CZ20003191A3 - Derivatives of benzofuryl-alpha-pyrone, pharmaceutical preparations, synergists, inhibitors and agents - Google Patents

Abstract

Benzophenyl-α-pyrone derivatives represented by the general or a salt thereof, wherein R 1 represents hydrogen or C 1-5 alkyl; R 2 represents hydrogen, -CO-R 5 or SO 2 R 6; R3 represents hydrogen, C 1-5 alkyl, etc .; and R 4 is a substituent of the structure attached to the 4-, 5-, 6- or 7-position of the benzofuran ring. These compounds are useful as pharmaceuticals hyperglyceridemia, lipid metabolism enhancing agents preventive / curative substances for arteriosclerosis, etc.

Description

The present invention relates to novel benzofuryl-α-pyrone derivatives and medicaments containing them as active ingredients. More particularly, the invention relates to novel benzofiiryl-apyrone derivatives and lipid metabolism synergists, arteriosclerotic prophylactic agents, arteriosclerotic treatment agents, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL enhancing agents which contain said derivatives as active ingredients.

BACKGROUND OF THE INVENTION

Blood cholesterol and triglycerides (TG) are generally insoluble in blood and exist as lipoproteins that are bound to apolipoproteins. In the body, triglycerides are primarily biosynthesized in the liver from acetyl CoA as a starting substance that is produced from sugars, etc., by six different enzymes and one enzyme group (acetyl CoA carboxylase, a group that synthesizes fatty acids and fatty acetyl CoA synthase, transferase glycerophosphoryl acid, lysophosphatidylacyl acid transferase, phosphatidic acid phosphate transferase, and diacylglycerolacyl) and are excreted from the liver to the blood as lipoproteins.

A condition of higher than normal amounts of cholesterol and / or triglycerides in the blood is known as hyperlipidemia. Hyperlipidemia is classified into 6 types based on blood lipoproteins according to the Fredrickson classification (WHO classification). Types I, IV and V are characterized only by elevated triglycerides, type IIa by increased cholesterol, and types IIb and III by both amounts ("Sogo Rinsho", 43, 871 (1994)). This means that hyperlipidemic drugs present (which lower only cholesterol or that lower both cholesterol and triglycerides) cannot always be suitably applied to all cases of hyperlipidemia, especially type XV, which accounts for 40% to 50% of male hyperlipidemic patients (“ Rinsho to Kenkyu, 69, 318 (1992)). Most of the secondary initial forms accompanied by diabetes are also type IV ("Sogo Rinsho", 43, 878 (1994)).

Hypertriglyceridemia is a condition in which triglycerides are elevated in the blood and have been accepted among clinicians and pharmaceutical manufacturers as a risk factor in arteriosclerosis and ischemic diseases in the past few years.

Since most hyperlipidemia treatments, including hypertriglyceridemia, were focused on single cholesterol, which is directly implied by arteriosclerosis, few drugs were invented to reduce triglycerides and treatment of hypertriglyceridemia was limited by the use of clolibrate-based or nicotinic acid-based hypolipidemic drugs, as existing hypolipidemic drugs. Since these must be used at high doses and affect many active sites of metabolism, relatively high side effects have occurred (The Lipid, 5, 65-72 (1994)). In the present invention, a desirable new type of drug should be described which has such a major effect that it reduces the amount of triglycerides in small doses, while showing little side effect and having a clear mechanism of action.

Hypertriglyceridemia occurs as a result of various causes, including the genetic background, and as mentioned above, the onset is secondary to diabetes, etc. (“Sogo Rinsho”, 43, 878 (1994)); more specifically is attributed to:

A. intensive synthesis of triglycerides (secretion) in the liver a

B. delayed digestion of synthesized triglycerides (present in blood as lipoproteins) by lipoprotein lipase (LPL) ("Rinsho to Kenkyu", 69, 340 (1992)). Especially for hypertriglyceridaemia accompanied by diabetes, A. is said to be the cause of non-insulin-dependent diabetes (NIDDM), while B. is said to be the cause of insulin-dependent diabetes (IDDM) (“Rinsho to Kenkyu”) 69, 379 (1992)). Consequently, it is believed that the mechanism of action of therapeutic agents for hypertriglyceride inhibits triglyceride synthesis (secretion) in the liver and / or accelerates the breakdown of synthesized triglycerides (present in blood as lipoproteins) by lipoprotein lipase (LPL).

It has been known in chemistry that α-pyrone derivatives having a heteroaromatic ring substitution at the C-6 position have the desired effect described, for example, in WO 9635664, WO 9514013, WO 9514014, EP 588137, US 4668803, FR 2665445, Japanese Unexamined Patent Publication SHO No . 49-5976, Japanese Unexamined Patent Publication no. 8-503216, Japanese Unexamined 9-505291, Japanese Unexamined Patent Publication no. 9-505293, Japanese Unexamined Patent Publication no. 9-505294, Japanese Unexamined Patent Publication no. 9-505295 or, for example, in Tetrahedron Letters, 37, 6461 (1996), J. Chem. Research (S), 86 (1994) Chem. Pharm. Bull., 32, 1665 (1984), Chem. Ber., 100, 658 (1967), etc. Org. Chem., 54, 3985 (1989).

However, no explanation or suggestion has been published regarding the effect of inhibiting triglyceride biosynthesis, the effect of lowering the amount of triglycerides in the blood or the effect of increasing the amount of HDL in the blood for some of these α-pyrone derivatives.

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The chemical publications WO 9635664 and EP 588137 disclose compounds with such structural features wherein phenyl is a substituent at the C-3 position of the α-pyron ring, but no description or suggestion has been made with respect to the use of an alkyl group as a substitute for phenyl which is a substituent on C-3 position of α-pyron ring.

Similarly, US 4668803 together with chemical publications disclose α-pyrone derivatives wherein the substituent at the C-3 position is an acyl group having from 2 to 11 carbon atoms or a phenyl group, but no description or suggestion has been made with respect to the use of alkyl as a substitute for acyl having from 2 to 11 carbon atoms or phenyl and is a substituent at the C-3 position of the α-pyron ring.

Also FR 2665445, together with chemical publications, describes α-pyrone derivatives having S (O) _n -R 'as a substituent at the C-4 position, where n is 1 or 2 and R ¹ represents an alkyl group having from 1 to 6 carbon atoms, benzyl or phenyl. However, no description or suggestion has been made with respect to the use of OH, OCOR or OSO2R as a substitute for SiO ¹ -R ¹ , which is a substituent at the C-4 position of the α-pyron ring.

Similarly, Japanese Unexamined Patent Publication No. 49-5976 together with chemical publications disclose α-pyrone derivatives with hydrogen, a shorter alkyl group or phenyl as a substituent at the C-4 position, but no description or suggestion was made with respect to the use of OH, OCOR or OSO2R as a replacement for hydrogen, a shorter alkyl group or a phenyl group which is a substituent at the C-4 position of the α-pyron ring.

Similarly, Chem. Ber., 100, 658 (1967) together with chemical publications disclose α-pyrone derivatives with hydrogen, methyl or ethyl as a substituent at the C-4 position, but no description or suggestion has been made with respect to the use of OH, OCOR or OSO2R as a substitute for hydrogen, methyl or ethyl, which is a substituent at the C-4 position of the α-pyron ring.

Similarly, J. Chem. Research (S), 86 (1994) together with chemical publications disclose α-pyrone derivatives with an SMe group as a substituent at the C-4 position, but no description or suggestion has been made with respect to the use of OH, OCOR or OSO2R as a substitute for the SMe group. , which is a substituent at the C-4 position of the α-pyron ring.

In addition, Tetrahedron Letters, 37, 6461 (1996), Chem. Pharm. Bull., 32, 1665 (1984); Org. Chem., 54, 3985 (1989) together with chemical publications disclose α-pyrone derivatives with pyridyl as a substituent at the C-6 position, but no description or suggestion has been made with respect to the use of benzofuryl as a substitute for pyridyl as a substituent on C -6 position of α-pyron ring.

SUMMARY OF THE INVENTION

The present invention provides benzofuryl-α-pyrone derivatives and in particular novel benzofuryl-α-pyrone derivatives having a benzoturyl group as a substituent at the C-6 position of the α-pyron ring.

Further, the invention provides lipid metabolism synergists, arteriosclerotic prophylactic agents, arteriosclerotic treatment agents, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL enhancing agents which contain novel benzofuryl-α-pyrone derivatives having a benzofuryl group as a C6 substituent position of the α-pyron ring.

The present inventors have many years of experience in the chemistry of the above compounds, and as a result of their work it is recognized that benzofuryl-α-pyrone derivatives and especially benzofuryl-α-pyrone derivatives having a benzofuryl substituent at the C-6 position of the α-pyron ring triglyceride biosynthesis inhibiting, blood triglyceride lowering effect and HDL blood raising effect; The present invention was achieved after years of research.

Specifically, the present invention provides benzofuryl-α-pyrone derivatives (and salts thereof) represented by the following structural formula I

r '(I) wherein R ¹ represents hydrogen or an alkyl group having from 1 to 5 carbon atoms;

wherein R ² represents hydrogen, -CO-R ⁵ (wherein R ⁵ represents hydrogen, alkyl having from 1 to 5 carbon atoms with preferred substituents, cycloalkyl having from 3 to 7 carbon atoms, aryl having from 6 to 5 carbon atoms) 10 carbon atoms or a heterocycle) or -SO ² R ⁶ (wherein R ⁶ represents preferably a halogen substituted alkyl group having from 1 to 5 carbon atoms or an aryl group having from 6 to 10 carbon atoms);

R represents hydrogen, alkyl having from 1 to 5 carbon atoms, alkenyl having from 2 to 5 carbon atoms, alkynyl having from 2 to 5 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkyl which has from 3 to 7 • ·

carbon atoms - an alkyl group having from 1 to 5 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group having from 7 to 20 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, or an aryloxy group having has from 6 to 10 carbon atoms;

R ⁴ is a substituent at the C-4 position, C-5 position, C-6 position or C-7 position of the benzofuran ring and represents:

R ^4a , which represents hydrogen, nitro, cyano, halogen, heterocycle, alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to 5 carbon atoms, aryl of 6 to 10 carbon atoms, A = CH (CH ₂ ) _n - (where A represents an alicyclic heterocycle, "=" represents a double bond and _n represents 0, 1 or 2), A = CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle and _m represents 1, 2 or 3), OR ⁷ (wherein R ⁷ represents hydrogen, a cycloalkyl group having from 3 to 7 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a heterocycle, preferably a halogen substituted alkylsulfonyl group having from 1 to 4 atoms -CO-R (wherein R represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an arylalkyl group having from 7 to 20 carbon atoms or heterocycle), -NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ independently of one another represent hydrogen, alkyl having 1 to 4 carbon atoms, aralkyl having 7 to 20 carbon atoms, phenyl, heterocycle, -SO 2 -R ¹¹ (wherein R ¹¹ preferably represents a halogen-substituted alkyl group having from 1 to 12 carbon atoms, a heterocycle-substituted alkyl group having from 1 to 6 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a heterocycle or an arylalkyl group having from 7 to 20 carbon atoms. or -CO-R (wherein R represents hydrogen, an alkyl group having from 1 to 12 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group having from 7 to 20 carbon atoms, a heterocycle, an alkoxy group having from 1 to 10 carbon atoms, a heterocycle-substituted alkyl group having from 1 to 6 carbon atoms, an aryloxy group having from 6 to 10 carbon atoms, a heteroaryloxy group or an aralkyloxy group having from 7 to 20 carbon atoms) -CO-R ¹³ (wherein R ¹³ represents hydrogen, -OH, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a heterocycle, an alkoxy group having from 1 to 4 atoms an aryloxy group having from 6 to 10 carbon atoms or an aralkyloxy group having from 7 to 20 carbon atoms) or -CO-NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ each independently represent hydrogen, an alkyl group having from 6 to 10 carbon atoms); C 1 -C 4, cycloalkyl having 3 to 7 carbon atoms, aryl having 6 to 10 carbon atoms, aralkyl having 7 to 20 carbon atoms, heterocycle or heterocycle substituted alkyl having 1 to 4 carbon atoms 4 carbon atoms);

R ^4b , which represents a saturated or unsaturated alkoxy group having from 1 to 6 carbon atoms, preferably substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups having from 3 to 7 carbon atoms, phenyl, naphthyl, heterocycle, OR ¹⁶ ( wherein R ¹⁶ represents an alkyl group having from 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), -O-CO-R ¹⁶ (wherein R ¹⁶ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, a phenyl group , naphthyl, benzyl or heterocycle), -NR ¹⁷ R ¹⁸ (wherein R ¹⁷ and R ¹⁸ independently represent hydrogen, alkyl of 1 to 4 carbon atoms, heterocycle, alkylsulfonyl of 1 to 4 carbon atoms, phenylsulfonyl, -SO ₂ -Het (where Het represents a heterocycle), aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl or an alkyl group having from 1 to 4 atoms carbon substituted with 1 or 2 groups obtained from phenyl, heterocycles, phenoxy, O-Het (where Het represents a heterocycle) and hydroxyl, -NH-CO-R ¹⁹ (wherein R ¹⁹ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms , phenyl, naphthyl, benzyl, heterocycle, alkoxy having from 1 to 4 carbon atoms or benzyloxy), -COR ²⁰ (wherein R ²⁰ represents hydrogen, heterocycle, alkoxy having from 1 to 4 carbon atoms, phenoxy, benzyloxy) or -OR ²¹ (wherein R ²¹ represents hydrogen or a heterocycle)) and -CO-NR R (wherein R and R independently represent hydrogen, alkyl having from 1 to 4 carbon atoms, benzyl or heterocycle); or

R ^4c which represents an alkyl group having from 1 to 4 carbon atoms preferably substituted by 1 to 3 groups obtained from the group comprising halogens, cycloalkyl groups having from 3 to 7 carbon atoms, phenyl, naphthyl, heterocycles, -SH, -OR ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, naphthyl, benzyl or heterocycle), -O-CO-R ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 atoms) N, R (where R and R are each independently hydrogen, alkyl of 1 to 4 carbon atoms, heterocycle, alkylsulfonyl of 1 to 4 carbon atoms, phenylsulfonyl) , -SO2-Het (wherein Het represents a heterocycle), amino sulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl or an alkyl group having from 1 to 4 carbon atoms substituted with 1 n or 2 groups derived from phenyl, heterocycles, phenoxy, O-Het (where Het represents a heterocycle) and hydroxyl, -NH-CO-R ¹⁹ (wherein R ¹⁹ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, a phenyl group, naphthyl, benzyl, heterocycle, alkoxy having from 1 to 4 carbon atoms or benzyloxy), -COR ²⁰ (wherein R ²⁰ represents hydrogen, heterocycle, alkoxy having from 1 to 4 carbon atoms, phenoxy, benzyloxy), or -OR ²¹ (wherein R ²¹ represents hydrogen or a heterocycle)) and -CO-NR ²² R ²³ (wherein R ²² and R ²³ independently represent hydrogen, alkyl having 1 to 4 carbon atoms, benzyl or heterocycle); and

Numbers in italics represent the position on the benzofuran ring.

The present invention further provides pharmaceutical compositions comprising a therapeutically effective dose of benzofuryl-α-pyrone derivatives, which is represented by Structural Formula (I) above, or salts thereof, with pharmaceutically acceptable carriers.

The invention further provides lipid metabolism synergists, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents, blood HDL enhancing agents, arteriosclerotic prophylactic agents, and arteriosclerotic treatment agents which contain the novel benzofuryl-α-pyrone derivatives which are represented by the structural general of formula (I) above or salts thereof.

Explanation of the terms used herein in the present invention

The terms used alone or in conjunction with other terms throughout the present invention will now be explained. Although, the invention is not in some sense limited by the specific examples set forth below.

"Alkyl" means a linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl or 3-pentyl.

"Alkenyl" means a linear or branched alkenyl group such as vinyl, 1-propenyl, aryl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl or 2-pentenyl.

"Alkynyl" means a linear or branched alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl or 4-pentynyl.

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

"C 3 -C 7 -cycloalkyl, C 1 -C 5 -alkyl" is a group containing the aforementioned C 3 -C 7 -cycloalkyl group and a C 1 -C 5 alkyl group, and for example herein mention may be made of cyclopropylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and cycloheptylmethyl.

"Aryl" means an aromatic ring of 6 to 10 carbon atoms such as phenyl or naphthyl.

"Heterocycle" is a heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and may be a 5- or 6-membered heteroaromatic group such as imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl , pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, oxazolyl or isoxazolyl, or a 5- to 7-membered heteroalicyclic group such as thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tetrahydrofuryl, tetrahydrofuryl, dioxolanyl, dioxanyl, oxazinyl, thiazinyl, diazinyl or pyrazolidinyl; it also includes bicyclic groups fused to benzene, cycloalkyl groups having 3 to 7 carbon atoms, and other heteroaromatic rings or heteroalicyclic rings, heteroaromatic rings or heteroalicyclic rings may also be preferably substituted, and when chemically possible, the nitrogen or sulfur atom may be in oxidized form. "Heteroaryl" means a heteroaromatic group of heterocycles as defined above.

"Aralkyl" represents a group having 7 to 20 carbon atoms containing the above-mentioned alkyl group having 1 to 5 carbon atoms and an aryl group having 6 to 10 carbon atoms, and for example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and naphthylmethyl.

"Alkoxy" means a linear or branched alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy or 2-ethylbutoxy.

"Unsaturated alkoxy" means an unsaturated linear or branched unsaturated alkoxy group such as vinyloxy, allyloxy, 2-propenyloxy, 2-propynyloxy, 2-methyl-2 'propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-butinyloxy, 2 -pentenyloxy, 3-hexenyloxy, 5-hexenyloxy or 5-hexinyloxy.

"Aryloxy" means an aryloxy group having 6 to 10 carbon atoms, such as phenoxy or naphthyloxy.

"Aralkyloxy" represents a group containing the above-mentioned alkoxy group having 1 to 5 carbon atoms and an aryl group having 6 to 10 carbon atoms, and for example, benzyloxy, phenethyloxy, phenylpropoxy, trityloxy and naphthylmethoxy may be mentioned here.

"Cycloalkoxy" means a cycloalkoxy group having 3 to 7 carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy.

"Acyl" means a linear or branched acyl group having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, trimethylacetyl or 3,3,3'-trimethylpropionyl.

"Arylcarbonyl" means an arylcarbonyl group having 7 to 11 carbon atoms, such as benzoyl or naphthylcarbonyl.

"Alkylsulfonyl" means an alkylsulfonyl group having 1 to 5 carbon atoms, such as methanesulfonyl, ethanesulfonyl or n-propanesulfonyl.

"Arylsulfonyl" means an arylsulfonyl group having 6 to 10 carbon atoms, such as phenylsulfonyl or naphthalenesulfonyl.

The "aryl", "phenyl", "naphthyl" and "heterocycle" rings may be substituted with 1 to 4 substituents selected from the group consisting of, for example, -OH, carboxyl, cyano, phenyl, heterocycles, -SO 2 NH 2, -SO 3 H, alkylsulfamoyl groups such as methylsulfamoyl , ethylsulfamoyl, dimethylsulfamoyl etc., phenylsulfamoyl, benzylsulfamoyl, morpholinesulfonyl, alkylsulfonyl groups such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl etc., arylsulfonyl groups such as phenylsulfonyl, naphthalenesulfonyl, etc., amino, methylenedioxio, etc. is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, etc., alkylamino groups such as methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, isopropylamino, nbutylamino, isobutylamino, t- butylamino etc., acylamino groups such as formamino, acetylamino, propionylamino, n-butyrylamino etc., alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, n-butoxycarbonylamino, t-butoxycarbonylamino etc., aralkyloxycarbonylamino groups such as benzyloxycarbonylamino, naphthylmethyloxycarbonylamino etc., alkylsulfonylamino groups such as methanesulfonylamino, ethanesulfonylamino, phenylsulfonylamino, n-propanesulfonylamino, n-propanesulfonylamino, n-propanesulfonylamino. have 1 to 5 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl etc., aralkyl groups such as benzyl, phenethyl, trityl, naphthylmethyl etc., aralkyloxy groups such as is benzyloxy, phenethyloxy, phenylpropoxy, trityloxy, naphthylmethyloxy etc., acyl groups such as formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, trimethylacetyl, 3,3,3-trimethylpropionyl etc., alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl , n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, etc., aryloxycarbonyl such as phenoxycarbonyl, na phyloxycarbonyl, etc., aralkyloxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, etc., carbamoyl, alkylcarbamoylmethyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl, ethylcarbamoyl and halogen atoms such as fluorine, chlorine, bromine and iodine; when chemically possible, they may be substituted with 1 to 3 oxo or thiooxo groups.

In the general formula (I) above, R ¹ represents hydrogen or an alkyl group having 1 to 5 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, butyl, n-pentyl, isopentyl and 3-pentyl.

As suitable groups for R ^1, mention may be made of hydrogen, methyl, ethyl, and isopropyl, and methyl may be mentioned as a particularly suitable group for R ¹ .

In the general formula (I) above, R ² represents hydrogen, -CO-R ⁵ (wherein R ⁵ represents hydrogen, an alkyl group having 1 to 5 carbon atoms, with preferred substituents, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heterocycle) or -SO ² R ⁶ (wherein R ⁶ represents a halogen-substituted alkyl group having 1 to 5 carbon atoms, or an aryl group having 6 to 10 carbon atoms).

When R ² is -CO-R ⁵ and the R ⁵ group is an alkyl group having 1 to 5 carbon atoms, with a suitable substituent, the alkyl group having 1 to 5 carbon atoms, for R ⁵ may be, for example, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 3-pentyl etc., among which methyl, ethyl and isopropyl are preferred.

Suitable alkyl substituents having 1 to 5 carbon atoms for R ⁵ include all alkyl substituents known to trained chemists, for example, include halogen atoms, -OH, carboxyl, formyl, acyl, cyano, nitro, amino, mercapto, sulfonate, aryl have 6 to 10 carbon atoms, heterocycles, cycloalkyl groups having 3 to 7 carbon atoms, and protected forms thereof; more particularly, -OH; hydroxyl protected with C 1 -C 4 alkyl, C 6 -C 10 aryl, C 7 -C 20 aralkyl, heterocycle, C 1 -C 5 acyl, C 7 -C 7 arylcarbonyl 11 carbon atoms, or an aralkylcarbonyl group having 8 to 21 carbon atoms, -O-CO-Het (wherein Het represents a heterocycle); cycloalkyl groups having 3 to 7 carbon atoms, aryl groups having 6 to 10 carbon atoms, heterocycles; amino protected with C1-C4 alkyl, aralkyl of 7 to 20 carbon atoms, suitably halogen substituted alkylsulfonyl of up to 4 carbon atoms, arylsulfonyl of 6 to 10 carbon atoms, acyl of 1 to 4 carbon atoms 5-carbon atoms, arylcarbonyl of 7 to 11 carbon atoms, aralkylcarbonyl of 8 to 21 carbon atoms, alkoxycarbonyl of up to 5 carbon atoms, aralkyloxycarbonyl of 8 to 21 carbon atoms, or

heterocycle; -NH-CO-Het (wherein Het represents a heterocycle); acyl groups having 1 to 5 carbon atoms, carboxyl groups; alkoxycarbonyl groups having 2 to 5 carbon atoms, aryloxycarbonyl groups having 7 to 11 carbon atoms, aralkyloxycarbonyl groups having 8 to 21 carbon atoms, -CO-O-Het (wherein Het represents a heterocycle);

carbamoyl, alkylcarbamoyl having 2 to 5 carbon atoms, aralkylcarbamoyl having 8 to 21 carbon atoms, -CO-NH-Het (wherein Het represents a heterocycle); -CO-Het (wherein Het represents a heterocycle). Along with these, phenyl, aryloxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonylamino) methylamino, acetylamino and morpholinylcarbonyl may be mentioned as preferred substituents herein.

When R ² is -COR ⁵ and the R ⁵ group is a cycloalkyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbons for ^R5 may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. among which cyclohexyl is preferred.

When R ² is -COR ⁵ and the R ⁵ group is an aryl group having 6 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, for R ⁵ , there may be, for example, phenyl, naphthyl, etc. among which is preferred phenyl.

When R ² is -COR ⁵ and the R ⁵ group is a heterocycle, the heterocycle for R ⁵ may be, for example, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl, oxazolidinyl , imidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, etc., among which pyridyl, pyrrolidinyl and furyl are preferred.

As preferred groups for ^R5 there may be mentioned alkyl groups having 1 to 5 carbon atoms, with suitable substituents, among which there may be mentioned methyl, methyl or ethyl substituted with phenyl, aryloxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonyl -N-methylamino, acetylamino or morpholinylcarbonyl, and isopropyl; aryl groups having 6 to 10 carbon atoms, among which phenyl may be mentioned; heterocycles, among which may be mentioned pyridyl, pyrrolidinyl and furyl.

When R is -SO 2 R and the R group is a halogen-substituted alkyl group having 1 to 5 carbon atoms, the halogen-substituted alkyl group having 1 to 5 carbon atoms, for R ⁶ may be, for example, methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, chloromethyl, bromomethyl, trifluoromethyl etc., among which methyl and trifluoromethyl are preferred.

• · · · · · · · · · · · · · · · · ·

When R ² is -SO ² R ⁶ and the R ⁶ group is an aryl group having 6 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms, for R ⁶ may be, for example, phenyl, naphthyl, etc. among which is preferred phenyl.

Preferred groups for R ⁶ include halogen-substituted alkyl groups having 1 to 5 carbon atoms, and especially preferred groups for R ⁶ include methyl and trifluoromethyl.

Preferred groups for R herein include hydrogen, -COR (wherein R represents an alkyl group having 1 to 5 carbon atoms, with a suitable substituent, an aryl group having 6 to 10 carbon atoms, or a heterocycle) and halogen optionally substituted alkylsulfonyl groups having 1 to 5 carbon atoms, and particularly preferred groups for R ² there may be mentioned hydrogen, -COR ⁷¹ (wherein R ⁷¹ represents a methyl group; a methyl or ethyl group substituted with phenyl, aryloxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, ( benzyloxycarbonyl) -N-methylamino, acetylamino or morpholinylcarbonyl;

isopropyl; phenyl; pyridyl; pyrrolidinyl; or furyl), methanesulfonyl and trifluoromethanesulfonyl.

• J

In the general formula (I) above, R represents hydrogen, 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 having 3 to 7 carbon atoms, alkyl having 1 to 5 carbon atoms, aryl having 6 to 10 carbon atoms, aralkyl having 7 to 20 carbon atoms, alkoxy having 1 to 5 carbon atoms, or aryloxy having 6 to 10 carbon atoms 10 carbon atoms,

When R ³ is ^an alkyl group having 1-5 carbon atoms, alkyl group having 1 to 5 carbons may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t butyl, n-pentyl, etc., among which methyl, ethyl, isopropyl and n-pentyl are preferred.

When R ³ is an alkenyl group having 2 to 5 carbon atoms, the alkenyl group having 2 to 5 carbon atoms may be vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, etc. , among which 2-butenyl is preferred.

When R is an alkynyl group having 2 to 5 carbon atoms, the alkynyl group having 2 to 5 carbon atoms can be ethynyl, 2-propynyl, 1-propynyl, isopropinyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2 -pentinyl etc., among which 2-butinyl is preferred.

When R ³ is a cycloalkyl group having 3 to 7 carbon atoms, the cycloalkyl group having 3 to 7 carbon atoms may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc., among which cyclohexyl is preferred.

• · · · · · · · · · ·

When R ³ is cycloalkyl from 3 to 7 carbon atoms, alkyl having 1-5 carbon atoms, cycloalkyl of 3-7 carbon atoms, alkyl having 1 to 5 carbons may be, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, , cycloheptylmethyl, etc., among which cyclopentylmethyl is preferred.

When R ³ is an aryl group having 6 to 10 carbon atoms, an aryl group having 6 to 10 carbon atoms may be, for example, phenyl, naphthyl, etc., among which phenyl is preferred.

When R ³ is an aralkyl group having 7 to 20 carbon atoms, the aralkyl group having 7 to 20 carbon atoms may be, for example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl etc., among which benzyl is preferred.

When R ³ is an alkoxy group having 1 to 5 carbon atoms, the alkoxy group having 1 to 5 carbon atoms may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, butoxy, etc., among which methoxy is preferred.

When R ³ is an aryloxy group having 6 to 10 carbon atoms, an aryloxy group having 6 to 10 carbon atoms may be, for example, phenoxy, naphthyloxy, etc., among which phenoxy is preferred.

O

Preferred groups for R include alkyl groups having 1 to 5 carbon atoms, alkenyl groups having 2 to 5 carbon atoms, cycloalkyl groups having 3 to 7 carbon atoms, alkyl groups having 1 to 5 carbon atoms, and aralkyl groups, those having 7 to 20 carbon atoms, and as especially preferred groups for R, alkyl groups having 1 to 5 carbon atoms may be mentioned, among which methyl, ethyl, isopropyl and n-pentyl are preferred; cycloalkyl groups having 3 to 7 carbon atoms, alkyl groups having 1 to 5 carbon atoms, among which cyclopentylmethyl is preferred; and benzyl.

In the general formula (I) above, R ⁴ is a substituent at position C-4, position C-5, position C6 or position C-7 of the benzofuran ring and represents:

R ^4a which represents hydrogen, nitro, cyano, halogen, heterocycle, alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to 5 carbon atoms, aryl of 6 to 10 carbon atoms, A = CH ( CH 2) _n - (where A represents an alicyclic heterocycle, "=" represents a double bond and _n represents 0, 1 or 2), A = CH (CH 2) _m O (where A represents an alicyclic heterocycle, "=" represents a double bond and represents 1 , 2 or 3), A-SO 2 - (CH 2) _m - (wherein A represents an alicyclic heterocycle and _m represents 1, 2 or 3), -OR (wherein R represents hydrogen, a C 3 -C 3 cycloalkyl group, an aryl group which has 6 to 10 carbon atoms, a heterocycle or a halogen-substituted alkylsulfonyl group having 1 to 4 carbon atoms, or an arylsulfonyl group having 6 to 10 carbon atoms, -O-CO-R ⁸ (wherein R ⁸ represents hydrogen,

(C 1 -C 4) alkyl, (C 6 -C 10) aryl, (C 7 -C 20) aralkyl, or heterocycle), -NR ⁹ R ¹⁰ (wherein each R ⁹ and R ¹⁰ independently represents hydrogen , (C 1 -C 4) alkyl, (C 7 -C 20) aralkyl, phenyl, heterocycle, -SO ² R ¹¹ (wherein R ¹¹ represents a halogen-substituted alkyl group having 1 to 12 carbon atoms, a heterocycle substituted alkyl group, having 1 to 6 carbon atoms, an aryl having 6 to 10 carbon atoms, a heterocycle or an aralkyl group having 7 to 20 carbon atoms, or -CO-R ¹² (wherein R ¹² represents hydrogen, an alkyl group having 1 to 12 carbon atoms) carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, heterocycle, alkoxy of 1 to 10 carbon atoms, heterocycle substituted alkyl of 1 to 6 and aryloxy group having 6 to 10 carbon atoms, heteroaryloxy or aralkyloxy having 7 to 20 carbon atoms,) -CO-R ¹³ (wherein R ¹³ represents hydrogen, -OH, alkyl having 1 to 4 carbon atoms) carbon atoms, an aryl group having 6 to 10 carbon atoms, a heterocycle, 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 ¹⁴ R ¹⁵ (wherein each R ¹⁴ and R ¹⁵ independently represents hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl of 6 to 10 carbon atoms, aralkyl of C7 -C20, heterocycle or heterocycle substituted alkyl having 1 to 4 carbon atoms;

R ^4b , which represents a saturated or unsaturated alkoxy group having 1 to 6 carbon atoms, suitably substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups of 3 to 7 carbon atoms, phenyl, naphthyl, heterocycles, -OR ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, naphthyl, benzyl or heterocycle), -O-CO-R ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, naphthyl, benzyl or heterocycle), - NR R (wherein each R and R independently represents hydrogen, alkyl of 1 to 4 carbon atoms, heterocycle, alkylsulfonyl of 1 to 4 carbon atoms, phenylsulfonyl, -SO ₂ -Het (wherein Het represents a heterocycle), an aminosulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group or an alkyl group having 1 to 4 carbon atoms, substituted with 1 or 2 groups selected from phenyl, heterocycles, phenoxy, -O-Het (where Het represents a heterocycle) and hydroxyl, NH-CO-R ¹⁹ (wherein R ¹⁹ represents hydrogen, C 1 -C 4 alkyl, phenyl, naphthyl, benzyl, heterocycle, alkoxy having 1 to 4 carbon atoms, or benzyloxy), -CO15

R ²⁰ (wherein R ²⁰ represents hydrogen, heterocycle, C 1 -C 4 alkoxy, phenoxy, benzyloxy or -OR ²¹ (where R ²¹ represents hydrogen or heterocycle)) and -CO-NR ²² R ²³ (wherein each R 20 ²² and R ²³ independently represent hydrogen, alkyl having 1 to 4 carbon atoms, benzyl or heterocycle); or

R ^4c , which represents an alkyl group having 1 to 4 carbon atoms, suitably substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups of 3 to 7 carbon atoms, phenyl, naphthyl, heterocycles, -SH, -OR ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, naphthyl, benzyl or heterocycle), -O-CO-R ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, naphthyl, benzyl or heterocycle), -NR R (wherein R ¹⁷ and R ^{18 each} independently represent hydrogen, alkyl of 1 to 4 carbon atoms, heterocycle, alkylsulfonyl of 1 to 4 carbon atoms, phenylsulfonyl, SCh-Het ( wherein Het represents a heterocycle), an amino sulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group or an alkyl group having 1 to 4 carbon atoms, substituted with 1 or 2 groups selected from selected from phenyl, heterocycles, phenoxy, -O-Het (where Het represents a heterocycle) and hydroxyl, NH-CO-R ¹⁹ (wherein R ¹⁹ represents hydrogen, C 1 -C 4 alkyl, phenyl, naphthyl, benzyl, heterocycle, alkoxy having 1 to 4 carbon atoms, or benzyloxy), -CO-R ²⁰ (wherein R ²⁰ represents hydrogen, heterocycle, alkoxy having 1 to 4 carbon atoms, phenoxy, benzyloxy or -OR (where R represents hydrogen or heterocycle)) and -CONR R (wherein each R and R independently represents hydrogen, alkyl having 1 to 4 carbon atoms, benzyl or heterocycle).

When R ⁴ is R ^4a , specific examples of R ^4a , hydrogen; nitro; cyano; halogen atoms such as fluorine, chlorine, bromine and iodine; heterocycles such as imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, 6-oxo-4,5-benzo-1,3-oxazine-2 -yl, 1-oxoisoindolin-2-yl, pyrrolidinyl, 2,5-dioxopyrrolidinyl, piperidyl, 2,6-dioxopiperidyl, 1- (4-bromobenzoyl) piperidin-9-yl, morpholinyl, piperazinyl, 2,3-dioxopiperazinyl, homopiperazinyl, tetrahydrofuryl and tetrahydropyranyl; alkenyl groups such as vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl and 2-pentenyl; alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl and 4-pentynyl; aryl groups such as phenyl and naphthyl; hydroxyl; cycloalkyloxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy;

Aryloxy groups such as phenoxy and naphthyloxy; groups represented by -O-Het (wherein Het represents a heterocycle) such as imidazolyloxy, thiazolyloxy, isothiazolyloxy, pyrazolyloxy, triazolyloxy, pyrrolyloxy, pyridyloxy, pyrimidinyloxy, pyrazinyloxy, furyloxy, thienyloxy, isoxazolyloxy, thiazolidinyloxy, piperazolidinyloxy, oxazolidinyloxy, oxazolidinyloxy, imidazolyinyloxy, imidazolynyloxy, pyrrolidinyl , piperazinyloxy, tetrahydrofuryloxy and tetrahydropyranyloxy; halogen-substituted alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy and trifluoromethanesulfonyloxy; arylsulfonyloxy groups such as phenylsulfonyloxy and naphthalenesulfonyloxy; acyloxy groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and trimethylacetyloxy; arylcarboxy groups such as benzoyloxy and naphthylcarboxy; aralkylcarboxy groups such as phenylacetyloxy, 2-phenylpropionyloxy, 3-phenylbutyryloxy, diphenylacetyloxy and naphthylacetyloxy; groups represented by -O-CO-Het (wherein Het represents a heterocycle) such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, thienylcarboxy, isoxazole morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy; amino; alkylamino groups such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino and dibutylamino; aralkylamino groups such as benzylamino and dibenzylamino; heterocycle substituted amino groups such as imidazolylamino, N-methyl-N-imidazolylamino, thiazolylamino, N-methyl-N-thiazolylamino, isothiazolylamino, pyrazolylamino, triazolylamino, N-methyl-N-triazolylamino, pyrrolylamino, pyridylamino, N-methyl-N-pyridylamino , dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolidinylamino, oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino, N-methyl-N-pyrrolidinylamino, piperidylamino, morpholinylamino, N-methyl-N-morpholinylamino, tetrahydrofurylamino and tetrahydropyranylamino; halogen-substituted alkylsulfonylamino groups such as methanesulfonylamino, N-methyl-N-methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino and trifluoromethanesulfonylamino;

arylsulfonylamino groups such as phenylsulfonylamino, N-methyl-N-phenylsulfonylamino, N- (4-chlorophenylsulfonyl) -N-methylamino and naphthalenesulfonylamino; acylamino groups such as formylamino, acetylamino, N-methyl-N-acetylamino, propionylamino, butyrylamino, isobutyrylamino, N-methyl-N-isobutyrylamino and trimethylacetylamino;

arylcarbonylamino groups such as benzoylamino, N-methyl-N-benzoylamino and

naphthylcarbonylamino; aralkylcarbonylamino groups such as phenylacetylamino, N-methyl-N-phenylacetyl amino, 2-phenylpropionylamino, 3-phenylbutyrylamino, diphenylacetylamino and naphthylacetylamino; amino groups substituted with a group represented by -CO-Het (wherein Het represents a heterocycle) such as imidazolylcarbonylamino, N-methyl-N-imidazolylcarbonylamino, thiazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, pyridylcarbonylamino, N-methyl-N-pyridylcarbonylamino, pyrimidinylcarbonylamino, pyrimidinylcarbonylamino - methyl-N-pyrimidinylcarbonylamino, pyrazinylcarbonylamino, N-methyl-Npyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N-methyl-N-tetrazolylcarbonylamino, thiazolidinylcarbonylamino, thiazolidinylcarbonylamino, and piperidylcarbonylamino; alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, t-butoxycarbonylamino and N-methyl-N- (t-butoxycarbonyl) amino; aryloxycarbonylamino groups such as phenoxycarbonylamino and naphthyloxycarbonylamino; aralkyloxycarbonylamino groups such as benzyloxycarbonylamino, phenethyloxycarbonylamino, phenylpropoxycarbonylamino, benzhydryloxycarbonylamino and naphthylmethoxycarbonylamino; formyl; carboxyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl and naphthyloxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl, phenethyloxy, carbonyl, phenylpropoxycarbonyl, benzhydryloxycarbonyl and naphthylmethoxycarbonyl; acyl groups such as acetyl, propionyl, butyryl and isobutyryl; arylcarbonyl groups such as benzoyl and naphthylcarbonyl; groups represented by -CO-Het (wherein Het represents a heterocycle) such as imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylkarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, thiazolidinylkarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl , piperazinylcarbonyl and 1,3,4-trihydroisoquinon-2-ylcarbonyl; carbamoyl groups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, 4-bromophenyl-2-bromophenyl, methylcarbamoyl, N-methyl-N-phenethylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, N-imidazolyl-N-methylcarbamoyl, N-benzimidazolyl-N4.

N 4-methyl-carbamoyl, thiazolylcarbamoyl, N-methyl-N-thiazolylcarbamoyl, benzothiazolylcarbamoyl, N-benzothiazolyl-N-methylcarbamoyl, isothiazolylcarbamoyl, oxazolylcarbamoyl, N-methyl-N-methyl-N, methylcarbamoyl, pyrazolylcarbamoyl, triazolylkarbamoyí, pyrrolylkarbamoyl, pyridylcarbamoyl, N-methyl-N-pyridylcarbamoyl, N-methyl-N- (pyridylmethyl) carbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylkarbamoyl, thiazolidinylkarbamoyl, oxazolidinylcarbamoyl, imidazolidinylcarbamoyl, pyrrolidinylkarbamoyl, piperidylcarbamoyl, tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl; groups represented by A = CH (CH ₂ ) n - (where A represents an alicyclic heterocycle, = represents a double bond and n represents 0, 1, or 2), such as (3,5-dioxo-2,4-thiazolidinylidene) methyl, ( 3,5-dioxo-2,4-oxazolidinylidene) methyl, (2,5-dioxoimidazolidin-4-ylidene) methyl, (5-oxo-3-thioxo-2,4-thiazolidinylidene) methyl, (2,4,6-trioxo-3) 5-diazaperhydroinylidene) methyl and (3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene) methyl; groups represented by A = CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle, = represents a double bond and _m represents 1, 2, or 3), such as 2- (3,5-dioxo-2,4-thiazolidinylidene) ethoxy, 2- (3,5-dioxo-2,4-oxazolidinylidene) ethoxy, 2- (2,5-dioxoimidazolidin-4-ylidene) ethoxy, 2- (5-oxo-3-thioxo-2,4-thiazolidinylidene) ethoxy 2- (2,4,6-trioxo-3,5-diazaperhydroinylidene) ethoxy and 2- (3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene) ethoxy; and groups represented by A-SO ₂ - (CH ₂ ) _m - (wherein A represents an alicyclic heterocycle and _m represents 1,2, or 3), such as (3,5-dioxo-2,4-thiazolidinyljsulfonylmethyl, (3,5- dioxo-2,4-oxazolidinyl) sulfonylmethyl, (2,5-dioxoimidazolidin-4-yl) sulfonylmethyl, and (5-oxo-3-thioxo-2,4-thiazolidinyl) sulfonylmethyl.

Particularly preferred groups for R ^4a herein are, for example, hydrogen, nitro, cyano, bromo, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, furyl, thienyl, morpholinyl, piperazinyl, hydroxyl, pyrrolidinyloxy, piperidyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, benzoyloxy, imidazolylcarboxy, thiazolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, dimethylamino, ethylamino, diethylamino, dibenzylamino, imidazolylamino, thiazolylamino, pyridylamino, pyrimidinylamino, N-methyl-N-methanesulfonylamino, methylsulfonylamino, N-methylsulfonylamino, N-methylsulfonylamino, N-methylsulfonylamino, N-methylsulfonylamino N-acetylamino, N-methyl-N-isobutyrylamino, N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino, N-methyl-N-imidazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N-tetrazolylcarbonylamino, N-methyl-N-pyridylcarbonylamino, N-methyl-N-pyrazinylcarbonylamino, N-methyl-N19

pyrimidinylcarbonylamino, N-methyl-N- (t-butoxycarbonyl) amino, dimethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, N-methyl-N-phenylcarbamoyl, N-benzyl-N-methylcarbamoyl, imidazolylcarbamoyl, benzimidazolylcarbamoyl, thiazol, , benzothiazolylkarbamoyl, isothiazolylkarbamoyl, -pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylkarbamoyl, pyridylcarbamoyl, N-methyl-N-pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, isoxazolylkarbamoyl, piperidylcarbamoyl, l, 3,4-trihydroisochinolin-2-ylcarbonyl, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, acetyl, benzoyl, (3,5-dioxo-2,4-thiazolidinylidene) methyl, (3,5-dioxo-2,4oxazolidinylidene) methyl, (2,5-dioxoimidazolidin-4) -ylidene) methyl, (5-oxo-3-thioxo-2,4-thiazolidinylidene) methyl, 2- (3,5-dioxo-2,4-thiazolidinylidene) ethoxy, 2- (3,5-dioxo-2, 4-oxazolidinylidene) ethoxy, 2- (2,5-dioxoimidazolidin-4-ylidene) ethoxy, 2- (5-oxo-3-thioxo-2,4-thia) zolidinylidene) ethoxy, (3,5-dioxo-2,4-thiazolidinyl) sulfonylmethyl, (3,5-dioxo-2,4oxazolidinyl) sulfonylmethyl, (2,5-dioxoimidazolidin-4-yl) sulfonylmethyl and (5-oxo- 3-thioxo-2,4-thiazolidinyl) sulfonylmethyl.

Particularly preferred groups for R ^4a herein may be specifically mentioned, for example, hydrogen, nitro, cyano, bromo, thienyl, piperazinyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy, -acetyloxy, dimethylamino, dibenzylamino, N-methyl-N-methanesulfonylamino, N-methyl- N-phenylsulfonylamino, N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino, N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino, N-methyl-N-thienylcarbonylamino, N-methylN-oxazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, N-methyl-N. pyridylcarbonylamino, thiazolylcarbamoyl, benzothiazolylcarbamoyl, benzimidazolylcarbamoyl, N-methyl-N-phenylcarbamoyl, 1,3,4-trihydroisoquinolin-2-ylcarbonyl, methoxycarbonyl, isopropoxycarbonyl and (3,5-dioxo-2,4-thiazolidinylidene).

When R ⁴ is R ^4b , they may be mentioned herein as specific examples of alkoxy substituents having 1 to 4 carbon atoms, for R ^4a , for example, halogen atoms such as fluorine, chlorine, bromine and iodine; cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; aryl groups having 6 to 10 carbon atoms such as phenyl, aminophenyl and naphthyl; heterocycles such as imidazolyl, N-tosylimidazolyl, thiazolyl, 2- (morpholinesulfonyl) thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, 2-methoxypyridyl, 5-hydroxypyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thiazolyl, triazinyl, thiazolyl, triazinyl, thiazolyl 2- (morpholinesulfonyl) thienyl, oxazolyl, 2-phenyloxazolyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl and dioxolanyl; -OH; alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, secbutoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2- dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy; aryloxy groups having 6 to 10 carbon atoms such as phenoxy and naphthyloxy; benzyloxy; groups represented by -O-Het (wherein Het represents a heterocycle) such as pyridyloxy and piperidyloxy; acyloxy groups having 1 to 5 carbon atoms such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and trimethylacetyloxy; arylcarboxy groups having 7 to 11 carbon atoms such as benzoyloxy and naphthylcarboxy; phenylacetyloxy; groups represented by -O-CO-Het (wherein Het represents a heterocycle) such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, thienylcarboxy, isoxazole morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy; amino; monosubstituted or disubstituted amino groups such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, dibutylamino, benzylamino, dibenzylamino, 2-hydroxy-2-phenethylamino, 2-hydroxy-3-phenoxypropylamino, imidazolylamino, thidazolylamino, thidazolylamino, thidazolylamino, thidazolylamino, pyrazolylamino, triazolylamino, pyrrolylamino, pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolidinylamino, oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino, piperidylamino, tetrahydrofurylamino and tetrahydropyranylamino; halogen-appropriately substituted alkylsulfonylamino groups having 1 to 4 carbon atoms such as methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino and triphenylmethanesulfonylamino; phenylsulfonylamino; acylamino groups having 1 to 5 carbon atoms such as dimethylaminosulfonylamino, methylaminosulfonylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino and trimethylacetylamino; arylcarbonylamino groups having 7 to 11 carbon atoms such as benzoylamino and naphthylcarbonylamino; phenylacetylamino; groups represented by -NH-CO-Het (where Het represents a heterocycle) such as imidazolylcarbonylamino, thiazolylcarbonylamino, isoxazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, pyrrolidinylcarbonylamino, pyrrolidinylcarbonylamino, pyrrolidinylcarbonylamino, pyrrolidinylcarbonylamino; alkoxycarbonylamino groups having 2 to 5 carbon atoms, such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,

..........

isopropoxycarbonylamino and t-butoxycarbonylamino; benzyloxycarbonylamino; formyl; carboxy; alkoxycarbonyl groups having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; acyl groups having 2 to 5 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl; groups represented by -CO-Het (wherein Het represents a heterocycle) such as imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylkarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, thiazolidinylkarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl and piperazinylcarbonyl; groups represented by -CO-O-Het (wherein Het represents a heterocycle) such as pyridyloxycarbonyl and piperidyloxycarbonyl; and carbamoyl groups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl, isothiazolylkarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylkarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylkarbamoyl, thiazolidinylkarbamoyl, oxazolidinylcarbamoyl, imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl, tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl.

As preferred groups for R ^4b there may be mentioned in particular, for example, saturated or unsaturated alkoxy groups such as methoxy, 2-propynyloxy, 2-butinyloxy, 3-hexenyloxy,

5-hexenyloxy and 2,2-dimethylpropoxy; halogen-substituted alkoxy groups such as 2-bromoethoxy and 2-chloroethoxy; cycloalkyl-alkoxy groups such as cyclopentylmethoxy and cyclohexylmethoxy; aryl-alkoxy such as benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy, bromobenzyloxy, nitrobenzyloxy, (trifluoromethyl) benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy) benzyloxy, carboxybenzyloxy, carboxybenzyloxy, carboxybenzyloxy, carboxybenzyloxy, carboxybenzyloxy, (methoxyphenyl) methoxy, 2,2-diphenylethoxy, 1-methyl-1-phenyl ethoxy and naphthylmethoxy; heterocycle substituted alkoxy groups such as thienylmethoxy, 2- (morpholinesulfonyl) thienylmethoxy, pyridylmethoxy, (5-hydroxypyridyl) methoxy, (2-methoxypyridyl) methoxy, 2- (pyridyl) ethoxy, pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy, oxazolylmethoxy, oxazolylmethoxy, oxazolylmethoxy, oxazolylmethoxy , thiazolylmethoxy, 2- (morpholinesulfonyl) thiazolylmethoxy, (3,5-dioxo-2,4-thiazolidinyl) methoxy, N-methylpiperidylmethoxy, Nt-butoxycarbonylpiperidylmethoxy, N ·

-acetylpiperidylmethoxy, N-methanesulfonylpiperidylmethoxy, (4-oxachroman-2-yl) methoxy, (3,3-dimethyl-2,4-dioxolanyl) methoxy, (1-methyl-3-oxetanyl) methoxy and 2- (morpholin-4) -yl) ethoxy; alkoxy-alkoxy groups such as methoxymethyl and 2-ethoxyethoxy; benzyloxyalkoxy groups such as 2- (benzyloxy) ethoxy; acyloxy-alkoxy such as 2- (acetyloxy) ethoxy; alkylaminoalkoxy groups such as bis (dimethylaminomethyl) methoxy; alkoxycarbonylamino-alkoxy groups such as 4- (t-butoxycarbonylamino) butoxy; and alkoxycarbonyl-alkoxy groups such as ethoxycarbonylmethoxy, 2- (methoxycarbonyl) ethoxy and 5- (ethoxycarbonyl) pentyloxy.

Particularly preferred groups for R ^4b herein may be mentioned, for example, methoxy, 2-propynyloxy, benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl) benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy) benzyloxy, carboxybenzyloxy;

(methoxycarbonyl) benzyloxy, n-butoxybenzyloxy, thienylmethoxy, 2- (morpholinesulfonyl) thienylmethoxy, pyridylmethoxy, (2-methoxypyridyl) methoxy, (5-hydroxypyridyl) methoxy, 2- (pyridyl) ethoxy, pyrazinylmethoxy, pyrimidinylmethoxymethoxy, N-tosylimidazol, 2-phenyloxazolylmethoxy, thiazolylmethoxy, 2- (morpholinesulfonyl) thiazolylmethoxy, (3,5-dioxo-2,4-thiazolidinyl) methoxy, N-methylpiperidylmethoxy and methoxymethyl.

When R ⁴ is R ^4c , they may be mentioned herein as specific examples of substituents on alkoxy groups having 1 to 4 carbon atoms, for R ^4c , for example, halogen atoms such as fluorine, chlorine, bromine, iodine; cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; aryl groups having 6 to 10 carbon atoms such as phenyl and naphthyl; heterocycles such as imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolidinyl, oxazolidinyl, 3,5-dioxooxazolidinyl,

imidazolidinyl, 2-oxoimidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, pyrazolidinyl, 3,5-dioxopyrazolidinyl, piperazinyl, 2,5-dioxopiperazinyl, tetrahydrofuryl, tetrahydropyranyl and dioxolanyl; -SH; -OH; alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2- dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy; aryloxy groups having 6 to 10 carbon atoms such as phenoxy and naphthyloxy; benzyloxy; groups represented by -O-Het (wherein Het represents a heterocycle) such as pyridyloxy and piperidyloxy; acyloxy groups having 1 to 5 carbon atoms such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and trimethylacetyloxy;

Arylcarboxy groups having 7 to 11 carbon atoms such as benzoyloxy and naphthylcarboxy; phenylacetyloxy; groups represented by -O-CO-Het (wherein Het represents a heterocycle) such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, thienylcarboxy, isoxazole morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy; amino; monosubstituted or disubstituted amino groups such as methylamino, dimethylamino, ethylamino, 2-hydroxy-2-phenethylamino, 2-hydroxy-3-phenoxypropylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, dibutylamino, benzylamino, dibenzylamino, thidazolylamino, thidazolylamino, thidazolylamino, thidazolylamino, thidazolylamino, thidazolylamino, pyrazolylamino, triazolylamino, pyrrolylamino, pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolidinylamino, oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino, piperidylamino, tetrahydrofurylamino and tetrahydropyranylamino; halogen-substituted alkylsulfonylamino groups having 1 to 4 carbon atoms, such as methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino and trifluoromethanesulfonylamino; phenylsulfonylamino; acylamino groups having 1 to 5 carbon atoms, such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino and trimethylacetylamino; arylcarbonylamino groups having 7 to 11 carbon atoms such as benzoylamino, 4-chlorobenzoylamino and naphthylcarbonylamino; phenylacetylamino; groups represented by -NHCO-Het (wherein Het represents a heterocycle) such as imidazolylcarbonylamino, thiazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, thiazolidinylcarbonylamino, oxazolidinylcarbonylamino, oxazolidinylcarbonylamino, oxazolidinylcarbonylamino, oxazolidinylcarbonylamino, oxazolidinylcarbonylamino, oxazolidinylcarbonylamino, oxazolidinylcarbonylamino; alkoxycarbonylamino groups having 2 to 5 carbon atoms such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and t-butoxycarbonylamino; benzyloxycarbonylamino; formyl; carboxyl; alkoxycarbonyl groups having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; acyl groups having 2 to 5 carbon atoms such as acetyl, propionyl, butyryl and isobutyryl; groups represented by -CO-Het (where Het represents a heterocycle) such as imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, thiazolylcarbonyl, thiazolylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, pyrazinylcarbonyl, pyrazinylcarbonyl, , thiazolidinylcarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl and piperazinylcarbonyl; groups represented by -CO-O-Het (wherein Het represents a heterocycle) such as pyridyloxycarbonyl and piperidyloxycarbonyl; and carbamoyl groups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl, isothiazolylkarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylkarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylkarbamoyl, thiazolidinylkarbamoyl, oxazolidinylcarbamoyl, imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl, tetrahydrofranylcarbamoyl and tetrahydropyranylcarbamoyl.

As preferred groups for R ^4c , particular mention may be made here, for example, of phenethyl, α-hydroxybenzyl, 1- (acetyloxy) ethyl and (3,5-dioxo-2,4-thiazolidinyl) methyl.

Thus, as specifically preferred combinations for R ¹ , R ² , R ³ , and R ⁴ , the following may be mentioned, in which, for example, R is methyl, ethyl, or isopropyl, R is acetyl or propionyl substituted with a substituent selected from phenyl , phenoxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonyl) -N-methylamino, acetylamino, and morpholinylcarbonyl; or hydrogen, acetyl, propionyl, isobutyryl, benzoyl, pyridylcarbonyl, pyrrolidinylcarbonyl, furylcarbonyl, methanesulfonyl, or trifluoromethanesulfonyl, R ³ is methyl, ethyl, isopropyl, n-pentyl, cyclopentylmethyl or benzyl, and R ⁴ is hydrogen, nitro, cyano, bromo , thienyl, piperazinyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, dimethylamino, dibenzylamino, N-methyl-N-methanesulfonylamino, N-methyl-N-phenylsulfonylamino, N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino, N-methyl N-benzoylamino, N-methyl-N-phenylacetylamino, N-methyl-N-imidazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, N-methyl-N-pyridylcarbonylamino, N-methyl-N-pyrimidinylcarbonylamino, N-methyl-N -pyrazinylcarbonylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N- (t-butoxycarbonyl) amino, thiazolylcarbamoyl, methoxycarbonyl, isopropoxycarbonyl, (3,5-dioxo-2,4-thiazolidinylidene) ) methyl, methoxy, 2-propynyloxy, benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyl oxy, (trifluoromethyl) benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy) benzyloxy, carboxybenzyloxy, (methoxycarbonyl) benzyloxy, n-butoxybenzyloxy, thienylmethoxy, 2 • ·

TC ··· ♦ ····

Z3 (morpholinesulfonyl) thienylmethoxy, pyridylmethoxy, (2-methoxypyridyl) methoxy, 2- (pyridyl) ethoxy, pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy, oxazolylmethoxy, 2-phenyloxazolylmethoxy, thiazolomethyl 2- (morpholinesulfonyl) thiazolylmethoxy, (3,5-dioxo-2,4-thiazolidinyl) methoxy, N-methylpiperidylmethoxy, methoxymethyl, phenethyl, α-hydroxybenzyl, 1- (acetyloxy) ethyl or (3,5-dioxo-2, 4-thiazolidinyl) methyl.

As specific compounds represented by the general structural formula (I) above, the following compounds mentioned in the examples of the present invention may be mentioned, but other non-limiting compounds may still be included:

6- (benzofuran-2-yl) -3-ethyl-4-hydroxy-5-methyl-2 H -pyran-2-one;

6- (benzofuran-2-yl) -4-hydroxy-5-methyl-3-n-propyl-2H-pyran-2-one;

4-Acetyloxy-6- (benzofuran-2-yl) -5-ethyl-3-methyl-2H-pyran-2-one;

4-Acetyloxy-6- (benzofuran-2-yl) -5-isopropyl-3-methyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -4- (2- (t-butoxycarbonylamino) acetyloxy) -5-ethyl-3-methyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -5-ethyl-3-methyl-4- (2-pyrrolidon-5-ylcarboxy) -2H-pyran-2-one;

4- (2-Amino-acetyloxy) -6- (benzofuran-2-yl) -5-ethyl-3-methyl-2H-pyran-2-one;

4- (3-acetylamino-4-morpholinyl-4-oxobutyryloxy) -6- (benzofuran-2-yl) -5-ethyl-3-methyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-propionyloxy-2 H- pyran-2-one;

6- (benzofuran-2-yl) -5-ethyl-4-isobutyryloxy-3-methyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-isovaleryloxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2,2,2-trimethylacetyloxy) -2H-pyran-2-one;

6- (benzofuran-2-yl) -4-cyclohexylcarboxy-3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -4- (2-cyclopropylacetyloxy) -3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -4- (2-cyclopentylacetyloxy) -3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -4-benzoyloxy-5-ethyl-3-methyl-2 H -pyran-2-one;

6- (benzofuran-2-yl) -4-benzoyloxy-5-isopropyl-3-methyl-2 H- pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-naphthylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-imidazolylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-thiazolylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-triazolylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -5-ethyl-3-methyl-4-pyridylcarboxy-2 H -pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-pyrimidinylcarboxy-2H-pyran-2-one;

• ·

6- (benzofuran-2-yl) -3,5-dimethyl-4-pyrazinylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-thienylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-isoxazolylcarboxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-imidazolylacetyloxy) -2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-pyridylacetyloxy) -2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-methoxyacetyloxy) -2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2- t -butoxyacetyloxy) -2H-pyran-2-one;

6- (benzofuran-2-yl) -4-hydroxy-3-methyl-5-n-propyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -5-cyclopentyl-4-hydroxy-3-methyl-2 H- pyran-2-one;

6- (benzofuran-2-yl) -5-cyclopropylmethyl-4-hydroxy-3-methyl-2 H -pyran-2-one;

6- (benzofuran-2-yl) -5-cyclohexylmethyl-4-hydroxy-3-methyl-2 H- pyran-2-one;

6- (benzofuran-2-aryl) -4-hydroxy-3-methyl-5-naphthylmethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -5-ethoxy-4-hydroxy-3-methyl-2 H -pyran-2-one;

6- (benzofuran-2-yl) -4-hydroxy-5-isopropoxy-3-methyl-2H-pyran-2-one;

4-Acetyloxy-3,5-dimethyl-6- (5- (2-thienyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-oxazolidinylidene) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((2,5-dioxoimidazolidin-4-ylidene) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5 - ((5-oxo-3-thioxo-2,4-thiazolidinylidene) methyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5 - ((2,4,6-trioxo-3,5-diaza-hydroinylidene) methyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran- 2-on;

3,5-dimethyl-6- (5- (2- (3,5-dioxo-2,4-thiazolidinylidene) ethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5- (2- (3,5-dioxo-2,4-oxazolidinylidene) ethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5- (2- (2,5-dioxoimidazolidin-4-ylidene) ethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (5-oxo-3-thioxo-2,4-thiazolidinylidene) ethoxy) benzofuran-2-yl) -2H-pyran-2-one;

• ·.:. .:. ·····

3,5-dimethyl-4-hydroxy-6- (5- (2- (2,4,6-trioxo-3,5-diazaperhydroinylidene) ethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5- (2- (3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene) ethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran- 2-on;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinyl) sulfonylmethyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-oxazolidinyl) sulfonylmethyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((2,5-dioxoimidazolidin-4-yl) sulfonylmethyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5 - ((5-oxo-3-thioxo-2,4-thiazolidinyl) sulfonylmethyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinyl) methoxy) benzofuran-2-yl) -4-hydroxy-2 H- pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-oxazolidinyl) methoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((2,5-dioxoimidazolidin-4-yl) methoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5 - ((5-oxo-3-thioxo-2,4-thiazolidinyl) methoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5 - ((2,4,6-trioxo-3,5-diazaperhydroinyl) methoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-Dimethyl-6- (5 - ((3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinyl) methoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2- he;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N-phenylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

6- (5- (N-benzyl-N-methylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N-pyridylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N-thiazolylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (pyridylmethyl) carbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (2-hydroxy-2-phenethylamino) ethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (2-hydroxy-3-phenoxypropylamino) ethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2-hydroxy-3-aminopropoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2-hydroxy-3-phenylaminopropoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (2-hydroxy-2-phenethylamino) propyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (2-hydroxy-3-phenoxypropylamino) propyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (2-hydroxy-2-phenethylamino) ethyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (2-hydroxy-3-phenoxypropylamino) ethyl) benzofuran-2-yl) 2H-pyran-2-one;

3,5-dimethyl-6- (5- (3,5-dioxopyrazolidin-4-ylmethyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5- (3,5-dioxooxazolidin-4-ylmethyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2-oxoimidazolidinylmethyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5- (2,5-dioxopiperazinylmethyl) benzofuran-2-yl) -4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (imidazolylmethyl) benzofuran-2-yl) -2H-pyran-2-one; 6- (5- (N-benzothiazolyl-N-methylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (6-oxo-4,5-benzoxazin-2-yl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3-pyridylaminomethyl) benzofuran-2-yl) -2H-pyran-2-one; 6- (5- (4-bromo-2-cyanophenylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (3-pyridyl) aminomethyl) benzofuran-2-yl) -2H-pyran-2-one;

* · • ·

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (3-pyridyl) carbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (4- (2-pyridyl) piperazinylcarbonyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (4- (2-pyrimidinyl) piperazinylcarbonyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (2-pyridyl) carbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N- (2-pyrimidinyl) carbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5 - ((2-pyridylmethyl) carbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (triazolylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5- (2,5-dioxopyrrolidinyl) benzofuran-2-yl) -4-hydroxy-2 H- pyran-2-one;

3,5-dimethyl-6- (5- (2,6-dioxopiperidinyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5- (2,3-dioxopiperazinyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one; 6- (5- (2- (4-chlorobenzoylamino) ethyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

6- (5- (3- (acetylamino) propoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (2-pyrazinylcarbonylamino) propoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (2-pyridylcarbonylamino) propoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (5-isoxazolylcarbonylamino) propoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (morpholinylcarbonylamino) propoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (methanesulfonylamino) propoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5- (3- (dimethylaminosulfonylamino) propoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (isoxazolylsulfonylamino) propoxy) benzofuran-2-yl) -2H-pyran-2-one;

6- (5- (N-acetylpiperidin-3-ylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N- (2-pyridylcarbonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N- (2-pyrazinylcarbonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N- (5-isoxazolylcarbonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N- (morpholinylcarbonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methanesulfonylpiperidin-3-ylmethoxy) benzofuran-2-yl) 2H-pyran-2-one;

3,5-dimethyl-6- (5- (N- (dimethylaminosulfonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N- (5-thiazolylsulfonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one; and

3,5-dimethyl-4-hydroxy-6- (5- (N- (5-isoxazolylsulfonyl) piperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one.

As preferred specific compounds represented by Structural Formula (I) above, the following examples may be mentioned:

4-Acetyloxy-6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one; 6- (benzofuran-2-yl) -4-benzoyloxy-3,5-dimethyl-2 H -pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4-methanesulfonyloxy-2 H- pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-pyridylcarboxy) -2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinylidene) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinyl) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

6- (benzofuran-2-yl) -4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5-methoxybenzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (7-methoxybenzofuran-2-yl) -2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (6- (trifluoromethanesulfonyloxy) benzofuran-2-yl) -2H-pyran-2-one;

• ·

4-acetyloxy-3,5-dimethyl-6- (6- (2-thienyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (6-methoxybenzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (5-pyrimidinylmethoxy) benzofuran-2-yl) -2H-pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4- (4-hydroxymethylbenzoyloxy) -2H-pyran-2-one; 6- (benzofuran-2-yl) -4- (2- (N-carbobenzyloxy-N-methylamino) acetyloxy) -3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (4-methoxybenzoyloxy) -2H-pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-phenylacetyloxy) -2H-pyran-2-one; 6- (benzofuran-2-yl) -5-ethyl-4-hydroxy-3-methyl-2 H -pyran-2-one; 6- (benzofuran-2-yl) -4-hydroxy-5-isopropyl-3-methyl-2 H- pyran-2-one; 6- (benzofuran-2-yl) -5-benzyl-4-hydroxy-3-methyl-2 H- pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4-isobutyryloxy-2H-pyran-2-one;

4-Acetyloxy-3,5-dimethyl-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one;

6- (benzophnran-2-yl) -3,5-dimethyl-4- (2-phenoxyacetyloxy) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5- (dimethylamino) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one; 6- (5- (dibenzylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (2-thienylcarbonyl) amino) benzofuran-2-yl) 2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (3-pyridylcarbonyl) amino) benzofuran-2-yl) 2H-pyran-2-one;

3,5-Dimethyl-4-hydroxy-6- (5- (N-isobutyryl-N-methylamino) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N- (phenylacetyl) amino) benzofuan-2-yl) -2H-pyran-2-one;

6- (5- (N-benzoyl-N-methylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one;

6- (5- (N-t-butoxycarbonyl-N-methylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

6- (5- (benzothiazolylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

6- (5- (benzimidazolylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (N-methyl-N-phenylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one;

·::: ·::

··· ·· ··· ··· ·· ··

6- (5- (N- (4-chlorophenylsulfonyl) -N-methylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (1,3,4-trihydroisoquinolin-2-ylcarbonyl) benzofuran-2-yl) 2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5-morpholinylbenzofuran-2-yl) -2H-pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one; 4- (2-Aminoacetyloxy) -6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one; 6- (5-benzyloxybenzofuran-2-yl) -4- (2- (t-butoxycarbonylamino) acetyloxy) -3,5-dimethyl-2H-pyran-2-one;

4- (2-Aminoacetyloxy) -6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

4- (4- (acetylamino) benzoyloxy) -6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

6- (5-benzyloxy-benzofuran-2-yl) -3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one;

6- (5-benzyloxy-benzofuran-2-yl) -3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one;

6- (5-benzyloxy-benzofuran, 2-yl) -5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one;

5-ethyl-4-hydroxy-3-methyl-6- (5- (3-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one; 4-acetyloxy-3,5-dimethyl-6- (5- (2-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (5-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one; 4-acetyloxy-6- (5- (2,4-dichloro-5-thiazolylmethoxy) benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (4-methyl-5-thiazolyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (5- (2- (4-methyl-5-thiazolyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (4-methyl-5-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (morpholinesulfonyl) -5-thiazolylmethoxy) benzofuran-2-yl) 2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (5- (4-methyl-1-tosyl-5-imidazolylmethoxy) benzofuran-2-yl) 2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (3-phenylpropionyloxy) -2H-pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-furoyloxy) -2H-pyran-2-one; 6- (benzofuran-2-yl) -3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one;

• ·

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-acetylamino-4- (morpholin-4-yl) -4-oxobutyryloxy) 2H-pyran-2-one;

4-acetyloxy-6- (5-bromobenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one; 6- (benzofuran-2-yl) -5-cyclopentylmethyl-4-hydroxy-3-methyl-2 H -pyran-2-one; 6- (benzofuran-2-yl) -4- (1-carbobenzyloxy-2-pyrrolidon-5-ylcarboxy) -3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-pyrrolidon-5-ylcarboxy) -2H-pyran-2-one;

6- (benzofuran-2-yl) -4- (2- (t-butoxycarbonylamino) acetyloxy) -3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -4- (2,4-dimethoxybenzoyloxy) -3,5-dimethyl-2H-pyran-2-one;

6- (benzofuran-2-yl) -3,5-dimethyl-4- (3-dimethylaminobenzoyloxy) -2H-pyran-2-one;

4- (4- (acetylamino) benzoyloxy) -6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

3,5-dimethyl-6- (5- (2-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3,4- (methylenedioxy) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (5-hydroxy-3-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (5- (2-methoxy-5-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (1-methylpiperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

6- (5- (4-carboxybenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one;

6- (5- (3,4-dimethylbenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2-thienylmethoxy) benzofuran-2-yl) -2H-pyran-2-one; 4-acetyloxy-3,5-dimethyl-6- (5- (2-thienylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3-thienylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2- (morpholinesulfonyl) -5-thienylmethoxy) benzofuran-2-yl) 2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (5- (2- (morpholinesulfonyl) -5-thienylmethoxy) benzofuran-2-yl) 2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (4-oxazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2-phenyl-4-oxazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one;

6- (5- (2,4-dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one; 6- (5- (3,4-dichlorobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one; 6- (5- (4-n-butoxybenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (6- (1,2,3,4-tetrahydronaphthalen-1-yloxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (2-propyn-1-yloxy) benzofuran-2-yl) -2H-pyran-2-one;

3,5-dimethyl-6- (5- (3-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2 H -pyran-2-one;

3,5-dimethyl-6- (5- (4-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (3-methoxybenzyloxy) benzofuran-2-yl) -2H-pyran-2-one; 6- (5- (3-chlorobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2 H -pyran-2-one; 6- (5- (3-aminobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

6- (5- (3- (t-butoxycarbonylamino) benzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one;

4-acetyloxy-6- (5- (3-t-butoxycarbonylamino) benzyloxy) benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (5-trifluoromethanesulfonyloxy-benzofuran-2-yl) -2H-pyran-2-one;

4-acetyloxy-3,5-dimethyl-6- (5- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one; 4-acetyloxy-6- (4-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one; 4-Acetyloxy-6- (4-acetyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one; 4-acetyloxy-3,5-dimethyl-6- (5-methoxybenzofuran-2-yl) -2H-pyran-2-one; 4-Acetyloxy-6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

6- (5-benzyloxy-benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one; 4-acetyloxy-3,5-dimethyl-6- (5-p-toluenesulfonyloxy-benzofuran-2-yl) -2H-pyran-2-one; 4-acetyloxy-6- (7-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one;

3,5-dimethyl-4-hydroxy-6- (5- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one;

3,5-Dimethyl-4-hydroxy-6- (6-methoxymethoxybenzofuran-2-yl) -2H-pyran-2-one. The compounds represented by Structural Formula (I) above may sometimes form salts by addition of an acid or addition of a base. As specific examples of acid addition salts, mention may be made of mineral acid salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as 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 ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid; as specific examples of base addition salts, mention may be made of metal salts such as lithium, sodium and potassium; salts of divalent or trivalence metals such as magnesium, calcium, zinc and aluminum; salts of basic amino acids such as lysine and arginine; as well as ammonium salts and organically bound ammonia such as methylamine, dimethylamine, trimethylamine, benzylamine and monoethanolamine. The present invention also includes hydrates of the compounds represented by Structural Formula (I), as well as various solutions thereof and crystalline polymorphic materials.

The compounds of the invention may generally be produced by the processes described below in Production Processes 1 to 5, if necessary, with modifications using readily available starting materials, reagents and conventional synthesis methods.

Process production

• ·

Specifically, for example, the benzofuryl-α-pyronic derivative of the present invention can be produced according to the method reported as production process 1. To a solution such as a THF solution

In the 2,4-disubstituted-β-ketoester, two equivalents of base, for example 1 equivalent of NaH and one equivalent of n-BuLi or two equivalents of LDA, are added to prepare the dienolate, and then the benzofurancarboxylic acid ester derivative is further reacted by Claisen condensation to form the diketoester intermediate. The diketoester intermediate is subjected to alkaline hydrolysis and then the acid is added to form α-pyrone. After the alkaline hydrolysis, the diketoester intermediate may be subjected to acid addition followed by addition of acetic anhydride and pyridine to form 4-pyridine-acetyloxy-α-pyrone, and this may again be subjected to alkaline hydrolysis to form 4-hydroxy-α-pyrone. Alternatively, an acid such as sulfuric, polyphosphoric or p-TsOH may be added to the diketoester intermediate or may be heated under reduced pressure to obtain 4-hydroxy-α-pyrone.

Production process 2

o o

O'M * OM *

The diketoester intermediate of production process 1 can also be produced by another method described as production process 2. A base such as LDA is added to the benzofuryl ketone to prepare the enolate, and this reacts with a malonic acid ester such as monomethyl ester monochloride of malonic acid to form the diketoester intermediate. Alternatively, the diketoester intermediate may be obtained by a process in which the diketone obtained is reacted with an acyl chloride or ester and further benzofuryl ketone enolate reacts with two equivalents of a base such as LDA to form a dienolate which is then reacted with a CO2 releasing compound such as carbon dioxide gas or dimethyl carbonate.

Production process 3

The benzofuryl-α-pyronic derivative of the present invention may be produced according to the method reported as production process 3. The benzofuryl-α-pyronic derivative may be obtained by a method in which the benzofuryl ketone is converted, for example, to a silylenol ether with TMSCl-E3 or TMSOTf-Et3 and reacts with malonic acid dichloride or malonic acid diester.

Production process 4

The benzofuryl-α-pyronic derivative of the present invention can be produced according to the method reported as production process 4. The benzofuryl-α-pyronic derivative can be obtained by a method wherein the α-ketone derivative with the -CH 2 X substituent on carbon 6 (where X represents a reactive group, such as Cl, Br, I, OMs or OTf) is reacted with a substituted salicylaldehyde in the presence of a base such as K 2 CO 3 and / or DBU.

Production process 5

2

The benzofuryl-α-pyronic derivatives of the present invention wherein R (where R represents a group as defined above) is -COR ⁵ or -SO ² R ⁶ (wherein R ⁵ and R ⁶ represent a group as defined above) may be produced according to the method 5. Benzofuryl-α-pyronic derivatives according to the invention, benzofuryl-α-pyronic derivatives wherein R is CO-R ⁵ can be produced according to the method of the invention as starting material, 6> benzofuryl-4-hydroxy-α- the pyronic derivative obtained according to any of the production processes 1 to 4 above with modifications, if necessary, reacts with an acid chloride or an acid anhydride in the presence of a base, for example a tertiary amine such as EtsN or a nitrogen-containing aromatic heterocycles such as pyridine; imidazole or alternatively, a method wherein the starting material is reacted with a carboxylic acid in the presence of a condensing agent such as WSC-HOBt, DCC-HOBt, CDI, diethyl cyanophosphate or diphenylphosphoryl azide or a method called the "Mitsunobu reaction", wherein the starting material reacts with a carboxylic acid in the presence of PI 13 P-DEAD. Similarly, a benzofuryl-α-pyron derivative wherein R ² is SO ² R ⁶ may be produced by reacting the starting material, i.e., the 6-benzofuryl-4-hydroxy-α-pyrone derivative with a sulfonyl chloride derivative represented by RSO 2 Cl in the presence of a base such as a tertiary amine such as Et ₃ N or aromatic nitrogen-containing heterocycles such as pyridine or imidazole.

The benzofuryl-α-pyronic derivatives of the present invention wherein R ⁴ is a substituent as defined above other than hydrogen may be produced by the method described as production processes 6 or 7. As described in production process 6, the readily available substituted salicylaldehyde derivative is used as a starting material for any of the production processes 1 to 5 described above, with modifications, if necessary, to obtain benzofuryl-α-pyrone (route A) or 2-benzofurancarboxylic acid ester intermediate (route B) substituted with hydroxy, methoxy, formyl, bromo, nitro, etc. groups. Pathway A is a method involving the conversion of a functional group from a hydroxy, methoxy, formyl, bromo, nitro substituent to a benzofuryl-α-pyron molecule, whereas pathway B is a motif in which the α-pyron ring is formed after conversion of a functional group R ⁴ in the intermediate molecule 2-Benzofurancarboxylic acid ester.

Production Process 6 • ·

• · ·

R * OMe, OH, OTf, CHO, Br, NO,

Route B v

Rc = OMe, OH, OTf, CHO. Br, NO,

Production process 7

R ^4h = alkylidene, alkyl, acyl, etc.

Conversion of the R ⁴ functional group from hydroxy, methoxy, formyl, bromo, nitro, groups, etc. can be accomplished by the method described in Production Process 7. For the benzofuran-α-pyron intermediate obtained via Route A in Production Process 6, the conversion of the hydroxyl functional group can be acylated with an acid chloride or acid anhydride, sulfonylated with a sulfonyl chloride or sulfonylanhydride, alkylated according to the Mitsunobo reaction, etc .; conversion of the bromo or trifluoromethylsulfonyloxy functionality may be carried out by carbonylation, allylation, cyanation, halogenation, amination, etc. in the presence of a transition metal catalyst such as a palladium catalyst; and the conversion of the formyl functional group may be accomplished by alkylation or acylation with a nucleophilic reagent such as an organometallic reagent or an enolate.

Conversion of the functional group R ⁴ from the benzofurancarboxylic acid ester intermediate obtained via route B in production process 6 can also be performed using the same method as in production process 7.

The production processes 1 to 7 mentioned above do not limit the synthesis processes for the compounds of the invention and any other processes known to the skilled chemist can also be used. The benzofuryl-α-pyrone derivatives of this invention and their salts obtained by the route described above have an inhibitory effect on triglyceride biosynthesis, further have a blood triglyceride lowering effect and a blood HDL elevating effect as described in the examples below, and can be used as active ingredients in combination with carriers, etc. described below, if necessary, providing pharmaceutical compositions and providing triglyceride biosynthesis inhibitors, lowering blood triglyceride levels, and providing a blood HDL enhancing effect according to the present invention.

For the clinical application of the benzofuryl-α-pyrone derivative of the invention or its salts as a prophylactic or therapeutic agent for hypertriglycerdemia, arteriosclerosis or the like, the derivative may be administered orally or parenterally, further intrarectally, subcutaneously, intramuscularly, intravenously or through the skin but oral or intravenous administration is preferable.

For oral administration, it may be in the form of a solid or liquid preparation. Solid form preparations include tablets, pills, powders, and granules. The active substances in such a solid preparation are mixed with pharmaceutically acceptable carriers such as sodium carbonate, calcium carbonate, potato starch, sucrose, mannitol and carboxymethylcellulose. The processing may be carried out by a conventional method and other additives, for example lubricants such as calcium stearate and magnesium stearate, may also be included in the processed additives (carrier). Membrane-coated formulations may also be prepared by coating the film-forming composition by spraying the aforementioned solid compositions, for example, in an aqueous or organic solvent solution onto a membrane-coated substance such as cellulose acetate phthalate, hydroxymethylcellulose phthalate, polyvinyl alcohol phthalate or styrene copolymer. and maleic anhydride or methacrylic acid or methyl methacrylate copolymer. Solid formulations such as powders or granules may also be encapsulated in membrane-coated capsules.

Liquid preparations for oral administration include, for example, an emulsifier, solution, suspension, syrup or elixir. These formulations include conventional pharmaceutically acceptable carriers such as water or liquid paraffin. Oil bases such as coconut oil, fractionated coconut oil, soybean oil or corn oil are also useful as carriers. Pharmaceutically acceptable carriers also include, if necessary, commonly used adjuvants, flavoring agents, stabilizers, or preservatives. The liquid preparation may be administered in the form of capsules formed from a substance capable of absorbing such as gelatin. Solid formulations for intrarectal administration include suppositories which are made by known methods to include the active ingredients.

The composition for parenteral administration is administered as a sterile aqueous or non-aqueous solution, suspension or emulsion. The non-aqueous solution or suspension may contain propylene glycol, polyethylene glycol, a vegetable oil such as olive oil or soybean oil or organic esters suitable for injection such as ethyl oleate as pharmaceutically acceptable carriers. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizers. These solutions, suspensions and emulsions may be sterilized by any suitable means, such as filtration through a filter that retains bacteria, heating, the use of a sterilizing agent, or treatment with ultraviolet radiation. After production and prior to the use of a sterile solid preparation, it may be dissolved in sterilized water or a sterilized injection solvent. Fatty emulsions prepared by adding water to a homogeneous solution of vegetable oil active ingredients such as soybean oil and phospholipids such as lecithin can be homogenized with a homogenizer such as a pressure homogenizer or an ultrasonic homogenizer and further used for injection.

Administration of the dosage form through the skin includes ointments, creams and the like. These can be produced by general methods.

When used as therapeutic agents for hypertriglyceridemia or as prophylactic agents for arteriosclerosis, the active agents of the invention can usually be administered in an amount of about 1 to 1000 mg per day for adults, although this will depend on the patient's condition, age, sex and body weight. and the mode of administration. The dose may be administered either at once or several times, for example 2 to 6 times daily.

The various routes of administration are more suitably selected according to the absorption efficiency in the body for a particularly physiologically active benzofuryl-α-pyron derivative, as determined by well-known pharmacological methods.

DETAILED DESCRIPTION OF THE INVENTION

The abbreviations used for derivatives used throughout the present invention, including the examples and groups in their structures, and the reagents used are those generally used in organic chemistry; An explanation of the abbreviations is given below.

THF: tetrahydrofuran, Et2O: diethyl ether, DMF: Ν, Ν-dimethylformamide, AcOEt: ethyl acetate, MeOH: methanol, EtOH: ethanol, DBU: 1,8-diazabicyclo [5,4,0] -7-undecene, DEAD: diethyl azodicarboxylate , TMAD: azodicarboxylic acid bis (dimethylamide), DMSO: dimethylsulfoxide, 13 N: triethylamine, Py: pyridine, n-BuLi: normal butyllithium,

LDA: lithium diisopropylamide, AC2O: acetic acid anhydride, WSC: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, CD1: carbonyldiimidazole, HOBt: 1-hydroxybenzotriazole, PPTS: pyridinium para-toluenesulfonate, TMSOTf:

trimethylsilyltrifluoromethanesulfonyl, TfOH: trifluoromethanesulfonic acid, Ms: methanesulfonyl, Tf: trifluoromethanesulfonyl, p-Ts: para-toluenesulfonyl, Ph: phenyl, Bu: butyl, Bzl: benzyl, Ac: acetyl, TMS: trimethylsilyl

Examples of productions

Synthesis of intermediates

Synthesis of methyl 2-benzofurancarboxylate

After addition of thionyl chloride (3.80 mL) to a solution of 2-benzofurancarboxylic acid (2.00 g) in MeOH (60 mL) at -40 ° C, the mixture was stirred for 19 hours at gradually increasing temperature to room temperature. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (N-hexane / AcOEt = 6/1) to obtain 2-benzofurancarboxylic acid methyl ester.

Yield: 2.16 g (y, 99.2%).

1 H NMR (CDCl 3): 3.99 (s, 3H), 7.28-7.50 (m, 2H), 7.54 (s, 1H), 7.60 (d, J = 8, 9 Hz, 1H), 7.69 (d, J = 7.6Hz, 1H)

Synthesis of 2-methyl-3-oxopentanoic acid methyl ester

Methyl iodide (57 mL) and K 2 CO 3 (127 g) were added to a solution of propionylacetic acid methyl ester (120 g) in acetone (800 mL) with ice cooling. The reaction mixture was stirred at room temperature for 96 hours and filtered through celite, then the mother liquors were slowly concentrated under reduced pressure and distilled under reduced pressure to give 2-methyl-3-oxopentanoate methyl ester.

Yield: 105 g (y. 94.8%) 1 H NMR (CDCl 3): 1.08 (t, J = 7.3 Hz, 3H), 1.35 (d, J = 7.3 Hz, 3H), 2.45-2.72 (m, 2H), 3.54 (q, J = 7.53Hz, 1H), 3.73 (s, 3H)

Synthesis of 3-oxononanoic acid methyl ester

Pyridim (11.2 mL) and N-heptanoyl chloride (11.8 mL) were added to a solution of merudoramic acid (10.0 g) in CHCl 2 (150 mL) at 0 ° C and the mixture was stirred at 0 ° C for 30 minutes and then 2 hours at room temperature. The reaction mixture solution was cooled to 0 ° C, dilute hydrochloric acid was added and the mixture was extracted with CH 2 Cl 2. The organic layer was washed with water and saturated aqueous NaCl, dried over Na 2 SO 4, and concentrated. MeoH (150 mL) was added to the residue before heating under reflux for 3 hours, after cooling the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane / AcOEt, 13/1) to obtain 3-Oxopropanoic acid methyl ester.

Yield: 8.51 g (y, 65.9%) 1 H NMR (δpm, CDCl ₃ ): 0.88 (t, J = 6.9 Hz, 3H), 1.22-1.40 (m, 6) H), 1.51-1.69 (m, 2H), 2.53 (t, J = 7.3 Hz, 2H), 3.45 (s, 2H), 3.74 (s, 3H)

Synthesis of methyl 2-methyl-3-oxononanoate

K 2 CO 3 (2.67 g) was added to a solution of methyl 2-methyl-3-oxononanoate (3.01 g) and methyl iodide (2.67 g) in acetone (100 mL), and the mixture was stirred at room temperature for 24 hours. hours. The reaction mixture was filtered through celite, and the mother liquors were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / AcOEt, 13/1) to give 2-methyl-3-oxopropanoic acid methyl ester.

Yield: 3.06 g (y. 94.6%) NMR (.delta.ppm, CDC1 _3): 0.90 (t, 3H), 1.21 to 1.39 (m, 9H), 1.51 to 1 65 (m, 2H), 2.47-2.56 (m, 2H), 3.53 (q, J = 7.53 Hz 1H), 3.73 (s, 3H)

Synthesis of ethyl 2- (benzyloxy) acetate

Benzyl alcohol (27.5 mL) was added to a suspension of NaH (1.1 g) in Et 2 O (250 mL) at 0 ° C and after stirring for 10 minutes and at room temperature for 5 minutes, the reaction mixture was cooled to -10 ° C. ° C to 0 ° C and trichloroacetonitryl (27 mL) were added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour until the temperature slowly rose to room temperature and then concentrated under reduced pressure. A solution of MeOH (1.0 mL) in n-pentane (100 mL) was added to the residue and the mixture was stirred rapidly, filtered and concentrated. When n-pentane was then added to the residue and the mixture was filtered again, the mother liquor was concentrated. Et 2 O (80 mL), n-pentane (80 mL) and ethyl glycolate (25 g) were added to the residue and then TiOH (1.5 mL) was added at 0 ° C and the mixture was further stirred for 10 minutes at 0 ° C and 2 hours at room temperature. The reaction mixture was filtered, the mother liquor was poured into a saturated aqueous NaHCO 3 solution, and extraction was performed with Et 2 O. The organic layer was washed with water, dried over MgSO ₄ and then 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 (CDCl ₃ ): 1.29 (t, J = 7.26 Hz, 3H), 4.09 (s, 2H), 4.23 (q, J = 7.26 Hz, 2H), 4.63 (s, 2H), 7.21-7.45 (m, 5H)

Synthesis of methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate

A solution of methyl 2-methyl-3-oxopentanoate (13.05 g) in THF (100 mL) was added to a suspension of NaH (3.80 g) in THF (100 mL) at 0 ° C and after stirring at 0 ° C after 1.63 M n-BuLi (58 mL) was added over 15 minutes and the mixture was stirred at 0 ° C for 20 minutes to give a pale yellow dienolate. The reaction mixture was cooled to -78 ° C and a solution of ethyl 2 (benzyloxy) acetate (17.56 g) in THF (30 mL) was added and the mixture was stirred at -78 ° C for 5 minutes and then at 0 ° C. 1 hour. The diluted HCl was poured into the reaction mixture with cooling and extraction was performed with AcOEt at neutral pH. The organic layer was washed with saturated NaCl solution and dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt, 5/1 → 3/1) to obtain methyl 6-benzyloxy-2,4-dimethyl-3,5-dioxohexanoate.

Yield: 9.78 g (y. 37%) 1 H NMR (dppm, CDCl ₃ ): 1.17-1.42 (m, 6H), 3.62-3.80 (m, 4H), 3, 98 to 4.28 (m,

3H), 4.48-4.65 (m, 2H), 7.12-7.42 (m, 5H)

Synthesis of 4-acetyloxy-6- (benzyloxy) methyl-3,5-dimethyl-2H-pyran-2-one An aqueous solution (6 mL) of LiOH hydrate (64 mL) was added to the solution of -benzyloxy-2,4-dimethyl-3, Of 5-dioxohexanoate (430 mg) in THF (10 mL) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was neutralized with dilute HCl and, after distilling off the volatile components under reduced pressure, it was extracted with AcOEt at pH 3. The organic layer was dried over MgSO ₄ , then filtered and concentrated. 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 mixture 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.

Yield: 212 mg (y, 47.7%) 1 H NMR (CDCl ₃ , CDCl ₃ ): 1.88 (s, 3H), 1.93 (s, 3H), 2.34 (s, 3H), 35 (s, 2H), 4.58 (s, 2H), 7.23-7.41 (m, 5H)

Synthesis of 6- (benzyloxy) methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

To ₂ CO ₃ (3 g) and water (10 mL) were added to a solution of 4-acetyloxy-6- (benzyloxy) methyl-3,5-dimethyl-2H-pyran-2-one (6.08 g) in MeOH (100 mL). ml) and stirring at room temperature overnight. The reaction mixture was filtered through celite and the mother liquor was concentrated under reduced pressure. Water was added to the residue and extraction was performed with AcOEt. The organic layer was dried over Na 2 SO ₄ and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt, 5/1 → 1/1) to obtain 6- (benzyloxy) methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one .

Yield: 4.82 g (y. 86%) (TLC Rf = 0.3; n-hexane / AcOEt = 1/1)

Synthesis of 6- (benzyloxy) methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one Diisopropylethylamine (2.1 mL) was added to a solution of 6- (benzyloxy) methyl-3,5-dimethyl-4. - hydroxy-2H-pyran-2-one (2.60 g) in THF (50 mL) and after stirring the mixture at room temperature for 1 hour, chloromethyl methyl ether (921 µL) was added at 0 ° C and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, water was added to the residue, and extraction was performed with AcOEt and the organic layer was dried over Na 2 SO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt, 5/1 → 1/1) to obtain 6- (benzyloxy) methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one .

Yield: 1.80 g (y. 60%) (TLC Rf = 0.6; n-hexane / AcOEt = 1/1)

Synthesis of 3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one% Pd (OH) ₂ / C (360 mg) was added to a solution of 6- (benzyloxy) methyl-3,5-dimethyl -4-methoxymethoxy-2H-pyran-2-one (1.80 g) in EtOH (50 mL) and the mixture was stirred vigorously at room temperature for 3 hours under a hydrogen atmosphere. 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 (n-hexane / AcOEt, 1/1) to obtain 3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one.

Yield: 1.26 g (y, 99%) (TLC Rf = 0.15; n-hexane / AcOEt = 1/1)

Synthesis of 3,5-dimethyl-4-methoxymethoxy-6- (methylsulfonyloxy) methyl-2H-pyran-2-one Triethylamine (606 mg) was added to a solution of 3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H- pyran-2-one (1.26 g) in THF (50 mL) and after stirring the mixture at room temperature for 1 hour, methanesulfonyl chloride (1.05 g) was added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extraction was performed with AcOEt, the organic layer was dried over Na 2 SO _4, and was then filtered and concentrated.

The residue was purified by silica gel column chromatography (n-hexane / AcOEt, 1/1) to obtain

3,5-dimethyl-4-methoxymethoxy-6- (methylsulfonyloxy) methyl-2 H -pyran-2-one.

Yield: 1.35 g (y. 73%) (TLC Rf = 0.5; n-hexane / AcOEt = 1/1)

Synthesis of 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one

Sodium bromide (500 mg) was added to a solution of 3,5-dimethyl-4-methoxymethoxy-6- (methylsulfonyloxy) methyl-2H-pyran-2-one (1.35 g) in DMF (20 mL) and after stirring the reaction of the mixture at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt, and the organic was dried over Na 2 SO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt, 1/1) to obtain 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)

Synthesis of methyl 6-hydroxybenzofuran-2-carboxylate

A suspension of 4-methoxysalicylaldehyde (50 g), K 2 CO 3 (65 g) and methyl bromoacetate (65 g) in DMF (500 mL) was stirred at 60 ° C for 1 hour and after cooling the reaction mixture was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt, and the organic was dried over Na 2 SO ₄ and was then filtered and concentrated. Toluene (500 mL) was added and DBU (70 g) was added to the suspension and the mixture was stirred at 130 ° C overnight. After cooling, the reaction solution was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt. The organic was dried over Na 2 SO ₄ and was then filtered and concentrated. The residue was dissolved with MeOH (500 mL), concentrated HCl (50 mL) was added, and the mixture was stirred at 60 ° C overnight. After cooling, the reaction mixture was concentrated under reduced pressure, AcOEt (500 mL) was added to the residue, 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 was dried over MgSO ₄ and was then filtered and concentrated. The residue was dissolved in CH 2 Cl 2 (1000 mL), boron tribromide (125 g) was added slowly at 0 ° C, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the resulting brown oil was dissolved in MeOH (500 mL), concentrated HCl (50 mL) was added, and the mixture was stirred at 60 ° C overnight. After cooling, the reaction mixture was concentrated under reduced pressure, AcOEt (500 mL) was added to the residue, a saturated aqueous NaHCO 3 solution (500 mL) was slowly added to allow the reaction to proceed.

separated the organic layer and the aqueous layer and the aqueous layer was extracted with AcOEt.

The organic was dried over MgSO ₄ and then 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%) ^! HNMR (CDCl3): 3.88 (s, 3H), 5.50 to 6.50 (brs, 1H), 6.80 to 7.80 (m, 4H)

Synthesis of methyl 6- (benzyloxy) benzofuran-2-carboxylate

A solution of methyl 6- (benzyloxy) benzofuran-2-carboxylate (3.58 g) in THF (30 mL) was slowly added to a suspension of NaH (800 mg) in THF (100 mL) at room temperature and after stirring for 1 hour DMF (35 mL) was added followed by slow addition of benzyl bromide (3.77 g) and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extraction was performed with AcOEt, and the organic was dried over MgSO ₄ , then 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 (CDCl ₃ , CDCl ₃ ): 3.95 (s, 3H), 5.19 (s, 2H), 6.85 (dd, J = 8, 1 Hz, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 7.43 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H) )

Synthesis of 2-hydroxy-4-morpholinobenzaldehyde

After slowly adding a solution of 3-morpholinophenol (5.0 g) in THF (100 mL) to a 3M solution (10 mL) of ethylmagnesium bromide in diethyl ether, the mixture was stirred at 30 ° C for 1.5 hours. Paraformaldehyde (3.0 g) and Et ₃ N (3.0 g) were added to the reaction mixture and the solution was stirred at 80 ° C for 4 hours. After cooling, aqueous 6N HCl solution (20 mL) was added and the mixture was stirred for 1 hour, then the organic layer and the aqueous layer were separated and the aqueous layer was made slightly alkaline before extraction with AcOEt. The organic layers were combined and dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 3/1) to obtain 2-hydroxy-4-morpholinobenzaldehyde.

Yield: 3.57 g (y, 62%) ^! 1 H NMR (δ ppm, CDCl ₃ ): 3.30 (t, J = 4.8 Hz, 4H), 3.84 (t, J = 4.8 Hz, 4H), 6.18 (d, J = 2) 1 Hz, 1H), 6.55 (dd, J = 8.9 Hz, 2.1 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 10.30 (s, ÍH)

Synthesis of methyl 6-morpholinobenzofuran-2-carboxylate.

Methyl bromoacetate (3 g) and K 2 CO 3 (3 g) were added to a solution of 2-hydroxy-4-morpholinobenzaldehyde (3.5 g) in acetonitrile (100 mL) and heated to reflux for 3 hours.

for 16 hours, the reaction mixture was filtered and the mother liquor was concentrated under reduced pressure. MeOH (100 mL) and concentrated HCl (10 mL) were added to the residue, and after refluxing for 5 hours, the reaction solution was concentrated under reduced pressure. Saturated aqueous NaHCO ₃ solution (100 mL) was added to the residue before extraction with AcOEt, the organic was dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 5/1) to obtain methyl 6-morpholinobenzofuran-2-carboxylate.

Yield: 3.1 g (y, 71%) 1 H NMR (δpm, CDCl ₃ ): 3.22 (t, J = 4.8 Hz, 4H), 3.80 (t, J = 4.8 Hz) 4H), 3.95 (s, 3H), 6.96-7.00 (m, 2H), 7.44 (s, 1H), 7.53 (d, J = 8.6 Hz, 1H)

Synthesis of methyl 5-formylbenzofuran-2-carboxylate

K2CO3 (30 g) was added to a solution of 5-formylsalicylaldehyde (25 g) and methyl bromoacetate (30 g) in acetonitrile (500 ml), followed by cooling for 24 hours, the reaction solution was filtered and the mother liquor was concentrated under reduced pressure. pressure. Saturated aqueous ammonium chloride solution (100 mL) was added to the residue, and the organic was dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 5/1) to obtain methyl 5-formylbenzofuran-2-carboxylate.

Yield: 15 g (y. 44%)

Mass analysis: [M + + H] = 205.2

Synthesis of 5- (dimethoxymethyl) benzofuran-2-carboxylate

Methyl orthoformate (1.0 g) and polymer bound PPTS (1.0 g) were added to a solution of methyl 5-formylbenzofuran-2-carboxylate (15 g) in MeOH (100 mL) and the mixture was allowed to react while standing 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 5- (dimethoxymethyl) benzofuran-2-carboxylate.

Yield: 10 g (y. 54%) 1 H NMR (δpm, CDCl ₃ ): 3.35 (s, 3H), 3.98 (s, 3H), 5.49 (s, 1H), 7.53 to 7.61 (m, 3H), 7.81 (s, 1H)

The following compound was formed in a side process similar to the previous production example using organic chemistry techniques well known to those skilled in chemistry.

Ethyl 5-bromobenzofuran-2-carboxylate

1 H NMR (CDCl ₃ ): 1.43 (t, J = 7.3 Hz, 3H), 4.45 (q, J = 7.3 Hz, 2H), 7.45 (s, 1H) 7.47 (d, J = 8.4, 1H), 7.54 (dd, J = 8.4 Hz and J = 2.2 Hz, IH), 7.82 (d, J = Hz, 2) , 2 H)

Example 1. Synthesis of 4-acetyloxy-6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one After adding 60% NaH (220 mg) to a solution of methyl 2-methyl-3-oxopentanoate (750 mg) in THF (5 mL) at 0 ° C and the mixture was stirred at 0 ° C for 5 minutes, then the mixture was cooled to -78 ° C. To this reaction solution was then added 1.63 M n-BuLi (3.3 mL) and the mixture was stirred at -78 ° C for 30 minutes to give the dienolate. A solution of methyl 2-benzofurancarboxylate (300 mg) in THF (10 mL) was added to the dienolate and the mixture was stirred at -78 ° C for 20 minutes. The reaction solution was allowed to reach 0 ° C, the aqueous KHSO 4 solution was added after cooling, and extraction was performed with AcOEt. The organic layer was washed with saturated NaCl solution and dried over MgSO 4, then filtered and concentrated. The residue was coarse purified by silica gel column chromatography (n-hexane / AcOEt ~ 3/1 → 2/1) to give methyl 5- (benzofuran-2-yl) -2,4-dimethyl-3,5-dioxopentanoate.

Yield: 433 mg (mixture)

Aqueous solution (30 mL) of LiOH-hydrate (2.62 g) was added to a solution of 5- (benzofuran-2-yl) -2,4-dimethyl-3,5-dioxopentanoate (14.98 g) in MeOH (50 mL). ml) and after stirring at room temperature for 20 minutes, MeOH was distilled off under reduced pressure. The aqueous residue solution was washed with Et 2 O and then cooled on ice and an aqueous KHSO 4 solution was added to adjust the pH to 2.0-2.5. The precipitated crystals were filtered off and washed with water. The mother liquor was saturated with NaCl and extracted with AcOEt, and the organic layer was concentrated. The residue was combined with the filtered crystals, and after addition of pyridine (40 mL) and AC 2 O (40 mL), 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- he

Yield: 6.11 g (y. 47.3%) 1 H NMR (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 = 8.2 Hz, 1H), 7.65 (d, J = 7.6 Hz) , IH)

Example 2. Synthesis of 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one An aqueous solution (30 mL) of LiOH-hydrate (465 mg) was added to a solution of 4- acetyloxy-6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one (3 g) in MeOH (100 mL) at 0 ° C and after stirring at room temperature for 2 hours MeOH was distilled off under reduced pressure. The residue was washed with Et 2 O, then an aqueous KHSO 4 solution was added at 0 ° C to adjust the pH to 2.0. The precipitated crystals were filtered and washed thoroughly with water and Et ₂ O, respectively, and then dried to give 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

Yield: 2.54 g (y. 98.5%)

NMR (CDCl3, DMSO-d6): 1.93 (s, 3H), 2.28 (s, 3H), 7.28-7.47 (m, 2H), 7.39 (s, 1H),

7.68 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 7.3 Hz, IH), 10.91 (brs, IH)

Example 3. Synthesis of 6- (benzofuran-2-yl) -4-benzoyloxy-3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Pyridine (64 μΐ) and benzoyl chloride (45 μΐ) were added to a suspension of 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in CH 2 Cl 2 (5 ml) and the mixture was stirred at room temperature for 50 minutes. The reaction solution was poured into aqueous KHSO4 solution and extracted with AcOEt, the organic layer was washed with saturated NaCl solution and dried over MgSO4, then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 5/1 → 4/1) to obtain 6- (benzofuran-2-yl) -4-benzoyloxy-3,5-dimethyl-4-hydroxy- 2H-pyran-2-one.

Yield: 48 mg (y. 71.2%) Light yellow crystals

1 H NMR (CDCl 3): 2.04 (s, 3H), 2.35 (s, 3H), 7.24 to 7.42 (m, 3H), 7.49 to 7.77 (m, 5H) 8.22 (d, J = 7.23 Hz, 2H)

Example 4. Synthesis of 6- (benzofuran-2-yl) -3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one

Et ₃ N (130 μΐ) and methylsulfonyl chloride (24 μΐ) were added to a suspension of 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in THF (5 mL) and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into aqueous KHSO4 solution and extracted with AcOEt, the organic layer was washed with saturated NaCl solution and dried over MgSO4, then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 2/1) to obtain 6- (benzofuran-2-yl) -3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one.

Yield: 46 mg (y. 88.2%) Yellow crystals * H NMR (δρρηι, CDC1 _3): 2.22 (s, 3H), 2.50 (s, 3H), 3.39 (s, 3H); 7.26 to 7.44 (m, 3H),

7.54 (d, J = 8.2Hz, IH), 7.62 (d, J = 7.6Hz, IH)

Example 5. Synthesis of 6- (benzofuran-2-yl) -3,5-dimethyl-4- (2-pyridylcarboxy) -2H-pyran-2-one

VSC (43 mg) was added to a solution of 6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg), picolic acid (23 mg) and HOBt ( 21 mg) in DMF (3 mL) and the mixture was

Stir at room temperature for 21.5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 2/1 -> 3/2) to obtain 6- (benzofuran-2-yl) -3,5-dimethyl- 4- (2-Pyridylcarboxy) -2H-pyran-2-one.

Yield: 30 mg (y. 53.2%) Light yellow crystals of 1 H NMR (δpm, CDCl ₃ ): 2.07 (s, 3H), 2.38 (s, 3H), 7.25-7.42 (s). m, 3H), 7.53 (d, J = 8.2 Hz, 1H), 7.61 to 7.69 (m, 2H), 7.99 (dd, J = 1.6 Hz and J = 7) 9 Hz, 1H), 8.32 (d, J = 7.9 Hz,

1 H), 8.90 (d, J = 4.6 Hz, 1 H)

Example 6. Synthesis of 3,5-dimethyl-4-hydroxy-6- (6-morpholinylbenzofuran-2-yl) -2H-pyran-2one

A solution of methyl 2-methyl-3-oxopentanoate (865 mg) in THF (30 mL) was slowly added to a suspension of NaH (240 mg) in THF (50 mL) and after stirring for 10 minutes the mixture was cooled to -78 ° C. and 1.58 M n-BuLi (3.8 mL) was slowly added dropwise, after stirring the reaction solution at -78 ° C for 30 minutes, a solution of methyl 6-morpholinylbenzofuran-2-carboxylate (1.3 g) in THF ( 15 ml) was added slowly and the reaction mixture was stirred at -78 ° C for 4 hours. Saturated aqueous NH 4 Cl solution (30 mL) was added to the reaction solution and after warming to room temperature, extraction was performed with AcOEt, and the organic layer was dried over MgSO ₄ , then filtered and concentrated. The residue was dissolved in MeOH (33 mL) and THF (30 mL), an aqueous solution of 4 N lithium hydroxide (10 mL) was added, and after stirring for 4 hours at room temperature, an aqueous saturated solution of KHSO ₄ (50 mL) was slowly added. . The resulting yellow precipitate was filtered off and washed with AcOEt to give 3,5-dimethyl-4-hydroxy-6- (6-morpholinylbenzofuran-2-yl) -2H-pyran-2-one.

Yield: 1.4 g (y. 82%) 1 H NMR (δpm, DMSO-d 6): 1.92 (s, 3H), 2.26 (s, 3H), 3.19 (t, J = 4) 8 Hz, 4H), 3.75 (t, J = 4.8 Hz, 4H), 7.05 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7, 25 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H),

10.8 (s, 1H)

Example 7. Synthesis of 3,5-dimethyl-6- (5-formylbenzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

A solution of methyl 2-methyl-3-oxopentanoate (7.5 g) in THF (50 mL) was slowly added to a suspension of NaH (2.1 g) in THF (200 mL) and after stirring for 10 minutes the mixture was cooled to -78 ° C and 1.58 M n-BuLi (32 mL) was slowly added dropwise. After stirring the reaction solution at -78 ° C for 30 minutes, a solution of methyl 5- (dimethoxymethyl) benzofuran-2-carboxylate (10 g) in THF (50 mL) was slowly added and the mixture was stirred at -78 ° C for 4 hours . Saturated aqueous NH 3 Cl (30 mL) was added to the reaction solution and after warming to room temperature, extraction was performed with AcOEt and the organic layer was dried.

MgSO ₄ and then filtered and concentrated. The residue was dissolved in MeOH (100 mL) and THF (100 mL), an aqueous solution of 4 N lithium hydroxide (25 mL) was added, and after stirring for 4 hours at room temperature, an aqueous saturated solution of KHSO ₄ (50 mL) was slowly added. .

The resulting yellow precipitate was filtered off and washed with AcOEt to give 3,5-dimethyl-6- (5'-formylbenzofuran-2-yl) -4-hydroxy-2H-pyran-2-one.

Yield: 10.8 g (y. 95%) 1 H NMR (δpm, DMSO-d 6): 1.87 (s, 3H), 2.23 (s, 3H), 7.51 (s, 1H), 7.78 to 7.92 (m, 2H), 8.28 (s, 1H), 10.0 (s, 1H)

Example 8. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (5-bromobenzofuran-2-yl) -2H-pyran-2-one After addition of Et ₃ N (1.7 g) to the suspension of 3,5- dimethyl-6- (5-formylbenzofuran-2-yl) -4-hydroxy-2H-pyran-2-one (5.0 g) in CH ₂ C1 ₂ (100 ml), the mixture was cooled with ice, was added acetyl chloride (1 , 32 g) and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, extraction was performed with AcOEt, the organic layer was dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 3/1) to obtain 4-acetyloxy-3,5-dimethyl-6- (5-formylbenzofuran-2-yl) -2H-pyran-2-one .

Yield: 5.1 g (y. 88%)

1 H NMR (δpm, CDCl 3): 2.02 (s, 3H), 2.32 (s, 3H), 2.41 (s, 3H), 7.46 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, IH), 8.20 (s, IH), 10.1 (s, IH)

Example 9. Synthesis of 3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinylidene) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Pyperidine (100 mg) was added to a solution of 4-acetyloxy-3,5-dimethyl-6- (5-formylbenzofuran-2-yl) -2H-pyran-2-one (374 mg) α1,3-thiazolidin-2, Of 4-dione (135 mg) in THF (50 mL) and the mixture was refluxed for 4 hours. After cooling, a 15% aqueous NaOH solution (10 mL) was added to the reaction mixture, and was then concentrated under reduced pressure for 1 hour with stirring. The residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 5/1) to give 3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinylidene) methyl) benzofuran -2-yl) -4-hydroxy-2 H -pyran-2-one.

Yield: 400 mg (y. 91%) 1 H NMR (δpm, DMSO-d 6): 1.96 (s, 3H), 2.22 (s, 3H), 7.32 (s, 1H), 45 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, IH), 8.12 (s, IH), 8.24 (s, IH), 10, 91 (s, 1H); 12.90 (s, M)

Example 10. Synthesis of 3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinyl) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one · • *

To 3,5-dimethyl-6- (5 - ((3,5-dioxo-2,4-thiazolidinylidene) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one (350 mg) in a mixed solvent of EtOH (10 mL) and 1,4-dioxane (10 mL) was added 10% Pd / C (70 mg) and the mixture was stirred under hydrogen atmosphere for 1 day. The reaction mixture was filtered and the mother liquor was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ / MeOH = 5/1) to obtain 3,5-dimethyl-6- (5 - ((3,5- dioxo-2,4-thiazolidinyl) methyl) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one.

Yield: 352 mg (quantitative) 1 H NMR (δpm, DMSO-d 6): 1.97 (s, 3H), 2.24 (s, 3H), 3.34 to 3.55 (m, 1H), 3 67 to 3.82 (m, 1H), 4.98 to 5.01 (m, 1H), 7.24 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 12.93 (s, 1H), 12.20 (s, IH)

Example 11. Synthesis of 6- (benzofuran-2-yl) -4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one

A solution of methyl 2-methyl-3-oxononanoate (3.06 g) in THF (5 mL) was added to a suspension of 60% NaH (608 mg) in THF (30 mL) under ice-cooling, and the mixture was stirred at 0 ° C 10 minutes at room temperature for 30 minutes. The reaction solution was cooled to -78 ° C, 1.66 M n-BuLi (9.2 mL) was added and the mixture was stirred at -78 ° C for 30 minutes to give the dienolate. A solution of methyl 2-benzofurancarboxylate (1.25 g) in THF (5 mL) was added to the dienolate and the mixture was stirred at -78 ° C for 30 minutes. The reaction solution was warmed to 0 ° C, after cooling, aqueous NH 4 Cl solution was added and extraction was performed with AcOEt. The organic layer was washed with water and then with saturated NaCl solution and then dried over Na ₂ SO 4, filtered and concentrated. The residue was dissolved in MeOH (50 mL) and after addition of 2 N LiOH (30 mL) and stirred at room temperature for 2 hours, acidified at 0 ° C with 1 N HCl to approximately pH 3 and extraction was performed with AcOEt. The organic layer was washed with water and then with saturated NaCl solution and then dried over Na ₂ SO 4, filtered and concentrated. Pyridine (20 mL) and Ac ₂ O (20 mL) were added to the residue and after stirring the mixture at room temperature for 5 hours, it was concentrated under reduced pressure. The residue was dissolved in MeOH (20 mL), imidazole (483 mg) was added at 0 ° C, and the mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 30 minutes, then concentrated under reduced pressure. AcOEt was added to the residue and the precipitated crystals were filtered off. The crystals were recrystallized from EtOH to give 6- (benzofuran-2-yl) -4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one.

Yield: 357.9 mg (y, 16.1%) 1 H NMR (δppm, DMSO-d 6): 0.87 (t, J = 6.9 Hz, 3H), 1.28-1.60 (m 6H), 1.93 (s, 3H), 2.74-2.85 (m, 2H), 7.28-7.46 (m, 3H), 7.63 (d, J = 8.3) Hz, IH), 7.75 (d, J = 7.3 Hz, IH), 10.86 (brs, IH). «_ ········ · · ··· <·····

Example 12. Synthesis of 3,5-dimethyl-4-hydroxy-6- (5-methoxybenzofuran-2-yl) -2H-pyran-2-one

K2CO3 (138 mg) was added to a solution of 5-methoxysalicyl aldehyde (152 mg) and 6-bromomethyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (277 mg) in DMF (5 mL) and the mixture was Stir at room temperature for 16 hours. Aqueous 6 N HCl solution was slowly added to the reaction solution, and after stirring for 1 hour, extraction was performed with AcOEt and the organic layer was dried over MgSO 4, then concentrated and filtered. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 1/1) to obtain 3,5-dimethyl-4-hydroxy-6- (5-methoxybenzofuran-2-yl) -2H-pyran-2-one .

Yield: 229 mg (y. 80%)

1 H NMR (bppm, CDCl 3): 2.01 (s, 3H), 2.25 (s, 3H), 4.00 (s, 3H), 5.50 to 6.50 (brs, 1H),

6.80 to 7.80 (m, 4H)

Example 13. Synthesis of 3,5-dimethyl-6-hydroxy-6- (7-methoxybenzofuran-2-yl) -2H-pyran-2-one

3,5-Dimethyl-6-hydroxy-6- (7-methoxybenzofuran-2-yl) -2H-pyran-2-one was obtained by the same procedure as in the previous example.

Yield: 78% 1 H NMR (δpm, CDCl 3): 2.10 (s, 3H), 2.26 (s, 3H), 4.00 (s, 3H), 5.50-6.50 (brs) (1H),

6.80 to 7.80 (m, 4H)

Example 14. Synthesis of 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

To a solution of 3,5-dimethyl-4-methoxymethoxy-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one (100 mg) in dioxane (20 mL) and EtOH (20 mL) was added 5 % Pd / C (5 mg) and after the atmosphere in the reaction vessel was changed to hydrogen, the mixture was stirred overnight at room temperature.

The reaction solution was filtered and concentrated and then purified by silica gel thin layer chromatography (n-hexane / 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.

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 =

2.83 Hz, J = 8.9 Hz, 1H), 6.96 (J = 2.3 Hz, 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 (δpm, CDCl ₃ ): 1.30 (t, J = 7.3 Hz, 3H), 2.1 L (s, 3H), 2.39 ( s, 3H), 3.19 (q, J = 7.3 Hz, 2H), 3.62 (s, 3H), 5.11 (s, 2H), 6.69 (dd, J = 2.3) Hz, J = 8.9 Hz, 1H), 6.75 (d, J = 2.3 Hz, 1H), 7.20 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H)

Example 15. Synthesis of 6- (5- (acetylamino) benzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one

Pyridine (400 μΐ) and AC2O (15 μΐ) was added to 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (45 mg) and after stirring of NH 4 Cl was added to the mixture at room temperature for 6 hours and extraction was performed with CH 2 Cl 2. The organic layer was dried, filtered and concentrated. The residue was purified by silica gel thin layer chromatography (CH 2 Cl 2) to give 6- (5- (acetylamino) benzofuran-2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one.

Yield: 20 mg (y. 39%) 1 H NMR (δpm, 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 = 8.9 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 0) (Hz, 1H)

Example 16. Synthesis of 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one THF (20 mL) was added with stirring to 6- (5-aminobenzofuran- 2-one). 2-yl) -3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (58 mg), 1 drop of concentrated HCl 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 thin layer chromatography (n-hexane / AcOEt = 1/1) to give 6- (5-aminobenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H -pyran-2-one

Yield: 13 mg (y. 27%) ^! 1 H NMR (δpm, DMSO-d 6): 1.93 (s, 3H), 2.27 (s, 3H), 6.71 (dd, J = 2.0 Hz, J = 8.9 Hz, 1H) 6.79 (d, J = 2.0 Hz, 1H), 7.16 (s, 1H), 7.33 (J = 8.9 Hz, 1H)

Example 17. Synthesis of 6- (6- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one and 4-acetyloxy-6- (6- (benzyloxy) benzofuran -2-yl) -3,5-dimethyl-2H-pyran-2-one

A solution of methyl 2-methyl-3-oxopentanoate (3.24 g) in THF (30 mL) was slowly added to a suspension of NaH (900 mg) in THF (50 mL) at 0 ° C and after stirring for 10 minutes the mixture was After cooling to -78 ° C, 1.58 M n-BuLi (14.2 mL) was added slowly dropwise. After stirring the reaction solution for 30 minutes at -78 ° C, methyl 6- (6- (benzyloxy) benzofuran-2-carboxylate (4.26 g) in THF (15 mL) was slowly added and the mixture was stirred at -78 ° The reaction solution was treated with aqueous saturated NH 4 Cl solution and after warming to room temperature, extraction was performed with AcOEt, and the organic layer was dried over MgSO ₄ , then filtered and concentrated, and the residue was dissolved in MeOH (30 mL) and THF ( 10 ml) and 4 N aqueous lithium hydroxide solution (5 ml) and water (50 ml) were added, and after stirring at room temperature for 4 hours, a saturated aqueous solution of KHSO ₄ (30 ml) was slowly added. , washed in AcOEt to give 6- (6- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one.

Yield: 964 mg (y. 25%) ^! 1 H NMR (δpm, DMSO-d 6): 2.00 (s, 3H), 2.24 (s, 3H), 5.27 (s, 2H), 7.11 (d, J = 8.4 Hz, 1H), 7.30-7.70 (m, 8H), 10.8 (brs, 1H)

The filtrate was further concentrated under reduced pressure, water (30 mL) and AcOEt (30 mL) were added, the organic layer and the aqueous layer were separated, and the organic 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, and after stirring overnight, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (nhexane / AcOEt = 5/1 -> 1/1) to obtain 4-Acetyloxy-6- (6- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one.

Yield: 904 mg (y. 21%) 1 H NMR (δpm, CDCl ₃ ): 1.92 (s, 3H), 1.97 (s, 3H), 2.37 (s, 3H), 5.09 (s, 2H) 6.80-7.80 (m, 9H)

Example 18. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (6-hydroxybenzofuran-2-yl) -2H-pyran-2-one

To a solution of 4-acetyloxy-6- (6- (benzyloxy) benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one (500 mg) in EtOH (50 mL) and 1,4-dioxane (50 mL) was added 10% Pd / C (100 mg) and the mixture was vigorously stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 1/1) to obtain 4-acetyloxy-3,5-dimethyl-6- (6). 2-Hydroxybenzofuran-2-yl) -2H-pyran-2-one.

Yield: 388 mg (y. 95%) 11 NMR (δppm, CDCl ₃ ): 1.92 (s, 3H), 1.97 (s, 3H), 2.37 (s, 3H), 5.50 up to 6.50 (brs, 1H),

6.80 to 7.80 (m, 4H)

Example 19. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (6- (trifluoromethanesulfonyloxy) benzofuran-2-yl) -2H-pyran-2-one

Pyridine (100 mg) was added to a solution of 4-acetyloxy-3,5-dimethyl-6- (6-hydroxybenzofuran-2-yl) -2H-pyran-2-one (385 mg) in CH 2 Cl 2 (10 mL) and after stirring at room temperature for 1 hour, trifluoromethanesulfonic anhydride (415 mg) was added slowly with ice-cooling, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCCE solution (10 mL) was added to the reaction solution, extraction was performed with AcOEt, and the organic layer was dried over Na ₂ SO 4, then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 2/1) to obtain 4-acetyloxy-3,5-dimethyl-6- (6- (trifluoromethanesulfonyloxy) benzofuran-2-yl) -2H-pyran- 2-on.

Yield: 392 mg (y. 72%)

Mass analysis: [M + + H] = 447.3

Example 20. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (6- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one

After addition of a solution of 4-acetyloxy-3,5-dimethyl-6- (6- (trifluoromethanesulfonyloxy) benzofuran-2-yl) -2H-pyran-2-one (350 mg) in THF (5 mL) and βίβ (80 mg) ) to a mixed solution of palladium acetate (3.5 mg) and diphenylphinopropane (6.5 mg) in DMSO (5 mL) and MeOH (5 mL) was stirred at room temperature for 1 hour under carbon monoxide and then further stirred for 2 hours at 80 ° C. The reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 1/1) to obtain 4-acetyloxy-3,5-dimethyl-6- (6- (methoxycarbonyl) benzofuran-2). -yl) -2H-pyran-2-one.

Yield: 92 mg (y. 33%)

Mass analysis: [M ⁴ + + H] = 357.3

Example 21. Synthesis of 6- (6-carboxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

A mixed solution of 4-acetyloxy-3,5-dimethyl-6- (6- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one (85 mg) and K ₂ CC 3 (45 mg) in MeOH (5 mL) and H ₂ O (1 mL) was stirred at room temperature for 1 hour and then the reaction solution was acidified with 1 N aqueous hydrochloric acid 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.

Yield: 71 mg (quantitative)

Mass analysis: [M + + H] = 301.2

Example 22. Synthesis of 3,5-dimethyl-4-hydroxy-6- (6- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one

Trimethylsilyldiazomethane (2 M hexane solution, 85 μΐ) was added to a mixed solution of 6- (6-carboxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (50 mg) in MeOH (5 mL) and toluene (1 mL) and the mixture was stirred at room temperature for 10 minutes. After addition of acetic acid to the reaction solution to quench excess trimethylsilyldiazomethane, it was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH = 9/1) to obtain 3,5-dimethyl-4-hydroxy-6- (6). - (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one.

Yield: 50 mg (y. 96%)

Mass analysis: [M + + H] = 315.3

Example 23. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (6-dimethylaminobenzofuran-2-yl) -2H-pyran-2-one

Tetrakis (triphenylphosphine) palladium (3 mg) and dimethylaminotrimethyl (34 mg) were added to a solution of 4-acetyloxy-3,5-dimethyl-6- (6- (trifluoromethanesulfonyloxy) benzofuran-2-yl) -2H-pyran-2- on (45 mg) in toluene (5 mL) and the mixture was stirred at 50 ° C overnight. After cooling, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane / AcOEt = 9/1) to obtain 4-acetyloxy-3,5-dimethyl-6- (6-dimethylaminobenzofuran-2-). yl) -2H-pyran-2-one.

Yield: 9.6 mg (y. 28%)

Mass analysis: [M + + H] = 342.3

Example 24. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (2- (furyl) benzofuran-2-yl) -2H-pyran-2-one

4-Acetyloxy-3,5-dimethyl-6- (2- (furyl) benzofuran-2-yl) -2H-pyran-2-one was obtained in the same manner as above using 2- (tributyltin) furan.

Yield: 31 mg (y. 87%)

Mass analysis: [Μ * + H] = 365.3

Example 25. Synthesis of 4-acetyloxy-3,5-dimethyl-6- (2- (thienyl) benzofuran-2-yl) -2H-pyran-2-one

4-Acetyloxy-3,5-dimethyl-6- (2- (thienyl) benzofuran-2-yl) -2H-pyran-2-one was obtained in the same manner as above using 2- (tributyltin) thiophene.

Yield: 31 mg (y. 85%)

Mass analysis: [M ⁺ + H] = 381.4.

Example 26. Synthesis of 3,5-dimethyl-4-hydroxy-6- (6-methoxybenzofuran-2-yl) -2H-pyran-2-one

K2CO3 (1.38 g) was added to a solution of 4-methoxysalicylaldehyde (1.52 g) and 6-bromo-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (2.77 g) in DMF (50 mL) and then stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Water (50 mL) was added to the residue and extraction was performed with AcOEt, and the organic layer was dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane / AcOEt = 1/1) to obtain 3.46 g of a yellow oil. Diisopropylethylamine (1.29 g) and DMF (20 mL) were added to 1.74 g of a yellow oil prior to refluxing overnight. After cooling, an aqueous solution of 6 N HCl (10 mL) was slowly added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Water (50 mL) was added to the residue and extraction was performed with AcOEt, and the organic layer was dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (nhexane / AcOEt = 1/1) to obtain 3,5-dimethyl-4-hydroxy-6- (6-methoxybenzofuran-2-yl) -2H-pyran-2-one.

Yield: 20 mg (s. 1.3%) 1 H NMR (CDCl ₃ , CDCl ₃ ): 2.12 (s, 3H), 2.27 (s, 3H), 4.00 (s, 3H), 50 to 6.50 (brs, 1H); 6.80 to 7.80 (m, 4H)

Example 27. Synthesis of 3,5-dimethyl-4-hydroxy-6- (5- (5-pyrimidinylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

A solution of tributylphosphine in 2 N THF (0.94 mL) and a solution of TMAD (323 mg) in CH 2 Cl 2 (3 mL) was added dropwise to a solution 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) at 0 ° C and the mixture was stirred at room temperature overnight. The reaction solution was ice-cooled and an aqueous solution of 1 N lithium hydroxide (5 mL) was added and the mixture was stirred at room temperature for 1 hour, and then the reaction solution was re-cooled with ice and an aqueous solution of 1 N HCl (5 mL) was added. and the AcOEt and the organic layer and the aqueous layer were separated, the aqueous layer was re-extracted with AcOEt. The organic layers were combined and dried over MgSO ₄ , then filtered and concentrated. The residue was purified by silica gel column chromatography (AcOEt / MeOH - 10/1) to obtain 3,5-dimethyl-4-hydroxy-6- (5- (5-pyrimidinylmethoxy) benzofuran-2-yl) -2H-pyran- 2-on.

Yield: 35 mg (y. 36%) · 1 H NMR (δ ppm, DMSO-d 6): 1.95 (s, 3H), 2.29 (s, 3H) 5.24 (s, 2H), 7.12 to 7.14 (m, 1H),

7.33 to 7.38 (m, 2H), 7.61 to 7.63 (m, 1H), 8.95 (s, 2H), 9.18 (s, 1H), 10.91 (brs, IH)

The following compounds were prepared by the processes described in the foregoing Examples and Production Examples using organic and chemical techniques well known to those skilled in chemistry.

Example 28. Synthesis of 6- (benzofuran-2-yl) -3,5-dimethyl-4- (4-hydroxymethylbenzoyloxy) 2H-pyran-2-one

NMR (δ ppm, CDCl ₃ ): 2.04 (s, 3H), 2.34 (s, 3H), 4.86 (s, 2H), 7.24-7.42 (m, 3H), 53) d, J = 8.2Hz, IH), 7.58 (d, J = 8.3Hz, IH), 7.66 (d, J = 7.9Hz, IH), 8.22 ( d, J = 8.3 Hz, 1H)

Example 29. Synthesis of 6- (benzofuran-2-yl) -4- (2- (N-carbobenzyloxy-N-methylamino) acetyloxy) -3,5-dimethyl-2H-pyran-2-one ¹ HNMR (δpm, CDCl 3) ₃ ): 1.84, 2.00 (s, 3H), 2.14, 2.32 (s, 3H), 3.13, 3.14 (s, 3H), 4.33, 4.36 (s) s, 2H), 5.18, 5.20 (s, 2H), 7.25 to 7.43 (m, 8H), 7.53 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 6.9Hz, 1H)

Example 3 0. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (4-methoxybenzoyloxy) -2H-pyran-2-one 1 H NMR (δpm, CDCl ₃ ): 2.03 (s) 3H), 2.34 (s, 3H), 3.93 (s, 3H), 7.04 (d, J = 8.9 Hz, 2H), 7.24-7.42 (m, 3H) 7.52 (d, J = 8.2Hz, IH), 7.66 (d, J = 7.9Hz, IH), 8.17 (d, J = 9.2Hz, IH)

Example 31. 6- (Benzofuran-2-yl) -3,5-dimethyl, -4-phenylacetyloxy-2H-pyran-2-one 1 H NMR (δpm, CDCl ₃ ): 1.86 (s, 3H), 2.14 (s, 3H), 3.93 (s, 2H), 7.21-7.45 (m, 8H), 7.50 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.9Hz, 1H)

Example 32. 6- (Benzofuran-2-yl) -4-hydroxy-3-methyl-2H-pyran-2-one ¹ H NMR (δpm, DMSO-d 6): 1.85 (s, 3H), 6, 73 (s, 1H), 7.29-7.46 (m, 3H), 7.67 (d, J =

7.9 Hz, 1H), 7.73 (d, J = 7.3 Hz, 1H), 11.58 (brs, IH)

Example 33. 6- (Benzofuran-2-yl) -5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one 1 H NMR (δppm, DMSO-d 6): 1.18 (t, J = 7.3 Hz, 3H), 1.93 (s, 3H), 2.79 (q, J = 7.3 Hz, 2H), 7.29 to 7.44 (m, 3H), 7.67 (d, J = 8.3 Hz, IH), 7.74 (d, J = 8.3 Hz, IH), 10.89 (brs, IH)

Example 34. 6- (Benzofuran-2-yl) -4-hydroxy-5-isopropyl-3-methyl-2H-pyran-2-one ¹ H NMR (δpm, DMSO-d 6): 1.33 (d, J) 6.9 Hz, 6H), 1.93 (s, 3H), 3.40 to 3.56 (m, 1H), 7.29 to 7.46 (m, 3H), 7.67 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 10.85 (s, 1H)

Example 35. 6- (Benzofuran-2-yl) -4-hydroxy-3-methyl-5-phenyl-2H-pyran-2-one

'NMR (δρριη, DMSO-d6): 2.06 (s, 3H), 6.32 (s, 1H), 7.27-7.63 (m, 9H), 10.79 (brs,

IH)

Example 36. 6- (Benzoturan-2-yl) -5-benzyl-4-hydroxy-3-methyl-2H-pyran-2-one 1 H NMR (d 6 -DMSO, DMSO-d 6): 1.93 (s, 3H) 4.23 (s, 2H), 7.13-7.37 (m, 8H), 7.62 (d, J =

8.3 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 11.01 (brs, IH)

Example 3 7. 6- (Benzofuran-2-yl) -4-hydroxy-5-methoxy-3-methyl-2H-pyran-2-one 1 H NMR (d 6 -DMSO, DMSO-d 6): 1.92 (s, 3H) 3.82 (s, 3H), 7.32-7.51 (m, 3H), 7.72 (d, J =

7.9 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 11.40 (brs, IH)

Example 38. 6- (Benzofuran-2-yl) -4-hydroxy-3-isopropyl-5-methyl-2H-pyran-2-one 1 H NMR (d 6, DMSO-d 6): 1.22 (d, J = 6.9 Hz, 6H), 2.29 (s, 3H), 3.20-3.30 (m, 1H),

7.30 to 7.45 (m, 3H), 7.68 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 10.68 (s , IH)

Example 3 9. 6- (benzofuran-2-yl) -3,5-dimethyl-4-isobutyryloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 1.39 (d, J = 6) 9 Hz, 6H), 1.98 (s, 3H), 2.29 (s, 3H), 2.83-3.01 (m, 1H), 7.25-7.42 (m, 2H) 7.36 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 7.6 Hz, IH) Example 40. 4-Acetyloxy-3, 5-dimethyl-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.02 (s, 3H), 2.32 (s, 3H), 2.42 (s, 3H), 7.46 (s, 1H), 7.64 (d, J =

8.9 Hz, IH), 8.30 (dd, J = 2.3 Hz, 8.9 Hz, IH), 8.59 (d, J = 2.3 Hz, IH)

Example 41. 3,5-Dimethyl-4-methoxymethoxy-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.14 (s, 3H) 2.43 (s, 3H), 3.64 (s, 3H), 5.14 (s, 2H), 7.43 (s, 1H),

7.63 (d, J = 9.0 Hz, 1H), 8.30 (dd, J = 2.1 Hz, 9.0 Hz, IH), 8.58 (d, J = 2.1 Hz, IH)

Example 42. 6- (Benzofuran-2-yl) -3,5-dimethyl-4-phenoxyacetyloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 1.97 (s, 3H), 2 28 (s, 3H), 4.98 (s, 2H), 6.95 to 7.12 (m, 3H),

7.23 to 7.44 (m, 5H), 7.52 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H)

Example 43. 6- (Benzofuran-2-yl) -3,5-dimethyl-4-trifluoromethanesulfonyloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.23 (s, 3H), 2 50 (s, 3H), 7.28-7.46 (m, 3H), 7.55 (d, J = 8.2)

Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H)

Example 44. 6- (Benzofuran-2-yl) -3,5-dimethyl-4-paratoluenesulfonyloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 1.81 (s, 3H), 2 33 (s, 3H), 2.51 (s, 3H), 7.28-7.48 (m, 5H),

7.53 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, IH), 7.90 (d, J = 8.3 Hz, 2H)

Example 45. 3,5-Dimethyl-4-hydroxy-6- (5-nitrobenzofuran-2-yl) -2H-pyran-2-one 1 H NMR (d 6, CD 3 OD): 1.96 (s, 3H), 2.32 (s, 3H), 7.61 (s, 1H), 7.95 (d, J = 9.2 Hz,

IH), 8.30 (dd, J = 2.3Hz, 9.2Hz, IH), 8.71 (d, J = 2.3Hz, IH), 11.00 (brs, IH)

Example 46. 3,5-Dimethyl-6- (5- (ethylamino) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one 1 H NMR (CDCl 3): 1.42 (t, J = 7.3 Hz, 3 H), 2.04 (s, 3 H), 2.43 (s, 3 H), 3.44 (q, J =

7.3 Hz, 2H), 7.37 (s, 1H), 7.50 (dd, J = 2.0 Hz, 8.9 Hz, 1H), 7.68 (d, J = 8.9 Hz) , 1H), 7.79 (d,

J = 2.0 Hz, 1H)

Example 47. 3,5-Dimethyl-4-hydroxy-6- (5- (p-toluenesulfonylamino) benzofuran-2-yl) -2H-pyran-2-one 1 H NMR (CDCl 3, 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, 1H)

Example 48. 3,5-Dimethyl-6- (5- (dimethylamino) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one 1 H NMR (CDCl 3, CD 3 OD): 1.95 (s, 3H), 2.30 (s, 3H), 3.12 (s, 6H), 7.41-7.75 (m, 4H)

Example 49. 6- (5- (Dibenzylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one 1 H NMR (CDCl 3, 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), 7.13-7.88 (m, 1H)

Example 50. 6- (Benzofuran-2-yl) -3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.04 (s, 3H), 2 34 (s, 3H), 7.26-7.42 (m, 3H), 7.53 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.3 Hz, 1 H), 8.03, 8.95 (ABq, J = 6.3 Hz, 4H)

Example 51. 4- (2-Aminoacetylox) -6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one hydrochloride 1 H NMR (d 6, DMSO-d 6): 1.96 ( s, 3H), 2.27 (s, 3H), 4.41 (s, 2H), 7.31-7.50 (m, 2H), 7.55 (s, 1H), 7.71 (d) J = 8.3 Hz (1H), 7.78 (d, J = 7.9 Hz, 1H), 8.61 (brs, 3H)

Example 52. 6- (5-Benzyloxybenzofuran-2-yl) -4- (2- (t-butoxycarbonylamino) acetyloxy) -3,5-dimethyl-2H-pyran-2-one 1 H NMR (CDCl ₃ ) 1.48 (s, 9H), 2.00 (s, 3H), 2.30 (s, 3H), 4.23 (d, J = 5.9 Hz, 2H), 5.06-5, 14 (m, 1H), 5.11 (s, 2H), 7.06 (dd, J = 2.6 Hz, 8.9 Hz, 1H), 7.14 (d, J = 2.6 Hz, 1 H), 7.27 to 7.50 (m, 7H)

Example 53. 4- (2-Aminoacetyloxy) -6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one hydrochloride 1 H NMR (d 6 -DMSO, DMSO-d6): 1, 95 (s, 3H), 2.24 (s, 3H), 4.41 (s, 2H), 5.16 (s, 2H), 7.13 (d,

J = 9.2 Hz, 1H), 7.29 to 7.51 (m, 7H), 7.62 (d, J = 9.6 Hz, 1H), 8.57 (brs, 2H)

Example 54. 4- (4- (acetylamino) benzoyloxy-6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one) 1 H NMR (CDCl ₃ ): 2, O 2 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H), 5.12 (s, 2H), 7.06 (dd, J =

2.6 Hz, 8.9 Hz (1H), 7.15 (d, J = 2.6 Hz, 1H), 7.21 to 7.50 (m, 8H), 7.72 (d, J = 8.9 Hz, 1H), 8.18 (d, J = 8.9 Hz, 1H) • ·

Example 55. 6- (5-Benzyloxybenzofuran-2-yl) -3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.04 (s, 3H) 2.33 (s, 3H), 5.12 (s, 2H), 7.07 (dd, J = 2.6 Hz, 8.9 Hz, 1H), 7.16 (d, J = 2, 6 Hz, 1H), 7.31 to 7.60 (m, 8H), 8.48 (d, J = 7.9 Hz, 1H), 8.94 (brs, 1H), 9.43 (s, IH)

Example 56. 6- (5-Benzyloxybenzofuran-2-yl) -3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.03 (s, 3H) 2.32 (s, 3H), 5.12 (s, 2H), 7.07 (dd, J = 2.3 Hz, 8.9 Hz, 1H), 7.16 (d, J = 2, 3 Hz, 1H), 7.30 to 7.50 (m, 7H), 8.03 (d, J = 5.9 Hz, 2H), 8.94 (d, J =

5.9 Hz, 2H)

Example 57.6- (5-benzyloxybenzofuran-2-yl) -5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one 1 H NMR (d 6, DMSO-d 6): 1.17 (t, J = 7.3 Hz, 3H), 1.93 (s, 3H), 2.78 (q, J = 7.3 Hz,

2H), 5.14 (s, 2H), 7.07 (dd, J = 2.6 Hz, 8.9 Hz, 1H), 7.29 to 7.48 (m, 7H), 7.57 ( d, J = 9.2 Hz, 1H), 10.87 (brs, 1H)

Example 5 8. 5-Ethyl-4-hydroxy-3-methyl-6- (5- (3-pyrimidinylbenzyl) methoxy) benzofuran-2-yl) -2H-pyran-2-one 1 HNMR (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)

Example 59. 4-Acetyloxy-3,5-dimethyl-6- (5- (2-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one 1 H NMR (CDCl ₃ ): 2.13 (s, 3H), 2.34 (s, 3H), 2.41 (s, 3H), 5.30 (s, 2H), 7.09 (dd, J =

8.6 Hz, 2.4 Hz, 1H), 7.32 (s, IH), 7.36 (d, J = 1.9 Hz, IH), 7.47 (d, J = 1.9 Hz) (IH), 7.51 (d, J = 8.6Hz, IH), 7.86 (d, J = 2.4Hz, IH)

Example 60. 4-Hydroxy-3,5-dimethyl-6- (5- (2-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one 1 H NMR (CDCl 3, CD 3 OD): 1.98 ( s, 3H), 2.29 (s, 3H), 5.41 (s, 2H), 6.87 (dd, J = 8.9 Hz,

2.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, IH), 7.48 (d, J = 8.9 Hz, IH), 7.87 (d, J = 3, 2 Hz, 1H), 7.91 (d, J = 3.2 Hz, 1H), 9.40 (s, 1H)

Example 61. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (3-phenylpropionyloxy) -2H-pyran-2-one 1 H NMR (CDCl ₃ ): 1.86 (s, 3H), 2.16 (s, 3H), 2.94 to 3.18 (m, 4H), 7.20 to 7.41 (m, 8H), 7.52 (d, J = 7.9 Hz) , 1H), 7.64 (d, J = 7.6Hz, 1H)

Example 62. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (2-futroyloxy) -2H-pyran-2-one

1 HNMR (δpm, CDCl ₃ ): 2.04 (s, 3H), 2.35 (s, 3H), 6.67 (dd, J = 1.7 Hz, 3.6 Hz, 1H), 7, 25-7.42 (m, 2H), 7.38 (s, 1H), 7.50 (d, J = 3.6 Hz, 1H), 7.53 (d, J = 8.6 Hz, IH) 7.66 (d, J =

7.6 Hz, 1H), 7.76 (d, J = 1.7 Hz, 1H)

Example 63.6- (Benzofuran-2-yl) -3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one 1 H NMR (δpm, CDCl ₃ ): 2.05 (s, 3H), 2.36 (s, 3H), 7.26 to 7.43 (m, 3H), 7.50 to 7.60 (m, 2H), 7.67 (d, J = 7.6 Hz, 1H), 49 (d, J = 7.9Hz, 1H), 8.95 (d, J = 4.3Hz, IH), 9.44 (s, IH)

Example 64. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (2-acetylamino-4- (morpholin-4-yl) -4-oxobutyryloxy) -2H-pyran-2-one

1 H NMR (δ ppm, CDCl ₃ ): 2.01 (s, 3H), 2.05 (s, 3H), 2.33 (s, 3H), 3.00 (dd, J = 4.4 Hz, 16 8 Hz, 1H), 3.16 (dd, J = 7.6 Hz, 16.8 Hz, 1H), 3.60-3.73 (m, 8H), 5.37-5.44 (m 1 H, 6.44 (d, J = 9.3 Hz, 1H), 7.27-7.40 (m, 3H), 7.52 (d, J = 8.3 Hz, 1H), 7 , 65 (d, J = 7.3Hz, 1H)

Example 65.4-Acetyloxy-6- (5-bromobenzophthiran-2-yl) -3,5-dimethyl-2H-pyran-2-one 1 H NMR (δpm, CDCl ₃ ): 2.00 (s, 3H), 2 30 (s, 3H), 2.40 (s, 3H), 7.29 (s, 1H), 7.40 (d, J =

8.9 Hz, 1H), 7.47 (dd, J = 8.9 Hz, 2.2 Hz, IH), 7.78 (d, J = 2.2 Hz, IH)

Example 66. 6- (Benzofuran-2-yl) -5-cyclopentylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one 1 HNMR (δpm, DMSO-d 6): 1.16-1.27 ( m, 2H), 1.40-1.69 (m, 6H), 1.94 (s, 3H),

2.02 to 2.17 (m, 1H), 2.90 (d, J = 7.3 Hz, 2H), 7.29 to 7.44 (m, 3H), 7.65 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.3 Hz, 1H), 10.85 (s, 1H)

Example 67. 6- (Benzophthiran-2-yl) -4-hydroxy-3-methyl-5-phenoxy-2H-pyran-2-one 1 HNMR (δpm, DMSO-d 6): 2.03 (s, 3H) 7.11 to 7.22 (m, 3H), 7.32 to 7.49 (m, 5H),

7.69 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 7.6 Hz, IH), 11.56 (brs, IH)

Example 68. 6- (Benzofuran-2-yl) -5- (2-butenyl) -4-hydroxy-3-methyl-2H-pyran-2-one 1 HNMR (δpm, DMSO-d 6): 1.70-1 78 (m, 3H), 2.03 (s, 3H), 3.57-3.64 (m, 2H),

5.61 to 5.67 (m, 2H), 7.39 to 7.54 (m, 3H), 7.78 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 7.6 Hz, IH), 11.00 (brs, IH)

Example 69. 6- (Benzofuran-2-yl) -4- (1-carbobenzyloxy-2-pyrrolidon-5-ylcarboxy) -3,5-dimethyl-2H-pyran-2-one 1 H NMR (δpm, CDCl ₃₎ 1.94 (s, 3H), 2.25 (s, 3H), 2.30-2.40 (m, 1H), 2.51-2.88 (m, 3H), 5.03 (s) dd, J = 2.6 Hz, 8.9 Hz, 1H), 5.33, 5.38 (ABq, J = 2.2 Hz, 2H), 7.28 to 7.48 (m,

8H), 7.52 (d, J = 8.6Hz, 1H), 7.66 (d, J = 7.9Hz, IH)

Example 70. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (2-pyrrolidon-5-ylcarboxy) -2H-pyran-2-one

1 H NMR (δpm, DMSO-d 6): 1.91 (s, 3H), 2.23 (s, 3H), 2.19-2.38 (m, 3H), 2.47-2.66 (m (1H), 4.65-4.73 (m, 1H), 7.31-7.40 (m, 1H), 7.41-7.50 (m, 1H), 7.53 (s, 1H) 7.71 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H)

Example 71.6- (Benzofuran-2-yl) -4- (2- (t-butoxycarbonylamino) acetyloxy) -3,5-dimethyl-2H-pyran-2-one

NMR (δ ppm, CDCl ₃ ): 1.48 (s, 9H), 2.00 (s, 3H), 2.32 (s, 3H), 4.23 (d, J = 6.3 Hz, 2H) ,

5.10 (brs, 1H), 7.25 to 7.42 (m, 3H), 7.53 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.9 Hz) , ÍH)

Example 72. 6- (Benzofuran-2-yl) -4- (2,4-dimethoxybenzoyloxy) -3,5-dimethyl-2H-pyran-2-one

NMR (δ ppm, CDCl ₃ ): 2.05 (s, 3H), 2.35 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H), 6.54-6, 66 (m, 2H), 7.25-7.41 (m, 3H), 7.52 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H) 8.08 (d, J =

8.6 Hz, 1H)

Example 73. 6- (Benzofuran-2-yl) -4- (2,6-dimethoxybenzoyloxy) -3,5-dimethyl-2H-pyran-2-one 1 H NMR (δppm, CDCl ₃ ): 2.17 ( s, 3H), 2.48 (s, 3H), 3.91 (s, 6H), 6.65 (d, J = 8.3 Hz, 2H), 7.25-7.45 (m, 4H) 7.54 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H)

Example 74. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (6-hydroxy-nicotinoyloxy) -2H-pyran-2-one 1 H NMR (δppm, DMSO-d 6): 1.91 (s 3H), 2.24 (s, 3H), 6.48 (d, J = 9.9 Hz, 1H), 7.31-

7.50 (m, 2H), 7.54 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 9.9 Hz, 1H), 8.43 (s, 1H), 12.51 (brs, 1H)

Example 75. 6- (Benzofuran-2-yl) -3,5-dimethyl-4- (3-dimethylaminobenzoyloxy) -2H-pyran-2-one

1 H NMR (δppm, CDCl ₃ ): 2.04 (s, 3H), 2.35 (s, 3H), 3.05 (s, 6H), 7.04 (dd, J = 2.6 Hz, 8) 6 Hz, 1H), 7.25 to 7.44 (m, 4H), 7.48 to 7.59 (m, 3H), 7.66 (d, J = 7.6 Hz, 1H)

Example 76. 4- (4- (acetylamino) benzoyloxy) -6- (benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one 1 H NMR (δpm, CDCl ₃ ): 2.03 (s, 3H), 2.26 (s, 3H), 2.33 (s, 3H), 7.24-7.41 (m, 3H),

7.49 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8) (Hz, 2H), 8.18 (d, J = 8.6 Hz, 2H)

Example 77. 3,5-Dimethyl-6- (6- (2-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: ^[4- M + H] = 381.0

Example 78.3,5-Dimethyl-6- (5- (2-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ + H] = 381.0

Example 79. 6- (5- (4-Chlorobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + H] = 397.0

Example 80. 6- (6- (2-Bromobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 442.0

Example 81. 6- (5- (2-Bromo-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + H] = 442.0

Example 82. 6- (6- (3-Bromobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 442.0

Example 83.6- (5- (3-Bromobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 442.0

Example 84.3,5-Dimethyl-4-hydroxy-6- (6- (3,4- (methylenedioxy) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [MT + H] = 407.0

Example 85.3,5-Dimethyl-4-hydroxy-6- (5- (3,4- (methylenedioxy) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ * + H] = 407.0

Example 86. 3,5-Dimethyl-4-hydroxy-6- (6- (2-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 364.4

Example 87. 3,5-Dimethyl-4-hydroxy-6- (5- (2-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 364.0

Example 88.3,5-Dimethyl-4-hydroxy-6- (6- (3-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2H Mass Analysis: [M ⁺ + H] = 364.0 •

Example 89. 3,5-Dimethyl-4-hydroxy-6- (5- (3-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 364.0

Example 90. 3,5-Dimethyl-4-hydroxy-6- (6- (4-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 364.0

Example 91. 3,5-Dimethyl-4-hydroxy-6- (5- (4-pyridylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 364.0

Example 92.3,5-Dimethyl-4-hydroxy-6- (6- (tetrahydrofuran-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ * + H] = 357.0

Example 93. 3,5-Dimethyl-4-hydroxy-6- (5- (tetrahydrofuran-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 357.0

Example 94. 3,5-Dimethyl-4-hydroxy-6- (6- (1-methylpiperidin-2-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 384.0

Example 95.3,5-Dimethyl-4-hydroxy-6- (5- (1-methylpiperidin-2-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] - 384.0

Example 96. 3,5-Dimethyl-4-hydroxy-6- (6- (1-methylpiperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [α] + H] = 384.0

Example 97.3,5-Dimethyl-4-hydroxy-6- (5- (1-methylpiperidin-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [f] + H] = 384.0

Example 98. 3,5-Dimethyl-4-hydroxy-6- (6- (1-methyl-3-piperidyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 370.0

Example 99. 3,5-Dimethyl-4-hydroxy-6- (5- (1-methyl-3-piperidyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 370.0 • ·

Example 100. 3,5-Dimethyl-4-hydroxy-6- (6- (1-methyl-3-pyrrolidyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 356.0

Example 101.3,5-Dimethyl-4-hydroxy-6- (5- (1-methyl-3-pyrrolidyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 356.0

Example 102.3,5-Dimethyl-4-hydroxy-6- (6- (2-pyrrolidinylethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + H] = 370.0

Example 103. 3,5-Dimethyl-4-hydroxy-6- (5- (2-pyrrolidinylethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + H] = 370.0

Example 104. 6- (6- (4- (Diethylamino) -1-methylbutoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 414.0

Example 105.6- (5- (4- (Diethylamino) -1-methylbutoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 414.0

Example 106. 6- (6- (1,3-Bis (dimethylamino) -2-propoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 401.0

Example 107. 6- (5- (1,3-Bis (dimethylamino) -2-propoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 401.0

Example 108. 3,5-Dimethyl-4-hydroxy-6- (6- (2-pyrrolidon-5-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] - 370.0

Example 109. 3,5-Dimethyl-4-hydroxy-6- (5- (2-pyrrolidon-5-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 370.0

Example 110. 6- (6- (Chroman-4-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 405.0

Example 111. 6- (5- (Chroman-4-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [IsH + H] = 405.0

Example 112. 6- (6- (1- (n-butoxycarbonyl) ethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 401.0

Example 113. 6- (5- (1- (n-Butoxycarbonyl) ethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 401.0

Example 114. 3,5-Dimethyl-4-hydroxy-6- (6- (2- (morpholin-4-yl) ethoxy) benzofnran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ * + H] = 386.0

Example 115. 3,5-Dimethyl-4-hydroxy-6- (5- (2- (morpholin-4-yl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 386.0

Example 116. 6- (6- (4-Carboxybenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 407.0

Example 117. 6- (5- (4-Carboxybenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 407.0

Example 118. 6- (6- (4-Chlorobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 397.0

Example 119. 3,5-Dimethyl-4-hydroxy-6- (6- (2- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 431.0

Example 120. 3,5-Dimethyl-4-hydroxy-6- (5- (2- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 431.0

Example 121.3,5-Dimethyl-4-hydroxy-6- (6- (3- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + H] = 431.0 ··· · · · ················· ·· ·· ··

Example 122. 3,5-Dimethyl-4-hydroxy-6- (5- (3- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 431.0

Example 123. 3,5-Dimethyl-4-hydroxy-6- (6- (4- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 431.0

Example 124. 3,5-Dimethyl-4-hydroxy-6- (5- (4- (trifluoromethyl) benzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 431.0

Example 125. 6- (6-Cyclopentylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 355.0

Example 126. 6- (5- (Cyclopentylmethoxy, benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 355.0

Example 127. 6- (6- (Cyclopropylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁴ + H] - 327.0

Example 128. 6- (5- (Cyclopropylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ ⁴ + H] - 327.0

Example 129. 6- (6- (2,4-Dimethyl-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 391.0

Example 130. 6- (5- (2,4-Dimethyl-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 131. 6- (6- (2,5-Dimethyl-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 132. 6- (5- (2,5-Dimethyl-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 13 3. 6- (6- (3,4-Dimethylbenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + H] = 391.0

Example 134. 6- (5- (3,4-Dimethyl-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 135. 6- (6- (3,5-dimethylbenzyloxy) benzofuran-2-yl) 3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 136.6- (5- (3,5-Dimethyl-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 137. 3,5-Dimethyl-4-hydroxy-6- (6 - ((2-thienyl) methoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ ⁴ + H] = 369.0

Example 138. 3,5-Dimethyl-4-hydroxy-6- (5 - ((2-thienyl) methoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 369.0

Example 139.3,5-Dimethyl-6- (6 - ((2-furyl) methoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 353.0

Example 140. 3,5-Dimethyl-6- (5 - ((2-furyl) methoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 353.0

Example 141. 3,5-Dimethyl-4-hydroxy-6- (6- (2-phenoxyethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 392.0

Example 142.3,5-Dimethyl-4-hydroxy-6- (5- (2-phenoxyethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [α] + H] = 392.0

Example 143.3,5-Dimethyl-4-hydroxy-6- (6- (1-2- (trifluoromethyl) phenyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 445.0 · · · ··· · ············

Example 144. 3,5-Dimethyl-4-hydroxy-6- (5- (1- (2- (trifluoromethyl) phenyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 445.0

Example 145. 6- (6- (2-Chloro-5-nitrobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 442.0

Example 146. 6- (6- (3-Chloro-6-nitrobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 442.0

Example 147. 6- (5- (3-Chloro-6-nitrobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 442.0

Example 148. 6- (6- (2-Cyclohexylethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 383.0

Example 149. 6- (5- (2-Cyclohexylethoxy) benzofuran-2-yl) -5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] - 383.0

Example 150. 3,5-Dimethyl-4-hydroxy-6- (6- (1,4-pentadien-3-yloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 339.0

Example 151. 3,5-Dimethyl-4-hydroxy-6- (5- (1,4-pentadien-3-yloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 339.0

Example 152. 6- (6- (2,4-Dichloro-benzyloxy) -benzofuran-2-l) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 432.0

Example 153. 6- (5- (2,4-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 432.0

Example 154. 6- (6- (2,5-Dichloro-benzyloxy-benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] - 432.0 ··· ··············

Example 155. 6- (5- (2,5-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 432.0

Example 156. 6- (6- (2,6-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 432.0

Example 157. 6- (5- (2,6-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] - 432.0

Example 158. 6- (6- (3,4-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 432.0

Example 159. 6- (5- (3,4-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 432.0

Example 160. 6- (6- (3,5-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + H] = 432.0

Example 161. 6- (5- (3,5-Dichloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 432.0

Example 162. 6- (6- (4-n-Butoxybenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 435.0

Example 163.6- (5- (4-n-Butoxybenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 435.0

Example 164. 3,5-Dimethyl-4-hydroxy-6- (6- (3-methyl-2-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ * + H] = 422.0

Example 165. 3,5-Dimethyl-4-hydroxy-6- (5- (3-methyl-2-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 422.0% · · · · · O ··· ·· ··· ··· ·· ··

Example 166. 3,5-Dimethyl-6- (6- (2,3-methyl-4-methoxybenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 421.0

Example 167. 3,5-Dimethyl-6- (5- (2,3-dimethyl-4-methoxybenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 421.0

Example 168. 3,5-Dimethyl-6- (6- (3,5-dinitrobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 453.0

Example 169.3,5-Dimethyl-6- (5- (3,5-dinitrobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 453.0

Example 170.3,5-Dimethyl-4-hydroxy-6- (6- (1,2,3,4-tetrahydronaphthalen-1-yloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 403.0

Example 171. 3,5-Dimethyl-4-hydroxy-6- (5- (1,2,3,4-tetrahydronaphthalen-1-yloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 403.0

Example 172. 3,5-Dimethyl-4-hydroxy-6- (6- (1-naphthylmethoxy) benzofuran-2-yl-2H-pyran-2-one)

Mass analysis: [M + + H] = 413.0

Example 173.3,5-Dimethyl-4-hydroxy-6- (5- (1-naphthylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 413.0

Example 174. 3,5-Dimethyl-4-hydroxy-6- (6- (2-naphthylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 413.0

Example 175. 3,5-Dimethyl-4-hydroxy-6- (5- (2-naphthylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 413.0

Example 176. 6- (6- (1,4-Benzodioxan-2-ylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 421.0

Example 177. 6- (5- (1,4-Benzodioxan-2-ylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 421.0

Example 178. 3,5-Dimethyl-6- (6- (3-hexen-1-yloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 355.0

Example 179. 3,5-Dimethyl-6- (5- (3-hexen-1-yloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 355.0

Example 180. 6- (6- (2-Butin-1-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [α] + H] = 325.0

Example 181. 6- (5- (2-Butin-1-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 325.0

Example 182. 3,5-Dimethyl-6- (6- (2,2-dimethyl-1,3-dioxolan-4-ylmethoxy) benzofuran-2-yl) 4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 387.0

Example 183. 3,5-Dimethyl-6- (5- (2,2-dimethyl-1,3-dioxolan-4-ylmethoxybenzofuran-2-yl) 4-hydroxy-2H-pyran-2-one)

Mass analysis: [Μ * + H] = 387.0

Example 184. 3,5-Dimethyl-6- (6- (2-ethoxyethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 345.0

Example 185. 3,5-Dimethyl-6- (5- (2-ethoxyethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 345.0

Example 186. 3,5-Dimethyl-4-hydroxy-6- (6- (3-methyloxetan-3-ylmethoxy) benzofuran-2-yl) 2H-pyran-2-one

Mass analysis: [M + + H] = 357.0

Example 187. 3,5-Dimethyl-4-hydroxy-6- (5- (3-methyloxetan-3-ylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 357.0

Example 188. 3,5-Dimethyl-6- (6- (5-hexin-1-yloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 353.0

Example 189. 3,5-Dimethyl-6- (5- (5-hexin-1-yloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 353.0

Example 190. 3,5-Dimethyl-6- (6- (5-hexen-1-yloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 355.0

Example 191.3,5-Dimethyl-6- (5- (5-hexen-1-yloxy) bezophthiran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 355.0

Example 192. 3,5-Dimethyl-6- (6- (2,2-dimethylpropoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 343.0

Example 193. 3,5-Dimethyl-6- (5- (2,2-dimethyl-propoxy) -benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [NO + H] = 343.0

Example 194. 3,5-Dimethyl-6- (6- (2,2-diphenylethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 453.0

Example 195. 3,5-Dimethyl-6- (5- (2,2-diphenylethoxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 453.0

Example 196. 3,5-Dimethyl-4-hydroxy-6- (6- (2-phenyl-2-propoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 197.3,5-Dimethyl-4-hydroxy-6- (5- (2-phenyl-2-propoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 198. 3,5-Dimethyl-4-hydroxy-6- (6- (2- (1-naphthyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [α] + H] = 427.0

•9 • Φ

♦ ♦ 9 9 · · 9 9 9 9 9 9 ♦ ♦ 9 9 9 9 9 9 9 9 9 9 9 9 99 99

Example 199, 3,5-Dimethyl-4-hydroxy-6- (5- (2- (1-naphthyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ * + Η] = 427.0

Example 200. 6- (6- (Bis (4-methoxyphenyl) methoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 499.0

Example 201. 6- (5- (bis (4-methoxyphenyl) methoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 499.0

Example 202. 3,5-Dimethyl-4-hydroxy-6- (6- (3-phenylpropoxy) benzofnran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 203. 3,5-Dimethyl-4-hydroxy-6- (5- (3-phenylpropoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 391.0

Example 204. 3,5-Dimethyl-4-hydroxy-6- (6- (4-phenylbutoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [IVF + H] = 405.0

Example 205. 3,5-Dimethyl-4-hydroxy-6- (5- (4-phenylbutoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 405.0

Example 206. 6- (6- (Cyclohexylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 369.0

Example 207. 6- (5- (Cyclohexylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 369.0

Example 208. 6- (6- (3-Cyclohexylpropoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ ⁴ + H] - 397.0

Example 209. 6- (5- (3-Cyclohexylpropoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 397.0 • 44 · 4 · 4 · 4 · 4 · 4 · 4

Example 210. 6- (6- (3-Buten-1-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 327.0

Example 211. 6- (5- (3-Buten-1-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Μ * + H] = 327.0

Example 212. 6- (6- (2- (Benzyloxy) ethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + H] = 407.0

Example 213.6- (5- (2- (Benzyloxy) ethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 407.0

Example 214.3,5-Dimethyl-4-hydroxy-6- (6- (2-propyn-1-yloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 311.0

Example 215. 3,5-Dimethyl-4-hydroxy-6- (5- (2-propyn-1-yloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 311.0

Example 216. 3,5-Dimethyl-6- (6- (5- (ethoxycarbonyl) pentyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 415.0

Example 217. 3,5-Dimethyl-6- (5- (5- (ethoxycarbonyl) pentyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 415.0

Example 218. 3,5-Dimethyl-6- (6-ethoxy-benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one Mass analysis: [M + + H] = 301.0

Example 219. 3,5-Dimethyl-4-hydroxy-6- (6-isopropoxybenzofuran-2-yl) -2H-pyran-2-one Mass analysis: [MT + H] = 329.0

Example 220. 6- (5- (1- t -Butoxycarbonylpiperidin-2-ylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] - 470.0

Example 221.6- (5- (1-t-butoxycarbonylpiperidin-4-ylmethoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 470.0

Example 222. 6- (5- (1- t -Butoxycarbonylpiperidin-4-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 456.0

Example 223. 6- (5- (1- t -Butoxycarbonylpyrrolidin-3-yloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [Nf + H] = 442.0

Example 224. 6- (5- (4- (t-butoxycarbonylamino) butoxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 444.0

Example 225. 3,5-Dimethyl-6- (6- (3-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] - 381.0

Example 226. 3,5-Dimethyl-6- (5- (3-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 381.0

Example 227. 3,5-Dimethyl-6- (6- (4-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 381.0

Example 228. 3,5-Dimethyl-6- (5- (4-fluorobenzyloxy) benzofuran-2-yl) -4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] - 381.0

Example 229. 3,5-Dimethyl-4-hydroxy-6- (6- (2-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 408.0

Example 230. 3,5-Dimethyl-4-hydroxy-6- (5- (2-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 408.0

Example 231. 3,5-Dimethyl-4-hydroxy-6- (6- (3-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 408.0

Example 232. 3,5-Dimethyl-4-hydroxy-6- (5- (3-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ * + H] = 408.0

Example 233. 3,5-Dimethyl-4-hydroxy-6- (6- (4-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran * 2-one

Mass analysis: [Μ * + H] = 408.0

Example 234. 3,5-Dimethyl-4-hydroxy-6- (5- (4-nitrobenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 408.0

Example 235. 3,5-Dimethyl-4-hydroxy-6- (6- (3-methoxybenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 393.0

Example 236. 3,5-Dimethyl-4-hydroxy-6- (5- (3-methoxybenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 393.0

Example 237. 3,5-Dimethyl-4-hydroxy-6- (6- (4-methoxybenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 393.0

Example 238.3,5-Dimethyl-4-hydroxy-6- (5- (4-methoxybenzyloxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 393.0

Example 239. 6- (6- (2-Chloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 397.0

Example 240. 6- (5- (2-chlorobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 397.0

Example 241. 6- (6- (3-Chlorobenzyloxy) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 397.0

Example 242. 6- (5- (3-Chloro-benzyloxy) -benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M + + H] = 397.0

Example 243.3,5-Dimethyl-4-hydroxy-6- (5- (5-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

1 H NMR (δpm, DMSO-d 6): 1.93 (s, 3H), 2.28 (s, 3H), 5.44 (s, 2H), 7.08 (dd, J = 8.9 Hz)

2.7 Hz, 1H), 7.31 (s, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 8 , 02 (s, 1H), 9.11 (s, 1H)

Example 244. 4-Acetyloxy-6- (5- (2,4-dichloro-5-thiazolylmethoxy) benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one 1 H NMR (δpm, CDCl 3) ₃ ): 2.00 (s, 3H), 2.30 (s, 3H), 2.39 (s, 3H), 5.21 (s, 2H), 7.01 (dd, J = 8.9) Hz, 2.4 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.9 Hz,

ÍH)

Example 245. 3,5-Dimethyl-4-hydroxy-6- (5- (2- (morpholinesulfonyl) -5,4-thiazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one 1 H NMR (δpm, DMSO-d6): 1.94 (s, 3H), 2.29 (s, 3H), 3.15-3.18 (m, 4H), 3.64-3.67 (m, 4H), 5 53 (s, 2H), 7.12 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 7.34 (s, 1H), 7.39 (d, J = 2.7 Hz) (1H), 7.63 (d, J = 8.8 Hz, 1H), 8.26 (s, 1H)

Example 246. 3,5-Dimethyl-4-hydroxy-6- (5- (3-thienylmethoxy) benzofuran-2-yl) -2H-pyran-2-one 1 H NMR (δpm, CD 3 OD): 1.93 ( s, 3H), 2.33 (s, 3H), 5.13 (s, 2H), 7.02 (dd, J = 8.9 Hz,

2.7 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 7.20 (s, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7 39-7.45 (m, 3H)

Example 247. 3,5-Dimethyl-4-hydroxy-6- (5- (2- (morpholinesulfonyl) -5-thienylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

1 H NMR (δ ppm, CDCl ₃ ): 1.91 (s, 3H), 2.31 (s, 3H), 2.98-3.03 (m, 4H), 3.71-3.75 (m, 4H), 5.38 (s, 2H), 7.03 (dd, J = 8.9 Hz, 2.7 Hz, 1H), 7.19 (s, 1H), 7.27 to 7.29 ( m, 2H), 7.51 (d, J = 2.7Hz, 1H)

Example 248. 4-Acetyloxy-3,5-dimethyl-6- (5- (2- (morpholinesulfonyl) -5-thienylmethoxy) benzofuran-2-yl) -2H-pyran-2-one 1 H NMR (δpm, CDCl 3) ₃ ): 2.00 (s, 3H), 2.30 (s, 3H), 2.40 (s, 3H), 3.06 to 3.10 (m, 4H),

3.74 to 3.81 (m, 4H), 5.29 (s, 2H), 7.04 (dd, J = 9.2 Hz, 2.7 Hz, 1H), 7.15 (d, J) = 2.7 Hz, 1H), 7.31 (s, 1H), 7.43 to 7.47 (m, 2H)

Example 249. 3,5-Dimethyl-4-hydroxy-6- (5- (4-oxazolylmethoxy) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [Μ ⁴ + H] = 354.0

Example 250.6- (5- (N-Benzoyl-N-methylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 390.0

Example 251. 3,5-Dimethyl-4-hydroxy-6- (5- (N-methyl-N- (phenylacetyl) amino) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 404.5

Example 252. 3,5-Dimethyl-4-hydroxy-6- (5- (N-methyl-N- (2-thienylcarbonyl) amino) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M + + H] = 396.0

Example 253. 3,5-Dimethyl-4-hydroxy-6- (5- (N-methyl-N- (3-pyridylcarbonyl) amino) benzofuran-2-yl) -2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 391.0

Example 254. 3,5-Dimethyl-4-hydroxy-6- (5- (N-isobutyryl-N-methylamino) benzofuran-2-yl) -2H-pyran-2-one Mass analysis: [M ⁺ + H] = 356 , 0

Example 255. 6- (5- (N- (t-butoxycarbonyl) -N-methylamino) benzofuran-2-yl) -3,5-dimethyl-4

hydroxy-2H-pyran-2-one

Mass analysis: [M ⁺ + H] = 386.0

The following compounds were also formed by processes similar to those described in the previous examples and manufacturing examples using chemical organic procedures well known to those skilled in the art.

Example 256. 6- (5-Benzoylamino-benzofuran-2-yl) -4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one

Example 257. 4-Acetyloxy-3,5-dimethyl-6- (5-trifluoromethanesulfonyloxybenzofuran-2-yl) -2H-pyran-2-one

Example 258. 6- (4-Benzyloxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Example 259. 4-Acetyloxy-3,5-dimethyl-6- (5- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one

Example 260. 4-Acetyloxy-6- (4-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one

Example 261.4-Acetyloxy-3,5-dimethyl-6- (5-hydroxybenzofuran-2-yl) -2H-pyran-2-one

Example 262. 3,5-Dimethyl-4-hydroxy-6- (5-hydroxybenzofuran-2-yl) -2H-pyran-2-one

Example 263. 4-Acetyloxy-3,5-dimethyl-6- (5- (4-methoxybenzoyloxy) benzofuran-2-yl) -2H-pyran-2-one

Example 264. 4-Acetyloxy-6- (5-carboxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one

Example 265. 4-Acetyloxy-6- (4-acetyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one

Example 266. 4-Acetyloxy-3,5-dimethyl-6- (4-methoxybenzofuran-2-yl) -2H-pyran-2-one

Example 267. 3,5-Dimethyl-4-hydroxy-6- (4-methoxybenzofuran-2-yl) -2H-pyran-2-one Example 268. 4-Acetyloxy-3,5-dimethyl-6- (5- methoxybenzofuran-2-yl) -2H-pyran-2-one Example 269. 4-Acetyloxy-6- (5-acetyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one Example 270. 4 -Acetyloxy-6- (5-benzyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one Example 271. 6- (5-Benzyloxybenzofuran-2-yl) -3,5-dimethyl-4 -hydroxy-2H-pyran-2-one Example 272. 3,5-dimethyl-4-hydroxy-6- (6-hydroxyenzofuran-2-yl) -2H-pyran-2-one Example 273. 4-Acetyloxy-3 5-dimethyl-6-methoxybenzofuran-2-yl) -2H-pyran-2-one Example 274. 4-Acetyloxy-3,5-dimethyl-6- (5-toluenesulfonyloxybenzofuran-2-yl) -2H-pyran- 2-on

Example 275. 4-Acetyloxy-6- (6-acetyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one Example 276. 6- (6-Cyclohexyloxybenzofuran-2-yl) -3,5-dimethyl -4-Hydroxy-2H-pyran-2-one Example 277.3,5-dimethyl-4-hydroxy-6- (6-trifluoromethanesulfonyloxybenzofuran-2-yl) -2H

-pyran-2-one

Example 278. 4-Acetyloxy-3,5-dimethyl-6- (6- (2- (methoxycarbonyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Example 279.3,5-Dimethyl-4-hydroxy-6- (6- (2- (methoxycarbonyl) ethoxy) benzofuran-2-yl) -2H-pyran-2-one

Example 280. 4-Acetyloxy-6- (6- (2- (acetyloxy) ethoxy) benzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one

Example 281. 3,5-Dimethyl-4-hydroxy-6- (7-hydroxybenzofuran-2-yl) -2H-pyran-2-one Example 282. 4-Acetyloxy-3,5-dimethyl-6- (7- methoxybenzofuran-2-yl) -2H-pyran-2-one Example 283. 3,5-Dimethyl-4-hydroxy-6- (4-hydroxybenzofuran-2-yl) -2H-pyran-2-one Example 284. 4 -Acetyloxy-6- (7-acetyloxybenzzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one Example 285. 4-Acetyloxy-6- (7-benzyloxybenzofuran-2-yl) -3,5 -dimethyl-2H-pyran-2-one Example 286. 6- (7-Benzyloxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one Example 287. 4-Acetyloxy-6 - (Benzofuran-2-yl) -3-isopropyl-5-methyl-2H-pyran-2-one Example 288. 6- (4,6-Dimethoxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy -2H-pyran-2-one Example 289. 4-Acetyloxy-6- (4,6-dimethoxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one Example 290.3,5-dimethyl-4 -hydroxy-6- (5- (methoxycarbonyl) benzofuran-2-yl) -2H-pyran-2-one

Example 291. 3,5-Dimethyl-4-hydroxy-6- (6-methoxymethoxybenzofuran-2-yl) -2H-pyran-2

-he

Example 292. 4-Acetyloxy-3,5-dimethyl-6- (6-methoxymethoxy-benzofuran-2-yl) -2H-pyran-2-one

Example 293. 6- (5-Carboxybenzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one Example 294. 4-Acetyloxy-3,5-dimethyl-6- (5- (phenoxycarbonyl) benzofuran-2-yl) -2H-pyran * 2-one

Example 295. 4-Acetyloxy-3,5-dimethyl-6- (5- (phenylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one

Example 296. 4-Acetyloxy-6- (5-benzoyloxybenzofuran-2-yl) -3,5-dimethyl-2H-pyran-2-one Example 297. 6- (5- (N- (4-chlorophenylsulfonyl) -N) (methylamino) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Example 298. 3,5-Dimethyl-4-hydroxy-6- (5- (N-methyl-N-phenylsulfonyl) benzofuran-2-yl) -2H-pyran-2-one

Example 299. 3,5-Dimethyl-4-hydroxy-6- (5- (N-methyl-N-phenylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one

Example 300.6- (5- (Benzimidazolylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Example 301. 6- (5- (Benzothiazolylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Example 302. 3,5-Dimethyl-4-hydroxy-6- (5- (1,3,4-trihydroisoquinolin-2-ylcarbonyl) -benzofuran-2-yl) -2H-pyran-2-one

Example 303. 3,5-dimethyl-4-hydroxy-6- (5-morpholinylbenzofuran-2-yl) -2H-pyran-2-one Example 304. 3,5-dimethyl-4-hydroxy-6- (5- (5-Hydroxy-3-pyridylmethoxy) benzofuran-2-yl)

2H-pyran-2-one

Example 305. 3,5-Dimethyl-4-hydroxy-6- (5- (4- (sulfamoyl) phenylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one

Example 306. 3,5-Dimethyl-4-hydroxy-6- (5- (4-pyridylmethylcarbamoyl) benzofuran-2-yl) -2H-pyran-2-one

Example 307. 3,5-Dimethyl-4-hydroxy-6- (5- (4-piperidinyl) benzofuran-2-yl) -2H-pyran-2-one Example 308. 6- (5 - (N-Benzyl- N-methylcarbamoyl) benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one

Example 309. 3,5-Dimethyl-4-hydroxy-6- (5- (N-methyl-N- (4-pyridyl) carbamoyl) benzofuran).

2-yl) -2H-pyran-2-one

Example 310 Preparation of cells

Human hepatic HepG2 tumor cells were seeded into a 24-well plate (Costar No. 3524) at 4 x 10 ⁴ cells / well and 1 ml of medium (eRDF medium containing 10% cow's serum (Kyokutu Chemical Co.)) was used after 6 days cultivation with 5% CO ₂ at 37 ° C. After sludge removal, cells were freshly washed with 1 ml PBS (-) buffer solution (Takara Shuzo) and discarded. This procedure was repeated twice and then 1 ml of fresh medium (eRDF medium) was added.

Sample preparation

6- (Benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (Example 2) was dissolved in dimethylsulfoxide (DMSO) to prepare a 20 mM sample of the stock solution. The diluted solution was obtained by diluting a sample of the DMSO solution.

TG production

Cells prepared as above were added to the stock solution or its reconstituted solution at 5 μΐ per well and 10 μΐ of ¹⁴ C-acetic acid solution (Amersham Code No. CFA 13 diluted 4.4-fold with PBS ( buffer) and cultivation was performed for one day with 5% CO ₂ at 37 ° C.

Quantification of TG

After the cultivation was complete, the culture solution was removed and 1 ml of extraction solution (2: 1 n-hexane: isopropanol) added to extract the lipid components in the cells. After processing, the extract containing the obtained lipid components was air dried, the residue was redissolved at 20 μΐ and the 9: 1 mixture of n-hexane and ethyl acetate then the solution was subjected to thin layer chromatography with the solution of the above solution. After air drying, the components were stained with iodine vapor, the corresponding portions of kTG were excised, and the amount of TG biosynthesized by liquid scintillation counter was measured. The results are shown in Table 1. 6 (Benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one has been shown to exhibit triglyceride biosynthesis inhibitory activity.

Table 1

Sample concentration Inhibiting (Example 2) TG production activity 1μ 22% 10μ 70% 100μ 98%

Example 311

The inhibitory activity of TG production of the compounds of the invention was evaluated in the same manner as the above examples. Depending on the result of the evaluation, the compounds of the following example exhibiting IC50 values less than 10 μΜ, less than 30% inhibitory TG production activity at 1 μΜ or at least 50% inhibitory TG production activity at 10 μΜ: 1, 2, 3, 4, 5 , 9, 10.11, 12, 13, 19, 25, 26, 27, 28, 29, 30, 31, 33, 34, 36

39, 40, 42, 45, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 69, 70, 71, 72, 75, 76, 78, 85, 89, 97, 117, 120, 122, 134, 138, 153, 159, 163, 170, 215, 226, 228, 236, 242,243,244, 245, 246, 247,248, 249, 250, 251, 252, 255, 257.259, 260.265, 268, 270, 271, 274.285, 290.291, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309.

The following example compound numbers exhibituj IC ₅ to the measuring value of at least about 10 μΜ and less than 100 μΜ; at least 5% and less than 30% of inhibitory TG production activity at 1 μ 1; or at least 30% and less than 50% inhibiting TG production activity at μ koncentraci: 6, 7, 8, 14, 17, 18, 20, 22, 23, 24, 32, 35, 37, 38, 43, 46, 47 60, 67, 68, 74, 79, 81, 83, 87, 95, 107, 115, 124, 126, 144, 155, 157, 175, 177, 179, 181, 183, 185, 187, 191, 193 , 195, 197, 201, 203, 207, 213, 217, 220, 222, 224, 230, 240, 253, 254, 258, 261, 262, 263, 264, 266, 267, 269,272,273,275, 278,280, 281, 282 , 283.284, 286, 287, 292.295, 296.

Example 312. Drug Effect Assay

6- (benzofuran-2-yl) -3,5-dimethyl-4-hydroxy-2H-pyran-2-one (Example 2) was suspended in 0.5% carboxymethylcellulose aqueous solution of Na (carrier) to prepare 20 mg / ml and 60 mg / ml of the administered solution, and these were orally administered to 6 week old SD male rats at 5 ml / kg once daily continuously for 7 days. CE-2 by Nihon Crea Co. was used for rat food. and rats were allowed free access to the water and food. Rats were separated into a medium-managed group of 6 rats and drug-treated group of 6 rats for testing. At 4 hours after the last drug administration, rats were killed by ether anesthesia, blood was collected from the abdominal aorta and serum TG, total cholesterol (TC) and HDL levels were measured.

Triglyceride ΕΠ-HA Wako Test (Wako Junyaku Kogyo product) was used to measure TG, HA Wako Test / Cholesterol E-HA Wko Test (Wako Junyaku Kogyo product) was used to measure total cholesterol (TC) and HDL-Cholesterol Wako (Wako Junyaku Kogyo product) was used to measure HDL.

As shown in Table 2, the inventive groups of administered compounds had lower dose-dependent TG levels. Also, as shown in Table 3, TC and HDL levels increased in dose depend on the method. Increase in TC levels was generally expected to increase overall

HDL. No case of rat death or body weight gain was found during the administration period.

Table 2

Solution to be administered Serum TG (mg / dl) (denotes ± SE) No sample was administered Example 2 (100 mg / kg) Example 2 (300 mg / kg) 108.3 ± 8.9 94.8 ± 6.5 74.8 ± 10.7

Table 3

Solution to be administered Serum HDL-C (mg / dl) (denotes ± SE) No sample was administered 30.5 ± 1.7 Example 2 (100 mg / kg) 35.0 ± 3.1 Example 2 (300 mg / kg) 42.2 ± 3.8

The above data demonstrates that the compounds of the invention have TG-lowering and / or HDL-increasing effects and are therefore useful as blood truglyceride lowering agents, lipid metabolism synergists, arteriosclerosis prophylactic agents, or arteriosclerosis treatment agents.

Example 313

Tablets were prepared with each tablet having the following composition.

Active ingredients 200 pg

Lactose 180 mg

Potato starch 50 mg

Polyvinylpyrrolidone 10 mg

Magnesium stearate 5 mg

The active ingredients, lactose and potato starch were combined and wetted with a 20% ethanol solution of polyvinylpyrrolidone. The wetted mixture was passed through a 20 mesh screen, dried at 45 ° C and then passed through a 15 mesh screen. The granules obtained in this process were mixed with magnesium stearate and compressed into tablets.

Example 314

Hard gelatin capsules were prepared with each capsule containing the following composition.

Active ingredients 100 pg

Fine crystalline cellulose 195 mg

Amphoteric silicic acid 5 mg

The active ingredient, fine crystalline cellulose and uncompressed amphoteric silicone acid were thoroughly mixed and filled into a hard gelatin capsule.

Example 315

The active ingredient was dissolved in fractional coconut oil. This was heated and dissolved in a drug coating component having the following general formula and a soft capsule-making apparatus was used to prepare soft capsules by a conventional procedure, with 100 µg of active ingredient in each capsule.

The general formula of the substance to coat the drug is 5 parts by weight 0.08 parts by weight 14 parts by weight

The pharmaceutical agents of the present invention exhibit triglyceride biosynthesis which inhibits blood triglyceride lowering or blood HDL elevating effects and can also be used as therapeutic agents for hypertriglyceridemia, as lipid metabolism synergists or as prophylactic and / or therapeutic agents for arteriosclerosis.

Claims (32)

A benzofuryl-α-pyrone derivative which is represented by the following structural formula I wherein R ¹ represents hydrogen or an alkyl group having from 1 to 5 carbon atoms; wherein R ² represents hydrogen, -CO-R ⁵ (wherein R ⁵ represents hydrogen, alkyl having from 1 to 5 carbon atoms with preferred substituents, cycloalkyl having from 3 to 7 carbon atoms, aryl having from 6 to 5 carbon atoms) 10-carbon atoms or heterocycle) or -SO ₂ R ⁶ (wherein R ⁶ represents preferably a halogen-substituted alkyl group having from 1 to 5 carbon atoms or an aryl group having from 6 to 10 carbon atoms); R ³ represents hydrogen, alkyl having 1 to 5 carbon atoms, alkenyl group having 2 to 5 carbon atoms, alkynyl having 2 to 5 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms - alkyl having 1 to 5 carbon atoms, aryl having 6 to 10 carbon atoms, aralkyl having 7 to 20 carbon atoms, alkoxy having 1 to 5 carbon atoms up to 5 carbon atoms or an aryloxy group having from 6 to 10 carbon atoms; R ⁴ is a substituent at the C-4 position, C-5 position, C-6 position or C-7 position of the benzofuran ring and represents: R ^4a , which represents hydrogen, nitro, cyano, halogen, heterocycle, alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to 5 carbon atoms, aryl of 6 to 10 carbon atoms, A = CH (CH ₂ ) _n - (where A represents an alicyclic heterocycle, "=" represents a double bond and _n represents 0,1 or 2), A = CH (CH ₂ ) _m O- (where A represents an alicyclic heterocycle and _m represents 1, 2 or 3), -OR ⁷ (wherein R ⁷ represents hydrogen, a cycloalkyl group having from 3 to 7 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a heterocycle, preferably a halogen substituted alkylsulfonyl group having from 1 to 4 or arylsulfonyl having from 6 to 10 carbon atoms), -CO-R (wherein R represents hydrogen, an alkyl having from 1 to 4 carbon atoms, an aryl having from 6 to 10 carbon atoms, an arylalkyl group, having from 7 to 20 carbon atoms or heterocycle), - NR ⁹ R ¹⁰ (where R ⁹ and R ¹⁰ independently of one another represent hydrogen, alkyl having 1 to 4 carbon atoms, aralkyl having 7 to 20 carbon atoms, phenyl, heterocycle, -SO 2 -R ¹¹ (wherein R ¹¹ represents preferably halogen substituted an alkyl group having from 1 to 12 carbon atoms, a heterocycle-substituted alkyl group having from 1 to 6 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a heterocycle or an arylalkyl group having from 7 to 20 carbon atoms), or - CO-R ¹² (wherein R ¹² represents hydrogen, an alkyl group having from 1 to 12 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group having from 7 to 20 carbon atoms, a heterocycle, an alkoxy group having from 1 to 10 carbon atoms, a heterocycle substituted alkyl group having from 1 to 6 carbon atoms, an aryloxy group having from 6 to 10 carbon atoms, a heteroaryloxy or aralkyloxy group having from 7 to 20 carbon atoms), -CO -R (wherein R represents hydrogen, -OH, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, a heterocycle, an alkoxy group having from 1 to 4 carbon atoms, an aryloxy group having has from 6 to 10 carbon atoms or an aralkyloxy group having from 7 to 20 carbon atoms) or -CO-NR ¹⁴ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ independently represent hydrogen, an alkyl group having from 1 to 4 carbon atoms a cycloalkyl group having from 3 to 7 carbon atoms, an aryl group having from 6 to 10 carbon atoms, an aralkyl group having from 7 to 20 carbon atoms, a heterocycle or a heterocycle substituted alkyl group having from 1 to 4 carbon atoms); R ^4b , which represents a saturated or unsaturated alkoxy group having from 1 to 6 carbon atoms, preferably substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups having from 3 to 7 carbon atoms, phenyl, naphthyl, heterocycle, OR ¹⁶ ( wherein R ¹⁶ represents an alkyl group having from 1 to 4 carbon atoms, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), -O-CO-R ¹⁶ (wherein R ¹⁶ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, a phenyl group , naphthyl, benzyl or heterocycle), -NR R (wherein R and R independently represent hydrogen, alkyl of 1 to 4 carbon atoms, heterocycle, alkylsulfonyl of 1 to 4 carbon atoms, phenylsulfonyl, -SC > 2-Het (where Het represents a heterocycle), aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl or an alkyl group having from 1 to 4 carbon atoms subs substituted with 1 or 2 groups obtained from phenyl, heterocycles, phenoxy, O-Het (where Het represents a heterocycle) and hydroxyl, -NH-CO-R ¹⁹ (wherein R ¹⁹ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, phenyl, naphthyl, benzyl, heterocycle, alkoxy having from 1 to 4 carbon atoms or benzyloxy), -CO • · ^-R20 (wherein ^R20 represents hydrogen, a heterocycle, an alkoxy group having 1 to 4 carbon atoms, phenoxy, benzyloxy), or -OR ²¹ (wherein R ²¹ represents hydrogen or a heterocycle)) and -CO-NR ²² R ²³ ( wherein R ²² and R ²³ independently of one another represent hydrogen, alkyl having from 1 to 4 carbon atoms, benzyl or heterocycle); or R ^4c which represents an alkyl group having from 1 to 4 carbon atoms preferably substituted by 1 to 3 groups obtained from the group comprising halogens, cycloalkyl groups having from 3 to 7 carbon atoms, phenyl, naphthyl, heterocycles, -SH, -OR ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, naphthyl, benzyl or heterocycle), -O-CO-R ¹⁶ (wherein R ¹⁶ represents hydrogen, alkyl having 1 to 4 atoms) N, R (where R and R are each independently hydrogen, alkyl of 1 to 4 carbon atoms, heterocycle, alkylsulfonyl of 1 to 4 carbon atoms, phenylsulfonyl) , -SCh-Het (where Het represents a heterocycle), aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl or an alkyl group having from 1 to 4 carbon atoms substituted with 1 n or 2 groups derived from phenyl, heterocycles, phenoxy, O-Het (where Het represents a heterocycle) and hydroxyl, -NH-CO-R ¹⁹ (wherein R ¹⁹ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, a phenyl group, naphthyl, benzyl, heterocycle, alkoxy having 1 to 4 carbon atoms or benzyloxy), -CO-R ²⁰ (wherein R ²⁰ represents hydrogen, heterocycle, alkoxy having 1 to 4 carbon atoms, phenoxy, benzyloxy) or -OR (wherein R represents hydrogen or a heterocycle)) and -CO-NR R (wherein R and R independently represent hydrogen, alkyl having from 1 to 4 carbon atoms, benzyl or heterocycle); and the numbers in italics represent the position on the benzofuran ring; or a salt thereof. The benzofuryl-α-pyrone derivative according to claim 1, wherein R ¹ is hydrogen, methyl, ethyl or isopropyl; or a salt thereof. The benzofuryl-α-pyrone derivative according to claim 1, wherein R ¹ is methyl; or a salt thereof. • · A benzofuryl-α-pyrone derivative according to any one of claims 1 to 3, characterized in that R ⁵ is (1) an alkyl group having from 1 to 5 carbon atoms, preferably substituted by 1 to 4 substituents obtained from the group comprising halogens, OR ⁵ (wherein R ⁵ represents hydrogen, alkyl having 1 to 4 carbon atoms, aryl having 6 to 10 carbon atoms, aralkyl having 7 to 20 carbon atoms, or heterocycle), -O-CO- R ⁸ (wherein R ⁸ represents hydrogen, alkyl having 1 to 4 carbon atoms, aryl having 6 to 10 carbon atoms, aralkyl having 7 to 20 carbon atoms, or heterocycle), -NR ⁹ R ¹⁰ (wherein R ⁹ and R ¹⁰ independently of one another represent hydrogen, an alkyl group having from 1 to 4 carbon atoms, an aralkyl group having from 7 to 20 carbon atoms, a heterocycle, preferably a halogen substituted alkylsulfonyl group having from 1 to 4 carbon atoms or an arylsulfonyl group having from 6 to 10 carbon atoms), -NH-CO-R ²⁴ (wherein R ²⁴ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, an aryl group having from 6 to 10 carbon atoms, and an aralkyl group having from 7 to 10 carbon atoms) 20 carbon atoms, heterocycle, alkoxy having 1 to 4 carbon atoms or aralkyloxy having 7 to 20 carbon atoms), cycloalkyl having 3 to 7 carbon atoms, aryl having 6 to 10 carbon atoms , heterocycle and -CO-R ²⁵ (wherein R ²⁵ represents hydrogen, alkyl having from 1 to 4 carbon atoms, heterocycle, -OR (wherein R represents hydrogen, alkyl having from 1 to 4 carbon atoms), aryl, having from 6 to 10 carbon atoms, an aralkyl group having from 7 to 20 carbon atoms or a heterocycle) or NR ²⁶ R ²⁷ (wherein R ²⁶ and R ²⁷ independently represent hydrogen, an alkyl group having from 1 to 4 carbon atoms , an aralkyl group having from 7 to 20 carbon atoms or a heterocycle); (3) a cycloalkyl group having from 3 to 7 carbon atoms, (4) an aryl group having from 6 to 10 carbon atoms, or (5) a heterocycle; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 3, characterized in that R ⁵ is (1) an alkyl group having from 1 to 5 carbon atoms, preferably substituted with 1 to 3 substituents obtained from the group consisting of -OH, alkoxy having from 1 to 4 carbon atoms, phenoxy, benzyloxy, -O-CO-R (where R represents hydrogen, alkyl having from 1 to 4 carbon atoms, phenyl or heterocycle), NR R (where R and R) represent independently of one another hydrogen, alkyl having 1 to 4 carbon atoms, benzyl, heterocycle or preferably halogen substituted alkylsulfonyl having 1 to 4 carbon atoms), -NH-CO-R (wherein R represents hydrogen, alkyl, having from 1 to 4 carbon atoms, a heterocycle, an alkoxy group having from 1 to 4 carbon atoms or a benzyloxy group), an aryl group having from 6 to 10 carbon atoms, a heterocycle and -CO-R 6 (wherein R ³² represents hydrogen -OR ³² (wherein R ³² represents hydrogen, alkyl having 1 to 4 carbon atoms, benzyl or heterocycle), -NR ³³ R ³⁴ (wherein R ³³ and R ³⁴ independently of one another are hydrogen, methyl, ethyl, benzyl or heterocycle) or heterocycle), (2) cycloalkyl having from 3 to 7 carbon atoms, (3) an aryl group having from 6 to 10 carbon atoms, or (4) a heterocycle; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 3, characterized in that R ⁵ is (1) an alkyl group having from 1 to 5 carbon atoms, preferably substituted with 1 to 3 substituents selected from the group consisting of phenoxy, NRR (wherein R and R independently represent hydrogen, alkyl of 1 to 4 carbon atoms, benzyl, heterocycle or preferably halogen substituted alkylsulfonyl of 1 to 4 carbon atoms), -NH-CO-R ³¹ (wherein R ³¹ represents hydrogen, an alkyl group having from 1 to 4 carbon atoms, a heterocycle, an alkoxy group having from 1 to 4 carbon atoms, or Benzyloxy), phenyl, and -CO-R (wherein R represents -OH, an alkoxy group having from 1 to 4 carbon atoms, benzyloxy, NR ³³ R ³⁴ (wherein R ³³ and R ³⁴ independently of one another represent hydrogen, methyl, ethyl, benzyl or heterocycle) or heterocycle), (2) an aryl group having from 6 to 10 carbon atoms, or (3) a heterocycle; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 3, characterized in that R ⁵ is (1) an alkyl group having from 1 to 5 carbon atoms, preferably substituted by 1 to 2 substituents selected from the group consisting of phenoxy, NR R (where R and R represent OO independently of each other hydrogen or methyl), -NH-CO-R (wherein R represents hydrogen, methyl, heterocycle, t-butoxy or benzyloxy), phenyl and -CO-R ³⁹ ( wherein R ³⁹ represents a heterocycle), (2) a phenyl group, or (3) a heterocycle; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 7, wherein R is hydrogen or -CO-R; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 3, wherein R ² is hydrogen, acetyl, isobutyryl, benzoyl, 4-methoxybenzoyl, 2,4-dimethoxybenzoyl, 4-hydroxymethylbenzoyl, 3-dimethylaminobenzoyl, 4. -acetylaminobenzoyl, phenylacetyl, 3-phenylpropionyl, phenoxyacetyl, furan-2-carbonyl, pyridine-4-carbonyl, pyridine-3-carbonyl, pyridine-2-carbonyl, 6-hydroxypyridine-3-carbonyl, 2-aminoacetyl, 2- ( t-butoxycarbonylamino) acetyl, 2- (N-carbobenzyloxy-N-methylamino) acetyl, 1-carbobenzyloxy-2-pyrrolidine-5-carbonyl, 2-pyrrolidine-5-carbonyl, 3-acetylamino-4-morpholinyl-4-oxobutyryl , trifluoromethanesulfonyl or methanesulfonyl; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 3, wherein R ² is hydrogen or acetyl; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 10, characterized in that R ³ is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkenyl group having from 2 to 5 carbon atoms, an alkynyl group having has from 2 to 5 carbon atoms, a 2-cycloalkylmethyl group having from 4 to 8 carbon atoms, a cycloalkylethyl group having from 5 to 9 carbon atoms, a phenyl group, a benzyl group, a phenethyl group, a methoxy group or a phenoxy group; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 10, wherein R ³ is hydrogen, an alkyl group having from 1 to 5 carbon atoms, an alkenyl group having from 2 to 4 carbon atoms, a cycloalkylmethyl group having has from 6 to 7 carbon atoms, 2cycloalkylethyl having from 7 to 8 carbon atoms, phenyl, benzyl, methoxy or phenoxy; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 10, characterized in that R ³ is an alkyl group having from 1 to 5 carbon atoms; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 10, wherein R ³ is methyl or ethyl; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 14, characterized in that R ^4c is an alkyl group having from 1 to 3 carbon atoms, preferably substituted by 1 to 3 substituents derived from the group consisting of heterocycles, -SH, - OH, alkoxy groups having from 1 to 4 carbon atoms, -NR ⁴⁰ R ⁴¹ (wherein R ⁴⁰ and R ⁴¹ independently represent hydrogen, an alkyl group having from 1 to 4 carbon atoms, preferably a halogen substituted alkylsulfonyl group having from 1 to 4 carbon atoms; 1 to 4 carbon atoms or an alkyl group having from 1 to 2 carbon atoms substituted with 1 to 2 substituents derived from phenyl, heterocycles, phenoxy, -O-Het (where Het represents a heterocycle) and hydroxyl), -NH-CO-R ⁴² (wherein R ⁴² represents hydrogen, phenyl, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 atoms -CO-R ⁴³ (wherein R ⁴³ represents hydrogen, a heterocycle, an alkoxy group having from 1 to 4 carbon atoms, or -OR ^{19 * 21} (wherein R ²¹ represents hydrogen or a heterocycle)) and -CO-NR ⁴⁴ R ⁴⁵ (wherein R ⁴⁴ and R ⁴⁵ independently of each other represent hydrogen, alkyl having 1 to 4 carbon atoms, or heterocycle); or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 14, characterized in that R ^4c is an alkyl group having from 1 to 3 carbon atoms, preferably substituted by a heterocycle, -SH, benzylamino, acylamino having from 1 to 3 carbon atoms. Or -NR ⁴⁰ R ⁴¹ (wherein R ⁴⁰ and R ⁴¹ independently represent hydrogen, an alkyl group having from 1 to 4 carbon atoms, preferably a halogen substituted alkylsulfonyl group having from 1 to 4 carbon atoms, or an alkyl group having has from 1 to 2 carbon atoms, substituted with 1 to 2 substituents derived from phenyl, heterocycles, phenoxy, -O-Het (where Het represents a heterocycle) and hydroxyl); or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 14, wherein R ^4c is (3,5-dioxo-2,4-thiazolidinyl) methyl, (3,5-dioxo-2,4-oxazolidinyl). methyl, (2,5-dioxoimidazolidin-4-yl) methyl or (5-oxo-3-thioxo-2,4-thiazolidinyl) methyl; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 14, wherein R ^4c is (3,5-dioxo-2,4-thiazolidinyl) methyl; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 18, characterized in that R ^4b is an alkoxy group having from 1 to 6 carbon atoms, preferably substituted by 1 to 3 substituents selected from the group consisting of halogens, cycloalkyl groups having from 3 to 7 carbon atoms, phenyl, naphthyl, heterocycles, acyloxy groups having from 1 to 4 carbon atoms, -CHO, -CO ₂ H, alkoxycarbonyl groups having from 2 to 5 carbon atoms, -OR ⁴⁶ (wherein R ⁴⁶ represents hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, benzyl or heterocycle) and -NR ⁴⁷ R ⁴⁸ (wherein R ⁴⁷ and R ⁴⁸ independently represent hydrogen, alkyl having 1 to 4 carbon atoms, alkoxycarbonyl having has from 2 to 5 carbon atoms, heterocycle, alkylsulfonyl having from 1 to 4 carbon atoms, phenylsulfonyl, -SO ₂ -Het (where Het represents heterocycle), aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, acyl 1 to 5 carbon atoms, benzoyl, -CO-Het (where Het represents a heterocycle), benzyloxycarbonyl or alkyl having from 1 to 4 carbon atoms, substituted with 1 to 2 groups obtained from a female 1u, haterocycles, phenoxy, -O-Het (where Het represents a heterocycle) and hydroxyl) or an unsaturated alkoxy group having from 3 to 6 carbon atoms; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 18 wherein R ^4b is methoxy, 2-propynyloxy, 2,2-dimethylpropoxy, cyclopentylmethoxy, 2-bromoethoxy, benzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl) benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy) benzyloxy, carboxybenzyloxy, (methoxycarbonyl) benzyloxy, n-butoxybenzyloxy, aminobenzyloxy, (t-butoxycarbonylamino) benzyloxy, 3-methoxypropoxy), 3-phenylpropoxy) 1-phenylethoxy and naphthylmethoxy, thienylmethoxy, 2- (morpholinesulfonyl) thienylmethoxy, pyridylmethoxy, (2-methoxypyridyl) methoxy, 2- (pyridyl) ethoxy, pyrazinylmethoxy, pyrimidinylmethoxy, oxazolylmethoxy, 4'-phenyloxazolylmethoxy, imidazolylmethoxy, 3-imazolazolylmethoxy, 3-imazolazolylmethoxy , thiazolylmethoxy, 4-methylthiazolylmethoxy, 2- (morpholinesulfonyl) thiazolylmethoxy, 2,4-dichlorothiazolylmethoxy, 2- (5-thiazolyl) ethoxy, 2- (4-methyl-5-thiazolyl) ethoxy, (3,5-dioxo 2,4) -thiazoli dinyl) methoxy, N-methylpiperidylmethoxy, (4-oxachroman-2-yl) methoxy, (3,3-dimethyl-2,4-dioxolanyl) methoxy, methoxymethyl, 2- (acetyloxy) ethoxy, bis (dimethylaminomethyl) methoxy, 4 - (t-butoxycarbonylamino) butoxy, ethoxycarbonylmethoxy, 2- (methoxycarbonyl) ethoxy, 5- (ethoxycarbonyl) pentyloxy or 2- (benzyloxy) ethoxy; or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 18, wherein R ^4b is methoxy, 2-propynyloxy, benzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl) benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy) benzyloxy, carboxybenzyloxy, (methoxycarbonyl) benzyloxy, n-butoxybenzyloxy, aminobenzyloxy, (t-butoxycarbonylamino) benzyloxy, thienylmethoxy, 2- (morpholinesulfonyl) thienylmethoxy, pyridylmethoxy, (2-methoxypyridyl) methoxy, 2- (pyridylmethoxy) methoxy, 2- (pyridyl) methoxy pyrimidinylmethoxy, oxazolylmethoxy, 4-phenyloxazolylmethoxy, imidazolylmethoxy, 399 -tosyl-5-methylimidazolylmethoxy, thiazolylmethoxy, 4-methylthiazolylmethoxy, 2 (morpholinesulfonyl) thiazolylmethoxy, 2,4-dichlorothiazolylmethoxy, 2- (5-thiazolyl) ethoxy, 2- (4-methyl-5-thiazolyl) ethoxy, (3, 5-dioxo-2,4-thiazolidinyl) methoxy, N-methylpiperidylmethoxy or methoxymethyl; or a salt thereof. A compound according to any one of claims 1 to 21, characterized in that R ^4a is hydrogen, nitro, cyano, halogen, heterocycle, A = CH (CH 2) _n (wherein A represents an alicyclic heterocycle, "= “Represents a double bond and n represents 0, 1 or 2), A = CH (CH2) _m O- (where A represents an alicyclic heterocycle and _m represents 1, 2 or 3), A-SO2- (CH2) m- (where A represents alicyclic heterocycle and m represents 1, 2 or 3), -OR ⁴⁹ (wherein R ⁴⁹ represents hydrogen, heterocycle, preferably halogen substituted alkylsulfonyl having from 1 to 4 carbon atoms or phenylsulfonyl), -O-CO-R ⁵⁰ (where R ⁵⁰ represents hydrogen, alkyl having 1 to 4 carbon atoms or phenyl), -NR R (wherein R and R independently represent hydrogen, alkyl having 1 to 4 carbon atoms, phenyl, benzyl, -SO 2 - R ⁵³ (wherein R ⁵³ represents phenyl, naphthyl, heterocycle or alkyl having from 1 to 3 carbon atoms, preferably substituted with 1 to 3 substituents derived from the group consisting of halogen atoms, heterocycles and phenyl) or -CO-R ⁵⁴ (wherein R ⁵⁴ represents hydrogen, phenyl, neftyl, heterocycle, alkoxy having from 1 to 4 carbon atoms, phenoxy, neftyloxy) , heteroaryloxy, aralkyloxy having from 7 to 11 carbon atoms or alkyl having from 1 to 3 carbon atoms, preferably substituted by phenyl or heterocycle)), -CO-R ⁵⁵ (wherein R ⁵⁵ represents hydrogen, -OH, heterocycle, alkoxy having from 1 to 4 carbon atoms or phenoxy) or -CO-NR ⁵⁶ R ⁵⁷ (wherein R ⁵⁶ and R ⁵⁷ independently represent hydrogen, an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group having from (3 to 7 carbon atoms, phenyl, benzyl, phenethyl, heterocycle or heterocycle substituted alkyl having from 1 to 4 carbon atoms); or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 21 wherein R ^4a is hydrogen, nitro, cyano, halogen, heterocycle, A = CH (CH 2) _n (wherein A represents an alicyclic heterocycle, "= “Represents a double bond and represents 0, 1 or 2), A = CH (CH2) _m O- (where A represents an alicyclic heterocycle and _m represents 1, 2 or 3), A-SO2- (CH2) _m - (where A represents alicyclic heterocycle and am CO 2 represents 1,2 or 3), -OR (wherein R represents hydrogen, preferably halogen 100 substituted alkylsulfonyl groups having from 1 to 4 carbon atoms or phenylsulfonyl), -O-CO-R ⁵⁹ (wherein R ⁵⁹ represents an alkyl group having from 1 to 4 carbon atoms or phenyl), -NR ⁶⁰ R ⁶¹ (wherein R ⁶⁰ and R ⁶¹ independently represent hydrogen, alkyl having from 1 to 4 carbon atoms, phenyl, benzyl, -SO ₂ -R ⁶² (wherein R ⁶² represents preferably a halogen substituted alkyl having from 1 to 3 carbon atoms, a heterocyclic-substituted alkyl group having from 1 to 3 carbon atoms, a phenyl group, a heterocycle, a benzyl group or a phenethyl group) or -CO-R (wherein R represents an alkyl group having from 1 to 4 carbon atoms, a phenyl group, an aralkyl group having from 7 to 9) carbon atoms, heterocycle, alkoxy having 1 to 4 carbon atoms, heterocyclic-substituted alkyl having 1 to 3 carbon atoms, phenoxy, heteroaryl or benzyloxy)), -CO-R ⁶⁴ (where R ⁶⁴ represents hydrogen, - OH neb o alkoxy having from 1 to 4 carbon atoms) or -CO-NR ⁶⁵ R ⁶⁶ (wherein R ⁶⁵ and R ⁶⁶ independently represent hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl having from 3 up to 7 carbon atoms, phenyl, benzyl, phenethyl, heterocycle or heterocycle substituted alkyl having from 1 to 4 carbon atoms); or a salt thereof. A benzofuryl-α-pyrone derivative according to any one of claims 1 to 21 wherein R ^4a is hydrogen, nitro, cyano, bromine, thiazole, furyl, thienyl, morpholinyl, piperazinyl, hydroxyl, methanesulfonyloxy, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy , benzoyloxy, dimethylamino, dibenzylamino, phenylsulfonylamino, dimethylcarbamoyl, N-methyl-N-phenylcarbamoyl, N-benzyl-N-methylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, imidazolylcarbamoyl, benzimidazolylcarbamoyl, thiazolylcarbamoyl, benzothiazolylkarbamoyl, isothiazolylkarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylkarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl , pyrazinylcarbamoyl, isoxazolylcarbamoyl, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, acetyl, benzoyl, 1,3,4-trihydroisoquinolin-2-ylcarbonyl, (3,5-dioxo-2,4- thiazolidinylidene) methyl, (3,5-dioxo-2,4-oxazolidinylidene) methyl, (2,5-dioxoimidazolidin-4-ylidene) methyl 1,1 (5-oxo-3-thioxo-2,4-thiazolidinylidene) methyl, ((3,5-dioxo-2,4-thiazolidinylidinyl) sulfonyl) methyl, ((3,5-dioxo-2,4-oxazolidinylidinyl) sulfonyl) methyl, ((2,5-dioxoimidazolidin-4-ylidinyl) sulfonyl) methyl, ((5-oxo-3-thioxo-2,4-thiazolidinylidinyl) sulfonyl) methyl or -NR ⁶⁷ -CO-R ⁶⁸ ( wherein R ⁶⁷ n represents an alkyl group having from 1 to 4 carbon atoms and R represents an alkyl group having from 1 to 3 carbon atoms, a phenyl group, a heterocycle, an aralkyl group having from 7 101 • · 4 · 4 · 4 · 4 · 4 · 4 · 9 9 9 9 9 9 4 9 9 4 4 4 4 9 9 9 9 9 9 4 9 9 9 4 949 99 994 444 49 up to 9 carbon atoms or alkoxy having from 1 to 4 carbon atoms); or a salt thereof. The benzofuryl-α-pyrone derivative according to any one of claims 1 to 21, wherein R ^4a is hydrogen, nitro, cyano, bromine, thienyl, morpholinyl, piperazinyl, hydroxyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, dimethylamino, dibenzylamino, thiazolylcarbamoyl, isopropoxycarbonyl, (3,5-dioxo-2,4-thiazolidinylidene) methyl or -N (Me) -CO-R ⁶⁹ , wherein R ⁶⁹ represents an alkyl group having from 1 to 3 carbon atoms, a phenyl group, a heterocycle, a benzyl group or an alkoxy group having from 1 to 4 carbon atoms; or a salt thereof. A therapeutically effective dose of a benzofuryl-α-pyrone derivative, a salt thereof, and a pharmaceutically acceptable carrier comprising the pharmaceutical composition of any one of claims 1 to 25. An active ingredient of a benzofuryl-α-pyrone derivative or a salt thereof comprising a lipid metabolism synergist according to any one of claims 1 to 25. An active ingredient of a benzofuryl-α-pyrone derivative or a salt thereof comprising a triglyceride biosynthesis inhibitor according to any one of claims 1 to 25. An active ingredient of a benzofuryl-α-pyrone derivative or salt thereof comprising a blood triglyceride reducing agent according to any one of claims 1 to 25. An active ingredient of a benzofuryl-α-pyrone derivative or salt thereof comprising a blood HDL-increasing agent according to any one of claims 1 to 25. An active ingredient of a benzofuryl-α-pyrone derivative or a salt thereof comprising a prophylactic arteriosclerosis agent according to any one of claims 1 to 25. An active ingredient of a benzofuryl-α-pyrone derivative or salt thereof comprising an arteriosclerosis treating agent according to any one of claims 1 to 25.