JPH0948780A - New naphthyridine derivatives - Google Patents

Abstract

(57) [Summary] [Object] To provide a compound having an acyl CoA: cholesterol acyltransferase inhibitory activity. [Structure] Formula [Chemical Formula 1] [In the formula, ring A represents a pyridine ring which may have a substituent, R ² represents a hydrogen atom, an alkyl group, a substituted alkyl group or the like, Z is a bond, —NH—, and a carbon atom number 1 Or 2 represents an alkylene group or -CH = CH-, Y represents an alkyl group, a substituted alkyl group, an aromatic group or a substituted aromatic group, and B represents an alkyl group, a substituted alkyl group, an aromatic group, or a substituted group. Represents an aromatic group and the like. A naphthyridine derivative or an acid addition salt thereof.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a naphthyridine derivative or an acid addition salt thereof having an acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory activity and useful as a therapeutic drug for hyperlipidemia and arteriosclerosis. Related to uses.

[0002]

2. Description of the Related Art Cerebrovascular disorders, such as stroke, and myocardial infarction, which are the leading causes of death in developed countries, all develop arteriosclerosis as a basic disease. From the results of epidemiological studies, it was pointed out that hypercholesterolemia is one of the risk factors for arteriosclerosis, and currently, antihyperlipidemic drugs that lower blood cholesterol are mainly used for the prevention and treatment of the disease. Is used, but nothing is definitive in terms of effectiveness. In recent years, it has been observed that macrophage-derived cells accumulate cholesterol esters as lipid droplets in cells in the lesions of arteriosclerosis and foam, indicating that they are deeply involved in the development of lesions (Arteriosclerosis
10,164-177, 1990). In addition, it has been reported that the ACAT activity of the blood vessel wall at the site of atherosclerotic lesion is high, and cholesterol ester is accumulated on the blood vessel wall (Bi).
ochem. Biophys. Acta 617, 458-471, 1980). Therefore, an inhibitor of ACAT, which is a cholesterol esterifying enzyme, can suppress the formation or progression of arteriosclerotic lesions by suppressing foaming of macrophages and suppressing accumulation of cholesterol esters at lesion sites. .

On the other hand, cholesterol in food is absorbed in intestinal epithelial cells in a free form, then esterified by ACAT and released into the blood in the form of chylomicron. Therefore, inhibitors of ACAT suppress the intestinal absorption of dietary cholesterol, further inhibit the reabsorption of cholesterol released into the intestinal tract, and lower blood cholesterol (J. Lipid. Research, 34, 279-). 294, 199
3). Published patent publication No. 181465, published patent publication No. 223254, published patent publication No. 223254, and published patent publication No. 501025, published in 1994
No. 32666 discloses certain quinoline derivatives having ACAT inhibitory activity, and Japanese Patent Publication No. 32666, 1993 discloses certain thienopyridine derivatives having ACAT inhibitory activity. Differs from its chemical structure.

[0004]

The object of the present invention is to provide an AC
It is intended to provide a naphthyridine derivative having AT inhibitory activity and useful as a therapeutic drug for hyperlipidemia and a therapeutic drug for arteriosclerosis.

[0005]

Means for Solving the Problems The present inventors have intensively studied to solve the above-mentioned problems, and the compound represented by the following general formula (1) and an acid addition salt thereof have a strong ACAT inhibitory action. And completed the present invention. The compound of the present invention is a novel compound having a different structure from the known compounds disclosed above.

Embedded image [In the formula, ring A represents a pyridine ring which may have a substituent. X is the formula

Embedded image (Wherein R ² represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group,
Represents a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group. ) Or expression

Embedded image [In the formula, W represents a hydrogen atom or a formula-OR ¹ (R ¹ represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, or a substituted alkynyl group.)
Represents ] Represents the group shown by these. Z is a bond, -NH
-, An alkylene group having 1 or 2 carbon atoms or -C
Represents H = CH-. Y is an alkyl group, a substituted alkyl group,
Represents a cycloalkyl group, a substituted cycloalkyl group, an aromatic group or a substituted aromatic group. B represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group. A naphthyridine derivative or an acid addition salt thereof.

The various groups in the present invention are described in detail below. Ring A represents a pyridine ring which may have a substituent, and the nitrogen atom may be located at any position except the fused position of the condensed ring (not a bridgehead atom of the condensed ring), And (b) and (c) are preferred.

[Chemical 12]

Embedded image

Embedded image Further, as the substituent of the pyridine ring, for example, a lower alkyl group, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, an amino group, a mono-lower alkylamino group,
Di-lower alkylamino group, hydroxyl group, lower alkoxy group,
Examples thereof include a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, and the like. In the present invention, lower means that the alkyl part of the group is a lower alkyl group, and such lower alkyl group is a carbon atom such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl and hexyl. Mention may be made of lower alkyl groups having a number of 1 to 6. Examples of the halogen atom include fluorine, chlorine, bromine and iodine. The pyridine ring may have one or a plurality of the same or different substituents.

The alkyl group in R ¹ , R ² and Y, or the alkyl group moiety of the substituted alkyl group includes, for example, a linear or branched alkyl group having 1 to 8 carbon atoms. For example, methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, 3-pentyl, 3-
Hexyl, 4-heptyl, 4-octyl and the like can be mentioned. Examples of the alkenyl group in R ¹ and R ² or the alkenyl group portion of the substituted alkenyl group include linear or branched alkenyl groups having 2 to 8 carbon atoms, specifically, vinyl, allyl, 2-propynyl, 2-butenyl, 3-methyl-2-butenyl, 3-hexenyl, 3-ethyl-2-pentenyl, 4-ethyl-
3-hexenyl and the like can be mentioned. Examples of the alkynyl group in R ¹ and R ² or the alkynyl group moiety of the substituted alkynyl group include, for example, a linear or branched C 3
To 8 alkynyl groups, specifically 2
-Propynyl, 3-butynyl, 4-pentynyl, 3-hexynyl, 5-methyl-2-hexynyl, 6-methyl-
4-heptinyl etc. are mentioned.

Examples of the alkyl group portion of the alkyl group or the substituted alkyl group in B include a linear or branched alkyl group having 1 to 20 carbon atoms, and specific examples include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1
-Dimethylethyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, undecyl, dodecyl, hexadecyl, 2,2-dimethyldodecyl, 2-tetradecyl, n-octadecyl and the like. The alkenyl group part of the alkenyl group or the substituted alkenyl group in B includes, for example, a straight chain or branched alkenyl group having 3 to 20 carbon atoms having 1 to 2 double bonds, and specifically, For example, 2-propenyl, 2-butenyl,
3-methyl-2-butenyl, 3-pentenyl, 2-octenyl, 5-nonenyl, 4-undecenyl, 5-heptadecenyl, 3-octadecenyl, 9-octadecenyl,
2,2-dimethyl-9-octadecenyl, 9,12-octadecadienyl and the like can be mentioned.

Examples of the cycloalkyl group portion of the cycloalkyl group or the substituted cycloalkyl group include a cycloalkyl group having 3 to 7 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclo. Examples include heptyl and the like.
Examples of the aromatic group include an aryl group and a heteroaryl group. Examples of the aryl group include aryl groups having 10 or less carbon atoms such as a phenyl group and a naphthyl group.

Examples of the heteroaryl group include a 5- to 6-membered monocyclic group containing 1 to 2 nitrogen atoms, and 1 to 1 nitrogen atom.
5 containing 2 and 1 oxygen atom or 1 sulfur atom
6-membered monocyclic group, one oxygen atom or one sulfur atom
A 5-membered monocyclic group containing 1 to 4 nitrogen atoms, a bicyclic group containing 1 to 4 nitrogen atoms, and a condensed 6-membered ring with a 5- or 6-membered ring, and the like. Pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 3-
Oxadiazolyl, 1-imidazolyl, 2-imidazolyl, 2-thiazolyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl, 3-furyl, 3-pyrrolyl, 8-quinolyl, 2-quinazolinyl,
8-Prinyl and the like can be mentioned. The substituent of the substituted aromatic group may be one or the same or different and may be plural, for example, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, a methylenedioxy group, a lower alkyl group, a lower alkyl group, Alkoxy group, lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group,
A carboxyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkanoylamino group, a lower alkylsulfonamide group or a formula -D ¹ -E-F {D ¹
Is a bond, an oxygen atom, a sulfur atom or the formula —NR ³ —
(R ³ represents a hydrogen atom or a lower alkyl group), and E is a carbon atom which may contain an unsaturated bond.
Represents a divalent hydrocarbon group or phenylene group of 6
F is a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a halogen atom,
Cyano group, benzyloxy group, lower alkoxy group, lower alkanoyloxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, lower alkylsulfonamide group, phthalimido group, heteroaryl group, formula- NR ⁴ R
⁵ (R ⁴ and R ⁵ independently of each other represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ are bonded to each other, and together with the nitrogen atom to which they are bonded, a —NR ⁸ - (R ⁸ is a hydrogen atom, a lower alkyl group, a phenyl group or a benzyl group.) 1 a,
Alternatively, it represents a saturated 5- to 7-membered cyclic amino group which may contain one oxygen atom. ), Or the formula -C (= O) N
R ⁴ R ⁵ (R ⁴ and R ⁵ have the above meanings). And the group represented by｝. Examples of the divalent hydrocarbon group having 1 to 6 carbon atoms which may contain an unsaturated bond include alkylene chains such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene, and alkenylenes such as propenylene. Chains, alkynylene chains such as propynylene. Examples of the heteroaryl group for F include a 5- to 6-membered ring group containing 1 to 3 nitrogen atoms, and a 5-membered ring group containing 1 oxygen atom or 1 sulfur atom. Is, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-pyrrolyl, 1-imidazolyl, 1- (1,2,4-triazolyl), 2-thienyl, 3-thienyl, 2-furyl,
3-furyl etc. are mentioned. One of these heteroaryl groups may be substituted with a lower alkyl group, or a plurality of the same or different substituents may be substituted. Examples of the cyclic amino group formed by NR ⁴ R ⁵ include 4-lower alkyl-1-piperazinyl, 4-phenyl-1-piperazinyl, and 4-benzyl-1-piperazinyl.

Embedded image (R ⁸ has the same meaning as described above), 1-pyrrolidinyl, 1-piperidinyl, 1-homopiperidinyl, 4-morpholinyl and the like.

A substituted alkyl group, a substituted cycloalkyl group,
The substituted alkenyl group and the substituted alkynyl group may have one substituent or the same or different substituents, and examples of the substituent include a halogen atom, a cyano group, a benzyloxy group, a trifluoromethyl group, a hydroxyl group and a lower alkoxy group. , Lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, lower alkoxycarbonylamino group, carboxyl group, lower alkoxycarbonyl group , Lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, lower alkylsulfonamide group, phthalimido group, heteroaryl group, saturated heterocyclic group or formula -D ²
-E-F {D ² represents an oxygen atom, a sulfur atom or the formula -N
R ³ — (R ³ represents the above meaning) and E and F represent the above meaning}. As the heteroaryl group, the same heteroaryl groups as those described above for F can be mentioned. Examples of the saturated heterocyclic group include 1
-Piperidinyl, 1-pyrrolidinyl, etc., a 5- to 8-membered ring group having 1 nitrogen atom, a 6- to 8-membered ring group having 2 nitrogen atoms, 6 to 8 having 1 nitrogen atom and 1 oxygen atom
Examples include 8-membered ring groups. Examples of the substituted alkyl group include a cycloalkyl group or an alkyl group having 1 to 6 carbon atoms substituted with a substituted cycloalkyl, or an aralkyl group or a substituted aralkyl group. Examples of the aralkyl group and the substituted aralkyl group include the above-mentioned aryl group and an alkyl group having 1 to 6 carbon atoms which is substituted with the substituted aryl group, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl and 2-naphthylmethyl. Is mentioned.

The preferred group for Y is, for example, a phenyl group or pyridyl group which may have a substituent. One or more substituents may be the same or different, and preferred substituents include, for example, fluorine, a halogen atom such as chlorine, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, a methylenedioxy group, Lower alkyl group, lower alkoxy group, lower alkanoyloxy group, amino group, mono-lower alkylamino group,
Di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, carboxyl group, lower alkoxycarbonyl group,
Lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group,
Lower alkyl sulfonamide group or formula -D ¹ -EF
(D ¹ , E and F have the above-mentioned meanings). The preferred group for E includes an alkylene chain having 1 to 6 carbon atoms, and the preferred group for F is a hydroxyl group, a halogen atom, a cyano group,
Lower alkoxy group, lower alkanoyloxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, lower alkylsulfonamide group, heteroaryl group, formula-NR
⁴ R ⁵ (R ⁴ and R ⁵ have the above meanings). Specific examples of the heteroaryl group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-imidazolyl, 1- (1,2,4-triazolyl) and the like. Examples of the formula —NR ⁴ R ⁵ (R ⁴ and R ⁵ have the above meanings) include dimethylamino, diethylamino, piperidinyl and the like.

The preferred group for B is, for example, a phenyl group or a heteroaryl group which may have a substituent. More preferred groups include, for example, a phenyl or pyridyl group in which 1 to 3 halogen atoms such as fluorine and chlorine, a lower alkyl group, a lower alkoxy group or a lower alkylthio group are substituted. Specifically, for example, 2,6-diisopropylphenyl, 2,
4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4-difluorophenyl, 2,4,6
-Trifluorophenyl, 2,6-dimethylthio-3-
Pyridyl, 2,6-dimethylthio-4-methyl-3-pyridyl and the like can be mentioned.

Examples of the preferable group of X include the following groups.

Embedded image Examples of preferred groups for R ² include a hydrogen atom, an alkyl group, and a substituted alkyl group. The substituent of the substituted alkyl group may be one or the same or different and may be plural, preferably a halogen atom such as fluorine and chlorine, a cyano group, a benzyloxy group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group. , Carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, carboxyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, aryl group, lower alkanoylamino group, lower alkylsulfone Examples thereof include an amide group, a phthalimido group, a heteroaryl group, and a saturated heterocyclic group. More preferable substituents include, for example, fluorine atom, chlorine atom, cyano group, hydroxyl group, carbamoyl group, 2-pyridyl group, 3-pyridyl,
4-pyridyl group etc. are mentioned. Examples of the acid forming an acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid, or acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, maleic acid, etc. Organic acids such as methanesulfonic acid may be mentioned.

The compound of the present invention may have asymmetric carbon atoms and stereoisomers. In such a case, the compound of the present invention includes a mixture of each isomer and an isolated one.
The compound of the present invention and an acid addition salt thereof are anhydrides thereof,
Alternatively, it may be a solvate such as a hydrate. The compound represented by the general formula (1) or an acid addition salt thereof can be administered parenterally or orally when it is used as the drug. That is, solutions, emulsions, suspensions and the like in the form of liquid preparations can be administered as injections, and buffers, solubilizers, isotonic agents and the like can be added if necessary. It can also be administered rectally in the form of suppositories. Also, commonly used dosage forms, such as tablets,
It can be orally administered in the form of capsules, syrups, suspensions and the like. Such dosage forms are conventional carriers,
By mixing an active ingredient with an excipient, a binder, a stabilizer and the like, it can be produced according to a general method. The dose and frequency of administration of the compound of the present invention will vary depending on the symptoms, age, body weight, dosage form, etc.
The amount is about 1 to 500 mg per person, which can be administered once or in 2 to 4 divided doses.

The naphthyridine derivative which is the active ingredient of the present invention can be synthesized by the following method. General formula (1)
Wherein Z is -NH-, the compound of the present invention can be synthesized by the following method.

Embedded image (In the formula, rings A, X, Y and B have the above-mentioned meanings. Ring A
¹ represents a group similar to that of ring A, but when it has a reactive group such as an amino group, an alkylamino group, a hydroxyl group, etc., these are assumed to be protected. X ¹ represents the same group as X, but if it has a reactive group such as an amino group, an alkylamino group, a hydroxyl group, or a carboxyl group as a substituent, these are protected. Y ¹ is Y
Represents a group similar to that described above. However, when it has a reactive group such as an amino group, an alkylamino group, a hydroxyl group, or a carboxyl group, it is assumed that these groups are protected. B
¹ represents a group similar to B, but if it has a reactive group such as an amino group, an alkylamino group, a hydroxyl group, or a carboxyl group as a substituent, these are protected. ) The isocyanate derivative represented by the general formula (2) and the amine derivative represented by the general formula (3) or an acid addition salt thereof,
The urea derivative represented by the general formula (4) is usually reacted in a solvent at a temperature from 0 ° C. to the boiling point of the solvent, preferably at room temperature to 120 ° C., and if necessary, deprotected. It can be suitably obtained. The solvent may be any solvent as long as it does not hinder the reaction, for example, ethyl ether, isopropyl ether, tetrahydrofuran, ether solvents such as dioxane, benzene, aromatic hydrocarbon solvents such as toluene, methyl acetate, ester solvents such as ethyl acetate,
N, N-dimethylformamide, dimethylsulfoxide and the like are used.

When the amine derivative represented by the general formula (3) is used in the form of an acid addition salt, the reaction can be favorably proceeded by desalting if necessary. in this case,
As the desalting agent, tertiary amines such as triethylamine or aromatic amines such as pyridine are suitable. On the other hand, the urea derivative (4) can be obtained in the same manner as described above by using the amine derivative represented by the general formula (5) or an acid addition salt thereof and the isocyanate derivative represented by the general formula (6). As a protecting group for an amino group, an alkylamino group, a hydroxyl group, a carboxyl group and the like, a general protecting group which is usually used in the field of synthetic organic chemistry (for example, a protecting group for a hydroxyl group is a benzyl group, an acetyl group, etc .; Examples of the protecting group include a benzyl group and the like, and these can be introduced or removed by a usual method (for example,
PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2nd ed.,
JOHN WILEY & SONS, INC .: New York).

Embedded image (In the formula, ring A, Y, B, ring A ¹ , Y ¹ , and B ¹ have the above-mentioned meanings. R ²¹ represents the same group as R ² , but its substituent is an amino group or an alkylamino group. , And those having a reactive group such as a hydroxyl group and a carboxyl group, these are protected. G represents a leaving group.) In the urea derivative (4), a group represented by the general formula (7) is used. The obtained derivative can be converted to the urea derivative represented by the general formula (9) by reacting with the alkylating agent represented by the general formula (8) and performing deprotection if necessary.
The alkylation reaction can be carried out in a solvent at 0 ° C to 100 ° C, preferably at room temperature to 70 ° C, in the presence of a base. Examples of the solvent include ether solvents such as tetrahydrofuran and dioxane, ketone solvents such as acetone and 2-butanone, aromatic hydrocarbon solvents such as benzene and toluene, and dimethylformamide. , Sodium carbonate, triethylamine and the like can be used. As the leaving group represented by G, a halogen atom such as chlorine, bromine or iodine is usually used.

The compound of the present invention in which Z is a bond, an alkylene group having 1 or 2 carbon atoms or -CH = CH- in the general formula (1) can be synthesized by the following method.

Embedded image (In the formula, ring A, Y, B, X, ring A ¹ , Y ¹ , B ¹ , X ¹
Represents the above meaning. Z ¹ represents a bond, an alkylene group having 1 or 2 carbon atoms or —CH ＝ CH—. The amine derivative represented by the general formula (5) or an acid addition salt thereof and the carboxylic acid derivative represented by the general formula (10) in a solvent at 0 ° C to 100 ° C, preferably 0 ° C to 100 ° C using a condensing agent.
The amide derivative represented by the general formula (11) can be obtained by condensation at 60 ° C. and deprotection if necessary. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate (DE
PC), 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide hydrochloride (WSC) and the like are used. This reaction is preferably carried out by adding 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents of a base to the amine derivative represented by the general formula (5) or an acid addition salt thereof. You can also. Suitable bases are tertiary amines such as triethylamine and aromatic amines such as pyridine. As the solvent, for example, ether solvents such as tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as benzene and toluene, ester solvents such as ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide and the like are used.

Further, after the carboxylic acid derivative represented by the general formula (10) is once converted into a reactive derivative, the amine derivative represented by the general formula (5) and -10 ° C to 120 ° C in a solvent are used.
By reacting at 0 ° C., preferably at 0 ° C. to 60 ° C., the amide derivative represented by the general formula (11) can also be obtained. As the reactive derivative of (10), for example, acid chloride, acid bromide, acid anhydride, mixed acid anhydride with methyl carbonate, ethyl carbonate and the like are used, and 1 to 5 mole equivalent, preferably 1 to 3 mole equivalent The reaction can be suitably carried out by adding an equivalent amount of a base. Examples of the base include tertiary amines such as triethylamine, aromatic amines such as pyridine, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate, and the like. Examples of the solvent include halogen solvents such as chloroform and dichloromethane, ether solvents such as tetrahydrofuran and dimethoxyethane, aromatic hydrocarbon solvents such as benzene and toluene, ester solvents such as ethyl acetate, pyridine, N, N-dimethylformamide and the like. Used.

In the amide derivative represented by the general formula (11), the compound in which Z ¹ is —CH ₂ CH ₂ — is represented by the general formula (1
It can also be obtained by reducing a compound in which Z ¹ is —CH ＝ CH— in the amide derivative represented by 0). Reduction is performed using a reducing agent such as lithium aluminum hydride, sodium borohydride, or lithium borohydride in a solvent in an amount of 0.5 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, at -5 ° C to 120 ° C. Preferably, it can be performed at 0 ° C to 80 ° C. As the solvent, an alcohol solvent such as methanol and ethanol, and an ether solvent such as ethyl ether, tetrahydrofuran and dioxane are used. The present reduction reaction can also be performed by a catalytic reduction reaction. For example, it can be carried out at 0 ° C. to 100 ° C., preferably room temperature to 60 ° C. in a hydrogen atmosphere at atmospheric pressure to 5 atm using palladium carbon, platinum oxide, Raney nickel, etc. in a solvent as a catalyst. As the solvent, alcohols such as methanol and ethanol, formic acid, acetic acid and the like are used.

The substituents contained in the ring A, Y, X or B of the urea derivative represented by the general formula (4) and the amide derivative represented by the general formula (11) thus obtained are The conversion can be performed as needed. For example, a lower alkylthio group can be converted to a lower alkylsulfonyl group by oxidation, a nitro group can be reduced and converted to an amino group, and a mono- or dialkyl derivative can be obtained by alkylating an amino group. Alternatively, the amino group can be acylated. Also, a 3-chloropropoxy group can be converted to a 3- (1-imidazolyl) propoxy group. Such a substituent conversion reaction can be carried out by a general technique usually performed in the field of synthetic organic chemistry. As one of such conversions of the substituent, an alkylation reaction represented by the following formula can be carried out.

Embedded image (In the formula, rings A, B, X, Z, E, F, G, D ² and rings A ¹ , B ¹ , X ¹ have the above meanings. F ¹ represents a group similar to F, In the case where the substituent has a reactive group such as an amino group, an alkylamino group, a hydroxyl group and a carboxyl group, these are protected.) A compound represented by the general formula (12) is generally used in a solvent Expression (1
The compound represented by the general formula (14) can be obtained by reacting with the alkylating agent represented by 3) and performing deprotection if necessary. The reaction is usually carried out in a solvent at 0 ° C to 1 ° C.
The reaction can be carried out at 00 ° C, preferably at room temperature to 70 ° C, in the presence of a base. Examples of the solvent include ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene and toluene; ketone solvents such as acetone and 2-butanone; and dimethylformamide. , Sodium carbonate, triethylamine and the like can be used. When potassium carbonate or sodium carbonate is used, the yield may be improved by adding sodium iodide or potassium iodide. The leaving group represented by G is usually chlorine,
A halogen atom such as bromine or iodine is used.

The starting compound (2) or (5) for synthesizing the compound (1) of the present invention or an acid addition salt thereof can be synthesized by, for example, the method shown below or a method analogous thereto.

[Chemical 21]

Embedded image (Wherein, rings A ¹ , Y ¹ , R ²¹ and G represent the same meaning as described above.
R ⁶ represents a lower alkyl group, X ² represents —NH—CO
^{-, - NR 21 -CO -,} - N = C (OR 21) - represents a. The starting compound represented by the general formula (15) can be prepared by a method described in the literature (for example, J. Heterocyclic Chem., 26, 105-112, 19).
89) Alternatively, it can be synthesized by a method similar thereto. As the lower alkyl group represented by R ⁶ , methyl,
Those having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl and butyl are suitable.

The aminoketone derivative represented by the general formula (15) is used in a solvent at -20 ° C to 150 ° C, preferably 0 ° C to
By reacting with an acid chloride represented by the general formula (16) at 120 ° C. in the presence of a base, an amide derivative represented by the general formula (17) can be obtained. Examples of the solvent include ether solvents such as ethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as benzene and toluene, halogen solvents such as dichloromethane and chloroform, pyridine and dimethylformamide.
As the base, triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like are used. The obtained amide derivative (17) is dissolved in a solvent such as benzene, toluene, tetrahydrofuran or dimethoxyethane at 0 ° C to 200 ° C, preferably at room temperature to 170 ° C, in an amount of 0.1 to 3 molar equivalents, preferably 0.1 to 0.1 molar equivalent. The compound (18) can be obtained by ring-closure using 1 to 2 molar equivalents of a base. As the base, potassium t-butoxide, sodium methoxide, sodium ethoxide, piperidine, triethylamine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5. 4.0] -7-undecene (DB
U), 1,4-diazabicyclo [2.2.2] octane (DABCO) can be used. In addition, compound (18) is obtained by converting compound (15) and a malonic acid diester derivative represented by the general formula (19), usually without solvent, into piperidine, pyrrolidine, triethylamine, pyridine, DB
In the presence of amines such as N, DBU, DABCO, or potassium fluoride, tetrabutylammonium fluoride, etc.
It can also be obtained by heating at 0 to 200 ° C.

On the other hand, the compound (18) was added in a solvent at 0 ° C to 15 ° C.
By reacting with an alkylating agent represented by the general formula (8) in the presence of a base at 0 ° C., preferably room temperature to 100 ° C., the N-alkyl compound (21) and / or the O-alkyl compound (22 ) Can be obtained. Examples of the solvent include alcohol solvents such as methanol and ethanol; ether solvents such as tetrahydrofuran and dioxane; acetone;
A ketone solvent such as butanone, dimethylformamide, or the like can be used, and as the base, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, triethylamine. Etc. can be used. As the leaving group represented by G, a halogen atom such as chlorine, bromine or iodine is usually used. In this reaction, a mixture of compound (21) and compound (22) is usually produced, but both can be separated by recrystallization or chromatography. Further, the compound (21) can be preferentially obtained by selecting the kind of the compound (18), the kind of the solvent, the kind of the base, the reaction temperature and the like.

Compounds (18), (21) and (22)
Can be hydrolyzed according to a known method.
For example, methanol, ethanol, isopropanol,
0 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C. in a solvent such as tetrahydrofuran, dioxane, or dimethoxyethane.
Can be carried out using a hydroxide of an alkali or alkaline earth metal such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like. The carboxylic acid derivatives represented by the general formulas (20), (23) and (24) can be led to the isocyanate derivative represented by the general formula (25) according to a known method, and if necessary, the compound (25) )
Can lead to an amine derivative represented by the general formula (26). For example, carboxylic acid derivatives (20), (2
3) and (24) in a solvent, triethylamine, N-
In the presence of a base such as methylmorpholine, 0 ° C to 150 ° C,
Preferably, at room temperature to 120 ° C., 1 to 3 molar equivalents of an azide agent such as diphenylphosphoryl azide (DPPA) is used to form an acid azide form, and then the reaction mixture is used as it is without isolating the acid azide form that is usually produced. 20-200 ℃,
The compound (25) can be obtained by preferably heating to 30 to 150 ° C. Furthermore, the compound (1
Compound (26) can be obtained by hydrolyzing compound (25) in the same manner as the hydrolysis of 8), (21) and (22).

A part of the compound (5) can be synthesized by, for example, the method shown below or a method analogous thereto.

Embedded image (Wherein, rings A ¹ and Y ¹ have the same meanings as above; R ⁷ represents an alkyl group.) The alkyl group represented by R ⁷ is the number of carbon atoms such as methyl, ethyl, propyl, isopropyl, and butyl. 1-4 are suitable. From the aminoketone derivative represented by the general formula (15), the compound represented by the general formula (30) can be prepared according to the method described in the above-mentioned reaction formula, Pharmaceutical Journal, 93, 1263 (1973) or a method analogous thereto. The aminonaphthyridine derivatives represented can be obtained.

The compound of the present invention and the synthetic intermediate thereof obtained by this synthetic method can be purified by a conventional method. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic solvents such as toluene, ketones such as acetone,
It can be appropriately selected from hydrocarbons such as hexane or a mixed solvent thereof depending on the compound.

The compounds of the present invention obtained by the above production method include the following. N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- (1-Methyl-4-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl) -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4-
(2-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-Methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (4-methoxyphenyl)
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (2-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4-
(3-hydroxyphenyl) -1,2-dihydro-2-
Oxo-1,8-naphthyridin-3-yl] -N′-
(2,6-diisopropylphenyl) urea. N- [1
-Methyl-4- (4-hydroxyphenyl) -1,2-
Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea.

N- [1-methyl-4- (2-aminophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl ) Urea. N- [1-methyl-4- (3-aminophenyl) -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4-
(4-Aminophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,
6-diisopropylphenyl) urea. N- [1-methyl-4- {3- (2-hydroxyethoxy) phenyl}
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- {3- (2-acetoxyethoxy) phenyl} -1,2-dihydro-2
-Oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-Methyl-4- {3- (2-diethylaminoethoxy)
Phenyl} -1,2-dihydro-2-oxo-1,8-
Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- {3
-(3-Hydroxypropoxy) phenyl} -1,2-
Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- {3- (3-acetoxypropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
-Diisopropylphenyl) urea. N- [1-methyl-4- {3- (3-dimethylaminopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6 -Diisopropylphenyl) urea. N- [1-methyl-4- [3- {3
-(4-phenyl-1-piperazinyl) propoxy} phenyl] -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- {3-
(2-Piperidinoethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]
-N '-(2,6-diisopropylphenyl) urea.

N- (1-methyl-4-butyl-1,2-
Dihydro-2-oxo-1,8-naphthyridin-3-yl) -N '-(2,6-diisopropylphenyl) urea. N- (1-methyl-4-cyclohexyl-1,2-
Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (2-pyridyl) -1,2
-Dihydro-2-oxo-1,8-naphthyridine-3-
Yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (3-pyridyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
Urea. N- [1-methyl-4- (4-pyridyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (2-furyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (3-furyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (2-thienyl)
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (3-thienyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-carboxymethyl-1,
2-Dihydro-4- (3-methoxyphenyl) -2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea.

N- [1-tert-butoxycarbonylmethyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]
-N '-(2,6-diisopropylphenyl) urea.
N- [1- (4-pyridylmethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1- (2-pyridylmethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6- Diisopropylphenyl) urea. N- [1-ethyl-4- (3-methoxyphenyl)
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1- (2-methoxyethyl) -4
-(3-methoxyphenyl) -1,2-dihydro-2-
Oxo-1,8-naphthyridin-3-yl] -N′-
(2,6-diisopropylphenyl) urea. N- [1
-(2-Hydroxyethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea . N- [1- (2-cyanoethyl)
-4- (3-methoxyphenyl) -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
-(2,6-diisopropylphenyl) urea. N-
[1- (2-diethylaminoethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-propyl-4
-(3-methoxyphenyl) -1,2-dihydro-2-
Oxo-1,8-naphthyridin-3-yl] -N′-
(2,6-diisopropylphenyl) urea.

N- [1- (3-cyanopropyl) -4-
(3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-(3-Cyanopropyl) -4- (3-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea . N- [1- (3-cyanopropyl) -4- {3- (2-hydroxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'- (2,6-diisopropylphenyl) urea. N- [1- (3-cyanopropyl)
-4- {3- (2-diethylaminoethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1- (3-cyanopropyl)
-4- {3- (3-hydroxypropoxy) phenyl}
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1- (3-cyanopropyl) -4
-[3- {3- (1-Imidazolyl) propoxy} phenyl] -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea . N- [1- (3-hydroxypropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]
-N '-(2,6-diisopropylphenyl) urea.
N- [1- (3-benzyloxypropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
-Diisopropylphenyl) urea. N- [1- (3-
Aminopropyl) -4- (3-methoxyphenyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1- (3-dimethylaminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea. N
-[1- (3-aminocarbonylpropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
-Diisopropylphenyl) urea. N- [1- (3-
Acetylaminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea.

N- [1- (3-phthalimidopropyl)
-4- (3-methoxyphenyl) -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
-(2,6-diisopropylphenyl) urea. N-
[1- (3-dimethylaminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Diisopropylphenyl) urea. N- [1- (3-Diethylaminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6- Diisopropylphenyl) urea. N- [1- (3-Piperidinopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea. N
-[1- {3- (1-imidazolyl) propyl} -4-
(3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-Isopropyl-4- (3-methoxyphenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
Urea. N- [1-butyl-4- (2-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4-
(4-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N′-
(2,6-diisopropylphenyl) urea. N- [1
-Butyl-4- (2-hydroxyphenyl) -1,2-
Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-Butyl-4- (3-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- (4-hydroxyphenyl) -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Diisopropylphenyl) urea.

N- [1-butyl-4- (2-aminophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl ) Urea. N- [1-butyl-4- (3-aminophenyl) -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4-
(4-Aminophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,
6-diisopropylphenyl) urea. N- [1-butyl-4- {3- (2-pyridylmethoxy) phenyl}-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-Butyl-4- {3- (3-pyridylmethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-Butyl-4- {3- (4-pyridylmethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea . N- [1-butyl-4- {3- (2
-Hydroxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea. N
-[1-Butyl-4- {3- (2-acetoxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4-
{3- (2-diethylaminoethoxy) phenyl}-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- {3- (2-dimethylaminoethoxy) phenyl} -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
-(2,6-diisopropylphenyl) urea. N-
[1-butyl-4- {3- (2-piperidinoethoxy)
Phenyl} -1,2-dihydro-2-oxo-1,8-
Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- {3
-(2- (1-pyrrolidinyl) ethoxy) phenyl}-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- {3- (2-morpholinoethoxy) phenyl} -1,2-dihydro-2-
Oxo-1,8-naphthyridin-3-yl] -N′-
(2,6-diisopropylphenyl) urea.

N- [1-butyl-4- {3- (3-chloropropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-Butyl-4- {3- (3-hydroxypropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea . N- [1-butyl-4- {3-
(3-acetoxypropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- {3- (3-benzyloxypropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea. N- [1
-Butyl-4- {3- (3-phthalimidopropoxy)
Phenyl} -1,2-dihydro-2-oxo-1,8-
Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- {3
-(3-Aminopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]
-N '-(2,6-diisopropylphenyl) urea.
N- [1-Butyl-4- {3- (3-dimethylaminopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
-Diisopropylphenyl) urea. N- [1-Butyl-4- {3- (3-diethylaminopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6- Diisopropylphenyl) urea. N- [1-butyl-4- {3- (3
-Piperidinopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea. N
-[1-Butyl-4- [3- {3- (4-phenyl-1
-Piperazinyl) propoxy {phenyl] -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- [3- {3- (1,2,4
-Triazol-1-yl) propoxydiphenyl]-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- [3- {3- (1
-Imidazolyl) propoxy} phenyl] -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-Butyl-4- {3- (3-diethylaminopropyl) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2
6-diisopropylphenyl) urea. N- [1-Butyl-4- {3- (2-diethylaminoethylthio) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6 -Diisopropylphenyl) urea.

N- [1-butyl-4- (2-pyridyl)
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- (3-pyridyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-butyl-4- (4-pyridyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-pentyl-4- (3-
Methoxyphenyl) -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Diisopropylphenyl) urea. N- [1- (4-methylpentyl) -4- (3-methoxyphenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
Urea. N- [1-methyl-4- (3-benzyloxyphenyl) -1,2-dihydro-2-oxo-1,8-
Naphthyridin-3-yl] -N'-butylurea. N-
[1-methyl-4- (3-methoxyphenyl) -1,2
-Dihydro-2-oxo-1,8-naphthyridine-3-
Il] -N'-butylurea. N- [1-methyl-4-
[3- {3- (4-phenyl-1-piperazinyl) propoxy} phenyl] -1,2-dihydro-2-oxo-
1,8-Naphthyridin-3-yl] -N'-butylurea. N- [1-methyl-4- (2-chlorophenyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,4-difluorophenyl)
Urea. N- [1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,4,6-trimethylphenyl) urea . N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,4-difluorophenyl) urea. N- [1-methyl-4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,
4,6-Trimethylphenyl) urea. N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2-trifluoromethylphenyl) urea. N
-[1-methyl-4- (3-methoxyphenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-dichlorophenyl) urea. N- [1-methyl-4- (3-methoxyphenyl)
-1,2-Dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2-methoxy-4-nitrophenyl) urea.

N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2-isopropylphenyl) urea . N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2-ethylphenyl) urea. N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-
Naphthyridin-3-yl] -N '-(2-isopropyl-6-methylphenyl) urea. N- [1-methyl-4
-(3-methoxyphenyl) -1,2-dihydro-2-
Oxo-1,8-naphthyridin-3-yl] -N′-
(2-Chloro-3-pyridyl) urea. N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(3,5-dichloro-2-pyridyl) urea. N
-[1-methyl-4- (3-methoxyphenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(8-quinolyl) urea. N- [1-
Methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,7-naphthyridin-3-yl]-
N '-(2,4,6-trimethylphenyl) urea. N
-[1-Methyl-4- (2-chlorophenyl) -1,2
-Dihydro-2-oxo-1,7-naphthyridine-3-
Yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,7-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea. N- [1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,6
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-methyl-4-
(2-Chlorophenyl) -1,2-dihydro-2-oxo-1,6-naphthyridin-3-yl] -N ′-(2
4,6-Trimethylphenyl) urea. N- [1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,6-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea. N
-[1-isopropyl-4- (3-methoxyphenyl)
-1,2-Dihydro-2-oxo-1,6-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea.

N- [1- (3-methyl-2-butenyl)
-4- {3- (2-diethylaminoethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1- (3-pentynyl) -4
-{3- (2-diethylaminoethoxy) phenyl}-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [1-benzyl-4- {3- (2-diethylaminoethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea. N
-[1-Cyclopropylmethyl-4- {3- (2-diethylaminoethoxy) phenyl} -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
-(2,6-diisopropylphenyl) urea. N-
[4- (2-chlorophenyl) -1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [4- (2-chlorophenyl) -1,
7-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. N- [4- (2-chlorophenyl) -1,6-naphthyridin-3-yl] -N '
-(2,6-diisopropylphenyl) urea. N-
[4- (2-chlorophenyl) -1,7-naphthyridin-3-yl] -N '-(2,4-difluorophenyl)
Urea.

1-methyl-3-benzoylamino-4-
(3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine. 1-methyl-3-benzoylamino-4- (3-methoxyphenyl) -1,2-
Dihydro-2-oxo-1,7-naphthyridine. 1-Methyl-3-benzoylamino-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,6-naphthyridine. 1-methyl-3-phenylacetylamino-
4- (3-methoxyphenyl) -1,2-dihydro-2
-Oxo-, 8-naphthyridine. 1-methyl-3- (3
-Phenylpropionylamino) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-
Naphthyridine. 1-methyl-3- (2,2-dimethyllauroylamino) -4- (3-methoxyphenyl)-
1,2-dihydro-2-oxo-1,8-naphthyridine.

[0040]

EXAMPLES The present invention will be described in more detail by reference examples and examples, but the present invention is not limited thereto. Example 1 Synthesis of N- [4- (2-chlorophenyl) -1,7-naphthyridin-3-yl] -N '-(2,4-difluorophenyl) urea

Embedded image A solution of 169 mg (0.66 mmol) of 3-amino-4- (2-chlorophenyl) -1,7-naphthyridine and 102 mg (0.66 mmol) of 2,4-difluorophenylisocyanate in 50 ml of tetrahydrofuran was heated to reflux for 8 hours. After concentration, the residue was purified by column chromatography (silica gel, methanol: chloroform 1: 9) and crystallized from hexane to give the title compound (98 mg, 0.24 mmol) as a colorless powder. mp 213-216 ° C. ¹ H-NMR δ (DMSO-d 6) 10.52 (1H, b
r), 8.25 (1H, d, J = 5.0Hz), 8.04-8.08
(2H, m), 7.59-7.75 (2H, m), 7.17-7.46
(4H, m), 6.91 to 7.00 (1H, m), 6.67 to 6.74
(0.5H, m), 6.62 (1H, d, J = 5.0Hz), 6.
30-6.36 (0.5H, m) IR (KBr) 1683, 1596, 1508, 1400cm-1

Example 2 N- [1-methyl-4- (2-chlorophenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,4-difluorophenyl) urea

Embedded image 315 mg (1 mmol) of 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid, 330 mg (1.2 mmol) of diphenylphosphoryl azide and triethylamine 101
A solution of mg (1 mmol) in 4 ml of benzene was stirred at room temperature for 0.5 hour, and then heated under reflux for 0.5 hour. After cooling, 152 mg (1.2 mmol) of 2,4-difluoroaniline was added, and the mixture was stirred at room temperature for 0.5 hour and refluxed for 2 hours. After cooling, the mixture was washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from isopropanol to give the title compound as colorless crystals (288 mg, 0.65 mmol). mp 225-226 ° C ¹ H-NMR δ (CDCl ₃ ) 8.61 (1H, dd, J
= 4.6 Hz, 1.7 Hz), 7.66 to 7.75 (2H, m), 7.
38 to 7.56 (6H, m), 7.16 (1H, dd, J = 7.9H)
z, 4.6 Hz), 6.67 to 6.77 (2H, m), 4.00 (3
H, s) IR (KBr) 1715, 1636, 1613, 1584, 1584, 155
0, 1500, 1434cm-1

Example 3 N- [1-methyl-4- (2-chlorophenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,4,6-trimethylphenyl)
Urea Synthesis

[Chemical formula 26] In the same manner as in Example 2, 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,8-
The title compound was synthesized from naphthyridine-3-carboxylic acid and 2,4,6-trimethylaniline. mp 250 ° C. or higher ¹ H-NMR δ (CDCl ₃ ) 8.55 (1 H, d, J =
4.6Hz, 2.0Hz), 7.37 ~ 7.53 (5H, m), 7.10
(1H, dd, J = 7.9Hz, 4.6Hz), 6.91 (2
H, brs), 6.36 (0.7 H, br), 5.73 (0.7 H,
br), 3.91 (3H, s), 2.27 (6H, brs), 2.
02 (3H, brs) IR (KBr) 3271, 1658, 1634, 1554, 1458, 1118
cm-1 Example 4 N- [1-methyl-4- (2-chlorophenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
Urea Synthesis

Embedded image In the same manner as in Example 2, 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,8-
The title compound was synthesized from naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 193-196 ° C ¹ H-NMRδ (CDCl ₃ ) 8.54 (1H, br),
7.53 to 7.57 (1H, m), 7.03 to 7.46 (8H, m), 6.
47 (0.7 H, brs), 5.65 (0.7 H, brs), 3.88
(3H, brs), 3.22 (m) and 2.94 (m) (1H in total), 1.02-1.38 (12H, m) IR (KBr) 3342, 2963, 1714, 1629, 1608, 158
1, 1509, 1461cm-1

Example 5 N- [1-methyl-4- (2-chlorophenyl) -1,
2-dihydro-2-oxo-1,7-naphthyridine-3
-Yl] -N '-(2,4,6-trimethylphenyl)
Urea Synthesis

Embedded image 315 mg (1 mmol) of 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,7-naphthyridine-3-carboxylic acid, 330 mg (1.2 mmol) of diphenylphosphoryl azide and triethylamine 101
A solution of 5 mg of dimethylformamide (DMF) in mg (1 mmol) was stirred at room temperature for 0.5 hours, and then heated under reflux at 80 to 90 ° C. for 0.5 hours. After allowing to cool, 162 mg (1.2 mmol) of 2,4,6-trimethylaniline was added, and the mixture was added at room temperature for 0.5 hour and 80 hours.
Stirred at ~ 90 ° C for 2 hours. After allowing to cool, the mixture was diluted with ethyl acetate, washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from ethanol to give 350 mg (0.78 mmol) of the title compound as colorless crystals. mp 222-224 ° C ¹ H-NMR δ (CDCl ₃ ) 8.83 (1H, s), 8.3
6 (1H, d, J = 5.3 Hz), 7.50 to 7.54 (1H,
m), 7.38 to 7.43 (3H, m), 7.02 (1H, d, J =
5.3Hz), 6.93 (1H, brs), 6.62 (0.5H, b
r), 5.68 (0.5 H, br), 3.86 (3 H, brs),
2.27 (6H, brs), 2.05 (3H, brs) IR (KBr) 1658, 1638, 1545, 1432cm-1 Example 6 N- [1-methyl-4- (2-chlorophenyl) -1,
2-dihydro-2-oxo-1,7-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
Urea Synthesis

[Chemical 29] 1-Methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,7-
The title compound was synthesized from naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 153-154 ° C ¹ H-NMR δ (CDCl ₃ ) 8.83 (1H, br),
8.34 (1H, d, J = 5.6 Hz), 7.01 to 7.61 (7H,
m), 6.97 (1H, d, J = 5.6 Hz), 6.72 (0.7
H, br), 5.80 (0.7 H, br), 3.80 (3H,
s), 3.21 (1H, m), 2.96 (1H, m), 1.03-1.
36 (12H, m) IR (KBr) 2963, 1645, 1591, 1505cm-1

Example 7 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image 1-methyl-4- (3-methoxyphenyl) -1,2-
315 mg (1 mmol) of dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid, 330 mg (1.2 mmol) of diphenylphosphoryl azide and triethylamine 10
A solution of 1 mg (1 mmol) in 4 ml of toluene was stirred at room temperature for 0.5 hours and then heated under reflux for 0.5 hours. After allowing to cool, 216 mg (1.2 mmol) of 2,6-diisopropylaniline was added, and the mixture was added at room temperature to 0.2 ml.
The mixture was stirred for 5 hours and under reflux for 2 hours. After allowing to cool, the mixture was diluted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane 1: 1) and crystallized from diethyl ether to give the title compound (30%).
2 mg (0.62 mmol) were obtained as colorless crystals. mp 169-170 ° C ¹ H-NMRδ (CDCl ₃ ) 7.64-7.72 (1H,
m), 6.85 to 7.39 (8H, m), 6.11 (0.5H, b
r), 5.90 (0.5 H, br), 3.92 (s) and 3.86
(S) (total 3H), 3.84 (3H, s), 2.85-3.
15 (2H, m), 1.08 to 1.29 (12H, m) IR (KBr) 2964,1716,1654,1509 cm-1 Example 8 N- [4- (3-methoxyphenyl) -1,2-dihydro-2 -Oxo-1,8-naphthyridin-3-yl]-
Synthesis of N '-(2,6-diisopropylphenyl) urea

[Chemical 31] In the same manner as in Example 7, 4- (3-methoxyphenyl)
The title compound was synthesized from -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. ¹ H-NMR δ (CDCl ₃ ) 11.45 (1H, brs), 8.5
8 (1H, br), 7.65 (1H, br), 6.96 to 7.40 (7H, m), 6.03
(1H, br), 3.84 (3H, s), 2.96 (br) and 3.18 (br)
H), 1.07 to 1.20 (12H, br)

Example 9 N- [1-methyl-4- (4-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 7, 1-methyl-4- (4-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 179-182 ° C. Example 10 N- [1-isopropyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2 Synthesis of (6-Diisopropylphenyl) urea

[Chemical 33] In the same manner as in Example 7, 1-isopropyl-4- (3-
Methoxyphenyl) -1,2-dihydro-2-oxo-
The title compound was synthesized from 1,8-naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. ¹ H-NMR δ (DMSO-d6) 8.58 (1H, dd.J = 4.
6Hz, 2.0Hz), 7.75 (2H, br), 7.62 (1H, dd, J = 4.6Hz, 2.0
Hz), 7.40 (1H, dd.J = 7.9Hz, 7.9Hz), 7.24 (1H, dd.J = 7.9H)
z, 4.6Hz), 7.13 to 7.18 (1H, m), 7.00 to 7.05 (3H, m), 6.9
1 to 6.98 (2H, m), 6.10 (1H, br), 3.77 (3H, s), 2.86 to 2.9
6 (2H, m), 1.63 (6H, dJ = 6.9 Hz), 1.08 (12H, br) Example 11 N- [1- (2-methoxyethyl) -4- (3-methoxyphenyl) -1,2 -Dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 7, 1- (2-methoxyethyl)-
4- (3-methoxyphenyl) -1,2-dihydro-2
The title compound was synthesized from -oxo-1,8-naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 164-165 ° C

Example 12 N- [1-methyl-4- (3-methoxyphenyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,4-difluorophenyl)
Urea Synthesis

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2,4-difluoroaniline. mp 203-205 ° C Example 13 N- [1-Methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,4,6-trimethylphenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2,4,6-trimethylaniline. mp> 230 ° C IR (KBr) 2956,1654,1585,1547,1460,1254 cm ^-1 Example 14 N- [1-Methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2-trifluoromethylphenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2-trifluoromethylaniline. ¹ H-NMR δ (CDCl ₃ ) 8.60 (1H, dd.J = 4.6Hz
, 2.0Hz), 7.78 (1H, dd.J = 8.3Hz.2.0Hz), 7.70 (1H, dJ =
8.3Hz), 7.32 to 7.54 (4H, m), 7.12 to 7.17 (3H, m), 6.90
~ 6.98 (3H, m), 3.85 (3H, s), 3.80 (3H, s)

Example 15 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-dichlorophenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2,6-dichloroaniline. mp 207-208 ° C Example 16 N- [1-Methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2-chloro-3-pyridyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 3-amino-2-chloropyridine. mp> 230 ° C. IR (KBr) 1652,1587,1535,1459,1390,1260 cm ^-1 Example 17 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(3,5-dichloro-2-pyridyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridine-3-carboxylic acid and 2-amino-3,5
-The title compound was synthesized from dichloropyridine. mp
78-79 ° C

Example 18 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(8-quinolyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 8-amino-quinoline. mp> 250 ° C. IR (KBr) 2924,1710,1661,1641,1545 cm ^-1 Example 19 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2-methoxy-4-nitrophenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridine-3-carboxylic acid and 2-methoxy-4-
The title compound was synthesized from nitroaniline. mp> 250 ° C. IR (KBr) 1715,1664,1645,1588,1550 cm ^-1 Example 20 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2-isopropylphenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2-isopropylaniline. mp 208-209 ° C

Example 21 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2-ethylphenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2-ethylaniline. mp 212-212.5 DEG C. Example 22 N- [1-methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2-isopropyl-6-methylphenyl) urea

Embedded image As in Example 7, 1-methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridine-3-carboxylic acid and 2-isopropyl-
The title compound was synthesized from 6-methylaniline. mp 196-198 ° C Example 23 N- [1-Methyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N′-butylurea

Embedded image 1-Methyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and butylamine. mp 208-210 ° C Example 24 N- [1-methyl-4- (2-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 5, 1-methyl-4- (2-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 179-180 ° C Example 25 N- [1-butyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 5, 1-butyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
The title compound was synthesized from -naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 179-182 ° C

Example 26 N- [1-pentyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 5, 1-pentyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,
The title compound was synthesized from 8-naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 189-190 ° C. Example 27 N- [1- (3-methylbutyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-
Synthesis of Naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image 1- (3-methylbutyl) -4 in the same manner as in Example 5.
-(3-methoxyphenyl) -1,2-dihydro-2-
Oxo-1,8-naphthyridine-3-carboxylic acid and 2,
The title compound was synthesized from 6-diisopropylaniline. mp 189.5-191 ° C Example 28 N- [1-butyl-4- (3-pyridyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-( Synthesis of 2,6-diisopropylphenyl) urea

[Chemical 51] In the same manner as in Example 5, the title compound was obtained from 1-butyl-4- (3-pyridyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. Was synthesized. Hydrochloride mp 170-172 ° C Example 29 N- [1- (3-cyanopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 5, 1- (3-cyanopropyl)-
4- (3-methoxyphenyl) -1,2-dihydro-2
The title compound was synthesized from -oxo-1,8-naphthyridine-3-carboxylic acid and 2,6-diisopropylaniline. mp 187-188.5 ° C. Example 30 N- (1-methyl-4-phenyl-1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl) -N '
Synthesis of-(2,6-diisopropylphenyl) urea

Embedded image N- [1-methyl-4- (2-chlorophenyl) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
350 mg (0.72 mmol) of urea in methanol 2
In a 0 ml solution, 135 mg of ammonium formate (2.15
(mmol), 100% palladium / carbon (100 mg) was added, and the mixture was heated under reflux for 4 hours. After allowing to cool, the mixture was filtered through celite and concentrated under reduced pressure. Dilute aqueous ammonia was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give 249 mg (mmol) of the title compound as a colorless powder. mp 188-190.5 ° C

Example 31 N- (1-methyl-4- (3-hydroxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl) -N ′-(2,6-diisopropylphenyl) urea

Embedded image N- [1-methyl-4- (3-methoxyphenyl)-
A solution of 1310 mg (2.7 mmol) of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea in 20 ml of methylene chloride at 0 ° C. 1.7 g of boron tribromide
(6.75 mmol) was added dropwise and the mixture was stirred for 6 hours. The mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The extract was washed with water, saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (3% methanol / chloroform) and crystallized from diethyl ether / hexane to obtain 830 mg (1.76 mmol) of the title compound as a colorless powder. mp 152-155 ° C Example 32 N- (1-butyl-4- (3-hydroxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl) -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 31, N- [1-butyl-4- (3-
Methoxyphenyl) -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
The title compound was synthesized from diisopropylphenyl) urea. mp 136-140 ° C Example 33 N- (1-methyl-4- (3-hydroxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl) -N′-butylurea

Embedded image In the same manner as in Example 31, N- [1-methyl-4- (3-
Methoxyphenyl) -1,2-dihydro-2-oxo-
The title compound was synthesized from 1,8-naphthyridin-3-yl] -N′-butylurea. mp 178-180.5 ° C. Example 34 N- [1-butyl-4- {3- (2-acetoxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image N- (1-butyl-4- (3-hydroxyphenyl)-
DMF1 of 300 mg (0.59 mmol) of 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl) -N ′-(2,6-diisopropylphenyl) urea
23 mg of sodium hydride (NaH) in 0 ml solution
(0.59 mmol) was added, and the mixture was stirred at room temperature for 0.5 hr. 98 mg of 2-bromoethyl acetate (0.59 mmol
1) was added, and the mixture was stirred at 40 to 50 ° C. for 6 hours. After cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (3% methanol / chloroform) to give 209 of the title compound.
mg (0.35 mmol) obtained as a colorless powder. ¹ H-NMR δ (CDCl ₃ ) 8.53 (1H, br), 7.65
(1H, br), 6.98 ~ 7.44 (9H, m), 6.27 (0.5H, br), 5.72
(0.5H, br), 4.53 (2H, br), 4.44 (2H, m), 4.20 (2H, m),
3.06 (2H, br), 2.11 (3H, s), 1.72 (2H, br), 1.45 (2H, br)
m), 1.11 to 1.24 (12H, m), 0.96 (3H, t, J = 7.3Hz)

Example 35 N- [1-methyl-4- [3- {3- (4-phenyl-
1-piperazinyl) propoxydiphenyl] -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 34, N- {1-methyl-4- (3-
(Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N ′-(2,6
The title compound was synthesized from -diisopropylphenyl) urea and 1- (3-chloropropyl) -4-phenylpiperazine. ¹ H-NMR δ (CDCl ₃ ) 8.54 (1H, m), 7.65 (1
H, m), 6.83-7.42 (14H, m), 6.10 (0.5H, br), 5.77 (1H,
br), 4.09 (2H, t, J = 6.3Hz), 3.87 (3H, br), 3.22 (4H, b
r), 2.51 to 3.10 (2H, br), 2.64 (6H, br), 2.05 (2H, t, J
= 6.3 Hz), 1.11 to 1.25 (12H, br) Example 36 N- [1-Methyl-4- {3- (2-acetoxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 34, N- {1-methyl-4- (3-
(Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N ′-(2,6
The title compound was synthesized from -diisopropylphenyl) urea and 2-bromoethyl acetate. ¹ H-NMR δ (CDCl ₃ ) 8.53 (1H, m), 7.62-
7.74 (1H, m), 6.87 ~ 7.40 (9H, m), 6.13 (0.5H, br), 5.93
(0.5H, br), 4.43 (2H, m), 4.20 (2H, m), 3.93 (3H, br),
2.94-3.21 (2H, br), 2.11 (3H, s), 1.08-1.26 (12H, br) Example 37 N- [1-butyl-4- {3- (3-phthalimidopropoxy) phenyl} -1, 2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image In the same manner as in Example 34, N- {1-butyl-4- (3-
(Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N ′-(2,6
The title compound was synthesized from -diisopropylphenyl) urea and N- (3-bromopropyl) phthalimide. ¹ H-NMR δ (CDCl ₃ ) 8.52 (1H, br), 7.79
~ 7.82 (2H, m), 7.64 ~ 7.68 (3H, m), 6.82 ~ 7.36 (9H, m),
6.21 (0.5H, br), 5.78 (0.5H, br), 4.54 (2H, br), 4.07
(2H, t, J = 5.9Hz), 3.91 (2H, t, J = 6.9Hz), 2.95 to 3.20 (2H, t, J = 6.9Hz)
br), 2.23 (2H, m), 1.73 (2H, m), 1.56 (2H, m), 1.09-1.
9 (12H, m), 0.97 (3H, brt, J = 7.3Hz)

Example 38 N- [1-methyl-4- [3- {3- (4-phenyl-
1-piperazinyl) propoxydiphenyl] -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridin-3-yl] -N′-butylurea

[Chemical formula 61] In the same manner as in Example 34, N- {1-methyl-4- (3-
The title compound was synthesized from (hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N′-butylurea and 1- (3-chloropropyl) -4-phenylpiperazine. mp 120.5-121.5 ° C. Example 39 N- [1-butyl-4- {3- (3-chloropropoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image N- {1-butyl-4- (3-hydroxyphenyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl {-N '-(2,6-diisopropylphenyl) urea 1000 mg (1.95 mmol), 1-bromo-3-chloropropane 460 mg (2 .93mmo
673 mg of potassium carbonate was added to a solution of
(4.88 mmol) was added, and the mixture was stirred at 50 to 60 ° C. for 6 hours. After cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane 50:50) and crystallized from hexane to give 1020 mg (1.73 m) of the title compound.
mol) as a colorless powder. mp 138-140 ° C Example 40 N- [1- (3-cyanopropyl) -4- {3- (3-
(Chloropropoxy) phenyl} -1,2-dihydro-2
-Oxo-1,8-naphthyridin-3-yl] -N'-
Synthesis of (2,6-diisopropylphenyl) urea

Embedded image As in Example 39, N- {1- (3-cyanopropyl) -4- (3-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl}- The title compound was synthesized from N ′-(2,6-diisopropylphenyl) urea and 1-bromo-3-chloropropane. _{^{1 H-NMR δ (CD 3}} OD) 8.60 (1H, d, J = 4.6H
z), 7.72 (1H, d, J = 6.3Hz), 7.45 (1H, dd, J = 7.9Hz, 7.9H
z,), 7.07 to 7.25 (5H, m), 6.96 (2H, br), 4.78 (2H, t, J =
6.6Hz), 4.16 (2H, t, J = 6.6Hz), 3.75 (2H, t, J = 6.6Hz), 2.
95 to 3.05 (2H, m), 2.60 (2H, t, J = 7.2Hz)

Example 41 N- [1-Butyl-4- {3- (3-dimethylaminopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

Embedded image N- {1-butyl-4- (3-hydroxyphenyl)-
1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl {-N '-(2,6-diisopropylphenyl) urea 200 mg (0.4 mmol), potassium carbonate 166 mg (1.2 mmol), iodine Sodium chloride 5
63 mg of 3-dimethylaminopropyl chloride hydrochloride was added to a suspension of
Stir at ~ 70 ° C for 10 hours. After cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (10% methanol / chloroform) to give 88 mg of the title compound (0.15 m
mol) was obtained. ¹ H-NMR δ (DMSO-d6) 8.59 (1H, d, J = 3.3
Hz), 7.76 (1H, s), 7.74 (1H, s), 7.61 (1H, d, J = 6.6Hz),
7.38 (1H, dd, J = 7.6Hz, 7.6Hz,), 7.12-7.26 (2H, m), 6.98
~ 7.04 (3H, m), 6.85 ~ 6.91 (2H, m), 4.52 (2H, br), 3.99
(2H, brt, J = 6.9Hz), 2.85 to 2.95 (2H, m), 2.38 (2H, t, J = 6.
9Hz), 1.82 to 1.91 (2H, m), 1.65 to 1.75 (2H, m), 1.37 to 1.
47 (2H, m), 0.95 to 1.00 (15H, m) Example 42 N- [1-Methyl-4- (3-benzyloxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine -3-yl] -N'-butylurea

Embedded image In the same manner as in Example 41, N- [1-methyl-4- (3-
The title compound was synthesized from (hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N′-butylurea and benzyl bromide. mp 183-184 ° C. Example 43 N- [1-butyl-4- {3- (4-pyridylmethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- {1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N '-(2
The title compound was synthesized from 6-diisopropylphenyl) urea and 4-picolyl chloride hydrochloride. mp 157-158 ° C

Example 44 N- [1-Butyl-4- {3- (2-pyridylmethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- {1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N '-(2
The title compound was synthesized from 6-diisopropylphenyl) urea and 2-picolyl chloride hydrochloride. Hydrochloride mp 145-146 ° C. Example 45 N- [1-butyl-4- {3- (3-piperidinopropoxy) phenyl} -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- {1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N '-(2
The title compound was synthesized from 6-diisopropylphenyl) urea and N- (3-chloropropyl) piperidine hydrochloride. Hydrochloride mp 142-145 ° C. Example 46 N- [1-butyl-4- {3- (2-diethylaminoethoxy) phenyl} -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- {1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N '-(2
The title compound was synthesized from 6-diisopropylphenyl) urea and 2-diethylaminoethyl chloride hydrochloride. Hydrochloride mp 141-144 ° C Example 47 N- [1-Butyl-4- {3- (2-dimethylaminoethoxy) phenyl} -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- {1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N '-(2
The title compound was synthesized from 6-diisopropylphenyl) urea and 2-dimethylaminoethyl chloride hydrochloride. _{^{1 H-NMR δ (CD 3}} OD) 8.59 (1H, d, J = 4.6H
z), 7.72 (1H, d, J = 6.3Hz), 7.44 (1H, dd, J = 8.3Hz, 8.3Hz)
, 7.15 to 7.22 (3H, m), 7.07 (2H, d, J = 7.3Hz), 6.98 (2H, m
m), 4.64 (2H, t, J = 7.6Hz), 4.15 (2H, t, J = 5.0Hz), 2.96 (2H, t, J = 5.0Hz)
H, sep, J = 6.9Hz), 2.83 (2H, t, J = 5.0Hz), 1.70 ~ 1.81 (2H,
m), 1.40 to 1.55 (2H, m), 1.10 (12H, d, J = 6.9Hz), 1.02 (3
(H, t, J = 7.3Hz)

Example 48 N- [1-Butyl-4- {3- (3-benzyloxypropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- {1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl} -N '-(2
6-diisopropylphenyl) urea and benzyl 3-
The title compound was synthesized from bromopropyl ether. ¹ H-NMR δ (CD ₃ OD) 8.58 (1H, br), 7.72
(1H, d, J = 8.3Hz), 7.39 (1H, t, J = 7.9Hz), 6.94 to 7.29 (12
H, m), 4.63 (2H, t, J = 7.6Hz), 4.12 (2H, t, J = 5.9Hz,),
3.66 (2H, t, J = 5.9Hz), 2.90 ~ 3.00 (2H, m), 2.00 ~ 2.10 (2
H, m), 1.73 to 1.85 (2H, m), 1.48 to 1.56 (2H, m), 1.10 (12
H, d, J = 6.9 Hz), 1.02 (3H, t, J = 7.3 Hz) Example 49 N- [1- (3-cyanopropyl) -4- {3- (2-
(Acetoxyethoxy) phenyl} -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
Synthesis of-(2,6-diisopropylphenyl) urea

Embedded image As in Example 41, N- {1- (3-cyanopropyl) -4- (3-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl}- The title compound was synthesized from N ′-(2,6-diisopropylphenyl) urea and 2-bromoethyl acetate. _{^{1 H-NMR δ (CD 3}} OD) 8.60 (1H, d, J = 2.6H
z), 7.72 (1H, d, J = 6.3Hz), 7.46 (1H, dd, J = 7.9Hz, 7.9Hz)
, 7.07 to 7.25 (5H, m), 6.98 (2H, br), 4.78 (2H, t, J = 6.9
Hz,), 4.38 (2H, t, J = 5.0Hz), 4.22 (2H, t, J = 5.0Hz), 2.8
6 ~ 3.00 (2H, m), 2.60 (2H, t, J = 7.3Hz), 2.10 ~ 2.22 (2H, m
m), 2.05 (3H, s), 1.11 (12H, brd, J = 5.9 Hz) Example 50 N- [1- (3-cyanopropyl) -4- {3- (2-
Diethylaminoethoxy) phenyl {-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
Synthesis of N '-(2,6-diisopropylphenyl) urea

Embedded image As in Example 41, N- {1- (3-cyanopropyl) -4- (3-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl}- The title compound was synthesized from N ′-(2,6-diisopropylphenyl) urea and 2-diethylaminoethyl chloride hydrochloride. ¹ H-NMR δ (CD ₃ OD) 8.58 (1 H, dd, J = 4.6 Hz,
1.6Hz), 7.70 (1H, dd, J = 7.9Hz, 1.6Hz), 7.45 (1H, dd, J =
7.9 Hz, 7.9 Hz), 7.06 to 7.22 (5H, m), 6.96 (2H, br), 4.7
5 (2H, t, J = 6.9Hz), 4.14 (2H, t, J = 4Hz), 2.92 ~ 3.04 (4H,
m), 2.69 (4H, q, J = 6.9Hz,), 2.57 (2H, t, J = 6.9Hz), 2.12
~ 2.02 (2H, m), 1.06 ~ 1.12 (18H, m)

Example 51 N- [1-Butyl-4- {3- (2-hydroxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image N- [1-butyl-4- {3- (2-acetoxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,
8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea 196 mg (0.33 mm
ol) in 10 ml of methanol
g was added, and the mixture was stirred at room temperature for 4 hours. Water was added, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from ether / hexane to give 145 mg (0.26 mm) of the title compound.
ol) obtained. mp 106-110 ° C Example 52 N- [1-Methyl-4- {3- (2-hydroxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 51, N- [1-methyl-4- {3
The title compound was synthesized from-(2-acetoxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea. ¹ H-NMR δ (CDCl ₃ ) 8.53 (1H, dd.J = 3.6Hz
), 7.42 (1H, m), 6.89 to 7.42 (9H, m), 6.11 (0.5H, br),
5.86 (0.5H, br), 4.13 (2H, br), 3.96 (3H, br), 3.87 (2
H, br), 2.90-3.25 (2H, br), 1.09-1.29 (12H, m) Example 53 N- [1- (3-cyanopropyl) -4- {3- (2-
(Hydroxyethoxy) phenyl} -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
Synthesis of-(2,6-diisopropylphenyl) urea

[Chemical 76] As in Example 51, N- [1- (3-cyanopropyl) -4- {3- (2-acetoxyethoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridine- The title compound was synthesized from 3-yl] -N '-(2,6-diisopropylphenyl) urea. _{^{1 H-NMR δ (CD 3}} OD) 8.60 (1H, d, J = 4.6H
z), 7.73 (1H, d, J = 6.3Hz), 7.45 (1H, dd, J = 8.3Hz, 8.3Hz)
, 7.07 to 7.25 (5H, m), 6.95 to 6.98 (2H, m), 4.78 (2H, t, J
= 6.9Hz), 4.08 (2H, t, J = 4.9Hz), 3.87 (2H, t, J = 4.9Hz),
2.93 to 3.04 (2H, m), 2.60 (2H, t, J = 7.3Hz), 1.12 (12H, br)

Example 54 N- [1-Butyl-4- {3- (3-hydroxypropoxy) phenyl} -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image N- [1-butyl-4- {3- (3-benzyloxypropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
-Diisopropylphenyl) urea 316 mg (0.4 mg)
To a 20 ml solution of 8 mmol) in methanol was added 91 mg (1.44 mmol) of ammonium formate and 100 mg of 10% palladium on carbon, and the mixture was refluxed for 10 hours. After allowing to cool, it was filtered through Celiro and concentrated under reduced pressure. It was dissolved in ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (1 to 3% methanol / chloroform) and crystallized from ether / hexane to give 85% of the title compound.
mg (0.15 mmol). ¹ H-NMR δ (CD ₃ OD) 8.58 (1H, dr), 7.72
(1H, d, J = 8.3Hz), 7.42 (1H, t, J = 8.3Hz), 7.06 ~ 7.20 (5H,
m), 6.95 (2H, br), 4.63 (2H, t, J = 7.3 Hz), 4.10 (2H, t, J =
6.3Hz), 3.72 (2H, t, J = 5.9Hz), 2.96 (2H, sep, J = 6.6Hz),
1.99 (2H, t, J = 6.3Hz), 1.78 (2H, br), 1.47 (2H, br), 1.
10 (12H, d, J = 6.6Hz), 1.02 (3H, t, J = 7.3Hz) Example 55 N- [1-butyl-4- {3- (3-aminopropoxy) phenyl} -1,2 -Dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image N- [1-butyl-4- {3- (3-phthalimidopropoxy) phenyl} -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
157 mg of diisopropylphenyl) urea (0.22
hydrazine monohydrate (100 mg, 2 mmol) was added to a 10 ml ethanol solution of
Stirred for hours. The precipitate was separated by filtration and concentrated under reduced pressure. Methylene chloride was added, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The title compound was purified by silica gel column chromatography (10% methanol / chloroform) to give 58 m
g (0.10 mmol) were obtained. Hydrochloride mp 106-110 ° C

Example 56 N- [1-Butyl-4- [3- {3- (1-imidazolyl) propoxy} phenyl] -1,2-dihydro-2-
Oxo-1,8-naphthyridin-3-yl] -N′-
Synthesis of (2,6-diisopropylphenyl) urea

Embedded image To a suspension of 97 mg (1.43 mmol) of imidazole, 246 mg (1.78 mmol) of potassium carbonate and 35 mg of sodium iodide in 20 ml of DMF were added N- at room temperature.
[1-Butyl-4- {3- (3-chloropropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl ) Urea 700 mg (1.19 mmol)
Was added, and the mixture was stirred at 50 to 60 ° C. for 10 hours. After cooling down,
The mixture was poured into water, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (5% methanol / chloroform) to give 286 of the title compound.
mg (0.46 mmol). ¹ H-NMR δ (DMSO-d6) 8.60 (1H, d, J = 4.6
Hz), 7.76 (1H, s), 7.74 (1H, s), 7.61 (1H, d, J = 7.0Hz),
7.60 (1H, s), 7.40 (1H, dd, J = 7.9Hz, 7.9Hz), 7.12 to 7.26
(3H, m), 7.02 to 7.05 (3H, m), 6.86 to 6.93 (3H, m), 4.53 (2
H, br), 4.08 to 4.14 (2H, m), 3.93 (2H, t, J = 5.6Hz), 2.85
~ 2.95 (2H, m), 2.20 (2H, br), 1.72 (2H, br), 1.39 ~ 1.
Example 47 N- [1-butyl-4- [3- {3- (1,2,4-triazol-1-yl) propoxy} phenyl] 47 (2H, m), 0.97-1.24 (15H, m) -1,
2-dihydro-2-oxo-1,8-naphthyridine-3
-Yl] -N '-(2,6-diisopropylphenyl)
Urea Synthesis

Embedded image In the same manner as in Example 56, N- [1-butyl-4- {3
-(3-Chloropropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]
The title compound was synthesized from -N '-(2,6-diisopropylphenyl) urea and 1,2,4-triazole. . _{^{1 H-NMR δ (CD 3}} OD) 8.60 (1H, d, J = 3.0H
z), 8.43 (1H, s), 7.96 (1H, s), 7.71 (1H, d, J = 7.9Hz), 7.
43 (1H, dd, J = 7.9Hz, 7.9Hz), 6.94 ~ 7.23 (7H, m), 4.64 (2
H, brt, J = 4.6Hz), 4.44 (2H, brt, J = 4.4Hz), 4.03 (2H, br)
, 2.90 ~ 3.05 (2H, m), 2.37 (2H, m), 1.75 ~ 1.85 (2H, m
m), 1.45 ~ 1.56 (2H, m), 0.99 ~ 1.11 (15H, m)

Example 58 N- [1- (3-phthalimidopropyl) -4- (3-
Methoxyphenyl) -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-
N '-(2,6-diisopropylphenyl) urea 20
0 mg (0.43 mmol) and 133 mg (0.50 mmol) of N- (3-bromopropyl) phthalimide
114 mg of potassium carbonate (0.83
mmol) was added and the mixture was stirred at 50 to 60 ° C. for 1 hour.
After cooling, the mixture was poured into water, extracted with ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, silica gel column chromatography (1-3
% Methanol / chloroform) and crystallized from hexane to give 229 mg (0.35 mmol) of the title compound. ¹ H-NMR δ (CD ₃ OD) 8.40 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.78 to 7.96 (4H, m), 7.72 (1H, dd, J = 7.9Hz, 1.7H
z), 7.48 (1H, dd, J = 8.2Hz, 7.9Hz,), 7.04-7.27 (5H,
m), 6.93 to 7.02 (2H, m), 4.66 to 4.78 (2H, m), 3.90 (2H, t,
J = 6.9Hz), 3.87 (3H, s), 3.02 (2H, sept, J = 6.6Hz), 2.17
~ 2.35 (2H, m), 1.13 (12H, brd, J = 6.6Hz) Example 59 N- [1- (3-aminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2. -Oxo-1,8
-Naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

[Chemical formula 82] In the same manner as in Example 55, N- [1- (phthalimidopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′ The title compound was synthesized from-(2,6-diisopropylphenyl) urea. ¹ H-NMR δ (CD ₃ OD) 8.40 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.78 to 7.96 (4H, m), 7.72 (1H, dd, J = 7.9Hz, 1.7H
z), 7.48 (1H, dd, J = 8.2Hz, 7.9Hz,), 7.04-7.27 (5H,
m), 6.93 to 7.02 (2H, m), 4.66 to 4.78 (2H, m), 3.90 (2H, t,
J = 6.9Hz), 3.87 (3H, s), 3.02 (2H, sept, J = 6.6Hz), 2.17
~ 2.35 (2H, m), 1.13 (12H, brd, J = 6.6Hz)

Example 60 N- [1- (3-acetylaminopropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

[Chemical 83] N- [1- (3-aminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea 50 mg (0.1 mmol)
Was dissolved in 1 ml of pyridine, 0.5 ml of acetic anhydride was added, and the mixture was stirred for 40 minutes. After concentration under reduced pressure, 49 mg of the title compound was obtained by purification by preparative thin layer chromatography.
(0.09 mmol) was obtained. ¹ H-NMR δ (CD ₃ OD) 8.65 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.77 (1H, dd, J = 7.9Hz, 1.7Hz), 7.50 (1H, dd, J =
8.2Hz, 8.2Hz,), 7.05 to 7.36 (5H, m), 6.95 to 7.03 (2H,
m), 4.78 (2H, t, J = 6.6Hz), 3.88 (3H, s), 3.04 (2H, sept, J
= 6.6Hz), 2.79 (2H, t, J = 6.9Hz), 2.00 to 2.18 (2H, m), 1.
15 (12H, brd, J = 6.6 Hz) Example 61 N- [1- (3-benzyloxypropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

Embedded image In the same manner as in Example 5, 1- (3-benzyloxypropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid and 2,2 The title compound was synthesized from 6-diisopropylaniline. ¹ H-NMR δ (CD ₃ OD) 8.63 (1 H, dd, J = 4.6 Hz,
2.0Hz), 7.75 (1H, dd, J = 7.9Hz, 2.0Hz), 7.48 (1H, dd, J =
8.3Hz, 7.6Hz), 7.03 ~ 7.40 (10H, m), 6.90 ~ 7.00 (2H,
m), 4.82 (2H, t, J = 7.3 Hz), 4.52 (2H, s), 3.87 (3H, s), 3.
71 (2H, t, J = 5.9Hz), 3.03 (2H, sept, J = 6.6Hz), 2.18 (2H,
m), 1.14 (12H, brd, J = 6.6 Hz) Example 62 N- [1- (3-hydroxypropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image N- [1- (3-benzyloxypropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
-Diisopropylphenyl) urea 1.31 g (2.1
2 mmol) in ethanol (80 ml), 10% palladium on carbon (150 mg) was added, and the mixture was added under a hydrogen atmosphere at room temperature.
Stirred for hours. 1N 12N hydrochloric acid was added, and the mixture was further stirred for 2 hours under a hydrogen atmosphere at room temperature for 3 hours. The mixture was filtered through Celiro, concentrated under reduced pressure, and purified by silica gel column chromatography (1-3% methanol / chloroform) to obtain 1.12 g (2.12 mmol) of the title compound. ¹ H-NMR δ (CD ₃ OD) 8.65 (1 H, dd, J = 4.6 Hz,
1.779), 7.79 (1H, dd, J = 7.9Hz, 1.7Hz), 7.49 (1H, dd, J =
8.2Hz, 8.2Hz), 7.05 ~ 7.35 (5H, m), 6.95 ~ 7.04 (2H,
m), 4.79 (2H, t, J = 7.3 Hz), 3.87 (3H, s), 3.71 (2H, t, J = 6.
3Hz), 3.03 (2H, sept, J = 6.3Hz), 2.10 (2H, m), 1.15 (12
(H, brd, J = 6.3Hz)

Example 63 N-[(1-tert-butoxycarbonylmethyl)-
4- (3-methoxyphenyl) -1,2-dihydro-2
-Oxo-1,8-naphthyridin-3-yl] -N'-
Synthesis of (2,6-diisopropylphenyl) urea

Embedded image N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6-diisopropyl was prepared in the same manner as in Example 58. The title compound was synthesized from (phenyl) urea and tert-butyl bromoacetate. ¹ H-NMR δ (CD ₃ OD) 8.59 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.78 (1H, dd, J = 7.9Hz, 1.9Hz), 7.51 (1H, dd, J =
7.9Hz, 7.9Hz,), 6.95 ~ 7.35 (7H, m), 5.32 (2H, s), 3.88
(3H, s), 2.93 to 3.12 (2H, m), 1.53 (9H, s), 1.14 (12H, d, J
Example 64 N- [1-carboxymethyl-4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2 Synthesis of (6-Diisopropylphenyl) urea

Embedded image N-[(1-tert-butoxycarbonylmethyl)-
4- (3-methoxyphenyl) -1,2-dihydro-2
-Oxo-1,8-naphthyridin-3-yl] -N'-
(2,6-diisopropylphenyl) urea 110mg
To a solution of (0.19 mmol) in 20 ml of methylene chloride, 1 ml (13 mmol) of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, dilute with water
The mixture was made basic with an aqueous solution of NNaOH and washed with ethyl acetate. The aqueous layer was made acidic with a 2N aqueous HCl solution, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography to give 41 mg (0.77 mmol) of the title compound.
l) Got it. ¹ H-NMR δ (CD ₃ OD) 8.50 to 8.65 (1H, m),
7.78 (1H, d, J = 7.6Hz), 7.50 (1H, dd, J = 7.9Hz, 7.9Hz), 6.
96 to 7.38 (7H, m), 5.40 (2H, s), 3.88 (3H, s), 2.92 (2H,
m), 1.14 (12H, d, J = 6.3 Hz) Example 65 N- [1- (2-hydroxyethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,
Synthesis of 8-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 58, N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropyl The title compound was synthesized from phenyl) urea and 2-bromoethanol. ¹ H-NMR δ (CD ₃ OD) 8.63 (1 H, dd, J = 4.6 Hz,
1.6Hz), 7.76 (1H, dd, J = 7.9Hz, 1.7Hz), 7.50 (1H, dd, J =
7.9Hz, 7.9Hz,), 6.95 to 7.35 (7H, m), 4.89 (2H, t, J = 6.3H
z), 3.98 (2H, t, J = 6.3Hz), 3.87 (3H, s), 2.92 ~ 3.13 (2H,
m), 1.15 (12H, d, J = 6.6Hz)

Example 66 N- [1- (4-pyridylmethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 58, N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropyl The title compound was synthesized from phenyl) urea and 4-picolyl chloride hydrochloride. ¹ H-NMR δ (CD ₃ OD) 8.57 (1 H, dd, J = 4.6 Hz,
1.7Hz), 8.40 to 8.50 (2H, m), 7.97 (1H, dd, J = 7.9Hz, 1.7H
z), 7.51 (1H, dd, J = 8.6Hz, 7.9Hz), 7.38-7.48 (2H,
m), 6.99 to 7.35 (7H, m), 5.94 (2H, s), 3.88 (3H, s), 2.93
~ 3.13 (2H, m), 1.14 (12H, d, J = 6.3Hz) Example 67 N- [1- (3-dimethylaminopropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

Embedded image N- [1- (3-aminopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea 100 mg (0.19 mmol
1) 30% HCl / ethanol solution 1 ml, 37% formaldehyde aqueous solution 46m
g (0.57 mmol), sodium borohydride 3
6 mg (0.57 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water, made basic with concentrated aqueous ammonia, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography to give the title compound (79 mg).
(0.14 mmol) was obtained. ¹ H-NMR δ (CD ₃ OD) 8.65 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.77 (1H, dd, J = 7.9Hz, 1.7Hz), 7.49 (1H, dd, J =
7.9 Hz, 7.9 Hz), 6.95 to 7.35 (7H, m), 4.65 to 4.78 (2H,
m), 3.87 (3H, s), 2.95-3.10 (2H, m), 2.52-2.68 (2H, m)
m), 2.37 (6H, s), 2.00 to 2.15 (2H, m), 1.15 (12H, d, J = 6.6
Hz) Example 68 N- [1- (3-aminocarbonylpropyl) -4-
(3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N'-
Synthesis of (2,6-diisopropylphenyl) urea

Embedded image N- [1- (3-cyanopropyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea 100 mg (0.19 mmol
1 ml of a 10% sodium carbonate aqueous solution and 1 ml of 30% hydrogen peroxide were added to a 3 ml solution of 1) methanol-acetone, and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography to give the title compound (96 mg, 0.17 mmol).
Obtained. ¹ H-NMR δ (DMSO-d6) 8.52 to 8.68 (1H,
m), 7.68 to 7.85 (2H, m), 7.55 to 7.68 (1H, m), 6.60 to 7.50
(10H, m), 4.40 to 4.65 (2H, m), 3.77 (3H, s), 2.80 to 3.00
(2H, m), 2.10 to 2.30 (2H, m), 1.80 to 2.07 (2H, m), 1.03 (b
(rs, 12H)

Example 69 N- [1- (3-cyanopropyl) -4- {3- (2-
Pyridylmethoxy) phenyl} -1,2-dihydro-2
-Oxo-1,8-naphthyridin-3-yl] -N'-
Synthesis of (2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- [1- (3-cyanopropyl) -4- (3-hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]- The title compound was synthesized from N '-(2,6-diisopropylphenyl) urea and 2-picolyl chloride hydrochloride. Hydrochloride mp 151-154 ° C. Example 70 N- [1- (2-pyridylmethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8
-Naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 58, N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropyl The title compound was synthesized from phenyl) urea and 2-picolyl chloride hydrochloride. ¹ H-NMR δ (CD ₃ OD) 8.50 (1 H, dd, J = 4.6 Hz,
1.7Hz), 8.44 (1H, m), 7.72 to 7.83 (2H, m), 7.52 (1H, dd,
J = 8.3Hz, 7.9Hz), 7.00 ~ 7.38 (9H, m), 6.02 (2H, s), 3.8
9 (3H, s), 2.90-3.13 (2H, m), 1.12 (12H, brs) Example 71 N- [1- (3-piperidinopropyl) -4- (3-methoxyphenyl) -1, 2-dihydro-2-oxo-
1,8-naphthyridin-3-yl] -N ′-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image N- (3-chloropropyl) piperidine hydrochloride 422m
To a solution of g (2.13 mmol) in DMF (30 ml), sodium bromide (330 mg, 3.20 mmol) was added, and the mixture was stirred at about 120 ° C for 1 hr and cooled to about 20 ° C. N-
[4- (3-methoxyphenyl) -1,2-dihydro-
2-oxo-1,8-naphthyridin-3-yl] -N '
-(2,6-diisopropylphenyl) urea 100m
g (0.21 mmol), potassium carbonate 147 mg
(1.06 mmol), 35 mg of potassium iodide (0.
(21 mmol) was sequentially added, and the mixture was stirred at about 50 ° C. for 3 hours. 660 mg (6.40 mmol) of sodium bromide was added, and the mixture was stirred at about 80 ° C. for 4.5 hours, cooled, and poured into water. The mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography to give the title compound (77 mg).
(0.12 mmol) was obtained. ¹ H-NMR δ (CD ₃ OD) 8.63 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.76 (1H, dd, J = 7.9Hz, 1.7Hz), 7.49 (1H, dd, J =
8.3Hz, 7.9Hz), 6.95 ~ 7.30 (7H, m), 4.71 (2H, t, J = 7.3H
z), 3.87 (3H, s), 2.95 ~ 3.12 (2H, m), 2.40 ~ 2.80 (6H,
m), 2.00 to 2.20 (2H, m), 1.40 to 1.80 (6H, m), 0.95 to 1.30
(12H, t, J = 5.9Hz)

Example 72 N- [1- (3-diethylaminopropyl) -4- (3
-Methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

Embedded image In the same manner as in Example 71, N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropyl The title compound was synthesized from phenyl) urea and 3-diethylaminopropyl chloride hydrochloride. ¹ H-NMR δ (CD ₃ OD) 8.64 (1 H, dd, J = 4.6 Hz,
1.7Hz), 7.76 (1H, dd, J = 7.9Hz, 1.7Hz), 7.50 (1H, dd, J =
8.3Hz, 8.3Hz), 6.93 ~ 7.33 (7H, m), 4.71 (2H, t, J = 7.3H
z), 3.88 (3H, s), 2.95-3.10 (2H, m), 2.85-2.93 (2H,
m), 2.80 (4H, q, J = 7.3 Hz), 2.00 to 2.20 (2H, m), 1.00 to 1.
30 (18H, m) Example 73 N- [1-butyl-4- {3- (3-diethylaminopropoxy) phenyl} -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N '-(2,6
Synthesis of -diisopropylphenyl) urea

[Chemical 96] In the same manner as in Example 41, N- [1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,
The title compound was synthesized from 6-diisopropylphenyl) urea and 3-diethylaminopropyl chloride hydrochloride. Hydrochloride ¹ H-NMR δ (DMSO-d6) 9.90 (1H,
brs), 8.50 to 8.70 (1H, m), 7.80 (1H, brs), 7.50 to 7.65 (1
H, m), 7.35 to 7.45 (1H, m), 6.72 to 7.30 (7H, m), 4.40 to 4.
62 (2H, m), 3.92 to 4.18 (2H, m), 2.70 to 3.22 (8H, m), 2.00
~ 2.21 (2H, m), 1.56-1.83 (2H, m), 1.30-1.50 (2H, m),
0.60-1.30 (21H, m) Example 74 N- [1-butyl-4- [3- {2- (1-pyrrolidinyl) ethoxy} phenyl] -1,2-dihydro-2-oxo-1,8- Naphthyridin-3-yl] -N'-
Synthesis of (2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- [1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,
The title compound was synthesized from 6-diisopropylphenyl) urea and 2- (1-pyrrolidinyl) ethyl chloride hydrochloride. Hydrochloride ¹ H-NMR delta (DMSO-d6) 8.55-8.
65 (1H, m), 7.75 to 7.90 (1H, m), 7.55 to 7.65 (1H, m), 7.35
~ 7.48 (1H, m), 6.85 ~ 7.20 (8H, m), 4.43 ~ 4.60 (2H, m),
4.25 to 4.30 (2H, m), 3.40 to 3.65 (4H, m), 2.75 to 3.15 (4H, m
m), 1.56 to 2.10 (6H, m), 1.25 to 1.53 (2H, m), 0.80 to 1.20
(15H, m)

Example 75 N- [1-butyl-4- {3- (2-piperidinoethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- [1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,
The title compound was synthesized from 6-diisopropylphenyl) urea and 2-piperidinoethyl chloride hydrochloride. Hydrochloride mp 154-156 ° C Example 76 N- [1- (3-tert-Butoxycarbonylaminopropyl) -4- (3-methoxyphenyl) -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 58, N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropyl The title compound was synthesized from phenyl) urea and 3-tert-butoxycarbonylaminopropyl iodide. ¹ H-NMR δ (CD ₃ OD) 8.64 (1 H, dd, J = 5.0 Hz,
1.7Hz), 7.77 (1H, dd, J = 8.3Hz, 1.7Hz), 7.49 (1H, dd, J =
8.3Hz, 7.6Hz), 6.95 ~ 7.35 (7H, m), 4.74 (2H, t, J = 6.9H
z), 3.87 (3H, s), 3.20 (2H, t, J = 6.6 Hz), 2.95 to 3.10 (2H,
m), 1.90-2.10 (2H, m), 1.49 (9H, s), 1.15 (12H, brd, J =
6.3) Example 77 N- [1- {3- (imidazol-1-yl) propyl} -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3- Il]
Synthesis of N '-(2,6-diisopropylphenyl) urea

[Chemical 100] In the same manner as in Example 58, N- [4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,6-diisopropyl The title compound was synthesized from phenyl) urea and 3- (imidazol-1-yl) propyl bromide hydrobromide. Hydrochloride ¹ H-NMR δ (DMSO-d6) 9.20 (1H,
brs), 8.57 (1H, dd, J = 4.6Hz, 1.3Hz), 7.55-8.00 (6H,
m), 7.37 to 7.48 (1H, m), 7.22 to 7.32 (1H, m), 7.11 to 7.18
(1H, m), 6.98 to 7.09 (3H, m), 6.86 to 6.94 (2H, m), 4.47 to
4.62 (2H, m), 4.20-4.40 (2H, m), 3.38 (3H, s), 2.84-2.
98 (2H, m), 2.25 ~ 2.40 (2H, m), 1.02 (12H, d, J = 5.9Hz)

Example 78 N- [1-Butyl-4- {3- (2-morpholinoethoxy) phenyl} -1,2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridin-3-yl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 41, N- [1-butyl-4- (3
-Hydroxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl] -N ′-(2,
The title compound was synthesized from 6-diisopropylphenyl) urea and 2-morpholinoethyl chloride hydrochloride. ¹ H-NMR δ (CD ₃ OD) 8.64 (1 H, d, J = 4.6 Hz,
1.7Hz), 7.75 (1H, d, J = 7.9Hz, 1.7Hz), 7.48 (1H, dd, J = 8.2
Hz, 7.9Hz), 6.95 to 7.20 (7H, m), 4.60 to 4.70 (2H, m), 4.
21 (2H, t, J = 5.6Hz), 3.65-3.80 (4H, m), 2.94-3.10 (2H,
m), 2.85 (2H, t, J = 5.6 Hz), 2.52 to 2.70 (4H, m), 1.70 to 1.
93 (2H, m), 1.43 ~ 1.65 (2H, m), 1.14 (12H, d, J = 6.6Hz),
1.06 (3H, t, J = 7.3Hz)

Reference Example 1 Synthesis of 3-amino-4- (2-chlorophenyl) -1,7-naphthyridine

Embedded image (A) 2-hydroxy-N- [α- (3-amino-4
Synthesis of -pyridyl) -2-chlorobenzylidene] ethylamine 3-amino-4- (2-chlorobenzoyl) pyridine 5.
65 g (24 mmol), 2-methylimidazole hydrochloride 4.7
g (40 mmol) and 12.2 g of ethanolamine (200 mm
ol) mixture was heated and melted at about 130 ° C. for 5 hours. After cooling, water was added, and the precipitated crystals were collected by filtration. Recrystallization from ethyl acetate gave the title compound as pale yellow crystals (6.28 g, 22 mmol). mp 175-178 ° C. 1H-NMRδ (DMSO-d6) 8.18 (1H,
s), 7.47 to 7.65 (6H, m), 7.24 to 7.27 (1H,
m), 6.32 (1H, d, J = 5.3 Hz), 4.73 (1H,
t, J = 5.6 Hz, D2O exchange disappeared), 3.62 to 3.68 (2
H, m), 3.17 to 3.30 (2H, m) IR (KBr) 3387, 1614, 1434, 1308, 1239, 1055
cm-1

(B) 2,2-diethoxy-N- [α-
Synthesis of (3-amino-4-pyridyl) -2-chlorobenzylidene] ethylamine 2-hydroxy-N- [α- (3-amino-4-pyridyl) -2-chlorobenzylidene] ethylamine 6.28 g
(22 mmol), 10 g (75.1 mmol) of aminoacetaldehyde diethyl acetal and 3 ml of acetic acid in ethanol 15
The 0 ml solution was heated to reflux for 30 hours. After concentration under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (silica gel, methanol: chloroform 1: 9) gave 4.27 g (11.9 mm) of the title compound.
ol) Obtained as a pale yellow solid. mp 94-95 ° C. 1H-NMRδ (CDCl ₃ ) 8.18 (1H, s), 7.7
4 (1H, d, J = 5.28), 7.35 to 7.51 (3H, m),
7.07 to 7.13 (1H, m), 6.64 (2H, brs), 6.50
(1H, d, J = 5.0 Hz), 4.88 (1H, dd, J =
5.9 Hz, 5.3 Hz), 3.33 to 3.76 (6 H, m), 1.21
(3H, t, J = 7.0 Hz), 1.20 (3H, t, J = 7.
3Hz) IR (KBr) 3393, 2978, 1608, 1594, 1429, 1236
cm-1 (c) 3-amino-4- (2-chlorophenyl)-
Synthesis of 1,7-naphthyridine 2,2-diethoxy-N- [α- (3-amino-4-pyridine) -2-chlorobenzylidene] ethylamine 4.00
g (11.17 mmol) of 10% hydrogen chloride / ethanol solution 6
The solution was dissolved in 0 ml and heated under reflux for 5 hours. After concentration under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (silica gel, methanol: chloroform 1:19) yielded 0.99 g (3.87 mmol) of the title compound as a colorless solid. 1H-NMRδ (CDCl ₃ ) 8.30 (1H, s), 7.8
6 (1H, dd, J = 5.3Hz, 0.7Hz), 7.27 to 7.5
0 (5H, m), 6.95 (1H, d, J = 5.3Hz), 6.2
8 (2H, br)

Reference Example 2 4- (2-chlorophenyl) -1,2-dihydro-1-
Synthesis of methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid

Embedded image (A) ethyl 4- (2-chlorophenyl) -1,2
-Dihydro-2-oxo-1,8-naphthyridine-3-
Synthesis of carboxylate 2-amino-3- (2-chlorobenzoyl) pyridine 3.
91 g (16.8 mmol), diethyl malonate 4.04 g (25.2 mm
ol) and 0.33 g (4.2 mmol) of pyridine in about 17
Heat at 0 ° C. for 5 hours. After allowing to cool, the precipitated crystals were recrystallized from ethanol to give 4.73 g (14.4 mmol) of the title compound.
Obtained as colorless crystals. mp 218-221 ° C. 1H-NMRδ (CDCl ₃ ) 11.53 (1H, br
s), 8.76 (1H, dd, J = 5.0 Hz, 1.32 Hz),
7.26 to 7.57 (5H, m), 7.17 (1H, dd, J = 7.9)
Hz, 5.0 Hz), 4.04-4.17 (2H, m), 0.97 (3
H, t, J = 7.0 Hz) IR (KBr) 1739, 1667, 1613, 1568, 1466, 142
5,1375 cm-1 (b) Synthesis of ethyl 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylate Ethyl 4- (2-chlorophenyl) ) -1,2-Dihydro-2-oxo-1,8-naphthyridine-3-carboxylate 4.50 (13.7 mmol) in 50 ml of N, N-dimethylformamide was added to sodium hydride (60% oily) 54
7 mg (13.7 mg) was added at room temperature, and the mixture was stirred for 0.5 hours. 1.9 g (13.7 mmol) of methyl iodide was added at 0 ° C to 5 ° C,
After stirring at the same temperature for 0.5 hours and at room temperature for 5 hours, the mixture was poured into water and extracted with ethyl acetate. Wash with water, brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure to give the title compound.
60 g (13.4 mmol) was obtained and used for the next reaction without purification. 1H-NMRδ (CDCl ₃ ) 8.65 (1H, dd, J
= 4.6 Hz, 1.7 Hz), 7.29 to 7.56 (5H, m), 7.
10-7.15 (1H, m), 4.07-4.13 (2H, m), 3.92
(3H, s), 0.98 (3H, t, J = 7.0Hz)

(C) Synthesis of 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid Ethyl 1-methyl-4- (2- Chlorophenyl)-
To a solution of 4.6 g (13.4 mmol) of 1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylate in 20 ml of ethanol was added 2.1 g (52.5 mmol) of sodium hydroxide, and the mixture was heated under reflux for 0.5 hour. did. After dilution with water, the mixture was adjusted to pH 4 with a 2N aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from ethyl acetate to give 3.52 g (11.2 mmol) of the title compound as colorless crystals. mp 178-180 ° C. 1H-NMRδ (CDCl ₃ ) 8.80 (1H, dd, J
= 4.6 Hz, 2.0 Hz), 7.39 to 7.57 (4H, m), 7.
24 to 7.29 (1H, dd, J = 7.9 Hz, 4.6 Hz), 7.
11 (1H, dd, J = 7.9 Hz, 2.0 Hz), 4.07 (3
H, s) IR (KBr) 1747, 1612, 1576, 1472, 1446, 1342
cm-1

Reference Example 3 Synthesis of 1-methyl-4- (2-chlorophenyl) -1,2-dihydro-2-oxo-1,7-naphthyridine-3-carboxylic acid

[Chemical 104] It was synthesized in the same manner as in Reference Example 2. mp 250 ° C. or higher 1H-NMRδ (DMSO-d6) 9.08 (1H,
s), 8.41 (1H, d, J = 5.3 Hz), 7.50 to 7.69
(3H, m), 7.40 (1H, dd, J = 7.3 Hz, 1.7
Hz), 6.86 (1H, d, J = 5.3 Hz), 3.82 (3
H, s) IR (KBr) 1722,1657,1434,1295,1251 cm-1 Reference Example 4 1-Methyl-4- (3-methoxyphenyl) -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid

Embedded image It was synthesized in the same manner as in Reference Example 2. mp 196-197 ° C. 1H-NMRδ (CDCl ₃ ) 8.77 (1H, dd, J
= 4.6 Hz, 2.0 Hz), 7.66 (1H, dd, J = 8.
3, 2.0 Hz), 7.44 (1H, t, J = 8.3 Hz), 7.
22-7.25 (1H, m), 7.01-7.05 (1H, m), 6.70
-6.78 (2H, m), 4.04 (3H, s), 3.83 (3H,
s) IR (KBr) 1734, 1624, 1604, 1573, 1462, 1249
cm-1 Reference Example 5 4- (3-methoxyphenyl) -1,2-dihydro-2
Synthesis of -oxo-1,8-naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.84 (1H, d, J = 3.0H
z), 7.69 (1H, d, J = 8.2Hz), 7.46 (1H, dd, J = 7.9Hz, 7.9Hz)
, 7.28 to 7.33 (1H, m), 7.05 (1H, dd, J = 8.3Hz, 1.7Hz), 6.
73 ~ 6.80 (2H, m), 3.84 (3H, s)

Reference Example 6 1-Butyl-4- (3-methoxyphenyl) -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.76 (1H, dd, J = 4.6 Hz,
2.0Hz), 7.65 (1H, dd, J = 7.9Hz, 2.0Hz), 7.43 (1H, dd, J =
7.9Hz, 7.9Hz), 7.22 (1H, dd, J = 7.9Hz, 4.6Hz), 7.02 (1
(H, dd, J = 7.6Hz, 1.6Hz), 6.70-6.78 (2H, m), 4.68-4.74
(2H, m), 3.82 (3H, s), 1.77 to 1.88 (2H, m), 1.45 to 1.59 (2
H, m), 1.03 (3H, t, J = 7.3 Hz) Reference Example 7 1- (2-methoxyethyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8 Synthesis of -naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.76 (1H, dd, J = 4.6 Hz,
2.0Hz), 7.65 (1H, dd, J = 7.9Hz, 2.0Hz), 7.43 (1H, dd, J =
7.9Hz, 7.9Hz), 7.23 (1H, dd, J = 8.3Hz, 4.6Hz), 7.03 (1
H, dd, J = 7.9Hz, 2.6Hz), 6.71-6.79 (2H, m), 4.99 (2H, t,
J = 6.0Hz), 3.88 (2H, t, J = 6.0Hz), 3.83 (3H, s), 3.42 (3H,
s) Reference example 8 1-isopropyl-4- (3-methoxyphenyl)-
Synthesis of 1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.73 (1H, dd, J = 4.6Hz,
1.0Hz), 7.64 (1H, dd, J = 7.9Hz, 2.0Hz), 7.43 (1H, dd, J =
7.9Hz, 7.9Hz), 7.21 (1H, dd, J = 7.9Hz), 6.99 ~ 7.04 (1
H, m), 6.70-6.78 (2H, m), 6.27 (1H, br), 3.82 (3H, s),
1.73 (6H, d, J = 6.9Hz) Reference Example 9 1-methyl-4- (4-methoxyphenyl) -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.76 (1H, dd, J = 4.6 Hz,
1.75), 7.25 (1H, dd, J = 7.9Hz, 4.6Hz), 7.11 (2H, d, J = 8
Hz), 7.05 (2H, d, J = 8.3Hz), 4.04 (3H, s), 3.89 (3H, s)

Reference Example 10 Synthesis of 1- (3-cyanopropyl) -4- (4-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid Reference Example 2 and It synthesize | combined similarly. ¹ H-NMR δ (CDCl ₃ ) 8.76 (1H, dd, J = 4.6 Hz,
2.0Hz), 7.69 (1H, dd, J = 7.9Hz, 2.0Hz), 7.44 (1H, dd, J =
7.9Hz, 7.9Hz), 7.25-7.29 (1H, m), 7.03 (1H, d, J = 7.9H
z), 6.76 (1H, d, J = 7.9 Hz), 6.71 (1H, s), 4.86 (2H, t, J = 6.
9Hz), 3.83 (3H, s), 2.56 (2H, t, J = 6.9 Hz), 2.29 (2H, m) Reference Example 11 1-methyl-4- (2-methoxyphenyl) -1,2-
Synthesis of dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.75 (1H, dd, J = 4.6 Hz,
2.0Hz), 7.63 (1H, dd, J = 8.3Hz, 2.0Hz), 7.44 ~ 7.51 (1
H, m), 7.23 (1H, dd, J = 7.9Hz, 4.6Hz), 6.98 to 7.13 (3H,
m), 4.04 (3H, s), 1.70 (3H, s) Reference Example 12 1-Pentyl-4- (3-methoxyphenyl) -1,2
-Dihydro-2-oxo-1,8-naphthyridine-3-
Synthesis of Carboxylic Acid Synthesis was carried out in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.76 (1H, dd, J = 4.6 Hz,
1.74), 7.64 (1H, dd, J = 8.3Hz, 1.7Hz), 7.42 (1H, dd, J =
7.9Hz, 7.9Hz), 7.22 (1H, dd, J = 8.3Hz, 4.6Hz), 7.02 (1
H, dd, J = 7.9Hz, 2.3Hz), 6.73 (1H, d, J = 7.9Hz), 6.71 (1H,
s), 4.70 (2H, t, J = 7.6Hz), 1.84 (2H, br), 1.46 (4H, br)
, 0.95 (3H, t, J = 6.9 Hz) Reference Example 13 1- (3-Methylbutyl) -4- (3-methoxyphenyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3- Synthesis of carboxylic acid It was synthesized in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.76 (1H, dd, J = 4.6 Hz,
2.0Hz), 7.64 (1H, dd, J = 8.3Hz, 2.0Hz), 7.42 (1H, dd, J =
7.9Hz, 7.9Hz), 7.22 (1H, dd, J = 8.3Hz, 4.6Hz), 7.02 (1
H, dd, J = 8.3Hz, 2.0Hz), 6.76 (1H, d, J = 7.6Hz), 6.71 (1H,
d, J = 2.0Hz), 4.73 (2H, t, J = 7.9Hz), 3.82 (3H, s), 1.67 ~
1.84 (3H, m), 1.06 (6H, d, J = 6.6Hz)

Reference Example 14 Synthesis of 1-butyl-4- (2-pyridyl) -1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid Synthesis was carried out in the same manner as in Reference Example 2. ¹ H-NMR δ (CDCl ₃ ) 8.80 (1H, dd, J = 4.6 Hz,
2.0Hz), 8.76 (1H, dd, J = 4.6Hz, 2.0Hz), 8.45 (1H, d, J =
1.3Hz), 7.55-7.59 (2H, m), 7.45-7.50 (1H, m), 7.26 (1H
H, dd, J = 7.9Hz, 4.6Hz), 4.73 (2H, t, J = 7.6Hz), 1.78-1.
89 (2H, m), 1.46 to 1.59 (2H, m), 1.07 (3H, t, J = 7.3 Hz) Reference Example 15 1- (3-benzyloxypropyl) -4- (3-methoxyphenyl) -1 , 2-dihydro-2-oxo-1,
Synthesis of 8-naphthyridine-3-carboxylic acid It was synthesized in the same manner as in Reference Example 2. _{^{1 H-NMR δ (CDCl 3}} ) 8.74 (1H, dd, J = 4.6Hz,
1.7Hz), 7.62 (1H, dd, J = 7.9Hz, 1.7Hz), 7.43 (1H, dd, J =
7.9Hz, 7.9Hz), 7.20 to 7.37 (5H, m), 7.21 (1H, dd, J = 7.9H
z, 4.6Hz), 7.02 (1H, dd, J = 7.9Hz, 2.6Hz), 6.60-6.75
(2H, m), 4.87 (2H, t, J = 7.3Hz), 4.51 (2H, s), 3.82 (3H,
s), 3.69 (2H, t, J = 5.9Hz), 2.19 (2H, dd, J = 7.3Hz, 5.9Hz)

[0076]

Industrial Applicability The naphthyridine derivative or an acid addition salt thereof of the present invention strongly inhibits ACAT activity in a preparation prepared from rabbit liver and in macrophages derived from rat intraperitoneal cavity. Therefore, not only as a blood lipid lowering agent,
Atherosclerosis itself or various diseases related to atherosclerosis, such as cerebral infarction, cerebral thrombosis, transient cerebral hemorrhage, angina,
It is useful for prevention and treatment of myocardial infarction, peripheral thrombus, occlusion, and the like. The ACAT inhibitory activity of the compound of the present invention is evaluated by the following method. Experimental example 1. Measurement of ACAT Inhibitory Activity in Standard Prepared from Rabbit Liver Enzyme specimen ACAT is described in the literature (J. Lipid. Research, 30, 6).
81-690, 1989), prepared from New Zealand white rabbit livers loaded with a 1% cholesterol diet for one month. ACAT activity is described in the literature (J. Lipid.
Research, 24, 1127-1134, 1983), using radioactive [1-14C] oleoyl-CoA and endogenous cholesterol contained in the liver microsomal fraction. The enzymatic activity was calculated from the radioactivity of the produced labeled cholesterol oleate. The results obtained are shown in Table 1.

[Table 1]

2. Measurement of ACAT Inhibitory Activity in Rat Intraperitoneal Macrophages Rat intraperitoneal macrophages are described in the literature (Biochimica e
t Biophysica Acta, 1126, 73-80, 1992). ACAT activity is described in the above literature (Biochi
mica et Biophysica Acta, 1126, 73-80, 1992) according to the method described in [9,
10-H] oleic acid and literature (Biochimicaet Biophysic
a Acta, 1213, 127-134, 1994), the enzymatic activity was calculated from the radioactivity of labeled cholesteryl oleate produced using exogenous cholesterol contained in the reconstituted liposomes. Table 2 shows the obtained results.

[Table 2]

Claims (16)

[Claims] 1. A compound of the general formula (1) [In the formula, ring A represents a pyridine ring which may have a substituent. X is a compound of the formula (Wherein R ² represents a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group,
Represents a substituted alkynyl group, a cycloalkyl group, or a substituted cycloalkyl group. ) Or the formula [In the formula, W represents a hydrogen atom or a formula-OR ¹ (R ¹ represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, or a substituted alkynyl group.)
Represents ] Represents the group shown by these. Z is a bond, -NH
-, An alkylene group having 1 or 2 carbon atoms or -C
Represents H = CH-. Y is an alkyl group, a substituted alkyl group,
Represents a cycloalkyl group, a substituted cycloalkyl group, an aromatic group or a substituted aromatic group. B represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, a cycloalkyl group, a substituted cycloalkyl group, an aromatic group, or a substituted aromatic group. A naphthyridine derivative or an acid addition salt thereof. 2. The naphthyridine derivative or the acid addition salt thereof according to claim 1, wherein Z is -NH-. (3) ring A is of the formula (a), (b) or (c): Embedded image [Chemical 6] The naphthyridine derivative or an acid addition salt thereof according to claim 1 or 2, which is a group represented by any of the above. 4. X is of the formula: (Wherein R ² represents the same meaning as in claim 1). The naphthyridine derivative or an acid addition salt thereof according to claim 3, which is a group represented by the formula: 5. A naphthyridine derivative or an acid addition salt thereof according to claim 4, wherein B is an aromatic group or a substituted aromatic group. 6. The naphthyridine derivative or an acid addition salt thereof according to claim 5, wherein Y is an aromatic group or a substituted aromatic group. 7. A naphthyridine derivative or an acid addition salt thereof according to claim 6, wherein R ² is an alkyl group, a substituted alkyl group, an alkenyl group or a substituted alkenyl group. 8. The naphthyridine derivative or the acid addition salt thereof according to claim 7, wherein Y is a phenyl group substituted by a lower alkoxy group. 9. Y is a substituted phenyl group, wherein the substituent has the formula -D ¹ -EF (D ¹ is a bond, an oxygen atom,
Represents a sulfur atom or a formula —NR ³ — (R ³ represents a hydrogen atom or a lower alkyl group), and E represents a divalent hydrocarbon group having 1 to 6 carbon atoms which may contain an unsaturated bond, or Represents a phenylene group, F is a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a halogen atom, a cyano group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group,
Lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group,
Lower alkylsulfonamide group, phthalimido group, heteroaryl group, formula -NR ⁴ R ⁵ (R ⁴ and R ⁵ independently of each other represent a hydrogen atom or a lower alkyl group, or R ⁴ and R ⁵ are bonded to each other. to, together with the nitrogen atom to which they are attached, further in the ring -NR ⁸ -
(R ⁸ represents a hydrogen atom, a lower alkyl group, a phenyl group, or a benzyl group.) Or a saturated 5- to 7-membered cyclic amino group which may contain one oxygen atom. ) Or the formula —C (═O) NR ⁴ R ⁵ (R ⁴ , R
⁵ represents the above meaning. ) Represents. The naphthyridine derivative or the acid addition salt thereof according to claim 7, which is represented by｝. 10. Y is of the formula -D ¹ -E-F {D ¹ and E.
Represents the same meaning as in claim 9, and F represents (R ⁸ represent. The same meaning as in claim 9) naphthyridine derivative or an acid addition salt according to claim 9, wherein a phenyl group substituted with}. 11. A naphthyridine derivative or an acid addition salt thereof according to claim 9, wherein D ¹ is an oxygen atom. 12. A naphthyridine derivative or an acid addition thereof according to claim 11, wherein F is a hydroxyl group, a heteroaryl group, or the formula --NR ⁴ R ⁵ (R ⁴ and R ⁵ have the same meanings as in claim 9). salt. 13. The naphthyridine derivative or its acid addition salt according to claim 7, 8, 9, 11 or 12, wherein ring A is an unsubstituted pyridine ring. 14. A medicine containing the naphthyridine derivative or the acid addition salt thereof according to any one of claims 1 to 13. 15. An acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor containing the naphthyridine derivative according to any one of claims 1 to 13 or an acid addition salt thereof as an active ingredient. 16. A therapeutic agent for hyperlipidemia or arteriosclerosis, which comprises the naphthyridine derivative according to any one of claims 1 to 13 or an acid addition salt thereof as an active ingredient.