Patent Description:
Picornaviruses are non-enveloped, positive single-stranded RNA viruses with an RNA genome <NUM>-<NUM> Kb long. These viruses are very small and globular in shape with a size of about <NUM>-<NUM>, and were first identified a long time ago. Among the viruses belonging to the family Picornaviridae are enteroviruses including rhinovirus, poliovirus, coxsackie virus A, coxsackie virus B, and echovirus, and hepatitis A virus.

The diseases that picornaviruses, RNA viruses, cause are varied, ranging from respiratory diseases to digestive diseases, to circulatory diseases and to dermal diseases, examples of which include poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, flu, herpangina, and foot-and-mouth disease. However, there are no therapeutic agents for curing these diseases. Most of the drugs under development are uncoating inhibitors. Viruses belonging to the family Picornaviridae cause various diseases including the aforementioned respiratory diseases, which evoke hygienic, social and economic issues. Picornaviruses are the main causative agents of waterborne diseases. Being very stable and difficult to disinfect, they incessantly cause related viral diseases.

Human rhinoviruses (hRV) have been recently associated with the majority of asthma exacerbations, and are known to exist even in bronchial tissues of many stable asthma patients. Comparison of respective bronchial mucosa biopsy specimens taken from asthma and non-asthma patients showed significantly higher frequencies of detection of human rhinoviruses in the lower respiratory tract of asthma patients, compared to non-asthma patients. It has also been reported that there is correlation between the presence of rhinovirus and the clinical severity of asthma. In addition, human rhinoviruses cause chronic obstructive pulmonary disease, pneumonia, sinusitis, and otitis media as well as asthma.

Rhinoviruses are the main causative of the common cold while enterovirus-induced diseases include meningitis, respiratory tract infection, etc. Extensive effort to provide vaccination against poliovirus has significantly reduced the onset of poliomyelitis worldwide, but there are still reports of cases of the disease in Niger, Nigeria, Egypt, India, Pakistan, and Afghanistan. Hepatitis A is now possible to control to some degree thanks to vaccines for hepatitis A viruses. However, no vaccines for coxsackieviruses, echoviruses, or rhinoviruses have been developed, thus far.

Particularly, coxsackievirus B is a main cause of myocarditis, which may develop, in serious cases, into idiopathic dilated cardiomyopathy, which requires heart transplantation.

Enviroxime derivatives are considered the most promising candidate with a broad anti-enterovirus- and anti-rhinovirus activity. Enviroxime interferes with the synthesis of plus-strand RNA by binding to the virus protein 3A that is required for the formation of RNA intermediates in the virus reproduction (<NPL>). In clinical studies, however, the compound was observed to have few or no therapeutic effects, with detection of insufficient pharmacokinetics and unwanted side effects (<NPL>).

The protease inhibitor AG <NUM> has been developed on the basis of the knowledge about the sophisticated structure and function of the viral protease 2C. In the cell culture in the nanomolar concentration range, AG <NUM> has shown an effect against <NUM> rhinovirus types and coxsackievirus A21, B3, enterovirus <NUM> and echovirus <NUM> (<NPL>).

Thanks to the clarification of the molecular structure of the viral capsids, the preconditions for a purposeful design of capsid blockers, the "WIN substances", have been obtained (<NPL>). They inhibit the adsorption and/or the uncoating of rhinoviruses and enteroviruses. Some of the WIN substances have a highly specific effect only against individual genera or virus types of the picornaviruses. Other derivatives inhibit the replication both of rhinoviruses and enteroviruses. Arildone, disoxaril and pirodavir belong, for example, to the WIN substances. These compounds showed very good antiviral effects in the cell culture. However, a poor solubility (arildone), low bioavailability (arildone and disoxaril), a rapid metabolization and excretion (disoxaril and WIN <NUM>) as well as side effects, such as skin rash (WIN <NUM>), made a clinical application impossible.

Pleconaril, another kind of WIN substance, has a very good oral bioavailability and after its binding to the hydrophobe pocket in the viruscapsid, it inhibits the penetration of rhino-, echo- and coxsackieviruses (<NPL>; <NPL>). Therefore, pleconaril is potentially effective against a broad spectrum of virus diseases, ranging from the common cold to the viral meningitis or myocarditis. Resistances were observed for rhinoviruses, enterovirus <NUM> and coxsackievirus B3 (<NPL>; <NPL>). 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 <NUM>, a corresponding application was refused by the Food and Drug Administration (FDA) because therapy success was too low and side effects were observed.

BTA-<NUM> was found to have higher antiviral activity than pleconaril, as evaluated in vitro and in vivo efficacy with rhinoviruses, and is now under clinical study (<NPL>).

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

Thus, while the present inventors were researching antiviral compounds against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus, they synthesized the novel compounds expressed by Formula <NUM> of the present specification and verified that said compounds had excellent antiviral activities against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus and rhinovirus to complete the present invention.

The objective of the present invention is to provide the compound expressed in Formula <NUM> or Formula <NUM> of Claim <NUM>, a pharmaceutically acceptable salt thereof or an optical isomer thereof.

Another objective of the present invention is to provide a method for preparing the compound expressed in Formula <NUM> or Formula <NUM> of Claim <NUM>.

Still another objective of the present invention is to provide a pharmaceutical composition for use in prevention or treatment of a viral disease comprised of the compound, the pharmaceutically acceptable salt thereof or the optical isomer thereof as an active ingredient.

To achieve the above objectives, the present invention provides the compound expressed in Formula <NUM> or Formula <NUM> below, a pharmaceutically acceptable salt thereof or an optical isomer thereof. <CHM>
<CHM>.

In Formulae <NUM> and <NUM> above,
R<NUM>, R<NUM>, R<NUM>, R4a, R4b, R4c and R4d, X, L and R<NUM> are respectively as defined in Claim <NUM>, and the compounds expressed in Formula <NUM> and Formula <NUM> above exist in an equilibrium state with each other.

In addition, the present invention provides, as shown in Reaction Equation <NUM> below, a method for preparing the compound expressed in Formula <NUM> or Formula <NUM> above, comprising a step (step <NUM>) in which the compound expressed in Formula <NUM> or Formula <NUM> and the compound expressed in Formula <NUM> are placed in a solvent with a reaction catalyst and then stirred. <CHM>
In Reaction Equation <NUM> above,.

Furthermore, the present invention provides a pharmaceutical composition for use in prevention or treatment of a viral disease containing the compound expressed in Formula <NUM> or Formula <NUM> above, the pharmaceutically acceptable salt thereof or the optical isomer thereof as an active ingredient.

The compound expressed in Formula <NUM> or Formula <NUM> according to Claim <NUM> which is in an equilibrium state with each other has not only low cytotoxicity but also very excellent antiviral activities against picornaviruses including coxsackieviruses, enteroviruses, echoviruses, polioviruses, and rhinoviruses so may be usefully used as the pharmaceutical composition for prevention or treatment of viral diseases including poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, flu, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

In the following is described the present invention in detail.

The present invention provides the compound expressed in Formula <NUM> or Formula <NUM> below, the pharmaceutically acceptable salt thereof or the optical isomer thereof. <CHM>
<CHM>.

The compounds expressed in Formula <NUM> and Formula <NUM> above exist in an equilibrium state with each other.

Examples of the compound expressed in Formula <NUM> of the invention may include the following compounds. Examples <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>, <NUM>, <NUM>, <NUM>-<NUM> and <NUM>-<NUM> are provided as reference compounds.

The compounds expressed in Formula <NUM> or Formula <NUM> of the present invention may be used in the form of pharmaceutically acceptable salts; acid addition salts formed by pharmaceutically acceptable free acids are useful. The expression "pharmaceutically acceptable salt" means any organic or inorganic salt of the basic compounds of Formula <NUM> or Formula <NUM> if the side effect caused by the salt at an efficacious concentration that is relatively non-toxic and non-harmful to the patient do not degrade the beneficial efficacy of the basic compounds of Formula <NUM> or Formula <NUM>.

For the salts in organic acid and organic acids may be used as free acids, and the inorganic acids used may include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid and the organic acids used may include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, gluconic acid, succinic acid, tartaric acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid, ethane sulfonic acid, <NUM>-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid, or malonic acid.

In addition, such salts include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salts (calcium salts, magnesium salt, etc.). For example, acid addition salts may include acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluoro phosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, <NUM>-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, alamine, potassium, sodium, tromethamine, and zinc salt, and hydrochloride and trifluoro acetate among them are preferred.

The acid addition salts according to the present invention may be prepared by typical methods. For example, they may be prepared by dissolving the compounds of Formula <NUM> or Formula <NUM> in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and then the precipitate formed by adding an organic and or inorganic acid is filtered and dried, or by distilling a solvent and an excess acid under reduced pressure and then drying or recrystallizing it in an organic solvent.

In addition, the pharmaceutically acceptable metal salts may be prepared with bases. Alkali metal salts or alkaline earth metal salts are, for example, obtained by dissolving a compound in an excess alkaline metal hydroxide or an alkaline earth metal hydroxide solution, filtering an undissolved compound salt and then evaporating and drying its filtrate. At this time, it is appropriate pharmaceutically to prepare sodium, potassium or calcium salts as metal salts. In addition, corresponding silver salts may be obtained by reacting the alkali metal or alkaline earth metal salts with suitable silver salt (e.g., silver nitrate).

Furthermore, the present invention includes not only the compounds expressed in Formula <NUM> or Formula <NUM> and their pharmaceutically acceptable salts but also solvates, hydrates, isomers, etc. that can be prepared therefrom.

In addition, the present invention provides a method for preparation of the compounds expressed in Formula <NUM> or Formula <NUM> above, comprising the step (step <NUM>) as shown in Reaction Equation <NUM> below in which the compound expressed in Formula <NUM> or Formula <NUM> and a compound expressed in Formula <NUM> are placed in a solvent with a reaction catalyst and then stirred.

In the following is described a preparation method of the present invention in detail.

In the preparation method according to the present invention, dimethyl formamide (DMF), methylene chloride (MC), ethanol, water, diisopropyl ether, diethyl ether, dioxane, tetrahydro furan (THF), dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), chlorobenzene, toluene, benzene may be used independently or mixed and used for the solvent.

In the preparation method according to the present invention, <NUM>-ethyl-<NUM>-(<NUM>-dimethylaminopropyl)carbodiimide) (EDCI), hydroxylbenzotriazole (HOBt), triethylamine (TEA), O-(<NUM>-azobenzotriazol-<NUM>-yl)- N, N, N', N' -tetramethyluronium hexafluorophosphate (HATU), pyridine, POCl<NUM>, Fe, HCl may be used independently or mixed and used, as the reaction catalyst.

In the preparation method according to the present invention, the reaction temperature of the step <NUM> is preferably <NUM>-<NUM>, and the reaction time is preferably <NUM> hour to <NUM> days but is not limited to this time.

Further, the present invention provides pharmaceutical compositions for use in prevention or treatment of viral diseases containing the compounds expressed in Formula <NUM> or Formula <NUM> above, pharmaceutically acceptable salts thereof, or optical isomers thereof as active ingredients.

At this time, the viral diseases are diseases caused by picornaviruses including coxsackievirus, enterovirus, poliovirus and rhinovirus. Herein, the viral diseases may include infantile paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina and foot-and-mouth disease.

Since the compounds expressed in Formula <NUM> or Formula <NUM> that are in equilibrium states with each other according to the present invention have not only low cytotoxicity but also very excellent antiviral activities against picornaviruses including coxsackievirus, enterovirus, poliovirus and rhinovirus, they can be used effectively as pharmaceutical compositions for use in prevention or treatment of viral diseases including poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, flu, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

The compounds expressed in Formula <NUM> or Formula <NUM> according to the present invention may be administered in the form of various formulations including oral and non-oral clinical administration, and are prepared for formulation using a typical diluent or excipient such as filler, thickening agent, binder, wetting agent, disintegrant, and surfactant.

Solid preparations intended for oral administration include tablets, pills, powders, granules, capsules and troches and such solid preparations are prepared by mixing at least one compound of the present invention with at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to a simple excipient, a lubricant such as magnesium stearate and talc is also used. While liquid preparations for oral administration include suspensions, internal use solutions, emulsions, and syrups, in addition to a simple diluent commonly used such as water, and liquid paraffin, various excipients may be included; for example, wetting agents, sweetening agents, aromatics, and preservatives.

Preparations intended for non-oral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilization, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and esters such as injectable ethyl oleate may be used for the non-aqueous solvents and suspensions. For suppository bases, witepsol, macrogol, tween <NUM>, cacao butter, laurin butter, glycerol, and gelatin may be used.

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 various factors including a patient's age, weight, sex, dosing method and health condition, and the severity of disease. Typically, the compound of the present invention may be administered at a daily dose of from <NUM> to <NUM>/kg; and preferably at a daily dose of from <NUM> to <NUM>/kg. For an adult with a weight of <NUM>, the dose of the compound of the present invention may typically range from <NUM> to <NUM>,<NUM>/day, and preferably from <NUM> to <NUM>,<NUM>/day. The formulations of the compound may be administered in a single dose/day or may be divided into multiple doses at regular intervals of time according to the determination of a physician or pharmacist who is responsible for monitoring or observing the administration of the drug.

In the following is described the present invention in further detail based on the examples below. However, the examples below merely illustrate the present invention, and details of the present invention are not limited by the examples below. Examples <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>, <NUM>, <NUM>, <NUM>-<NUM> and <NUM>-<NUM> are provided for reference.

After <NUM>-(<NUM>-indol-<NUM>-yl)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol), EDCI (<NUM>-ethyl-<NUM>-(<NUM>-dimethyl amino propyl) carbodiimide) (<NUM>, <NUM> mmol), and HOBt (hydroxyl benzotriazole) (<NUM>, <NUM> mmol) are dissolved in methylene chloride (MC) (<NUM>), and 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH- benzo [d] indeno [<NUM>, <NUM>-b] furan-<NUM> (9bH)-one (<NUM>, <NUM> mmol) is added and the mixture is stirred at normal temperature for one day. The reaction mixture is extracted with methylene chloride to collect an organic layer and the layer is dried under MgSO<NUM> and concentrated under reduced pressure. The concentrated compound is purified using silica gel column chromatography (ethyl acetate: n-hexane = <NUM> : <NUM>) to obtain N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-oxo-9b, <NUM>-dihydro-4bH-benzo [d] indeno [<NUM>, <NUM>-b] furan-9b- yl)-<NUM>-(<NUM>-indol-<NUM>-yl)-<NUM>-oxo acetamide (<NUM>, <NUM>%).

After <NUM>-oxo-<NUM>-(thiopen-<NUM>-yl) acetic acid (<NUM>, <NUM> mmol) is dissolved in DMF (<NUM>), the temperature is lowered to <NUM> and the solution is stirred. After <NUM> minutes, triethyl amine (TEA) (<NUM>, <NUM> mmol) and HATU (<NUM>, <NUM> mmol) are added, and stirred for <NUM> before the temperature is lowered to <NUM> and 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) is added. Next, the temperature is raised to normal temperature, and then the solution is stirred overnight. After washing with water, moisture is removed with Na<NUM>SO<NUM>. After filtering and concentration, purification is carried out with column chromatography (EA: Hex = <NUM> : <NUM>) to obtain the target compound (<NUM>, <NUM>%).

After <NUM>-nitrophenyl pyruvic acid (<NUM>, <NUM> mmol) is placed in DMF : DCM (<NUM> : <NUM>, <NUM>), EDCI (<NUM>, <NUM> mmol) is added at <NUM>. Next, after <NUM>-hydroxy benzotriazole (<NUM>, <NUM> mmol) is added, stirring is carried out at room temperature for <NUM>-<NUM> minutes. Next, after 9b-amino-4b-hydroxy- <NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) is added, TEA (<NUM>, <NUM> mmol) is added. After stirring at <NUM> for two days, water (<NUM>) is added. After organic layers are separated with ethyl acetate (<NUM> x <NUM>) they are collected and washed with water (<NUM>) and brine (<NUM>), moisture is removed with sodium sulfate. After concentration, purification is carried out in a silica gel column chromatography (<NUM>% ethyl acetate : hexane) to obtain the target compound <NUM> (<NUM>%).

After adding 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) in anhydrous DCM (<NUM>) and lowering the temperature to <NUM>° C, pyridine (<NUM>, <NUM> mmol) is added. Then pyruvic acid (<NUM>, <NUM>,<NUM> mmol) and POCl<NUM> (<NUM>, <NUM> mmol) are added in that order at <NUM>° C. After stirring at room temperature, organic layers separated using water (<NUM>) and DCM (<NUM> x <NUM>) are collected and washed with dil HCl (1N, <NUM>), water (<NUM>) and brine (<NUM>) in this order. After removing moisture with anhydrous sodium sulfate and then concentrating, purification is carried out in a flash silica gel column chromatography (<NUM>% ethyl acetate in hexane) to obtain the white target compound <NUM> (<NUM>%).

After adding 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)- one (<NUM>, <NUM> mmol) in anhydrous DCM (<NUM>) and lowering the temperature to <NUM>° C, pyridine (<NUM>, <NUM> mmol) is added. Then <NUM>-oxa valeric acid (<NUM>, <NUM> mmol) and POCl<NUM> (<NUM>, <NUM> mmol) are added in that order at <NUM>° C. After stirring at room temperature for <NUM> hours, organic layers separated using water (<NUM>) and DCM (<NUM> x <NUM>) are collected and washed with dil HCl (1N, <NUM>), water (<NUM>) and brine (<NUM>) in this order. After removing moisture with anhydrous sodium sulfate and them concentrating, purification is carried out in a flash silica gel column chromatography (<NUM>% ethyl acetate in hexane) to obtain the white target compound <NUM> (<NUM>%).

After 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) is added in anhydrous DCM (<NUM>), the temperature is lowered to <NUM>. After pyridine (<NUM>, <NUM> mmol) is added, <NUM>-oxa octanoic acid (<NUM>, <NUM> mmol) and POCl<NUM> (<NUM>, <NUM> mmol) are added in that order at <NUM>. After stirring at room temperature for <NUM> hours, organic layers separated using water (<NUM>) and DCM (<NUM> x <NUM>) are collected and washed with dil HCl (1N, <NUM>), water (<NUM>) and brine (<NUM>) in this order. After removing moisture with anhydrous sodium sulfate and them concentrating, purification is carried out in a flash silica gel column chromatography (<NUM>% ethyl acetate in hexane) to obtain the white target compound <NUM> (<NUM>%).

After <NUM>-oxa-<NUM>-furyl acetic acid (<NUM>, <NUM> mmol) is added in DMF: DCM (<NUM> : <NUM>, <NUM>), EDCI (<NUM>, <NUM> mmol) is added at <NUM>. After adding <NUM>-hydroxy benzotriazole (<NUM>, <NUM> mmol), stirring is carried out at room temperature for <NUM>-<NUM>. After adding 9b-amino-4b-hydroxy-<NUM>- isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol), stirring is carried out at room temperature for two days. Organic layers separated using water (<NUM>) and ethyl acetate (<NUM> x <NUM>) are collected and then washed with water (<NUM>) and brine (<NUM>) in that order. After removing moisture with anhydrous sodium sulfate and then concentrating, purification is carried out in a flash silica gel column chromatography (<NUM>% ethyl acetate: hexane) to obtain the target compound <NUM> (<NUM>%).

After <NUM>-indol glyoxalic acid (<NUM>, <NUM> mmol) is placed in DMF: DCM (<NUM> : <NUM>, <NUM>), EDCI (<NUM>, <NUM> mmol) is added at <NUM>. After <NUM>-hydroxy benzotriazole (<NUM>, <NUM> mmol) is added, stirring is carried out at room temperature for <NUM>-<NUM>. After 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) is added, stirring is carried out at room temperature overnight. Organic layers separated using water (<NUM>) and ethyl acetate (<NUM> x <NUM>) are collected and then washed with water (<NUM>) and brine (<NUM>) in that order. After removing moisture with anhydrous sodium sulfate and then concentrating, purification is carried out in a flash silica gel column chromatography (<NUM>%, ethyl acetate: hexane) to obtain the white target compound (<NUM>, <NUM>%).

After <NUM>-(<NUM>-hydroxy phenyl)-<NUM>-oxo propanoic acid (<NUM>, <NUM> mmol) is dissolved in DMF (<NUM>), the temperature is lowered to <NUM> and stirring is carried out. After <NUM>, triethyl amine (TEA) (<NUM>, <NUM> mmol) and HATU (<NUM>, <NUM> mmol) are added. After stirring for <NUM>, the temperature is lowered to <NUM>, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) is added. The temperature is raised to normal temperature, and stirring is carried out overnight. After rinsing with water, moisture is removed with Na<NUM>SO<NUM>, and filtering and concentration is carried out, purification is carried out in a column chromatography (EA : Hex = <NUM> : <NUM>) to obtain the target compound (<NUM>, <NUM>%).

After b-hydroxy- <NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-7b, <NUM>-dihydro-4bH-indemo [<NUM>, <NUM>-b] benzofuran-9b- yl)-<NUM>-(<NUM>-inolol-<NUM>-yl)-<NUM>-oxo acetamide (<NUM>, <NUM> mmol) is placed in ethanol: water (<NUM>: <NUM>, <NUM>: <NUM>), the mixture is heated to <NUM>. After adding iron (<NUM>, <NUM> mmol) and two drops of conc. HCl, heating and refluxing is carried out for <NUM> hours. After the derived compound is filtered in a celite bed at high temperature, the liquid is washed with ethyl acetate (<NUM> x <NUM>) and then concentrated before ethyl acetate (<NUM>) is added. After washing with sat. NaHCO<NUM> (<NUM>), water (<NUM>) and brine (<NUM>) in that order, moisture is removed with anhydrous sodium sulfate. After concentration and drying, a small amount of DCM is added and then ultrasonic waves are applied. The solid compound formed at this time is filtered to obtain the yellow target compound (<NUM>, <NUM>%).

After N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-9b, <NUM>-dihydro-4bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-oxo-phenyl acetamide (<NUM>, <NUM> mmol) is added in ethanol: water (<NUM>: <NUM>, <NUM> : <NUM>), the mixture is heated to <NUM>. After iron (<NUM>, <NUM> mmol) and two drops of conc. HCl are added, refluxing is carried out by heating for <NUM> hours. After the derived compound is filtered on a celite bed at high temperature, the liquid is washed with ethyl acetate (<NUM> x <NUM>) and then concentrated before ethyl acetate (<NUM>) is added. After washing it with sat. NaHCO<NUM> (<NUM>), water (<NUM>) and brine (<NUM>) in that order, moisture is removed with anhydrous sodium sulfate. After concentration and drying, a small amount of DCM is added and then ultrasonic waves are applied. The solid compound formed at this time is filtered to obtain the yellow target compound (<NUM>, <NUM>%).

After dissolving <NUM>-oxo-<NUM>-phenyl acetate (<NUM>, <NUM> mmol) in DCM (<NUM>), the temperature is lowered to <NUM>. After EDCI (<NUM>, <NUM> mmol) is placed at <NUM>, stirring is carried out for <NUM>. After adding HOBt (<NUM>, <NUM> mmol) at <NUM> and then stirring for <NUM>, 9b-amino-4b-hydroxy-<NUM>- dimethyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mol) is added at <NUM> and then stirring is carried out at room temperature for <NUM> hours. After washing with water, removing moisture with Na<NUM>SO<NUM>, concentrating under reduced pressure, and purifying in a column, the target compound (<NUM>, <NUM>%) is obtained.

After dissolving <NUM>-(<NUM>-indol-<NUM>-yl)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol) in DCM (<NUM>), the temperature is lowered to <NUM>. After EDCI (<NUM>, <NUM> mmol) is placed at <NUM>, stirring is carried out for <NUM>. After adding HOBt (<NUM>, <NUM> mmol) at <NUM> and then stirring for <NUM>, 9b-amino-4b- hydroxy-<NUM>-dimethyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mol) is added at <NUM> and then stirring is carried out at room temperature for <NUM> hours. After washing with water, removing moisture with Na<NUM>SO<NUM>, concentrating under reduced pressure, and purifying in a column, the target compound (<NUM>, <NUM>%) is obtained.

After adding 9b-amino-4b-hydroxy-<NUM>, <NUM>-dimethyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) in DCM (<NUM>), the temperature is lowered to <NUM>. After adding pyridine (<NUM>, <NUM> mmol) and stirring for <NUM>, <NUM>-oxo propanoic acid (<NUM>, <NUM> mmol) is added. After adding POCl<NUM> (<NUM>, <NUM> mmol) in a stirred state, stirring is carried out at room temperature for <NUM> hours. After an organic layer is separated using DCM (<NUM>) and H<NUM>O (<NUM>), washing is carried out with 1N HCl and NaCl in that order, moisture is removed with Na<NUM>SO<NUM> and concentration is carried out. Next, purification is carried out in a column to obtain the target compound (<NUM>, <NUM>%).

After dissolving phenyl glyoxylic acid (<NUM>, <NUM> mmol) in anhydrous methylene chloride (<NUM>), EDCI (<NUM>, <NUM> mmol), HOBt (<NUM>, <NUM> mmol), <NUM>-(<NUM>-amino ethyl)-9b-amino-4b-hydroxy-<NUM>- isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) and triethyl amine (<NUM>, <NUM> mmol) are added and stirring is carried out at room temperature for <NUM> hours. After diluting with methylene chloride and washing with water several times, the organic layer is dried and filtered. After purifying in a column chromatography (ethyl acetate: hexane= <NUM> : <NUM>), the target compound (<NUM>, <NUM>%) is obtained.

After adding phenyl glyoxalic acid (<NUM>, <NUM> mmol) in DMF: DCM (<NUM> : <NUM><NUM>), EDCI (<NUM>, <NUM> mmol) is added at <NUM>. After adding <NUM>-hydroxy benzotrinaole (<NUM>, <NUM> mmol), stirring is carried out at room temperature for <NUM>-<NUM>. After adding 9b-amino-4b-hydroxy-<NUM>- isopropyl-<NUM>-nitro-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol), stirring is carried out at room temperature overnight. The organic layers separated using water (<NUM>) and ethyl acetate (<NUM> x <NUM>) are collected and washed with water (<NUM>) and brine (<NUM>) in that order. After removing moisture with anhydrous sodium sulfate and then concentrating, purification is carried out in a flash silica gel column chromatography (<NUM>% ethyl acetate hexane) to obtain the target compound (<NUM>, <NUM>%).

9b-amino-4b-hydroxy-<NUM>-isopropyl-4bH-indeno [<NUM>, <NUM>-b] benzofuran-<NUM> (9bH)-one (<NUM>, <NUM> mmol) and pyridine (<NUM>, <NUM> mmol) are dissolved in DCM. After adding POCl<NUM> (<NUM>, <NUM> mmol) and then <NUM>-(methylthio)-<NUM>-oxo butanoic acid sodium salt (<NUM>, <NUM> mmol), stirring is carried out at normal temperature overnight. After washing with water, moisture is removed with Na<NUM>SO<NUM>, and filtration and concentration is carried out, purification is performed in a column chromatography (EA : Hex= <NUM> : <NUM>) to obtain the target compound (<NUM>, <NUM>%).

<NUM>H-NMR (<NUM>, DMSO-d6) δ <NUM> (d, <NUM>, J=<NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>).

After dissolving 9b-hydroxy- <NUM>-isopropyl-4b-methoxy-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in DCM (<NUM>), stirring is carried out at <NUM>. After dissolving Triphosgene (phosgene) (<NUM>, <NUM> mmol) in TEA (<NUM>, <NUM> mmol), it is added at <NUM>. After dissolving the reaction for <NUM> and concentrating under reduced pressure, any remaining phosgene is removed. After verifying that the starting material has disappeared using TLC, n-propyl amine (<NUM>, <NUM> eq. ) and TEA (<NUM> eq. ) are added in DCM (<NUM>) and dissolved prior to addition. After reacting at normal temperature for <NUM> hours, the reactants are concentrated upon completion of the reaction and then purification is carried out in a silica gel chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After dissolving 9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in anhydrous THF (<NUM>, <NUM>), TEA (<NUM>, <NUM> mmol) is added while stirring slowly. Next, pyruvic acid (<NUM>, <NUM> mmol) is added at <NUM>. Phosphorous oxy chloride (<NUM>, <NUM>,<NUM>) is added slowly drop by drop. After reacting at normal temperature for <NUM> hours, extraction is carried out with ethyl acetate (EA) upon completion of the reaction, washing is carried out with water, water is removed with Na<NUM>SO<NUM>, and the reactants are concentrated. Next, purification is performed in a silica gel chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%) and to recover <NUM> of the starting material.

After dissolving <NUM>-((<NUM>, <NUM>-dimethyl phenyl) amino)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>), EDCI (<NUM>, <NUM> mmol) is added at <NUM> while stirring and <NUM>-hydroxy benzotriazole (<NUM>, <NUM> mmol) is also added. While stirring, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added, and then the reaction is carried out at normal temperature for <NUM> hours by adding TEA (<NUM>, <NUM> mmol) drop by drop. Upon completion of the reaction, water (<NUM>) and ethyl acetate (<NUM> x <NUM>) are used for extraction and then washing is carried out once more with brine (<NUM>). After removing water with Na<NUM>SO<NUM>, the mixture obtained by concentration under pressure is purified in a silica gel column chromatography (<NUM>-<NUM> % EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After dissolving <NUM>-(dimethyl amino)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol) in DCM (<NUM>), EDCI (<NUM>, <NUM> mmol) is added at <NUM> while stirring, and <NUM>-hydroxy benzotriazole (<NUM>, <NUM> mmol) is added. While stirring, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added, and then the reaction is carried out at normal temperature for <NUM> hours by adding TEA (<NUM>, <NUM> mmol) drop by drop. Upon completion of the reaction, water (<NUM>) and ethyl acetate (<NUM> x <NUM>) are used to extract and then washing is carried out once more with brine (<NUM>). After removing water with Na<NUM>SO<NUM>, the mixture obtained by concentration under pressure is purified in a silica gel column chromatography (<NUM> % EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After dissolving N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-oxo propanamide (<NUM>, <NUM> mmol) in ethanol: water (<NUM>: <NUM>, <NUM>), iron (<NUM>, <NUM> mmol) is added. After adding conc. HCl (<NUM> drops) and reacting at <NUM> for <NUM> hours, filtration is carried out with celite under high temperature upon completion of the reaction and then washing is carried out with ethyl acetate. After extracting with DCM and washing with water, washing is carried out with brine (<NUM>) again. Water is removed with Na<NUM>SO<NUM> and the reactants are concentrated before purification is carried out in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After <NUM>-oxo-<NUM>-(<NUM>, <NUM>, <NUM>-trimethoxy phenyl) acetic acid (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added in sequence while stirring at <NUM>. After approximately <NUM>, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>- indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added and reaction is carried out for <NUM> hours. Upon completion of the reaction, DCM (<NUM> x <NUM>) and water are used for extraction and washing is carried out with brine. After removing water with Na<NUM>SO<NUM> and then concentrating under reduced pressure, purification is carried out in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After dissolving (E)-<NUM>-(<NUM>,<NUM>-dimethoxy phenyl)-<NUM>-oxobut-<NUM>-enoic acid (<NUM>, <NUM> mmol) in DCM (<NUM>), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) is added in that order while stirring at <NUM>.

After approximately <NUM>, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added and then reaction is carried out for <NUM> hours. Upon completion of the reaction, DCM (<NUM> x <NUM>) and water are used for extraction and washing is carried out with brine. After removing water with Na<NUM>SO<NUM> and then concentrating under reduced pressure, purification is carried out in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

<NUM>-(<NUM>-nitrophenyl)-<NUM>-oxo propionic acid (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>, <NUM>). After stirring at <NUM> for <NUM>, HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added. After stirring at <NUM> for <NUM>, 9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro- <NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added and then stirring is carried out at normal temperature for <NUM> hours. After extracting with ethyl acetate (EA) and washing with water, the reactant is concentrated and purification is carried out in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

<NUM>-((<NUM>, <NUM>-dimethyl phenyl) amino)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>, <NUM>). After stirring at <NUM> for <NUM>, EDCI (<NUM>, <NUM> mmol) and HOBt (<NUM>, <NUM> mmol) are added. After stirring at <NUM> for <NUM>, TEA (<NUM>, <NUM> mmol) and 9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added prior to stirring at normal temperature for <NUM> hours. After extracting with ethyl acetate (EA) and washing with water, the reactants are concentrated and purified on silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

Mono-(N-methyl)-amide oxalate (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>, <NUM>). After stirring at <NUM> for <NUM>, HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added. After stirring at <NUM> for <NUM>, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added prior to stirring at normal temperature for <NUM> hours. After stirring further at <NUM> for <NUM> hours, DMF (<NUM>) is added and stirring is carried out again for <NUM> hour. After extracting with ethyl acetate (EA) and washing with water, the reactants are concentrated and purified on silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After adding and dissolving sodium salt <NUM>-methyl-<NUM>- oxo pentanoic acid (<NUM> mgl) is 1N HCl, stirring is carried out for <NUM>, extraction is carried out with ethyl acetate, and concentration is carried out under reduced pressure to obtain <NUM>-methyl-<NUM>-oxo pentanoic acid (<NUM>, <NUM> mmol) which is dissolved in THF (<NUM>, <NUM>). Next, 9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>- indeno [<NUM>,<NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added, and while stirring is carried out at - <NUM> for <NUM>, POCl<NUM> (<NUM>, (<NUM> THF), <NUM> mmol) is slowly added with a syringe pump for <NUM> and stirring is carried out. After adding POCl<NUM>, the reaction is carried out at normal temperature for <NUM> hours, and upon completion of the reaction, concentration is carried out under reduced pressured. EA and water is used to carry out extraction, and the organic layer is washed with water and brine before removing water with Na<NUM>SO<NUM> and concentrating under reduced pressure. Finally, a column filled with silica is used to carry out purification before the target compound (<NUM>, <NUM>%) is obtained.

After adding and dissolving sodium salt <NUM>-methyl-<NUM>- oxo pentanoic acid (<NUM>) is 1N HCl, stirring is carried out for <NUM>, extraction is carried out with ethyl acetate, and concentration is carried out under reduced pressure to obtain <NUM>-methyl-<NUM>-oxo pentanoic acid (<NUM>, <NUM> mmol) which is dissolved in THF (<NUM>, <NUM>). Next, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added, and while stirring is carried out at -<NUM> for <NUM>, POCl<NUM> (<NUM>, (<NUM> in THF), <NUM> mmol) is slowly added with a syringe pump for <NUM> and stirring is carried out. After adding POCl<NUM>, the reaction is carried out at normal temperature for <NUM> hours, and upon completion of the reaction, concentration is carried out under reduced pressured. EA and water is used to carry out extraction, and the organic layer is washed with water and brine before removing water with Na<NUM>SO<NUM> and concentrating under reduced pressure. Finally, a column filled with silica is used to carry out purification before the target compound (<NUM>, <NUM>%) is obtained.

While <NUM>-(dimethyl amino)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol) is added in DCM (<NUM>, <NUM>) at <NUM> and stirred, HATU (<NUM>, <NUM> mmol) is added and the DIPEA (<NUM>, <NUM> mmol) is added before stirring is carried out. Finally, 9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>- indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added and then stirring is carried out at normal temperature for <NUM> hours. Upon completion of the reaction, water and DCM is used for extraction, washing is carried out with water again, and water is removed with Na<NUM>SO<NUM> before concentration is carried out under reduced pressure. Finally, a column filled with silica is used to carry out purification before the target compound (<NUM>, <NUM>%) is obtained.

After dissolving N1-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-N2, N2-dimethyl oxal amide (<NUM>, <NUM> mmol) is dissolved in EtOH: H2O (<NUM>: <NUM>) (<NUM>, <NUM>), iron powder (<NUM>, <NUM> mmol) is added. While stirring, conc. HCl (<NUM> drops) is slowly added and the reaction is allowed to take placed at <NUM> for <NUM> hours. Upon completion of the reaction, cooling is carried out to normal temperature, concentration under reduced pressure is carried out, water and ethyl acetate is used for extraction, and washing with water is carried out again before water is removed with Na<NUM>SO<NUM> and then concentration is carried out under reduced pressure. Finally, a column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is dissolved in THF (<NUM>, <NUM> mmol). TEA (<NUM>, <NUM> mmol) and ethyl-<NUM>-chloro-<NUM>- oxo acetate (<NUM>, <NUM> mmol) are slowly added at -<NUM>. After stirring for <NUM> hours, THF is concentrated. After adding DCM, washing is carried out with water and brine. After adding Na<NUM>SO<NUM> and filtration, concentration is carried out. A column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

<NUM>-oxo pentanoic acid (<NUM>, <NUM> mmol) is dissolved in THF (<NUM>, <NUM>). Next, 9b-amino- 4b-hydroxy- <NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) and TEA (<NUM>, <NUM> mmol) are added and the temperature is lowered to -<NUM> before POCl<NUM> (<NUM>, <NUM> mmol) is slowly added in drops. While raising the temperature slowly to normal temperature, stirring is carried out for <NUM> hours and then THF is concentrated. After adding DCM, washing is carried out with water and brine. After adding Na<NUM>SO<NUM> and filtration, concentration is carried out. A column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

<NUM>-oxo octanoic acid (<NUM>, <NUM> mmol) is dissolved in THF (<NUM>, <NUM>). Next, 9b-amino- 4b-hydroxy- <NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) and TEA (<NUM>, <NUM> mmol) are added and the temperature is lowered to - <NUM> before POCl<NUM> (<NUM>, <NUM> mmol) is slowly added in drops. While raising the temperature slowly to normal temperature, stirring is carried out for <NUM> hours and then THF is concentrated. After adding DCM, washing is carried out with water and brine. After adding Na<NUM>SO<NUM> and filtration, concentration is carried out. A column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

Ethyl <NUM>-((4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl) amino)-<NUM>-oxo acetate (<NUM>, <NUM> mmol) is dissolved in EtOH: water = <NUM> : <NUM> (<NUM>, <NUM>). Fe (<NUM>, <NUM> mmol) and <NUM> drop HCl (Cat) is added. Refluxing is carried out for <NUM> hours. After diluting with ethyl acetate (EA) and then washing with water, its EA layer is extracted. Ethyl acetate is concentrated, and the reactants are dissolved in DCM. After washing with water and brine, Na<NUM>SO<NUM> is added, and filtration and concentration is carried out. A column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

<Example <NUM>> Preparation of N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-oxo-4b, <NUM>-dihydro-9bH- indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>, <NUM>-dimethyl-<NUM>-oxo butanamide.

9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added to THF (<NUM>, <NUM>). After adding <NUM>,<NUM>-dimethyl-<NUM>-oxo butyric acid (<NUM>, <NUM> mmol) and then TEA (<NUM>, <NUM> mmol), cooling is carried out to - <NUM>. While POCl<NUM> (<NUM>, <NUM> mmol) is slowly added and the temperature is maintained, stirring is carried out for <NUM> hours. Concentration is carried out under reduced pressure, ethyl acetate is added in excess, water is removed with Na<NUM>SO<NUM>, and concentration is carried out under reduced pressure before separation is carried out in a silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

<Example <NUM>> Preparation of N-(4b hydroxyl-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro- 9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-methyl-<NUM>-oxo pentanamide.

9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>- one (<NUM>, <NUM> mmol) is added in DCM (<NUM>, <NUM>). EDCI (<NUM>, <NUM> mmol) and TEA (<NUM>, <NUM> mmol) are added. After adding HOBt (<NUM>, <NUM> mmol) and <NUM>-methyl-<NUM>-oxo pentanoic acid (<NUM>, <NUM> mmol), stirring is carried out at normal temperature for <NUM> hours. DCM is farther added for dilution and then washing is carried out with water. Water is removed with Na<NUM>SO<NUM>, concentration is carried out under reduced pressure, and then purification is carried out with silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

While <NUM>-oxo-<NUM>-phenyl butyric acid (<NUM>, <NUM> mmol) is added in DCM (<NUM>, <NUM>) at <NUM> and stirred, HATU (<NUM>, <NUM> mmol) and then DIPEA (<NUM>, <NUM> mmol) are added prior to stirring. Finally, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added and stirring is carried out at normal temperature for <NUM> hours. Upon completion of the reaction, water and DCM are used for extraction and washing with water is carried out again before water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Finally, a column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

After N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-methyl-<NUM>-oxo pentanamide (<NUM>, <NUM> mmol) is dissolved in EtOH: H2O (<NUM>: <NUM>) (<NUM>, <NUM>), iron powder (<NUM>, <NUM> mmol) is added and stirred before conc. HCl (<NUM> drops) is finally added slowly and then the reaction is carried out at <NUM> for <NUM> hours.

Upon completion of the reaction, cooling is carried out to normal temperature, concentration under reduced pressure is carried out, water and ethyl acetate are used for extraction, and washing with water is carried out again before water is removed with Na<NUM>SO<NUM> and then concentration is carried out under reduced pressure. Finally, a column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%).

9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added in THF (<NUM>, <NUM>). After slowly adding TEA (<NUM>, <NUM> mmol), <NUM>-bromo-<NUM>-oxopropionic acid (<NUM>, <NUM> mmol) is added. After cooling to -<NUM> and then slowly adding a <NUM> phosphorous oxy chloride solution (<NUM>, <NUM> mmol), stirring is carried out for <NUM>-<NUM> hours. Upon completion of the reaction, concentration under reduced pressure is carried out to remove THF and water and ethyl acetate are used for extraction. After washing with water is carried out again, water is removed with Na<NUM>SO<NUM> and concentration under reduced pressure is carried out. Finally, a column filled with silica is used for purification to obtain the target compound (<NUM>, <NUM>%). <NUM>H-NMR (<NUM>, CDC13) δ <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM> (sept, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>) <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

<NUM>,<NUM>-dioxo-<NUM>-(pyridine-<NUM>-yl) butyric acid (<NUM>, <NUM> mmol) is added to DCM (<NUM>) and cooled to <NUM>. HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added. After <NUM> minutes, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added and then stirring is carried out for <NUM> hours. Upon quenching with water, DCM (<NUM> x <NUM>) is added. After water and ethyl acetate is used for extraction and then washing with water is carried out again, water is removed with Na<NUM>SO<NUM> and concentration under reduced pressure is carried out. Finally, a column filled with silica is used (<NUM>% MeOH in DCM) for purification to obtain the target compound (<NUM>, <NUM>%).

<NUM>-((4b-hydroxy-<NUM>-isopropyl-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl) amino)-<NUM>-oxo butyric acid triethyl amine salt (<NUM>, <NUM> mmol) is added in EtOAc (<NUM>, <NUM>). After adding HCl (<NUM> N, <NUM>) at normal temperature, stirring is carried out for <NUM>. After water and ethyl acetate are used for extraction and then washing with water is carried out again, water is removed with Na<NUM>SO<NUM> and concentration under reduced pressure is carried out. Finally, a column filled with silica is used for purification to obtain the target compound (<NUM>, Quant.

<NUM>-((4b-hydroxy-<NUM>-isopropyl-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl) amino)-<NUM>-oxo butyric acid (<NUM>, <NUM> mmol) is added in DCM (<NUM>) and cooled to <NUM>. After HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added, stirring is carried out for <NUM>. After dimethyl amine chloride (<NUM>, <NUM> mmol), stirring is carried out for <NUM> hours. Upon quenching with water, DCM (<NUM> x <NUM>) is added. After water and ethyl acetate are used for extraction and then washing with water is carried out again, water is removed with Na<NUM>SO<NUM> and concentration under reduced pressure is carried out. Finally, a column filled with silica is used (<NUM> : <NUM> = EtOAc : Hx) for purification to obtain the target compound (<NUM>, <NUM>%).

<NUM>-((4b-hydroxy-<NUM>-isopropyl-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)amino)-<NUM>-oxo butyric acid (<NUM>, <NUM> mmol) is added in DCM (<NUM>) and cooled to <NUM>. After adding HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol), stirring is carried out for <NUM>. After adding isopropyl amine (<NUM>, <NUM> mmol), stirring is carried out for <NUM> hours. Upon quenching with water, DCM (<NUM> x <NUM>) is added. After water and ethyl acetate are used for extraction and then washing with water is carried out again, water is removed with Na<NUM>SO<NUM> and concentration under reduced pressure is carried out. Finally, a column filled with silica is used (DCM : EtOAc = <NUM> : <NUM>) for purification to obtain the target compound (<NUM>, <NUM>%).

9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added in THF (<NUM>, <NUM>) and cooled to <NUM>. TEA (<NUM>, <NUM> mmol) is slowly added. A cyanogen bromide (<NUM>, <NUM> mmol) solution <NUM> is slowly added for <NUM> and stirred. Stirring is carried out at <NUM> for <NUM> hours. Solid is filtered and separated and the solid is washed with THF. The liquid separated by filtration is concentrated under reduced pressure (DCM/Hx) and recrystallized to obtain the target compound (<NUM>, <NUM>%).

After adding N1-(<NUM>, <NUM>-dimmethyl phenyl)-N2-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl) oxal amide (<NUM>, <NUM> mmol), Fe (<NUM>, <NUM> mmol) and HCl (<NUM> drops) are added in the <NUM> : <NUM><NUM> mixture of EtOH and H<NUM>O, stirring is carried out at <NUM> for <NUM> hours. After filtration with celite, concentration is carried out. After diluting with ethyl acetate (EA) and washing with water, the EA layer is extracted. The reactants are concentrated and purification is carried out in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

After <NUM>-(<NUM>-methyl piperazin-<NUM>-yl)-<NUM>-oxo acetic acid (<NUM>, <NUM> mmol) is added in DCM (<NUM>, <NUM>) at <NUM> and stirred, HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added and then stirred. Finally, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran- <NUM>-one (<NUM>, <NUM> mmol) is added and stirring is carried out at normal temperature for <NUM> hours. Upon completion of the reaction, the solid formed is filtered and then dissolved in EA again. Water and ethyl acetate are used for extraction and washing is carried out with water before water is removed with Na<NUM>SO<NUM> and concentration under reduced is carried out to obtain the target compound (<NUM>, <NUM>%).

N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-methyl-<NUM>-oxo pentanamide (<NUM>, <NUM> mmol) is added in EtOH: H<NUM>O (<NUM>: <NUM>, <NUM>, <NUM>) and Fe (<NUM>, <NUM> mmol) and acetic acid (<NUM> drops) are added before heating and stirring is carried out at <NUM> for <NUM> hours. A separation tube filled with celite is used to remove Fe and then concentration under reduced pressured is carried out. After ethyl acetate is added in excess, washing with water is carried out, water is removed with Na<NUM>SO<NUM>, and concentration under reduced pressure is carried out, separation is carried out in a silica gel column chromatography to obtain target compound (<NUM>, <NUM>%).

N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-oxo hexanamide (<NUM>, <NUM> mmol) is added in EtOH : H<NUM>O (<NUM> : <NUM>, <NUM>, <NUM>) and Fe (<NUM>, <NUM> mmol) and acetic acid (<NUM> drops) are added before heating and stirring is carried out at <NUM> for <NUM> hours. A separation tube filled with celite is used to remove Fe and then concentration under reduced pressured is carried out. After ethyl acetate is added in excess, washing with water was carried, water is removed with Na<NUM>SO<NUM>, and concentration under reduced pressure is carried out, separation is carried out in a silica gel column chromatography to obtain target compound (<NUM>.

After dissolving mesityl glyoxalic acid (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>, <NUM>), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added. Finally, an amine compound (<NUM>, <NUM> mmol) is added before stirring is carried out for <NUM> hours. Upon completion of the reaction, washing is carried out with dichloromethane, NaHCO<NUM> aqueous solution and water and then water is removed with Na<NUM>SO<NUM> before concentration under reduced pressure is carried out. Separation is carried out in a silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-oxo pentanamide (<NUM>, <NUM> mmol) is dissolved in EtOH: water= <NUM>: <NUM> (<NUM>, <NUM>) before Fe (<NUM>, <NUM> mmol) and one drop of HCl (Cat) is added and then stirring is carried out at <NUM> for <NUM> hours. Upon completion of the reaction, washing is carried out with dichloromethane and water and water is removed with Na<NUM>SO<NUM> to obtain the target compound (<NUM>, <NUM>%) with prep TLC.

After dissolving <NUM>-oxo-<NUM>-phenyl butyric acid (<NUM>, <NUM> mmol) in DCM (<NUM>, <NUM>), HATU (<NUM>, <NUM> mmol), and DIPEA (<NUM>, <NUM> mmol) are added, and a nitro compound (<NUM>, <NUM> mmol) is added and then stirring is carried out at room temperature for <NUM> hours. Upon completion of the reaction, dichloromethane, an NaHCO<NUM> aqueous solution, and water are used for washing before water is removed with Na<NUM>SO<NUM> and separation is carried out in a silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-oxo pentanamide (<NUM>, <NUM> mmol) is dissolved in EtOH: water= <NUM>: <NUM> (<NUM>, <NUM>) before Fe (<NUM>, <NUM> mmol) and one drop of HCl (Cat) are added and then stirring is carried out at <NUM> for <NUM> hours. Upon completion of the reaction, washing is carried out with dichloromethane and water and prep TLC is used to obtain the target compound (<NUM>, <NUM>%).

In 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added DMF (<NUM>, <NUM>) and <NUM>,<NUM>-bis (tert-butoxy carbonyl)-<NUM>-methyl-<NUM>-thiopseudo urea (<NUM>, <NUM> mmol). After adding HgCl<NUM> (<NUM>, <NUM> mmol) and then adding triethyl amine (<NUM>, <NUM> mmol) at <NUM>, stirring is carried out for <NUM>. Upon completion of the reaction, ethyl acetate (<NUM>) is added and then filtration is carried out on celite. After washing the filtrate with water and brine, water is removed with Na<NUM>SO<NUM> and then separation is carried out in a silica gel column chromatography (<NUM>% ethyl acetate in hexanes) to obtain the target compound (<NUM>, <NUM>%).

In <NUM>-isopropyl-<NUM>-4b, 9b-(epoxy metanooxy) indeno [<NUM>, <NUM>-b] benzofuran-<NUM>, <NUM>-dione (<NUM>, <NUM> mmol) is added THF : DMF (<NUM> : <NUM>) and tert-butyl (<NUM>-amino ethyl) carbamate (<NUM>, <NUM> mmol). Afterward DMAP (<NUM> - <NUM>) and TEA (<NUM>, <NUM> mmol) are added before stirring is carried out at room temperature for <NUM> hours. Upon completion of the reaction, concentration under reduced pressure is carried out and then separation is carried out in a silica gel column chromatography (<NUM>% EtAc in hexane) to obtain the target compound (<NUM>, <NUM>%).

In 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) and anhydrous succinic acid are added dry THF (<NUM>, <NUM>) and TEA (<NUM>, <NUM> mmol). After adding DMAP (<NUM>), stirring is carried out in a refluxing apparatus for <NUM> hours. Upon completion of the reaction, cooling to room temperature is carried out and then solid is filtered. The filtrate is washed with THF to obtain the target compound (<NUM>, <NUM>%).

After 9b-amino-4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran- <NUM>-one (<NUM>, <NUM> mmol) is added in DMF (<NUM>, <NUM>. <NUM> mmol), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added. After adding <NUM>-oxo-<NUM>-(<NUM>, <NUM>, <NUM>-trimethoxy phenyl) acetic acid (<NUM>, <NUM>), stirring is carried out at normal temperature for <NUM> hours. After adding DCM in excess and washing with water, water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Separation is carried out in a silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

After dissolving N-(4b-hydroxy-<NUM>-isopropyl-<NUM>-nitro-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)-<NUM>-oxo-<NUM>-phenyl butanamide (<NUM>, <NUM> mmol) in ECOH: water = <NUM> : <NUM> (<NUM>, <NUM>), Fe (<NUM>, <NUM> mmol) is added and then stirred. Lastly, one drop of HCl is added and then stirring is carried out at <NUM> for <NUM> hours. Upon completion of the reaction, cooling to normal temperature is carried out and then concentration under reduced pressure is carried out. Water and ethyl acetate are used for extraction before washing with water, removing water with Na<NUM>SO<NUM>, and concentration under reduced pressure. Finally, a column filled with silica is used for purification to obtain the target compound (<NUM> <NUM>%).

After dissolving 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in acetonitrile (ACN) (<NUM>, <NUM>), stirring is carried out while adding ethyl acetamidate (<NUM>, <NUM> mmol). After adding DIPEA (<NUM>, <NUM> mmol), refluxing is carried out for <NUM> hours. Upon completion of the reaction, cooling to normal temperature is carried out and then concentration under reduced pressure is carried out. Water and ethyl acetate are used for extraction before washing with water, removing water with Na<NUM>SO<NUM>, and concentration under reduced pressure. Finally, DCM/Hx is added to the mixture for recrystallization to obtain the target compound (<NUM>, <NUM>%).

After dissolving 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in acetone: water (<NUM> : <NUM>, <NUM>), potassium thiocyanate (<NUM>, <NUM> mmol) are added. After adding conc. HCl (<NUM>), stirring is carried out at normal temperature for <NUM> hours. Upon completion of the reaction, water and ethyl acetate are used for extraction and then washing with brine is carried out again. After removing water with Na<NUM>SO<NUM> and then concentrating under reduced pressure, the mixture obtained is purified in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

9b-hydroxy-<NUM>-isopropyl-4b-methoxy-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is added in DCM (<NUM>) at <NUM> and stirred before triphosgene (<NUM>, <NUM> mmol) is dissolved in TEA (<NUM>, <NUM> mmol) and then slowly added. After approximately <NUM>, concentration under reduced pressure is carried out to remove any excess phosgene and then DCM (<NUM>) is again dissolved before a solution (<NUM>, <NUM> mmol) prepared by mixing ethyl amine with methanol (<NUM>) is added and then TEA (<NUM>, <NUM> mmol) is added. After reacting at normal temperature for <NUM> hours, water and DCM are used for extraction and washing with brine is carried out again. After removing water with Na<NUM>SO<NUM> and then concentrating under reduced pressure, the mixture obtained is purified in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

While glycine (<NUM>, <NUM> mmol) is dissolved in DCM (<NUM>, <NUM>) at <NUM> and then stirred, HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) are added to carry out the reaction. After approximately <NUM>, 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran- <NUM>-one (<NUM>, <NUM> mmol) is added to carry out the reaction for <NUM> hours. Upon completion of the reaction, water and DCM (<NUM> X <NUM>) are used for extraction and washing is carried out again with brine. After removing water with Na<NUM>SO<NUM> and then concentrating under reduced pressure, the mixture obtained is purified in a silica gel column chromatography (<NUM>% EA in Hex) to obtain the target compound (<NUM>, <NUM>%).

While tert-butyl (<NUM>-((4b-hydroxy- <NUM>-isopropyl-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl) amino)-<NUM>-oxo ethyl) carbamate (<NUM>, <NUM> mmol) is added in DCM (<NUM>, <NUM>) and stirred, trifluoroacetic acid (<NUM>, <NUM> mmol) is added. After reacting at normal temperature for <NUM> hours, DCM (<NUM>) and over-saturated NaHCO<NUM> (<NUM> x <NUM>) is used for extraction upon completion of the reaction and then brine (<NUM>) washing is carried out again. Water was removed with Na<NUM>SO<NUM> and concentration under reduced pressure is carried out to obtain the target compound (<NUM>, <NUM>%).

After dissolving 9b-chloro-4b-hydroxy-<NUM>, <NUM>-dimethyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in THF (<NUM>, <NUM>), the reaction temperature is kept at -<NUM>. After adding methyl amine (<NUM>, <NUM> mmol) in that order, the reaction is carried out for <NUM> hours. Upon completion of the reaction, THF is concentrated under reduced pressure and removed and then DCM and water are used for extraction before brine washing is carried out again. After removing water with Na<NUM>SO<NUM>, silica gel chromatography is used for purification to obtain the target compound (<NUM>, <NUM>%).

After dissolving N', N'-di-tert-butoxycarbonyl [<NUM>-(4b-hydroxy-<NUM>-isopropyl-<NUM>-oxo-4b, <NUM>-dihydro-9bH-indeno [<NUM>, <NUM>-b] benzofuran-9b-yl)] guanidine (<NUM>, <NUM> mmol) in MeOH (<NUM>, <NUM>), stirring is carried out while adding <NUM> N HCl (<NUM>, <NUM> eq. After reacting at normal temperature for <NUM> hours, concentration under reduced pressure is carried out upon completion of the reaction before a silica gel column chromatography (<NUM>% MeOH in DCM) is used for purification immediately. Concentration under reduced pressure and drying is carried out to obtain the target compound (<NUM>, <NUM>%).

After dissolving 4b-hydroxy-<NUM>, <NUM>-dimethyl-9b-(methyl amino)-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in DMF (<NUM>, <NUM>), <NUM>, <NUM>, <NUM>, <NUM>, <NUM>-pentamethyl isothiouronium iodide (<NUM>, <NUM> mmol) is added. While stirring at <NUM>, TEA and HgCl<NUM> (<NUM>, <NUM> mmol) are added to carry out the reaction for <NUM> hours. Upon completion of the reaction, water and ethyl acetate are used for extraction and brine washing is carried out again. After removing water with Na<NUM>SO<NUM>, a silica gel chromatography is used for purification to obtain the target compound (<NUM>, <NUM>%).

After adding and dissolving 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>- b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in acetonitrile (ACN) (<NUM>, <NUM>), benzene sulfonyl chloride (<NUM>, <NUM> mmol) is added. After adding pyridine (<NUM>, <NUM> mmol), the reaction is carried out at normal temperature for <NUM> hours. Upon completion of the reaction, water and DCM are used for extraction and then brine washing is carried out. After removing water with Na<NUM>SO<NUM>, purification is carried out on silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

After dissolving 9b-amino-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in DCM (<NUM>, <NUM>) and adding benzene sulfonyl chloride (<NUM>, <NUM> mmol), K<NUM>CO<NUM> (<NUM>, <NUM> mmol) and <NUM>-crown-<NUM> (<NUM>, <NUM> mmol) are added and then stirring is carried out at room temperature for <NUM> hours. After diluting the reaction mixture with DCM and washing with water and brine, Na<NUM>SO<NUM> is used to remove water and then concentration under reduced pressure is carried out. Purification is carried out in a silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

After dissolving 9b-chloro-4b-hydroxy-<NUM>, <NUM>-dimethyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in THF (<NUM>, <NUM>) and cooling to -<NUM>, <NUM>-amino pyridine (<NUM>, <NUM> mmol) is added. After adding TEA (<NUM>, <NUM> mmol) at the same temperature, the reaction mixture is allowed to stand for <NUM> hours until it reaches room temperature. Upon completion of the reaction, concentration under reduced pressure is carried out. After the concentrated reaction mixture is diluted with ethyl acetate (<NUM>), and then washed with water and brine; water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Purification is carried out in a silica gel column chromatography (<NUM> - <NUM>%. EtAc in hexane) to obtain the target compound (<NUM>, <NUM>%).

After dissolving 9b-chloro-4b-hydroxy-<NUM>, <NUM>-dimethyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in acetonitrile (ACN) (<NUM>, <NUM>), <NUM>-propane sulfonyl chloride (<NUM>, <NUM> mmol) is added. After pyridine (<NUM>, <NUM> mmol) is added at room temperature, stirring is carried out for <NUM> hours. Upon completion of the reaction, concentration under reduced pressure is carried out. After the concentrated reaction mixture is diluted with ethyl acetate (<NUM>), it is then washed with water and brine. Water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Purification is carried at in a silica gel column chromatography (<NUM>% EA in hexanes) to obtain the target compound (<NUM>, <NUM>%, yellow solid).

After dissolving 9b-chloro-4b-hydroxy-<NUM>, <NUM>-dimethyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in acetonitrile (ACN) (<NUM>, <NUM>) at room temperature and then adding chloromethane sulfonyl chloride (<NUM>, <NUM> mmol), pyridine (<NUM>, <NUM> mmol) is added before stirring is carried out for <NUM> hours. Upon completion of the reaction, concentration under reduced pressure is carried out. After the concentrated reaction mixture is diluted with ethyl acetate (<NUM>), it is then washed with water and brine. Water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Purification is carried at in a silica gel column chromatography (<NUM>% EA in hexanes) to obtain the target compound (<NUM>, <NUM>%, yellow solid).

After dissolving 9b-chloro-4b-hydroxy-<NUM>, <NUM>-dimethyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) in THF (<NUM>, <NUM>) and cooling to -<NUM>, <NUM>-amino thiazoline chloride (<NUM>, <NUM> mmol) is added. TEA (<NUM>, <NUM> mmol) is added at same temperature. Stirring is carried out at room temperature for <NUM> hours. Upon completion of the reaction, concentration under reduced pressure is carried out. After the concentrated reaction mixture is diluted with ethyl acetate (<NUM>), it is then washed with water and brine. Water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Purification is carried at in a silica gel column chromatography (<NUM> : <NUM> =EA: hexanes) to obtain the target compound (<NUM>, <NUM>%).

9b-chloro-4b-hydroxy-<NUM>-isopropyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is dissolved in THF (<NUM>, <NUM>). After adding <NUM>-amino isooxazole (<NUM>, <NUM> mmol) and TEA (<NUM>, <NUM> mmol) at -<NUM>, stirring is carried out at room temperature for <NUM> hours. After concentrating THF and dissolving in DCM, washing is carried out with water and brine. After extracting organic layers, water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Purification is carried out in a silica gel column chromatography to obtain the target compound (<NUM>, <NUM>%).

9b-chloro-4b-hydroxy-<NUM>,<NUM>-dimethyl-4b, 9b-dihydro-<NUM>-indeno [<NUM>, <NUM>-b] benzofuran-<NUM>-one (<NUM>, <NUM> mmol) is dissolved in THF (<NUM>, <NUM>). After adding <NUM>-amino pyridine (<NUM>, <NUM> mmol) at -<NUM>, TEA (<NUM>, <NUM> mmol) is added. The temperature is raised to normal temperature and then stirring is carried out for <NUM> hours. After the reactants are concentrated and diluted with ethyl acetate (<NUM>), washing is carried out with water (<NUM> x <NUM>) and brine (<NUM>). After extracting organic layers, water is removed with Na<NUM>SO<NUM> and then concentration under reduced pressure is carried out. Purification is carried out in a silica gel column chromatography (<NUM>% EA in hexanes) to obtain the target compound (<NUM>, <NUM>%).

In Table <NUM> below are listed chemical structural formulae of the compounds prepared in Examples <NUM> - <NUM> above. Compounds <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>, <NUM>, <NUM>, <NUM>-<NUM> and <NUM>-<NUM> are provided as reference compounds.

In the assay, HeLa (human cervical cancer cells), MRC-<NUM> (human fetal lung fibroblast cells), and RD cells (derived from human rhabdomyosarcoma) were employed. For comparison, ribavirin (Riv), Pleconaril (pleco), and BTA-<NUM> (BTA) were used as controls. Reagents were dissolved at a concentration of <NUM>-<NUM>/ml in <NUM>% dimethyl sulfoxide (DMSO). Water-soluble reagents were dissolved in PBS (-) solution and stored at -<NUM>° C. On the day of the experiment, they were used in <NUM> fold to <NUM> fold concentrations in such a manner that the concentration of dimethyl sulfoxide in each well was between <NUM>% and <NUM>%.

Pharmaceutical efficacy was determined using a virus-induced cytopathic effect (CPE) inhibition assay. In this regard, after cells suitable for viruses were grown in <NUM>-well plates, dilutions of viruses in DME supplemented with <NUM>% FBS (DME/ <NUM>% FBS) or MEM supplemented with <NUM>% FBS (MEM/ <NUM>% FBS) were inoculated in an amount of <NUM>µl with a concentration corresponding to <NUM> CCID50 (<NUM>% cell culture infective dose) into each well of the plates, and incubated for <NUM> - <NUM> hr at <NUM>° C or <NUM>° C to allow the viruses to adsorb onto the cells. The culture medium was removed before aliquots of drug dilutions with various concentrations were added in an amount of <NUM>µl to each well. While HRV (human rhinovirus) was grown at <NUM>° C, the other viruses were incubated in a <NUM>° C CO<NUM> incubator for <NUM>-<NUM> days. Alternatively, the cells were cultured for <NUM>-<NUM> days without removal of the medium after they were added with <NUM>µl of each drug dilution having a <NUM>-fold higher concentration and then with <NUM>µl of the virus dilution.

Test conditions for each virus are summarized in Table <NUM> below:.

For HeLa cells, the drugs were measured for EC<NUM> (<NUM>% maximal effective concentration), which is the concentration of a drug inducing a response halfway between the baseline and maximum, using an MTT assay. With regard to RD and MRC-<NUM> cells, CPE was determined using FDA (Fluorescein diacetate). In order to determine the effect of drug toxicity on efficacy results, at the time of inoculation with the virus, a virus-free medium was added to a cell culture, which was then subjected to the same treatment as the mock-infected cells inoculated with the virus. That is, the medium was removed after one hour of incubation, and dilutions of drugs in the medium were added once more. Following incubation for <NUM>-<NUM> days, the cells were observed under a microscope and the drugs were determined for CC<NUM> (<NUM>% cytotoxic concentration) at which <NUM>% of the cells were killed, using an MTT assay in which counts of viable cells in mock-infected wells containing drugs were compared to those of viable cells in control wells containing no drugs. In an FDA hydrolysis assay, FDA was added to each well after removal of the medium, and incubated for <NUM>-<NUM> before fluorescence intensity was measured using a spectrofluorometer to determine CPE in the same manner as in MTT.

That is, the survival rate (% survival) of mock-infected cells for cytotoxicity measurement was calculated using the Mathematical Formula <NUM> below: <MAT>.

While <NUM>% cell survival means no cytotoxicity of the drug, the highest cytotoxicity is reflected by <NUM>% cell survival. The <NUM>% cytotoxic concentration was defined as the concentration required to reduce the cell number by <NUM>%. This concentration of the drug is represented as CC<NUM>. Higher values mean lower cytotoxicity.

In addition, antiviral effects can be calculated using Mathematical Formula <NUM> below: <MAT>.

If the survival rate is <NUM>%, its antiviral effect is <NUM>% whereas if the survival rate is <NUM>%, its antiviral effect is none. While the concentration of a drug at which the cell in a well infected with a virus can exhibit <NUM>% survival rate is calculated as EC<NUM>, the lower this value is, the more superior the antiviral effect is.

In Table <NUM> below are listed LC<NUM> concentrations that exhibit cytotoxicity against the compounds in some examples and EC<NUM> concentrations that exhibit activities against a number of rhinoviruses belonging to the picornaviruses. Examples <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>, <NUM>, <NUM>, <NUM>-<NUM> and <NUM>-<NUM> are provided as reference examples.

As is indicated in Table <NUM> above, most of the novel compounds according to the present invention exhibit high CC<NUM> concentrations so are found to have low cytotoxicity. In addition, the novel compounds according to the present invention were mostly found to have very high antiviral activities against a number of rhinoviruses (HRV).

Therefore, since the compounds in the example according to the present invention exhibit low cytotoxicity and high antiviral activities against various rhinoviruses, they may be usefully used for a pharmacological composition for preventing or treating diseases caused by the picornaviruses to which they belong.

The multicycle CPE reduction assay was used to conduct determination of drug efficacy against picornaviruses. The antiviral activity of a compound was initially determined by the CPE reduction assay based on MIS [<NUM>-(<NUM>, <NUM>-dimethyl thiazol-<NUM>-yl)-<NUM>-(<NUM>-carboxy methoxy phenyl)-<NUM>-(<NUM>-sulfophenyl)-<NUM>- tetrazolium.

Specifically, cells grown to confluence in <NUM>-well plates were infected with <NUM><NUM>% cell culture infected doses (CCID<NUM>) of virus. After an adsorption period of <NUM> hrs at <NUM>° C, the virus was removed and serial dilutions of the compounds were added. The cultures were further incubated at <NUM>° C for <NUM> days until complete CPE was observed in the infected and untreated virus control (VC). After removal of the medium, <NUM>µl of a culture medium and <NUM>µl of MTS-phenazine methosulfate (Promega, Leiden, The Netherlands) were added to each well. After an incubation period of <NUM> hrs at <NUM>° C, the optical density (OD) of each well was read at <NUM> in a microplate reader.

The % CPE values for evaluating antiviral activity were calculated using Mathematical Formula <NUM> below: <MAT>.

The % CPE value for measuring cytotoxicity of a drug was calculated by Mathematical Formula <NUM> below: <MAT>.

In Mathematical Formulae <NUM> and <NUM> above,.

The effective concentration (EC<NUM>) represents the concentration of a drug at which <NUM>% of cells are allowed to survive by CPE of an induced virus, and the cytotoxicity concentration (CC50) represents the concentration of a drug at which a compound has killed <NUM>% of cells, and they were calculated be the logarithmic interpolation.

In Table <NUM> below are listed the toxicity concentrations (CC<NUM>) and effective concentrations (EC<NUM>) against various viruses for some compounds of the examples. Examples <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>, <NUM>, <NUM>, <NUM>-<NUM> and <NUM>-<NUM> are provided for reference.

As indicated in Table <NUM> above, the novel compounds according to the present invention mostly exhibit high CC<NUM> concentrations and are found to have low cytotoxicity. In addition, it was found that the novel compounds according to the present invention mostly had high antiviral activities against coxsackievirus B1 (Cox B1), coxsackievirus B3 (Cox B3) and poliovirus <NUM> (PV3).

Therefore, since the compounds in the examples according to the present invention have low cytotoxicity and exhibit superior antiviral activities against picornaviruses to which coxsackieviruses, polioviruses and rhinoviruses belong, they can be used effectively for prevention or treatment of the diseases caused by such viruses, for example, respiratory, cardiocirculatory, and nervous system diseases, including poliomyelitis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, flu, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis and otitis media.

The above ingredients are mixed and filled in an airtight sac to prepare as a powder agent.

The above ingredients are mixed and prepared into tablets according to the typical method for preparing tablets.

The above ingredients are mixed and put into gelatin capsules according to the typical method for preparing capsules.

With the sodium chloride BP for injection, an appropriate volume of the compound is dissolved according to the present invention, dilute hydrochloric acid BP is used to adjust the pH of the solution to a pH <NUM>, and sodium chloride BP for injection is used to control a volume prior to sufficient mixing. After the solution is put in a <NUM>-ml type I ampule made of transparent glass, the air is sealed in the upper lattice by melting the glass. Autoclaving and sterilization is carried out at <NUM> for at least <NUM> to prepare an injection.

Claim 1:
A compound of Formula <NUM> or Formula <NUM>, a pharmaceutically acceptable salt thereof or an optical isomer thereof:
<CHM>
<CHM>
wherein
R<NUM> is -H, linear or branched C<NUM>-<NUM> alkyl, or -NO<NUM>;
R<NUM> is -NH<NUM>;
R<NUM> is -H or linear or branched C<NUM>-<NUM> alkyl;
R4a, R4b, R4c and R4d are independently -H or linear or branched C<NUM>-<NUM> alkyl;
X is -O-, -NH-, or -NR<NUM>-, wherein R<NUM> is linear or branched C<NUM>-<NUM> alkyl;
L is a single bond,
<CHM>
wherein R<NUM> is O, NH, or S, and wherein a, b, c, d, and e are independently integers of <NUM>-<NUM>;
R<NUM> is -CN; linear or branched C<NUM>-<NUM> alkyl; linear or branched C<NUM>-<NUM> haloalkyl; phenyl; phenyl linear or branched C<NUM>-<NUM> alkyl; phenyl linear or branched C<NUM>-<NUM> alkenyl; <NUM>-<NUM> atom heteroaryl including one or more heteroatoms of one or more species selected from a group consisting of N, O and S; <NUM>-<NUM> atom heterocycloalkyl including one or more heteroatoms of one or more species selected from a group consisting of N, O and S; <NUM>-<NUM> atom heterocycloalkenyl including one or more heteroatoms of one or more species selected from a group consisting of N, O and S;
<CHM>
or
<CHM>
wherein the phenyl group in the phenyl, phenyl linear or branched C<NUM>-<NUM> alkyl, and phenyl linear or branched C<NUM>-<NUM> alkenyl, may be substituted with one or more substituents of one or more species selected from a group consisting of -OH, halogen, linear or branched C<NUM>-<NUM> alkyl, linear or branched C<NUM>-<NUM> alkoxy, and -NO<NUM>,
wherein the heteroaryl, heterocycloalkyl, and heterocycloalkenyl may be substituted with one or more species selected from a group consisting of -OH, halogen, and linear or branched C<NUM>-<NUM> alkyl;
R<NUM> and R<NUM> are independently -H, linear or branched C<NUM>-<NUM> alkyl, unsubstituted phenyl, or phenyl substituted with one or more linear or branched C<NUM>-<NUM> alkyl,
<CHM>
R<NUM>, R<NUM>, and R<NUM> are independently -H, or linear or branched C<NUM>-<NUM> alkyl,
Z is -O- or -S-, and
f, g, h and i are independently integers of <NUM>-<NUM>.