KR20010010728A - 2,2-Dialkyl-4,5-diaryl-3(2H)furanone derivatives as cyclooxygenase-2 inhibitor - Google Patents

Abstract

PURPOSE: Provided are 2,2-dialkyl-4,5-diaryl-3(2H)-furanone derivatives represented by formula (I), a pharmaceutically acceptable salt thereof and cyclooxygenase-2 (COX-2) inhibitor composition comprising an effective amount of the derivatives. The compounds of formula (I) is useful in treating COX-2 mediated disease by effectively inhibiting biosynthesis of a prostaglandin and by improving the selectivity to COX-2. CONSTITUTION: 2,2-dialkyl-4,5-diaryl-3(2H)-furanone derivatives as COX-2 are represented by formula (I), wherein A is CH3S, CH3SO or CH3SO2; B and C, which may be the same or different, is methyl or ethyl (in case of B is methyl, then C is not methyl group), or cyclohexylidene or cyclopentylidene group formed together with each other; D is benzo£b|thienyl, 1-naphtyl, 2-naphtyl, benzofuranyl, furanyl or a substituent having following structural formula, wherein R1-5, which may be the same or different, are hydrogen, halogen, C1-C5 lower alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, nitro, nitrile, azido, methylenedioxy, phenyl, C1-C5 lower alkylthio, C1-C5 lower alkyl sulfonyl, COR6 or NR7R8, wherein R6 is hydrogen or C1-C5 lower alkyl and R7-8, which may be the same or different, are hydrogen, methyl, ethyl or acetyl group.

Description

Derivatives of 2,2-dialkyl-4,5-diaryl-3 (2H) furanone and cyclooxygenase-2 inhibitor compositions containing same {2,2-Dialkyl-4,5-diaryl-3 (2H furanone derivatives as cyclooxygenase-2 inhibitor}

The present invention is 2,2-dialkyl-4,5-diaryl-3 (2H) furanone (2,2-Dialkyl-4,5-diaryl-3 (2H)-represented by the following general formula (I) furanone) derivatives and pharmaceutically acceptable salts thereof, and cyclooxygenase-2 inhibitor compositions containing them in effective amounts.

(Ⅰ)

In the above formula,

A is CH ₃ S, CH ₃ SO or CH ₃ SO ₂ ,

B and C are the same as or different from each other, and are a methyl or ethyl group (but, when B is a methyl group, C is not a methyl group) or a cyclohexylidene or cyclopentylidene group formed by bonding to each other,

D is benzo [b] thienyl, 1-naphthyl, 2-naphthyl, benzofuranyl, furanyl or a substituent having the following structural formula.

Wherein R ¹ to ⁵ are the same or different, hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, nitro, nitrile, azido, methylenedi Oxy, phenyl, lower alkyl thio having 1 to 5 carbon atoms, lower alkyl sulfonyl having 1 to 5 carbon atoms, COR ⁶ or NR ⁷ R ⁸ .

Wherein R ⁶ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms,

R ^7-8 are the same or different from each other and are a hydrogen, methyl, ethyl or acetyl group.

In the above formula,

R ⁹ is hydrogen, acetyl, 1,3-dioxanyl 2-yl, formyl or methyl group.

In the above formula,

R ¹⁰ is hydrogen, methyl or methoxy group.

In the above formula,

R ¹¹ is a hydrogen, methyl, trityl or isopropyl group, provided that both B and C are methyl groups in this case.

Non-steroidal antiinflammatory drugs (SASAs), represented by aspirin, have anti-inflammatory analgesic effects by inhibiting the activity of cyclooxygenase (hereinafter, abbreviated as 'COX'), a prostaglandin biosynthetic enzyme that is evenly distributed throughout the body. (Annu. Rev. Pharmacol. Toxicol. 38, 97 (1998)). These COXs have recently been shown to have two kinds of isoenzymes in vivo (Cell, 83, 345, (1995)). COX-1 and COX-2 have been shown to increase intracellular expression by mitogen or cytokines during inflammation or other immune responses (J. Biol. Chem., 271, 33157 ( 1996). NSAIDs are known to have anti-inflammatory analgesic effects by inhibiting COX-2 enzymes, but they also inhibit COX-1 enzymes unnecessarily, causing side effects such as gastrointestinal bleeding and kidney toxicity (Proc. Natl. Acad. Sci). USA, 91, 3228 (1994); Proc. Natl. Acad. Sci. USA, 91, 12013 (1994)).

Accordingly, studies on substances capable of selectively inhibiting COX-2 have been actively conducted, and examples thereof include WO 9606840; Bioorg. Med. Chem. Lett., 5, 2377 (1995); Ann. Report. Med. Many documents, such as Chem., 211 (1997), disclose COX-2 inhibitors having a heterocyclic compound as a basis.

However, the present inventors have studied to provide a compound which can selectively inhibit the action of COX-2 as a new compound that is not structurally similar to these known compounds. As a result, 2,2-dialkyl-4 It has been found that, 5-diaryl-3 (2H) furanone derivatives have strong COX-2 inhibitory power and selectivity, particularly as the alkyl substituent at position 2 of diaryl-3 (2H) furanone changes The present invention was completed by discovering that diaryl-3 (2H) furanone derivatives inhibited COX-2 while decreasing their inhibitory effect on COX-1, thereby increasing selectivity.

It is therefore an object of the present invention to provide 2,2-dialkyl-4,5-diaryl-3 (2H) furanone derivatives represented by the general formula (I) and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a cyclooxygenase-2 inhibitor composition containing an effective amount of the compound of formula (I) and a pharmaceutically acceptable salt thereof.

Other objects, features and applications of the present invention will become apparent to those skilled in the art by the following detailed description.

Hereinafter, the present invention will be described in detail.

The 2,2-dialkyl-4,5-diaryl-3 (2H) furanone and pharmaceutically acceptable salts thereof of the present invention are those of prostaglandin that play a more important role in the progression of inflammation than COX-1. It is effective in selectively and strongly inhibiting the action of COX-2 involved in biosynthesis.

2,2-dialkyl-4,5-diaryl-3 (2H) furanone (hereinafter referred to as 'diaryl-3 (2H) furanone') derivatives of the present invention useful as COX-2 selective inhibitors It is represented by Formula (I).

(Ⅰ)

In the above formula,

A is CH ₃ S, CH ₃ SO or CH ₃ SO ₂ ,

B and C are the same as or different from each other, and are a methyl or ethyl group (but, when B is a methyl group, C is not a methyl group) or a cyclohexylidene or cyclopentylidene group formed by bonding to each other,

D is benzo [b] thienyl, 1-naphthyl, 2-naphthyl, benzofuranyl, furanyl or a substituent having the following structural formula.

Wherein R ¹ to ⁵ are the same or different, hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, nitro, nitrile, azido, methylenedi Oxy, phenyl, lower alkyl thio having 1 to 5 carbon atoms, lower alkyl sulfonyl having 1 to 5 carbon atoms, COR ⁶ or NR ⁷ R ⁸ .

Wherein R ⁶ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms,

R ^7-8 are the same or different from each other and are a hydrogen, methyl, ethyl or acetyl group.

In the above formula,

R ⁹ is hydrogen, acetyl, 1,3-dioxanyl 2-yl, formyl or methyl group.

In the above formula,

R ¹⁰ is hydrogen, methyl or methoxy group.

In the above formula,

R ¹¹ is a hydrogen, methyl, trityl or isopropyl group, provided that both B and C are methyl groups in this case.

In addition, the diaryl-3 (2H) furanone derivative of the general formula (I) may form a pharmaceutically acceptable salt, which is generally an alkali metal salt and an acid addition salt or a base addition salt. It refers to a salt capable of forming a pharmaceutically acceptable because it is non-toxic. Pharmaceutically acceptable acid addition salts of formula (I) are those derived from organic or inorganic acids. Inorganic acids used in the present invention include, for example, hydrochloric acid, bromic acid, iodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, and the like. Organic acids include formic acid, acetic acid, propionic acid, succinic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, ethylsulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

Pharmaceutically acceptable base addition salts of general formula (I) are metal salts derived from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or N, N'-dibenzylethylenediamine, choline, chloroprop Organic salts derived from Chloroprocaine, diethanolamine, ethylenediamine, N-methylglucamine and procaine.

The diaryl-3 (2H) furanone derivative (I) of the present invention is not particularly limited, but is related to inflammation such as, for example, an analgesic agent for treating inflammation, analgesic and headache, or an antipyretic agent for treating fever. It is useful for the treatment of diseases. For example, the compounds of the present invention are not particularly limited, but are useful for the treatment of arthritis such as rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, osteoarthritis and the like. In addition, the compounds of the present invention are useful for the treatment of asthma, bronchitis, menstrual irregularities, tendinitis, bursititis, and skin-related diseases such as psoriasis, eczema, burns and dermatitis. The compounds of the present invention are also useful for the treatment of diseases such as gastritis, topical enteritis, colon diverticulitis. In addition, the compounds of the present invention can be used in the treatment of cancer by inhibiting cell culture modification and metastatic cancer growth, and exhibit abnormalities in the proliferation involving cyclooxygenase in diabetic retinal abnormalities and cancerous angiogenesis. It can be used for the treatment and prevention of diseases. It is also effective in the treatment of Alzheimer's disease and in the prevention of osteoporosis and the treatment of glaucoma.

In addition, the diaryl-3 (2H) furanone derivative (I) of the present invention specifically inhibits COX-2 as compared to COX-1, so nonsteroidal anti-inflammatory drugs are used in patients whose use of nonsteroidal anti-inflammatory drugs is limited. It can be used as an alternative to analgesics. In particular, it can be used as a substitute for nonsteroidal anti-inflammatory drugs in patients who have a history of recurrence in the gastrointestinal system such as hypoprothrombinemia, hemophilia or kidney disease, preoperative conditions, and cohesion problems with other bleeding problems, such as when taking anticoagulants. have.

As described above, the compound of the present invention can be usefully used in the treatment of warm-blooded rats, mice, horses, cows, sheep, dogs, cats, etc. in addition to being useful for treating human diseases. .

The compounds of the present invention can also be used as complete or partial replacements for formulations comprising conventional nonsteroidal anti-inflammatory agents. That is, the diaryl-3 (2H) furanone derivative (I) and pharmaceutically acceptable salts thereof include other pain relief agents including acetoaminophen or phenacetin; Potentiators, including caffeine; H ₂ -antagonist; Aluminum hydroxide, magnesium hydroxide, simethicone, phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, ephinephrine, napazoline Decongestant, including xylometazoline, xylometazoline, propylhexedrine or levodesoxyephedrine; Antitussives including codeine, hydrocodone, caramiphene, carbetapentane or dextromethorphan; diuretic; It can be used with one or several ingredients, such as antihistamines, which do not have a calming or calming effect.

In the present invention, preferred compounds of the general formula (I) include the following compounds.

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (phenyl) -3 (2H) furanone

2-ethyl-4- (4-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (3-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (2-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (4-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,5-difluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,4-difluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-chloro-4-fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-pyridyl) -3 (2H) furanone

2-ethyl-4- (4-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-4- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-trifluoromethylphenyl) -3 (2H) furanone

4- (3-chlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-N-acetoamidophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-4- (3,4-methylenedioxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-4- (5-methyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (3-chloro-4-trifluoromethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (4-ethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (3-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (3-isopropylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-n-propylphenyl) -3 (2H) furanone

4- (4-t-butylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-4- (6-methyl-3-pyridyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (6-methoxy-3-pyridyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-thienyl) -3 (2H) furanone

4- (4-n-butylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,4-dimethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (2-furanyl) -3 (2H) furanone

4- (3,4-dichlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (2-benzo [b] thienyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (2-benzo [b] furanyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-aminophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-Difluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (4-fluoromethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (4-chlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethoxyphenyl) -3 (2H) furanone

4- (4-Chloro-3-fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (2-thienyl) -3 (2H) furanone

4- (5-acetyl-2-thienyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (4-fluoro-2-methylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (5-fluoro-2-methylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,4-dimethoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-4- (3-fluoro-4-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,5-Ditrifluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,5-dichlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3,5-dimethyl-4-methoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3,4,5-trimethoxyphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (5-methyl-2-thienyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-methyl-2-thienyl) -3 (2H) furanone

2,2-diethyl-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

2,2-diethyl-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-chlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (4-chlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (4-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethylphenyl) -3 (2H) furanone

2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-trifluoromethylphenyl) -3 (2H) furanone

4- (4-acetylphenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-n-propylphenyl) -3 (2H) furanone

4- (2,4-dichlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3,4-dimethoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (2,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3,5-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (3-chloro-4-fluorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3-fluoro-4-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3-fluoro-5-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-4- (3,4-dimethylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-thienyl) -3 (2H) furanone

2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-pyridyl) -3 (2H) furanone

2,2-dimethyl-4- (1-methyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (3-pyrazole) -3 (2H) furanone

2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (1-trityl-3-pyrazole) -3 (2H) furanone

2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (1-isopropyl-3-pyrazole) -3 (2H) furanone

2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

2,2-cyclopentylidene-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-cyclopentylidene-4- (4-isopropylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-cyclopentylidene-4- (3,5-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-cyclopentylidene-4- (2-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-cyclopentylidene-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-cyclopentylidene-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (4-acetylphenyl) -2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

2,2-cyclohexylidene-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

4- (4-acetylphenyl) -2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

Diaryl-3 (2H) furanone derivative (I) of the present invention may be prepared according to the following Scheme 1. Unless otherwise specified in the scheme, B and C are as defined in general formula (I).

Scheme 1 shows a six step reaction to prepare a diaryl-3 (2H) furanone derivative. In the first step, 2 equivalents of n-butyllithium is added to alcohol (2) having a triple bond under -78 ° C and argon atmosphere, and stirred for 1 hour. Substituted benzaldehyde (1) in this solution and reacted for 3 hours to prepare a diol (3). In step 2, diol (3) prepared in step 1 was added chromium trioxide and some concentrated sulfuric acid in pyridinium dichromate (PDC) or acetone solvent in dichloromethane solvent, and stirred overnight at room temperature. Compound (4) of ketone alcohol, in which primary alcohol was oxidized to ketone, was prepared. In step 3, as a cyclization reaction of ketone alcohol (4), the compound (4) is dissolved in methanol solvent, diethylamine is added and stirred at room temperature for 3 hours to convert the ketone (4) to furanone (5). (J. Chem. Soc., 3871 (1958)). Step 4 is a step of converting the methylsulphide group of furanone to methylsulfone, adding methylsulphide (5) of furanone to a mixed solvent of methanol and tetrahydrofuran, adding oxone (potassium peroxymonosulfate (OXONE)), and then adding water. The mixture was stirred at room temperature to prepare furanone (6) converted to methylsulfone. In step 5, hydrogen of the vinyl group is halogenated to obtain diaryl-3 (2H) furanone. In other words, the halogenation reaction can be divided into bromination reaction and iodide reaction. First, the reaction of replacing with bromine has two conditions, which are stirred for 1 hour at room temperature under bromine, some acetic acid and carbon tetrachloride (CCl ₄ ) solvent, or N. 4-bromo-5- (methylsulfonylphenyl) -3 (2H) furanone (7a) was stirred for 3 hours at room temperature in a tetrahydrofuran solvent with bromosuccinimide (NBS). Manufacture. The iodination reaction was carried out with furanone (6) and solid iodine and BTI [Bis (trifluoroacetosy) iodobenzene; Synthesis, 923 (1988)] was added to dichloromethane and stirred at room temperature to prepare 4-iodine-5-methylsulfonylphenyl-3 (2H) furanone (7b). In the sixth step, boron acid (ArB (OH) ₂ ) substituted with phenyl, furan, pyridine, pyrazole or thienyl with 3 (2H) furanone (7) in which the 4-position is substituted with halogen (0) By cross-coupling under conditions (Org. React., 50 (1997)), a diaryl-3 (2H) furanone derivative 8 having various substituents such as aryl at position 4 is obtained. Reaction conditions include 4-bromo-5-aryl-3 (2H) furanone (7a) or 4-iodine-5-aryl-3 (2H) furanone (7b), arylboronic acid, tetrakis (triphenyl Diaryl-3 (2H) furanone (8) was prepared by stirring phosphine) palladium (0), sodium carbonate (Na ₂ CO ₃ ) solution and the like under reflux in ethanol and toluene solvents overnight.

The diaryl-3 (2H) furanone derivative (I) of the present invention may be prepared according to Scheme 2 below.

Scheme 2 is a method for preparing diaryl-3 (2H) furanone using an arylboronate salt which acts as arylboronic acid (J. Med. Chem., 1274 (1999)). The aromatic bromo compound is lithiated and triisopropylborate is added to prepare an arylborate lithium salt. After removing the solvent by distillation under reduced pressure, Suzuki's cross coupling reaction is performed.

Hereinafter, the present invention will be described in detail through Examples and Test Examples, but the present invention is not limited only to these examples.

Example 1 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

Step 1: 4-methyl-1- (4-methylthiophenyl) -2-hectin-1,4-diol

23.3 g of 3-methyl-1-pentin-3-ol was added to 150 ml of tetrahydrofuran and 130 ml of n-butyllithium (2.5 M solution in Hexane) was added, followed by argon while maintaining at -78 ° C. It reacted in atmosphere. After 40 minutes, 16 ml of p-methylthiobenzaldehyde was added. After 2 hours, the solution was neutralized with 7% aqueous HCl solution, the solvent was distilled off under reduced pressure, and extracted three times with 100 ml of dichloromethane. The separated organic layer was distilled under reduced pressure to remove the solvent, and the concentrated portion was separated by column chromatography (hexane: ethyl acetate = 1: 1) to give 30 g of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.048 (t, 3H, CH ₃ ), 1.511 (s, 3H, CH ₃ ), 1.729 (m, 2H, CH ₂ ), 2.182 (s, 1H, OH ), 2.496 (s, 3H, CH ₃ S), 5.491 (s, H, OH), 7.256 (d, 2H, ArH), 7.451 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 3348, 2974, 2930, 1492, 1092, 983, 795, 523

Step 2: 4-hydroxy-4-methyl-1- (4-methylthiophenyl) -2-hexyn-1-one

9.9 g of 4-methyl-1- (4-methylthiophenyl) -2-hectin-1,4-diol prepared in step 1 was dissolved in 200 ml of dichloromethane, and 15 g of pyridine dichlorochromate (PDC), 15 g of celite was added. After stirring overnight, the solid was removed using Florisil and the filtrate was concentrated under reduced pressure, followed by column chromatography (hexane: ethyl acetate = 4: 1) to give 5.34 g of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.125 (t, 3H, CH ₃ ), 1.619 (s, 3H, CH ₃ ), 1.852 (q, 2H, CH ₂ ), 2.537 (s, 3H, CH ₃ S), 7.278 (d, 2H, ArH), 8.014 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 3427, 2974, 1588, 1095, 914, 745

Step 3: 2-ethyl-2-methyl-5- (4-methylthiophenyl) -3 (2H) furanone

5.34 g of 4-hydroxy-4-methyl-1- (4-methylthiophenyl) -2-hexyn-1-one prepared in step 2 was dissolved in 200 ml of ethanol, and then 3 ml of diethylamine. The solution dissolved in 50 ml of ethanol was slowly added dropwise. After reacting at room temperature for 4 hours, the solvent was removed by distillation under reduced pressure. 50 ml of water was added, followed by extraction three times with 100 ml of dichloromethane. After distilling the extracted organic layer under reduced pressure to remove the solvent, the obtained compound was subjected to the following four step reaction without undergoing purification.

Step 4: 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

2-ethyl-2-methyl-5- (4-methylthiophenyl) -3 (2H) furanone prepared in step 3 was dissolved in 50 ml of tetrahydrofuran, 50 ml of ethanol, and 50 ml of water. , 10 g of oxone was added and stirred overnight. The solid was filtered off, distilled under reduced pressure, 50 ml of water and 100 ml of dichloromethane were added, followed by extraction twice with 50 ml of dichloromethane. The organic layer was distilled under reduced pressure to remove the solvent, and the remaining portion was subjected to column chromatography (hexane: ethyl acetate = 2: 1) to obtain 4.5 g of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.894 (t, 3H, CH ₃ ), 1.478 (s, 3H, CH ₃ ), 1.909 (m, 2H, CH ₂ ), 3.109 (s, 3H, SO ₂ CH ₃ ), 6.129 (s, 1H, vinyl), 8.067 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2974, 2927, 1696, 1591, 1314, 1152, 774, 552, 533

Step 5: 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

4.5 g of 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 4 was dissolved in 100 ml of carbon tetrachloride, followed by 3 ml of acetic acid and 1 ml. Liquid bromine was added. After stirring for 1 hour at room temperature, the reaction was stopped with an aqueous sodium thiosulfate solution. 50 ml of water was added, followed by extraction three times with 30 ml of dichloromethane. The organic layer was distilled under reduced pressure to remove the solvent, and the remaining portion was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to obtain 4 g of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.907 (t, 3H, CH ₃ ), 1.521 (s, 3H, CH ₃ ), 1.946 (m, 2H, CH ₂ ), 3.109 (s, 3H, SO ₂ CH ₃ ), 8.110 (d, 2H, ArH), 8.409 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2928, 1703, 1583, 1316, 1160, 552

Step 6: 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

200 mg of 4-bromo-2-methyl-2-ethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 was dissolved in 15 ml of toluene, followed by tetrakis (triphenylforce). Pin) palladium (0) 40 mg was added. Then 5 ml of 2 M aqueous sodium carbonate solution and 100 mg of benzeneboronic acid were added. After refluxing at 95 ° C. for 12 hours, the solvent was removed by distillation under reduced pressure. 50 ml of water was added, followed by extraction three times with 30 ml of dichloromethane. The organic layer was distilled under reduced pressure to remove the solvent, and the remaining portion was subjected to column chromatography (hexane: ethyl acetate = 2: 1) to obtain 60 mg of the title compound.

mp: 115-117 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.958 (t, 3H, CH ₃ ), 1.546 (s, 3H, CH ₃ ), 1.974 (m, 2H, CH ₂ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 7.369 (m, 4H, ArH), 7.846 (d, 2H, ArH), 7.926 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2928, 1697, 1620, 1403, 1318, 1149, 959, 769, 552

Example 2 2-ethyl-4- (4-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 100 mg of 4-fluorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 64 mg of the title compound.

mp: 111-114 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.949 (t, 3H, CH ₃ ), 1.541 (s, 3H, CH ₃ ), 1.966 (m, 2H, CH ₂ ), 3.075 (s, 3H, SO ₂ CH ₃ ), 7.085 (m, 2H, ArH), 7.240 (m, 2H, ArH), 7.837 (d, 2H, ArH), 7.947 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1696, 1591, 1511, 1318, 1149, 913, 745, 551

Example 3 4- (3-Fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 100 mg of 3-fluorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 75 mg of the title compound.

mp: 107-108 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.951 (t, 3H, CH ₃ ), 1.545 (s, 3H, CH ₃ ), 1.974 (m, 2H, CH ₂ ), 3.081 (s, 3H, SO ₂ CH ₃ ), 7.040 (m, 2H, ArH), 7.345 (m, 2H, ArH), 7.840 (d, 2H, ArH), 7.955 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2926, 1698, 1403, 1319, 1149, 961, 850, 769, 552

Example 4 2-ethyl-4- (2-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 100 mg of 2-fluorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 53 mg of the title compound.

mp: 108-109 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.961 (t, 3H, CH ₃ ), 1.563 (s, 3H, CH ₃ ), 1.989 (m, 2H, CH ₂ ), 3.063 (s, 3H, SO ₂ CH ₃ ), 7.098 (m, 1H, ArH), 7.278 (m, 3H, ArH), 7.828 (d, 2H, ArH), 7.935 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2975, 2929, 1699, 1595, 1404, 1319, 1150, 969, 766, 552

Example 5 4- (4-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

Step 1: 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

8.88 g of 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 4 of Example 1 was dissolved in 50 ml of carbon tetrachloride and 50 ml of chloroform, 6.82 g of bis (trifluoroacetoxy) iodine benzene and 4 g of iodine were added thereto, followed by stirring at room temperature. After stirring for 4 hours, the reaction was stopped with aqueous sodium thiosulfate solution, 50 ml of water was added, and then extracted three times with 100 ml of dichloromethane. The organic layer was distilled under reduced pressure to remove the solvent, and the remaining portion was subjected to column chromatography (hexane: ethyl acetate = 1: 1) to obtain 8.7 g of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.893 (s, 3H, CH ₃ ), 1.511 (s, 3H, CH ₃ ), 1.931 (m, 2H, CH ₂ ), 3.112 (s, 3H, SO ₂ CH ₃ ), 8.105 (d, 2H, ArH), 8.340 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2928, 1701, 1552, 1314, 1148, 747, 551

Step 2: 4- (4-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 was dissolved in a mixed solvent of 15 ml of toluene and 5 ml of ethanol. , 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 4-acetylbenzeneboronic acid were added and reacted at 95 ° C. for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

mp: 147-148 캜

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.965 (t, 3H, CH ₃ ), 1.561 (s, 3H, CH ₃ ), 1.986 (m, 2H, CH ₂ ), 2.621 (s, 3H, COCH ₃ ), 3.082 (s, 3H, SO ₂ CH ₃ ), 7.389 (d, 2H, ArH), 7.830 (d, 2H, ArH), 7.965 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2929, 1684, 1410, 1317, 1149, 1016, 769, 552

Example 6 4- (3,5-difluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) 34 mg was added, and then 5 ml of 2M aqueous sodium carbonate solution and 110 mg of 3,5-difluorobenzeneboronic acid were added thereto for 12 hours at 95 ° C. Reacted for a while. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound.

mp: 122-124 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.946 (t, 3H, CH ₃ ), 1.543 (s, 3H, CH ₃ ), 1.971 (m, 2H, CH ₂ ), 3.095 (s, 3H, SO ₂ CH ₃ ), 6.813 (m, 3H, ArH), 7.839 (d, 2H, ArH), 7.987 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2975, 2928, 1698, 1627, 1693, 1321, 1150, 990, 769, 552

Example 7 4- (3,4-difluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 110 mg of 3,4-difluorobenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. I was. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 100 mg of the title compound.

mp: 106-108 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.943 (t, 3H, CH ₃ ), 1.538 (s, 3H, CH ₃ ), 1.966 (m, 2H, CH ₂ ), 3.086 (s, 3H, SO ₂ CH ₃ ), 6.995 (m, 1H, ArH), 7.163 (m, 2H, ArH), 7.833 (d, 2H, ArH), 7.973 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2931, 1698, 1597, 1518, 1277, 1160, 959, 868, 770, 552

Example 8 4- (3-Chloro-4-fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 110 mg of 3-chloro-4-fluorobenzeneboronic acid were added for 12 hours at 95 ° C. Reacted. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 75 mg of the title compound.

mp: 145-146 캜

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.947 (t, 3H, CH ₃ ), 1.541 (s, 3H, CH ₃ ), 1.969 (m, 2H, CH ₂ ), 3.086 (s, 3H, SO ₂ CH ₃ ), 7.132 (m, 2H, ArH), 7.373 (m, 1H, ArH), 7.838 (d, 2H, ArH), 7.972 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2974, 1696, 1622, 1502, 1319, 1252, 1150, 956, 766, 726, 552

Example 9 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-pyridyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 110 mg of pyridine-3-trimethoxyboronic acid salt were added for 12 hours at 95 ° C. Reacted. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 35 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.969 (t, 3H, CH ₃ ), 1.567 (s, 3H, CH ₃ ), 2.000 (m, 2H, CH ₂ ), 3.088 (s, 3H, SO ₂ CH ₃ ), 7.368 (m, 1H, ArH), 7.707 (m, 1H, ArH), 7.832 (d, 2H, ArH), 7.976 (d, 2H, ArH), 8.462 (d, 1H, ArH), 8.578 (d, 1H, ArH)

IR (Neat, cm ^-1 ): 3058, 2976, 2929, 1696, 1621, 1401, 1318, 1149, 926, 769, 726, 552

Example 10 2-ethyl-4- (4-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. After dissolving in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 5 ml of a 2M aqueous sodium carbonate solution and 110 mg of 4-methoxybenzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 110 mg of the title compound.

mp: 130-133 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.944 (t, 3H, CH ₃ ), 1.552 (s, 3H, CH ₃ ), 1.970 (m, 2H, CH ₂ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 3.834 (s, 3H, OCH ₃ ), 6.925 (d, 2H, ArH), 7.194 (d, 2H, ArH), 7.898 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2929, 1694, 1593, 1613, 1317, 1148, 913, 744, 552

Example 11 2-ethyl-2-methyl-4- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 110 mg of 4-methylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.948 (t, 3H, CH ₃ ), 1.535 (s, 3H, CH ₃ ), 1.962 (m, 2H, CH ₂ ), 2.377 (s, 3H, ArCH ₃ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 7.172 (m, 4H, ArH), 7.893 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2974, 2927, 1696, 1624, 1514, 1402, 1318, 1149, 958, 769, 552

Example 12 2-ethyl-2-methyl-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 110 mg of 3-methylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 90 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.953 (t, 3H, CH ₃ ), 1.538 (s, 3H, CH ₃ ), 1.968 (m, 2H, CH ₂ ), 2.345 (s, 3H, ArCH ₃ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 7.003 (m, 1H, ArH), 7.143 (m, 2H, ArH), 7.260 (m, 1H, ArH), 7.853 (d, 2H, ArH), 7.923 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2974, 2928, 1696, 1621, 1403, 1319, 1149, 957, 768, 552

Example 13 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-trifluoromethylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and 5 ml of 2M aqueous sodium carbonate solution and 120 mg of 3-trifluoromethylbenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 53 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.970 (t, 3H, CH ₃ ), 1.564 (s, 3H, CH ₃ ), 1.989 (m, 2H, CH ₂ ), 3.075 (s, 3H, SO ₂ CH ₃ ), 7.040 (m, 2H, ArH), 7.530 (m, 4H, ArH), 7.826 (d, 2H, ArH), 7.963 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2977, 2932, 1696, 1625, 1594, 1404, 1326, 1232, 1151, 1091, 958, 912, 769, 701, 552

Example 14 4- (3-chlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 110 mg of 3-chlorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 85 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.951 (t, 3H, CH ₃ ), 1.544 (s, 3H, CH ₃ ), 1.975 (m, 2H, CH ₂ ), 3.081 (s, 3H, SO ₂ CH ₃ ), 7.130 (m, 1H, ArH), 7.303 (m, 3H, ArH), 7.839 (d, 2H, ArH), 7.961 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2975, 2930, 1699, 1620, 1403, 1319, 1150, 958, 742, 552

Example 15 4- (3-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was mixed with 15 ml of toluene and 5 ml of ethanol. After dissolving in a solvent, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 5 ml of a 2 M aqueous sodium carbonate solution and 120 mg of 3-acetylbenzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 130 mg of the title compound.

mp: 135-136 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.972 (t, 3H, CH ₃ ), 1.543 (s, 3H, CH ₃ ), 1.982 (m, 2H, CH ₂ ), 2.584 (s, 3H, COCH ₃ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 7.484 (m, 3H, ArH), 7.824 (d, 2H, ArH), 7.875 (m, 1H, ArH), 7.938 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2927, 1694, 1590, 1318, 1149, 959, 801, 771, 552

Example 16 4- (3-N-acetamidophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and 5 ml of 2M aqueous sodium carbonate solution and 120 mg of 3-acetamidobenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. . Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.946 (t, 3H, CH ₃ ), 1.535 (s, 3H, CH ₃ ), 1.951 (m, 2H, CH ₂ ), 2.070 (s, 3H, COCH ₃ ), 3.067 (s, 3H, SO ₂ CH ₃ ), 6.921 (m, 1H, ArH), 7.334 (m, 1H, ArH), 7.556 (m, 2H, ArH), 7.846 (d, 2H, ArH) , 7.926 (d, 2H, ArH), 7.995 (s, 1H, NH)

IR (Neat, cm ^-1 ): 3312, 3077, 2928, 2881, 1695, 1619, 1553, 1318, 1149, 958, 725, 641

Example 17 2-ethyl-2-methyl-4- (3,4-methylenedioxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 120 mg of 3,4-methylenedioxybenzeneboronic acid were added for 12 hours at 95 ° C. Reacted. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 72 mg of the title compound.

mp: 160-163 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.936 (t, 3H, CH ₃ ), 1.527 (s, 3H, CH ₃ ), 1.956 (m, 2H, CH ₂ ), 3.079 (s, 3H, SO ₂ CH ₃ ), 5.995 (s, 2H, OCH ₂ O), 6.730 (m, 2H, ArH), 6.835 (m, 1H, ArH), 7.878 (d, 2H, ArH), 7.947 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2922, 2851, 1696, 1596, 1507, 1438, 1404, 1318, 1243, 1149, 1035, 958, 769, 552

Example 18 2-ethyl-2-methyl-4- (5-methyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

210 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in a solvent, and 25 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 15 ml of 2M aqueous sodium bicarbonate solution and 1-methylpyrazole-4-trimethylboronic acid lithium salt (step 2 of Example 85). Method) 170mg was added and reacted at 90 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 100 mg of the title compound.

mp: 78-80 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.557 (s, 6H, 2CH ₃ ), 3.094 (s, 3H, SO ₂ CH ₃ ), 6.936 to 6.993 (m, 2H, ArH), 7.203 to 7.249 (m , 2H, ArH), 8.059-8.087 (m, 2H, ArH), 8.442-8.471 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2926, 1694, 1538, 1315, 1148, 888, 697, 642

Example 19 4- (3-chloro-4-trifluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and 5 ml of 2M aqueous sodium carbonate solution and 120 mg of 3-chloro-4-trifluoromethylbenzeneboronic acid were added thereto at 12O < 0 > C The reaction was carried out for a time. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 85 mg of the title compound.

mp: 168-170 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.960 (t, 3H, CH ₃ ), 1.555 (s, 3H, CH ₃ ), 1.982 (m, 2H, CH ₂ ), 3.085 (s, 3H, SO ₂ CH ₃ ), 7.369 (m, 1H, ArH), 7.506 (m, 1H, ArH), 7.636 (m, 1H, ArH), 7.822 (d, 2H, ArH), 7.991 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2929, 1697, 1624, 1592, 1317, 1149, 913, 744, 552

Example 20 2-ethyl-4- (4-ethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

150 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in a solvent, 25 mg of tetrakis (triphenylphosphine) palladium (0) was added, and 15 ml of 2M aqueous sodium bicarbonate solution and 67 mg of 4-ethylbenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

mp: 45 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.921-0.969 (t, 3H, CH ₃ ), 1.228-1.281 (t, 3H, CH ₃ ), 1.533 (s, 3H, SO ₂ CH ₃ ), 1.940- 1.983 (q, 2H, CH ₂ ), 2.659 to 2.685 (q, 2H, CH ₂ ), 3.067 (s, 3H, SO ₂ CH ₃ ), 7.154 to 2.258 (m, 4H, ArH), 7.849 to 7.939 (m , 4H, ArH)

IR (Neat, cm ^-1 ): 1693, 1594, 1319, 1149, 913, 745, 552

Example 21 2-ethyl-4- (3-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 100 mg of 3-methoxybenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification was carried out in the same manner as in the sixth step of Example 1 to obtain 74 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.954 (t, 3H, CH ₃ ), 1.543 (s, 3H, CH ₃ ), 1.981 (m, 2H, CH ₂ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 3.782 (s, 3H, OCH ₃ ), 6.852 (m, 3H, ArH), 7.276 (m, 1H, ArH), 7.863 (d, 2H, ArH), 7.932 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2931, 2838, 1696, 1621, 1403, 1318, 1149, 1036, 957, 769, 552

Example 22 2-ethyl-4- (3-isopropylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 4-bromo-2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 1 was charged with 15 ml of toluene and 5 ml of ethanol. It was dissolved in a mixed solvent, 40 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 110 mg of 3-isopropylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 170 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.962 (t, 3H, CH ₃ ), 1.189 (s, 3H, CH ₃ ), 1.212 (s, 3H, CH ₃ ), 1.544 (s, 3H, CH ₃ ), 1.973 (m, 2H, CH ₂ ), 2.873 (m, 1H, CH), 3.056 (s, 3H, SO ₂ CH ₃ ), 7.086 (m, 2H, ArH), 7.262 (m, 2H, ArH ), 7.892 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2964, 2928, 1696, 1620, 1402, 1319, 1149, 958, 771, 552

Example 23 4- (4-t-butylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

150 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in and 25 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 15 ml of a 2M aqueous sodium bicarbonate solution and 117 mg of 4-t-butylbenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 100 mg of the title compound.

mp: 45 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.921-0.970 (t, 3H, CH ₃ ), 1.333 (s, 9H, 3CH ₃ ), 1.535 (s, 3H, CH ₃ ), 1.941-1.998 (m, 2H, CH ₂ ), 3.076 (s, 3H, SO ₂ CH ₃ ), 7.179 ~ 7.208 (m, 2H, ArH), 7.380 ~ 7.409 (m, 2H, ArH), 7.863 ~ 7.952 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2967, 2871, 1696, 1594, 1385, 1320, 1149, 769, 552

Example 24 2-ethyl-4- (6-methoxy-3-pyridyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

150 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in water, and 25 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 15 ml of 2M aqueous sodium bicarbonate solution and 98 mg of 6-methoxy-3-pyridyl-trimethylboronic acid, and then 90 ° C. Reaction was carried out for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 100 mg of the title compound.

mp: 61 ° C.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.926-0.975 (t, 3H, CH ₃ ), 1.545 (s, 3H, CH ₃ ), 1.950-1.987 (m, 2H, CH ₂ ), 3.084 (s, 3H, SO ₂ CH ₃ ), 3.952 (s, 3H, CH ₃ ), 6.781 to 6.812 (d, 1H, ArH), 7.511 to 7.548 (dd, 1H, ArH), 7.849 to 7.879 (m, 2H, ArH) , 7.953-7.982 (m, 2H, ArH), 8.031-8.042 (d, 1H, ArH)

IR (Neat, cm ^-1 ): 2977, 2929, 1695, 1591, 1500, 1318, 1287, 1149, 1021, 769, 552

Example 25 2-ethyl-2-methyl-4- (6-methyl-3-pyridyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

150 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. Dissolved in, 25 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 15 ml of ₂ M sodium bicarbonate (Na ₂ CO ₃ ) and 91 mg of 6-methyl-3-pyridyl trimethylboronic acid salt. Reacted at 90 ° C. for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 110 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.933-0.982 (t, 3H, CH ₃ ), 1.556 (s, 3H, CH ₃ ), 1.961-1.998 (q, 2H, CH ₂ ), 2.593 (s, 3H, CH ₃ ), 3.084 (s, 3H, SO ₂ CH ₃ ), 7.213 ~ 7.255 (d, 1H, ArH), 7.637 ~ 7.669 (dd, 1H, ArH), 7.825 ~ 7.855 (m, 2H, ArH) , 7.952-7.981 (m, 2H, ArH), 8.324-8.330 (d, 1H, ArH)

IR (Neat, cm ^-1 ): 2927, 1696, 1590, 1406, 1318, 1150, 769, 550

Example 26 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-n-propylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 4-n-propylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.955 (m, 6H, CH ₃ ), 1.534 (s, 3H, CH ₃ ), 1.660 (m, 2H, CH ₂ ), 1.951 (m, 2H, CH ₂ ), 2.606 (t, 2H, CH ₂ ), 3.069 (s, 3H, SO ₂ CH ₃ ), 7.180 (m, 4H, ArH), 7.892 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2966, 2930, 1697, 1510, 1401, 1319, 1149, 958, 769, 552

Example 27 2-Ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-thienyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 100 mg of thiophene-3-boronic acid were added and reacted at 95 DEG C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 76 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.941 (t, 3H, CH ₃ ), 1.529 (s, 3H, CH ₃ ), 1.982 (m, 2H, CH ₂ ), 3.097 (s, 3H, SO ₂ CH ₃ ), 6.934 (m, 1H, ArH), 7.309 (m, 1H, ArH), 7.505 (m, 1H, ArH), 7.369 (m, 4H, ArH), 7.921 (d, 2H, ArH), 7.994 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 3106, 2975, 2929, 1696, 1621, 1447, 1316, 1148, 959, 852, 770, 552

Example 28 4- (4-n-butylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 4-n-butylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 171 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.943 (m, 6H, CH ₃ ), 1.376 (m, 2H, CH ₂ ), 1.533 (s, 3H, CH ₃ ), 1.617 (m, 2H, CH ₂ ) 1.962 (m, 2H, CH ₂ ), 2.627 (t, 2H, CH ₂ ) _, 3.069 (s, 3H, SO ₂ CH ₃ ), 7.179 (m, 4H, ArH), 7.861 (d, 2H, ArH) , 7.926 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2969, 2929, 1697, 1622, 1594, 1401, 1319, 1149, 958, 769, 552

Example 29 4- (3,4-dimethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 3,4-dimethylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

mp: 124-126 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.946 (t, 3H, CH ₃ ), 1.529 (s, 3H, CH ₃ ), 1.960 (m, 2H, CH ₂ ), 2.249 (s, 3H, ArCH ₃ ), 2.281 (s, 3H, ArCH ₃ ), 3.060 (s, 3H, SO ₂ CH ₃ ), 6.930 (m, 1H, ArH), 7.060 (m, 1H, ArH), 7.131 (m, 1H, ArH) , 7.895 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2973, 2926, 1696, 1624, 1404, 1319, 1149, 959, 769, 552

Example 30 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (2-furanyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 95 mg of 2-furanylboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 25 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.930 (t, 3H, CH ₃ ), 1.524 (s, 3H, CH ₃ ), 1.954 (m, 2H, CH ₂ ), 3.114 (s, 3H, SO ₂ CH ₃ ), 6.512 (m, 1H, ArH), 6.894 (m, 1H, ArH), 7.372 (m, 1H, ArH), 8.023 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2976, 2930, 1701, 1642, 1545, 1409, 1317, 1149, 1090, 1069, 958, 875, 770, 730, 552

Example 31 4- (3,4-dichlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 3,4-dichlorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 140 mg of the title compound.

mp: 120-123 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.946 (t, 3H, CH ₃ ), 1.542 (s, 3H, CH ₃ ), 1.970 (m, 2H, CH ₂ ), 3.088 (s, 3H, SO ₂ CH ₃ ), 7.078 (m, 1H, ArH), 7.441 (m, 2H, ArH), 7.840 (d, 2H, ArH), 7.982 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2875, 2930, 1696, 1620, 1406, 1319, 1150, 957, 769, 730, 552

Example 32 4- (2-benzo [b] thienyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 130 mg of benzothiophene-2-boronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 49 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.970 (t, 3H, CH ₃ ), 1.540 (s, 3H, CH ₃ ), 1.988 (m, 2H, CH ₂ ), 3.102 (s, 3H, SO ₂ CH ₃ ), 7.333 (m, 2H, ArH), 7.499 (s, 1H, ArH), 7.760 (m, 2H, ArH), 8.012 (s, 4H, ArH)

IR (Neat, cm ^-1 ): 2925, 2866, 1701, 1620, 1457, 1317, 1148, 957, 762, 760.551

Example 33 4- (2-benzo [b] furanyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 130 mg of benzofuran-2-boronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 85 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.957 (t, 3H, CH ₃ ), 1.542 (s, 3H, CH ₃ ), 1.980 (m, 2H, CH ₂ ), 3.128 (s, 3H, SO ₂ CH ₃ ), 7.278 (m, 2H, ArH), 7.604 (m, 1H, ArH), 8.072 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2927, 1702, 1539, 1454, 1318. 1149, 959, 766, 747, 655, 551

Example 34 4- (3-aminophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 110 mg of 3-aminobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, extraction and purification was carried out in the same manner as in the sixth step of Example 1 to obtain 105 mg of the title compound.

mp: 77-78 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.942 (t, 3H, CH ₃ ), 1.528 (s, 3H, CH ₃ ), 1.958 (m, 2H, CH ₂ ), 3.067 (s, 3H, SO ₂ CH ₃ ), 6.569 (m, 1H, ArH), 6.659 (m, 2H, ArH), 7.140 (m, 1H, ArH), 7.905 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 3457, 3370, 2926, 1692, 1620, 1403, 1317, 1148, 959, 854, 769, 552

Example 35 4- (3-difluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 110 mg of 3-difluoromethylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 30 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.964 (t, 3H, CH ₃ ), 1.555 (s, 3H, CH ₃ ), 1.971 (dq, 2H, CH ₂ ), 3.071 (s, 3H, SO ₂ CH ₃ ), 6.631 (t, 1H, ArCHF ₂ ), 7.364 (m, 1H, ArH), 7.468 (m, 3H, ArH), 7.828 (d, 2H, ArH), 7.948 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2976, 2931, 1697, 1624, 1594, 1319, 1150, 1028, 769, 552

Example 36 2-ethyl-4- (4-fluoromethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 110 mg of 4-fluoromethylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 70 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.958 (t, 3H, CH ₃ ), 1.546 (s, 3H, CH ₃ ), 1.974 (m, 2H, CH ₂ ), 3.068 (s, 3H, SO ₂ CH ₃ ), 5.408 (d, 2H, ArCH ₂ F), 7.369 (m, 4H, ArH), 7.846 (d, 2H, ArH), 7.926 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2974, 2929, 1697, 1319, 1150, 769, 552

Example 37 4- (4-Chloromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in and 25 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 15 ml of 2M sodium bicarbonate and 95 mg of 4-chloromethylphenylboronic acid were added and reacted at 90 DEG C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 175 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.922-0.970 (t, 3H, CH ₃ ), 1.542 (s, 3H, CH ₃ ), 1.950-1.987 (m, 2H, CH ₂ ), 3.082 (s, 3H, SO ₂ CH ₃ ), 7.199 ~ 7.228 (m, 2H, ArH), 7.349 ~ 7.377 (m, 2H, ArH), 7.826 ~ 7.855 (m, 2H, ArH), 7.943 ~ 7.970 (m, 2H, ArH )

IR (Neat, cm ^-1 ): 1696, 1588, 1319, 1150, 1090, 968, 769, 552

Example 38 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in and 25 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 15 ml of 2M aqueous sodium bicarbonate solution and 87 mg of 4-trifluoromethylbenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 130 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.939-0.989 (t, 3H, CH ₃ ), 1.564 (s, 3H, CH ₃ ), 1.971-2.008 (m, 2H, CH ₂ ), 3.090 (s, 3H, SO ₂ CH ₃ ), 7.398-7.424 (m, 2H, ArH), 7.626-7.653 (m, 2H, ArH), 7.818-7.847 (m, 2H, ArH), 7.960-7.989 (m, 2H, ArH )

IR (Neat, cm ^-1 ): 2978, 2932, 1696, 1623, 1326, 1151, 1071, 846, 771, 552

Example 39 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethoxyphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 50 ml of toluene and 15 ml of ethanol. It was dissolved in, 25 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 15 ml of 2M aqueous sodium bicarbonate solution and 95 mg of 4-trifluoromethoxybenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 135 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.926-0.975 (t, 3H, CH ₃ ), 1.549 (s, 3H, CH ₃ ), 1.956-1.995 (m, 2H, CH ₂ ), 3.087 (s, 3H, SO ₂ CH ₃ ), 7.246 ~ 7.329 (m, 4H, ArH), 7.826 ~ 7.856 (m, 2H, ArH), 7.952 ~ 7.981 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2976, 2931, 1697, 1567, 1259, 1150, 769, 552

Example 40 4- (4-Chloro-3-fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. After dissolving in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 4-chloro-3-fluorobenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 50 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.951 (t, 3H, CH ₃ ), 1.551 (s, 3H, CH ₃ ), 1.977 (m, 2H, CH ₂ ), 3.102 (s, 3H, SO ₂ CH ₃ ), 6.994 (m, 1H, ArH), 7.137 (m, 1H, ArH), 7.401 (m, 1H, ArH), 7.848 (d, 2H, ArH), 7.991 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2930, 1715, 1698, 1622, 1403, 1319, 1150, 1074, 959, 858, 768, 552

Example 41 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (2-thienyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 5 ml of a 2M aqueous sodium carbonate solution and 95 mg of thiophene-2-boronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 70 mg of the title compound.

mp: 112-114 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.947 (t, 3H, CH ₃ ), 1.543 (s, 3H, CH ₃ ), 1.964 (m, 2H, CH ₂ ), 3.097 (s, 3H, SO ₂ CH ₃ ), 7.059 (m, 1H, ArH), 7.110 (m, 1H, ArH), 7.359 (m, 1H, ArH), 7.986 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 3100, 2975, 2929, 1700, 1619, 1317, 1149, 770, 552

Example 42 4- (5-acetyl-2-thienyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 100 mg of 5-acetylthiophene-2-boronic acid were added and reacted at 95 DEG C for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 70 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.946 (t, 3H, CH ₃ ), 1.555 (s, 3H, CH ₃ ), 1.950 (m, 2H, CH ₂ ), 2.549 (s, 3H, COCH ₃ ), 3.131 (s, 3H, SO ₂ CH ₃ ), 7.208 (d, 1H, ArH), 7.954 (d, 1H, ArH), 7.846 (d, 2H, ArH), 8.083 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2926, 1690, 1315, 1150, 772, 552

Example 43 2-ethyl-4- (4-fluoro-2-methylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 4-fluoro-2-methylbenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 60 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.961 (t, 3H, CH ₃ ), 1.544 (s, 3H, CH ₃ ), 1.985 (m, 2H, CH ₂ ), 2.105 (m, 3H, ArCH ₃ ), 3.038 (s, 3H, SO ₂ CH ₃ ), 6.996 (m, 3H, ArH), 7.739 (m, 2H, ArH), 7.900 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2976, 2929, 1696, 1612, 1564, 1320, 1246, 1160, 958, 769, 730, 551

Example 44 2-Ethyl-4- (5-fluoro-2-methylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 5-fluoro-2-methylbenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 54 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.954 (t, 3H, CH ₃ ), 1.553 (s, 3H, CH ₃ ), 1.981 (m, 2H, CH ₂ ), 2.349 (s, 3H, ArCH ₃ ), 3.060 (s, 3H, SO ₂ CH ₃ ), 6.971 (m, 1H, ArH), 7.190 (m, 2H, ArH), 7.839 (m, 2H, ArH), 7.933 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2977, 2930, 1697, 1632, 1503, 1405, 1320, 1150, 958, 771, 552

Example 45 4- (3,4-dimethoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 3,4-dimethoxybenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 185 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.959 (t, 3H, CH ₃ ), 1.542 (s, 3H, CH ₃ ), 1.959 (m, 2H, CH ₂ ), 3.070 (s, 3H, SO ₂ CH ₃ ), 3.817 (s, 3H, OCH ₃ ), 3.905 (s, 3H, OCH ₃ ), 6.795 (m, 2H, ArH), 6.872 (m, 1H, ArH), 7.914 (m, 4H, ArH )

IR (Neat, cm ^-1 ): 2974, 2933, 1696, 1592, 1516, 1319, 1260, 1150, 1027, 770, 552

Example 46 4- (3-Fluoro-4-methoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 3-fluoro-4-methoxybenzeneboronic acid, followed by reaction at 95 ° C for 12 hours. I was. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 110 mg of the title compound.

mp: 158-160 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.940 (t, 3H, CH ₃ ), 1.533 (s, 3H, CH ₃ ), 1.961 (m, 2H, CH ₂ ), 3.087 (s, 3H, SO ₂ CH ₃ ), 3.918 (s, 3H, OCH ₃ ), 7.005 (m, 3H, ArH), 7.859 (m, 2H, ArH), 7.957 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2932, 1697, 1519, 1318, 1270, 1149, 1024, 768, 552

Example 47 4- (3,5-Ditrifluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 130 mg of 3,5-ditrifluoromethylbenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. I was. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 87 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.984 (t, 3H, CH ₃ ), 1.584 (s, 3H, CH ₃ ), 2.009 (m, 2H, CH ₂ ), 3.082 (s, 3H, SO ₂ CH ₃ ), 7.756 (s, 2H, ArH), 7.822 (m, 3H, ArH), 8.008 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2979, 2934, 1698.1628, 1593, 1407, 1282, 1150, 1138, 959, 896, 772, 704, 552

Example 48 4- (3,5-dichlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of a 2M aqueous sodium carbonate solution and 120 mg of 3,5-dichlorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 150 mg of the title compound.

mp: 188-190 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.945 (t, 3H, CH ₃ ), 1.543 (s, 3H, CH ₃ ), 1.973 (m, 2H, CH ₂ ), 3.097 (s, 3H, SO ₂ CH ₃ ), 7.171 (m, 2H, ArH), 7.348 (m, 1H, ArH), 7.840 (m, 2H, ArH), 7.996 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2974, 2931, 1696, 1596, 1559, 1319, 1150, 801, 551

Example 49 4- (3,5-dimethyl-4-methoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It dissolved in and added 34 mg of tetrakis (triphenylphosphine) palladium (0), and then 5 ml of a 2M aqueous sodium carbonate solution and 150 mg of 3,5-dimethyl-4-methoxybenzeneboronic acid were added thereto for 12 hours at 95 ° C. Reacted for a while. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.941 (t, 3H, CH ₃ ), 1.525 (s, 3H, CH ₃ ), 1.958 (m, 2H, CH ₂ ), 2.258 (s, 6H, ArCH ₃ ), 3.069 (s, 3H, SO ₂ CH ₃ ), 3.745 (s, 3H, OCH ₃ ), 6.896 (s, 2H, ArH), 7.904 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2974, 2930, 1688, 1622, 1591, 1330, 1149, 1014, 850, 769, 552

Example 50 2-Ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3,4,5-trimethoxyphenyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. Was dissolved in the solution, and 34 mg of tetrakis (triphenylphosphine) palladium (0) was added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 150 mg of 3,4,5-trimethoxybenzeneboronic acid were added for 12 hours at 95 ° C. Reacted. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 177 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.964 (t, 3H, CH ₃ ), 1.543 (s, 3H, CH ₃ ), 1.968 (m, 2H, CH ₂ ), 3.062 (s, 3H, SO ₂ CH ₃ ), 3.757 (s, 6H, OCH ₃ ), 3.867 (s, 3H, OCH ₃ ), 6.454 (s, 2H, ArH), 7.927 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2973, 2934, 1696, 1582, 1394, 1321, 1149, 1126, 770, 552

Example 51 2-Ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (5-methyl-2-thienyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It was dissolved in the solution, 34 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 100 mg of 5-methylthiophene-2-trimethoxy boronic acid salt were added thereto at 95 ° C. The reaction was carried out for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 70 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.930 (t, 3H, CH ₃ ), 1.523 (s, 3H, CH ₃ ), 1.988 (m, 2H, CH ₂ ), 2.480 (s, 3H, ArCH 3) , 3.097 (s, 3H, SO ₂ CH ₃ ), 6.702 (m, 1H, ArH), 6.907 (m, 1H, ArH), 7.999 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2973, 2924, 1701, 1318, 1140, 769, 551

Example 52 2-Ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-methyl-2-thienyl) -3 (2H) furanone

200 mg of 2-ethyl-4-iodine-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 1 of Example 5 was mixed with 15 ml of toluene and 5 ml of ethanol. It dissolved in and added 34 mg of tetrakis (triphenylphosphine) palladium (0), and then 5 ml of 2M aqueous sodium carbonate solution and 100 mg of 3-methylthiophene-2-trimethoxy boronic acid salt were added thereto at 95 ° C. The reaction was carried out for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 150 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.954 (t, 3H, CH ₃ ), 1.554 (s, 3H, CH ₃ ), 1.956 (s, 3H, ArCH 3), 1.988 (m, 2H, CH ₂ ) , 3.063 (s, 3H, SO ₂ CH ₃ ), 6.801 (d, 1H, ArH), 7.356 (d, 1H, ArH), 7.911 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2974, 2926, 1701, 1618, 1318, 1149, 770, 729, 552

Example 53 2,2-diethyl-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 140 mg of benzeneboronic acid were added and reacted at 95 DEG C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 130 mg of the title compound.

mp: 139-140 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.933 (t, 6H, 2CH ₃ ), 1.990 (q, 4H, 2CH ₂ ), 3.070 (s, 3H, SO ₂ CH ₃ ), 7.244 (dd, 2H, ArH), 7.372 (m, 3H, ArH), 7.858 (d, 2H, ArH), 7.932 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1695, 1621, 1403, 1318, 1149

Example 54 2,2-diethyl-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2M aqueous sodium carbonate solution and 150 mg of 3-fluorobenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 130 mg of the title compound.

mp: 131-132 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.927 (t, 6H, 2CH ₃ ), 1.985 (q, 4H, 2CH ₂ ), 3.084 (s, 3H, SO ₂ CH ₃ ), 7.032 (m, 3H, ArH), 7.333 (m, 1H, ArH), 7.852 (d, 2H, ArH), 7.962 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1693, 1622, 1409, 1318, 1143

Example 55 4- (3-chlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 160 mg of 3-chlorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 160 mg of the title compound.

mp: 131-132 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.926 (t, 6H, 2CH ₃ ), 1.978 (q, 4H, 2CH ₂ ), 3.083 (s, 3H, SO ₂ CH ₃ ), 7.116 (m, 1H, ArH), 7.296 (m, 3H, ArH), 7.850 (d, 2H, ArH), 7.953 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2973, 1695, 1620, 1403, 1318, 1150

Example 56 2,2-diethyl-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 160 mg of 3-methylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 150 mg of the title compound.

mp: 95 ~ 96 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.931 (t, 6H, 2CH ₃ ), 1.978 (q, 4H, 2CH ₂ ), 2.345 (s, 3H, CH ₃ ), 3.065 (s, 3H, SO ₂ CH ₃ ), 6.990 (d, 1H, ArH), 7.097 (d, 1H, ArH), 7.160 (d, 1H, ArH), 7.273 (m, 1H, ArH), 7.870 (d, 2H, ArH), 7.930 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1694, 1622, 1319, 1150

Example 57 2,2-diethyl-4- (3-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2M aqueous sodium carbonate solution and 160 mg of 3-methoxybenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 150 mg of the title compound.

mp: 80 ~ 81 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.929 (t, 6H, 2CH ₃ ), 1.974 (q, 4H, 2CH ₂ ), 3.070 (s, 3H, SO ₂ CH ₃ ), 3.782 (s, 3H, OCH ₃ ), 6.902 (m, 2H, ArH), 6.894 (dd, 1H, ArH), 7.288 (dd, 1H, ArH), 7.875 (d, 2H, ArH), 7.938 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1694, 1622, 1403, 1318, 1150

Example 58 2,2-diethyl-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 150 mg of 4-fluorobenzeneboronic acid were added and reacted at 95 DEG C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 150 mg of the title compound.

mp: 174 ~ 175 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.926 (t, 6H, 2CH ₃ ), 1.976 (q, 4H, 2CH ₂ ), 3.080 (s, 3H, SO ₂ CH ₃ ), 7.082 (m, 2H, ArH), 7.235 (m, 2H, ArH), 7.852 (d, 2H, ArH), 7.952 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2975, 1694, 1592, 1391, 1321, 1150

Example 59 4- (4-chlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 160 mg of 4-chlorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 150 mg of the title compound.

mp: 144 ~ 145 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.923 (t, 6H, 2CH ₃ ), 1.975 (q, 4H, 2CH ₂ ), 3.020 (s, 3H, SO ₂ CH ₃ ), 7.198 (d, 2H, ArH), 7.360 (m, 1H, ArH), 7.854 (d, 2H, ArH), 7.962 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1695, 1408, 1318, 1150

Example 60 2,2-diethyl-4- (4-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2M aqueous sodium carbonate solution and 160 mg of 4-methoxybenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

mp: 166 ~ 167 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.919 (t, 6H, 2CH ₃ ), 1.964 (q, 4H, 2CH ₂ ), 3.071 (s, 3H, SO ₂ CH ₃ ), 3.832 (s, 3H, OCH ₃ ), 6.919 (d, 2H, ArH), 7.174 (d, 2H, ArH), 7.879 (d, 2H, ArH), 7.936 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2971, 1692, 1593, 1513, 1317, 1149,

Example 61 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-methylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, followed by addition of 10 ml of a 2 M aqueous sodium carbonate solution and 160 mg of 4-methylbenzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 140 mg of the title compound.

mp: 96-97 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.922 (t, 6H, 2CH ₃ ), 1.968 (q, 4H, 2CH ₂ ), 2.375 (s, 3H, CH ₃ ), 3.067 (s, 3H, SO ₂ CH ₃ ), 7.129 (d, 2H, ArH), 7.294 (d, 2H, ArH), 7.862 (d, 2H, ArH), 7.930 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2971, 1693, 1594, 1401, 1317, 1149

Example 62 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 190 mg of 4-trifluoromethylbenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound.

mp: 121-122 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.939 (t, 6H, 2CH ₃ ), 1.997 (q, 4H, 2CH ₂ ), 3.092 (s, 3H, SO ₂ CH ₃ ), 7.396 (d, 2H, ArH), 7.637 (d, 2H, ArH), 7.845 (d, 2H, ArH), 7.981 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2973, 1697, 1622, 1392, 1325, 1151

Example 63 4- (4-acetylphenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, followed by addition of 10 ml of 2 M aqueous sodium carbonate solution and 160 mg of 4-acetylbenzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound in the form of a foam.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.944 (t, 6H, 2CH ₃ ), 1.998 (q, 4H, 2CH ₂ ), 2.622 (s, 3H, COCH ₃ ), 3.110 (s, 3H, SO ₂ CH ₃ ), 7.386 (d, 2H, ArH), 7.856 (d, 2H, ArH), 7.970 (dd, 4H, ArH)

IR (Neat, cm ^-1 ): 2973, 1693, 1617, 1410, 1317, 1151

Example 64 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-n-propylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, followed by addition of 10 ml of a 2 M aqueous sodium carbonate solution and 170 mg of 4-n-propylbenzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 90 mg of the title compound in the form of a foam.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.961 (t, 6H, 2CH ₃ ), 1.002 (q, 3H, CH ₃ ), 1.686 (m, 2H, CH ₂ ), 2.008 (dd, 2H, CH ₂₎ ), 2.646 (t, 2H, CH ₂ ), 3.113 (s, 3H, SO ₂ CH ₃ ), 7.188 (d, 2H, ArH), 7.237 (d, 2H, ArH), 7.912 (d, 2H, ArH) , 7.968 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2969, 1694, 1594, 1318, 1150

Example 65 2,2-diethyl-4- (3,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2M aqueous sodium carbonate solution and 160 mg of 3,4-difluorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 140 mg of the title compound.

mp: 159-160 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.918 (t, 6H, 2CH ₂ ), 1.978 (q, 4H, 2CH ₂ ), 3.094 (s, 3H, SO ₂ CH ₃ ), 6.963 (m, 1H, ArH), 7.153 (m, 2H, ArH), 7.851 (d, 2H, ArH), 7.983 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1696, 1516, 1318, 1276, 1149

Example 66 2,2-diethyl-4- (3,4-dimethoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

80 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone is dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 20 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 60 mg of 3,4-dimethoxybenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 30 mg of the title compound.

mp: 130-131 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.934 (t, 6H, 2CH ₃ ), 1.973 (q, 4H, 2CH ₂ ), 3.071 (s, 3H, SO ₂ CH ₃ ), 3.815 (s, 3H, OCH ₃ ), 3.903 (s, 3H, OCH ₃ ), 6.767 (m, 2H, ArH), 6.870 (d, 2H, ArH), 7.898 (d, 2H, ArH), 7.947 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2973, 1694, 1593, 1516, 1319, 1149

Example 67 2,2-diethyl-4- (2,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 160 mg of 2,4-difluorobenzeneboronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 50 mg of the title compound.

mp: 165-166 deg.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.929 (t, 6H, 2CH ₃ ), 1.988 (q, 4H, 2CH ₂ ), 3.072 (s, 3H, SO ₂ CH ₃ ), 6.873 (m, 1H, ArH), 6.981 (m, 1H, ArH), 7.268 (m, 1H, ArH), 7.835 (d, 2H, ArH), 7.960 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1695, 1593, 1318, 1150

Example 68 2,2-diethyl-4- (3-chloro-4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, followed by addition of 10 ml of a 2 M aqueous sodium carbonate solution and 180 mg of 3-chloro-4-fluoro benzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

mp: 173-174 deg.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.921 (t, 6H, 2CH ₃ ), 1.978 (q, 4H, 2CH ₂ ), 3.092 (s, 3H, SO ₂ CH ₃ ), 7.094 (m, 1H, ArH), 7.156 (t, 1H, ArH), 7.355 (dd, 1H, ArH), 7.853 (d, 2H, ArH), 7.983 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2973, 1694, 1503, 1308, 1149

Example 69 2,2-diethyl-4- (3-fluoro-4-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, followed by addition of 10 ml of a 2 M aqueous sodium carbonate solution and 180 mg of 3-fluoro-4-methoxy benzeneboronic acid, followed by reaction at 95 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 100 mg of the title compound.

mp: 183 ~ 184 ℃

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.915 (t, 6H, 2CH ₃ ), 1.967 (q, 4H, 2CH ₂ ), 3.088 (s, 3H, SO ₂ CH ₃ ), 3.916 (s, 3H, OCH ₃ ), 6.987 (m, 3H, ArH), 7.871 (d, 2H, ArH), 7.962 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2972, 1694, 1518, 1317, 1149

Example 70 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-thienyl) -3 (2H) furanone

300 mg of 4-bromo-2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, followed by tetrakis (triphenylforce). 40 mg of pin) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 130 mg of thiophene-3-boronic acid were added and reacted at 95 ° C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 80 mg of the title compound in the form of a foam.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.936 (t, 6H, 2CH ₃ ), 1.978 (q, 4H, 2CH ₂ ), 3.100 (s, 3H, SO ₂ CH ₃ ), 6.912 (dd, 1H, ArH), 7.333 (dd, 1H, ArH), 7.496 (dd, 1H, ArH), 7.930 (d, 2H, ArH), 7.998 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2971, 1693, 1311, 1149

Example 71 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-pyridyl) -3 (2H) furanone

300 mg of 2,2-diethyl-4-iodine-5- (4-methylsulfonylphenyl) -3 (2H) furanone was dissolved in a mixed solvent of 25 ml of toluene and 10 ml of ethanol, and 40 mg of tetrakis (triphenyl Phosphine) palladium (0) was added, and then 10 ml of a 2 M aqueous sodium carbonate solution and 130 mg of 3-pyridyl-trimethylboronic acid lithium salt were added and reacted at 95 DEG C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 30 mg of the title compound in the form of a foam.

¹ H NMR (CDCl ₃ , 300 MHz): δ 0.940 (t, 6H, 2CH ₃ ), 1.999 (q, 4H, 2CH ₂ ), 3.089 (s, 3H, SO ₂ CH ₃ ), 7.374 (dd, 1H, ArH), 7.705 (m, 1H, ArH), 7.847 (d, 1H, ArH), 8.439 (d, 1H, ArH), 8.581 (dd, 1H, ArH)

Example 72 2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

Step 1: 4-cyclopentylidene-1- (4-methylthiophenyl) -2-butyne-1,4-diol

18.5 mmol of 1-cyclopentylidene-ethyn-1-ol, 18 ml of n-butyllithium (2.5 M solution in Hexane) and 18 mmol of p-methylthiobenzaldehyde, the same method as in step 1 of Example 1 3.48 g of the title compound were obtained.

mp: 118-120 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ .726 (m, 4H, 2CH ₂ ), 1.865 (m, 4H, 2CH ₂ ), 2.159 (s, 1H, OH), 2.476 (s, 3H, SCH ₃ ), 2.551 (s, 1H, CH), 5.4326 (d, H, OH), 7.237 (d, 2H, ArH), 7.423 (d, 2H, ArH)

Step 2: 4-cyclopentylidene-4-hydroxy-1- (4-methylthiophenyl) -2-butyn-1-one

Except that 1.54 g of 4-cyclopentylidene-1- (4-methylthiophenyl) -2-butyne-1,4-diol prepared in step 1 and 3.32 g of pyridinedichlorochromate (PCC) were used. 1 g of the title compound was obtained by the same method as the second step of Example 1.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.848 (m, 4H, 2CH ₂ ), 2.120 (m, 4H, 2CH ₂ ), 2.534 (s, 3H, CH ₃ S), 5.954 (s, 1H, OH ), 7.267 (d, 2H, ArH), 8.014 (d, 2H, ArH)

Step 3: 2,2-cyclopentylidene-5- (4-methylthiophenyl) -3 (2H) furanone

Except that 1.54 g of 4-cyclopentylidene-4-hydroxy-1- (4-methylthiophenyl) -2-butyn-1-one prepared in step 2 and 0.75 ml of diethylamine were used. 858 mg of the title compound was obtained in the same manner as Step 3 of Example 1.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.889 (m, 6H, 3CH ₂ ), 1.921 (m, 2H, CH ₂ ), 2.469 (s, 3H, CH ₃ S), 5.886 (s, 1H, vinyl ), 7.235 (d, 2H, ArH), 7.645 (d, 2H, ArH)

Step 4: 4-bromo-2,2-cyclopentylidene-5- (4-methylthiophenyl) -3 (2H) furanone

Except that 147 mg of 2,2-cyclopentylidene-5- (4-methylthiophenyl) -3 (2H) furanone prepared in step 3, 1 ml of bromine and 0.1 ml of acetic acid were used 50 mg of the title compound were obtained in the same manner as step 5 of 1.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.978 (m, 6H, 2CH ₂ ), 2.107 (m, 2H, CH ₂ ), 2.545 (s, 3H, CH ₃ ), 7.316 (m, 2H, ArH ), 8.126 (m, 2H, ArH)

Step 5: 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

Example 1 except that 50 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylthiophenyl) -3 (2H) furanone prepared in step 4 and 292 mg of oxone were used 68 mg of the title compound was obtained in the same manner as step 4 of.

mp: 127-128 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.983 (m, 6H, 2CH ₂ ), 2.124 (m, 2H, CH ₂ ), 3.107 (s, 3H, CH ₃ ), 8.090 (m, 2H, ArH) , 8.371 (m, 2H, ArH)

Step 6: 2,2-cyclopentylidene-4-phenyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone

77 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 was added to a mixed solvent of 5 ml of toluene and 15 ml of ethanol. After dissolving, 15 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 5 ml of a 2M aqueous sodium carbonate solution and 27 mg of benzeneboronic acid, followed by reaction at 90 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 57 mg of the title compound.

mp: 184-185 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.086 (m, 8H, 4CH ₂ ), 2.168 (m, 2H, CH ₂ ) 3.060 (s, 3H, SO ₂ CH ₃ ), 7.262 (m, 2H, ArH ), 7.354 (m, 3H, ArH) 7.813 (m, 2H, ArH), 7.915 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2925, 1695, 1591, 1403, 1150, 771

Example 73 2,2-cyclopentylidene-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -x3 (2H) furanone

107 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. It was dissolved in a mixed solvent of, 29 mg of tetrakis (triphenylphosphine) palladium (0) was added, and 5 ml of 2M aqueous sodium carbonate solution and 41 mg of 3-methylbenzeneboronic acid were added and reacted at 90 ° C. for 12 hours. . Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 75 mg of the title compound.

mp: 142-143 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.026 (m, 8H, 4CH ₂ ), 2.102 (m, 2H, CH ₂ ), 2.344 (s, 3H, CH ₃ ), 3.060 (s, 3H, SO ₂ CH ₃ ), 6.998 (d, 1H, ArH), 7.142 (m, 1H, ArH), 7.262 (m, 2H, ArH) 7.831 (m, 2H, ArH), 7.919 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2962, 1693, 1620, 1403, 1150, 958, 770

Example 74 2,2-cyclopentylidene-4- (4-isopropylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

105 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. Was dissolved in a mixed solvent of 20 mg of tetrakis (triphenylphosphine) palladium (0), and then 5 ml of 2M aqueous sodium carbonate solution and 50 mg of 4-isopropylbenzeneboronic acid were added for 12 hours at 90 ° C. Reacted. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 87 mg of the title compound.

mp: 139-140 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.248 (s, 3H, CH 3), 1.272 (s, 3H, CH 3), 2.038 (m, 8H, 4CH ₂ ), 2.152 (m, 2H, CH ₂ ), 2.916 (m, 1H, CH), 3.062 (s, 3H, SO ₂ CH ₃ ), 6.998 (d, 1H, ArH), 7.207 (m, 4H, ArH), 7.831 (m, 2H, ArH) 7.932 (m , 2H, ArH)

IR (Neat, cm ^-1 ): 2960, 1694, 1622, 1386, 1318, 1161, 768

Example 75 2,2-cyclopentylidene-4- (3,5-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

103 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. Dissolved in a mixed solvent of 20 mg of tetrakis (triphenylphosphine) palladium (0), and then 5 ml of a 2M aqueous sodium carbonate solution and 47 mg of 3,5-difluorobenzeneboronic acid were added to the mixture at 90 캜. The reaction was carried out for a time. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 87 mg of the title compound.

mp: 127-128 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.030 (m, 8H, 4CH ₂ ), 2.160 (m, 2H, CH ₂ ), 3.093 (s, 3H, SO ₂ CH ₃ ), 6.798 (d, 1H, ArH), 6.834 (m, 2H, ArH), 7.815 (m, 2H, ArH) 7.982 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2962, 1702, 1626, 1591, 1393, 1287, 1197, 987

Example 76 2,2-cyclopentylidene-4- (2-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

99 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. Was dissolved in a mixed solvent of hexane, 18 mg of tetrakis (triphenylphosphine) palladium (0) was added, and then 5 ml of 2M aqueous sodium carbonate solution and 43 mg of 2-fluorobenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. I was. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 32 mg of the title compound.

mp: 120-121 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.047 (m, 8H, 4CH ₂ ), 2.173 (m, 2H, CH ₂ ), 3.060 (s, 3H, SO ₂ CH ₃ ), 7.091 (d, 1H, ArH), 7.235 (m, 1H, ArH), 7.381 (m, 1H, ArH), 7.819 (m, 2H, ArH) 7.834 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2960, 1696, 1594, 1404, 1319, 1150

Example 77 2,2-cyclopentylidene-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

104 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. Dissolved in a mixed solvent of 15 mg of tetrakis (triphenylphosphine) palladium (0), and then 5 ml of a 2M aqueous sodium carbonate solution and 47 mg of 4-fluorobenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. I was. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 93 mg of the title compound.

mp: 109-113 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.031 (m, 8H, 4CH ₂ ), 2.161 (m, 2H, CH ₂ ), 3.077 (s, 3H, SO ₂ CH ₃ ), 7.084 (d, 2H, ArH), 7.276 (m, 2H, ArH), 7.809 (m, 2H, ArH) 7.850 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2960, 1696, 1594, 1404, 1319, 1150

Example 78 2,2-cyclopentylidene-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

104 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. Dissolved in a mixed solvent of 15 mg of tetrakis (triphenylphosphine) palladium (0), and then 5 ml of a 2M aqueous sodium carbonate solution and 47 mg of 3-fluorobenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. I was. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 93 mg of the title compound.

mp: 158-160 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.028 (m, 8H, 4CH ₂ ), 2.167 (m, 2H, CH ₂ ), 3.079 (s, 3H, SO ₂ CH ₃ ), 7.060 (d, 2H, ArH), 7.351 (m, 2H, ArH), 7.815 (m, 2H, ArH) 7.945 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2961, 1695, 1621, 1403, 1318, 1151, 770

Example 79 4- (4-acetylphenyl) -2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

110 mg of 4-bromo-2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 of Example 72 was charged with 5 ml of toluene and 15 ml of ethanol. Was dissolved in a mixed solvent of tetramethyl (triphenylphosphine) palladium (0) and 21 mg were added. Then, 5 ml of a 2M aqueous sodium carbonate solution and 55 mg of 4-acetylbenzeneboronic acid were added and reacted at 90 DEG C for 12 hours. I was. Hereinafter, extraction and purification were carried out in the same manner as in the sixth step of Example 1 to obtain 93 mg of the title compound.

mp: 126-130 ° C

¹ H NMR (CDCl ₃ , 300 MHz): δ 2.038 (m, 8H, 4CH ₂ ), 2.169 (m, 2H, CH ₂ ), 2.614 (s, 3H, CH ₃ ), 3.077 (s, 3H, SO ₂ CH ₃ ), 7.390 (d, 2H, ArH), 7.810 (m, 2H, ArH), 7.935 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2963, 1689, 1317, 1150, 771

Example 80 2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

Step 1: 4-cyclohexylidene-1- (4-methylthiophenyl) -2-butyne-1,4-diol

Example 1, except that 3.20 mg of 1-cyclohexylidene-ethyn-1-ol, 35 ml of n-butyllithium (2.5 M solution in Hexane) and 3.2 ml of p-methylthiobenzaldehyde were used. In the same manner, 4.67 g of the title compound was obtained.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.489 (m, 6H, 2CH ₂ ), 1.704 (m, 2H, 2CH ₂ ), 1.901 (m, 2H, 2CH ₂ ), 2.168 (d, 1H, OH ), 2.491 (s, 3H, SCH ₃ ), 3.566 (s, 1H, CH), 5.483 (d, 1H, OH), 7.260 (d, 2H, ArH), 7.459 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 3343, 2934, 1445, 1091

Step 2: 4-cyclohexylidene-4-hydroxy-1- (4-methylthiophenyl) -2-butyn-1-one

Example 1 except that 3.564 g of 4-cyclohexylidene-1- (4-methylthiophenyl) -2-butyne-1,4-diol prepared in step 1 and 1.79 g of chromium oxide were used. 1.42 g of the title compound was obtained by the same method as the step 2 below.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.577 (m, 4H, 2CH ₂ ), 1.764 (m, 4H, 2CH ₂ ), 2.030 (m, 2H, CH ₂ ), 2.328 (s, 1H, OH) , 2.529 (s, 3H, CH ₃ S), 7.261 (d, 2H, ArH), 8.006 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 3416, 2936, 1637, 1588, 1263, 1096

Step 3: 2,2-cyclohexylidene-5- (4-methylthiophenyl) -3 (2H) furanone

Except that 1.30 g of 4-cyclohexylidene-4-hydroxy-1- (4-methylthiophenyl) -2-butyn-1-one prepared in step 2 and 0.6 ml of diethylamine were used. The procedure was carried out in the same manner as in the third step of Example 1, whereby 858 mg of the title compound was obtained.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.707 (m, 5H, 5CH ₂ ), 2.537 (s, 3H, CH ₃ S), 5.915 (s, 1H, vinyl), 7.301 (d, 2H, ArH) , 7.745 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2933, 1686, 1588, 1408, 1095, 744

Step 4: 2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

In the same manner as in step 4 of 1 above, except that 1 g of 2,2-cyclohexylidene-5- (4-methylthiophenyl) -3 (2H) furanone and oxone prepared in step 3 are used. 470 mg of the title compound was obtained.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.772 (m, 5H, 5CH ₂ ), 3.094 (s, 3H, SO ₂ CH ₃ ), 6.100 (s, 1H, vinyl), 8.047 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2935, 1694, 1589, 1408, 1315, 1153, 775

Step 5: 4-bromo-2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

Except for using 50 mg of 2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 4, 0.1 ml of acetic acid and 0.5 ml of liquid bromine. 68 mg of the title compound was obtained by the same method as the step 5 of Example 1.

mp: 163-164 ^o C

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.791 (m, 10H, 5CH ₂ ), 3.106 (s, 3H, CH ₃ ), 8.101 (m, 2H, ArH), 8.402 (m, 2H, ArH)

IR (Neat, cm ^-1 ): 2936, 1709, 1583, 1316, 1149, 912, 744

Step 6: 2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone

102 mg of 4-bromo-2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 was added to a mixed solvent of 3 ml of toluene and 15 ml of ethanol. After dissolving, 16 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 3 ml of a 2M aqueous sodium carbonate solution and 35 mg of benzeneboronic acid, followed by reaction at 90 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 50 mg of the title compound.

mp: 126-127 캜

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.816 (m, 10H, 5CH ₂ ), 3.063 (s, 3H, SO ₂ CH ₃ ), 7.265 (m, 2H, ArH), 7.346 (m, 3H, ArH ), 7.832 (d, 2H, ArH), 7.936 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2936, 1693, 1621, 1404, 1318, 1147, 1129, 730

Example 81 2,2-cyclohexylidene-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

106 mg of 4-bromo-2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 was added to a mixed solvent of 3 ml of toluene and 15 ml of ethanol. After dissolving, 17 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 3 ml of a 2M aqueous sodium carbonate solution and 39 mg of 3-methylbenzeneboronic acid, followed by reaction at 90 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 65 mg of the title compound.

mp: 154-155 캜

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.816 (m, 10H, 5CH ₂ ), 2.338 (s, 3H, CH ₃ ) 3.060 (s, 3H, SO ₂ CH ₃ ), 6.990 (d, 2H, ArH ), 7.131 (d, 1H, ArH), 7.250 (m, 2H, ArH), 7.860 (m, 2H, ArH), 7.927 (d, 2H, ArH)

IR (Neat, cm ^-1 ): 2934, 1693, 1621, 1403, 1147, 1129, 716

Example 82 4- (4-acetylphenyl) -2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone

84 mg of 4-bromo-2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone prepared in step 5 was added to a mixed solvent of 3 ml of toluene and 15 ml of ethanol. After dissolving, 15 mg of tetrakis (triphenylphosphine) palladium (0) was added, followed by 3 ml of a 2M aqueous sodium carbonate solution and 40 mg of 4-acetylbenzeneboronic acid, followed by reaction at 90 ° C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 35 mg of the title compound.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.817 (m, 10H, 5CH ₂ ) 2.614 (s, 3H, COCH ₃ ) 3.082 (s, 3H, SO ₂ CH ₃ ), 7.374 (d, 2H, ArH) , 7.839 (d, 2H, ArH), 7.967 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2963, 1689, 1621, 1317, 1150, 771

Example 83 2,2-dimethyl-4- (1-methyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

445 mg of 2,2-dimethyl-4-iodo-5- (4-methylsulfonylphenyl) -3 (2H) furanone is dissolved in a mixed solvent of 50 ml of toluene and 15 ml of ethanol, followed by tetrakis (triphenylphosphine). ) 25 mg of palladium (0) was added, and then 15 ml of a 2M aqueous sodium carbonate solution and 547 mg of lithium-1-methylpyrazole-4-trimethylboronate were added and reacted at 90 ° C. for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 290 mg of the title compound.

mp: 114-115 degreeC

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.541 (s, 6H, 2CH ₂ ), 3.104 (s, 3H, SO ₂ CH ₃ ), 3.937 (s, 3H, NCH ₃ ), 7.338 (s, 1H, ArH), 7.338 (s, 1H, ArH), 7.994-8.063 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2930, 1700, 1538, 1314, 1148, 884, 771

Example 84 2,2-dimethyl-4- (1-isopropyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone

250 mg of 2,2-dimethyl-4-iodo-5- (4-methylsulfonylphenyl) -3 (2H) furanone is dissolved in a mixed solvent of 50 ml of toluene and 15 ml of ethanol, followed by tetrakis (triphenylforce). 25 mg of pin) palladium (0) was added, and then 15 ml of a 2 M aqueous sodium carbonate solution and 170 mg of lithium-1-isopropylpyrazole-4-trimethylboronate were added and reacted at 90 DEG C for 12 hours. Hereinafter, the extraction and purification process was carried out in the same manner as in the sixth step of Example 1 to obtain 90 mg of the title compound.

mp: 143-145 캜

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.454 (m, 6H, 2CH ₂ ), 1.515 (s, 6H, 2CH ₃ ), 3.098 (s, 3H, SO ₂ CH ₃ ), 4.320 (m, 1H, CH), 7.113 (s, 1H, ArH), 7.159 (s, 1H, ArH), 8.050 (m, 4H, ArH)

IR (Neat, cm ^-1 ): 2981, 2931, 1698, 1561, 1409, 1315, 1152, 967, 775, 552

Example 85 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (3-pyrazole) -3 (2H) furanone

Step 1: 1-trityl-4-bromopyrazole

0.5 g of 4-bromopyrazole and 1.43 g of trityl chloride are dissolved in 30 ml and reacted under reflux for 18 hours. The pyridine was removed by distillation under reduced pressure and purified by column chromatography (nucleic acid: ethyl acetate = 1: 1) to give 1.32 g.

Step 2: 1-tritylpyrazole-4-trimethylboronic acid lithium salt

1.4 mL of n-butyllidium and 1-trityl-4-bromopyrazole of the above step are added to 30 mL of tetrahydrofuran solvent and stirred at -78 ^° C for 30 minutes. 0.76 ml of triisopropylborate is added and stirred for 1 hour. 20 ml of methanol is added and the mixed solvent is removed by distillation under reduced pressure. Distillation under reduced pressure three times in this way. The reaction is carried out in the form of a salt without further purification.

Step 3: 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (1-trityl-3-pyrazole) -3 (2H) furanone

300 mg of 2,2-dimethyl-4-iodo-5- (4-methylsulfonylphenyl) -3 (2H) furanone is dissolved in a mixed solvent of 50 ml of toluene and 15 ml of ethanol, followed by tetrakis (triphenylforce). 25 mg of pin) palladium (0) was added, and then 15 ml of a 2M aqueous sodium carbonate solution and 480 mg of 1-tritylpyrazole-4-trimethylboronic acid lithium salt were added and reacted at 90 DEG C for 12 hours. Hereinafter, extraction and purification were carried out in the same manner as in Example 6, to obtain 120 mg of the title compound.

Step 4: 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (3-pyrazole) -3 (2H) furanone

120 mg of 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (1-trityl-3-pyrazole) -3 (2H) furanone and 36 mg of p-toluenesulfonic acid in the above three steps Stir in 23 ml of methanol for 3 hours. After methanol was removed by distillation under reduced pressure, 30 ml of water was added thereto. 30 ml of dichloromethane was extracted three times. Dichloromethane was removed by distillation under reduced pressure and purified by column chromatography (nucleic acid: ethyl acetate = 1: 4) to give 60 mg.

¹ H NMR (CDCl ₃ , 300 MHz): δ 1.562 (s, 6H, 2CH ₃ ), 3.113 (s, 3H, SO ₂ CH ₃ ), 7.876 (s, 2H, pyrazol), 8.050 (m, 5H, ArH + NH)

IR (Neat, cm ^-1 ): 3325, 1702, 1408, 1316, 1148, 913

[Test Example 1]

Inhibitory effect of COX-2 and COX-1 on indomethacin as the compound and the reference material was measured according to the following experimental method and the results are shown in Table 1, and induced by carrageenan. The foot edema inhibition effect of the rats was measured by the following experimental method, and the results are shown in Table 2.

1.Evaluation of COX-2 Inhibitory Effect (J. Pharmacol.Exp. Ther. V. 166, 96 (1969))

After disinfecting the abdomen of C57BL / 6 mice with 70% ethanol, remove the abdominal skin, taking care not to damage the peritoneum, add 5 ml of cold phosphate buffer (PBS) into the abdominal cavity, and let the macrophage out after a certain period of time. The prepared abdominal fluid was collected using a syringe. The collected solution was dispersed by centrifugation at 1500 rpm for 5 minutes by adding RPMI-1640 medium containing 100 unit / ml penicillin and 100 mg / ml streptomycin. At this time, 500 μM of aspirin was treated to inactivate COX-1 present in the cells. Cell number 1 × 10 ⁶ cells / ㎖ is a cell suspension, a 24-well microtiter was added to each well of the plate by 1㎖ macrophages were cultured for 2 hours under conditions of _{37 ℃, 5% CO 2/} 95% O 2 to be Was attached to the bottom of the plate. Other non-attached cells were removed by washing twice with PBS. The purity of macrophages obtained through this procedure was confirmed by differential counting. RPMI-1640 medium containing 3% fetal bovine serum was added to the macrophages (usually 5 × 10 ⁵ cells / ml) and LPS (lipopolysaccharide) was treated to give a final concentration of 10µg / ml at 37 ° C and 5% CO _2. Incubated for 16 hours under the conditions of. After inducing COX-2 with LPS, the cell culture was removed and the macrophages were washed twice with PBS. Again, 1 ml of RRPI-1640 medium was added to each well, and the sample was incubated at 37 ° C. for 10 minutes, treated with arachidonic acid so that the final concentration was 10 μM, and further incubated for 10 minutes. The whole amount was taken. The amount of PGE ₂ produced in the reaction supernatant was quantified using radioimmunoassay or enzyme immunoassay (Methods in Enzymology, 86, 258 (1982); Methods in Enzymology, 187, 24 (1990). )). The activity of 100% COX-2 was based on the difference in the amount of PGE ₂ produced in the supernatant of the arachidonic acid treated group and the untreated group of 10 µg / ml.

2. Evaluation of COX-1 Inhibitory Effect

Except for the aspirin pretreatment and LPS treatment when macrophages are attached, the evaluation was performed in the same manner as in the evaluation of COX-2 inhibition efficacy.

Evaluation of the Inhibitory Effect of COX-2 and COX-1 Comparison from Table 1, the 2-position of 2-methyl-2-ethyl-aryl-3 (2H) furanone in the alkyl derivative of diarylfuranone is substituted with an alkyl group. It can be seen that the selectivity to COX-2 is very excellent when the derivative is used. That is, the alkyl derivative of the diarylfuranone according to the present invention can be said to be a compound suitable as an inhibitor capable of selectively inhibiting cyclooxygenase that inhibits COX-2 but does not inhibit COX-1.

3. Determination of plantar edema suppression induced by carrageenan

After 1 hour oral administration of a solution in which an appropriate amount of a sample was suspended in 0.5% carboxymethylcellulose and 0.2% TWEEN solution in a male Sprague-Dawley rat weighing 150-200 g, 1% carrageenin on the right foot of the rat Edema was induced by injection of 0.1 ml of carrageenan-saline solution. The edema rate was calculated by measuring the volume of the rats with a displacement plethysmometer (Ugo Basile, Italy) immediately after and 3 hours after inflammation caused by carrageenan (Br. J. Pharmacol., 41, 132 (1971)). The drug was administered 1 hour before the carrageenan injection. Edema inhibition rate was calculated by the following equation (1).

ΔV: change in volume

Suppression rate of edema caused by carrageenin (% inhibition rate) Oral administration (mg / Kg) Indomethacin 47 ± 29 3 Example 14 28 ± 8 3 Example 73 31 ± 15 3 Example 83 36 ± 11 3

As can be seen from Table 1 and Table 2, the diaryl-3 (2H) furanone derivative of the general formula (I) according to the present invention has a high selectivity with respect to COX-2 and selectively COX- 2 may inhibit the action. Diaryl-3 (2H) furanone derivatives can effectively inhibit COX-2 in very small amounts because the effective inhibitory concentration (IC ₅₀ ) is less than 0.1 μg / mL and the COX-2 has very good selectivity to COX-1. It can be called a drug.

The present invention relates to cyclooxygenase-2 inhibitors containing a therapeutically effective amount of a compound of formula (I) together with one or more non-toxic, pharmaceutically acceptable carriers, adjuvants or diluents, or other active ingredients. (cyclooxygenase-2 inhibitor) composition, wherein the composition of the present invention is in the form of a solution, suspension or emulsion in an oil or an aqueous medium, or a dry powder that is dissolved in sterile, pyrogen-free water before use. Oral formulations, subcutaneous injections, intravenous injections, intramuscular injections, intramuscular injections, parenteral formulations such as suppositories, topical formulations such as creams, gels, ointments or suspensions, mouthwashes and the like.

In the case of oral formulations, the compositions of the present invention may be used in known manner using pharmaceutically acceptable carriers and excipients, for example tablets, troches, sugar-containing tablets, aqueous or oily suspensions, dispersible flours or particles. , Formulations such as emulsions, soft or hard capsules, syrups, elixirs, which are contained in unit dosage forms and in multidose containers.

In oral formulations, tablets may be inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; Granulating agents such as corn, starch and alginic acid; Disintegrants; Binders such as starch, gelatin and acacia; The compound of the present invention is mixed with an excipient which can be used for the preparation of tablets, such as lubricants such as magnesium stearate, stearic acid and talc. Tablets may be used uncoated or coated to inhibit absorption and degradation of the tablets in the gastrointestinal tract. For example, you may apply time inhibiting substances, such as glyceryl monostearate and glyceryl distearate. Hard capsule is a compound of the present invention is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin, etc., soft capsule is a solvent such as polypropylene glycol, PEGs (polyethylene glycol), ethanol, etc. that can be mixed with water And the active ingredients in oil solvents such as peanut oil, liquid paraffin and olive oil.

The water-soluble suspending agent is a mixture of excipients and active ingredients suitable for the preparation of water-soluble suspending agents. Excipients include, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxy-propyl methyl cellulose, sodium alginate, polyvinyl-pi Suspending agents such as ralidone, gum tragacanth, gum acacia and the like; Compounds condensing fatty acids such as polyoxyethylene stearate and alkylene oxides; Compounds in which alkylene oxides are condensed with long fatty acids such as heptadecaethyleneoxycetanol; Compounds which condensate partial esters derived from anhydrous hexitol anhydride and fatty acids, such as polyoxyethylene sorbitol monooleate, with ethylene oxide; Wetting agents; Or dispersing agents. Water-soluble suspensions contain preservatives, colorants, spices, sweeteners and the like.

The oily suspension is a suspension of an active ingredient in a vegetable oil such as olive oil, sesami oil, or a mineral oil such as liquid paraffin. For example, a thickening agent such as beeswax, hardened paraffin, cetyl alcohol, etc. may be used. It contains. It also contains preservatives, colorants, spices, sweeteners and the like, which can be preserved by adding antioxidants such as vitamin C.

Dispersible powders and particles have an active ingredient in a state in which a dispersing agent, a wetting agent, a suspending agent, a preservative and the like are mixed together. Suitable dispersing, wetting or suspending agents can be mentioned by way of example already mentioned above. Additional excipients are, for example, sweeteners, spices, colorants and the like.

Water-in-oil emulsions are derived from vegetable oils such as olive oil or mineral oils such as liquid paraffin, and are derived from natural phospholipids such as soy bean lecithin, and esters of anhydrous hecitol or fatty acids such as sorbitan monooleate. The active ingredient is emulsified using compounds obtained by condensation of ethylene oxide with partial esters derived from anhydrous hexitol anhydride and fatty acids such as oxyoxysorbitol monooleate.

Syrups and elixirs are a mixture of active ingredients with sweeteners such as glycerol, propylene glycol, sorbitol and sucrose.

Parenteral formulations are injected by formulation in sterile injectable solutions or suspensions in which the active ingredient is suspended in a non-toxic usable diluent or solvent such as 1,3-butanediol. Among the excipients or solvents available are water, Ringer's solution and isotonic saline solution. Cosolvents such as ethanol, polyethylene glycol, and polypropylene glycol can also be used. In addition, sterile, nonvolatile oils can be customarily used as solvents or suspending solvents. Mixed, non-stimulating, bland fixed oils for this purpose include synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid can be used for the preparation of injectables. The suppository form is formulated by mixing the drug with a suitable non-irritating excipient such as cocoa butter or polyethylene glycol, which is solid at room temperature but liquid at the rectal temperature and will melt in the rectum to release the drug. Administration.

Topical formulations generally consist of pharmaceutical carriers, cosolvents, emulsifiers, penetration enhancers, preservatives, emollients.

When treating a disease using the composition of the present invention, the dose of active compound (I) is determined by the patient's age, weight, general state of health, sex, meal, time of administration, rate of excretion, drug combination, during treatment. Depending on the severity of the disease, depending on the disease can be used daily up to 0.01 ~ 140mg / kg body weight, 0.5mg ~ 7g per patient can be used. For example, inflammation can be effectively treated by administering the compositions of the present invention to 0.01-50 mg / kg body weight, or up to 0.5 mg-3.5 g per patient per day.

On the other hand, the amount of the compound of the present invention mixed with the carrier material to determine one dosage form depends on the mode of administration and the patient being treated. For example, a formulation intended for oral administration to humans will contain from 5 to 95 percent of the carrier material and 0.5 mg to 5 g of active ingredient, while a formulation intended for parenteral administration to humans Carrier materials account for 5 to 99% of the total composition and 0.1 mg to 2.5 g of active ingredient.

As described above, the compound (I) of the present invention greatly improves selectivity with respect to cyclooxygenase-2 (COX-2), so that the prostaglandin of COX-2 is reduced even with a lower amount of drug. It can effectively inhibit the biosynthetic action of the COX-2 is very effective in the treatment of diseases involving.

Claims (3)

2,2-dialkyl-4,5-diaryl-3 (2H) furanone (2,2-dialkyl-4,5-diaryl- as a cyclooxygenase-2 inhibitor represented by the following general formula (I) 3 (2H) furanone) derivatives and pharmaceutically acceptable salts thereof: (Ⅰ) In the above formula, A is CH ₃ S, CH ₃ SO or CH ₃ SO ₂ , B and C are the same as or different from each other, and are a methyl or ethyl group (but, when B is a methyl group, C is not a methyl group) or a cyclohexylidene or cyclopentylidene group formed by bonding to each other, D is benzo [b] thienyl, 1-naphthyl, 2-naphthyl, benzofuranyl, furanyl or a substituent having the following structural formula. Wherein R ¹ to ⁵ are the same or different, hydrogen, halogen, lower alkyl having 1 to 5 carbon atoms, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, nitro, nitrile, azido, methylenedi Oxy, phenyl, lower alkyl thio having 1 to 5 carbon atoms, lower alkyl sulfonyl having 1 to 5 carbon atoms, COR ⁶ or NR ⁷ R ⁸ . Wherein R ⁶ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms, R ^7-8 are the same or different from each other and are a hydrogen, methyl, ethyl or acetyl group. In the above formula, R ⁹ is hydrogen, acetyl, 1,3-dioxanyl 2-yl, formyl or methyl group. In the above formula, R ¹⁰ is hydrogen, methyl or methoxy group. In the above formula, R ¹¹ is a hydrogen, methyl, trityl or isopropyl group, provided that both B and C are methyl groups in this case. A diaryl-3 (2H) furanone alkyl derivative and a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by the general formula (I) is a compound described below. 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (phenyl) -3 (2H) furanone 2-ethyl-4- (4-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (3-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (2-fluorophenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (4-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,5-difluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,4-difluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-chloro-4-fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-pyridyl) -3 (2H) furanone 2-ethyl-4- (4-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-4- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-trifluoromethylphenyl) -3 (2H) furanone 4- (3-chlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-acetylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-N-acetoamidophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-4- (3,4-methylenedioxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-4- (5-methyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (3-chloro-4-trifluoromethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (4-ethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (3-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (3-isopropylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-n-propylphenyl) -3 (2H) furanone 4- (4-t-butylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-4- (6-methyl-3-pyridyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (6-methoxy-3-pyridyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-thienyl) -3 (2H) furanone 4- (4-n-butylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,4-dimethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (2-furanyl) -3 (2H) furanone 4- (3,4-dichlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (2-benzo [b] thienyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (2-benzo [b] furanyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-aminophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-Difluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (4-fluoromethylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (4-chlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethoxyphenyl) -3 (2H) furanone 4- (4-Chloro-3-fluorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (2-thienyl) -3 (2H) furanone 4- (5-acetyl-2-thienyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (4-fluoro-2-methylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (5-fluoro-2-methylphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,4-dimethoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-4- (3-fluoro-4-methoxyphenyl) -2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,5-Ditrifluoromethylphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,5-dichlorophenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3,5-dimethyl-4-methoxyphenyl) -2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3,4,5-trimethoxyphenyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (5-methyl-2-thienyl) -3 (2H) furanone 2-ethyl-2-methyl-5- (4-methylsulfonylphenyl) -4- (3-methyl-2-thienyl) -3 (2H) furanone 2,2-diethyl-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone 2,2-diethyl-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-chlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (4-chlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (4-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (4-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-trifluoromethylphenyl) -3 (2H) furanone 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-trifluoromethylphenyl) -3 (2H) furanone 4- (4-acetylphenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (4-n-propylphenyl) -3 (2H) furanone 4- (2,4-dichlorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3,4-dimethoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (2,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3,4-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3,5-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (3-chloro-4-fluorophenyl) -2,2-diethyl-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3-fluoro-4-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3-fluoro-5-methoxyphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-4- (3,4-dimethylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-thienyl) -3 (2H) furanone 2,2-diethyl-5- (4-methylsulfonylphenyl) -4- (3-pyridyl) -3 (2H) furanone 2,2-dimethyl-4- (1-methyl-3-pyrazole) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (3-pyrazole) -3 (2H) furanone 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (1-trityl-3-pyrazole) -3 (2H) furanone 2,2-dimethyl-5- (4-methylsulfonylphenyl) -4- (1-isopropyl-3-pyrazole) -3 (2H) furanone 2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone 2,2-cyclopentylidene-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-cyclopentylidene-4- (4-isopropylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-cyclopentylidene-4- (3,5-difluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-cyclopentylidene-4- (2-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-cyclopentylidene-4- (3-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-cyclopentylidene-4- (4-fluorophenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (4-acetylphenyl) -2,2-cyclopentylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone 2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -4-phenyl-3 (2H) furanone 2,2-cyclohexylidene-4- (3-methylphenyl) -5- (4-methylsulfonylphenyl) -3 (2H) furanone 4- (4-acetylphenyl) -2,2-cyclohexylidene-5- (4-methylsulfonylphenyl) -3 (2H) furanone Cyclooxygenase-2, characterized by containing an effective amount of the 2,2-dialkyl-4,5-diaryl-3 (2H) furanone derivative and pharmaceutically acceptable salt thereof according to claim 1 (cyclooxygenase-2) inhibitor composition.