JPH10291988A - Heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new heterocyclic compound having a vacuole type H<+> - adenosince trihosphosphatase-inhibiting activity and a bone resorption-inhibiting activity and useful for preventing and treating bone diseases caused by abnormal bone metabolism. SOLUTION: A compound of fomrula I (R' is a substitutable heterocyclic group, an aryl; R<2> is H, a lower alkyl; R<3> is H, a halogen, etc.; R<4> is a substituted amino or hydrazino, a heterocyclic group, etc.; R<5> , R<6> , R<7> are each H, a halogen, a lower alkyl; A is CONH, etc.), e.g. 8-(2,6- dichlorobenzoylamino)-4-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-3-methyl quionline. The compound of formula I is obtained by reacting a compound of formula II with a compound of the formula: R<1> -COOH. The compound of formula I can prevent and treat osteoporosis, hypercalcemia, hyperparathyroidism, Paget's disease of bone, rheumatic arthropathia, periodontal disease, hypertrophic arthritis, osteocopic pain, osteopenia, cancer cachexia, malignant tumor, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to heterocyclic compounds and pharmaceutically acceptable salts thereof.

More specifically, the present invention relates to vacuolar H ⁺ -adenosine triphosphatase (H ⁺ -ATPase),
In particular, it has osteoclast H ⁺ -ATPase inhibitory activity and bone resorption inhibitory activity, and thus is useful as a bone resorption inhibitor or a bone metastasis inhibitor for the prevention and / or treatment of bone diseases caused by abnormal bone metabolism in humans or animals. It relates to heterocyclic compounds and pharmaceutically acceptable salts thereof.

[0003]

2. Related Background Art Chem. Soc. Pa
k. (1995), 17 (4), 232-6; A
m. Chem. Soc. (1994), 116 (2
4), 11014-19; or Chem. Phar
m. Bull. (1990), 38 (10), 2841
As described in -6, some heterocyclic compounds are known. However, it is not known that the above compounds have an inhibitory activity on vacuolar H ⁺ -ATPase or an activity on inhibiting bone resorption.

[0004]

The heterocyclic compound aimed at by the present invention is novel and has the following general formula [I]:

[0005]

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Wherein R ¹ is a heterocyclic group or an aryl group, each of which is halogen, nitro, lower alkyl, lower alkoxy, hydroxy, ar (lower) alkoxy, halo (lower) alkyl, acyl, aryl, heterocyclic R ² is hydrogen or a lower alkyl group, R ³ is hydrogen, a halogen, a cyano group, which may be substituted with a substituent selected from the group consisting of a group, lower alkenyl and lower alkylthio.
A lower alkyl group, a hydroxy (lower) alkyl group or a lower alkoxy (lower) alkyl group, wherein R ⁴ is hydrogen, an amino group, a substituted amino group, a hydrazino group, a substituted hydrazino group, a hydroxy group, a substituted hydroxy group; A mercapto group, a substituted mercapto group, an ar (lower) alkylsulfinyl group, an ar (lower) alkylsulfonyl group, a substituted or unsubstituted heterocyclic group, or a substituent selected from the group consisting of acyl and cyano Or R ³ and R ⁴ together form a group of the formula

[0007]

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(Wherein R ⁸ represents hydrogen or a lower alkyl group), R ⁵ , R ⁶ and R
⁷ is hydrogen, a halogen or a lower alkyl group,
A is -CONH -, - NHCO -, - NHSO 2 - or -NHCONH- the mean, respectively. Where R ⁴
When is hydrogen, R ³ is not hydrogen. ].

The target compound [I] or a salt thereof can be produced by various methods represented by the following reaction formulas.

Manufacturing method 1

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Manufacturing method 2

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Manufacturing method 3

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Manufacturing method 4

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Manufacturing method 5

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Manufacturing method 6

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[0016] (In the above formulas, R ⁴ _a is a substituted amino group, a hydrazino group, a substituted hydrazino group or a substituted or unsubstituted N- containing heterocyclic -N- yl group,, Q is a lower alkylene group , X is halogen, Y is -O- or

[0017]

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(Wherein R ⁹ is hydrogen, a lower alkyl group, a lower alkoxy (lower) alkyl group, an acyl (lower) alkyl group, a lower alkenyl group, an aryl group, or an optionally substituted halogen atom. (Indicating a (lower) alkyl group), and Z is O or S, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , R ⁷ and A each represent the same as defined above. )

In the foregoing and following description of this specification, preferred examples of various definitions falling within the scope of the present invention will be described in detail below. Unless otherwise specified,
It means a group having 1 to 6 carbon atoms. In this connection, the term "lower" in the lower alkenyl moiety in the various definitions means a group having 2 to 6 carbon atoms.

All suitable heterocyclic moieties in the various definitions described herein, such as preferred "heterocyclic groups" and "heterocyclic (lower) alkyl" include nitrogen, oxygen or sulfur atoms And a saturated or unsaturated monocyclic or polycyclic group having at least one heteroatom, more preferably an N, O and / or S-containing heterocyclic group, and more preferably. , Morpholinyl, piperazinyl, pyridyl, dihydropyridyl, tetrahydropyridyl, pyrimidinyl, hexahydropyrimidinyl, pyrazinyl, pyridazinyl, piperidyl, thienyl, furyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl Zolyl, azetidinyl, pyrrolidinyl, pyrrolyl, oxiranyl, tetrahydrofuryl, piperonyl, indolyl, indolinyl, quinolyl, isoquinolyl, cinnolinyl, acridinyl, benzimidazolyl, benzimidazolidinyl, benzoxazolyl, imidazolinyl, imidazolidinyl, pyridinyl 4,5-b] pyridyl and pyrazolo [3,4-b] pyridyl.

Preferred "aryl" include phenyl,
Examples include naphthyl, fluorenyl, phenyl substituted with lower alkyl [eg, tolyl, xylyl, mesityl, cumenyl, di (tert-butyl) phenyl and the like], and more preferred are phenyl, naphthyl and tolyl. Can be mentioned.

Suitable "halogens" include fluorine, chlorine, bromine and iodine.

Preferred "lower alkyl" and "heterocyclic (lower) alkyl", "hydroxy (lower) alkyl", "lower alkoxy (lower) alkyl", "lower alkylthio", "lower alkylsulfonyl", "acyl ( All suitable lower alkyl moieties in the various definitions described herein, such as "lower) alkyl" include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. tertiary butyl, may be mentioned pentyl, hexyl, and the like, and more preferred are, C ₁ -C ₄ alkyl, for example may be mentioned methyl, ethyl, propyl, butyl, isobutyl or tert-butyl.

Suitable lower alkoxy moieties in the preferred "lower alkoxy" and "lower alkoxy (lower) alkyl" include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, can be exemplified pentyloxy, etc. hexyloxy, more preferred are, C ₁ -C ₄ alkoxy, for example may be mentioned methoxy, ethoxy or isopropoxy.

Preferred "ar (lower) alkoxy" include benzyloxy, phenethyloxy, benzhydryloxy, trityloxy and the like, and most preferred is benzyloxy.

Preferred "halo (lower) alkyl" include chloromethyl, bromoethyl, dichloromethyl, difluoromethyl, trifluoromethyl and the like, and most preferred is trifluoromethyl. .

Suitable "ar (lower) alkyl" and "ar (lower) alkylsulfinyl", "ar (lower) alkylsulfonyl", "ar (lower) alkylamino (lower) alkyl" and the like are described herein. All suitable ar (lower) alkyl moieties in the various definitions given may include benzyl, phenethyl, benzhydryl, trityl, naphthylmethyl and the like.

Preferred "N-containing heterocyclic-N-yl groups" include morpholino, thiomorpholino, pyrrolidine-1
-Yl, piperidino, 1,2,3,6-tetrahydropyridin-1-yl, piperazin-1-yl, imidazol-1-yl, imidazolin-1-yl, imidazolidine-1-yl, benzimidazole-1- Yl, benzimidazolidin-1-yl, pyrazol-1-yl, pyrazolidin-1-yl, hexahydropyrimidin-1-
Yl, oxazolidine-1-yl, triazole-1-
And the like.

Suitable "lower alkylenes" are straight-chain or branched, for example, methylene, ethylene, trimethylene, methylmethylene, dimethylmethylene, tetramethylene, ethylethylene, dimethylethylene, propylene, pentamethylene, hexamethylene. And the most preferable one is methylene.

Suitable substituents for amino in "substituted amino" include hydroxy (lower) alkyl [eg, hydroxymethyl, hydroxyethyl, etc.], amino (lower) alkyl [eg, aminomethyl, aminoethyl, aminopropyl, 2-amino-2-methylpropyl, etc.], lower alkylamino (lower) alkyl [eg, methylaminomethyl, methylaminoethyl, ethylaminoethyl, n-propylaminoethyl, isopropylaminoethyl, methylaminopropyl, etc.], al ( Lower) alkylamino (lower) alkyl [for example, phenyl (lower) alkylamino (lower) alkyl (for example, benzylaminoethyl etc.)], lower alkoxy (lower) alkylamino (lower) alkyl [for example, methoxyethyla Aminoethyl, etc.], lower alkanoyl [e.g. acetyl, etc.], lower alkylsulfonyl [e.g., methylsulfonyl] and the like.

Suitable substituents for hydrazino in “substituted hydrazino” include lower alkyl, acyl [eg lower alkanoyl, aroyl (eg benzoyl etc.), heterocyclic carbonyl (eg furoyl,
Tenoyl, etc.), heterocyclic (lower) alkanoyl (eg, pyridylacetyl, thienylacetyl, etc.), lower alkylsulfonyl, etc.].

Suitable substituents for hydroxy in "substituted hydroxy" include lower alkyl [eg, methyl, ethyl, isopropyl, etc.] and hydroxy (lower) alkyl [eg, hydroxymethyl, hydroxyethyl, 3-hydroxy-3- Methylbutyl etc.], lower alkoxy (lower) alkyl [eg methoxymethyl, methoxyethyl etc.], acyl [eg lower alkylcarbamoyl etc.], substituted or unsubstituted ar (lower) alkyl [eg benzyl; nitro, lower alkyl, lower alkylthio] Benzyl substituted with halo (lower) alkyl, carboxy, lower alkoxycarbonyl or halogen; etc.], substituted or unsubstituted heterocyclic lower alkyl [eg furyl (lower) alkyl; thienyl (lower) alkyl Pyridyl (lower) alkyl; benzimidazolyl (lower) alkyl; thiazolyl (lower) alkyl substituted with lower alkyl; pyridyl (lower) alkyl substituted with lower alkyl, carboxy, lower alkoxycarbonyl or lower alkylcarbamoyl; Acyl (lower) alkyl [for example, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, carbamoyl (lower) alkyl, lower alkylcarbamoyl (lower) alkyl, lower alkoxycarbamoyl (lower) alkyl, N- (lower alkyl)
-N- (lower alkoxy) carbamoyl (lower) alkyl, lower alkoxy (lower) alkylcarbamoyl (lower) alkyl, lower alkylsulfonyl (lower) alkyl, phenylcarbamoyl (lower) alkyl, N- (lower alkyl) -N-phenyl Carbamoyl (lower) alkyl, benzylcarbamoyl (lower) alkyl, N-
(Lower alkyl) -N-benzylcarbamoyl (lower)
Alkyl, piperidinocarbonyl (lower) alkyl, azetidinylcarbonyl (lower) alkyl, pyrrolidinylcarbonyl (lower) alkyl, 4- (lower alkyl) piperazinylcarbonyl (lower) alkyl, N- (lower alkyl) -N-pyridylcarbamoyl (lower) alkyl, morpholinocarbonyl (lower) alkyl, etc.], substituted or unsubstituted aryl [eg, phenyl; lower alkoxy, imidazolyl, halogen, nitro, hydroxy (lower) alkyl, lower alkanoyl, carboxy,
Phenyl substituted with lower alkoxycarbonyl, carbamoyl or lower alkylcarbamoyl; etc.), substituted or unsubstituted heterocyclic groups [eg benzimidazolyl; halogen, lower alkyl, lower alkylamino (lower) alkyl, carboxy or lower alkoxycarbonyl Optionally substituted pyridyl; and the like].

Suitable substituents of mercapto in "substituted mercapto" include ar (lower) alkyl [eg benzyl etc.] and substituted or unsubstituted heterocyclic groups [eg optionally substituted with lower alkyl. Good imidazolyl; pyridyl; benzoxazolyl; benzimidazolyl; imidazo [4,5-b] pyridyl; thiazolyl; thiazolinyl; thiadiazolyl optionally substituted with lower alkyl; optionally substituted with lower alkyl Good tetrazolyl; triazolyl optionally substituted with lower alkyl; and the like].

Heterocyclic group in "substituted or unsubstituted heterocyclic group", "substituted or unsubstituted N-containing heterocyclic-N-yl group" or "substituted or unsubstituted heterocyclic (lower) alkyl group" Examples of suitable substituents include halogen, lower alkyl, lower alkenyl, hydroxy (lower) alkyl [eg, hydroxymethyl, hydroxyethyl and the like], lower alkoxy (lower) alkyl [eg methoxymethyl, methoxyethyl, ethoxyethyl and the like],
Oxo, thioxo, hydroxy, acyl [eg, lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, etc.],
Acyl (lower) alkyl [eg carboxy (lower)
Alkyl, lower alkoxycarbonyl (lower) alkyl, carbamoyl (lower) alkyl, lower alkylcarbamoyl (lower) alkyl, etc.], acyl (lower) alkenyl [eg, lower alkoxycarbonyl (lower) alkenyl (eg, methoxycarbonylvinyl, etc.)], Examples include aryl [eg, phenyl], ar (lower) alkyl optionally substituted with halogen [eg, benzyl, chlorobenzyl, etc.], cyanoimino and the like.

Suitable substituents for aryl in "substituted or unsubstituted aryl" or "substituted or unsubstituted ar (lower) alkyl" include halogen, nitro,
Hydroxy (lower) alkyl [eg, hydroxymethyl, hydroxyethyl, 1-hydroxy-1-methylethyl, etc.], lower alkyl, halo (lower) alkyl, acyl [eg lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl] Etc.] and lower alkylthio.

Preferred "acyl" and "acyl (lower)"
All suitable acyl moieties in the various definitions described herein, such as "alkenyl", "acyl (lower) alkyl" include lower alkanoyl [e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, Pivaloyl, hexanoyl, 3,3-dimethylbutyryl, etc.], heterocyclic (lower)
Alkanoyl [eg thienylacetyl, imidazolylacetyl, pyridylacetyl, pyridylpropionyl etc.], carboxy, eg lower alkoxycarbonyl [eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl , Pentyloxycarbonyl,
Hexyloxycarbonyl or the like], an esterified carboxy, a heterocyclic carbonyl optionally substituted with a substituent [for example, furoyl, thenoyl, pyridylcarbonyl, imidazolylcarbonyl, morpholinocarbonyl, piperidinocarbonyl, azetidinylcarbonyl,
Pyrrolidinylcarbonyl, 1-methylimidazolylcarbonyl, 4-methyl-1-piperazinylcarbonyl, 4
-Ethyl-1-piperazinylcarbonyl, dimethylaminopiperidinocarbonyl, 4-methylcarbamoyl-1
-Piperazinylcarbonyl, 4-acetyl-1-piperazinylcarbonyl, 4-phenyl-1-piperazinylcarbonyl, chlorothenoyl, 1,2,3,6-tetrahydropyridylcarbonyl, pyrrolidinylcarbonyl, indolylcarbonyl Etc.], aroyl optionally substituted with a substituent [eg benzoyl, naphthoyl, methoxybenzoyl, dichlorobenzoyl, trifluoromethylbenzoyl etc.], eg carbamoyl, lower alkylcarbamoyl [eg methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropyl] Carbamoyl, butylcarbamoyl, isobutylcarbamoyl, tertiary butylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N Methylcarbamoyl, etc.], lower alkoxy (lower) alkylcarbamoyl [e.g. methoxy methylcarbamoyl, etc. methoxyethylcarbamoyl, lower alkoxycarbonyl carbamoyl [e.g. methoxycarbamoyl, an ethoxy carbamoyl, N-
(Lower alkyl) -N- (lower alkoxy) carbamoyl [eg N-methyl-N-methoxycarbamoyl etc.], such as arylcarbamoyl [eg phenylcarbamoyl, tolylcarbamoyl, xylylcarbamoyl, naphthylcarbamoyl, ethylphenylcarbamoyl etc.], halo ( Substituted or unsubstituted arylcarbamoyl such as lower) alkylarylcarbamoyl [eg trifluoromethylphenylcarbamoyl], N-aryl-N- (loweralkyl) carbamoyl [eg N-phenyl-N-methylcarbamoyl etc.], al ( Lower) alkylcarbamoyl [eg benzylcarbamoyl, phenethylcarbamoyl and the like],
N-Al (lower) alkyl-N- (lower alkyl) carbamoyl [eg N-benzyl-N-methylcarbamoyl, N-phenethyl-N-methylcarbamoyl etc.], lower alkylsulfonylcarbamoyl [eg methylsulfonylcarbamoyl, ethylsulfonylcarbamoyl Etc.], heterocyclic carbamoyl [eg pyridylcarbamoyl, imidazolylcarbamoyl, pyrazolylcarbamoyl etc.], N-heterocycle-N- (lower alkyl) carbamoyl [eg N-pyridyl-N-methylcarbamoyl etc.], eg heterocycle (lower) Alkylcarbamoyl [eg pyridylmethylcarbamoyl,
Pyridylethylcarbamoyl, oxadiazolylmethylcarbamoyl, furylmethylcarbamoyl, thienylmethylcarbamoyl, tetrahydrofurylmethylcarbamoyl, piperonylmethylcarbamoyl, indolylethylcarbamoyl, imidazolylethylcarbamoyl, etc.], lower alkyl heterocyclic (lower) alkylcarbamoyl [ Substituted or unsubstituted heterocyclic (lower) alkylcarbamoyl such as methylpyridylmethylcarbamoyl, methyloxadiazolylmethylcarbamoyl and the like; substituted or unsubstituted carbamoyl and lower alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propyl Sulfonyl etc.] and arylsulfonyl [eg phenylsulfonyl, tolylsulfonyl etc.] Can. "Acyl (lower) alkenyl" or "lower alkoxycarbonyl (lower)
Suitable lower alkenyl moieties in "alkenyl" include vinyl, allyl, 1-propenyl, methylpropenyl, butenyl, methylbutenyl, pentenyl and the like.

Suitable pharmaceutically acceptable salts of the target compound [I] are conventional non-toxic salts, and include metal salts such as alkali metal salts [eg sodium salt, potassium salt and the like] and alkaline earth metal salts. [For example, calcium salt, magnesium salt, etc.]; ammonium salt; organic base salt [for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt and the like];
Organic acid addition salts [eg, formate, acetate, trifluoroacetate, maleate, tartrate, oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]; inorganic acid addition salts [ For example, hydrochloride, hydrobromide, sulfate, phosphate, etc.]; salts with amino acids [eg, arginine, aspartate, glutamate, etc.]; inner salts and the like. Manufacturing method 1
As for the salts of the compounds [Ia] to [Ig] in the above-mentioned to 6, since these compounds are included in the scope of the compound [I], preferable examples of the salts of these compounds include
The same compounds as those described for the target compound [I] can be mentioned.

Preferred examples of the target compound [I] include:
The following can be mentioned. R ¹ is a heterocyclic group or an aryl group, each of which is halogen, nitro, lower alkyl, lower alkoxy, hydroxy, ar (lower) alkoxy, halo (lower) alkyl, acyl, aryl, heterocyclic group, lower alkenyl and lower alkylthio. Which may be substituted with a substituent selected from the group consisting of [more preferably, phenyl substituted with 1 or 2 halogens; phenyl substituted with nitro; 1 or 2 halo (lower)] Phenyl substituted with alkyl; phenyl substituted with halo (lower) alkyl and hydroxy; phenyl substituted with 1 or 2 halogen and hydroxy; phenyl substituted with 1 or 2 or 3 hydroxy Phenyl substituted with one or two or three benzyloxys; substituted with phenyl Phenyl substituted with halogen and halo (lower) alkyl; naphthyl; naphthyl substituted with halogen; naphthyl substituted with lower alkyl; quinolyl; pyridyl; pyrazinyl; pyridyl substituted with hydroxy; Pyridyl substituted with two lower alkyls; pyridyl substituted with a lower alkoxy; pyridyl substituted with one or two halogens; pyridyl substituted with halo (lower) alkyl; pyridyl substituted with lower alkylthio Pyridyl substituted with one or two halogens and lower alkyl; lower alkenyl-substituted pyridyl; pyrimidinyl substituted with lower alkyl; indolyl; indolyl substituted with lower alkyl; indolinyl; substituted with lower alkoxycarbonyl Indolinyl Cinnolinyl; acridinyl; 1
Pyrrolyl substituted with one or two lower alkyl and halogen; pyrazolyl substituted with lower alkyl and nitro; pyrazolyl substituted with halo (lower) alkyl and phenyl; substituted with one or two lower alkyl and halogen Pyrazolyl substituted with one or two lower alkyls; thiazolyl substituted with one or two lower alkyls; thiazolyl substituted with one or two lower alkyls; or one or two lower alkyls and halogens Pyrazolo [3,4-
b] pyridyl], R ² is hydrogen or a lower alkyl group, R ³
Is hydrogen, halogen, cyano group, lower alkyl group, hydroxy (lower) alkyl group or lower alkoxy (lower)
Alkyl group, R ⁴ is hydrogen, amino group, substituted amino group [more preferably hydroxy (lower) alkyl, amino (lower) alkyl, lower alkylamino (lower) alkyl, ar (lower) alkylamino (lower) Alkyl (for example, phenyl (lower) alkylamino (lower) alkyl, etc.), lower alkoxy (lower) alkylamino (lower) alkyl, lower alkylsulfonyl and lower alkanoyl, an amino group substituted with a substituent selected from the group consisting of hydrazino Group, a substituted hydrazino group [more preferably, a hydrazino substituted with a substituent selected from the group consisting of lower alkyl and acyl (eg, lower alkanoyl, lower alkylsulfonyl, thienyl (lower) alkanoyl, benzoyl, furylcarbonyl, etc.) Group],

Hydroxy group, substituted hydroxy group [more preferably lower alkyl, hydroxy (lower) alkyl, lower alkoxy (lower) alkyl, acyl (eg lower alkylcarbamoyl etc.), substituted or unsubstituted ar (lower) alkyl (Eg benzyl; lower alkyl, lower alkylthio, halo (lower) alkyl,
Benzyl substituted with carboxy, lower alkoxycarbonyl, nitro or halogen; and the like; substituted or unsubstituted heterocyclic (lower) alkyl (eg, furyl (lower) alkyl; thienyl (lower) alkyl; pyridyl (lower) alkyl; benz Imidazolyl (lower) alkyl; thiazolyl (lower) alkyl substituted with lower alkyl; pyridyl (lower) substituted with carboxy, lower alkoxycarbonyl or lower alkylcarbamoyl
Alkyl; etc.), acyl (lower) alkyl (eg, carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, carbamoyl (lower) alkyl,
Lower alkylcarbamoyl (lower) alkyl, lower alkoxycarbamoyl (lower) alkyl, N- (lower alkyl) -N- (lower alkoxy) carbamoyl (lower)
Alkyl, lower alkoxy (lower) alkylcarbamoyl (lower) alkyl, lower alkylsulfonyl (lower)
Alkyl, phenylcarbamoyl (lower) alkyl, N
-(Lower alkyl) -N-phenylcarbamoyl (lower) alkyl, benzylcarbamoyl (lower) alkyl, N- (lower alkyl) -N-benzylcarbamoyl (lower) alkyl, piperidinocarbonyl (lower) alkyl, azetidinyl Carbonyl (lower) alkyl, pyrrolidinylcarbonyl (lower) alkyl, 4- (lower alkyl) piperazinylcarbonyl (lower) alkyl, N-
(Lower alkyl) -N-pyridylcarbamoyl (lower)
Alkyl, morpholinocarbonyl (lower) alkyl, etc.), substituted or unsubstituted aryl (eg, phenyl; halogen, nitro, hydroxy (lower) alkyl,
Phenyl substituted with lower alkanoyl, carboxy, lower alkoxycarbonyl, carbamoyl or lower alkylcarbamoyl; etc.) and substituted or unsubstituted heterocyclic groups (for example, optionally substituted with lower alkyl, carboxy, lower alkoxycarbonyl, etc.) A hydroxy group substituted with a substituent selected from the group consisting of

A mercapto group, a substituted mercapto group [more preferably, an ar (lower) alkyl (eg, benzyl and the like) and a substituted or unsubstituted heterocyclic group (eg, imidazolyl optionally substituted with a lower alkyl; Pyridyl; benzoxazolyl; thiazolyl;
Tetrazolyl optionally substituted with lower alkyl; triazolyl optionally substituted with lower alkyl; benzimidazolyl; imidazo [4,5-b]
A mercapto group substituted with a substituent selected from the group consisting of pyridyl; etc.), an alk (lower) alkylsulfinyl group [more preferably benzylsulfinyl], an alk (lower) alkylsulfonyl group [more preferably benzylsulfonyl],

A substituted or unsubstituted heterocyclic group [more preferably imidazolyl optionally substituted with lower alkyl, hydroxy (lower) alkyl, phenyl or lower alkoxycarbonyl (lower) alkenyl; triazolyl; benzimidazolyl; oxo Or oxazolidinyl optionally substituted with thioxo; pyrrolidinyl optionally substituted with lower alkoxy (lower) alkyl; optionally substituted with lower alkyl, lower alkoxy (lower) alkyl, and halogen Ar (lower) alkyl, cyanoimino, aryl, lower alkenyl, acyl (lower) alkyl, oxo and / or
Or imidazolidinyl optionally substituted with thioxo; or lower alkyl, lower alkoxy (lower) alkyl, ar (lower) alkyl, cyano imino,
Hexahydropyrimidinyl optionally substituted with oxo and / or thioxo], or

A lower alkyl group optionally substituted with a substituent selected from the group consisting of acyl and cyano [more preferably a lower alkyl group optionally substituted with carbamoyl, lower alkoxycarbonyl and / or cyano group], R ⁵ is hydrogen, halogen or a lower alkyl group, R ⁶ is hydrogen, halogen or lower alkyl, R ⁷ is hydrogen, halogen or lower alkyl, A is -CONH -, - NHCO -, - NHSO 2 - Or -NHCONH- [more preferably -NHCO-].

More preferred examples of the target compound [I] include the following.

Equation

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Wherein R ¹ is a phenyl group substituted with one or two halogens; a phenyl group substituted with trifluoromethyl; a phenyl group substituted with one or two halogens and hydroxy; Or a phenyl group substituted with trifluoromethyl and hydroxy, R ² is hydrogen, R ³ is a lower alkyl group [more preferably C ₁ -C ₄ alkyl, most preferably methyl], and Q is a lower alkylene group [more preferably C ₂ -C ₄ alkyl, most preferably ethylene], Y is —O— or

[0046]

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(Wherein R ⁹ represents a lower alkyl group [more preferably C1-C4 alkyl, most preferably ethyl]), and Z represents O or S, respectively. ] It is a compound represented by these.

The production method of the desired compound [I] is described in detail below. Production Method 1 The target compound [Ia] or a salt thereof is prepared by reacting the compound [II] or a reactive derivative thereof at an amino group or a salt thereof with the compound [III] or a reactive derivative thereof at a carboxy group or a salt thereof. Can be manufactured. A suitable reactive derivative at the amino group of compound [II] may be a silyl derivative formed by reacting compound [II] with a silyl compound such as bis (trimethylsilyl) acetamide or mono (trimethylsilyl) acetamide.

Suitable salts of the compound [II] and its reactive derivative are the same as those described for the compound [I]. Suitable reactive derivatives at the carboxy group of the compound [III] include acid halides, acid anhydrides, active amides, active esters and the like.

Preferred examples of the reactive derivative include acid chlorides; acid azides; mixed acid anhydrides with acids such as dialkyl phosphoric acid, sulfuric acid, aliphatic carboxylic acids or aromatic carboxylic acids;
Symmetric acid anhydrides; active amides with imidazole; or active esters, such as p-nitrophenyl ester. These reactive derivatives are
It can be arbitrarily selected depending on the type of the compound [III] used. Suitable salts of compound [III] and its reactive derivative include the same salts as those described for compound [I].

This reaction is usually carried out in a conventional solvent such as methylene chloride, chloroform, ethylene chloride, pyridine, dioxane, tetrahydrofuran, N, N-dimethylformamide and the like. When compound [III] is used in free acid or salt form, the reaction is carried out with a conventional condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N'-dicyclohexylcarbodiimide. It is preferably performed in the presence. The reaction temperature is not particularly limited, and the reaction is performed under cooling, at room temperature, or under heating. This reaction is preferably performed in the presence of a conventional inorganic base or a conventional organic base.

Production Method 2 The target compound [Ib] or a salt thereof is obtained by reacting a compound [IV] or a reactive derivative thereof at a carboxy group or a salt thereof with a compound [V] or a reactive derivative thereof at an amino group or a salt thereof. It can be manufactured by doing. Suitable salts of the compounds [IV] and [V] and their reactive derivatives include the same salts as those described for the compound [I]. Since this reaction is carried out in substantially the same manner as in Production Method 1, the description of Production Method 1 may be referred to for the reaction format and reaction conditions of this reaction.

Production Method 3 The target compound [Ic] or a salt thereof can be produced by reacting the compound [II] or a salt thereof with the compound [VI] or a reactive derivative thereof at a sulfo group or a salt thereof. . Suitable reactive derivatives in the sulfo group include sulfonyl halide and the like. These reactive derivatives can be arbitrarily selected depending on the type of the compound [VI] to be used. Suitable salts of compound [VI] and its reactive derivative include:
The same compounds as those described for the compound [I] can be mentioned. Since this reaction is carried out in substantially the same manner as in Production Method 1, the description of Production Method 1 may be referred to for the reaction format and reaction conditions of this reaction.

Production Method 4 The target compound [Id] or a salt thereof can be produced by reacting the compound [II] or a salt thereof with the compound [VII] or a salt thereof. Compound [VI
Suitable salts of I] can be the same as those given for compound [I]. This reaction is usually performed in a conventional solvent such as tetrahydrofuran, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, toluene and the like. The reaction temperature is not particularly limited.
The reaction is carried out at room temperature, under heating or under heating.

Production Method 5 The target compound [Ie] or a salt thereof is prepared by reacting the compound [VII]
I] or a salt thereof with compound [IX] or a salt thereof. Compound [V
Suitable salts of [III] and [IX] include the same as those shown for compound [I]. This reaction usually involves tetrahydrofuran, dioxane,
It is carried out in a conventional solvent such as N, N-dimethylformamide, N-methylpyrrolidone. The reaction temperature is not particularly limited, and the reaction is usually performed under heating or heating.

Production Method 6 The desired compound [Ig] or a salt thereof can be produced by subjecting the compound [If] or a salt thereof to a reaction for introducing a carbonyl group or a thiocarbonyl group. In this reaction, a reagent for introducing a carbonyl group or a thiocarbonyl group, for example, phosgene, triphosgene, a haloformate compound [eg, ethyl chloroformate, trichloromethyl chloroformate, etc.], 1,1′-carbonyldiimidazole, 1,1′- The reaction is performed in the presence of thiocarbonyldiimidazole or the like.

This reaction is usually carried out in a solvent which does not adversely influence the reaction, for example, dioxane, tetrahydrofuran,
Benzene, toluene, chloroform, methylene chloride,
It is performed in N, N-dimethylformamide or other organic solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. The target compound [I] and the starting compound can also be produced by the methods of the following Examples and Production Examples, the same methods as those described above, or conventional methods. The compound obtained according to the above-mentioned production method can be separated and purified by a conventional method such as grinding, recrystallization, chromatography, reprecipitation and the like.

The compound [I] and other compounds may have one or more stereoisomers and geometric isomers based on asymmetric carbon atoms and double bonds. All of the mixtures of the above are also included in the scope of the present invention.

The compounds of the formula [I] and salts thereof may be solvates, which are also included in the scope of the present invention. Preferred solvates include hydrates and ethanolates.

The target compound [I] and a pharmaceutically acceptable salt thereof have an activity of inhibiting vacuolar H ⁺ -ATPase, particularly osteoclast H ⁺ -ATPase, and an activity of inhibiting bone resorption. Diseases due to abnormal bone metabolism in humans or animals as agents or bone metastasis inhibitors
For example, osteoporosis (particularly postmenopausal osteoporosis); hypercalcemia; hyperparathyroidism; bone Paget disease; osteolysis; malignant hypercalcemia with or without bone metastasis; rheumatoid arthritis; periodontitis; Osteoarthritis; bone pain;
Osteopenia; cancer cachexia; useful for prevention and / or treatment of malignant tumors and the like.

Furthermore, the target compound [I] of the present invention and a pharmaceutically acceptable salt thereof can be used in a tumor in humans or animals, particularly tumors associated with renal cancer, melanoma, colon cancer, lung cancer and leukemia; For example, Semliki Forest fever, vesicular stomatitis, Newcastle disease, influenza A and B, those associated with the HIV virus); ulcers (eg, chronic gastritis, peptic ulcer induced by Helicobacter pylori); autoimmune diseases; organ transplantation; Useful in the prevention and / or treatment of hypercholesterolemia and atherosclerotic diseases; AIDS; Alzheimer's disease; diabetic retinopathy, vascular-derived diseases such as psoriasis and solid tumors; and men in humans or animals It is expected to be useful for adjusting fertility.

In order to show the usefulness of the target compound [I],
Pharmacological test data of some representative compounds of compound [I] are shown below.

Test 1 (Inhibition of vacuolar H ⁺ -ATPase proton transport) Test method (a) Preparation of microsomes from mouse peritoneal macrophages To 7-week-old male ddy mice, 2 ml of 3% thioglycolate medium was intraperitoneally injected. Injected. Three to five days later, the mice were decapitated and washed intraperitoneally with 5 to 6 ml of Hank's solution (HBSS) to obtain peritoneal macrophages. Cells were washed twice with cold HBSS. Vesicles were prepared from the cells and 10 ml of 250 mM sucrose, 5 ml using a Dounce homogenizer.
M Tris, 1 mM EGTA, 1 mM KHCO ₃ and 1 mM dithiothreitol (pH 7.0 at 4 ° C.).
Times homogenized. After an initial centrifugation (1000 × g for 5 minutes), the supernatant was centrifuged (6000 × g for 15 minutes) to remove mitochondria and lysosomes. The supernatant was centrifuged at 42000 × g for 30 minutes, and the microsomal pellet was collected and stored at −80 ° C.

(B) Measurement of proton transport Proton transport includes 150 mM KCl, 10 mM bis-trispropane, ₂ mM MgCl ₂ , 10 μM acridine orange, 1 μM valinomycin, 10 μg / ml oligomycin and the test compound (concentration: 1 × 10 ⁻⁶ M). Using aliquots of membrane vesicles suspended in 300 μl of reaction buffer (pH 7.0), the incorporation of acridine orange was measured by a dual wavelength spectrophotometer (reference wavelength 540 n
m, measurement wavelength 492 nm). C. Blair, J .; Cell. Biol. ,
102, 1164 (1986)]. Reaction is 1 mM AT
Started by addition of P. The results were expressed as percentage inhibition relative to controls.

Test results

[0066]

[Table 1]

Test 2 (Bone tissue culture) Test method The calvaria was removed from Wistar rats, and 10% fetal bovine serum and 10 ^-8 M human parathyroid hormone were present in the presence of the test compound (concentration: 1 × 10 ⁻⁶ M). Piece (1-34) [P
[TH] was added to a well of a 12-well culture dish containing 2 ml of Dulbecco's modified minimum essential medium. No PTH was added to control wells. Controls and PTH controls were exposed to equal concentrations of vehicle. Six days later, the calcium ([Ca]) concentration in the medium was measured by the methyl xylenol blue method, and the inhibition rate of PTH-induced bone resorption was calculated by the following equation.

[0068]

(Equation 1)

Test results

[Table 2]

For treatment, the compounds [I] of the invention
And pharmaceutically acceptable salts thereof, using one of the compounds as an active ingredient, orally; parenteral administration such as intravenous, intramuscular, subcutaneous or intraarticular administration; external use such as transdermal, intestinal, In the form of a pharmaceutical formulation containing a pharmaceutically acceptable carrier such as an organic or inorganic solid, semi-solid or liquid excipient suitable for rectal, vaginal, inhalation, ocular, intranasal or sublingual administration Can be used. The pharmaceutical preparation may be a capsule, tablet, dragee, granule, suppository, liquid, lotion, suspension, emulsion, ointment, gel, cream, and the like. If necessary, the above preparations may contain adjuvants, stabilizers, wetting or emulsifying agents, buffers and other conventional additives.

The dose of compound [I] varies depending on the age and symptoms of the patient, but the average dose of compound [I] is about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 m
g, 250 mg, 500 mg and 1000 mg are effective in preventing and / or treating the above-mentioned diseases. Generally, an amount in the range of 0.1 mg to about 1000 mg per day may be administered per person.

[0072]

The following examples and manufacturing examples are provided to illustrate the present invention.

Example 1 (1) 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (2.0 g) in water (30 m
The suspension in 1) was refluxed for 15 minutes and allowed to stand at room temperature. The resulting precipitate was collected by filtration and washed with water to give 1,4-dihydro-3-hydroxymethyl-8-nitro-4-oxoquinoline (1.82 g). mp: 182-184 ° C NMR (DMSO-d ₆ , δ): 4.41 (2H, s), 5.14 (1H, br),
7.49 (1H, t, J = 7Hz), 8.00 (1H, s), 8.59 (1H, d, J = 7
Hz), 8.66 (1H, d, J = 7Hz)

(2) 1,4-dihydro-3-hydroxymethyl-8-nitro-4-oxoquinoline (3.1
g) in trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was added to a solution of triethylsilane (6.55).
g) was added and the mixture was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography to give 1,4-dihydro-
3-methyl-8-nitro-4-oxoquinoline (2.3
g) was obtained. mp: 235-243 ° C NMR (CDCl ₃ , δ): 2.16 (3H, s), 7.41 (1H, t, J = 7H
z), 7.69 (1H, d, J = 7Hz), 8.65 (1H, d, J = 7Hz), 8.82
(1H, d, J = 7Hz)

(3) Phosphoryl chloride (1.72 g) was added to stirred N, N-dimethylformamide (20 ml).
Was added dropwise under cooling with an ice bath, and the mixture was stirred at the same temperature for 15 minutes and at room temperature for 15 minutes. Add 1,4-dihydro-3 to the mixture.
-Methyl-8-nitro-4-oxoquinoline (2.08
g) was added dropwise and the mixture was stirred at room temperature for 2 hours. To it was added water (20 ml) and the mixture was neutralized with 5N sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water to give 4-chloro-3-methyl-8-nitroquinoline (2.25 g) as a pale yellow powder. mp: 126 ° C NMR (CDCl ₃ , δ): 2.61 (3H, s), 7.68 (1H, t, J = 8H
z), 8.00 (1H, d, J = 8Hz), 8.46 (1H, d, J = 8Hz), 8.88
(1H, s)

(4) 4-chloro-3-methyl-8-nitroquinoline (2.1 g), ammonium chloride (303
mg) and iron (3.16 g) in ethanol (20 ml) and water (4 ml) was refluxed for 1 hour. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was washed with hot 80% ethanol and the suspension was allowed to cool to room temperature. The resulting precipitate was collected by filtration, dried and treated with 8-amino-4-chloro-
3-Methylquinoline (980 mg) was obtained as pale brown needles. mp: 112-114 ° C NMR (CDCl ₃ , δ): 2.54 (3H, s), 4.99 (2H, br s),
6.90 (1H, d, J = 8Hz), 7.38 (1H, t, J = 8Hz), 7.50 (1H,
d, J = 8Hz), 8.55 (1H, s)

(5) 8-amino-4-chloro-3-methylquinoline (1.70 g), 2,6-dichlorobenzoyl chloride (2.22 g) and triethylamine (2.46)
ml) of ethylene chloride (20 ml) was refluxed for 6 hours. After cooling, the mixture was diluted with dichloromethane,
After washing with water and drying over magnesium sulfate, the solvent was distilled off in vacuo. The residue was washed with hot 80% ethanol and the suspension was allowed to cool to room temperature. The resulting precipitate was collected by filtration and dried to give 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (3.06 g) as a pale yellow powder. mp: 216-227 ° C NMR (CDCl ₃ , δ): 2.57 (3H, s), 7.28-7.46 (3H, m),
7.67 (1H, t, J = 8Hz), 7.96 (1H, d, J = 8Hz), 8.59 (1
H, s), 8.94 (1H, d, J = 8Hz)

(6) 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (289
mg) and 1,2-diamino-2-methylpropane (69
A mixture of 7 mg) of N-methylpyrrolidone (3 ml) was heated at 120 ° C. for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water (twice) and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash chromatography (methanol-dichloromethane) and recrystallized from hot ethanol to give 4- (2-
Amino-2-methylpropylamino) -8- (2,6-
Dichlorobenzoylamino) -3-methylquinoline (1
75 mg) were obtained as pale yellow crystals. mp: 184-186 ° C NMR (DMSO-d ₆ , δ): 1.05 (2x3H, s), 1.70 (2H, br),
2.37 (3H, s), 3.35 (2H, d, J = 5Hz), 5.97 (1H, t, J =
5Hz), 7.46 (1H, dd, J = 8, 8Hz), 7.50-7.63 (3H, m),
7.90 (1H, d, J = 8Hz), 8.32 (1H, s), 8.57 (1H, d, J = 8
Hz), 10.49 (1H, s)

(7) A solution of 4- (2-amino-2-methylpropylamino) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (146 mg) in N-methylpyrrolidone (3 ml) To the mixture was added 1,1′-carbonyldiimidazole (113 mg) at 60 ° C., and the mixture was stirred at the same temperature for 1 hour. 1,8-Diazabicyclo [5.4.0] undec-7-ene (107 m
g) was added and the mixture was stirred at 140 ° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. Heat residue 8
After washing with 0% ethanol, the suspension was allowed to cool to room temperature. The resulting precipitate was collected by filtration, dried, and treated with 8- (2,6-
Dichlorobenzoylamino) -4- (4,4-dimethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline (100 mg) was obtained as white crystals. NMR (DMSO-d ₆ , δ): 1.38 (3H, s), 1.46 (3H, s), 2.
38 (3H, s), 3.50 (1H, d, J = 9Hz), 3.60 (1H, d, J = 9H
z), 7.17 (1H, s), 7.47-7.74 (5H, m), 8.67 (1H, d, J
= 8Hz), 8.84 (1H, s), 10.79 (1H, s)

Example 2 (1) 8- (2,6-dichlorobenzoylamino)-
4-[(2-ethylaminoethyl) amino] -3-methylquinoline was prepared from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and N-ethylethylenediamine according to Example 1- Obtained in the same manner as in (6). NMR (CDCl ₃ , δ): 1.18 (3H, t, J = 8Hz), 2.38 (3H,
s), 2.73 (2H, m), 2.90-2.97 (2H, m), 3.60 (2H, q, J
= 8Hz), 5.37 (1H, brt, J = 9Hz), 7.26-7.50 (4H, m),
7.78 (1H, d, J = 8Hz), 8.30 (1H, s), 8.81 (1H, d, J = 8
Hz)

(2) 8- (2,6-dichlorobenzoylamino) -4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline is converted to 8- (2,2-
6-dichlorobenzoylamino) -4-[(2-ethylaminoethyl) amino] -3-methylquinoline and 1,
From 1′-carbonyldiimidazole, Example 1
Obtained in the same manner as (7). mp: 139-146 ° C NMR (CDCl ₃ , δ): 1.25 (3H, t, J = 8Hz), 2.42 (3H,
s), 3.30-3.52 (2H, m), 3.60-3.76 (3H, m), 3.79-3.94
(1H, m), 7.30-7.44 (3H, m), 7.56-7.65 (2H, m), 8.
67 (1H, s), 8.89 (1H, m)

Example 3 8- (2,6-dichlorobenzoylamino) -4- (3
-Ethyl-2-thioxoimidazolidin-1-yl)-
3-Methylquinoline was prepared from 8- (2,6-dichlorobenzoylamino) -4-[(2-ethylaminoethyl) amino] -3-methylquinoline and 1,1′-thiocarbonyldiimidazole in Example 1. -Obtained in the same manner as (7). mp: 146-152 ° C NMR (CDCl ₃ , δ): 1.32 (3H, t, J = 8Hz), 2.44 (3H,
s), 3.66-4.06 (6H, m), 7.28-7.44 (3H, m), 7.49 (1H,
d, J = 8Hz), 7.62 (1H, t, J = 8Hz), 8.71 (1H, s), 8.91
(1H, d, J = 8Hz)

Example 4 (1) 8- (2,6-dichlorobenzoylamino)-
4-[(2-isopropylaminoethyl) amino] -3
-Methylquinoline was obtained from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and N-isopropylethylenediamine in the same manner as in Example 1- (6). NMR (DMSO-d ₆ , δ): 0.98 (2x3H, d, J = 7Hz), 2.37 (3
H, s), 2.63-2.82 (3H, m), 3.56 (2H, dt, J = 6, 6Hz),
6.03 (1H, t, J = 6Hz), 7.46 (1H, dd, J = 8, 8Hz), 7.50-
7.63 (3H, m), 7.95 (1H, d, J = 8Hz), 8.32 (1H, s), 8.
57 (1H, d, J = 8Hz), 10.49 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -4- (3-isopropyl-2-oxoimidazolidin-1-yl) -3-methylquinoline was prepared in the same manner as in Example 1- (7). I got it. mp: 257-259 ° C NMR (CDCl ₃ , δ): 1.18 (3H, d, J = 7Hz), 1.20 (3H,
d, J = 7Hz), 2.35 (3H, s), 3.53-3.73 (3H, m), 3.81 (1
H, m), 4.04 (1H, qq, J = 7, 7Hz), 7.47-7.71 (5H, m),
8.66 (1H, m), 8.75 (1H, s), 10.78 (1H, s)

Example 5 (1) 4-[(2-benzylaminoethyl) amino]
Example 1 was prepared by converting -8- (2,6-dichlorobenzoylamino) -3-methylquinoline from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and N-benzylethylenediamine. Obtained in the same manner as in (6). NMR (CDCl ₃ , δ): 2.38 (3H, s), 2.92 (2H, t, J = 6H
z), 3.38 (1H, t, J = 6Hz), 3.61 (2H, q, J = 6Hz), 3.84
(2H, s), 5.33 (1H, br), 7.27-7.50 (9H, m), 7.78 (1
H, d, J = 8Hz), 8.31 (1H, s), 8.83 (1H, d, J = 8Hz)

(2) 4- (3-benzyl-2-oxoimidazolidin-1-yl) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline was prepared in Example 1
Obtained in the same manner as (7). mp: 205-208 ° C NMR (CDCl ₃ , δ): 2.48 (3H, s), 3.45-3.70 (3H, m),
3.80-3.91 (1H, m), 4.48 (1H, d, J = 12Hz), 4.60 (1H,
d, J = 12Hz), 7.30-7.48 (8H, m), 7.58-7.67 (2H, m),
8.70 (1H, s), 8.91 (1H, d, J = 8Hz)

Example 6 (1) 1,4-dihydro-8-nitro-4-oxoquinoline (10 g) and 1,3,5-trioxane (23.
7 g) of dioxane (100 ml) and concentrated hydrochloric acid (200 m
The mixture in 1) was stirred at 90 ° C. for 3.5 hours and allowed to stand at room temperature. Ice water (700 g) was added to the mixture and the mixture was stirred for 1 hour. The resulting precipitate was collected by filtration and washed with cold water to give 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (6.5 g). mp: 228-235 ° C NMR (DMSO-d ₆ , δ): 4.70 (2H, s), 7.53 (1H, t, J = 7
Hz), 8.25 (1H, d, J = 7Hz), 8.59 (1H, d, J = 7Hz), 8.66
(1H, d, J = 7Hz)

(2) A suspension of 3-chloromethyl-1,4-dihydro-8-nitro-4-oxoquinoline (2 g) in dichloromethane (70 ml) and methanol (30 ml) was refluxed for 15 minutes and vacuum Concentrated in. The crystalline residue was suspended in hot methanol (30 ml) and the mixture was allowed to stand at room temperature. The resulting precipitate was collected by filtration and 1,4-
Dihydro-3-methoxymethyl-8-nitro-4-oxoquinoline (1.5 g) was obtained. mp:> 250 ° C NMR (DMSO-d ₆ , δ): 3.33 (3H, s), 4.32 (2H, s), 7.
51 (1H, t, J = 7Hz), 7.98 (1H, d, J = 7Hz), 8.59 (1H,
d, J = 7Hz), 8.67 (1H, d, J = 7Hz)

(3) 4-chloro-3-methoxymethyl-8-nitroquinoline was obtained in the same manner as in Example 1- (3). mp: 91-94 ° C NMR (CDCl ₃ , δ): 3.51 (3H, s), 4.81 (2H, s), 7.73
(1H, t, J = 8Hz), 8.05 (1H, d, J = 8Hz), 8.48 (1H, d,
J = 8Hz), 9.10 (1H, s)

(4) 8-amino-4-chloro-3-
(Methoxymethyl) quinoline was obtained in the same manner as in Example 1- (4). mp: 107 ° C NMR (CDCl ₃ , δ): 3.50 (3H, s), 4.79 (2H, s), 5.03
(2H, br s), 6.95 (1H, d, J = 8Hz), 7.41 (1H, t, J = 8H
z), 7.54 (1H, d, J = 8Hz), 8.77 (1H, s)

(5) 4-chloro-8- (2,6-dichlorobenzoylamino) -3- (methoxymethyl) quinoline was obtained in the same manner as in Example 1- (5). mp: 177 ° C NMR (CDCl ₃ , δ): 3.50 (3H, s), 4.79 (2H, s), 7.30
-7.44 (3H, m), 7.70 (1H, t, J = 8Hz), 8.00 (1H, d, J =
8Hz), 8.80 (1H, s), 9.00 (1H, d, J = 8Hz)

(6) Using 8- (2,6-dichlorobenzoylamino) -4-[(2-ethylaminoethyl) amino] -3-methoxymethylquinoline as in Example 1- (6)
Was obtained in the same manner as described above. NMR (DMSO-d ₆ , δ): 1.03 (3H, t, J = 7Hz), 2.56 (2H,
q, J = 7Hz), 2.77 (2H, t, J = 6Hz), 3.30 (3H, s), 3.64
(2H, dt, J = 6,5Hz), 4.54 (2H, s), 6.59 (1H, t, J = 5
Hz), 7.42-7.63 (4H, m), 7.98 (1H, d, J = 8Hz), 8.43
(1H, s), 8.62 (1H, d, J = 8Hz), 10.50 (1H, s)

(7) 8- (2,6-Dichlorobenzoylamino) -4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methoxymethylquinoline was prepared in the same manner as in Example 1- (7). Obtained similarly. mp: 169-171 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7Hz), 3.28 (2H,
m), 3.32 (3H, s), 3.59-3.75 (3H, m), 3.87 (1H, m),
4.07 (1H, d, J = 12Hz), 4.11 (1H, d, J = 12Hz), 7.48-
7.62 (3H, m), 7.67-7.76 (2H, m), 8.72 (1H, m), 8.95
(1H, s), 10.86 (1H, s)

Example 7 8- (2,6-dichlorobenzoylamino) -4- (3
-Ethyl-2-thioxoimidazolidin-1-yl)-
3-methoxymethylquinoline is converted to 8- (2,6-dichlorobenzoylamino) -4-[(2-ethylaminoethyl) amino] -3-methoxymethylquinoline and 1,1 ′
Obtained from -thiocarbonyldiimidazole in the same manner as in Example 3. mp: 203-205 ° C NMR (DMSO-d ₆ , δ): 1.22 (3H, t, J = 7Hz), 3.36 (3H,
s), 3.68 (2H, m), 3.84-4.07 (4H, m), 4.56 (1H, d,
J = 12Hz), 4.63 (1H, d, J = 12Hz), 7.48-7.63 (4H, m),
7.71 (1H, dd, J = 8, 8Hz), 8.73 (1H, d, J = 8Hz), 9.00
(1H, s)

Example 8 (1) 4-Chloro-3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline was converted to 8-amino-4-chloro-3-methylquinoline and 2-trifluoromethyl chloride. Obtained from benzoyl in the same manner as in Example 1- (5). mp: 169-173 ° C NMR (CDCl ₃ , δ): 2.57 (3H, s), 7.58-7.86 (5H, m),
7.95 (1H, d, J = 8Hz), 8.55 (1H, s), 8.90 (1H, d, J =
8Hz)

(2) 3-methyl-4-[(2-methylaminoethyl) amino] -8- (2-trifluoromethylbenzoylamino) quinoline was converted to 4-chloro-3-methyl-8- (2- It was obtained from (trifluoromethylbenzoylamino) quinoline and N-methylethylenediamine in the same manner as in Example 1- (6). NMR (CDCl ₃ , δ): 2.40 (3H, s), 2.50 (3H, s), 2.88
(2H, t, J = 6Hz), 3.62 (2H, q, J = 6Hz), 5.30 (1H, s),
7.48 (1H, t, J = 8Hz), 7.55-7.85 (5H, m), 8.30 (1H,
s), 8.80 (1H, d, J = 8Hz)

(3) 3-methyl-4- (3-methyl-
2-thioxoimidazolidin-1-yl) -8- (2-
(Trifluoromethylbenzoylamino) quinoline was obtained in the same manner as in Example 3. mp: 225-234 ° C NMR (CDCl ₃ , δ): 2.45 (3H, s), 3.30 (3H, s), 3.77
-4.05 (4H, m), 7.50 (1H, d, J = 8Hz), 7.58-7.84 (5H,
m), 8.71 (1H, s), 8.88 (1H, d, J = 8Hz)

Example 9 (1) 4-[(2-ethylaminoethyl) amino]-
3-Methyl-8- (2-trifluoromethylbenzoylamino) quinoline is converted to 4-chloro-3-methyl-8-
Example 1- (6) from (2-trifluoromethylbenzoylamino) quinoline and N-ethylethylenediamine
Was obtained in the same manner as described above. NMR (CDCl ₃ , δ): 1.18 (3H, t, J = 8Hz), 2.38 (3H,
s), 2.72 (2H, q, J = 8Hz), 2.93 (2H, t, J = 6Hz), 3.62
(2H, q, J = 6Hz), 5.37 (1H, br), 7.45 (1H, t, J = 8Hz),
7.55-7.81 (5H, m), 8.29 (1H, s), 8.78 (1H, d, J = 8H
z)

(2) 4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline was prepared in the same manner as in Example 1- (7). I got it. mp: 133-135 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 8Hz), 2.35 (3H,
s), 3.25 (2H, q, J = 8Hz), 3.60-3.87 (4H, m), 7.53-
7.95 (6H, m), 8.63 (1H, t, J = 4Hz), 8.83 (1H, s)

Example 10 4- (3-ethyl-2-thioxoimidazolidin-1-
Yl) -3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline is converted to 4-[(2-ethylaminoethyl) amino] -3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline And 1,1′-thiocarbonyldiimidazole in the same manner as in Example 3. mp: 211-214 ° C NMR (CDCl ₃ , δ): 1.32 (3H, t, J = 8Hz), 2.43 (3H,
s), 3.72-4.05 (6H, m), 7.48 (1H, d, J = 8Hz), 7.58-7.
83 (5H, m), 8.70 (1H, s), 8.88 (1H, d, J = 8Hz)

Example 11 (1) 8- (2,6-dichlorobenzoylamino)-
4- (2-Hydroxyethylamino) -3-methylquinoline was prepared from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 2-aminoethanol in Example 1- (6). Was obtained in the same manner as described above. mp: 167-169 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 3.50-3.64 (4H,
m), 4.82 (1H, t, J = 4Hz), 5.88 (1H, t, J = 4Hz), 7.40-
7.63 (4H, m), 7.96 (1H, d, J = 8Hz), 8.31 (1H, s), 8.
57 (1H, d, J = 8Hz), 10.49 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -4- (2-hydroxyethylamino) -3
-To a solution of methylquinoline (202 mg) in tetrahydrofuran (3 ml) was added triphosgene (76.8 m
g), N-methylpyrrolidone and 1,8-diazabicyclo [5.4.0] undec-7-ene (110 mg) were added, and the mixture was stirred at 80 ° C. overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol), crystallized from ethanol, and 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (2-oxazolidinone-3-yl ) Quinoline (46 mg) was obtained. mp: 243-246 ° C NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 3.91-4.12 (2H,
m), 4.60-4.81 (2H, m), 7.46-7.66 (3H, m), 7.68-7.83
(2H, m), 8.70 (1H, d, J = 8Hz), 8.90 (1H, s), 10.85
(1H, s)

Example 12 N-methylpyrrolidone (5 mg) of 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (250 mg) and 3-methylimidazole (1.6 g)
ml) was heated at 150 ° C. for 1 week. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol), crystallized from diisopropyl ether and ethanol, and 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (4-methylimidazole -1
-Yl) quinoline (90 mg) was obtained as white crystals. mp: 231-233 ° C NMR (DMSO-d ₆ , δ): 2.26 (2x3H, s), 7.07 (1H, d, J =
8Hz), 7.20 (1H, s), 7.48-7.62 (3H, m), 7.66 (1H, d
d, J = 8,8Hz), 7.81 (1H, s), 8.70 (1H, d, J = 8Hz), 8.
97 (1H, s), 10.90 (1H, s)

Example 13 8- (2,6-Dichlorobenzoylamino) -3-methyl-4- (4-phenylimidazol-1-yl) quinoline was converted to 4-chloro-8- (2,6-dichlorobenzoyl). Obtained in the same manner as in Example 12 from amino) -3-methylquinoline and 4-phenylimidazole. NMR (CDCl ₃ , δ): 2.37 (3H, s), 7.23 (1H, d, J = 8H
z), 7.28-7.50 (7H, m), 7.63 (1H, dd, J = 8, 8Hz), 7.6
8 (1H, s), 7.90 (2x1H, d, J = 8Hz), 8.80 (1H, s), 8.9
8 (1H, d, J = 8Hz), 10.00 (1H, s)

Example 14 (1) 8- (2,6-dichlorobenzoylamino)-
4-hydrazino-3-methylquinoline is converted to 4-chloro-
Example 1 was prepared from 8- (2,6-dichlorobenzoylamino) -3-methylquinoline and hydrazine monohydrate.
Obtained in the same manner as in (6). mp: 190-197 ° C NMR (CDCl ₃ , δ): 2.30 (3H, s), 4.04 (2H, br s),
5.93 (1H, br s), 7.20-7.51 (4H, m), 8.12 (1H, d, J =
8Hz), 8.31 (1H, s), 8.83 (1H, d, J = 8Hz)

(2) 8- (2,6-dichlorobenzoylamino) -4-hydrazino-3-methylquinoline (3
To a solution of 90 mg) in pyridine (3 ml) was added mesyl chloride (136 mg) dropwise and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol), crystallized from ethanol and water, and treated with 8- (2,6-dichlorobenzoylamino) -4.
-(2-Methanesulfonylhydrazino) -3-methylquinoline (50 mg) was obtained. mp: 188-198 ° C NMR (DMSO-d ₆ , δ): 2.47 (3H, s), 3.03 (3H, s), 7.4
8-7.60 (4H, m), 8.21 (1H, d, J = 8Hz), 8.39 (1H, s),
8.50 (1H, s), 8.60 (1H, d, J = 8Hz), 9.55 (1H, s), 1
0.55 (1H, s)

Example 15 To a solution of 8- (2,6-dichlorobenzoylamino) -4-hydrazino-3-methylquinoline (200 mg) in pyridine (3 ml) was added 2-thienylacetyl chloride (9
(7.8 mg) was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and methanol, washed with water and sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8- (2,6-dichlorobenzoylamino)-
3-Methyl-4- [2- (2-thienylacetyl) hydrazino] quinoline (30 mg) was obtained. mp: 140-143 ° C NMR (DMSO-d ₆ , δ): 2.34 (3H, s), 3.74 (2H, s), 6.9
1-6.96 (2H, m), 7.35 (1H, d, J = 4.5Hz), 7.45 (1H, d
d, J = 8,8Hz), 7.50-7.60 (3H, m), 8.10 (1H, d, J = 8H
z), 8.34 (2H, br s), 8.57 (1H, d, J = 8Hz), 10.45 (1
H, s), 10.52 (1H, s)

Example 16 (1) A solution of 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (500 mg) in acetic acid (16 ml) and 6N hydrochloric acid (20 ml) was dissolved in 130 ml.
Heated at ° C. for 5 days. The mixture was concentrated in vacuo and the precipitate was collected and washed with water. The residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 2).
0, V / V) to give yellow crystals. The solid was treated with hot ethanol (5 ml), allowed to cool to room temperature, filtered, washed with water and treated with 8- (2,6-dichlorobenzoylamino) -1,4-dihydro-3-methyl-4-methyl-4-. Oxoquinoline (280 mg) was obtained as yellow crystals. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 2.00 (3H, s), 7.35 (1H, t, J = 8
Hz), 7.52-7.57 (1H, m), 7.63-7.66 (2H, m), 7.95 (1
H, br), 8.04 (1H, d, J = 8Hz), 8.12 (1H, br d, J = 8H
z), 10.36 (1H, br), 10.52 (1H, br)

(2) 8- (2,6-dichlorobenzoylamino) -1,4-dihydro-3-methyl-4-oxoquinoline (500 mg) and potassium carbonate (398 m)
To a suspension of g) in N, N-dimethylformamide (5 ml) was added ethyl bromoacetate (289 mg) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate,
The solvent was removed in vacuo. The residue was purified by flash chromatography (dichloromethane) to give 8- (2,2
6-dichlorobenzoylamino) -4-ethoxycarbonylmethoxy-3-methylquinoline (360 mg) and 8
-[N- (2,6-Dichlorobenzoyl) -N-ethoxycarbonylmethylamino] -4-ethoxycarbonylmethoxy-3-methylquinoline (90 mg) was obtained.

8- (2,6-dichlorobenzoylamino) -4-ethoxycarbonylmethoxy-3-methylquinoline mp: 188-191 ° C. NMR (DMSO-d ₆ , δ): 1.24 (3H, t, J = 7.5) Hz), 2.47 (3
H, s), 4.23 (2H, q, J = 7.5Hz), 4.91 (2H, s), 7.48-7.
60 (3H, m), 7.65 (1H, dd, J = 8, 8Hz), 8.02 (1H, d, J
= 8Hz), 8.66 (1H, d, J = 8Hz), 8.74 (1H, s), 10.75 (1
H, s)

8- [N- (2,6-dichlorobenzoyl) -N-ethoxycarbonylmethylamino] -4-ethoxycarbonylmethoxy-3-methylquinoline mp: 151-153 ° C. NMR (DMSO-d ₆ , δ) : 1.15-1.23 (6H, m), 2.45 (3H,
s), 4.05-4.20 (4H, m), 4.58 (1H, br d, J = 18Hz), 4.8
8 (2H, s), 5.21 (1H, br d, J = 18Hz), 7.05 (1H, br d,
J = 7.5Hz), 7.20 (1H, dd, J = 7.5, 7.5Hz), 7.38 (1H, d
d, J = 7.5, 7.5Hz), 7.46 (1H, br d, J = 7.5Hz), 7.73 (1
H, d, J = 7.5Hz), 8.16 (1H, d, J = 7.5Hz), 8.80 (1H, s)

Example 17 8- (2,6-dichlorobenzoylamino) -4-ethoxycarbonylmethoxy-3-methylquinoline (100
mg) in methanol (2 ml) was added 1N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was neutralized with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with hot ethanol and the suspension was cooled to room temperature. The resulting precipitate was collected by filtration and dried to give 4-carboxymethoxy-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (40 mg) as white crystals. mp: 232-234 ° C NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 4.75 (2H, s), 7.4
7-7.65 (4H, m), 8.01 (1H, d, J = 8Hz), 8.65 (1H, d,
J = 8Hz), 8.72 (1H, s), 10.65 (1H, s)

Example 18 8- (2,6-dichlorobenzoylamino) -4-ethoxycarbonylmethoxy-3-methylquinoline (100
mg) and a 15% ammonia solution in ethanol (4 m
The mixture with 1) was stirred at room temperature overnight. After concentration in vacuo, the residue was washed with hot ethanol and the suspension was cooled to room temperature. The resulting precipitate was collected by filtration and dried to give 4-carbamoylmethoxy-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (60 mg) as white crystals. mp: 216-222 ° C NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 4.51 (2H, s), 7.4
8-7.61 (4H, m), 7.66 (1H, dd, J = 8, 8Hz), 7.84 (1H,
br), 7.95 (1H, d, J = 8Hz), 8.67 (1H, d, J = 8Hz), 8.7
5 (1H, s), 10.71 (1H, s)

Example 19 8- (2,6-Dichlorobenzoylamino) -3-methyl-4- (N-methylcarbamoylmethoxy) quinoline was converted to 8- (2,6-dichlorobenzoylamino) -4-
Ethoxycarbonylmethoxy-3-methylquinoline;
Obtained in a similar manner to Example 18 from a solution of methylamine in methanol. mp: 130-134 ° C NMR (DMSO-d ₆ , δ): 2.31 (3Hx1 / 4, s), 2.38 (3Hx3 /
4, s), 3.19 (3Hx3 / 4, s), 3.28 (3Hx1 / 4, s), 3.56 (1H
x3 / 4, d, J = 6Hz), 3.62 (1Hx1 / 4, d, J = 6Hz), 4.85 (1Hx
3/4, m), 4.92 (1Hx1 / 4, m), 7.46-7.66 (4H, m), 7.73
(1H, dd, J = 8, 8Hz), 8.65 (1Hx1 / 4, d, J = 8Hz), 8.71
(1Hx3 / 4, d, J = 8Hz), 8.86 (1Hx1 / 3, s), 8.911Hx3 / 4,
s), 10.71 (1H, s), 10.80 (1Hx1 / 4, s), 10.88 (1Hx3 /
4, s)

Example 20 To a solution of 4-chlorophenol (139 mg) in N-methylpyrrolidone (3 ml) was added sodium hydride (60% in oil, 28.9 mg) under ice-cooling, and the mixture was heated at the same temperature. With stirring. The mixture was added to 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (200
mg) was added and the mixture was stirred at 120 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from hot ethanol to give 4- (4-chlorophenoxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (165 mg) as white crystals. mp: 188-190 ° C NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 6.91 (2H, d, J = 8.
5Hz), 7.37 (2H, d, J = 8.5Hz), 7.48-7.63 (5H, m), 8.
69 (1H, d, J = 8Hz), 8.88 (1H, s), 10.86 (1H, s)

Example 21 The following compounds were obtained in the same manner as in Example 20. (1) 8- (2,6-dichlorobenzoylamino)-
4- (3,4-dichlorophenoxy) -3-methylquinoline (from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 3,4-dichlorophenol) mp: 180-182 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 6.85 (1H, d, J =
8.5,2Hz), 7.31 (1H, d, J = 2Hz), 7.48-7.65 (6H, m),
8.70 (1H, d, J = 8Hz), 8.90 (1H, s), 10.88 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (4-nitrophenoxy) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3- Mp: 219-220 ° C NMR (DMSO-d ₆ , δ): 2.29 (3H, s), 7.13 (2H, d, J = 8.
5Hz), 7.50-7.66 (5H, m), 8.23 (2H, d, J = 8.5Hz), 8.
71 (1H, d, J = 8Hz), 8.96 (1H, s), 10.92 (1H, s)

(3) 8- (2,6-dichlorobenzoylamino) -4- (4-methoxycarbonylphenoxy) -3-methylquinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3 -Methylquinoline and methyl 4-hydroxybenzoate) mp: 189-191 ° C NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 3.82 (3H, s), 7.
01 (2H, d, J = 8.5Hz), 7.50-7.64 (5H, m), 7.94 (2H,
d, J = 8.5Hz), 8.70 (1H, d, J = 8Hz), 8.82 (1H, s), 10.
89 (1H, s)

(4) 4- (4-acetamidophenoxy) -8- (2,6-dichlorobenzoylamino) -3
- (4-chloro-8- (2,6-dichloro benzoylamino) -3-methyl-quinoline and 4-acetamidophenol) methyl quinoline mp: 263-265 ℃ NMR (DMSO- d 6, δ): 2.00 (3H , s), 2.26 (3H, s), 6.
83 (2H, d, J = 8.5Hz), 7.48 (2H, d, J = 8.5Hz), 7.54-7.
60 (5H, m), 8.63-8.70 (1H, m), 8.86 (1H, s), 9.88
(1H, s), 10.84 (1H, s)

(5) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (4-methylbenzyloxy) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3 -Methylquinoline and 4-methylbenzyl alcohol) mp: 145-147 ° C NMR (DMSO-d ₆ , δ): 2.34 (3H, s), 2.40 (3H, s), 5.
14 (2H, s), 7.23 (2H, d, J = 7.5Hz), 7.42 (2H, d, J =
7.5Hz), 7.48-7.63 (4H, m), 7.83 (1H, d, J = 8Hz), 8.
65 (1H, d, J = 8Hz), 8.74 (1H, s), 10.70 (1H, s)

(6) 4- (4-chlorobenzyloxy) -8- (2,6-dichlorobenzoylamino) -3
-Methylquinoline (from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 4-chlorobenzyl alcohol) mp: 142-148 ° C NMR (DMSO-d ₆ , δ): 2.41 ( 3H, s), 5.18 (2H, s), 7.4
8-7.64 (8H, m), 7.82 (1H, d, J = 8Hz), 8.66 (1H, d,
J = 8Hz), 8.75 (1H, s), 10.73 (1H, s)

(7) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (3-thienylmethoxy) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3- From methylquinoline and 3-hydroxymethylthiophene) mp: 126-131 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 5.19 (2H, s), 7.
28 (1H, d, J = 5Hz), 7.48-7.67 (6H, m), 7.83 (1H, d,
J = 8Hz), 8.66 (1H, d, J = 8Hz), 8.73 (1H, s), 10.71 (1
H, s)

(8) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (thiazol-2-ylthio) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3 - methyl quinoline and 2-mercapto thiazole) mp: 211-213 ℃ NMR (DMSO -d 6, δ): 2.66 (3H, s), 7.48-7.60 (4H,
m), 7.70 (1H, d, J = 2Hz), 7.75 (1H, dd, J = 8, 8Hz),
8.63 (1H, d, J = 8Hz), 8.70 (1H, d, J = 8Hz), 9.00 (1H,
s), 10.92 (1H, s)

(9) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (5-methyl-1H-
1,2,4-Triazol-3-ylthio) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 3-mercapto-5-methyl-1H-1,2,4 - triazole) mp: 227-229 ℃ NMR (DMSO -d 6, δ): 2.23 (3H, s), 2.60 (3H, s), 7.4
8-7.58 (4H, m), 7.67 (1H, dd, J = 8, 8Hz), 8.13 (1H,
d, J = 8Hz), 8.65 (1H, d, J = 8Hz), 8.87 (1H, s), 10.8
2 (1H, s)

(10) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (pyridin-2-ylthio) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3 -Methylquinoline and 2-mercaptopyridine) mp: 208-209 ° C NMR (DMSO-d ₆ , δ): 2.58 (3H, s), 7.00 (1H, d, J = 7.
5Hz), 7.13-7.18 (1H, m), 7.50-7.68 (5H, m), 8.07
(1H, d, J = 8Hz), 8.31 (1H, d, J = 4.5Hz), 8.68 (1H, d,
J = 8Hz), 8.96 (1H, s), 10.88 (1H, s)

(11) 4- (benzoxazole-2)
-Ylthio) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 2-mercaptobenzoxazole) mp : 220-222 ° C NMR (DMSO-d ₆ , δ): 2.68 (3H, s), 7.25-7.31 (2H,
m), 7.49-7.63 (5H, m), 7.73 (1H, dd, J = 8, 8Hz), 8.1
0 (1H, d, J = 8Hz), 8.70 (1H, d, J = 8Hz), 9.02 (1H, s)

(12) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (4-methylthiobenzyloxy) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3 - methyl quinoline and 4-methylthiophenyl benzyl alcohol) mp: 153-155 ℃ NMR (DMSO -d 6, δ): 2.37 (3H, s), 2.40 (3H, s), 5.
14 (2H, s), 7.03 (1H, d, J = 7.5Hz), 7.32 (2H, d, J =
7.5Hz), 7.47-7.66 (5H, m), 7.85 (1H, d, J = 7.5Hz),
8.65 (1H, d, J = 7.5Hz), 8.76 (1H, s), 10.70 (1H, s)

(13) 8- (2,6-dichlorobenzoylamino) -4- (5-methoxycarbonylpyridin-2-yloxy) -3-methylquinoline (4-chloro-8- (2,6-dichlorobenzoyl) Amino) -3-methylquinoline and 2-hydroxypyridine-
Mp: 120-122 ° C NMR (DMSO-d ₆ , δ): 2.57 (3H, s), 3.63 (3H, s), 6.
40 (1H, d, J = 10Hz), 7.56 (1H, d, J = 7.5Hz), 7.64-7.7
5 (3H, m), 7.80 (1H, d, J = 7.5Hz), 7.91 (1H, d, J = 8H
z), 8.45 (1H, d, J = 8Hz), 8.54 (1H, d, J = 2Hz), 8.78
(1H, s), 10.60 (1H, s)

(14) 8- (2,6-dichlorobenzoylamino) -4- (3-furylmethoxy) -3-methylquinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3- Mp: 107-119 ° C NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 5.08 (2H, s), 6.
68 (1H, br), 7.49-7.64 (4H, m), 7.71 (1H, br s), 7.
83 (1H, br), 7.84 (1H, d, J = 8Hz), 8.65 (1H, d, J = 8H
z), 8.74 (1H, s)

Example 22 (1) 4- (4-acetylphenoxy) -8- (2,
6-Dichlorobenzoylamino) -3-methylquinoline was obtained in the same manner as in Example 20 from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 4-acetylphenol. mp: 196-199 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 2.48 (3H, s), 7.
00 (2H, d, J = 8.5Hz), 7.48-7.64 (5H, m), 7.95 (2H,
d, J = 8.5Hz), 8.70 (1H, d, J = 8Hz), 8.92 (1H, s), 10.
88 (1H, s)

(2) To a solution of 0.92 M methylmagnesium bromide in tetrahydrofuran (3 ml) was added 4- (4-
A solution of (acetylphenoxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (160 mg) in anhydrous tetrahydrofuran (1 ml) was added dropwise at 0 ° C under a nitrogen atmosphere, and the mixture was stirred at the same temperature. . The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from hot ethanol to give 8- (2,6-dichlorobenzoylamino) -4- [4- (1-hydroxy-1-methylethyl) phenoxy] -3-methylquinoline (14
0 mg) as yellow crystals. mp: 273-275 ° C NMR (DMSO-d ₆ , δ): 1.40 (6H, s), 2.26 (3H, s),
6.77 (2H, d, J = 8.5Hz), 7.40 (2H, d, J = 8.5Hz), 7.50-
7.60 (5H, m), 8.65 (1H, dd, J = 4, 4Hz), 8.86 (1H,
s), 10.82 (1H, s)

Example 23 (1) 8- (2,6-dichlorobenzoylamino)-
As in Example 20, 4- (3-methoxycarbonylphenoxy) -3-methylquinoline was prepared from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and methyl 3-hydroxybenzoate. I got it. mp: 131-134 ° C NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 3.80 (3H, s), 7.
22 (1H, dd, J = 8, 3Hz), 7.32 (1H, d, J = 3Hz), 7.49-7.
63 (6H, m), 7.70 (1H, d, J = 8Hz), 8.70 (1H, dd, J = 8,
3Hz), 8.92 (1H, s), 10.90 (1H, s)

(2) To a suspension of 8- (2,6-dichlorobenzoylamino) -4- (3-methoxycarbonylphenoxy) -3-methylquinoline (100 mg) in methanol (2 ml) was added 1N hydroxide. An aqueous sodium solution (1 ml) was added under ice cooling, and the mixture was stirred at 50 ° C. for 3 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with hot ethanol and the suspension was cooled to room temperature. The resulting precipitate was collected by filtration and dried to give 4- (3-carboxyphenoxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (80 mg) as white crystals. mp: 274-275 ° C NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 7.18 (1H, dd, J =
7.5,2Hz), 7.27 (1H, d, J = 2Hz), 7.45-7.61 (6H, m),
7.67 (1H, d, J = 7.5Hz), 8.70 (1H, dd, J = 7.5, 2Hz),
8.92 (1H, s), 10.88 (1H, s)

(3) 4- (3-carboxyphenoxy) -8- (2,6-dichlorobenzoylamino) -3
To a solution of -methylquinoline (80 mg) in dimethylformamide (1 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (39.4 m3).
g) and 1-hydroxybenzotriazole (27.8 m
g) was added and the mixture was stirred at room temperature for 1 hour. A concentrated aqueous ammonia solution (2 ml) was added to the mixture with stirring, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution and brine,
After drying over magnesium sulfate, the solvent was distilled off in vacuo.
The residue was recrystallized from ethanol and water to give 4- (3-carbamoylphenoxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (60 mg) as white crystals. mp: 212-214 ° C NMR (DMSO-d ₆ , δ): 2.25 (3H, s), 7.08 (1H, dd, J =
8.5,4Hz), 7.30 (1H, br), 7.40-7.45 (2H, m), 7.50-
7.62 (6H, m), 8.00 (1H, br), 8.70 (1H, dd, J = 8.5, 4
Hz), 8.90 (1H, s), 10.88 (1H, s)

Example 24 Methyl 5-hydroxypyridine-3-carboxylate (13
To a solution of 9 mg) in N-methylpyrrolidone (3 ml) was added sodium hydride (60% in oil, 57.8 mg) under ice-cooling and the mixture was stirred at the same temperature. 4- in the mixture
Chloro-8- (2,6-dichlorobenzoylamino)-
3-Methylquinoline (200 mg) was added and the mixture was added to 1
Stirred at 50 ° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate,
The solvent was removed in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol),
8- (2,6-dichlorobenzoylamino) -4- (5
-Methoxycarbonylpyridin-3-yloxy) -3
-Methylquinoline (25 mg) and 4- (5-carboxypyridin-3-yloxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (30 mg)
I got 8- (2,6-dichlorobenzoylamino)-
4- (5-methoxycarbonylpyridin-3-yloxy) -3-methylquinoline mp: 188-191 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 3.82 (3H, s), 7.4
8-7.63 (6H, m), 8.66-8.73 (2H, m), 8.83 (1H, s),
8.92 (1H, s)

4- (5-carboxypyridin-3-yloxy) -8- (2,6-dichlorobenzoylamino)
3-methylquinoline mp: 175-180 ℃ NMR (DMSO- d 6, δ): 2.30 (3H, s), 7.36 (1H, d, J = 2
Hz), 7.50-7.65 (5H, m), 8.56 (1H, d, J = 2Hz), 8.72
(1H, dd, J = 2,2Hz), 8.78 (1H, s), 8.82 (1H, s), 10.
88 (1H, s)

Example 25 8- (2,6-Dichlorobenzoylamino) -1,4-
Dihydro-3-methyl-4-oxoquinoline (200 m
To a suspension of g) and potassium carbonate (159 mg) in N, N-dimethylformamide (3 ml) was added 3-chlorobenzyl bromide (142 mg) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane) to give 4- (3-chlorobenzyloxy) -8- (2,6-dichlorobenzoylamino) -3.
-Methylquinoline (115 mg) was obtained as white crystals. mp: 149-151 ° C NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 5.19 (2H, s), 7.
45-7.65 (8H, m), 7.84 (1H, d, J = 8Hz), 8.67 (1H, d,
J = 8Hz), 8.76 (1H, s), 10.73 (1H, s)

Example 26 The following compound was obtained in the same manner as in Example 25. (1) 8- (2,6-dichlorobenzoylamino)-
3-methyl-4- (4-trifluoromethylbenzyloxy) quinoline (8- (2,6-dichlorobenzoylamino) -1,4
Dihydro-3-methyl-4-oxoquinoline and bromide 4
Mp: 210-213 ° C NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 5.30 (2H, s), 7.4
9-7.65 (4H, m), 7.78-7.84 (5H, m), 8.66 (1H, d, J =
8Hz), 8.76 (1H, s), 10.73 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (pyridin-2-ylmethoxy) quinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxo-quinoline with 2-chloromethylpyridine hydrochloride) mp: 155-158 ℃ NMR (DMSO -d 6, δ): 2.43 (3H, s), 5.26 (2H, s) , 7.
39-7.43 (1H, m), 7.48-7.64 (4H, m), 7.72 (2H, d, J
= 8Hz), 7.87-7.93 (2H, m), 8.62 (1H, d, J = 4Hz), 8.6
6 (1H, d, J = 8Hz), 8.75 (1H, s)

(3) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (pyridin-3-ylmethoxy) quinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxo-quinoline and 3-chloromethylpyridine hydrochloride) mp: 192-195 ℃ NMR (DMSO -d 6, δ): 2.43 (3H, s), 5.25 (2H, s) , 7.4
5-7.64 (5H, m), 7.84 (1H, d, J = 8Hz), 8.00 (1H, dd,
J = 7.5,3Hz), 8.60 (1H, d, J = 3Hz), 8.66 (1H, d, J = 8
Hz), 8.72-8.76 (2H, m), 10.72 (1H, s)

(4) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (pyridin-4-ylmethoxy) quinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxo-quinoline with 4-chloromethyl-pyridine hydrochloride) mp: 204-207 ℃ NMR (DMSO -d 6, δ): 2.43 (3H, s), 5.24 (2H, s) , 7.4
9-7.65 (6H, m), 7.85 (1H, d, J = 8Hz), 8.65-8.68 (3
H, m), 8.76 (1H, s), 10.73 (1H, s)

(5) 4- (1H-benzimidazol-2-ylmethoxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (8- (2,6-dichlorobenzoylamino) -1, 4
-Dihydro-3-methyl-4-oxoquinoline and 2-chloromethyl-1H-benzimidazole mp: 140-148 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 5.37 (2H, s), 7.
22 (2H, br), 7.47-7.63 (6H, m), 7.93 (1H, d, J = 8H
z), 8.66 (1H, d, J = 8Hz), 8.75 (1H, s), 10.75 (1H,
s)

(6) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (2-methylthiazol-4-ylmethoxy) quinoline (8- (2,6-dichlorobenzoylamino) -1, 4
- from dihydro-3-methyl-4-oxo-quinoline with 4-chloromethyl-2-methylthiazole) mp: 116-119 ℃ NMR (DMSO -d 6, δ): 2.05 (3H, s), 2.50 (3H, s), 5.
08 (1H, d, J = 15Hz), 5.17 (1H, d, J = 15Hz), 7.03 (1H,
d, J = 7.5Hz), 7.16 (1H, s), 7.43-7.55 (3H, m), 7.84
(1H, d, J = 7.5Hz), 7.93 (1H, d, J = 7.5Hz), 8.17 (1H,
s)

(7) 8- (2,6-dichlorobenzoylamino) -4- (4-methoxycarbonylbenzyloxy) -3-methylquinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxo-quinoline and 4-bromomethyl-benzoic acid methyl) mp: 207-213 ℃ NMR (DMSO -d 6, δ): 2.05 (3H, s), 4.81 (3H, s), Five.
28 (2H, s), 7.05 (1H, d, J = 8Hz), 7.33 (2H, d, J = 7.5
Hz), 7.40-7.60 (3H, m), 7.73 (1H, d, J = 8Hz), 7.81-
7.85 (3H, m), 8.16 (1H, s)

(8) 4- (2-chlorobenzyloxy) -8- (2,6-dichlorobenzoylamino) -3
-Methylquinoline (8- (2,6-dichlorobenzoylamino) -1,4
-Dihydro-3-methyl-4-oxoquinoline and bromide 2
- From chlorobenzyl) mp: 158-160 ℃ NMR (DMSO -d 6, δ): 2.40 (3H, s), 5.27 (2H, s), 7.4
0-7.68 (8H, m), 7.83 (1H, d, J = 8Hz), 8.65 (1H, d,
J = 8Hz), 8.75 (1H, s), 10.73 (1H, s)

(9) 8- (2,6-dichlorobenzoylamino) -4- (3,4-dichlorobenzyloxy)
-3-Methylquinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxoquinoline bromide 3,4-dichlorobenzyl) mp: 219-222 ℃ NMR (DMSO -d 6, δ): 2.43 (3H, s), 5.20 (2H, s ), 7.4
8-7.60 (4H, m), 7.64 (1H, d, J = 8Hz), 7.72 (1H, d,
(J = 8Hz), 7.81-7.87 (2H, m), 8.66 (1H, d, J = 8Hz), 8.7
5 (1H, s), 10.73 (1H, s)

(10) 8- (2,6-dichlorobenzoylamino) -4- (2,6-difluorobenzyloxy) -3-methylquinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxoquinoline bromide 2,6-difluorobenzyl) mp: 180-183 ℃ NMR (DMSO -d 6, δ): 2.42 (3H, s), 5.26 (2H, s ), 7.
21 (2H, dd, J = 8, 8Hz), 7.47-7.65 (5H, m), 7.79 (1H,
d, J = 8Hz), 8.66 (1H, d, J = 8Hz), 8.76 (1H, s), 10.7
3 (1H, s)

(11) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (2,3,4,5,6
-Pentafluorobenzyloxy) quinoline (8- (2,6-dichlorobenzoylamino) -1,4
- from dihydro-3-methyl-4-oxoquinoline bromide 2,3,4,5,6-pentafluoro benzyl) mp: 288-290 ℃ NMR (DMSO -d 6, δ): 2.02 (3H, s ), 5.01 (1H, br d, J
= 15Hz), 5.58 (1H, br d, J = 15Hz), 7.06-7.17 (3H,
m), 7.38 (1H, dd, J = 8, 8Hz), 7.60-7.64 (1H, m), 8.0
7-8.12 (2H, m)

Example 27 (1) 8-amino-1,4-dihydro-3-methoxymethyl-4-oxoquinoline was converted to 1,4-dihydro-3
Obtained in the same manner as in Example 1- (4) from -methoxymethyl-8-nitro-4-oxoquinoline. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 3.30 (3H, s), 4.30 (2H, s), 5.
45 (2H, s), 6.90 (1H, d, J = 8Hz), 7.04 (1H, dd, J = 8,
8Hz), 7.39 (1H, d, J = 8Hz), 7.85 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -4- (2,6-dichlorobenzoyloxy) -3-methoxymethylquinoline was converted to 8-amino-
It was obtained in the same manner as in Example 1- (5) from 1,4-dihydro-3-methoxymethyl-4-oxoquinoline and 2,6-dichlorobenzoyl chloride. mp: 241-243 ° C NMR (DMSO-d ₆ , δ): 3.36 (3H, s), 4.80 (2H, s), 7.4
6-7.62 (3H, m), 7.72 (1H, m), 7.79-7.87 (3H, m),
8.01 (1H, d, J = 8Hz), 8.81 (1H, d, J = 8Hz), 9.07 (1H,
s), 11.01 (1H, s)

(3) 8- (2,6-dichlorobenzoylamino) -4- (2,6-dichlorobenzoyloxy) -3-methoxymethylquinoline (4.88 g) in ethanol (100 ml) and 1N sodium hydroxide The suspension of the aqueous solution (30 ml) was stirred at 90 ° C. for 2 hours. After evaporation of the solvent, the residue was diluted with water and the solution was neutralized with 1N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and diethyl ether to give 8- (2,6-dichlorobenzoylamino)-
1,4-Dihydro-3-methoxymethyl-4-oxoquinoline (3.41 g) was obtained as a white powder. mp: 290 ° C (decomposition) NMR (DMSO-d ₆ , δ): 3.32 (3H, s), 4.32 (2H, s), 7.
40 (1H, dd, J = 8, 8Hz), 7.52-7.68 (3H, m), 8.01 (1H,
d, J = 7Hz), 8.05 (1H, d, J = 8Hz), 8.10 (1H, d, J = 8H)
z), 10.45 (1H, s), 10.66 (1H, d, J = 7Hz)

(4) 4-methanesulfonyloxy-2
To a solution of -methyl-2-butanol (116 mg) in N, N-dimethylformamide (3 ml) was added potassium carbonate (147 mg) and the reaction mixture was stirred at room temperature for 30 minutes. 8- (2,6-dichlorobenzoylamino) -1,4-dihydro-3-methoxymethyl-4 was added to the mixture.
-Oxoquinoline (200 mg) was added and the mixture was
Stirred at C overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was triturated with ethanol to give 8- (2,6-dichlorobenzoylamino) -4- (3-hydroxy-3-methylbutoxy)-
3-methoxymethylquinoline (40 mg) was obtained as pale brown crystals. mp: 115-118 ° C NMR (DMSO-d ₆ , δ): 1.15 (6H, s), 2.03 (2H, dd, J =
7.5,7.5Hz), 3.37 (3H, s), 4.32 (2H, dd, J = 7.5, 7.5
Hz), 4.42 (1H, s), 4.65 (2H, s), 7.47-7.59 (3H, m),
7.66 (1H, dd, J = 8, 8Hz), 7.91 (1H, d, J = 8Hz), 8.70
(1H, d, J = 8Hz), 8.80 (1H, s), 10.76 (1H, s)

Example 28 (1) 5-Methyl-2-nitroaniline (10.0
g) in a stirred suspension of ethanol (20 ml),
2-dimethyl-1,3-dioxane-4,6-dione (9.95 g) and triethyl orthoformate (10.7 g)
Was added at 50 ° C. The resulting mixture was heated at 120 ° C. for 1 hour, during which time ethanol (20 ml) was added to the mixture and the liberated ethanol was distilled off. After cooling, ethyl acetate (40 ml) was added thereto, and the resulting precipitate was collected by filtration. The solid was washed with hot ethanol (40 ml) and allowed to cool to room temperature. The precipitate was collected by filtration, air-dried, and (5
-Methyl-2-nitroanilino) isopropylidene methylenemalonate (15.2 g) was obtained as yellow needles. mp: 218-220 ° C NMR (CDCl ₃ , δ): 1.77 (6H, s), 2.50 (3H, s), 7.16
(1H, d, J = 8Hz), 7.40 (1H, br s), 8.20 (1H, d, J = 8H
z), 8.73 (1H, d, J = 15Hz)

(2) A stirred mixture of diphenyl ether (37 g) and biphenyl (13 g) was added with (5-methyl-
2-Nitroanilino) isopropylidene methylenemalonate (14.6 g) was added at 220 ° C. and the mixture was heated at the same temperature for half an hour. The reaction mixture was cooled to 100 ° C. and n
-Hexane (100 ml) was added dropwise to the mixture. After cooling to room temperature, the precipitate was collected by filtration. The solid was washed with hot ethanol (70 ml) and allowed to cool to room temperature. The solid was collected by filtration and air dried to give 1,4-dihydro-5-methyl-8-nitro-4-oxoquinoline (8.8 g) as a dark brown solid. mp: 219-225 ° C NMR (DMSO-d ₆ , δ): 2.87 (3H, s), 6.15 (1H, d, J = 8
Hz), 7.20 (1H, d, J = 8Hz), 7.86 (1H, d, J = 8Hz), 8.45
(1H, d, J = 8Hz)

(3) 1,4-dihydro-5-methyl-
8-nitro-4-oxoquinoline (1.5 g) and 1,
3,5-Trioxane (3.31 g) in dioxane (1
5 ml) to the stirred mixture was added concentrated hydrochloric acid (30 ml),
The mixture was stirred at 100 ° C. overnight. The mixture was evaporated in vacuo and the residue was treated with acetonitrile,
1,4-Dihydro-3-hydroxymethyl-5-methyl-8-nitro-4-oxoquinoline (1.3 g) was obtained. mp: 251-255 ° C NMR (DMSO-d ₆ , δ): 4.37 (2H, s), 7.20 (1H, d, J = 8
Hz), 7.93 (1H, d, J = 6Hz), 8.47 (1H, d, J = 8Hz)

(4) To a suspension of 1,4-dihydro-3-hydroxymethyl-5-methyl-8-nitro-4-oxoquinoline (1.12 g) in dichloromethane (10 ml) was added thionyl chloride (569 mg). ) In dichloromethane (5 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. The mixture was concentrated in vacuo, suspended in dichloromethane-methanol and refluxed for 2 hours. The solvent was distilled off from the mixture in vacuo, and the residue was recrystallized from methanol to give 1,4-dihydro-3-methoxymethyl-5-methyl-8-nitro-4-oxoquinoline (889 mg). . mp: 210-213 ° C NMR (CDCl ₃ , δ): 3.05 (3H, s), 3.50 (3H, s), 4.45
(2H, s), 7.14 (1H, d, J = 8Hz), 7.77 (1H, d, J = 6Hz),
8.48 (1H, d, J = 8Hz)

(5) 4-Chloro-3-methoxymethyl-5-methyl-8-nitroquinoline was prepared according to Example 1- (3).
Was obtained in the same manner as described above. mp: 120-124 ° C NMR (CDCl ₃ , δ): 3.10 (3H, s), 3.53 (3H, s), 4.76
(2H, s), 7.43 (1H, d, J = 8Hz), 7.80 (1H, d, J = 8Hz),
9.01 (1H, s)

(6) 8-amino-4-chloro-3-methoxymethyl-5-methylquinoline was prepared in Example 1- (4)
Was obtained in the same manner as described above. NMR (CDCl ₃ , δ): 2.90 (3H, s), 3.50 (3H, s), 4.75
(2H, s), 4.92 (2H, br s), 6.82 (1H, d, J = 8Hz), 7.1
6 (1H, d, J = 8Hz), 8.71 (1H, s)

(7) 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methoxymethyl-5-methylquinoline was obtained in the same manner as in Example 1- (5). mp: 180 ° C NMR (CDCl ₃ , δ): 3.01 (3H, s), 3.52 (3H, s), 4.75
(2H, s), 7.28-7.48 (4H, m), 8.75 (1H, s), 8.82 (1
(H, d, J = 8Hz)

(8) 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methoxymethyl-5-methylquinoline (220 mg) and hydrazine monohydrate (2
A mixture in 69 mg) of N-methylpyrrolidone (3 ml) was heated at 120 ° C. for 6.5 hours. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration. The residue was recrystallized from hot ethanol to give 6- (2,6-dichlorobenzoylamino) -9-methyl-1H-pyrazolo [4,3-c] quinoline (93 mg) as a pale yellow powder. mp: 285-290 ° C (decomposition) NMR (DMSO-d ₆ , δ): 2.96 (3H, s), 7.50-7.67 (5H,
m), 8.62 (1H, br), 8.67 (1H, d, J = 8Hz), 9.26 (1H, br)
s), 10.63 (1H, br s)

Example 29 (1) (5-chloro-2-nitroanilino) isopropylidene methylenemalonate was prepared from 5-chloro-2-nitroaniline and isopropylidene malonate in Example 28.
-Obtained in the same manner as in (1). mp: 217-220 ° C NMR (CDCl ₃ , δ): 1.78 (6H, s), 7.34 (1H, d, J = 7H
z), 7.62 (1H, br s), 8.28 (1H, d, J = 7Hz), 8.67 (1H,
d, J = 9Hz), 13.60 (1H, br d, J = 9Hz)

(2) 5-chloro-1,4-dihydro-
8-Nitro-4-oxoquinoline was prepared according to Example 28- (2).
Was obtained in the same manner as described above. mp: 220-225 ° C (decomposition) NMR (DMSO-d ₆ , δ): 6.21 (1H, d, J = 8Hz), 7.45 (1H,
d, J = 8Hz), 7.87 (1H, t, J = 8Hz), 8.50 (1H, d, J = 8H
z), 11.88 (1H, br s)

(3) 4,5-Dichloro-8-nitroquinoline was obtained in the same manner as in Example 1- (3). mp: 116-118 ° C NMR (CDCl ₃ , δ): 7.68 (1H, d, J = 6Hz), 7.74 (1H,
d, J = 8Hz), 7.86 (1H, d, J = 8Hz), 8.85 (1H, d, J = 6Hz)

(4) 8-amino-4,5-dichloroquinoline was obtained in the same manner as in Example 1- (4). mp: 135 ° C NMR (CDCl ₃ , δ): 5.10 (2H, br s), 6.85 (1H, d, J =
8Hz), 7.43 (1H, d, J = 8Hz), 7.50 (1H, d, J = 6Hz), 8.5
5 (1H, d, J = 6Hz)

(5) 4,5-dichloro-8- (2,6
-Dichlorobenzoylamino) quinoline in Example 1
Obtained in the same manner as in (5). mp: 243-247 ° C NMR (DMSO-d ₆ , δ): 7.46-7.61 (3H, m), 7.88-7.95
(2H, m), 8.75 (1H, d, J = 8Hz), 8.81 (1H, d, J = 4Hz)

(6) To a stirred solution of 3-hydroxymethylpyridine (283 mg) in N-methylpyrrolidone was added potassium tert-butoxide (291 mg) at 0 ° C. The mixture was stirred at room temperature for 45 minutes,
5-Dichloro-8- (2,6-dichlorobenzoylamino) quinoline (195 mg) was added, and the mixture was stirred for 2 hours.
The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The precipitated solid was collected by filtration with ethyl acetate and washed with ethanol to give 5-chloro-8- (2,6-dichlorobenzoylamino) -4- (pyridin-3-ylmethoxy) quinoline (157 mg) as pale yellow crystals. As obtained. mp: 193-195 ° C NMR (DMSO-d ₆ , δ): 5.48 (2H, s), 7.38 (1H, d, J = 6
Hz), 7.45-7.62 (4H, m), 7.68 (1H, d, J = 8Hz), 8.02
(1H, br d, J = 7.5Hz), 8.59 (1H, br d, J = 5Hz), 8.67
(1H, d, J = 8Hz), 8.77 (1H, d, J = 6Hz), 8.81 (1H, s),
10.74 (1H, s)

Example 30 The following compounds were obtained in the same manner as in Example 20. (1) 5-chloro-8- (2,6-dichlorobenzoylamino) -4- (pyridin-3-yloxy) quinoline (4,5-dichloro-8- (2,6-dichlorobenzoylamino) quinoline and 3 - hydroxy pyridine) mp: 148-150 ℃ NMR (DMSO -d 6, δ): 7.05 (1H, d, J = 6Hz), 7.49-7.63
(4H, m), 7.73 (1H, dd, J = 7, 2Hz), 7.82 (1H, d, J = 8
Hz), 8.53 (1H, d, J = 5Hz), 8.60 (1H, d, J = 2Hz), 8.76
(1H, d, J = 8Hz), 8.78 (1H, d, J = 6Hz), 10.87 (1H, s)

(2) 5-chloro-8- (2,6-dichlorobenzoylamino) -4- (imidazol-2-ylthio) quinoline (4,5-dichloro-8- (2,6-dichlorobenzoylamino) quinoline and 2-mercapto-imidazole) mp: 252-254 ℃ NMR (DMSO -d 6, δ): 6.56 (1H, d, J = 6Hz), 7.32 (1H,
s), 7.46-7.61 (4H, m), 7.85 (1H, d, J = 8Hz), 8.57
(1H, d, J = 6Hz), 8.72 (1H, d, J = 8Hz), 10.85 (1H, s)

(3) 5-chloro-8- (2,6-dichlorobenzoylamino) -4- (1-methylimidazol-2-ylthio) quinoline (4,5-dichloro-8- (2,6-dichloro) From benzoylamino) quinoline and 2-mercapto-1-methylimidazole NMR (DMSO-d ₆ , δ): 3.62 (3H, s), 6.38 (1H, d, J = 6)
Hz), 7.30 (1H, s), 7.47-7.60 (3H, m), 7.67 (1H, s),
7.86 (1H, d, J = 8Hz), 8.57 (1H, d, J = 6Hz), 8.73 (1
(H, d, J = 8Hz), 10.86 (1H, s)

Example 31 (1) 5-chloro-1,4-dihydro-3-hydroxymethyl-8-nitro-4-oxoquinoline was converted to 5-chloro-1,4-dihydro-8-nitro-4- Obtained from oxoquinoline in the same manner as in Example 28- (3). mp:> 250 ° C NMR (DMSO-d ₆ , δ): 4.37 (2H, s), 7.45 (1H, d, J = 8
Hz), 7.93 (1H, d, J = 4Hz), 8.52 (1H, d, J = 8Hz)

(2) 5-chloro-1,4-dihydro-
3-Methyl-8-nitro-4-oxoquinoline was obtained in the same manner as in Example 1- (2). mp:> 250 ° C NMR (DMSO-d ₆ , δ): 1.97 (3H, s), 7.42 (1H, d, J = 8
Hz), 7.87 (1H, d, J = 6Hz), 8.49 (1H, d, J = 8Hz)

(3) 4,5-dichloro-3-methyl-
8-Nitroquinoline was obtained in the same manner as in Example 1- (3). mp: 136-138 ° C NMR (CDCl ₃ , δ): 2.61 (3H, s), 7.73 (1H, d, J = 8H
z), 7.80 (1H, d, J = 8Hz), 8.84 (1H, s)

(4) 8-amino-4,5-dichloro-
3-Methylquinoline was obtained in the same manner as in Example 1- (4). mp: 128-130 ° C NMR (CDCl ₃ , δ): 2.53 (3H, s), 5.07 (2H, s), 6.79
(1H, d, J = 8Hz), 7.42 (1H, d, J = 8Hz), 8.55 (1H, s)

(5) 4,5-Dichloro-8- (2,6
-Dichlorobenzoylamino) -3-methylquinoline was obtained in the same manner as in Example 1- (5). mp: 222-233 ° C NMR (CDCl ₃ , δ): 2.56 (3H, s), 7.30-7.44 (3H, m),
7.71 (1H, d, J = 8Hz), 8.58 (1H, s), 8.83 (1H, d, J =
8Hz)

(6) 5-chloro-8- (2,6-dichlorobenzoylamino) -4-hydrazino-3-methylquinoline was converted to 4,5-dichloro-8- (2,6-dichlorobenzoylamino)- It was obtained in the same manner as in Example 1- (6) from 3-methylquinoline and hydrazine monohydrate. mp: 208-213 ° C NMR (DMSO-d ₆ , δ): 2.49 (3H, s), 4.65 (2H, br s),
7.48-7.60 (4H, m), 7.68 (1H, br s), 8.41 (1H, s),
8.50 (1H, d, J = 8Hz)

(7) 5-chloro-8- (2,6-dichlorobenzoylamino) -4-hydrazino-3-methylquinoline (200 mg) of 1,2-dichloroethane (3
Acetic anhydride (57 mg) was added to the suspension in ml) and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (5% methanol-dichloromethane). The crystalline product is triturated with ethanol to give 4-
(2-acetylhydrazino) -5-chloro-8- (2,
6-Dichlorobenzoylamino) -3-methylquinoline was obtained as white crystals (150 mg). mp: 274-276 ° C NMR (DMSO-d ₆ , δ): 1.83 (3H, s), 2.38 (3H, s), 7.4
8-7.60 (3H, m), 7.63 (1H, d, J = 8Hz), 8.43 (2H, s),
8.56 (1H, d, J = 8Hz), 10.04 (1H, br s), 10.67 (1H,
s)

Example 32 5-Chloro-8- (2,6-dichlorobenzoylamino) -3-methyl-4- (1-methyl-1H-tetrazol-5-ylthio) quinoline was converted to 4,5-dichloro-
Obtained in the same manner as in Example 20 from 8- (2,6-dichlorobenzoylamino) quinoline and 5-mercapto-1-methyl-1H-tetrazole. mp: 250 ° C NMR (DMSO-d ₆ , δ): 2.60 (3H, s), 4.10 (3H, s), 7.4
6-7.61 (3H, m), 7.81 (1H, d, J = 8Hz), 8.66 (1H, d,
J = 8Hz), 9.00 (1H, s)

Example 33 (1) 5-chloro-8- (2,6-dichlorobenzoylamino) -4-[(2-ethylaminoethyl) amino] -3-methylquinoline was converted to 4,5-dichloro- 8-
Example 1 was prepared from (2,6-dichlorobenzoylamino) -3-methylquinoline and N-ethylethylenediamine.
Obtained in the same manner as in (6). NMR (DMSO-d ₆ , δ): 0.98 (3H, t, J = 7.5Hz), 2.38 (3
H, s), 2.51 (2H, q, J = 7.5Hz), 2.67-2.71 (2H, m), 3.
36-3.43 (2H, m), 6.65 (1H, t, J = 6Hz), 7.50-7.61 (4
H, m), 8.36 (1H, s), 8.51 (1H, d, J = 8Hz), 10.58 (1
H, s)

(2) 5-chloro-8- (2,6-dichlorobenzoylamino) -4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline was prepared according to Example 1- ( It was obtained in the same manner as in 7). mp: 262-265 ° C NMR (DMSO-d ₆ , δ): 1.10 (3H, t, J = 7.5Hz), 2.38 (3
H, s), 3.18-3.27 (2H, m), 3.59-3.66 (2H, m), 3.69-
3.78 (2H, m), 7.48-7.59 (3H, m), 7.77 (1H, d, J = 8H
z), 8.63 (1H, d, J = 8Hz), 8.93 (1H, s), 10.89 (1H,
s)

Example 34 (1) 1,4-dihydro-6-methyl-8-nitro-
A mixture of 4-oxoquinoline (12.0 g) and paraformaldehyde (17.6 g) in dioxane (100 ml) and concentrated hydrochloric acid (100 ml) was stirred at 120 ° C. for 2 days and allowed to stand at room temperature. The mixture was azeotropically concentrated with toluene and dioxane. The residue was collected by filtration and washed with water. The residue was suspended in water and refluxed for 1 hour. The mixture was allowed to cool to room temperature, the resulting precipitate was collected by filtration, washed with water and acetonitrile, dried and 1,4-dihydro-3-hydroxymethyl-6-methyl-8-nitro-4-oxoquinoline (6.9 g) was obtained. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 4.41 (2H, s), 7.
96 (1H, d, J = 7Hz), 8.40 (1H, s), 8.50 (1H, s), 11.8
5 (1H, d, J = 7Hz)

(2) 1,4-dihydro-3,6-dimethyl-8-nitro-4-oxoquinoline was prepared in Example 1
Obtained in the same manner as in (2). mp:> 300 ° C NMR (DMSO-d ₆ , δ): 2.00 (3H, s), 2.50 (3H, s), 7.
87 (1H, d, J = 6Hz), 8.40 (1H, s), 8.48 (1H, s), 11.7
0 (1H, br d, J = 6Hz)

(3) 4-chloro-3,6-dimethyl-
8-Nitroquinoline was obtained in the same manner as in Example 1- (3). mp: 155-156 ° C NMR (DMSO-d ₆ , δ): 2.56 (3H, s), 2.61 (3H, s), 8.
20 (1H, d, J = 0.5Hz), 8.23 (1H, d, J = 0.5Hz), 8.90 (1
H, s)

(4) 8-amino-4-chloro-3,6
-Dimethylquinoline was obtained in the same manner as in Example 1- (4). mp: 148-150 ° C NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.48 (3H, s), 5.
99 (2H, s), 6.71 (1H, s), 7.03 (1H, s), 8.55 (1H,
s)

(5) 4-Chloro-8- (2,6-dichlorobenzoylamino) -3,6-dimethylquinoline was obtained in the same manner as in Example 1- (5). mp: 193-196 ° C NMR (DMSO-d ₆ , δ): 2.54 (3H, s), 2.60 (3H, s), 7.
47-7.60 (3H, m), 7.75 (1H, s), 8.62 (1H, s), 8.75
(1H, s), 10.79 (1H, s)

(6) 8- (2,6-dichlorobenzoylamino) -3,6-dimethyl-4- (imidazole-
1-yl) quinoline was obtained in the same manner as in Example 12. mp: 181-183 ° C NMR (DMSO-d ₆ , δ): 2.22 (3H, s), 2.47 (3H, s), 6.
78 (1H, s), 7.29 (1H, s), 7.48-7.61 (4H, m), 7.95
(1H, s), 8.60 (1H, s), 8.90 (1H, s), 10.89 (1H, s)

Example 35 (1) (4-Fluoro-2-nitroanilino) methylenemalonic acid isopropylidene was prepared from 4-fluoro-2-nitroaniline and isopropylidene malonate in the same manner as in Example 28- (1). I got it. mp: 195-196 ° C NMR (CDCl ₃ , δ): 1.78 (2x3H, s), 7.53 (1H, ddd, J
= 8,5,3Hz), 7.63 (1H, dd, J = 8, 5Hz), 8.05 (1H, dd,
J = 8, 3Hz), 8.67 (1H, d, J = 15Hz)

(2) 6-Fluoro-1,4-dihydro-8-nitro-4-oxoquinoline was prepared in Example 28-
Obtained in the same manner as in (2). mp: 178-182 ° C NMR (CDCl ₃ , δ): 6.40 (1H, d, J = 7.5Hz), 7.76 (1
H, dd, J = 7.5, 7Hz), 8.42 (1H, dd, J = 7, 1Hz), 8.50
(1H, dd, J = 8, 1Hz)

(3) 6-Fluoro-1,4-dihydro-8-nitro-4-oxoquinoline (15.0 g) and trioxane (32.5 g) in dioxane (150 ml)
And concentrated hydrochloric acid (300 ml) was heated at 90 ° C. for 5 days. The solvent was distilled off from the mixture, and residual hydrochloric acid was azeotropically removed with toluene under reduced pressure. The residue was subjected to silica gel chromatography (methanol: methylene chloride = 1: 20, V /
V). The upper fractions were collected and 6-fluoro-1,
4-dihydro-3-methoxymethyl-8-nitro-4-
Oxoquinoline (2.28 g) was obtained as an orange powder. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 3.34 (3H, s), 4.32 (2H, s), 7.
97 (1H, s), 8.28 (1H, dd, J = 8, 2Hz), 8.60 (1H, dd,
(J = 8, 2Hz)

(4) 4-chloro-6-fluoro-3-
Methoxymethyl-8-nitroquinoline was prepared in Example 1
Obtained in the same manner as (3). mp: 107-108 ° C NMR (DMSO-d ₆ , δ): 3.42 (3H, s), 4.77 (2H, s), 8.
27 (1H, dd, J = 10, 3Hz), 8.60 (1H, dd, J = 10, 3Hz),
9.01 (1H, s)

(5) 8-amino-4-chloro-6-fluoro-3-methoxymethylquinoline was prepared in Example 1
Obtained in the same manner as (4). mp: 110.5-112.5 ℃ NMR (DMSO-d ₆ , δ): 3.40 (3H, s), 4.71 (2H, s), 6.
55 (2H, s), 6.71 (1H, dd, J = 11, 3Hz), 6.90 (1H, dd,
J = 11, 3Hz), 8.47 (1H, s)

(6) 4-chloro-8- (2,6-dichlorobenzoylamino) -6-fluoro-3-methoxymethylquinoline was obtained in the same manner as in Example 1- (5). mp: 186-188 ° C NMR (DMSO-d ₆ , δ): 3.41 (3H, s), 4.77 (2H, s), 7.4
8-7.61 (3H, m), 7.73 (1H, dd, J = 11, 3Hz), 8.69 (1
H, dd, J = 11, 3Hz), 8.88 (1H, s), 11.12 (1H, s)

(7) 8- (2,6-dichlorobenzoylamino) -6-fluoro-3-methoxymethyl-4-
[(2-Methylaminoethyl) amino] quinoline was obtained in the same manner as in Example 1- (6). NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 2.88 (2H, t, J = 6
Hz), 3.37 (3H, s), 3.71 (2H, dt, J = 6, 5Hz), 4.57 (2
H, s), 5.97 (1H, br t, J = 5Hz), 7.29-7.49 (4H, m),
8.24 (1H, s), 8.72 (1H, dd, J = 11, 2Hz), 10.20 (1H,
br s)

(8) 8- (2,6-dichlorobenzoylamino) -6-fluoro-3-methoxymethyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline was obtained in the same manner as in Example 1- (7). mp: 173-174 ° C NMR (DMSO-d ₆ , δ): 2.82 (3H, s), 3.33 (3H, s), 3.5
5-3.75 (3H, m), 3.85 (1H, m), 4.58 (2H, s), 7.45
(1H, dd, J = 10, 3Hz), 7.48 (3H, m), 8.62 (1H, dd, J =
11, 3Hz), 8.91 (1H, s), 11.22 (1H, s)

Example 36 8- (2,6-Dichlorobenzoylamino) -6-fluoro-3-methoxymethyl-4- (3-methyl-2-thioxoimidazolidin-1-yl) quinoline was converted to 8-
(2,6-Dichlorobenzoylamino) -6-fluoro-3-methoxymethyl-4-[(2-methylaminoethyl) amino] quinoline and 1,1′-thiocarbonyldiimidazole in the same manner as in Example 3. I got it. mp: 179-180 ° C NMR (DMSO-d ₆ , δ): 3.16 (3H, s), 3.37 (3H, s), 3.8
0-4.10 (4H, m), 4.56 (1H, d, J = 13Hz), 4.63 (1H, d,
J = 13Hz), 7.40 (1H, dd, J = 10, 2Hz), 7.49-7.61 (3H,
m), 8.62 (1H, dd, J = 10, 2Hz), 8.97 (1H, s), 11.26
(1H, s)

Example 37 8- (2,6-Dichlorobenzoylamino) -6-fluoro-3-methoxymethyl-4- (1-methyl-1H-
The tetrazol-5-ylthio) quinoline was prepared from 4-chloro-8- (2,6-dichlorobenzoylamino) -6-fluoro-3-methoxymethylquinoline and 5-mercapto-1-methyl-1H-tetrazole by way of example. Obtained in the same manner as 20. mp: 203-204 ℃ NMR (DMSO-d ₆ , δ): 3.32 (3H, s), 4.11 (3H, s), 4.
85 (2H, s), 7.48-7.61 (3H, m), 7.82 (1H, dd, J = 10,
2Hz), 8.67 (1H, dd, J = 10, 2Hz), 9.03 (1H, s), 11.37
(1H, s)

Example 38 (1) 8-Amino-4-chloro-2-methylquinoline was obtained from 4-chloro-2-methyl-8-nitroquinoline in the same manner as in Example 1- (4). . NMR (CDCl ₃ ,
δ): 2.66 (3H, s), 5.00 (2H, br s), 6.91 (1H, d,
J = 8Hz), 7.29-7.37 (2H, m), 7.46 (1H, d, J = 8Hz)

(2) 4-chloro-8- (2,6-dichlorobenzoylamino) -2-methylquinoline was obtained in the same manner as in Example 1- (5). mp: 184-189 ° C NMR (DMSO-d ₆ , δ): 2.67 (3H, s), 7.48-7.62 (3H,
m), 7.73 (1H, t, J = 8Hz), 7.80 (1H, s), 7.92 (1H, d,
J = 8Hz), 8.76 (1H, d, J = 8Hz)

(3) 8- (2,6-dichlorobenzoylamino) -4- (2-methoxyethoxy) -2-methylquinoline was converted to 4-chloro-8- (2,6-dichlorobenzoylamino) -2 Obtained from -methylquinoline and 2-methoxyethanol in the same manner as in Example 29- (6). mp: 195-198 ° C NMR (DMSO-d ₆ , δ): 2.60 (3H, s), 3.38 (3H, s), 3.
82 (2H, dd, J = 5.5, 5.5Hz), 4.48 (2H, dd, J = 5.5, 5.5
Hz), 7.04 (1H, s), 7.50-7.62 (4H, m), 7.84 (1H, d,
J = 8Hz), 8.68 (1H, d, J = 8Hz), 10.38 (1H, s)

Example 39 The following compounds were obtained in the same manner as in Example 20. (1) 8- (2,6-dichlorobenzoylamino)-
2-Methyl-4- (6-methylpyridin-3-yloxy) quinoline (from 4-chloro-8- (2,6-dichlorobenzoylamino) -2-methylquinoline and 5-hydroxy-2-methylpyridine) mp : 204-206 ℃ NMR (DMSO-d ₆ , δ): 2.53 (3H, s), 2.55 (3H, s), 6.
63 (1H, s), 7.48 (1H, d, J = 8Hz), 7.50-7.73 (5H, m),
8.03 (1H, d, J = 8Hz), 8.48 (1H, d, J = 2Hz), 8.75 (1
(H, d, J = 7.5Hz), 10.49 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -2-methyl-4- (1-methyl-1H-tetrazol-5-ylthio) quinoline (4-chloro-8- (2,6- Dichlorobenzoylamino) -2-methylquinoline and 5-mercapto-1-methyl-1H-tetrazole) mp: 215-217 ° C. NMR (DMSO-d ₆ , δ): 2.62 (3H, s), 4.10 (3H, s), 7.
28 (1H, s), 7.50-7.62 (3H, m), 7.73 (1H, dd, J = 8, 8
Hz), 7.96 (1H, d, J = 8Hz), 8.76 (1H, d, J = 8Hz), 10.6
2 (1H, s)

Example 40 8- (2,6-Dichlorobenzoylamino) -4- (imidazol-1-yl) -2-methylquinoline was converted to 4-
Chloro-8- (2,6-dichlorobenzoylamino)-
Obtained in the same manner as in Example 12 from 2-methylquinoline and imidazole. mp: 210 ° C NMR (CDCl ₃ , δ): 2.76 (3H, s), 7.28-7.47 (6H, m),
7.52 (1H, d, J = 8Hz), 7.61 (1H, t, J = 8Hz), 7.84 (1
H, s), 9.02 (1H, d, J = 8Hz)

The hydrochloride mp: 276-279 ° C. NMR (DMSO-d ₆ , δ): 2.78 (3H, s), 7.44-7.65 (4H,
m), 7.72 (1H, t, J = 8Hz), 7.72 (1H, t, J = 8Hz), 7.89
(1H, s), 7.96 (1H, sd), 8.18 (1H, sd), 8.80 (1H, d,
J = 8Hz), 9.48 (1H, s)

Example 41 (1) 8- (2,6-dichlorobenzoylamino)-
2-methyl-4-[(2-methylaminoethyl) amino] quinoline was prepared from 4-chloro-8- (2,6-dichlorobenzoylamino) -2-methylquinoline and N-methylethylenediamine according to Example 1- Obtained in the same manner as in (6). mp: 176-183 ° C NMR (CDCl ₃ , δ): 2.50 (3H, s), 2.54 (3H, s), 3.01
(2H, t, J = 6Hz), 3.36 (2H, q, J = 6Hz), 5.72 (1H, b
r), 6.35 (1H, s), 7.28-7.50 (5H, m), 8.86 (1H, d, J
= 8Hz)

(2) 8- (2,6-Dichlorobenzoylamino) -2-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline was prepared in Example 1
Obtained in the same manner as (7). mp: 215-224 ° C NMR (CDCl ₃ , δ): 2.66 (3H, s), 2.99 (3H, s), 3.62
(2H, t, J = 8Hz), 3.91 (2H, t, J = 8Hz), 7.23-7.45 (4
H, m), 7.52 (1H, t, J = 8Hz), 7.67 (1H, d, J = 8Hz), 8.
92 (1H, d, J = 8Hz)

Example 42 (1) 1,4-dihydro-2-methyl-8-nitro-
A mixture of 4-oxoquinoline (4.5 g) and 1,3,5-trioxane (10.0 g) in dioxane (45 ml) and concentrated hydrochloric acid (90 ml) was stirred at 90 ° C. for 24 hours,
Allowed to cool to room temperature. The mixture was azeotropically concentrated with toluene and dioxane. The residue was washed with hot ethyl acetate and allowed to cool to room temperature. The resulting precipitate was collected by filtration and washed with ethyl acetate. The residue was suspended in water (50ml) and refluxed for 1.5 hours. The mixture was cooled to room temperature, and the resulting precipitate was collected by filtration, washed with water, and dried to give 1,4-dihydro-3.
-Hydroxymethyl-2-methyl-8-nitro-4-oxoquinoline (4.78 g) was obtained as a pale yellow solid. mp: 259-261 ° C NMR (DMSO-d ₆ , δ): 2.57 (3H, s), 4.46 (2H, d, J = 5
Hz), 4.69 (1H, t, J = 5Hz), 7.46 (1H, t, J = 8Hz), 8.49
-8.58 (2H, m)

(2) 1,4-Dihydro-2,3-dimethyl-8-nitro-4-oxoquinoline was prepared in Example 1
Obtained in the same manner as in (2). mp: 250 ° C NMR (CDCl ₃ , δ): 2.14 (3H, s), 2.50 (3H, s), 7.37
(1H, t, J = 8Hz), 8.60 (1H, d, J = 8Hz), 8.77 (1H, d,
(J = 8Hz)

(3) 4-chloro-2,3-dimethyl-
8-Nitroquinoline was obtained in the same manner as in Example 1- (3). mp: 108-112 ° C NMR (CDCl ₃ , δ): 2.58 (3H, s), 2.75 (3H, s), 7.60
(1H, t, J = 8Hz), 7.92 (1H, d, J = 8Hz), 8.36 (1H, d,
(J = 8Hz)

(4) 8-amino-4-chloro-2,3
-Dimethylquinoline was obtained in the same manner as in Example 1- (4). mp: 100-102 ° C NMR (CDCl ₃ , δ): 2.52 (3H, s), 2.70 (3H, s), 4.98
(2H, s), 6.88 (1H, d, J = 8Hz), 7.32 (1H, t, J = 8Hz),
7.46 (1H, d, J = 8Hz)

(5) 4-Chloro-8- (2,6-dichlorobenzoylamino) -2,3-dimethylquinoline was obtained in the same manner as in Example 1- (5). mp: 195-198 ° C NMR (CDCl ₃ , δ): 2.55 (3H, s), 2.70 (3H, s), 7.30
-7.45 (3H, m), 7.62 (1H, t, J = 8Hz), 7.91 (1H, d, J =
8Hz), 8.91 (1H, d, J = 8Hz)

(6) 8- (2,6-dichlorobenzoylamino) -2,3-dimethyl-4- (imidazole-
1-yl) quinoline was obtained in the same manner as in Example 12. mp: 227-234 ° C NMR (CDCl ₃ , δ): 2.18 (3H, s), 2.74 (3H, s), 6.98
(1H, d, J = 8Hz), 7.09 (1H, s), 7.32-7.47 (4H, m), 7.
52 (1H, t, J = 8Hz), 7.60 (1H, s), 8.92 (1H, d, J = 8H
z)

The hydrochloride mp: 280-285 ° C. NMR (DMSO-d ₆ , δ): 2.16 (3H, s), 2.50 (3H, s), 6.
99 (1H, d, J = 8Hz), 7.50-7.70 (4H, m), 8.00-8.09 (2
H, m), 8.70 (1H, d, J = 8Hz), 9.40 (1H, s)

Example 43 The following compounds were obtained in the same manner as in Example 20. (1) 8- (2,6-dichlorobenzoylamino)-
2,3-dimethyl-4- (6-methylpyridin-3-yloxy) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -2,3-dimethylquinoline and 5-hydroxy-2
Mp: 185 ° C NMR (CDCl ₃ , δ): 2.23 (3H, s), 2.50 (3H, s), 2.69
(3H, s), 6.82 (1H, dd, J = 8, 2Hz), 7.00 (1H, d, J = 8
Hz), 7.30-7.53 (5H, m), 8.24 (1H, d, J = 2Hz), 8.88
(1H, d, J = 8Hz)

(2) 8- (2,6-dichlorobenzoylamino) -2,3-dimethyl-4- (1-methylimidazol-2-ylthio) quinoline (4-chloro-8- (2,6-dichloro) Benzoylamino) -2,3-dimethylquinoline and 2-mercapto-1
- methyl imidazole) mp: 226-235 ℃ NMR (CDCl 3, δ): 2.62 (3H, s), 2.66 (3H, s), 3.54
(3H, s), 6.89 (1H, s), 7.01 (1H, s), 7.30-7.44 (3
H, m), 7.56 (1H, t, J = 8Hz), 8.19 (1H, d, J = 8Hz), 8.
85 (1H, d, J = 8Hz)

Example 44 (1) 8- (2,6-dichlorobenzoylamino)-
2,3-dimethyl-4-[(2-methylaminoethyl)
Amino] quinoline was obtained in the same manner as in Example 1- (6) from 4-chloro-8- (2,6-dichlorobenzoylamino) -2,3-dimethylquinoline and N-methylethylenediamine. mp: 134-136 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 2.31 (3H, s), 2.
53 (3H, s), 2.64-2.69 (2H, m), 3.36-3.44 (2H, m),
5.57 (1H, t, J = 7Hz), 7.41 (1H, dd, J = 8, 8Hz), 7.51-
7.63 (3H, m), 7.90 (1H, d, J = 8Hz), 8.55 (1H, d, J = 8
Hz), 10.40 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -2,3-dimethyl-4- (3-methyl-2
-Oxoimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 1- (7). mp: 195-199 ° C NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 2.67 (3H, s), 2.
80 (3H, s), 3.62-3.70 (3H, m), 3.71-3.74 (1H, m),
7.50-7.61 (5H, m), 8.60-8.63 (1H, m), 10.55 (1H, s)

Example 45 (1) 8- (2,6-dichlorobenzoylamino)-
2,3-dimethyl-4-[(2-ethylaminoethyl)
Amino] quinoline is converted to 4-chloro-8- (2,6-dichlorobenzoylamino) -2,3-dimethylquinoline and N
Obtained from -ethylethylenediamine in the same manner as in Example 1- (6). NMR (DMSO-d ₆ , δ): 1.06 (3H, t, J = 7.5Hz), 2.28 (3
H, s), 2.53 (3H, s), 2.54-2.62 (2H, m), 2.71-2.77
(2H, m), 3.37-3.44 (2H, m), 5.62 (1H, t, J = 6Hz),
7.42 (1H, dd, J = 8, 8Hz), 7.50-7.63 (3H, m), 7.90 (1
H, d, J = 8Hz), 8.56 (1H, d, J = 8Hz), 10.40 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -2,3-dimethyl-4- (3-ethyl-2
-Oxoimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 1- (7). mp: 250-251 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7.5Hz), 2.26 (3
H, s), 2.67 (3H, s), 3.18-3.31 (2H, m), 3.62-3.68
(2H, m), 3.71-3.78 (2H, m), 7.50-7.62 (5H, m), 8.6
3 (1H, d, J = 8Hz), 10.55 (1H, s)

Example 46 (1) 4-chloro-2,3-dimethyl-8- (2-trifluoromethylbenzoylamino) quinoline was converted to 8-
Example 1 was prepared from amino-4-chloro-2,3-dimethylquinoline and 2-trifluoromethylbenzoyl chloride.
Obtained in the same manner as in (5). mp: 150-162 ° C NMR (CDCl ₃ , δ): 2.55 (3H, s), 2.65 (3H, s), 7.52
-7.85 (5H, m), 7.90 (1H, d, J = 8Hz), 8.88 (1H, d, J =
8Hz)

(2) 2,3-dimethyl-4-[(2-
Methylaminoethyl) amino] -8- (2-trifluoromethylbenzoylamino) quinoline in Example 1
Obtained in the same manner as in (6). NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 2.29 (3H, s), 2.
50 (3H, s), 2.70 (2H, t, J = 6Hz), 3.43 (2H, dt, J = 6,
6Hz), 5.60 (1H, t, J = 6Hz), 7.42 (1H, dd, J = 8, 8H
z), 7.74-7.95 (5H, m), 8.54 (1H, d, J = 8Hz), 10.36
(1H, s)

(3) 2,3-dimethyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-
(2-Trifluoromethylbenzoylamino) quinoline was obtained in the same manner as in Example 1- (7). mp: 179.5-182.5 ° C NMR (DMSO-d ₆ , δ): 2.27 (3H, s), 2.64 (3H, s), 2.
81 (3H, s), 3.59-3.80 (4H, m), 7.52-7.63 (2H, m),
7.74-7.95 (4H, m), 8.61 (1H, d, J = 8Hz), 10.35 (1H,
s)

Example 47 2,3-Dimethyl-4- (3-methyl-2-thioxoimidazolidin-1-yl) -8- (2-trifluoromethylbenzoylamino) quinoline was converted to 2,3-dimethyl -4-[(2-methylaminoethyl) amino] -8-
It was obtained in the same manner as in Example 3 from (2-trifluoromethylbenzoylamino) quinoline and 1,1′-thiocarbonyldiimidazole. mp: 194-196 ° C NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 2.67 (3H, s), 3.
15 (3H, s), 3.76-4.07 (4H, m), 7.47 (1H, d, J = 8Hz),
7.57 (1H, dd, J = 8, 8Hz), 7.75-7.96 (4H, m), 8.60
(1H, d, J = 8Hz), 10.35 (1H, s)

Example 48 (1) 2,3-Dimethyl-4-[(2-ethylaminoethyl) amino] -8- (2-trifluoromethylbenzoylamino) quinoline was converted to 4-chloro-2,3- It was obtained in the same manner as in Example 1- (6) from dimethyl-8- (2-trifluoromethylbenzoylamino) quinoline and N-ethylethylenediamine. NMR (DMSO-d ₆ , δ): 1.02 (3H, t, J = 7Hz), 2.29 (3H,
s), 2.51 (3H, s), 2.56 (2H, q, J = 7Hz), 2.73 (2H,
t, J = 6Hz), 3.43 (2H, dt, J = 6, 6Hz), 5.65 (1H, t, J =
6Hz), 7.42 (1H, dd, J = 8,8Hz), 7.73-7.95 (5H, m),
8.54 (1H, d, J = 8Hz), 10.35 (1H, s)

(2) 2,3-dimethyl-4- (3-ethyl-2-oxoimidazolidin-1-yl) -8-
(2-Trifluoromethylbenzoylamino) quinoline was obtained in the same manner as in Example 1- (7). mp: 166-168 ° C NMR (DMSO-d ₆ , δ): 1.14 (3H, t, J = 7Hz), 2.27 (3H,
s), 2.64 (3H, s), 3.25 (2H, m), 3.59-3.80 (4H, m),
7.50-7.65 (2H, m), 7.73-7.96 (4H, m), 8.60 (1H, d,
J = 7.5Hz), 10.35 (1H, s)

Example 49 8-amino-3-bromoquinoline (100 mg), 2-
Hydroxy-3-pyridinecarboxylic acid (74.8 m
g), a mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (120 mg) and 1-hydroxybenzotriazole (121 mg) in dimethylformamide (2 ml) was stirred at room temperature overnight.
Water (2 ml) was added dropwise to the mixture under ice-cooling, and the resulting precipitate was collected by filtration and 3-bromo-8-[(2-hydroxypyridin-3-yl) carbonylamino] quinoline (85 m2).
g) was obtained as a dark green powder. mp: 285-297 ° C NMR (DMSO-d ₆ , δ): 6.55 (1H, t, J = 8Hz), 7.62-7.71
(2H, m), 7.83 (1H, br d, J = 6Hz), 8.50 (1H, d, J = 6H
z), 8.76 (1H, s), 8.90-9.01 (2H, m)

Example 50 The following compounds were obtained in the same manner as in Example 20. (1) 3-methyl-4- (pyridin-3-yloxy) -8- (2-trifluoromethylbenzoylamino) quinoline (4-chloro-3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline Mp: 102-108 ° C NMR (CDCl ₃ , δ): 2.29 (3H, s), 6.98 (1H, dd, J = 8,
3Hz), 7.15-7.29 (2H, m), 7.48-7.85 (6H, m), 8.30-
8.40 (2H, m), 8.67 (1H, s), 8.88 (1H, d, J = 8Hz)

The hydrochloride mp: 153-163 ° C. NMR (DMSO-d ₆ , δ): 7.50-7.69 (4H, m), 7.74-7.96
(4H, m), 8.47 (1H, d, J = 8Hz), 8.60 (1H, d, J = 3Hz),
8.66 (1H, br d, J = 8Hz), 8.91 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (pyridin-3-yloxy) quinoline (4-chloro-8- (2,6-dichlorobenzoylamino) -3 -Methylquinoline and 3-hydroxypyridine) mp: 202-204 ° C NMR (DMSO-d ₆ , δ): 2.27 (3H, s), 7.20 (1H, dd, J =
8,2Hz), 7.31-7.36 (1H, m), 7.49-7.64 (5H, m), 8.31
(1H, d, J = 6Hz), 8.40 (1H, d, J = 2Hz), 8.70 (1H, dd,
J = 7, 2Hz), 8.90 (1H, s), 10.88 (1H, s)

The hydrochloride mp: 198-201 ° C. NMR (DMSO-d ₆ , δ): 2.30 (3H, s), 7.49-7.71 (7H,
m), 8.50 (1H, m), 8.66 (1H, m), 8.73 (1H, dd, J = 7,
2Hz), 8.93 (1H, s), 10.92 (1H, s)

(3) 8- (2,6-dichlorobenzoylamino) -4- (imidazol-2-ylthio) -3
- (4-chloro-8- (2,6-dichloro benzoylamino) -3-methyl-quinoline and 2-mercapto-imidazole) methyl quinoline mp: 193-195 ℃ NMR (DMSO- d 6, δ): 2.58 (3H , s), 7.02 (2H, br), 7.
48-7.57 (3H, m), 7.65 (1H, dd, J = 8, 8Hz), 8.22 (1
H, d, J = 8Hz), 8.63 (1H, d, J = 8Hz), 8.82 (1H, s), 1
0.79 (1H, s)

The hydrochloride mp: 272-275 ° C. NMR (DMSO-d ₆ , δ): 2.62 (3H, s), 7.48-7.60 (5H,
m), 7.74 (1H, dd, J = 8, 8Hz), 8.05 (1H, d, J = 8Hz),
8.72 (1H, d, J = 8Hz), 8.95 (1H, s), 10.92 (1H, s)

(4) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (6-methylpyridine-
3-yloxy) quinoline (from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 5-hydroxy-2-methylpyridine) NMR (DMSO-d ₆ , δ): 2.27 (3H , s), 2.43 (3H, s), 7.
10 (1H, dd, J = 9, 2Hz), 7.15 (1H, d, J = 7.5Hz), 7.50-
7.66 (5H, m), 8.23 (1H, d, J = 2Hz), 8.70 (1H, dd, J
= 9,2Hz), 8.88 (1H, s), 10.85 (1H, s)

The hydrochloride NMR (DMSO-d ₆ , δ): 2.30 (3H, s), 2.59 (3H, s), 7.5
0-7.67 (7H, m), 8.53 (1H, d, J = 3Hz), 8.72 (1H, dd,
J = 7.5,3Hz), 8.93 (1H, s), 10.92 (1H, s)

Example 51 (1) Example 28- (1) was prepared by converting (4,5-dimethyl-2-nitroanilino) methylenemalonate isopropylidene from 4,5-dimethyl-2-nitroaniline and isopropylidene malonate. ). mp: 242-244 ° C NMR (CDCl ₃ , δ): 1.77 (6H, s), 2.36 (3H, s), 2.41
(3H, s), 7.36 (1H, s), 8.07 (1H, s), 8.71 (1H, d,
(J = 10Hz)

(2) 1,4-dihydro-5,6-dimethyl-8-nitro-4-oxoquinoline was prepared in Example 28-
Obtained in the same manner as in (2). mp: 197-227 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 2.85 (3H, s), 6.
15 (1H, d, J = 8Hz), 7.84 (1H, d, J = 8Hz), 8.45 (1H,
s)

(3) 4-chloro-5,6-dimethyl-
8-Nitroquinoline was obtained in the same manner as in Example 1- (3). mp: 153-157 ° C NMR (CDCl ₃ , δ): 2.55 (3H, s), 2.96 (3H, s), 7.57
(1H, d, J = 3Hz), 7.83 (1H, s), 8.75 (1H, d, J = 3Hz)

(4) 8-amino-4-chloro-5,6
-Dimethylquinoline was obtained in the same manner as in Example 1- (4). mp: 95-97 ° C NMR (CDCl ₃ , δ): 2.40 (3H, s), 2.77 (3H, s), 4.85
(2H, s), 6.86 (1H, s), 7.40 (1H, d, J = 6Hz), 8.46
(1H, d, J = 4Hz)

(5) 4-Chloro-8- (2,6-dichlorobenzoylamino) -5,6-dimethylquinoline was obtained in the same manner as in Example 1- (5). mp: 190-193 ° C NMR (CDCl ₃ , δ): 2.55 (3H, s), 2.88 (3H, s), 7.29
-7.44 (3H, m), 7.50 (1H, d, J = 4Hz), 8.47 (1H, d, J =
4Hz), 8.89 (1H, s)

(6) 8- (2,6-dichlorobenzoylamino) -5,6-dimethyl-4- (imidazole-
1-yl) quinoline was obtained in the same manner as in Example 12. mp: 200-215 ° C NMR (CDCl ₃ , δ): 1.88 (3H, s), 2.52 (3H, s), 7.17
(1H, s), 7.30-7.47 (5H, m), 7.67 (1H, s), 8.24 (1
(H, d, J = 4Hz), 8.96 (1H, s)

The hydrochloride mp: 161-175 ° C. NMR (DMSO-d ₆ , δ): 1.83 (3H, s), 2.50 (3H, s), 7.4
9-7.63 (3H, m), 7.83 (1H, d, J = 4Hz), 7.92 (1H, s),
8.11 (1H, s), 8.77 (1H, s), 9.01 (1H, d, J = 4Hz),
9.37 (1H, s)

Example 52 3-hydroxymethylimidazole hydrochloride (368 m
To a solution of g) in N-methylpyrrolidone (3 ml) was added sodium hydride (60% in oil, 197 mg) under ice-cooling and the mixture was stirred at the same temperature. 4-chloro- in the mixture
8- (2,6-Dichlorobenzoylamino) -3-methylquinoline (200 mg) was added and the mixture was stirred at 120 C overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash chromatography (dichloromethane-methanol) to give 8-
(2,6-Dichlorobenzoylamino) -4- (4-hydroxymethylimidazol-1-yl) -3-methylquinoline (30 mg) was obtained as a yellow powder. mp: 137-147 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 4.50 (2H, s), 5.
06 (1H, br), 7.06 (1H, d, J = 8Hz), 7.31 (1H, s), 7.4
8-7.62 (4H, m), 7.67 (1H, dd, J = 8, 8Hz), 7.88 (1H,
s), 8.70 (1H, d, J = 8Hz), 8.88 (1H, s), 10.92 (1H,
s)

Example 53 The following compound was obtained in the same manner as in Example 12. (1) 8- (2,6-dichlorobenzoylamino)-
4- [4-((E) -2-methoxycarbonylvinyl)
Imidazol-1-yl] -3-methylquinoline (4-
Chloro-8- (2,6-dichlorobenzoylamino)-
From 3-methylquinoline and methyl (E) -3- (4-imidazolyl) acrylate) mp: 132-133 ° C NMR (DMSO-d ₆ , δ): 2.28 (3H, s), 3.72 (3H, s) , 6.
53 (1H, d, J = 14Hz), 7.08 (1H, d, J = 8Hz), 7.48-7.72
(5H, m), 7.98 (1H, s), 8.11 (1H, s), 8.73 (1H, d, J
= 8Hz), 9.00 (1H, s), 10.97 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -4-[(S) -2- (methoxymethyl) pyrrolidin-1-yl] -3-methylquinoline (4-chloro-8- ( (From 2,6-dichlorobenzoylamino) -3-methylquinoline and (S) -2- (methoxymethyl) pyrrolidine) mp: 158-160 ° C NMR (DMSO-d ₆ , δ): 1.83-1.92 (1H, m ), 1.99-2.15
(2H, m), 2.25-2.32 (1H, m), 2.40 (3H, s), 3.04 (3H,
s), 3.10-3.18 (3H, m), 3.52-3.59 (1H, m), 3.96-4.0
4 (1H, m), 7.48-7.60 (4H, m), 7.83 (1H, d, J = 8Hz),
8.60 (1H, d, J = 8Hz), 8.65 (1H, s), 10.62 (1H, s)

Example 54 (1) 8- (2,6-dichlorobenzoylamino)-
4- [2- (2-methoxyethylamino) ethylamino] -3-methylquinoline is converted to 4-chloro-8- (2,
It was obtained in the same manner as in Example 1- (6) from 6-dichlorobenzoylamino) -3-methylquinoline and 2- (2-methoxyethylamino) ethylamine. NMR (CDCl ₃ , δ): 2.40 (3H, s), 2.83 (2H, t, J = 6H
z), 2.92 (2H, t, J = 6Hz), 3.39 (3H, s), 3.53 (2H, t,
J = 6Hz), 3.60 (2H, q, J = 6Hz), 5.32 (1H, br), 7.28-
7.52 (4H, m), 7.79 (1H, d, J = 8Hz), 8.31 (1H, s), 8.
83 (1H, d, J = 8Hz)

(2) 8- (2,6-dichlorobenzoylamino) -4- [3- (2-methoxyethyl) -2-
[Oxoimidazolidin-1-yl] -3-methylquinoline was obtained in the same manner as in Example 1- (7). NMR (CDCl ₃ , δ): 2.43 (3H, s), 3.43 (3H, s), 3.45
-3.95 (8H, m), 7.29-7.68 (5H, m), 8.70 (1H, d, J = 8H
z), 8.90 (1H, t, J = 8Hz)

Example 55 (1) 8- (2,6-dichlorobenzoylamino)-
3-methyl-4-[[2- (propylamino) ethyl]
Amino] quinoline was obtained in the same manner as in Example 1- (6) from 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and N-propylethylenediamine. NMR (DMSO-d ₆ , δ): 0.85 (3H, t, J = 7Hz), 1.40 (2H,
tq, J = 7,7Hz), 2.37 (3H, s), 2.46 (2H, t, J = 7Hz),
2.73 (2H, t, J = 6Hz), 3.56 (2H, dt, J = 6, 6Hz), 6.02
(1H, t, J = 6Hz), 7.42-7.65 (4H, m), 7.95 (1H, d, J =
8Hz), 8.32 (1H, s), 8.57 (1H, d, J = 8Hz), 10.49 (1H,
s)

(2) Using 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (3-propyl-2-oxoimidazolidin-1-yl) quinoline as in Example 1
Obtained in the same manner as (7). mp: 197-199 ° C NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7Hz), 1.58 (2H,
tq, J = 7,7Hz), 2.35 (3H, s), 3.07-3.30 (2H, m), 3.
60-3.73 (3H, m), 3.82 (1H, m), 3.56 (2H, dt, J = 6, 6
Hz), 7.47-7.61 (3H, m), 7.64-7.71 (2H, m), 8.66 (1
H, m), 8.85 (1H, s), 10.79 (1H, s)

Example 56 8- (2,6-Dichlorobenzoylamino) -3-methyl-4- (3-propyl-2-thioxoimidazolidin-1-yl) quinoline was converted to 8- (2,6- Obtained in the same manner as in Example 3 from dichlorobenzoylamino) -3-methyl-4-[[2- (propylamino) ethyl] amino] quinoline and 1,1′-thiocarbonyldiimidazole. mp: 218-220 ° C NMR (DMSO-d ₆ , δ): 0.94 (3H, t, J = 7Hz), 1.68 (2H,
tq, J = 7, 7Hz), 2.35 (3H, s), 3.50-3.72 (2H, m), 3.8
5-4.05 (4H, m), 7.48-7.71 (5H, m), 8.67 (1H, d, J =
8Hz), 8.90 (1H, s), 10.83 (1H, s)

Example 57 (1) 4-[((R) -2-aminopropyl) amino] -8- (2,6-dichlorobenzoylamino) -3
-Methylquinoline is represented by the formula: 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and (R)
Example 1 was prepared from -1,2-diaminopropane dihydrochloride.
Obtained in the same manner as in (6). NMR (DMSO-d ₆ , δ): 0.99 (3H, d, J = 7Hz), 1.63 (2H,
br), 2.37 (3H, s), 2.96 (1H, m), 3.28 (1H, m), 3.4
2 (1H, m), 6.09 (1H, t, J = 6Hz), 7.41-7.63 (4H, m),
7.98 (1H, d, J = 8Hz), 8.30 (1H, s), 8.57 (1H, d, J = 8
Hz), 10.48 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -3-methyl-4-((R) -4-methyl-
2-Oxoimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 1- (7). mp: 270-276 ° C NMR (DMSO-d ₆ , δ): 1.29 (1 / 2x3H, d, J = 7Hz), 1.38
(1 / 2x3H, d, J = 7Hz), 2.38 (3H, s), 3.25-3.47 (1H,
m), 3.84-4.15 (2H, m), 7.11 (1H, d, J = 7Hz), 7.48-7.
73 (5H, m), 8.67 (1H, d, J = 8Hz), 8.84 (1H, s), 10.8
8 (1H, s)

Example 58 8- (2,6-Dichlorobenzoylamino) -3-methyl-4-((R) -4-methyl-2-thioxoimidazolidin-1-yl) quinoline was converted to 4- [ ((R) -2-
Aminopropyl) amino] -8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 1,1′-thiocarbonyldiimidazole were obtained in the same manner as in Example 3. mp: 275-280 ° C NMR (DMSO-d ₆ , δ): 1.32 (1 / 2x3H, d, J = 7Hz), 1.41
(1 / 2x3H, d, J = 7Hz), 2.39 (1 / 2x3H, s), 2.40 (1 / 2x3
H, s), 3.48-3.62 (1H, m), 4.07-4.33 (2H, m), 7.48-
7.74 (5H, m), 8.67 (1H, d, J = 7Hz), 8.89 (1H, s), 9.
00 (1H, d, J = 8Hz), 10.82 (1H, s)

Example 59 (1) 8- (2,6-dichlorobenzoylamino)-
4- (6-ethoxycarbonylpyridin-2-ylmethoxy) -3-methylquinoline is converted to 8- (2,6-dichlorobenzoylamino) -1,4-dihydro-3-methyl-4-oxoquinoline and 6-tosyl It was obtained in the same manner as in Example 27- (4) from ethyl oxymethylpyridine-2-carboxylate. mp: 148-150 ° C NMR (DMSO-d ₆ , δ): 1.35 (3H, t, J = 7Hz), 2.46 (3H,
s), 4.37 (2H, q, J = 7Hz), 5.35 (2H, s), 7.48-7.64
(4H, m), 7.96 (2H, dd, J = 8, 8Hz), 8.05-8.15 (2H,
m), 8.66 (1H, d, J = 8Hz), 8.77 (1H, s), 10.73 (1H,
s)

(2) 8- (2,6-dichlorobenzoylamino) -4- (6-ethoxycarbonylpyridine-
2-ylmethoxy) -3-methylquinoline (93 mg)
To a suspension of in methanol (2 ml) was added a 1N aqueous sodium hydroxide solution (3.6 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was neutralized with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo.
-(6-carboxypyridin-2-ylmethoxy) -8
-(2,6-Dichlorobenzoylamino) -3-methylquinoline (80 mg) was obtained as a white amorphous. NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 5.33 (2H, s), 7.4
8-7.65 (4H, m), 7.92-7.97 (2H, m), 8.05-8.13 (2H,
m), 8.67 (1H, d, J = 8Hz), 8.77 (1H, s), 10.73 (1H,
s)

(3) 4- (6-carboxypyridine-
To a solution of 2-ylmethoxy) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (75 mg) in dimethylformamide (3 ml) was added a 2.0 M solution of dimethylamine in tetrahydrofuran (0.1 ml).
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (35.8 mg) and 1-hydroxybenzotriazole (25.2 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8- (2,6-dichlorobenzoylamino) -4- [6- (N, N-dimethylcarbamoyl) pyridin-2-ylmethoxy] -3-methylquinoline (30 mg). Obtained as white crystals. mp: 191-194 ° C NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 2.81 (3H, s), 2.
98 (3H, s), 5.27 (2H, s), 7.50-7.62 (5H, m), 7.78
(2H, m), 8.04 (1H, dd, J = 8Hz), 8.65 (1H, d, J = 8Hz),
8.75 (1H, s), 10.72 (1H, s)

Example 60 To a solution of 4-carboxymethoxy-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (100 mg) in dimethylformamide (1 ml) was added 2.0M.
Dimethylamine in tetrahydrofuran solution (4 ml),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (56.8 mg) and 1-hydroxybenzotriazole (40 mg) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give 8- (2,6-dichlorobenzoylamino) -4- (N, N-dimethylcarbamoylmethoxy) -3-methylquinoline (80 mg) as white crystals. mp: 187-188 ° C NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 2.90 (3H, s), 2.
97 (3H, s), 4.93 (2H, s), 7.47-7.66 (4H, m), 7.98
(1H, d, J = 8Hz), 8.15 (1H, d, J = 8Hz), 8.71 (1H, s),
10.69 (1H, s)

Example 61 8- (2,6-Dichlorobenzoylamino) -3-methyl-4- (morpholinocarbonylmethoxy) quinoline was converted to 4-carboxymethoxy-8- (2,6-dichlorobenzoylamino) -3 -Obtained from methylquinoline and morpholine as in Example 60. mp: 204-206 ° C NMR (DMSO-d ₆ , δ): 2.47 (3H, s), 3.41 (2H, br),
3.50 (2H, br), 3.58 (4H, br), 4.97 (2H, s), 7.48-7.
67 (4H, m), 8.00 (1H, d, J = 8Hz), 8.65 (1H, d, J = 8H
z), 8.73 (1H, s), 10.70 (1H, s)

Example 62 (1) 4-Benzylthio-8- (2,6-dichlorobenzoylamino) -3-methylquinoline was converted to 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methyl Example 2 from quinoline and benzenemethanethiol
Obtained in the same manner as 0. mp: 165-167 ° C NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 4.11 (2H, s), 7.
03-7.07 (2H, m), 7.16-7.20 (3H, m), 7.48-7.60 (3H,
m), 7.70 (1H, dd, J = 8, 8Hz), 8.25 (1H, d, J = 8Hz),
8.67 (1H, d, J = 8Hz), 8.75 (1H, s), 10.77 (1H, s)

(2) 4-benzylthio-8- (2,6
-Dichlorobenzoylamino) -3-methylquinoline (50 mg) in dichloromethane (2 ml)
m-Chloroperbenzoic acid (38 mg) was added and the reaction mixture was stirred in an ice bath for 3 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crystalline product was triturated with ethanol to give 4-benzylsulfinyl-8- (2,6
-Dichlorobenzoylamino) -3-methylquinoline (60 mg) was obtained as pale yellow crystals. mp: 206-208 ° C NMR (DMSO-d ₆ , δ): 2.33 (3H, s), 4.60 (1H, d, J = 1
3Hz), 4.68 (1H, d, J = 13Hz), 7.13 (2H, br d, J = 7.5H
z), 7.22-7.30 (3H, m), 7.47-7.60 (3H, m), 7.68 (1H,
dd, J = 8, 8Hz), 8.56 (1H, brd, J = 8Hz), 8.68-8.71
(2H, m), 10.88 (1H, s)

Example 63 To a solution of 4-benzylthio-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (50 mg) in dichloromethane (2 ml) was added m-chloroperbenzoic acid (38 mg). The reaction mixture was stirred in an ice bath for 2 hours. The mixture was poured into water and extracted with dichloromethane.
The organic layer was washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crystalline product was triturated with ethanol to give 4-benzylsulfonyl-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (30 mg) as white crystals. mp: 229-232 ℃ NMR (DMSO-d ₆ , δ): 2.49 (3H, s), 4.89 (2H, s), 7.
10-7.13 (2H, m), 7.24-7.33 (3H, m), 7.48-7.59 (3H,
m), 7.77 (1H, dd, J = 8Hz), 8.53 (1H, d, J = 8Hz), 8.7
3 (1H, d, J = 8Hz), 8.85 (1H, s), 10.94 (1H, s)

Example 64 (1) 8- (2,6-dichlorobenzoylamino)-
4-[(2-methylaminoethyl) amino] -3-methylquinoline (130 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (58.9 mg) in N-methylpyrrolidone (1 .3 ml) with N
-Dimethyl cyanodithioiminocarbonate (51.8 mg) was added under ice cooling, and the mixture was stirred at 60 ° C overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane: ethyl acetate = 1: 2, v / v) to give 4- [2-((E
Z) -3-Cyano-1,2-dimethyl-1-isothioureido) ethylamino] -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (94 mg). mp: 152-155 ° C NMR (CDCl ₃ , δ): 2.40 (3H, s), 2.81 (3H, s), 3.20
(3H, s), 3.75-3.96 (4H, m), 7.27-7.44 (3H, m), 7.5
1 (1H, t, J = 6Hz), 7.68 (1H, d, J = 6Hz), 8.34 (1H,
s), 8.85 (1H, d, J = 6Hz)

(2) 4- [2-((EZ) -3-cyano-1,2-dimethyl-1-isothioureido) ethylamino] -8- (2,6-dichlorobenzoylamino)
-3-Methylquinoline (80 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (26.7 m
g) in 1 ml N-methylpyrrolidone
Stirred at 20 ° C. for 20 minutes. Water was added to the mixture, and the resulting precipitate was collected by filtration, washed with water, and treated with 4-((EZ) -2-
Cyanoimino-3-methylimidazolidin-1-yl)
-8- (2,6-Dichlorobenzoylamino) -3-methylquinoline (37 mg) was obtained. mp: 103-120 ° C NMR (CDCl ₃ , δ): 2.50 (3H, s), 3.15 (3H, s), 2.74
-4.03 (4H, m), 7.29-7.45 (3H, m), 7.52 (1H, d, J = 6H
z), 7.68 (1H, t, J = 6Hz), 8.74 (1H, s), 8.96 (1H, d,
(J = 6Hz)

Example 65 (1) 3-Methyl-4-[(2-methylaminoethyl) amino] -8-nitroquinoline was converted to 4-chloro-3
It was obtained in the same manner as in Example 1- (6) from -methyl-8-nitroquinoline and N-methylethylenediamine. NMR (CDCl ₃ , δ): 2.40 (3H, s), 2.48 (3H, s), 2.82
-2.90 (2H, m), 3.54-3.63 (2H, m), 5.40 (1H, br s),
7.40 (1H, t, J = 8Hz), 7.84 (1H, d, J = 8Hz), 8.24 (1H,
d, J = 8Hz), 8.57 (1H, s)

(2) 3-methyl-4- (3-methyl-
2-Oxoimidazolidin-1-yl) -8-nitroquinoline was obtained in the same manner as in Example 1- (7). mp: 139-143 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 2.97 (3H, s), 3.64
-3.86 (4H, m), 7.60 (1H, t, J = 8Hz), 7.97 (1H, d, J =
8Hz), 8.07 (1H, d, J = 8Hz), 8.97 (1H, s)

(3) 8-amino-3-methyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline was obtained in the same manner as in Example 1- (4). mp: 229 ° C NMR (CDCl ₃ , δ): 2.40 (3H, s), 2.95 (3H, s), 3.56
-3.70 (3H, m), 3.79-3.89 (1H, m), 4.96 (2H, br s),
6.84 (1H, d, J = 8Hz), 7.13 (1H, d, J = 8Hz), 7.31 (1H,
t, J = 8Hz), 8.66 (1H, s)

(4) 8- (2,6-Difluorobenzoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline was converted to 8-amino-3-methyl- It was obtained in the same manner as in Example 1- (5) from 4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2,6-difluorobenzoyl chloride. mp: 260-261 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.80 (3H, s), 3.
56-3.73 (3H, m), 3.78 (1H, m), 7.25 (1H, dd, J = 8,
8Hz), 7.27 (1H, d, J = 8Hz), 7.55-7.70 (3H, m), 8.64
(1H, m), 8.86 (1H, s), 10.83 (1H, s)

Example 66 The following compound was obtained in the same manner as in Example 49. (1) 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(2-methylpyridin-3-yl) carbonylamino] quinoline (8-amino-3-methyl 4- from (3-methyl-2-oxo-imidazolidin-1-yl) quinoline and 2-methylpyridin-3-carboxylic acid) mp: 132-135 ℃ NMR (CDCl 3, δ): 2.44 (3H, s ), 2.81 (3H, s), 2.97
(3H, s), 3.63-3.74 (3H, m), 3.83-3.91 (1H, m), 7.2
9 (1H, dd, J = 7.5,7Hz), 7.56-7.63 (2H, m), 7.97 (1
H, dd, J = 7.5, 2.5Hz), 8.65 (1H, d, J = 6Hz), 8.69 (1
H, s), 8.84 (1H, dd, J = 7, 2.5Hz)

(2) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(6-
Methylpyridin-2-yl) carbonylamino] quinoline (from (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 6-methylpyridine-2-carboxylic acid) mp: 178-180 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 2.74 (3H, s), 2.99
(3H, s), 3.63-3.73 (3H, m), 3.82-3.91 (1H, m), 7.3
4 (1H, d, J = 7.5Hz), 7.51-7.62 (2H, m), 7.80 (1H, t,
J = 7.5Hz), 8.14 (1H, d, J = 7.5Hz), 8.87 (1H, s), 8.9
2 (1H, dd, J = 7.5, 2Hz)

(3) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(quinolin-8-yl) carbonylamino] quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) ) quinoline and 8-quinolinecarboxylic acid) mp: 227.5-229 ℃ NMR (CDCl 3, δ): 2.48 (3H, s), 2.99 (3H, s), 3.64
-3.77 (3H, m), 3.85-3.93 (1H, m), 7.53-7.60 (2H,
m), 7.61 (1H, t, J = 7.5Hz), 7.74 (1H, t, J = 7.5Hz),
8.01 (1H, d, J = 7.5Hz), 8.32 (1H, d, J = 7.5Hz), 8.93
(1H, s), 8.98 (1H, d, J = 7.5Hz), 9.10 (1H, d, J = 7.5H
z), 9.23 (1H, d, J = 2.5Hz)

(4) 8-[(6-hydroxypyridin-2-yl) carbonylamino] -3-methyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline (from 8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 6-hydroxypyridine-2-carboxylic acid) mp: 249-254 ° C NMR (CDCl ₃ , δ): 2.43 (3H, s), 2.97 (3H, s), 3.63
-3.73 (3H, m), 3.80-3.89 (1H, m), 6.84 (1H, d, J = 9H
z), 7.19 (1H, d, J = 7Hz), 7.51-7.64 (3H, m), 8.70 (1
H, s), 8.72 (1H, dd, J = 7,2.5Hz)

(5) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8- (1-naphthoylamino) quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 1 Mp: 203-205 ° C NMR (CDCl ₃ , δ): 2.41 (3H, s), 2.97 (3H, s), 3.66
-3.74 (3H, m), 3.81-3.91 (1H, m), 7.51-7.61 (4H,
m), 7.63 (1H, t, J = 8.5Hz), 7.89-7.95 (2H, m), 8.01
(1H, d, J = 8.5Hz), 8.50 (1H, d, J = 8.5Hz), 8.66 (1H,
s), 8.99 (1H, d, J = 8.5Hz)

(6) 8-[(2-chloropyridine-3)
-Yl) carbonylamino] -3-methyl-4- (3-
Methyl-2-oxoimidazolidin-1-yl) quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2-chloropyridine-3-carboxylic acid Mp: 182-185 ° C NMR (CDCl ₃ , δ): 2.43 (3H, s), 2.97 (3H, s), 3.66
-3.74 (3H, m), 3.83-3.90 (1H, m), 7.43 (1H, dd, J =
8.5, 5.5Hz), 7.60 (2H, d, J = 5.5Hz), 8.22 (1H, d, J =
8.5Hz), 8.54 (1H, d, J = 5.5Hz), 8.72 (1H, s), 8.85
(1H, t, J = 5.5Hz)

(7) 8-[(2-methoxypyridine-
3-yl) carbonylamino] -3-methyl-4- (3
-Methyl-2-oxoimidazolidin-1-yl) quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2-methoxypyridine-3-carboxylic acid Mp: 221-223 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 2.97 (3H, s), 3.63
-3.72 (3H, m), 3.84-3.91 (1H, m), 4.33 (3H, s), 7.1
2 (1H, dd, J = 7.5,2.5Hz), 7.56 (1H, m), 7.59 (1H,
t, J = 7.5Hz), 8.34 (1H, t, J = 2.5Hz), 8.63 (1H, dd, J
= 7.5, 2.5Hz), 8.81 (1H, s), 8.93 (1H, dd, J = 7.5, 2.
(5Hz)

(8) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(3-
Hydroxypyridin-2-yl) carbonylamino] quinoline (from (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 3-hydroxypyridine-2-carboxylic acid) mp: 211-215 ° C NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.81 (3H, s), 3.5
6-3.87 (4H, m), 7.54 (1H, d, J = 9Hz), 7.61-7.73 (3
H, m), 8.36 (1H, d, J = 5Hz), 8.74 (1H, m), 8.98 (1H,
s)

(9) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(pyrazin-2-yl) carbonylamino] quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) ) From quinoline and 2-pyrazinecarboxylic acid) mp: 225 ° C NMR (CDCl ₃ , δ): 2.45 (3H, s), 2.97 (3H, s), 3.60
-3.76 (3H, m), 3.79-3.94 (1H, m), 7.56-7.64 (2H,
m), 8.73 (1H, m), 8.82 (2H, d, J = 9Hz), 8.91 (1H,
m), 9.53 (1H, s)

(10) 8- (2-chloro-6-fluorobenzoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (8-amino-3-methyl) 4- from (3-methyl-2-oxo-imidazolidin-1-yl) quinoline and 2-chloro-6-fluorobenzoic acid) mp: 236-238 ℃ NMR (DMSO -d 6, δ): 2.36 (3H , s), 2.82 (3H, s), 3.6
0-3.84 (4H, m), 7.37 (1H, dd, J = 8, 8Hz), 7.44 (1H,
d, J = 7Hz), 7.52-7.72 (3H, m), 8.65 (1H, m), 8.85
(1H, s), 10.84 (1H, s)

(11) 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(pyridin-2-yl) carbonylamino] quinoline (8-amino-3-methyl -4- (3-Methyl-2-oxoimidazolidin-1-yl) quinoline and 2-pyridinecarboxylic acid) mp: 227-231 ° C NMR (CDCl ₃ , δ): 2.45 (3H, s), 2.97 ( 3H, s), 3.59
-3.95 (4H, m), 7.50 (1H, dd, J = 9, 8Hz), 7.53-7.65
(2H, m), 7.93 (1H, t, J = 8Hz), 8.35 (1H, d, J = 9Hz),
8.79 (1H, d, J = 5Hz), 8.88 (1H, s), 8.94 (1H, d, J = 9
Hz)

(12) 8- (2-benzyloxybenzoylamino) -3-methyl-4- (3-methyl-2-
Oxoimidazolidin-1-yl) quinoline (from 8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2-benzyloxybenzoic acid) mp: 195-196 ° C NMR (CDCl ₃ , δ): 2.36 (3H, s), 2.97 (3H, s), 3.60
-3.71 (3H, m), 3.81-3.90 (1H, m), 5.51 (2H, s), 7.0
6 (1H, d, J = 7.5Hz), 7.11 (1H, t, J = 7.5Hz), 7.27-7.3
4 (3H, m), 7.41 (1H, m), 7.48-7.60 (4H, m), 8.32 (1
H, d, J = 7.5Hz), 8.36 (1H, s), 8.98 (1H, d, J = 7.5Hz)

Example 67 (1) In a stirred solution of 2,4-dichlorophenol (4.02 g) in N, N-dimethylformamide (40 ml), imidazole (3.35 g) and triisopropylsilyl chloride (5. 00g) was added at room temperature. The mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water. After drying over anhydrous magnesium sulfate, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (n-hexane) to give 2,4-
Dichloro-1- (triisopropylsilyloxy) benzene (7.80 g) was obtained as a colorless oil. NMR (CDCl ₃ , δ): 1.10 (18H, d, J = 7Hz), 1.21-1.35
(3H, m), 6.81 (1H, d, J = 8Hz), 7.07 (1H, dd, J = 8 and 2Hz), 7.33 (1H, d, J = 2Hz)

(2) A stirred solution of 2,4-dichloro-1- (triisopropylsilyloxy) benzene (7.50 g) in tetrahydrofuran (45 ml) was added to 1.6.
Mn-butyllithium hexane solution (16 ml)
It was added dropwise at 78 ° C. The resulting solution was stirred at -50 C to -45 C for a while and poured into dry ice in diethyl ether. The mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane and 2N aqueous sodium hydroxide was added thereto. The separated organic layer was concentrated in vacuo, and the residue was crystallized from diisopropyl ether and n-hexane to give 2,6-dichloro-3- (triisopropylsilyloxy) benzoic acid (2.47 g) as a colorless solid. As obtained. mp: 161-164 ° C NMR (CDCl ₃ , δ): 1.08 (18H, d, J = 7Hz), 1.20-1.31
(3H, m), 6.67 (1H, d, J = 8Hz), 7.00 (1H, d, J = 8Hz)

(3) To a solution of 2,6-dichloro-3- (triisopropylsilyloxy) benzoic acid (170 mg) in dichloroethane (1 ml) was added thionyl chloride (0.7 ml), and the mixture was stirred at room temperature for 2 hours. Stirred for hours. The solvent was removed and the residue was treated with dichloroethane (2 ml)
Was dissolved. Triethylamine (142 mg) and 8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (96 mg) were added to the solution, and the mixture was gently refluxed for 20 hours. After cooling, the mixture was diluted with dichloromethane, washed with water and brine,
After drying over magnesium sulfate, the solvent was distilled off in vacuo.
The residue was purified by preparative thin layer chromatography (10% methanol-dichloromethane) to give 8- (2,6-dichloro-3-triisopropylsilyloxybenzoylamino) -3-methyl-4- (3-methyl 2-Oxoimidazolidin-1-yl) quinoline (110 mg) was obtained as a pale yellow amorphous. NMR (CDCl ₃ , δ): 1.13 (18H, d, J = 8Hz), 1.20-1.40
(3H, m), 2.42 (3H, s), 2.97 (3H, s), 3.59-3.93 (4H,
m), 6.91 (1H, d, J = 9Hz), 7.20 (1H, d, J = 9Hz), 7.57
-7.65 (2H, m), 8.68 (1H, s), 8.88-8.95 (1H, m)

(4) 8- (2,6-dichloro-3-triisopropylsilyloxybenzoylamino) -3-
To a solution of methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (105 mg) in tetrahydrofuran (1 ml) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.22 ml).
Was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Acetic acid (3 drops) was added to the reaction mixture, the mixture was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (10% methanol-dichloromethane), crystallized from acetonitrile to give 8- (2,6-dichloro-3-hydroxybenzoylamino) -3-methyl-4- (3 -Methyl-2-oxoimidazolidin-1
-Yl) quinoline (32 mg) was obtained. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.81 (3H, s), 3.5
7-3.84 (4H, m), 7.06 (1H, d, J = 8Hz), 7.34 (1H, d,
J = 8Hz), 7.60-7.72 (2H, m), 8.63 (1H, t, J = 6Hz), 8.8
3 (1H, s)

Example 68 (1) 4-[(2-ethylaminoethyl) amino]-
3-methyl-8-nitroquinoline is converted to 4-chloro-3-
It was obtained in the same manner as in Example 1- (6) from methyl-8-nitroquinoline and N-ethylethylenediamine. NMR (CDCl ₃ , δ): 1.19 (3H, t, J = 8Hz), 2.37 (3H,
s), 2.74 (2H, q, J = 8Hz), 2.88-2.99 (2H, m), 3.53-3.
67 (2H, m), 7.41 (1H, t, J = 8Hz), 7.84 (1H, d, J = 8H
z), 8.28 (1H, d, J = 8Hz), 8.53 (1H, s)

(2) 4- (3-Ethyl-2-oxoimidazolidin-1-yl) -3-methyl-8-nitroquinoline was obtained in the same manner as in Example 1- (7). mp: 173 ° C NMR (CDCl ₃ , δ): 1.25 (3H, t, J = 8Hz), 2.45 (3H,
s), 3.29-3.51 (2H, m), 3.29-3.51 (2H, m), 3.62-3.88
(4H, m), 7.61 (1H, t, J = 8Hz), 7.97 (1H, d, J = 8Hz),
8.07 (1H, d, J = 8Hz), 8.97 (1H, s)

(3) 8-amino-4- (3-ethyl-
2-Oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Example 1- (4). mp: 159 ° C NMR (CDCl ₃ , δ): 1.22 (3H, t, J = 9Hz), 2.38 (3H,
s), 3.29-3.51 (2H, m), 3.56-3.70 (3H, m), 3.84 (1H,
m), 4.96 (2H, br s), 6.85 (1H, d, J = 9Hz), 7.13 (1
H, d, J = 9Hz), 7.32 (1H, t, J = 9Hz), 8.67 (1H, s)

(4) 8- (2,6-dichloro-3-triisopropylsilyloxybenzoylamino) -4-
(3-ethyl-2-oxoimidazolidin-1-yl)
-3-methylquinoline can be obtained by converting 8-amino-4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline and 2,6-dichloro-3- (triisopropylsilyloxy) benzoic acid From Example 67- (3). NMR (CDCl ₃ , δ): 1.14 (18H, d, J = 8Hz), 1.23-1.39
(3H, m), 1.25 (3H, t, J = 8Hz), 2.41 (3H, s), 3.32-3.
52 (2H, m), 3.60-3.90 (4H, m), 6.91 (1H, d, J = 9Hz),
7.13-7.29 (2H, m), 7.56-7.66 (2H, m), 8.67 (1H,
s), 8.86-8.93 (1H, m)

(5) 8- (2,6-dichloro-3-hydroxybenzoylamino) -4- (3-ethyl-2-
Oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Example 67- (4). mp: 226-237 ° C NMR (DMSO-d ₆ , δ): 1.14 (3H, t, J = 8Hz), 2.35 (3H,
s), 3.12-3.36 (2H, m), 3.57-3.88 (4H, m), 7.07 (0.
7H, d, J = 8Hz), 7.16 (0.3H, d, J = 8Hz), 7.34 (0.7H,
d, J = 8Hz), 7.46 (0.3H, d, J = 8Hz), 7.57 (0.3H, d, J =
8Hz), 7.63-7.86 (1.7H, m), 8.60-8.71 (1H, m), 8.83
(0.7H, s), 8.86 (0.3H, s)

Example 69 To a suspension of 8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (60 mg) in pyridine (0.6 ml) was added chloride. 2,6-Dichlorobenzenesulfonyl (69 mg) was added and the mixture was stirred at room temperature. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diisopropyl ether and ethanol to give 8- (2,6-dichlorobenzenesulfonylamino) -3-methyl-4- (3-methyl-2-
Oxoimidazolidin-1-yl) quinoline (67 m
g) was obtained. mp: 149-152 ° C NMR (CDCl ₃ , δ): 2.42 (3H, s), 2.94 (3H, s), 3.60
-3.83 (4H, m), 7.23 (1H, t, J = 8Hz), 7.34-7.47 (4H,
m), 7.79 (1H, d, J = 6Hz), 8.72 (1H, s), 10.01 (1H,
s)

Example 70 3-Methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8- (2-trifluoromethylbenzenesulfonylamino) quinoline was converted to 8-amino-3-
Obtained in the same manner as in Example 69 from methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2-trifluoromethylbenzenesulfonyl chloride. mp: 210-213 ° C NMR (CDCl ₃ , δ): 2.38 (3H, s), 2.91 (3H, s), 3.56
-3.82 (4H, m), 7.34-7.49 (2H, m), 7.50-7.64 (2H,
m), 7.74-7.84 (2H, m), 8.19 (1H, d, J = 9Hz), 8.68 (1
H, s), 9.58 (1H, br s)

Example 71 2-trifluoromethylphenyl isocyanate (37
mg) in toluene (3 ml) was added to 8-amino-3-methyl-4- in tetrahydrofuran (1 ml).
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline (50 mg) was added and the reaction mixture was
Stirred for hours. The mixture was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (2% methanol-dichloromethane). The crystalline product was triturated with ethanol to give 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8- [3
-(2-Trifluoromethylphenyl) ureido] quinoline (60 mg) was obtained as white crystals. mp: 259-261 ° C NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.83 (3H, s), 3.6
0-3.71 (3H, m), 3.75-3.81 (1H, m), 7.33 (1H, dd, J
= 8, 8Hz), 7.46 (1H, d, J = 8Hz), 7.55 (1H, d, J = 8Hz),
7.64-7.73 (2H, m), 7.82 (1H, d, J = 8Hz), 8.50 (1H,
d, J = 8Hz), 8.89 (1H, s), 9.32 (1H, s), 10.25 (1H,
s)

Example 72 The following compounds were obtained in the same manner as in Example 1- (5). (1) 8- (2-bromobenzoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-
1-yl) quinoline (from 8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2-bromobenzoyl chloride) mp: 177-179 ° C NMR (DMSO- d ₆ , δ): 2.35 (3H, s), 2.82 (3H, s), 3.
60-3.71 (3H, m), 3.76-3.83 (1H, m), 7.46-7.58 (2H,
m), 7.65-7.67 (2H, m), 7.72-7.80 (2H, m), 8.66 (1
H, br), 8.85 (1H, s), 10.32 (1H, s)

(2) 8- (2-chlorobenzoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (8-amino-3-methyl-4- ( 3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2-chlorobenzoyl chloride) mp: 181-182.5 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.81 (3H, s), 3.
57-3.74 (3H, m), 3.80 (1H, m), 7.49-7.71 (5H, m),
7.79 (1H, d, J = 8Hz), 8.67 (1H, m), 8.85 (1H, s), 1
0.46 (1H, s)

(3) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8- (2-nitrobenzoylamino) quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and chloride Mp: 250 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.82 (3H, s), 3.
56-3.84 (4H, m), 7.64 (1H, s), 7.66 (1H, s), 7.78
(1H, t, J = 9Hz), 7.81-7.95 (2H, m), 8.17 (1H, d, J = 9
Hz), 8.59 (1H, br.t, J = 9Hz), 8.83 (1H, s)

(4) 8- (2,4-dichlorobenzoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (8-amino-3-methyl-4 -(3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2,4 chloride
- from dichlorobenzoyl) mp: 150-153 ℃ NMR (CDCl 3, δ): 2.42 (3H, s), 2.97 (3H, s) 3.62-
3.72 (3H, m), 3.80-3.90 (1H, m), 7.39 (1H, d, J = 8H
z), 7.52 (1H, s), 7.56 -7.61 (2H, m), 7.77 (1H, d,
J = 8Hz), 8.70 (1H, s), 8.81-8.87 (1H, m)

Example 73 (1) 3,5-Dichloro-1- (triisopropylsilyloxy) benzene was prepared from 3,5-dichlorophenol and triisopropylsilyl chloride in Example 67-.
Obtained in the same manner as in (1). NMR (CDCl ₃ , δ): 1.09 (6x3H, d, J = 7Hz), 1.18-1.33
(3H, m), 6.73-6.79 (2H, m), 6.95 (1H, m).

(2) 2,6-Dichloro-4- (triisopropylsilyloxy) benzoic acid was prepared in Example 67-
Obtained in the same manner as in (2). NMR (DMSO-d ₆ , δ): 0.82-1.13 (21H, m), 6.86 (2x1H,
s)

(3) 8- (2,6-dichloro-4-triisopropylsilyloxybenzoylamino) -3-
Methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 67- (3). NMR (DMSO-d ₆ , δ): 1.10 (6x3H, d, J = 7Hz), 1.33 (3
x1H, qq, J = 7,7Hz), 2.36 (3H, s), 2.82 (3H, s), 3.56
-3.73 (3H, m), 3.79 (1H, m) 7.02 (2x1H, s), 7.63-7.
70 (2H, m), 8.64 (1H, m), 8.85 (1H, s), 10.69 (1H,
s)

(4) 8- (2,6-dichloro-4-hydroxybenzoylamino) -3-methyl-4- (3-
Methyl-2-oxoimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 67- (4). mp: 181-185 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.81 (3H, s), 3.5
7-3.74 (3H, m), 3.80 (1H, m), 6.92 (2x1H, s), 7.65
(2x1H, d, J = 4Hz), 8.65 (1H, dd, J = 4,4Hz), 8.84 (1
H, s), 10.45 (1H, s), 10.69 (1H, br-s)

Example 74 The following compounds were obtained in the same manner as in Example 67- (3). (1) 8- (2,3-dibenzyloxybenzoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (8-amino-3-methyl-4- (From (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2,3-dibenzyloxybenzoic acid) NMR (CDCl ₃ , δ): 2.33 (3H, s), 2.98 (3H, s), 3.61
-3.72 (3H, m), 3.82-3.90 (1H, m), 5.20 (2H, s), 5.2
7 (1H, d, J = 10.0Hz), 5.32 (1H, d, J = 10.0Hz), 7.06-
7.61 (13H, m), 7.86 (1H, d, J = 7.5Hz), 8.10 (1H, s),
8.79 (1H, m), 8.92 (1H, d, J = 7.5Hz)

(2) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8- (2,
3,4-Tribenzyloxybenzoylamino) quinoline (8-amino-3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline and 2,3,4
- from birds benzyloxy benzoic _{acid) NMR (CDCl 3, δ)} : 2.37 (3H, s), 2.96 (3H, s), 3.6
1-3.73 (3H, m), 3.82-3.91 (1H, m), 5.11 (2H, s),
5.18 (2H, s), 5.35 (1H, d, J = 10.0Hz), 5.42 (1H, d,
J = 10.0Hz), 6.91 (1H, d, J = 8.5Hz), 7.09-7.47 (15H,
m), 7.51-7.61 (2H, m), 7.99 (1H, d, J = 8.5Hz), 8.30
(1H, s), 8.81 (1H, d, J = 8.5Hz)

Example 75 8- (2,6-Dichlorobenzoylamino) -3-methyl-4- [N-methyl-N- (2-pyridyl) carbamoylmethoxy] quinoline was converted to 4-carboxymethoxy-
Example 6 from 8- (2,6-dichlorobenzoylamino) -3-methylquinoline and 2-methylaminopyridine
Obtained in the same manner as 0. mp: 175-176 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 4.98 (2H, s), 7.
26-7.31 (1H, m), 7.49-7.63 (5H, m), 7.85-7.93 (2H,
m), 8.39 (1H, d, J = 4.5Hz), 8.63 (1H, d, J = 7.0Hz),
8.68 (1H, s), 10.68 (1H, s)

Example 76 (1) 8- (2,6-dichlorobenzoylamino)-
4-[(3-methylaminopropyl) amino] -3-methylquinoline is obtained by converting 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline and N-methyl-1,3-propanediamine From the same manner as in Example 1- (6). NMR (DMSO-d ₆ , δ): 1.73 (2H, tt, J = 7, 6Hz), 2.30
(3H, s), 2.36 (3H, s), 2.60 (2H, t, J = 7Hz), 3.62 (2
H, dt, J = 6,6Hz), 6.60 (1H, t, J = 6Hz), 7.45 (1H, d
d, J = 8, 8Hz), 7.48-7.66 (3H, m), 7.98 (1H, d, J = 8H
z), 8.28 (1H, s), 8.56 (1H, d, J = 8Hz), 10.48 (1H,
s)

(2) To a solution of 8- (2,6-dichlorobenzoylamino) -4-[(3-methylaminopropyl) amino] -3-methylquinoline (250 mg) in tetrahydrofuran (5 ml) was added triphosgene ( 71.
1 mg) was added under ice cooling, and the mixture was stirred for 30 minutes.
The mixture was concentrated in vacuo and the residue was dissolved in N-methylpyrrolidone (3ml). To the solution was added 1,8-diazabicyclo [5.4.0] undec-7-ene (182 mg) and the mixture was stirred at 100 ° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane-methanol) to give 8- (2,6-dichlorobenzoylamino)-
4- (3-methyl-3,4,5,6-tetrahydro-2
(1H) -Pyrimidinone-1-yl) -3-methylquinoline (16 mg) was obtained. mp: 227-229 ° C NMR (DMSO-d ₆ , δ): 2.06-2.30 (2H, m), 2.34 (3H,
s), 2.90 (3H, s), 3.41-3.60 (4H, m), 7.48-7.70 (5H,
m), 8.64 (1H, m), 8.83 (1H, s), 10.75 (1H, s)

Example 77 (1) Isopropylidene (2-ethoxycarbonylanilino) methylenemalonate was converted to ethyl 2-aminobenzoate, 2,2-dimethyl-1,3-dioxane-4,6-
From dione and triethyl orthoformate, Example 28-
Obtained in the same manner as in (1). mp: 144-146 ° C NMR (CDCl ₃ , δ): 1.43 (3H, t, J = 6Hz), 1.77 (6H,
s), 4.51 (2H, q, J = 6Hz), 7.29 (1H, t, J = 8Hz), 7.52
(1H, d, J = 8Hz), 7.64 (1H, t, J = 8Hz), 8.14 (1H, d, J
= 8Hz), 8.75 (1H, d, J = 12Hz)

(2) Ethyl 1,4-dihydro-4-oxoquinoline-8-carboxylate was obtained in the same manner as in Example 28- (2). mp: 144-146 ° C NMR (CDCl ₃ , δ): 1.47 (3H, t, J = 6Hz), 4.48 (2H,
q, J = 6Hz), 6.50 (1H, d, J = 8Hz), 7.40 (1H, t, J = 8H
z), 7.75 (1H, t, J = 8Hz), 8.43 (1H, d, J = 8Hz), 8.67
(1H, d, J = 8Hz)

(3) Ethyl 4-chloroquinoline-8-carboxylate was obtained in the same manner as in Example 1- (3). _{NMR (CDCl 3, δ):} 1.45 (3H, t, J = 6Hz), 4.54 (2H,
q, J = 6Hz), 7.56 (1H, d, J = 4Hz), 7.69 (1H, t, J = 8H
z), 8.06 (1H, d, J = 8Hz), 8.40 (1H, d, J = 8Hz), 8.92
(1H, d, J = 4Hz)

(4) To a solution of ethyl 4-chloroquinoline-8-carboxylate (285 mg) in ethanol (4 ml) was added 2N aqueous sodium hydroxide solution (0.9 ml), and the mixture was stirred at 70 ° C. for 30 minutes. did. Mix 1
Neutralized with N hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulfate and the solvent was distilled off in vacuo.
The residue was triturated with diisopropyl ether and ethanol to give 4-chloroquinoline-8-carboxylic acid (215 m
g) was obtained. mp: 198-200 ° C NMR (CDCl ₃ , δ): 7.72 (1H, d, J = 4Hz), 7.88 (1H,
t, J = 8Hz), 8.54 (1H, d, J = 8Hz), 8.82 (1H, d, J = 4H)
z), 8.90 (1H, d, J = 8Hz)

(5) Oxalyl chloride (183 mg) and dimethylformamide (1 drop) were added to a suspension of 4-chloroquinoline-8-carboxylic acid (200 mg) in dichloromethane (2 ml), and the mixture was added at room temperature for 30 minutes. Stirred for minutes. The mixture was concentrated in vacuo and the residue was suspended in dichloroethane (2ml). 2,6-Dichloroaniline (172 mg) and triethylamine (244 m
g) was added and the mixture was stirred at room temperature for 1 hour. The mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (n-hexane: ethyl acetate = 4: 1, v / v), triturated with diisopropyl ether to give 4-chloro-
8- [N- (2,6-dichlorophenyl) carbamoyl] quinoline (254 mg) was obtained. mp: 180-190 ° C NMR (CDCl ₃ , δ): 7.21 (1H, t, J = 8Hz), 7.44 (2H,
d, J = 8Hz), 7.66 (1H, d, J = 4Hz), 7.85 (1H, t, J = 8H
z), 8.51 (1H, d, J = 8Hz), 8.87 (1H, d, J = 4Hz), 9.04
(1H, d, J = 8Hz)

(6) 8- [N- (2,6-dichlorophenyl) carbamoyl] -4-hydrazinoquinoline was obtained in the same manner as in Example 31- (6). mp: 209-212 ° C NMR (DMSO-d ₆ , δ): 4.62 (2H, s), 7.05 (1H, d, J = 4
Hz), 7.37 (1H, t, J = 8Hz), 7.54 (1H, d, J = 8Hz), 7.61
(2H, d, J = 8Hz), 8.47 (1H, d, J = 8Hz), 8.53 (1H, d,
J = 4Hz), 8.57 (1H, d, J = 8Hz), 9.03 (1H, s)

(7) 4- (2-acetylhydrazino)
-8- [N- (2,6-dichlorophenyl) carbamoyl] quinoline was obtained in the same manner as in Example 31- (7). mp:> 250 ° C NMR (DMSO-d ₆ , δ): 2.05 (3H, s), 5.76 (1H, s), 6.
74 (1H, d, J = 4Hz), 7.38 (1H, t, J = 8Hz), 7.61 (2H,
d, J = 8Hz), 7.69 (1H, t, J = 8Hz), 8.54 (1H, d, J = 8H
z), 8.62 (1H, d, J = 4Hz), 8.65 (1H, d, J = 8Hz)

Production Example 1 (1) 3,4-Dichloro-8-nitroquinoline was converted to 3
Obtained from -chloro-1,4-dihydro-8-nitro-4-oxoquinoline in the same manner as in Example 1- (3). mp: 125.5-126 ° C NMR (DMSO-d ₆ , δ): 7.99 (1H, t, J = 7.5Hz), 8.42 (1
H, d, J = 7.5Hz), 8.50 (1H, d, J = 7.5Hz), 9.17 (1H, s)

(2) 3,4-Dichloro-8-nitroquinoline (3.0 g) and N-ethylethylenediamine (2
9.9 ml) was stirred at 50 ° C. for 1 hour. The reaction mixture is concentrated in vacuo with toluene and the residue is purified by column chromatography on silica gel (methanol: chloroform = 1: 10, v / v) to give 3-chloro-
4- (2-Ethylaminoethylamino) -8-nitroquinoline (4.3 g) was obtained. mp: 74.5-75 ° C NMR (CDCl ₃ , δ): 1.15 (3H, t, J = 7.5Hz), 2.71 (2H,
q, J = 7.5Hz), 2.97 (2H, t, J = 6.0Hz), 3.78 (2H, q, J
= 6.0Hz), 6.21 (1H, m), 7.47 (1H, t, J = 7.5Hz), 7.88
(1H, d, J = 7.5Hz), 8.27 (1H, d, J = 7.5Hz), 8.63 (1H,
s)

(3) 3-chloro-4- (3-ethyl-
2-Oxoimidazolidin-1-yl) -8-nitroquinoline was obtained in the same manner as in Example 1- (7). mp: 188.5-189.5 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7.5Hz), 3.17-3.
37 (2H, m), 3.63-3.95 (4H, m), 7.88 (1H, t, J = 7.5H
z), 8.23 (1H, d, J = 7.5Hz), 8.37 (1H, d, J = 7.5Hz),
9.15 (1H, s)

(4) 8-amino-3-chloro-4-
(3-ethyl-2-oxoimidazolidin-1-yl)
Quinoline was obtained in the same manner as in Example 1- (4). mp: 137.5-140 ° C NMR (CDCl ₃ , δ): 1.23 (3H, t, J = 7.5Hz), 3.31-3.48
(2H, m), 3.63-3.93 (4H, m), 5.00 (2H, bs), 6.91
(1H, d, J = 7.5Hz), 7.19 (1H, d, J = 7.5Hz), 7.38 (1H, d, J = 7.5Hz)
t, J = 7.5Hz), 8.72 (1H, s)

Production Example 2 (1) 3-Bromo-4- (2-ethylaminoethylamino) -8-nitroquinoline was prepared from 3-bromo-4-chloro-8-nitroquinoline and N-ethylethylenediamine. Obtained in the same manner as in Example 1- (6). NMR (CDCl ₃ , δ): 1.17 (3H, t, J = 8Hz), 2.72 (2H,
q, J = 8Hz), 2.95 (2H, t, J = 7Hz), 3.76 (2H, t, J = 7H
z), 6.16-6.24 (1H, brs), 7.44 (1H, t, J = 8Hz), 7.88
(1H, d, J = 8Hz), 8.29 (1H, d, J = 8Hz), 8.72 (1H, s)

(2) 3-bromo-4- (3-ethyl-
2-Oxoimidazolidin-1-yl) -8-nitroquinoline was obtained in the same manner as in Example 1- (7). NMR (DMSO-d ₆ , δ): 1.14 (3H, t, J = 8Hz), 3.18-3.22
(2H, m), 3.63-3.83 (3H, m), 3.86-3.96 (1H, m), 7.8
7 (1H, t, J = 8Hz), 8.22 (1H, d, J = 8Hz), 8.38 (1H, d,
J = 8Hz), 9.23 (1H, s)

(3) 8-amino-3-bromo-4-
(3-ethyl-2-oxoimidazolidin-1-yl)
Quinoline was obtained in the same manner as in Example 1- (4). NMR (CDCl ₃ , δ): 1.24 (3H, t, J = 8Hz), 3.36-3.48
(2H, m), 3.63-3.80 (3H, m), 3.86-3.96 (1H, m), 4.96
-5.04 (2H, br s), 6.91 (1H, d, J = 8Hz), 7.19 (1H, d,
J = 8Hz), 7.37 (1H, t, J = 8Hz), 8.82 (1H, s)

Production Example 3 (1) To a solution of 3-methyl-8-nitro-4- (2-oxoimidazolidin-1-yl) quinoline (1017 mg) in dimethylformamide (30 ml) was added sodium hydride (oil). (60%, 108 mg) in a dry ice-acetone bath under a nitrogen atmosphere, and the mixture was stirred at the same temperature. Allyl bromide (497 mg) was added to the mixture and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate-n-hexane) to give 4- (3-allyl-2-oxoimidazolidin-1-yl) -3-methyl-8-nitroquinoline (84
7 mg) as pale yellow crystals. mp: 104-106 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 3.55-3.95 (6H,
m), 5.25 (1H, d, J = 10Hz), 5.32 (1H, d, J = 17Hz), 5.8
8 (1H, m), 7.78 (1H, dd, J = 8, 8Hz), 8.17 (1H, d, J =
8Hz), 8.23 (1H, d, J = 8Hz), 9.00 (1H, s)

(2) 4- (3-allyl-2-oxoimidazolidin-1-yl) -3-methyl-8-nitroquinoline (413 mg) and methanol of platinum oxide (8 m
The mixture in l) was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate-n-hexane) to give 8-amino-3-methyl-4- (3-propyl-2-oxoimidazolidin-
1-yl) quinoline (350 mg) was obtained as pale yellow crystals. mp: 161-163 ° C NMR (DMSO-d ₆ , δ): 0.91 (3H, t, J = 7Hz), 1.57 (2H,
ddq, J = 7, 7, 7Hz), 2.29 (3H, s), 3.04-3.26 (2H,
m), 3.55-3.68 (3H, m), 3.77 (1H, m), 5.94 (1H, s),
6.80 (1H, d, J = 8Hz), 6.95 (1H, d, J = 8Hz), 7.28 (1H,
dd, J = 8, 8Hz), 8.65 (1H, s)

Production Example 4 4- (3-allyl-2-oxoimidazolidin-1-yl) -8-amino-3-methylquinoline was converted to 4- (3-
Allyl-2-oxoimidazolidin-1-yl) -3-
It was obtained in the same manner as in Example 1- (4) from methyl-8-nitroquinoline. mp: 108-110 ° C NMR (CDCl ₃ , δ): 2.40 (3H, s), 3.56-3.69 (3H, m),
3.83-3.90 (1H, m), 3.89 (1H, dd, J = 15.0, 7.0Hz),
4.00 (1H, dd, J = 15.0,7.0Hz), 4.98 (2H, bs), 5.27
(1H, d, J = 10.0Hz), 5.31 (1H, d, J = 17.5Hz), 5.82-5.9
6 (1H, m), 6.86 (1H, d, J = 7.5Hz), 7.13 (1H, d, J = 7.
5Hz), 7.32 (1H, t, J = 7.5Hz), 8.66 (1H, s)

Production Example 5 (1) 4- (3-butyl-2-oxoimidazolidin-1-yl) -3-methyl-8-nitroquinoline was converted to 3
It was obtained in the same manner as in Production Example 3- (1) from -methyl-8-nitro-4- (2-oxoimidazolidin-1-yl) quinoline and n-butyl iodide. mp: 138-139 ° C NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J = 7.5Hz), 1.37 (2
H, qt, J = 7.5,7.5Hz), 1.57 (2H, tt, J = 7.5, 7.5Hz),
2.38 (3H, s), 3.12-3.28 (2H, m), 3.63-3.71 (3H, m),
3.76-3.85 (1H, m), 7.77 (1H, dd, J = 8.0, 8.0Hz), 8.
16 (1H, d, J = 8.0Hz), 8.23 (1H, d, J = 8.0Hz), 9.00 (1
H, s)

(2) 8-amino-4- (3-butyl-
2-Oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Production Example 3- (2). mp: 137-138 ° C NMR (DMSO-d ₆ , δ): 0.94 (3H, t, J = 7.0Hz), 1.35 (2
H, qt, J = 7.0, 7.0Hz), 1.54 (2H, tt, J = 7.0, 7.0Hz),
2.29 (3H, s), 3.08-3.27 (2H, m), 3.56-3.66 (3H, m),
3.71-3.77 (1H, m), 5.92 (2H, s), 6.81 (1H, d, J = 8.
0Hz), 6.95 (1H, d, J = 8.0Hz), 7.28 (1H, dd, J = 8.0,
8.0Hz), 8.65 (1H, s)

Production Example 6 (1) 4- (3-Isobutyl-2-oxoimidazolidin-1-yl) -3-methyl-8-nitroquinoline was converted to 3-methyl-8-nitro-4- (2- Oxoimidazolidine-1-yl) quinoline and isobutyl iodide,
It was obtained in the same manner as in Production Example 3- (1). NMR (CDCl ₃ , δ): 0.98-1.04 (6H, m), 1.92-2.07 (1
H, m), 2.47 (3H, s), 3.08 (1H, dd, J = 7, 14Hz), 3.23
(1H, dd, J = 7, 14Hz), 3.67-3.76 (3H, m), 3.79-3.88
(1H, m), 7.61 (1H, t, J = 8Hz), 7.97 (1H, d, J = 8Hz),
8.08 (1H, d, J = 8Hz), 8.98 (1H, s)

(2) 8-Amino-4- (3-isobutyl-2-oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Example 1- (4). NMR (CDCl ₃ , δ): 0.97-1.06 (6H, m), 1.90-2.04 (1
H, m), 2.40 (3H, s), 3.07 (1H, dd, J = 7, 14Hz), 3.21
(1H, dd, J = 7, 14Hz), 3.58-3.74 (3H, m), 3.84-3.92
(1H, m) 4.91-5.01 (2H, br s), 6.87 (1H, d, J = 8Hz),
7.16 (1H, d, J = 8Hz), 7.31 (1H, t, J = 8Hz), 8.67 (1H,
s)

Production Example 7 (1) 3-Methyl-4- [3- (2-methyl-2-propenyl) -2-oxoimidazolidin-1-yl]-
8-nitroquinoline is converted to 3-methyl-8-nitro-4-
Production Example 3- (1) from (2-oxoimidazolidin-1-yl) quinoline and 2-methyl-2-propenyl bromide
Was obtained in the same manner as described above. NMR (CDCl ₃ , δ): 1.81 (3H, s), 2.48 (3H, s), 3.59
-3.67 (2H, m), 3.73 (1H, t, J = 7.5Hz), 3.77-3.87 (2
H, m), 3.99 (1H, d, J = 15.0Hz), 4.99 (2H, d, J = 4.5H
z), 7.61 (1H, t, J = 7.5Hz), 7.98 (1H, d, J = 7.5Hz),
8.08 (1H, d, J = 7.5Hz), 8.99 (1H, s)

(2) 8-amino-3-methyl-4-
[3- (2-Methyl-2-propenyl) -2-oxoimidazolidin-1-yl] quinoline was prepared according to Example 1- (4).
Was obtained in the same manner as described above. NMR (CDCl ₃ , δ): 1.81 (3H, s), 2.40 (3H, s), 3.53
-3.68 (3H, m), 3.80 (1H, d, J = 15.0z), 3.84-3.93 (1
H, m), 3.98 (1H, d, J = 15.0z), 4.98 (2H, bs), 6.86
(1H, d, J = 7.5Hz), 7.13 (1H, d, J = 7.5Hz), 7.32 (1H,
t, J = 7.5Hz), 8.67 (1H, s)

Production Example 8 (1) N-phenylethylenediamine (1.61 m
l) and potassium carbonate (1.71 g) in dimethylformamide (15 ml) were added to 3,4-dichloro-8
Nitroquinoline (1.5 g) at 0 ° C. under nitrogen atmosphere
And the mixture was stirred at 60 ° C. for 6 hours. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration to give 3-chloro-8.
-Nitro-4- (2-phenylaminoethylamino) quinoline (1.75 g) was obtained as a yellow solid. mp: 113-116 ° C NMR (CDCl ₃ , δ): 3.34 (2H, q, J = 7.0Hz), 3.92 (2H,
q, J = 7.0Hz), 5.78 (1H, t, J = 7.0Hz), 6.52 (1H, t, J
= 7.5Hz), 6.59 (2H, d, J = 7.5Hz), 7.01-7.11 (2H, m),
7.05 (1H, t, J = 7.5Hz), 7.62 (1H, t, J = 7.5Hz), 8.13
(1H, d, J = 7.5Hz), 8.52 (1H, d, J = 7.5Hz), 8.52 (1H,
s)

(2) 3-chloro-8-nitro-4-
(2-Oxo-3-phenylimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 11- (2). NMR (DMSO-d ₆ , δ): 3.93-4.09 (2H, m), 4.17-4.33
(2H, m), 7.10 (1H, t, J = 7.5Hz), 7.40 (2H, t, J = 7.5H
z), 7.65 (2H, d, J = 7.5Hz), 7.90 (1H, t, J = 7.5Hz),
8.38 (1H, d, J = 7.5Hz), 8.43 (1H, d, J = 7.5Hz), 9.23
(1H, s)

(3) 8-amino-3-chloro-4-
(2-Oxo-3-phenylimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 1- (4). mp: 174.5-175.5 ° C NMR (DMSO-d ₆ , δ): 3.83-3.97 (2H, m), 4.12-4.30
(2H, m), 6.14 (2H, s), 6.93 (1H, d, J = 7.5Hz), 7.08
(1H, t, J = 7.5Hz), 7.14 (1H, d, J = 7.5Hz), 7.33-7.44
(3H, m), 7.65 (2H, d, J = 7.5Hz), 8.83 (1H, s)

Production Example 9 (1) 4- (3-ethoxycarbonylmethyl-2-oxoimidazolidin-1-yl) -3-methyl-8-nitroquinoline was converted to 3-methyl-8-nitro-4- ( 2-
It was obtained from oxoimidazolidin-1-yl) quinoline and ethyl bromoacetate in the same manner as in Production Example 3- (1). NMR (CDCl ₃ , δ): 1.32 (3H, t, J = 7.5Hz), 2.50 (3H,
s), 3.77-3.96 (4H, m), 4.07 (1H, d, J = 17.5Hz), 4.1
7 (1H, d, J = 17.5Hz), 4.27 (2H, q, J = 7.5Hz), 7.63 (1
H, t, J = 7.5Hz), 7.99 (1H, d, J = 7.5Hz), 8.16 (1H, d,
J = 7.5Hz), 8.99 (1H, s)

(2) 8-Amino-4- (3-ethoxycarbonylmethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Example 1- (4). NMR (CDCl ₃ , δ): 1.32 (3H, t, J = 7.5Hz), 2.42 (3H,
s), 3.67-3.98 (4H, m), 4.07 (1H, d, J = 17.5Hz), 4.1
6 (1H, d, J = 17.5Hz), 4.25 (2H, q, J = 7.5Hz), 4.97 (2
H, s), 6.86 (1H, d, J = 7.5Hz), 7.19 (1H, d, J = 7.5H
z), 7.33 (1H, t, J = 7.5Hz), 8.67 (1H, s)

Production Example 10 (1) 4- [3- (4-Chlorobenzyl) -2-oxoimidazolidin-1-yl] -3-methyl-8-nitroquinoline was converted to 3-methyl-8-nitro- It was obtained in the same manner as in Production Example 3- (1) from 4- (2-oxoimidazolidin-1-yl) quinoline and 4-chlorobenzyl bromide. mp: 175-178 ° C NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 3.50-3.65 (2H,
m), 3.70-3.85 (2H, m), 4.37 (1H, d, J = 15.0Hz), 4.47
(1H, d, J = 15.0Hz), 7.40 (2H, d, J = 8.5Hz), 7.48 (2
H, d, J = 8.5Hz), 7.79 (1H, dd, J = 8.0,8.0Hz), 8.20
(1H, d, J = 8.0Hz), 8.25 (1H, d, J = 8.0Hz), 9.01 (1H,
s)

(2) 8-Amino-4- [3- (4-chlorobenzyl) -2-oxoimidazolidin-1-yl] -3-methylquinoline was obtained in the same manner as in Example 1- (4). Was. mp: 151-153 ° C NMR (DMSO-d ₆ , δ): 2.33 (3H, s), 3.45-3.68 (3H,
m), 3.75-3.83 (1H, m), 4.38 (1H, d, J = 15.0Hz), 4.45
(1H, d, J = 15.0Hz), 5.96 (2H, s), 6.82 (1H, d, J = 8.
0Hz), 6.96 (1H, d, J = 8.0Hz), 7.30 (1H, dd, J = 8.0,
8.0Hz), 7.38 (2H, d, J = 8.5Hz), 7.46 (2H, d, J = 8.5H
z), 8.68 (1H, s)

Production Example 11 (1) Dimethylformamide (15 g) of 4-methylimidazole (1.01 g) and potassium carbonate (1.71 g)
3,4-Dichloro-8-nitroquinoline (1.5 g) was added dropwise at 0 ° C. under a nitrogen atmosphere to the mixture in 50 ml) and the mixture was stirred at 50 ° C. for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 30, v / v) to give 3-chloro-4- (4-methylimidazole-1-).
Yl) -8-Nitroquinoline (1.06 g) was obtained as an off-white solid. mp: 174-176 ° C NMR (CDCl ₃ , δ): 2.39 (3H, s), 6.89 (1H, s), 7.61
(1H, s), 7.67-7.77 (2H, m), 8.10 (1H, d, J = 7.5Hz),
9.12 (1H, s)

(2) 8-amino-3-chloro-4-
(4-Methylimidazol-1-yl) quinoline was obtained in the same manner as in Example 1- (4). mp: 156-158 ° C NMR (CDCl ₃ , δ): 2.38 (3H, s), 5.09 (2H, bs), 6.
77 (1H, d, J = 7.5Hz), 6.87 (1H, s), 6.95 (1H, d, J =
7.5Hz), 7.37 (1H, t, J = 7.5Hz), 7.58 (1H, s), 8.79
(1H, s)

Production Example 12 (1) 1,4-Dihydro-3-methyl-8-nitro-
To a suspension of 4-oxoquinoline (16.1 g) in acetonitrile (100 ml) was added p-toluenesulfonyl isocyanate (31.1 g) at room temperature under a nitrogen atmosphere and the mixture was refluxed for 3 hours. The reaction mixture was concentrated in vacuo and the residue was crystallized from ethanol to give 3-methyl-8-nitro-4- (4-toluenesulfonamido) quinoline (18.9 g) as a light brown solid. mp: 206-207.5 ° C NMR (DMSO-d ₆ , δ): 2.06 (3H, s), 2.40 (3H, s), 7.
36 (2H, d, J = 7.5Hz), 7.52 (2H, d, J = 7.5Hz), 7.60 (1
H, t, J = 7.5Hz), 8.11 (1H, d, J = 7.5Hz), 8.18 (1H, d,
J = 7.5Hz), 8.86 (1H, s)

(2) 8-amino-3-methyl-4-
Production Example 3 of (4-Toluenesulfonamide) quinoline
Obtained in the same manner as in (2). NMR (DMSO-d ₆ , δ): 2.13 (3H, s), 2.37 (3H, s), 5.
86 (2H, br s), 6.71 (1H, d, J = 9Hz), 6.84 (1H, br d,
J = 9Hz), 7.04 (1H, t, J = 9Hz), 7.33 (2H, d, J = 8Hz),
7.51 (2H, d, J = 8Hz), 8.56 (1H, s), 9.96 (1H, br s)

Production Example 13 (1) 97% sulfuric acid (57 ml) was cooled to 5 ° C.
-Methyl-8-nitro-4- (p-toluenesulfonamido) quinoline (7.6 g) was added to the solution in portions in an ice bath over 10 minutes. The resulting mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour. The reaction mixture was placed on ice (100 g)
The mixture was added dropwise in an ice bath over 30 minutes while stirring at 5 to 15 ° C. Then, 10N sodium hydroxide (about 220 ml)
Was added dropwise to the solution in an ice bath with stirring at 5 to 30 ° C. over 1 hour (final pH = 10 to 12). The mixture was stirred at room temperature for 1 hour and the precipitate was collected in vacuo. The yellow solid was washed with hot ethanol (500 ml) to give 4-amino-
3-Methyl-8-nitroquinoline (4.56 g) was obtained as a yellow solid. mp: 262-263.5 ° C NMR (DMSO-d ₆ , δ): 2.21 (3H, s), 6.87 (2H, bs),
7.47 (1H, t, J = 7.5Hz), 7.97 (1H, d, J = 7.5Hz), 8.31
(1H, s), 8.47 (1H, d, J = 7.5Hz)

(2) A mixture of 4-amino-3-methyl-8-nitroquinoline (1.0 g) and acetic anhydride (10 ml) was stirred at 120 ° C. for 2 hours. The mixture was dissolved in methanol and aqueous sodium bicarbonate and stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo. The residue was washed with water and collected by filtration to give 4-acetamido-3-methyl-8-nitroquinoline (958.3 mg) as an off-white solid. mp: 244-245 ° C NMR (DMSO-d ₆ , δ): 2.22 (3H, s), 2.35 (3H, s), 7.
74 (1H, t, J = 7.5Hz), 8.20 (1H, d, J = 7.5Hz), 8.22 (1
(H, d, J = 7.5Hz), 8.93 (1H, s)

(3) 4-acetamido-8-amino-
3-Methylquinoline was obtained in the same manner as in Example 1- (4). mp: 208-209.5 ° C NMR (DMSO-d ₆ , δ): 2.17 (3H, s), 2.27 (3H, s), 5.
91 (2H, s), 6.79 (1H, d, J = 7.5Hz), 7.05 (1H, d, J =
7.5Hz), 7.26 (1H, t, J = 7.5Hz), 8.60 (1H, s)

Production Example 14 (1) 4-Isopropoxy-3-methyl-8-nitroquinoline was prepared from 1,4-dihydro-3-methyl-8-nitro-4-oxoquinoline and isopropyl iodide by the following procedure. Obtained in the same manner as 25. NMR (DMSO-d ₆ , δ): 1.35 (6H, d, J = 7.5Hz), 2.44 (3
H, s), 4.62 (1H, qq, J = 7.5, 7.5Hz), 7.71 (1H, dd, J
= 8.0, 8.0Hz), 8.17 (1H, d, J = 8.0Hz), 8.34 (1H, d, J
= 8.0Hz), 8.85 (1H, s)

(2) 8-amino-4-isopropoxy-3-methylquinoline was obtained in the same manner as in Example 1- (4). NMR (DMSO-d ₆ , δ): 1.31 (6H, d, J = 7.0Hz), 2.35 (3
H, s), 4.52 (1H, qq, J = 7.0Hz), 5.85 (2H, s), 6.77
(1H, d, J = 8.0Hz), 7.15 (1H, d, J = 8.0Hz), 7.23 (1H,
(dd, J = 8.0, 8.0Hz), 8.55 (1H, s)

Preparation Example 15 (1) 4-Benzyloxy-3-methyl-8-nitroquinoline was prepared from 1,4-dihydro-3-methyl-8-nitro-4-oxoquinoline and benzyl bromide in the same manner as in Example 1. 2
Obtained in the same manner as in Example 5. mp: 130-132 ℃ NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 5.23 (2H, s), 7.
37-7.49 (3H, m), 7.55 (2x1H, d, J = 7.5Hz), 7.71 (1H,
dd, J = 8, 8Hz), 8.20 (1H, d, J = 8Hz), 8.29 (1H, d, J
= 8Hz), 8.90 (1H, s)

(2) 8-amino-4-benzyloxy-3-methylquinoline was obtained in the same manner as in Example 1- (4). NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 5.08 (2H, s), 5.
90 (2H, s), 6.80 (1H, d, J = 8Hz), 7.17 (1H, d, J = 8H
z), 7.26 (1H, dd, J = 8,8Hz), 7.35-7.48 (3H, m), 7.5
3 (2x1H, d, J = 8Hz), 8.57 (1H, s)

Example 78 The following compounds were obtained in the same manner as in Example 1- (5). (1) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 288-290 ° C NMR (CDCl ₃ , δ): 2.43 (3H, s), 2.98 (3H, s), 3.64
-3.73 (3H, m), 3.81-3.90 (1H, m), 7.41 (1H, d, J = 6.
0Hz), 7.59-7.66 (2H, m), 8.40 (1H, d, J = 6.0Hz), 8.6
9 (1H, s), 8.83-8.89 (1H, m)

(2) 8- (2-fluoro-6-trifluoromethylbenzoylamino) -3-methyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline mp: 243-245 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.81 (3H, s), 3.
57-3.84 (4H, m), 7.62-7.82 (5H, m), 8.63 (1H, m),
8.84 (1H, s), 10.96 (1H, s)

(3) 8- (4-Fluoro-2-trifluoromethylbenzoylamino) -3-methyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline mp: 214-216 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.81 (3H, s), 3.
60-3.73 (3H, m), 3.79 (1H, m), 7.62-7.75 (3H, m),
7.82 (1H, dd, J = 9,2Hz), 7.92 (1H, m), 8.60 (1H,
m), 8.83 (1H, s), 10.49 (1H, s)

(4) 3-Methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(1-
Phenyl-5-trifluoromethylpyrazol-4-yl) carbonylamino] quinoline mp: 244-246 ° C NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.82 (3H, s), 3.
55-3.85 (4H, m), 7.55-7.71 (7H, m), 8.45 (1H, s),
8.60 (1H, m), 8.90 (1H, s), 10.54 (1H, s)

(5) 8-[(4-Bromo-2-ethyl-5-methylpyrazol-3-yl) carbonylamino] -3-methyl-4- (3-methyl-2-oxoimidazolidin-1- Il) quinoline mp: 183-184 ° C NMR (DMSO-d ₆ , δ): 1.37 (3H, t, J = 7Hz), 2.25 (3H,
s), 2.37 (3H, s), 2.82 (3H, s), 3.60-3.85 (4H, m),
4.45 (2H, q, J = 7Hz), 7.62-7.70 (2H, m), 8.70 (1H,
m), 8.90 (1H, s), 10.82 (1H, s)

(6) 3-bromo-8-[(2-chloropyridin-3-yl) carbonylamino] -4- (3-
Methyl-2-oxoimidazolidin-1-yl) quinoline mp: 199.5-201 ° C. NMR (DMSO-d ₆ , δ): 2.82 (3H, s), 3.60-3.89 (4H,
m), 7.58 (1H, dd, J = 7.5, 4.5Hz), 7.77 (2H, d, J = 4.5
Hz), 8.17 (1H, dd, J = 7.5, 1.5Hz), 8.56 (1H, dd, J =
4.5, 1.5Hz), 8.74 (1H, m), 9.08 (1H, s)

(7) 3-bromo-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8- (2-trifluoromethylbenzoylamino) quinoline mp: 192-193 ° C. NMR (DMSO-d ₆ , δ): 2.82 (3H, s), 3.60-3.87 ( 4H,
m), 7.73-7.80 (3H, m), 7.83-7.90 (3H, m), 8.68 (1H,
m), 9.06 (1H, s), 10.46 (1H, s)

(8) 3-chloro-8- (2,6-dichlorobenzoylamino) -4- (3-ethyl-2-oxoimidazolidin-1-yl) quinoline mp: 251-252 ° C NMR (DMSO- d ₆ , δ): 1.16 (3H, t, J = 7.5Hz), 3.17-3.
31 (2H, m), 3.62-3.87 (4H, m), 7.51 (1H, dd, J = 7.5,
4.5Hz), 7.55-7.62 (2H, m), 7.71-7.80 (2H, m), 8.73
(1H, dd, J = 7.5, 1.5Hz), 8.98 (1H, s)

(9) 3-Chloro-8-[(2-chloropyridin-3-yl) carbonylamino] -4- (3-
Ethyl-2-oxoimidazolidin-1-yl) quinoline mp: 173.5-175 ° C NMR (DMSO-d ₆ , δ): 1.16 (3H, t, J = 7.5Hz), 3.17-3.
31 (2H, m), 3.62-3.87 (4H, m), 7.59 (1H, dd, J = 7.5,
4.5Hz), 7.71-7.82 (2H, m), 8.17 (1H, d, J = 7.5Hz),
8.57 (1H, d, J = 4.5Hz), 8.73 (1H, dd, J = 7.5, 1.5Hz),
9.01 (1H, s)

(10) 3-bromo-8-[(2-chloropyridin-3-yl) carbonylamino] -4- (3
-Ethyl-2-oxoimidazolidin-1-yl) quinoline mp: 188-189 ° C NMR (DMSO-d ₆ , δ): 1.16 (3H, t, J = 7.5 Hz), 3.28 (2
H, q, J = 7.5Hz), 3.65-3.87 (4H, m), 7.59 (1H, dd, J =
8.5, 5.0Hz), 7.72-7.80 (2H, m), 8.17 (1H, d, J = 8.0H
z), 8.57 (1H, d, J = 5.0Hz), 8.73 (1H, d, J = 8.0Hz),
9.08 (1H, s), 10.87 (1H, s)

(11) 3-bromo-8- (2,6-dichlorobenzoylamino) -4- (3-ethyl-2-oxoimidazolidin-1-yl) quinoline mp: 257-259 ° C NMR (DMSO- d ₆ , δ): 1.16 (3H, t, J = 8Hz), 3.19-3.48
(2H, m), 3.62-3.88 (4H, m), 7.48-7.60 (3H, m), 7.7
1-7.80 (2H, m), 8.72-8.77 (1H, m), 9.07 (1H, s)

(12) 8-[(2-chloropyridine-
3-yl) carbonylamino] -3-methyl-4- (3
-Methyl-2-oxoimidazolidin-1-yl) quinoline mp: 157-159 ° C NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7Hz), 1.60 (2H,
ddq, J = 7, 7, 7Hz), 2.37 (3H, s), 3.09-3.30 (2H,
m), 3.60-3.73 (3H, m), 3.83 (1H, m), 7.59 (1H, dd,
J = 7.5, 5Hz), 7.65-7.71 (2H, m), 8.20 (1H, d, J = 7.5H
z), 8.56 (1H, d, J = 5Hz), 8.68 (1H, dd, J = 4, 4Hz),
8.87 (1H, s), 10.83 (1H, s)

(13) 4- (3-allyl-2-oxoimidazolidin-1-yl) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline mp: 217-218 ° C NMR (DMSO- d ₆ , δ): 2.36 (3H, s), 3.53-3.96 (6H,
m), 5.25 (1H, d, J = 10Hz), 5.32 (1H, d, J = 17Hz), 5.8
8 (1H, m), 7.47-7.61 (3H, m), 7.68 (2x1H, d, J = 4H
z), 8.67 (1H, m), 8.85 (1H, s), 10.80 (1H, s)

(14) 4- (3-butyl-2-oxoimidazolidin-1-yl) -3-methyl-8- (2-
Trifluoromethylbenzoylamino) quinoline mp: 100-102 ° C NMR (DMSO-d ₆ , δ): 0.96 (3H, t, J = 7.5Hz), 1.38 (2
H, qt, J = 7.5, 7.5Hz), 1.57 (2H, tt, J = 7.5, 7.5Hz),
2.35 (3H, s), 3.12-3.30 (2H, m), 3.63-3.72 (3H, m),
3.78-3.85 (1H, m), 7.65 (2H, d, J = 5.0Hz), 7.74-7.7
9 (1H, m), 7.84-7.91 (3H, m), 8.62 (1H, dd, J = 5.0,
5.0Hz), 8.83 (1H, s), 10.40 (1H, s)

(15) 4- (3-butyl-2-oxoimidazolidin-1-yl) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline mp: 125-135 ° C NMR (DMSO- d ₆ , δ): 0.95 (3H, t, J = 7.5Hz), 1.37 (2
H, qt, J = 7.5,7.5Hz), 1.56 (2H, tt, J = 7.5, 7.5Hz),
2.35 (3H, s), 3.11-3.28 (2H, m), 3.60-3.70 (3H, m),
3.77-3.83 (1H, m), 7.66 (1H, d, J = 4.0Hz), 8.65 (1
H, dd, J = 4.0, 4.0Hz), 8.85 (1H, s), 10.80 (1H, s)

(16) 4- (3-butyl-2-oxoimidazolidin-1-yl) -8-[(2-chloropyridin-3-yl) carbonylamino] -3-methylquinoline mp: 127-133 ° C NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J = 7.5Hz), 1.38 (2
H, qt, J = 7.5,7.5Hz), 1.58 (2H, tt, J = 7.5, 7.5Hz),
2.36 (3H, s), 3.12-3.30 (2H, m), 3.61-3.70 (3H, m),
3.78-3.85 (1H, m), 7.57-7.61 (1H, m), 7.67 (2H, d,
J = 4.0Hz), 8.20 (1H, d, J = 8.0Hz), 8.54-8.58 (1H,
m), 8.67 (1H, dd, J = 4.0, 4.0Hz), 8.87 (2H, s)

(17) 8- (2,6-dichlorobenzoylamino) -4- (3-isobutyl-2-oxoimidazolidin-1-yl) -3-methylquinoline mp: 188-190 ° C NMR (CDCl ₃ , δ): 0.98-1.04 (6H, m), 1.92-2.05 (1
H, m), 2.42 (3H, s), 3.08 (1H, dd, J = 7, 14Hz), 3.23
(1H, dd, J = 7, 14Hz), 3.60-3.72 (3H, m), 3.85-3.92
(1H, m), 7.32 (1H, dd, J = 7, 9Hz), 7.38-7.42 (2H,
m), 7.60 (2H, d, J = 6Hz), 8.68 (1H, s), 8.87-8.92
(1H, m), 10.03 (1H, s)

(18) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- [3- (2-methyl-
2-propenyl) -2-oxoimidazolidin-1-yl] quinoline mp: 237-238 ° C NMR (DMSO-d ₆ , δ): 1.76 (3H, s), 2.38 (3H, s), 3.
52-3.90 (6H, m), 4.97 (2H, d, J = 6.0Hz), 7.52 (1H, d
d, J = 8.5, 7.0Hz), 7.57 (1H, d, J = 7.0Hz), 7.58 (1H,
d, J = 8.5Hz), 7.65-7.72 (2H, m), 8.67 (1H, m), 8.87
(1H, s)

(19) 3-chloro-8- (2,6-dichlorobenzoylamino) -4- (2-oxo-3-phenylimidazolidin-1-yl) quinoline mp: 220-221 ° C NMR (DMSO- d ₆ , δ): 3.99 (2H, t, J = 7.5Hz), 4.16-4.
36 (2H, m), 7.09 (1H, t, J = 7.5Hz), 7.40 (2H, t, J =
7.5Hz), 7.52 (1H, dd, J = 8.5, 7.5Hz), 7.58 (2H, d, J
= 7.5Hz), 7.66 (2H, d, J = 7.5Hz), 7.80 (1H, t, J = 7.5H
z), 7.92 (1H, d, J = 7.5Hz), 8.76 (1H, d, J = 7.5Hz),
9.05 (1H, s)

(20) 8- (2,6-dichlorobenzoylamino) -4- (3-ethoxycarbonylmethyl-
2-oxoimidazolidin-1-yl) -3-methylquinoline mp: 209-211 ° C. NMR (CDCl ₃ , δ): 1.33 (3H, t, J = 8.0 Hz), 2.45 (3H,
s), 3.67-3.99 (4H, m), 4.00 (1H, d, J = 16.0Hz), 4.1
6 (1H, d, J = 16.0Hz), 4.26 (2H, q, J = 8.0Hz), 7.28-7.
45 (3H, m), 7.58-7.70 (2H, m), 8.68 (1H, s), 8.90
(1H, m), 10.01 (1H, s)

(21) 4- [3- (4-Chlorobenzyl) -2-oxoimidazolidin-1-yl] -8-
(2,6-dichlorobenzoylamino) -3-methylquinoline mp: 124-127 ° C. NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 3.45-3.61 (2H,
m), 3.66-3.73 (1H, m), 3.80-3.87 (1H, m), 4.37 (1H,
d, J = 15.0Hz), 4.47 (1H, d, J = 15.0Hz), 7.40 (2H, d,
J = 7.5Hz), 7.47-7.60 (5H, m), 7.70 (1H, d, J = 6.0H
z), 8.67 (1H, dd, J = 6.0, 6.0Hz), 8.87 (1H, s), 10.8
0 (1H, s)

(22) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (4-toluenesulfonamido) quinoline NMR (DMSO-d ₆ , δ): 2.13 (3H, s), 2.39 (3H, s), 7.
35 (2H, d, J = 8Hz), 7.43 (1H, t, J = 8Hz), 7.48-7.60
(6H, m), 8.58 (1H, d, J = 8Hz), 8.77 (1H, s)

(23) 4-acetamido-8- (2,
6-dichlorobenzoylamino) -3-methylquinoline mp: 245-246 ° C NMR (DMSO-d ₆ , δ): 2.22 (3H, s), 2.32 (3H, s), 7.
52 (1H, dd, J = 9.0, 7.5Hz), 7.58 (1H, d, J = 9.0Hz),
7.59 (1H, t, J = 7.5Hz), 7.65 (1H, d, J = 7.5Hz), 7.76
(1H, d, J = 7.5Hz), 8.63 (1H, d, J = 7.5Hz), 8.79 (1H,
s)

(24) 4-benzyloxy-3-methyl-8- (2-trifluoromethylbenzoylamino)
Quinoline mp: 171-172 ° C NMR (DMSO-d ₆ , δ): 2.41 (3H, s), 5.20 (2H, s), 7.
36-7.50 (3H, m), 7.55 (2x1H, d, J = 7.5Hz), 7.63 (1H,
dd, J = 8, 8Hz), 7.73-7.95 (5H, m), 8.62 (1H, d, J = 8
Hz), 8.75 (1H, s), 10.35 (1H, s)

(25) 3-bromo-8- (2,6-dichlorobenzoylamino) -4- (ethoxycarbonylmethyl) quinoline mp: 173-174 ° C. NMR (DMSO-d ₆ , δ): 1.17 (3H, t, J = 7.0Hz), 4.13 (2
(H, q, J = 7.0Hz), 4.43 (2H, s), 7.48-7.60 (3H, m), 7.
76 (1H, dd, J = 8.0, 8.0Hz), 7.97 (1H, d, J = 8.0Hz),
8.75 (1H, d, J = 8.0Hz), 9.00 (1H, s), 10.88 (1H, s)

Example 79 The following compound was obtained in the same manner as in Example 49. (1) 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(4-trifluoromethylpyridin-3-yl) carbonylamino] quinoline mp: 258-260 ° C NMR (CDCl ₃ , δ): 2.43 (3H, s), 2.99 (3H, s), 3.63
-3.72 (3H, m), 3.80-3.91 (1H, m), 7.59-7.66 (2H,
m), 7.69 (1H, d, J = 5.5Hz), 8.68 (1H, s), 8.83 (1H,
dd, J = 7.5, 2.5Hz), 8.96 (1H, d, J = 5.5Hz), 9.09 (1H,
s)

(2) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(pyridin-4-yl) carbonylamino] quinoline mp: 213-215 ° C NMR (CDCl ₃ , δ): 2.47 (3H, s), 2.98 (3H, s), 3.63
-3.74 (3H, m), 3.81-3.93 (1H, m), 7.60 (2H, d, J = 4.
5Hz), 7.94 (2H, d, J = 4.5Hz), 8.77 (1H, s), 8.83 (1
(H, d, J = 4.5Hz), 8.86-8.92 (2H, m)

(3) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8-[(quinolin-4-yl) carbonylamino] quinoline mp: 221-222.5 ° C NMR (CDCl ₃ , δ): 2.42 (3H, s), 2.98 (3H, s), 3.63
-3.75 (3H, m), 3.80-3.93 (1H, m), 7.60-7.70 (3H, m
m), 7.75 (1H, d, J = 4.0Hz), 7.81 (1H, t, J = 7.5Hz),
8.25 (1H, d, J = 7.5Hz), 8.44 (1H, d, J = 7.5Hz), 8.67
(1H, s), 8.94 (1H, m), 9.10 (1H, d, J = 4.0Hz)

(4) 3-methyl-8-[(1-methylindol-2-yl) carbonylamino] -4- (3
-Methyl-2-oxoimidazolidin-1-yl) quinoline mp: 225-226 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 2.83 (3H, s), 3.
61-3.72 (3H, m), 3.77-3.83 (1H, m), 4.10 (3H, s),
7.17 (1H, dd, J = 8.0,8.0Hz), 7.35 (2H, dd, J = 7.5,
7.5Hz), 7.60-7.69 (3H, m), 7.78 (1H, d, J = 8.0Hz),
8.66 (1H, d, J = 8.0Hz), 8.93 (1H, s), 10.63 (1H, s)

(5) 3-Methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8- (2-methylthionicotinoylamino) quinoline mp: 220-222 ° C NMR (CDCl ₃ , δ): 2.45 (3H, s), 2.60 (3H, s), 2.98
(3H, s), 3.65-3.73 (3H, m), 3.83-3.90 (1H, m), 7.1
7 (1H, t, J = 7Hz), 7.57-7.63 (2H, m), 7.99-8.03 (1H,
m), 8.60 (1H, d, J = 7Hz), 8.73 (1H, s), 8.84-8.90
(1H, m)

(6) 8- (4-cinnolinylcarbonylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 215-218 ° C NMR (CDCl ₃ , δ): 2.44 (3H, s), 3.00 (3H, s), 3.66
-3.77 (3H, m), 3.83-3.92 (1H, m), 7.62-7.69 (2H,
m), 7.86-8.00 (2H, m), 8.58 (1H, d, J = 9Hz), 8.68 (1
(H, d, J = 9Hz), 8.69 (1H, s), 8.88-8.97 (1H, m), 9.67
(1H, s)

(7) 8- (9-acridinylcarbonylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 263-266 ° C NMR (CDCl ₃ , δ): 2.38 (3H, s), 3.98 (3H, s), 3.64
-3.76 (3H, m), 3.84-3.92 (1H, m), 7.54-7.74 (4H,
m), 7.79-7.88 (2H, m), 8.21 (2H, d, J = 8Hz), 8.30 (2
H, d, J = 8Hz), 8.52 (1H, s), 9.12 (1H, dd, J = 2, 8Hz)

(8) 8- (2-chloro-6-methylisonicotinoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 198-201 ° C NMR (CDCl ₃ , δ): 2.48 (3H, s), 2.69 (3H, s), 2.98
(3H, s), 3.65-3.73 (3H, m), 3.82-3.92 (1H, m), 7.5
8-7.62 (2H, m), 7.66 (1H, s), 7.72 (1H, s), 8.78 (1
H, s), 8.79-8.84 (1H, m)

(9) 8- (Indol-4-ylcarbonylamino) -3-methyl-4- (3-methyl-2-
Oxoimidazolidin-1-yl) quinoline mp: 236-238 ° C NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.81 (3H, s), 3.
61-3.74 (3H, m), 3.77-3.84 (1H, m), 7.10 (1H, d, J =
2.0Hz), 7.32 (1H, dd, J = 8.0, 8.0Hz), 7.60-7.73 (5H,
m), 8.83 (1H, d, J = 8.0Hz), 8.92 (1H, s), 10.77 (1
H, s), 11.63 (1H, br)

(10) 8-[(2,4-dimethylthiazol-5-yl) carbonylamino] -3-methyl-
4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 194-195 ° C. NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.70 (3H, s), 2.
78 (3H, s), 2.81 (3H, s), 3.60-3.70 (3H, m), 3.75-
3.81 (1H, m), 7.63 (2H, d, J = 4.0Hz), 8.60 (1H, dd,
J = 4.0, 4.0Hz), 8.90 (1H, s), 10.33 (1H, s)

(11) 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8- [2-
(3-pyridyl) thiazol-4-yl carbonylamino] quinoline _{mp: 238-241 ℃ NMR (CDCl 3} , δ): 2.48 (3H, s), 2.98 (3H, s), 3.65
-3.73 (3H, m), 3.86-3.93 (1H, m), 7.49 (1H, dd, J =
5, 9Hz), 7.57-7.63 (2H, m), 8.32 (1H, s), 8.38 (1H,
dd, J = 7, 9Hz), 8.74 (1H, d, J = 5Hz), 8.86-8.90 (2H,
m), 9.37 (1H, d, J = 2Hz)

(12) 3-Methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(4
-Methylpyrimidin-5-yl) carbonylamino] quinoline mp: 237-247 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 2.65 (3H, s), 2.
81 (3H, s), 3.54-3.85 (4H, m), 7.61-7.72 (2H, m),
8.60 (1H, m), 8.89 (1H, s), 8.96 (1H, s), 9.17 (1H,
s)

(13) 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(2
- vinylpyridine-3-yl) carbonylamino] quinoline _{mp: 173-175.5 ℃ NMR (CDCl 3} , δ): 2.43 (3H, s), 2.97 (3H, s), 3.64
-3.73 (3H, m), 3.81-3.90 (1H, m), 5.58 (1H, d, J = 1
3.0Hz), 6.53 (1H, d, J = 16.0Hz), 7.28 (1H, dd, J = 16.
0, 13.0Hz), 7.33 (1H, dd, J = 7.5,5.5Hz), 7.57-7.63
(2H, m), 8.00 (1H, d, J = 7.5Hz), 8.67 (1H, s), 8.73
(1H, m), 8.86 (1H, m)

(14) 8-[(2-ethylpyridine-
3-yl) carbonylamino] -3-methyl-4- (3
-Methyl-2-oxoimidazolidin-1-yl) quinoline mp: 174.5-176 ° C NMR (DMSO-d ₆ , δ): 1.27 (3H, t, J = 7.5 Hz), 2.36 (3
H, s), 2.81 (3H, s), 2.97 (2H, q, J = 7.5Hz), 3.58-3.
84 (4H, m), 7.39 (1H, dd, J = 7.5, 4.5Hz), 7.67 (2H,
d, J = 4.5Hz), 8.01 (1H, d, J = 7.5Hz), 8.63 (1H, t, J =
4.5Hz), 8.66 (1H, d, J = 4.5Hz), 8.86 (1H, s)

(15) 3-methyl-8-[(1-methylindol-4-yl) carbonylamino] -4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline mp: 117-119 ℃ NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.81 (3H, s), 3.
60-3.73 (3H, m), 3.77-3.84 (1H, m), 3.90 (3H, s),
7.07 (1H, m), 7.39 (1H, dd, J = 7.5, 7.5Hz), 7.60-7.6
4 (2H, m), 7.67 (1H, d, J = 7.5Hz), 7.71-7.80 (3H,
m), 8.83 (1H, d, J = 7.5Hz), 8.91 (1H, s)

(16) 3-bromo-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(4
-Trifluoromethylpyridin-3-yl) carbonylamino] quinoline mp: 195-197 ° C NMR (DMSO-d ₆ , δ): 2.83 (3H, s), 3.62-3.78 (3H,
m), 3.81-3.86 (1H, m), 7.76-7.79 (2H, m), 7.90 (1H,
d, J = 6.0Hz), 8.70 (1H, dd, J = 6.0, 6.0Hz), 8.98 (1
H, d, J = 6.0Hz), 9.07 (2H, d, J = 6.0Hz), 11.15 (1H,
s)

(17) 3-bromo-4- (3-methyl-2-oxoimidazolidin-1-yl) -8-[(2
- methylpyridin-3-yl) carbonylamino] quinoline mp: 192-194 ℃ NMR (DMSO- d 6, δ): 2.68 (3H, s), 2.82 (3H, s), 3.
61-3.87 (4H, m), 7.45 (1H, dd, J = 8.0, 5.0Hz), 7.75
(2H, m), 8.09 (1H, d, J = 8.0Hz), 8.64 (1H, d, J = 5.0H
z), 8.70 (1H, dd, J = 5.0,5.0Hz), 9.10 (1H, s), 10.4
8 (1H, s)

(18) 3-chloro-4- (3-ethyl-2-oxoimidazolidin-1-yl) -8-[(2
- methylpyridin-3-yl) carbonylamino] quinoline mp: 172-174 ℃ NMR (DMSO- d 6, δ): 1.14 (3H, t, J = 7.5Hz), 2.64 (3
H, s), 3.17-3.29 (2H, m), 3.60-3.85 (4H, m), 7.39
(1H, dd, J = 7.5, 6.0Hz), 7.69-7.79 (2H, m), 8.02 (1
H, d, J = 7.5Hz), 8.59 (1H, m), 8.66 (1H, dd, J = 7.5,
1.5Hz), 8.99 (1H, s)

(19) 3-bromo-4- (3-ethyl-2-oxoimidazolidin-1-yl) -8-[(4
- trifluoromethyl-3-yl) carbonylamino] quinoline mp: 158-160 ℃ NMR (DMSO- d 6, δ): 1.15 (3H, t, J = 7.5Hz), 3.17-3.
35 (2H, m), 3.65-3.87 (4H, m), 7.77 (2H, d, J = 5.0H
z), 7.90 (1H, d, J = 6.0Hz), 8.70 (1H, dd, J = 6.0, 6.0
Hz), 8.98 (1H, d, J = 6.0Hz), 9.05 (1H, s), 9.08 (1H,
s), 11.00 (1H, s)

(20) 3-chloro-4- (3-ethyl-2-oxoimidazolidin-1-yl) -8-[(4
- trifluoromethyl-3-yl) carbonylamino] quinoline mp: 142-148 ℃ NMR (DMSO- d 6, δ): 1.15 (3H, t, J = 7Hz), 3.27 (2H,
m), 3.63-3.87 (4H, m), 7.73-7.81 (2H, m), 7.90 (1
(H, d, J = 8Hz), 8.70 (1H, m), 8.96-9.02 (2H, m), 9.04
(1H, s), 11.00 (1H, s)

(21) 3-bromo-4- (3-ethyl-2-oxoimidazolidin-1-yl) -8-[(2
- methylpyridin-3-yl) carbonylamino] quinoline mp: 162-164 ℃ NMR (DMSO- d 6, δ): 1.15 (3H, t, J = 7Hz), 2.66 (3H,
s), 3.19-3.36 (2H, m), 3.61-3.90 (4H, m), 7.40 (1
H, dd, J = 7.5, 5Hz), 7.69-7.81 (2H, m), 8.03 (1H,
d, J = 8Hz), 8.61 (1H, br d, J = 5Hz), 8.70 (1H, d, J = 8
Hz), 9.08 (1H, s), 10.45 (1H, s)

(22) 3-methyl-8-[(2-methylpyridin-3-yl) carbonylamino] -4- (3
-Propyl-2-oxoimidazolidin-1-yl) quinoline mp: 140-142 ° C NMR (CDCl ₃ , δ): 1.01 (3H, t, J = 7.5Hz), 1.60-1.74
(2H, m), 2.43 (3H, s), 2.83 (3H, s), 3.20-3.43 (2
H, m), 3.63-3.72 (3H, m), 3.82-3.91 (1H, m), 7.29
(1H, dd, J = 7.5, 4.0Hz), 7.57-7.63 (2H, m), 7.98 (1
H, d, J = 7.5Hz), 8.65 (1H, t, J = 4.0Hz), 8.68 (1H,
s), 8.83 (1H, t, J = 4.0Hz)

Example 80 The following compounds were obtained in the same manner as in Example 67- (3). (1) 3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) -8- (2-phenylbenzoylamino) quinoline NMR (DMSO-d ₆ , δ): 2.30 (3H, s ), 2.80 (3H, s), 3.
53-3.70 (3H, m), 3.73 (1H, m), 7.24 (1H, dd, J = 7.5,
7.5Hz), 7.35 (2x1H, dd, J = 7.5, 7.5Hz), 7.44-7.61
(6H, m), 7.75 (1H, dd, J = 7.5, 7.5Hz), 7.82 (1H, d,
J = 8Hz), 8.55 (1H, br d, J = 6Hz), 8.62 (1H, s), 9.83
(1H, s)

(2) 3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) -8- (3-phenylbenzoylamino) quinoline mp: 104-108 ° C NMR (DMSO-d ₆ , δ): 2.48 (3H, s), 2.83 (3H, s) , 3.
63-3.71 (3H, m), 3.78-3.82 (1H, m), 7.40-7.46 (1H,
m), 7.53 (2H, dd, J = 7.5, 7.5Hz), 7.64-7.80 (5H, m),
7.96 (1H, d, J = 8Hz), 8.02 (1H, d, J = 8.0Hz), 8.27
(1H, br s), 8.64-8.68 (1H, m), 8.92 (1H, s), 10.72
(1H, s)

(3) 8-[(2,6-dichloropyridin-3-yl) carbonylamino] -3-methyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline mp: 117-121 ° C NMR (DMSO-d ₆ , δ): 2.36 (3H, s), 2.82 (3H, s), 3.
57-3.85 (4H, m), 7.62-7.70 (2H, m), 7.73 (1H, d, J =
8Hz), 8.23 (1H, d, J = 8Hz), 8.67 (1H, m), 8.87 (1H,
s), 10.95 (1H, s)

(4) 8-[(3,5-dichloropyridin-4-yl) carbonylamino] -3-methyl-4-
(3-methyl-2-oxoimidazolidin-1-yl)
Quinoline mp: 240-241 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 2.82 (3H, s), 3.
57-3.84 (4H, m), 7.63-7.74 (2H, m), 8.67 (1H, m),
8.75 (2H, s), 8.87 (1H, s), 11.32 (1H, s)

(5) 8-[(2-Chloro-6-methylpyridin-3-yl) carbonylamino] -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-
Il) quinoline mp: 217-220 ° C NMR (DMSO-d ₆ , δ): 2.36 (3H, s), 2.56 (3H, s), 2.
83 (3H, s), 3.60-3.71 (3H, m), 3.76-3.83 (1H, m),
7.45 (1H, d, J = 8.0Hz), 7.67 (2H, d, J = 4.0Hz), 8.11
(1H, d, J = 8.0Hz), 8.67 (1H, m), 8.87 (1H, s)

(6) 8- [2,4-bis (trifluoromethyl) benzoylamino] -3-methyl-4- (3
-Methyl-2-oxoimidazolidin-1-yl) quinoline mp: 202-204 ° C NMR (DMSO-d ₆ , δ): 2.36 (3H, s), 2.82 (3H, s), 3.
59-3.74 (3H, m), 3.80 (1H, m), 7.63-7.72 (2H, m),
8.05 (1H, d, J = 8Hz), 8.20 (1H, s), 8.24 (1H, d, J = 8
Hz), 8.62 (1H, m), 8.83 (1H, s), 10.80 (1H, s)

(7) 3-methyl-8-[(1-methyl-5-nitropyrazol-4-yl) carbonylamino] -4- (3-methyl-2-oxoimidazolidin-
1-yl) quinoline mp: 204-205 ° C NMR (DMSO-d ₆ , δ): 2.35 (3H, s), 2.81 (3H, s), 3.
56-3.83 (4H, m), 4.18 (3H, s), 7.64 (2H, d, J = 4Hz),
8.09 (1H, s), 8.67 (1H, dd, J = 4, 4Hz), 8.86 (1H,
s), 10.98 (1H, s)

(8) 8- (2,4-Dimethylnicotinoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline NMR (CDCl ₃ , δ): 2.42 (6H, s), 2.66 (3H, s), 2.98
(3H, s), 3.64-3.74 (3H, m), 3.82-3.90 (1H, m), 7.0
8 (1H, d, J = 6Hz), 7.58-7.63 (2H, m), 8.46 (1H, d, J
= 6Hz), 8.67 (1H, s), 8.87-8.90 (1H, m), 9.97 (1H,
s) its hydrochloride NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.58 (3H, s), 2.
76 (3H, s), 2.81 (3H, s), 3.60-3.82 (4H, m), 7.67-
7.77 (2H, m), 7.89 (1H, d, J = 8Hz), 8.62 (1H, d, J = 8
Hz), 8.76 (1H, d, J = 8Hz), 8.88 (1H, s)

(9) 8-[(2,4-dichloro-6-
Methylpyridin-3-yl) carbonylamino] -3-
Methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 247-248 ° C NMR (DMSO-d ₆ , δ): 2.36 (3H, s), 2.52 (3H, s), 2.
81 (3H, s), 3.57-3.83 (4H, m), 7.62 (1H, s), 7.64-
7.70 (2H, m), 8.67 (1H, m), 8.85 (1H, s), 11.08 (1
H, s)

(10) 3-methyl-8- (2-methyl-1-naphthoylamino) -4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 220-221 ° C. NMR ( DMSO-d ₆ , δ): 2.35 (3H, s), 2.82 (3H, s), 3.
60-3.71 (3H, m), 3.77-3.84 (1H, m), 7.50-7.56 (3H,
m), 7.67-7.76 (2H, m), 7.85-7.89 (1H, m), 8.00 (2H,
d, J = 8.5Hz), 8.73-8.78 (2H, m), 10.30 (1H, s)

(11) 8- (4-chloronicotinoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 223-230 ° C NMR (CDCl ₃ , δ): 2.46 (3H, s), 2.98 (3H, s), 3.61
-3.78 (3H, m), 3.82-3.92 (1H, m), 7.48 (1H, d, J = 6H
z), 7.58-7.68 (2H, m), 8.62 (1H, d, J = 6Hz), 8.71 (1
H, s), 8.83-8.91 (1H, m), 9.04 (1H, s)

(12) 8- (3-chloroisonicotinoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 183-185 ° C NMR (CDCl ₃ , δ): 2.45 (3H, s), 2.98 (3H, s), 3.63
-3.73 (3H, m), 3.82-3.90 (1H, m), 7.53-7.63 (2H,
m), 7.73 (1H, d, J = 5Hz), 8.68 (1H, d, J = 5Hz), 8.72
(1H, s), 8.78 (1H, s), 8.81-8.88 (1H, m)

(13) 8- (1-bromo-2-naphthoylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 202-204 ° C NMR ( DMSO-d ₆ , δ): 2.35 (3H, s), 2.83 (3H, s), 3.
60-3.72 (3H, m), 3.76-3.84 (1H, m), 7.65-7.83 (5H,
m), 8.13 (2H, dd, J = 8.5, 8.5Hz), 8.32 (1H, d, J = 8.5
Hz), 8.72 (1H, dd, J = 7.0,3.0Hz), 8.83 (1H, s), 10.
47 (1H, s)

(14) 8-[(2-ethyl-5-methylpyrazol-3-yl) carbonylamino] -3-methyl-4- (3-methyl-2-oxoimidazolidin-
1-yl) quinoline NMR (DMSO-d ₆ , δ): 1.36 (3H, t, J = 7 Hz), 2.25 (3H,
s), 2.37 (3H, s), 2.82 (3H, s), 3.57-3.84 (4H, m),
4.49 (2H, q, J = 7Hz), 6.83 (1H, s), 7.60-7.68 (2H,
m), 8.56 (1H, m), 8.90 (1H, s), 10.38 (1H, s)

(15) 3-bromo-8-[(3,5-
Dichloropyridin-4-yl) carbonylamino] -4
- (3-methyl-2-oxo-imidazolidin-1-yl) quinoline mp: 241-242.5 ℃ NMR (DMSO- d 6, δ): 2.82 (3H, s), 3.60-3.88 (4H,
m), 7.72-7.81 (2H, m), 8.72-8.77 (3H, m), 9.07 (1H,
s)

(16) 3-bromo-8-[(2,4-
Dimethylpyridin-3-yl) carbonylamino] -4
-(3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 200-202 ° C NMR (DMSO-d ₆ , δ): 2.33 (3H, s), 2.50 (3H, s), 2.
82 (3H, s), 3.57-3.90 (4H, m), 7.20 (1H, d, J = 4Hz),
7.27-7.80 (2H, m), 8.40 (1H, d, J = 4Hz), 8.64 (1H,
(dd, J = 4, 4Hz), 9.06 (1H, s), 10.55 (1H, s)

(17) 3-bromo-8-[(2,4-
Dichloro-6-methyl-pyridin-3-yl) carbonylamino] -4- (3-methyl-2-oxo-imidazolidin-1-yl) quinoline mp: 249-251 ℃ NMR (DMSO- d 6, δ): 2.53 (3H, s), 2.82 (3H, s), 3.
60-3.90 (4H, m), 7.62 (1H, s), 7.73-7.80 (2H, m),
8.76 (1H, m), 9.06 (1H, s), 11.21 (1H, s)

(18) 8-[(3,5-dichloropyridin-4-yl) carbonylamino] -4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline mp: 195 -197 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7.5Hz), 2.35 (3
H, s), 3.15-3.29 (2H, m), 3.62-3.70 (3H, m), 3.78-
3.83 (1H, m), 7.64-7.72 (2H, m), 8.67 (1H, dd, J = 4.
0, 4.0Hz), 8.76 (2H, s), 8.88 (1H, s), 11.30 (1H,
s)

(19) 3-chloro-8-[(2,4-
Dichloropyridin-3-yl) carbonylamino] -4
-(3-ethyl-2-oxoimidazolidin-1-yl) quinoline mp: 229-230 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7.5 Hz), 3.17-3.
31 (2H, m), 3.62-3.85 (4H, m), 7.73 (1H, d, J = 6.0H
z), 7.75-7.81 (2H, m), 8.48 (1H, d, J = 6.0Hz), 8.77
(1H, dd, J = 7.0, 4.0Hz), 8.99 (1H, s)

(20) 3-bromo-8-[(2,4-
Dichloropyridin-3-yl) carbonylamino] -4
-(3-ethyl-2-oxoimidazolidin-1-yl) quinoline mp: 229-231 ° C NMR (DMSO-d ₆ , δ): 1.17 (3H, t, J = 8Hz), 3.21-3.33
(2H, m), 3.62-3.89 (4H, m), 7.70 (3H, m), 8.48 (1
(H, d, J = 4Hz), 8.76-8.81 (1H, m), 9.08 (1H, s)

(21) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -4- (3-ethyl-2-oxoimidazolidin-1-yl) -3-methylquinoline mp: 234 -236 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 7Hz), 2.35 (3H,
s), 3.15-3.40 (2H, m), 3.60-3.86 (4H, m), 7.63-7.
71 (2H, m), 7.73 (1H, d, J = 6Hz), 8.48 (1H, d, J = 6H
z), 8.69 (1H, m), 8.87 (1H, s), 11.26 (1H, s)

(22) 8-[(3,5-dichloropyridin-4-yl) carbonylamino] -3-methyl-4
-(2-oxo-3-propylimidazolidin-1-yl) quinoline mp: 203-205 ° C. NMR (DMSO-d ₆ , δ): 0.94 (3H, t, J = 7.5 Hz), 1.60 (2
H, tq, J = 7.5, 7.5Hz), 2.36 (3H, s), 3.10-3.30 (2H,
m), 3.62-3.73 (3H, m), 3.80-3.85 (1H, m), 7.64-7.73
(2H, m), 8.67 (1H, dd, J = 4.0,4.0Hz), 8.75 (2H,
s), 8.88 (1H, s), 11.31 (1H, s)

(23) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methyl-4
- (2-oxo-3-propyl-imidazolidin-1-yl) quinoline mp: 157-158 ℃ NMR (DMSO- d 6, δ): 0.93 (3H, t, J = 7Hz), 1.59 (2H,
ddq, J = 7, 7, 7Hz), 2.35 (3H, s), 3.07-3.30 (2H,
m), 3.58-3.73 (3H, m), 3.91 (1H, m), 7.63-7.70 (2H,
m), 7.73 (1H, d, J = 6Hz), 8.48 (1H, d, J = 6Hz), 8.69
(1H, m), 8.87 (1H, s), 11.26 (1H, s)

(24) 8-[(2,4-dichloro-6)
-Methylpyridin-3-yl) carbonylamino] -3
- methyl-4- (2-oxo-3-propyl-imidazolidin-1-yl) quinoline mp: 126-128 ℃ NMR (DMSO- d 6, δ): 0.93 (3H, t, J = 7Hz), 1.59 ( 2H,
q, J = 7Hz), 2.35 (3H, s), 3.07-3.30 (2H, m), 3.60-
3.86 (4H, m), 7.62 (1H, s), 7.64-7.71 (2H, m), 8.67
(1H, m), 8.85 (1H, s), 11.11 (1H, s)

(25) 4- (3-butyl-2-oxoimidazolidin-1-yl) -8-[(3,5-dichloropyridin-4-yl) carbonylamino] -3-methylquinoline mp: 103 -105 ° C NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J = 7.5Hz), 1.37 (2
H, qt, J = 7.5, 7.5Hz), 1.58 (2H, tt, J = 7.5, 7.5Hz),
2.36 (3H, s), 3.10-3.28 (2H, m), 3.60-3.70 (3H, m),
3.68-3.74 (1H, m), 7.70 (2H, d, J = 7.0Hz), 8.65 (1
H, dd, J = 7.0, 7.0Hz), 8.74 (2H, s), 8.86 (1H, s), 1
1.30 (1H, s)

(26) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methyl-4
- (4-toluene-sulfonamido) quinoline mp: 275 ℃ NMR (DMSO- d 6, δ): 2.14 (3H, s), 2.38 (3H, s), 7.
35 (2H, d, J = 7Hz), 7.41 (1H, t, J = 9Hz), 7.47-7.59
(3H, m), 7.70 (1H, d, J = 5Hz), 8.47 (1H, d, J = 5Hz),
8.59 (1H, d, J = 9Hz), 8.76 (1H, s)

(27) 3-bromo-8-[(2-methylpyridin-3-yl) carbonylamino] quinoline mp: 182-184 ° C. NMR (DMSO-d ₆ , δ): 2.65 (3H, s), 7.38-7.42 (1H,
m), 7.69-7.77 (2H, m), 8.03 (1H, d, J = 8.0Hz), 8.60
(1H, d, J = 3.0Hz), 8.67 (1H, d, J = 8.0Hz), 8.81 (1H,
d, J = 2.0Hz), 8.95 (1H, d, J = 2.0Hz), 10.36 (1H, s)

(28) 8- (4-Chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-
Carbonylamino) -3-methyl-4- (3-methyl-
2-oxoimidazolidin-1-yl) quinoline mp: 205-208 ° C NMR (CDCl ₃ , δ): 2.44 (3H, s), 2.80 (3H, s), 2.99
(3H, s), 3.63-3.76 (3H, m), 3.83-3.92 (1H, m), 4.1
2 (3H, s), 7.58-7.67 (2H, m), 8.72 (1H, s), 8.87-8.
96 (2H, m)

Example 81 8-Amino-3-methyl-4- (3-propyl-2-oxoimidazolidin-1-yl) quinoline (300 m
g), a mixture of 4-trifluoromethylpyridine-3-carboxylic acid (302 mg), triethylamine (320 mg) and diphenyl chlorophosphate (567 mg) in ethylene chloride (5 ml) was stirred at 80 ° C. for 1 hour. The reaction mixture was diluted with chloroform, washed with a saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (methanol-chloroform) to give 3-methyl-4- (3-propyl-2-oxoimidazolidin-
1-yl) -8-[(4-trifluoromethylpyridin-3-yl) carbonylamino] quinoline (558 m
g) was obtained as a light brown oil. NMR (CDCl ₃ , δ): 1.01 (3H, t, J = 8Hz), 1.60-1.76
(2H, m), 2.43 (3H, s), 3.20-3.44 (2H, m), 3.64-3.74
(3H, m), 3.81-3.91 (1H, m), 7.56-7.65 (2H, m), 7.7
0 (1H, d, J = 8Hz), 8.67 (1H, s), 8.82 (1H, dd, J = 8,
5Hz), 8.95 (1H, d, J = 8Hz), 9.08 (1H, s)

The hydrochloride mp: 219 ° C. NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 9 Hz), 1.50-1.68
(2H, m), 2.37 (3H, s), 3.07-3.30 (2H, m), 3.59-3.8
9 (4H, m), 7.63-7.75 (2H, m), 7.90 (1H, d, J = 6Hz),
8.60 (1H, m), 8.86 (1H, s), 8.99 (1H, d, J = 6Hz), 9.
06 (1H, s)

Example 82 The following compounds were obtained in the same manner as in Example 81. (1) 8- (4-bromo-2,5-dimethylpyrrol-3-ylcarbonylamino) -3-methyl-4- (3
- methyl-2-oxo-imidazolidin-1-yl) quinoline _{mp: 215-219 ℃ NMR (CDCl 3} , δ): 2.14 (3H, s), 2.42 (3H, s), 2.48
(3H, s), 2.98 (3H, s), 3.63-3.73 (3H, m), 3.82-3.9
0 (1H, m), 7.47 (1H, d, J = 9Hz), 7.53 (1H, t, J = 9H
z), 8.33-8.40 (1H, br s), 8.74 (1H, s), 8.87 (1H,
d, J = 9Hz)

(2) 8- (1-tert-butoxycarbonylindoline-4-ylcarbonylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-
1-yl) quinoline NMR (CDCl ₃ , δ): 1.58 (9H, s), 2.45 (3H, s), 2.98
(3H, s), 3.57 (2H, t, J = 9Hz), 3.63-3.74 (3H, m),
3.82-3.91 (1H, m), 4.07 (2H, t, J = 9Hz), 7.17 (2H,
m), 7.47-7.61 (3H, m), 8.75 (1H, s), 8.81-8.88 (1H,
m)

(3) 3-bromo-8-[(2,4-dimethylpyridin-3-yl) carbonylamino] -4-
(3-ethyl-2-oxoimidazolidin-1-yl)
Quinoline NMR (CDCl ₃ , δ): 1.27 (3H, t, J = 8Hz), 2.43 (3H,
s), 2.67 (3H, s), 3.38-3.52 (2H, m), 3.65-3.84 (3H,
m), 3.93-4.06 (1H, m), 7.08 (1H, d, J = 8Hz), 7.63-
7.77 (2H, m), 8.47 (1H, d, J = 5Hz), 8.86 (1H, s), 8.
98 (1H, d, J = 5Hz), 9.82 (1H, s)

(4) 8-[(2,4-dimethylpyridin-3-yl) carbonylamino] -3-methyl-4-
(3-Propyl-2-oxoimidazolidin-1-yl) quinoline NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7.5 Hz), 1.58 (2
H, m), 2.33 (3H, s), 2.35 (3H, s), 2.50 (3H, s), 3.
07-3.30 (2H, m), 3.62-3.74 (3H, m), 3.82 (1H, m),
7.20 (1H, d, J = 6Hz), 7.63-7.72 (2H, m), 8.40 (1H,
d, J = 8Hz), 8.58 (1H, m), 8.84 (1H, s), 10.49 (1H,
s)

(5) 4- (3-allyl-2-oxoimidazolidin-1-yl) -8-[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methylquinoline mp: 205 -206 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 3.55-3.97 (6H,
m), 5.26 (1H, d, J = 9.0Hz), 5.32 (1H, d, J = 16.0Hz),
5.81-5.96 (1H, m), 7.63-7.72 (2H, m), 7.73 (1H, d,
J = 5.5Hz), 8.48 (1H, d, J = 5.5Hz), 8.70 (1H, m), 8.88
(1H, s)

(6) 4- (3-allyl-2-oxoimidazolidin-1-yl) -8-[(2,4-dichloro-6-methylpyridin-3-yl) carbonylamino]
-3-Methylquinoline mp: 208.5-210 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 2.53 (3H, s), 3.
56-3.95 (6H, m), 5.25 (1H, d, J = 9.0Hz), 5.33 (1H,
d, J = 16.0Hz), 5.81-5.96 (1H, m), 7.63 (1H, s), 7.6
5-7.71 (2H, m), 8.68 (1H, dd, J = 7.0, 2.5Hz), 8.87
(1H, s)

(7) 4- (3-butyl-2-oxoimidazolidin-1-yl) -8-[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methylquinoline mp: 187 -194 ° C NMR (DMSO-d ₆ , δ): 0.95 (3H, t, J = 7Hz), 1.36 (2H,
tq, J = 7,7Hz), 1.55 (2H, ddt, J = 7, 7, 7Hz), 2.35
(3H, s), 3.11-3.34 (2H, m), 3.57-3.72 (3H, m), 3.82
(3H, m), 7.63-7.71 (2H, m), 7.73 (1H, d, J = 6Hz),
8.48 (1H, d, J = 6Hz), 8.70 (1H, m), 8.87 (1H, s), 1
1.26 (1H, s)

(8) 4- (3-butyl-2-oxoimidazolidin-1-yl) -8-[(2,4-dichloro-6-methylpyridin-3-yl) carbonylamino]
3-methylquinoline mp: 179-181 ℃ NMR (DMSO- d 6, δ): 0.95 (3H, t, J = 7Hz), 1.35 (2H,
tq, J = 7,7Hz), 1.56 (2H, ddt, J = 7,7,7Hz), 2.35
(3H, s), 2.53 (3H, s), 3.11-3.37 (2H, m), 3.55-3.88
(4H, m), 7.60-7.73 (3H, m), 8.67 (1H, m), 8.85 (1
H, s), 11.10 (1H, s)

(9) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -4- (3-isobutyl-2-oxoimidazolidin-1-yl) -3-methylquinoline mp: 197 -199 ° C NMR (DMSO-d ₆ , δ): 0.92 (3H, d, J = 7.0Hz), 0.93 (3
H, d, J = 7.0Hz), 1.95 (1H, m), 2.38 (3H, s), 2.97 (1
H, dd, J = 14.5, 7.5Hz), 3.09 (1H, dd, J = 14.5, 7.5H
z), 3.63-3.73 (3H, m), 3.80-3.87 (1H, m), 7.68 (1H,
d, J = 7.5Hz), 7.69 (1H, t, J = 7.5Hz), 7.73 (1H, d, J
= 5.5Hz), 8.49 (1H, d, J = 5.5Hz), 8.70 (1H, d, J = 7.5
Hz), 8.83 (1H, s)

(10) 8-[(2,4-dichloro-6
-Methylpyridin-3-yl) carbonylamino] -4
-(3-isobutyl-2-oxoimidazolidin-1-
Yl) -3-methylquinoline mp: 213.5-215 ℃ NMR (DMSO- d 6, δ): 0.93 (3H, d, J = 6.0Hz), 0.95 (3
H, d, J = 6.0Hz), 1.95 (1H, m), 2.36 (3H, s), 2.53 (3
H, s), 2.96 (1H, dd, J = 14.5, 7.5Hz), 3.09 (1H, dd,
J = 14.5, 7.5Hz), 3.63-3.72 (3H, m), 3.80-3.87 (1H,
m), 7.62 (1H, s), 7.65-7.71 (2H, m), 8.68 (1H, d, J
= 7.5Hz), 8.87 (1H, s)

(11) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methyl-4
- [3- (2-methyl-2-propenyl) -2-oxo-imidazolidin-1-yl] quinoline mp: 185-186 ℃ NMR (DMSO- d 6, δ): 1.73 (3H, s), 2.38 ( 3H, s), 3.
51-3.91 (6H, m), 4.97 (2H, d, J = 6.0Hz), 7.66-7.73
(2H, m), 7.73 (1H, d, J = 7.0Hz), 8.47 (1H, d, J = 7.0H
z), 8.69 (1H, m), 8.87 (1H, s)

(12) 3-chloro-8-[(2,4-
Dichloropyridin-3-yl) carbonylamino] -4
- (2-oxo-3-phenyl-imidazolidin-1-yl) quinoline mp: 223-224 ℃ NMR (DMSO- d 6, δ): 3.98 (2H, t, J = 7.5Hz), 4.13-4.
33 (2H, m), 7.09 (1H, t, J = 7.5Hz), 7.40 (2H, t, J =
7.5Hz), 7.66 (2H, d, J = 7.5Hz), 7.74 (1H, d, J = 6.0H
z), 7.81 (1H, t, J = 7.5Hz), 7.93 (1H, d, J = 7.5Hz),
8.48 (1H, d, J = 6.0Hz), 8.79 (1H, d, J = 7.5Hz), 9.07
(1H, s)

(13) 3-chloro-8-[(2,4-
Dichloro-6-methylpyridin-3-yl) carbonylamino] -4- (2-oxo-3-phenylimidazolidin-1-yl) quinoline mp: 127-129 ° C NMR (DMSO-d ₆ , δ): 2.53 (3H, s), 3.97 (2H, t, J =
7.5Hz), 4.16-4.34 (2H, m), 7.09 (1H, t, J = 7.5Hz),
7.39 (2H, t, J = 7.5Hz), 7.64 (1H, s), 7.66 (2H, d, J
= 7.5Hz), 7.79 (1H, t, J = 7.5Hz), 7.92 (1H, d, J = 7.5H
z), 8.78 (1H, d, J = 7.5Hz), 9.05 (1H, s)

(14) 3-chloro-4- (2-oxo-3-phenylimidazolidin-1-yl) -8-
[(4-trifluoromethyl-3-yl) carbonylamino] quinoline mp: 210.5-212 ℃ NMR (DMSO- d 6, δ): 3.98 (2H, t, J = 7.5Hz), 4.15-4.
39 (2H, m), 7.09 (1H, t, J = 7.5Hz), 7.39 (2H, t, J =
7.5Hz), 7.66 (2H, d, J = 7.5Hz), 7.79 (1H, t, J = 7.5H
z), 7.90 (1H, d, J = 5.5Hz), 7.93 (1H, d, J = 7.5Hz),
8.71 (1H, d, J = 7.5Hz), 9.00 (1H, d, J = 5.5Hz), 9.04
(2H, s)

(15) 3-chloro-8-[(2,4-
Dimethylpyridin-3-yl) carbonylamino] -4
- (4-methyl-imidazol-1-yl) quinoline mp: 182-184 ℃ NMR (DMSO- d 6, δ): 2.25 (3H, s), 2.35 (3H, s), 2.
50 (3H, s), 7.16 (1H, d, J = 7.5Hz), 7.20 (1H, d, J =
5.5Hz), 7.25 (1H, s), 7.78 (1H, t, J = 7.5Hz), 7.89
(1H, s), 8.40 (1H, d, J = 5.5Hz), 8.68 (1H, d, J = 7.5H
z), 9.11 (1H, s)

(16) 3-chloro-8-[(2,4-
Dichloropyridin-3-yl) carbonylamino] -4
- (4-methyl-imidazol-1-yl) quinoline mp: 185-187 ℃ NMR (DMSO- d 6, δ): 2.27 (3H, s), 7.17 (1H, d, J =
7.5Hz), 7.28 (1H, s), 7.73 (1H, d, J = 5.5Hz), 7.77
(1H, t, J = 7.5Hz), 7.89 (1H, s), 8.49 (1H, d, J = 5.5H
z), 8.81 (1H, d, J = 7.5Hz), 9.12 (1H, s)

(17) 3-chloro-4- (4-methylimidazol-1-yl) -8-[(4-trifluoromethylpyridin-3-yl) carbonylamino] quinoline mp: 207.5-208 ° C NMR ( DMSO-d ₆ , δ): 2.27 (3H, s), 7.17 (1H, d, J =
7.5Hz), 7.28 (1H, s), 7.78 (1H, t, J = 7.5Hz), 7.90
(1H, s), 7.91 (1H, d, J = 5.5Hz), 8.73 (1H, d, J = 7.5H
z), 9.00 (1H, d, J = 5.5Hz), 9.06 (1H, s), 9.12 (1H,
s)

(18) 4-acetamido-8-
[(2,4-dichloro-3-yl) carbonylamino] -3-methylquinoline mp: 265.5-266 ℃ NMR (DMSO- d 6, δ): 2.22 (3H, s), 2.33 (3H, s) , 7.
63 (1H, t, J = 7.5Hz), 7.73 (1H, d, J = 7.0Hz), 7.77 (1
H, d, J = 7.5Hz), 8.48 (1H, d, J = 7.0Hz), 8.68 (1H, d,
J = 7.5Hz), 8.82 (1H, s)

(19) 4-acetamido-3-methyl-8-[(4-trifluoromethylpyridin-3-yl) carbonylamino] quinoline mp: 255-255.5 ° C. NMR (DMSO-d ₆ , δ): 2.22 (3H, s), 2.32 (3H, s), 7.
63 (1H, t, J = 7.5Hz), 7.77 (1H, d, J = 7.5Hz), 7.90 (1
H, d, J = 5.5Hz), 8.62 (1H, d, J = 7.5Hz), 8.79 (1H,
s), 8.98 (1H, d, J = 5.5Hz), 9.05 (1H, s)

(20) 8-[(2,4-dichloropyridin-3-yl) carbonylamino] -4-isopropoxy-3-methylquinoline mp: 132-135 ° C. NMR (DMSO-d ₆ , δ): 1.36 (6H, d, J = 6.0Hz), 2.44 (3
H, s), 4.58 (1H, qq, J = 6.0, 6.0Hz), 7.60 (1H, dd, J
= 8.0, 8.0Hz), 7.73 (1H, d, J = 5.0Hz), 7.88 (1H, d, J
= 8.0Hz), 8.47 (1H, d, J = 5.0Hz), 8.67 (1H, d, J = 8.0H
z), 8.75 (1H, s), 11.16 (1H, s)

(21) 4-Isopropoxy-3-methyl-8-[(4-trifluoromethylpyridin-3-yl) carbonylamino] quinoline mp: 93-95 ° C. NMR (DMSO-d ₆ , δ): 1.35 (6H, d, J = 6.0Hz), 2.43 (3
H, s), 4.59 (1H, qq, J = 6.0, 6.0Hz), 7.61 (1H, dd, J
= 8.0, 8.0Hz), 7.86 (1H, d, J = 8.0Hz), 7.90 (1H, d, J
= 5.5Hz), 8.60 (1H, d, J = 8.0Hz), 8.74 (1H, s), 9.00
(1H, d, J = 5.5Hz), 9.05 (1H, s), 10.83 (1H, s)

(22) 8-[(2,4-dimethylpyridin-3-yl) carbonylamino] -4-isopropoxy-3-methylquinoline mp: 96-98 ° C. NMR (DMSO-d ₆ , δ): 1.35 (6H, d, J = 6.0Hz), 2.35 (3
H, s), 2.43 (3H, s), 2.50 (3H, s), 4.59 (1H, qq, J =
6.0Hz), 7.21 (1H, d, J = 5.0Hz), 7.63 (1H, dd, J = 8.0,
8.0Hz), 7.87 (1H, d, J = 8.0Hz), 8.40 (1H, d, J = 5.0H
z), 8.58 (1H, d, J = 8.0Hz), 8.72 (1H, s), 10.39 (1H,
s)

(23) 4-benzyloxy-8-
[(2,4-dichloropyridin-3-yl) carbonylamino] -3-methylquinoline mp: 158-159 ° C NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 5.19 (2H, s) , 7.
36-7.50 (3H, m), 7.55 (2x1H, d, J = 7.5Hz), 7.63 (1H,
dd, J = 8, 8Hz), 7.73 (1H, d, J = 6Hz), 7.85 (1H, d, J
= 8Hz), 8.48 (1H, d, J = 6Hz), 8.70 (1H, d, J = 8Hz), 8.
78 (1H, s), 11.21 (1H, s)

(24) 4-benzyloxy-3-methyl-8-[(4-trifluoromethylpyridin-3-yl) carbonylamino] quinoline mp: 155-156 ° C NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 5.18 (2H, s), 7.
35-7.45 (3H, m), 7.55 (2x1H, d, J = 7.5Hz), 7.62 (1H,
dd, J = 8, 8Hz), 7.85 (1H, d, J = 8Hz), 7.90 (1H, d, J
= 6Hz), 8.62 (1H, d, J = 8Hz), 8.87 (1H, s), 8.98 (1H,
d, J = 6Hz), 9.05 (1H, s), 10.86 (1H, s)

(25) 8-[(2,4-dichloro-6)
-Methylpyridin-3-yl) carbonylamino] -4
- isopropoxy-3-methylquinoline mp: 153-155 ℃ NMR (DMSO- d 6, δ): 1.34 (6H, d, J = 7.0Hz), 2.43 (3
H, s), 2.52 (3H, s), 4.58 (1H, qq, J = 7.0, 7.0Hz),
7.58-7.63 (2H, m), 7.86 (1H, d, J = 8.0Hz), 8.65 (1H,
d, J = 8.0Hz), 8.74 (1H, s), 11.03 (1H, s)

Example 83 The following compounds were obtained in the same manner as in Example 1- (6). (1) 3-cyano-8- (2,6-dichlorobenzoylamino) -4- (2-methylaminoethylamino) quinoline mp: 207-209 ° C NMR (DMSO-d ₆ , δ): 2.33 (3H, s), 2.85 (2H, t, J =
7.0Hz), 3.87 (2H, t, J = 7.0Hz), 7.47-7.63 (4H, m),
8.12 (1H, d, J = 8.0Hz), 8.48 (1H, s), 8.73 (1H, d, J
= 8.0Hz), 10.55 (1H, s)

(2) 3-bromo-8- (2,6-dichlorobenzoylamino) -4- (2-methylaminoethylamino) quinoline mp: 138-140 ° C. NMR (DMSO-d ₆ , δ): 2.30 (3H, s), 2.75 (2H, t, J =
7.5Hz), 3.76 (2H, br), 6.52 (1H, br), 7.47-7.60 (4
H, m), 8.03 (1H, d, J = 8.0Hz), 8.53 (1H, s), 8.66 (1
(H, d, J = 8.0Hz)

(3) 3-Methyl-4- [2- (propylamino) ethylamino] -8- (2-trifluoromethylbenzoylamino) quinoline NMR (DMSO-d ₆ , δ): 0.85 (3H, t , J = 7Hz), 1.40 (2H,
tq, J = 7,7Hz), 2.37 (3H, s), 2.46 (2H, t, J = 7Hz),
2.73 (2H, t, J = 6Hz), 3.56 (2H, dt, J = 6, 6Hz), 6.02
(1H, t, J = 6Hz), 7.42-7.65 (4H, m), 7.95 (1H, d, J =
8Hz), 8.32 (1H, s), 8.57 (1H, d, J = 8Hz), 10.49 (1H,
s)

Example 84 The following compounds were obtained in the same manner as in Example 1- (7) or 3. (1) 3-cyano-8- (2,6-dichlorobenzoylamino) -4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 169-171 ° C NMR (DMSO-d ₆ , δ): 2.87 (3H, s), 3.70 (2H, t, J =
7.5Hz), 4.00 (2H, t, J = 7.5Hz), 7.47-7.57 (3H, m),
7.78-7.90 (2H, m), 8.86 (2H, d, J = 8.0Hz), 9.17 (1H,
s), 11.04 (1H, s)

(2) 3-cyano-8- (2,6-dichlorobenzoylamino) -4- (3-methyl-2-thioxoimidazolidin-1-yl) quinoline mp: 163-166 ° C NMR (DMSO -d ₆ , δ): 3.20 (3H, s), 4.01-4.05 (2H,
m), 4.08-4.11 (2H, m), 7.48-7.59 (3H, m), 7.84 (1H,
m), 8.85-8.88 (1H, m), 9.28 (1H, s), 11.10 (1H, s)

(3) 3-bromo-8- (2,6-dichlorobenzoylamino) -4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline mp: 240-247 ° C NMR (DMSO- d ₆ , δ): 2.82 (3H, s), 3.63-3.86 (4H,
m), 7.48-7.60 (3H, m), 7.75 (2H, d, J = 4.0Hz), 8.74
(1H, dd, J = 4.0, 4.0Hz), 9.06 (1H, s), 10.91 (1H, s)

(4) 3-bromo-8- (2,6-dichlorobenzoylamino) -4- (3-methyl-2-thioxoimidazolidin-1-yl) quinoline mp: 270-272 ° C NMR (DMSO -d ₆ , δ): 3.15 (3H, s), 3.89-4.07 (4H,
m), 7.48-7.60 (3H, m), 7.67-7.77 (2H, m), 8.73 (1H,
d, J = 8.0Hz), 9.09 (1H, s), 10.95 (1H, s)

(5) 3-Methyl-4- (2-oxo-
3-propylimidazolidin-1-yl) -8- (2-
Trifluoromethylbenzoylamino) quinoline mp: 139-141 ° C NMR (DMSO-d ₆ , δ): 0.93 (3H, t, J = 7Hz), 1.59 (2H,
ddq, J = 7, 7, 7Hz), 2.35 (3H, s), 3.07-3.30 (2H,
m), 3.59-3.77 (3H, m), 3.83 (1H, m), 7.67 (2x1H, d,
J = 6Hz), 7.77 (1H, m), 7.82-7.94 (3H, m), 8.63 (1
H, m), 8.83 (1H, s), 10.40 (1H, s)

Example 85 (1) 4- (3-Carboxymethyl-2-oxoimidazolidin-1-yl) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline was converted to 4- (3 -Ethoxycarbonylmethyl-2-oxoimidazolidine-
It was obtained in the same manner as in Example 23- (2) from 1-yl) -8- (2,6-dichlorobenzoylamino) -3-methylquinoline. mp: 261-270 ° C NMR (DMSO-d ₆ , δ): 2.37 (3H, s), 3.65-3.89 (4H,
m), 3.85 (3H, s), 7.55-7.77 (5H, m), 8.65 (1H, d, J
= 7Hz), 8.84 (1H, s)

(2) 8- (2,6-dichlorobenzoylamino) -4- (3-methylcarbamoylmethyl-2
-Oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Example 23- (3). NMR (CDCl ₃ , δ): 2.44 (3H, s), 2.86 (3H, d, J = 5H
z), 3.67-4.06 (6H, m), 6.23 (1H, m), 7.29-7.45 (3H,
m), 7.56-7.70 (2H, m), 8.20 (1H, s), 8.91 (1H, d,
(J = 9Hz)

(3) 8- (2,6-dichlorobenzoylamino) -4- (3-dimethylcarbamoylmethyl-
2-Oxoimidazolidin-1-yl) -3-methylquinoline was obtained in the same manner as in Example 23- (3). NMR (CDCl ₃ , δ): 2.46 (3H, s), 3.00 (3H, s), 3.05
(3H, s), 3.65-3.71 (1H, m), 3.73-3.98 (3H, m), 4.1
0 (1H, d, J = 15Hz), 4.21 (1H, d, J = 15Hz), 7.28-7.45
(3H, m), 7.63 (1H, t, J = 9Hz), 7.71 (1H, d, J = 9Hz),
8.69 (1H, s), 8.89 (1H, d, J = 9Hz)

Example 86 The following compounds were obtained in the same manner as in Example 14- (1). (1) 4-hydrazino-3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline mp: 168-172 ° C NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 4.70 (2H, s), 7.
33 (1H, dd, J = 8, 8Hz), 7.72 (1H, s), 7.77 (1H, m),
7.82-7.87 (2H, m), 7.90 (1H, d, J = 8Hz), 8.17 (1H,
s), 8.50 (1H, d, J = 8Hz), 8.63 (1H, d, J = 8Hz), 10.31
(1H, s)

(2) 4-hydrazino-8-[(2-methylpyridin-3-yl) carbonylamino] quinoline mp: 243-248 ° C. NMR (DMSO-d ₆ , δ): 2.68 (3H, s), 4.48 (2H, s), 6.
97 (1H, d, J = 5.0Hz), 7.37-7.43 (2H, m), 7.89 (1H,
d, J = 8.0Hz), 8.03 (1H, d, J = 8.0Hz), 8.40 (1H, d, J =
5.0Hz), 8.58-8.62 (2H, m), 8.67 (1H, s), 10.40 (1H,
s)

Example 87 The following compounds were obtained in the same manner as in Example 31- (7). (1) 4- [2- (propionyl) hydrazino] -3
-Methyl-8- (2-trifluoromethylbenzoylamino) quinoline mp: 106-109 ° C NMR (DMSO-d ₆ , δ): 1.01 (3H, t, J = 7.5 Hz), 2.15 (2
H, q, J = 7.5Hz), 7.46 (1H, dd, J = 8.0, 8.0Hz), 7.73-
7.80 (1H, m), 7.84 (2H, m), 7.90 (1H, d, J = 7.5Hz),
8.11 (1H, d, J = 8.0Hz), 8.27 (1H, s), 8.33 (1H, s),
8.55 (1H, d, J = 8.0Hz), 10.14 (1H, s), 10.30 (1H, s)

(2) 4- (2-acetylhydrazino)
-8 - [(2-methylpyridin-3-yl) carbonylamino] quinoline mp: 246-248 ℃ NMR (DMSO- d 6, δ): 2.02 (3H, s), 2.66 (3H, s), 6.
64 (1H, d, J = 5.0Hz), 7.40 (1H, dd, J = 8.5, 4.0Hz),
7.50 (1H, dd, J = 8.0, 8.0Hz), 7.96 (1H, d, J = 8.0Hz),
8.04 (1H, d, J = 8.0Hz), 8.45 (1H, d, J = 5.0Hz), 8.61
(1H, d, J = 4.0Hz), 8.67 (1H, d, J = 8.5Hz), 9.28 (1H,
br), 10.27 (1H, br), 10.40 (1H, s)

Example 88 4- [2- (furan-3-ylcarbonyl) hydrazino] -3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline was obtained in the same manner as in Example 15. NMR (CDCl ₃ , δ): 2.53 (3H, s), 6.67 (1H, s), 6.72
-6.79 (1H, br s), 7.42-7.50 (2H, m), 7.56-7.86 (6H,
m), 7.98 (1H, s), 8.07-8.15 (1H, br), 8.38 (1H,
s), 8.73-8.81 (1H, m)

Example 89 4- (2-Methanesulfonylhydrazino) -3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline was obtained in the same manner as in Example 14- (2). mp: 189-191.5 ° C NMR (CDCl ₃ -CD ₃ OD, δ): 2.51 (3H, s), 2.57 (3H,
s), 7.56 (1H, t, J = 7.5Hz), 7.59-7.68 (1H, m), 7.70
(1H, t, J = 4.0Hz), 7.73-7.83 (2H, m), 8.12 (1H, bd,
J = 7.5Hz), 8.41 (1H, s), 8.75 (1H, m)

Example 90 4- (2-benzoylhydrazino) -3-methyl-8-
(2-Trifluoromethylbenzoylamino) quinoline was obtained in the same manner as in Example 15. mp: 196-199 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 7.45-7.63 (4H,
m), 7.77 (1H, m), 7.82-7.95 (4H, m), 8.22 (1H, d, J
= 8Hz), 8.35 (1H, s), 8.53 (1H, s), 8.57 (1H, d, J = 8
Hz), 10.32 (1H, s), 10.89 (1H, s)

Example 91 The following compounds were obtained in the same manner as in Example 12. (1) 3-methyl-4- (1,2,4-triazol-1-yl) -8- (2-trifluoromethylbenzoyl) quinoline mp: 240-243 ° C. NMR (DMSO-d ₆ , δ): 2.24 (3H, s), 7.01 (1H, d, J = 9
Hz), 7.68 (1H, t, J = 8Hz), 7.72-7.93 (4H, m), 8.47
(1H, s), 8.67 (1H, brd, J = 8Hz), 9.01 (1H, s), 9.08
(1H, s)

(2) 3-methyl-4- (2-methylimidazol-1-yl) -8- (2-trifluoromethylbenzoyl) quinoline mp: 162 ° C. NMR (DMSO-d ₆ , δ): 1.99 ( 3H, s), 2.20 (3H, s), 6.
85 (1H, d, J = 9Hz), 7.13 (1H, s), 7.30 (1H, s), 7.66
(1H, t, J = 9Hz), 7.71-7.95 (4H, m), 8.66 (1H, br
d, J = 9Hz), 8.99 (1H, s)

(3) 3-Methyl-4- (4-methylimidazol-1-yl) -8- (2-trifluoromethylbenzoylamino) quinoline NMR (DMSO-d ₆ , δ): 2.25 (2 × 3H, s ), 7.07 (1H, d, J
= 8Hz), 7.20 (1H, s), 7.67 (1H, dd, J = 8, 8Hz), 7.73-
7.93 (5H, m), 8.65 (1H, d, J = 8Hz), 8.95 (1H, s), 1
0.47 (1H, s)

(4) 3-Methyl-4- (5-methylimidazol-1-yl) -8- (2-trifluoromethylbenzoylamino) quinoline NMR (DMSO-d ₆ , δ): 1.89 (3H, s ), 2.21 (3H, s), 6.
86 (1H, d, J = 8Hz), 7.13 (1H, br), 7.69 (1H, dd, J =
8, 8Hz), 7.73-8.03 (5H, m), 8.67 (1H, d, J = 8Hz),
9.02 (1H, s), 10.52 (1H, s)

(5) 4- (Imidazol-1-yl)
3-methyl-8 - [(2-methylpyridin-3-yl) carbonylamino] quinoline mp: 152-154 ℃ NMR (DMSO- d 6, δ): 2.25 (3H, s), 2.67 (3H, s ), 7.
02 (1H, d, J = 8.0Hz), 7.30 (1H, s), 7.43 (1H, dd, J =
8.5, 5.0Hz), 7.04 (1H, s), 7.68 (1H, dd, J = 8.0, 8.0
Hz), 7.99 (1H, s), 8.06 (1H, d, J = 8.5Hz), 8.63 (1H,
d, J = 5.0Hz), 8.68 (1H, d, J = 8.0Hz), 9.00 (1H, s)

Example 92 (1) 4-Chloro-8-[(2-methylpyridine-3)
-Yl) carbonylamino] quinoline is 8-amino-
It was obtained in the same manner as in Example 67- (3) from 4-chloroquinoline and 2-methylnicotinic acid. NMR (DMSO-d ₆ , δ): 2.67 (3H, s), 7.41 (1H, dd, J =
8.5, 6.0Hz), 7.85 (1H, dd, J = 8.0, 8.0Hz), 7.92 (1H,
d, J = 5.0Hz), 8.00 (1H, d, J = 8.5Hz), 8.07 (1H, d, J
= 8.0Hz), 8.61 (1H, d, J = 6.0Hz), 8.80 (1H, d, J = 8.0H
z), 8.87 (1H, d, J = 5.0Hz), 10.46 (1H, s)

(2) 4- (Imidazol-1-yl)
-8-[(2-Methylpyridin-3-yl) carbonylamino] quinoline was obtained in the same manner as in Example 12. mp: 200-202 ° C NMR (DMSO-d ₆ , δ): 2.68 (3H, s), 7.27 (3H, s), 7.
41 (1H, dd, J = 8.5, 5.5Hz), 7.58 (1H, d, J = 8.5Hz),
7.75-7.78 (3H, m), 8.07 (1H, d, J = 8.0Hz), 8.18 (1H,
s), 8.63 (1H, d, J = 5.5Hz), 8.78 (1H, d, J = 8.0Hz),
9.04 (1H, d, J = 5.0Hz), 10.53 (1H, s)

Example 93 (1) 8-Amino-3,4-dichloroquinoline was obtained in the same manner as in Example 1- (4). mp: 120-121.5 ° C NMR (DMSO-d ₆ , δ): 6.21 (2H, bs), 6.97 (1H, d, J
= 7.5Hz), 7.23 (1H, d, J = 7.5Hz), 7.49 (1H, t, J = 7.5H
z), 8.78 (1H, s)

(2) 3,4-dichloro-8- (2,6
-Dichlorobenzoylamino) quinoline in Example 1
Obtained in the same manner as in (5). mp: 219-220 ° C NMR (DMSO-d ₆ , δ): 7.52 (1H, dd, J = 8.5, 7.0Hz),
7.57 (1H, d, J = 7.0Hz), 7.58 (1H, d, J = 8.5Hz), 7.89
(1H, t, J = 7.5Hz), 8.02 (1H, d, J = 7.5Hz), 8.81 (1H,
d, J = 7.5Hz), 8.99 (1H, s)

(3) 4- (1H-benzimidazol-1-yl) -8- (2,6-dichlorobenzoylamino) -3-chloroquinoline was obtained in the same manner as in Example 12. mp: 275-275.5 ° C NMR (DMSO-d ₆ , δ): 6.99 (1H, d, J = 7.5Hz), 7.18 (1
H, d, J = 7.5Hz), 7.28 (1H, t, J = 7.5Hz), 7.37 (1H, t,
J = 7.5Hz), 7.53 (1H, dd, J = 9.0, 7.5Hz), 7.56-7.63
(2H, m), 7.72 (1H, t, J = 7.5Hz), 7.89 (1H, d, J = 7.5H
z), 8.61 (1H, s), 8.80 (1H, d, J = 7.5Hz), 9.21 (1H,
s)

Example 94 8- (2,6-Dichlorobenzoylamino) -3-methyl-4- (3-nitrobenzyloxy) quinoline was treated with 8
It was obtained in the same manner as in Example 16- (2) from-(2,6-dichlorobenzoylamino) -1,4-dihydro-3-methyl-4-oxoquinoline and 3-nitrobenzyl bromide. mp: 188-190 ° C NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 5.35 (2H, s), 7.
46-7.65 (4H, m), 7.76 (1H, dd, J = 8.0, 8.0Hz), 7.86
(1H, d, J = 8.0Hz), 8.06 (1H, d, J = 8.0Hz), 8.27 (1H,
d, J = 8.0Hz), 8.45 (1H, s), 8.67 (1H, d, J = 8.0Hz),
8.77 (1H, s), 10.73 (1H, s)

Example 95 (1) 4-Chloro-3-methyl-8-[(2-methylpyridin-3-yl) carbonylamino] quinoline was obtained in the same manner as in Example 67- (3). NMR (DMSO-d ₆ , δ): 2.58 (3H, s), 2.67 (3H, s), 7.
40 (1H, dd, J = 8.5, 4.0Hz), 7.77 (1H, dd, J = 8.0, 8.0
Hz), 7.95 (1H, d, J = 8.5Hz), 8.04 (1H, d, J = 8.0Hz),
8.60 (1H, d, J = 4.0Hz), 8.70 (1H, d, J = 8.0Hz), 8.85
(1H, s), 10.41 (1H, s)

(2) 4- (4-chlorobenzyloxy) -3-methyl-8-[(2-methylpyridine-3-
Yl) carbonylamino] quinoline was obtained in the same manner as in Example 20. mp: 169-173 ° C NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 2.64 (3H, s), 5.
20 (2H, s), 7.40 (1H, dd, J = 8.5, 4.0Hz), 7.50 (2H,
d, J = 7.5Hz), 7.58-7.64 (3H, m), 7.80 (1H, d, J = 8.5H
z), 8.03 (1H, d, J = 8.0Hz), 8.60-8.63 (2H, m), 8.77
(1H, s), 10.36 (1H, s)

Example 96 The following compound was obtained in the same manner as in Example 60. (1) 8- (2,6-dichlorobenzoylamino)-
3-methyl-4-[(1-pyrrolidinyl) carbonylmethoxy] quinoline mp: 183-185 ° C NMR (CDCl ₃ , δ): 1.85-2.05 (4H, m), 2.48 (3H, s),
3.43 (2H, t, J = 7.0Hz), 3.60 (2H, t, J = 7.0Hz), 4.67
(2H, s), 7.29-7.43 (3H, m), 7.59 (1H, t, J = 7.5H
z), 7.90 (1H, d, J = 7.5Hz), 8.58 (1H, s), 8.89 (1H,
d, J = 7.5Hz)

(2) 8- (2,6-dichlorobenzoylamino) -4- (N, N-diethylcarbamoylmethoxy) -3-methylquinoline mp: 155-157 ° C. NMR (CDCl ₃ , δ): 1.21 ( 3H, t, J = 7.5Hz), 1.23 (3H,
t, J = 7.5Hz), 2.50 (3H, s), 3.34 (2H, q, J = 7.5Hz),
3.49 (2H, q, J = 7.5Hz), 4.72 (2H, s), 7.29-7.42 (3H,
m), 7.60 (1H, t, J = 7.5Hz), 7.88 (1H, d, J = 7.5Hz),
8.58 (1H, s), 8.90 (1H, d, J = 7.5Hz), 10.00 (1H, b
s)

(3) 4-[(1-azetidinyl) carbonylmethoxy] -8- (2,6-dichlorobenzoylamino) -3-methylquinoline mp: 179.5-182.5 ° C. NMR (CDCl ₃ , δ): 2.40 ( 2H, quint, J = 7.0Hz), 2.48
(3H, s), 4.19 (2H, t, J = 7.0Hz), 4.40 (2H, t, J = 7.0H
z), 4.58 (2H, s), 7.30-7.43 (3H, m), 7.61 (1H, t, J
= 7.5Hz), 7.81 (1H, d, J = 7.5Hz), 8.58 (1H, s), 8.90
(1H, d, J = 7.5Hz), 10.01 (1H, s)

(4) 8- (2,6-dichlorobenzoylamino) -3-methyl-4-[(N-methyl-N-benzylcarbamoyl) methoxy] quinoline mp: 160-161.5 ° C. NMR (CDCl ₃ , δ) ): 2.41 (3Hx2 / 5, s), 2.50 (3Hx3 / 5,
s), 2.95 (3Hx3 / 5, s), 3.08 (3Hx2 / 5, s), 4.56 (2Hx2 /
5, s), 4.68 (2Hx3 / 5, s), 4.80 (2Hx2 / 5, s), 4.82 (2H
x3 / 5, s), 7.15-7.43 (8H, m), 7.53-7.64 (1H, m), 7.8
3 (1Hx2 / 5, d, J = 7.5Hz), 7.88 (1Hx3 / 5, d, J = 7.5Hz),
8.56 (1Hx2 / 5, s), 8.59 (1Hx3 / 5, s), 8.86-8.93 (1H,
m), 10.01 (1H, s)

(5) 8- (2,6-dichlorobenzoylamino) -3-methyl-4-[(N-methyl-N-phenylcarbamoyl) methoxy] quinoline mp: 220.5-222 ° C. NMR (CDCl ₃ , δ) ): 2.34 (3H, s), 3.35 (3H, s), 4.47
(2H, s), 7.19 (2H, d, J = 7.5Hz), 7.28-7.46 (6H, m),
7.57 (1H, t, J = 7.5Hz), 7.79 (1H, d, J = 7.5Hz), 8.51
(1H, s), 8.89 (1H, d, J = 7.5Hz), 10.10 (1H, bs)

(6) 8- (2,6-dichlorobenzoylamino) -3-methyl-4-[(4-methylpiperazino) carbonylmethoxy] quinoline mp: 160-162 ° C. NMR (CDCl ₃ , δ): 2.43 ( 3H, s), 2.47 (3H, s), 2.53
-2.70 (4H, m), 3.60-3.71 (2H, m), 3.78-3.91 (2H,
m), 4.76 (2H, s), 7.30-7.43 (3H, m), 7.60 (1H, t, J
= 7.5Hz), 7.81 (1H, d, J = 7.5Hz), 8.59 (1H, s), 8.90
(1H, d, J = 7.5Hz), 9.98 (1H, s)

(7) 8- (2,4-dichlorobenzoylamino) -3-methyl-4- (n-propylcarbamoylmethoxy) quinoline mp: 183-186 ° C. NMR (CDCl ₃ , δ): 1.04 (3H, t, J = 8Hz), 1.70 (2H, s
ixtet, J = 8Hz), 2.44 (3H, s), 3.44 (2H, q, J = 8Hz),
4.52 (2H, s), 6.93-7.02 (1H, br), 7.33 (1H, dd, J =
8, 8Hz), 7.40 (2H, d, J = 8Hz), 7.62 (1H, d, J = 8Hz),
7.68 (1H, d, J = 8Hz), 8.61 (1H, s), 8.93 (1H, d, J = 7
Hz), 10.00 (1H, s)

(8) 4- (benzylcarbamoylmethoxy) -8- (2,6-dichlorobenzoylamino)-
3-methylquinoline mp: 212-214 ° C NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 4.40 (2H, d, J =
5.0Hz), 4.64 (2H, s), 7.26-7.37 (5H, m), 7.48-7.65
(4H, m), 7.95 (1H, d, J = 8.0Hz), 8.66 (1H, d, J = 8.0H
z), 8.75 (1H, s), 8.95 (1H, t, J = 5.0Hz), 10.75 (1H,
s)

(9) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (2-pyridylmethylcarbamoylmethoxy) quinoline mp: 186-189 ° C. NMR (CDCl ₃ , δ): 2.48 (3H , s), 4.63 (2H, s), 4.80
(2H, d, J = 5Hz), 7.28-7.47 (5H, m), 7.59 (1H, t, J =
9Hz), 7.77-7.86 (2H, m), 8.28-8.37 (1H, m), 8.60 (2H
H, s), 8.92 (1H, d, J = 8Hz), 10.00 (1H, s)

(10) 8- (2,6-dichlorobenzoylamino) -4-[(N-methoxy-N-methylcarbamoyl) methoxy] -3-methylquinoline mp: 164-165 ° C. NMR (CDCl ₃ , δ) ): 2.49 (3H, s), 3.28 (3H, s), 3.69
(3H, s), 4.88 (2H, s), 7.29-7.43 (3H, m), 7.61 (1
H, t, J = 7.5Hz), 7.93 (1H, d, J = 7.5Hz), 8.59 (1H,
s), 8.90 (1H, d, J = 7.5Hz), 10.02 (1H, bs)

(11) 8- (2,6-dichlorobenzoylamino) -4- (2-methoxyethylcarbamoylmethoxy) -3-methylquinoline mp: 124-126 ° C. NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 3.29 (3H, s), 3.
37-3.47 (4H, m), 4.57 (2H, s), 7.48-7.67 (4H, m),
7.48-7.67 (4H, m), 7.93 (1H, d, J = 8.0Hz), 8.38 (1H,
t, J = 7.0Hz), 8.66 (1H, d, J = 8.0Hz), 8.74 (1H, s),
10.71 (1H, s)

(12) 8- (2,6-dichlorobenzoylamino) -3-methyl-4- (piperidinocarbonylmethoxy) quinoline mp: 153-155 ° C. NMR (DMSO-d ₆ , δ): 1.42- 1.65 (6H, m), 2.45 (3H,
s), 3.30-3.52 (4H, m), 4.92 (2H, s), 7.46-7.67 (4H,
m), 7.97 (1H, d, J = 8Hz), 8.64 (1H, d, J = 8Hz), 8.71
(1H, s), 10.69 (1H, s)

(13) 8- (2,6-dichlorobenzoylamino) -4-methoxycarbamoylmethoxy-3
- methylquinoline _{NMR (DMSO-d 6, δ} ): 2.43 (3H, s), 3.69 (3H, s), 4.
60 (1H, dd, J = 17, 7Hz), 4.70 (1H, dd, J = 17, 7Hz),
5.16 (1H, dd, J = 7, 7Hz), 7.48-7.62 (3H, m), 7.65-7.
73 (2H, m), 8.68 (1H, m), 8.94 (1H, s), 10.98 (1H,
s)

Example 97 4-Carboxymethoxy-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (200 mg) and 1,1'-carbonyldiimidazole (120 mg) in dimethylformamide (4 ml) To the mixture was added methanesulfonamide (70.4 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (113 mg).
At room temperature under a nitrogen atmosphere, and the mixture
Stir for 16 hours at room temperature then for 16 hours. 1 reaction mixture
Acidified with N hydrochloric acid and extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 15, v / v
Purification in v) gave 8- (2,6-dichlorobenzoylamino) -4-[(methanesulfonylamino) carbonylmethoxy] -3-methylquinoline (41.4 mg) as an off-white solid. mp: 254.5-257 ℃ NMR (CDCl ₃ -CD ₃ OD, δ): 2.43 (3H, s), 3.15 (3H,
s), 4.56 (2H, s), 7.31-7.46 (3H, m), 7.60 (1H, t, J
= 7.5Hz), 7.88 (1H, d, J = 7.5Hz), 8.57 (1H, s), 8.87
(1H, d, J = 7.5Hz)

Example 98 8- (2,6-dichlorobenzoylamino) -1,4-
To a solution of dihydro-4-oxoquinoline (200 mg) in N-methylpyrrolidone (2 ml) was added N, N-dimethylcarbamoyl chloride (142 mg) in pyridine (1 m).
The solution in l) was added and the mixture was stirred at 60 ° C. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was treated with hot ethanol and the mixture was cooled to room temperature. The precipitate was collected by filtration to give 8- (2,6-dichlorobenzoylamino) -4- (N, N-dimethylcarbamoyloxy) quinoline (185 mg) as an off-white powder. mp: 179-180 ° C NMR (DMSO-d ₆ , δ): 3.00 (3H, s), 3.22 (3H, s), 7.
50-7.60 (4H, m), 7.70 (1H, dd, J = 8.0, 8.0Hz), 7.82
(1H, d, J = 8.0Hz), 8.76 (1H, d, J = 8.0Hz), 8.88 (1H,
d, J = 5.0Hz), 10.80 (1H, s)

Example 99 8- (2,6-dichlorobenzoylamino) -4-
(N, N-dimethylcarbamoyloxy) -3-methylquinoline was obtained in the same manner as in Example 98. mp: 215-216 ° C NMR (DMSO-d ₆ , δ): 2.33 (3H, s), 2.98 (3H, s), 3.
25 (3H, s), 7.48-7.59 (3H, m), 7.67 (2H, m), 8.67
(1H, m), 8.82 (1H, s), 10.80 (1H, s)

Example 100 The following compounds were obtained in the same manner as in Example 20. (1) 3-methyl-4- (1-methylimidazole-
2-ylthio) -8- (2-trifluoromethylbenzoylamino) quinoline mp: 143-146 ° C NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 3.57 (3H, s), 6.
92 (1H, s), 7.29 (1H, s), 7.68 (1H, t, J = 9Hz), 7.72
-7.87 (3H, m), 7.89 (1H, d, J = 9Hz), 8.21 (1H, d, J =
9Hz), 8.62 (1H, d, J = 9Hz), 8.80 (1H, s)

(2) 3-methyl-4- (1-methyltetrazol-5-ylthio) -8- (2-trifluoromethylbenzoylamino) quinoline mp: 166-169 ° C. NMR (DMSO-d ₆ , δ) : 2.62 (3H, s), 4.12 (3H, s), 7.
72 (1H, t, J = 9Hz), 7.73-7.81 (1H, m), 7.83-7.92 (3
H, m), 8.07 (1H, d, J = 9Hz), 8.67 (1H, d, J = 9Hz), 8.
96 (1H, s)

(3) 4- (1H-benzimidazol-2-ylthio) -3-methyl-8- (2-trifluoromethylbenzoylamino) quinoline mp: 208-211 ° C. NMR (DMSO-d ₆ , δ) : 2.20 (3H, s), 6.86 (1H, d, J =
7.0Hz), 7.05 (1H, d, J = 7.0Hz), 7.27 (1H, dd, J = 7.0,
7.0Hz), 7.35 (1H, dd, J = 7.0, 7.0Hz), 7.62 (1H, dd,
J = 8.0, 8.0Hz), 7.75-7.80 (1H, m), 7.86-7.96 (5H,
m), 8.56 (1H, s), 8.67 (1H, d, J = 8.0Hz), 9.07 (1H,
s), 10.55 (1H, s)

(4) 4- (imidazo [4,5-b] pyridin-2-ylthio) -3-methyl-8- (2-trifluoromethylbenzoyl) quinoline NMR (CDCl ₃ , δ): 2.60 (3H , s), 7.49-7.86 (7H, m),
7.95 (1H, d, J = 9Hz), 8.06 (1H, d, J = 9Hz), 8.80 (1
(H, d, J = 9Hz)

Example 101 (1) To a solution of ethyl cyanoacetate (464 mg) in N-methylpyrrolidone (3 ml) was added potassium tert-butoxide (442 mg) at 0 ° C., and the mixture was stirred at room temperature. To the mixture was added 4-chloro-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (150 m
g) was added and the mixture was stirred at 100 ° C. overnight. The mixture was diluted with ethyl acetate, the solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. Flash chromatography of the residue (chloroform)
And crystallized from ethanol to give 4- [cyano (ethoxycarbonyl) methyl] -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (150 m
g) was obtained as white crystals. mp: 196-199 ° C NMR (DMSO-d ₆ , δ): 1.15 (3H, t, J = 6.0Hz), 2.57 (3
H, s), 4.17-4.26 (2H, m), 6.57 (1H, s), 7.49-7.60
(3H, m), 7.74-7.88 (2H, m), 8.72 (1H, s), 8.87 (1H,
s), 10.88 (1H, s)

(2) 4- [Cyano (ethoxycarbonyl) methyl] -8- (2,6-dichlorobenzoylamino) -3-methylquinoline (360 mg), lithium chloride (69 mg) and water (14.7 mg) The mixture in dimethylsulfoxide (4 ml) was stirred at 130 ° C. Water was added to the reaction mixture, and the resulting precipitate was collected by filtration to obtain 4-cyanomethyl-8- (2,6-dichlorobenzoylamino) -3-methylquinoline (285 mg) as an off-white powder. mp: 249-253 ° C NMR (DMSO-d ₆ , δ): 2.56 (3H, s), 4.54 (2H, s), 7.
48-7.59 (3H, m), 7.77 (1H, dd, J = 8.0, 8.0Hz), 8.04
(1H, d, J = 8.0Hz), 8.70 (1H, d, J = 8.0Hz), 8.81 (1H,
s), 10.82 (1H, s)

(3) 4-cyanomethyl-8- (2,6
-Dichlorobenzoylamino) -3-methylquinoline (100 mg) in dioxane (2 ml)
Concentrated hydrochloric acid (2 ml) was added and the mixture was refluxed overnight. The mixture is concentrated in vacuo, the residue is treated with hot ethanol,
The mixture was cooled to room temperature. The precipitate is collected by filtration and
(2,6-Dichlorobenzoylamino) -3,4-dimethylquinoline (90 mg) was obtained as yellow crystals. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 2.63 (3H, s), 7.
48-7.68 (4H, m), 7.94 (1H, d, J = 8.0Hz), 8.65 (1H,
d, J = 8.0Hz), 8.68 (1H, s), 10.70 (1H, s)

(4) 4-cyanomethyl-8- (2,6
-Dichlorobenzoylamino) -3-methylquinoline (1.5 g) in ethanol (20 ml)
A 1N aqueous sodium hydroxide solution (16 ml) was added and the mixture was refluxed overnight. The mixture was concentrated in vacuo and the residue was neutralized with 1N hydrochloric acid. The resulting precipitate was collected by filtration. The residue was treated with hot ethanol and the mixture was cooled to room temperature.
The precipitate was collected by filtration and 4-carbamoylmethyl-8-
(2,6-Dichlorobenzoylamino) -3-methylquinoline (1.55 g) was obtained as an off-white powder. mp:> 300 ° C NMR (DMSO-d ₆ , δ): 2.48 (3H, s), 4.02 (2H, s), 7.
48-7.67 (4H, m), 7.90 (1H, d, J = 8.0Hz), 8.64 (1H,
d, J = 8.0Hz), 8.71 (1H, s)

Example 102 8- (1-tert-butoxycarbonylindoline-4-
A solution of ylcarbonylamino) -3-methyl-4- (3-methyl-2-oxoimidazolidin-1-yl) quinoline (110 mg) in trifluoroacetic acid was added at room temperature in 1 part.
Stirred for minutes. The mixture is concentrated in vacuo to give 8- (indoline-4-ylcarbonylamino) -3-methyl-4
-(3-Methyl-2-oxoimidazolidin-1-yl) quinoline (49 mg) was obtained. mp: 220-222 ° C NMR (CDCl ₃ , δ): 2.43 (3H, s), 2.98 (3H, s), 3.50
(2H, t, J = 8Hz), 3.59-3.72 (5H, m), 3.83-3.91 (1H,
m), 6.79 (1H, d, J = 8Hz), 7.18 (1H, t, J = 8Hz), 7.23-
7.29 (1H, m), 7.49-7.61 (2H, m), 8.73 (1H, s), 8.83
-8.88 (1H, m)

Example 103 (1) 3,4-Dichloro-8-[(2,6-dichlorophenyl) carbamoyl] quinoline was prepared from 3,4-dichloroquinoline-8-carboxylic acid and 2,6-dichloroaniline. Obtained in the same manner as in Example 67- (3). mp: 198-199 ° C NMR (DMSO-d ₆ , δ): 7.41 (1H, t, J = 7.5Hz), 7.63 (2
H, d, J = 7.5Hz), 8.02 (1H, t, J = 7.5Hz), 8.53 (1H, d,
J = 7.5Hz), 8.67 (1H, t, J = 7.5Hz), 9.21 (1H, s)

(2) 3-Chloro-8-[(2,6-dichlorophenyl) carbamoyl] -4- (2-methylaminoethylamino) quinoline was obtained in the same manner as in Production Example 1- (2). NMR (DMSO-d ₆ , δ): 2.30 (3H, s), 2.80 (2H, t, J =
6.0Hz), 3.85 (2H, t, J = 6.0Hz), 7.39 (1H, t, J = 7.5H
z), 7.61 (2H, d, J = 7.5Hz), 7.69 (1H, t, J = 7.5Hz),
8.58 (1H, d, J = 7.5Hz), 8.60 (1H, d, J = 7.5Hz), 8.64
(1H, s)

(3) 3-chloro-8-[(2,6-dichlorophenyl) carbamoyl] -4- (3-methyl-
2-Oxoimidazolidin-1-yl) quinoline was obtained in the same manner as in Example 1- (7). NMR (DMSO-d ₆ , δ): 2.84 (3H, s), 3.62-3.95 (4H,
m), 7.41 (1H, t, J = 7.5Hz), 7.63 (2H, d, J = 7.5Hz),
7.92 (1H, t, J = 7.5Hz), 8.30 (1H, d, J = 7.5Hz), 8.63
(1H, d, J = 7.5Hz), 9.22 (1H, s)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/47 AED A61K 31/47 AED C07D 215/40 C07D 215/40 401/12 213 401/12 213 401/14 401/14 409/12 215 409/12 215 413/04 215 413/04 215 (72) Inventor Tatsuya Zenko 6-3-3 -A101, Keyakidai, Moriya-cho, Kitasoma-gun, Ibaraki-ken (72) Noriko Yoshida 2-Matsushiro, Tsukuba-shi 23-4-408

Claims (4)

[Claims] (1) Formula (1) [Wherein, R ¹ is a heterocyclic group or an aryl group, each of which is halogen, nitro, lower alkyl, lower alkoxy, hydroxy, ar (lower) alkoxy, halo (lower) alkyl, acyl, aryl, heterocyclic group, lower R ² may be hydrogen or a lower alkyl group, R ³ may be hydrogen, a halogen, a cyano group, a lower alkyl group, a hydroxy (lower) alkyl group or a alkenyl or lower alkylthio group. A lower alkoxy (lower) alkyl group, wherein R ⁴ is hydrogen, an amino group, a substituted amino group, a hydrazino group, a substituted hydrazino group, a hydroxy group, a substituted hydroxy group, a mercapto group, a substituted mercapto group, Alk (lower) alkylsulfinyl group, alk (lower) alkylsulfonyl group, substituted or unsubstituted Or a heterocyclic group, or acyl and lower alkyl group which may optionally be substituted with a substituent selected from the group consisting of cyano, or R ³ and R ^4, taken together, the formula ## STR2 ## Wherein R ⁸ represents hydrogen or a lower alkyl group. R ⁵ , R ⁶ and R ⁷ are each a hydrogen, halogen or lower alkyl group, A is —CONH—, -NHCO -, - NHSO ₂ - or -NHCONH- the mean, respectively. Where R ⁴
When is hydrogen, R ³ is not hydrogen. And a pharmaceutically acceptable salt thereof. 2. The formula: [Wherein, R ¹ is a heterocyclic group or an aryl group, each of which is halogen, nitro, lower alkyl, lower alkoxy, hydroxy, ar (lower) alkoxy, halo (lower) alkyl, acyl, aryl, heterocyclic group, lower May be substituted with a substituent selected from the group consisting of alkenyl and lower alkylthio, R ² is hydrogen or lower alkyl, R ³ is hydrogen, halogen, cyano, lower alkyl, hydroxy (lower) alkyl Or lower alkoxy (lower) alkyl group, R ⁴ is hydrogen, amino group, substituted amino group, hydrazino group, substituted hydrazino group, hydroxy group, substituted hydroxy group, mercapto group, substituted mercapto group, Alk (lower) alkylsulfinyl group, alk (lower) alkylsulfonyl group, substituted or unsubstituted Or a heterocyclic group, or acyl and lower alkyl group which may optionally be substituted with a substituent selected from the group consisting of cyano, or R ³ and R ^4, taken together, the formula ## STR4 ## Wherein R ⁸ represents hydrogen or a lower alkyl group. R ⁵ , R ⁶ and R ⁷ are each a hydrogen, halogen or lower alkyl group, A is —CONH—, -NHCO -, - NHSO ₂ - or -NHCONH- the mean, respectively. Where R ⁴
When is hydrogen, R ³ is not hydrogen. Or a salt thereof, comprising: a) a compound represented by the formula: (Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above), or a reactive derivative thereof at an amino group or a salt thereof, Reacting with a compound represented by R ¹ —COOH (wherein R ¹ is as defined above) or a reactive derivative thereof or a salt thereof at the carboxy group to obtain a compound represented by the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above, or a salt thereof, or b) a compound of the formula Embedded image Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above, or a reactive derivative thereof or a salt thereof at the carboxy group, By reacting with a compound represented by R ¹ —NH ₂ (wherein R ¹ is as defined above) or a reactive derivative thereof at an amino group or a salt thereof, a compound represented by the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above, or a salt thereof, or c) Embedded image (Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above) or a salt thereof is represented by the formula R ¹ —SO ₃ H (formula Wherein R ¹ is as defined above) or a reactive derivative thereof at a sulfo group or a salt thereof to obtain a compound represented by the formula: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above, or a salt thereof, or d) Embedded image (Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above) or a salt thereof is represented by the formula R ¹ -NCO (wherein R ¹ is as defined above), or a salt thereof, to give a compound of the formula (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined above) or a salt thereof, or e) Embedded image (Wherein X is halogen, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and A are each as defined above) or a salt thereof is represented by the formula R ⁴ _a -H (wherein, R ⁴ _a is a substituted amino group, a hydrazino group, a substituted hydrazino group or a substituted or unsubstituted, N-
And a containing heterocyclic-N-yl group. ) Or a salt thereof to give a compound of the formula ^{(Wherein, R 1, R 2, R} 3, R 5, R 6, R 7, R 4 a and A
Is as defined above. Or a salt thereof, or f) a compound of the formula: (Wherein Y is -O- or (Wherein, R ⁹ is hydrogen, lower alkyl group, lower alkoxy (lower) alkyl group, acyl (lower) alkyl group, lower alkenyl group, aryl group, or al (lower) optionally substituted with halogen. Q represents a lower alkylene group, and R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ and A each represent the same as defined above. ) Or a salt thereof is subjected to an introduction reaction of a carbonyl group or a thiocarbonyl group to give a compound of the formula (Wherein, Z represents O or S, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , A, Q and Y each represent the same as defined above). Or obtaining the salt thereof. 3. A pharmaceutical comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 4. An agent for preventing and / or treating a bone disease caused by abnormal bone metabolism, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.