JP2000128878A - Benzofuryl-alpha-pyridone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzofuryl-α-pyridone derivative, where α-pyridone group is substituted for denzofuryl one, useful as a lipid metabolism-improving agent, an arteriosclerosis-preventing agent, and especially useful as a triglyceride biosynthesis-inhibiting agent, an in-blood triglyceride-lowering agent or the like. SOLUTION: This new compound is expressed by the formula [wherein, R1 is H, a 7-20C aralkyl or the like; R2 is a 1-5C alkyl; R3 is H, CO-R6 (wherein, R6 is H, a heterocycle or the like) or the like; R4 is H, a 2-5C alkenyl or the like; R5 is R5a (wherein, R5a is H, nitro or the like) or the like, and a substituent located at the 4, 5, 6, or 7 position of benzofuran ring] and is, e.g. 6-[5-(3- pyridyl)methyloxybenzofuran-2-yl]-3,5-dimethyl-4-hydroxy-2H-pyrid-2-one. The compound of the formula is obtained, e.g. by treating a solution of a 2,4-two substitution-β-keto ester with a base to convert into a dienolate, by reacting it with a benozofurancarboxylate to form a diketo ester intermediate and by its alkaline hydrolysis, followed by the acid treatment of a product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel benzofuryl-α-pyridone derivative and a medicament containing the same as an active ingredient. More specifically, the present invention relates to a novel benzofuryl-α-pyridone derivative, a lipid metabolism improving agent, an arteriosclerosis preventive or a therapeutic agent for arteriosclerosis, and a triglyceride biosynthesis inhibitor, a blood triglyceride containing the same as an active ingredient. It relates to a lowering agent or a blood HDL-elevating agent.

[0002]

2. Description of the Related Art Generally, cholesterol and triglyceride (TG; neutral fat) in blood do not dissolve in blood by themselves, and therefore exist as lipoprotein by binding to apoprotein. Triglycerides are mainly derived from acetyl-CoA produced from sugars and other raw materials in the body, mainly from the liver.
It is biosynthesized by fatty acid acyl-CoA synthetase, glycerophosphate acyltransferase, lysophosphatidic acid acyltransferase, phosphatidic acid phosphatase, diacylglycerol acyltransferase) and secreted from the liver into the blood as lipoproteins.

[0003] A condition in which cholesterol and / or triglyceride in the blood is higher than a standard value is called hyperlipidemia.
According to the Fredrickson classification (WHO classification), the condition called hyperlipidemia is classified into six types by lipoproteins in blood. Of these, types I, IV, and V have only increased triglycerides, type IIa has increased cholesterol, and types IIb and III have increased both (Clinical Studies, 43 , 871 (1994)). For this reason, existing hyperlipidemic drugs (those that lower only cholesterol or those that lower both cholesterol and triglycerides) cannot always cope with all types of hyperlipidemia. In particular, type IV accounts for 40-50% of male hyperlipidemic patients (Clinical and Research, 69 , 318 (199
2)). In the case of secondary onset due to diabetes or the like, most of them are type IV (general clinical studies, 43 , 878 (199
Four)).

[0004] So-called hypertriglyceridemia is a condition in which the amount of triglyceride in the blood is increasing. In recent years, clinicians and pharmaceutical manufacturers have been attracting attention as a risk factor for arteriosclerosis and ischemic heart disease. It has come to be.

[0005] In the field of hyperlipidemia including hypertriglyceridemia, only cholesterol, which is considered to be directly related to arteriosclerosis, has attracted attention so far, and there are still few drugs aimed at lowering triglyceride. For treatment of triglyceridemia, clofibrate antilipidemic agents and nicotinic acid preparations, which are present as antilipidemic agents, are merely used. In addition, these are used in high doses, and multiple points of action have been reported,
Some side effects (The Lipid, 5 , 64-72 (1994)) are also of concern. From these facts, a new type of drug that has a triglyceride lowering effect at a low dose, has no side effects, and has a clear mode of action has been desired. Hypertriglyceridemia can be caused by a variety of causes, such as when there is a genetic background or as described above, secondary to diabetes, etc. (Comprehensive Clinic, 43 , 878 (1994)). A. Increased triglyceride synthesis (secretion) in the liver B. Delayed degradation of synthesized triglyceride (present in blood as lipoprotein) by lipoprotein lipase (LPL) (Clinical and research, 69 , 340 (1992)) Conceivable. In particular, in hypertriglyceridemia associated with diabetes, non-insulin-dependent diabetes (N
It is said that the cause is A. in the case of IDDM) and B. in the case of insulin-dependent diabetes mellitus (IDDM) (Clinical and Research, 69 , 379 (1992)). Therefore, the mechanism of action of the therapeutic agent for hypertriglyceridemia may be to inhibit triglyceride synthesis (secretion) in the liver and / or lipoprotein lipase (LPL) of synthesized triglyceride (present in the blood as lipoprotein). ) May be promoted.

On the other hand, conventionally, α-pyridone derivatives in which an oxygen functional group such as a hydroxy group or an acyloxy group is substituted in the 4-position and a heteroaromatic ring is substituted in the 6-position are described in, for example, WO 96
No. 30342, DE 4138819, US 4124714,
It is known from US 4064251.

However, any of these conventional α-pyridone derivatives has a triglyceride biosynthesis inhibitory action, a blood triglyceride lowering action or a blood HD.
There is no description or suggestion of an L-elevating effect.

[0008] Among the above-mentioned prior arts, the one described in WO 9630342 has a structural feature in which the 1-position nitrogen atom of the α-pyridone ring is substituted with an oxygen functional group such as a hydroxy group or an alkoxy group. And α-
There is no description or suggestion of using a hydrogen atom or an alkyl group in place of the substituent at the 1-position nitrogen atom of the pyridone ring for an oxygen functional group such as a hydroxy group or an alkoxy group.

[0009] Among the above-mentioned prior arts, the one described in DE 4138819 discloses that the substituent at the 3-position of the α-pyridone ring is a carbamoyl group (CO-NR1R2) or a thiocarbamoyl group (CS-NR1R2). There is no description or suggestion about using a hydrogen atom or an alkyl group instead of the carbamoyl group or thiocarbamoyl group for the substituent at the 3-position of the α-pyridone ring.

[0010] Similarly, of the prior art, US Pat.
No. 4714 or US Pat. No. 4,064,251 discloses that the substituent at the 3-position of the α-pyridone ring is a C ((NX) Ph group or C (= NX) R (where X is a nitrogen atom). Represents a substituent, R
Represents a lower alkyl group), and the use of a hydrogen atom or an alkyl group instead of the C (= NX) Ph group or C (= NX) R for the substituent at the 3-position of the α-pyridone ring is described. No mention or suggestion.

[0011]

That is, an object of the present invention is to provide a benzofuryl-α-pyridone derivative, especially a novel benzofuryl-α-pyridone derivative in which a benzofuryl group is substituted at the 6-position of an α-pyridone ring. is there.

It is a further object of the present invention to provide a novel benzofuryl-α wherein the benzofuryl group is substituted at the 6-position of the α-pyridone ring.
-To provide a lipid metabolism improving agent containing a pyridone derivative as an active ingredient, an arteriosclerosis preventive agent or an arteriosclerosis therapeutic agent,
In particular, an object of the present invention is to provide a triglyceride biosynthesis inhibitor, a blood triglyceride lowering agent or a blood HDL increasing agent.

[0013]

In view of such prior art, the present inventors have conducted various studies and found that benzofuryl-α-pyridone derivatives, in particular, benzofuryl having a benzofuryl group substituted at the 6-position of the α-pyridone ring. The present invention has been accomplished by finding that -α-pyridone derivatives have a triglyceride biosynthesis inhibitory action, a blood triglyceride lowering action or a blood HDL increasing action.

That is, the present invention provides the following formula (I)

[0015]

Embedded image

[Wherein, R ¹ is a hydrogen atom or a carbon number of 1 to 5
R ² is a hydrogen atom or a carbon number of 1 to 5
R ³ is a hydrogen atom, -CO-R ⁶ (where R ⁶
Is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may be substituted with an optional substituent, a cycloalkyl group having 3 to 7 carbon atoms,
Represents an aryl group or a hetero ring having 6 to 10 carbon atoms. ) Or -SO ₂ R ⁷ (where R ⁷ represents an alkyl group having 1 to 5 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with a halogen atom), and R ⁴ is hydrogen. Atom, carbon number
Alkyl group of 1-5, alkenyl group of 2-5 carbon atoms, carbon number
2-5 alkynyl group, C3-C7 cycloalkyl group,
C3-7 cycloalkyl-C1-5 alkyl group, C6-10 aryl group, C7-20 aralkyl group,
Represents an alkoxy group having 1 to 5 carbon atoms or an aryloxy group having 6 to 10 carbon atoms, and R ⁵ is the 4-position, 5-position of the benzofuran ring,
A 6-position or 7-position substituent, R ^5a (wherein R ^5a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a heterocyclic, alkenyl group having 2 to 5 carbon atoms, 2 to 5 carbon atoms Alkynyl group, aryl group having 6 to 10 carbon atoms, A = CH (CH ₂ ) _n- (where
A represents an alicyclic heterocycle, = represents a double bond,
n represents 0, 1 or 2. ), A = CH (CH ₂ ) _m O- (where A
Represents an alicyclic heterocyclic ring, = represents a double bond, m
Represents 1, 2 or 3. ), A-SO _2- (CH ₂ ) _m- (where A
Represents an alicyclic heterocycle, and m represents 1, 2 or 3. ), -OR ⁸ (where R ⁸ is a hydrogen atom, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heterocycle, or a carbon atom which may be substituted with a halogen atom having 1 to 4 carbon atoms. Represents an alkylsulfonyl group or an arylsulfonyl group having 6 to 10 carbon atoms.), —O—CO—R ⁹ (where R ⁹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and an alkyl group having 6 to 10 carbon atoms) An aryl group, an aralkyl group having 7 to 20 carbon atoms or a heterocyclic ring.), -NR ¹⁰ R ¹¹ (where R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, 7-20 carbon atoms
Represents an aralkyl group, a heterocyclic ring, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, or an arylsulfonyl group having 6 to 10 carbon atoms. ), -NR ¹² -C
OR ¹³ (where R ¹² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, and R ¹³ represents a hydrogen atom, Alkyl group of 1-4, aryl group of 6-10 carbon atoms, aralkyl group of 7-20 carbon atoms, heterocycle, alkoxy group of 1-4 carbon atoms, carbon number
Represents an aryloxy group having 6 to 10 or an aralkyloxy group having 7 to 20 carbon atoms. ), -CO-R ¹⁴ (where R ¹⁴ is a hydrogen atom, -OH, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, carbon atom number
Represents an aryloxy group having 6 to 10 or an aralkyloxy group having 7 to 20 carbon atoms. ) Or -CO-NR ¹⁵ R ¹⁶ (where
R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms,
Represents an aryl group having from 10 to 10; an aralkyl group having from 7 to 20 carbon atoms; or a heterocyclic ring. ). ), R ^5b (where R ^5b is a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a heterocyclic ring, -OR ¹⁷ (where R ¹⁷ is a hydrogen atom, Represents an alkyl group, a phenyl group, a naphthyl group, a benzyl group or a hetero ring.), -O-CO-R
¹⁸ (where R ¹⁸ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Represents a phenyl group, a naphthyl group, a benzyl group or a hetero ring. ), -NR ¹⁹ R ²⁰ (where R ¹⁹ and R ²⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a heterocyclic ring, a carbon atom which may be substituted with a halogen atom) Represents an alkylsulfonyl group or a phenylsulfonyl group of 1 to 4), —NR ²¹ —CO—R ²² (where R
²¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, 6 to 1 carbon atoms
Represents an aryl group of 0, an aralkyl group having 7 to 20 carbon atoms,
R ²² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, a hetero ring, an alkoxy group or a benzyloxy group having 1 to 4 carbon atoms. ), -C
OR ²³ (where R ²³ is a hydrogen atom, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, a benzyloxy group or
-OR ²⁴ (where R ²⁴ represents a hydrogen atom or a heterocyclic ring). ) And -CO-NR ²⁵ R ²⁶ (where R ²⁵ , R
²⁶ each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a heterocyclic ring. Represents a saturated or unsaturated alkoxy group having 1 to 6 carbon atoms which may be substituted by 1 to 3 groups selected from the group consisting of: ) Or R ^5c (where R ^5c is a halogen atom, carbon number
3 to 7 cycloalkyl group, phenyl group, naphthyl group, hetero ring, -OR ²⁷ (where R ²⁷ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, phenyl group, naphthyl group, benzyl group or hetero ring represents), -. O-CO- R 28 ( wherein R ²⁸ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, or a heterocyclic), -. NR ²⁹ R ³⁰
(Where R ²⁹ and R ³⁰ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a heterocyclic ring, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom. Or a phenylsulfonyl group.), -NR
³¹ -CO-R ³² (where R ³¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, and R ³² represents a hydrogen atom Represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms or a benzyloxy group.), -CO-R ³³ (where R ³³ is hydrogen atom, a hetero ring, an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, a benzyloxy group or -OR ³⁴ (wherein R ³⁴ represents a hydrogen atom or a hetero ring.).) and -CO-NR ³⁵ R
³⁶ (where R ³⁵ and R ³⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a heterocyclic ring), and are substituted with 1 to 3 groups selected from the group consisting of Represents an optionally substituted alkyl group having 1 to 4 carbon atoms. ), And the numbers in italics 4 to 7 represent the position numbers on the benzofuran ring. A benzofuryl-α-pyridone derivative or a salt thereof.

Further, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the benzofuryl-α-pyridone derivative or a salt thereof and a pharmaceutically acceptable carrier, and a benzofuryl-α-pyridone derivative or a salt thereof. They are a triglyceride biosynthesis inhibitor, a blood triglyceride lowering agent, and a blood HDL raising agent as active ingredients.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The terms used herein alone or in combination are described below. It should be noted that the present invention is not limited to the range specifically illustrated below.

The term "alkyl" refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,
It means a straight-chain or branched-chain alkyl group such as an isopentyl group and a 3-pentyl group.

The term "alkenyl" refers to linear or branched such as vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl and the like. Means a chain alkenyl group.

The term "alkynyl" refers to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 1-pentynyl , 2-pentynyl, 3-pentynyl, 4-pentynyl and the like.

The term "cycloalkyl" means a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

The term "C3-C7 cycloalkyl-C1
`` -5 alkyl group '' represents a group consisting of the above-mentioned cycloalkyl group having 3 to 7 carbon atoms and the alkyl group having 1 to 5 carbon atoms, for example, a cyclopropylmethyl group, a cyclopentylmethyl group, a cyclopentylethyl group , Cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like.

The term "aryl" means an aromatic ring having 6 to 10 carbon atoms such as a phenyl group and a naphthyl group.

The term "heterocycle" is a heterocycle containing 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as a component of the ring, and includes an imidazolyl group, a thiazolyl group, Isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyrrolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, triazinyl group, furyl group, thienyl group,
An oxazolyl group, a 5- or 6-membered heteroaromatic group such as an isoxazolyl group, or a thiazolidinyl group, an oxazolidinyl group, an imidazolidinyl group, a pyrrolidinyl group, a piperidyl group, a morpholinyl group, a piperazinyl group,
A 5- or 6-membered alicyclic heterocyclic group such as a tetrahydrofuryl group, a tetrahydropyranyl group, or a dioxolanyl group, which is a benzene ring, a cycloalkyl having 3 to 7 carbon atoms or another heteroaromatic or alicyclic heterocyclic group; It also contains a bicyclic group fused to the ring, and may have an arbitrary substituent on the ring of the heteroaromatic ring and the alicyclic heterocyclic ring.If chemically possible, the nitrogen atom and the sulfur atom are oxidized. It may be a type.

The term "heteroaryl" means a heteroaromatic group of the heterocycle defined above.

The term "aralkyl" refers to the above-mentioned C 1 -C 5
Represents a group having 7 to 20 carbon atoms consisting of an alkyl group and the aryl group having 6 to 10 carbon atoms, for example, a benzyl group, a phenethyl group, a phenylpropyl group, a benzhydryl group,
Examples include a trityl group and a naphthylmethyl group.

The term "alkoxy" refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyl It means a linear or branched alkoxy group such as an oxy group, a 3-pentyloxy group, a 2,2-dimethylpropoxy group, an n-hexyloxy group, a 4-methylpentyloxy group, and a 2-ethylbutoxy group.

The term "unsaturated alkoxy" includes vinyloxy, allyloxy, 2-propenyloxy, 2-propynyloxy, 2-methyl-2-propenyloxy, 1-
Butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 2-butynyloxy group, 2-pentenyloxy group,
It means a linear or branched unsaturated alkoxy group such as a 3-hexenyloxy group, a 5-hexenyloxy group, and a 5-hexynyloxy group.

The term "aryloxy" means an aryloxy group having 6 to 10 carbon atoms such as a phenoxy group and a naphthyloxy group.

The term "aralkyloxy" represents a group consisting of the above-mentioned alkoxy group having 1 to 5 carbon atoms and the above-mentioned aryl group having 6 to 10 carbon atoms, for example, benzyloxy group, phenethyloxy group, phenylpropoxy group. Group, trityloxy group, naphthylmethyloxy group and the like.

The term "cycloalkyloxy" means a cycloalkyloxy group having 3 to 7 carbon atoms such as a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group.

The term "acyl" is intended to include formyl, acetyl, propionyl, n-butyryl, isobutyryl,
It means a linear or branched acyl group having 1 to 6 carbon atoms such as n-valeryl group, trimethylacetyl group, 3,3,3-trimethylpropionyl group and the like.

The term "arylcarbonyl" means an arylcarbonyl group having 7 to 11 carbon atoms such as a benzoyl group and a naphthylcarbonyl group.

The term "alkylsulfonyl" means an alkylsulfonyl group having 1 to 5 carbon atoms such as a methanesulfonyl group, an ethanesulfonyl group and an n-propanesulfonyl group.

The term "arylsulfonyl" refers to a phenylsulfonyl group, a naphthalenesulfonyl group or the like having 6 to 1 carbon atoms.
It means 0 arylsulfonyl group.

Aromatic rings such as the terms "aryl", "phenyl", "naphthyl", "heteroaryl" and the like are known as substituents on such aromatic rings, for example, --OH, carboxyl, cyano, sulfone. amide groups, -SO ₃ H, amino group, a methylenedioxy group, an alkoxy group having 1 to 5 carbon atoms, such as methoxy, ethoxy, n- propoxy group,
Isopropoxy group, n-butoxy group, isobutoxy group, t-
Butoxy group, n-pentyloxy group and the like; alkylamino group such as methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, isobutylamino group, t-butylamino group and the like; acylamino group such as formamino group, acetylamino group, propionylamino group and n-butyrylamino group; alkoxycarbonylamino group such as methoxycarbonylamino group, ethoxycarbonylamino group and n-propoxycarbonylamino Groups, n-butoxycarbonylamino groups, t-butoxycarbonylamino groups, etc .; aralkyloxycarbonylamino groups, such as benzyloxycarbonylamino groups, naphthylmethyloxycarbonylamino groups, etc .; alkylsulfonylamino groups, such as methanes Ruphonylamino group, ethanesulfonylamino group, n-propanesulfonylamino group, etc .; arylsulfonylamino group, for example, phenylsulfonylamino group, naphthalenesulfonylamino group, etc .; Methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-
An aralkyl group such as a benzyl group, a phenethyl group, a trityl group, a naphthylmethyl group; an aralkyloxy group such as a benzyloxy group, a phenethyloxy group, a phenylpropoxy group, a trityloxy group, a naphthylmethyloxy group; Groups such as formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, trimethylacetyl,
3,3,3-trimethylpropionyl group and the like; alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group and the like; aryloxy A carbonyl group such as a phenoxycarbonyl group or a naphthyloxycarbonyl group; an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a trityloxycarbonyl group or a naphthylmethyloxycarbonyl group; a carbamoyl group or an alkylcarbamoyl group; Methyl carbamoyl group, dimethyl carbamoyl group, ethyl carbamoyl group, diethyl carbamoyl group, n-propyl carbamoyl group, n-butyl carbamoyl group; halogenated methyl group, For example, a chloromethyl group, a bromomethyl group, a trifluoromethyl group and the like; and a halogen atom, that is, even if substituted with 1 to 4 substituents selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom And, if chemically possible, it may be substituted with 1-3 oxo or thioxo groups.

In the above formula (I), R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. Examples of such an alkyl group having 1 to 5 carbon atoms include a methyl group, an ethyl group, and an n-
Examples thereof include propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, and 3-pentyl.

Preferred examples of R ¹ include a hydrogen atom, a methyl group, an ethyl group and an isopropyl group, and particularly preferred groups of R ¹ include a hydrogen atom.

Preferred examples of R ² include a hydrogen atom, a methyl group, an ethyl group and an isopropyl group, and particularly preferred groups of R ¹ include a methyl group.

In the above formula (I), R ³ is a hydrogen atom, -C
OR ⁶ (where R ⁶ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may be substituted with an arbitrary substituent, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms or Represents a heterocyclic ring) or —SO ₂ R ⁷ (where R ⁷ represents an alkyl group having 1 to 5 carbon atoms or an aryl group having 6 to 10 carbon atoms, which may be substituted with a halogen atom). .

[0042] Here, R ³ is -CO-R ^6, such a case R ⁶ is an alkyl group having carbon atoms which may be have 1-5 substituted with any substituent, the number of carbon atoms of R ⁶ 1 Examples of the alkyl group of 5 to 5 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, an isopentyl group and
Examples thereof include a 3-pentyl group, and among them, a methyl group, an ethyl group, and an isopropyl group are preferable.

The optional substituent of the alkyl group having 1 to 5 carbon atoms of R ⁶ includes all the substituents for the alkyl group known to those skilled in the art, for example, a halogen atom, -O
H, carboxyl group, formyl group, acyl group, cyano group, nitro group, amino group, mercapto group, sulfonic acid group, aryl group having 6 to 10 carbon atoms, heterocycle, 3 to 7 carbon atoms
And protected groups thereof, and more specifically, -OH; an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, and 7 to 20 carbon atoms. Aralkyl group, heterocyclic ring, acyl group having 1 to 5 carbon atoms, 7 carbon atoms
A hydroxyl group protected by an arylcarbonyl group having from 11 to 11 or an aralkylcarbonyl group having from 8 to 21 carbon atoms; -O-CO-Het
(Where Het represents a heterocycle); a cycloalkyl group having 3 to 7 carbon atoms; an aryl group having 6 to 10 carbon atoms;
An amino group; an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, an arylsulfonyl group having 6 to 10 carbon atoms, Acyl group having 1 to 5 carbon atoms, 7 to 11 carbon atoms
An arylcarbonyl group, an aralkylcarbonyl group having 8 to 21 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an aralkyloxycarbonyl group having 8 to 21 carbon atoms or an amino group protected with a heterocyclic ring; -NH-CO- Het (where Het represents a heterocycle); an acyl group having 1 to 5 carbon atoms; a carboxyl group; an alkoxycarbonyl group having 2 to 5 carbon atoms;
An aryloxycarbonyl group having 7 to 11; an aralkyloxycarbonyl group having 8 to 21 carbon atoms; -CO-OHet (where Het represents a heterocycle); a carbamoyl group; an alkylcarbamoyl group having 2 to 5 carbon atoms; 8-21 aralkylcarbamoyl groups; -CO-NH-Het (where Het represents a heterocycle); and -CO-Het (where Het represents a heterocycle)
Among them, phenyl group, aryloxy group,
Amino group, t-butoxycarbonylamino group, benzyloxycarbonylamino group, (benzyloxycarbonylamino) methylamino group, acetylamino group and morpholinecarbonyl group are mentioned as preferred substituents.

R ³ is —COR ⁶ , wherein R ⁶ has 3 to 7 carbon atoms
When it is a cycloalkyl group, as the cycloalkyl group having 3 to 7 carbon atoms of R ⁶ , for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and cycloheptyl group, and the like, among which cyclohexyl group Is preferred.

R ³ is —COR ⁶ , wherein R ⁶ has 6 to 10 carbon atoms
In the case of the aryl group, the aryl group having 6 to 10 carbon atoms of R ⁶ includes, for example, a phenyl group and a naphthyl group, among which a phenyl group is preferable.

When R ³ is —COR ⁶ and R ⁶ is a heterocyclic ring, examples of the heterocyclic ring of R ⁶ include an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, a triazolyl group, a pyrrolyl group, Pyridyl group, pyrimidinyl group, pyrazinyl group, furyl group, thienyl group, isoxazolyl group, thiazolidinyl group, oxazolidinyl group, imidazolidinyl group, pyrrolidinyl group, piperidyl group, morpholinyl group, piperazinyl group, tetrahydrofuryl group, tetrahydropyranyl group and the like. And
Among them, a pyridyl group, a pyrrolidinyl group and a furyl group are preferred.

As such a preferable group of R ⁶ , an alkyl group having 1 to 5 carbon atoms which may be substituted by an arbitrary substituent, among which a methyl group, or a phenyl group, an aryloxy group, an amino group, t-butoxycarbonylamino group,
Benzyloxycarbonylamino, (benzyloxycarbonyl) -N-methylamino, methyl or ethyl substituted with acetylamino or morpholinecarbonyl, and isopropyl; aryl having 6 to 10 carbon atoms, A phenyl group; and a heterocyclic ring, among which a pyridyl group, a pyrrolidinyl group and a furyl group can be exemplified.

When R ³ is —SO ₂ R ⁷ and R ⁷ is an alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom, even when R 3 is substituted with a halogen atom for R ⁷ Examples of good alkyl groups having 1 to 5 carbon atoms include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
Examples include an isobutyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, a chloromethyl group, a bromomethyl group, and a trifluoromethyl group. Among them, a methyl group and a trifluoromethyl group are preferable.

R ³ is —SO ₂ R ⁷ , wherein R ⁷ has 6 to 1 carbon atoms
When the aryl group is 0, examples of the aryl group having 6 to 10 carbon atoms for R ⁷ include a phenyl group and a naphthyl group, with a phenyl group being preferred.

Preferred examples of such a group represented by R ⁷ include an alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom. Particularly preferred groups represented by R ⁷ are a methyl group and a trifluoromethyl group. Groups.

Preferred examples of such a group represented by R ³ include a hydrogen atom, —COR ⁹⁴ (where R ⁹⁴ is an alkyl group having 1 to 5 carbon atoms, which may be substituted with an arbitrary substituent, and 6 to 10 carbon atoms). And an alkylsulfonyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom. Particularly preferred groups for R ³ are a hydrogen atom and —COR ⁹⁵ ( Here, R ⁹⁵ is a methyl group, a phenyl group, an aryloxy group, an amino group, a t-butoxycarbonylamino group, a benzyloxycarbonylamino group, a (benzyloxycarbonyl) -N-methylamino group, an acetylamino group, or a morpholinecarbonyl group. A methyl or ethyl group substituted with: an isopropyl group; a phenyl group;
Pyridyl group; represents a pyrrolidinyl group or a furyl group. ), A methanesulfonyl group and a trifluoromethanesulfonyl group.

In the above formula (I), R ⁴ represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, and a cycloalkyl having 3 to 7 carbon atoms. Alkyl group, C3-C7 cycloalkyl-C1-C5 alkyl group, C6-C10 aryl group, C7-C20 aralkyl group, C1-C5 alkoxy group or C6-C6 Represents 10 aryloxy groups.

When R ⁴ is an alkyl group having 1 to 5 carbon atoms, examples of the alkyl group having 1 to 5 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -Butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group and the like, and among them, methyl group, ethyl group, isopropyl group and n-pentyl group are preferable.

When R ⁴ is an alkenyl group having 2 to 5 carbon atoms, examples of the alkenyl group having 2 to 5 carbon atoms include vinyl, allyl, 1-propenyl, isopropenyl, 2-
Examples thereof include a butenyl group, a 3-butenyl group, a 1-pentenyl group and a 2-pentenyl group, with a 2-butenyl group being preferred.

When R ⁴ is an alkynyl group having 2 to 5 carbon atoms, examples of the alkenyl group having 2 to 5 carbon atoms include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group,
Examples thereof include a butenyl group, a 3-butenyl group, a 1-pentenyl group and a 2-pentenyl group, with a 2-butenyl group being preferred.

When R ⁴ is a cycloalkyl group having 3 to 7 carbon atoms, the cycloalkyl group having 3 to 7 carbon atoms includes
For example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like can be mentioned, and among them, a cyclohexyl group is preferable.

R ⁴ is a cycloalkyl having 3 to 7 carbon atoms and a carbon number of 1 to
When it is a 5-alkyl group, such a C3-C7 cycloalkyl-C1-C5 alkyl group includes, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and a cycloheptylmethyl group. And the like, and among them, a cyclopentylmethyl group is preferable.

When R ⁴ is an aryl group having 6 to 10 carbon atoms, examples of the aryl group having 6 to 10 carbon atoms include a phenyl group and a naphthyl group, and among them, a phenyl group is preferable.

When R ⁴ is an aralkyl group having 7 to 20 carbon atoms, examples of the aralkyl group having 7 to 20 carbon atoms include a benzyl group, a phenethyl group, a phenylpropyl group,
Examples include a benzhydryl group, a trityl group, and a naphthylmethyl group, and among them, a benzyl group is preferable.

When R ⁴ is an alkoxy group having 1 to 5 carbon atoms, examples of the alkoxy group having 1 to 5 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. Groups, isobutoxy group, sec-butoxy group, t-butoxy group and the like, among which methoxy group is preferable.

When R ⁴ is an aryloxy group having 6 to 10 carbon atoms, examples of the aryloxy group having 6 to 10 carbon atoms include a phenoxy group and a naphthyloxy group. preferable.

A preferable group for R ^{4 is} a group having carbon atoms
Alkyl group of 1-5, alkenyl group of 2-5 carbon atoms, carbon number
3-7 cycloalkyl-an alkyl group having 1 to 5 carbon atoms and an aralkyl group having 7 to 20 carbon atoms, and a particularly preferable group of R ⁴ is an alkyl group having 1 to 5 carbon atoms, among which a methyl group, Examples include ethyl group, isopropyl group and n-pentyl group; C 3-7 cycloalkyl-C 1-5 alkyl group, especially cyclopentylmethyl group; and benzyl group.

In the above formula (I), R ⁵ is a substituent at the 4-, 5-, 6- or 7-position of the benzofuran ring;
^5a (where R ^5a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a heterocyclic ring, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, an aryl group having 6 to 10 carbon atoms, A = C
H (CH ₂ ) _n- (where A represents an alicyclic heterocycle, = represents a double bond, and n represents 0, 1 or 2), A = CH (C
H ₂ ) _m O- (where A represents an alicyclic heterocycle, = represents a double bond, and m represents 1, 2 or 3), A-SO _2- (C
H ₂ ) _m- (where A represents an alicyclic heterocycle, m is 1, 2
Or 3 ), -OR ⁸ (where R ⁸ is a hydrogen atom, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heterocyclic ring, a carbon atom which may be substituted with a halogen atom having 1 to 4 carbon atoms. Represents an alkylsulfonyl group or an arylsulfonyl group having 6 to 10 carbon atoms.), —O—CO—R ⁹ (wherein
R ⁹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, 6 to 10 carbon atoms
An aralkyl group having 7 to 20 carbon atoms or a heterocyclic ring. ), -NR ¹⁰ R ¹¹ (where R ¹⁰ and R ¹¹ are each independently substituted with a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a heterocyclic ring, a halogen atom) Represents an alkylsulfonyl group having 1 to 4 carbon atoms or an arylsulfonyl group having 6 to 10 carbon atoms.), -NR ¹² -CO-R ¹³ (where R ¹² is a hydrogen atom, a carbon atom having 1 to 4 carbon atoms). Represents an alkyl group of 4, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, R ¹³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, Represents an aralkyl group having 7 to 20 carbon atoms, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, or an aralkyloxy group having 7 to 20 carbon atoms.), -CO-R
¹⁴ (where R ¹⁴ is a hydrogen atom, -OH, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heterocyclic ring,
An aryloxy group having 6 to 10 carbon atoms or an aralkyloxy group having 7 to 20 carbon atoms. ) Or -CO-NR ¹⁵ R ¹⁶ (where R ¹⁵ and R ¹⁶ are each independently
Hydrogen atom, alkyl group having 1 to 4 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, aryl group having 6 to 10 carbon atoms, 7 to 20 carbon atoms
Represents an aralkyl group or a hetero ring. ). ), R ^5b (where R ^5b is a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a heterocyclic ring, -OR ¹⁷ (where R ¹⁷ is a hydrogen atom, Represents an alkyl group, a phenyl group, a naphthyl group, a benzyl group or a hetero ring.), -O-CO-R ¹⁸ (where R ¹⁸ is a hydrogen atom,
Represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group or a hetero ring. ), -NR ¹⁹ R ²⁰ (where R ¹⁹ and R ²⁰ each independently represent a hydrogen atom,
An alkyl group, a benzyl group, a heterocyclic ring, an alkylsulfonyl group having 1 to 4 carbon atoms and a phenylsulfonyl group which may be substituted with a halogen atom. ), -NR ²¹ -CO-R
²² (where R ²¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, and R ²² represents a hydrogen atom, 4, alkyl group, phenyl group, naphthyl group, benzyl group, heterocycle,
Represents an alkoxy group having 1 to 4 carbon atoms or a benzyloxy group. ), -CO-R ²³ (where R ²³ is a hydrogen atom, a heterocycle,
Represents an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, a benzyloxy group or —OR ²⁴ (where R ²⁴ represents a hydrogen atom or a heterocyclic ring). ) And -CO-NR ²⁵ R ²⁶ (where R ²⁵ and R ²⁶ are each independently a hydrogen atom, a carbon number 1-4)
Represents an alkyl group, a benzyl group or a hetero ring. Represents a saturated or unsaturated alkoxy group having 1 to 6 carbon atoms which may be substituted by 1 to 3 groups selected from the group consisting of: ) Or R ^5c (where R ^5c is a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group,
Heterocycle, -OR ²⁷ (wherein R ²⁷ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, or a heterocyclic.), - O-CO- R 28 ( wherein R ²⁸ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group or a heterocyclic ring.), —NR ²⁹ R ³⁰
(Where R ²⁹ and R ³⁰ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a heterocyclic ring, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom. Or a phenylsulfonyl group.), -NR
³¹ -CO-R ³² (where R ³¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, and R ³² represents a hydrogen atom Represents an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms or a benzyloxy group.), -CO-R ³³ (where R ³³ is hydrogen atom, a hetero ring, an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, a benzyloxy group or -OR ³⁴ (wherein R ³⁴ represents a hydrogen atom or a hetero ring.).) and -CO-NR ³⁵ R
³⁶ (where R ³⁵ and R ³⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a heterocyclic ring), and are substituted with 1 to 3 groups selected from the group consisting of Represents an optionally substituted alkyl group having 1 to 4 carbon atoms. ), And the numbers in italics 4 to 7 represent the position numbers on the benzofuran ring.

When R ⁵ is R ^5a , specific examples of such R ^5a include, for example, a hydrogen atom; a nitro group; a cyano group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl Group, morpholinyl group, piperazinyl group, tetrahydrofuryl group, heterocyclic ring such as tetrahydropyranyl group; phenyl group, allyl group, 1-propenyl group, isopropenyl group, 2-butenyl group, 3-butenyl group,
An alkenyl group having 2 to 5 carbon atoms such as a 1-pentenyl group and a 2-pentenyl group; an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, C2-5 alkynyl groups such as methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group and 4-pentynyl group; 6-1 carbon atoms such as phenyl group and naphthyl group
0 aryl group; hydroxyl group; carbon number of cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, etc.
3 to 7 cycloalkyloxy groups; aryloxy groups having 6 to 10 carbon atoms such as phenoxy and naphthyloxy; imidazolyloxy, thiazolyloxy, isothiazolyloxy, pyrazolyloxy, triazolyloxy, and pyrrolyloxy Group, pyridyloxy group, pyrimidinyloxy group, pyrazinyloxy group, furyloxy group, thienyloxy group, isoxazolyloxy group, thiazolidinyloxy group, oxazolidinyloxy group, imidazolidinyloxy group, pyrrolidini -O-Het (here, Het represents a heterocyclic ring) such as a ruoxy group, a piperidyloxy group, a morpholinyloxy group, a piperazinyloxy group, a tetrahydrofuryloxy group, and a tetrahydropyranyloxy group. Group: methanesulfonyloxy group, ethanesulfonyloxy group, n- An alkylsulfonyloxy group having 1 to 4 carbon atoms which may be substituted with a halogen atom such as a propanesulfonyloxy group and a trifluoromethanesulfonyloxy group; an aryl having 6 to 10 carbon atoms such as a phenylsulfonyloxy group and a naphthalenesulfonyloxy group Sulfonyloxy group; acyloxy group having 1 to 5 carbon atoms such as formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, trimethylacetyloxy group; carbon such as benzoyloxy group and naphthylcarboxy group An aralkylcarboxy group having 8 to 21 carbon atoms, such as a phenylacetyloxy group, a 2-phenylpropionyloxy group, a 3-phenylbutyryloxy group, a diphenylacetyloxy group, and a naphthylacetyloxy group; Imidazolylka Ruboxyl group, thiazolyl carboxy group, isothiazolyl carboxy group, pyrazolyl carboxy group, triazolyl carboxy group, pyrrolyl carboxy group, pyridyl carboxy group, pyrimidinyl carboxy group, pyrazinyl carboxy group, furyl carboxy group, thienyl carboxy Group, isoxazolyl carboxy group, thiazolidinyl carboxy group, oxazolidinyl carboxy group, imidazolidinyl carboxy group, pyrrolidinyl carboxy group, piperidyl carboxy group, morpholinyl carboxy group, piperazinyl carboxy group , Tetrahydrofurylcarboxy group, -O-CO-He such as tetrahydropyranylcarboxy group
a group represented by t (where Het represents a heterocycle);
Amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group, diisopropylamino group, dibutylamino group, benzylamino group, dibenzylamino group, imidazolylamino Group, thiazolylamino group, isothiazolylamino group, pyrazolylamino group, triazolylamino group, pyrrolylamino group, pyridylamino group, dipyridylamino group, pyrimidinylamino group, pyrazinylamino group, furylamino group, thienylamino group, isoxazolyl Amino group, thiazolidinylamino group, oxazolidinylamino group, imidazolidinylamino group, pyrrolidinylamino group, piperidylamino group, tetrahydrofurylamino group, tetrahydropyranylamino group, etc. Or a disubstituted amino group; an alkylsulfonylamino group having 1 to 4 carbon atoms which may be substituted with a halogen atom such as a methanesulfonylamino group, an ethanesulfonylamino group, an n-propanesulfonylamino group, and a trifluoromethanesulfonylamino group. An arylsulfonylamino group having 6 to 10 carbon atoms such as a phenylsulfonylamino group and a naphthalenesulfonylamino group; a formylamino group, an acetylamino group, a propionylamino group,
An acylamino group having 1 to 5 carbon atoms such as a butyrylamino group, an isobutyrylamino group, and a trimethylacetylamino group;
An arylcarbonylamino group having 7 to 11 carbon atoms such as a benzoylamino group or a naphthylcarbonylamino group; a phenylacetylamino group, a 2-phenylpropionylamino group, a 3-phenylbutyrylamino group, a diphenylacetylamino group, a naphthylacetylamino group 8-21 carbon atoms such as
Aralkylcarbonylamino group; imidazolylcarbonylamino group, thiazolylcarbonylamino group, pyridylcarbonylamino group, pyrimidinylcarbonylamino group, pyrazinylcarbonylamino group, furylcarbonylamino group, thienylcarbonylamino group, thiazolidinylcarbonyl -NR ⁹⁶ -CO-Het such as amino group, oxazolidinylcarbonylamino group, imidazolidinylcarbonylamino group, pyrrolidinylcarbonylamino group, piperidylcarbonylamino group (where R ⁹⁶ is a hydrogen atom, carbon number An alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, and Het represents a heterocycle.); A methoxycarbonylamino group, an ethoxycarbonylamino group, n-propoxycarbonylamino group, isopropoxy Ruboniruamino group, t-
An alkoxycarbonylamino group having 2 to 5 carbon atoms such as a butoxycarbonylamino group; a carbon atom having 7 to 1 carbon atoms such as a phenoxycarbonylamino group and a naphthyloxycarbonylamino group
Aryloxycarbonyl having 8 to 21 carbon atoms, such as benzyloxycarbonylamino, phenethyloxycarbonylamino, phenylpropoxycarbonylamino, benzhydryloxycarbonylamino, and naphthylmethoxycarbonylamino; Amino group; formyl group; carboxyl group; methoxycarbonyl group, ethoxycarbonyl group, n-
C2-5 alkoxycarbonyl groups such as propoxycarbonyl group, isopropoxycarbonyl group and t-butoxycarbonyl group; C7-11 aryloxycarbonyl groups such as phenoxycarbonyl group and naphthyloxycarbonyl group; benzyloxycarbonyl An aralkyloxycarbonyl group having 8 to 21 carbon atoms, such as a phenethyloxycarbonyl group, a phenylpropoxycarbonyl group, a benzhydryloxycarbonyl group, or a naphthylmethoxycarbonyl group; a carbon atom, such as an acetyl group, a propionyl group, a butyryl group, and an isobutyryl group. An acyl group having 2 to 5 carbon atoms; an arylcarbonyl group having 7 to 11 carbon atoms such as a benzoyl group and a naphthylcarbonyl group; an imidazolylcarbonyl group, a thiazolylcarbonyl group, an isothiazolylcarbonyl group, a pyrazolylcarbonyl group, and a triazo group Carbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, thiazolidinylcarbonyl, oxazolidinylcarbonyl Group, imidazolidinylcarbonyl group,
Pyrrolidinylcarbonyl group, piperidylcarbonyl group,
A group represented by -CO-Het (where Het represents a heterocyclic ring) such as a morpholinylcarbonyl group and a piperazinylcarbonyl group; a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, and a diethylcarbamoyl group Group, propylcarbamoyl, dipropylcarbamoyl, cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl, isothiazolylcarbamoyl Group, pyrazolylcarbamoyl group, triazolylcarbamoyl group, pyrrolylcarbamoyl group, pyridylcarbamoyl group, pyrimidinylcarbamoyl group, pyrazinylcarbamoyl group , A furylcarbamoyl group, a thienylcarbamoyl group, an isoxazolylcarbamoyl group,
(3,5-dioxo-2,4 -Thiazolidinylidene) methyl group, (3,5-dioxo-
(2,4-oxazolidinylidene) methyl group, (2,5-dioxoimidazolidin-4-ylidene) methyl group, (5-oxo-3-thioxo-2,4-thiazolidinylidene) methyl group, (2,4,6-trioxo-3,5-diazaperhydroinylidene) methyl group,
A = CH (CH ₂ ) _n -such as (3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene) methyl group (where A is an alicyclic heterocycle , = Represents a double bond, and n represents
Represents 0, 1 or 2. 2- (3,5-dioxo-2,4-thiazolidinylidene) ethoxy group, 2- (3,5-dioxo-2,4-oxazolidinylidene) ethoxy group, 2- (2,5
-Dioxoimidazolidin-4-ylidene) ethoxy group, 2-
(5-oxo-3-thioxo-2,4-thiazolidinylidene) ethoxy group, 2- (2,4,6-trioxo-3,5-diazaperhydroinylidene) ethoxy group, 2- (3 , 5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)
A group represented by CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle, = represents a double bond, and m represents 1, 2 or 3); and (( 3,5-dioxo-2,4-thiazolidinyl) sulfonyl) methyl group, ((3,5-dioxo-2,4-oxazolidinyl) sulfonyl) methyl group, ((2,5-dioxoimidazolidin-4-yl ) Sulfonyl) methyl and ((5-oxo-3-thioxo-2,4-thiazolidinyl) sulfonyl) methyl groups and other A-SO _2- (CH ₂ ) _m- (where A is an alicyclic heterocycle And m represents 1, 2 or 3.) and the like.

Specific examples of such preferred groups of R ^5a include, for example, hydrogen atom, nitro group, cyano group, bromine atom, imidazolyl group, thiazolyl group, pyridyl group, pyrimidinyl group, furyl group, thienyl group, morpholinyl Group,
Piperazinyl, hydroxyl, pyrrolidinyloxy, piperidyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, benzoyloxy, imidazolylcarboxy, thiazolylcarboxy, pyridyl Carboxy group, pyrimidinylcarboxy group, pyrazinylcarboxy group, dimethylamino group, ethylamino group, diethylamino group, dibenzylamino group, imidazolylamino group, thiazolylamino group, pyridylamino group, pyrimidinylamino group, phenylsulfonylamino group, dimethylcarbamoyl Group, cyclohexylcarbamoyl group, phenylcarbamoyl group, imidazolylcarbamoyl group, thiazolylcarbamoyl group, isothiazolylcarbamoyl group, pyra Rilcarbamoyl group, triazolylcarbamoyl group, pyrrolylcarbamoyl group, pyridylcarbamoyl group, pyrimidinylcarbamoyl group, pyrazinylcarbamoyl group, isoxazolylcarbamoyl group, piperidylcarbamoyl group, formyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, acetyl group, benzoyl group, (3,5-dioxo-2,4-thiazolidinylidene) methyl group, (3,5-dioxo-2 , 4-oxazolidinylidene) methyl group, (2,5-dioxoimidazolidin-4-ylidene) methyl group, (5-oxo-3-thioxo-2,4-thiazolidinylidene)
Methyl group, 2- (3,5-dioxo-2,4-thiazolidinylidene)
Ethoxy group, 2- (3,5-dioxo-2,4-oxazolidinylidene) ethoxy group, 2- (2,5-dioxoimidazolidin-4-ylidene) ethoxy group, 2- (5-oxo- 3-thioxo-2,4-thiazolidinylidene) ethoxy group, ((3,5-dioxo-2,4-thiazolidinyl) sulfonyl) methyl group, ((3,5-dioxo-2,4
-Oxazolidinyl) sulfonyl) methyl group, ((2,5-dioxoimidazolidin-4-yl) sulfonyl) methyl group, ((5
-Oxo-3-thioxo-2,4-thiazolidinyl) sulfonyl)
A methyl group can be mentioned.

Specific examples of particularly preferred groups for R ^5a include:
For example, hydrogen atom, nitro group, cyano group, bromine atom, thienyl group, piperazinyl group, trifluoromethanesulfonyloxy group, phenylsulfonyloxy group, acetyloxy group, dimethylamino group, dibenzylamino group, thiazolylcarbamoyl group, methoxy Examples include a carbonyl group, an isopropoxycarbonyl group and a (3,5-dioxo-2,4-thiazolidinylidene) methyl group.

When R ⁵ is R ^5b , the carbon number of R ^5b is 1
Specific examples of the substituents of the alkoxy groups of to 4 include, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a cyclopropyl group, a cyclobutyl group,
A cycloalkyl group having 3 to 7 carbon atoms such as a cyclopentyl group, a cyclohexyl group and a cycloheptyl group; an aryl group having 6 to 10 carbon atoms such as a phenyl group and a naphthyl group; an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group;
Triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl , Morpholinyl group, piperazinyl group,
Heterocycles such as tetrahydrofuryl, tetrahydropyranyl, and dioxolanyl; -OH; methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy Group,
C1-C4 such as n-pentyloxy group, isopentyloxy group, 3-pentyloxy group, 2,2-dimethylpropoxy group, n-hexyloxy group, 4-methylpentyloxy group, 2-ethylbutoxy group An aryloxy group having 6 to 10 carbon atoms such as a phenoxy group and a naphthyloxy group; a benzyloxy group; and -O-Het such as a pyridyloxy group and a piperidyloxy group (where Het represents a heterocycle). A group represented by 1 to 5 carbon atoms such as a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, and a trimethylacetyloxy group.
An aryloxy group having 7 to 11 carbon atoms such as a benzoyloxy group and a naphthylcarboxy group;
Phenylacetyloxy group; imidazolyl carboxy group, thiazolyl carboxy group, isothiazolyl carboxy group, pyrazolyl carboxy group, triazolyl carboxy group, pyrrolyl carboxy group, pyridyl carboxy group,
Pyrimidinyl carboxy group, pyrazinyl carboxy group,
Furyl carboxy group, thienyl carboxy group, isoxazolyl carboxy group, thiazolidinyl carboxy group,
Oxazolidinyl carboxy group, imidazolidinyl carboxy group, pyrrolidinyl carboxy group, piperidyl carboxy group, morpholinyl carboxy group, piperazinyl carboxy group, tetrahydrofuryl carboxy group, -O- such as tetrahydropyranyl carboxy group CO-Het (where Het
Represents a heterocyclic ring. A) an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a dipropylamino group, an isopropylamino group, a diisopropylamino group,
Dibutylamino group, benzylamino group, dibenzylamino group, imidazolylamino group, thiazolylamino group, isothiazolylamino group, pyrazolylamino group, triazolylamino group, pyrrolylamino group, pyridylamino group,
Dipyridylamino group, pyrimidinylamino group, pyrazinylamino group, furylamino group, thienylamino group, isoxazolylamino group, thiazolidinylamino group, oxazolidinylamino group, imidazolidinylamino group, pyrrolidinylamino Group, piperidylamino group, tetrahydrofurylamino group, tetrahydropyranylamino group or other mono- or disubstituted amino group; methanesulfonylamino group, ethanesulfonylamino group, n-propanesulfonylamino group, trifluoromethanesulfonylamino group, etc. An alkylsulfonylamino group having 1 to 4 carbon atoms which may be substituted with a halogen atom; phenylsulfonylamino group; formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, trimethylacetyl An acylamino group having 1 to 5 carbon atoms such as a ruamino group; an arylcarbonylamino group having 7 to 11 carbon atoms such as a benzoylamino group and a naphthylcarbonylamino group; a phenylacetylamino group; an imidazolylcarbonylamino group and a thiazolylcarbonylamino group , Pyridylcarbonylamino group, pyrimidinylcarbonylamino group, pyrazinylcarbonylamino group, furylcarbonylamino group, thienylcarbonylamino group, pyrrolidinylcarbonylamino group, piperidylcarbonylamino group, etc. -NH-CO-Het (where Het represents a heterocycle.)
A methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, an isopropoxycarbonylamino group, a t-butoxycarbonylamino group or the like; an alkoxycarbonylamino group having 2 to 5 carbon atoms; benzyloxycarbonyl Amino group; formyl group; carboxyl group; methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group and other alkoxycarbonyl groups having 2 to 5 carbon atoms; phenoxycarbonyl group; benzyl Oxycarbonyl group; carbon number of acetyl group, propionyl group, butyryl group, isobutyryl group, etc.
2-5 acyl groups; imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl Group, furylcarbonyl group, thienylcarbonyl group, isoxazolylcarbonyl group, thiazolidinylcarbonyl group, oxazolidinylcarbonyl group, imidazolidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidylcarbonyl group, morpholinyl A group represented by -CO-Het such as a carbonyl group or a piperazinylcarbonyl group (where Het represents a heterocycle); a -CO-O-Het such as a pyridyloxycarbonyl group or a piperidyloxycarbonyl group (wherein Het represents a heterocyclic ring.) Carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl, isothiazolylcarbamoyl Group, pyrazolylcarbamoyl group, triazolylcarbamoyl group, pyrrolylcarbamoyl group, pyridylcarbamoyl group, pyrimidinylcarbamoyl group, pyrazinylcarbamoyl group, furylcarbamoyl group, thienylcarbamoyl group, isoxazolylcarbamoyl group, thiazolidinylcarbamoyl group, oxazoly Dinylcarbamoyl group, imidazolidinylcarbamoyl group, pyrrolidinylcarbamoyl group, piperidylcarba Yl group, tetrahydrofur-carbamoyl group include a carbamoyl group such as tetrahydropyranyl carbamoyl group.

Specific examples of such a preferable group of R ^5b include, for example, a methoxy group, a 2-propynyloxy group,
Saturated or unsaturated alkoxy groups such as butynyloxy group, 3-hexenyloxy group, 5-hexenyloxy group and 2,2-dimethylpropoxy group; substituted with halogen atoms such as 2-bromoethoxy group and 2-chloroethoxy group C3-7 cycloalkyl-alkoxy groups such as cyclopentylmethoxy and cyclohexylmethoxy; benzyloxy, chlorobenzyloxy, fluorobenzyloxy, bromobenzyloxy, nitrobenzyloxy, (Fluoromethyl) benzyloxy group, dichlorobenzyloxy group, dimethylbenzyloxy group, methoxybenzyloxy group, sulfamoylbenzyloxy group, (methylenedioxy) benzyloxy group,
Carboxybenzyloxy group, (methoxycarbonyl) benzyloxy group, n-butoxybenzyloxy group, 3-phenylpropoxy group, di (methoxyphenyl) methoxy group,
C2-C10 aryl such as 2,2-diphenylethoxy group, 1-methyl-1-phenylethoxy group, and naphthylmethoxy group
Alkoxy group; thienylmethoxy group, pyridylmethoxy group, pyrazinylmethoxy group, pyrimidinylmethoxy group,
Thiazolylmethoxy group, (3,5-dioxo-2,4-thiazolidinyl) methoxy group, N-methylpiperidylmethoxy group, Nt
-Butoxycarbonylpiperidylmethoxy group, (4-oxachroman-2-yl) methoxy group, (3,3-dimethyl-2,4-dioxolanyl) methoxy group, (1-methyl-3-oxetanyl) methoxy group, 2- ( An alkoxy group substituted with a heterocycle such as morpholin-4-yl) ethoxy group; a C1-4 alkoxy-alkoxy group such as a methoxymethyl group and a 2-ethoxyethoxy group; a 2- (benzyloxy) ethoxy group and the like Benzyloxy
-Alkoxy group; C2-5 acyloxy-alkoxy group such as 2- (acetyloxy) ethoxy group; C1-4 alkylamino such as bis (dimethylaminomethyl) methoxy group
Alkoxy group; C2-5 alkoxycarbonylamino-alkoxy group such as 4- (t-butoxycarbonylamino) butoxy group; ethoxycarbonylmethoxy group, 2- (methoxycarbonyl) ethoxy group, 5- (ethoxycarbonyl) pentyloxy C 2-5 alkoxycarbonyl such as a group
An alkoxy group can be mentioned.

Specific examples of particularly preferred groups for R ^5b include:
For example, a methoxy group, a 2-propynyloxy group, a benzyloxy group, a chlorobenzyloxy group, a fluorobenzyloxy group, a (trifluoromethyl) benzyloxy group, a dichlorobenzyloxy group, a dimethylbenzyloxy group,
Methoxybenzyloxy group, sulfamoylbenzyloxy group, (methylenedioxy) benzyloxy group, carboxybenzyloxy group, (methoxycarbonyl) benzyloxy group, n-butoxybenzyloxy group, thienylmethoxy group, pyridylmethoxy group, Radinyl methoxy group,
Pyrimidinylmethoxy group, thiazolylmethoxy group, (3,5
-Dioxo-2,4-thiazolidinyl) methoxy group, N-methylpiperidylmethoxy group and methoxymethyl group.

When R ⁵ is R ^5c , the carbon number of such R ^5c is 1
Specific examples of the substituent of the alkyl group of ~ 4 include, for example,
A halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a cycloalkyl group having 3 to 7 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group; a phenyl group and a naphthyl group An aryl group having 6 to 10 carbon atoms; imidazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, pyrrolyl group, pyridyl group,
Pyrimidinyl group, pyrazinyl group, pyridazinyl group, triazinyl group, furyl group, thienyl group, oxazolyl group,
Hetero ring such as isoxazolyl group, thiazolidinyl group, oxazolidinyl group, imidazolidinyl group, pyrrolidinyl group, piperidyl group, morpholinyl group, piperazinyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxolanyl group and the like; -OH; methoxy group, ethoxy group, n -Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy , N-hexyloxy group,
C1-C4 alkoxy groups such as 4-methylpentyloxy group and 2-ethylbutoxy group; C6-C10 aryloxy groups such as phenoxy group and naphthyloxy group; benzyloxy group; pyridyloxy group and piperidyl -O such as oxy group
A group represented by -Het (where Het represents a heterocycle); a carbon number of 1 to 5 such as a formyloxy group, an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, and a trimethylacetyloxy group. An aryloxy group having 7 to 11 carbon atoms such as a benzoyloxy group and a naphthylcarboxy group; a phenylacetyloxy group; an imidazolylcarboxy group, a thiazolylcarboxy group, an isothiazolylcarboxy group, a pyrazolylcarboxy group, and a triazolyl group. Carboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, isoxazolylcarboxy, thiazolidinylcarboxy, oxazolidinylcarboxy Ki, Imi Isoxazolidinyl carboxy group,
Pyrrolidinyl carboxy group, piperidyl carboxy group,
A group represented by -O-CO-Het (where Het represents a heterocyclic ring) such as a morpholinylcarboxy group, a piperazinylcarboxy group, a tetrahydrofurylcarboxy group, a tetrahydropyranylcarboxy group; an amino group; methyl Amino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group, diisopropylamino group, dibutylamino group, benzylamino group, dibenzylamino group, imidazolylamino group, thiazolylamino group , Isothiazolylamino, pyrazolylamino, triazolylamino, pyrrolylamino, pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolyl Monosubstituted or disubstituted amino groups such as nilamino group, oxazolidinylamino group, imidazolidinylamino group, pyrrolidinylamino group, piperidylamino group, tetrahydrofurylamino group and tetrahydropyranylamino group; methanesulfonylamino Group, an ethanesulfonylamino group, an n-propanesulfonylamino group, an alkylsulfonylamino group having 1 to 4 carbon atoms which may be substituted with a halogen atom such as a trifluoromethanesulfonylamino group; a phenylsulfonylamino group; a formylamino group; C1-5 acylamino groups such as acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group and trimethylacetylamino group; C7-11 arylcarbonyl such as benzoylamino group and naphthylcarbonylamino group Amino group Phenyl acetylamino group; imidazolylcarbonyl group, thiazolyl carbonylamino group, pyridylcarbonyl group, pyrimidinyl carbonylamino group, pyrazinylcarbonyl group, a furyl carbonyl group,
Thienylcarbonylamino group, thiazolidinylcarbonylamino group, oxazolidinylcarbonylamino group, imidazolidinylcarbonylamino group, pyrrolidinylcarbonylamino group, piperidylcarbonylamino group, imidazolylcarbonylmethylamino group, thiazolylcarbonyl Methylamino group, pyridylcarbonylmethylamino group, pyrimidinylcarbonylmethylamino group, pyrazinylcarbonylmethylamino group, furylcarbonylmethylamino group, thienylcarbonylmethylamino group, thiazolidinylcarbonylmethylamino group, oxazolidinylcarbonyl -NR-CO-Het such as methylamino group, imidazolidinylcarbonylmethylamino group, pyrrolidinylcarbonylmethylamino group, piperidylcarbonylamino group
(Where R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, and Het represents a heterocyclic ring); A methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, an isopropoxycarbonylamino group, a t-butoxycarbonylamino group, an alkoxycarbonylamino group having 2 to 5 carbon atoms; a benzyloxycarbonylamino group; a formyl group A carboxyl group; a methoxycarbonyl group, an ethoxycarbonyl group,
C2-C5 alkoxycarbonyl groups such as n-propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group; phenoxycarbonyl group; benzyloxycarbonyl group; acetyl group, propionyl group, butyryl group, isobutyryl group, etc. An acyl group having 2 to 5 carbon atoms; an imidazolylcarbonyl group, a thiazolylcarbonyl group, an isothiazolylcarbonyl group, a pyrazolylcarbonyl group,
Triazolylcarbonyl group, pyrrolylcarbonyl group, pyridylcarbonyl group, pyrimidinylcarbonyl group, pyrazinylcarbonyl group, furylcarbonyl group, thienylcarbonyl group, isoxazolylcarbonyl group, thiazolidinylcarbonyl group, oxazolidini Carbonyl group,
-CO-Het such as imidazolidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidylcarbonyl group, morpholinylcarbonyl group, piperazinylcarbonyl group (where H
et represents a heterocyclic ring. A group represented by); a pyridyloxycarbonyl group, a piperidyloxycarbonyl group, etc.
A group represented by -CO-O-Het (where Het represents a heterocycle); a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an ethylcarbamoyl group, a diethylcarbamoyl group, a propylcarbamoyl group, a dipropylcarbamoyl group, Benzylcarbamoyl group, dibenzylcarbamoyl group, imidazolylcarbamoyl group, thiazolylcarbamoyl group, isothiazolylcarbamoyl group,
Pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylcarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl And a carbamoyl group such as an imidazolidinylcarbamoyl group, a pyrrolidinylcarbamoyl group, a piperidylcarbamoyl group, a tetrahydrofurylcarbamoyl group, and a tetrahydropyranylcarbamoyl group.

Specific examples of such a preferable group of R ^5c include, for example, phenethyl group, α-hydroxybenzyl group, 1- (acetyloxy) ethyl group, (3,5-dioxo-2,4-
Thiazolidinyl) methyl group and the like.

Accordingly, such R ¹ , R ² , R ³ , R ⁴ and
Specific examples of preferred combinations of R ⁵ include, for example, R ¹
Is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, R ² is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, R ³ is a phenyl group, a phenoxy group, an amino group, a t-butoxycarbonylamino group, A benzyloxycarbonylamino group, an acetyl group or a propionyl group substituted with a group selected from the group consisting of a (benzyloxycarbonyl) -N-methylamino group, an acetylamino group and a morpholinecarbonyl group; or a hydrogen atom, an acetyl group, propionyl group, an isobutyryl group, a benzoyl group, pyridylcarbonyl group, pyrrolidinylcarbonyl group, a furyl carbonyl group, methanesulfonyl group or a trifluoromethanesulfonyl group, R ⁴ is a methyl group, an ethyl group, an isopropyl group, n- pentyl group, With cyclopentylmethyl or benzyl R ⁵ is a hydrogen atom, a nitro group, a cyano group, a bromine atom, a thienyl group, a piperazinyl group, a trifluoromethanesulfonyloxy group, a phenylsulfonyloxy group, acetyloxy group, dimethylamino group, dibenzylamino group, thiazolyl carbamoyl group, Methoxycarbonyl group, isopropoxycarbonyl group, (3,5-dioxo-2,4-thiazolidinylidene) methyl group, methoxy group, 2-propynyloxy group, benzyloxy group, chlorobenzyloxy group, fluorobenzyloxy group , (Trifluoromethyl) benzyloxy group, dichlorobenzyloxy group, dimethylbenzyloxy group, methoxybenzyloxy group, sulfamoylbenzyloxy group, (methylenedioxy) benzyloxy group, carboxybenzyloxy group, (methoxycarbonyl) Benzyloxy group, n- Toxylbenzyloxy group, thienylmethoxy group, pyridylmethoxy group, pyrazinylmethoxy group, pyrimidinylmethoxy group, thiazolylmethoxy group, (3,5-dioxo-2,4-thiazolidinyl) methoxy group, N-methylpiperidylmethoxy Group, methoxymethyl group, (5-morphonylsulfonamido) thienylmethoxy group, phenethyl group, α-hydroxybenzyl group, 1- (acetyloxy) ethyl group or (3,5-dioxo-2,4-thiazolidinyl) methyl Group.

Specific examples of the compound of the formula (I) include the compounds described in Examples in the present specification, and other specific examples include the following compounds: The compounds of I) may form acid addition salts. As such salts, specifically, hydrochloric acid, hydrobromic acid,
Mineral acids such as sulfuric acid, nitric acid and phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid And organic acids such as ethanesulfonic acid; addition salts with acidic amino acids such as aspartic acid and glutamic acid. The present invention further includes hydrates, various solvates and polymorphic substances of the compound of the formula (I).

The compounds of the present invention can generally be prepared using readily available starting materials, drugs, and conventional synthetic methods, by the methods illustrated in the following Schemes 1 to 4 or variations thereof.

Manufacturing process diagram 1

[0076]

Embedded image

The benzofuryl-α-pyridone derivative of the present invention can be produced, for example, by the method shown in FIG.
A solution of a 2,4-disubstituted-β-ketoester, such as a THF solution, is treated with two equivalents of a base, such as one equivalent of NaH and one equivalent of n-BuLi,
Alternatively, a dienolate is obtained by treating with 2 equivalents of LDA, and a benzofuran carboxylate derivative is allowed to act on the resulting dienolate to carry out Claisen condensation to obtain a diketoester intermediate. The α-pyridone form can be obtained by subjecting this diketoester intermediate to alkaline hydrolysis followed by acid treatment in the presence of ammonium acetate or ammonium chloride.

Manufacturing Process Diagram 2

[0079]

Embedded image

The diketoester intermediate in the above-mentioned production process diagram 1 can be produced by another method illustrated in the production process diagram 2. Treatment of benzofuryl ketone with a base, such as LDA, gives the enolate, which is then reacted with malonic esters, such as malonic acid monomethyl ester-monochloride, to give the diketo ester intermediate. Alternatively, a diketone obtained by reacting an acid chloride or ester with benzofuryl ketone enolate is treated with 2 equivalents of a base, for example, LDA to give a dienolate,
A diketoester intermediate can also be obtained by a method involving the action of an O ₂ analog such as carbon dioxide or dimethyl carbonate.

Manufacturing process diagram 3

[0082]

Embedded image

The benzofuryl-α-pyridone derivative of the present invention can also be produced by the method illustrated in FIG. Benzofurylnitrile is converted to a solution of a 2,4-disubstituted-β-ketoester, for example a THF solution, in two equivalents of a base, for example 1
A dienolate is obtained by treating with an equivalent of NaH and 1 equivalent of n-BuLi or 2 equivalents of LDA, and an iminoketoester intermediate is obtained by subjecting this dienolate and benzofurylnitrile to Claisen condensation. The α-pyridone form can be obtained by alkaline hydrolysis and treatment of this iminoketoester intermediate.

Manufacturing Process Diagram 4

[0085]

Embedded image

Further, the benzofuryl-α-pyridone derivative of the present invention can be produced by the method illustrated in the production process in FIG. The α-pyridone form is obtained by reacting the benzofuryl α-pyrone form with ammonium acetate in an ether-based solvent such as dioxane or an alcohol-based solvent such as ethanol.
By converting the ammonium acetate used at this time into various alkylamines, a compound having a substituted nitrogen atom can be obtained.

The above production steps 1 to 4 do not limit the method for synthesizing the compound of the present invention, and other methods known in the art can be used.

The benzofuryl of the present invention thus obtained is
The α-pyridone derivative or a salt thereof has a triglyceride biosynthesis inhibitory action, a blood triglyceride lowering action or a blood HDL increasing action as shown in Examples described later. The present invention provides a triglyceride biosynthesis inhibitor, a blood triglyceride-lowering agent or a blood HDL-elevating agent of the present invention by combining a carrier described below.

Furthermore, a therapeutically effective amount of the benzofuryl of the invention
There is provided a pharmaceutical composition comprising a -α-pyridone derivative, or a salt thereof, and a pharmaceutically acceptable carrier.

When the benzofuryl-α-pyridone derivative of the present invention or a salt thereof is clinically applied as a prophylactic or therapeutic agent for hypertriglyceridemia or arteriosclerosis, for example, it is orally or rectally, subcutaneously or intramuscularly. Parenteral administration, such as internal, intravenous, or transdermal administration, is preferred, but oral or intravenous administration is preferred.

For oral administration, a solid preparation or a liquid preparation can be prepared. Solid preparations include, for example, tablets, pills, powders, or granules. In such solid preparations, the active substance is a pharmaceutically acceptable carrier,
For example, it is mixed with sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethyl cellulose and the like. The preparation operation is carried out by a conventional method, but may contain additives other than the above-mentioned carriers for preparation, for example, lubricants such as calcium stearate and magnesium stearate. Further, for example, in the solid preparation as described above, for example, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, styrene maleic anhydride copolymer or methacrylic acid, organic enteric substances such as methyl methacrylate copolymer. A solution or an aqueous solution of a solvent may be sprayed to form an enteric coating by applying an enteric coating. Solid preparations such as powders and granules can be enclosed in enteric capsules.

[0092] Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, syrups and elixirs. These preparations contain commonly used pharmaceutically acceptable carriers such as water or liquid paraffin. An oily base such as coconut oil, fractionated coconut oil, soybean oil, and corn oil can be used as a carrier. Pharmaceutically acceptable carriers include other commonly used adjuvants, fragrances, stabilizers, or preservatives as necessary. Liquid preparations may also be administered in capsules made of an absorbable substance such as gelatin.
Solid preparations for rectal administration include suppositories containing the active ingredient and produced by known methods.

Preparations for parenteral administration are administered as sterile aqueous or non-aqueous solutions, suspensions or emulsions. Non-aqueous solutions or suspensions are pharmaceutically acceptable carriers, for example, propyl glycol, polyethylene glycol, vegetable oils such as olive oil or soybean oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents. These solutions, suspensions, and emulsions can be sterilized by appropriate treatment such as filtration through a bacteria-retaining filter, heating, blending of a bactericide, or irradiation with ultraviolet light. Alternatively, a sterile solid preparation can be produced and dissolved in sterile water or a sterile solvent for injection immediately before use. In addition, vegetable oils such as soybean oil and phospholipids such as lecithin, water are added to a uniform solution of the active ingredient, and, for example, a fat emulsion and the like homogenized by a homogenizer such as a pressure injection homogenizer and an ultrasonic homogenizer are also used as injections. Can be used.

Examples of the dosage form for transdermal administration include ointments,
Creams and the like. These are manufactured by a usual method.

When the active ingredient according to the present invention is used as a therapeutic agent for hyperTGemia and further as a preventive agent for arteriosclerosis,
Depending on the patient's medical condition, age, sex, weight, route of administration, etc., it can be usually administered in an amount of about 1 mg to 1000 mg per adult per day. Such a dose can be administered once or several times a day, for example, divided into 2 to 6 times.

For each route of administration, it is desirable to determine the absorption efficiency into the body for each bioactive benzofuryl-α-pyridone derivative individually by methods well known in pharmacy.

[0097]

EXAMPLES The derivatives used herein, including the examples, or the groups present in these structures,
Abbreviations for reaction reagents and the like are those commonly used in the field of organic chemistry, and the meanings of the abbreviations are shown below.

THF: tetrahydrofuran, Et ₂ O: diethyl ether, DMF: N, N-dimethylformamide, AcOEt:
Ethyl acetate, MeOH: methanol, EtOH: ethanol, DB
U: 1,8-diazabicyclo [5.4.0] -7-undecene, DEA
D: diethyl azodicarboxylate, TMAD: azodicarboxylic acid bis (dimethylamide), DMSO: dimethyl sulfoxide, Et ₃ N: triethylamine, Py: pyridine, n-Bu
Li: normal butyl lithium, LDA: lithium diisopropylamide, Ac ₂ O: acetic anhydride, WSC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, DCC:
1,3-dicyclohexylcarbodiimide, CDI: carbonyldiimidazole, HOBt: 1-hydroxybenzotriazole, PPTS: pyridinium paratoluenesulfonate, TMSOTf: trimethylsilyl trifluoromethanesulfonate, TfOH: trifluoromethanesulfonic acid, M
s: methanesulfonyl, Tf: trifluoromethanesulfonyl, p-Ts: paratoluenesulfonyl, Ph: phenyl, Bu: butyl, Bzl: benzyl, Ac: acetyl, TMS:
Trimethylsilyl

[Production Example] <Synthesis of Intermediate> Synthesis of methyl 2-benzofurancarboxylate A solution of 2-benzofurancarboxylic acid (2.00 g) in MeOH (60 ml) was added.
40. After adding thionyl chloride (3.80 ml) with C, the mixture was stirred for 19 hours while gradually warming to room temperature. The reaction was concentrated under reduced pressure,
The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 6/1)
Purification was performed to obtain methyl 2-benzofurancarboxylate. Yield 2.16 g (y. 99.2%) ¹ H NMR (δ ppm, CDCl ₃ ): 3.99 (s, 3H) 7.28-7.50 (m, 2
H) 7.54 (s, 1H) 7.60 (d, J = 8.9Hz, 1H) 7.69 (d, J =
(7.6Hz, 1H)

Methyl 2-methyl-3-oxopentanoate
Synthesis under ice-cooling, methyl propionyl acetate (100 g) Acetone (800 ml) was added methyl iodide (57 ml) and of K ₂ CO ₃ (127
g) was added. The reaction solution was stirred at room temperature for 96 hours, filtered through celite, and the mother liquor was gently concentrated under reduced pressure and then distilled under reduced pressure to obtain methyl 2-methyl-3-oxopentanoate. Yield 105 g (y. 94.8%) ¹ H NMR (δ ppm, CDCl ₃ ): 1.08 (t, J = 7.3 Hz, 3H) 1.35
(d, J = 7.3Hz, 3H) 2.45-2.72 (m, 2H) 3.54 (q, J = 7.3H
z, 1H) 3.73 (s, 3H)

Ethyl 2- (benzyloxy) acetate
0 to a suspension of synthetic NaH (1.1 g) in Et ₂ O (250 ml). In C, benzyl alcohol (27.5 ml) was added. After stirring at C for 10 minutes and at room temperature for 5 minutes, the reaction was -10-0. After cooling to C, trichloroacetonitrile (27 ml) was added dropwise over 15 minutes. The reaction solution was stirred for 1 hour while gradually warming to room temperature, and then concentrated under reduced pressure. To the residue was added a solution of MeOH (1.0 ml) in n-pentane (100 ml), stirred vigorously, filtered and concentrated. N-pentane in the residue
Was added, the mixture was filtered again, and the mother liquor was concentrated. Et ₂ O (80m
l), n-pentane (80 ml) and ethyl glycolate (25 g) were added. Add TfOH (1.5 ml) with C and set to 0. 10 minutes at C, 2 at room temperature
Stirred for hours. The reaction was filtered, the mother liquor was poured into saturated aqueous NaHCO ₃ and extracted with Et ₂ O. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 10/1 → 6/1) to obtain ethyl 2- (benzyloxy) acetate. Yield 38.76 g (y. 83.2%) ¹ H NMR (δ ppm, CDCl ₃ ): 1.29 (t, J = 7.26)
Hz, 3H) 4.09 (s, 2H) 4.2
3 (q, J = 7.26 Hz, 2H) 4.63
(S, 2H) 7.21-7.45 (m, 5H)

Methyl 6-benzyloxy-2,4-dimethyl
Synthesis of 3,5- dioxohexanoate 0 in a suspension of NaH (3.80 g) in THF (100 ml). Methyl at C
A solution of -3-oxopentanoate (13.05 g) in THF (100 ml) was added. After stirring at C for 15 minutes, 1.63 M n-BuLi (58 ml) was added. The mixture was stirred at C for 20 minutes to prepare a pale yellow dienolate. The reaction was -78. C., and a solution of ethyl 2- (benzyloxy) acetate (17.56 g) in THF (30 ml) was added.
8. After stirring at C for 5 minutes, 0. Stirred at C for 1 hour. The reaction solution was quenched by pouring dilute hydrochloric acid, and extracted with AcOEt near neutrality. The organic layer was washed with saturated brine, dried over MgSO _4,
Filtration and concentration. The residue was purified by silica gel column chromatography (nh
exane / AcOEt = 5/1 → 3/1)
6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate was obtained. Yield 9.78 g (y. 37%) ¹ H NMR (δ ppm, CDCl ₃ ): 1.17-1.42 (m, 6H) 3.62-3.80
(m, 4H) 3.98-4.28 (m, 3H) 4.48-4.65 (m, 2H) 7.12-
7.42 (m, 5H)

4-Acetyloxy-6- (benzyloxy) meth
Synthesis of methyl- 3,5-dimethyl-2H-pyran-2-oneMethyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate (430 mg) was added to a solution of LiOH in THF (10 ml). Hydrate
(64 mg) in water (6 ml) was added, and the mixture was stirred at room temperature for 1.5 hours.
The reaction solution was neutralized with dilute hydrochloric acid, the volatile components were distilled off under reduced pressure, and the mixture was extracted with AcOEt at pH 3. The organic layer was dried over MgSO _4,
Filtration and concentration. Ac ₂ O (6 ml) was added to the residue, and after stirring at room temperature for 30 minutes, pyridine (4 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 3/1 → 12/5) to give 4-acetyloxy-6- (benzyloxy) methyl-3,
5-Dimethyl-2H-pyran-2-one was obtained. Yield 212 mg (y. 47.7%) ¹ H NMR (δ ppm, CDCl ₃ ): 1.88 (s, 3H)
1.93 (s, 3H) 2.34 (s, 3H)
4.35 (s, 2H) 4.58 (s, 2H)
7.23-7.41 (m, 5H)

6- (benzyloxy) methyl-3,5-dimethyl
Synthesis of 4 -hydroxy-2H-pyran-2-one 4-acetyloxy-6- (benzyloxy) methyl-3,5-dimethyl-2H-pyran-2-one (6.08 g) in MeOH (100 ml) K ₂ C in solution
O ₃ (3.0 g) and water (10 ml) were added, and the mixture was stirred at room temperature overnight, filtered through celite, and the mother liquor was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. The residue is purified by silica gel column chromatography.
(n-hexane / AcOEt = 5/1 → 1/1)
(Benzyloxy) methyl-3,5-dimethyl-4-hydroxy-2
H-pyran-2-one was obtained. Yield 4.82 g (y.86%) (TLC Rf = 0.3; n-hexane / AcOEt = 1/1)

6- (benzyloxy) methyl-3,5-dimethyl-
Synthesis of 4-methoxymethoxy-2H-pyran-2-one 6- (benzyloxy) methyl-3,5-dimethyl-4-hydroxy
To a solution of -2H-pyran-2-one (2.60 g) in THF (50 ml) was added diisopropylethylamine (2.1 ml). Chloromethyl methyl ether (921 μl) was added at C, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution under reduced pressure,
Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 5/1 → 1/1) to give 6
-(Benzyloxy) methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one was obtained. Yield 1.80 g (y.60%) (TLC Rf = 0.6; n-hexane / AcOEt = 1/1)

3,5-dimethyl-6-hydroxymethyl-4-metho
Synthesis of 6- (benzyloxy) methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (1.80 g) in EtOH (50 ml) solution of xymethoxy-2H-pyran-2-one
% Pd (OH) ₂ / C (360 mg) was added, and the mixture was added at room temperature under a hydrogen gas atmosphere.
Stir vigorously for hours. The reaction solution was filtered through celite, and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (nh
3,5-dimethyl by purification on exane / AcOEt = 1/1)
-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2
-Got it. Yield 1.26 g (y.99%) (TLC Rf = 0.15; n-hexane / AcOEt = 1 /
1)

3,5-dimethyl-4-methoxymethoxy-6- (meth
Tylsulfonyloxy) methyl-2H-pyran-2-one
Forming 3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy
To a solution of -2H-pyran-2-one (1.26 g) in THF (50 ml) was added triethylamine (606 mg), and the mixture was stirred at room temperature for 1 hour, and methanesulfonyl chloride (1.05 g) was added, followed by stirring at room temperature overnight . Water was added to the reaction solution, extracted with AcOEt, and the organic layer was washed with Na ₂ SO
After drying at ₄ , the mixture was filtered and concentrated. The residue is purified by silica gel column chromatography (n-hexane / AcOEt = 1/1)
3,5-Dimethyl-4-methoxymethoxy-6- (methylsulfonyloxy) methyl-2H-pyran-2-one was obtained. Yield 1.35 g (y.73%) (TLC Rf = 0.5; n-hexane / AcOEt = 1 /
1)

6-bromomethyl-3,5-dimethyl-4-methoxy
Synthesis of methoxy-2H-pyran-2-one DMF of 3,5-dimethyl-4-methoxymethoxy-6- (methylsulfonyloxy) methyl-2H-pyran-2-one (1.35 g)
l) To the solution was added sodium bromide (500 mg), and the mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. Add water to the residue
After extraction with AcOEt, the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOE).
Purification by t = 1/1) yielded 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one. Yield 1.21 g (y.99%) (TLC Rf = 0.7; n-hexane / AcOEt = 1 /
1)

Methyl 6-hydroxybenzofuran-2-cal
Synthesis of Boxylate 60 A suspension of 4-methoxysalicylaldehyde (50 g), K ₂ CO ₃ (65 g) and methyl bromoacetate (65 g) in DMF (500 ml). 1 in C
After stirring for an hour and cooling, the reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. Toluene (500 ml) was added to the residue to form a suspension, and DBU (70 g) was added to obtain 130. Stirred at C overnight. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. Residue M
Dissolve in eOH (500 ml) and add concentrated hydrochloric acid (50 ml). Stirred at C overnight. After cooling, the reaction solution was concentrated under reduced pressure, and AcOEt was added to the residue.
(500 ml), a saturated aqueous NaHCO ₃ solution (500 ml) was slowly added to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. Residue C
Dissolve in H ₂ Cl ₂ (1000 ml), 0. After slowly adding boron tribromide (125 g) with C, the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the obtained brown oil was dissolved in MeOH (500 ml), and concentrated hydrochloric acid (50 ml) was added thereto. Stirred at C overnight. After cooling, the reaction solution was concentrated under reduced pressure, and AcOEt (500 ml) was added to the residue.
Was added, and a saturated aqueous solution of NaHCO ₃ (500 ml) was slowly added to separate an organic layer and an aqueous layer, and the aqueous layer was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 3/1) to obtain methyl 6-hydroxybenzofuran-2-carboxylate. Yield 37.9 g (y. 60%) ¹ H NMR (δ ppm, CDCl ₃ ): 3.88 (s, 3H) 5.50-6.50 (brs,
1H) 6.80-7.80 (m, 4H)

Methyl 6- (benzyloxy) benzofuran-
Synthesis of 2-carboxylate To a suspension of NaH (800 mg) in THF (100 ml) at room temperature was added methyl 6-hydroxybenzofuran-2-carboxylate (3.58 g) in THF.
A solution of F (30 ml) was slowly added, and the mixture was stirred for 1 hour.
5 ml), benzyl bromide (3.77 g) was slowly added, and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 10/1) to obtain methyl 6- (benzyloxy) benzofuran-2-carboxylate. Yield 4.85 g (y.95%) ¹ H NMR (δ ppm, CDCl ₃ ): 3.95 (s, 3H) 5.19 (s, 2H) 6.
85 (dd, J = 8.1Hz, 2.0Hz, 1H) 7.05 (d, J = 2.0Hz, 1H)
7.43 (s, 1H) 7.51 (d, J = 8.1Hz, 1H)

Methyl 5-formylbenzofuran-2-carbo
Synthesis of 5-formyl salicylaldehyde Kishireto (25 g) and acetonitrile methyl bromoacetate (30g) (500ml) was added K ₂ CO ₃ (30g)
Was added and the mixture was heated under reflux for 24 hours. After cooling, the reaction solution was filtered, and the mother liquor was concentrated under reduced pressure. A saturated aqueous ammonium chloride solution (100 ml) was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 5/1) to give methyl
5-Formylbenzofuran-2-carboxylate was obtained. Yield 15g (y 44%.) Mass ^{analysis: [M + + H] =} 205.2

Methyl 5- (dimethoxymethyl) benzofura
Synthesis of methyl 2-formylbenzofuran-2-carboxylate (1
To a solution of 5 g) in MeOH (100 ml) was added methyl orthoformate (1.0 g) and polymer-bound-PPTS (1.0 g), and after 8 hours at room temperature, the reaction solution was filtered and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 9/1) to obtain methyl 5- (dimethoxymethyl) benzofuran-2-carboxylate. Yield 10 g (y. 54%) ¹ H NMR (δ ppm, CDCl ₃ ): 3.35 (s, 3H) 3.98 (s, 3H) 5.
49 (s, 1H) 7.53-7.61 (m, 3H) 7.81 (s, 1H)

The following compounds were prepared by using a method similar to that of the above Preparation Examples and organic chemistry well known to those skilled in the art.

Ethyl 5-bromobenzofuran-2-carboxy
Silate ¹ H NMR (δppm, CDCl ₃ ): 1.43 (t, J = 7.3 Hz, 3H) 4.45
(q, J = 7.3Hz, 2H) 7.45 (s, 1H) 7.47 (d, J = 8.4Hz, 1
H) 7.54 (dd, J = 8.4Hz, 2.2Hz, 1H) 7.82 (d, J = 2.2Hz,
1H)

4-Acetyloxy-6- (benzofuran-2-i
Synthesis of 3,5-dimethyl-2H-pyran-2-one Methyl 2-methyl-3-oxopentanoate (750 mg) in THF
(5 ml) 0 in solution. Add 60% NaH (220 mg) at C and add 0%. -78 after stirring at C for 5 minutes. Cooled to C. 1.63M n-BuL
i (3.3 ml) was added and -78. The dienolate was prepared by stirring at C for 30 minutes. Methyl 2 in this dienolate
A solution of -benzofurancarboxylate (300 mg) in THF (10 ml) was added and -78. Stirred at C for 20 minutes. Reaction solution 0. The temperature was raised and C, and quenched by addition of aq.KHSO _4, and extracted with AcOEt.
The organic layer was washed with saturated saline, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / Ac
OEt = 3/1 → 2/1) to give methyl 5-
(Benzofuran-2-yl) -2,4-dimethyl-3,5-dioxopentanoate was obtained. Yield 433mg (mixture)

Methyl 5- (benzofuran-2-yl) -2,4-dimethyl-3,5-dioxopentanoate (14.98 g) in MeOH (50
aqueous solution (30 ml) of LiOH monohydrate (2.62 g) was added to the solution,
After stirring at room temperature for 20 minutes, MeOH was distilled off under reduced pressure. The residual aqueous solution was washed with Et ₂ O, cooled on ice, and added with an aqueous KHSO ₄ solution to add p.
H2.0-2.5. The precipitated crystals were collected by filtration and washed with water. The mother liquor was saturated with brine, extracted with AcOEt, and the organic layer was concentrated. The residue and the crystals collected by filtration were combined, pyridine (40 ml) and Ac ₂ O (40 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from n-hexane / AcOEt = 3/1 to give 4-acetyloxy-6- (benzofuran.
2-yl) -3,5-dimethyl-2H-pyran-2-one was obtained. Yield 6.11 g (y. 47.3%) ¹ H NMR (δ ppm, CDCl ₃ ): 2.00 (s, 3H) 2.31 (s, 3H) 2.
40 (s, 3H) 7.23-7.42 (m, 2H) 7.36 (s, 1H) 7.53 (d,
J = 8.2Hz, 1H) 7.65 (d, J = 7.6Hz, 1H)

6- (benzofuran-2-yl) -3,5-dimethyl-4
Synthesis of 4- hydroxy-2H-pyran-2-one 4-acetyloxy-6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one (3.00 g) in MeOH (100 ml) To 0. C
After adding an aqueous solution (30 ml) of LiOH monohydrate (465 mg) with stirring at room temperature for 2 hours, MeOH was distilled off under reduced pressure. The residue was washed with Et ₂ O, 0. Aqueous KHSO ₄ was added to adjust the pH to 2.0.
The precipitated crystals are collected by filtration, washed sufficiently with water and Et ₂ O in that order, and dried to give 6- (benzofuran-2-yl) -3,
5-Dimethyl-4-hydroxy-2H-pyran-2-one was obtained. Yield 2.54 g (y. 98.5%) ¹ H NMR (δppm, DMSO-d6): 1.93 (s, 3H) 2.28 (s, 3H)
7.28-7.47 (m, 2H) 7.39 (s, 1H) 7.68 (d, J = 8.3Hz, 1
H) 7.74 (d, J = 7.3Hz, 1H) 10.91 (brs, 1H)

3,5-dimethyl-6- (5-formylbenzofuran
Synthesis of 2- ( 2-yl) -4-hydroxy-2H-pyran-2-oneMethyl 2 -methyl-3-oxopentanoate (7.5 g) in a suspension of NaH (2.1 g) in THF (200 ml) (50 ml) solution was added slowly and stirred for 10 minutes before -78. Cool to 1.58Mn-BuLi
(32 ml) was slowly added dropwise. The reaction was -78. After stirring at C for 30 minutes, a solution of methyl 5- (dimethoxymethyl) benzofuran-2-carboxylate (10 g) in THF (50 ml) was slowly added, and -78. Stirred at C for 4 hours. A saturated aqueous ammonium chloride solution (30 ml) was added to the reaction solution, and the temperature was raised to room temperature.
After extraction with OEt, the organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in MeOH (100 ml) and THF (100 ml), a 4N aqueous lithium hydroxide solution (25 ml) was added, and the mixture was stirred at room temperature for 4 hours, and then a saturated aqueous KHSO ₄ solution (50 ml) was slowly added.
The precipitated yellow precipitate was collected by filtration and washed with AcOEt to give 3,5-dimethyl-6- (5-formylbenzofuran-2-yl) -4.
-Hydroxy-2H-pyran-2-one was obtained. Yield 10.8 g (y. 95%) ¹ H NMR (δ ppm, DMSO-d6): 1.87 (s, 3H) 2.23 (s, 3H)
7.51 (s, 1H) 7.78-7.92 (m, 2H) 8.28 (s, 1H) 10.0
(s, 1H)

4-Acetyloxy-3,5-dimethyl-6- (5-e
Synthesis of (Rumylbenzofuran-2-yl) -2H-pyran-2-one 3,5-dimethyl-6- (5-formylbenzofuran-2-yl) -4-
After adding Et ₃ N (1.7 g) to a suspension of hydroxy-2H-pyran-2-one (5.0 g) in CH ₂ Cl ₂ (100 ml), acetyl chloride was added under ice cooling.
(1.32 g) was added slowly, and the mixture was stirred at room temperature for 1 hour. Water (100 ml) was added to the reaction solution, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 3/1) to give 4-acetyloxy-3,5-dimethyl-6- (5-formylbenzofuran-2-yl) -2H-pyran-2. -Got it. Yield 5.1 g (y.88%) ¹ H NMR (δ ppm, CDCl ₃ ): 2.02 (s, 3H) 2.32 (s, 3H) 2.
41 (s, 3H) 7.46 (s, 1H) 7.66 (d, J = 8.4Hz, 1H) 7.96
(d, J = 8.4Hz, 1H) 8.20 (s, 1H) 10.1 (s, 1H)

[0120] 3,5-Dimethyl-4-hydroxy-6- (5-methoxy
Synthesis of (Cibenzofuran -2-yl) -2H-pyran-2-one 5-methoxysalicylaldehyde (152 mg) and 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (277 mg in DMF (5 ml) solution of) was added K ₂ CO ₃ (138mg) was stirred at room temperature for 16 hours. A 6N hydrochloric acid aqueous solution was slowly added to the reaction solution, and the mixture was stirred for 1 hour and extracted with AcOEt.
After drying over SO ₄ , the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 1/1) to give 3,5-dimethyl-4-hydroxy-6- (5-methoxybenzofuran-2-yl) -2H-pyran-2- Got on. Yield 229 mg (y.80%) ¹ H NMR (δ ppm, CDCl ₃ ): 2.01 (s, 3H) 2.25 (s, 3H) 4.
00 (s, 3H) 5.50-6.50 (brs, 1H) 6.80-7.80 (m, 4H)

[0121] 3,5-dimethyl-4-hydroxy-6- (7-methoxy
Synthesis of Cibenzofuran-2-yl) -2H-pyran-2-one 3,5-dimethyl-4-hydroxy-6- (7-
Methoxybenzofuran-2-yl) -2H-pyran-2-one was obtained. Yield 78% ¹ H NMR (δ ppm, CDCl ₃ ): 2.10 (s, 3H) 2.26 (s, 3H) 4.
00 (s, 3H) 5.50-6.50 (brs, 1H) 6.80-7.80 (m, 4H)

6- (5-aminobenzofuran-2-yl) -3,5-di
Methyl-4-methoxymethoxy-2H-pyran-2-one and 3,
5-dimethyl-6- (5- (ethylamino) benzofuran-2-yl)
Synthesis of -4-methoxymethoxy-2H-pyran-2-one 3,5-dimethyl-4-methoxymethoxy-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one (100 mg) Dioxane
(20 ml) and 5% Pd / C (5 mg) were added to a solution of EtOH (20 ml), the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred at room temperature overnight. After filtration and concentration of the reaction solution, silica gel thin-layer chromatography (nh
exane / AcOEt = 1/1) to give 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one and 3,5-dimethyl -6- (5- (ethylamino) benzofuran-2-yl) -4-methoxymethoxy-2H-
Pyran-2-one was obtained. 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one; yield 45 mg (y. 49%) ¹ H NMR (δ ppm, CDCl ₃ ): 2.12 (s, 3H) 2.42 (s, 3H) 3.
64 (s, 3H) 5.16 (s, 2H) 6.83 (dd, J = 2.3Hz, 8.9Hz, 1H)
6.96 (d, J = 2.3Hz, 1H) 7.20 (s, 1H) 7.33 (d, J = 8.9
Hz, 1H) 7.42 (s, 2H) 3,5-dimethyl-6- (5- (ethylamino) benzofuran-2-yl) -4-methoxymethoxy-2H-pyran-2-one; yield 33 mg (y. 33%) ¹ H NMR (δppm, CDCl ₃ ): 1.30 (t, J = 7.3 Hz, 3H) 2.11
(s, 3H) 2.39 (s, 3H) 3.19 (q, J = 7.3Hz, 2H) 3.62
(s, 3H) 5.11 (s, 2H) 6.69 (dd, J = 2.3Hz, 8.9Hz, 1H)
6.75 (d, J = 2.3Hz, 1H) 7.20 (s, 1H) 7.31 (d, J = 8.9
(Hz, 1H)

6- (5- (acetylamino) benzofuran-2-i
) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-o
Synthesis of 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (45 mg) and pyridine (40
0 μl) and Ac ₂ O (15 μl), and the mixture was stirred at room temperature for 6 hours. Then, an aqueous NH ₄ Cl solution was added, and the mixture was extracted with CH ₂ Cl ₂ . The organic layer was dried, filtered, concentrated and the residue purified by silica gel thin layer chromatography _{(CH 2 Cl 2) 6- (} 5- ( acetylamino) benzofuran-2-yl) -3,5-dimethyl 4-Methoxymethoxy-2H-pyran-2-one was obtained. Yield 20 mg (y. 39%) ¹ H NMR (δ ppm, CDCl ₃ ): 2.10 (s, 3H) 2.17 (s, 3H) 2.
43 (s, 3H) 3.64 (s, 3H) 5.20 (s, 2H) 7.32 (s, 1H) 7.
45 (d, J = 8.9Hz, 1H) 7.50 (d, J = 8.9Hz, 1H) 7.97 (d, J =
(0.7Hz, 1H)

6- (5-aminobenzofuran-2-yl) -3,5-di
Synthesis of methyl-4-hydroxy-2H-pyran-2-one 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (58 mg) THF (20 ml) was added and the mixture was stirred, 1 drop of concentrated hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is purified by thin-layer chromatography (n-hexane / AcOEt = 1/1).
6- (5-Aminobenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one was obtained. Yield 13 mg (y. 27%) ¹ H NMR (δ ppm, DMSO-d6): 1.93 (s, 3H) 2.27 (s, 3H)
6.71 (dd, J = 2.0Hz, 8.9Hz, 1H) 6.79 (d, J = 2.0Hz, 1H)
7.16 (s, 1H) 7.33 (d, J = 8.9Hz, 1H)

6- (6- (benzyloxy) benzofuran-2-i
) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one and 4-acetyloxy-6- (6- (benzyloxy) benzof
Lan-2-yl) -3,5-dimethyl-2H-pyran-2-one 0 in a suspension of NaH (900 mg) in THF (50 ml). C is methyl 2-methyl-
A solution of 3-oxopentanoate (3.24 g) in THF (30 ml) was slowly added, and the mixture was stirred for 10 minutes and then -78. Cool to 1.58M n
-BuLi (14.2 ml) was slowly added dropwise. The reaction was -78. 30 at C
After stirring for minutes, a solution of methyl 6- (benzyloxy) benzofuran-2-carboxylate (4.26 g) in THF (15 ml) was added slowly and -78. Stirred at C for 4 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the temperature was raised to room temperature.
After extraction with OEt, the organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in MeOH (30 ml) and THF (10 ml), 4N aqueous lithium hydroxide (5 ml) and water (50 ml) were added, and the mixture was added at room temperature.
After stirring for an hour, a saturated aqueous solution of KHSO ₄ (30 ml) was slowly added. The precipitated yellow precipitate was collected by filtration and washed with AcOEt to give 6- (6- (benzyloxy) benzofuran-2-yl)-
3,5-Dimethyl-4-hydroxy-2H-pyran-2-one was obtained. Yield 964 mg (y. 25%) ¹ H NMR (δ ppm, DMSO-d6): 2.00 (s, 3H) 2.24 (s, 3H)
5.27 (s, 2H) 7.11 (d, J = 8.4Hz, 1H) 7.30-7.70 (m, 8
H) 10.8 (brs, 1H) The filtrate was further concentrated under reduced pressure, water (30 ml) and AcOEt (30 ml) were added to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with AcOEt. The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. Acetic anhydride (10 ml) and pyridine (3 ml) were added to the residue to give 1
After stirring overnight, the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (n-hexane / AcOEt = 5/1 → 1/1) to give 4-acetyloxy-6- (6- (benzyloxy) (Benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one was obtained. Yield 904 mg (y. 21%) ¹ H NMR (δ ppm, CDCl ₃ ): 1.92 (s, 3H) 1.97 (s, 3H) 2.
37 (s, 3H) 5.09 (s, 2H) 6.80-7.80 (m, 9H)

4-Acetyloxy-3,5-dimethyl-6- (6-h
(Droxybenzofuran-2-yl) -2H-pyran-2-one
Formation of 4-acetyloxy-6- (6- (benzyloxy) benzofuran
-2-yl) -3,5-dimethyl-2H-pyran-2-one (500 mg) in EtO
H (50 ml) and 1,4-dioxane (50 ml) in 10% Pd / C (100
mg) and stirred vigorously at room temperature under a hydrogen gas atmosphere for 3 hours. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / AcOEt =
By purification in 1/1), 4-acetyloxy-3,5-dimethyl-6- (6-hydroxybenzofuran-2-yl) -2H-pyran-2-one was obtained. Yield 388 mg (y.95%) ¹ H NMR (δ ppm, CDCl ₃ ): 1.92 (s, 3H) 1.97 (s, 3H) 2.
37 (s, 3H) 5.50-6.50 (brs, 1H) 6.80-7.80 (m, 4H)

The 4-acetyloxy-3,5-dimethyl-6- (6- (me
(Toxicarbonyl) benzofuran-2-yl) -2H-pyran-2-
Synthesis of palladium acetate (3.5 mg) and diphenylphosphinopropane (6.5 mg) in DMSO (5 ml) and MeOH (5 m
l) Add 4-acetyloxy-3,5-dimethyl-6- (6-
(Trifluoromethanesulfonyloxy) benzofuran-2
-Yl) -2H-pyran-2-one (350 mg) in THF (5 ml) and
After adding Et ₃ N (80 mg), the mixture was stirred at room temperature for 1 hour under a carbon monoxide atmosphere, and further stirred at 80 ° C. Stirred at C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hex.
Purification by ane / AcOEt = 1/1) gave 4-acetyloxy-3,5-dimethyl-6- (6- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one. . Yield 92mg (y 33%.) Mass ^{analysis: [M + + H] =} 357.3

6- (6-carboxybenzofuran-2-yl) -3,
Synthesis of 5-dimethyl-4-hydroxy-2H-pyran-2-one 4-acetyloxy-3,5-dimethyl-6- (6- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2- ON (85mg)
After a mixed solution of K ₂ CO ₃ (45 mg) in MeOH (5 ml) and H ₂ O (1 ml) was stirred at room temperature for 1 hour, the reaction solution was acidified with a 1N aqueous hydrochloric acid solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt / MeOH = 5/1) to give 6- (6-carboxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one. Obtained. Yield 71mg Mass spectrometry value (y quant..): [ M + + H] = 301.2

3,5-dimethyl-4-hydroxy-6- (6- (methoxy
(Cicarbonyl) benzofuran-2-yl) -2H-pyran-2-one
Synthesis of 6- (6-carboxybenzofuran-2-yl) -3,5-dimethyl-4
To a mixed solution of -hydroxy-2H-pyran-2-one (50 mg) in MeOH (5 ml) and toluene (1 ml) was added trimethylsilyldiazomethane (2 M in hexane, 85 μl), and the mixture was stirred at room temperature for 10 minutes. Acetic acid was added to the reaction solution to quench excess trimethylsilyldiazomethane, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography _{(CH 2 Cl 2 / MeOH =} 9/1) 3,5- dimethyl-4-hydroxy-6- (6- (methoxycarbonyl) benzofuran-2-yl) -2H- Pyran-2-
Got on. Yield 50mg (y 96%.) Mass ^{analysis: [M + + H] =} 315.3

4-Acetyloxy-3,5-dimethyl-6- (6-di
Synthesis of methylaminobenzofuran-2-yl) -2H-pyran-2-one 4-acetyloxy-3,5-dimethyl-6- (6- (trifluoromethanesulfonyloxy) benzofuran-2-yl) To a solution of -2H-pyran-2-one (45 mg) in toluene (5 ml) was added tetrakistriphenylphosphinepalladium (3 mg) and dimethylaminotrimethyltin (34 mg). Stirred at C overnight. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 5/1) to give 4-acetyloxy-3,5-dimethyl-6- (6-dimethylamino). (Benzofuran-2-yl) -2H-pyran-2-one was obtained. Yield 9.6mg (y 28%.) Mass ^{analysis: [M + + H] =} 342.3

4-Acetyloxy-3,5-dimethyl-6- (6- (2-
Synthesis of furyl) benzofuran-2-yl) -2H-pyran-2-one In the same manner as described above, 4-acetyloxy-3,5-dimethyl-6- ( 6
There was obtained-(2-furyl) benzofuran-2-yl) -2H-pyran-2-one. Yield 31mg (y 87%.) Mass ^{analysis: [M + + H] =} 365.3

4-acetyloxy-3,5-dimethyl-6- (6- (2-
Thienyl) benzofuran-2-yl) -2H-pyran-2-one
In the same manner as in the above Example, 4-acetyloxy-3,5-dimethyl-6- (6- (2-thienyl) benzofuran-2-yl) -2H was obtained by using 2- (tributylstannyl) thiophene. -Pyran-2-one was obtained. Yield 31mg (y 85%.) Mass ^{analysis: [M + + H] =} 381.4

3,5-dimethyl-4-hydroxy-6- (6-methoxy
Synthesis of (Cibenzofuran -2-yl) -2H-pyran-2-one 4-methoxysalicylaldehyde (1.52 g) and 6-bromo-
3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one
In DMF (50 ml) solution of (2.77 g) at room temperature was added the K ₂ CO ₃ (1.38g)
After stirring overnight, the reaction solution was concentrated under reduced pressure. Water (50 ml) was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue is purified by silica gel column chromatography.
Purification with (n-hexane / AcOEt = 1/1) yielded 3.46 g of a yellow oil. Diisopropylethylamine (1.29 g) and DMF (20 ml) were added to 1.74 g of the obtained yellow oil.
Heated to reflux overnight. After cooling, add 6N hydrochloric acid aqueous solution (1
0 ml) was added slowly, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Water (50 ml) was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 1/1) to give 3,5-dimethyl-4-hydroxy-6- (6-methoxybenzofuran-2-yl) -2H-pyran-2- Got on. Yield 20 mg (y. 1.3%) ¹ H NMR (δ ppm, CDCl ₃ ): 2.12 (s, 3H) 2.27 (s, 3H) 4.
00 (s, 3H) 5.50-6.50 (brs, 1H) 6.80-7.80 (m, 4H)

3,5-dimethyl-4-hydroxy-6- (5- (5-pyrid
(Midinylmethoxy) benzofuran-2-yl) -2H-pyran-2-
Synthesis of 4-acetyloxy-3,5-dimethyl-6- (5-hydroxybenzofuran-2-yl) -2H-pyran-2-one (118 mg) and 5-hydroxymethylpyrimidine (202 mg) in THF (30 ml 0) solution.
C. Tributylphosphine in 2N THF (0.94 ml) solution and TMA
A solution of D (323 mg) in CH ₂ Cl ₂ (3 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was cooled on ice, and a 1N aqueous solution of lithium hydroxide (5 m
l) and stirred at room temperature for 1 hour, then the reaction solution was ice-cooled again, 1N hydrochloric acid aqueous solution (5 ml) and AcOEt were added to separate the organic layer and the aqueous layer, and the aqueous layer was extracted with AcOEt. . The organic layers were combined, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography (AcOEt / MeOH = 10/1) to give 3,5-dimethyl-4-hydroxy-6- (5- (5-pyrimidinylmethoxy) benzofuran-2-yl) -2H-pyran. -
I got 2-one. Yield 35 mg (y. 26%) ¹ H NMR (δppm, DMSO-d6): 1.95 (s, 3H) 2.29 (s, 3H)
5.24 (s, 2H) 7.12-7.14 (m, 1H) 7.33-7.38 (m, 2H)
7.61-7.63 (m, 1H) 8.95 (s, 2H) 9.18 (s, 1H) 10.91
(brs, 1H)

The following compounds were prepared by a method similar to the above Examples and Preparation Examples, and by using organic chemistry techniques well known to those skilled in the art.

3,5-dimethyl-4-hydroxy-6- (5-nitro
Benzofuran-2-yl) -2H-pyran-2-one ¹ H NMR (δ ppm, CD ₃ OD): 1.96 (s, 3H) 2.32 (s, 3H) 7.
61 (s, 1H) 7.95 (d, J = 9.2Hz, 1H) 8.30 (dd, J = 2.3Hz,
9.2Hz, 1H) 8.71 (d, J = 2.3Hz, 1H) 11.00 (brs, 1H)

3,5-dimethyl-6- (5- (ethylamino) benzo
Furan-2-yl) -4-hydroxy-2H-pyran-2-one ¹ H NMR (δ ppm, CD ₃ OD): 1.42 (t, J = 7.3 Hz, 3H) 2.04
(s, 3H) 2.43 (s, 3H) 3.44 (q, J = 7.3Hz, 2H) 7.37
(s, 1H) 7.50 (dd, J = 2.0Hz, 8.9Hz, 1H) 7.68 (d, J =
8.9Hz, 1H) 7.79 (d, J = 2.0Hz, 1H)

3,5-dimethyl-4-hydroxy-6- (5- (p-toluene
Ensulfonylamino) benzofuran-2-yl) -2H-pyra
Down _{^{2-1 H NMR (δppm, CD 3}} OD): 2.00 (s, 3H)
2.36 (s, 6H) 7.07-7.11 (m,
1H) 7.21-7.26 (m, 2H)
7.34-7.41 (m, 2H) 7.57-7.
61 (m, 2H) 7.70-7.77 (m, 1
H)

3,5-dimethyl-6- (5- (dimethylamino)
Benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one ¹ H NMR (δ ppm, CD ₃ OD): 1.95 (s, 3H) 2.30 (s, 3H) 3.
12 (s, 6H) 7.41-7.75 (m, 4H)

6- (5- (dibenzylamino) benzofuran-2-
Yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one ¹ H NMR (δ ppm, CD ₃ OD): 1.94 (s, 3H) 2.31 (s, 3H) 4.
65 (s, 4H) 6.89-6.94 (m, 2H) 7.07 (s, 1H) 7.13-7.8
8 (m, 11H)

6- (benzofuran-2-yl) -3,5-dimethyl-4
-Isonicotinoyloxy-2H-pyran-2-one ¹ H NMR (δ ppm, CDCl ₃ ): 2.04 (s, 3H) 2.34 (s, 3H) 7.
26-7.42 (m, 3H) 7.53 (d, J = 7.9Hz, 1H) 7.67 (d, J = 7.
3Hz, 1H) 8.03, 8.95 (ABq, J = 6.3Hz, 4H)

6- (5-benzyloxybenzofuran-2-i
) -4- (2- (t-butoxycarbonylamino) acetyloxy
B) -3,5-Dimethyl-2H-pyran-2-one ¹ H NMR (δ ppm, CDCl ₃ ): 1.48 (s, 9H) 2.00 (s, 3H) 2.
30 (s, 3H) 4.23 (d, J = 5.9Hz, 2H) 5.06-5.14 (m, 1H)
5.11 (s, 2H) 7.06 (dd, J = 2.6Hz, 8.9Hz, 1H) 7.14 (d,
J = 2.6Hz, 1H) 7.27-7.50 (m, 7H)

5-Ethyl-4-hydroxy-3-methyl-6- (5- (3
-Pyrimidinylmethoxy) benzofuran-2-yl) -2H-pyra
Down ^{2-1 H NMR (δppm, DMSO-} d6): 1.24 (t, J = 7.3Hz, 3H) 1.99
(s, 3H) 2.93 (q, J = 7.3Hz, 2H) 5.20 (s, 2H) 7.07-
7.10 (m, 1H) 7.27-7.28 (m, 2H) 7.45-7.49 (m, 2H)
7.97 (d, J = 7.6Hz, 1H) 8.51 (m, 1H) 8.67 (s, 1H)

4-Acetyloxy-3,5-dimethyl-6- (5- (2-
Thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-
On ¹ H NMR (δ ppm, CDCl ₃ ): 2.13 (s, 3H) 2.34 (s, 3H) 2.
41 (s, 3H) 5.30 (s, 2H) 7.09 (dd, J = 8.6Hz, 2.4Hz, 1H)
7.32 (s, 1H) 7.36 (d, J = 1.9Hz, 1H) 7.47 (d, J = 1.9
Hz, 1H) 7.51 (d, J = 8.6Hz, 1H) 7.86 (d, J = 2.4Hz, 1
H)

4-Hydroxy-3,5-dimethyl-6- (5- (2-thia
Zolylmethoxy) benzofuran-2-yl) -2H-pyran-2-o
Down _{^{1 H NMR (δppm, CD 3}} OD): 1.98 (s, 3H) 2.29 (s, 3H) 5.
41 (s, 2H) 6.87 (dd, J = 8.9Hz, 2.4Hz, 1H) 7.03 (d, J
= 2.4Hz, 1H) 7.48 (d, J = 8.9Hz, 1H) 7.87 (d, J = 3.2H
z, 1H) 7.91 (d, J = 3.2Hz, 1H) 9.40 (s, 1H)

4-Acetyloxy-6- (5-bromobenzofura
-2-yl) -3,5-dimethyl-2H-pyran-2-one ¹ H NMR (δ ppm, CDCl ₃ ): 2.00 (s, 3H) 2.30 (s, 3H) 2.
40 (s, 3H) 7.29 (s, 1H) 7.40 (d, J = 8.9Hz, 1H) 7.47 (d
d, J = 8.9Hz, 2.2Hz, 1H) 7.78 (d, J = 2.2Hz, 1H)

Synthesis of 2-cyano 5-methoxybenzofuran 5-methoxysalicylaldehyde (1.52 g), K ₂ CO ₃ (1.66 g)
And bromoacetonitrile (1.44 g) in acetonitrile
(50 ml) 60 suspensions. After stirring at C for 1 hour and cooling, the reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. Toluene in residue
(50 ml) to give a suspension, and DBU (1.83 g) was added to give 110. C
And stirred overnight. After cooling, the reaction solution was concentrated under reduced pressure, a saturated aqueous NH ₄ Cl solution was added to the residue, and the mixture was extracted with AcOEt. Organic layer Mg
After drying over SO ₄ , the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 9/1) to obtain 2-cyano-5-methoxybenzofuran. Yield 0.93 g (y. 54%) ¹ H NMR (δ ppm, CDCl ₃ ): 3.86 (s, 3H)
7.05-7.46 (m, 4H)

2-Cyano-5-benzyloxybenzofura
Synthesis of 5-benzyloxysalicylaldehyde (2.28 g), K ₂ CO
_A suspension of ₃ (1.66 g) and bromoacetonitrile (1.44 g) in acetonitrile (50 ml) was prepared. After stirring at C for 1 hour and cooling, the reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. Toluene (50 ml) was added to the residue to form a suspension, and DBU (1.83 g) was added to the residue. Stirred at C overnight. After cooling, the reaction solution was concentrated under reduced pressure,
A saturated aqueous NH ₄ Cl solution was added to the residue, and the mixture was extracted with AcOEt. The organic layer was dried over MgSO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 9/1) to obtain 2-cyano-5-benzyloxybenzofuran. Yield 1.25 g (y. 50%) ¹ H NMR (δ ppm, CDCl ₃ ): 5.10 (s, 2H) 7.12-7.46 (m, 9
H)

Example 1 6- (5-Methoxybenzofuran-2-yl) -3,5-dimethyl-4-
Hydroxy-2H-pyrid-2-one 0 in a suspension of NaH (60 mg) in THF (10 ml). Methyl at C 2-methyl-3
A solution of -oxopentanoate (0.22 g) in THF (2 ml) was slowly added and stirred for 10 minutes before -78. Cool to C, 1.58M nB
uLi (0.95 ml) was slowly added dropwise. The reaction was -78. After stirring at C for 30 minutes, 2-cyano-5-methoxybenzofuran (1
A solution of 73 mg) in THF (4 ml) was added slowly and -78. Stirred at C for 4 hours. A 4N LiOH aqueous solution was added to the reaction solution, and the temperature was raised to room temperature. After stirring for 1 hour, a saturated KHSO ₄ aqueous solution (10 ml) was slowly added. The precipitated yellow precipitate was collected by filtration and washed with water and AcOEt to give 6- (5-methoxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyrid-2-one. Yield 131 mg (y. 46%) ¹ H NMR (δ ppm, DMSO-d6): 1.88 (s, 3H) 2.11 (s, 3H)
3.72 (s, 3H) 6.86-7.45 (m, 4H)

Example 2 6- (5-benzyloxybenzo)
(Furan-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyrido
0 to a suspension of 2-one NaH (60 mg) in THF (10 ml). Methyl at C 2-methyl-3
A solution of -oxopentanoate (0.22 g) in THF (2 ml) was slowly added and stirred for 10 minutes before -78. Cool to C, 1.58M nB
uLi (0.95 ml) was slowly added dropwise. The reaction was -78. After stirring at C for 30 minutes, a solution of 2-cyano-5-benzyloxybenzofuran (249 mg) in THF (4 ml) was added slowly and -78. 4 in C
Stirred for hours. A 4N LiOH aqueous solution was added to the reaction solution, and the temperature was raised to room temperature. After stirring for 1 hour, a saturated KHSO ₄ aqueous solution (10 ml) was slowly added. The precipitated yellow precipitate was collected by filtration, and water and AcOE
6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyrido-2 by washing with t
-Got it. Yield 162 mg (y. 45%) ¹ H NMR (δ ppm, DMSO-d6): 2.03 (s, 3H) 2.39 (s, 3H)
5.11 (s, 2H) 7.02-7.65 (m, 9H)

Example 3 3,5-Dimethyl-4-hydroxy-6- (5-((2-pyrimidinyl) methine
(Toxi) benzofuran-2-yl) -2H-pyrid-2-one 3,5-dimethyl-4-hydroxy-6- (5-((2-pyrimidinyl) methoxy) benzofuran-2-yl) -2H-pyran- 2-on (850m
AcONH ₄ (54 g) and 1,4-dioxane (150 ml) were added to g), and the mixture was heated under reflux for 8 hours. After the reaction solution was concentrated under reduced pressure, the residue was removed.
By recrystallization from a mixed solvent of EtOH and 1,4-dioxane, 3,5-dimethyl-4-hydroxy-6- (5-((2-pyrimidinyl) methoxy) benzofuran-2-yl) -2H-pyrido- Two
-On (790 mg) was obtained. ¹ H NMR (d ppm, DMSO-d6): 1.94 (s, 3H) 2.18 (s, 3H)
5.25 (s, 2H) 7.09 (dd, J = 9.0Hz, 2.7Hz, 1H) 7.28 (s,
1H) 7.35 (d, J = 2.7Hz, 1H) 7.56 (d, J = 9.0Hz, 1H) 8.
94 (s, 2H) 9.18 (s, 1H) 9.61 (brs, 1H)

The following compounds were prepared by a method similar to the above Examples and Preparation Examples, and by using organic chemistry well known to those skilled in the art.

Example 4 3,5-Dimethyl-4-hydroxy-6- (5- (pyrazinylmethoxy)
B) Benzofuran-2-yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.95 (s, 3H) 2.17 (s, 3H)
5.31 (s, 2H) 7.09-7.12 (m, 1H) 7.26 (s, 1H) 7.35
(d, J = 2.4Hz, 1H) 7.55 (d, J = 8.8Hz, 1H) 8.63 (d, J =
2.4Hz, 1H) 8.84 (s, 1H)

Example 5 6- (5- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl
Tyl-4-hydroxy-2H-pyrid-2-one 6- (5- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (18 mg) AcONH
₄ (1.0 g) and EtOH (10 ml) were added, and the mixture was heated under reflux for 27 hours. After the reaction solution was concentrated under reduced pressure, AcONH ₄ (250 mg) and 1,4
-Dioxane (7 ml) was added and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure to give 6- (5- (benzyloxy)
(Benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-
Pyrid-2-one (18 mg) was obtained. ^{1 H NMR (d ppm, DMSO} -d6): 1.95 (s, 3H) 2.17 (s, 3H)
5.16 (s, 2H) 7.05 (dd, J = 9.0Hz, 2.7Hz, 1H) 7.25 (s,
1H) 7.29 (d, J = 2.7Hz, 1H) 7.33-7.50 (m, 5H) 7.53 (d,
J = 9.0Hz, 1H) 9.61 (brs, 1H)

Example 6 6- (Benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-
1-methyl-2H-pyrid-2-one 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-
40% CH ₃ NH ₂ (MeOH solution, 4.2m
l) and AcOH (2.5 ml) were added, and the mixture was heated under reflux for 18 hours. After concentrating the reaction solution under reduced pressure, the residue is purified by silica gel column chromatography (5% MeOH / CH ₂ Cl ₂ → 10%) to give 6- (benzofuran-2-yl) -3,5-dimethyl 4-Hydroxy-1-methyl-2H-pyrid-2-one (9 mg) was obtained. ¹ H NMR (d ppm, DMSO-d6): 1.88 (s, 3H) 1.99 (s, 3H)
3.15 (s, 3H) 7.21 (s, 1H) 7.34 (t, J = 7.8Hz, 1H) 7.
41 (t, J = 7.8Hz, 1H) 7.66 (d, J = 7.8Hz, 1H) 7.75 (d,
J = 7.8Hz, 1H) 9.66 (brs, 1H)

Example 7 3,5-dimethyl-4-hydroxy-1-methyl-6- (5- (3-pyridi
Lmethoxy) benzofuran-2-yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.86 (s, 3H) 1.98 (s, 3H)
3.14 (s, 3H) 5.22 (s, 2H) 7.09 (dd, J = 9.0Hz, 2.7Hz,
1H) 7.13 (s, 1H) 7.36 (d, J = 2.7Hz, 1H) 7.44 (dd,
J = 7.8Hz, J = 4.9Hz, 1H) 7.58 (d, J = 9.0Hz, 1H) 7.90
(d, J = 7.8Hz, 1H) 8.55 (d, J = 4.9Hz, 1H) 8.70 (s, 1H)
9.65 (s, 1H)

Example 8 3,5-Dimethyl-4-hydroxy-6- (4,6-dimethoxybenzo
Furan-2-yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.93 (s, 3H) 2.16 (s, 3H)
3.82 (s, 3H) 3.89 (s, 3H) 6.45 (s, 1H) 6.83 (s, 1H)
7.23 (s, 1H)

Example 9 3,5-Dimethyl-4-hydroxy-6- (5-hydroxybenzofu)
(Ran-2-yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.94 (s, 3H) 2.16 (s, 3H)
6.82 (dd, J = 8.7Hz, 2.4Hz, 1H) 6.98 (d, J = 2.4Hz, 1H)
7.18 (s, 1H) 7.41 (d, J = 8.7Hz, 1H) 9.30 (brs, 1H)

Example 10 3,5-dimethyl-4-hydroxy-6-((4,5-methylenedioxy
B) Benzofuran-2-yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.94 (s, 3H) 2.17 (s, 3H)
6.14 (s, 2H) 7.02 (d, J = 8.6Hz, 1H) 7.13 (d, J = 8.6H
z, 1H) 7.27 (s, 1H)

Example 11 6- (7- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl
Tyl-4-hydroxy-2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.95 (s, 3H) 2.16 (s, 3H)
5.34 (s, 2H) 7.06 (d, J = 7.8Hz, 1H) 7.19 (t, J = 7.8H
z, 1H) 7.27 (d, J = 7.8Hz, 1H) 7.30 (s, 1H) 7.34 (t,
J = 7.3Hz, 1H) 7.41 (t, J = 7.3Hz, 2H) 7.52 (d, J = 7.3
Hz, 2H) 11.03 (brs, 1H)

Example 12 3,5-dimethyl-4-hydroxy-6- (5-((5- (morpholine-4-
Ylsulfonyl) -2-thienyl) methoxy) benzofuran-2
-Yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.95 (s, 3H) 2.17 (s, 3H)
2.92 (t, J = 4.4Hz, 4H) 3.67 (t, J = 4.4Hz, 4H) 5.45 (s,
2H) 7.08 (dd, J = 9.0Hz, 2.7Hz, 1H) 7.27 (s, 1H) 7.3
5 (d, J = 2.7Hz, 1H) 7.38 (d, J = 3.6Hz, 1H) 7.56 (d, J
= 9.0Hz, 1H) 7.59 (d, J = 3.6Hz, 1H) 9.61 (brs, 1H)

Example 13 3,5-Dimethyl-6- (5-formylbenzofuran-2-yl) -4-
Hydroxy-2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.97 (s, 3H) 2.20 (s, 3H)
7.50 (s, 1H) 7.84 (d, J = 8.4Hz, 1H) 7.94 (d, J = 8.4H
z, 1H) 8.32 (s, 1H) 10.09 (s, 1H)

Example 14 3,5-Dimethyl-4-hydroxy-6- (5-((2,4-thiazolyl) methyl
Toxi) benzofuran-2-yl) -2H-pyrid-2-one ¹ H NMR (d ppm, DMSO-d6): 1.95 (s, 3H) 2.17 (s, 3H)
5.44 (s, 2H) 7.04 (dd, J = 9.0Hz, 1.7Hz, 1H) 7.27 (s,
1H) 7.34 (d, J = 1.7Hz, 1H) 7.54 (d, J = 9.0Hz, 1H) 8.
02 (s, 1H) 9.11 (s, 1H)

Example 15 6- (Benzofuran-2-yl) -3,5-dimethyl-4-hydroxy
Si-2H-pyrid-2- ^one 1H NMR (d ppm, DMSO-d6): 1.96 (s, 3H) 2.17 (s, 3H)
7.21-7.60 (m, 5H)

Example 16 6- (5- (3-pyridyl) methyloxybenzofuran-2-yl)
-3,5-Dimethyl-4-hydroxy-2H-pyrid-2-one 0 in a suspension of NaH (3.1 g) in THF (200 ml). C is methyl 2-methyl-
Slowly add 3-oxopentanoate (11.2 g) solution and add 1
-78 after stirring for 5 minutes. C to 1.6M n-BuLi (48.5m
l) was slowly added dropwise. The reaction was -78. After stirring at C for 30 minutes, a solution of methyl 5- (3-pyridyl) methyloxybenzofuran-2-carboxylate (17.6 g) in THF (100 ml) was slowly added, and the mixture was -78. Stirred at C for 4 hours. The reaction system was warmed to room temperature and stirred for 16 hours. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with 100 ml of ethyl acetate, and then the solvent of the organic layer was distilled off under reduced pressure. THF / MeOH / H2O / 4 in orange liquid
200 mL of a solution of NLiOH = 1/1/1/1 was added, and after stirring for 2 hours, ammonium acetate (10 g) and ammonium chloride (10 g), saturated
KHSO ₄ aqueous solution was added slowly to pH = 2. The precipitated yellow precipitate was collected by filtration and washed with water and AcOEt to give a yellow solid, which was recrystallized from hot ethanol to give white 6- (5- (3-pyridyl) methyloxybenzofuran-2-yl). -3,5-dimethyl-4-hydroxy-2H-pyrido-2-
Got on. Yield 16.8 g (y. 75%) ¹ H NMR (δ ppm, DMSO-d6): 1.94 (s, 3H) 2.18 (s, 3H)
5.21 (s, 2H) 7.04 (dd, J = 9.0Hz, 1.7Hz, 1H) 7.26 (s,
1H) 7.31 (d, J = 1.7Hz, 1H) 7.42 (dd, J = 9.0Hz, 7.8H
z, 1H) 7.54 (d, J = 9.0Hz, 1H) 7.89 (d, J = 7.8Hz, 1H)
8.30 (s, 1H) 8.54 ( m, 1H), 8.70 (s, 1H) Mass ^{analysis: [M + + H] =} 363.0

Example 17 Cell Preparation Human hepatoma cells Hep cells were placed in a 24-well plate (Costar No. 3524).
G2 was seeded at 4 × 10 ⁴ cells / well, and 37 ml using 1 ml of medium (eRDF medium containing 10% bovine serum (Kyokuto Kagaku)). C, and cultured for 6 days in 5% CO ₂ . After aspirating the supernatant medium, add 1 ml of PBS
The cells were washed with (-) buffer (Takara Shuzo) and aspirated. After repeating this operation twice, add a fresh 1 ml medium (eRDF medium)
Was added.

Preparation of sample 6- (5- (3-pyridyl) methyloxybenzofuran-2-yl)
-3,5-Dimethyl-4-hydroxy-2H-pyrid-2-one (Example 16) was dissolved in dimethyl sulfoxide (DMSO) and dissolved in 20 mM.
A sample stock solution was prepared. The diluent was obtained by diluting the sample solution with DMSO.

The sample stock solution or its diluent was added to the cells prepared before the production of TG for 1 hour.
5 μl per well and ¹⁴ C-acetic acid solution (Amersham Code
No.CFA13 diluted 4.4 times with PBS (-) buffer)
l Add, 37. C, and cultured for 1 day at 5% CO ₂ .

After completion of the quantitative culture of TG , the culture solution was removed, and 1 ml of an extract (a mixture of n-hexane and isopropyl alcohol at a ratio of 2: 1) was added to extract lipid components in the cells. After the treatment, the obtained extract containing the lipid component is air-dried, and the residue is redissolved in a developing solution obtained by mixing 20 μl of a mixture of n-hexane and ethyl acetate at a ratio of 9: 1. S
319), and thin layer chromatography was performed in the developing solution described above. After air drying, the lipid component was colored in iodine vapor, a portion corresponding to TG was cut off, and the amount of biosynthesized TG was measured with a liquid scintillation counter. Table 1 shows the results. Thereby, 6- (5- (3-pyridyl) methyloxybenzofuran-2-yl) -3,5-dimethyl-
It can be seen that 4-hydroxy-2H-pyrid-2-one has triglyceride biosynthesis inhibitory activity.

[0170]

[Table 1]

Example 18 The TG production inhibitory activity of the compound of the present invention was evaluated in accordance with the above-mentioned Example. As a result of the evaluation, the IC ₅₀ value is less than 10 mM or 30% or more at a concentration of 1 mM.
Examples of the compound exhibiting TG production inhibitory activity or exhibiting TG production inhibitory activity of 50% or more at a concentration of 10 mM include the compounds of the following Example Nos .: 6, 12, 14, 15
Further, the IC ₅₀ value is 10 mM or more and less than 100 mM, or shows a TG production inhibitory activity of 5% or more and less than 30% at a concentration of 1 mM, or 1
Examples of the compound exhibiting a TG production inhibitory activity of 30% or more and less than 50% at a concentration of 0 mM include the compounds of the following Example numbers; 4

Example 19 Efficacy Evaluation Test 6- (5- (3-pyridyl) methyloxybenzofuran-2-yl)
-3,5-Dimethyl-4-hydroxy-2H-pyrid-2-one (Example 16) was suspended in a 0.5% carboxymethylcellulose Na salt aqueous solution (Vehicle) to give a 2,6,20 mg / ml administration solution. Once a day at 7 ml of SD male rats at the rate of 5 ml / kg
Oral administration was continued for 7 days. Rats were fed with CLEA Japan CE-2 and were allowed to freely feed and drink water. The rats in each group were subjected to the test, with 6 rats administered with the vehicle and 6 rats each administered with the drug. Four hours after the last drug administration, the rats were sacrificed under ether anesthesia, blood was collected from the abdominal aorta, TG in serum,
Total cholesterol (TC) and HDL levels were measured.

Triglyceride E II-HA Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used for the measurement of TG, and HA Test Wako Cholesterol E- was used for the measurement of total cholesterol (TC).
HA Test Wako (manufactured by Wako Pure Chemical Industries) was used, and HDL-cholesterol test Wako (manufactured by Wako Pure Chemical Industries) was used for HDL measurement.

As shown in Table 2, TG was reduced in a dose-dependent manner in the group administered with the compound of the present invention. In addition, as shown in Table 3, the HDL / TC ratio increased in a dose-dependent manner. Note that, during the administration period, there were no rat death cases or body weight increase suppression cases.

As described above, the compound of the present invention has a TG lowering action and / or an HDL / TC ratio increasing action and is effective as a blood triglyceride lowering agent, lipid metabolism improving agent, arteriosclerosis preventive agent or therapeutic agent for arteriosclerosis. You can see that there is.

[0176]

[Table 2]

[0177]

[Table 3]

Example 20 A tablet was prepared in which one tablet had the following composition. Active ingredient 200μg Lactose 180mg Potato starch 50mg Polyvinylpyrrolidone 10mg Magnesium stearate 5mg Mix active ingredient, lactose and potato starch,
This was evenly wetted with a 20% solution of polyvinylpyrrolidone in ethanol. Pass this through a 20mm mesh sieve,
45. C and dried again through a 15 mm mesh. The granules thus obtained were mixed with magnesium stearate and compressed into tablets.

Example 21 Hard gelatin capsules having one capsule containing the following composition were produced. Active ingredient 100 μg Microcrystalline cellulose 195 mg Amorphous silica 5 mg The active ingredient, microcrystalline cellulose, and unpressed amorphous silicic acid were thoroughly mixed and filled into hard gelatin capsules.

Example 22 The active ingredient was dissolved in fractionated coconut oil. Further, the capsule was heated and dissolved in a skin component having the following formulation, and a soft capsule was produced by a conventional method using a soft capsule maker so that 100 μg of the active ingredient was contained in one capsule. Skin formulation Gelatin 10 parts by weight Glycerin 5 parts by weight Sorbic acid 0.08 parts by weight Purified water 14 parts by weight

[0181]

The drug of the present invention has a triglyceride biosynthesis inhibitory effect, a blood triglyceride lowering effect or a blood HDL / TC ratio increasing effect, a therapeutic agent for hypertriglyceridemia, and an improvement in lipid metabolism. It can be used as an agent, and also as a preventive and / or therapeutic agent for arterial effects.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/506 A61K 31/505 601 31/5375 31/535 605 C07D 405/14 213 C07D 405/14 213 409 / 14 213 409/14 213 417/14 213 417/14 213 (72) Inventor Yushi Imai 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin, Ltd. Tokyo Research Center Co., Ltd. (72) Yoshimitsu Namika, Tokyo 4-3-2 Asahigaoka, Hino-shi Teijin, Ltd. Tokyo Research Center (72) Inventor Emiko Muratani 4-2-2, Asahigaoka, Hino-shi, Tokyo Teijin Co., Ltd. Tokyo Research Center (72) Inventor Tomomi Kosugi Tokyo 4-3-2 Asahigaoka, Hino-shi Teijin Tokyo Research Center Co., Ltd. (72) Inventor Kazuo Kitai Tokyo Metropolitan Government 4-3-2 Asahigaoka, Tokyo Teijin Tokyo Research Center Co., Ltd. (72) Inventor Kenichiro Takagi 4-3-2 Asahigaoka, Hino City, Tokyo Teijin Co., Ltd. Tokyo Research Center (72) Inventor Kunito Watanabe Hino, Tokyo 4-3-2 Asahigaoka, Tokyo Teijin Co., Ltd. Tokyo Research Center (72) Inventor Keinori Sugimoto 4-3-2 Asahigaoka, Hino City, Tokyo Teijin Co., Ltd. Tokyo Research Center Co., Ltd. (72) Inventor Mizuho Tamura Tokyo 4-3-2 Asahigaoka, Hino-shi Teijin Tokyo Research Center Co., Ltd. (72) Inventor Tomio Takeuchi 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo Inside the Microbiological Chemistry Laboratory (72) Inventor Masaru Hamada Tokyo 3-14-23 Kami-Osaki, Shinagawa-ku F term in the Laboratory for Bioscience and Biochemistry (Reference) 4C063 AA01 BB01 CC76 DD12 EE01 4C086 AA01 AA02 AA03 BC17 GA02 GA08 GA12 MA01 MA02 MA03 MA04 MA05 NA14 ZA45 ZC33

Claims (31)

[Claims] 1. A compound represented by the following formula (I): Wherein R ¹ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, R ² represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ³ represents hydrogen atom, -CO-R ⁶ (wherein R ⁶ is a hydrogen atom, optionally substituted optionally substituted alkyl group having 1 to 5 carbon atoms in the group, carbon atoms 3-7
Represents a cycloalkyl group, an aryl group having 6 to 10 carbon atoms or a heterocyclic ring. ) Or -SO ₂ R ⁷ (where R ⁷ represents an alkyl group having 1 to 5 carbon atoms or an aryl group having 6 to 10 carbon atoms which may be substituted with a halogen atom);
⁴ is a hydrogen atom, a C1-5 alkyl group, a C2-5 alkenyl group, a C2-5 alkynyl group, a C3-7
A cycloalkyl group, a C3-7 cycloalkyl-C1-5 alkyl group, a C6-10 aryl group, a carbon number 7
20 aralkyl group, an aryloxy group of an alkoxy group or a C 6-10 having 1 to 5 carbon atoms, R ⁵ is 4-position of the benzofuran ring, 5-position, a 6-position or 7-position substituent , R ^5a (where R ^5a is a hydrogen atom, a nitro group, a cyano group,
A halogen atom, a heterocyclic ring, an alkenyl group having 2 to 5 carbon atoms,
An alkynyl group having 2 to 5 carbon atoms, an aryl group having 6 to 10 carbon atoms, A = CH (CH ₂ ) _n- (where A represents an alicyclic heterocyclic ring, = represents a double bond, and n represents Represents 0, 1 or 2), A = CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle, = represents a double bond, and m represents 1, 2 or 3 ), A-SO _2- (CH ₂ ) _m- (where A represents an alicyclic heterocycle and m represents 1, 2 or 3), -OR ⁸ (where R ^{8 represents}
Is a hydrogen atom, a cycloalkyl group having 3 to 7 carbon atoms, 6 carbon atoms
Represents an aryl group having 1 to 10 carbon atoms, a heterocyclic ring, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, or an arylsulfonyl group having 6 to 10 carbon atoms. ), -O-
CO-R ⁹ (where R ⁹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or a heterocyclic ring), -NR ¹⁰ R ¹¹ (where R
¹⁰ and R ¹¹ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a heterocyclic ring,
Represents an alkylsulfonyl group having 1 to 4 carbon atoms or an arylsulfonyl group having 6 to 10 carbon atoms which may be substituted with a halogen atom. ), -NR ¹² -CO-R ¹³ (where R ¹² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, ¹³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, and having 6 to 10 carbon atoms. Represents an aryloxy group or an aralkyloxy group having 7 to 20 carbon atoms.), —CO—R ¹⁴ (where R ¹⁴ is a hydrogen atom, —OH,
Represents an alkyl group having 4 to 4, an aryl group having 6 to 10 carbon atoms, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, or an aralkyloxy group having 7 to 20 carbon atoms. ) Or -CO-NR ¹⁵ R ¹⁶ (where R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, Represents an aryl group, an aralkyl group having 7 to 20 carbon atoms or a heterocyclic ring.). ), R ^5b (where R ^5b is a halogen atom,
A cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a heterocyclic ring, -OR ¹⁷ (where R ¹⁷ is a hydrogen atom,
Represents an alkyl group, a phenyl group, a naphthyl group, a benzyl group or a heterocyclic ring. ), -O-CO-R ¹⁸ (where R ¹⁸
Represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group or a hetero ring. ), -N
R ¹⁹ R ²⁰ (wherein R ^{1 9,} R ²⁰ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a hetero ring,
Represents an alkylsulfonyl group having 1 to 4 carbon atoms or a phenylsulfonyl group which may be substituted with a halogen atom. ), -NR ²¹ -CO-R ²² (where R ²¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or an aralkyl group having 7 to 20 carbon atoms) , R ²² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group, a hetero ring, an alkoxy group or a benzyloxy group having 1 to 4 carbon atoms), -. CO-R ²³ (Where R ²³ represents a hydrogen atom, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, a benzyloxy group, or —OR ²⁴ (where R ²⁴ represents a hydrogen atom or a heterocyclic ring).) And -CO-NR ²⁵ R ²⁶ (where R ²⁵ and R ²⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a heterocyclic ring). And represents a saturated or unsaturated alkoxy group having 1 to 6 carbon atoms which may be substituted with 1 to 3 groups. ) Or R ^5c
(Where R ^5c is a halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a heterocyclic ring, -OR
²⁷ (where R ²⁷ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Represents a phenyl group, a naphthyl group, a benzyl group or a hetero ring. ), -O-CO-R ²⁸ (where R ²⁸ is a hydrogen atom, carbon number
Represents an alkyl group of 1 to 4, a phenyl group, a naphthyl group, a benzyl group or a hetero ring. ), -NR ²⁹ R ³⁰ (where
R ²⁹ and R ³⁰ are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a heterocyclic ring, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, or phenylsulfonyl. Represents a group. ), -NR ³¹ -CO-R ³²
(Where R ³¹ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Represents an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, R ³² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
Represents a phenyl group, a naphthyl group, a benzyl group, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms or a benzyloxy group. ), -CO-R ³³ (where R ³³ is a hydrogen atom, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, a phenoxy group, a benzyloxy group or -OR ³⁴ (where R ³⁴ is a hydrogen atom or a heterocyclic ring) ) And -CO-NR ³⁵ R ³⁶ (where R
³⁵ and R ³⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a heterocyclic ring. ) Represents an alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 3 groups selected from the group consisting of: ). A benzofuryl-α-pyridone derivative or a salt thereof. 2. The benzofuryl according to claim 1, wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group.
-α-pyridone derivatives or salts thereof. 3. The benzofuryl-α-pyridone derivative or a salt thereof according to claim 1, wherein R ¹ is a hydrogen atom. 4. The benzofuryl-α-pyridone derivative or a salt thereof according to claim 1, wherein R ² is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group. 5. The benzofuryl-α-pyridone derivative or a salt thereof according to claim 1, wherein R ² is a methyl group. 6. R ⁵ is a halogen atom, —OR ³⁷ (where R ³⁷ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or Represents a heterocycle.), -O-CO-R ³⁸ (where R ³⁸ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or Represents a heterocycle.),-
NR ³⁹ R ⁴⁰ (where R ³⁹ and R ⁴⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a heterocyclic ring, Good alkylsulfonyl group having 1 to 4 carbon atoms or 6 to 10 carbon atoms
Represents an arylsulfonyl group. ), -NR ⁴¹ -CO-R ⁴² (where R ⁴¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, ⁴² is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms or 7 to 20 carbon atoms.
Represents an aralkyloxy group. ), A cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, heterocycles and -CO-R ⁴³ (wherein R ⁴³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, heterocycle, -OR ⁴⁴ (where R ⁴⁴ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or a heterocyclic ring) or -NR ⁴⁵ R ⁴⁶ (wherein R ⁴⁵ and R ⁴⁶ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 7 to 20 carbon atoms or a heterocyclic ring). An alkyl group having 1 to 5 carbon atoms which may be substituted by a selected 1 to 4 groups, or a hydrogen atom,
The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 5, which is a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heterocyclic ring. 7. R ⁵ is —OH, an alkoxy group having 1 to 4 carbon atoms,
Phenoxy group, benzyloxy group, -O-CO-R ⁴⁷ (where R
⁴⁷ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a hetero ring. ), -NR ⁴⁸ R ⁴⁹ (where R ⁴⁸ , R ⁴⁹
Each independently represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a heterocyclic ring or an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted by a halogen atom. ), -NR ⁵⁰ -CO-R ⁵¹ (where R ⁵⁰ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, ⁵¹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a heterocyclic ring, an alkoxy group or a benzyloxy group having 1 to 4 carbon atoms.), And 6 to 1 carbon atoms.
0 aryl group, hetero ring and -CO-R ⁵² (where R ⁵² represents a hydrogen atom, -OR ⁵³ (where R ⁵³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a hetero ring) .),
—NR ⁵⁴ R ⁵⁵ (where R ⁵⁴ and R ⁵⁵ each independently represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a heterocycle) or a heterocycle. ) Having 1 to 5 carbon atoms which may be substituted with 1 to 3 groups selected from the group consisting of
Or a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms or a heterocyclic ring, the benzofuryl according to any one of claims 1 to 5.
-α-pyridone derivatives or salts thereof. 8. R ⁵ is a phenoxy group, —NR ⁵⁶ R ⁵⁷ (where R
⁵⁶ and R ⁵⁷ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, a heterocyclic ring or an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom. ), -NR ⁵⁸ -CO-R ⁵⁹ (where R ⁵⁸ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, ⁵⁹ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, heterocyclic, alkoxy or benzyloxy group having 1 to 4 carbon atoms.), a phenyl group and -CO-R ⁶⁰ (wherein R ⁶⁰ is -OH , Carbon number 1-4
An alkoxy group, a benzyloxy group, -NR ⁶¹ R ⁶² (where
R ⁶¹ and R ⁶² each independently represent a hydrogen atom, a methyl group, an ethyl group, a benzyl group or a heterocyclic ring. ) Or heterocycle. A) an alkyl group having 1 to 5 carbon atoms which may be substituted by 1 to 3 groups selected from the group consisting of: or an aryl group or a heterocyclic ring having 6 to 10 carbon atoms. 6. The benzofuryl-α-pyridone derivative or a salt thereof according to any one of 5. 9. R ⁵ is phenoxy, -NR ⁶³ R ⁶⁴ (wherein R
⁶³ and R ⁶⁴ each independently represent a hydrogen atom or a methyl group. ), -NR ⁶⁵ -CO-R ⁶⁶ (where R ⁶⁵ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, ⁶⁶ represents a hydrogen atom, a methyl group, a heterocyclic, t-butoxy or benzyloxy group.), a phenyl group and -CO-R ⁶⁷ (wherein R ⁶⁷ is selected from the group consisting of a heterocyclic.) The benzofuryl-α- according to any one of claims 1 to 5, which is an alkyl group having 1 to 5 carbon atoms which may be substituted with 1 to 2 groups, or a phenyl group or a heterocyclic ring. Pyridone derivatives or salts thereof. 10. The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 9, wherein R ³ is a hydrogen atom or —CO—R ⁶ . 11. R ³ is a hydrogen atom, an acetyl group, an isobutyryl group, a benzoyl group, 4-methoxybenzoyl group, 2,4
Dimethoxybenzoyl, 4-hydroxymethylbenzoyl, 3-dimethylaminobenzoyl, 4-acetylaminobenzoyl, phenylacetyl, 3-phenylpropionyl, phenoxyacetyl, furan-2-carbonyl, pyridine-4- Carbonyl group, pyridine-3-carbonyl group, pyridine-2-carbonyl group, 6-hydroxypyridine-3-carbonyl group, 2-aminoacetyl group, 2- (t-butoxycarbonylamino) acetyl group, 2- (N- (Carbobenzyloxy-N-methylamino) acetyl group, 1-carbobenzyloxy-2-pyrrolidone-5-carbonyl group, 2-pyrrolidone
-5-carbonyl group, 3-acetylamino-4-morpholino-4-
The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 5, which is an oxobutyryl group, a trifluoromethanesulfonyl group, or a methanesulfonyl group. 12. The benzofuryl-α- according to any one of claims 1 to 5, wherein R ³ is a hydrogen atom or an acetyl group.
Pyridone derivatives or salts thereof. 13. R ⁴ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, a cycloalkyl-methyl group having 3 to 7 carbon atoms, Number 3 ~
7 cycloalkyl-ethyl group, phenyl group, benzyl group,
The benzofuryl-α- according to any one of claims 1 to 12, which is a phenethyl group, a methoxy group, or a phenoxy group.
Pyridone derivatives or salts thereof. 14. R ⁴ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl-methyl group having 5 to 6 carbon atoms, a cycloalkyl-ethyl group having 5 to 6 carbon atoms. ,
The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 12, which is a phenyl group, a benzyl group, a methoxy group, or a phenoxy group. 15. The benzofuryl-α- according to any one of claims 1 to 12, wherein R ⁴ is an alkyl group having 1 to 5 carbon atoms.
Pyridone derivatives or salts thereof. The benzofuryl-α- according to any one of claims 1 to 12, wherein R ⁴ is a methyl group or an ethyl group.
Pyridone derivatives or salts thereof. 17. R ^5c is a heterocycle, —OH, an alkoxy group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, —NR ⁶⁸ R
⁶⁹ (here, R ⁶⁸ and R ⁶⁹ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom); -NR ⁷⁰ -CO-R ⁷¹ (where R ⁷⁰ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R ⁷¹ represents a hydrogen atom, 1 to 4 carbon atoms. Represents an alkyl group or an alkoxy group having 1 to 4 carbon atoms.), -CO-R ⁷²
(Where R ⁷² represents a hydrogen atom, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms, or —OR ⁷³ (where R ⁷³ represents a hydrogen atom or a heterocyclic ring)) and —CO—NR ⁷⁴ R ⁷⁵ (where R ⁷⁴ and R ⁷⁵ each independently represent a hydrogen atom,
Represents an alkyl group or a hetero ring of 4 to 4; 17) An alkyl group having 1 to 3 carbon atoms which may be substituted with 1 to 3 groups selected from the group consisting of:
Item 4. The benzofuryl-α-pyridone derivative or a salt thereof according to item 1. 18. A compound having 1 to 5 carbon atoms wherein R ^5c is substituted with a heterocyclic ring.
The benzofuryl-α-pyridone derivative according to any one of claims 1 to 16, which is an alkyl group of 3, or a salt thereof. 19. R ^5c is a (3,5-dioxo-2,4-thiazolidinyl) methyl group, (3,5-dioxo-2,4-oxazolidinyl)
Methyl group, (2,5-dioxoimidazolidin-4-yl) methyl group or (5-oxo-3-thioxo-2,4-thiazolidinyl)
The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 16, which is a methyl group. 20. The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 16, wherein R ^5c is a (3,5-dioxo-2,4-thiazolidinyl) methyl group. 21. R ^5b is halogen atom, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a naphthyl group, a hetero ring,
An acyloxy group having 1 to 4 carbon atoms, -CHO, _-CO 2 H, alkoxycarbonyl groups of 2 to 5 carbon atoms, -OR ⁵⁵ (wherein R ⁵⁵
Represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group or a heterocyclic ring. ) And -NR ⁷⁶ R
⁷⁷ (where R ⁷⁶ and R ⁷⁷ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxycarbonyl group having 2 to 5 carbon atoms).
The benzofuryl-α- according to any one of claims 1 to 20, which is an alkoxy group having 1 to 6 carbon atoms which may be substituted with a group, or an unsaturated alkoxy group having 3 to 6 carbon atoms.
Pyridone derivatives or salts thereof. (22) R ^5b is methoxy, 2-propynyloxy, 2,2-dimethylpropoxy, cyclopentylmethoxy, 2-bromoethoxy, benzyloxy, chlorobenzyloxy, fluorobenzyloxy, (Trifluoromethyl) benzyloxy group, dichlorobenzyloxy group, dimethylbenzyloxy group, methoxybenzyloxy group, sulfamoylbenzyloxy group, (methylenedioxy) benzyloxy group, carboxybenzyloxy group, (methoxycarbonyl) benzyloxy Group,
n-butoxybenzyloxy group, 3-phenylpropoxy group, di (methoxyphenyl) methoxy group, 1-methyl-1-phenylethoxy group, naphthylmethoxy group, thienylmethoxy group, pyridylmethoxy group, pyrazinylmethoxy group,
Pyrimidinylmethoxy group, thiazolylmethoxy group, (3,5
-Dioxo-2,4-thiazolidinyl) methoxy group, N-methylpiperidylmethoxy group, (4-oxachroman-2-yl) methoxy group, (3,3-dimethyl-2,4-dioxolanyl) methoxy group, methoxymethyl group , 2- (acetyloxy) ethoxy group, bis (dimethylaminomethyl) methoxy group, 4- (t-butoxycarbonylamino) butoxy, ethoxycarbonylmethoxy group, 2- (methoxycarbonyl) ethoxy group, 5-
The benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 20, which is a (ethoxycarbonyl) pentyloxy group or a 2- (benzyloxy) ethoxy group. 23. R ^5b is methoxy, 2-propynyloxy, benzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl) benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, Methoxybenzyloxy group, sulfamoylbenzyloxy group, (methylenedioxy) benzyloxy group, carboxybenzyloxy group, (methoxycarbonyl) benzyloxy group, n-butoxybenzyloxy group, thienylmethoxy group, pyridylmethoxy group, A radinylmethoxy group, a pyrimidinylmethoxy group, a thiazolylmethoxy group, a (3,5-dioxo-2,4-thiazolidinyl) methoxy group, an N-methylpiperidylmethoxy group or a methoxymethyl group. The benzofuryl-α-pyridone derivative according to claim 1 The other is a salt thereof. 24. R ^5a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a heterocycle, A = CH (CH ₂ ) _n- (where A represents an alicyclic heterocycle, and = represents a double Represents a bond, and n is
Represents 0, 1 or 2. ), A = CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle, = represents a double bond, and m represents
Represents 1, 2 or 3. ), A-SO _2- (CH ₂ ) _m- (where A represents an alicyclic heterocycle and m represents 1, 2 or 3), -OR ⁷⁸ (where R ⁷⁸ is a hydrogen atom A heterocycle, an alkylsulfonyl group or a phenylsulfonyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom.), -O-CO-R ⁷⁹ (where R ⁷⁹ is a hydrogen atom, 1 carbon atom) ~Four
Represents an alkyl group or a phenyl group. ), -NR ⁸⁰ R ⁸¹
(Where R ⁸⁰ and R ⁸¹ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group, an alkylsulfonyl group having 1 to 4 carbon atoms which may be substituted by a halogen atom, or phenylsulfonyl Represents a group.), -NR ⁸² -CO-R
⁸³ (where R ⁸² represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, and R ⁸³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a phenyl group. ), -CO-R ⁸⁴ (where R ⁸⁴ represents a hydrogen atom, -OH, a heterocyclic ring, an alkoxy group having 1 to 4 carbon atoms or a phenoxy group) or -CO-NR ⁸⁵ R ⁸⁶ (where R ^{85 represents} , ^R86 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, or a heterocyclic ring.). 2. The benzofuryl-α-pyridone derivative or a salt thereof according to item 1. 25. R ^25a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a heterocyclic ring, A = CH (CH ₂ ) _n- (where A represents an alicyclic heterocyclic ring, Represents a bond, and n is
Represents 0, 1 or 2. ), A = CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle, = represents a double bond, and m represents
Represents 1, 2 or 3. ), A-SO _2- (CH ₂ ) _m- (where A represents an alicyclic heterocycle, m represents 1, 2 or 3), -OR ⁸⁷ (where R ⁸⁷ is a hydrogen atom Represents an alkylsulfonyl group having 1 to 4 carbon atoms or a phenylsulfonyl group which may be substituted with a halogen atom.), -O-CO-R
⁸⁸ (where R ⁸⁸ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group), -NR ⁸⁹ R ⁹⁰ (where R ⁸⁹ and R ⁹⁰ each independently represent a hydrogen atom, a carbon atom of 1 to 4 Alkyl group, benzyl group, carbon atom 1 which may be substituted with a halogen atom
And represents an alkylsulfonyl group or a phenylsulfonyl group. ), -CO-R ⁹¹ (where R ⁹¹ represents a hydrogen atom, -OH or an alkoxy group having 1 to 4 carbon atoms) or -CO-
NR ⁹² R ⁹³ (where R ⁹² and R ⁹³ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group or a heterocyclic ring). The benzofuryl- according to any one of claims 1 to 23.
α-pyridone derivatives or salts thereof. (26) R ^5a is a hydrogen atom, a nitro group, a cyano group, a bromine atom, a thiazolyl group, a furyl group, a thienyl group,
Morpholinyl group, hydroxyl group, methanesulfonyloxy group,
Trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, benzoyloxy, dimethylamino, dibenzylamino, phenylsulfonylamino, dimethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, imidazolylcarbamoyl, thia Zolylcarbamoyl group, isothiazolylcarbamoyl group, pyrazolylcarbamoyl group, triazolylcarbamoyl group, pyridylcarbamoyl group, pyrimidinylcarbamoyl group, pyrazinylcarbamoyl group, isoxazolylcarbamoyl group, formyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl Group, n-propoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, acetyl group, benzoyl Group, (3,5-dioxo-2,4-thiazolidinylidene) methyl group, (3,5-dioxo-2,4-oxazolidinylidene) methyl group, (2,5-dioxoimidazolidin- Four
-Ylidene) methyl group, (5-oxo-3-thioxo-2,4-thiazolidinylidene) methyl group, ((3,5-dioxo-2,4-thiazolidinyl) sulfonyl) methyl group, ((3, 5-dioxo-2,4
-Oxazolidinyl) sulfonyl) methyl group, ((2,5-dioxoimidazolidin-4-yl) sulfonyl) methyl group or ((5-oxo-3-thioxo-2,4-thiazolidinyl) sulfonyl) methyl group A benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 23. 27. R ^5a is a hydrogen atom, a nitro group, a cyano group, a bromine atom, a thienyl group, a hydroxyl group, a trifluoromethanesulfonyloxy group, a phenylsulfonyloxy group,
Acetyloxy group, dimethylamino group, dibenzylamino group, thiazolylcarbamoyl group, methoxycarbonyl group, isopropoxycarbonyl group or (3,5-dioxo-
(2,4-thiazolidinylidene) methyl group.
4. The benzofuryl-α-pyridone derivative or a salt thereof according to any one of 3. 28. A pharmaceutical composition comprising a therapeutically effective amount of the benzofuryl-α-pyridone derivative according to any one of claims 1 to 27, or a salt thereof, and a pharmaceutically acceptable carrier. 29. An agent for improving lipid metabolism comprising the benzofuryl-α-pyridone derivative or a salt thereof according to claim 1 as an active ingredient. 30. A triglyceride biosynthesis inhibitor, a blood triglyceride lowering agent or a blood HDL increasing agent comprising the benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 28 as an active ingredient. 31. An agent for preventing or treating arteriosclerosis, comprising the benzofuryl-α-pyridone derivative or a salt thereof according to any one of claims 1 to 28 as an active ingredient.