JPH0559052A - New cyclic compound or its salt and antimicrobial agent containing the same compound or salt - Google Patents

Abstract

PURPOSE:To obtain a new compound having a 1,8-quinolinecarboxylic acid structure, having excellent antimicrobial action and oral absorption. CONSTITUTION:A compound shown by formula I [R<1> is H or carboxyl-protecting group; R<2> is H, halogen or (protected) amino; R<3> is H or alkyl; R<4> is H, alkyl, acryl or aralkyl; X is H or halogen; Y is halogen, NH2, OH, cycloalkylamino, mono- or dialkylamino, cyclic amino, alkyl, cycloalkenyl, R<5>-(CH2)n-A (R<5> is H, NH2, nitrogen-containing heterocyclic group, etc.; A is O or S; m is 0-3), etc.; n is 0-2] such as ethyl 4,5-difluoro-2,3-dihydro-7-oxo-1H,7H-pyrido[3,2- ij]cinnoline-8-carboxylate. The compound is obtained by subjecting a compound shown by formula III (R<1a> is alkyl; Z<2> and Z<3> are H, alkyl, acyl, etc.) derived from a compound shown by formula II to ring formation and N-alkylating or N-acylating the prepared compound shown by formula IV.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel tricyclic compound having excellent antibacterial activity and oral absorbability or a salt thereof, and an antibacterial agent containing the same.

[0002]

2. Description of the Related Art Among compounds having pyridonecarboxylic acid as a basic skeleton, many useful as synthetic antibacterial agents are known because of their excellent antibacterial activity and broad antibacterial spectrum. Among them, norfloxacin (JP-A-53-141286) and enoxacin (JP-A-5-154).
No. 5-31042), ofloxacin (JP-A-57 / 57).
No. 46986), ciprofloxacin (Japanese Patent Laid-Open No. Sho 5)
8-76667) and the like are widely used clinically as therapeutic agents for infectious diseases.

[0003]

However, these compounds are not yet sufficiently satisfactory in terms of antibacterial activity, intestinal absorbability, metabolic stability, side effects, etc., and new compounds satisfying these requirements have been proposed. Creation was desired.

[0004]

Under the circumstances, the inventors of the present invention have conducted earnest studies to provide a clinically excellent synthetic antibacterial agent which has improved the above-mentioned requirements, and as a result, the following general formula (1) The compound having a 1,8-bridged quinolinecarboxylic acid structure represented by) shows excellent antibacterial activity against Gram-negative bacteria and Gram-positive bacteria and satisfies other requirements, and is useful as a synthetic antibacterial agent. Heading, completed the present invention. That is, the present invention provides the following general formula (1)

[0005]

[Chemical 2]

[Wherein R ¹ represents a hydrogen atom or a carboxy protecting group, R ² represents a hydrogen atom, a halogen atom, an amino group or a protected amino group, and R ³ represents a hydrogen atom or a lower alkyl group. , R ⁴ represents a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group or an aralkyl group, X represents a hydrogen atom or a halogen atom, and Y represents a halogen atom, an amino group, a hydroxyl group, cyclo Lower alkylamino group, mono- or di-lower alkylamino group, cyclic amino group optionally having substituent (s), lower alkyl group optionally having substituent (s), cyclo lower optionally having substituent (s) An alkenyl group, a formula R ^5- (CH ₂ ) _m -A- (wherein R ⁵ contains a hydrogen atom, an amino group which may have a substituent, a nitrogen atom which may have a substituent) A saturated heterocyclic group or substituent Represents a cyclo lower alkyl group which may have, A represents an oxygen atom or a sulfur atom, m
Represents an integer of 0 to 3) or a group represented by the formula R ⁶ -SO ₂ O-
(Wherein R ⁶ represents a lower alkyl group, a halo lower alkyl group or a phenyl group optionally substituted by 1 to 3 with a lower alkyl group), and n represents an integer of 0 to 2. ] The tricyclic compound or its salt represented by these, and the antibacterial agent which uses this as an active ingredient are provided.

In the present invention, the term "lower" used in the description of each substituent of the formula (1) has 1 to 7 carbon atoms, preferably 1 when the substituent is a linear or branched group. ~
5 means a group of 5 and, when it is a cyclic group, has 3 to 7 carbon atoms.
Means the group.

The carboxy protecting group represented by R ¹ refers to an ester residue of a carboxylic acid ester, and means any group which is cleaved relatively easily to give a corresponding free carboxyl group. Specific examples thereof include lower alkyl groups (eg, methyl group, ethyl group, n-propyl group, t-butyl group, etc.), aralkyl groups (eg, benzyl group) or aryl groups (eg, phenyl group). Those which are eliminated by treatment under mild conditions such as hydrolysis and catalytic reduction; etc .; or lower alkanoyloxy lower alkyl groups (eg acetoxymethyl group, pivaloyloxymethyl group etc.), lower alkoxycarbonyloxy Lower alkyl group (eg, methoxycarbonyloxymethyl group, 1-ethoxycarbonyloxyethyl group, etc.), lower alkoxymethyl group (eg,
Methoxymethyl group etc.), lactonyl group (eg phthalidyl group etc.), di-lower alkylamino lower alkyl group (eg 1-dimethylaminoethyl group etc.), (5-
Methyl-2-oxo-1,3-dioxol-4-yl) methyl group and the like which are easily eliminated in vivo are included.

Examples of the halogen atom represented by R ² include a fluorine atom, a chlorine atom and a bromine atom, and among these, a fluorine atom is preferable. Suitable "protecting group" for the protected amino group represented by R ² is, for example, lower alkanoyl group such as formyl, acetyl, propionyl, pivaloyl, hexanoyl, etc., such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc. A mono (or di or tri) halo (lower) alkanoyl group of, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl,
Lower alkoxycarbonyl groups such as t-pentyloxycarbonyl and hexyloxycarbonyl, carbamoyl groups such as aroyl groups such as benzoyl, toluoyl and naphthoyl, and alk (lower) alkanoyl groups such as phenylacetyl and phenylpropionyl such as phenoxycarbonyl and naphthyl. Aryloxycarbonyl group such as oxycarbonyl, for example, aryloxy (lower) alkanoyl group such as phenoxyacetyl, phenoxypropionyl, etc., arylglyoxyloyl group such as phenylglyoxyloyl, naphthylglyoxyloyl, for example, benzyloxycarbonyl, phenethyl An ar (lower) alkoxycarbonyl group which may have a suitable substituent such as oxycarbonyl, p-nitrobenzyloxycarbonyl, etc., for example, Optionally substituted alk (lower) alkylidene group such as benzylidene, hydroxybenzylidene, etc., alk (lower) such as benzyl, 1-phenylethyl, benzhydryl, trityl and other mono- or di- or triphenyl (lower) alkyl group An alkyl group etc. are mentioned.

The lower alkyl group represented by R ³ is
Examples thereof include a methyl group and an ethyl group.

The lower alkyl group which may have a substituent represented by R ⁴ includes, for example, methyl group, ethyl group,
In addition to lower alkyl groups such as isopropyl group, t-butyl group, t-pentyl group, etc., lower alkyl groups substituted with hydroxyl group, halogen atom, lower alkoxy group etc. (eg hydroxymethyl group, fluoromethyl group, methoxymethyl group) Groups, etc.) and the like.

Examples of the acyl group represented by R ⁴ include lower alkanoyl groups such as formyl and acetyl, lower alkoxycarbonyl groups such as methoxycarbonyl and ethoxycarbonyl, and aromatic acyl groups such as benzoyl and phenoxycarbonyl. Examples of the aralkyl group represented by R ⁴ include a benzyl group and a 1-phenylethyl group.

Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom and a bromine atom.
A fluorine atom is preferred.

Examples of the halogen atom represented by Y include those similar to X, and among these, a fluorine atom or a chlorine atom is preferable. Examples of the cyclo lower alkylamino group represented by Y include a cyclopropylamino group, a cyclobutylamino group and a dicyclohexylamino group. Examples of the mono- or di-lower alkylamino group represented by Y include a methylamino group, an ethylamino group,
Examples thereof include a dimethylamino group and a benzylamino group.
The cyclic amino group which may have a substituent represented by Y may be either a saturated cyclic amino group or an unsaturated cyclic amino group, and one or more nitrogen atoms may be further contained in the ring. , A hetero atom such as an oxygen atom or a sulfur atom, and a carbonyl carbon, and even if it is a monocyclic ring, 2
It may be a tricyclic. As such a cyclic amino group,
Preferred are those represented by the following formulas (a) to (t).

[0015]

[Chemical 3]

[0016]

[Chemical 4]

[0017]

[Chemical 5]

[0018]

[Chemical 6]

(Here, B is an oxygen atom, a sulfur atom, -NR ⁷
Or -CONR ⁷ (wherein R ⁷ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an alkenyl group, an acyl group or a hydroxyl lower alkyl group), and D represents CH or N. , E is 3, 4 or 5, f is 1, 2 or 3, g is 0, 1 or 2, h is 3 or 4, and i is 1 or 2.)

The groups which can be substituted on these cyclic amino groups include a lower alkyl group, a lower alkenyl group, a lower aralkyl group, an aryl group, a hydroxyl group, a hydroxy lower alkyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted group. Substituted amino lower alkyl group, cyclic amino group as described above, alkoxy group, alkoxy lower alkyl group, halogen atom, halo lower alkyl group, acyloxy group, acyloxy lower alkyl group, acyl group, carboxyl group, carboxy lower alkyl group, Examples thereof include an alkoxycarbonyl lower alkyl group, a mercapto group, a lower alkylthio group, a cyano group and a nitro group.

Here, the lower alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, etc., the lower alkenyl group is, for example, a vinyl group, an allyl group, etc., and the lower aralkyl group is, for example, a benzyl group. An aryl group such as a 1-phenylethyl group is, for example, a phenyl group, a hydroxy lower alkyl group is, for example, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, etc., and an amino lower alkyl group is, for example, an aminomethyl group, 1-aminoethyl group, 2-aminoethyl group, 1-amino-1-methylethyl group and the like, alkoxy group such as methoxy group, ethoxy group, n-propoxy group and the like, and alkoxy lower alkyl group such as methoxy group. As a halogen atom such as a methyl group and an ethoxymethyl group, Elemental atom, chlorine atom, bromine atom and the like, halo lower alkyl group, for example, fluoromethyl group, trifluoromethyl group and the like, acyloxy group, for example, acetoxy group, benzoyloxy group and the like, as acyloxy lower alkyl group, For example, an acetoxymethyl group, a benzoyloxymethyl group and the like, an acyl group such as a group as exemplified for R ⁴ and a carboxy lower alkyl group such as a carboxymethyl group and a carboxyethyl group such as an alkoxycarbonyl lower alkyl group. Are, for example, a methoxycarbonylmethyl group, a t-butoxycarbonylmethyl group, and the lower alkylthio group is, for example, a methylthio group, an ethylthio group, and the like.

Of the above, examples of the substituent in the substituted amino group and the substituted amino lower alkyl group include a lower alkyl group (eg, methyl group, ethyl group, etc.), a cyclo lower alkyl group (eg, cyclopropyl group, cyclobutyl group,
Cyclopentyl group, etc.), lower alkenyl group (eg vinyl group, allyl group etc.), lower aralkyl group (eg benzyl group, 1-phenylethyl group etc.), aryl group (eg phenyl group etc.), acyl group (eg R ⁴ Groups such as exemplified), amino acid residues or peptide residues (eg glycyl, leucyl, valyl, alanyl,
Phenylalanyl, alanyl-alanyl, glycyl-valyl, glycyl-glycyl-valyl, etc.) and amino acid residues or peptide residues in which these functional groups are protected by a protecting group commonly used in peptide chemistry such as acyl group or lower aralkyl , Or a cyclic amino group and the like, and these substituents can be arbitrarily selected from 1 to 2 same or different substituents. Compounds protected by such amino acid residues or peptide residues are expected to have improved water solubility. Particularly preferred examples of these substituted amino groups and substituted amino lower alkyl groups are methylamino group, ethylamino group, dimethylamino group, methylaminomethyl group, ethylaminomethyl group, dimethylaminomethyl group, glycyl-amino group, leucyl group. -Amino group, valyl-amino group, alanyl-amino group, alanyl-alanyl-amino group and the like.

The lower alkyl group represented by R ⁷ is
For example, a methyl group, an ethyl group, a cyclo-lower alkyl group, for example, a cyclopropyl group, a cyclobutyl group, etc., an aralkyl group, for example, a benzyl group, 1-phenylethyl group, etc., and an alkenyl group, for example, a vinyl group, allyl group. Examples of the acyl group such as a group include a formyl group, acetyl group, methoxycarbonyl group and ethoxycarbonyl group, and examples of the hydroxy lower alkyl group include a hydroxymethyl group and a hydroxyethyl group. Among the compounds represented by the formulas (a) and (b), preferred compounds include those represented by the following formulas (a ′) and (b ′).

[0024]

[Chemical 7]

(In the formula, B, e, f and g have the same meanings as defined in formula (a) and formula (b), and W ¹ , W
² and W ³ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower aralkyl group, an aryl group, a hydroxyl group, a hydroxy lower alkyl group, an amino group which may have a substituent, a substituent Optionally having an amino lower alkyl group, a pyrrolidinyl group, a piperidino group, an azetidinyl group, an alkoxy group, an alkoxy lower alkyl group, a halogen atom, a halo lower alkyl group, an acyloxy group, an acyloxy lower alkyl group, an acyl group,
A carboxyl group, a carboxy lower alkyl group, an alkoxycarbonyl lower alkyl group, a mercapto group, a lower alkylthio group, a cyano group, and a nitro group are shown.) Description of the substituents of W ¹ , W ² and W ³ and their preferred Specific examples thereof include the same ones as described above for the group capable of substituting the cyclic amino group. Examples of the heterocyclic group represented by the formula (a ′) include an azetidinyl group, a pyrrolidinyl group and a piperidino group. Examples of the heterocyclic group represented by the formula (b ′) include a piperazinyl group, a morpholino group and a thiol group. Morpholino group, homopiperazinyl group, thiazolidinyl group, oxazolidinyl group, 3
Examples include -oxo-1-piperazinyl group.

Particularly preferred specific examples of the groups represented by the formulas (a) and (b) are as follows. 3-hydroxyazetidinyl group, 3-aminoazetidinyl group, 3-
(Nt-butoxycarbonylamino) azetidinyl group, 3-acetylaminoazetidinyl group, 3-methylaminoazetidinyl group, 3-dimethylaminoazetidinyl group, 3-methylazetidinyl group, 3-amino -2-methylazetidinyl group,

Pyrrolidinyl group, 3-hydroxypyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group, 3-methoxypyrrolidinyl group, 3-methylpyrrolidinyl group, 3
-Hydroxy-4-methyl-pyrrolidinyl group, 3-aminopyrrolidinyl group, 3-methylaminopyrrolidinyl group,
3-dimethylaminopyrrolidinyl group, 3-ethylaminopyrrolidinyl group, 3-diethylaminopyrrolidinyl group,
3-acetylaminopyrrolidinyl group, 3-t-butoxycarbonylaminopyrrolidinyl group, 3- (N-acetyl) methylaminopyrrolidinyl group, 3- (t-butoxycarbonyl) methylaminopyrrolidinyl group, 3-aminomethylpyrrolidinyl group, 3-methylaminomethylpyrrolidinyl group, 3-dimethylaminomethylpyrrolidinyl group,
3-ethylaminomethylpyrrolidinyl group, 3-diethylaminomethylpyrrolidinyl group, 3- (N-acetyl) aminomethylpyrrolidinyl group, 3- (t-butoxycarbonyl) aminomethylpyrrolidinyl group, 3- (N-acetyl) methylaminomethylpyrrolidinyl group, 3- (t-butoxycarbonyl) methylaminomethylpyrrolidinyl group, 3- (1-aminoethyl) pyrrolidinyl group, 3-
(2-aminoethyl) pyrrolidinyl group, 3- (1-amino-1-methylethyl) pyrrolidinyl group, 3- (1-methylaminoethyl) pyrrolidinyl group, 3- (1-dimethylaminoethyl) pyrrolidinyl group, 3- Amino-4-methylpyrrolidinyl group, 3-amino-5-methylpyrrolidinyl group, 3-methylamino-4-methylpyrrolidinyl group, 3-dimethylamino-4-methylpyrrolidinyl group,
3-ethylamino-4-methylpyrrolidinyl group, 3-diethylamino-3-methylpyrrolidinyl group, 3-diethylamino-4-methylpyrrolidinyl group, 3-aminomethyl-4-methylpyrrolidinyl group, 3-methylaminomethyl-4-methylpyrrolidinyl group, 3-dimethylaminomethyl-4-methylpyrrolidinyl group, 3-ethylaminomethyl-4-methylpyrrolidinyl group, 3- (1-aminoethyl ) -4-Methylpyrrolidinyl group, 3- (2-aminoethyl) -4-methylpyrrolidinyl group, 3-amino-
4-ethylpyrrolidinyl group, 3-methylamino-4-ethylpyrrolidinyl group, 3-dimethylamino-4-ethylpyrrolidinyl group, 3-ethylamino-4-ethylpyrrolidinyl group, 3-diethylamino -4-ethylpyrrolidinyl group, 3-aminomethyl-4-ethylpyrrolidinyl group,
3-methylaminomethyl-4-ethylpyrrolidinyl group,
3-dimethylaminomethyl-4-ethylpyrrolidinyl group, 3-amino-3-methylpyrrolidinyl group, 3-methylamino-3-methylpyrrolidinyl group, 3-dimethylamino-3-methylpyrrolidinyl group Group, 3-amino-3,4
-Dimethylpyrrolidinyl group, 3-amino-4,5-dimethylpyrrolidinyl group, 3-amino-4,5-dimethylpyrrolidinyl group, 3-amino-2,4-dimethylpyrrolidinyl group, 3 -Methylamino-3,4-dimethylpyrrolidinyl group, 2-methyl-3-aminopyrrolidinyl group, 2-
Methyl-3-dimethylaminopyrrolidinyl group, 3-amino-4-vinylpyrrolidinyl group, 3-amino-4-methoxypyrrolidinyl group, 3-amino-4-methoxymethylpyrrolidinyl group, 3- Methylamino-4-methoxypyrrolidinyl group, 3-dimethylamino-4-methoxypyrrolidinyl group, 3-ethylamino-4-methoxypyrrolidinyl group, 3-diethylamino-4-methoxypyrrolidinyl group, 3 -Benzylamino-4-methoxypyrrolidinyl group, 3-aminomethyl-4-methoxypyrrolidinyl group,
3-methylaminomethyl-4-methoxypyrrolidinyl group, 3-dimethylaminomethyl-4-methoxypyrrolidinyl group, 3-ethylaminomethyl-4-methoxypyrrolidinyl group, 3-aminomethyl-3-methoxy Pyrrolidinyl group, 3-methylaminomethyl-3-methoxypyrrolidinyl group, 3-dimethylaminomethyl-3-methoxypyrrolidinyl group, 3-amino-4-ethoxypyrrolidinyl group, 3-methylamino- 4-ethoxypyrrolidinyl group,
3-dimethylamino-4-ethoxypyrrolidinyl group, 3
-Methylamino-4-ethoxypyrrolidinyl group, 3-aminomethyl-4-ethoxypyrrolidinyl group, 3-dimethylaminomethyl-4-ethoxypyrrolidinyl group, 3-amino-4-aminocarbamoylpyrrolidinyl group Group, 3-amino-4-dimethylaminocarbamoylpyrrolidinyl group, 3-amino-4-hydroxypyrrolidinyl group, 3-
Amino-4-hydroxymethylpyrrolidinyl group, 3-amino-4-hydroxyethylpyrrolidinyl group, 3-amino-4-methyl-4-hydroxymethylpyrrolidinyl group, 3-aminomethyl-4-hydroxypyrrolidyl group Dinyl group, 3-dimethylaminomethyl-4-hydroxypyrrolidinyl group, 3,4-dihydroxypyrrolidinyl group, 3,
4-dimethoxypyrrolidinyl group, 3-hydroxy-4-
Methylpyrrolidinyl group, 3-amino-4-fluoropyrrolidinyl group, 3-amino-4-fluoromethylpyrrolidinyl group, 3-amino-4-trifluoromethylpyrrolidinyl group, 3-methylamino- 4-fluoropyrrolidinyl group, 3-dimethylamino-4-fluoropyrrolidinyl group, 3-aminomethyl-4-fluoropyrrolidinyl group,
3-methylaminomethyl-4-fluoropyrrolidinyl group, 3-dimethylaminomethyl-4-fluoropyrrolidinyl group, 3-methylamino-4-chloropyrrolidinyl group, 3-aminomethyl-4-chloropyrrolidyl group Dinyl group, 3
-Methylaminomethyl-4-chloropyrrolidinyl group, 3
-(2-hydroxyethyl) aminomethylpyrrolidinyl group, 3- (2-fluoroethyl) aminomethylpyrrolidinyl group, 3-amino-4-methylthiopyrrolidinyl group,
3-amino-4-methylsulfinylpyrrolidinyl group,
3-formimidoylaminopyrrolidinyl group, 3- (2
-Dimethylhydrazino) pyrrolidinyl group, 3-amino-
4-methylenepyrrolidinyl group, 3- (t-butoxycarbonylaminoacetyl) amino-4-methylpyrrolidinyl group, 3-aminoacetylamino-4-methylpyrrolidinyl group, 3- (2-aminopropanoyl) ) Amino-4-
Methylpyrrolidinyl group, 3- (2-amino-3-phenylpropanoyl) amino-4-methylpyrrolidinyl group,
3- (2-benzyloxycarbonylamino-3-methylbutanoylamino-4-methylpyrrolidinyl group, 3-
(2-Amino-3-methylbutanoyl) amino-4-methylpyrrolidinyl group, 3- (2-amino-2-methylpropanoyl) amino-4-methylpyrrolidinyl group, 7-
Amino-5-azaspiro [2.4] heptan-5-yl group,

Piperazinyl group, 4-methylpiperazinyl group, 3-methylpiperazinyl group, 2-methylpiperazinyl group, 3,4-dimethylpiperazinyl group, 3,5-dimethylpiperazinyl group, 3,3-dimethylpiperazinyl group, 3,4,5-trimethylpiperazinyl group, 4-ethoxycarbonylpiperazinyl group, 4-t-butoxycarbonylpiperazinyl group, 4-acetylpiperazinyl group,
4-benzyloxycarnylpiperazinyl group, 4-ethylpiperazinyl group, 3,4-diethylpiperazinyl group,
3,4,5-Triethylpiperazinyl group, 4-ethyl-
3,5-Dimethylpiperazinyl group, 3-methyl-4-acetylpiperazinyl group, 3-methyl-4-t-butoxycarbonylpiperazinyl group, 4-benzylpiperazinyl group, 4-n-propyl Piperazinyl group, 4-isopropylpiperazinyl group, 4-t-butylpiperazinyl group, 4
-Cyclopropylpiperazinyl group, 4-cyclopentylpiperazinyl group, 4-cyclopropylmethylpiperazinyl group, 4-phenylpiperazinyl group, 4- (p-dimethylaminophenyl) piperazinyl group, 4- (p -Methoxyphenyl) piperazinyl group, 4- (p-fluorophenyl) piperazinyl group, 3-phenylpiperazinyl group,
3- (p-fluorophenyl) piperazinyl group, 3-
(P-chlorophenyl) piperazinyl group, 3- (p-hydroxyphenyl) piperazinyl group, 3- (p-methylphenyl) piperazinyl group, 4-hydroxyethylpiperazinyl group, 4-aminoethylpiperazinyl group, 4- Allylpiperazinyl group, 4-cinnamylpiperazinyl group,
4-cyanoethylpiperazinyl group, 4-carboxyethylpiperazinyl group, 4-carboxymethylpiperazinyl group, 4- (1,2-dicarboxyethyl) piperazinyl group, 4-hydroxypiperazinyl group, 3- Fluoromethylpiperazinyl group, 3-trifluoromethylpiperazinyl group, 4-formimidoylpiperazinyl group, 4-acetimidoylpiperazinyl group,

A piperidino group, a 4-aminopiperidino group,
4-dimethylaminopiperidino group, 4-hydroxypiperidino group, morpholino group, 2-aminomethylmorpholino group, 2-methylaminomorpholino group, 2-dimethylaminomorpholino group, thiomorpholino group, homopiperazinyl group, 4- Methylhomopiperazinyl group, thiazolidinyl group, oxazolidinyl group.

When Y represents a group represented by R ^5- (CH ₂ ) _m -A-, a group in which R ⁵ is an amino group, a saturated heterocyclic group containing a nitrogen atom, or a cyclo-lower alkyl group is Examples of the substitutable group include the same groups as those described above for substituting the cyclic amino group. Examples of the cyclo lower alkyl group include cyclopropyl group and cyclobutyl group;
The saturated heterocyclic group containing a nitrogen atom is preferably a 4- to 9-membered ring, and examples thereof include the same saturated heterocycles as the examples of the cyclic amino group described above, but azetidine 3-
An yl group and a pyrrolidin-3-yl group are particularly preferable. The bond between these saturated heterocyclic groups and-(CH ₂ ) _m -A- is
It may occur at any atom on the ring.

[0031] In R ⁶ where Y represents a group represented by R ⁶ -SO ₂ O-, lower alkyl groups as is, for example, methyl group, an ethyl group. Examples of the halo lower alkyl group, for example, fluoromethyl Group, a trifluoromethyl group and the like, and examples of the phenyl group which may be 1 to 3 substituted with a lower alkyl group include a phenyl group and a para-methylphenyl group, and further R ⁶ -SO ₂ O Preferable examples represented by-include a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a para-toluenesulfonyloxy group and the like.

Examples of the lower alkyl group which may have a substituent represented by Y include a lower alkyl group such as a methyl group and an ethyl group, as well as a carboxyl group, an alkoxycarbonyl group, a hydroxyl group, a lower alkoxy group and aryl. Base,
Examples thereof include a lower alkyl group which is 1 or 2 substituted with a cyano group and the like, and preferably a carboxymethyl group, an ethoxycarbonyl (cyano) methyl group, a t-butoxycarbonyl (cyano) methyl group and the like.

Examples of the cyclo-lower alkenyl group which may have a substituent represented by Y include an oxo-cyclohexenyl group and an oxo-cyclopentenyl group, and preferably a 3-oxo-1-cyclopentenyl group. , 3-oxo-1-cyclohexenyl group and the like.

The compound (1) of the present invention can form both an acid addition salt and a base addition salt. In addition, this salt also includes a salt formed with a chelate salt with a boron compound. Examples of the acid addition salt include (a) salts with mineral acids such as hydrochloric acid and sulfuric acid, (b) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid, (C) Salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and examples of base addition salts include (a) sodium and potassium. Salts with alkali metals, (b) salts with alkaline earth metals such as calcium and magnesium, (c) ammonium salts, (d) trimethylamine,
Triethylamine, tributylamine, pyridine, N,
N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β
Examples thereof include salts with nitrogen-containing organic bases such as phenethylamine, 1-ephenamine, and N, N'-dibenzylethylenediamine. Further, as the boron compound,
Examples thereof include boron halides such as boron fluoride and lower acyloxyboron such as acetoxyboron.

The compound (1) of the present invention can exist not only in unsolvated form but also as hydrate or solvate. Accordingly, the compounds of the present invention extend to all crystalline forms and hydrates or solvates thereof.

Further, the compound (1) of the present invention, which includes one having an asymmetric carbon atom, can exist as an optically active substance. These optically active substances are also included in the compound of the present invention. Furthermore, some of the compounds (1) of the present invention have two or more asymmetric carbon atoms, and they can exist as different stereoisomers (cis type, trans type). These stereoisomers are also included in the compound of the present invention.

The compound (1) of the present invention can be produced by any method suitable for the kind of the substituent and the like. Preferred examples thereof are as follows. [Step-1] In the compound represented by the general formula (1), R ¹ is a hydrogen atom or a lower alkyl group, Y is a halogen atom or a formula R ⁶ —SO ₂ O— (wherein R ⁶ is a lower group). An alkyl group, a halo lower alkyl group or a lower alkyl group having 1 to 3
The compound which is a group represented by an optionally substituted phenyl group) is produced by, for example, a series of steps represented by the following reaction formula [1].

[0038]

[Chemical 8]

[0039]

[Chemical 9]

(In the formula, Y ¹ is a halogen atom or the formula R ⁶ -SO ₂
O- (wherein R ⁶ represents a lower alkyl group, a halo lower alkyl group, or a phenyl group optionally substituted by 1 to 3 with a lower alkyl group), and Z ¹ represents a hydroxyl-protecting group. Z ² and Z ³ may be the same or different and each represents a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group or an amino protecting group, and R ^1a represents a lower alkyl group. , R ² , R ³ , R ⁴ , X and n have the same meanings as above).

The starting material in this step is an o-hydroxyalkylaniline derivative represented by the general formula (A) or (C) or a hydroxy protected form thereof. Here, the hydroxyl-protecting group represented by Z ¹ may be any of those usually used for protecting hydroxyl groups, and examples thereof include an acyl group, a trialkylsilyl group, a benzyl group, and a tetrahydropyranyl group. Of these, the acyl group is an acetyl group,
A propionyl group, a benzoyl group, a pivaloyl group and the like are preferable, and a trialkylsilyl group is preferably a t-butyldimethylsilyl group, a triethylsilyl group, a t-butyldiphenylsilyl group and the like.

In this step, first, compound (A) or compound (C) is reacted with diethyl ethoxymethylenemalonate to obtain compound (B) or compound (D). This reaction can be usually performed without a solvent at a reaction temperature of 80 to 150 ° C., but can also be performed using a solvent having no active hydrogen such as toluene or xylene. The compound (B) is converted to the compound (D) by protecting the hydroxyl group. When the protecting group is an acyl group, the protection can be carried out by a reaction usually used for acylation of a hydroxyl group. For example, an acyl chloride corresponding to Z ¹ and a compound (B) can be converted into dichloromethane,
It can be carried out by reacting in a solvent having no active hydrogen such as ether or acetone at 0 ° C. to room temperature in the presence or absence of a base such as pyridine, triethylamine, sodium carbonate or potassium carbonate. The acyl group represented by Z ¹ is arbitrary as long as it is usually used for protecting a hydroxyl group, and examples thereof include an acetyl group, a propionyl group and a benzoyl group. When the protecting group is a trialkylsilyl group, the protection can be carried out by a reaction usually used for trialkylsilylation of a hydroxyl group. For example, the trialkylsilyl halide corresponding to Z ¹ and the compound (B) are mixed with dichloromethane, N, N. It can be carried out by reacting in a solvent having no active hydrogen such as dimethylformamide or acetone at 0 to 60 ° C. in the presence of a base such as imidazole, triethylamine or 2,6-lutidine.

The compound (D) is subjected to a cyclization reaction to obtain a compound (E). This reaction can be carried out by various methods. For example, compound (D) is added to 180 to 27 in an inert solvent such as diphenyl ether or dibenzyl ether.
Method of heating to 0 ° C, or 100 to 100 in polyphosphoric acid
It can be performed by a method of heating to 160 ° C.

Compound (F) is obtained by removing the protective group for the hydroxyl group of compound (E). When the protecting group is an acyl group, compound (E) is subjected to alcoholysis to obtain compound (F). In this reaction, an alcohol corresponding to R ^1a to be substituted on the carboxyl group of the compound (F) is used as a solvent, and benzene, toluene, dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone is simultaneously used as a solvent, or an alcohol is used. Compounds at room temperature to 100 ° C using a catalytic amount of a base such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate or a metal alcoholate corresponding to R ^1a , without using a solvent other than It can be carried out by reacting (E). When the protective group is a trialkylsilyl group, compound (F) is obtained by acid-hydrolyzing compound (E). This reaction is
Using tetrahydrofuran, alcohol, ether or the like as a solvent, acetic acid, hydrochloric acid in the presence or absence of water,
It can be carried out using an acid such as p-toluenesulfonic acid. Alternatively, by reacting the compound (E) with a fluorine compound,
It is also possible to obtain the compound (F). This reaction can be carried out by using tetrahydrofuran as a solvent and using tetra-n-butylammonium fluoride at 0 ° C. to room temperature.

Compound (G) is obtained by reacting compound (F) with an aminating agent such as mesitylenesulfonylhydroxyamine or O- (2,4-dinitrophenyl) hydroxyamine. This reaction can be carried out in the presence of a base such as sodium carbonate or potassium carbonate in a solvent such as dimethylformamide or N-methylpyrrolidone at a temperature of about 0 to 60 ° C.

Compound (H) is obtained by subjecting compound (G) to a cyclization reaction. This cyclization reaction can be carried out by various methods. For example, the compound (G) is reacted with triphenylphosphine and diethylazodicarboxylate in a solvent such as tetrahydrofuran at a temperature of about 0 to 60 ° C. It can be done by The cyclization reaction can also be carried out after previously protecting the amino group with a lower alkyl group represented by Z ² or Z ³ or an amino-protecting group, if desired. Where Z ² and Z
The optionally substituted lower alkyl group and acyl group represented by ^3, is exemplified in R ^4, the amino-protecting group, as a protecting group for amino group protected in R ² What was illustrated is mentioned.

Compound (I) is obtained by optionally alkylating or acylating compound (H). The alkylation reaction is carried out in the presence of an alkylating agent such as dialkylsulfate, alkyliodide or alkylbromide corresponding to the desired alkyl group, preferably in the presence of a base such as sodium carbonate or potassium carbonate, dimethylformamide, N-methylpyrrolidone or the like. It can be carried out by reacting with the compound (H) in the solvent of room temperature at a temperature of about room temperature to about 150 ° C. The acylation reaction can be carried out by any reaction usually used for acylation of an amino group, and for example, an acyl chloride corresponding to a desired acyl group and a compound (H) can be used in dichloromethane, ether or acetone at 0 ° C. to room temperature. In, the reaction can be carried out in the presence or absence of a base such as pyridine, triethylamine, sodium carbonate or potassium carbonate. Alternatively, the acylation reaction can be carried out by reacting an acid such as formic acid or acetic acid or an acid anhydride thereof at room temperature to 150 ° C.

The compound (J) is obtained by hydrolyzing the compound (I). Although any known reaction can be used for this reaction, for example, an aqueous sodium hydroxide solution,
Whether a solvent that can be mixed with water such as ethanol, methanol, tetrahydrofuran, dimethylformamide or N, N-dimethylsulfoxide in an alkaline aqueous solution such as an aqueous potassium hydroxide solution or an aqueous sodium carbonate solution or an acidic solution such as hydrochloric acid or acetic acid is used. Alternatively, it can be carried out by reacting compound (I) at room temperature to 100 ° C. without using a solvent.

[Step-2] In the compound represented by the general formula (1), R ¹ is a hydrogen atom or a lower alkyl group, and Y is an amino group, a hydroxyl group, a cyclo-lower alkylamino group, a mono- or di-lower group. Alkylamino group, optionally substituted cyclic amino group, optionally substituted lower alkyl group, optionally substituted cyclolower alkenyl group, formula R ^5- (CH ₂ ) _m -A- (where R
⁵ is a hydrogen atom, an amino group which may have a substituent, a saturated heterocyclic group which contains a nitrogen atom which may have a substituent, or a cyclo lower alkyl group which may have a substituent. , A represents an oxygen atom or a sulfur atom, and m is 0 to
The compound which is a group represented by the formula (indicating the integer of 3) is produced, for example, by the process shown in the following reaction formula [2]. Reaction formula [2]

[0050]

[Chemical 10]

(In the formula, R ^1b represents a hydrogen atom or a lower alkyl group, Y ² represents an amino group, a cyclo lower alkylamino group, a mono- or di-lower alkylamino group, and a cyclic amino group which may have a substituent. Group, a lower alkyl group which may have a substituent, a cyclo lower alkenyl group which may have a substituent, or a formula R ^5- (CH ₂ ) _m -A- (wherein R ⁵ is hydrogen. Atom, an amino group which may have a substituent, a saturated heterocyclic group containing a nitrogen atom which may have a substituent or a cyclo lower alkyl group which may have a substituent, A represents an oxygen atom or a sulfur atom, m represents a group represented by 0 to 3, and M represents a hydrogen atom, an alkali metal atom or an organometallic compound (provided that Y ²
Is an optionally substituted cyclo-lower alkenyl group, M represents an organometallic compound), R ² , R
³ , R ⁴ , X, Y ¹ and n have the same meanings as above)

That is, the compound (L) is obtained by reacting the compound (K) obtained in [Step-1] with a compound represented by the formula Y ² -M or a salt thereof or an alkali metal alcoholate.

This reaction is preferably carried out in an inert reaction solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane or N-methylpyrrolidone or a mixture thereof. In addition, this reaction is carried out in the presence of a chelate compound obtained by reacting compound (K) with boron trifluoride or a complex thereof or tris-lower acyloxyboron in the presence of a chelate salt. It is also possible to react with the amine compound. The reaction temperature is preferably 50 to 200 ° C, more preferably 80 to 150 ° C. This reaction consists of triethylamine, 2,6-lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, alkali metal It is preferable to use a base such as a carbonate while neutralizing the generated hydrogen halide. It is also possible to neutralize the generated hydrogen halide by using an alkali metal alcoholate or amine used in the reaction in excess. When Y ² is a cyclo-lower alkenyl group which may have a substituent, M represents an organometallic compound, and the organometallic compound is preferably trialkyltin such as tributyltin, and the reaction is tetrakis (trialkyl). Phenylphosphine) palladium, bis (acetonitrile)
It is preferable to use a palladium catalyst such as palladium (II) chloride or bis (triphenylphosphine) palladium (II) chloride. In this reaction, the product may be obtained in the form of a salt.
Trifluoroacetic acid, acid such as hydrochloric acid, or sodium carbonate,
It is possible to convert the product to the free form by treating with a base such as potassium carbonate, sodium hydroxide, potassium hydroxide.

In this reaction, when the compound represented by Y ² -M is substituted with a hydroxyl group, a mercapto group, a carboxyl group or an amino group, the yield of the compound (L) in the above reaction is remarkably high. However, in such a case, after modifying the hydroxyl group, mercapto group, carboxyl group or amino group in the compound with an appropriate protecting group, the compound is subjected to the reaction step represented by the reaction formula [2]. After that, a good yield can be obtained by deprotecting the obtained compound. As the protective group in this case, any known protective group can be used, for example, for a hydroxyl group, an acyl group, an alkoxycarbonyl group or a benzyl group; for a mercapto group, an acyl group or an ethylthio group. A benzyl group for a carboxyl group; an acyl group, an alkoxycarbonyl group for an amino group,
A benzyl group or the like can be used, and these protecting groups can be removed by a known appropriate method such as acid hydrolysis, base hydrolysis or catalytic hydrogenation.

[Step-3] Among the compounds represented by the general formula (1), the compound in which R ¹ is a carboxy protecting group is produced, for example, by the step shown in the following reaction formula [3]. Reaction formula [3]

[0056]

[Chemical 11]

(In the formula, R ^1c represents a carboxy protecting group,
X ¹ represents a hydrogen atom or a halogen atom, and R ² , R ³ ,
R ⁴ , X, Y and n have the same meaning as described above. That is, the compound (N) is obtained by reacting the compound (M) with a halide (R ^1c -X ¹ ).

The reaction is carried out in the presence of a base such as triethylamine, trimethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and an inert solvent such as N, N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone. Using room temperature to 100 ℃
It is preferable to carry out at the temperature of. In this step as well, the yield may be reduced due to the substituents on Y as described in [Step-2], but this problem is solved in the same manner as in the method described in [Step-2]. be able to.

Through the above-mentioned [Step-1], [Step-2] and [Step-3], the novel tricyclic compound (1) according to the present invention
However, the method for producing the compound according to the present invention is not limited to the above production method. For example, in compounds represented by the formula (I), R ³ is a hydrogen atom and n
The compound of = 1 can also be obtained by [Step-4] to [Step-7] shown in the following reaction formula [4]. Reaction formula [4]

[0060]

[Chemical formula 12]

[0061]

[Chemical 13]

(In the formula, R ^2a represents a hydrogen atom or a halogen atom, R ⁸ and R ⁹ each represent a hydrogen atom or a carboxy protecting group, Z ⁴ represents a leaving group, and R ⁴ , X and Y represent
¹ has the same meaning as above)

[Step-4] The compound (P) or a salt thereof is
It can be produced by subjecting the compound (O) or a salt thereof to a Michael addition reaction with the conjugated double bond compound (Q). Suitable salts of the compounds (O) and (P) are the compounds (1)
The above may be referred to. The reaction is carried out in the presence of base or Lewis acid. Suitable bases include
Examples thereof include alkali metal hydrides such as sodium hydride and potassium hydride, alkaline earth metal hydrides such as calcium hydride, alkali metal alkoxides such as potassium t-butoxide, potassium fluoride and the like. Suitable Lewis acid, for example, zinc bromide, zinc halide such as zinc chloride, for example magnesium bromide, magnesium halide such as magnesium chloride, for example titanium tetrachloride, tetraethoxy titanium, titanium compounds such as tetrapropoxy titanium, Examples thereof include boron trifluoride. The reaction is usually water, alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran,
The reaction is carried out in a solvent such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone or a mixture thereof, but the reaction can be carried out in any other solvent as long as it does not adversely influence the reaction. As a solvent or an auxiliary agent when a Lewis acid is used, for example, a compound having an ether bond for modifying Lewis acidity such as diethyl ether, 1,2-epoxypropane, tetrahydrofuran, dioxane or the like can be used. The reaction temperature is not particularly limited, but the reaction is usually performed under heating.

[Step-5] The compound (R) or a salt thereof is
It can be produced by subjecting compound (P) or a salt thereof to a ring closure reaction. For the suitable salt of the compound (R), those exemplified for the compound (1) may be referred to. Z
Examples of the leaving group represented by ⁴ include a halogen atom such as a fluorine atom. The ring closure reaction is carried out in the presence of a base. Examples of suitable bases and solvents include [Step-4]
The above may be referred to. The reaction temperature is not particularly limited, but the reaction is usually performed under heating. Depending on the reaction conditions (for example, using dimethyl sulfoxide as a solvent), the Michael addition of [Step-4] causes the ring-closing reaction of [Step-5] to occur successively, and the reaction proceeds as a whole in one step.

[Step-6] The compound (S) or a salt thereof is
It can be produced by subjecting compound (R) or a salt thereof to a solvolysis reaction. For the suitable salt of the compound (S), those exemplified for the compound (1) may be referred to. Solvolysis reaction is a base or acid (including Lewis acid)
Is preferably carried out in the presence of Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, or hydroxides or carbonates or hydrogen carbonates thereof, such as trialkylamines such as trimethylamine and triethylamine, picoline. , 1,5-diazabicyclo [4.3.0]
Non-5-ene, 1,4-diazabicyclo [2.2.
2] Octane, 1,8-diazabicyclo [5.4.0]
Inorganic and organic bases such as undec-7-ene and the like can be mentioned. Examples of suitable acids include organic acids such as formic acid, acetic acid, glacial acetic acid, propionic acid, trichloroacetic acid and trifluoroacetic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and hydrogen bromide. Can be mentioned. The elimination using a Lewis acid such as trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid is preferably performed in the presence of a cation trapping agent such as anisole or phenol. The reaction is usually water, alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran,
The reaction is carried out in a solvent such as N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, but the reaction can be carried out in any other solvent as long as it does not adversely influence the reaction. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

[Step-7] Compound (I-1) or a salt thereof can be produced by subjecting compound (S) or a salt thereof to a decarboxylic acid reaction. Compound (I-1)
For the suitable salt of, the examples of the compound (1) may be referred to. This reaction is carried out by heating under an atmosphere of an inert gas such as nitrogen or by a conventional method such as reduction. The reaction is usually carried out in a solvent such as water, alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, but it does not adversely influence the reaction. The reaction can be carried out in any other solvent as long as it is a solvent. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

[0067] According to the method from the [Process -4] by [Step -7], compound R ^2a is a halogen atom (I-
2) can be obtained particularly efficiently, and further, the compound (I
By applying -2) to [Step-8] and [Step-9] represented by the following reaction formula [5], the compound (I-3) having an amino group can be easily introduced. Reaction formula [5]

[0068]

[Chemical 14]

(In the formula, R ^2b represents a halogen atom, and R ¹⁰
Represents an amino-protecting group, and R ¹ , R ⁴ , X and Y ¹ have the same meanings as described above.

[Step-8] The compound (T) or a salt thereof is
It can be produced by reacting compound (I-2) or a salt thereof with amine compound (U) or a salt thereof.
For the suitable salt of the compound (T), those exemplified for the compound (1) may be referred to. Examples of the amino protecting group represented by R ¹⁰ include those exemplified as the protecting group for the protected amino group in R ² . This reaction is carried out in the presence of an acid acceptor such as sodium carbonate, calcium carbonate, sodium hydrogen carbonate, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene,
The compound (U) or a salt thereof is generally used in an equivalent or slightly excessive amount with respect to the compound (I-2) or a salt thereof, but an excessive amount of the compound (U) is used as an acid acceptor. You may also have the role of. The reaction is usually carried out by aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran, dioxane and monoglyme, halogenated hydrocarbons such as methylene chloride and chloroform, N, N-dimethylformamide, The reaction can be carried out in any other solvent as long as it does not adversely influence the reaction, such as dimethyl sulfoxide, acetonitrile or pyridine. The reaction temperature is not particularly limited, but the reaction is usually performed under heating.

[Step-9] Compound (I-3) or a salt thereof can be produced by subjecting compound (T) or a salt thereof to an elimination reaction of an amino-protecting group. Compound (I-
For the suitable salt of 3), those exemplified for the compound (1) may be referred to. As the elimination reaction of the amino-protecting group, both ordinary hydrolysis reaction conditions and ordinary catalytic reduction reaction conditions can be applied. Specifically, in the case of hydrolysis,
Sodium hydroxide, potassium hydroxide, barium hydroxide,
In the presence of basic compounds such as potassium carbonate, mineral acids such as sulfuric acid, hydrochloric acid and nitric acid, organic acids such as acetic acid and aromatic sulfonic acid,
Water, alcohols such as methanol, ethanol and 2-propanol, ketones such as acetone and methyl ethyl ketone, ethers such as dioxane and ethylene glycol diethyl ether, solvents such as acetic acid, and a mixed solvent thereof are used. The reaction is usually performed at room temperature to 200 ° C, preferably at room temperature to 120 ° C. In the case of catalytic reduction, palladium carbon, palladium black, in the presence of a catalyst such as platinum dioxide, in a solvent such as methanol, ethanol, propanol, acetic acid, tetrahydrofuran, dioxane, ethyl acetate, water or a mixed solvent thereof. It is usually carried out by stirring under a hydrogen stream at atmospheric pressure to 100 atm. The reaction temperature is usually from room temperature to around 100 ° C., and usually from 1 to
The reaction is completed in 48 hours.

Further, particularly in the case of the group represented by Y, the substituents present therein can be interconverted by various known methods. In [Step-2], an example of the above-mentioned interconversion was partially described as the addition and deprotection of a protecting group, but some of the other reaction examples are as follows. These are conversion of hydroxyl groups to halogen atoms; acylation of hydroxyl groups, mercapto groups, primary and secondary amino groups; conversion of halogen atoms to amino groups or cyano groups; removal of alkoxycarbonyl groups, benzyl groups, acyl groups; hydroxyl groups , Mercapto group, carboxy group, alkylation of primary and secondary amino groups; conversion from alkenyl group to alkyl group; cyclization reaction by bonding substituents.

A method for producing a compound in which n = 0 among the starting materials (A) or (C) in [Step-1] is disclosed in, for example, Japanese Patent Application Laid-Open No. 2-157282. For the compound in which n = 1, the following reaction formula [6]
And J. Heterocycle. Chem. , 2
5 , 1567 (1988), and more specifically, the methods described in Reference Examples and methods equivalent thereto. Reaction formula [6]

[0074]

[Chemical 15]

(In the formula, Z ⁵ represents a hydrogen atom or an acyl group, and R ² , X and Y ¹ have the same meanings as described above.) Preferable examples of the acyl group for Z ⁵ include the acyl group for Z ^1. The same thing as what was explained is mentioned. In addition, the starting material (O) of [Step-4] is produced, for example, by the reaction formula [7] shown below. Reaction formula [7]

[0076]

[Chemical 16]

(In the formula, R ¹¹ represents a lower alkyl group,
¹² represents an amino protecting group, Z ⁶ represents a leaving group, R ¹ ,
R ^2a , R ⁴ , X, Y ¹ and Z ⁴ have the same meanings as described above. Here, the amino protecting group represented by R ¹² is exemplified as the protecting group for the protected amino group in R ² . Examples of the leaving group represented by Z ⁶ include the same groups as those represented by Z ⁴ . Reagents to be used in the method of synthesizing the starting material (O) and eg solvents,
For the reaction conditions such as reaction temperature, refer to the production examples described below, for example. In addition, the starting material in the synthetic method (a)
Are described, for example, in JP-A-59-212474. In addition, in the present specification, as for the substituents of the compound and those which are not particularly illustrated, the same substituents as those described for the other compounds can be referred to.

[0078]

[Action]

(1) Antibacterial action For typical compounds of the present invention (1), the Japanese Society of Chemotherapy standard method [CHEMOTHERAPY Vol. 29,
No. 1, pp. 76-79 (1981)], the minimum inhibitory concentration [MIC: μg / ml] was measured. The results are shown in Table 1.
The compound numbers in the table are as shown in the examples.

[0079]

[Table 1]

(2) Absorption / Excretion The absorption and excretion of the compound of the present invention in oral administration were tested by measuring the urinary recovery rate and bile recovery rate by the following methods.

(A) Recovery rate in urine To 6-week-old male JCL-SD rats (1 group), fasted overnight, the test compound was added at 20 mg / 0.5% methylcellulose solution.
After adjusted to 10 ml / kg, it was orally administered using an oral probe. Sampling was performed by collecting urine from 0 to 6 hours and 6 to 24 hours. The concentration of the test compound in the urine sample was assayed by the thin layer disc method using Bacillus subtilis ATCC 6633 as a test bacterium, and the 24-hour urinary excretion rate was determined.

(B) Recovery rate in bile After the test compound was prepared in the same manner as in the measurement of recovery rate in urine, it was orally administered to a rat in which a polyethylene tube was inserted into the common bile duct, and bile collected over 24 hours was collected. .. The concentration of the test compound in bile was assayed by the same method as above, and the 24-hour bile excretion rate was determined. The results obtained are shown in Table 2.

[0083]

[Table 2]

As described above, the compound (1) of the present invention and salts thereof are novel compounds, exhibit extremely excellent antibacterial activity against Gram-negative bacteria and Gram-positive bacteria, and have a high oral absorption rate. is there.

When the compound (1) of the present invention is used as an antibacterial agent, it is combined with a pharmaceutically acceptable carrier for parenteral administration such as injection, rectal administration and eye drop administration, and oral administration in solid or liquid form. It can be prescribed as a product.

The forms of the compositions according to the invention for injections include pharmaceutically acceptable sterile water or non-aqueous solutions, suspensions or emulsions. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. These compositions may be sterilized, for example, by filtration through a bacteria-retaining filter or by admixing a sterilant in the form of a sterile solid composition which may be dissolved in sterile water, or some other sterile injectable medium immediately before use. it can.
The preparation for eye drop administration may preferably contain, in addition to the present compound, a solubilizing agent, a preservative, an isotonicity agent, a thickening agent and the like.

Solid preparations for oral administration include capsules, tablets, pills, powders and granules. In preparing this solid dosage form, the compound of the invention is generally admixed with at least one inert diluent such as sucrose, lactose or starch. The formulation may also include, in a conventional formulation, additional substances other than an inert diluent such as a lubricant (eg magnesium stearate). Buffers may also be included in the case of capsules, tablets and pills. The tablets and pills may be further coated with an enteric coating.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used by those skilled in the art, such as water. Included. In addition to such inert diluents, the composition can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, and sweetening, flavoring and flavoring agents. Formulations for rectal administration may preferably contain, in addition to a compound of this invention, an excipient such as cocoa butter or a suppository wax.

The dose of the compound (1) of the present invention depends on the nature of the compound to be administered, the route of administration, the desired treatment period and other factors, but it is generally about 0.1 to 100 per day.
0 mg / kg, especially about 1-100 mg / kg is preferred. Also,
If desired, this daily dose can be divided into 2 to 4 divided doses for administration.

[0090]

INDUSTRIAL APPLICABILITY The compound (1) of the present invention and a salt thereof are extremely valuable as antibacterial agents and can be used as pharmaceuticals for humans and animals, and as preservatives for fish diseases, agricultural chemicals and foods. .. Furthermore, the compound of the present invention can be expected to have an antiviral action, particularly an anti-HIV (human immunodeficiency virus) action, and is considered to have an effect on the prevention or treatment of AIDS.

[0091]

The present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these. The position numbers of the novel tricyclic compounds of the present invention in these Reference Examples and Examples are as follows for compounds in which n is 0 or 1.

[0092]

[Chemical 17]

Reference Example 1 2,3-Difluoro-6-nitrophenylacetic acid (1) 64 g of 60% sodium hydride was added to 200 ml of tetrahydrofuran and 400 ml of 258 g of diethyl malonate was added while stirring under ice cooling. What was melt | dissolved in tetrahydrofuran of above was dripped over 1 hour and 40 minutes so that reaction temperature might not exceed 20 degreeC. Subsequently, a solution of 142 g of 2,3,4-trifluoronitrobenzene in 200 ml of tetrahydrofuran was added dropwise over 2 hours while the reaction solution was being stirred under ice cooling so that the reaction temperature did not exceed 10 ° C. After reacting for 2 hours at room temperature, 100 ml of acetic acid was added, and tetrahydrofuran was distilled off. To the residue were added 1 liter of chloroform, 1.5 liter of water and 100 ml of concentrated hydrochloric acid for liquid separation, the organic layer was separated, and the solvent was evaporated. To the residue, 250 ml of 4
Normal hydrochloric acid and 200 ml of acetic acid were added, and the mixture was heated under reflux for 11 hours. 150 ml of the inner solution was distilled off under normal pressure, and 50 ml of acetic acid,
50 ml of water was added and the mixture was heated under reflux for 31 hours. After cooling, the precipitated crystals were collected by filtration, washed with diisopropyl ether, and then 4
It was dissolved in 00 ml of methanol. After treatment with activated carbon, the solvent was distilled off. The precipitated crystals were dispersed in diisopropyl ether and collected by filtration to give 100 g of the title compound (1) (yield 56%).

Reference Example 2 Diethyl {2- (2-acetoxyethyl) -3,4-difluoroanilino} methylene malonate (2) 19.8 g of sodium borohydride was added to tetrahydrofuran 6
In addition to 0 ml, a solution of 60 g (276 mmol) of 2,3-difluoro-6-nitrophenylacetic acid in 20 ml of tetrahydrofuran was added dropwise under ice cooling at 10 ° C or lower over 1 hour.
Subsequently, a solution of 90 ml of boron trifluoride ethyl ether complex in 120 ml of tetrahydrofuran was added dropwise at 10 ° C. or lower over 1 hour. The mixture was stirred under ice cooling for 15 minutes and at room temperature for 20 minutes. To 1.5 l of methylene chloride and 1.2 l of ice water, 84 g of sodium hydrogen carbonate was added, and the reaction solution was slowly added while stirring well. The mixture was stirred as it was overnight. Separate the organic layer,
After drying over magnesium sulfate, the solvent was distilled off. 61 g of oily 3,4-difluoro-2- (2-hydroxyethyl) nitrobenzene was obtained. To this oily substance, 58 ml (414 mmol) of triethylamine and 500 ml of methylene chloride were added, and a solution of 19 ml (331 mmol) of acetyl chloride in 100 ml of methylene chloride was added dropwise under ice cooling. After stirring for 1 hour and 30 minutes, 5 ml of acetyl chloride was added, and after 30 minutes,
It was washed twice with 200 ml of water. After drying with magnesium sulfate,
The solvent was distilled off. 76.5 g of 2- (2-acetoxyethyl) -3,4-difluoro-nitrobenzene was obtained.

43 g of iron powder, 4 ml of concentrated hydrochloric acid, 450 ml of water,
The mixture was added to 100 ml of ethanol, heated at 80 ° C., and the nitro compound was added dropwise over 30 minutes while stirring well. The mixture was stirred as it was for 1 hour. After allowing to cool, add 500 ml of ethyl acetate,
The insoluble matter was filtered and the organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off to obtain 61.8 g of 2- (2-acetoxyethyl) 3,4-difluoroaniline. 60g (276mmol) of ethyl ethoxymethylene malonate
Was added and heated at 120 ° C. for 5 hours. After allowing to cool, the crystals were collected by filtration and washed with ether to obtain 78.2 g of the title compound (2) (yield 74%).

Reference Example 3 Ethyl 6,7-difluoro-4-hydroxy-8-
(2-Hydroxyethyl) quinoline-3-carboxylate (3) 78 g (203 mmol) of the compound (2) obtained in Reference Example 2
Was added to Dowtherm A1.01 and boiled for 2 minutes. After allowing to cool, the precipitated crystals were collected by filtration. Wash with ether, ethyl 8
-(2-acetoxyethyl) -6,7-difluoro-4
32 g of a mixture of -hydroxyquinoline-3-carboxylate and ethyl 8,9-difluoro-6-oxo-6H-pyrrolo [3,2,1-ij] quinoline-5-carboxylate were obtained. The obtained mixture, sodium ethoxide (4.26 g), was added to ethanol (730 ml), and the mixture was heated under reflux for one day. After cooling to room temperature, 5.1 g of precipitated crystals of the pyrroloquinoline derivative were collected by filtration, and the filtrate was concentrated to 150 ml. The crystals were collected by filtration and washed with ethanol and then ether. 23.8 g of the title compound (3) was obtained (yield 40%).

Reference Example 4 Ethyl 1-amino-6,7-difluoro-8- (2-
Hydroxyethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate (4) 6.13 g (20 mmo) of the quinoline derivative (3) obtained in Reference Example 3
l), anhydrous potassium carbonate 8.8 g (60 mmol), N, N
-Add to 100 ml of dimethylformamide and stir at room temperature for 4 hours. 20 g of hydrated mesitylenesulfonylhydroxyamine (NET 17 g, 82 mmol) was added to 100 ml of methylene chloride.
Was dissolved in water, dried over sodium sulfate, and added dropwise over 20 minutes under ice cooling. The mixture was stirred as it was overnight. Methylene chloride was distilled off under reduced pressure, 100 ml of water was added, and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration and washed with water, ethanol and ether in this order. 3.30 g of the title compound (4) was obtained (yield 53
%).

Example 1 Ethyl 4,5-difluoro-2,3-dihydro-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (5) 11.3 g of 1-aminoquinolone (4) obtained in Reference Example 4
(36 mmol), 15.1 g of triphenylphosphine (58
mmol) to 300 ml of tetrahydrofuran, and at room temperature,
A solution of 9.9 g (57 mmol) of diethyl azodicarboxylate in 500 ml of tetrahydrofuran was added dropwise over 3 hours and a half. The mixture was stirred as it was for 3 hours, and the solvent was distilled off. The crystals were dispersed in ethanol and collected by filtration. It was washed with ethanol and ether in this order to obtain 9.5 g of the title compound (5) (yield 89%). ¹ H-NMR (DMSO-d ₆ ) 1.27 (t, J = 7.3Hz, 3H), 2.95 (t, J = 5.1Hz, 2H), 3.31 (s, 3
H), 3.40 (t, J = 5.8Hz, 2H), 4.21 (q, J = 7.3Hz, 2H) _, 6.86 (t,
J = 6.6Hz, 1H), 7.91 (dd, J = 11.0Hz, J = 8.8Hz, 1H), 8.42 (s, 1
H)

Example 2 (1) Methyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (6) 9.5 g (33) of pyridocinnoline (5) obtained in Example 1
95 ml of dimethylsulfate is added to 100) to 120 ° C.
Heated for 8 hours. After cooling down, anhydrous potassium carbonate 137g
Was added to 900 ml of water and the mixture was stirred at room temperature for 30 minutes. After extraction with 800 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. The residue was chromatographed on silica gel (silica gel 250 g, elution solvent: chloroform).
The resulting crystals were collected by filtration, washed with ether, and 5.
3 g of the title compound (6) was obtained (yield 56%). ¹ H-NMR (CDCl ₃ ) 2.87 (s, 3H), 3.09 (t, J = 6.2Hz, 2H), 3.50 (t, J = 6.2Hz, 2
H), 3.93 (s, 3H), 8.17 (dd, J = 9.6Hz, J = 9.5Hz, 1H), 8.61
(s, 1H)

(2) The following compound (7) was obtained in the same manner as in Example 2 (1). Ethyl 4,5-difluoro-
2,3-dihydro-1-ethyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (7) ¹ H-NMR (CDCl ₃ ) 1.19 (t, J = 6.9Hz, 3H), 1.41 (t, J = 7.0Hz, 3H), 2.96-3.06
(m, 4H), 3.56 (t, J = 6.9Hz, 2H), 4.39 (q, J = 7.0Hz, 2H), 8.14
(dd, J = 9.5Hz, 9.5Hz, 1H), 8.54 (s, 1H)

Example 3 (1) 4,5-Difluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid (8) 5.3 g of the methyl ester (6) obtained in Example 2 (1)
(18 mmol) was added to 250 ml of tetrahydrofuran, and 0.76 g (19 mmol) of sodium hydroxide was added under heating and refluxing to 10 ml.
0 ml of an aqueous solution was added and heating and refluxing were continued for 1 hour and a half. After allowing to cool, 4.2 g (20 mmol) of citric acid hydrate was added under ice cooling,
The mixture was neutralized and stirred under ice cooling for 1 hour. The solid was collected by filtration. water,
It was washed with ethanol and ether in this order to obtain 3.78 g of the title compound (8) (yield 75%). Colorless powder Melting point 264-265 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.88 (s, 3H), 3.14 (t, J = 5.9Hz, 2H), 3.54 (t, J = 5.9Hz, 2
H), 8.18 (dd, J = 11Hz, J = 8Hz, 1H), 8.82 (s, 1H)

(2) 29.1 g of the methyl ester (6) obtained in Example 2 (1) was added to 80 ml of concentrated hydrochloric acid and 320 ml of acetic acid, and the mixture was heated under reflux for 3 and a half hours. After cooling, 500 ml of water was added and the crystals were collected by filtration. Washing with water, ethanol and ether in this order gave 23.2 g of crude crystals. The obtained crude crystals were recrystallized from ethanol and chloroform to obtain 21 g of the title compound (8) (yield 80%). Colorless prism, melting point 264-265 ℃ (decomp.)

(3)-(4) According to Example 3 (2),
The following compounds (9) and (10) were obtained. 4,5-difluoro-2,3-dihydro-1-ethyl-
7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (9) colorless prism, melting point 231-232.5 ° C ¹ H-NMR (DMSO-d ₆ ) 1.09 (t, J = 7.3Hz, 3H), 3.01-3.12 (m, 4H), 3.61 (t, J = 5.9H
z, 2H), 8.16 (dd, J = 10.3Hz, 10.3Hz, 1H), 8.71 (s, 1H) 4,5-difluoro-2,3-dihydro-7-oxo-
1H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid (10) Colorless powder Melting point 265 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 3.03, 3.47 (each brs, each 2H), 7.27 (brs, 1H), 8.12 (d
d, J = 8.4Hz, 8.4Hz, 1H), 8.68 (s, 1H)

Example 4 (Method A) (1) 4- (3-aminopyrrolidin-1-yl) -5
-Fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (11) Obtained in Example 3 (1). 4,5-Difluoro form (8)
50 mg (0.18 mmol), 3-aminopyrrolidine 80 mg (0.93 m
mol) to 1 ml of N, N-dimethylformamide,
Heated at 00 ° C. for 1 hour. The solvent was distilled off, and the residue was azeotropically distilled with toluene. Ethanol was added, solidified, and collected by filtration. Wash with ethanol and ether in this order to obtain 50 mg of the title compound (1
1) was obtained (81% yield). Colorless powder Melting point 217-218 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.65-1.76 (m, 1H), 2.01-2.11 (m, 1H), 2.91 (s, 3H), 2.95
(t, J = 5.5Hz, 2H), 3.27-3.76 (m, 7H), 7.81 (d, J = 14.2Hz, 1
H), 8.66 (s, 1H) (2) to (22) According to Method A, compounds (12) to (29) and compounds (101) shown in Tables 3 to 7 below.
From Compound (103) was obtained.

[0105]

[Table 3]

[0106]

[Table 4]

[0107]

[Table 5]

[0108]

[Table 6]

[0109]

[Table 7]

Example 5 (Method B) (1) 4- (cis (-) 3-amino-4-methylpyrrolidin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7- Oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylic acid (30) 1.0 g (3.6 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1), cis (-) 3-amino- 4-methylpyrrolidine dihydrochloride 0.93 g (5.4 mmol) and 1,8
-Diazabicyclo [5.4.0] -7-undecene 2.95
g (19.4 mmol), 20 ml of N, N-dimethylformamide
In addition, the mixture was heated at 110 to 120 ° C. for 40 minutes. The solvent was distilled off. Azeotrope with toluene, ethanol 20 ml, acetic acid 1.
2g was added. The mixture was allowed to stand at room temperature and the precipitated solid was collected by filtration. The solid was washed with ethanol and ether in this order to obtain 750 mg of the title compound (30) (yield 58%). Yellow powder Melting point 160-162 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.07 (d, J = 6.6Hz, 3H), 2.39-2.44 (m, 1H), 2.91 (s, 3H), 2 .
95 (brs, 2H), 3.21-3.70 (m, 6H), 3.94-3.99 (m, 1H), 7.82
(d, J = 14.3 Hz, 1H), 8.67 (s, 1H) The powder obtained in this example was recrystallized with a mixed solvent of ethanol and water and subjected to X-ray analysis. Since the torsion angle between the 3-amino group and the 4-methyl group on the pyrrolidine ring of this crystal was 48.9 °, it was confirmed that this coordination was cis. (2) to (26) According to the B method,
From compound (31) to compound (5 shown in Tables 8 to 12 below.
4) and compound (104) were obtained.

[0111]

[Table 8]

[0112]

[Table 9]

[0113]

[Table 10]

[0114]

[Table 11]

[0115]

[Table 12]

Example 6 (Method C) (1) 4- {3,7-diazabicyclo [3.3.0]
Octan-3-yl} -5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid hydrochloride (55) 50 mg (0.18 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1), 92 mg of 3-t-butoxycarbonyl-3,7-diazabicyclo [3.3.0] octane carbonate ( 0.34 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene 109 mg (0.72 mmol)
Was added to 1 ml of N, N-dimethylformamide, and 110
Heated at ~ 120 ° C for 40 minutes. The solvent was distilled off, 20 ml of chloroform and 10 ml of water were added, and the mixture was acidified with citric acid.
The organic layer was separated, dried over sodium sulfate and evaporated.
It was azeotropically distilled with toluene, ethanol was added to the residue to disperse the solid, and the solid was collected by filtration. The solid was washed with ethanol and then ether to obtain 40 mg. To the obtained solid, 0.9 ml of acetic acid was added, followed by 0.2 mg of concentrated hydrochloric acid, the mixture was stirred at room temperature for 15 minutes, and the solvent was distilled off.

It was azeotropically distilled with ethanol, ethanol was added to the residue to disperse the solid, and the solid was collected by filtration. It was washed with ethanol and ether in this order to obtain 25 mg of the title compound (55) (yield 34%). Yellow powder Melting point 265-269 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.91 (s, 3H), 2.93-3.19 (m, 6H), 3.29-3.59 (m, 8H), 7.92
(d, J = 13.2Hz, 1H), 8.74 (s, 1H), 9.06 (brs, 2H) (2) to (18) Compounds (56) shown in Tables 13 to 16 below in the same manner as in Method C. (71) and the compound (1
05) was obtained.

[0118]

[Table 13]

[0119]

[Table 14]

[0120]

[Table 15]

[0121]

[Table 16]

Example 7 (Method D) (1) 5-fluoro-4-{(3-pyrrolidine-3-
Yl) oxy} -2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid hydrochloride (72) 278 mg (1 mmol) of 4,5-difluoro compound (8) obtained in Example 3 (1) ), 1-t-butoxycarbonyl-3-pyrrolidinol (374 mg, 2 mmol) was added to N, N
-In addition to 3 ml of dimethylformamide, 120 mg (3 mmol) of 60% sodium hydride was added at room temperature, and 1
After stirring for an hour, the solvent was distilled off. Chloroform (15 ml) and water (10 ml) were added to acidify citric acid. Separate the organic layer,
It was dried over magnesium sulfate and evaporated. Azeotroped with toluene, added ether to disperse the solid, and collected by filtration 314mg
To give a solid. To 180 mg of the obtained solid, 4 ml of acetic acid was added at room temperature, and subsequently 1 ml of concentrated hydrochloric acid was added, and 1 was added as it was.
After stirring for 5 minutes, the solvent was distilled off. It was azeotropically distilled with ethanol, ethanol was added to the residue, and the solid was dispersed. The solid was collected by filtration, washed with ethanol and then with ether to give 144 mg of the title compound (72) (yield 67%).

Light yellow powder Melting point 241 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.12-2.31 (m, 2H), 2.89 (s, 3H), 2.98-3.59 (m, 8H), 5.40
(brs, 1H), 8.06 (d, J = 12.1Hz, 1H), 8.78 (s, 1H), 9.60,9.7
5 (each brs, each 1H) (2) to (4) Compound (75) was obtained from compound (73) shown in Table 17 below in the same manner as in Method D.

[0124]

[Table 17]

Example 8 (Method E) 5-Fluoro-4-methoxy-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid (76) Example 3
50 mg of the 4,5-difluoro body (8) obtained in (1)
(0.18 mmol) and 30 mg of sodium methoxide were added to 5 ml of methanol, and the mixture was heated under reflux for 5 hours and a half. After allowing to cool, acetic acid is reduced to 0.
5 ml and 10 ml of methanol were added, and the precipitated solid was collected by filtration.
Methanol and ether were washed in this order to obtain 50 mg of the title compound (76) (yield 96%). Colorless powder Melting point 236-241 ℃ ¹ H-NMR (DMSO-d ₆ ) 2.86 (s, 3H), 3.04 (t, J = 5.9Hz, 2H), 3.50 (t, J = 6.2Hz, 2
H), 4.10 (s, 3H), 8.02 (d, J = 12.5Hz, 1H), 8.76 (s, 1H)

Example 9 (1) 4- (cis (-) 3-amino-4-methylpyrrolidin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,
2,1-ij] Cinnoline-8-carboxylic acid hydrochloride (7
7) 5.1 g of the compound (30) obtained in Example 5 (1) was added to acetic acid 1
It was dissolved in 10 ml, concentrated hydrochloric acid (25 ml) was added, and the mixture was stirred overnight at room temperature. The crystals were collected by filtration and washed with ethanol and ether in this order to obtain 4.6 g of crude crystals. The filtrate is distilled off and ethanol 8
0 ml was added and the precipitated crystals were collected by filtration. The crude crystals were combined and recrystallized from ethanol to give 4.61 g of the title compound (7
7) was obtained. Yellow prism Crystal melting point 211-214 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.15 (d, J = 7.0Hz, 3H), 2.57-2.70 (m, 1H), 2.91 (s, 3H), 3.
07 (brs, 2H), 3.30-3.72 (m, 5H), 3.84 (brs, 1H), 4.04-4.1
4 (m, 1H), 7.84 (d, J = 14.3Hz, 1H), 8.68 (s, 1H)

(2) 4- (cis (-) 3-amino-4
-Methylpyrrolidin-1-yl) -5-fluoro-2,
3-dihydro-1-methyl-7-oxo-1H, 7H-
Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid tosylate salt (78) 3.2 g of the compound (30) obtained in Example 5 (1) was dissolved in 110 ml of chloroform and 110 ml of methanol to give p. −
A solution of 6.37 g of toluenesulfonic acid hydrate in 40 ml of methanol was added, and the mixture was stirred at room temperature for 40 minutes. The solvent was evaporated, the crystals were dispersed in ethanol, collected by filtration and washed with ethanol and ether in this order to obtain 4.52 g of crude crystals. Recrystallization from a mixed solvent of ethanol-water gave 3.59 g of the title compound (78). Colorless needles melting point 258-260 ℃ ¹ H-NMR (DMSO-d ₆ ) 1.12 (d, J = 6.9Hz, 3H), 2.28, 2.91 (eachs, each 3H), 2.60
-2.70 (m, 1H), 3.00 (brs, 2H), 3.35-3.68 (m, 5H), 3.88 (br
s, 1H), 4.01-4.06 (m, 1H), 7.10 (d, J = 7.7Hz, 2H), 7.45
(d, J = 8.0Hz, 2H), 7.86 (d, J = 13.9Hz, 1H), 8.69 (s, 1H) (3) to (7) According to Example 9 (2), the compounds shown in Table 18 below. Compound (83) was obtained from (79).

[0128]

[Table 18]

Example 10 (1) 4- {cis (-) 3- (t-butoxycarbonylaminoacetylamino) -4-methylpyrrolidine-1
-Yl} -5-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-i
j] Cinnoline-8-carboxylic acid (84) Nt-butoxycarbonylglycine 350 mg (2 mmo
l) and 202 mg (2 mmol) of N-methylmorpholine were added to 6 ml of methylene chloride, ice-cooled with a freezing agent, and 0.26 ml (2 mmol) of isobutyl chlorocarbonate was added. After 20 minutes, 716 mg (2 mmo of compound (30) obtained in Example 5 (1)
l) was added, and the mixture was stirred at room temperature for 30 minutes. Add 10 ml of water,
Acidified with citric acid. The organic layer was separated, dried over sodium sulfate, and the solvent was evaporated. It was solidified with ethyl acetate-ether and collected by filtration. 776 mg of the title compound (84) was obtained (yield 75%). Yellow powder Melting point 142-145 ℃ ¹ H-NMR (CDCl ₃ ) 1.12 (d, J = 7.0Hz, 3H), 1.45 (s, 9H), 2.54-2.65 (m, 1H), 2.
87 (brs, 2H), 2.95 (s, 3H), 3.42-3.55 (m, 5H), 3.83-3.89
(m, 2H), 3.98-4.05 (m, 1H), 4.62, 5.46, 7.05 (each brs,
each 1H), 7.70 (d, J = 13.5Hz, 1H), 8.63 (s, 1H) (2) to (4) According to Example 10 (1), the following Table 19
The compound (87) was obtained from the compound (85) shown in.

[0130]

[Table 19]

Example 11 (1) 4- {cis (-) 3- (aminoacetylamino) -4-methylpyrrolidin-1-yl} -5-fluoro-2,3-dihydro-1-methyl-7- Oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8-
Carboxylic acid hydrochloride (88) 750 mg of the compound (84) obtained in Example 10 (1)
(1.5 mmol) was added to 10 ml of dioxane and 10 ml of ethanol, and 2.5 ml of 4N dioxane hydrochloride was added. The mixture was stirred at room temperature for 1 hour. The solvent was distilled off. The powder was collected by filtration and washed with ethanol and then ether. 324 mg of the title compound (8
8) was obtained (yield 49%). Yellow powder Melting point 196 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.01 (d, J = 6.6Hz, 3H), 2.91 (s, 3H), 3.00 (brs, 2H), 3.30-
3.70 (m, 7H), 4.06, 4.49 (each brs, each 1H), 7.83 (d, J =
14.3Hz, 1H), 8.13, 8.67 (each brs, each 2H) (2) to (8) According to Example 11 (1), the following Table 20 is used.
And Compound (94) and Compound (106) shown in Table 21 were obtained.

[0132]

[Table 20]

[0133]

[Table 21]

Example 12 4- {cis (-) 3- (2-amino-3-methylbutanoyl) amino-4-methylpyrrolidin-1-yl} -5
-Fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid hydrochloride (95) Obtained in Example 10 (3). 850 mg of the compound (86)
(1.4 mmol) was added to 60 ml of methanol and 10 ml of acetic acid,
5% Palladium on carbon (300 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. Palladium on carbon was filtered and the solvent was distilled off. It was dissolved in 10 ml of methanol and 2 ml of 4N dioxane hydrochloride was added. The solvent was distilled off. The powder was collected by filtration and washed with ethanol and then ether. 600 mg of the title compound (95) was obtained (yield 87%). Yellow powder Melting point 198-199.5 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 0.93 (d, J = 6.6Hz, 6H), 1.07 (d, J = 6.6Hz, 3H) _, 2.05-2.15
(m, 1H), 2.91 (s, 3H), 3.02 (brs, 2H), 3.30-3.50 (m, 3H), 3.
62 (t, J = 8.4Hz, 2H), 3.80, 4.04, 4.48 (each brs, each 1
H), 7.82 (d, J = 14.3Hz, 1H), 8.29 (brs, 2H), 8.66 (s, 1H),
8.73 (d, J = 7.7Hz, 1H)

Example 13 4- {cis (-) 3-((2-amino-3-methylbutanoyl) aminoacetylamino) -4-methylpyrrolidin-1-yl} -5-fluoro-2,3- Dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-8-carboxylic acid hydrochloride (96) (Nt-butoxycarbonylvalyl) glycine p-
758 mg (2 mmol) of nitrophenyl ester, 202 mg (2 mmol) of triethylamine, and 716 mg (2 mmol) of compound (30) obtained in Example 5 (1) were added to 10 ml of methylene chloride, and the mixture was stirred at room temperature overnight. 10 ml of water was added and acidified with citric acid. The organic layer was separated, dried over sodium sulfate, and the solvent was evaporated. It was solidified with ethyl acetate-ether and collected by filtration. In addition to 10 ml of methanol, 2.5 ml of 4N dioxane hydrochloride was added. After stirring at room temperature for 30 minutes, the solvent was distilled off. The powder was collected by filtration and washed with ethanol and then ether. 618 mg of the title compound (96) was obtained (yield 58%). Yellow powder Melting point 189-191 ℃ ¹ H-NMR (DMSO-d ₆ ) 0.94-1.00 (m, 9H), 2.00-2.18 (m, 1H), 2.91 (s, 3H), 3.01
(brs, 2H), 3.30-3.55 (m, 4H), 3.65 (brs, 2H), 3.73-3.89
(m, 1H), 3.94-4.05 (m, 2H), 4.47 (brs, 1H), 7.82 (d, J = 14.
3Hz, 1H), 8.22 (brs, 3H), 8.66 (s, 1H), 8.74 (brs, 1H)

Example 14 Ethyl 1-amino-6,7-difluoro-8-acetoxymethyl-1,4-dihydro-4-oxoquinoline-
3-carboxylate (97) ethyl 6,7-difluoro-4-hydroxy-8-acetoxymethylquinoline-3-carboxylate 10.7 g
(32.9 mmol), anhydrous potassium carbonate 14.2 g (65.8 mmol),
To 130 ml of N, N-dimethylformamide was added, and the mixture was stirred at room temperature for 4 hours. 14 g of hydrated mesitylenesulfonylhydroxyamine (NET 8.97 g, 49 mmol) was dissolved in 100 ml of methylene chloride, dried over sodium sulfate, and added dropwise under ice cooling over 20 minutes. Then, the mixture was stirred as it was overnight. To this, 100 ml of water was added and stirred at room temperature for 1 hour. It was extracted with methylene chloride and the organic layer was washed with water. After drying over sodium sulfate, the solvent was evaporated under reduced pressure, ether was added to the solidified residue, and the solid residue was collected by filtration and washed with ether to obtain 6.4 g of the title compound (97) (yield 57
%). Colorless needle crystal Melting point 217-221 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.3Hz, 3H) _, 2.05 (s, 3H) _, 4.25 (q, J = 7.3Hz , 2H)
_, 5.74 (s, 2H) _, 6.59 (brs, 2H) _, 8.15 (dd, J = 9.2Hz, 10.3H
z, 1H) _, 8.59 (s, 1H)

Example 15 Ethyl 1-acetylamino-6,7-difluoro-8
-Hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (98) 1-aminoquinoline (97) obtained in Example 14 2 g
(5.8 mmol) and 80 mg of sodium ethoxide were added to 60 ml of ethanol, and the mixture was heated under reflux for one day. After allowing to cool to room temperature, the precipitated crystals were collected by filtration and the filtrate was concentrated. The crystals are filtered off,
It was washed with ethanol and ether. 1.8 g of the title compound was obtained (yield 90%). Colorless needle crystal Melting point 243-248 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.0Hz, 3H), 2.04 (s, 3H), 4.25 (q, J = 7.1Hz , 2
H), 4.82 (brs, 2H), 8.09 (dd, J = 8.8Hz, 10.3Hz, 1H), 8.42
(s, 1H)

Example 16 Ethyl 3,4-difluoro-1,2-dihydro-1-
Acetyl-6-oxo-1H, 6H-pyrido [3,2,2]
1-hi] indazole-7-carboxylate (99) 0.85 g (2.5 mmol) of the compound (98) obtained in Example 15 (98)
, 0.98 g (3.75 mmol) of triphenylphosphine was added to 20 ml of tetrahydrofuran, and a solution of 0.65 g (3.75 mmol) of diethylazodicarboxylate in 30 ml of tetrahydrofuran was added dropwise at room temperature over 3 hours. The mixture was stirred as it was overnight, and the solvent was distilled off. The crystals were dispersed in ether and collected by filtration. It was washed with ethanol and ether in this order to obtain 0.51 g of the title compound (99) (yield 63%). Colorless needle crystal Melting point 235-237 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.27 (t, J = 6.6Hz, 3H), 2.31 (s, 3H), 4.23 (q, J = 7.3Hz , 2
H), 5.67 (s, 2H), 7.84 (dd, J = 7.3Hz, 10.3Hz, 1H), 9.49 (s,
1H)

Example 17 3,4-Difluoro-1,2-dihydro-6-oxo-
1H, 6H-pyrido [3,2,1-hi] indazole-
7-Carboxylic acid (100) 0.51 g (1.55 mmol) of the compound (99) of Example 16 was added to 5 ml of a mixture of concentrated hydrochloric acid and acetic acid (volume ratio 1: 4), and the mixture was heated under reflux for 8 hours. After cooling, the mixture was diluted with 100 ml of water, and the precipitated crystals were collected by filtration. It was washed with water, ethanol, and ether in this order.
200 mg of the title compound (100) was obtained (yield 51%). Colorless needle crystal Melting point 232-237 ℃ (decomp.) ¹ H-NMR (DMSO-d ₆ ) 4.99 (s, 2H), 8.02 (dd, J = 7.0Hz, 3.3Hz, 1H), 8.96 (s, 1H )

Example 18 4,5-Difluoro-2,3-dihydro-1-methyl-
7-oxo-1H, 7H-pyrido [3,2,1-ij]
Cinnoline-8-carboxylic acid BF ₂ chelate (107) 2.78 g of the compound (8) obtained in Example 3 (2) was suspended in 30 ml of ether, and 5 ml of boron trifluoride-ether complex 80 ml was added under ice cooling. I added it over a minute. The mixture was stirred as it was overnight, and the precipitated solid was collected by filtration. 3.07 g of the title compound (10
7) was obtained (94% yield). Colorless powder Melting point 285 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 3.01 (s, 1H), 3.25, 3.64 (each brs, each 2H), 8.49 (dd,
J = 9.0Hz, 9.0Hz, 1H), 9.38 (s, 1H)

Example 19 (Method F) (1) 4-((3R) -methylpiperazin-1-yl)
-5-Fluoro-2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (108) Compound (107) 164 mg (0.5 mmol), (2R) -methylpiperazine dihydrochloride 173 mg (1 mmol) and Triethylamine
Add 0.36 ml (2.5 mmol) to 2 ml of dimethyl sulfoxide,
Stir overnight at room temperature. Add ether, remove the supernatant,
Ethanol and ether were added to the residue, and the crystals were collected by filtration,
Washed with ether. 20 ml of 80% methanol aqueous solution to the crystal,
1 ml of triethylamine was added and the mixture was heated under reflux for 3 hours. After allowing to cool, it was concentrated under reduced pressure, ethanol was added to the residue, and the crystals were collected by filtration and washed with ether to give 105 mg of the title compound (108).
Was obtained (yield 58%). Light yellow powder Melting point> 210 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.27 (d, J = 6.4Hz, 3H), 2.91 (s, 3H), 3.09-3.28 (m, 4H), 3 .
29-3.57 (m, 7H), 7.95 (d, J = 12.7Hz, 1H), 8.77 (s, 1H) (2) to (11) According to Example 19 (1), the following Table 2
2-Compound (109) -Compound (118) shown in Table 23
Got

[0142]

[Table 22]

[0143]

[Table 23]

Example 20 5-Fluoro-4- (pyrrolidin-1-yl) -2,3
-Dihydro-1-formyl-7-oxo-1H, 7H-
Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (119) 315 mg of the compound (102) obtained in Example 4 (21) was added to 1.17 g of formic acid and heated at 100 ° C for 4 hours. After cooling, 10 ml of ether was added and the mixture was stirred for 5 minutes. The resulting solid was collected by filtration and washed with ether. 250 mg of the title compound (1
19) was obtained. Light brown needles Melting point 238-243 ° C ¹ H-NMR (DMSO-d ₆ ) 1.91 (brs, 4H), 2.83-3.15 (m, 2H), 3.49 (s, 4H), 3.65-3.
85 (m, 1H), 7.83 (d, J = 13.9Hz, 1H), 8.57 (s, 1H), 8.65 (s, 1
H)

Example 21 1-Acetyl-5-fluoro-4- (pyrrolidine-1-
Yl) -2,3-dihydro-7-oxo-1H, 7H-
Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (120) 100 mg of the compound (102) obtained in Example 4 (21) was dissolved in 1 ml of acetic acid and 1 ml of acetic anhydride, and the mixture was stirred at 110 ° C for 3 hours. Heated. After cooling, the resulting solid was collected by filtration and washed with ether. 80 mg of the title compound (120) was obtained. Light brown powder Melting point 278-283 ° C ¹ H-NMR (DMSO-d ₆ ) 1.90 (brs, 4H), 2.38 (s, 3H), 2.80-3.90 (m, 8H), 7.80 (d, J
= 14.0Hz, 1H), 8.57 (s, 1H)

Example 22 Methyl 4- (cis (-)-3-amino-4-methylpyrrolidin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7-oxo 1H, 7H- Pyrido [3,2,1, -ij] cinnoline-8-carboxylate (121) 2 ml of thionyl chloride was added to 20 ml of methanol under ice cooling,
The compound (3 obtained in Example 5 (1) (3) was stirred at room temperature.
0) 358 mg was added, and the mixture was heated under reflux for 8 hours. The solvent was evaporated, 40 ml of chloroform and 20 ml of water were added, the mixture was made alkaline with sodium hydrogen carbonate, and the organic layer was separated. It was dried over magnesium sulfate and evaporated. Crystallization was achieved by adding ether followed by ethyl acetate. The crystals are filtered off,
It was washed with ethyl acetate and ether in this order to obtain 270 mg of the title compound (121) (yield 72%). Colorless needles melting point 199-202 (decomp.) ¹ H-NMR (CDCl ₃ ) 1.13 (d, J = 6.9Hz, 3H), 1.74 (brs, 2H), 2.36-2.48 (m, 1H),
2.82-3.06 (m, 2H), 2.87 (s, 3H), 3.20-3.57 (m, 6H), 3.80-
3.97 (m, 1H), 3.91 (s, 3H), 7.96 (d, J = 13.9Hz, 1H), 8.56
(s, 1H)

Example 23 Methyl 4- (pyrrolidin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7-oxo 1H, 7
H-pyrido [3,2,1, -ij] cinnoline-8-carboxylate (122) 2.92 g of the compound (6) obtained in Example 2 (1), 1.07 g of pyrrolidine and 1,8-diazabicyclo [5]. .4.0]
2.25 g of -7-undecene was added to 20 ml of N, N-dimethylformamide and heated at 80 ° C for 12 hours. The solvent was distilled off, and 100 ml of chloroform was added. It was washed with water and the organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off.
50 ml of isopropyl ether was added to the residue, and the solid was collected by filtration. 2.60 g of the title compound (122) was obtained. Light yellow powder Melting point 203-206 ° C ¹ H-NMR (CDCl ₃ ) 1.99 (s, 4H), 2.87 (s, 3H), 2.95 (brs, 2H), 3.30-3.55 (m,
6H), 3.92 (s, 3H), 7.99 (d, J = 14.0Hz, 1H), 8.57 (s, 1H)

Reference Example 5 4-t-butylamino-3-fluoro-2- (2-hydroxyethyl) nitrobenzene (123) 3,4-difluoro-2- (2-hydroxyethyl) nitrobenzene 30.5 g (150 mmol), t-butylamine 90 ml
(900 mmol) of dimethyl sulfoxide 150 ml, toluene 25
The mixture was added to ml and heated under reflux for 8 hours and a half. After cooling down, 1500 ml of water
And the precipitated crystals were collected by filtration. After dissolving in 500 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. n-
Crystallized with hexane and collected by filtration. 35.6 g of the title compound (123) was obtained (yield 93%).

Reference Example 6 4-Amino-3-fluoro-2- (2-hydroxyethyl) nitrobenzene (124) 11 g of the compound (123) was added to 200 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2.5 hours. After cooling, the mixture was extracted 4 times with 500 ml of ethyl acetate and washed with 100 ml of 10% sodium hydrogen carbonate. After drying over magnesium sulfate, the solvent was distilled off. Crystallized with n-hexane and collected by filtration. 8.33 g of the title compound (124) was obtained (yield 97%).

Reference Example 7 4-chloro-3-fluoro-2- (2-hydroxyethyl) nitrobenzene (125) 7.33 g (37 mmol) of the compound (124) was dissolved in 60 ml of 6N-hydrochloric acid and cooled under ice-cooling. 2.95 g (43 mmol) of sodium nitrate 15
A ml aqueous solution was added dropwise over 5 minutes. The mixture was stirred as it was for 30 minutes. 20 ml of concentrated hydrochloric acid and 20 ml of acetic acid were added. Stir for 1 hour.
Cuprous chloride 6.20 g (63 mmol) in concentrated hydrochloric acid 35 ml solution under ice cooling,
It dripped over 40 minutes. The mixture was stirred as it was for 3 hours. The mixture was extracted with 300 ml of ethyl acetate, dried over magnesium sulfate, and the solvent was distilled off. Column chromatography (silica gel
100 g, elution solvent; chloroform: methanol = 50:
Separation in 1) gave 6.69 g of the title compound (125) (83% yield).

Reference Example 8 4-chloro-3-fluoro-2- (2-hydroxyethyl) aniline (126) 4.8 g of iron powder and 0.45 ml of concentrated hydrochloric acid were added to a mixed solvent of 50 ml of water and 10 ml of ethanol to give a mixture of 80-90. Heat to ℃, 4-chloro-3-fluoro-2- (2-hydroxyethyl) nitrobenzene
6.69 g (31 mmol) was added over 10 minutes. It was heated as it was for 1 hour. After cooling, 100 ml of ethyl acetate was added, and the insoluble matter was filtered. The organic layer was separated, washed with 10% aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and the solvent was evaporated. 4.68 g of the title compound (126) was obtained (yield 80
%).

Reference Example 9 Diethyl {4-chloro-3-fluoro-2- (2-hydroxyethyl) anilino} methylene malonate (12
7) To 5.68 g (25 mmol) of compound (126) was added 5.36 g (25 mmol) of diethyl ethoxymethylene malonate, and the mixture was heated at 120 ° C.
Heated for 2 hours. Ethanol was distilled off, the crystals were dispersed in n-hexane and collected by filtration. 8.55 g of the title compound (12
7) was obtained (yield 95%).

Reference Example 10 Diethyl {4-chloro-3-fluoro-2- (2-t
-Butyldimethylsilyloxyethyl) anilino} methylene malonate (128) Compound (127) 8.55 g (24 mmol) and imidazole 1.70
g (25 mol) was added to 50 ml of methylene chloride, and a solution of 3.77 g (25 mmol) of t-butyldimethylchlorosilane in 10 ml of methylene chloride was added dropwise over 10 minutes. After stirring at room temperature for 1 hour, 0.30 g of imidazole and t-butyldimethylchlorosilane.
67 g was added and the mixture was stirred for 1 hour. After washing with 50 ml of water and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 200 g, elution solvent; chloroform) gave 9.35 g of the title compound (128) as an oil (yield 82%).

Reference Example 11 Ethyl 6-chloro-7-fluoro-8- (2-t-butyldimethylsilyloxyethyl) -4-hydroxyquinoline-3-carboxylate (129) Compound (128) 8.35 g (17.1 mmol) ) To Dowtherm A 80ml
Was added, and the mixture was heated until a distillate of 200 ° C. came out, and further heated and refluxed for 5 minutes. After cooling, 50 ml of ether was added, and the precipitated crystals were collected by filtration. 5.62 g of the title compound (129) was obtained (yield 74%).

Reference Example 12 Ethyl 6-chloro-7-fluoro-8- (2-hydroxyethyl) -4-hydroxyquinoline-3-carboxylate (130) 5.62 g (13 mmol) of compound (129) was added to 100 ml of chloroform.
, 100 ml of methanol and 4N hydrochloric acid-
15 ml of dioxane was added. After stirring for 30 minutes at room temperature, the solvent was distilled off. The crystals were dispersed in ethanol and collected by filtration.
It was washed with ethanol and ether in this order to obtain 3.70 g of the title compound (130) (yield 90%).

Reference Example 13 Ethyl 1-amino-6-chloro-7-fluoro-8-
(2-Hydroxyethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate (131) Compound (130) 4 g (12.8 mmol) and anhydrous potassium carbonate 3.
53 g (25.6 mmol) was added to 70 ml of dimethylformamide, and the mixture was stirred at room temperature for 2 hours. 7.29 g (25.6 mmol) of ethyl O- (mesitylenesulfonyl) acetohydroxamate was added to 10 ml of dioxane, and 10 ml of 2.6 ml of 70% perchloric acid was added under ice cooling.
It was added dropwise at 15 ° C or lower over 15 minutes. The mixture was stirred as it was for 20 minutes. It was poured into 50 ml of ice water and the crystals were collected by filtration. Wash with ice water,
It was dissolved in 50 ml of methylene chloride, the organic layer was separated, dried over magnesium sulfate, and then added dropwise to the reaction solution of dimethylformamide over 5 minutes under ice cooling. The mixture was stirred as it was for 1 hour. 100 ml of water was added and the crystals were collected by filtration. Wash with water, ethanol, and ether in this order to obtain 2.08 g of the title compound (13
1) was obtained (yield 50%).

Example 24 Ethyl 5-chloro-4-fluoro-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2,1-i
j] Cinnoline-8-carboxylate (132) 2.08 g (6.3 mmol) of the compound (131) obtained in Reference Example 13
And 2.62 g (10 mmol) of triphenylphosphine were added to 50 ml of tetrahydrofuran, and a solution of 1.74 g (10 mmol) of diethyl azodicarboxylate in 50 ml of tetrahydrofuran was added dropwise at room temperature over 2 hours. After 20 minutes, the solvent was distilled off. The solid was dispersed in ethanol and collected by filtration. Wash with ethanol and ether in this order to obtain 1.69 g of the title compound (13
2) was obtained (yield 86%). Colorless powder Melting point 235 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.0Hz, 3H), 2.93 (brs, 2H), 3.41 (dt, J = 6.2Hz,
5.9Hz, 2H), 4.21 (q, J = 7.0Hz, 2H), 6.85 (t, J = 6.9Hz, 1H),
8.09 (d, J = 8.1Hz, 1H), 8.42 (s, 1H)

Example 25 Methyl 5-chloro-4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.
2,1-ij] Cinnoline-8-carboxylate (1
33) 1.69 g (5.5 mmol) of the compound (132) obtained in Example 24
Dimethylsulfate (10 ml, 109 mmol) was added to and heated at 120 ° C. for 4 hours and a half. After cooling down, anhydrous potassium carbonate 15 g (109 mmol)
Was added to 90 ml of ice water and the mixture was stirred for 1 hour. It was extracted with 200 ml of chloroform, dried over magnesium sulfate, and the solvent was distilled off. Column chromatography (silica gel 60 g
, Elution solvent; chloroform: methanol = 100:
Separation in 1) gave 600 mg of the title compound (132) (yield 36%). Light yellow powder, melting point 199 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 2.86 (s, 3H), 3.07 (t, J = 5.8Hz, 2H), 3.49 (t, J = 5.9Hz, 2
H), 3.92 (s, 3H), 8.42 (d, J = 8.0Hz, 1H), 8.60 (s, 1H)

Example 26 5-Chloro-4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-
ij] Cinnoline-8-carboxylic acid (134) 600 mg (1.9 mmol) of the compound (133) obtained in Example 25
To this, 5 ml of concentrated hydrochloric acid and 20 ml of acetic acid were added, and the mixture was heated under reflux for 2 hours. After cooling, 20 ml of water was added and the solid was collected by filtration. Wash with water, ethanol, and ether in this order to obtain 461 mg of the title compound (1
34) was obtained (yield 80%). Light yellow powder, melting point 223-225 ° C ¹ H-NMR (DMSO-d ₆ ) 2.88 (s, 3H), 3.11 (brs, 2H), 3.53 (t, J = 5.5Hz, 2H), 8.33
(d, J = 7.3Hz, 1H), 8.83 (s, 1H)

Example 27 5-chloro-4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-
ij] Cinnoline-8-carboxylic acid BF ₂ chelate (13
5) 300 mg (1 mmol) of the compound 134 obtained in Example 26 was added to 6 ml of ether, and 9 ml of boron trifluoride-ether complex was added.
Was added, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration.
Washing with ether gave 218 mg of the title compound (135) (yield 63%). Colorless powder, melting point 275 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 3.01 (s, 3H), 3.23 (t, J = 4.9Hz, 2H), 3.63 (t, J = 6.3Hz, 2
H), 8.65 (d, J = 7.8Hz, 1H), 9.41 (s, 1H)

Example 28 5-Chloro-4- (1-pyrrolidinyl) -2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8- Carboxylic acid (1
36) 100 mg (0.29 mmo) of the compound (135) obtained in Example 27
l) was added to 0.5 ml of dimethyl sulfoxide, and pyrrolidine 5 was added.
5 mg (0.64 mmol) was added, and the mixture was stirred at room temperature for one day. 1 ml of ether and 2 ml of ethanol were added to crystallize, and the crystals were collected by filtration and washed with ethanol and ether in this order to obtain 80 mg of crystals. The crystals obtained were mixed with 5% of 80% methanol and triethylamine.
0.5 ml was added and the mixture was heated under reflux for 4 hours. The solvent was distilled off.
The crystals were dispersed in ethanol and collected by filtration. It was washed with ethanol and ether in this order to obtain 55 mg of the title compound (136) (yield 52%). Light yellow prism, melting point 244 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.00 (brs, 4H), 2.90 (s, 3H), 3.01 (brs, 2H), 3.41 (brs, 4
H), 3.47 (brs, 2H), 8.20 (s, 1H), 8.75 (s, 1H)

Reference Example 14 2-Chloro-6-nitrophenylacetic acid (137) 8.08 g (202 mmol) of 60% sodium hydride was added to 30 ml of tetrahydrofuran, and 32.0 g of diethyl malonate under cooling with a freezing agent.
A solution of (200 mmol) in 60 ml of tetrahydrofuran was added dropwise at 20 ° C or lower over 1 hour. After stirring for 1 hour, a solution of 2,3-dichloronitrobenzene (19.2 g, 100 mmol) in tetrahydrofuran (60 ml) was added dropwise at 10 ° C or lower over 10 minutes. After stirring for 3 hours and a half at room temperature, the mixture was heated under reflux for 48 hours. 18 ml of acetic acid was added and the solvent was distilled off. After extracting with 200 ml of chloroform and drying over magnesium sulfate,
The solvent was distilled off. 30 ml of 4N hydrochloric acid and 25 ml of acetic acid were added, and the mixture was heated under reflux for one day. After cooling, the precipitated crystals were collected by filtration and washed with water.
The crystals were dissolved in 250 ml of ethyl acetate. The filtrate was extracted with 250 ml of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and then the solvent was distilled off. The crystals were washed with n-hexane to obtain 6.78 g of the title compound (137) (yield 31
%).

Reference Example 15 3-Chloro-2- (2-hydroxyethyl) nitrobenzene (138) 2.26 g (59.8 mmol) of sodium borohydride was added to 7 ml of tetrahydrofuran and, under ice cooling, 6.78 g of compound (137).
A solution of (31.5 mmol) in 15 ml of tetrahydrofuran was added dropwise over 20 minutes. Subsequently, a solution of 10 ml of boron trifluoride-ether complex in 15 ml of tetrahydrofuran was added dropwise over 10 minutes. The mixture was stirred as it was for 30 minutes and then at room temperature for 1 hour. The reaction solution was slowly added to 130 ml of water containing 9.6 g of sodium hydrogen carbonate and 170 ml of methylene chloride, and the mixture was stirred overnight at room temperature. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The residue was crystallized by adding n-hexane and collected by filtration. It was washed with n-hexane to obtain 5.43 g of the title compound (138) (yield 86%).

Reference Example 16 3-Chloro-2- (2-hydroxyethyl) aniline (139) 4.5 g of iron powder and 0.45 ml of concentrated hydrochloric acid were added to a mixed solvent of 50 ml of water and 10 ml of ethanol and heated to 80 to 90 ° C. , Compound (138) 5.
43g was added over 10 minutes. It was heated for 30 minutes as it was. After cooling, 100 ml of ethyl acetate was added, and the insoluble matter was filtered. The organic layer was separated, washed with 10% aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and the solvent was evaporated. The crystals were washed with n-hexane to give 4.40 g of the title compound (13
9) was obtained (yield 95%).

Reference Example 17 Diethyl {3-chloro-2- (2-hydroxyethyl) anilino} methylenemalonate (140) Compound (139) 4.40 g (25.6 mmol), diethyl ethoxymethylene malonate 5.55 g (256 mmol) And add 120 ℃
Heated for 4 hours. After cooling, the crystals were dispersed in n-hexane and collected by filtration. 8.52 g of the title compound (140) was obtained (yield 97%).

Reference Example 18 Diethyl {3-chloro-2- (2-t-butyldimethylsilyloxyethyl) anilino} methylenemalonate (141) Compound (140) 8.52 g (25 mmol) and imidazole 1.77
g (26 mmol) was added to 50 ml of methylene chloride, and a solution of 3.92 g (26 mmol) of t-butyldimethylchlorosilane in 10 ml of methylene chloride was added dropwise over 10 minutes. Stir at room temperature for 1 hour, then imidazole 0.30g, t-butyldimethylchlorosilane 0.67g
Was added and stirred for 1 hour. After washing with 50 ml of water and drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 200g, elution solvent: chloroform)
The title compound (141) was obtained as an oily substance (11.5 g).

Reference Example 19 Ethyl 7-chloro-8- (2-hydroxyethyl)-
4-hydroxyquinoline-3-carboxylate (14
2) To 11 g (24 mmol) of the compound (141) was added 80 ml of Dowtherm A, and the mixture was heated until a distillate of 200 ° C. appeared, and further heated and refluxed for 20 minutes. After cooling, 10 ml of concentrated hydrochloric acid was added. After stirring for 30 minutes at room temperature, the precipitated crystals were collected by filtration. It was washed with ethanol and ether in this order to obtain 4.96 g of the title compound (142) (yield 70%).

Reference Example 20 Ethyl 1-amino-7-chloro-8- (2-hydroxyethyl) -1,4-dihydro-4-oxoquinoline-
3-carboxylate (143) 4.96 g (16.8 mmol) of compound (142) and 4.65 g of anhydrous potassium carbonate were added to 90 ml of N, N-dimethylformamide,
The mixture was stirred at room temperature for 2 hours. Ethyl O- (mesitylene sulfonyl) acetohydroxamate 9.60 g in dioxane 13
In addition to ml, 70% perchloric acid (3.4 ml) was added dropwise at 10 ° C or lower over 15 minutes under ice cooling. The mixture was stirred as it was for 20 minutes, poured into 50 ml of ice water, and the crystals were collected by filtration. It was washed with ice water, dissolved in 50 ml of methylene chloride, the organic layer was separated, dried over magnesium sulfate, and then added dropwise to the reaction solution of dimethylformamide over 5 minutes under ice cooling. Stir as it is for 1 hour, then add water 10
0 ml was added and the crystals were collected by filtration. Washing with water, ethanol, and ether in this order gave 0.69 g of the title compound (143) (yield 13%).

Example 29 Ethyl 4-chloro-2,3-dihydro-7-oxo-
1H, 7H-pyrido [3,2,1-ij] cinnoline-
8-Carboxylate (144) 1.02 g (3.3 mmol) of the compound (143) obtained in Reference Example 20
And 1.37 g (5.2 mmol) of triphenylphosphine were added to 25 ml of tetrahydrofuran, and a solution of 0.91 g (5.2 mmol) of diethyl azodicarboxylate in 25 ml of tetrahydrofuran was added dropwise at room temperature over 1 hour. After 20 minutes, the solvent was distilled off. The solid was dispersed in ethanol and collected by filtration. Wash with ethanol and ether in this order to give 0.81 g of the title compound (14
4) was obtained (yield 84%). Colorless powder, melting point 210.5-213 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.27 (t, J = 7.3Hz, 3H), 2.93 (t, J = 5.9Hz, 2H), 3.44 (dt , J =
2.9Hz, 6.2Hz, 2H), 4.21 (q, J = 7.0Hz, 2H), 6.84 (t, J = 7.3H
z, 1H), 7.55 (d, J = 8.8Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 8.44
(s, 1H)

Example 30 Methyl 4-chloro-2,3-dihydro-1-methyl-
7-oxo-1H, 7H-pyrido [3,2,1-ij]
Cinnoline-8-carboxylate (145) 810 mg (2.8 mmol) of the compound (144) obtained in Example 29
5 ml (55 mmol) of dimethylsulfate was added to and heated at 120 ° C. for 5 hours and a half. After allowing to cool, it was added to 45 ml of ice water to which 7.5 g (55 mmol) of anhydrous potassium carbonate was added and stirred for 1 hour. Chloroform
After extraction with 50 ml and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 8 g, elution solvent; chloroform: methanol = 100: 1) gave 371 mg of the title compound (145) (yield 46
%). Colorless powder Melting point 225 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 2.85 (s, 3H), 3.09 (t, J = 6.2Hz, 2H), 3.51 (t, J = 5.9Hz, 2
H), 3.93 (s, 3H), 7.45, 8.33 (each d, each J = 8.8Hz, each
1H), 8.62 (s, 1H)

Example 31 4-Chloro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (146) Example 30 370 mg (1.3 mmol) of the compound (145) obtained in
To this, 2 ml of concentrated hydrochloric acid and 10 ml of acetic acid were added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off. The crystals were dispersed in ethanol and collected by filtration. It was washed with ethanol and ether in this order to obtain 270 mg of the title compound (146) (yield 77%). Colorless prism Melting point> 240 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.88 (s, 3H), 3.10, 3.57 (each brs, each 2H), 7.77, 8.2
5 (each d, each J = 8.4Hz, each 1H), 8.81 (s, 1H)

Example 32 4-Chloro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid BF ₂ chelate (147) 240 mg (0.86 mmo) of the compound (146) obtained in Example 31
l) was added to 6 ml of ether, 9 ml of boron trifluoride-ether complex was added, and the mixture was stirred overnight at room temperature. The precipitated crystals were collected by filtration. The crystals were washed with ether to give 266 mg of the title compound (147) (yield 94%). Colorless powder Melting point> 285 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 3.02 (s, 3H), 3.23, 3.67 (each brs, each 2H), 8.06, 8.4
6 (each d, each J = 9.4Hz, each 1H), 9.37 (s, 1H)

Reference Example 21 3,4-Difluoro-2- (2-oxopropyl) nitrobenzene (148) 60% sodium hydride 12.1 g (303 mmol) was added to tetrahydrofuran 45 ml, and under ice cooling, ethyl acetoacetate 39.0 g.
A solution of (300 mmol) in 90 ml of tetrahydrofuran was added dropwise at 20 ° C or lower over 30 minutes. After stirring for 1 hour as it is, 2,3,4-trifluoronitrobenzene 26.6 g (15
A solution of 0 mmol) in 90 ml of tetrahydrofuran was added dropwise at 10 ° C or lower over 30 minutes. Stir overnight at room temperature. Acetic acid
27 ml was added and the solvent was distilled off. The mixture was extracted with 500 ml of chloroform, dried over magnesium sulfate, and the solvent was distilled off. Four
30 ml of normal hydrochloric acid and 25 ml of acetic acid were added, and the mixture was heated under reflux for one day. Concentrated hydrochloric acid (550 ml) and acetic acid (550 ml) were added, and the mixture was heated under reflux for 16 hours. After allowing to cool, extract with 1 liter of chloroform and add 2 with 500 ml of water.
I washed it twice. Further, it was washed twice with 300 ml of saturated sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off. Separation by column chromatography (silica gel 300 g, elution solvent; chloroform: n-hexane = 1: 3) gave 31.2 g.
The title compound (148) of was obtained (yield 90%).

Reference Example 22 3,4-difluoro-2- (2-hydroxypropyl)
Nitrobenzene (149) 31.2 g (145 mmol) of the compound (148) was added to 500 ml of methanol, and 6.04 g (160 mmol) of sodium borohydride was added over 5 minutes under ice cooling. After stirring for 30 minutes as it was, the mixture was stirred overnight at room temperature. Slowly add 100 ml of 4N hydrochloric acid,
The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off. Chloroform
It was extracted with 400 ml, dried over magnesium sulfate, and the solvent was distilled off. 27.7 g of the title compound (149) was obtained (yield 8
9%).

Reference Example 23 3,4-difluoro-2- (2-hydroxypropyl)
Aniline (150) Iron powder 23 g, concentrated hydrochloric acid 2.3 ml was added to a mixed solvent of water 250 ml and ethanol 50 ml, and the mixture was heated to 80 to 90 ° C to give compound (149).
27.7 g (128 mmol) was added over 30 minutes. 40 as it is
Heated for minutes. After allowing to cool, 200 ml of ethyl acetate was added, and the insoluble material was filtered. Separate the organic layer and add ethyl acetate from the aqueous layer.
The mixture was extracted with 200 ml, the organic layers were combined, dried over magnesium sulfate, and the solvent was evaporated. 21.1 g of the title compound (15
0) was obtained (yield 89%).

Reference Example 24 Diethyl {3,4-difluoro-2- (2-hydroxypropyl) anilino} methylenemalonate (151) 21.1 g (113 mmol) of compound (150) and 24.4 g (113 mmol of diethyl ethoxymethylenemalonate) ) Is added and 120 ° C
Heated for 3 hours. After cooling, the crystals were dispersed in n-hexane and collected by filtration. 25.0 g of the title compound (151) was obtained (yield 62%).

Reference Example 25 Diethyl {3,4-difluoro-2- (2-t-butyldimethylsilyloxypropyl) anilino} methylenemalonate (152) 14.2 g (40 mmol) of compound (151) and imidazole 3.2.
Add 7 g (48 mmol) to 100 ml of methylene chloride and add 7.23 g (48 mmol) of t-butyldimethylchlorosilane to 20 ml of methylene chloride.
The solution was added dropwise over 30 minutes. After stirring for 2.5 hours at room temperature,
The mixture was heated under reflux for 2 hours. Imidazole (3.27 g) and t-butyldimethylchlorosilane (7.23 g) were added, and the mixture was heated under reflux for 11 hours. The extract was washed with 100 ml of water, 50 ml of 5% citric acid and 50 ml of saturated sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off. Column chromatography (silica gel 600 g, elution solvent; chloroform: n-hexane =
1: 1) and 14.2 g of the oily title compound (15
2) was obtained (yield 76%).

Reference Example 26 Ethyl 6,7-difluoro-8- (2-hydroxypropyl) -4-hydroxyquinoline-3-carboxylate (153) Compound (152) 14.2 g (30 mmol) and Dowtherm A 130 ml.
Was added, and the mixture was heated until a distillate of 200 ° C. came out, and further heated and refluxed for 20 minutes. 15 ml of concentrated hydrochloric acid was added. After stirring for 1 hour and a half at room temperature, the precipitated crystals were collected by filtration. It was washed with ethanol and ether in this order to obtain 5.32 g of the title compound (153) (yield 57%).

Reference Example 27 Ethyl 1-amino-6,7-difluoro-8- (2-
Hydroxypropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate (154) Compound (153) 2.40 g (7.7 mmol) and anhydrous potassium carbonate
2.13 g (15.4 mmol) was added to 50 ml of dimethylformamide,
Stir at room temperature for 4 hours. 6.58 g (23.1 mmol) of ethyl O- (mesitylenesulfonyl) acetohydroxamate was added to 10 ml of dioxane, and 1% of 2.5 ml of 70% perchloric acid was added under ice cooling.
The solution was added dropwise at 0 ° C or lower over 15 minutes. The mixture was stirred as it was for 20 minutes, poured into 50 ml of ice water, and the crystals were collected by filtration. Wash with ice water,
It was dissolved in 50 ml of methylene chloride, the organic layer was separated, dried over magnesium sulfate, and then added dropwise to the reaction solution of dimethylformamide over 5 minutes under ice cooling. The mixture was stirred as it was for 1 hour, 100 ml of water was added, and the crystals were collected by filtration. Wash with water, ethanol, and ether in this order to obtain 1.00 g of the title compound (15
4) was obtained (yield 40%).

Example 33 Ethyl 4,5-difluoro-2-methyl-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2,1]
-Ij] Cinnoline-8-carboxylate (155) 2.35 g (7.2 mmol) of the compound (154) obtained in Reference Example 27
And 3.98 g (11.3 mmol) of triphenylphosphine were added to 50 ml of tetrahydrofuran, and a solution of 1.97 g (11.3 mmol) of diethyl azodicarboxylate in 50 ml of tetrahydrofuran was added dropwise at room temperature over 2 hours. After 20 minutes, the solvent was distilled off. The solid was dispersed in ethanol and collected by filtration. Wash with ethanol and ether in this order to obtain 1.45 g of the title compound (15
5) was obtained (yield 65%). Colorless powder, melting point 226-230 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.25 (t, J = 5.9Hz, 3H), 1.29 (d, J = 7.0Hz, 3H), 2.61 (dd, J =
8.4Hz, 17.0Hz, 1H), 3.12 (d, J = 16.8Hz, 1H), 3.37-3.51 (m,
1H), 4.20 (q, J = 7.0Hz, 2H), 6.77 (d, J = 9.9Hz, 1H), 7.90 (d
d, J = 10.2Hz, 10.2Hz, 1H), 8.44 (s, 1H)

Example 34 Methyl 4,5-difluoro-2,3-dihydro-1,
2-Dimethyl-7-oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylate (1
56) 1.45 g (4.7 mmol) of the compound (155) obtained in Example 33
Dimethylsulfate (10 ml, 109 mmol) was added to and heated at 120 ° C. for 3 hours and a half. After cooling down, anhydrous potassium carbonate 15 g (109 mmol)
Was added to 90 ml of ice water and the mixture was stirred overnight. Chloroform
After extraction with 50 ml and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 8 g, elution solvent; chloroform: methanol = 100: 1) gave 830 mg of the title compound (156) (yield 57
%). Colorless powder Melting point 184-185 ° C ¹ H-NMR (CDCl ₃ ) 1.27 (d, J = 6.9Hz, 3H), 2.77 (s, 3H), 2.82 (dd, J = 5.5Hz, 1
8.3Hz, 1H), 3.16 (dd, J = 5.1Hz, 17.6Hz, 1H), 3.93 (s, 3H),
3.54-3.66 (m, 1H), 8.15 (dd, J = 9.2Hz, 9.2Hz, 1H), 8.59 (s,
1H)

Example 35 4,5-Difluoro-2,3-dihydro-1,2-dimethyl-7-oxo-1H, 7H-pyrido [3,2,1-
ij] Cinnoline-8-carboxylic acid (157) 830 mg (2.7 mmol) of the compound (156) obtained in Example 34
To this, 4 ml of concentrated hydrochloric acid and 16 ml of acetic acid were added, and the mixture was heated under reflux for 3 hours. 10 ml of water was added, and the precipitated solid was collected by filtration. ethanol,
The crystals were washed successively with ether to give 700 mg of the title compound (157) (yield 88%). Colorless powder, melting point 270-271 ° C ¹ H-NMR (DMSO-d ₆ ) 1.13 (d, J = 7.0Hz, 3H), 2.80 (s, 3H), 2.91 (dd, J = 5.1Hz, 1
8.5Hz, 1H), 3.25 (dd, J = 4.8Hz, 18.1Hz, 1H), 3.71-3.78 (m,
1H), 8.19 (dd, J = 8.4Hz, 8.4Hz, 1H), 8.79 (s, 1H)

Example 36 5-Fluoro-4-{(cis (-)-3-amino-4
-Methylpyrrolidin) -1-yl} -2,3-dihydro-1,2α, β-dimethyl-7-oxo-1H, 7H-
Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (158) 100 mg (0.34 mmo) of compound (157) obtained in Example 35
l), cis (−)-3-amino-4-methylpyrrolidine dihydrochloride 118 mg (0.68 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene 310 mg (2.04 mmol)
Was added to 1 ml of acetonitrile and heated under reflux for 3 hours. The solvent was distilled off, extracted with 40 ml of chloroform, dried over magnesium sulfate, and then the solvent was distilled off. The solid was dispersed in ethanol and ether and collected by filtration. 80 mg of the title compound (15
8) was obtained (yield 64%). Light brown powder Melting point 228-230 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.00-1.21 (m, 6H), 2.80-2.86 (m, 4H), 3.94-4.04 (m, 1H),
7.84 (d, J = 13.5Hz, 1H), 8.64 (s, 1H)

Example 37 5-Fluoro-4-{((3R)-((1'S) -aminoethyl) pyrrolidin) -1-yl} -2,3-dihydro-1,2α, β-dimethyl- 7-oxo-1H, 7H
-Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (159) 100 mg (0.34 mmo) of the compound (157) obtained in Example 35.
l), (3R)-((1 ′S) -aminoethyl) pyrrolidine dihydrochloride 127 mg (0.68 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene 310 mg (2.04 mmol)
Was added to 1 ml of acetonitrile and heated under reflux for 3 hours. The solvent was distilled off, 5 ml of ethanol and 1 ml of concentrated hydrochloric acid were added, and the solvent was distilled off. The precipitated solid was dispersed in ethanol and collected by filtration. 10 mg of the title compound (159) was obtained (yield 8%). Yellow powder Melting point> 210 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.00,1.23 (each d, each J = 8.1Hz, each 1.5H), 1.32 (d, J
= 8.1Hz, 3H), 1.67-1.79 (m, 1H), 2.10 (brs, 1H), 2.39-2.4
8 (m, 1H), 2.79-3.00 (m, 4H), 3.30 (brs, 1H), 3.49-3.80
(m, 6H), 7.85 (d, J = 13.5Hz, 1H), 8.30 (brs, 1H), 8.65 (s, 1
H)

Example 38 5-Fluoro-4- (pyrrolidin-1-yl) -2,3
-Dihydro-1,2-dimethyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (160) 100 mg (0.34 mmo) of compound (157) obtained in Example 35
l) and pyrrolidine 88 mg (1.24 mmol) in acetonitrile 1 ml
In addition, the mixture was heated under reflux for 3 hours. The solvent was distilled off and the residue was extracted with 20 ml of chloroform. After drying over sodium sulfate, the solvent was distilled off. It was solidified with ether and collected by filtration. 70 mg of the title compound (160) was obtained (60% yield). Colorless powder, melting point 224-225 ° C. (decomp.) ¹ H-NMR (CDCl ₃ ) 1.19 (d, J = 7.0Hz, 3H), 2.01 (brs, 4H), 2.68 (dd, J = 5.9Hz,
16.8Hz, 1H), 2.82 (s, 3H), 3.01 (dd, J = 5.1Hz, 17.0Hz, 1H),
3.52 (brs, 5H), 7.97 (d, J = 13.9Hz, 1H), 8.77 (s, 1H)

Example 39 (1) Ethyl 5-fluoro-4- (cyano (ethoxycarbonyl) methyl) -2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1] -I
j] Cinnoline-8-carboxylate (161) 60% Sodium hydride 168 mg (4.2 mmol) was added to N, N-dimethylformamide 20 ml, and cyanoacetic acid ethyl ester 452 mg (4 mmol) was added dropwise under ice cooling, and at room temperature. Stir for 1 hour. Ethyl 4,5-difluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3
2,1-ij] Cinnoline-8-carboxylate 612
mg (2 mmol) was added, the mixture was stirred at room temperature overnight, and heated at 70 ° C. for 2 hours. The solvent was distilled off, 80 ml of chloroform and 20 ml of water were added, and the mixture was acidified with citric acid. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. Separation by column chromatography (silica gel 20 g, elution solvent; ethyl acetate) gave 450 mg of the title compound (161). Colorless prism crystal Melting point 153-154.5 ° C ¹ H-NMR (CDCl ₃ ) 1.33, 1.42 (each t, each J = 7.0Hz, each3H), 2.87 (s, 3
H), 2.91-2.96, 3.27-3.39 (each m, each 1H), 3.55 (brs,
2H), 4.30-4.41 (m, 4H), 5.35 (s, 1H), 8.18 (d, J = 10.3Hz, 1
H), 8.62 (s, 1H) (2) In the same manner as in Example 39 (1), the following compound was obtained. Ethyl 5-fluoro-4- (cyano (t-butoxycarbonyl) methyl) -2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-
ij] Cinnoline-8-carboxylate (162) colorless needle crystal melting point 169-170.5 ° C ¹ H-NMR (CDCl ₃ ) 1.41 (t, J = 7.3Hz, 3H), 1.50 (s, 9H), 2.87 (s, 3H), 2.92-3.
00, 3.29-3.40 (each m, each 1H), 3.55 (brs, 2H), 4.40
(q, J = 6.9Hz, 2H), 5.27 (s, 1H), 8.17 (d, J = 10.3Hz, 1H), 8.
62 (s, 1H)

Example 40 8-Carboxy-5-fluoro-2,3-dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-4-acetic acid (163) 450 mg of compound (161) obtained in Example 39 (1)
To this, 4 ml of hydrochloric acid and 16 ml of acetic acid were added, and the mixture was heated under reflux for 7 hours and a half. The solvent was evaporated, the crystals were collected by filtration, and washed with ethanol and ether in this order. 124 mg of the title compound (163) was obtained. Colorless prism crystal Melting point 215 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.85 (s, 3H), 3.09, 3.56, 3.92 (each brs, each 2H), 7.9
5 (d, J = 9.5Hz, 1H), 8.78 (s, 1H)

Example 41 5-Fluoro-1,4-dimethyl-2,3-dihydro-
7-oxo-1H, 7H-pyrido [3,2,1-ij]
Cinnoline-8-carboxylic acid (164) 100 mg of the compound (163) obtained in Example 40 and 1.4 ml of triethylamine were added to 5 ml of ethanol, and the mixture was heated under reflux for 15 hours and a half. After allowing to cool, the precipitated solid was collected by filtration. Wash with ethanol and ether in this order to obtain 65 mg of the title compound (164).
Got Colorless powder Melting point> 260 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.38, 2.86 (each s, each 3H), 3.07 (t, J = 5.5Hz, 2H), 3.3
1 (t, J = 3.3Hz, 2H), 7.91 (d, J = 9.5Hz, 1H), 8.76 (s, 1H)

Example 42 Ethyl 4-cyanomethyl-5-fluoro-1-methyl-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate ( 165) 1.60 g of the compound (162) obtained in Example 39 (2)
Was added to 20 ml of methylene chloride, and 6 ml of trifluoroacetic acid was added.
Was added and stirred for 1 hour and a half. 4 ml of trifluoroacetic acid was added, and the mixture was stirred overnight. The solvent was distilled off, the residue was crystallized from ethyl acetate-ether and collected by filtration. 410 mg of the title compound (16
5) was obtained. Light brown powder Melting point 208.5-210.5 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 1.42 (t, J = 7.0Hz, 3H), 2.88 (s, 3H), 3.13 (t, J = 5.9 Hz, 2
H), 3.58 (t, J = 5.9Hz, 2H), 3.88 (s, 2H), 4.40 (q, J = 7.0Hz,
2H), 8.11 (d, J = 9.5Hz, 1H), 8.61 (s, 1H) IR (KBr) 2250cm ^-1 (CN)

Example 43 5-Fluoro-4-hydroxy-2,3-dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-8-carboxylic acid (166) 30% of 2.78 g of the compound (8) obtained in Example 3 (1) was obtained.
The mixture was added to 10 ml of an aqueous potassium hydroxide solution and heated under reflux for 6 hours. After cooling, the mixture was acidified with 6N hydrochloric acid, and the precipitated solid was collected by filtration. It was washed with water, ethanol and isopropyl ether in this order to obtain 2.60 g of the title compound (166). Colorless powder Melting point> 290 ° C ¹ H-NMR (DMSO-d ₆ ) 2.84 (s, 3H), 2.94 (brs, 2H), 3.49 (brs, 2H), 7.90 (d, J = 1
1.0Hz, 1H), 8.70 (s, 1H)

Example 44 Methyl 5-fluoro-4-hydroxy-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate ( 167) Thionyl chloride (9 ml) was added to methanol (100 ml) under ice cooling. The mixture was stirred at the same temperature for 30 minutes. 2.60 g of the compound (166) obtained in Example 43 was added, and the mixture was heated under reflux for one day. After cooling, the insoluble material was filtered off. The filtrate was evaporated, chloroform was added to the residue, and the resulting solid was collected by filtration. 2.20 g of the title compound (167) was obtained. Light yellow powder Melting point> 290 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.78 (s, 3H), 2.90, 3.43 (each brs, each 2H), 3.74 (s, 3
H), 7.74 (d, J = 11.4Hz, 1H), 8.46 (s, 1H)

Example 45 Methyl 5-fluoro-4-methanesulfonyloxy-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (168) 304 mg of the compound (167) obtained in Example 44 was added to 2 ml of pyridine, and 120 mg of methanesulfonic acid chloride was added. Stir at room temperature for 3 hours. Add 50 ml of chloroform,
It was washed with 5% citric acid. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. Ethanol was added to the residue and the solid was collected by filtration. Wash with isopropyl ether, 26
0 mg of the title compound (168) was obtained. Colorless powder Melting point 247-250 ° C ¹ H-NMR (DMSO-d ₆ ) 2.82 (s, 3H), 3.11, 3.48 (each brs, each 2H), 3.70, 3.7
6 (each s, each 3H), 7.95 (d, J = 10.3Hz, 1H), 8.57 (s, 1
H)

Example 46 Methyl 5-fluoro-4- (4-methylphenylsulfonyloxy) -2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (169) 304 mg of the compound (167) obtained in Example 44 was added to 2 ml of pyridine, and 260 mg of p-toluenesulfonic acid chloride was added.
Was added. The mixture was stirred at room temperature for 2 hours. Chloroform (50 ml) was added, and the mixture was washed with water and 5% citric acid. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. Ethanol was added to the residue and the solid was collected by filtration. Washing with isopropyl ether gave 220 mg of the title compound (169). Light yellow powder Melting point 182-186 ° C ¹ H-NMR (CDCl ₃ ) 2.51 (s, 3H), 2.88 (s, 3H), 3.23, 3.47 (each t, each J =
6.0Hz, each 2H), 3.92 (s, 3H), 7.40, 7.86 (each d, each
J = 8.1Hz, each 2H), 8.04 (d, J = 9.9Hz, 1H), 8.64 (s, 1H)

Example 47 Methyl 5-fluoro-4- (trifluoromethanesulfonyloxy) -2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (170) 2.8 g of the compound (167) obtained in Example 46 was added to pyridine.
In addition to 10 ml, 2.35 ml of trifluoromethanesulfonic anhydride was added over 20 minutes under ice cooling. It was stirred at room temperature for 1 day.
200 ml of chloroform was added and the mixture was washed with 5% citric acid. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. Ethanol was added to the residue and the solid was collected by filtration. It was separated by column chromatography (silica gel, elution solvent; chloroform: ethyl acetate = 1: 1), and the solid was collected by filtration and washed with isopropyl ether to obtain 1.2 g of the title compound (170). Colorless powder Melting point 170-172 ° C ¹ H-NMR (CDCl ₃ ) 2.90 (s, 3H), 3.20, 3.55 (each t, each J = 6.0Hz, each 2
H), 3.96 (s, 3H), 8.25 (d, J = 10.0Hz, 1H), 8.65 (s, 1H)

Example 48 Methyl 5-fluoro-4- (3-oxo-1-cyclohexen-1-yl) -2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2] , 1-i
j] Cinnoline-8-carboxylate (171) 424 mg of the compound (170) obtained in Example 47, 3-tributylstannyl-2-cyclohexen-1-one 404m
g, lithium chloride 127 mg and bis (triphenylphosphine) palladium (II) chloride 14 mg were added to tetrahydrofuran 5 ml, and the mixture was heated under reflux for 3 days in a nitrogen atmosphere.
The solvent was distilled off, n-hexane was added to the residue, and the solid was collected by filtration. Separated by column chromatography (silica gel, elution solvent; chloroform: ethyl acetate = 8: 1).
0 mg of the title compound (171) was obtained. Pale yellow oil ¹ H-NMR (DMSO-d ₆ ) 2.05-2.20 (m, 2H), 2.59 (s, 2H), 2.84 (s, 3H), 2.85-3.03
(m, 2H), 3.44 (brs, 2H), 3.75 (s, 3H), 6.13 (s, 1H), 7.83
(d, J = 10.0Hz, 1H), 8.56 (s, 1H)

Example 49 5-Fluoro-4- (3-oxo-1-cyclohexen-1-yl) -2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,2] 1-ij] Cinnoline-8-carboxylic acid (172) 120 mg of the compound (171) obtained in Example 48 was added to a mixed solution of 3 ml of tetrahydrofuran, 1 ml of 6N hydrochloric acid and 1 ml of water, and the mixture was stirred at room temperature for 4 days. The precipitated solid was collected by filtration. Washing with water and ethanol in this order gave 44 mg of the title compound (172). Colorless needle crystals Melting point> 300 ° C ¹ H-NMR (DMSO-d ₆ ) 2.00-2.20 (m, 2H), 2.60 (brs, 2H), 2.91 (s, 3H), 3.05 (br
s, 2H), 3.45-3.55 (m, 2H), 6.17 (s, 1H), 8.01 (d, J = 10.0H
z, 1H), 8.81 (s, 1H)

Example 50 Ethyl 3,4-difluoro-1,2-dihydro-6-
Oxo-1H, 6H-pyrido [3,2,1-hi] indazole-7-carboxylate (173) 1.29 g (4 mmol) of the compound (99) obtained in Example 16 was added to concentrated hydrochloric acid / acetic acid (volume ratio 1 : 4) The mixture was added to 8 ml and heated under reflux for 30 minutes. After allowing to cool, it was diluted with 50 ml of water, and the precipitated solid was collected by filtration. It was washed with water, ethanol, and ether in this order. 1.07 g of the title compound (173) was obtained (yield 97%). Light yellow powder Melting point 192-197 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.27 (t, J = 7.0Hz, 3H), 4.19 (q, J = 7.0Hz, 2H), 4.88 (d, J =
7.5Hz, 2H), 7.77 (dd, J = 7.0Hz, 10.6Hz, 1H), 7.98 (t, J = 7.5
Hz, 1H), 8.68 (s, 1H)

Example 51 Ethyl 3,4-difluoro-1,2-dihydro-1-
Hydroxymethyl-6-oxo-1H, 6H-pyrido [3,2,1-hi] indazole-7-carboxylate (174) 1.07 g (3.9 mmol) of the compound (173) obtained in Example 50
Was added to a mixed solution of 20 ml of formic acid and 10 ml of 37% formaldehyde solution, and the mixture was heated under reflux for 2 hours. After allowing to cool, it was diluted with 50 ml of water, and the precipitated crystals were collected by filtration. It was washed with water, cold ethanol, and ether in this order. 1.14 g of the title compound (174) was obtained (yield 96%). Colorless needle crystal Melting point 194-201 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.0Hz, 3H), 4.22 (q, J = 7.0Hz, 2H), 4.71 (d , J =
7.0Hz, 2H), 4.93 (s, 2H), 6.26 (t, J = 7.0Hz, 1H), 7.75 (dd,
J = 7.0Hz, 10.6Hz, 1H), 8.83 (s, 1H)

Example 52 3,4-Difluoro-1,2-dihydro-1-hydroxymethyl-6-oxo-1H, 6H-pyrido [3,2,2]
1-hi] indazole-7-carboxylic acid (175) 61 mg (0.2 mmol) of the compound (174) obtained in Example 51
Was added to a mixed solution of 1 ml of formic acid and 1 ml of water, and the mixture was heated under reflux for 6 hours. After allowing to cool, the precipitated crystals were collected by filtration. It was washed with water, ethanol, and ether in this order. Title compound (175) 41
mg was obtained (yield 73%). Colorless needle crystal melting point 265-277 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 4.85 (d, J = 7.0Hz, 2H), 5.04 (s, 2H), 6.31 (t, J = 7.0Hz , 1
H), 8.02 (dd, J = 7.0Hz, 10.6Hz, 1H), 9.30 (s, 1H)

Example 53 Ethyl 3,4-difluoro-1,2-dihydro-1-
Methoxymethyl-6-oxo-1H, 6H-pyrido [3,2,1-hi] indazole-7-carboxylate (176) 61 mg (0.2 mmol) of the compound (174) obtained in Example 52
Was added to 2 ml of dimethyl sulfate, and the mixture was stirred at 120 ° C. for 6 hours.
After allowing to cool, the contents were added to 50 ml of a saturated aqueous sodium carbonate solution, and the mixture was stirred at room temperature for 4 hours. After extraction with chloroform, the extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The solid residue was dispersed in ether and the precipitate was collected by filtration and washed with ether to obtain 57 mg of the title compound (176) (yield 89%). Yellow powder Melting point 183-199 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.0Hz, 3H), 3.34 (s, 3H), 4.24 (q, J = 7.0Hz, 2
H), 4.67 (s, 2H), 4.98 (s, 2H), 7.79 (dd, J = 7.0Hz, 10.6Hz,
1H), 8.88 (s, 1H)

Example 54 Ethyl 4,5-difluoro-1-hydroxymethyl-
2,3-Dihydro-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (177) 100 mg of the compound (5) obtained in Example 1 was dissolved in 3 ml of acetic acid. Then, while stirring, 1.5 ml of formalin was added and stirred for 30 minutes. The precipitated solid was collected by filtration, washed with ether, and washed with 64
This gave mg of the title compound (177). Colorless needle crystals Melting point> 245 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.27 (t, J = 7.0Hz, 3H), 3.01 (brs, 2H), 3.63 (t, J = 6.4Hz, 2
H), 4.21 (q, J = 7.0Hz, 2H), 4.50 (d, J = 6.3Hz, 2H), 6.20 (t,
J = 6.3Hz, 1H), 7.92 (dd, J = 8.8Hz, 10.7Hz, 1H), 8.48 (s, 1H)

Example 55 4,5-Difluoro-1-hydroxymethyl-2,3-
Dihydro-7-oxo-1H, 7H-pyrido [3,2,
1-ij] Cinnoline-8-carboxylic acid (178) 50 mg of the compound (10) obtained in Example 3 (4) was added to 3 m of acetic acid.
suspended in l, add 1.5 ml of formalin with stirring,
Stir for 1 hour. Ether was added and the precipitated solid was collected by filtration. Washing with ether gave 40 mg of the title compound (178). Colorless needle crystals Melting point> 255 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 3.01 (brs, 2H), 3.69 (t, J = 5.9Hz, 2H), 4.57 (d, J = 7.0Hz, 2
H), 6.22 (t, J = 7.0Hz, 1H), 8.17 (dd, J = 8.8Hz, 10.3Hz, 1H),
8.77 (s, 1H)

Example 56 5-Fluoro-4- (pyrrolidin-1-yl) -1-hydroxymethyl-2,3-dihydro-7-oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid (179) 200 mg of the compound (102) obtained in Example 4 (21) was added to a mixed solvent of 8 ml of acetic acid and 4 ml of formalin, and the mixture was heated at 80 ° C for 2 hours. The precipitated solid was collected by filtration and washed with ether to give 50 mg of the title compound (179). Yellow powder Melting point 258-261 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.51 (brs, 2H), 2.90 (t, J = 5.9Hz, 2H), 3.24-3.72 (m, 6H),
4.55 (d, J = 6.8Hz, 2H), 6.25 (t, J = 6.8Hz, 1H), 7.82 (d, J = 1
4.2Hz, 1H), 8.62 (s, 1H)

Example 57 Ethyl 4,5-difluoro-1-methoxymethyl-
2,3-Dihydro-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (180) 65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran. It became turbid, 270 μl of diethylaminosulfur trifluoride was added, and the mixture was stirred for 4 hours. 1 ml of methanol was added, and the precipitated solid was collected by filtration. Washing with ether gave 34 mg of the title compound (180). Colorless needle crystals Melting point> 240 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 1.41 (t, J = 7.0Hz, 3H), 3.05 (t, J = 5.9Hz, 2H), 3.36 (s, 3
H), 3.63 (t, J = 6.4Hz, 2H), 4.35-4.42 (m, 4H), 8,13 (dd, J =
8.8Hz, 10.3Hz, 1H), 8.50 (s, 1H)

Example 58 Ethyl 4,5-difluoro-1-ethoxymethyl-
2,3-Dihydro-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (181) 65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran. It became turbid, 270 μl of diethylaminosulfur trifluoride was added, and the mixture was stirred for 4 hours. 1 ml of ethanol was added, and the precipitated solid was collected by filtration. Washing with ether gave 28 mg of the title compound (181). Colorless powder Melting point> 190 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 1.11 (t, J = 7.3Hz, 3H), 1.40 (t, J = 7.0Hz, 3H), 3.05 (t, J =
5.9Hz, 2H), 3.55 (q, J = 7.3Hz, 2H), 3.64 (t, J = 6.4Hz, 2H),
4.34-4.46 (m, 4H), 8.13 (dd, J = 8.8Hz, 10.3Hz, 1H), 8.50
(s, 1H)

Example 59 4,5-Difluoro-1-benzyl-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2,1-i
j] Cinnoline-8-carboxylic acid (182) 530 mg of the compound (10) obtained in Example 3 (4) was added to 15 ml of toluene, and 1 ml of benzyl alcohol and p- were added.
Toluenesulfonic acid monohydrate (456 mg) was added, and the mixture was heated at 130 ° C. for 48 hours while removing water produced. The solvent was evaporated, ether was added to the residue, and the solid was collected by filtration. Washing with ether gave 370 mg of the title compound (182). Pale yellow needles Melting point> 194 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 3.18 (t, J = 5.9Hz, 2H), 3.59 (t, J = 6.4Hz, 2H), 4.11 (s, 2
H), 7.27-7.40 (m, 5H), 8.20 (dd, J = 8.8Hz, 9.8Hz, 1H), 8.4
9 (s, 1H)

Example 60 5-Fluoro-4- (pyrrolidin-1-yl) -1-benzyl-2,3-dihydro-7-oxo-1H, 7H-
Pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (183) 50 mg of the compound (182) obtained in Example 59, 26 mg of pyrrolidine, and 10 mg of triethylamine were added to acetonitrile.
It was added to 3 ml and heated at 80 ° C. for 3 hours. Evaporate the solvent,
Ethanol was added to the residue, and the solid was collected by filtration. Wash with ethanol and then ether to give 33 mg of the title compound (183).
Got Pale yellow needle melting point 174-180 ° C ¹ H-NMR (CDCl ₃ ) 2.04 (brs, 4H), 2.97 (t, J = 5.9Hz, 2H), 3.46 (t, J = 6.4Hz, 2
H), 3.58 (brs, 4H), 4.16 (s, 2H), 7.26-7.39 (m, 5H), 7.99
(d, J = 13.7Hz, 1H), 8.46 (s, 1H)

Example 61 4- (2-aminoethylthio) -5-fluoro-1-methyl-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline- 8-Carboxylic acid (184) 100 mg of the compound (8) obtained in Example 3 (1), 56 mg of 2-aminoethanethiol and 109 m of triethylamine.
g was added to 2 ml of acetonitrile and heated under reflux for 2 hours.
After allowing to cool, the solvent was distilled off. Ethanol was added to the residue, and the precipitated solid was collected by filtration and washed with ether. 60 mg of the title compound (184) was obtained. Colorless powder Melting point> 200 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.68 (t, J = 6.4Hz, 2H), 2.87 (s, 3H), 3.07 (t, J = 6.8Hz, 2
H), 3.22-3.30, 3.51-3.62 (each m, each 2H), 7.99 (d, J =
9.8Hz, 1H), 8.79 (s, 1H)

Reference Example 28 3-Fluoro-2- (2-hydroxyethyl) nitrobenzene (185) 6.52 g (94.5 mmol) of sodium nitrite was added to 45 ml of concentrated sulfuric acid over 30 minutes under ice cooling. Subsequently, a solution of 14.5 g (72.9 mmol) of the compound (124) obtained in Reference Example 6 in 180 ml of acetic acid was added dropwise over 1 hour and 30 minutes so as not to exceed 20 ° C. The mixture was stirred as it was for 20 minutes. It was added dropwise to a suspension of 40.9 g (285.8 mmol) of copper oxide in 300 ml of ethanol. The reaction solution was heated to 50 ° C. and stirred for 20 minutes. Pour into 1.0 l of ice water and add chloroform.
1.0 l was added. The insoluble material was filtered off, and the organic layer was separated.
After drying over magnesium sulfate, the solvent was distilled off. Separation was performed by column chromatography (silica gel 500 g, elution solvent: chloroform) to obtain 6.22 g of the title compound (185) (yield 46%).

Reference Example 29 Diethyl {3-fluoro-2- (2-hydroxyethyl) anilino} methylenemalonate (186) Iron powder 15.4 g, concentrated hydrochloric acid 1.4 ml, water 160 ml, ethanol 30 ml.
Of the compound (18
5) 20.3 g (110 mmol) was added over 15 minutes. It was heated for 10 minutes as it was. After allowing to cool, 200 ml of ethyl acetate was added, and the insoluble material was filtered. The organic layer was separated, washed with 10% aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and the solvent was evaporated. To the obtained oily substance, 23.2 g (107 mmol) of diethyl ethoxymethylene malonate was added, and the mixture was heated at 120 ° C for 4 hours. After cooling, the crystals were dispersed in n-hexane and collected by filtration. 21.9 g of the title compound (186) was obtained (yield 6
1%).

Reference Example 30 Ethyl 7-fluoro-8- (2-hydroxyethyl)
-4-Hydroxyquinoline-3-carboxylate (1
87) Compound (186) 20.0 g (61.7 mmol) and imidazole
5.11 g (75 mmol) was added to 120 ml of methylene chloride, and a solution of 11.2 g (74.4 mmol) of t-butyldimethylchlorosilane in 25 ml of methylene chloride was added dropwise over 5 minutes. The mixture was stirred at room temperature for 40 minutes, washed with 50 ml of water, dried over magnesium sulfate, and the solvent was distilled off. To the obtained oily substance, 210 ml of Dowtherm A was added, and the mixture was heated until a distillate of 200 ° C. was produced, and the mixture was heated under reflux for 20 minutes. After allowing to cool, 30 ml of concentrated hydrochloric acid was added. After stirring for 20 minutes at room temperature, the mixture was neutralized with sodium hydrogen carbonate. The precipitated crystals were collected by filtration. Wash in the order of water, ethanol, ether,
8.99 g of the title compound (187) was obtained (yield 52%).

Reference Example 31 Ethyl 1-amino-7-fluoro-8- (2-hydroxyethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylate (188) Compound (187) 8.99 g (32.2) mmol) and 8.89 g (64.4 mmol) of anhydrous potassium carbonate were added to N, N-dimethylformamide 21.
It was added to 0 ml and stirred at room temperature for 4 hours. Ethyl O- (mesitylene sulfonyl) acetohydroxamate 27.6 g (96.7
mmol) to 40 ml of dioxane, and under ice cooling, 70% perchloric acid
10.5 ml was added dropwise at 10 ° C or lower over 30 minutes. The mixture was stirred as it was for 20 minutes, poured into 400 ml of ice water, and the crystals were collected by filtration.
It was washed with ice water, dissolved in 150 ml of methylene chloride, the organic layer was separated, dried over magnesium sulfate, and then added dropwise to the reaction solution of N, N-dimethylformamide over 10 minutes under ice cooling. The mixture was stirred as it was for 1 hour, 200 ml of water was added, and the crystals were collected by filtration. Wash in the order of water, ethanol, ether, 1.81g
The title compound (188) of was obtained (yield 19%).

Example 62 Ethyl 4-fluoro-2,3-dihydro-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (189) Obtained in Reference Example 31. Compound (188) 1.81 g (6.2 mmol)
And 2.55 g (9.7 mmol) of triphenylphosphine were added to 40 ml of tetrahydrofuran, and a solution of 1.69 g (9.7 mmol) of diethyl azodicarboxylate in 40 ml of tetrahydrofuran was added dropwise at room temperature over 1 hour and a half. After 30 minutes, the solvent was distilled off. The solid was dispersed in ethanol and collected by filtration. Wash with ethanol and ether in this order to obtain 1.24 g of the title compound (18
9) was obtained (yield 72%). Colorless powder, melting point 224-225 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.27 (t, J = 6.9Hz, 3H), 2.88 (brs, 2H), 3.39 (brs, 2H), 4.2
0 (q, J = 7.0Hz, 2H), 6.85 (brs, 1H), 7.34 (dd, J = 8.8Hz, 8.8
Hz, 1H), 8.09 (dd, J = 6.6Hz, 6.6Hz, 1H), 8.42 (s, 1H)

Example 63 Methyl 4-fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-i
j] Cinnoline-8-carboxylate (190) 1.24 g (4.5 mmol) of the compound (189) obtained in Example 62.
To the solution was added 8 ml (87 mmol) of dimethylsulfate, and the mixture was heated at 120 ° C for 3 hours. After allowing to cool, the mixture was added to 70 ml of ice water containing 12 g (87 mmol) of anhydrous potassium carbonate and stirred for 1 hour. Chloroform 10
The mixture was extracted with 0 ml, dried over magnesium sulfate, and the solvent was distilled off. Separation by column chromatography (silica gel 40 g, elution solvent; chloroform: methanol = 100: 1) gave 571 mg of the title compound (190) (yield 46
%). Colorless powder Melting point 199-203 ° C (decomp.) ¹ H-NMR (CDCl ₃ ) 2.87 (s, 3H), 3.04 (t, J = 5.9Hz, 2H), 3.50 (t, J = 5.9Hz, 2
H), 3.92 (s, 3H), 7.15 (dd, J = 8.4Hz, 8.4Hz, 1H), 8.35 (dd,
J = 6.2Hz, 9.0Hz, 1H), 8.59 (s, 1H)

Example 64 4-Fluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid (191) Example 63 40 mg (0.14 mmol) of the compound (190) obtained in
To this, 0.3 ml of concentrated hydrochloric acid and 1.2 ml of acetic acid were added, and the mixture was heated under reflux for 3 hours. 5 ml of water was added, and the precipitated crystals were collected by filtration. Wash with water, ethanol, and ether in this order to obtain 30 mg of the title compound (190).
Was obtained (yield 79%). Colorless needle crystal Melting point 213 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.89 (s, 3H), 3.07 (t, J = 5.9Hz, 2H), 3.53 (t, J = 6.2Hz, 2
H), 7.59 (dd, J = 8.8Hz, 8.8Hz, 1H), 8.32 (dd, J = 6.9Hz, 9.2H
z, 1H), 8.81 (s, 1H)

Example 65 4- (Pyrozin-1-yl) -2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid (192) 15 mg (0.06 mmol) of the compound (191) obtained in Example 64
And 0.1 ml of pyrrolidine were added to 5 ml of acetonitrile, and 2
Heated to reflux for hours. The solvent was distilled off. The crystals were dispersed in ethanol and collected by filtration. The crystals were washed with ether in this order to obtain 15 mg of the title compound (192) (yield 84%). Light yellow prism, melting point 272 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.94 (brs, 4H), 2.92 (s, 3H), 3.01 (brs, 2H), 3.54 (brs, 4)
H), 7.15 (d, J = 10.6Hz, 1H), 8.08 (d, J = 9.5Hz, 1H), 8.60 (s,
1H)

Reference Example 32 Ethyl 1- (Nt-butyloxycarbonyl-N-
Methylamino) -5,6,7,8-tetrafluoro-
1,4-Dihydro-4-oxoquinoline-3-carboxylate (193) 2,3,4,5,6-pentafluorobenzoyl ethyl acetate 28.6 g, ethyl orthoformate 23.2 g and acetic anhydride 32.3.
The g mixture was heated to reflux for 8 hours. The solvent was distilled off.
The obtained oily substance was dissolved in 100 ml of methylene chloride, and N-
A solution of 14.6 g of (t-butyloxycarbonyl) -N-methylhydrazine in 30 ml of methylene chloride was added dropwise under ice cooling, and the mixture was stirred for 2 hours. The solvent was distilled off. The oily matter obtained was n-
Crystallized with hexane and collected by filtration. 18.2 g of 2- (2,
3,4,5,6-Pentafluorobenzoyl) -3-
Ethyl (2-t-butyloxycarbonyl-2-methylhydrazino) acrylate was obtained. The obtained ethyl acrylate and 6.2 g of anhydrous potassium carbonate were added to 50 ml of N, N-dimethylformamide and heated at 70 ° C. for 1 hour. The reaction solution was poured into 200 ml of ice water, and the precipitate was collected by filtration. The precipitate was dissolved in 200 ml of chloroform, washed with water and dried over magnesium sulfate, and the solvent was distilled off. The obtained oily substance was crystallized from n-hexane to obtain 13.7 g of the title compound (193) (yield 33%).

Reference Example 33 Ethyl 1- (N-methylamino) -5,6,7,8-
Tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (194) 4.2 g of compound (193) was dissolved in 30 ml of ethyl acetate, and under ice cooling, 40 ml of 4N hydrochloric acid-dioxane solution was added, and the mixture was cooled to room temperature. Stirred overnight. The solvent was distilled off. Chloroform 100m
Dissolve in l, add 50 ml of 10% sodium carbonate aqueous solution,
The mixture was stirred at room temperature for 30 minutes. The organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The crystals were dispersed in ether and collected by filtration to obtain 2.9 g of the title compound (194) (yield
91%).

Example 66 Ethyl 1- [N- {2,2-bis (t-butyloxycarbonyl) ethyl} -N-methyl] amino-5,6.
7,8-Tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (195) 9.5 g of the compound (194) obtained in Reference Example 33 and di-t
-Butyl methylidene malonate 13.7 g in methylene chloride
It was dissolved in 90 ml, 3.3 ml of titanium tetrachloride was added dropwise over 40 minutes under ice cooling, and the mixture was further stirred for 1 hour. The reaction solution was poured into ice water, the organic layer was separated, dried over magnesium sulfate, and the solvent was evaporated. The obtained oil was separated by silica gel chromatography (silica gel, elution solvent; ethyl acetate: methylene chloride = 1: 20) to give 8.6 g of the title compound (19
5) was obtained (yield 47%). Colorless powder Melting point 118-122 ° C ¹ H-NMR (CDCl ₃ ) 1.39 (s, 12H), 1.46 (s, 9H), 3.00 (s, 3H), 3.19-3.23 (m, 1
H), 3.48-3.62 (m, 2H), 4.40 (q, J = 7.1Hz, 2H), 8.52 (s, 1H)

Example 67 Ethyl 3,3-bis (t-butyloxycarbonyl)
-4,5,6-trifluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylate (196) 10.0 g of the compound (195) obtained in Example 66 was dissolved in 150 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature, 3.0 g of cesium carbonate was added, and the mixture was heated at 80 ° C for 3 hours. It was stirred. After cooling down,
The reaction solution was 5% citric acid aqueous solution 500 ml, ethyl acetate 500 m
The organic layer was separated, dried over magnesium sulfate, and then the solvent was distilled off. The residue was dissolved in ether and the insoluble material was filtered off. The filtrate was evaporated, and the residue was separated by silica gel chromatography (silica gel, eluting solvent: chloroform) to give 1.6 g of the title compound (196) (yield 17
%). Colorless powder Melting point 169-173 ° C ¹ H-NMR (CDCl ₃ ) 1.40 (t, J = 7.1Hz, 3H), 1.49 (s, 18H), 2.76 (s, 3H), 4.04
(s, 2H), 4.39 (q, J = 7.1Hz, 2H), 8.47 (s, 1H)

Example 68 4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-8-ethoxycarbonyl-1H, 7
H-pyrido [3,2,1-ij] cinnoline-3-carboxylic acid (197) 1.0 g of the compound (196) obtained in Example 67 was dissolved in 2 ml of trifluoroacetic acid and heated at 60 ° C for 2 hours. .. The reaction solution was poured into 50 ml of isopropyl ether, and the precipitated solid was collected by filtration. 0.67 g of the title compound (197) was obtained (yield 99
%). Colorless powder, melting point 219-223 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.1Hz, 3H), 2.78 (s, 3H), 3.73-3.76 (m, 2H),
4.18-4.25 (m, 3H), 8.45 (s, 1H)

Example 69 Ethyl 4,5,6-trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3.
2,1-ij] Cinnoline-8-carboxylate (1
98) 300 mg of the compound (197) obtained in Example 68 was dissolved in 6 ml of N-methylpyrrolidone and heated at 160 ° C. for 3 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted 3 times with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was separated by silica gel chromatography (silica gel, eluting solvent: chloroform) to obtain 128 mg of the title compound (198) (yield 49%). Colorless powder Melting point 236-240 ° C ¹ H-NMR (CDCl ₃ ) 1.40 (t, J = 7.1Hz, 3H), 2.83 (s, 3H), 3.00-3.08, 3.44-3.5
1 (each m, each 2H), 4.38 (q, J = 7.1Hz, 2H), 8.49 (s, 1H)

Example 70 4,5,6-Trifluoro-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-
ij] Cinnoline-8-carboxylic acid (199) Example 6
30 mg of the compound (198) obtained in 9 was added to 0.4 ml of acetic acid, 12
The mixture was added to 0.1 ml of normal hydrochloric acid and heated at 100 ° C for 2 hours. After allowing to cool, water was added and the precipitated solid was collected by filtration. Wash with water, ethanol, and ether in this order to obtain 22 mg of the title compound (199).
Was obtained (yield 81%). Colorless powder, melting point 255-260 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.85 (s, 3H), 3.07-3.10, 3.49-3.55 (each m, each 2H),
8.78 (s, 1H)

Example 71 Ethyl 4,5-difluoro-6-benzylamino-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylate (200) 62 mg of the compound (198) obtained in Example 69 and 50 mg of benzylamine were added to 2 ml of toluene and heated at 80 ° C for 24 hours. .. The reaction solution was dissolved in chloroform, washed with 5% aqueous citric acid solution, dried over magnesium sulfate, and the solvent was evaporated. The solid was dispersed in ether and collected by filtration. 59 mg of the title compound (200) was obtained (74% yield). Colorless powder Melting point 186-190 ° C ¹ H-NMR (CDCl ₃ ) 1.38 (t, J = 7.3Hz, 3H), 2.78 (s, 3H), 2.83-2.90, 3.33-3.3
9 (each m, each 2H), 4.36 (q, J = 7.3Hz, 2H), 4.68, 4.70 (e
ach d, each J = 3.9Hz, each 1H), 7.22-7.38 (m, 5H), 8.40
(s, 1H), 10.81 (brs, 1H)

Example 72 Ethyl 4,5-difluoro-6-amino-2,3-dihydro-1-methyl-7-oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxy Rate (201) 59 mg of the compound (200) obtained in Example 71 was dissolved in 10 ml of ethanol and 10 ml of acetic acid, and 5 mg of 10% palladium on carbon was dissolved.
Was added, and the mixture was stirred under a hydrogen atmosphere for 24 hours. The catalyst was filtered off and the filtrate was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and the solvent was evaporated. Disperse the solid in ether,
It was collected by filtration. 27 mg of the title compound (201) was obtained (yield 59
%). Yellow powder Melting point 255-257 ° C ¹ H-NMR (CDCl ₃ ) 1.39 (t, J = 7.1Hz, 3H), 2.80 (s, 3H), 2.89, 3.39 (each t, e
ach J = 6.0Hz, each 2H), 4.38 (q, J = 7.1Hz, 2H), 7.03 (brs,
2H), 8.44 (s, 1H)

Example 73 6-Amino-4,5-difluoro-2,3-dihydro-
1-methyl-7-oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylic acid (202) 20 mg of the compound (201) obtained in Example 72 was added to 0.4 m of acetic acid.
1, 12N hydrochloric acid (0.1 ml) and heated at 100 ° C. for 2 hours. After allowing to cool, water was added and the precipitated solid was collected by filtration. Wash with water, ethanol, and ether in this order to obtain 13 mg of the title compound (2
02) was obtained (yield 72%). Pale yellow powder Melting point> 290 ° C ¹ H-NMR (DMSO-d ₆ ) 2.80 (s, 3H), 2.86-2.91, 3.40-3.45 (each m, each 2H),
7.71 (brs, 2H), 8.61 (s, 1H)

Example 74 6-Amino-5-fluoro-4- (pyrrolidin-1-yl) -2,3-dihydro-1-methyl-7-oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid (203) 4 mg of the compound (202) obtained in Example 73 and 10 µl of pyrrolidine were added to 1 ml of acetonitrile and heated at 80 ° C for 3 hours. The solvent was distilled off. The residue was washed with ethanol and ether to give 2 mg of the title compound (203). Light yellow powder Melting point> 290 ° C ¹ H-NMR (CDCl ₃ ) 1.97-2.06 (m, 4H), 2.79-2.85 (m, 2H), 2.86 (s, 3H), 3.30-
3.35 (m, 2H), 3.44-3.53 (m, 4H), 6.57 (brs, 2H), 8.66 (s,
1H)

Example 75 5-Fluoro-4- (3-hydroxy-2-methylazetidin-1-yl) -2,3-dihydro-1-methyl-
7-oxo-1H, 7H-pyrido [3,2,1-ij]
Cinnoline-8-carboxylic acid (204) The title compound (204) was obtained in the same manner as in Example 61. Light yellow powder Melting point 261-263 ° C ¹ H-NMR (DMSO-d ₆ ) 1.41 (d, J = 6.4Hz, 3H), 2.87 (s, 3H), 3.82-3.97 (m, 1H), 4.
06 (brs, 1H), 4.52-4.70, 4.70-4.87 (each m, each 1H), 5.
76 (brs, 1H), 7.78 (d, J = 14.7Hz, 1H), 8.61 (s, 1H)

Example 76 (3-Amino-methylazetidin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7-oxo-
1H, 7H-pyrido [3,2,1-ij] cinnoline-
8-Carboxylic acid / hydrochloride (205) The title compound (205) was obtained in the same manner as in Example 61. Yellow powder Melting point 205-210 ° C ¹ H-NMR (DMSO-d ₆ ) 1.48 (d, J = 5.9Hz, 3H), 2.56-2.75 (m, 1H), 2.88 (s, 3H), 3.
00-3.22 (m, 1H), 3.72 (brs, 1H), 4.10-4.28, 4.75-4.90,
4.90-5.10 (each m, each 1H), 7.81 (d, J = 14.2Hz, 1H), 8.6
3 (s, 1H), 8.70 (brs, 3H)

Example 77 Ethyl 8-acetoxymethyl-1- (N, N-diacetylamino) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (20
6) The compound (97) 680 mg (2 mmol) obtained in Example 14 was added to acetic anhydride 10 ml, and the mixture was stirred at 110 ° C. for 4 hours. After allowing to cool, it was concentrated under reduced pressure. The solid residue was dispersed in petroleum ether and collected by filtration. 776 mg of the title compound (206) was obtained (yield 90%). Brown amorphous solid ¹ H-NMR (DMSO-d ₆ ) 1.30 (t, J = 7.0Hz, 3H), 2.00 (s, 3H), 2.39 (s, 6H), 4.28
(q, J = 7.0Hz, 2H), 5.07 (s, 2H), 8.30 (dd, J = 7.0Hz, J = 10.6H
z, 1H), 9.01 (s, 1H)

Example 78 Ethyl 8-acetoxymethyl-1- (N-acetylamino) -6,7-difluoro-1,4-dihydro-4-
Oxoquinoline-3-carboxylate (207) 424 mg (1 mmol) of the compound (206) obtained in Example 77 was dissolved in 10 ml of dimethyl sulfoxide, and 71 mg (1 mmol) of pyrrolidine was dissolved in 1 ml of dimethyl sulfoxide while stirring at room temperature. Was added over 2 hours. 20 at room temperature
After stirring for 50 hours, 50 ml of water was added and the mixture was stirred at room temperature for 2 hours. The deposited precipitate was collected by filtration, washed successively with water and diethyl ether, and dried under vacuum. Title compound (207) 353m
g was obtained (yield 97%). Slight yellow prism crystal Melting point 119-121 ° C ¹ H-NMR (DMSO-d ₆ ) 1.29 (t, J = 7.0Hz, 3H), 2.03 (s, 6H), 4.27 (q, J = 7.0Hz, 2
H), 5.40 (s, 2H), 8.22 (dd, J = 7.0Hz, J = 10.6Hz, 1H), 8.59
(s, 1H)

Example 79 Ethyl 8-acetoxymethyl-1- (N-acetyl-
N-methylamino) -6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (208) Compound (207) obtained in Example 78 650 mg (1.7 mmol)
Was dissolved in 17 ml of N, N-dimethylformamide, 510 mg of anhydrous potassium carbonate was added, and 374 mg (2.55 mmol) of methyl iodide was added with stirring at room temperature. After stirring at room temperature for 20 hours, 50 ml of water was added and the mixture was stirred for 2 hours. The deposited precipitate was collected by filtration, washed with water and diethyl ether in this order, and dried under vacuum. 362 mg of the title compound (208) was obtained (yield 54
%). Few yellow needles Melting point 196-198 ° C ¹ H-NMR (DMSO-d ₆ ) 1.30 (t, J = 7.0Hz, 3H), 1.72-2.23 (m, 6H), 3.34 (s, 0.3
H), 3.56 (s, 0.7H), 4.18-4.25 (m, 2H), 4.87-5.39 (m, 2
H), 8.08-8.32 (m, 1H), 8.82 (s, 0.7H), 8.95 (s, 0.3H)

Example 80 Ethyl 1- (N-methylamino) -6,7-difluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (209) Example (79) Compound (208) obtained in 793 mg (2 mmo
l) ethanol 4 ml and 4N hydrochloric acid-dioxane solution 8 ml
The resulting mixture was added and the mixture was stirred at 60 ° C. for 5 hours. After allowing to cool, the saturated aqueous sodium hydrogencarbonate solution was added dropwise to the mixture while stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The deposited precipitate was collected by filtration, washed with water and diethyl ether in this order, and dried under vacuum. 506 mg of the title compound (209) was obtained as pale yellow crystals. Slightly yellow prism crystal Melting point 217-222 ° C ¹ H-NMR (DMSO-d ₆ ) 1.30 (t, J = 7.0Hz, 3H), 2.85 (s, 3H), 3.37 (s, 3H), 4.24 (q,
J = 7.0Hz, 2H), 5.02 (brs, 2H), 5.11 (brs, 1H), 6.93 (m, 1
H), 8.10 (dd, J = 7.0Hz, J = 10.6Hz, 1H), 8.77 (s, 1H)

Example 81 Ethyl 3,4-difluoro-1,2-dihydro-1-
Methyl-6-oxo-1H, 6H-pyrido [3,2,1
-Hi] indazole-7-carboxylate (21
0) 437 mg (1.4 mmol) of the compound (209) obtained in Example 80
Was added to 14 ml of tetrahydrofuran and triethylamine 283 mg (2.8 mmol), 4-toluenesulfonyl chloride 266 mg (1.4 mmol), 4-dimethylaminopyridine while stirring at room temperature.
10 mg was added, and the mixture was stirred at 60 ° C. for 6 hours. After cooling, the precipitated crystals were collected by filtration and washed with tetrahydrofuran, water and tetrahydrofuran in this order. 257 mg of the title compound (210)
Was obtained (yield 62%). Colorless needle crystals Melting point> 215 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, J = 7.0Hz, 3H), 3.06 (s, 3H), 4.21 (q, J = 7.0Hz, 2
H), 4.87 (s, 2H), 7.79 (dd, J = 7.0Hz, J = 11.4Hz, 1H), 8.89
(s, 1H)

Example 82 3,4-Difluoro-1,2-dihydro-1-methyl-
6-oxo-1H, 6H-pyrido [3,2,1-hi]
Indazole-7-carboxylic acid (211) 88 mg (0.3 mmol) of the compound (210) obtained in Example 81
Was added to a mixed solution of 2 ml of formic acid and 2 ml of water, and the mixture was heated under reflux for 6 hours. After allowing to cool, the precipitated crystals were collected by filtration, washed with water and diethyl ether in this order, and dried under vacuum. Title compound (21
1) 58 mg was obtained (yield 73%). Colorless needle crystals Melting point> 250 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 3.21 (s, 3H), 4.99 (s, 2H), 8.07 (dd, J = 7.0Hz, J = 11.1Hz, 1
H), 9.27 (s, 1H)

Example 83 4-Fluoro-3- (pyrrolidin-1-yl) -1,2
-Dihydro-1-methyl-6-oxo-1H, 6H-pyrido [3,2,1-hi] indazole-7-carboxylic acid (212) 25 mg of the compound (211) obtained in Example 82 and 21 mg of pyrrolidine Add 0.6 ml of dimethyl sulfoxide and add 1 at room temperature.
Stir for hours. The precipitated solid was collected by filtration, ether, n-
It was washed with hexane in that order to obtain 18 mg of the title compound (212). Yellow powder Melting point> 248 ° C. (decomp.) ¹ H-NMR (CDCl ₃ / CD ₃ OD = 5/1) 2.03 (brs, 4H), 3.12 (s, 3H), 5.04 (s, 2H), 7.67 (d , J = 14.
0Hz, 1H), 8.70 (s, 1H)

Example 84 4- (7-Amino-5-azaspiro [2.4] heptan-5-yl) -5-fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid (214) The title compound (214) was obtained in the same manner as in Example 6 (1). Yellow powder Melting point 222-225 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.14
-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H), 8.7
1 (s, 1H)

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] November 8, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0229

[Correction method] Change

[Correction content]

Example 76 4- (3-Amino-2- methylazetidin-1-yl)
-5-Fluoro-2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid · hydrochloride (205) In the same manner as in Example 61, the title compound (205) was obtained. Yellow powder Melting point 205-210 ° C ¹ H-NMR (DMSO-d ₆ ) 1.48 (d, J = 5.9Hz, 3H), 2.56-2.75 (m, 1H), 2.88 (s, 3H), 3.
00-3.22 (m, 1H), 3.72 (brs, 1H), 4.10-4.28, 4.75-4.90,
4.90-5.10 (each m, each 1H), 7.81 (d, J = 14.2Hz, 1H), 8.6
3 (s, 1H), 8.70 (brs, 3H)

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0237

[Correction method] Change

[Correction content]

Example 84 4- (7-Amino-5-azaspiro [2.4] heptan-5-yl) -5-fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid ( 213 ) The title compound ( 213 ) was obtained in the same manner as in Example 6 (1). Yellow powder Melting point 222-225 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.14
-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H), 8.7
1 (s, 1H) Example 85 4-{(3R)-((1'S)-(2-aminopropano
Ilamino) ethyl) pyrrolidin-1-yl} -5-fu
Luoro-2,3-dihydro-1-methyl-7-oxo-
1H, 7H-pyrido [3,2,1-ij] cinnoline-
8-Carboxylic acid / hydrochloride (214) The title compound (214) was prepared in the same manner as in Example 11 (1).
Got Yellow prism melting point 189-193 ° C ¹ H-NMR (DMS0-d ₆ ) 1.18, 1.34 (each d, each J = 6.6Hz, each 3H), 1.60-1.7
5, 2.00-2.13, 2.30-2.40, 2.27-2.86 (each m, each 1H),
2.90 (s, 3H), 3.00-3.10 (m, 1H), 3.33-3.52 (m, 5H), 3.69
-3.84 (m, 2H), 3.89-3.97 (m, 1H), 7.84 (d, J = 13.9Hz, 1H),
8.14 (brs, 1H), 8.57 (d, J = 8.4Hz, 1H), 8.68 (s, 1H) Example 86 4- (7-amino-5-azaspiro [2.4] heptane
-5-yl) -5-fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid / hydrochloride (isomer
B) (215) The title compound was prepared in the same manner as in Example 6 (1).
The product (215) was obtained. Yellow powder melting point 204-210 ° C ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.1
4-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H), 8.
71 (s, 1H) Example 87 4- (7-amino-5-azaspiro [2.4] heptane
-5-yl) -5-fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid / hydrochloride (isomer
A) (216) The title compound (216) was prepared in the same manner as in Example 6 (1).
Obtained. Pale yellow powder melting point 217-224 ° C ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.1
4-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H), 8.
71 (s, 1H) Example 88 4- (3-Amino-2-methylazetidin-1-yl)
-5-Fluoro-2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cin
Norrin-8-carboxylic acid / hydrochloride (isomer B) (21
7) In the same manner as in Example 61, the title compound (217) was obtained.
It was Pale yellow powder melting point 210-215 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.35 (d, J = 6.4Hz, 3H), 2.82 (s, 3H), 3.52 (brs, 2H), 3.92
-4.11 (m, 2H), 7.86 (d, J = 14.2Hz, 1H), 8.64 (s, 1H), 8.69
(brs, 3H) Example 89 6-amino-4- (cis (-) 3-amino-4-methyl
Pyrrolidin-1-yl) -5-fluoro-2,3-dihi
Doro-1-methyl-7-oxo-1H, 7H-pyrido
[3,2,1-ij] Cinnoline-8-carboxylic acid / salt
Acid salt (218) The title compound (218) was obtained in the same manner as in Example 6. Brown amorphous ¹ H-NMR (DMSO-d ₆ ) 1.13 (d, J = 13.5Hz, 3H), 2.58-2.76 (m, 2H), 2.84 (s, 3H),
3.17-4.07 (m, 7H), 8.45 (brs, 2H), 8.51 (s, 1H) Example 90 6-amino-4-{(3R)-((1'S) -1-ami
Noethyl) pyrrolidin-1-yl} -5-fluoro-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-cal
Boronic acid / hydrochloride (219) The title compound (219) was obtained in the same manner as in Example 6. Brown powder melting point 196-206 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.29 (d, J = 5.4Hz, 3H), 1.51-1.80, 1.99-2.15, 2.31-2.4
7 (each m, each 1H), 2.57-3.06 (m, 2H), 2.85 (s, 3H), 3.1
8-4.41 (m, 7H), 8.19 (brs, 2H), 8.51 (s, 1H) Example 91 6-amino-4,5-difluoro-2,3-dihydro-
1-methyl-7-oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylic acid BF ₂
(220) The title compound (220) was obtained in the same manner as in Example 18.
It was Yellow powder melting point 257-261 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.91 (s, 1H), 2.99, 3.50, 7.40 (each brs, each 2H), 9.
12 (s, 1H) Example 92 6-Amino-4- (piperazin-1-yl) -5-flu
Oro-2,3-dihydro-1-methyl-7-oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid (221) The title compound (221) was obtained in the same manner as in Example 19.
It was Yellow prism Crystal melting point> 270 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.81 (s, 3H), 2.83 (brs, 2H), 3.11 (brs, 4H), 3.34 (brs, 6
H), 7.36 (brs, 2H), 8.54 (s, 1H) Example 93 4-Fluoro-3-((3S) -aminopyrrolidine-1
-Yl) -1,2-dihydro-1-methyl-6-oxo
-1H, 6H-pyrido [3,2,1-hi] indazo
Ru-7-carboxylic acid (222) The title compound (222) was obtained in the same manner as in Example 83.
It was Pale yellow powder melting point> 270 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.61-1.72, 1.89-1.72 (each m, each 1H), 3.09 (s, 3H),
3.69-3.94 (m, 3H), 5.09 (s, 2H), 7.56 (d, J = 14.5Hz, 1H),
8.93 (s, 1H) Example 94 4-Fluoro-3- (4-methylpiperazin-1-i)
) -1,2-Dihydro-1-methyl-6-oxo-1
H, 6H-pyrido [3,2,1-hi] indazole-
7-Carboxylic acid (223) The title compound (223) was obtained in the same manner as in Example 83.
It was Colorless powder Melting point> 278 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.24 (s, 3H), 2.50 (s, 4H), 3.14 (s, 3H), 3.34 (s, 4H), 5.
04 (s, 2H), 7.69 (d, J = 12.7Hz, 1H), 9.07 (s, 1H) Example 95 4-Fluoro-3- (piperazin-1-yl) -1,2
-Dihydro-1-methyl-6-oxo-1H, 6H-pi
Lido [3,2,1-hi] indazole-7-carvone
Acid (224) The title compound (224) was obtained in the same manner as in Example 83.
It was Colorless powder, melting point 254-256 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.82 (s, 4H), 3.15 (s, 3H), 3.24 (s, 4H), 5.02 (s, 2H), 7 .
67 (d, J = 12.8Hz, 1H), 9.05 (s, 1H) Example 96 4-Fluoro-3- (cis (−) 3-amino-4-methyl)
Rupyrrolidin-1-yl) -1,2-dihydro-1-me
Cyl-6-oxo-1H, 6H-pyrido [3,2,1-
hi] Indazole-7-carboxylic acid (225) The title compound (225) was obtained in the same manner as in Example 83.
It was Yellow powder melting point> 196 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.00 (d, J = 6.6Hz, 3H), 2.14-2.23 (m, 1H), 3.09 (s, 3H),
3.73-3.81, 3.86- 3.93 (each m, each 1H), 5.09 (s, 2H),
7.54 (d, J = 14.5Hz, 1H), 8.92 (s, 1H) ───────────────────────────────── ─────────────────────

[Procedure amendment]

[Submission date] November 8, 1991

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0237

[Correction method] Change

[Correction content]

Example 84 4- (7-Amino-5-azaspiro [2.4] heptan-5-yl) -5-fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid (213) The title compound (213) was obtained in the same manner as in Example 6 (1). Yellow powder Melting point 222-225 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.14
-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H), 8.7
1 (s, 1H) Example 85 4-{(3R)-((1'S)-(2-aminopropanoylamino) ethyl) pyrrolidin-1-yl} -5-fluoro-2,3-dihydro- 1-methyl-7-oxo-
1H, 7H-pyrido [3,2,1-ij] cinnoline-
8-Carboxylic acid / hydrochloride (214) The title compound (214) was prepared in the same manner as in Example 11 (1).
Got Yellow prism crystal Melting point 189-193 ° C ¹ H-NMR (DMS0-d ₆ ) 1.18, 1.34 (each d, each J = 6.6Hz, each3H), 1.60-1.75,
2.00-2.13,2.30-2.40, 2.27-2.86 (each m, each 1H),
2.90 (s, 3H), 3.00-3.10 (m, 1H), 3.33-3.52 (m, 5H), 3.69-
3.84 (m, 2H), 3.89-3.97 (m, 1H), 7.84 (d, J = 13.9Hz, 1H),
8.14 (brs, 1H), 8.57 (d, J = 8.4Hz, 1H), 8.68 (s, 1H) Example 86 4- (7-Amino-5-azaspiro [2.4] heptan-5-yl) -5 -Fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid / hydrochloride (isomer B) (215) The title compound (215) was obtained in the same manner as in Example 6 (1). Yellow powder Melting point 204-210 ° C ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.1
4-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H),
8.71 (s, 1H) Example 87 4- (7-amino-5-azaspiro [2.4] heptan-5-yl) -5-fluoro-2,3-dihydro-1-
Methyl-7-oxo-1H, 7H-pyrido [3,2,1
-Ij] Cinnoline-8-carboxylic acid / hydrochloride (isomer A) (216) The title compound (216) was obtained in the same manner as in Example 6 (1). Light yellow powder Melting point 217-224 ° C ¹ H-NMR (DMSO-d ₆ ) 0.75 (brs, 2H), 0.87-0.95 (m, 1H), 1.12-1.22 (m, 1H), 2.
90 (s, 3H), 3.04-3.19 (m, 3H), 4.07 (d, J = 9.5Hz, 1H), 4.1
4-4.25 (m, 1H), 7.89 (d, J = 13.9Hz, 1H), 8.43 (brs, 2H),
8.71 (s, 1H) Example 88 4- (3-Amino-2-methylazetidin-1-yl)
-5-Fluoro-2,3-dihydro-1-methyl-7-
Oxo-1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (isomer B) (21
7) The title compound (217) was obtained in the same manner as in Example 61. Light yellow powder, melting point 210-215 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.35 (d, J = 6.4Hz, 3H), 2.82 (s, 3H), 3.52 (brs, 2H), 3.92
-4.11 (m, 2H), 7.86 (d, J = 14.2Hz, 1H), 8.64 (s, 1H), 8.69
(brs, 3H) Example 89 6-Amino-4- (cis (-) 3-amino-4-methylpyrrolidin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7-oxo -1H, 7H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid hydrochloride (218) In the same manner as in Example 6, the title compound (218) was obtained. Brown amorphous ¹ H-NMR (DMSO-d ₆ ) 1.13 (d, J = 13.5Hz, 3H), 2.58-2.76 (m, 2H), 2.84 (s, 3H),
3.17-4.07 (m, 7H), 8.45 (brs, 2H), 8.51 (s, 1H) Example 90 6-amino-4-{(3R)-((1'S) -1-aminoethyl) pyrrolidine- 1-yl} -5-fluoro-
2,3-dihydro-1-methyl-7-oxo-1H, 7
H-pyrido [3,2,1-ij] cinnoline-8-carboxylic acid / hydrochloride (219) In the same manner as in Example 6, the title compound (219) was obtained. Brown powder Melting point 196-206 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.29 (d, J = 5.4Hz, 3H), 1.51-1.80, 1.99-2.15, 2.31-2.4
7 (each m, each 1H), 2.57-3.06 (m, 2H), 2.85 (s, 3H), 3.1
8-4.41 (m, 7H), 8.19 (brs, 2H), 8.51 (s, 1H) Example 91 6-amino-4,5-difluoro-2,3-dihydro-
1-methyl-7-oxo-1H, 7H-pyrido [3,3
2,1-ij] Cinnoline-8-carboxylic acid BF ₂ chelate (220) In the same manner as in Example 18, the title compound (220) was obtained. Yellow powder Melting point 257-261 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.91 (s, 1H), 2.99, 3.50, 7.40 (each brs, each 2H), 9.
12 (s, 1H) Example 92 6-Amino-4- (piperazin-1-yl) -5-fluoro-2,3-dihydro-1-methyl-7-oxo-1
H, 7H-pyrido [3,2,1-ij] cinnoline-8
-Carboxylic acid (221) The title compound (221) was obtained in the same manner as in Example 19. Yellow prism crystal Melting point> 270 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.81 (s, 3H), 2.83 (brs, 2H), 3.11 (brs, 4H), 3.34 (brs, 6
H), 7.36 (brs, 2H), 8.54 (s, 1H) Example 93 4-Fluoro-3-((3S) -aminopyrrolidine-1
-Yl) -1,2-dihydro-1-methyl-6-oxo-1H, 6H-pyrido [3,2,1-hi] indazole-7-carboxylic acid (222) In a manner similar to that of Example 83. Compound (222) was obtained. Light yellow powder Melting point> 270 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.61-1.72, 1.89-1.72 (each m, each 1H), 3.09 (s, 3H),
3.69-3.94 (m, 3H), 5.09 (s, 2H), 7.56 (d, J = 14.5Hz, 1H),
8.93 (s, 1H) Example 94 4-Fluoro-3- (4-methylpiperazin-1-yl) -1,2-dihydro-1-methyl-6-oxo-1
H, 6H-pyrido [3,2,1-hi] indazole-
7-Carboxylic acid (223) The title compound (223) was obtained in the same manner as in Example 83. Colorless powder Melting point> 278 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.24 (s, 3H), 2.50 (s, 4H), 3.14 (s, 3H), 3.34 (s, 4H), 5.0
4 (s, 2H), 7.69 (d, J = 12.7Hz, 1H), 9.07 (s, 1H) Example 95 4-Fluoro-3- (piperazin-1-yl) -1,2
-Dihydro-1-methyl-6-oxo-1H, 6H-pyrido [3,2,1-hi] indazole-7-carboxylic acid (224) In the same manner as in Example 83, the title compound (224) was obtained. .. Colorless powder Melting point 254-256 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 2.82 (s, 4H), 3.15 (s, 3H), 3.24 (s, 4H), 5.02 (s, 2H), 7.6
7 (d, J = 12.8Hz, 1H), 9.05 (s, 1H) Example 96 4-Fluoro-3- (cis (−) 3-amino-4-methylpyrrolidin-1-yl) -1,2- Dihydro-1-methyl-6-oxo-1H, 6H-pyrido [3,2,1-
hi] Indazole-7-carboxylic acid (225) The title compound (225) was obtained in the same manner as in Example 83. Yellow powder Melting point> 196 ° C. (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.00 (d, J = 6.6Hz, 3H), 2.14-2.23 (m, 1H), 3.09 (s, 3H),
3.73-3.81, 3.86-3.93 (each m, each 1H), 5.09 (s, 2H),
7.54 (d, J = 14.5Hz, 1H), 8.92 (s, 1H) Example 97 5-Fluoro-4-piperidino-2,3-dihydro-1
-Methyl-7-oxo-1H, 7H-pyrido [3,2,2]
1-ij] Cinnoline-8-carboxylic acid (226) In the same manner as in Example 19, the title compound (226) was obtained.
It was Colorless powder Melting point 261-262 ° C (decomp.) ¹ H-NMR (DMSO-d ₆ ) 1.65 (brs, 6H), 2.90 (s, 3H), 3.04, 3.46 (each t, each J
= 5.9Hz, each 2H), 3.21 (brs, 4H), 7.90 (d, J = 12.8Hz, 1H),
8.73 (s, 1H)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location // (C07D 519/00 471: 00) (C07D 519/00 471: 00 487: 00) (72 ) Inventor Norihiro Hayashi 1624 Shimokatsu, Koda-cho, Takada-gun, Hiroshima Prefecture Yunai Pharmaceutical Co., Ltd. Toshi, 1624 Shimodate, Koda-cho, Takada-gun, Hiroshima Prefecture Yunai Pharmaceutical Co., Ltd.

Claims (2)

[Claims] 1. The following general formula (1): [In the formula, R ¹ represents a hydrogen atom or a carboxy protecting group,
R ² represents a hydrogen atom, a halogen atom, an amino group or a protected amino group, R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ represents a hydrogen atom or a lower alkyl group which may have a substituent. , An acyl group or an aralkyl group, X represents a hydrogen atom or a halogen atom, Y represents a halogen atom,
An amino group, a hydroxyl group, a cyclo lower alkylamino group, a mono- or di-lower alkylamino group, a cyclic amino group which may have a substituent, a lower alkyl group which may have a substituent, and a substituent Optionally substituted cyclo-lower alkenyl group, formula R ^5- (CH ₂ ) _m -A- (wherein R ⁵ is a hydrogen atom, an optionally substituted amino group, or a substituted group Optionally represents a saturated heterocyclic group containing a nitrogen atom or a cyclo lower alkyl group which may have a substituent, A represents an oxygen atom or a sulfur atom, and m represents an integer of 0 to 3). A group represented by or a formula R ⁶ -SO ₂ O- (where R
⁶ represents a lower alkyl group, a halo lower alkyl group or a phenyl group optionally substituted by 1 to 3 with a lower alkyl group), and n represents an integer of 0 to 2]
A tricyclic compound represented by or a salt thereof. 2. An antibacterial agent containing the tricyclic compound or its salt according to claim 1 as an active ingredient.