alkenyl, substituted Which may be lower alkyl or aralkyl group, or the general formula, (II), - (CH 2) nCOR 8 (II) ( wherein, n is 0 to 4, R ⁸ is a hydrogen atom, a lower alkoxy group or, Represents an optionally substituted amino, lower alkyl or aryl group], which is useful as an active ingredient of an antibacterial agent represented by [3,2,1-ij] The present invention relates to a 1,3,4-benzoxadiazine derivative and a pharmaceutically acceptable salt thereof, and a hydrate or solvate of the compound of formula (I) and a salt thereof.

Hereinafter, the substituents in the above formula (I) will be described in more detail;
Unless otherwise specified, the term "lower" preferably has 7 carbon atoms.
It means a carbon chain containing up to 20 carbon atoms.

Description of R ^1: R ¹ is a hydrogen atom or a carboxy protecting group.

In the above, the carboxy protecting group is, for example, a methyl group,
Represents a lower alkyl group such as an ethyl group, an n-propyl group, a t-butyl group; other meanings include, for example, a lower alkanoyloxyalkyl group (eg, acetoxymethyl group,
Pivaloyloxymethyl group, 1-acetoxyethyl group and 1-pivaloyloxyethyl group); lower alkoxycarbonyloxyalkyl group (for example, methoxycarbonyloxymethyl group, 1-ethoxycarbonyloxyethyl group and 1-isopropoxycarbonyl group) Oxyethyl group); lactonyl group (eg phthalidyl group and thiophthalidyl group); lower alkoxymethyl group (eg methoxymethyl group); benzyloxymethyl group; (5-methyl-2-oxo-1,3-dioxol-4-yl ) Methyl group; or lower alkanoylaminomethyl group (for example, acetamidomethyl group) and the like, which means a carboxy protecting group which can be easily hydrolyzed in vivo. Other ester groups such as benzyl group, cyanomethyl group, phenacyl group, phenyl group and the like may also be used.

Description of R ^2: R ² is a lower alkyl group optionally substituted by a hydrogen atom or a halogen atom.

In the above, the lower alkyl group preferably contains 1 to 4 carbon atoms, and is particularly a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or the like, and the halogen atom is fluorine or chlorine. , Bromine, preferably fluorine.

R ³ and R ⁴ are each independently a hydrogen atom, or a lower alkyl group optionally substituted with a hydroxyl group or a substituted or unsubstituted amino group.

In the above, the lower alkyl group preferably contains 1 to 4 carbon atoms, and is particularly a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or the like. The substituted amino group includes a di-lower alkylamino group such as a dimethylamino group and a diethylamino group; a lower alkylamino group such as a methylamino group and an ethylamino group; a lower cyclic alkylamino group such as a cyclopropylamino group.

Description of R ⁵ and R ^6: R ⁵ and R ⁶ each independently represent a hydrogen atom or a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted lower alkyl group optionally substituted with an amino group; or R ⁵ and R ⁶ together with the adjacent nitrogen atom
It may form a 7-membered heterocycle, the heterocycle may be substituted with one or more substituents at the carbon atom, and the heterocycle may be —NR ⁷ —, —O.
-, - S -, - SO -, - SO 2 - or -NR ⁷ -CO- [where, R ⁷ is a hydrogen atom, a lower alkenyl group, an optionally substituted lower alkyl group or aralkyl group, or, formula _{(II), - (CH 2} ) nCOR 8 (II) ( wherein, n is 0 to 4, R ⁸ is a hydrogen atom, a lower alkoxy group, or an optionally substituted amino, lower alkyl or Which represents an aryl group)].

The groups shown above will be described in more detail below.

The lower alkyl group is preferably methyl group, ethyl group, n
-Propyl group, isopropyl group, n-butyl group and the like 1 to
Represents a group containing 4 carbon atoms. The lower alkoxy group is
Preferred is a group containing 1 to 4 carbon atoms such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, and n-butoxy group. The substituted amino group is a di-lower alkylamino group such as dimethylamino group, diethylamino group or ethylmethylamino group; lower alkylamino group such as methylamino group, ethylamino group, n-propylamino group or isopropylamino group; It represents a lower cyclic alkylamino group such as a cyclopropylamino group. The 5- to 7-membered heterocycle formed by R ⁵ and R ⁶ includes a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a piperidyl group, a homopiperazinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, an imidazolyl group, a triazolyl group and the like. Represents Examples of the substituent on the carbon atom of the heterocycle include a hydroxyl group; a lower alkoxy group such as a methoxy group, an ethoxy group, and an n-propoxy group; an amino group; a methylamino group, an ethylamino group, an n-propylamino group, and isopropylamino. A lower alkylamino group such as a group; a lower cyclic alkylamino group such as a cyclopropylamino group; a dilower alkylamino group such as a dimethylamino group, a diethylamino group, an ethylmethylamino group; a lower alkanoylamino group such as an acetylamino group; any A nitro group, an amino group, a halogen atom, a hydroxyl group and / or a benzylamino group which may be substituted with a lower alkoxy group, for example, a (4-aminobenzyl) amino group; A group represented by the formula (wherein R ⁵⁰ and R ⁵¹ are a lower alkyl group or a 5- to 8-membered saturated nitrogen-containing heterocycle together with a nitrogen atom), for example, a (dimethylamino) methyleneamino group, ( Hexahydro-1H-azepin-1-yl) methyleneamino group; benzyloxycarbonylamino group;
Fluorine, chlorine, bromine, etc. halogen atoms; methyl, ethyl, n-propyl, isopropyl, etc. lower alkyl groups; amino lower alkyl groups, lower alkylamino-lower alkyl groups, lower cyclic alkylamino-lower alkyl Group, di-lower alkylamino-lower alkyl group, or lower alkanoylamino-lower alkyl group, and examples of these substituents include aminomethyl group, (methylamino) methyl group, (ethylamino) methyl group, ( n-propylamino) methyl group, (isopropylamino) methyl group, (cyclopropylamino) methyl group, (dimethylamino) methyl group, (diethylamino) methyl group, (ethylmethylamino) methyl group, acetylaminomethyl group,
2-aminoethyl group, 2- (methylamino) ethyl group,
2- (ethylamino) ethyl group, 2- (diethylamino) ethyl group, 2- (dimethylamino) ethyl group, 2-
(Ethylmethylamino) ethyl group; hydroxy-lower alkyl group such as hydroxymethyl group and 2-hydroxyethyl group; phenyl optionally substituted with amino group, halogen atom, hydroxyl group and / or lower alkoxy group Group, for example, 4-aminophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-hydroxyphenyl group, 4-methoxyphenyl group; or heterocycle such as pyrrolyl group, 4-methyl-1-piperazinyl group Etc.

The lower alkenyl group represented by R ⁷ is, for example, an allyl group,
A 3-methyl-2-butenyl group, a 2-butenyl group, a 1-methyl-2-propenyl group, a 3-butenyl group and the like.

The substituted alkyl group represented by R ⁷ is, for example, hydroxy-lower alkyl group such as 2-hydroxyethyl or 3-hydroxybutyl; lower alkoxy-lower alkyl group such as 2-methoxyethyl or 2-ethoxyethyl; 2- Amino-lower alkyl groups such as aminoethyl and 3-aminobutyl; 2
Lower alkylamino-lower alkyl group such as (methylamino) ethyl group, 2- (ethylamino) ethyl group, 3- (methylamino) butyl group, 3- (ethylamino) butyl group; 2- (dimethylamino) ethyl Group, 2- (diethylamino) ethyl group, 3- (dimethylamino) butyl group, 3
Di-lower alkylamino-lower alkyl group such as-(diethylamino) butyl group; halogen-lower alkyl group such as 2-fluoroethyl group, 3-fluoro-n-butyl group; carboxymethyl group, 2-carboxyethyl group, etc. A carboxy-lower alkyl group; a sulfo-lower alkyl group such as a sulfo-methyl group and a 2-sulfoethyl group.

The optionally substituted aralkyl group R ⁷ is, for example, a benzyl group, and is a 4-aminobenzyl group, a 4-nitrobenzyl group, a 4- (dimethylamino) benzyl group, a 4-fluorobenzyl group, a 4-chlorobenzyl group. , 3-methoxybenzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, and one or more amino groups, nitro groups, lower alkylamino groups, di-lower alkylamino groups, halogen atoms and / or lower alkoxy. It may be substituted with a group or the like.

The amino group R ⁸ is unsubstituted or is a lower alkyl group such as a methylamino group or a dimethylamino group,
Alternatively, it may be substituted with a lower cyclic alkyl group such as a cyclopropylamino group.

The lower alkyl group R ⁸ may be similarly unsubstituted or substituted, and examples of the substituted alkyl group represented by R ⁸ include 2-carboxyethyl group,
3-carboxy-n-propyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 3-
A group containing a carboxy group such as a methoxycarbonyl-n-propyl group or a lower alkoxycarbonyl group.

The aryl group represented by R ⁸ is preferably a phenyl group; examples of the substituted aryl group include a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group, It contains at least one halogen, lower alkoxy group, hydroxyl group, nitro group and / or amino group such as 2-carboxyphenyl group, 4-hydroxyphenyl group, 4-nitrophenyl group and 4-aminophenyl group. It is preferable.

Particularly preferred groups represented by R ⁷ are hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 3-amino- group. n-butyl group, 2- (methylamino) ethyl, 2- (ethylamino) ethyl, 2-fluoroethyl group, carboxymethyl group, sulfomethyl group, allyl group, 4-aminobenzyl group, 4-fluorobenzyl group, formyl Group, acetyl group, propionyl group, benzoyl group, 4-aminobenzoyl group, 2-oxo-n-propyl group, 2-oxo-n-butyl group, 3-oxo-n
-Butyl group, 3-oxo-n-pentyl group, 3-carboxypropionyl group, 3-ethoxycarbonylpropionyl group, 4-carboxy-n-butyryl group, phenacyl group, 4'-aminophenacyl group, ethoxycarbonyl group, methoxycarbonyl group Group, carbamoyl group and the like.

Particularly preferred groups represented by R ⁵ R ⁶ N- in formula (1) are 1-piperazinyl group, 4-methyl-1-piperazinyl group, 3-methyl-1-piperazinyl group, 3-phenyl. -1-piperazinyl group, 3,4-dimethyl-1-piperazinyl group, 4-ethyl-1-piperazinyl group, 3- (4
-Aminophenyl) -1-piperazinyl group, 4-n-propyl-1-piperazinyl group, 4- (2-fluoroethyl) -1-piperazinyl group, 4-allyl-1-piperazinyl group, 4- (2-oxo- n-propyl) -1-piperazinyl group, 4- (carboxymethyl) -1-piperazinyl group, 4- (3-oxo-n-butyl) -1-piperazinyl group, 4- (sulfomethyl) -1-piperazinyl group, 4- (4-aminobenzyl) -1-piperazinyl group, 4- (2-hydroxyethyl) -1-piperazinyl group, 3-oxo-1-piperazinyl group, 4-phenacyl-1-piperazinyl group, 4- (3 -Carboxypropionyl) -1-piperazinyl group, 4-acetyl-1-piperazinyl group, 4- (4-nitrobenzyl) -1-piperazinyl group, morpholino , 2-methyl-4-morpholinyl group, 2,6-dimethyl-4-morpholinyl group, 4-thiomorpholinyl group, 1-oxide-4-thiomorpholinyl group, 1,1-dioxide-4-thiomorpholinyl group, 4
(Aminomethyl) -1-piperidyl group, 4-[(methylamino) methyl] -1-piperidyl group, 4-methoxy-
1-piperidyl group, 4-hydroxy-1-piperidyl group, 4- (1-pyrrolyl) -1-piperidyl group, 4-amino-1-piperidyl group, 4- (methylamino) -1-
Piperidyl group, 4- (ethylamino) -1-piperidyl group, 1-homopiperazinyl group, 4-methyl-1-homopiperazinyl group, 3-amino-1-pyrrolidinyl group, 3-
(Methylamino) -1-pyrrolidinyl group, 3- (ethylamino) -1-pyrrolidinyl group, 3- (benzyloxycarbonylamino) -1-pyrrolidinyl group, 3- (aminomethyl) -1-pyrrolidinyl group, 3- Amino-4-phenyl-1-pyrrolidinyl group, 3-amino-3-methyl-1-pyrrolidinyl group, 3-amino-4-methyl-1-
Pyrrolidinyl group, 3- (4-aminobenzylamino)-
1-pyrrolidinyl group, 3- (4-methyl-1-piperazinyl) -1-pyrrolidinyl group, 3-[(dimethylamino) methyleneamino] -1-pyrrolidinyl group, 3-
[(Methylamino) methyl] -1-pyrrolidinyl group, 3
-[(Methylamino) methyl] -4-phenyl-1-pyrrolidinyl group, 3-methyl-3-[(methylamino) methyl] -1-pyrrolidinyl group, 3-[(ethylamino)
Methyl] -1-pyrrolidinyl group, 3- (acetylaminomethyl) -1-pyrrolidinyl group, 3-[(dimethylamino) methyl] -1-pyrrolidinyl group, 3-[(ethylmethylamino) methyl] -1-pyrrolidinyl group Group, 3-amino-4-methoxy-1-pyrrolidinyl group, 3-methoxy-4- (methylamino) -1-pyrrolidinyl group, 3-
(Ethylamino) -4-methoxy-1-pyrrolidinyl group, 3-amino-4-chloro-1-pyrrolidinyl group, 3
-Chloro-4- (methylamino) -1-pyrrolidinyl group, 3-chloro-4- (ethylamino) -1-pyrrolidinyl group, 3-amino-4-fluoro-1-pyrrolidinyl group, 3-fluoro-4- (Methylamino) -1-pyrrolidinyl group, 3- (ethylamino) -4-fluoro-1-
Pyrrolidinyl group, 3- (aminomethyl) -4-chloro-
1-pyrrolidinyl group, 3-chloro-4-[(methylamino) methyl] -1-pyrrolidinyl group, 3-chloro-4-
[(Ethylamino) methyl] -1-pyrrolidinyl group, 3
-(Aminomethyl) -4-fluoro-1-pyrrolidinyl group, 3-fluoro-4-[(methylamino) methyl]-
1-pyrrolidinyl group, 3-[(ethylamino) methyl]
-4-fluoro-1-pyrrolidinyl group, 3- (aminomethyl) -4-methyl-1-pyrrolidinyl group, 3-methyl-4-[(methylamino) methyl] -1-pyrrolidinyl group, 3-[(ethyl Amino) methyl] -4-methyl-1
-Pyrrolidinyl group, 3-hydroxy-1-pyrrolidinyl group, 3-methoxy-1-pyrrolidinyl group, 3-chloro-
1-pyrrolidinyl group, 3-fluoro-1-pyrrolidinyl group, 3-hydroxy-4-methoxy-1-pyrrolidinyl group, 1-imidazolyl group, 4-methyl-1-imidazolyl group, 3-amino-4-hydroxy-1 -Pyrrolidinyl group, 3- (methylamino) -4-hydroxy-1-pyrrolidinyl group, 3- (ethylamino) -4-hydroxy-
1-pyrrolidinyl group, 3- (dimethylamino) -4-hydroxy-1-pyrrolidinyl group [2- (dimethylamino) ethyl] methylamino group and the like.

Description of X: X represents a halogen atom such as fluorine, chlorine or bromine, preferably fluorine or chlorine.

Novel pyrido [3,2,1-ij] -1,3,4-benzoxadiazine derivative of the general formula (I) and a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof The article is manufactured according to the present invention by the following steps.

(A) General formula (III) In the formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as described in formula (I); and X ′ represents a halogen atom; amino group, hydroxyl group and / or carboxy in the formula The group may be protected. The compound represented by the general formula (IV) In the formula, R ⁵ and R ⁶ have the same meanings as described in formula (I).

Or a protecting group is removed if desired by reacting with an amine represented by (b) the general formula (V) In the formula, R ¹ , R ² , R ⁵ , R ⁶ and X have the same meanings as described in the formula (I);
Alternatively, the carboxy group may be protected, and a compound represented by the general formula (VI) In the formula, R ³ and R ⁴ have the same meanings as described in the formula (I). A carbonyl compound represented by: or a polymer thereof, an acetal, a ketal or an enol ether is reacted, and a protecting group is optionally removed. Alternatively, (c) in order to produce a compound of formula (I) in which R ⁷ is a group other than a hydrogen atom, a compound of formula (I) in which R ⁷ is a hydrogen atom is substituted with a substituent R ⁷⁰ (wherein R ⁷⁰ is Or (d) R ⁵ and / or R ⁶ is a lower alkyl group (or a di-lower alkylamino group or a lower alkoxy group), which has the same meaning as R ⁷ but is not a hydrogen atom. To obtain a compound of formula (I) wherein R ⁵ and / or R ⁶ is a hydrogen atom, or a compound of formula (I) containing an amino group, a lower alkylamino group or a hydroxyl group is converted into a lower alkyl group. Or (e) R ⁵ R ⁶ N-is -SO- or -SO ₂ - for the production of a 5-7 membered heterocyclic ring containing compound of formula (I), oxidizing a compound of the heterocycle including the corresponding -S- When subjected to a reaction or (f) to produce a compound of formula (I) having a free amino group, hydroxyl group and / or carboxy group, a compound of formula (I) having a protected amino group, hydroxyl group and / or carboxy group Or a corresponding hydroxyl group of formula (I) in which R ¹ is a carboxy protecting group, in order to remove the corresponding compound of () or a protecting group (g) to produce a compound of formula (I) containing a halogen atom. The corresponding nitro-substituted compound of formula (I) to halogenate the compound and optionally remove its protecting group R ¹ or (h) to prepare a compound of formula (I) containing an amino group. The nitro group of (Wherein R ⁵⁰ and R ⁵¹ are lower alkyl groups or together with the nitrogen atom represent a 5-8 membered saturated nitrogen-containing heterocycle) a compound of formula (I) To prepare the corresponding amino-substituted compound of formula (I), a compound of general formula (VII) Wherein R ⁵⁰ and R ⁵¹ have the same meanings as described above, or react with a reactive derivative of a formamide derivative of (j) to prepare a compound of formula (I) wherein R ¹ is a carboxy protecting group. To this end, the carboxylic acid of formula (I) is subjected to the corresponding esterification, or a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula (I), or of said salt When preparing a hydrate or solvate, the compound of formula (I) is converted into a salt, hydrate or solvate or a hydrate or solvate of the salt.

Step A: As described above, the general formula (III), (In the formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meanings as in formula (I); and X ′ is a halogen atom; further, an amino group, a hydroxyl group and / or A carboxy group may be protected) and a compound of the general formula (IV) (Wherein R ⁵ and R ⁶ have the same meanings as described in the formula (I)) and the protecting group is removed if desired to obtain the desired compound.

Formula (III) used as a starting material in step A
The compound represented by is a novel compound.
For example, it can be synthesized by the following reaction scheme a) or b).

(In the formula, R ² , R ³ , R ⁴ , X and X ′ have the same meanings as described above, and R ′ represents a benzyl group, a methoxybenzyl group, a methoxymethyl group, a methoxyethoxymethyl group or a tetrahydropyranyl group. , Allyl group, t-butyl group, t-butyldimethylsilyl group, acetyl group, benzoyl group and the like; R ″ represents formyl group, acetyl group, trifluoroacetyl group, benzoyl group, ethoxycarbonyl group. , 2,2,
Represents a protecting group such as a 2-trichloroethoxycarbonyl group, a phenoxycarbonyl group, a benzyloxycarbonyl group, a t-butoxycarbonyl group; R represents a hydrogen atom or an ethyl group) and the compound of the formula (IV) is an amino group. In the case of containing a group or a monoalkylamino group, those groups are, if desired, a formyl group, an acetyl group, a trifluoroacetyl group, a benzoyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a phenyl group. Enoxycarbonyl group, benzyloxycarbonyl group, t
-It may be protected by an amino-protecting group such as butoxycarbonyl group.

The reaction of the compound of formula (III) with the amine of formula (IV) or an appropriately protected amine may be carried out in a solvent or without solvent, if necessary, in order to complete the reaction sufficiently. It is preferable to raise the temperature for a period of time.
The preferred reaction temperature is about 30 ° C to 200 ° C, and 80 ° C to 150 ° C is particularly preferred in order to obtain a sufficiently fast reaction rate.

The reaction is preferably triethylamine, pyridine, picoline, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane, alkali metal hydroxide. Compound, an alkali metal carbonate or the like in the presence of an acid binder. Alternatively, it is also possible to use an excess of the amine of formula (IV) as acid binder.

Preferred solvents for this reaction are non-reactive solvents such as acetonitrile, alcohols, dimethylsulfoxide, dimethylformamide, dimethylacetamide, pyridine, picoline, lutidine, N, N'dimethylpropyleneurea. It is also possible to use mixtures of two or more solvents.

After completion of the reaction, the protecting group can be removed by a known method. For example, a formyl group can be removed by acid or base hydrolysis, preferably base hydrolysis, and a benzyloxycarbonyl group can be removed by hydrogenolysis.

Examples of the starting material represented by the formula (III) include the following materials.

9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9,10 -Dichloro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-chloro-10- Fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzooxadiazine-6-carboxylic acid, ethyl = 9,10-difluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylate, benzyl = 9,10-difluoro-3-methyl-7-oxo-2 , 3-Dihydro-7H-pyrido [3.2.1-ij] -1,3,4-
Benzoxadiazine-6-carboxylate, 9,10-difluoro-3- (2-fluoroethyl) -7-
Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,
3,4-Benzoxadiazine-6-carboxylic acid, 9,10-difluoro-2,3-dimethyl-7-oxo-2,3-
Dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9,10-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo- 2,3-dihydro-7H-pyrido [3.2.1
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid, 9,10-difluoro-2-[(dimethylamino) methyl]
-3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-
Carboxylic acid and 9,10-difluoro-2,2,3-trimethyl-7-oxo-
2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid and the like.

The amine of the formula (IV) used in the above reaction is, for example, piperazine, 4-methylpiperazine, 3-methylpiperazine, 3-phenylpiperazine, 3- (4-aminophenyl) piperazine, 3- (4-nitrophenyl) piperazine. , 4- (2-hydroxyethyl) piperazine, morpholine, 2-methylmorpholine, 2,6-dimethylmorpholine, thiomorpholine, 4- (aminomethyl) piperidine, 4-[(methylamino) methyl] piperidine, 4-
[(Ethylamino) methyl] piperidine, 4-aminopiperidine, 4- (methylamino) piperidine, 4- (ethylamino) piperidine, 4- (benzyloxycarbonylamino) piperidine, 4- (benzyloxycarbonylmethylamino) piperidine , 4- (benzyloxycarbonylethylamino) piperidine, 4-hydroxypiperidine, 4-methoxypiperazine, 4- (1-pyrrolyl) piperidine, homopiperidine, 3-[(methylamino) methyl] pyrrolidine, 3-[(ethyl Amino) methyl] pyrrolidine, 3- (acetylaminomethyl) pyrrolidine, 3-hydroxypyrrolidine, 3-methoxypyrrolidine, 3-aminopyrrolidine, 3- (benzyloxycarbonylamino) pyrrolidine, 3-amino-4-methylpyrrolidine, 3 (4-aminobenzylamino) pyrrolidine, 3- (methylamino) pyrrolidine, 3- (benzyloxycarbonylamino) pyrrolidine, 3-amino-4-phenylpyrrolidine, 3-amino-3-methylpyrrolidine, 3- (4 -Methyl-1-piperazinyl) pyrrolidine, 3-[(dimethylamino) methyleneamino] pyrrolidine, 3-[(methylamino) methyl] -4-phenylpyrrolidine, 3-methyl-3-[(methylamino)
Methyl] pyrrolidine, 3- (ethylamino) pyrrolidine, 3- (benzyloxycarbonylethylamino) pyrrolidine, 3-[(dimethylamino) methyl] pyrrolidine, 3-[(ethylmethylamino) methyl] pyrrolidine, 3-azido- 4-methoxypyrrolidine, 3-amino-4-methoxypyrrolidine, 3-methoxy-4- (methylamino) pyrrolidine, 3- (ethylamino) -4-methoxypyrrolidine, 3-azido-4-hydroxypyrrolidine, 3-amino -4-hydroxypyrrolidine, 3-
(Methylamino) -4-hydroxypyrrolidine, 3-
(Ethylamino) -4-hydroxypyrrolidine, 3-
(Aminomethyl) -4-methylpyrrolidine, 3-methyl-4-[(methylamino) methyl] pyrrolidine, 3-
[(Ethylamino) methyl] -4-methylpyrrolidine,
3-hydroxy-4-methoxypyrrolidine, 3- (acetylaminomethyl) -4-hydroxypyrrolidine, imidazole, 4-methylimidazole, N, N, N'-trimethylethylethylenediamine, and the like.

Process B: General formula (V) (In the formula, R ¹ , R ² , R ⁵ , R ⁶ and X have the same meanings as described above; further, the amino group, hydroxyl group and / or carboxy group in the formula may be protected) And a compound represented by the general formula (VI) (Wherein R ³ and R ⁴ have the same meanings as described above) or by reacting with a carbonyl compound or a polymer thereof, an acetal, a ketal or an enol ether, and optionally removing a protecting group. The desired compound can be obtained.

In step B, the compound represented by the formula (V) used as a starting material is a novel compound and is a compound according to the above reaction scheme a) or b), or a compound (H) or (Va) It can be produced by reacting with an amine of formula (IV).

If the carbonyl compound formula (VI) or a polymer, acetal, ketal or enol ether thereof, has an amino or monoalkylamino substituent, optionally, that substituent is R ″ in formulas (G) and (H). May be protected by a group described as.

If desired, this reaction can be carried out in a solvent such as dioxane, human lahydrofuran, acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea, acetic acid and the like. Mixtures of two or more solvents can also be used.

If desired, this reaction is carried out by acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, pyridinium = p.
-Toluene sulfonate, ferric chloride, zinc chloride, chlorotrimethylsilane, Nafion-H (perfluorinated sulfonic acid resin: manufactured by Aldrich Chemical Co., Ltd.), Amberlyst-
15 (Strongly acidic giant network resin: manufactured by Aldrich Chemical Co., Ltd.)
It may be carried out in the presence of an acid catalyst such as

The reaction temperature can be varied within a relatively wide range, and generally, the reaction is carried out at a temperature of 20 ° C to 150 ° C.

In a preferred embodiment of the present invention, about 1 mol or an excess of the carbonyl compound of formula (VI) or its polymer, acetal, ketal or enol ether is used per mol of the compound of formula (V).

The amino or monoalkylamino protecting group can be removed by a known method after the completion of the reaction, if desired.
For example, the formyl group can be removed by acid or base hydrolysis, preferably base hydrolysis, and the benzyloxycarbonyl group can be removed by hydrogenolysis.

Examples of the starting material represented by the formula (V) are as follows: 6,7-
Difluoro-8-hydroxy-1- (methylamino)-
4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, ethyl = 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate , Benzyl = 6,7-difluoro-8-hydroxy-1-
(Methylamino) -4-oxo-1,4-dihydro-3-
Quinoline carboxylate, 6,7-dichloro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6-chloro-7-fluoro-8-hydroxy-1 -(Methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6,7-difluoro-1-[(2-fluoroethyl) amino] -8-hydroxy-4-oxo-1, 4-dihydro-
3-quinolinecarboxylic acid, 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxy-1,4-dihydro-3-quinolinecarboxylic acid, ethyl = 6-fluoro -8-Hydroxy-7- (1-imidazolyl) -1-
(Methylamino) -4-oxo-1,4-dihydro-3-
Quinoline carboxylate, benzyl = 6-fluoro-8-hydroxy-7- (1-
Imidazolyl) -1- (methylamino) -4-oxo-
1,4-dihydro-3-quinolinecarboxylate, 6-fluoro-1-[(2-fluoroethyl) amino]
-8-Hydroxy-7- (1-imidazolyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6-chloro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino ) -4-Oxo-1,4-dihydro-3-quinolinecarboxylic acid, 6-fluoro-8-hydroxy-1- (methylamino)
-7- (4-Methyl-1-piperazinyl) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, 7- (3,4) -dimethyl-1-piperazinyl) -6-fluoro-8- Hydroxy-1- (methylamino) -4-
Oxo-1,4-dihydro-3-quinolinecarboxylic acid, 7- [3-[(benzyloxycarbonylethylamino) methyl] -1-pyrrolidinyl] -6-fluoro-8
-Hydroxy-1- (methylamino) -4-oxo-1,
4-dihydro-3-quinolinecarboxylic acid, 7- [3- (benzyloxycarbonylamino) -1-
Pyrrolidinyl] -6-fluoro-8-hydroxy-1-
(Methylamino) -4-oxo-1,4-dihydro-3-
Quinolinecarboxylic acid, 7- [3-[(benzyloxycarbonylmethylamino) methyl] -4-methyl-1-pyrrolidinyl] -6-
Fluoro-8-hydroxy-1- (methylamino) -4
-Oxo-1,4-dihydro-3-quinolinecarboxylic acid,
And 7- [3-[(benzyloxycarbonylmethylamino) methyl] -4-chloro-1-pyrrolidinyl] -6-
Fluoro-8-hydroxy-1- (methylamino) -4
-Oxo-1,4-dihydro-3-quinolinecarboxylic acid and the like.

Examples of the compound capable of reacting the compound of the formula (V) include carbonyl compound such as formaldehyde, acetaldehyde, acetone and methyl ethyl ketone (V
I); paraformaldehyde, paraacetaldehyde,
Polymers such as trioxane; acetals such as dimethoxymethane, 1,1-dimethoxyethane, 1,3-dioxolane, glycolaldehyde dimethyl acetal, dimethylaminoacetaldehyde dimethyl acetal; ketals such as 2,2-dimethoxypropane; and 2- Examples thereof include enol ethers such as methoxypropene and 2-trimethylsilyloxypropene.

Step C: The group R ⁵ , R ⁶ N- in the formula (I) is a 5- to 7-membered heterocycle,
The heterocycle includes -NR ⁷ , wherein R ⁷ is a group other than hydrogen, for example, [In the formula, the piperazinyl group may be substituted on a carbon atom, and R ⁷⁰ is a lower alkyl group or an aralkyl group which may be substituted with a lower alkenyl group, or is represented by the general formula:-(CH ₂ ) nCOR ⁸ (II) (wherein n represents a number from 0 to 4, and R ⁸ represents a hydrogen atom,
A lower alkoxy group, or an optionally substituted amino group, a lower alkyl group or an aryl group) which is a group represented by the formula (I). It can be synthesized by reacting a compound of formula (I) in which ⁷ is a hydrogen atom with a reagent capable of forming the substituent R ⁷⁰ .

The reaction of N-alkylation (or N-acylation) can be performed as follows.

N-alkylation: general formula (IX), (In the formula, R ¹ , R ² , R ³ , R ⁴ and X have the same meaning as described above, the piperazine group may be substituted on a carbon atom, and further, an amino group in the formula, A hydroxyl group and / or a carboxy group may be protected), (i) the general formula (X) R ⁷⁰ -Y (X) (wherein Y is a leaving group and R ⁷⁰ is the same as above). meaning having) or reacting a compound represented Te Niyotsu, or (R ⁷
To obtain a compound which is a group of R ⁹ CO—CH ₂ CH ₂ —) (ii) General formula (XI) R ⁹ —CO—CH═CH ₂ (XI) (wherein R ⁹ is a lower group) An alkyl group or a lower alkoxy group), or (for obtaining a compound in which R ⁷ is methyl or sulfomethyl), (iii) formaldehyde and formic acid, or alkali metal bisulfite React with salt.

N-acylation: In order to obtain a compound of formula (I) in which R ⁷ is HOOC-Z-CO-, a compound of formula (IX) as defined above (Wherein Z represents an alkylene chain or an arylene group having 2 or 3 carbon atoms, which may be optionally substituted).

If desired, the protecting group, if any, may be removed after completion of all these reactions.

In this way, the desired compound can be synthesized by reacting the compound represented by the formula (IX) with the compound represented by the formula (X). Examples of the leaving group Y include halogen atoms such as chlorine, bromine and iodine, acyloxy groups such as acetoxy group, lower alkanesulfonyloxy groups such as methanesulfonyloxy group, p-
It is an allylsulfonyloxy group such as a toluenesulfonyloxy group, or a phenoxy group optionally nitrated such as a phenoxy group or a 4-nitrophenoxy group, or a succinimidooxy group or a phthalimidooxy group.

If the compound of formula (X) contains an amino group or a monoalkylamino substituent, those substituents are optionally protected by groups described for R ″ in formulas (G) and (H) above. If desired, this reaction can be carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea, dioxane, tetrahydrofuran, pyridine and the like.

It is also possible to use mixtures of two or more solvents.

This reaction is preferably triethylamine, pyridine,
N, N-dimethylaniline, 1,4-diazabicyclo [2.2.
2] Octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium hydride, alkali metal hydroxide, alkali metal carbonate or the like in the presence of an acid binder.

The reaction temperature can be varied within a relatively wide range, and generally, the reaction is carried out between about 0 ° C and 180 ° C, preferably 0 ° C to 1 ° C.
It is carried out between 10 ° C.

In a preferred embodiment of the present invention, 1 to 4 mol, preferably 1 to 2 mol, of the compound of formula (X) is used per 1 mol of the compound of formula (IX).

In the present invention, examples of the compound of the formula (X) include iodomethane, iodoethane, bromoethane, 1-iodobutane, 1-bromobutane, 1-iodopropane, 2-iodopropane, 1-fluoro-2-iodoethane, 1-
Iodo-2-methoxyethane, N- (2-iodoethyl) acetamide, N- (2-iodoethyl) -N-ethylacetamide, bromoacetic acid, allyl bromide, 4-
Fluorobenzyl bromide, acetic acid-formic anhydride, acetic anhydride, acetyl chloride, propionic anhydride, propionyl chloride, benzoic anhydride, benzoyl chloride, 4-[(trifluoroacetyl) amino] benzoic anhydride, chloroacetone, 1- Chloro-2-butanone, phenacyl chloride, 4-
Acetylaminophenyl chloromethyl ketone, ethyl chloroformate, methyl chloroformate, chloromethyl-4-nitrophenyl-ketone, 4-nitrobenzyl bromide, dimethylcarbamoyl chloride and the like can be mentioned.

Alternatively, the desired compound can be synthesized by reacting a compound of formula (IX) with a Michael acceptor of formula (XI).

If desired, this reaction can be carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran, methanol, ethanol, propanol, ethylene glycol monomethyl ether and the like. Mixtures of two or more solvents can also be used. The reaction temperature can be varied within a relatively wide range and, generally, the reaction is carried out between about 30 ° C and about 170 ° C, preferably between 50 ° C and 140 ° C.

In a preferred embodiment of the present invention, preferably 1 to 5 mol, particularly preferably 1 to 2 mol, of the compound of formula (XI) is used per 1 mol of the compound of formula (IX).

In a preferred embodiment of the present invention, preferably 1 to 5 mol, particularly preferably 1 to 2 mol, of the compound of formula (XI) is used per 1 mol of the compound of formula (IX).

The Michael acceptor used in the present invention is, for example, methyl vinyl ketone or ethyl vinyl ketone.

Alternatively, the desired compound (to obtain a compound of formula (I) where R ⁷ is methyl or sulfomethyl) is synthesized by reaction of formaldehyde with formic acid or an alkali metal bisulfite with compound (IX), This reaction is usually
It is carried out under slight heating, for example, between about 50 ° C and 100 ° C.

Further, the desired compound can be obtained by treating the anhydride of formula (XII) with the formula (I
It can be synthesized by reacting with the compound of X).

If desired, this reaction can be carried out in a solvent such as pyridine, dimethylformamide, dioxane, tetrahydrofuran and the like. Mixtures of two or more solvents can also be used.

This reaction is preferably triethylamine, pyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.
2.2] It is carried out in the presence of an acid binder such as octane, an alkali metal hydroxide or an alkali metal carbonate.

The reaction temperature can be varied within a relatively wide range, and is generally performed at about 0 ° C to 120 ° C, preferably 0 ° C to 100 ° C.

In a preferred embodiment of the present invention, 1 mol of the compound of formula (XII) or an excess of mol is used per 1 mol of the compound of formula (IX).

The anhydride used in the present invention is, for example, succinic anhydride, daltaric anhydride, N-benzyloxycarbonylaspartic anhydride, N-benzyloxycarbonylglutamic anhydride, phthalic anhydride and the like.

If desired, the protecting group may be removed by a known method after the reaction. For example, the formyl group can be removed by acid or chlorinated hydrolysis, preferably chlorinated hydrolysis, and the benzyloxycarbonyl group can be removed by hydrogenolysis. The protecting groups may be removed before the product is isolated or after isolation.

Step D: When R ⁵ and / or R ⁶ is a compound of formula (I) in which a lower alkyl group (or a di-lower alkylamino group or a lower alkoxy group is included) is produced, these compounds are An alkylated compound, ie a compound of formula (I) in which R ⁵ and / or R ⁶ contains a hydrogen atom, or an amino group, a lower alkylamino group or a hydroxyl group, can be produced by lower alkylation, N -Alkylation can be carried out by a reaction with a compound of the general formula (XIII), R ¹⁰ Y (XIII), wherein R ¹⁰ is a lower alkyl group and Y is a leaving group. The leaving group is
It is of the same type used in the compounds of formula (X). This reaction can also be carried out by a similar reaction when compound (IX) is alkylated with compound (X) described above. O-alkylation is carried out in the same way as N-alkylation, but preferably a proton acceptor such as an alkali metal hydride such as sodium hydride is added.

Step E: When R ⁵ R ⁶ N- is a compound of formula (I) wherein 5 to 7 membered heterocycle containing -SO- or -SO _2- is prepared, these compounds are It can be prepared by oxidizing a deoxygenated compound of I), that is, a compound containing -S- in this heterocycle.

Oxidation can be carried out using organic or inorganic oxidants. Various compounds that readily generate oxygen can be used as oxidants; for example, C _1- , such as monosubstituted organic peroxides (eg, t-butyl hydroperoxide).
C ₄ alkyl or alkanoyl hydroperoxide),
Formic acid, peracetic acid and phenyl-substituted derivatives of these hydroperoxides such as cumene hydroperoxide and perbenzoic acid can be used. If desired, a C ₁ -C ₄ alkyl group, an alkoxy group, a halogen atom or a carboxy group, such as 4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid and monoperphthalic acid. Peracids containing substituted phenyl groups can also be used. Many inorganic oxidants, such as hydrogen peroxide, ozone, permanganates such as potassium permanganate or sodium permanganate, sodium hypochlorite, potassium hypochlorite, or secondary hypochlorites such as ammonium hypochlorite. Chlorites, peroxysulfates and peroxydisulfates can also be used as oxidizing agents. Preferably 3-chloroperbenzoic acid is used. Oxidation is preferably a non-reactive solvent such as tetrohydrofuran, dioxane, methylene chloride,
It is carried out in an aprotic, non-reactive solvent such as chloroform or ethyl acetate. This oxidation is generally
It is carried out in the temperature range of 20 ° C to 50 ° C.

When equimolar or a slight excess of oxidizing agent is used, based on the starting material, mainly the corresponding sulfoxide, i.e., -SO
A compound of formula (I) having a heterocycle containing-is obtained.

Increasing the amount of oxidizing agent from 2-fold moles and beyond yields compounds of formula (I) having a corresponding sulfone, ie a heterocycle containing —SO ₂ —. The sulfone can be obtained by treating the corresponding sulfoxide with an equimolar or more oxidizing agent.

Step F: When preparing compounds of formula (I) having a free amino group, a hydroxyl group and / or a carboxy group, these compounds contain one or more protected amino groups, hydroxyl groups and / or carboxy groups. It can be prepared from the corresponding compound of formula (I).

Amino protecting groups include, for example, lower alkanoyl groups such as acetyl groups; benzoyl groups; alkoxycarbonyl groups such as t-butoxycarbonyl or ethoxycarbonyl; substituted alkoxycarbonyl groups such as trichloroethoxycarbonyl; phenoxycarbonyl groups, benzyloxycarbonyl. Group, aralkyl group such as p-nitrobenzyloxycarboxylic group, trityl group or benzhydryl group; or halogenalkanoyl group such as trifluoroacetyl.

The amino protecting group can be removed by acid hydrolysis (eg t-butoxycarbonyl group or trityl group) or base hydrolysis (eg trifluoroacetyl group). The benzyloxycarbonyl group and the p-nitrobenzyloxycarbonyl group can be removed by hydrogenolysis.

Amino protecting groups removed by acid hydrolysis can preferably be removed using optionally halogenated lower alkanecarboxylic acids. In particular, formic acid or trifluoroacetic acid may be used. Acid hydrolysis is generally carried out at room temperature, but can also be carried out at somewhat higher or somewhat lower temperatures (eg temperatures of about 0 ° C to 40 ° C). Protecting groups removed under basic conditions are generally hydrolyzed at 0 ° C to 30 ° C with a dilute aqueous alkaline solution. The carboxy-protecting group has the same meaning as, for example, the carboxy-protecting group described in the description of R ¹ .

Removal of these protecting groups can be carried out by known methods, for example, by hydrogenolysis (benzyl group) or by acid or base hydrolysis. This reaction is preferably 0
It can be carried out in a non-reactive solvent between ℃ and room temperature.

The following special methods are also useful. For example, a p-nitrobenzyl group is hydrolyzed in the presence of sodium sulfide in a temperature range of about 0 ° C. or lower to room temperature in a solvent such as dimethylformamide (containing water); a t-butyl group is
Removed by reacting with trifluoroacetic acid in the presence of anisole in a solvent such as methylene chloride or without solvent at about 0 ° C to room temperature; or the allyl group in the presence of sodium or potassium salt of 2-ethylhexanoic acid. For example, it is removed by a transallylation reaction using a palladium (O) catalyst [see (J. Org. Chem.) 1982, 47 , 587].

Process G: R ⁵ R ⁶ N- When a compound of formula (I) containing a halogen atom such as a compound of formula (I) is prepared, the compound is a compound substituted with a corresponding hydroxyl group (for example, R ⁵ R ⁶ N is Can be produced by halogenating The halogenating agent is preferably thionyl halide, especially thionyl chloride, or phosphorus trichloride, phosphorine chloride or phosphorus pentachloride. The reaction temperature is about 0 ° C
It is preferably between 80 ° C. The carboxy group is preferably protected with, for example, a benzyl group, and if desired, it can be subsequently returned to a free carboxy group by, for example, hydrogenolysis (removal of the benzyl group).

Process H: R ⁵ R ⁶ N- A compound of formula (I) containing an amino group, such as a compound of formula I, is prepared by reducing the nitro group of a compound of formula (I) substituted with the corresponding nitro group. You can The reduction can be carried out by hydrogenation in the presence of a noble metal catalyst such as palladium-carbon. This reaction can be carried out in water or a lower alcohol such as methanol or ethanol, and optionally in a mixture with another solvent. Reaction temperature is about 10-40 ℃
It is within the range of, and room temperature is particularly preferable.

Step I: R ⁵ R ⁶ N- A compound like the formula When a compound of formula (I) having a group of the formula: (wherein R ⁵⁰ and R ⁵¹ have the meanings given above) is prepared, this compound is of formula (I) substituted with the corresponding amino group. (For example, R ⁵ R ⁶ N- Is represented by the general formula (VII), (Wherein R ⁵⁰ and R ⁵¹ have the same meanings as described above) and can be produced by reacting with a reactive derivative of the formamide derivative.

As the reactive derivative of the compound of formula (VII), the corresponding di-lower alkyl acetal such as dimethyl acetal can be used. This reaction is preferably carried out in a non-reactive solvent such as diethyl ether, dimethylformamide or dimethylsulfoxide. The temperature is preferably around room temperature, but can be lower or higher, for example in the range of about 0 ° C to 100 ° C.

Step J: When R ¹ produces an ester of formula (I) which is a carboxy protecting group, the compound is a carboxylic acid of formula (I) and a corresponding halide, preferably an iodide containing the desired ester group. , Can be synthesized by reacting with bromide.

This reaction can be promoted by a base such as an alkali metal hydroxide, an alkali metal carbonate or an organic amine such as triethylamine.

The esterification reaction is preferably carried out in a non-reactive solvent such as dimethylacetamide, hexamethylphosphoric triamide, dimethylsulfoxide or, in particular, dimethylformamide, the reaction being carried out in the temperature range from about 0 ° C to 40 ° C. Is preferred.

Step K: In the case of producing a pharmaceutically acceptable salt of the compound of formula (I), or a hydrate or solvate of a salt thereof, they are prepared by a known method, for example, a compound of formula (I) Can be synthesized by reacting the carboxylic acid of 1 with 1 equivalent of the desired base, or conversely by reacting the free base of formula (I) with an organic acid or an inorganic acid. This reaction can be conveniently carried out in water or an organic solvent (eg ethanol, methanol, acetone, etc.). The temperature is not critical in forming the salt. The salt formation is generally carried out at room temperature or can be carried out at a temperature somewhat above or below room temperature, for example in the range 0 ° C to 50 ° C.

Examples of pharmaceutically acceptable acids useful in the above process include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, Tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid,
4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, aminosalicylic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, gluconic acid, glucuronic acid Acids, galacturonic acid, aspartic acid and glutamic acid; methionine, tryptophan, lysine, arginine and the like.

The acid addition salt can be converted to a free form by a base treatment with a metal hydroxide, ammonia or the like.

The base addition salt of the compound of formula (I) can be synthesized by reacting the compound of formula (I) with a metal base such as an alkali or alkaline earth metal hydroxide, or an organic amine.

Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of amines are diethanolamine, N, N'-benzylethylenediamine, choline, ethylenediamine and the like.

Acid or base addition salts of the compounds of formula (I) differ from certain physical properties or of the corresponding free form, such as solubility in water.

The compounds of formula (I) and their pharmaceutically acceptable salts can exist in unsolvated forms as well as solvated forms, including hydrates.

Hydrates may occur during the manufacturing process or may be formed by gradual hydration due to the hygroscopic nature of the initially anhydrous product. Controlled production of hydrates produces completely or incompletely anhydrous product, e.g., about 10 ° C to 40 ° C.
Then, it can be carried out by maintaining a certain constant humidity. The solvate containing pharmaceutically acceptable ethanol and the like is obtained during crystallization and the like.

Certain compounds provided by this invention have asymmetric centers. Pure D-isomers, pure L-isomers and mixtures thereof including racemates are also included in the invention.

The compounds provided by the present invention exhibit a wide range of antibacterial activity against Gram-positive and Gram-negative bacteria and Mycoplasma, and can be used as agents for the treatment and prevention of infectious diseases.

The in vitro and in vivo antibacterial activities provided by the present invention are shown below.

1. In vitro antibacterial activity The in vitro antibacterial activity of the representative pyrido [3,2,1, -ij] -1,3,4-veszoxadiazine derivatives of the present invention was tested by standard agar dilution method. [Chemosera 22 , 11
26 (1974)]. Their minimum inhibitory concentration (MIC
μg / ml) is shown in Tables 1 and 2. The compounds used here were synthesized by the methods described in the respective examples below.

． In Vivo Therapeutic Effect The pyrido [3,2,1- synthesized in Examples 5, 30, 65 and 66 described later.
In vivo antibacterial activity of ij] -1,3,4-benzoxadiazine derivatives was determined by Escherichia coll ML 4707, Pseudomo
nas aeruginosa 4 au 542 and Streptococcus pneumon
Tested against lethal infection of iae 6-001. I about 20g in weight
CR mice were infected with each bacterial solution by intraperitoneal administration.
The test compound was orally or subcutaneously administered at the same time as the infection. Mortality was determined after 5 days and expressed as an effective dose (ED ₅₀ , mg / kg) that rescues 50% of the animals from infection death (Table 3).

3. Acute toxicity Examples 5, 6, 7, 16, 17, 18, 30, 36 and 56 described later.
The 50% lethal dose (LD ₅₀ ) for each of the compounds obtained in
It was 2000 mg / kg or more. The acute toxicity of these compounds was investigated by oral administration to ICR mice.

The compounds provided by the present invention have broad antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and mycoplasma, and in particular, they are resistant to various antibiotics such as penicillins, cephalosporins, aminoglycosides, tetracyclines and the like. It also shows a wide range of antibacterial activity against microorganisms.

Furthermore, the compounds provided by the present invention have low toxicity, potent and broad antibacterial activity. The protective effect of the compounds of the present invention against systemic bacterial infection in mice is far superior to that of synthetic antibacterial agents already on the market. Therefore, the compounds of the present invention can be expected to have excellent effects when used for the prevention and treatment of diseases caused by Gram-positive bacteria, Gram-negative bacteria and bacterial microorganisms in humans and animals. For example, it is possible to treat and / or prevent the diseases caused by the following microorganisms or their combined infections: Staphylococcu
s, Streptococcus, Aerococcus, Enterococcus, Micrococcu
s, Lactbacillus, Bifidobacterium, Clostridium, Eubacte
rium, Peptococcus, Peptostreptococcus, Propionibacter
ium, Escherishia, Citrobacter Compylobacter, Enteroba
cter, Klebsiella, Proteus, Pseudomonas, Serratia, Salmo
nella, Shigella, Vibrio, Aeromonas, Haemophilus, Neisse
ria, Acinetobacter, Alcaligenes, Bordetella, Bacteroid
es, Fusobacterium, Mycoplasma and other microorganisms.

The present invention further includes pharmaceutical compositions containing one or more compounds of the present invention.

The compounds of the present invention can be administered by a variety of common administration methods.
It can be administered orally or parenterally to humans or animals.

Furthermore, the compound of the present invention is used alone or together with an auxiliary agent, a diluent, a binder, a lubricant, a wetting agent and the like, for example, tablets, granules, dragees, powders, capsules,
It can be used in the form of common pharmaceutical compositions such as gels, dry syrups, syrups, ampoules, suspensions, solutions, emulsions, ointments, pastes, creams, suppositories and the like.

Furthermore, dissolution retarders, absorption enhancers, surfactants and the like can be used as other additives for the formulation. That is, all pharmaceutically acceptable dosage forms can be used.

The compounds of the present invention can be used alone or as a mixture of two or more different types of compounds, the total amount of the compounds being about 0.1-99.5% by weight of the total pharmaceutical composition,
Preferably, it is 0.5 to 95% by weight.

The pharmaceutical composition of the present invention may be formulated by combining the compound of the present invention or a mixture of the compounds of the present invention with another compound having a medicinal effect.

The daily dose of a novel compound provided by the present invention to a patient will vary depending on individual differences, animal species, body weight and treatment condition, but is generally 0.5 to 500 m / kg body weight.
It is in the range of g, preferably 1 to 300 mg.

Hereinafter, examples will be used to explain desirable methods for synthesizing the compounds of the present invention.

Synthesis of starting materials Reference example Synthesis of diethyl N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonate (a) 2,3-difluoro-6-nitrophenol (500 m
g) was dissolved in methanol (7 ml), 5% Pd / C (60 mg) was added, and the mixture was hydrogenated at room temperature and atmospheric pressure for 6 hours. The catalyst was filtered under a stream of nitrogen and the filtrate was concentrated under reduced pressure to give crude 2-amino-5,
414 mg of 6-difluorophenol was obtained.

(B) A mixture of the above amine (414 mg) and diethyl ethoxymethylene malonate (618 mg) was added under a nitrogen atmosphere for 5
Heated to 130 ° C for minutes. The crystalline residue was triturated in ethanol and collected by filtration to give diethyl = N- (3,4-difluoro-2-hydroxyphenyl) aminomethylene malonate (590 mg). Melting point 178-180 ° C, MS m / z 315 (M ⁺ ).

The mother liquor was purified by silica gel chromatography using chloroform / acetone (20/1) as an elution solvent to obtain 59 mg of crystals of the compound.

Ethyl = 8-benzyloxy-6,7-difluoro-4-
Synthesis of hydroxy-3-quinolinecarboxylate (Route 1) (c) Benzyl bromide (30 μl) was added to diethyl N-
(3,4-difluoro-2-hydroxyphenyl) aminomethylene malonate (80mg), anhydrous potassium carbonate (70m
g) and dry dimethylformamide (1.5 ml). The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane, and the precipitate was filtered. The filtrate was washed with water, dried over Glauber's salt, and concentrated under reduced pressure. The crystalline residue was washed with hexane and recrystallized from methanol to give diethyl = N- (2-
90 ml of benzyloxy-3,4-difluorophenyl) aminomethylene malonate were obtained. Melting point 87 ° C, MS m / z 405
(M ⁺ ).

(D) A solution of the above malonate (280 ml) in diphenyl ether (2.8 ml) was heated at 250 ° C. for 30 minutes in a nitrogen atmosphere, and then allowed to cool. The ethanol produced by the reaction was distilled off under reduced pressure, the remaining dark brown solution was poured into a silica gel (10 g) column, and eluted successively with a mixed solvent of benzene, dichloromethane and dichloromethane / acetone (30/1). The pure product fractions were collected and the solvent was evaporated under reduced pressure.

The residue was washed with a mixed solvent of hexane and ethyl acetate, and ethyl = 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate 90 mg.
Got This crude crystal can be used as it is in the next reaction, but it could be recrystallized from methanol to give an analytically pure crystal. Melting point 200-201 [deg.] C, MS m / z 359 (M ⁺ ).

Ethyl = 8-benzyloxy-6,7-difluoro-4-
Synthesis of Hydroxy-3-quinolinecarboxylate (Route 2) Ethyl = 6,7-difluoro-4,8-dihydroxy-3-quinolinecarboxylate (300 mg) in dry dimethylformamide (6 ml) with stirring under anhydrous carbonic acid Potassium (308 mg) was added followed by benzyl chloride (145 μl). After stirring this mixture at 55-65 ° C for 11 hours, water (30 ml)
Diluted with. The solvent was extracted with chloroform, dried over Glauber's salt, and concentrated under reduced pressure. The residue was separated by chromatography using silica gel (7 g) with acetone / chloroform (1/20) as an elution solvent and then recrystallized from methanol to obtain ethyl = 8-benzyloxy-6,7-difluoro-
4-hydroxy-3-quinolinecarboxylate 113 mg
Got Melting point 200-201 [deg.] C, MS m / z 359 (M ⁺ ).

Ethyl = 8-benzyloxy-6,7-difluoro-1-
Synthesis of (formylmethylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate (e) Ethyl = 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (41)
0 mg), anhydrous potassium carbonate (315 mg) and dry dimethylformamide (10 ml) were stirred at room temperature for 3 hours,
O- (2,4-dinitrophenyl) hydroxylamine (2
60 mg) was added. The reaction mixture was stirred at room temperature for another 6.5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with water (12 m
l) was added, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with cold water and then with ether to give ethyl = 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 405 mg.
Got This precipitate can be used as it is in the next reaction, but can be recrystallized from methanol to give analytically pure crystals. Mp 143-144 [deg.] C, MS m / z 374 (M ⁺ ).

(F) 0% 98% formic acid (0.60 ml) in acetic anhydride (1.51 ml)
At 0 ° C., the mixture was stirred at 0 ° C. for 15 minutes, 50 ° C. for 15 minutes and then cooled to 0 ° C. 98 of the above amines (400 mg)
A formic acid (2.1 ml) solution was added dropwise to this reaction solution. The mixture was stirred at room temperature for 2 days and then concentrated under reduced pressure. The crystalline residue was recrystallized from ethanol to give 410 mg of ethyl 8-benzyloxy-6,7-difluoro-1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate. . Melting point 188-190 ° C, MS m / z 402
(M ⁺ ).

(G) A mixture of the above formamide (400 mg), anhydrous potassium carbonate (275 mg) and dry dimethylformamide (17 ml) was stirred at room temperature for 1.5 hours. Methyl iodide (0.19 ml) was added to this mixture and stirring was continued for another 2.5 hours.
The solvent was distilled off under reduced pressure, and the residue was partitioned between water and chloroform. The organic layer was dried over Glauber's salt, evaporated to dryness under reduced pressure, and the residue was crystallized from ethanol to give ethyl 8-benzyloxy-6,7-difluoro-1- (formylmethylamino) -4-oxo-1. 335 mg of 4,4-dihydro-3-quinolinecarboxylate was obtained. Melting point 180-181 ° C, MS m / z 416
(M ⁺ ).

Synthesis of 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (h) Ethyl = 8-benzyloxy-6,7-difluoro- 1- (formylmethylamino) -4-oxo-1,4-
Dihydro-3-quinolinecarboxylate (330 mg) was dissolved in chloroform, 5% Pd / C (50 mg) was added, and hydrogenolysis was carried out at room temperature and atmospheric pressure for 4 hours. The reaction mixture was diluted with methanol (14 ml), the catalyst was filtered, and the filtered catalyst was washed with a mixed solvent of chloroform / methanol (1/1). The filtrate was collected and concentrated, the residue was recrystallized from ethanol, and ethyl = 6,7-difluoro-1- (formylmethylamino) -8-hydroxy-4-oxo-
239 mg of 1,4-dihydro-3-quinolinecarboxylate was obtained. Melting point 221-225 [deg.] C (decomposition), MS m / z 326 (M ⁺ ).

(I) A mixture of the above ester (210 mg) and 0.5N sodium hydroxide solution (5.2 ml) was heated at 100 ° C for 2 hours under a nitrogen atmosphere. A precipitate formed when acetic acid (0.16 ml) was added to the reaction mixture to acidify it. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinoline. 168 mg of carboxylic acid was obtained. This precipitate can be used as it is in the next reaction, but recrystallized from ethanol to obtain analytically pure crystals.
Melting point 248-250 ° C (decomposition), MS m / z 270 (M ⁺ ).

Example 1 Of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid Synthesis 6,7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (105 mg) obtained in Reference Example (i), paraformaldehyde (150 mg) ) And dry dioxane (5 ml) was heated at 100 ° C. for 3 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and dimethylformamide (20 ml) was added to the residue. The mixture was stirred for 20 minutes and then filtered. Further, the residue collected by filtration was washed with dimethylformamide, and the filtrate was collected and evaporated under reduced pressure. After grinding the residue in water,
It is collected by filtration to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-
97 mg of benzoxadiazine-6-carboxylic acid was obtained. An analytically pure sample was obtained by recrystallization from dimethylformamide. Melting point 290-292 ° C (decomposition), MSm / z2
82 (M ⁺ ).

Example 2 9,10-Difluoro-2,3-dimethyl-7-oxo-2,3-
Synthesis of dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzooxadiazine-6-carboxylic acid 6,7-difluoro-8-hydroxy-1 obtained in Reference Example (i) A mixture of-(methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg), 90% acetaldehyde (1 ml) and dioxane (5 ml) was heated at 100 ° C for 3 hours under a nitrogen atmosphere. . The reaction mixture was evaporated under reduced pressure to give 9,10-difluoro-2,3-dimethyl-7.
-Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]-
52 mg of 1,3,4-benzooxadiazine-6-carboxylic acid was obtained. Melting point 285-289 ° C, MS m / z 296 (M ⁺ ).

Example 3 9,10-Difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1
-Ij] -1,3,4-Benzoxadiazine-6-carboxylic acid synthesis 6,7-difluoro-8-hydroxy-1- (methylamino) -4-oxo obtained in Reference Example (i) -1,4-Dihydro-3-quinolinecarboxylic acid (50 mg), glycolaldehyde diethyl acetal (45 μl) and pyridinium p-toluenesulfonate (7 mg) in dry dioxane (2 ml)
And was heated at 110 ° C. for 5 hours under a nitrogen stream. The crystalline residue obtained by removing the solvent under reduced pressure was washed with water and methanol to give 9,10-difluoro-2- (hydroxymethyl) -3-methyl-7-oxo-2,3-dihydro-. 7
52 mg of H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid were obtained. Melting point 254-258 [deg.] C (decomposition), MS m / z 312 (M ⁺ ).

Example 4 9,10-Difluoro-2-[(dimethylamino) methyl]
-3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-
Carboxylic Acid = Synthesis of p-toluenesulfonate 6,7-Difluoro-8-hydroxy-1- (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarvone obtained in Reference Example (i) Acid (50 mg), dimethylaminoacetaldehyde dimethyl acetal (37 mg) and p-
Toluenesulfonic acid monohydrate (53 mg) was suspended in dry sioxane (2 ml) and heated at 110 ° C. for 17 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to give 9,10-difluoro-2-[(dimethylamino).
Methyl] -3-methyl-7-oxo-2,3-dihydro-7
61 mg of H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid = p-toluenesulfonate were obtained. Melting point 232-236 ° C (decomposition), FAB-MS m / z340 (M
H ⁺ ).

Example 5 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4- Benzoxadiazine-6-
Synthesis of carboxylic acid 9,10-difluoro-3-methyl-7 obtained in Example 1
-Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]-
1,3,4-Benzoxadiazine-6-carboxylic acid (30m
g), N-methylpiperazine (47 μl) and dry pyridine (3 ml) were heated at 100-110 ° C. for 9 hours under a nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 9-fluoro-3-methyl-10- (4-
23 mg of methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid were obtained. Melting point 268-269 ° C
(Decomposition), MS m / z 362 (M ⁺ ).

The following compounds were synthesized by a method similar to that in Example 5.

Example 24 9-Fluoro-3-methyl-7-oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4- Benzoxadiazine-6-
Synthesis of carboxylic acid 9,10-difluoro-acid-methyl-7 obtained in Example 1
-Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]-
1,3,4-Benzoxadiazine-6-carboxylic acid (40m
g), 2-piperazinone (31.1 mg), 1,4-siazabicyclo [2.2.2] octane (31.8 mg) and dry dimethyl sulfoxide (1 ml) under nitrogen atmosphere at 130 ° C.
Heated for 8.5 hours. After removing the solvent under reduced pressure, the residue was separated by TLC (silica gel; chloroform / methanol = 10/1.
Separated in 5) and recrystallized from a mixed solvent of dichloromethane and methanol to give 9-fluoro-3-methyl-7-oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-. 6.3 mg of pyrido [3.2.1-ij] -1,3,4-benzooxadiazine-6-carboxylic acid was obtained. Melting point> 300
C., FAB-MS m / z 363 (MH ^<+> ).

The following compounds were synthesized by a method similar to that in Example 5, using the compounds obtained in Examples 2, 3 and 4 as raw materials.

Example 29 10- [3- (benzyloxycarbonylamino) -1-
Pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4
-Synthesis of benzooxadiazine-6-carboxylic acid 9,10-difluoro-3-methyl-7 obtained in Example 1
-Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]-
1,3,4-Benzoxadiazine-6-carboxylic acid (28m
g), 3- (benzyloxycarbonylamino) pyrrolidine (94 mg) and dry pyridine (3 ml) were heated at 100 ° C. for 3 hours under a nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl].
36 mg of -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid were obtained. Melting point 227-230
° C, MS m / z 482 (M ⁺ ).

Example 30 10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4- Benzoxadiazine-6-
Synthesis of carboxylic acid 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3 obtained in Example 29
-Methyl-7-oxo-2,3-dihydro-7H-, lid [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (30 mg) in dimethylformamide (2 ml) After dissolution, 5% Pd / C (10 mg) was added, and hydrogenolysis was carried out at room temperature and atmospheric pressure for 4.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from methanol to give 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]
-1,3,4-benzoxadiazine-6-carboxylic acid 16mg
Got Melting point 230-234 [deg.] C (decomposition), MS m / z 348 (M ⁺ ).

The following compounds were synthesized in an analogous manner to Examples 29 and 30.

Example 36 10- (3,4-Dimethyl-1-piperazinyl) -9-fluoro-3
-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid synthesis 9-Fluoro-3-methyl-10- (3-methyl-1-piperazinyl) -7-oxo obtained in Example 7 -2,3-dihydro-7H
-Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6
-A mixture of carboxylic acid (60 mg), 98% formic acid (1 ml) and 35% formalin (1 ml) was heated with stirring at 100-110 ° C for 2 hours. The reaction mixture was evaporated under reduced pressure, dissolved in water and then neutralized with 1N sodium hydroxide solution. It was extracted with chloroform, washed with water, and then dried with mirabilite. The crystalline residue obtained by removing the solvent under reduced pressure was recrystallized from methanol to give 10- (3,4-dimethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2. 43 mg of 3,3-sihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid was obtained. Melting point 257-259 ° C, FAB-MS m / z377 (M
H ⁺ ).

Example 37 9-Fluoro-10- (3-methoxy-1-pyrrolidinyl) -3-
Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-i
Synthesis of j] -1,3,4-benzoxadiazine-6-carboxylic acid The 9-fluoro-10- (3-hydroxy-1 obtained in Example 21
-Pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (100 mg) in dry dimethyl Suspend in formamide (10 ml) and add 60% sodium hydride to it.
Oily (30 mg) was added followed by methyl iodide (40 μl).
After the mixture was stirred at room temperature for 2 hours, 60% sodium hydride, oil (30 mg) and then methyl iodide (40 μl) were added, and the mixture was further stirred at 45 ° C. for 3 hours. Cold water (2 ml) and 0.5 N sodium hydroxide solution (2.3 ml) were added to the residue obtained by removing the solvent under reduced pressure. The suspension was heated at 100 ° C. for 2 hours. After cooling to room temperature, it was neutralized with acetic acid and diluted with water.

The mixture was extracted with chloroform, washed with water, dried over Glauber's salt, and concentrated under reduced pressure. Acetone / chloroform (1/9) of crystalline residue
Was separated by silica gel chromatography using eluent as the elution solvent. Recrystallized from methanol to give 9-fluoro-10- (3
-Methoxy-1-pyrrolidinyl) -3-methyl-7-oxo-
42 mg of 2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxiazine-6-carboxylic acid were obtained. Melting point 233-234
C, FAB-MS m / z 364 (MH ^<+> ).

Example 38 9-Fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-i
Synthesis of j] -1,3,4-benzoxadiazine-6-carboxylic acid The 9-fluoro-10- (4-hydroxy-1 obtained in Example 13
-Piperidyl) -3-methyl-7-oxo-2,3-dihydro-7
H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-
Using 6-carboxylic acid as a raw material and in the same manner as in Example 37, 9-
Fluoro-10- (4-methoxy-1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]
-1,3,4-Benzoxadiazine-6-carboxylic acid was synthesized. Chloroform was recrystallized from a mixed solvent of n-hexane. Melting point 229-233 [deg.] C (decomposition), MS m / z 377 (M ⁺ ).

Example 39 10- (1,1-Dioxide-4-thiomorpholinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3, Synthesis of 4-benzoxazian-6-carboxylic acid 9-fluoro-3-methyl-7-oxo-obtained in Example 11
10- (4-thiomorpholinyl) -2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzooxodiazine-6-carboxylic acid (50 mg) was suspended in dichloromethane (5 ml). It was made turbid, and m-chloroperbenzoic acid (purity 70%, 74 mg) was added thereto.
After stirring this mixture at room temperature for 18 hours, the solvent was evaporated under reduced pressure. The residue was washed with ether, dichloromethane, then with a mixed solvent of chloroform and methanol, and recrystallized from dimethylformamide to give 10- (1,1-dioxide-4-thiomorpholinyl) -9-fluoro-3-methyl-7-oxo. -2,
22 mg of 3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid were obtained. Melting point> 300
° C, MS m / z 397 (M ⁺ ).

Example 40 9-Fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -2,3-dihydro-7H
-Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6
Synthesis of 9-fluoro-3-methyl-7-oxo-obtained in Example 6
10- (1-Piperazinyl) -2,3-dihydro-7H-pyrido [3.
2.1-ij] -1,3,4-Benzoxadiazine-6-carboxylic acid (50 mg), chloroacetone (17 μl), triethylamine (40 μl) and dry dimethylformamide (1 ml)
The mixture was heated at 80 ° C. for 3.5 hours. The volatile substances were distilled off under reduced pressure, the residue was suspended in water, and the precipitate was collected by filtration. Recrystallized from a mixed solvent of dichloromethane and methanol to give 9-fluoro-3-methyl-7-oxo-10- [4- (2-
32 mg of oxo-n-propyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid were obtained. Melting point 225-229 [deg.] C (decomposition), FAB-MS m / z 405 (MH ^<+> ).

The following compounds were synthesized by a method similar to that in Example 40.

Example 48 10- [3-[(Ethylmethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] Synthesis of -1,3,4-benzooxadiazine-6-carboxylic acid 9-Fluoro-3-methyl-10- [3- obtained in Example 17
[(Methylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-
Using 10- [3-[(ethylmethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3-methyl- as in Example 40, starting from benzoxadiazine-6-carboxylic acid and ethyl iodide. 7-oxo-2,3-dihydro-7H-pyrido [3.
2.1-ij] -1,3,4-Benzoxadiazine-6-carboxylic acid was obtained. Recrystallization from a mixed solvent of chloroform, methanol and n-hexane was performed. Melting point 210-225 ° C (decomposition), FA
B-MS m / z 405 (MH ^<+> ).

Example 49 10- [4-[(3-Carboxypropionyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij]- Synthesis of 1,3,4-benzoxadiazine-6-carboxylic acid 9-Fluoro-3-methyl-7-oxo-10-obtained in Example 6
(1-Piperazinyl) -2,3-dihydro-7H-pyrido [3.2.1
-ij] -1,3,4-Benzoxadiazine-6-carboxylic acid (5
0 mg), succinic anhydride (21.6 mg), triethylamine (4
A mixture of 0 μl) and dry dimethylformamide (4 ml) was heated at 80 ° C. for 2 hours. The solvent was further removed under reduced pressure and the residue was suspended in water. The precipitate is collected by filtration,
Then recrystallize with a mixture of dichloromethane and methanol to give 50 mg of 10- [4- (3-carboxypropionyl) -1-.
Piperazinyl] -9-fluoro-3-methyl-7-oxo-2,
3-Dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid was obtained. mp.257-259 ℃ (de
c.); FAB-MS m / z 449 (MH ⁺ ).

Example 50 10- (4-Acetyl-1-piperazinyl) -9-fluoro-3-
Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-i
Synthesis of j] -1,3,4-benzoxadiazine-6-carboxylic acid 10- (4-acetyl-1-piperazinyl] -9-fluoro-3-
Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid was prepared in the same manner as in Example 49 except that 9-fluoro-3-methyl-7-oxo-10- (1- Piperazinyl) -2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid synthesized from acetic anhydride and recrystallized from dichloromethane / methanol To give a crystalline powder. mp.294-296 ° C (dec.); FAB-MSm / z391 (M
H ⁺ ).

Example 51 9-Fluoro-3-methyl-7-oxo-10- [4- (3-oxo-n-butyl) -1-piperazinyl] -2,3-dihydro-7H-
Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-
Synthesis of carboxylic acid 9-chloro-3-methyl-7-oxo-10-1-obtained in Example 6
Piperazinyl] -2,3-dihydro-7H-pyrido [3.2.1-i
j] -1,3,4-benzoxadiazine-6-carboxylic acid (30m
A mixture of g), methyl vinyl ketone (36 μl) and ethanol (1 ml) was refluxed for 12 hours and then cooled to room temperature.

The precipitated precipitate was collected by filtration and crystallized from ethanol to give 28 mg of 9-fluoro-3-methyl-7-oxo-10- [4- (3-oxo-n-butyl) -1-piperazinyl. ]
-2,3-Dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid was obtained. mp.187-189 ℃
(Dec.); FAB-MS m / z 419 (MH ^<+> ).

Example 52 9-Fluoro-3-methyl-7-oxo-10- [4- (3-sulfonate methyl) -1-piperazinyl] -2,3-dihydro-7H
-Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6
-Synthesis of carboxylic acid disodium salt 35% formalin (26mg) and sodium bisulfate (32mg)
And water (0.5 ml) were mixed, heated at 75 ° C. for 30 minutes, and then cooled to room temperature.

To this solution was obtained 9-fluoro-3-methyl-obtained in Example 6.
7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-
Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-
Carboxylic acid (100 mg) and sodium hydroxide (15 mg) were added. This solution was heated at 75 ° C for 1 hour, ethanol (2 ml) was added, and the mixture was cooled to room temperature. The separated precipitate was collected by filtration and recrystallized from water / ethanol (1: 2).
-Fluoro-acid-methyl-7-oxo-10- [4- (sulfonate methyl) -1-piperazinyl] -2,3-dihydro-7H-
Pyrido [3.2.1-ij] -1,3-4-benzoxadiazine-6-
A carboxylic acid disodium salt was obtained. Melting point 260-263 ℃ (de
c.); 1H NMR (D ₂ O) δ: 2.98 (3H, s), 3.05 (4H,
m), 3.39 (4H, m), 3.84 (2H, s), 5.18 (2H,
s), 7.55 (1H, d, J = 13.4Hz), 8.34 (1H, s).

Example 53 10- [4- (4-aminobenzyl) -1-piperazinyl] -9-
Synthesis of Fluoro-3-methyl-7-oxo-2,3, dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid Obtained in Example 47 9-Fluoro-3-methyl-10- [4- (4-nitrobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3, 4-benzooxadiazine-6-carboxylic acid (100 mg) in dichloromethane /
In a methanol (1: 1) solution, hydrogenation was carried out for 2 hours under a solvent of 5% Pd / C (10 mg) (palladium thiol).

After removing the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure.

The residue was recrystallized from ethanol to give 69 mg of 10- [4- (4-aminobenzyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3, dihydro-7H-pyrido [3.2 .1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid was obtained. Melting point 237-238 [deg.] C (dec.); FAB-MS m / z 454 (MH ^<+> ).

Example 54 10- [3- (aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3, dihydro-7H-pyrido [3.2.1-ij] -1,3 Synthesis of 1,4-benzooxadiazine-6-carboxylic acid 10- [3- (acetylaminomethyl) -1-obtained in Example 19
Pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,
3, dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (40mg) and 1N sodium hydroxide (2.5ml) heated at 100 ℃ for 3 hours . After cooling to room temperature, the reaction was neutralized with acetic acid. The separated precipitate was collected by filtration and recrystallized from methanol to give 15 mg of 10- [3-
(Aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-
Methyl-7-oxo-2,3, dihydro-7H-pyrido [3.2.1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid was obtained. Melting point 177-180 [deg.] C (dec.); FAB-MS m / z 363 (MH ^<+> ).

Example 55 6-Fluoro-8-hydroxy-7- (1-imidazolyl) -1-
Synthesis of (methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 6,7-difluoro-8-hydroxy-1-obtained in Reference Example (i)
(Methylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (50 mg) was dried over dimethylformamide (2 m
l) Dissolve in carbonyldiimidazole (3
2 mg) was added. After stirring at room temperature for 2 hours, the mixture was heated at 80 ° C. for 5 hours. The solvent was removed under reduced pressure, the residue was suspended in water and adjusted to pH 5 with acetic acid. The precipitate is separated by filtration, washed with methanol and 35 mg of 6-fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1 in the form of a pale yellow powder. , 4-Dihydro-3-quinolinecarboxylic acid was obtained. FAB-MS m / z 319 (MH ⁺ ); ¹ H-NMR spectrum (d ₆ -DMSO) δ: 2.82 (3H, s), 7.10 (1H, d,
J = 10.7Hz), 7.61 (1H, d), 7.75 (1H, d), 8.62
(1H, s), 8.92 (1H, s), 15.33 (1H, br.s).

Example 56 9-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-
Synthesis of Benzoxadiazine-6-carboxylic acid 6-Fluoro-8-hydroxy-7- (1-imidazolyl) -1- (methylamino) -4-oxo-1,4-dihydro-obtained in Example 55 3-Quinolinecarboxylic acid (15 mg) was suspended in a mixed solution of 35% formalin (1 ml) and dioxane (1 ml), and heated at 100 to 110 ° C for 1.5 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure, the crystalline residue was washed with methanol, 15 mg of pale pink powder 9-fluoro-10- (1-imidazolyl)
-3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.
2.1-ij] -1,3,4-Benzoxadiazine-6-carboxylic acid was obtained. An analytical sample was prepared by recrystallization from a mixed solvent of dimethylformamide and ether. mp> 300 ℃; FAB-M
Sm / z 331 (MH ⁺ ).

9-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-
Benzoxadiazine-6-carboxylic acid was treated with 9-10-fluoro-3 in dimethyl sulfoxide as in Example 5.
-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-
It was also prepared from ij] -1,3,4-benzoxadiazine-6-carboxylic acid and imidazole.

Example 57 Benzyl = 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3, Synthesis of 4-benzooxadiazine-6-carboxylate 9-Fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H obtained in Example 21
-Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6
-Carboxylic acid (10 mg), anhydrous potassium carbonate (8 mg) and dimethylformamide (0.5 ml) were mixed and stirred at room temperature for 1.5 hours, and then benzyl bromide (10.8 mg) was added. The mixture was stirred at room temperature for 3 hours and the solvent was distilled off under reduced pressure.

The residue was suspended in water, extracted with chloroform, and the extract was concentrated to dryness under reduced pressure. The residue is treated with ether, 11 mg
Benzyl = 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-
Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-
The carboxylate was obtained. mp.196-198 ° C (dec.); FAB
-MS m / z 440 (MH ⁺ ).

Example 58 benzyl = 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3, Synthesis of 4-benzooxadiazine-6-carboxylate Benzyl 9-fluoro-10- (3-hydroshiki-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro obtained in Example 57 -7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylate (8 mg) was dissolved in 0.2 ml thionyl chloride and stirred at 60 ° C for 15 minutes. The reaction mixture was diluted with water and extracted with chloroform.

The extract was concentrated under reduced pressure and the residue was washed with silica gel (2
g) Chromatograph and develop with chloroform to give 2.8 mg of benzyl = 10- (3-chloro-1-pyrrolidinyl).
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H
-Pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6
-I got a carboxylate. Melting point> 300 ° C; FAB-MS m / z458
(MH ⁺ ), 460 (MH +2) ⁺ .

Example 59 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1-i
Synthesis of j] -1,3,4-benzoxadiazine-6-carboxylic acid Benzyl-10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-obtained in Example 58 Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylate (2.5 mg) in chloroform with 5% Pd / C (1 mg ) Hydrogenated under catalyst.

After removing the catalyst by filtration, the filtrate was concentrated to dryness under reduced pressure.

The residue was recrystallized from ethanol to give 1.0 mg of 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3.2.1- ij] -1,3,4-
Benzoxadiazine-6-carboxylic acid was obtained. Melting point 269
-272 degreeC (dec.); FAB-MSm / z368 (MH ^<+> ), 370 (MH + 2) ^<+> .

Example 60 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-via fluoroborane intermediate
Synthesis of dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid a) 9,10-difluoro-3-methyl-7 obtained in Example 1 -Oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-
Benzoxadiazine-6-carboxylic acid (100mg) and 60%
A mixture of aqueous borofluoric acid solution (1 ml) was heated at 90 ° C. for 12 hours. After cooling the reaction mixture to room temperature, the precipitate was collected by filtration, washed with methanol and concentrated to dryness under reduced pressure to give 110 ml of crude 9,10-difluoro-6-.
Obtained [[(difluoroboryl) oxy] carbonyl] -3-methyl-2,3-dihydro-7H-pyrido [3.2.1-ij] 1,3,4-benzooxadiazin-7-one; FAB -MSm / z331 (MH
₊ ).

b) The above borane intermediate (33 mg) was dissolved in dimethyl sulfoxide (1 ml) and N-methylpiperazine (15 μl) and triethylamine (20 μl) were added with stirring.
After stirring at room temperature for 3 hours, the reaction mixture was freeze-dried. The residue was crystallized from methanol and 28 mg of yellow crystals 6-
[[(Difluoroboryl) oxy] carbonyl] -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl)
Obtained -2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzooxadiazin-7-one. Melting point 228-230 ℃ (de
c.); FAB-MS m / z 411 (MH ^<+> ).

c) Triethylamine (3 μl) was added to a solution of the borane intermediate (5 mg) in 95% ethanol (1 ml). After heating under reflux for 4 hours, the reaction solution was cooled to room temperature. The precipitate formed was collected by filtration and used as 9-fluoro-3-methyl-10
(4-Methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3.2.1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid was obtained. Melting point 268-269 ° C (dec.).

Example 61 9-Fluoro-3-via an acetoxyborane intermediate
Methyl-10- (4-methyl-1-piperazinyl) -7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
Method for synthesizing 3,4-benzooxadiazine-6-carboxylic acid a) 9,10-difluoro-3-methyl-7 obtained in Example 1
-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]-
1,3,4-Benzoxadiazine-6-carboxylic acid (100m
g), acetic anhydride (1 ml) and triacetoxyborane (100 m
g) were mixed and heated for 15 minutes at 140 ° C. The reaction mixture was evaporated under reduced pressure. The residue was treated with acetone, filtered and filtered to give 138 mg of 6-[[(diacetoxyboryl).
Oxy] carbonyl] -9,10-difluoro-3-methyl-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-
Benzoxadiazin-7-one was obtained; FAB-MS m / z
411 (MH ⁺ ).

b) N-Methylpiperazine (15 μl) and triethylamine (20 μl) were added to a solution of the borane intermediate (41 mg) in dimethyl sulfoxide (1 ml). After stirring the mixture at room temperature for 2 hours, the reaction mixture was lyophilized. The residue was crystallized from methanol / ether, 34 mg
Yellow crystals of 6-[[(diacetoxyboryl) oxy] carbonyl] -9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2 , 1-ij] -1,3,4-Benzoxadiazine-7-
Got on. Melting point 156-157 ° C (dec.); FAB-MS m / z 491
(MH ⁺ ).

c) The above borane intermediate (5 mg) was suspended in acetone (0.1 ml) and concentrated hydrochloric acid (2.5 μl) was added. The reaction mixture was stirred at room temperature for 30 minutes and cooled in ice. The resulting precipitate is
It was collected by filtration and dissolved in 95% ethanol (0.1 ml). Triethylamine (2 μl) was added to this solution and the mixture was heated to reflux for 1 hour. The solution was cooled to room temperature and the resulting precipitate was collected by filtration, and 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H -Pyrido [3,2,1-ij] -1,3,
4-Benzoxadiazine-6-carboxylic acid was obtained.
Melting point 268-269 ° C (dec.).

Example 62 Pivaloyloxymethyl = 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3, 2,1-ij] -1,3,4-benzoxadiazine-6
-Synthesis of carboxylate 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [obtained in Example 29 3,2,1
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid (290 mg) and pivaloyloxymethyl chloride (1
A mixture of 30 μl), anhydrous potassium carbonate (166 mg) and dry dimethylformamide (10 ml) was stirred for 8 hours at 45 ° C. The solvent was distilled off under reduced pressure and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate to give 325 mg of pivaloyloxymethyl = 10- [3- (benzyloxycarbonylamino) -1.
-Pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,
4-Benzoxadiazine-6-carboxylate was obtained; mp 185-188 [deg.] C; FAB-MS m / z 597 (MH ^<+> ).

Example 63 Pivaloyloxymethyl = 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-
Synthesis of 2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate Pivaloyloxymethyl 10- (3-amino-1- Pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate was prepared according to
Similarly to 30, pivaloyloxymethyl obtained in Example 62 = 10- [3- (benzyloxycarbonylamino)-
1-Pyrrolidinyl] -9-fluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
3,4-Benzoxadiazine-6-carboxylate (2
00 mg) and precipitated from a concentrated solvent of ethyl acetate and n-hexane to obtain a pale brown powder. ¹ H NMR (CDCl ³ ) δ: 1.22 (9H, s), 1.6 to 2.4 (2H, s)
m), 2.99 (3H, s), 3.3 to 4.0 (5H, m), 4.98 (2H, s)
s), 5.96 (2H, s), 7.64 (1H, d, J = 14.4Hz), 8.37 (1
H, s); FAB-MS m / z 463 (MH ^<+> ).

Example 64 Ethyl = 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1- i
j] -1,3,4-Benzoxadiazine-6-carboxylate synthesis 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl obtained in Example 29 -7-oxo-2,3-dihydro-7H-pyrido [3,2,1
-Ij] -1,3,4-Benzoxadiazine-6-carboxylic acid (337 mg), ethyl iodide (84 μl), anhydrous potassium carbonate (193 mg) and dry dimethylformamide (12 ml)
The mixture was stirred at 45 ° C for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with a mixture of chloroform and acetone (20: 1). The purified fractions were collected and dried under reduced pressure. Recrystallization from the residue and ethyl acetate gave 271 mg of ethyl = 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-.
Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-
6-carboxylate was obtained. Melting point 204-207 ° C; FAB-MS
m / z 511 (MH ⁺ ).

Example 65 Ethyl = 10- (3-amino-1-pyrrolidinyl) -9-
Fluoro-3-methyl-7-oxo-2,3-dihydro-7
Synthesis of H-pyrido [3,2,1-idi] -1,3,4-benzooxadiazine-6-carboxylate Ethyl obtained in Example 64 = 10- [3- (benzyloxycarbonylamino)- 1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-
Carboxylate (200 mg) in a mixed solvent of chloroform (25 ml) and methanol (10 ml) 5% Pd / c (120 mg)
Hydrogenated under catalyst for 23 hours. After removing the catalyst by filtration,
The filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with a mixed solvent of chloroform and methanol (4: 1). The purified fractions were collected and concentrated to dryness under reduced pressure.
The residue was further purified by preparative TLC (silica gel; chloroform / methanol 3: 1); recrystallized from ethanol and 71 mg of ethyl = 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3. -Methyl-7-oxo-2,3
-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate was obtained. Melting point 18
7-192 ° C (dec.); FAB-MS m / z 377 (MH ⁺ ).

Example 66 10- (3-Amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, 4-benzooxadiazine-6-
Synthesis of Carboxylic Acid Hydrochloride 10- (3-Amino-1-pyrrolidinyl)]-9-fluoro-3-methyl-7-oxo-2,3 obtained in Example 30
-Dihydro-7-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid (20 mg) dissolved in 1 ml of water to adjust the pH to 1 with 6N hydrochloric acid did. The clear solution was freeze-dried, the residue was crystallized from water / ethanol (1: 2) and 19 ml of 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2. , 3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid hydrochloride was obtained. Melting point 226
~ 228 ° C (dec.).

Example 67 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, 4-benzooxadiazine-6-
Synthesis of Carboxylic Hydrochloride Hydrochloride 9-Fluoro-3-methyl-10 was prepared in the same manner as in Example 66.
-(4-methyl-1-piperazinyl) -7-oxo-2,
There was obtained 3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid hydrochloride. Melting point
264 flat 266 ℃ (dec.).

Example 68 9-Fluoro-3-methyl-10-monofolino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4
-Synthesis of benzooxadiazine-6-carboxylic acid sodium salt 9-Fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [3,2, obtained in Example 9 1
-Ij] -1,3,4-Benzoxadiazine-6-carboxylic acid (14 mg) was suspended in water (0.4 ml), and 1N-sodium hydroxide (40 μl) was added with stirring. The clear solution was lyophilized and the residue was crystallized from water / ethanol (1: 4), 12 mg of 9-fluoro-3-methyl-10-morpholino-7-oxo-2,3-dihydro-7H-pyrido [ 3,2,1-
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid sodium salt was obtained. Melting point> 300 ° C. Example 69 9-Fluoro-3- (2-fluoroethyl) -10- (4
-Methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid synthesis reference example Ethyl-8-benzyloxy-obtained in (f)
Starting from 6,7-difluoro-1- (formylamino) -4-oxo-1,4-dihydro-3-quinolinecarboxylate as a starting material, reference examples (g), (h) and (i) (of methyl iodide 1-Bromo-2-fluoroethane was used instead), according to the procedure of Example 1 and Example 5,
9-fluoro-3- (2-fluoroethyl) -10- (4
-Methyl-1-piperazinyl) -7-oxo-2,3-sihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, Recrystallization from methanol gave a crystalline powder. Melting point 220-224 ° C, MS
m / z 394 (M ⁺ ).

Examples 70-77 The following compounds were obtained from the compound obtained in Example 1 using a method similar to any of those described in Example 5 or Example 29/30.

The following compounds were also obtained from the compound obtained in Example 1 using a method similar to any of those described in Example 5 or Example 29/30.

10- [3- (aminomethyl) -4-methyl-1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- [3- (ethylamino) methyl] -4-methyl-1
-Pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,
4-benzooxadiazine-6-carboxylic acid, 10- [3- (aminomethyl) -4-chloro-1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- [3- (aminomethyl) -4-fluoro-1-pyrrolidinyl ] -9-Fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- [3-chloro-4 [(methylamino) methyl] -1
-Pyrrolidinyl [-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,
4-benzooxadiazine-6-carboxylic acid, 9-fluoro-10- [3-fluoro-4 [(methylamino) methyl] -1-pyrrolidinyl] -3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
3,4-Benzoxadiazine-6-carboxylic acid, 10- [3-chloro-4 [(ethylamino) methyl] -1
-Pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,
4-benzooxadiazine-6-carboxylic acid, 10- [3-[(ethylamino) methyl] 4-fluoro-
1-Pyrrolidinyl] -9-fluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
3,4-Benzoxadiazine-6-carboxylic acid, 9-fluoro-10- [3-methoxy-4- (methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- [3-[(ethylamino) -4-methoxy- 1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-
Benzoxadiazine-6-carboxylic acid, 9-fluoro-10- (3-hydroxy-4-methoxy-
1-pyrrolidinyl) -3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- (3-amino-4-chloro-1-pyrrolidinyl)-
9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- ( 3-amino-4-fluoro-1-pyrrolidinyl)
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 10- [3-chloro-4- (methylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10- [3-fluoro-4- (methylamino) -Pyrrolidinyl] -3-methyl-7-oxo-2,3
-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-3-methyl-10- (1-oxide-4-
Thiomorpholinyl) -7-oxo-2,3-dihydro-7H
-Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid, 9-fluoro-10- [3-hydroxy-4- (methylamino) -1pyrrolidinyl]- 3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid.

Example 78 10- [3-[(4-aminobenzyl) amino] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1 −ij] -1,3,4−
Synthesis of Benzoxadiazine-6-carboxylic acid 10- [3-[(4-aminobenzyl) amino] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H -Pyrid [3,2,1-ij] -1,3,4-
The benzoxadiazine-6-carboxylic acid is the 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H- obtained in Example 30.
Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-
Obtained in a similar manner to that described in Examples 47 and 53, using 6-carboxylic acid as the starting material. Melting point 180-182 ℃ (dec.), FA
B-MS m / z 453 (MH ⁺ ).

Example 79 9-Fluoro-10- [3-[[(dimethylamino) methylene] -amino] -1-pyrrolidinyl] -3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]
Synthesis of -1,3,4-benzooxadiazine-6-carboxylic acid 10- (3-amino-1-pyrrolidinyl) obtained in Example 30
-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxazazine-6-carboxylic acid (14 mg) Dry N, N-dimethylformamide dimethylacetal (6 μl) with DMF
It was suspended in (0.5 ml) and stirred at room temperature for 8.5 hours. The precipitate was collected by filtration, washed with dimethylformamide and ether, and recrystallized from dimethylformamide to give 8 mg of 9
-Fluoro-10- [3-[[(dimethylamino) methylene] -amino] -1-pyrrolidinyl] -3-methyl-7
-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]-
1,3,4-Benzoxadiazine-6-carboxylic acid was obtained as pale yellow crystals. Melting point 218-220 ° C (dec.), FAB-MS
m / z 404 (MH ⁺ ).

Example 80 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3, 4-benzooxadiazine-6-
Synthesis of sodium carboxylic acid salt 9-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1 , 3,4-Benzoxadiazine-6-
Carboxylic acid (520 mg) was added to 0.5 N sodium hydroxide (2.88 m
l) dissolved in. The clear solution was evaporated under reduced pressure to give 555 mg of a pale yellow powder which was recrystallized from ethanol and dried at 80 ° C for 2 days to give 9-fluoro-3-methyl-10- (4-methyl). -1-Piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-
Benzoxadiazine-6-carboxylic acid sodium salt 47
Obtained 5 mg. Further, it was dried at 80 ° C. for 2 days to obtain a sample for obtaining physical properties. Melting point 252-254 ° C (dec.), FAB-MS m / z 38
Five.

The following examples demonstrate pharmaceutical compositions containing the compounds provided by this invention.

Example A Each of the interlocking (inte
rlocking) Gelatin capsules were prepared by conventional method; 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1 , -ij] -1,3,4-Benzooxadiazine-6-carboxylic acid 200 mg Luviskol 20 mg (water-soluble polyvinylpyrrolidone) Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mg 257 mg Example B Tablets containing were made by a conventional method; 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,4-Benzooxadiazine-6-carboxylic acid 200mg Starch 44mg Carboxymethylcellulose calcium 30mg Crystalline cellulose 40mg Magnesium stearate 6mg 320mg

Claims (110)

[Claims] 1. A general formula (I) In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group;
R ² represents a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom; R ³ and R ⁴ are each independently substituted with a hydrogen atom, a hydroxyl group, or a substituted or unsubstituted amino group. Also represents a lower alkyl group; X represents a halogen atom; and R ⁵ and R ⁶ are each independently substituted with a hydrogen atom, a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group. Represents a lower alkyl group; or R ⁵ and R ⁶ may form, together with the adjacent nitrogen atom, a 5- to 7-membered heterocycle, wherein the heterocycle has one or more carbon atoms at its carbon atom. may be substituted with a substituent, further the heterocyclic ring ^{-NR 7 -, - O -,} - S -, - SO -, - SO 2 -
Alternatively, —NR ⁷ —CO— [wherein R ⁷ is a hydrogen atom, a lower alkenyl group, an optionally substituted lower alkyl group or an aralkyl group, or a compound represented by the general formula (II) — (CH ₂ ) nCOR ⁸ (II (In the formula, n is 1 to 4, and R ⁸ is a hydrogen atom, a lower alkoxy group, or an optionally substituted amino, lower alkyl or aryl group). A tricyclic compound represented by: and a pharmaceutically acceptable salt thereof, and a hydrate or solvate of the compound of formula (I) and a salt thereof. 2. R ³ and / or R ⁴ in the case of a substituted amino-lower alkyl group is di-lower alkylamino-
The compound according to claim 1, which is a lower alkyl group, a lower alkylamino-lower alkyl group or a lower cycloalkylamino-lower alkyl group. 3. R ⁵ and / or R ⁶ when it is a substituted amino-lower alkyl group is di-lower alkylamino-
The compound according to claim 1 or 2, which is a lower alkyl group, a lower alkylamino-lower alkyl group or a lower cycloalkylamino-lower alkyl group. 4. R ⁵ and R in the case where a 5- to 7-membered heterocyclic ring is formed together with an adjacent nitrogen atom and is substituted with one or more substituents at the carbon atom of the heterocyclic ring. ⁶ is a hydroxyl group, lower alkoxy group, amino group, lower alkylamino group, lower cycloalkylamino group, di-lower alkylamino group, lower alkanoylamino group, benzyloxycarbonylamino group, halogen atom, lower alkyl group, amino-lower Alkyl group, lower alkylamino-lower alkyl group, lower cycloalkylamino-lower alkyl group, di-lower alkylamino-lower alkyl group, lower alkanoylamino-lower alkyl group, hydroxy-
A lower alkyl group; a phenyl group (which may be optionally substituted with an amino group, a halogen atom, a hydroxyl group and / or a lower alkoxy group) and a substituent selected from a heterocycle at a carbon atom. Alternatively, the compound according to item 2. 5. R ⁵ and R in the case where a 5- to 7-membered heterocyclic ring is formed together with an adjacent nitrogen atom and is substituted with one or more substituents at the carbon atom of the heterocyclic ring. ⁶ is a benzylamino group optionally substituted by a nitro group, an amino group, a halogen atom, a hydroxyl group and / or a lower alkoxy group; or a general formula (Wherein R ⁵⁰ and R ⁵¹ are substituted with a lower alkyl group or a 5- to 8-membered saturated nitrogen-containing heterocycle together with a nitrogen atom). The compound according to claim 1 or 2. 6. R ⁷ when it is a substituted lower alkyl group
Is a hydroxyl group, a lower alkoxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a halogen atom, a carboxy group and / or a lower alkyl group substituted with a sulfo group. A compound according to any one of paragraphs. 7. A substituted aralkyl group, wherein R ⁷ is substituted with one or more amino groups, nitro groups, lower alkylamino groups, di-lower alkylamino groups, halogen atoms and / or lower alkoxy groups. The compound according to any one of claims 1 to 5, wherein the compound is an aralkyl group. 8. A compound as claimed in claim 7 wherein the aralkyl group is a benzyl group optionally substituted by a group as claimed in claim 7. 9. A general formula (II) having a substituted amino group.
The group of the formula (II) wherein R ⁷ is a group of formula (II) having an amino group substituted by a lower alkyl group and / or a lower cycloalkyl group.
A compound according to any one of paragraphs. 10. A general formula (II) in which R ⁷ in the case of a group of the general formula (II) having a substituted lower alkyl group has a lower alkyl group substituted by a carboxy group and / or a lower alkoxycarbonyl group. The compound according to any one of claims 1 to 5, which is a group of. 11. A group represented by the general formula (II) having a substituted aryl group, wherein R ⁷ is substituted with one or more halogen atoms, a lower alkoxy group, a hydroxyl group, a nitro group and / or an amino group. Claims 1 to 5 which are groups of the general formula (II) having an aryl group.
A compound according to any one of paragraphs. 12. A compound as claimed in claim 11 in which the aryl group is a phenyl group optionally substituted by a group as claimed in claim 11. 13. The compound according to any one of claims 1 to 12, wherein X is fluorine. 14. A method according to claim ¹ , wherein R ¹ is a hydrogen atom.
Item 14. A compound according to any one of items 13 to 13. 15. A method according to claim 1, wherein R ² is a methyl group.
Item 15. A compound according to any one of items 14 to 14. 16. A method according to claim 1, wherein R ³ is a hydrogen atom.
Item 16. A compound according to any one of items 15 to 15. 17. A scope of claim 1 in which R ⁴ is a hydrogen atom.
Item 17. A compound according to any one of items 3 to 16. 18. The R ⁵ R ⁶ N-group is Claims 1, 2, 3, 4 and 13 which are
Item 18. A compound according to any one of items 17 to 17. 19. The R ⁵ R ⁶ N-group is What is claimed is: Claims 1, 2, 4, and
The compound according to any one of items 13 to 17. 20. 9-Fluoro-3-methyl-10- (4-
Methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutical thereof The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 21. 9-Fluoro-3-methyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4- Benzoxadiazine-6
-The compound according to claim 1, which is a carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 22. 9-Fluoro-3-methyl-10- (3-
Methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutical thereof The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 23. 9-Fluoro-3-methyl-7-oxo-10- (3-phenyl-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1, The 3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof, according to claim 1. Compound of. 24. 9-Fluoro-3-methyl-10-monofolino-7-oxo-2,3-dihydro-7H-pyrido [3,2,1
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. A compound according to the first section. 25. 9-Fluoro-3-methyl-10- [3-
[(Methylamino) methyl] -1-pyrrolidinyl] -7
-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]-
The 1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to. 26. 10- [3-[(ethylamino) methyl]
-1-Pyrrolidinyl] -9-fluoro-3-methyl-7
-Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]-
The 1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to. 27. 10- (3-Amino-1-pyrrolidinyl)
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceuticals The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 28. 9-Fluoro-3-methyl-10- [3-
(Methylamino) -1-pyrrolidinyl] -7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or them The compound according to claim 1, which is a hydrate or solvate of a salt of. 29. 10- [3- (Ethylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or them The compound according to claim 1, which is a hydrate or solvate of a salt of. 30. 10- (3,4-Dimethyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or water of the compound or a salt thereof The compound according to claim 1, which is a solvate or a solvate. 31. 9-Fluoro-10- (3-methoxy-1)
-Pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutical preparation thereof The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 32. 9-Fluoro-3-methyl-7-oxo-10- [4- (3-oxo-n-butyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2 , 1−ij] −
The 1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to. 33. Disodium = 9-fluoro-3-methyl-7-oxo-10- [4- (sulfonatomethyl) -1
-Piperazinyl] -2,3-dihydro-7H-pyrido [3,2,1
-Ij] -1,3,4-Benzoxadiazine-6-carboxylate or a hydrate or solvate thereof, according to claim 1. 34. 10- [4- (Aminobenzyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-
A benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof.
The compound according to the item. 35. 10- [3- (Aminomethyl) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or them The compound according to claim 1, which is a hydrate or solvate of a salt of. 36. 9-Fluoro-10- (1-imidazolyl) -3-methyl-7-oxo-2,3-dihydro-7H-
Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-
The compound according to claim 1, which is a 6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 37. 10- (4-Ethyl-1-piperazinyl)
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceuticals The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 38. 9-Fluoro-10- [4- (2-hydroxyethyl) -1-piperazinyl] -3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
The 3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof, according to claim 1. Compound of. 39. 9-Fluoro-3-methyl-10- (4-
Methyl-1-imidazolyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutical The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 40. 9-Fluoro-3-methyl-10- [3-
Methyl-4-[(methylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine The compound according to claim 1, which is a -6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 41. 10- [3- (Aminomethyl) -4-methyl-1-pyrrolidinyl] -9-fluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]
A -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to the item. 42. 10- [3-[(ethylamino) methyl]
-4-Methyl-1-pyrrolidinyl] -9-fluoro-3
-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutically acceptable The compound according to claim 1, which is a salt, a compound thereof, or a hydrate or solvate of a salt thereof. 43. 10- [3- (Aminomethyl) -4-chloro-1-pyrrolidinyl] -9-fluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]
A -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to the item. 44. 10- [3- (Aminomethyl) -4-fluoro-1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2, 1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 45. 10- [3-Chloro-4-[(methylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3
-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutically acceptable The compound according to claim 1, which is a salt, a compound thereof, or a hydrate or solvate of a salt thereof. 46. 9-Fluoro-10- [3-fluoro-4
-[(Methylamino) methyl] -1-pyrrolidinyl]-
3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutically acceptable 3. The compound according to claim 1, which is a salt thereof, or a compound thereof or a hydrate or solvate of a salt thereof. 47. 10- [3-Chloro-4-[(ethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3
-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutically acceptable The compound according to claim 1, which is a salt, a compound thereof, or a hydrate or solvate of a salt thereof. 48. 10- [3-[(ethylamino) methyl]
-4-Fluoro-1-pyrrolidinyl] -9-fluoro-
3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutically acceptable 3. The compound according to claim 1, which is a salt thereof, or a compound thereof or a hydrate or solvate of a salt thereof. 49. 10- (3-Amino-4-methoxy-1-)
Pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4
-The compound according to claim 1, which is a benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 50. 9-Fluoro-10- [3-methoxy-4
-(Methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 51. 10- [3- (Ethylamino) -4-methoxy-1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2, 1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 52. 9-Fluoro-10- (3-hydroxy-
4-Methoxy-1-pyrrolidinyl] -3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
The 3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof, according to claim 1. Compound of. 53. 10- (3-Amino-4-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij ] -1,3,4-
A benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof.
The compound according to the item. 54. 10- (3-Amino-4-fluoro-1-)
Pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4
-The compound according to claim 1, which is a benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 55. 10- [3-Chloro-4- (methylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2, 1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 56. 9-Fluoro-10- [3-fluoro-4
-(Methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 57. 10- [4- (Aminomethyl) -1-piperidyl] -9-fluoro-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or solvate of the compound. 58. 9-Fluoro-10- (4-hydroxy-
1-piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceuticals The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 59. 9-Fluoro-3-methyl-7-oxo-10- [4- (1-pyrrolyl) -1-piperidyl] -2,
3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or solvate of the compound. 60. 9-Fluoro-10- (1-homopiperazinyl) -3-methyl-7-oxo-2,3-dihydro-7H
-Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof,
Alternatively, the compound according to claim 1, which is a hydrate or solvate of the compound or a salt thereof. 61. 9-Fluoro-10- (3-hydroxy-
1-pyrrolidinyl) -3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or water of the compound or a salt thereof The compound according to claim 1, which is a solvate or a solvate. 62. 9-Fluoro-3-methyl-7-oxo-10- (4-n-propyl-1-piperazinyl) -2,3
-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or a solvate. 63. 9-Fluoro-10- [4- (2-fluoroethyl) -1-piperazinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,
The compound according to claim 1, which is 4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. . 64. 10- [4- (carboxymethyl) -1-
Piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4
-The compound according to claim 1, which is a benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 65. 10- (4-allyl-1-piperazinyl)
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceuticals The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 66. 10- (1,1-Dioxide-4-thiomorpholinyl) -9-fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or them The compound according to claim 1, which is a hydrate or solvate of a salt of. 67. 9-Fluoro-3-methyl-10- (1-
Oxido-4-thiomorpholinyl) -7-oxo-2,3
-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or a solvate. 68. 9-Fluoro-3-methyl-7-oxo-10- [4- (2-oxo-n-propyl) -1-piperazinyl] -2,3-dihydro-7H-pyrido [3,2 , 1-ij]
A 1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to the item. 69. 10- (3-Chloro-1-pyrrolidinyl)
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceuticals The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 70. 9-Fluoro-3- (2-fluoroethyl) -10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1- ij] -1,3,
The compound according to claim 1, which is 4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. . 71. 10- (4-Amino-1-piperidyl)-
9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or pharmaceutical preparation thereof The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 72. 9-Fluoro-3-methyl-10- [4-
(Methylamino) -1-piperidyl] -7-oxo-2,
3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or solvate of the compound. 73. 10- [4- (Ethylamino) -1-piperidyl] -9-fluoro-3-methyl-7-oxo-2,
3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or solvate of the compound. 74. 10- [3-[(Ethylmethylamino) methyl] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2, 1-
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 75. 10- (3-Amino-4-hydroxy-1)
-Pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,
The compound according to claim 1, which is 4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. . 76. 9-Fluoro-10- [3-hydroxy-
4- (Methylamino) -1-pyrrolidinyl] -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 77. 9-Fluoro-3-methyl-7-oxo-10- (4-thiomorpholinyl) -2,3-dihydro-7H
-Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof,
Alternatively, the compound according to claim 1, which is a hydrate or solvate of the compound or a salt thereof. 78. 10- (2,6-Dimethyl-4-morpholinyl) -9-fluoro-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or water of the compound or a salt thereof The compound according to claim 1, which is a solvate or a solvate. 79. 10- [3- (acetylaminomethyl)-
1-Pyrrolidinyl] -9-fluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
The 3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof, according to claim 1. Compound of. 80. 10-[[2- (Dimethylamino) ethyl] methylamino] -9-fluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,
The 3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof, according to claim 1. Compound of. 81. 9-Fluoro-3-methyl-7-oxo-10- (3-oxo-1-piperazinyl) -2,3-dihydro-7H-pyrido [3,2,1-ij] -1, The 3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof, according to claim 1. Compound of. 82. 9-Fluoro-2- (hydroxymethyl) -3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2, 1
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. A compound according to the first section. 83. 2-[(dimethylamino) methyl] -9
-Fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzooxa The compound according to claim 1, which is diazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 84. 10- [3- (Benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1]
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. A compound according to the first section. 85. 9-Fluoro-3-methyl-7-oxo-10- (4-phenacyl-1-piperazinyl) -2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or water of the compound or a salt thereof The compound according to claim 1, which is a solvate or a solvate. 86. 9-Fluoro-3-methyl-10- [4-
(4-Nitrobenzyl) -1-piperazinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,
The compound according to claim 1, which is 4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. . 87. 10- [4- (3-Carboxypropionyl) -1-piperazinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1- i
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 88. 10- (4-Acetyl-1-piperazinyl) -9-fluoro-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or water of the compound or a salt thereof The compound according to claim 1, which is a solvate or a solvate. 89. 9-Fluoro-10- (4-methoxy-1)
-Piperidyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutical preparation thereof The compound according to claim 1, which is a pharmaceutically acceptable salt, or a hydrate or solvate of the compound or salt thereof. 90. 9-Fluoro-2,3-dimethyl-10-
(4-Methyl-1-piperazinyl) -7-oxo-2,3
-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or a solvate. 91. 9-Fluoro-2,3-dimethyl-7-oxo-10- (1-piperazinyl) -2,3-dihydro-7H
-Pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof,
Alternatively, the compound according to claim 1, which is a hydrate or solvate of the compound or a salt thereof. 92. Ethyl = 10- [3- (benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2, 1-ij] -1,3,4-benzoxadiazine-6-
Carboxylate or a pharmaceutically acceptable salt thereof,
Alternatively, the compound according to claim 1, which is a hydrate or solvate of the compound or a salt thereof. 93. Ethyl = 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,
3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate or a pharmaceutically acceptable salt thereof, a compound thereof or a salt thereof The compound according to claim 1, which is a hydrate or solvate of the compound. 94. Benzyl = 9-fluoro-10- (3-hydroxy-1-pyrrolidinyl) -3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij]- 1,3,4
-The compound according to claim 1, which is benzooxadiazine-6-carboxylate or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 95. Benzyl = 10- (3-chloro-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-
2,3-Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate or a pharmaceutically acceptable salt thereof, or a compound thereof or them The compound according to claim 1, which is a hydrate or solvate of a salt of. 96. Pivaloyloxymethyl = 10- [3-
(Benzyloxycarbonylamino) -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-
Dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylate or a pharmaceutically acceptable salt thereof, or a water of the compound or a salt thereof The compound according to claim 1, which is a solvate or a solvate. 97. Pivaloyloxymethyl = 10- (3-amino-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1] -I
j] -1,3,4-Benzoxadiazine-6-carboxylate or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. The compound according to claim 1. 98. 10- [3-[(4-Aminobenzyl) amino] -1-pyrrolidinyl] -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2] , 1−
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 99. Fluoro-10- [3-[[(dimethylamino) methylene] amino] -1-pyrrolidinyl]-
3-Methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine-6-carboxylic acid or its pharmaceutically acceptable 3. The compound according to claim 1, which is a salt thereof, or a compound thereof or a hydrate or solvate of a salt thereof. 100-Fluoro-3-methyl-10- [3
-(4-Methyl-1-piperazinyl) -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. A compound according to the first section. 101. 10- (3-amino-3-methyl-1-
Pyridinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-
A benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof.
The compound according to the item. 102. 10- (trans-3-Amino-4-methyl-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1] -I
j] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 103. 10- (trans-3-Amino-4-phenyl-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1] −
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 104. 9-Fluoro-3-methyl-10- [3
-Methyl-3 [(methylamino) methyl] -1-pyrrolidinyl] -7-oxo-2,3-dihydro-7H-pyrido [3,2,1-ij] -1,3,4-benzoxadiazine The compound according to claim 1, which is a -6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. 105. 9-Fluoro-3-methyl-10- [trans-3-[(methylamino) methyl] -4-phenyl-1-pyridinyl] -7-oxo-2,3-dihydro-7.
H-pyrido [3,2,1-ij] -1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate of the compound or a salt thereof Alternatively, the compound according to claim 1, which is a solvate. 106. 10- (Trans-3-amino-4-methoxy-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1] −
ij] -1,3,4-Benzoxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. The compound according to item 1. 107. 10- (Trans-3-amino-4-hydroxy-1-pyrrolidinyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [3,2,1]
-Ij] -1,3,4-benzooxadiazine-6-carboxylic acid or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound or a salt thereof. A compound according to the first section. 108. (a) General formula (III) In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group;
R ² represents a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom; R ³ and R ⁴ are each independently substituted with a hydrogen atom, a hydroxyl group, or a substituted or unsubstituted amino group. Represents a lower alkyl group; X represents a halogen atom; and X ′ represents a halogen atom; the amino group, hydroxyl group and / or carboxy group in the formula may be protected. General formula (IV) In the formula, R ⁵ and R ⁶ each independently represent a hydrogen atom, or a hydroxyl group, a lower alkoxy group or a lower alkyl group optionally substituted with a substituted or unsubstituted amino group; or R ⁵ and R ⁶ are It may form a 5- to 7-membered heterocycle together with the adjacent nitrogen atom, and the heterocycle may be substituted with one or more substituents at the carbon atom thereof, and The ring is -NR ⁷ -,-
O -, - S -, - SO -, - SO 2 - or -NR ⁷ -CO-
[Wherein R ⁷ is a hydrogen atom, a lower alkenyl group, an optionally substituted lower alkyl or aralkyl group, or the general formula (II)-(CH ₂ ) nCOR ⁸ (II) (wherein n is 1 And R ⁸ is a hydrogen atom, a lower alkoxy group, or an optionally substituted amino, lower alkyl or aryl group). If desired, the protecting group is removed, or (b) the general formula (V) Wherein R ¹ , R ² , R ⁵ , R ⁶ and X have the same meaning as described above; and the amino group, hydroxyl group and / or carboxy group in the formula may be protected. The compound represented by the general formula (VI) In the formula, R ³ and R ⁴ have the same meanings as described above, and are reacted with a carbonyl compound represented by: or a polymer thereof, an acetal, a ketal or an enol ether to remove a protecting group, if desired, or (c ) for R ⁷ to produce a compound of formula (I) is a group other than a hydrogen atom, a compound with a substituent group R ⁷⁰ (wherein in the formula R ⁷ is a hydrogen atom (I), R ⁷⁰ and R ⁷ (D) R ⁵ and / or R ⁶ is a lower alkyl group (or a di-lower alkylamino group or a lower alkoxy group) which has the same meaning but not a hydrogen atom. In order to produce a compound of formula (I), R ⁵ and / or R ⁶ is a hydrogen atom, or a compound of formula (I) containing an amino group, a lower alkylamino group or a hydroxyl group is lower alkylated, (E) R ⁵ R ⁶ N- -SO- or -SO ₂ - for the preparation of compounds of formula (I) is a 5- to 7-membered heterocyclic ring containing either subjecting the compound heterocyclic ring including the corresponding -S- to an oxidation reaction, ( f) protection from corresponding compounds of formula (I) having protected amino, hydroxyl and / or carboxy groups to produce compounds of formula (I) having free amino, hydroxyl and / or carboxy groups Removing a group or (g) halogenating a compound of the formula (I) in which R ¹ is a carboxy-protecting group, substituted with a corresponding hydroxyl group to prepare a compound of the formula (I) containing a halogen atom, If desired, the protecting group R ¹ is removed or (h) the nitro group of the compound substituted with the corresponding nitro group of the formula (I) is reduced in order to prepare a compound of the formula (I) containing an amino group. Do you do (i) (Wherein R ⁵⁰ and R ⁵¹ are lower alkyl groups or taken together with the nitrogen atom represent a 5-8 membered saturated nitrogen-containing heterocycle). In order to obtain a compound of formula (I) substituted with an amino group of general formula (VII) Wherein R ⁵⁰ and R ⁵¹ have the same meanings as described above, or are reacted with a reactive derivative of a formamide derivative of (j) to prepare a compound of formula (I) wherein R ¹ is a carboxy protecting group. Thus, a carboxylic acid of formula (I) is subjected to the corresponding esterification, or (k) a pharmaceutically acceptable salt, hydrate or solvate of a compound of formula (I), or a salt thereof. A compound of formula (I) is converted into a salt, a hydrate or a solvate or a hydrate or solvate of a salt thereof to produce a hydrate or a solvate thereof. (I), In the formula, R ¹ , R ² , R ³ , R ⁴ , X, R ⁵ and R ⁶ have the same meanings as described above, and are represented by: a tricyclic compound and a pharmaceutically acceptable salt thereof. And a hydrate or solvate of the compound of formula (I) and salts thereof. 109. The manufacturing method according to claim 108, wherein any one of (a) to (h), (j) and (k) is performed. 110. A compound of formula (I), In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group;
R ² represents a hydrogen atom or a lower alkyl group optionally substituted with a halogen atom; R ³ and R ⁴ are each independently substituted with a hydrogen atom, a hydroxyl group, or a substituted or unsubstituted amino group. Also represents a lower alkyl group; X represents a halogen atom; and R ⁵ and R ⁶ are each independently substituted with a hydrogen atom, a hydroxyl group, a lower alkoxy group, or a substituted or unsubstituted amino group. Represents a lower alkyl group; or R ⁵ and R ⁶ may form, together with the adjacent nitrogen atom, a 5- to 7-membered heterocycle, wherein the heterocycle has one or more carbon atoms at its carbon atom. may be substituted with a substituent, further the heterocyclic ring ^{-NR 7 -, - O -,} - S -, - SO -, - SO 2 -
Alternatively, —NR ⁷ —CO— [wherein R ⁷ is a hydrogen atom, a lower alkenyl group, an optionally substituted lower alkyl group or an aralkyl group, or a compound represented by the general formula (II) — (CH ₂ ) nCOR ⁸ (II (In the formula, n is 1 to 4, and R ⁸ is a hydrogen atom, a lower alkoxy group, or an optionally substituted amino, lower alkyl or aryl group). An infection comprising a tricyclic compound represented by: or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of the compound of formula (I) or a salt thereof as an active ingredient. A treatment or preventive agent for diseases.