ES2974025T3 - Derivative of 1,3-di-oxo-indene, pharmaceutically acceptable salt or optical isomer thereof, method of preparation thereof, and pharmaceutical composition containing the same, active ingredient, antiviral - Google Patents

Abstract

1,3-Dioxoindene derivatives of Formula 1, their pharmaceutically acceptable salts or enantiomers, a method of preparing them and a pharmaceutical composition for the prevention or treatment of viral diseases, comprising them as an active ingredient, are disclosed. 1,3-Dioxoindene derivatives have excellent inhibitory activity against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus, and exhibit low cytotoxicity, so they may be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media. (Automatic translation with Google Translate, without legal value)

Description

DESCRIPTION

Derivative of 1,3-di-oxo-indene, pharmaceutically acceptable salt or optical isomer thereof, method of preparation thereof, and pharmaceutical composition containing the same, active ingredient, antiviral

[Technical field]

The present invention relates to Formula 1, pharmaceutically acceptable salts thereof or enantiomers thereof, methods of preparation thereof, and pharmaceutical compositions for the prevention and treatment of viral diseases, comprising the same.

[Background of the art]

Picornaviruses are positive, non-enveloped, single-stranded RNA viruses with an RNA genome of 7.2 - 8.5 Kb in length. These viruses are very small and globular in shape with a size of approximately 22 - 30 nm, and were first identified a long time ago. Among the viruses that belong to the Picomaviridae family are enteroviruses, including rhinoviruses, polioviruses, coxsackievirus A, coxsackievirus B, and ecoviruses, and hepatitis A viruses.

The diseases caused by picornaviruses are varied, ranging from respiratory diseases to digestive diseases, circulatory diseases and skin diseases, examples of which include poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, and foot and mouth disease. However, there are no therapeutic agents to cure these diseases. Most drugs in development are coating inhibitors. Viruses belonging to the Picornaviridae family cause various diseases, including the respiratory diseases already mentioned, which raise hygienic, social and economic issues. Picornaviruses are the main causative agents of waterborne diseases. Being very stable and difficult to disinfect, RNA viruses incessantly cause related diseases.

Human rhinoviruses (hRV) have recently been associated with most asthma exacerbations, and are known to exist even in bronchial tissues of many patients with stable asthma. Comparison of respective bronchial mucosa biopsy samples taken from patients with and without asthma showed significantly higher frequencies of human rhinovirus detection in the lower respiratory tract of patients with asthma, compared to non-asthmatic patients. It has also been reported that there is a correlation between the presence of human rhinovirus and the clinical severity of asthma. Additionally, rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media as well as asthma.

Rhinoviruses are the main cause of common cold, while enterovirus-induced diseases include meningitis, respiratory tract infection, etc. The widespread effort to provide poliovirus vaccination has significantly reduced the occurrence of polio around the world, but there are still reports of cases of the disease in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. It is now possible to control hepatitis A to some extent with hepatitis A virus vaccines. However, no vaccines have been developed for coxsackieviruses, ecoviruses, or rhinoviruses, until now.

In particular, coxsackievirus B is a leading cause of myocarditis, which can develop, in severe cases, idiopathic dilated cardiomyopathy, requiring heart transplantation.

Enviroxime derivatives are considered the most promising candidate with broad anti-enterovirus and anti-rhinovirus activity. Enviroxime interferes with multistrand RNA synthesis by binding to the viral protein 3A that is required for the formation of RNA intermediates in virus reproduction (Heinz B A and Vance L M: J Virol, 1995, 69(7), 4189 -97). In clinical studies, however, the compound was observed to have negligible or few therapeutic effects, with the simultaneous detection of poor pharmacokinetics and unwanted side effects (Miller FDet al.:Antimicrob Agents Chemother, 1985, 27(1), 102- 6).

The protease inhibitor AG 7088 has been developed based on knowledge about the fine structure and function of the viral 2C protease. In cell culture in the nanomolar concentration range, AG 7088 has an effect against 48 types of rhinoviruses and coxsackieviruses A21, B3, enterovirus 70 and ecovirus 11 (Pattick A Ket al.:Antimicrobila Agents Chemother, 1999, 43(10) , 2444-50).

Thanks to the elimination of the molecular structure of viral capsids, the preconditions for a useful design of capsid blockers, "WIN substances", have been obtained (Diana G D: Curr Med Chem 2003, 2, 1-12). They inhibit the adsorption and/or non-coating of rhinoviruses and enteroviruses. Some of the WIN substances have a highly specific effect only against individual genera or virus types of picornaviruses. Other derivatives inhibit the replication of both rhinoviruses and enteroviruses. Arildone, disoxaril and pirodavir belong to the WIN substances, for example. These compounds showed very good antiviral effects in cell culture. However, poor solubility (arildone), low bioavailability (arildone and disoxaril), rapid metabolism and excretion (disoxaril and WIN 54954) as well as side effects, as well as skin rash (WIN 54954), made clinical application impossible.

Pleconaril, a type of WIN substance, has very good oral bioavailability and after binding to the hydrophobic pocket in the virus capsid, it inhibits the penetration of rhino-, echo- and coxsackie viruses (Pevear D Cet al.:Antimicrob Agents Chemother 1999, 43(9), 2109-15; McKinlay M Aet al.: Annu Rev Microbiol 1992, 46, 635-54). Therefore, pleconaril is potentially effective against a broad spectrum of viral diseases, ranging from common cold to viral meningitis or myocarditis. Resistance was observed for rhinovirus, enterovirus 71 and coxsackievirus B3 (Ledford R Met al.:J Virol 2004, 78(7), 3663-74; Groarke J Met al.:J Infect Dis 1999, 179(6), 1538- 41). However, the proven therapeutic effect was not sufficient for the registration of pleconaril (Picovir, Viropharma, USA) as an agent for the treatment of rhinovirus infections in the USA. In March 2002, the Food and Drug Administration (FDA) rejected a corresponding request because the success of the therapy was too low and side effects were observed.

BTA-798 was found to have greater antiviral activity than pleconaril, as evaluated in vitro and in vivo with rhinovirus, and is now undergoing clinical trials (Ryan, J. et al. Antiviral Res [18th Intl Conf Antiviral Res (11-14 April, Barcelona) 2005] 2005, 65(3): Abst LB-11).

However, no antiviral drugs have been developed that have gained approval for use in the treatment of entero- or rhinovirus, until now.

In carrying out the present invention, an extensive and thorough investigation into virustatics effective against picornaviruses including coxsackie-, entero-, eco-, polio-, and rhinoviruses, culminated in the finding that the new 1,3-Dioxoindene derivatives present a highly inhibitory activity against picornaviruses including coxsackie-, entero-, eco-, polio-, and rhinoviruses.

Poupelin Jean Pierre et al: "Synthese et proprieties pharmalogiques de derivas de l'hydroxy-2-indanedione-1,3; produits de condensation de la ninhydrine avec les phenols C-alkyles = Synthesis and pharmacological properties of 2-hydroxyindan-1, 3-dione derivatives, I. Compounds of condensation of ninhydrin with C-alkylphenols", Chimie Therapeutique, Editions Dimeo, Arcueil, FR, vol. 14, no. 2, January 1, 1979 (1979-01-01), pages 171-179 refers to the derivatives of 2-hydroxyindan-1,3-dione formed by condensation of ninhydrin with C-alkylphenols .

GB1533388 relates to a ninhydrin derivative of a particular formula given therein.

Gerard Schmitt et al: "A New and Mild Synthesis of Substituted Salicylic Acid", SYNTHESIS, vol. 1984, no. 09, January 1, 1984 (1984-01-01), pages 758-760 refers to a method of synthesis of salicylic acids involving ninhydrin as a reagent.

Benders J et al: "ESR spectra of semidions derived from indandione-1,3", JOURNAL OF MOLECULAR STRUCTURE, vol. 19, December 1, 1973 (1973-12-01), pages 431-440 refers to the free radical anions of 1,3-indandione derivatives and their aza analogs during the electrochemical reduction process at a metal electrode. mercury in N,Ndimethylformamide.

L. E. Neiland et al: "2-Aryl-4-azaindain-1,3-diones", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 3, No. 1, January 1, 1969 (1969-01-01), pages 81-83 refers to the synthesis of 2-phenyl-4-azaindan-1,3-dione and 2-(pdimethylaminophenyl)- 4 -azaindan-1,3-dione.

A. Ya. Ozola et al: "A new method of synthesizing 4-azaindan-1,3-dione derivatives", CHEMISTRY OF HETEROCYLIC COMPOUNDS, vol. 9, No. 8, August 1, 1973 (1973-08-01), pages 1062-1062 refers to a one-step method for the synthesis of 4-azaindan-1,3-dione derivatives.

A. NOW. Ozola et al: "4-Azaindane-1,3-dione derivative. III. Reactivities and prototropic transformations of new 4-azaindane-1,3-diones", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 12, No. 2, February 1, 1976 (1976 02-01), pages 220-226 refers to the synthesis of 4-azaindane-1,3-dione derivatives.

Document US 2002/091261 refers to compounds of a particular formula given therein. The compounds are said to inhibit angiogenesis.

William A. Mosher et al: "Reactions of some methylene ketones with dimethyl phthalate. New route to 2-substituted 1,3-indandiones", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 36, no. 11, June 1, 1971 (1971-06-01), pages 1561-1563 refers to reactions of methyl ketones with dialkyl phthalates to produce 2-acyl-1,3-indandones.

Courant J et al: "1,3-Indandiones VIII. 2-Hydroxy-2-indolyl-1,3-indandiones, 2-(indol-3-ylmethylene indandiones and derivatives: search for anti-inflammatory activity", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 24, no. 2, March 1, 1989 (1989-03-01), pages 145-154 refers to the synthesis of 2-hydroxy-2-indolyl- 1,3-indandiones.

Yaya Liu et al: "Investigating the Origin of the Slow-Binding Inhibition of HCV NS3 Serine Protease by a Novel Substrate Based Inhibitor", BIOCHEMISTRY, vol. 42, no. 29, July 1, 2003, pp. 8862-8869 refers to a study of the structure-activity relationships and inhibition mechanisms of this class of compounds.

Document US4569945 refers to arylindane-1,3-diones of a particular formula given therein which are said to be useful in inflammations, psoriasis and asthma.

Suven Das et al: "A simple synthesis of 4-substituted 2,3-benzoxazinones from C-2 arylated 1,3-indanedions", TETRAHEDRON LETTERS, ELSEVIER LTD, AMSTERDAM, NL, vol. 52, no. 25, April 19, 2011 (2011-04-19), pages 3243-3246 refers to a one-step procedure for the conversion of 2-hydroxy-2-(2'-hydroxy-aryl)-1,3 -indanediones in 4-substituted benzoxazinones.

Mona Kapoor et al: "Stereoselective synthesis of Z-3-alkoxy-2-[(4'-methoxyphenyl)methylidene]-1(3H)-isobenzofuranones", TETRAHEDRON, vol. 59, no. 27, June 1, 2003 (2003-06-01), pages 5027-5031 refers to the photoreorganization of 2-alkoxy-2-[(4'-methoxyphenyl)-1H-indene-1,3(2H)- diones in anhydrous acetone to produce Z-3-alkoxy-2-[(4'-methoxyphenyl)methylidene]-1(3H)-isobenzofurans.

Hyun Nam Song et al: "The Reaction of Ninhydrin with Polymethylbenzenes in the Presence of Acid Catalyst: Formation of 2-Aryl-1,3-indanedione and Indenoindanone Derivatives", BULL. KOREAN CHEM. SOC., vol. 20, No. 10, January 1, 1999 (1999-01-01), pages 1229-1231 refers to the synthesis of the formation of 2-aryl-1,3-indanedione and indenoindanone derivatives.

[Divulgation]

[Technical problem]

Therefore an object of the present invention is to provide a compound of Formula 1 as defined in claim 1 or a pharmaceutically acceptable salt or optical isomer thereof.

Another object of the present invention is to provide a method for the preparation of a compound expressed with Formula 1 as defined in claim 1, or pharmaceutically acceptable salt thereof.

Furthermore, another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of a viral disease, comprising a compound expressed with Formula 1 as defined in claim 1 or a pharmaceutically acceptable salt thereof, or an optical isomer. of it, as an active principle.

[Technical solution]

According to one aspect thereof, the present invention provides a compound represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof:

(in which,

A1, A2, A3, A4, D1, D3, X, Y, E and G are respectively as defined in the specification).

According to another aspect thereof, the present invention provides a method for the preparation of the compound of the invention, pharmaceutically acceptable salt or enantiomer.

According to a further aspect thereof, the present invention provides a pharmaceutical composition for the prevention or treatment of a viral disease, comprising the compound of the invention, pharmaceutically acceptable salt or enantiomer as active ingredient.

[Advantageous effects]

By having excellent inhibitory activity against picornaviruses including coxsackie-, entero-, eco-, Polio-, and rhinovirus, as well as presenting low cytotoxicity, the compound of Chemical Formula 1 may be useful as the active ingredient of a pharmaceutical composition for prevention or treatment. of viral diseases including poliomelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot and mouth, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

[Best mode]

A detailed description of the present invention will now be provided.

According to one aspect thereof, the present invention is directed to compounds expressed with Formula 1, pharmaceutically acceptable salt thereof or optical isomer thereof:

where A<1>is -NR<1>R<2>;

A<2>, A<3>and A<4>are, independently or optionally, any one selected from a group consisting of -H, halogen, -OH, -CN, -N<3>, C<1 alkoxy >-C<10>, linear or branched chain C<1>-C<10>alkyl, -O(C=O)R<1>, -(C=O)R<1>, -(C= O)OR<1>, - O(C=O)OR<1>, -O(C=O)NR<1>R<2>, -NO<2>, -NR<1>R<2> , -NR<1>(C=O)R<2>, - NR<1>(C=S)R<2>, -NR<1>(C=O)OR<2>, -NR<1 >(C=O)-NR<2>R<3>and -NR1(C=S)-N<r>2R3, or two or more neighboring substituents of A<1>, A<2>, A<3 >and A<4>together can form a ring, wherein a ring formed by two or more neighboring substituents of D<1>, D<2>, D<3>and D<4>can include one or more heteroatoms , and the heteroatom is N, O or S;

G is halogen, -OH, -CN, -N<3>, alkoxy C<1>-C<10>, -O(C=O)R<1>, -(C=O)R<1>, -(C=O)OR<1>, -O(C=O)OR<1>, -O(C=O)NR<1>R<2>, -NO<2>, -NR<1> R<2>, -NR<1>(C=O)R<2>, -NR<1>(C=S)R<2>, -NR<1>(C=O)OR<2>, -NR<1>(C=O)-NR<2>R<3>, -NR<1>(C=S)-NR<2>R<3>o

D<1>, D<2>, D<3>and D<4>are, independently or optionally, any one selected from a group consisting of -H, halogen, -OH, -CN, C<1>alkoxy -C<10>, straight or branched chain C-C<10>alkyl, C<6>-C<12> aryl, -(CH<2>)<n>-(C=O)OR<1>, - O(C=O)R<1>, -(C=O)R<1>, -(C=O)OR<1>, -O(C=O)OR<1>, -O(C= O)NR<1>R<2>, -NO<2>, -NR<1>R<2>, -NR<1>(C=O)R<2>, -NR<1>(C= S)R<2>, -NR<1>(C=O)OR<2>, -NR<1>(C=O)-NR<2>R<3>, -SR<1>and -NR <1>(C=S)-NR<2>R<3>, or two or more neighboring substituents of D<1>, D<2>, D<3>and D<4> together can form a ring, wherein a ring formed by two or more neighboring substituents of D<1>, D<2>, D<3>and D<4> may include one or more heteroatoms, and the heteroatom is N, O or S;

E is -H, -OH, -OR<1>, -O(C=O)R<1>, -(C=O)R<1>, -(C=O)OR<1>, - O (C=O)OR<1>, -O(C=O)NR<1>R<2>, -NO<2>, -NR<1>R<2>, -NR<1>(C= O)R<2>, -SR<1>, - NR<1>(C=S)R<2>, -NR<1>(C=O)OR<2>, -NR<1>(C =O)-NR<2>R<3>or -NR<1>(C=S)-NR<2>R<3>;

R<1>, R<2>and R<3>are, each independently, hydrogen, C<1>-C<10>alkyl, straight or branched chain, unsubstituted or substituted with phenyl, C<1>alkoxy. -C<10>, C<1>-C<10>alkenyl straight or branched chain, unsubstituted or substituted with phenyl, C<3>-C<7>cycloalkyl or C<6>-C<12>aryl unsubstituted or substituted with phenyl;

X and Y are oxygen;

Z<1>, Z<2>and Z<3>are carbon or nitrogen;

n is an integer between 1 -10; and

’— ’ represents a double bond.

In a preferred embodiment,

A2, A3 and A4 are, independently or optionally, any one selected from a group consisting of -H, halogen, C1-C10 straight or branched chain alkyl, -NR1R2, -NR1(C=O)R2, or two or more neighboring substituents of A1, A2, A3 and A4 together can form a ring, in which a ring formed by two or more neighboring substituents of A1, A2, A3 and A4 can include one or more heteroatoms, and the heteroatom is N, O or S;

G is -OH, -O(C=O)R1, -O(C=O)OR1, -NR1(C=O)R2, -NR1(C=O)OR2 or

D<1>, D<2>, D<3>and D<4>are, independently or optionally, any one selected from a group consisting of halogen, C<1>-C<10>straight chain alkyl or branched, -NR<1>(C=O)R<2>, -NR<1>(C=O)OR<2>and -NR<1>(C=O)-NR<2>R<3 >, or two or more neighboring substituents of D<1>, D<2>, D<3>and D<4> together can form a ring, wherein a ring formed by two or more neighboring substituents of D<1 >, D<2>, D<3>and D<4>may include one or more heteroatoms, and the heteroatom is N, O or S; E is -H, -OH, -OR<1>, -O(C=O)R<1>, -O(C=O)OR<1>, -O(C=O)NR<1>R <2>, -NR<1>(C=O)R<2>or -NR<1>(C=O)OR<2>;

R<1>, R<2>and R<3>are each independently hydrogen, C<1>-C<9>alkyl, straight or branched chain, unsubstituted or substituted with phenyl, C<1>alkenyl. -C<5>straight or branched chain, unsubstituted or substituted with phenyl or aryl C<6>-C<10>;

Z<1>, Z<2>and Z<3>are carbon;

n is an integer between 1-5; and

represents a double bond.

In a more preferred embodiment,

A<2>, A<3>and A<4>are, independently or optionally, any one selected from a group consisting of -H, halogen and -NR<1>R<2>;

G is -OH, -NR<1>(C=O)R<2>or -NR<1>(C=O)OR<2>;

D<1>, D<2>, D<3>and D<4>are, independently or optionally, any one selected from a group consisting of halogen, C<1>-C<10>straight chain alkyl or branched and - NR<1>(C=O)R<2>;

E is -H, -OH, -OR<1>, -O(C=O)R<1>, -O(C=O)OR<1>or - O(C=O)NR<1>R <2>;

R<1>, R<2>and R<3>are, each independently, hydrogen, C<1>-C<8>alkyl, straight or branched chain, unsubstituted or substituted with phenyl, C<1>alkenyl. -C<4>straight or branched chain, unsubstituted or substituted with phenyl or aryl C<6>-C<10>;

Z<1>, Z<2>and Z<3>are carbon;

n is an integer between 1-3; and

represents a double bond.

Furthermore, in a more preferred embodiment,

A<2>, A<3>and A<4>are, independently or optionally, any one selected from a group consisting of -H and -NR<1>R<2>; and at least one of A<1>, A<2>, A<3>and A<4>are, independently or optionally, -NR<1>R<2>;

G is -NR<1>(C=O)R<2>;

D<1>, D<2>, D<3>and D<4>are straight-chain or branched C<1>-C<10>alkyl;

E is -O(C=O)R<1>;

R<1>, R<2>and R<3>are, each independently, hydrogen or C<1>-C<7>alkyl of straight or branched chain;

Z<1>, Z<2>and Z<3>are carbon;

n is an integer between 1-3; and

represents a double bond.

Compounds of the present invention further include:

36) 2-(2-acetoxy-4-isopropyl-phenyl)-4-amino-1,3-dioxo-indan-2-yl ester of acetic acid;

41) 4-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;

44) N-(7-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide;

46) 4,7-diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;

47) 4,5-diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione;

81) 2-(4-amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate;

82) 2-(4-amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate;

83) 2-(4-amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate;

84) 2-(4-amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate;

85) 2-(4-amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate;

91) 2-(4-amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl octanoate;

96) 2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate;

100) 2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate;

103) 2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate;

107) N-[2-(4-amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide; and

Preferred examples of the compound represented by Chemical Formula 1 are the following:

Compounds 36) 41), 44), 46), 47), 81), 82), 83), 84), 85), 91), 96), 100), 103), and 107).

The most preferred examples of compounds of the invention of the compound represented by the Chemical Formula include:

Compounds 36), 81) - 85), 96), and 100 - 103).

The compound represented by Chemical Formula 1, according to the present invention can be used in the form of pharmaceutically acceptable salts. Acid addition salts formed with pharmaceutically acceptable free acids are useful. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic salt of the compounds of Chemical Formula 1, which do not exhibit a side effect in which the beneficial activity of the base compounds of Chemical Formula 1 It degrades when it is present at a concentration that does not cause toxicity or damage to the body. Free acids can be inorganic or organic. Examples of useful inorganic free acids include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Such as organic acids, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, gluconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, acid (D)- or (L)-malic, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, benzoic acid, or malonic acid may be used. Pharmaceutically acceptable salts may include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salt, magnesium salt, etc.). Acid addition salts useful in the present invention include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate , gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, iodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate , pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, alamin, potassium, sodium, tromethamine , and zinc salt, with hydrochloride or trifluoroacetate being preferred. Addition salts according to the present invention can be prepared by usual methods. For example, they can be prepared by dissolving the compound of Chemical Formula 1 in an organic solvent, such as methanol, ethanol, acetone, methylene chloride, or acetonitrile, and adding an excess of organic acids or an excess of aqueous solutions of inorganic acid to precipitate or crystallize salts. These addition salts can be obtained by precipitation or crystallization, or by evaporation of the solution or excess acid and drying or suction filtration of the precipitated salt.

Also, pharmaceutically acceptable metal salts formed with bases may be within the pharmaceutically acceptable sales range of the compound of the present invention. Examples of the metal salts useful in the present invention include alkali metal salts and alkaline earth metal salts. As an example, the compound of the present invention can be dissolved in excess alkali metal hydroxide or alkaline earth metal hydroxide in water, and, after filtration of the solution to remove salts of undissolved compounds, the filtrate can be dried to providing the pharmaceutically acceptable salts of the compound of the present invention. Sodium, potassium or calcium salts are suitable for pharmaceutical compounds. Corresponding silver salts can be obtained by reacting alkali or alkaline earth metal salts with suitable silver salt (for example, silver nitrate).

Not only the compounds of Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, hydrates and isomers prepared therefrom, if they have the same effect, are within the scope of the present invention.

Also, the present invention relates to a method for the preparation of the compounds according to the present invention. In one embodiment, the method comprises acylating or alkylating the compound of Chemical Formula 2 with a base in a solvent to provide a compound of Chemical Formula 1a (step 1), as illustrated in the following Reaction Scheme 1:

in which,

the compound of Chemical Formula 1a is a derivative of the compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof,

A1, A2, A3, A4, D1, D2, D3, D4, Z1, Z2, and Z3 as defined in Chemical Formula 1, respectively,

J and L are, independently or optionally, the same as A1, A2, A3, A4, D1, D2, D3, or D4

As a useful solvent in Reaction Scheme 1, diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methylene chloride (MC), chlorobenzene, toluene, or benzene they can be used.

The base used in this reaction can be pyridine (PPTs), 4-dimethyl aminopyridine, trimethylamine, or ethylamine.

In another embodiment, the method comprises:

reacting the compound of Chemical Formula 2 with thionyl chloride or oxalic chloride in the presence of a base in a solvent and then with ammonia to give a compound of Chemical Formula 3 (step 1); and acylate or alkylate the compound of Chemical Formula 3 in the presence of a base in a solvent to provide a compound of Chemical Formula 1b (step 2), as illustrated in the following Reaction Scheme 2:

in which,

the compound of Chemical Formula 1b is a derivative of the compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof,

A1, A2, A3, A4, D1, D2, D3, D4, Z1, Z2, and Z3 as defined in Formula Q J and L are, independently or optionally, the same as A1, A2, A3, A4, D1 , D2, D3, or D4

The solvents used in steps 1 and 2 in Reaction Scheme 2 of this method can be independently selected from the group consisting of diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran

(THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), methylene chloride (MC), chlorobenzene, toluene, and benzene.

As a base for the acylation or alkylation reaction in this method, pyridine (PPTs), trimethylamine, ethylamine, or triphosgene can be used.

According to one aspect of the present invention there is also contemplated a pharmaceutical composition for prevention or treatment of a viral disease, comprising a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, or peak isomer thereof as a principle. asset.

The viral disease targeted by the pharmaceutical composition of the present invention is a disease caused by picornaviruses including coxsackie-, entero-, polio-, and rhinoviruses. Examples of viral disease include poliomelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, epidemic myalgia, encephalitis, influenza, herpangina, and disease.

foot-and-mouth.

By having excellent antiviral activity against picornaviruses such as coxsackie-, entero-, echo-, polio- and rhinoviruses as well as presenting low cytotoxicity, the compound of Chemical Formula 1 may be useful as the active ingredient of a pharmaceutical composition for the prevention or treatment of various viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina , disease

foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media.

Clinically, the compound of the present invention can be administered in the form of various formulations. For

Therefore, the compound is usually formulated together with a diluent or excipient, such as a filler, a thickening agent, a binder, a wetting agent, a disintegrant, a surfactant, etc.

Solid preparations intended for oral administration of the compound of the present invention can take the form

form of tablets, pills, powders, granules, capsules, and troches. These solid preparations are formulated together

with at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to an excipient

Simply, you can also add a lubricant such as magnesium stearate and talc. Liquid preparations intended for oral administration include suspensions, solutions for internal use, emulsion, and syrups. In addition to

a simple diluent such as water or liquid paraffin, various excipients, such as wetting agents, sweetening agents, aromatics and preservatives, may be contained in liquid preparations for administration

oral of the compound of the present invention.

Also, the compound of the present invention may be in a parenteral dosage form such as sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilisates, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and esters such as ethyl oleate may be suitable for non-aqueous solvents and suspensions. The basic materials of suppositories include Witepsol, macrogol,

Tween 61, cocoa butter, laurine butter and glycerogelatin.

The compound of the present invention is administered in a therapeutically effective amount. The effective dose of the compound of the present invention varies depending on several factors including the patient's age, weight, sex, and health status, the route of administration, and the severity of the disease. Typically, the compound of the present invention can be administered at a daily dose of 0.001 to 100 mg/kg, and preferably at a daily dose of 0.01

at 35 mg/kg. For an adult weighing 70 kg, the dose of the compound of the present invention can typically range from 0.07 to 7,000 mg/day, and preferably from 0.7 to 2,500 mg/day. The compound formulations are

They may be administered in a single dose or may be divided into multiple doses at regular time intervals according to the instructions of the physician-pharmacist who is responsible for monitoring and observing administration.

of the drug.

[Mode for invention]

A better understanding of the present invention can be obtained through the following examples presented

to illustrate, but should not be construed as limiting the present invention. Compounds not included in

The scope of the claims are provided for reference.

<EXAMPLE 1> Ethyl 2-(4-acetoxy-3-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-methoxyphenyl)acetate

Ethyl 2-(4b,9b-dihydroxy-6-methoxy-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-8-yl)acetate (0.50 g, 1.4 mmol) was completely dissolved in anhydrous dichloromethane (30 ml). This solution was added with anhydrous acetic acid (0.37 ml, 3.9 mmol), pyridine (0.11 ml, 1.4 mmol) and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature. for 3 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.03 g, 4%). mp: 102-107 °C.

NMR<1>H (300 MHz, CDCh) 81.25(t, J = 7.2 Hz, 3H, CH3) 1.98(s, 3H, OAc) 2.19(s, 3H, OAc) 3, 60(s, 2H, CH2) 3.73(s, 3H OCH3) 4.12-4.19(c, J = 7.2, 14.4 Hz, 2H, CH2) 6.93(s, 1H, ArH) 7.23(s, 1H, ArH) 7.85-8.00(m, 4H, ArH). MS(EI): 454.

<EXAMPLE 2> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl acetate

4b,9b-Dihydroxy-7,8-dimethyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (1.00 g, 3.5 mmol) was dissolved in THF anhydrous (50 ml). This solution was added with anhydrous acetic acid (0.67 ml, 7.1 mmol), pyridine (0.30 ml, 3.5 mmol) and 4-dimethyl aminopyridine (0.1 g), and stirred at room temperature. for 3 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.55 g, 42%).

mp: 206-207 °C.

NMR<1>H(300 MHz, CDCl<a>) 82.05(s, 3H, CH<3>) 2.19(s, 3H, OAc) 2.23(s, 3H, OAc) 6.74 (s, 1H, ArH) 7.44(s, 1H, ArH) 7.83-8.00(m, 4H, ArH). MS(EI): 366.

<EXAMPLE 3> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-chlorophenyl acetate

7-Chloro-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 6.9 mmol) was completely dissolved in anhydrous THF (20ml). This solution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol), pyridine (0.55 ml, 6.9 mmol) and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:3) to provide the title compound (0.51 g, 19%).

mp: 148-150 °C.

H NMR (300 MHz, CDCh) 82.04(s, 3H, OAc) 2.20(s, 3H, OAc) 7.04(d, J = 2.1 Hz, 1H, ArH) 7. 30(d, J = 1.8 Hz, 1H, ArH) 7.68(d, J = 9.0 Hz, 1H, ArH) 7.89-7.93(m, 2H, ArH) 7.99- 8.03(m, 2H, ArH). MS(EI): 372.

<EXAMPLE 4> (for reference) 6-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-2,3-dichlorophenyl acetate

2-(3,4-Dichloro-2-hydroxyphenyl)-2-hydroxy-1H-inden-1,3(2H)-dione (2.00 g, 6.9 mmol) was completely dissolved in anhydrous THF (20 mL ). This solution was added with anhydrous acetic acid (1.41 ml, 13.8 mmol), pyridine (0.55 ml, 6.9 mmol) and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2.5) to provide the title compound (0.037 g, 1, 5 %).

mp: 129-136 °C.

H NMR (300 MHz, CDCh) 82.07(s, 3H, OAc) 2.19(s, 3H, OAc) 7.42 (d, J = 8.8 Hz, 1H, ArH) 7. 64(d, J = 8.7 Hz, 1H, ArH) 7.89-8.03(m, 4H, ArH). MS(EI): 407.

<EXAMPLE 5> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,6-dichlorophenyl acetate

2-(3,5-Dichloro-2-hydroxyphenyl)-2-hydroxy-1H-inden-1,3(2H)-dione (1.50 g, 4.6 mmol) was completely dissolved in anhydrous THF (20 mL ). This solution was added with anhydrous acetic acid (0.95 ml, 9.28 mmol), pyridine (0.37 ml, 4.6 mmol) and 4-dimethyl aminopyridine (0.15 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (80 g, 4.2%).

mp: 178-180 °C.

H NMR (200 MHz, CDCl<s>) 82.07(s, 3H, OAc) 2.20(s, 3H, OAc) 7.48 (d, J = 3.6 Hz, 1H, ArH ) 7.72(d, J = 3.3 Hz, 1H, ArH) 7.92-8.08(m, 4H, ArH). MS(EI): 407.

<EXAMPLE 6> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-ethylphenyl acetate

7-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (2.00 g, 7.0 mmol) was completely dissolved in anhydrous THF (20ml). This solution was added with anhydrous acetic acid (1.44 ml, 14.1 mmol), pyridine (0.56 ml, 7.0 mmol) and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (2.28 g, 88%).

mp: 136-137 °C.

NMR<1>H (300 MHz, CDCl<s>) 81.19 (t, J = 7.6 Hz, 3H, CH<3>) 2.08(s, 3H, OAc) 2.19(s, 3H, OAc) 2.57-2.64(c, J = 15.3 Hz, J=7.8 Hz, 2H, CH<2>) 6.81 (s, 1H, ArH) 7.11(d , J = 9.0 Hz, 1H, ArH) 7.59(d, J = 8.4 Hz, 1H, ArH) 7.86-7.90(m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 366.

<EXAMPLE 7 Acetate> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-methoxyphenyl

4b,9b-Dihydroxy-8-methyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (3.03 g, 10.6 mmol) was dissolved in anhydrous THF ( 20ml). This solution was added with anhydrous acetic acid (2.01 g, 21.3 mmol), pyridine (0.84 ml, 10.6 mmol) and 4-dimethyl aminopyridine (0.3 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:3 to 1:2.5) to provide the title compound (0.44 g, eleven%).

mp: 184-186 °C.

NMR<1>H (300 MHz, CDCh) 82.15 (s, 3H, OAc) 2.17 (s, 3H, OAc) 3.78 (s, 3H, OCH<3>) 6.78(d, J = 8.7 Hz, 1H, ArH) 6.91(dd, J = 2.7, 9.0 Hz, 1H, ArH) 7.12(d, J = 2.7 Hz, 1H, ArH) 7 .60(t, J = 7.5 Hz, 1H, ArH) 7.76-7.85(m, 2H, ArH) 8.14(d, J = 7.8 Hz, 1H, ArH). MS(EI): 368.

<EXAMPLE 8> (for reference) 4-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-3-yl acetate

4b,9b-Dihydroxy-7-phenyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (2.00 g, 6.0 mmol) was dissolved in anhydrous THF ( 20 ml). This solution was added with anhydrous acetic acid (1.24 ml, 12.1 mmol), pyridine (0.48 ml, 6.0 mmol) and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.41 g, 11%).

mp: 165-167 °C.

H NMR (300 MHz, CDCl<a>) 82.05 (s, 3H, OAc) 2.22 (s, 3H, OAc) 7.20 (s, 1H, ArH) 7.33-7, 43(m, 3H, ArH) 7.51(d, J = 6.0 Hz, 3H, ArH) 7.78(dd, J = 8.4 Hz, J=1.8 Hz, 1H, ArH) 7 .88-7.92(m, 2H, ArH) 8.01-8.05 (m, 2H, ArH). MS(EI): 414.

<EXAMPLE 9> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-nitrophenyl acetate

4b,9b-Dihydroxy-8-nitro-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.80 g, 2.6 mmol) was dissolved in anhydrous THF ( 20 ml). This solution was added with anhydrous acetic acid (0.54 ml, 5.3 mmol), pyridine (0.21 ml, 2.6 mmol) and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature. for 30 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:2 to 1:1) to provide the title compound (0.44 g, 11%). ).

mp: 163-167 °C.

H NMR (300 MHz, CDCh) 81.92 (s, 3H, OAc) 2.24 (s, 3H, OAc) 7.22 (d, J = 9.0 Hz, 1H, ArH) 7. 93-7.97 (m, 2H, ArH) 8.03-8.08(m, 2H, ArH) 8.24 (dd, J = 8.4 Hz, J=3.0 Hz, 1H, ArH) 8.72(d, J = 2.7 Hz, 1H, ArH). MS(EI): 383.

<EXAMPLE 10> (for reference) 3-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)biphenyl-4-yl acetate

4b,9b-Dihydroxy-8-phenyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (1.00 g, 3.0 mmol) was dissolved in anhydrous THF ( 20 ml). This solution was added with anhydrous acetic acid (0.62 ml, 6.0 mmol), pyridine (0.25 ml, 3.0 mmol) and 4-dimethyl aminopyridine (0.1 g), and stirred at room temperature. for 30 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.12 g, 6%).

mp: 196-198 °C.

H NMR (300 MHz, CDCh) 82.08 (s, 3H, OAc) 2.22 (s, 3H, OAc) 7.06(d, J = 8.4 Hz, 1H, ArH) 7. 35-7.48 (m, 3H, ArH) 7.54-7.58 (m, 3H, ArH) 7.88-7.92 (m, 3H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 414.

<EXAMPLE 11> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-propylphenyl acetate

4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.80 g, 2.70 mmol) was dissolved in anhydrous THF ( 20ml). This solution was added with anhydrous acetic acid (0.55 ml, 5.40 mmol), pyridine (0.21 ml, 2.7 mmol) and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.85 g, 56%).

mp: 108-111 °C.

NMR<1>H (300 MHz, CDCl<s>) 80.96 (t, J = 8.0 Hz, 3H, CH<3>) 1.55-1.70(m, 2H, CH<2> ) 2.08 (s, 3H, OAc) 2.24 (s, 3H, OAc) 2.61 (t, J = 8.4 Hz, 2H, CH<2>) 6.92(d, J = 8 .2 Hz, 1H, ArH) 7.28(s, 1H, ArH) 7.55(m, 1H, ArH) 7.78-8.07(m, 4H, ArH). MS(EI): 380.

<EXAMPLE 12> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-ethylphenyl acetate

8-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.80 g, 2.70 mmol) was completely dissolved in anhydrous THF (20ml). This solution was added with anhydrous acetic acid (0.57 ml, 5.66 mmol), pyridine (0.22 ml, 2.83 mmol) and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.56 g, 27%). ).

mp: 153-154 °C.

NMR<1>H (300 MHz, CDCh) 81.25 (t, J = 7.2 Hz, 3H, CH<3>) 2.16(s, 3H, OAc) 2.20(s, 3H, OAc) ) 2.61-2.69(c, J = 15.0, 7.5 Hz, 2H, CH<2>) 6.89(d, J = 8.4 Hz, 1H, ArH) 7.20( d, J = 8.4 Hz, 1H, ArH) 7.53(s, 1H, ArH) 7.86-7.90(m, 2H, ArH) 7.98-8.02(m, 2H, ArH) ). MS(EI): 366.

<EXAMPLE 13> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-sec-butylphenyl acetate

8-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.58 g, 1.8mmol) was completely dissolved in THF anhydrous (10 ml). This solution was added with anhydrous acetic acid (0.39 ml, 3.7 mmol), pyridine (0.15 ml, 1.8 mmol) and 4-dimethyl aminopyridine (0.06 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.70 g, 48%). ).

mp: 118-120 °C.

NMR<1>H (300 MHz, CDCh) 80.82 (t, J = 9.0 Hz, 3H, CH<3>) 1.21(d, J = 6.9 Hz, 3H, CH<3> ) 1.52-1.61 (m, 2H, CH<2>) 2.06(s, 3H, OAc) 2.21(s, 3H, OAc) 2.59-2.66(m, 1H, CH) 6.90(d, J = 8.4 Hz, 1H, ArH) 7.20(dd, J = 2.1,8.4 Hz, 1H, ArH) 7.50(d, J = 1, 8 Hz, 1H, ArH) 7.87-7.91 (m, 2H, ArH) 7.98-8.03 (m, 2H, ArH). MS(EI): 394.

<EXAMPLE 14> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-ferc-butylphenyl acetate

8-ferc-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.50 g, 1.6 mmol) was completely dissolved in Anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.32 ml, 3.7 mmol), pyridine (0.13 ml, 1.8 mmol) and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.44 g, 36%). ).

mp: 195-196 °C.

NMR<1>H(300 MHz, CDCl<a>) 81.29 (s, 9H, CH<3>) 2.14 (s, 3H, OAc) 2.18 (s, 3H, OAc) 6.80 (d, J = 8.7 Hz, 1H, ArH) 7.37-7.40(dd, J = 2.1,8.7 Hz, 1H, ArH) 7.52-7.61(m, 2H , ArH) 7.75-7.85(m, 2H, ArH) 8.16(d, J = 8.1 Hz, 1H, ArH). MS(EI): 394.

<EXAMPLE 15> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-ferc-butylphenyl acetate

7-sec-Butyl-4b,9b-dihydroxy-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.52 g, 1.67 mmol) was completely dissolved in Anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (0.34 g, 3.3 mmol), pyridine (0.13 g, 1.6 mmol) and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.53 g, 42%). ).

mp: 119-120 °C.

NMR<1>H(300 MHz, CDCh) 81.25 (s, 9H, CH<3>) 2.04 (s, 3H, OAc) 2.10(s, 3H, OAc) 6.95(d, J = 2.1 Hz, 1H, ArH) 7.29(dd, J = 8.4, 2.1 Hz, 1H, ArH) 7.60(d, J = 8.4 Hz, 1H, ArH) 7 .84-7.90(m, 2H, ArH) 7.97-8.02 (m, 2H, ArH). MS(EI): 394.

<EXAMPLE 16> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3,4,5-trimethylphenyl acetate

4b,9b-Dihydroxy-8-propyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.69 g, 2.33 mmol) was dissolved in anhydrous THF ( 20 ml). This solution was added with anhydrous acetic acid (0.48 ml, 4.66 mmol), pyridine (0.18 g, 2.33 mmol) and 4-dimethyl aminopyridine (0.07 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:1) to provide the title compound (0.016 g, 2%).

mp: 238-242 °C.

NMR<1>H(300 MHz, CDCh) 82.05 (s, 6H, CH<3>) 2.22 (s, 6H, OAc) 2.59(s, 3H, CH<3>) 6.54 (s, 1H, ArH) 7.56(t, J = 7.5 Hz, 1H, ArH) 7.78 (t, J = 7.5 Hz, 2H, ArH) 7.94 (d, J = 6 ,6 Hz, 1H, ArH). MS (EI): 380.

<EXAMPLE 17> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4-ferc-pentylphenyl acetate

4b,9b-Dihydroxy-8-ferc-pentyl-4bH-benzo[d]indene[1,2-b]-furan-10(9bH)-one (0.80 g, 2.46 mmol) was dissolved in THF anhydrous (20 ml). This solution was added with anhydrous acetic acid (0.50 g, 4.93 mmol), pyridine (0.19 mL, 2.46 mmol) and 4-dimethyl aminopyridine (0.08 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:3) to provide the title compound (0.71 g, 38%).

mp: 146-151 °C.

NMR<1>H (300 MHz, CDCh) 80.68 (t, J = 7.5 Hz, 3H, CH<3>) 1.26 (s, 6H, CH<3>) 1.56-1, 66 (m, 2H, CH<2>) 2.06 (s, 3H, OAc) 2.20(s, 3H, OAc) 6.90(d, J = 8.7 Hz, 1H, ArH) 7. 31(dd, J = 8.7 Hz, 2.7 Hz, 1H, ArH) 7.64(d, J = 2.4 Hz, 1H, ArH) 7.86-7.91(m, 2H, ArH ) 7.98-8.02(m, 2H, ArH). MS(EI) = 408.

<EXAMPLE 18> (for reference) Acetic acid 2-(2,3-diacetoxy-5-methylphenyl)-1,3-dioxo-indan-2-yl ester 4b,6,9b-Trihydroxy-8-methyl-4b ,9b-Dihydro-5-oxa-indene[1,2-a]-inden-10-one (0.50 g, 1.70 mmol) was dissolved in anhydrous THF (20 mL). This solution was added with anhydrous acetic acid (0.36 g, 3.5 mmol), pyridine (0.14 ml, 1.7 mmol) and 4-dimethyl aminopyridine (0.05 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.47 g, 65%).

mp: 192-194 °C.

<1>H NMR (300 MHz, CDCh) 82.08 (s, 3H, OAc) 2.17 (s, 3H, OAc) 2.19 (s, 3H, OAc) 2.35 (s, 3H, CH <3>) 7.06(s, 1H, ArH) 7.35(s, 1H, ArH) 7.86-7.89(m, 2H, ArH) 7.98-8.01(m, 2H, ArH). MS(EI): 410.

<EXAMPLE 19> (for reference) Acetic acid 2-(2-acetoxy-4-isopropylphenyl)-1,3-dioxo-indan-2-yl ester

4b,9b-Dihydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]-inden-10-one (0.80 g, 2.70 mmol) was dissolved in anhydrous THF (100ml). This solution was added with anhydrous acetic acid (11.46 g, 121.4 mmol), pyridine (4.9 g, 60.7 mmol) and 4-dimethyl aminopyridine (1.8 g), and stirred at room temperature. for 12 hours. After extracting the reaction mixture with dichloromethane, the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (19.0 g, 82%).

mp: 136-137 °C.

NMR<1>H (300 MHz, CDCl<a>) 81.18 (d, J = 6.9 Hz, 6H, CH<3>) 2.09 (s, 3H, OAc) 2.20(s, 3H, OAc) 2.83-2.88(c, J = 6.9 Hz, 1H, CH) 6.83(d, J = 1.6 Hz, 1H, ArH) 7.14(dd, J = 8.4 Hz, J=1.8 Hz, 1H, ArH) 7.59 (d, J = 8.4 Hz, 1H, ArH) 7.77-7.88 (m, 2H, ArH) 7.97 -8.01(m, 2H, ArH). MS(EI): 380.

<EXAMPLE 20> (for reference) 2-(4-Acetyl-2-hydroxy-phenyl)-2-hydroxy-indan-1,3-dione

To a solution of ninhydrin (1.00 g, 5.61 mmol) in acetic acid (20 ml) was added 1-(3-hydroxy-phenyl)-ethanone (0.76 g, 5.61 mmol), followed by heating for 3 h at 110 °C. The reaction mixture was diluted with methylene chloride, extracted with 2N aqueous NaOH solution, and the concentrated organic phase was purified using column chromatography (ethylene acetate: hexane = 1:2) to provide the title compound ( White, 1.32 g, 79%). mp: 177-180 °C.

NMR<1>H (300 MHz, CDCh) 83.87 (s, 3H, CH<3>) 7.07 (d, J = 7.0 Hz, 1H, ArH) 7.32(d, J = 7 .9 Hz, 1H, ArH) 7.43(d, J = 8.1 Hz, 1H, ArH) 7.91-7.94(c, J = 5.7, 3.0 Hz, 2H, ArH) 8.06-8.08(c, J = 5.7, 3.0 Hz, 2H, ArH). MS(EI): 296.

<EXAMPLE 21> (for reference) 2-(1,3-dioxo-2-(propionyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate

2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous THF (20 mL). This solution was added with propionyl chloride (0.62 g, 6.74 mmol) and triethylamine (0.41 g, 4.04 mmol), followed by heating for 12 h at reflux. The reaction mixture was then concentrated, extracted with dichloromethane, and the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (Blank, 0.23 g , 17%).

mp: 123-125 °C.

NMR<1>H (300 MHz, CDCh) 81.10-1.19 (m, 12H, CH<3>) 2.31-2.39(c, J = 15.0, 7.5 Hz, 2H , CH<2>) 2.46-2.54(c, J = 15.0, 7.5 Hz, 2H, CH<2>) 2.80-2.89(m, 1H, CH) 6, 82 (s, 1H, ArH) 7.14(d, J = 8.4 Hz, 1H, ArH) 7.61 (d, J = 8.1 Hz, 1H, ArH) 7.83-7.86 ( m, 2H, ArH) 7.95-7.99(m, 2H, ArH). MS(EI) = 408.

<EXAMPLE 22> (for reference) 2-(2-(butyryloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate

2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 mL). This solution was added with butyryl chloride (0.72 g, 6.74 mmol) and triethylamine (0.41 g, 4.04 mmol), followed by heating for 24 h at reflux. The reaction mixture was then concentrated, extracted with dichloromethane, and the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (Blank, 0.20 g , 14%).

mp: 98-102 °C.

NMR<1>H (300 MHz, CDCh) 80.94-1.02 (m, 6H, CH<3>) 1.17 (s, 3H, CH<3>) 1.20 (s, 3H, CH <3>) 1.59-1.73 (m, 4H, CH<2>) 2.29 (t, J = 7.2 Hz, 2H, CH<2>) 2.45 (t, J = 7 .5 Hz, 2H, CH<2>) 2.81-2.90 (m, 1H, CH) 6.80 (s, 1H, ArH) 7.13 (dd, J = 8.4 Hz, 1.4H , 1H, ArH) 7.60 (d, J = 8.4 Hz, 1H, ArH) 7.85-7.89 (m, 2H, ArH) 7.96-8.01 (m, 2H, ArH) . MS(EI): 436.

<EXAMPLE 23> (for reference) 2-(2-hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl benzoate;

2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 mL). This solution was added with benzoyl chloride (0.94 g, 6.74 mmol), triethylamine (0.41 g, 4.04 mmol) and DMPA (0.01 g), followed by heating for 24 h at reflux. The reaction mixture was then concentrated, extracted with dichloromethane, and the organic phase was concentrated and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.81 g, 14 %).

mp: 117-119 °C.

NMR<1>H (300 MHz, CDC<h>) 81.19-1.28 (m, 6H, CH<3>) 2.84-2.97 (m, 1H, CH) 6.91-8 .09 (m, 12H, ArH). MS(EI): 400.

<EXAMPLE 24> (for reference) 2-(2-Benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione

4b,9b-dihydroxy-7-isopropyl-4b,9b-dihydroxy-5-oxa-indene[2,1-a]inden-10-one (0.50 g, 1.68 mmol) was completely dissolved in anhydrous DMF (10ml). This solution was added with potassium carbonate (0.46 g, 3.26 mmol) and benzyl bromide (0.26 g, 1.51 mmol) and stirred at room temperature for 13 h. The reaction mixture was washed with 1N NaOH, extracted with dichloromethane, and the concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.40 g, 61%).

mp: 197-199 °C.

NMR<1>H (300 MHz, CDCh) 81.21 (d, J = 6.9 Hz, 6H, CH<3>) 2.83-2.93 (m, 1H, CH) 3.04 (s , 1H, OH) 4.67 (s, 2H, OCH<2>) 6.69 (s, 1H, ArH) 6.91 (d, J = 7.5 Hz, 2H, ArH) 6.99 (d , J = 8.1 Hz, 1H, ArH) 7.11-7.23 (m, 3H, ArH) 7.57-7.60 (m, 2H, ArH) 7.61-7.71 (m, 3H, ArH). MS(EI): 386.

<EXAMPLE 25> (for reference) 2-(2-Benzyloxy-4-isopropyl-phenyl)-2-methoxy-indan-1,3-dione

2-(2-Benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione (0.10 g, 0.25 mmol) was completely dissolved in anhydrous DMF (2 mL). This solution was added with sodium hydride (0.007 g, 0.31 mmol) and methyl iodide (0.04 g, 0.28 mmol) and stirred at room temperature for 13 h. The reaction mixture was extracted with dichloromethane, and the concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (12 mg, 12%).

mp: 140-144 °C.

NMR<1>H (300 MHz, CDCl<a>) 81.21 (d, J = 6.9 Hz, 6H, CH<3>) 2.82-2.92 (m, 1H, CH) 3, 44(s, 1H, OCH<3>) 4.63 (s, 2H, OCH<2>) 6.68 (s, 1H, ArH) 6.88 (d, J = 7.8 Hz, 2H, ArH ) 6.99 (d, J = 8.1 Hz, 1H, ArH) 7.09-7.21 (m, 3H, ArH) 7.54-7.58 (m, 2H, ArH) 7.63- 7.70 (m, 3H, ArH). MS(EI): 400.

<EXAMPLE 26> (for reference) 2-Hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-indan-1,3-dione

Ninhydrin (1.00 g, 5.61 mmol) was dissolved in acetic acid (15 mL), and this solution was heated for 13 h. The reaction mixture was concentrated, and extracted with dichloromethane, and then the concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.31 g, 20%). ). mp: 210-213 °C.

H NMR (300 MHz, CDCh) 82.16 (s, 6H, CH<3>) 3.27 (s, 1H, OH) 4.81 (s, 1H, OH) 7.02 (s, 2H, ArH) 7.90-7.92 (m, 2H, ArH) 8.04-8.07 (m, 2H, ArH). MS(EI): 282.

<EXAMPLE 27> (for reference) 2-(2-acetoxy-4-isopropylphenyl)-5-methoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl acetate

4b,9b-dihydroxy-7-isopropyl-2-methoxy-4bH-benzo[d]indene[1,2-b]furan-10(9bH)-one (0.30 g, 0.91 mmol) was completely dissolved in anhydrous THF (10 ml). This solution was added with anhydrous acetic acid (0.18 g, 1.82 mmol), pyridine (0.07 g, 0.91 mmol) and DMAP (0.03 g), and stirred at room temperature. The reaction mixture was concentrated, and extracted with ethyl acetate, and the concentrated organic phase was purified using column chromatography (ethyl acetate:hexane = 1:3) to provide the title compound (0.19 g, 51%) .

mp: 146-148 °C.

NMR<1>H (300 MHz, CDC<h>) 81.19 (dd, J = 2.1, 6.9 Hz, 6H, CH<3>) 2.13 (s, 3H, OAc) 2, 18 (s, 3H, OAc) 2.81-2.90 (m, 1H, CH) 3.93 (s, 3H, OCH<3>) 6.84 (s, 1H, ArH) 7.13 (d , J = 1.2 Hz, 8.4 Hz, 1H, ArH) 7.33-7.36 (m, 2H, ArH) 7.57 (d, J = 8.4 Hz, 1H, ArH) 7.91 ( d, J = 6.0 Hz, 1H, ArH). MS(EI): 410.

<EXAMPLE 28> (for reference) 2-(2-Hydroxy-4-isopropylphenyl)-2-methoxy-1H-inden-1,3(2H)-dione

2-(2-(tert-butyldimethylsilyloxy)-4-isopropylphenyl)-2-methoxy-1H-indene-1,3(2H)-dione (0.2 g, 0.47 mmol) was completely dissolved in anhydrous THF ( 10ml). This solution was added with quaternary ammonium fluoride (0.27 g, 1.04 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, and extracted with ethyl acetate, and the concentrated organic phase was purified using column chromatography (ethyl acetate:hexane = 1:4) to provide the title compound (38 mg, 27%) .

mp: 272-274 °C.

NMR<1>H (300 MHz, CDCh) 81.20 (d, J = 7.2 Hz, 6H, CH<3>) 2.82-2.91 (m, 1H, CH) 3.36 (s , 3H, OCH<3>) 3.47 (s, 1H, OH) 6.59 (s, 1H, ArH) 6.94 (d, J = 8.1 Hz, 1H, ArH) 7.62 (d , J = 8.1 Hz, 1H, ArH) 7.87-8.05 (m, 4H, ArH). MS(EI) = 310.

<EXAMPLE 29> (for reference) 2-(1,3-dioxo-2-(pivaloyloxy)-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pivalate

To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indene[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in THF Anhydrous 2,2-dimethylpropionyl chloride (0.81 g, 6.7 mmol), trimethylamine (0.40 g, 4.0 mmol) and DMAP (0.1 g) were added, followed by heating for 24 h to reflux. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:6) to provide the title compound (0.38 g, 24%).

mp: 121-124 °C.

NMR<1>H (300 MHz, CDC<h>) 81.18 (d, J = 8.7 Hz, 6H, CH<3>) 1.26 (s, 9H, CH<3>) 1.35 (s, 9H, CH<3>) 6.67 (s, 1H, ArH) 7.07 (d, J = 8.4 Hz, 1H, ArH) 7.42 (d, J = 8.4 Hz, 1H, ArH) 7.79-7.83 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 464.

<EXAMPLE 30> (for reference) 2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl cinnamate

To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indene[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in THF anhydrous (10 ml), 3-phenyl-acyloyl chloride (1.12 g, 6.7 mmol), trimethylamine (0.40 g, 4.0 mmol) and DMAP (0.1 g) were added, followed by heating for 24 h at reflux. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:8 to 1:4) to provide the title compound (0.05 g, 3.5%).

mp: 95-97 °C.

NMR<1>H (300 MHz, CDCh) 81.20 (dd, J = 2.7 Hz, 6.8 Hz, 6H, CH<3>) 2.86-2.91 (m, 1H, CH) 4.20 (m, 1H, OH) 6.24 (d, J = 16.0 Hz, 1H, CH) 6.49 (d, J = 16.0 Hz, 1H, CH) 6.93 (s, 1H, ArH) 7.20 (d, J = 8.3 Hz, 1H, ArH) 7.35-7.59 (m, 6H, ArH) 7.67-7.76 (m, 3H, ArH) 7 .67-7.98(m, 1H, ArH). MS(EI) = 426.

<EXAMPLE 31> (for reference) Dimethylcarbamic acid 2-(2-dimethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indene[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in THF anhydrous (10 ml), dimethylcarbamoyl chloride (0.72 g, 6.7 mmol), trimethylamine (0.41 g, 4.0 mmol) and DMAP (0.1 g) were added, followed by heating for 24 h at reflux. . The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.20 g, 13%).

mp: 203-205 °C.

NMR<1>H (300 MHz, CDCl<a>) 81.19 (d, J = 6.8 Hz, 6H, CH<3>) 2.73 (s, 3H, NCH<3>) 2.83 (s, 3H, NCH<3>) 2.93 (s, 3H, NCH<3>) 3.08 (s, 3H, NCH<3>) 6.78 (s, 1H, ArH) 7.12( d, J = 8.0 Hz, 1H, ArH) 7.59 (d, J = 8.0 Hz, 1H, ArH) 7.79-7.82 (m, 2H, ArH) 7.95- 7.98 ( m, 2H, ArH). MS(EI): 438.

<EXAMPLE 32> (for reference) 2-(2-(acryloyloxy)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl acrylate

To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indene[2,1-a]inden-10-one (1.00 g, 3.37 mmol) in THF anhydrous (10 ml), acyloyl chloride (0.61 g, 6.74 mmol), trimethylamine (0.41 g, 4.0 mmol) and DMAP (0.1 g) were added, followed by heating for 24 h at reflux. . The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:2 to 1:1) to provide the title compound (0.26 g, 19%).

NMR<1>H (300 MHz, CDCh) 81.18 (d, J = 2.1 Hz, 7.2 Hz, 6H, CH<3>) 2.81-2.87 (m, 1H, CH) 5.94-6.24 (m, 4H, CH<2>) 6.44 6.47 (m, 2H, CH) 6.87 (s, 1H, ArH) 7.15 (d, J = 8, 1 Hz, 1H, ArH) 7.58 (d, J = 8.1 Hz, 1H, ArH) 7.83-7.86 (m, 2H, ArH) 7.96- 7.99 (m, 2H, ArH) . MS(EI): 404

<EXAMPLE 33> (for reference) diethylcarbamic acid 2-(2-diethylcarbamoyloxy-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indene[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in THF Anhydrous, trimethylamine (0.40 g, 4.0 mmol), diethylcarbamoyl chloride (0.91 g, 6.7 mmol) and DMAP (0.1 g) were added, followed by heating for 24 h at reflux. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.54 g, 32%).

mp: 103-105 °C.

NMR<1>H (300 MHz, CDCh) 81.02-1.28 (m, 18H, CH<3>) 2.82-2.86 (m, 1H, CH) 3.10-3.26 ( m, 6H, NCH<2>) 3.40 (c, J = 14.2 Hz, 7.1 Hz, 2H, NCH<2>) 6.73 (s, 1H, ArH) 7.10 (d, J = 8.3 Hz, 1H, ArH) 7.60 (d, J = 8.3 Hz, 1H, ArH) 7.76-7.79 (m, 2H, ArH) 7.93-7.96 ( m, 2H, ArH). MS(EI): 494.

<EXAMPLE 34> (for reference) 2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl diethylcarbamate

To a solution of 4b,9b-dihydroxy-7-isopropyl-4b,9H-dihydro-5-oxa-indene[2,1-a]inden-10-one (1.00 g, 3.3 mmol) in THF Anhydrous, triethylamine (0.40 g, 4.0 mmol), diethylcarbamoyl chloride (0.91 g, 6.7 mmol) and DMAP (0.1 g) were added, followed by heating for 24 h at reflux. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (0.06 g, 5%).

mp: 103-106 °C.

NMR<1>H (300 MHz, CDCh) 80.94-1.04 (m, 6H, CH<3>) 1.20 (d, J = 6.9 Hz, 6H, CH<3>) 2, 81-2.89 (m, 3H, CH, NCH<2>) 3.08 (c, J = 14.2 Hz, 7.1 Hz, 2H, NCH<2>) 4.03 (s, 1H, OH) 6.74 (s, 1H, ArH) 7.14 (d, J = 8.1 Hz, 1H, ArH) 7.70 (d, J = 7.8 Hz, 1H, ArH) 7.84- 7.89 (m, 2H, ArH) 7.99-8.03 (m, 2H, ArH). MS(EI): 395

<EXAMPLE 35> (for reference) 2-Hydroxy-2-(4-hydroxy-2,5-dimethylphenyl)-1H-inden-1,3(2H)-dione

To a solution of ninhydrin (1.00 g, 5.6 mmol) in glacial acetic acid (20 mL) was added 2,5-dimethyl phenol (0.68 g, 5.6 mmol), followed by heating for 24 h at Reflux. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:6 to 1:4) to provide the title compound (0.13 g, 8%).

mp: 228-230 °C.

NMR<1>H (300 MHz, CDCh CD<3>OD) 82.12 (s, 3H, CH<3>) 2.24 (s, 3H, CH<3>) 3.39 (s, 1H, OH) 5.59 (s, 1H, OH) 6.54 (s, 1H, ArH) 7.02 (s, 1H, ArH) 7.90-7.93 (m, 2H, ArH) 8.03- 8.06 (m, 2H, ArH). MS(EI) = 282.

<EXAMPLE 36> 2-(2-acetoxy-4-isopropylphenyl)-4-amino-1,3-dioxo-indan-2-yl ester of acetic acid

Triethylamine (0.10 g, 0.6 mmol) was added to a solution of 1-amino-4b,9b-dihydroxy-7-isopropyl-4b,9b-dihydro-5-oxaindeno[2,1-a]inden- 10-one (0.20 g, 0.6 mmol) in methylene chloride (5 mL) at room temperature. To this reaction mixture, a dilution of 10% acetyl chloride (1 mL) in methylene chloride was added slowly at 0 °C and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (100 mg, 40%).

mp: 148-151 °C.

NMR<1>H (300 MHz, CDCl<a>) 81.19 (d, J = 6.9 Hz, 6H, CH<3>) 2.07 (s, 3H, OAc) 2.18 (s, 3H, OAc) 2.83-2.88 (m, 1H, CH) 5.67 (s, 2H, NH<2>) 6.83 (d, J = 1.8 Hz, 1H, ArH) 6. 88 (d, J = 8.4 Hz, 1H, ArH) 7.14 (dd, J = 8.4 Hz, 2.1 Hz, 1H, ArH) 7.22 (d, J = 7.2 Hz, 1H, ArH) 7.53 (t, J = 7.2 Hz, 1H, ArH) 7.59 (d, J = 8.4 Hz, 1H, ArH). 13C NMR (300 MHz, DMSO) 8 19.86, 20.83, 23.98, 34.89, 82.49, 111.47, 122.19, 122.52, 123.17, 123.91, 125 .54, 130.59, 138.55, 141.87, 148.87, 149.94, 153.17, 17.077, 171.10, 195.88, 196.68. MS(EI): 395.

<EXAMPLE 37> (for reference) 2-(2-acetoxy-4-isopropylphenyl)-4-nitro-1,3-dioxo-indan-2-yl ester of acetic acid

Triethylamine (0.11 g, 1.16 mmol) was added to a solution of 4b,9b-dihydroxy-7-isopropyl-1-nitro-4b,9b-dihydro-5-oxaindeno[2,1-a]inden- 10-one (0.20 g, 0.58 mmol) in anhydrous chloroform (10 mL) at room temperature. To this reaction mixture, acetyl chloride (1 mL) was added slowly at 0 °C and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (30 mg, 12%).

mp: 94-98 °C.

H NMR (300 MHz, CDCh) 81.20 (dd, J = 6.9 Hz, 6H, CH<3>) 2.19 (s, 3H, OAc) 2.27 (s, 3H, OAc) ) 2.83-2.92 (m, 1H, CH) 6.91 (s, 1H, ArH) 7.15 (dd, J = 8.2 Hz, 1.7 Hz, 1H, ArH) 7.53 (d, J = 8.2 Hz, 1H, ArH) 7.99 (t, J = 7.8 Hz, 1H, ArH) 8.23 (dd, J = 3.0 Hz, 7.8 Hz, 2H , ArH). NMR<13>C (300 MHz, CDCh) 8 19.72, 20.92, 23.45, 33.71, 82.07, 119.57, 12.83, 125.03, 127.88, 129, 86, 130.24, 131.48, 136.49, 141.09, 145.18, 148.77, 153.02, 168.90, 169.92, 187.91, 190.47. MS(EI): 425.

<EXAMPLE 38> (for reference) 2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione

A solution of 4-nitro-2,3-dihydro-1H-inden-1-one (4.00 g, 20.9 mmol) in 1,4-dioxane (40 ml) and glacial acetic acid (4 ml) was added with selenium dioxide (5.10 g, 46.03 mmol) and heated at reflux for 3 h. After filtration at elevated temperature, the filtrate was concentrated to provide 2,2-dihydroxy-4-nitro-2H-inden-1,3-dione (4.67 g, 100%). To a solution of 2,2-dihydroxy-4-nitro-2H-inden-1,3-dione (4.67 g, 20.9 mmol) in TFA (10 mL) was added isopropyl anisole (3.14 g, 20.9 mmol), followed by stirring at 60 °C for 6 h. The reaction mixture was concentrated in vacuo, and extracted with aq. sodium bicarbonate. and ethyl acetate. The concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (1.19 mg, 16%).

NMR<1>H (300 MHz, CDCh) 81.21 (d, J = 6.9 Hz, 6H, CH<3>) 2.82-2.92 (m, H, CH) 3.05 (s , 3H, OCH<3>) 3.75 (s, 3H, OH) 6.60 (s, 1H, ArH) 6.96 (dd, J = 7.8 Hz, 1H, ArH) 7.65 (d , J = 8.1 Hz, 1H, ArH) 8.01 (t, J = 7.8 Hz, 1H, ArH) 8.20-8.26 (m, 2H, ArH). MS(EI): 355.3.

<EXAMPLE 39> (for reference) 2-Chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione

2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (1.00 g, 2.8 mmol) was dissolved in excess thionyl chloride (10 ml), stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, and extracted with aq. sodium bicarbonate. and ethyl acetate. The organic phase was concentrated to give the title compound (1.05 g, 77%).

mp: 81-84 °C.

NMR<1>H (300 MHz, CDCh) 81.25 (d, J = 6.9 Hz, 6H, CH<3>) 2.87-2.96 (m, 1H, CH) 3.44 (s , 3H, OCH<3>) 6.65 (s, 1H, ArH) 7.02 (dd, J = 1.2 Hz, 7.8 Hz, 1H, ArH) 8.05-8.12 (m, 1H, ArH) 8.22 (dd, J = 1.2 Hz, 7.8 Hz, 1H, ArH) 8.28-8.35 (m, 2H, ArH). MS(EI): 373.

<EXAMPLE 40> (for reference) 2-Azido-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione

2-Chloro-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (1.23 g, 3.2 mmol) was completely dissolved in acetone (30 mL). This solution was added with sodium azide (0.47 g, 7.2 mmol), sodium iodide (0.59 g, 3.9 mmol), water (6 ml), followed by heating for 12 h at reflux. The reaction mixture was concentrated, and extracted with ethyl acetate, and the concentrated organic phase was purified using column chromatography (ethyl acetate:hexane = 1:4) to provide the title compound (brown syrup, 600 mg, 48%).

1H NMR (300 MHz, CDCh) 8 1.23 (d, J = 6.9 Hz, 6H, CH3) 2.28-2.94 (m, 1H, CH) 3.40 (s, 3H, OCH3) 6.63 (d, J = 1.5 Hz, 1H, ArH) 7.01 (dd, J = 1.5 Hz, 8.1 Hz, 1H, ArH) 7.56-7.60 (m, 2H , ArH) 7.78-7.90 (m, 2H, ArH). MS (EI): 380.

<EXAMPLE 41> 4-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-indene-1,3-dione

2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-4-nitro-2H-inden-1,3-dione (52 mg, 1.4 mmol) was completely dissolved in anhydrous ethanol (10 mL). This solution was added with iron (0.59 g, 10.6 mmol), conc. HCl (0.01 ml) and water (1 ml). The reaction mixture was heated for 3 h at reflux. After filtration at elevated temperature to remove iron, the filtrate was concentrated in vacuo and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.32 g, 68%) .

mp: 219-220 °C.

1H NMR (300 MHz, CDCla) 81.21 (d, J = 6.9 Hz, 6H, CH3) 2.82-2.91 (m, 1H, CH) 3.41-3.45 (s, 3H , OCH3) 6.60 (d, J = 1.2 Hz, 1H, ArH) 6.89-6.98 (m, 2H, ArH) 7.21-7.27 (m, 1H, ArH) 7, 56-7.66 (m, 2H, ArH). MS(EI): 325.

<EXAMPLE 42> (for reference) N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl )acetamide

N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (1.50 g, 6.4 mmol) was completely dissolved in dioxane anhydrous (15 ml). This solution was added with selenium oxide (1.56 g, 14.0 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 12 h at reflux. After filtration at elevated temperature, the filtrate was concentrated to provide 1.79 g (100%). The resulting product was extracted with ethyl acetate, and the concentrated organic phase was purified using column chromatography (ethyl acetate: hexane = 1:1) to provide the title compound (0.52 g, 20%). mp: 110-115 °C.

1H NMR (300 MHz, CDCh) 81.23 (d, J = 6.9 Hz, 6H, CH3) 2.29 (s, 3H, CH3), 2.84-2.93 (m, 1H, CH) 3.57 (s, 3H, OCH3), 3.78 (s, 1H, OH), 6.63 (s, 1H, ArH) 7.00 (dd, J = 1.5, 8.1 Hz, 1H, ArH ) 7.68 (d, J = 8.1 Hz, 1H, ArH) 8.28 (d, J = 8.7 Hz, 1H, ArH) 9.04 (d, J = 2.4, 9.0 Hz, 1H, ArH) 10.54 (s, 1H, NH). MS(EI): 412.39.

<EXAMPLE 43> (for reference) N-(2-Hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl )acetamide

N-(2,2-dihydroxy-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (2.60 g, 11.1 mmol) was completely dissolved in dioxane anhydrous (20 ml). This solution was added with selenium oxide (2.70 g, 24.4 mmol) and AcOH (1.5 ml). The reaction mixture was heated for 7 h at reflux. After filtration at elevated temperature, the filtrate was concentrated to provide 1.79 g (100%). A trifluoroacetic solution of the resulting product was added with isopropyl-3-methoxybenzene (1.66 g, 11.1 mmol), followed by stirring for 12 h. The remainder was extracted with ethyl acetate, and the concentrated organic phase was purified using column chromatography (100% ethyl acetate) to provide the title compound (0.64 g, 14%). mp: 199-201 °C.

1H NMR (300 MHz, CDCh) 81.23 (d, J = 6.9 Hz, 6H, CH3) 2.28 (s, 3H, CH3), 2.84-2.91 (m, 1H, CH) 3.42 (s, 3H, OCH3), 3.77 (s, 1H, OH), 6.65 (s, 1H, ArH) 7.00 (dd, J = 1.4, 7.9 Hz, 1H, ArH) 7 .63 (d, J = 7.9 Hz, 1H, ArH) 7.85 (d, J = 8.1 Hz, 1H, ArH) 8.35 (d, J = 8.1 Hz, 1H, ArH) 9.79 (s, 1H, NH). MS(EI): 412.

<EXAMPLE 44> N-(7-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl. (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 h at reflux. After filtration at elevated temperature to remove iron, the filtrate was concentrated in vacuo and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (65 mg, 71%).

1H NMR (300 MHz, CDCh) 81.22 (s, 6H, CH3) 2.20 (s, 3H, CH3) 2.83-2.92 (m, 1H, CH) 3.50 (s, 3H, OCH3) 3.78 (s, 1H, OH) 5.54 (s, 2H, NH2) 6.66 (d, J = 2.7 Hz, 1H, ArH) 6.91-7.07 (m, 2H , ArH) 7.56 (d, J = 7.8 Hz, 1H, ArH) 8.76 (d, J = 3.3, 9.0 Hz, 1H, ArH) 9.81 (s, 1H, NH). MS (EI): 382.

<EXAMPLE 45> (for reference) N-(5-Amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl )acetamide

N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-5-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.10 g, 0.24 mmol) was completely dissolved in anhydrous ethanol (3 ml). This solution was added with iron (0.098 g), conc. HCl. (0.05 ml) and water (0.3 ml). The reaction mixture was heated for 2 h at reflux. After filtration at elevated temperature to remove iron, the filtrate was concentrated in vacuo and purified using column chromatography (100% ethyl acetate) to provide the title compound (90 mg, 98%).

mp: 124-131 °C.

1H NMR (300 MHz, CDCh) 81.21 (d, J = 6.9 Hz, 6H, CH3) 2.30 (s, 3H, CH3) 2.83-2.92 (m, CH) 3.46 (s, 3H, OCH3) 3.78 (s, 1H, OH) 5.36 (s, 2H, NH2) 6.62 (s, 1H, ArH) 6.93 (d, J = 8.1 Hz, 1H, ArH) 7.14 (d, J = 8.4 Hz, 1H, ArH) 7.56 (d, J = 8.1 Hz, 1H, ArH) 7.70 (d, J = 8.1 Hz, 1H , ArH) 9.56 (s, 1H, NH). MS(EI): 382.

<EXAMPLE 46> 4,7-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

N-(7-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (45 mg, 0. 10 mmol) was completely dissolved in 6M HCl (1.4 mL) and methanol (0.1 mL), followed by heating for 90 min at 80 □. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic phase was purified using column chromatography (ethyl acetate:hexane=1:1) to provide the title compound ( 80mg, 200%).

mp: 243-247 °C.

NMR<1>H (300 MHz, CDC<h>) 81.21 (d, J = 6.9 Hz, 6H, CH<3>) 2.84-2.88 (m, 1H, CH) 3, 55 (s, 3H, OCH<3>) 3.78 (s, 1H, OH) 5.20 (s, 2H, NH<2>) 6.64 (s, 1H, ArH) 6.90 (s, 3H, ArH) 7.52 (d, J = 7.8 Hz, 1H, ArH). MS(EI): 340.

<EXAMPLE 47> 4,5-Diamino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

N-(5-amino-2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (85 mg, 0. 19 mmol) was completely dissolved in 6M HCl (1.4 ml) and methanol (0.1 ml), followed by heating for 40 min at 80 □. The reaction mixture was diluted with methylene chloride, extracted with 2N NaOH aqueous solution, and the concentrated organic phase was purified using column chromatography (ethyl acetate:hexane=1:1) to provide the title compound ( 30 mg, 44%).

mp: 272-274 °C.

NMR<1>H (300 MHz, CDCl<a>) 81.21 (d, J = 6.9 Hz, 6H, CH<3>) 2.83-2.92 (m, 1H, CH) 3, 33 (s, 3H, OCH<3>) 3.76 (s, 1H, OH) 4.13 (s, 2H, NH<2>) 6.63 (s, 1H, ArH) 6.96 (d, J = 7.8 Hz, 1H, ArH) 7.68 (d, J = 7.8 Hz, 1H, ArH) 7.83 (d, J = 8.1 Hz, 1H, ArH) 8.08 (d , J = 8.4 Hz, 1H, ArH). MS(EI): 340.

<EXAMPLE 48> (for reference) methyl 2-(4-isopropyl-2(methoxycarbonyloxy)phenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl carbamate

9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]inden-10-one (0.30 g, 1.01 mmol) was completely dissolved in THF (10 ml). This solution was added with triethylamine (0.17 ml, 1.21 mmol) and methylchloroformate (0.07 ml, 1.01 mmol), followed by heating for 3 h at room temperature. The reaction mixture was then concentrated in vacuo, extracted with water and methylene chloride, and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.30 g, 72 %). mp: 105-107 °C.

H NMR (300 MHz, CDCh) 81.18 (d, J = 6.9 Hz, 6H), 2.85 (c, J = 7.1 Hz, 1H), 3.61 (s, 3H ), 3.89 (s, 3H), 5.97 (s, 1H), 6.91 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.51 (d , J = 8.4 Hz, 1H), 7.82-7.87 (m, 2H), 7.97-8.03 (m, 2H).

<EXAMPLE 49> (for reference) 2-(1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate

9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]inden-10-one (0.30 g, 1.01 mmol) was dissolved in THF (10ml). This solution was added with valeryl chloride (0.12 ml, 1.01 mmol), followed by heating for 1 h at room temperature. The reaction mixture was then concentrated in vacuo, extracted with water and methylene chloride, and purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.10 g, 20 %).

mp: 117-118 °C.

H NMR (300 MHz, CDCh) 80.89 (t, J = 7.8 Hz, 3H), 1.00 (t, J = 8.1 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H), 1.29-1.40 (m, 2H), 1.42-1.62 (m, 4H), 1.77 (c, J = 8.8 Hz, 2H) , 2.24 (t, J = 8.3 Hz, 2H), 2.65 (t, J = 9.4 Hz, 2H), 2.84 (c, J = 7.8 Hz, 1H), 6 .67 (s, 1H), 6.85 (s, 1H), 7.05 (dd, J = 1.4 Hz, 8.3 Hz, 1H), 7.34 (d, J = 8.1 Hz , 1H), 7.79-7.84 (m, 2H), 7.93-7.99 (m, 2H).

<EXAMPLE 50> (for reference) 2-(2-isobutylamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl isobutyrate

9b-Amino-4b-hydro-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]-inden-10-one (0.30 g, 1.01 mmol) was dissolved in THF (10 ml). This solution was added with triethylamine (0.17 ml, 1.21 mmol), isobutyryl chloride (0.10 ml, 1.01 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and extracted with water and methylene chloride. The extracted organic phase was purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.10 g, 23%).

mp: 195-197 °C.

H NMR (300 MHz, CDCh) 81.15 (d, J = 6.9 Hz, 6H), 1.17 (d, J = 6.9 Hz, 6H), 1.38 (d, J = 7.0 Hz, 6H), 2.45 (c, J = 7.3 Hz, 1H), 2.77-3.00 (m, 2H), 6.70 (s, 1H), 6.82 (d, J = 1.7 Hz, 1H), 7.04 (dd, J = 1.7 Hz, 8.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.77-7.84 (m, 2H), 7.93-7.99 (m, 2H).

<EXAMPLE 51> (for reference) 2-Hydroxy-2-(2-hydroxy-4-isopropylphenyl)-2,3-dihydro-1H-inden-1-one

To a solution of 4b,9b-dihydroxy-7-isopropyl-4bH-benzo[d]indene[1,2-b]furan-10(9bH)-one (1.0 g, 3.3 mmol) in diethylene glycol ( 10 ml) was added with hydrazine hydrate (80%, 0.36 g, 9.6 mmol), followed by stirring at 150 °C for 15 min. Potassium hydroxide (360 mg, 6.4 mmol) was added to the reaction mixture and stirred at 165-170 °C for 1 h. The reaction mixture was extracted with ethyl acetate, and purified using column chromatography (20% ethyl acetate in hexane) to provide the title compound (60 g, 6.5%).

mp: 144-146 °C.

NMR<1>H (300 MHz, CDCh) 81.17 (d, J = 7 Hz, 6H, CH<3>) 2.75-2.79 (septuplet, 1H, CH) 3.52-3.69 (m, 2H, CH<2>) 6.57 (d, J = 8.0 Hz, 1H, ArH) 6.70 (d, J = 8.0 Hz, 1H, ArH) 6.79 (s, 1H, ArH) 7.41 (t, J = 6.8 Hz, 2H, ArH) 7.65 (t, J = 7.1 Hz, 1H, ArH) 7.82 (d, J = 7.7 Hz , 1H, ArH). MS(EI): 282.

<EXAMPLE 52> (for reference) 2-Azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

To a solution of 2-chloro-2-(4-isopropyl-2-methoxyphenyl)-1H-inden-1,3(2H)-dione (0.10 g, 0.3 mmol) in acetone (5 ml) added with sodium iodide (54 mg, 0.36 mmol) and sodium azide (50 mg, 0.76 mmol) and distilled water (1 mL), followed by stirring at 80 °C for 6 h. Water was added to the reaction mixture, and it was extracted with diethyl ether, and washed with water and brine in that order. The washed organic phase was concentrated to give the title compound (100 g, 98%).

mp: 175-177 °C.

H NMR (300 MHz, CDCl<a>) 81.24 (d, J = 6.9 Hz, 6H, CH<3>) 2.89 (septuplet, J = 6.9 Hz, 1H, CH ) 3.43 (s, 3H, OCH<3>) 6.62 (d, J = 1.2 Hz, 1H, ArH) 7.02 (dd, J = 7.8 Hz, J=1.2 Hz , 1H, ArH) 7.61 (d, J = 8.1 Hz, 1H, ArH) 7.89-7.95 (m, 2H, ArH) 8.03-8.09 (m, 2H, ArH) . MS(EI): 335.

<EXAMPLE 53> (for reference) 2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione

To a solution of 2-azido-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (50 mg, 0.15 mmol) in methanol (10 ml) was added with triphenylphosphine (47 mg, 0.18 mmol), followed by stirring at 60 °C for 4 h. The concentrated reaction mixture was purified using silica column chromatography (25% ethyl acetate in hexane) to provide the title compound (25 g, 54%).

mp: 164-166 °C.

NMR<1>H (300 MHz, CDC<h>) 81.22 (d, J = 6.9 Hz, 6H, CH<3>) 2.88 (septuplet, J = 6.9 Hz, 1H, CH ) 3.30 (s, 3H, OCH<3>) 6.57 (d, J = 1.2 Hz, 1H, ArH) 6.97 (dd, J = 7.8 Hz, J=1.5 Hz, 1H , ArH) 7.60 (d, J = 7.8 Hz, 1H, ArH) 7.86-7.90 (m, 2H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 309.

<EXAMPLE 54> (for reference) N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)acetamide

2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.10 g, 0.32 mmol) was dissolved in methylene chloride (4 ml). This solution was added with acetyl chloride (0.05 ml, 0.70 mmol), followed by stirring at room temperature for 15 min, and added with triethylamine (0.12 ml, 0.86 mmol), and stirred. for 6 hours. After extracting the reaction mixture with methylene chloride (50 ml X 3), the organic phase was purified using column chromatography (45% ethyl acetate in hexane) to provide the title compound (70 g, 62%) .

mp: 222-224 °C.

NMR<1>H (300 MHz, CDCh) 81.18 (d, J = 6.9 Hz, 6H, CH<3>) 1.95 (s, 3H, OAc) 2.82 (septuplet, J = 6 .9 Hz, 1H, CH) 3.51 (s, 3H, OCH3) 6.63 (d, J = 1.5 Hz, 1H, ArH) 6.85-6.90 (m, 2H, NH, ArH ) 7.41 (d, J = 8.4 Hz, 1H, ArH) 7.76-7.82 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 351.

<EXAMPLE 55> (for reference) N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)benzamide

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with benzoyl chloride (0.09 ml, 0.77 mmol) and triethylamine (0.27 ml, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (250 mg, 97%). mp: 106-108 °C.

NMR<1>H (300 MHz, CDCh) 81.21 (d, J = 6.9 Hz, 6H, CH<3>) 2.86 (septuplet, J = 6.9 Hz, 1H, CH) 3, 64 (s, 3H, OCH<3>) 6.72 (s, 1H, ArH) 6.90 (d, J = 8.1 Hz, 1H, ArH) 7.40-7.45 (m, 3H, ArH) 7.50-7.55 (m, 2H, ArH) 7.80-7.87 (m, 4H, ArH) 8.01-8.06 (m, 2H, ArH). MS(EI): 413.

<EXAMPLE 56> (for reference) N-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)cyclopropancarboxamide

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with cyclopropyl carbonyl chloride (0.07 ml, 0.77 mmol) and triethylamine (0.27 ml, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (235 mg, 96%).

mp: 145-147 °C.

NMR<1>H (300 MHz, CDC<h>) 81.22 (d, J = 6.9 Hz, 6H, CH<3>) 2.88 (septuplet, J = 6.9 Hz, 1H, CH ) 3.30 (s, 3H, OCH<3>) 6.57 (d, J = 1.2 Hz, 1H, ArH) 6.97 (dd, J = 7.8 Hz, J=1.5 Hz, 1H , ArH) 7.60 (d, J = 7.8 Hz, 1H, ArH) 7.86-7.90 (m, 2H, ArH) 8.00-8.04 (m, 2H, ArH). MS(EI): 377.

<EXAMPLE 57> (for reference) 2-(2-(Methylthio)phenyl)-2H-inden-1,3-dione

Ninhydrin (0.10 g, 0.56 mmol) and thioanisole (0.07 mL, 0.56 mmol) were dissolved in trifluoroacetic acid (3 mL) and stirred for 90 min at room temperature. The reaction mixture was neutralized with aqueous sodium bicarbonate solution and extracted with ethyl acetate and purified by silica gel column chromatography to give the title compound (20 mg, 13%).

mp: 191-193 °C.

<1>H NMR (300 MHz, CDCh) 82.11 (s, 3H, SMe) 3.70 (a, 1H, OH) 7.34-7.42 (m, 3H, ArH) 7.82 (m , 1H, ArH) 7.87-7.96 (m, 2H, ArH) 8.01-8.05 (m, 2H, ArH). MS(EI): 284.

<EXAMPLE 58> (for reference) 2-(4-(Methylthio)phenyl)-2H-inden-1,3-dione

The title compound (115 mg, 77%) was obtained in a manner similar to that described in EXAMPLE 70. mp: 153-155 °C.

H NMR (300 MHz, CDCl<a>) 82.14 (s, 3H, SMe) 3.74 (a, 1H, OH) 7.13-7.17 (m, 2H, ArH) 7. 26-7.31 (m, 2H, ArH) 7.90 7.95 (m, 2H, ArH) 8.03-8.06 (m, 2H, ArH). MS(EI): 284.

<EXAMPLE 59> Methyl 2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 mL) was added to triphosgene ( 0.21 g, 0.71 mmol) and stirred for 30 min. The reaction mixture was concentrated and dissolved in methanol (6 mL) and stirred for 2 h and concentrated to give the title compound (220 mg, 93%). mp: 153-155 °C.

NMR<1>H (300 MHz, CDCh) 81.18 (d, J = 6.9 Hz, 6H, CH<3>) 2.83 (septuplet, J = 6.9 Hz, 1H, CH) 3, 50 (s, 3H, O C ^ ) 3.65 (s, 3H, OCH<3>) 5.94 (a, 1H, NH) 6.63 (d, J = 1.5 Hz, 1H, ArH) 6 .89 (dd, J = 8.1 Hz, J=1.5 Hz, 1H, ArH) 7.44 (d, J = 8.1 Hz, 1H, ArH) 7.79-7.85 (m, 2H, ArH) 7.97-8.03 (m, 2H, ArH). MS(EI): 367.

<EXAMPLE 60> (for reference) 1-Ethyl-3-(2,3-dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 mL) was added to triphosgene ( 0.52 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and dissolved in anhydrous THF (10 mL) and ethylamine (2.0M in methanol, 2 mL, 400 mmol) was added and stirred for 2 h. Dichloromethane was added to the concentrated reaction mixture to provide the title compound (450 mg, 74%). mp: 267 269 °C.

H NMR (300 MHz, CDCh) 81.17,1.23 (m, 9H, CH<3>) 2.72 (a, 1H, NH) 2.89 (septuplet, J = 6.9 Hz, 1H , CH) 3.30-3.44 (m, 4H, C H and CH<2>) 3.50-3.62 (m, 1H, CH2) 5.33 (s, 1H, NH) 6.70 ( s, 1H, ArH) 6.96 (dd, J = 8.1 Hz, J=1.2 Hz, 1H, ArH) 7.51 (d, J = 8.1 Hz, 1H, ArH) 7.59 -7.64 (m, 1H, ArH) 7.75-7.83 (m, 2H, ArH) 7.94 (d, J = 7.8 Hz, 1H, ArH). MS(EI): 380.

<EXAMPLE 61> (for reference) 1-(2,3-Dihydro-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-1H-inden-2-yl)urea

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.62 mmol) in anhydrous THF (10 mL) was added to triphosgene ( 0.52 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and dissolved in anhydrous THF (10 ml) and ammonia ((2.0M in IPA, 1.6 ml, 3.23 mmol) was added and stirred for 2 h. The reaction mixture was concentrated and purified using silica gel column chromatography to give the title compound (150 mg, 29%).

mp: 272-274 °C.

NMR<1>H (300 MHz, A c e to n a ^ ) 81.24 (d, J = 6.9 Hz, 6H, CH<3>) 2.84-2.96 (m, 3H, CH, NH <2>) 3.30 (s, 3H, OMe) 6.81 (d, J = 1.5 Hz, 1H, ArH) 6.91-6.95 (m, 1.7H, ArH and NH) 7 .18 (a, 0.63H, NH) 7.51(d, J = 7.8 Hz, 1H, ArH) 7.59-7.64(m, 1H, ArH) 7.79-7.86(m , 3H, ArH). MS(EI): 352.

<EXAMPLE 62> (for reference) Isopropyl 2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

The title compound (150 mg, 23%) was obtained in a manner similar to that described in EXAMPLE 75. mp: 159-161 °C.

NMR<1>H (300 MHz, CDCh) 81.10-1.17 (m, 12H, CH<3>) 2.82 (septuplet, J = 6.9 Hz, 1H, CH) 3.48 (s , 3H, OMe) 4.76 (m, 1H, CH) 5.83 (s, 1H, NH) 6.62 (d, J = 1.5 Hz, 1H, ArH) 6.88-6.93 ( m, 1H, ArH) 7.45-7.49 (m, 1H, ArH) 7.80-7.84 (m, 2H, ArH) 7.97-8.01 (m, 2H, ArH). MS(EI): 395.

<EXAMPLE 63> (for reference) 1-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-3-methoxy urea

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.50 g, 1.61 mmol) in anhydrous THF (20 mL) was added to triphosgene ( 0.528 g, 1.77 mmol) and stirred for 15 min. The reaction mixture was concentrated and dissolved in anhydrous THF (20 mL) and hydroxylamine hydrochloride (0.28 g, 4.04 mmol) was added and stirred for 2 h at room temperature. The reaction mixture was concentrated and purified using silica gel column chromatography (1:1 = ethyl acetate: hexane) to provide the title compound (420 mg, 69%).

mp: 153-155 °C.

NMR<1>H (300 MHz, CDCh) 81.25 (dd, J = 1.5 Hz, J=6.9 Hz, 6H, CH<3>) 2.91 (septuplet, J = 6.9 Hz , 1H, CH) 2.97 (s, 1H, NH) 3.45 (s, 3H, OCH<3>) 4.02 (s, 3H, OCH<3>) 5.51 (a, 1H, NH ) 6.76 (d, J = 1.5 Hz, 1H, ArH) 7.00 (dd, J = 1.5 Hz, J=7.8 Hz, 1H, ArH) 7.47 (d, J = 7.8 Hz, 1H, ArH) 7.60-7.65 (m, 1H, ArH) 7.76-7.81 (m, 1H, ArH) 7.89-7.95 (t, J = 8 ,4 Hz, 2H, ArH). MS(EI): 382.

<EXAMPLE 64> (for reference) ethyl 2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-ylcarbamate

A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.80 g, 2.58 mmol) in anhydrous THF (20 ml) was added to triphosgene ( 0.84 g, 2.84 mmol) and stirred for 15 min. The reaction mixture was concentrated and dissolved in ethanol (20 ml) and stirred for 2 h at room temperature to give the title compound (0.95 g, 96%). mp: 149-150 °C.

NMR<1>H (300 MHz, CDCl<a>) 81.17-1.24 (m, 9H, CH<3>) 2.83 (septuplet, J = 6.9 Hz, 1H, CH) 3, 49 (s, 3H, OCH<3>) 4.02 (c, 2H, CH<2>) 5.89 (a, 1H, NH) 6.62 (s, 1H, ArH) 6.89 (d, J = 8.1 Hz, 1H, ArH) 7.46 (d, J = 8.1 Hz, 1H, ArH) 7.80-7.83 (m, 2H, ArH) 7.98-8.01( m, 2H, ArH). MS(EI): 381.

<EXAMPLE 65> (for reference) N-(2-Bromo-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

A solution of N-(2-hydroxy-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide(0. 25 g, 0.68 mmol) in dichloromethane (10 ml) and thionyl bromide (0.08 ml, 1.02 mmol) was added and DMF (2 drops) was stirred for 2 h at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (20% ethyl acetate in hexane) to provide the title compound (0.22 g, 75%). mp: 143-145 °C.

H NMR (300 MHz, CDCh) 81.24 (d, J = 6.9 Hz, 6H, CH<3>) 2.63 (s, 3H, NAc) 2.91 (septuplet, J = 6 .9 Hz, 1H, CH) 3.41 (s, 3H, OCH3) 6.61 (d, J = 1.2 Hz, 1H, ArH) 6.98 (dd, J = 8.1 Hz, J= 1.2 Hz, 1H, ArH) 7.70 (d, J = 8.1 Hz, 1H, ArH) 7.81 (d, J = 7.8 Hz, 1H, ArH) 7.86-7.91 (m, 1H, ArH) 9.00 (d, J = 8.4 Hz, 1H, ArH) 10.31 (a, 1H, NH). MS(EI): 430.2.

<EXAMPLE 66> (for reference) N-(2-Amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide

A solution of N-(2-azido-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (115 mg, 0.29 mmol) in methanol (5 ml) and triphenylphosphine (A mg, 0.35 mmol) was added and water (1 ml) was stirred for 2.5 h at 50 °C. The reaction mixture was concentrated and purified using silica gel column chromatography (30% ethyl acetate in hexane, 1% triethylamine) to provide the title compound (75 mg, 70%).

mp: 183-185 °C.

NMR<1>H (300 MHz, CDC<h>) 81.23 (d, J = 6.9 Hz, 6H, CH<3>) 1.99 (a, 2H, NH<2>) 2.24 (s, 3H, NAc) 2.88 (septuplet, J = 6.9 Hz, 1H, CH) 3.35 (s, 3H, OCH<3>) 6.59 (d, J = 1.5 Hz, 1H, ArH) 6.98 (dd, J = 7.8 Hz, J=1.5 Hz, 1H, ArH) 7.60 (d, J = 7.8 Hz, 1H, ArH) 7.66 (d, J = 7.2 Hz, 1H, ArH) 7.84 (t, J = 7.8 Hz, 1H, ArH) 8.93 (d, J = 8.1 Hz, 1H, ArH) 10.2 (a, 1H, NH). MS(EI): 366.

<EXAMPLE 67> (for reference) N,N'-(2-(4-Isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2,4-diyl)diacetamide

A solution of N-(2-amino-2-(4-isopropyl-2-methoxyphenyl)-1,3-dioxo-2,3-2,3-dihydro-1H-inden-4-yl)acetamide(0. 20 g, 0.54 mmol) in dichloromethane (10 ml) and triethylamine (0.23 ml, 1.6 mmol) was added and then stirred overnight. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (50% ethyl acetate in hexane) to provide the title compound (210 mg, 95%). mp: 241-243 °C.

NMR<1>H (300 MHz, CDC<h>) 81.19 (d, J = 6.9 Hz, 6H, CH<3>) 2.05 (s, 3H, NAc) 2.23 (s, 3H, NAc) 2.85 (septuplet, J = 6.9 Hz, 1H, CH) 3.55 (s, 3H, OCH3) 6.65-6.74 (m, 2H, ArH and NH) 6.91 (dd , J = 8.1 Hz, J=1.5 Hz, 1H, ArH) 7.39 (d, J = 8.1 Hz, 1H, ArH) 7.62 (d, J = 7.5 Hz, 1H , ArH) 7.78 (t, J = 8.1 Hz, 1H, ArH) 8.86 (d, J = 8.4 Hz, 1H, ArH) 10.1 (a,1H, NH). MS(EI): 408.

<EXAMPLE 68> (for reference) 2-(1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indene[1,2-b]furan-10(9bH)-one (0.10 g, 0.34 mmol) in dichloromethane (5 ml) triethylamine (0.14 ml, 1.02 mmol) and propionyl chloride (32.5 pl, 0.37 mmol) were added at 0 °C and then stirred for 4 h at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (40% ethyl acetate in hexane) to give the title compound (116 mg, 85%).

mp: 173-175 °C.

NMR<1>H (300 MHz, CDC<h>) 81.07-1.19 (m, 9H, CH<3>) 1.23-1.33 (m, 3H, CH<3>) 2, 27 (c, J = 7.5 Hz, 2H, CH<2>) 2.68 (c, J = 7.5 Hz, 2H, CH<2>) 2.84 (septuplet, J = 6.9 Hz , 1H, CH) 6.69 (s, 1H, NH) 6.86 (d, J = 1.5 Hz, 1H, ArH) 7.06 (dd, J = 1.5 Hz, J=8.1 Hz, 1H, ArH) 7.35 (d, J = 8.1 Hz, 1H, ArH) 7.80-7.83 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH ). MS(EI): 407.

<EXAMPLE 69> (for reference) 2-(1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indene[1,2-b]furan-10(9bH)-one (0.15 g, 0.50 mmol) in dichloromethane (5 ml) Triethylamine (0.2 mL, 1.52 mmol) and valeroyl chloride (74 mL, 0.61 mmol) were added at 0 °C and then stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (150 mg, 68%).

mp: 128-130 °C.

NMR<1>H (300 MHz, CDCh) 80.89 (t, J = 7.2 Hz, 3H, CH<3>) 0.99 (t, J = 7.2 Hz, 3H, CH<3> ) 1.18 (d, J = 6.9 Hz, 6H, CH<3>) 1.23-1.40 (m, 2H, CH<2>) 1.42-1.62 (m, 4H, CH<2>) 1.72-1.82 (m, 2H, CH<2>) 2.43 (t, J = 7.5 Hz, 2H, CH<2>) 2.65 (t, J = 7.8 Hz, 2H, CH<2>) 2.84 (septuplet, J = 6.9 Hz, 1H, CH) 6.67 (s, 1H, NH) 6.85 (d, J = 1.5 Hz, 1H, ArH) 7.06 (dd, J = 1.5 Hz, J=8.4 Hz, 1H, ArH) 7.34 (d, J = 8.4 Hz, 1H, ArH) 7.79 -7.84 (m, 2H, ArH) 7.93-7.97 (m, 2H, ArH). MS(EI): 463.

<EXAMPLE 70> (for reference) 2-(2-benzamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl benzoate

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4bH-benzo[d]indene[1,2-b]furan-10(9bH)-one (0.25 g, 0.85 mmol) in dichloromethane (15 ml) diisopropylethylamine (0.73 ml, 4.22 mmol) and benzoyl chloride (0.29 ml, 2.54 mmol) were added at 0 °C and then stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane and purified using silica gel column chromatography (20% ethyl acetate in hexane) to provide the title compound (280 mg, 66%).

mp: 138-140 °C.

H NMR (300 MHz, CDCl<a>) 81.22 (d, J = 6.9 Hz, 6H, CH<3>) 2.90 (septuplet, J = 6.9 Hz, 1H, CH ) 7.00 (d, J = 1.5 Hz, 1H, ArH) 7.16 (dd, J = 1.5 Hz, J=8.1 Hz, 1H, ArH) 7.34-7.61 ( m, 9H, ArH) 7.73-7.76 (m, 4H, ArH) 7.77-7.86 (m, 2H, ArH) 8.10-8.12 (m, 2H, ArH). MS(EI): 503.

<EXAMPLE 71> (for reference) 2-(2-acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-6-methylpyridin-3-yl acetate

The title compound was obtained in a manner similar to that described in EXAMPLE 2.

H NMR (200 MHz, CDCh): 88.33 (d, J = 7.7 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.52-7.44 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 2.59 (s,3 H), 2 .35(s, 3H), 2.30 (s, 3H).

<EXAMPLE 72> (for reference) 2-Hydroxy-2-(4-hydroxy-5-methylpyridin-3-yl)-1H-inden-1,3(2H)-dione

The title compound was obtained in a manner similar to that described in EXAMPLE 24.

<1>H NMR (200 MHz, DMSO-d<6>): 810.5 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.90 (m, 2H) , 7.65 (m, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.6 Hz,1H), 2.51 (s, 3H) .

<EXAMPLE 73> (for reference) 2-(5-Chloro-3-hydroxypyridin-2-yl)-2-hydroxy-1H-inden-1,3(2H)-dione

The title compound was obtained in a manner similar to that described in EXAMPLE 24.

NMR<1>H (200 MHz, CDCh): 88.32 (d, J = 7.9 Hz, 1H), 8.08 (m, 1H), 7.89 (td, J = 8.2, 1 .2 Hz, 1H), 7.65 (t, J = 7.0 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 1.4 Hz, 1H).

<EXAMPLE 74> (for reference) 2-2-Acetoxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl

A solution of 4b,9b-dihydroxy-7-methyl-4bH-benzo[d]indene[1,2-b]furan-10(9bH)-one (0.25 g, 0.85 mmol) in anhydrous dichloromethane ( 50 ml) anhydrous acetic acid (0.7 ml, 7.4 mmol), pyridine (0.3 ml, 3.7 mmol), 4-dimethylaminopyridine (0.1 g) was added and then stirred for 3 h at temperature atmosphere. The reaction mixture was extracted with dichloromethane, the concentrated organic phase was purified using silica gel column chromatography (ethyl acetate: hexane = 1:8) to give the title compound (1.1 g, 84%).

m.p.: 145-147 °C.

H NMR (300 MHz, CDCh): 82.07 (s, 3H, OAc), 2.19 (s, 3H, OAc), 2.31 (s, 3H, CH<3>), 6, 80 (s, 1H, ArH), 7.08 (d, J = 8.1 Hz, 1H, ArH), 7.57 (d, J = 8.1 Hz, 1H, ArH), 7.86-8 .02 (m, 4H, ArH). MS(EI): 352.

<EXAMPLE 75> (for reference) 2-Hydroxy-2-(6-hydroxyquinolin-7-yl)-1H-inden-1,3(2H)-dione

The title compound was obtained in a manner similar to that described in EXAMPLE 24.

NMR<1>H (200 MHz, CDCh): 88.86 (d, J = 8.5 Hz, 1H), 8.75 (m, 1H), 8.35 (s, 1H), 8.05- 7.88 (m, 3H), 7.75-7.55 (m, 3H), 7.36 (d, J = 9.1 Hz, 1H), 6.87 (s, 1H).

<EXAMPLE 76> (for reference) butyric acid 2-(2-butyrylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml), triethylamine (0.20 g, 2.01 mmol) and butyryl chloride (0.18 g, 1.69 mmol) were added at room temperature and then stirred for 3 h. The reaction mixture was diluted in ethyl acetate, and washed with water several times. The organic phase was dried, filtered, and purified using silica gel column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (230 mg, 79%).

NMR<1>H (300 MHz, CDCh) 80.95 (t, J = 7.5 Hz, 3H, CH<3>) 1.08 (t, J = 7.5 Hz, 3H, CH<3> ) 1.18 (d, J = 6.9 Hz, 6H, CH<3>) 1.57-1.67 (m, 2H, CH<2>) 1.78-1.86 (m, 2H, CH<2>) 2.23 (t, J = 7.5 Hz, 2H, CH<2>) 2.64 (t, J = 7.5 Hz, 2H, CH<2>) 2.82-2 .86 (m, 1H, CH) 6.61 (s, 1H, NH) 6.85 (d, J = 1.5 Hz, 1H, ArH) 7.06 (dd, J = 1.5, 8.1 Hz , 1H, ArH) 7.33 (d, J = 8.1 Hz, 1H, ArH) 7.80-7.85 (m, 2H, ArH) 7.94-7.98(m, 2H, ArH) .

<EXAMPLE 77> (for reference) 7-isopropyl-9b-octanoylamino-10-oxo-9b,10-dihydro-5-oxa-indene[2,1-a]inden-4b-yl ester of octanoic acid

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml), added triethylamine (0.20 g, 2.01 mmol) and octanoyl chloride (0.27 g, 1.67 mmol) and then stirred for 28 h. The reaction mixture was concentrated and extracted with ethyl acetate. The concentrated organic phase was purified using silica gel column chromatography (ethyl acetate: hexane = 1:6 to 1:4) to provide the title compound as a syrup (55 mg, 15%).

NMR<1>H (300 MHz, CDCh) 80.88 (t, J = 7.5 Hz, 3H, CH<3>) 1.18 (d, J = 6.9 Hz, 6H, CH<3> ) 1.26-1.45 (m, 12H, CH<2>) 1.54 1.65 (m, 4H, CH<2>) 1.73-1.83 (m, 2H, CH<2> ) 2.24 (t, J = 7.8 Hz, 2H, CH<2>) 2.34 (t, J = 7.5 Hz, 2H, CH<2>) 2.65 (t, J = 7 .5 Hz, 2H, CH<2>) 2.80-2.89 (m, 1H, CH) 6.61 (s, 1H, NH) 6.85 (d, J = 1.5 Hz, 1H, ArH) 7.06 (dd, J = 1.8, 8.4 Hz, 1H, ArH) 7.33 (d, J = 8.4 Hz, 1H, ArH) 7.79-7.84 (m, 2H, ArH) 7.94-7.99 (m, 2H, ArH).

<EXAMPLE 78> (for reference) hexanoic acid 2-(2-hexanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml), added triethylamine (0.20 g, 2.01 mmol) and hexanoyl chloride (0.22 g, 1.69 mmol) and then stirred for 5 h. The reaction mixture was concentrated and extracted with ethyl acetate. The concentrated organic phase was purified using silica gel column chromatography (ethyl acetate: hexane = 1:6 to 1:4) to provide the title compound as a syrup (0.14 g, 46%).

NMR<1>H (300 MHz, CDCl<a>) 80.88 (t, J = 6.9 Hz, 3H, CH<3>) 0.95 (t, J = 6.9 Hz, 3H, CH <3>) 1.18 (d, J = 6.9 Hz, 6H, CH<3>) 1.25-1.37 (m, 6H, CH<2>) 1.40-1.47 (m , 2H, CH<2>) 1.55-1.65 (m, 2H, CH<2>) 1.74-1.84 (m, 2H, CH<2>) 2.24 (t, J = 7.5 Hz, 2H, CH<2>) 2.65 (t, J = 7.5 Hz, 2H, CH<2>) 280-2.89 (m, 1H, CH) 6.60 (s, 1H, NH) 6.85 (d, J = 1.8 Hz, 1H, ArH) 7.05 (dd, J = 1.8, 8.1 Hz, 1H, ArH) 7.33 (d, J = 8, 4 Hz, 1H, ArH) 7.80-7.84 (m, 2H, ArH) 7.93-7.98 (m, 2H, ArH).

<EXAMPLE 79> (for reference) 2-(2-heptanoylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester of heptanoic acid

A solution of 9b-amino-4b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indene[2,1-a]inden-10-one (0.20 g, 0.67 mmol) in anhydrous methylene chloride (10 ml), added triethylamine (0.20 g, 2.01 mmol) and heptanoyl chloride (0.25 g, 1.69 mmol) and then stirred for 3 h. The reaction mixture was concentrated and extracted with ethyl acetate. The concentrated organic phase was purified using silica gel column chromatography (ethyl acetate: hexane = 1:6 to 1:4) to provide the title compound as a syrup (0.21 g, 60%).

NMR<1>H (300 MHz, CDCh) 80.85-0.94 (m, 6H, CH<3>) 1.18 (d, J = 7.2 Hz, 6H, CH<3>) 1, 25-1.37 (m, 10H, CH<2>) 1.54-1.63 (m, 4H, CH<2>) 1.73-1.80 (m, 2H, CH<2>) 2 .24 (t, J = 7.5 Hz, 2H, CH<2>) 2.65 (t, J = 7.5 Hz, 2H, CH<2>) 2.82-2.86 (m, 1H , CH) 6.60 (s, 1H, NH) 6.85 (d, J = 1.5 Hz, 1H, ArH) 7.05 (dd, J = 1.5, 8.4 Hz, 1H, ArH) 7 .33 (d, J = 8.1 Hz, 1H, ArH) 7.80 7.83 (m, 2H, ArH) 7.95-7.98 (m, 2H, ArH).

<EXAMPLE 80> (for reference) 2-(1,3-dioxo-2-pentanoylamino-indan-2-yl)-5-isopropyl-phenyl ester of 2,2-dimethyl-propionic acid

A solution of pentanoic acid [2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g, 0.26 mmol) in anhydrous methylene chloride (10 ml) triethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride (0.047 g, 0.39 mmol) were added and then stirred for 2 h. The reaction mixture was concentrated and extracted with ethyl acetate. The concentrated organic phase was purified using silica gel column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.11 g, 91%).

NMR<1>H (300 MHz, CDCh) 80.88 (t, J = 7.2 Hz, 3H, CH<3>) 1.17 (d, J = 6.9 Hz, 6H, CH<3> ) 1.44-1.25 (m, 2H, CH<2>) 1.50 (s, 9H, CH<3>) 1.53-1.61 (m, 2H, CH<2>) 2, 23 (t, J = 7.2 Hz, 2H, ArH) 2.78-2.88 (m, 1H, CH) 6.77-6.79 (m, 2H, NH, ArH) 6.97 (d , J = 1.2, 8.1 Hz, 1H, ArH) 7.08 (d, J = 1.2, 8.1 Hz, 1H, ArH) 7.79-7.82 (m, 2H, ArH) 7 .95-7.98 (m, 2H, ArH).

<EXAMPLE 81> 2-(4-amino-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate

Iron powder (0.03 g, 0.6 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-pentanamido-2,3) pentanoate -dihydro-1H-inden-2-yl)phenyl (43 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 h at reflux. The reaction mixture was filtered hot, the filtrate was concentrated in vacuo and purified by column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to give the title compound (22 mg, 55%) .

1H NMR (300 MHz, CDCh) 80.90 (t, J = 7.2 Hz, 3H, CH3) 0.98 (t, J = 7.2 Hz, 3H, CH3) 1.16-1.61 ( m, 12H, CH2, CH3) 1.73 (t, J = 7.5 Hz, 2H, CH2) 2.25 (t, J = 7.5 Hz, 2H, CH2) 2.63 (t, J = 8.1 Hz, 2H, CH2) 2.80-2.89 (m, 1H, CH) 5.69 (s, 2H, NH2) 6.62 (s, 1H, NH) 6.77 (d, J = 8.1 Hz, 1H, ArH) 6.85 (s, 1H, ArH) 7.05 (d, J = 6.9 Hz, 1H, ArH) 7.13 (d, J = 6.9 Hz, 1H, ArH) 7.30 (d, J = 8.1 Hz, 1H, ArH) 7.40 (t, J = 7.8 Hz, 1H, ArH).

<EXAMPLE 82> 2-(4-Amino-2-hexanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl hexanoate

Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-hexanamido-4-nitro-1,3-dioxo-2,3-dihydro-1H hexanoate -inden-2-yl)-5-isopropylphenyl (40 mg, 0.07 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 h at reflux. The reaction mixture was filtered hot, the filtrate was concentrated in vacuo and purified by column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to give the title compound (21 mg, 57%) .

1H NMR (300 MHz, CDCh) 80.79-0.96 (m, 6H, CH3) 1.18 (dd, J = 6.9 Hz, 6H, CH3) 1.22-1.32 (m, 6H , CH3) 1.36-1.41 (m, 2H, CH2) 1.47-1.63 (m, 3H, CH2) 1.73-1.82 (m, 1H, CH2) 2.24 (t , J = 7.5 Hz, 2H, CH2) 2.65 (t, J = 7.8 Hz, 2H, CH2) 2.80-2.89 (m, 1H, CH) 5.66 (s, 2H , NH2) 6.59 (s, 1H, NH) 6.80 (d, J = 8.1 Hz, 1H, ArH) 6.86 (d, J = 1.8 Hz, 1H, ArH) 7.05 (dd , J = 1.8, 8.1 Hz, 1H, ArH) 7.15 (d, J = 7.2 Hz, 1H, ArH) 7.30 (d, J = 8.4 Hz, 1H, ArH) 7.44 (d, J = 7.8 Hz, 1H, ArH).

<EXAMPLE 83> 2-(4-Amino-2-heptanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl heptanoate

Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 2-(2-heptanamido-4nitro-1,3-dioxo-2,3-dihydro-1H-inden heptanoate -2-yl)-5-isopropylphenyl (60 mg, 0.10 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 h at reflux. The reaction mixture was filtered hot, the filtrate was concentrated in vacuo and purified by column chromatography (ethyl acetate: hexane = 1:6 to 1:4) to give the title compound (20 mg, 36%) .

1H NMR (300 MHz, CDCla) 80.79-0.97 (m, 6H, CH3) 1.18 (dd, J = 6.9 Hz, 6H, CH3) 1.25-1.49 (m, 12H , CH2) 1.58 (t, J = 7.2 Hz, 2H, CH2) 1.82 (t, J = 7.2 Hz, 2H, CH2) 2.22 (t, J = 7.5 Hz, 2H, CH2) 2.65 (t, J = 7.5 Hz, 2H, CH2) 2.80-2.89 (m, 1H, CH) 5.66 (s, 2H, NH2) 6.59 (s , 1H, NH) 6.79 (d, J = 8.1 Hz, 1H, ArH) 6.85 (d, J = 1.5 Hz, 1H, ArH) 7.05 (dd, J = 1.8, 8 .4 Hz, 1H, ArH) 7.15 (d, J = 7.2 Hz, 1H, ArH) 7.29 (d, J = 8.1 Hz, 1H, ArH) 7.42 (t, J = 8.1 Hz, 1H, ArH).

<EXAMPLE 84> 2-(4-Amino-1,3-dioxo-2-propionamido-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl propionate

Iron powder (0.03 g, 0.5 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-propionamido-2,3) propionate -dihydro-1H-inden-2-yl)phenyl (40 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 h at reflux. The reaction mixture was filtered hot, the filtrate was concentrated in vacuo and purified by column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to give the title compound (28 mg, 75%) .

1H NMR (300 MHz, CDCh) 81.18 (dd, J = 6.9 Hz, 6H, CH3) 1.27 (dd, J = 3.3, 7.5 Hz, 6H, CH3) 2.29 ( c, J = 7.5 Hz, 2H, CH2) 2.70 (c, J = 7.5 Hz, 2H, CH2) 2.80-2.89 (m, 1H, CH) 5.67 (s, 2H, NH2) 6.60 (s, 1H, NH) 6.80 (d, J = 8.1 Hz, 1H, ArH) 6.87 (d, J = 1.5 Hz, 1H, ArH) 7.06 ( dd, J = 1.5, 6.9 Hz, 1H, ArH) 7.16 (d, J = 7.2 Hz, 1H, ArH) 7.32 (t, J = 8.1 Hz, 1H, ArH) ) 7.43 (t, J = 7.5 Hz, 1H, ArH).

<EXAMPLE 85> 2-(4-amino-2-butyramido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate

Iron powder (0.07 g, 1.3 mmol), conc. HCl (0.05 ml), and water (1 ml) were added in that order to a solution of 2-(2-butyramido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden butyrate -2-yl)-5-isopropylphenyl (90 mg, 0.18 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 h at reflux. After filtration at elevated temperature, the filtrate was concentrated in vacuo and purified using column chromatography (ethyl acetate: hexane = 1:4 to 1:2) to provide the title compound (70 mg, 83%).

1H NMR (300 MHz, CDCh) 80.95 (t, J = 7.5 Hz, 3H, CH3) 1.07 (t, J = 7.5 Hz, 3H, CH3) 1.18 (d, J = 6.9 Hz, 6H, CH3) 1.64 (c, J = 7.5, 14.7 Hz, 2H, CH2) 1.80 (c, J = 7.5, 14.7 Hz, 2H, CH2 ) 2.23 (t, J = 7.5 Hz, 2H, CH2) 2.64 (t, J = 7.5 Hz, 2H, CH2) 2.80-2.89 (m, 1H, CH) 5 .70(s, 2H, NH2) 6.62 (s, 1H, NH) 6.74 (d, J = 8.4 Hz, 1H, ArH) 6.86 (d, J = 1.5 Hz, 1H , ArH) 7.05 (dd, J = 1.5, 8.4 Hz, 1H, ArH) 7.12 (d, J = 7.2 Hz, 1H, ArH) 7.28 (t, J = 7.5 Hz, 1H, ArH) 7.38 (t, J = 7.5 Hz, 1H, ArH).

<EXAMPLE 86> (for reference) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)acetamide

N-(3,4-dimethylphenyl)acetamide (915 mg, 5.62 mmol) and ninhydrin (1.00 g, 5.62 mmol) were dissolved in conc. sulfuric acid. (20 ml) and stirred at room temperature for 1.5 h. The reaction was stopped by slowly pouring the solution into 150 g of ice and stirring. The reaction mixture was extracted with ethyl acetate and water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (30% ethyl acetate in hexane) to provide the title compound (yellow solid, 800 mg, 44%). 1H NMR (300 MHz, CDCh) 82.02 (s, 3H, NAc) 2.20 (s, 3H, CH3) 2.22 (s, 3H, CH3) 6.11 (s, 1H, ArH) 7. 03 (s, 1H, ArH) 7.99-8.02 (m, 2H, ArH) 8.13-8.16 (m, 2H, ArH).

<EXAMPLE 87> (for reference) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)propionamide

N-(3,4-dimethylphenyl)propionamide (500 mg, 2.82 mmol) and ninhydrin (500 mg, 2.82 mmol) were dissolved in conc. sulfuric acid. (10 ml) and stirred at room temperature for 1.5 h. The reaction was stopped by slowly pouring the solution into 150 g of ice and stirring. The reaction mixture was extracted with ethyl acetate and water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (yellow solid, 430 mg, 450 mg). %). NMR<1>H (300 MHz, DMSO) 81.26 (t, J = 7.5 Hz, 3H, CH<3>) 2.14 (s, 6H, CH<3>) 3.06-3, 58 (m, 2H, CH<2>) 6.84 (s, 1H, ArH/OH) 7.16 (s, 1H, ArH/OH) 7.48 (s, 1H, ArH/OH) 7.56 -7.61 (m, 1H, ArH) 7.70 (d, J = 7.8 Hz, 1H, ArH) 7.80-7.86 (m, 2H, ArH) 7.95-8.01 ( m, 1H, ArH).

<EXAMPLE 88> (for reference) N-(5-Ethyl-2-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)phenyl)acetamide

N-(3-ethylphenyl)acetamide (500 mg, 3.06 mmol) and ninhydrin (546 mg, 3.06 mmol) were dissolved in conc. sulfuric acid. (10 ml) and stirred at room temperature for 3 h. The reaction was stopped by slowly pouring the solution into 150 g of ice and stirring. The reaction mixture was extracted with ethyl acetate and water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (30% ethyl acetate in hexane) to give the title compound (90 mg, 9%).

NMR<1>H (300 MHz, CDCh) 81.17 (t, J = 7.5 Hz, 3H, CH<3>) 2.45 (s, 3H, NAc) 2.57 (c, J = 7 .5 Hz, 2H, CH<2>) 6.30 (d, J = 7.5 Hz, 1H, ArH) 6.81 (dd, J = 7.5 Hz, J=1.5 Hz, 1H, ArH) 7.09 (d, J = 1.5 Hz, 1H, ArH) 7.98-8.03 (m, 2H, ArH) 8.11 8.15 (m, 2H, ArH).

<EXAMPLE 89> (for reference) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)butyramide

N-(3,4-dimethylphenyl)butyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid. (15 ml) and stirred at room temperature for 5 h. The reaction was stopped by slowly pouring the solution into 150 g of ice and stirring. The reaction mixture was extracted with ethyl acetate and water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (yellow solid, 1.10 g , 56%). NMR<1>H (300 MHz, CDCh) 81.028 (t, J = 7.5 Hz, 3H, CH<3>) 1.69-1.79 (m, 2H, CH<2>) 2.01 ( s, 3H, CH<3>) 2.17 (s, 3H, CH<3>) 2.43 (t, J = 7.5 Hz, 2H, CH<2>) 6.11 (s, 1H, ArH) 7.05 (s, 1H, ArH) 7.99-8.03 (m, 2H, ArH) 8.11 8.16 (m, 2H, ArH).

<EXAMPLE 90> (for reference) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethylphenyl)isobutyramide

N-(3,4-dimethylphenyl)isobutyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid. (15 ml) and stirred at room temperature for 5 h. The reaction was stopped by slowly pouring the solution into 200 g of ice and stirring. The reaction mixture was extracted with ethyl acetate and water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (yellow solid, 1.85 g , 94%). NMR<1>H (300 MHz, CDCh) 81.26 (d, J = 6.9 Hz, 6H, CH<3>) 2.01(s, 3H, CH<3>) 2.18(s, 3H, CH<3>) 2.68 (sept, J = 6.9 Hz, 1H, CH) 6.11(s, 1H, ArH) 7.08(s, 1H, ArH) 7.99-8, 03(m, 2H, ArH) 8.11-8.16(m, 2H, ArH).

<EXAMPLE 91> 2-(4-amino-2-octanamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl octanoate

Powdered iron (58 mg, 1.03 mmol) and conc. HCl (3 drops) were added in that order to a solution of 5-isopropyl-2-(4-nitro-2-octanamino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl) octanoate. phenyl (80 mg, 0.14 mmol) in ethanol:water (9:1, 7 ml). The reaction mixture was heated for 3 h at reflux. After filtration at elevated temperature, the filtrate was concentrated in vacuo and purified using silica gel column chromatography (20% ethyl acetate in hexane, 1% triethylamine) to provide the title compound (45 mg, 59%).

NMR<1>H (300 MHz, CDCh) 80.84-0.88 (m, 6H, CH<3>) 1.16-1.28 (m, 16H 6H, CH<2>+ CH<3> ) 1.51-1.64 (m, 4H, CH<2>) 2.10-2.46(m, 4H, CH<2>) 2.85(sept, J = 6.9 Hz, 1H, CH) 4.40(a, 2H, NH<2>) 5.98(s, 1H, ArH/NH) 6.72(s, 1H, ArH/NH) 6.89-6.96(m, 2H , ArH) 7.22-7.34(m, 2H, ArH) 7.40-7.43(m, 1H, ArH).

<EXAMPLE 92> (for reference) 2-(2-acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl methyl carbonate

Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH -benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in Th F (5 ml). The reaction mixture was stirred at room temperature for 12 h, concentrated in vacuo to remove the solvent. The reaction mixture was extracted with water and methylene chloride, and purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to give the title compound (0.10 g, 14 %). .

H NMR (300 MHz, CDCh) 81.17 (d, J = 6.8 Hz, 6H), 1.89 (s, 3H), 2.84 (c, J = 7.8 Hz, 1H ), 3.89 (s, 3H), 6.90 (s, 1H), 7.01 (s, 1H), 7.10 (d,J =7.7 Hz, 1H), 7.44 (d ,J =8.2 Hz, 1H), 7.77-7.83 (m, 2H), 7.92-7.96 (m, 2H).

<EXAMPLE 93> (for reference) 2-(2-acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl pentanoate

Triethylamine (0.24 ml, 1.77 mmol) and Valeroyl chloride (0.18 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro -4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 12 h, concentrated in vacuo to remove the solvent. The reaction mixture was extracted with water and methylene chloride, and purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to give the title compound (0.20 g, 32%) .

NMR<1>H (300 MHz, CDCl<3>) 80.99 (t, J = 8.9 Hz, 3H), 1.17 (d,J= 7.0 Hz, 6H), 1.44- 1.52 (m, 2H), 1.75 (c, J = 8.3 Hz, 2H), 2.62 (t, J = 8.9 Hz, 2H), 2.83 (c, J = 7 .7 Hz, 1H), 6.81-6.87 (m, 2H), 7.06 (dd, J = 1.3 Hz, 8.3 Hz, 1H), 7.38 (d,J= 7 .7 Hz, 1H), 7.79-7.85 (m, 2H), 7.92-7.98 (m, 2H).

<EXAMPLE 94> (for reference) N-(2-(4-Acetamido-2-hydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5 -dimethylphenyl)isobutyramide

N-(2,2-dihydroxy-7-nitro-1,3-dioxo-2,3-dihydro-1H-inden-4-yl)acetamide (0.20 g, 0.71 mmol) and N-(3 ,4-dimethylphenyl)isobutyramide (136 mg, 0.71 mmol) were dissolved in conc. sulfuric acid. (5 ml) and stirred at room temperature for 3 h. The reaction mixture was extracted with ethyl acetate and ice-water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (30% ethyl acetate in hexane) to provide the title compound (30 mg, 10%).

NMR<1>H (300 MHz, CDCl<a>) 8 1.27 (d, J = 6.9 Hz, 6H, CH<3>) 2.08(s, 3H, NAc) 2.19(s , 6H, CH<3>) 2.69(sept, J = 6.9 Hz, 1H, CH) 6.30(s, 1H, ArH), 7.02(d, J = 9 Hz, 1H, ArH ) 7.08(s, 1H, ArH) 8.22(d, J = 9 Hz, 1H, ArH).

<EXAMPLE 95> (for reference) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl)isobutyramide

Ninhydrin (0.5 g, 2.80 mmol) and N-(4-isopropylphenyl)acetamide (575 mg, 2.80 mmol) were dissolved in conc. sulfuric acid. (5-6 ml) and stirred at room temperature for 15 h. The reaction mixture was extracted with ethyl acetate and ice-water, washed with brine. The washed organic phase was dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (20% ethyl acetate in hexane) to give the title compound (320 mg, 31%).

NMR<1>H (300 MHz, CDCl<3>) 81.19 (d, J = 6.9 Hz, 6H, CH<3>) 1.29(d, J = 6.9 Hz, 6H, CH <3>) 2.71(sept, J = 6.9 Hz, 1H, CH) 2.81(sept, J = 6.9 Hz, 1H, CH) 6.31(d, J = 7.8 Hz , 1H, ArH) 6.83(dd, J = 1.5 Hz, J=7.8 Hz, 1H, ArH) 7.17(d, J = 1.5 Hz, 1H, ArH) 7.98- 8.02(m, 2H, ArH) 8.11-8.15(m, 2H, ArH).

<EXAMPLE 96> 2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyl carbonate

9b-acetamido-7-isopropyl-1-nitro-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-4b-yl butylcarbonate (0.11 g, 0 .22 mmol) was completely dissolved in anhydrous ethanol (5 ml). This solution was added with iron (0.09 g, 1.66 mmol), conc. HCl (0.05 ml) and water (0.5 ml). The reaction mixture was heated for 1.5 h at reflux. After filtration at elevated temperature to remove iron, the filtrate was concentrated in vacuo and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (50 mg, 50%).

NMR<1>H (300 MHz, CDCl<3>) 80.91(t, J = 7.2 Hz, 3H, CH<3>) 1.22(dd, J = 7.2 Hz, 16.8 Hz, 6H, CH<3>) 1.33-1.44(m, 2H, CH<2>) 1.59-1.73 (m, 2H, CH<2>) 1.95(s, 3H , CH<3>) 2.04-2.90 (m, 1H, CH) 4.07-4.46 (m, 2H, OCH<2>) 5.59(s, 1H, NH) 6.10 (s, 1H, ArH) 6.60(d, J = 8.1 Hz, 1H, ArH) 6.75(s, 1H, ArH) 6.91(dd, J = 1.5, 7.8 Hz , 1H, ArH) 7.12(d, J = 7.2 Hz, 1H, ArH) 7.39-7.48(m, 1H, ArH).

<EXAMPLE 97> (for reference) 2-(2-Acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl methylcarbamate

9b-chloro-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with methyl isocyanate (0.12 g, 2.22 mmol), trimethylamine (0.18 g, 1.77 mmol). The reaction mixture was heated for 5 h at reflux. After concentrating in vacuo to remove THF, the remainder was diluted with methylene chloride and washed with water several times. After drying and filtering, the organic phase was purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.25 g, 44%).

NMR<1>H (300 MHz, CDCl<3>) 8 1.17 (d, J = 6.9 Hz, 6H, CH<3>) 2.01(s, 3H, CH<3>) 2, 79-2.91 (m, 4H, CH, CH<3>) 5.22(s, 1H, NH) 6.86(s, 1H, NH) 6.95(s, 1H, ArH) 7.04 (d, J = 7.8 Hz, 1H, ArH) 7.32(d, J = 8.4 Hz, 1H, ArH) 7.80-7.83(m, 2H, ArH) 7.94-7 .97(m, 2H, ArH).

<EXAMPLE 98> (for reference) dimethylcarbamic acid 2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester

N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indene[2,1-a]inden-9b-yl)-acetamide (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with dimethylcarbamyl chloride (0.23 g, 2.22 mmol), Trimethylamine (0.17 g, 1.77 mmol). The reaction mixture was heated for 24 h at reflux. After vacuum concentration to remove THF, the remainder was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution several times. After drying and filtering, the organic phase was purified using column chromatography (ethyl acetate: hexane = 1:1) to provide the title compound (0.26 g, 43%).

1H NMR (300 MHz, CDCh) 81.17 (d, J = 6.9 Hz, 6H, CH3) 1.98 (s, 3H, CH3) 2.80-2.88 (sept, 1H, CH) 3 .04(s, 3H, CH3) 3.23(s, 3H, CH3) 6.88(s, 1H, ArH) 7.01(d, J = 8.1 Hz, 1H, ArH) 7.16( s, 1H, ArH) 7.23(d, J = 8.4 Hz, 1H, ArH) 7.79-7.82(m, 2H, ArH) 7.94-7.97(m, 2H, ArH) ).

<EXAMPLE 99> (for reference) phenyl ester of 2-(2-acetylamino-1,3-dioxo-indan-2-yl)-5-isopropyl-phenyl ester of carbonic acid

N-(4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-5-oxa-indene[2,1-a]inden-9b-yl)-acetamide (0.50 g, 1.48 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with phenyl chloroformate (0.35 g, 2.22 mmol), Trimethylamine (0.18 g, 1.77 mmol). The reaction mixture was heated for 24 h at reflux. After vacuum concentration to remove THF, the remainder was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution several times. After drying and filtering, the organic phase was purified using column chromatography (ethyl acetate: hexane = 1:1) to provide the title compound (0.18 g, 26%).

1H NMR (300 MHz, CDCh) 81.19 (d, J = 6.9 Hz, 6H, CH3) 2.04(s, 3H, CH3) 2.82-2.91(sept, 1H, CH) 6 .67(s, 1H, NH) 7.03(s, 1H, ArH) 7.15(d, J = 8.4 Hz, 1H, ArH) 7.30-7.34(m, 1H, ArH) 7.45-7.47(m, 5H, ArH) 7.81-7.84(m, 2H, ArH) 8.00-8.02(m, 2H, ArH).

<EXAMPLE 100> 2-(2-Acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate

2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate (0.20 g, 0.4 mmol) was dissolved in anhydrous ethanol (10 ml) and water (1 ml). This solution was added with iron (0.18 g, 3.2 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 h at reflux. After filtering and washing with MeOH, the remainder was concentrated in vacuo and purified using column chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (90 mg, 50%).

1H NMR (300 MHz, CDCla) 81.18 (d, J = 6.9 Hz, 6H, CH3) 1.98(s, 3H, CH3) 2.97(s, 3H, CH3) 2.79-2 .89 (m, 1H, CH) 3.05(s, 3H, CH3) 3.23(s, 3H, CH3) 5.67(s, 2H, NH2) 6.81(d, J = 8.1 Hz, 1H, ArH) 6.85(s, 1H, NH) 7.01(d, J = 8.4 Hz, 1H, ArH) 7.08(s, 1H, ArH) 7.13-7.21 (m, 2H, ArH) 7.44(t, J = 8.1 Hz, 1H, ArH).

<EXAMPLE 101> (for reference) 2-(2-acetamido-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethyl carbonate

9b-chloro-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with ethyl chloroformate (0.32 g, 3.11 mmol) and Trimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for 4 h. After concentrating in vacuo to remove THF, the remainder was diluted with methylene chloride and washed with water several times. After drying and filtering, the organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (30 mg, 3.6%).

1H NMR (300 MHz, CDCh) 81.16-1.28 (m, 9H, CH3) 2.33(s, 3H, CH3) 2.79-2.88 (m, 1H, CH) 4.02- 4.15 (m, 2H, OCH2) 5.90(s, 1H, NH) 6.68(s, 1H, ArH) 7.07(dd, J = 1.5, 8.3 Hz, 1H, ArH ) 7.42(d, J = 8.3 Hz, 1H, ArH) 7.81-7.90(m, 2H, ArH) 7.96-8.02(m, 2H, ArH).

<EXAMPLE 102> (for reference) ethyl acetyl(2-(2-hydroxy-4-isopropylphenyl)-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)carbamate

9b-chloro-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.70 g, 2.07 mmol) was dissolved in anhydrous THF (15 ml). This solution was added with ethyl chloroformate (0.32 g, 3.11 mmol) and Trimethylamine (0.25 g, 2.48 mmol). The reaction mixture was stirred for 4 h. After concentrating in vacuo to remove THF, the remainder was diluted with methylene chloride and washed with water several times. After drying and filtering, the organic phase was purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (0.64 g, 71%).

1H NMR (300 MHz, CDCh) 81.18 (d, J = 6.9 Hz, 6H, CH3) 1.46(t, J = 7.1 Hz, 3H, CH3) 2.03(s, 3H, CH3) 2.83-2.88(m, 1H, CH) 4.31-4.38(c, J = 7.1 Hz, 2H, OCH2) 6.67(s, 1H, NH) 6.92(s , 1H, ArH) 7.12(dd, J = 1.2, 8.2 Hz, 1H, ArH) 7.43(d, J = 8.2 Hz, 1H, ArH) 7.81-7.84 (m, 2H, ArH) 7.96-7.99(m, 2H, ArH).

<EXAMPLE 103> 2-(2-acetamido-4-amino-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate

2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl ethylcarbamate (0.27 g, 0.59 mmol) was dissolved in Ethanol (10 ml) and water (1 ml). This solution was added with iron (0.24 g, 4.3 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 h at reflux. After filtering and washing with MeOH, the remainder was concentrated in vacuo and purified using column chromatography (ethyl acetate: hexane = 1:1) to provide the title compound (90 mg, 36%).

1H NMR (300 MHz, CDCh) 81.11-1.92(d, J = 6.9 Hz, 6H, CH3) 1.95(s, 3H, CH3) 2.79-2.88 (m, 1H , CH) 3.10-3.26(m, 2H, CH<3>) 5.24(s, 1H, NCH) 5.56(s, 2H, NH<2>) 6.21(s, 1H , NH) 6.60(d, J = 8.4 Hz, 1H, ArH) 6.71(s, 1H, ArH) 6.88(d, J = 7.8 Hz, 1H, ArH) 7.06 (d, J = 7.5 Hz, 1H, ArH) 7.42(t, J = 7.8 Hz, 2H, ArH).

<EXAMPLE 104> (for reference) 2-(3-Methoxyphenyl)-2H-inden-1,3-dione

Sodium (1.1 g) was dissolved in anhydrous Ethanol (90 ml). This solution was added with phthalide (4.43 g, 33.04 mmol) and m-Methoxy benzaldehyde (3.00 g, 22.03 mmol). The reaction mixture was heated for 3 h at reflux. The reaction mixture was concentrated in vacuo. A white solid was obtained by adding conc. HCl. and then the white solid was recrystallized from ethyl acetate:hexane(=1:2) to give the title compound (2.45 g, 44%).

NMR<1>H (300 MHz, CDCh) 83.78(s, 3H, OCH<3>) 6.73-6.76(m, 2H, ArH) 6.85(d, J = 7.2 Hz , 1H, ArH) 7.26(t, J = 7.8 Hz, 1H, ArH) 7.89-7.93(m, 2H, ArH) 8.06-8.09(m, 2H, ArH) .

<EXAMPLE 105> (for reference) (6-(2-((ethoxycarbonyl)oxy)-4-isopropylphenyl)-5,7-dioxo-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl) ethyl carbonate

4b,9b-dihydroxy-7-isopropyl-4bH-benzofuro[2',3':3,4]cyclopenta[1,2-b]pyridin-10(9bH)-one (0.50 g, 1.68 mmol ) was dissolved in THF (10 ml) and Et<3>N (0.70 ml, 5.04 mmol). This solution was added with ethyl chloroformate (0.40 ml, 4.20 mmol). The reaction mixture was stirred for 2 h. After concentration in vacuo, the remainder was purified using chromatography (ethyl acetate: hexane = 1:2) to provide the title compound (0.20 g, 27%). H NMR (300 MHz, CDCl<a>) 81.19 (d, J = 6.8 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H), 1.32 ( t, J = 7.6 Hz, 3H), 2.87 (c, J = 7.1 Hz, 1H), 4.10-4.18 (m, 4H), 6.92 (s, 1H), 6.20 (dd, J = 1.1 Hz, 8.4 Hz, 1H), 7.73-7.79 (m, 2H), 8.33 (d,J= 7.9 Hz, 1H), 9.16 (d, J = 4.7 Hz, 1H).

<EXAMPLE 106> (for reference) N-(2-(2-Hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-4,5-dimethoxyphenyl)isobutyramide

Ninhydrin (1.00 g, 5.6 mmol) was dissolved in H<2>SO<4>conc. (10ml). This solution was added with N-(3,4-dimethoxyphenyl)isobutyramide (1.25 g, 5.62 mmol) at 0 °C and stirred for 30 min at room temperature. Ice water was added to the reaction mixture, and then it was washed with ice water and ethyl acetate. After drying and filtering, the ethyl acetate phase was purified using column chromatography (ethyl acetate: hexane = 1:4) to provide the title compound (1.37 g, 63%).

NMR<1>H (300 MHz, CDCh) 81.28 (d, J = 6.9 Hz, 6H, CH<3>) 2.63-2.72(m, 1H, CH) 3.56(s , 3H, OCH<3>) 3.86(s, 3H, OCH<3>) 5.84(s, 1H, ArH) 6.87(s, 1H, ArH) 7.99-8.04(m , 2H, ArH) 8.13-8.18(m, 2H, ArH).

<EXAMPLE 107> N-[2-(4-Amino-2-hydroxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide

N-[2-(2-hydroxy-4-nitro-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide (150 mg, 0.35 mmol) was dissolved in ethanol (3 ml) and water (0.3 ml). This solution was added with iron (Fe) (0.14 g, 2.55 mmol) and conc. HCl (0.03 ml), followed by heating for 3 h at reflux. The reaction mixture was filtered with MeOH through the band through a pad of celite, and the filtrate was concentrated in vacuo. The concentrated organic phase was purified using column chromatography (ethyl acetate:hexane=1:4) to provide the title compound (17 mg, 12%).

NMR<1>H (300 MHz, CDCh) 80.77 (d, J = 6.9 Hz, 3H, CH<3>) 1.19(d, J = 6.9 Hz, 3H, CH<3> ) 2.01-2.10(m, 1H, CH), 3.91(s, 3H, OMe) 4.07(s, 3H, OMe) 5.36(s, 2H, NH<2>) 6 .49(d, J = 7.2 Hz, 1H, ArH) 6.74(d, J = 8.1 Hz, 1H, ArH) 7.15(s, 1H, ArH) 7.37(t, J = 7.5 Hz, 1H, ArH) 8.35(s, 1H, ArH).

<EXAMPLE 108> (for reference) N-[2-(2-Hydroxy-5,6-dimethoxy-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide

5,6-Dimethoxy-indan-1-one (3.0 g, 15.6 mmol) was dissolved in anhydrous dioxane (30 ml). This solution was added with SeO2 (3.80 g, 34.3 mmol) and acetic acid (3 ml), followed by heating for 5 h at reflux. The reaction mixture was filtered with MeOH through a pad of celite, and the filtrate was concentrated in vacuo to remove the solvent. The remainder (2.13 g, 8.95 mmol) was dissolved in conc. H2SO4. (20 ml), and added with isobutyramide (3.50 g, 15.6 mmol), followed by stirring for 2 h at room temperature. After stirring, the reaction mixture was washed with ethyl acetate and water several times. The organic phase obtained was dried, filtered and concentrated in vacuo. The concentrated organic phase was purified using column chromatography (ethyl acetate:hexane=1:4) to provide the title compound (218 mg, 3%).

NMR<1>H (300 MHz, CDCh) 81.36 (d, J = 6.6 Hz, 6H, CH<3>) 2.67-2.76 (m, 1H, CH) 3.63(s , 3H, OMe) 3.85(s, 3H, OMe) 4.06(s, 6H, OMe) 6.24(s, 1H, ArH) 7.15(s, 1H, ArH) 7.99(s , 1H, ArH) 9.70(s, 1H, ArH).

Chemical formulas of the compounds of examples 1 to 108 are shown in Table 1.

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<EXPERIMENTAL EXAMPLE 1> Cytopathic Effect (CPE)

Inhibition assay for antiviral activity against Picornavirus

HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblast cells), and RD (human rhabdiomsarcoma-derived) cells were used in the trial. For comparison, ribavirin (Riv), pleconaril (pleco), and BTA-798 (BTA) were used as controls. The reagents were dissolved at a concentration of 10 - 40 mg/ml in 100% dimethyl sulfoxide (DMSO). The water-soluble reagents were dissolved in PBS (−) solution and stored at −20 °C. On the day of the experiment, they were used at 3x to 5x concentrations so that the concentration of dimethyl sulfoxide in each well was between 0.5% and 1%.

Pharmaceutical effects were determined using a virus-induced cytopathic effect (CPE) inhibition assay. In this regard, after culturing virus-appropriate cells in 96-well plates, virus dilutions in DME supplemented with 2% FBS (DME/2% FBS) or M<e>M supplemented with F<b>S 2% (MEM/2% FBS) were inoculated in an amount of 100 μl with a concentration corresponding to 100 CCDI50 (50% cell culture infectious dose) in each well of the plates, and incubated for 30 min - 1 h at 33°C or 37°C to allow viruses to adsorb to cells. Culture medium was removed before adding aliquots of drug dilutions with various concentrations in an amount of 100 μl to each well. Although HRV grew at 33 °C, the other viruses were incubated in a CO2 incubator at 37 °C for 2 - 3 days. Alternatively, the cells were cultured for 2-3 days without removing the medium after which they were added with 50 µl of each drug dilution with a concentration greater than 2-fold and then with 50 µl of the virus dilution.

The assay conditions for each virus are summarized in Table 2, below.

TABLE 2

For HeLa cells, drugs were measured for EC50 (50% maximum effective concentration), which is the concentration of a drug that induces a mean response between baseline and maximum, using an MTT assay. Regarding RD and MRC-5 cells, CPE was determined using FDA (fluorescein diacetate). For pharmacological potency evaluation results to reflect the toxic effect of the drug, mock-infected cells that were prepared by adding virus-free medium to a cell culture were treated in the same way. That is, the medium was removed after one hour of incubation, and drug illustrations were added to the medium once again. After incubation for 2 - 3 days, the cells are observed under a microscope and the drugs are determined for CC50 (cytotoxicity concentration at 50%), using an MTT assay in which viable cell counts in mock-infected wells were compared with those of viable cells in control wells containing no drugs. In an FDA hydrolysis assay, FDA was added to each well after removing the medium, and incubated for 20 - 30 min before measuring the fluorescence intensity using a spectrofluorometer to determine CPE in the same manner as in MTT.

The survival rate (% survival) of mock-infected cells was calculated using the following Mathematical Formula 1:

[Mathematical Formula 1]

Although 100% cell survival means no drug cytotoxicity, the highest cytotoxicity is reflected with 0% cell survival. The 50% cytotoxic concentration (CC50) was defined as the concentration required to reduce the cell number to 50% compared to that of untreated controls. Higher CC50 values mean lower cytotoxicity.

Additionally, the antiviral effects can be calculated using the following Mathematical Formula 2:

[Mathematical Formula 2]

A survival rate of 100% means a perfect antiviral effect (100%) while drugs are considered to be devoid of antiviral effects at a survival rate of 0%. The viral cytopathic effect (CPE) was recorded, and the 50% effective concentration (EC50) was defined as the concentration of the compound required to reduce the viral CPE to 50% compared to that of the untreated control. Lower EC50 values mean higher antiviral activities.

The CC50 and EC50 values of the compounds representing cytotoxicity and antiviral activity against picornavirus, respectively, are provided in Tables 3 and 4.

TABLE 4

As understood from the data in Tables 3 and 4, most of the compounds of the present invention exhibited low cytotoxicity because they had high CC50 values. Furthermore, most of the compounds of the present invention were found to be highly inhibitory of coxsackie-, polio-, rhino-, and enteroviruses because their EC50 values were 0.01 pg/ml or less.

Accordingly, the compounds represented with Chemical Formula 1 according to the present invention exhibit low cytotoxicity and high inhibitory activity against a broad spectrum of picornaviruses, and therefore can be usefully applied to a pharmaceutical composition for preventing or treating diseases caused by picornaviruses. .

<EXPERIMENTAL EXAMPLE 2> Multicycle Cytopathic Effect (CPE) Reduction Assay for Antiviral Effect against Picornavirus

Test compounds were evaluated for anti-picornavirus activity with a multicycle cytopathic effect (CPE) reduction assay. Antiviral activity was initially determined using a CPE reduction assay based on MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymatoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium ].

In this sense, the cells were cultured to confluency in 96-well plates infected with 100 infectious doses of 50% cell culture (CCID50) of virus. After a 2 h adsorption period at 37 °C, the virus was removed and serial dilutions of the compounds were added. Cultures were further incubated at 37°C for 3 days, until complete CPE was observed in the infected and untreated virus control (VC). After removing the medium, 90 μl of a culture medium and 10 μl of MTS-phenazine methosulfate (Promega, Leiden, The Netherlands) were added to each well. After a 2 h incubation period at 37 °C, the optical density (OD) of each well was read at 498 nm in a microplate reader.

CPE values to evaluate antiviral activity were calculated using the following Mathematical Formula 3: [Mathematical Formula 3]

CPE values to evaluate cytotoxicity were calculated using the following Mathematical Formula 4:

[Mathematical Formula 4]

In Formulas 3 and 4,

OD<cc>corresponds to the OD of the uninfected and untreated background cell cultures,

DOvc represents the OD of the infected and untreated control cell cultures,

ODvirus+compound represents the OD of virus-infected cell cultures treated with a given concentration of compound, and

White OD represents the OD of the well added with culture medium alone.

The 50% effective concentration (EC50) and the 50% cytotoxic concentration (CC50) were defined as the concentrations of compound that offered 50% protection against God-induced CPE and killed 50% of cells, respectively, and were calculated using logarithmic interpolation.

CC50 and EC50 against various viruses of some compounds are given in Table 5, below.

TABLE 5

continued

In Table 5, superscript c represents incubation at 37 °C in Vero cells, superscript d represents incubation at 37 °C in MRC-5 cells, superscript e represents incubation at 37 °C in RD cells, superscript f represents incubation at 37 °C in BGM cells, superscript g represents incubation at 37 °C in HeLa cells, and superscript i represents 100% inhibition of viral replication with compounds of 0.078 pM or greater.

As can be seen in Table 5, the compounds according to the present invention have low cytotoxicity because their CC50 was measured at 50 pM or higher, especially the compound of EXAMPLE 19 and EXAMPLE 74 have low cytotoxicity because their CC50 was measured at 100 pM or greater. Furthermore, the compounds were observed to have an EC50 of 26 pM or less against coxsackie viruses B3, A16, A9, and A21. Particularly high antiviral activity was detected in the compound of EXAMPLE 19 and EXAMPLE 36 with an EC50 as low as 0.01 pM.

With respect to enterovirus 71, compounds according to the present invention showed an EC50 of 3.3 pM or less. Particularly high antiviral activity was detected in the compound of EXAMPLE 36 with an EC as low as 0.0067 pM.

The compounds according to the invention showed an EC50 of 0.70 pM or less against ecovirus 9 and ecovirus 11, although the highest antiviral activity was detected in the compound of EXAMPLE 36 as demonstrated with the EC50 of 0.0082 pM.

In the case of polioviruses 1, 2 and 3, the EC50 values of the compounds according to the present invention were measured as 20 pM or less. Particularly high antiviral activity was detected in the compound of EXAMPLE 36 with an EC50 as low as 0.01 pM.

Also, the compounds according to the invention were highly inhibitory of rhinovirus. For example, EC50 of 50 pM or more was detected against rhinoviruses 2, 9, 15, 29, 39, 41,45, 59, 63, 85, 89, 14, 42, 70, 72, and 86. In the compound EXAMPLE 36 Particularly high antiviral activity was detected with an EC50 of 0.078 pM or less against rhinoviruses 45 and 70.

Therefore, the compounds of the present invention have low cytotoxicity and exhibit excellent antiviral activity against picornaviruses including coxsackie-, entero-, echo-, polio- and rhinoviruses, so that they can be usefully applied for the prevention or treatment of respiratory diseases, cardiocirculatory, and nervous system caused by picornavirus, including poliomelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis and otitis media.

<FORMULATION EXAMPLE 1> Preparation of pharmaceutical formulations

<1-1> Powder Preparation

Compound of the invention: 2 g

Lactose: 1 g

The above ingredients were mixed and loaded into a medical bag to produce a powdered agent.

<1-2> Tablet preparation

Compound of the invention: 100 mg

corn starch: 100 mg

Lactose: 100 mg

Mg stearate: 2 mg

These ingredients were mixed and prepared into tablets using a common content formation method.

<1-3> Capsule preparation

Compound of the invention: 100 mg

corn starch: 100 mg

Lactose: 100 mg

Mg stearate: 2 mg

These ingredients were mixed and filled into gelatin capsules according to a common method for producing capsules.

<1-4> Injection preparation

Compound of the invention: 10 pg/ml

Diluted BP hydrochloric acid: for pH 3.5

Sodium chloride BP for injection: maximum 1 ml

The compound of the present invention was dissolved in an appropriate volume of sodium chloride BP for injection. The pH of the resulting solution was regulated to be pH 3.5 with dil HCl. BP, and then its volume was regulated with sodium chloride BP for injection and the solution was mixed completely. The solution was then filled into a 5 ml clear glass type 1 ampoule. The air was sealed in an upper net by melting glass. The solution contained in the ampoule was autoclaved at 120 °C for 15 min or more to sterilize and therefore obtain an injection.

[Industrial applicability]

By having excellent inhibitory activity against picornaviruses including coxsackie-, entero-, echo-, Polio-, and rhinovirus, as well as presenting low cytotoxicity, as described so far, the compound of Chemical Formula 1 may be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of viral diseases including poliomelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis , influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

Claims (12)

CLAIMS 1. A compound expressed by Formula 1, pharmaceutically acceptable salt thereof or optical isomer thereof: where A1 is -NR1R2; A2, A3 and A4 are, independently or optionally, any selected from the group consisting of -H, halogen, -OH, -CN, -N3, C1-C10 alkoxy, straight or branched chain C1-C10 alkyl, C6-aryl C12, -O (C=O) R1, - (C=O) R1, - (C=O) OR1, - O(C=O) OR1, -O(C=O) NR1R2, -NO2, -NR1R2 , -NR^(C=O)R2, - NR1(C=S) R2, -NR1(C=O) OR2, -NR1(C=O) -NR2R3 and -NR1(C=S) -NR2R3, or two or more neighboring substituents of A1, A2, A3 and A4 may together form a ring, wherein a ring formed by two or more neighboring substituents of A1, A2, A3 and A4 may include one or more heteroatoms, and the heteroatom is N, O or S; G is halogen, -OH, -CN, -N3, C1-C10 alkoxy, -O (C=O) R1, -(C=O)R2, -(C=O)OR1, -O(C=O) OR1, -O(C=O) NR1R2, -NO2, -NR1R2, - NR1(C=O) R2, -NR1(C=S) R2, -NR1(C=O) OR2, -NR1(C=O) ) -NR2R3, - NR1(C=S) -NR2R3 or D1, D2, D3 and D4 are, independently or optionally, any one selected from a group consisting of -H, halogen, -OH, -CN, C1-C10 alkoxy, straight or branched chain C1-C10 alkyl, C6 aryl -C12, -(CH2)n-(C=O) OR1, - O (C=O) R1, - (C=O) R1, - (C=O) OR1, -O(C=O) OR1, -O(C=O)NR1R2, -NO2, -NR1R2, -NR1(C=O) R2, -NR1(C=S) R2, -NR1(C=O) OR2, -NR1(C=O) - NR2R3, -SR1 and -NR1(C=S) -NR2R3, or two or more neighboring substituents of D1, D2, D3 and D4 can form a ring together, a ring formed by two or more neighboring substituents of D1, D2, D3 and D4 may include one or more heteroatoms, and the heteroatom is N, O or S; E is -H, -OH, -OR1, -O(C=O)R1, -(C=O)R1, -(C=O)OR1, - O(C=O) OR1, -O (C= O) NR1R2, -NO2, -NR1R2, -NR1(C=O) R2, -SR1, - NR1(C=S)R2, -NR1(C=O) OR2, -NR1(C=O) -NR2R3 or -NR1(C=S) -NR2R3; R1, R2 and R3 are each independently hydrogen, C1-C10 straight or branched chain alkyl, unsubstituted or substituted with phenyl, C1-C10 alkoxy, C1-C10 straight or branched chain alkenyl, unsubstituted or substituted with phenyl, C3-C7 cycloalkyl or C6-C12 aryl unsubstituted or substituted with phenyl; X and Y are oxygen; Z1, Z2 and Z3 are carbon or nitrogen; n is an integer between 1-10; and '—' represents a double bond. 2. The compound, pharmaceutically acceptable salt thereof or optical isomer thereof as set forth in claim 1, wherein A2, A3 and A4 are, independently or optionally, any selected from a group consisting of -H, halogen , C1-C10 straight or branched chain alkyl, -NR1R2, - NR1(C=O)R2, or two or more neighboring substituents of A1, A2, A3 and A4 may together form a ring, in which a ring formed by two or more neighboring substituents of A1, A2, A3 and A4 may include one or more heteroatoms, and the heteroatom is N, O or S; G is -OH, -O(C=O) R1, -O(C=O) OR1, -NR1(C=O) R2, - NR1(C=O) OR2 or — D1, D2, D3 and D4 are, independently or optionally, any of those selected from a group consisting of halogen, straight-chain or branched C1-C10 alkyl, -NR1(C=O) R2, -NR1(C=O) OR2 and -NR1(C=O) -NR2R3, or two or more neighboring substituents of D1, D2, D3 and D4 may together form a ring, wherein a ring formed by two or more neighboring substituents of D1, D2, D3 and D4 may include one or more heteroatoms, and the heteroatom is N, O or S; E is -H, -OH, -OR1, -O(C=O)R1, -O(C=O)OR1, -O(C=O)NR1R2, -NR1(C=O) R2 or -NR1( C=O) OR2; R1, R2 and R3 are, each independently, hydrogen, C1-C9 straight or branched chain alkyl unsubstituted or substituted with phenyl, C1-C5 straight or side chain alkenyl unsubstituted or substituted with phenyl or C6-C10 aryl; Z1, Z2 and Z3 are carbon; n is an integer between 1-5; and '—' represents a double bond. 3. The compound, pharmaceutically acceptable salt thereof or optical isomer thereof as set forth in claim 1, wherein A2, A3 and A4 are, independently or optionally, any selected from a group consisting of -H, halogen and -NR1R2; G is -OH, -NR1(C=O) R2 or -NR1(C=O) OR2; D1, D2, D3 and D4 are, independently or optionally, any selected from the group consisting of halogen, C1-C10 straight or branched chain alkyl and - NR1(C=O)R2; E is -H, -OH, -OR1, -O(C=O)R1, -O(C=O)OR1 or -O(C=O)NR2R2; R1, R2 and R3 are, each independently, hydrogen, C1-C8 straight or branched chain alkyl unsubstituted or substituted by phenyl, C1-C4 straight or branched chain alkenyl unsubstituted or substituted by phenyl or C6-C10 aryl; Z1, Z2 and Z3 are carbon; n is an integer between 1-3; and '—' represents a double bond. 4. The compound, pharmaceutically acceptable salt thereof or optical isomer thereof as set forth in claim 1, wherein A2, A3 and A4 are, independently or optionally, any selected from a group consisting of -H and -N <r>1R2; G is -NR1(C=O)R2; D1, D2, D3 and D4 are straight or branched chain C1-C10 alkyl; E is -O(C=O)R1; R1, R2 and R3 are each independently hydrogen or straight-chain or branched C1-C7 alkyl; Z1, Z2 and Z3 are carbon; n is an integer between 1-3; and '—' represents a double bond. 5. A method for preparing a compound as set forth in claim 1, comprising a step (step 1) of obtaining a compound of Formula 1a by acylation or alkylation of a compound of Formula 2 in the presence of a base and a solvent , as expressed by Reaction Formula 1 below: wherein, the compound of Formula 1a is the compound of Formula 1 of claim 1, pharmaceutically acceptable salt thereof, or optical isomer thereof, A1, A2, A3, A4, D1, D2, D3, D4, Z1, Z2 and Z3 are those defined in formula 1 of claim 1, and J is -R1, - (C=O)R2, - (C=O)OR1, -(C=O)NR1R2, and L is C1-C10 alkyl, - (C=O)R1, - (C=O) OR1, - (C=O)NR1R2. 6. A method for preparing a compound as set forth in claim 1, comprising: a step (step 1) of obtaining a compound of Formula 3 by reacting a compound of Formula 2 with thionyl chloride or oxalic chloride in the presence of a reactant base and a solvent, and then reacting with ammonia; and a step (step 2) of obtaining a compound of Formula 1b by acylation or alkylation of the compound of Formula 3 prepared in step 1 in the presence of a base and a solvent, as expressed below by Reaction Formula 2: A1, A2, A3, A4, D1, D2, D3, D4, Z1, Z2 and Z3 are those defined in formula 1 of claim 1, and J is -R1, - (C=O)R1, - (C=O)OR1, - (C=O)NR1R2, and L is -R2, -(C=O)R2, -(C=S)R2, -(C=O)OR2, -(C=O)-NR2R3, or -(C=S)-NR2R3. 7. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof as set forth in any of claims 1 to 4. 8. A pharmaceutical composition according to claim 7 comprising a pharmaceutically acceptable excipient. 9. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof as set forth in claims 1-4, or a pharmaceutical composition as set forth in claims 7-8, for use as a medicament. 10. The compound, pharmaceutically acceptable salt thereof, or optical isomer thereof as set forth in claims 1-4, or a pharmaceutical composition as set forth in claims 7-8, for use in the prevention or treatment of diseases viral. 11. The pharmaceutical composition or compound, pharmaceutically acceptable salt thereof, or optical isomer thereof for use as set forth in claim 10, wherein the viral disease is a disease caused by: a) Coxsackie virus; either: b) polio virus; either: c) ecovirus; either: d) enterovirus; either: f) rhinovirus; either: g) picornavirus. 12. The pharmaceutical composition or compound, pharmaceutically acceptable salt thereof, or optical isomer thereof for use according to claim 10, wherein the viral disease comprises: poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand- foot-and-mouth disease, swine vesicular disease (SVD), hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, influenza, herpangina or foot-and-mouth disease.