Patent Description:
Our body's immune system has various defense systems to protect the body against internal stimuli or exterior pathogens. This immune system includes an immunity which increases an immune response, and an immune tolerance which regulates an excessive immune response. These two immune reactions are tightly regulated and maintain a balance of immunity and immune tolerance, which is called an immune homeostasis and is very important in maintaining optimal health.

However, the immune reactions may be dysfunctional due to the various internal or external factors. When the immunity is stronger than an immune tolerance, that is, when there are excessively activated immune cells around, inflammatory disorders or auto-immune diseases may occur. On the other hand, when the immune tolerance is stronger than immunity, that is, when the immune systems do not function properly, a body will get infectious diseases or cancers. Therefore, an ideal immunotherapy would be to enhance the homeostasis of immune system between immunity and immune tolerance and thereby to cure immune-related disorders.

Ulcerative colitis among inflammatory disorders is an inflammatory bowel disease (IBD) caused by genetic factors or excessive immune reactions, resulting in an inflammation or intestinal ulcer in colon. Its common symptoms are diarrhea containing mucus and blood, abdominal pain, weight loss, blood in stool, and the like. In many cases, IBD showed recurrent episodes of remission and induction, and may lead to colon cancer or to other complications. Despite many research in the area of IBD being performed, there is no therapy developed yet to cure the disease completely. Generally anti-inflammatory or adrenocortical hormone is being used in common, and depending on the disease condition of patients, immunosuppressive agents, steroids, antibiotics, or the like is used. There are several surgical treatments available; however, the complications of more problems after the surgery lead to suggest therapeutic treatment.

The autoimmune diseases have overly activated immune system resulting in attacking the host healthy cells and disrupt homeostasis. They include rheumatoid arthritis, Type <NUM> diabetes, inflammatory bowel disease, atopic dermatitis, and the like.

Our body possesses various immune suppressive cells to maintain immune homeostasis through inhibiting the autoimmune diseases or reducing overly activated immune responses, and macrophages among such cells play an important role in innate immunity and are present in many tissues in the body with various phenotypes.

Macrophages can protect our body from the attack of external pathogens through phagocytosis or secreting antimicrobial mediators. In addition, macrophages perform many diverse reactions such as wound healing as well as inflammatory responses. Macrophages can be categorized into two traditional phenotypes, M1 and M2 based on their pathological conditions. Instead of describing macrophage polarization dichotomically with M1 and M2, now it has been known as having diverse phenotypes based on their origins, places, microenvironment, and disease status (<NPL>; <NPL>). Pro-inflammatory macrophages with M1 phenotype are activated by lipopolysaccharides (LPS) or by TNF-a ·and release IL-1β, IL-<NUM>, and TNF-α, and their major metabolic pathway is glycolysis in the cytosol, rather than mitochondrial metabolism. In contrast, the major metabolic pathway of M2-like macrophages is mitochondrial oxidative phosphorylation, and they are activated by IL-<NUM> or IL-<NUM> and play an important role in reducing inflammation and wound healing (<NPL>).

When NAD(P)H quinone oxidoreductase <NUM> (NQO1) enzyme is activated in the body, NAD+ and NAD+/NADH ratio is increased, resulting in the activation of mitochondria, and therefore, the cell metabolism is converted from glycolysis to mitochondrial oxidative phosphorylation. This metabolic reprogramming induces macrophage polarization into anti-inflammatory M2 macrophages resulting in inhibition of expressions and activities of pro-inflammatory cytokines (<NPL>).

A <NUM>,<NUM>-naphthoquinone derivative and method for preparing same are known from <CIT>.

An object of the present invention is to provide a novel benzoindazolone compound, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diasteromer or tautomer thereof, which exhibits treatment effects against inflammatory diseases; and an intermediate thereof.

The inventors have experimentally found that the novel benzoindazolone compound of the present invention is used as a substrate for NQO1 to facilitate a redox reaction of NQO1, and thus, it can be developed as a medicine for preventing or treating inflammatory diseases, by which the present invention has been completed.

Therefore, the first aspect of the present invention relates to a compound represented by the following Chemical Formula <NUM>, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diasteromer or tautomer thereof:
<CHM>
wherein,.

The second aspect of the present invention relates to a compound, which is an intermediate for preparing the compound of Chemical Formula <NUM> as described above, represented by the following Chemical Formula <NUM>:
<CHM>
wherein, R<NUM>, R<NUM>, R<NUM>, R<NUM>, X<NUM>, X<NUM>, X<NUM> and - - - are the same as those defined for Chemical Formula <NUM>, and R<NUM> is a typical protecting group for hydroxyl group which has been well known in the art.

According to the prevent invention, a novel benzoindazolone compound and an intermediate for preparing the same were provided.

Through measurements of the amount of cytochrome C being reduced, it was found that the compound of the present invention was used as an effective substrate for NQO1. A redox reaction of NQO1 facilitated by the compound of the present invention can inhibit the expression and activities of inflammatory cytokines, and thus, the compound of the present invention is expected to be developed as a medicine for preventing or treating inflammatory diseases.

The terms used in the present disclosure are briefly defined herein.

The term "pharmaceutically acceptable salt" means a salt form of a compound which does not cause any serious stimuli in an organism to which the compound is administered, and does not destroy biological activities and physical properties of the compound.

The terms "hydrate", "solvate", "tautomer", "enantiomer" and "diastereomer" also mean forms of a compound which does not cause any serious stimuli in an organism to which the compound is administered, and does not destroy biological activities and physical properties of the compound.

The pharmaceutically acceptable salt includes an acid-adduct salt which is formed by addition of an inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid and the like, or an organic acid, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, fluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

In case that a carboxyl acid group is present in the compound of Chemical Formula <NUM> above, an example of a pharmaceutically acceptable carboxylic acid salt includes a metal salt or an alkaline earth metal salt formed with lithium, sodium, potassium, calcium, magnesium or the like; an amino acid salt formed with lysine, arginine, guanidine or the like; and an organic salt formed with dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, trimethylamine or the like. The compound of Chemical Formula <NUM> according to the present invention may be converted into its salt by a conventional method.

The term "hydrate" means a compound according to the present invention containing a stoichiometric or non-stoichiometric amount of water bound through non-covalent intermolecular forces, or a salt thereof.

The term "solvate" means a compound according to the present invention containing a stoichiometric or non-stoichiometric amount of solvent bound through non-covalent intermolecular forces, or a salt thereof. A solvent for the solvate may be any solvent which is volatile, non-toxic and/or suitable for administration to a human.

The term "tautomer" means a type of structural isomers having an identical chemical or molecular formula, but different coupling between constituent atoms. For example, its structure is converted into each other between both isomers, such as a keto-enol structure.

The term "enantiomer" or "diastereomer" means an isomer which occurs due to different arrangements of atoms in a molecule even having an identical chemical formula or molecular formula. The term "enantiomer" means an isomer which is not superimposed with its mirror image, like a relation between a right hand and a left hand. In addition, the term "diastereomer" means a stereoisomer which is not in a mirror image relation. All isomers and mixtures thereof are also within the scope of the present invention.

The term "alkyl" means an aliphatic hydrocarbon group, which includes "saturated alkyl," and "unsaturated alkyl" containing at least one double bond or triple bond, and includes a linear, branched and cyclic alkyl.

The term "heterocyclyl" means a <NUM>- to <NUM>-membered cyclic group having at least one hetero atom selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S) in the cycle, and the term "heteroaryl" means a <NUM>- to <NUM>-membered aromatic ring at least one hetero atom selected from the group consisting of nitrogen (N), oxygen (O) and sulfur (S) in the ring.

The first aspect of the present invention relates to a compound represented by the following Chemical Formula <NUM>, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diasteromer or tautomer thereof:
<CHM>
wherein,.

In one embodiment of the compound of Chemical Formula <NUM> of the present invention, at least one of R<NUM>, R<NUM> and R<NUM> may be C<NUM>-<NUM> alkoxy, wherein an alkyl consisting of the alkoxy is a linear, branched or cyclic alkyl.

In another embodiment of the compound of Chemical Formula <NUM> of the present invention, at least one of bonds between R<NUM> and X<NUM>, R<NUM> and X<NUM>, and R<NUM> and X<NUM> may be C=O.

In still another embodiment of the compound of Chemical Formula <NUM> of the present invention, at least two of - - - may be double bond.

In still another embodiment of the compound of Chemical Formula <NUM> of the present invention, X<NUM> and X<NUM> may be C, and X<NUM> and X<NUM> may be N. Herein, R<NUM> may be C<NUM>-<NUM> alkoxy, or the bond between R<NUM> and X<NUM> may be C=O.

In still another embodiment of the compound of Chemical Formula <NUM> of the present invention, X<NUM> and X<NUM> may be C, and X<NUM> and X<NUM> may be N. Herein, R<NUM> may be C<NUM>-<NUM> alkyl-substituted or unsubstituted aryl.

In the compound of Chemical Formula <NUM>, the halo is any of fluoro, chloro, bromo and iodo.

The compound of Chemical Formula <NUM> according to the present invention includes the following Compounds <NUM> to <NUM>:.

The second aspect of the present invention relates to a compound, which is an intermediate for preparing the compound of Chemical Formula <NUM> as described above, represented by the following Chemical Formula <NUM>:
<CHM>
wherein, R<NUM>, R<NUM>, R<NUM>, R<NUM>, X<NUM>, X<NUM>, X<NUM> and - - - are the same as those defined for Chemical Formula <NUM>, and R<NUM> is a typical protecting group for hydroxyl group which has been well known in the art. Examples of the protecting group include C<NUM>-<NUM> alkyl; C<NUM>-<NUM> aryl-substituted C<NUM>-<NUM> alkyl, such as benzyl, trityl, methoxybenzyl and the like; C<NUM>-<NUM> alkoxy-substituted C<NUM>-<NUM> alkyl, such as methoxymethyl, methoxyethoxymethyl and the like; <NUM>- to <NUM>-membered heterocyclyl containing at least one hetero atom, such as tetrahydropyranyl, tetrahydrofuranyl and the like; C<NUM>-<NUM> alkyl-substituted silyl, such as trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and the like; C<NUM>-<NUM> alkyl carbonyl, such as acetyl, pivaloyl and the like, but not limited thereto.

The compound of Chemical Formula <NUM> may be selected from the group consisting of the following:.

The third aspect of the present description relates to a pharmaceutical composition comprising as an active ingredient the compound of Chemical Formula <NUM>, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diastereomer or tautomer thereof.

The pharmaceutical composition may further comprise at least one component selected from the group consisting of a carrier, an excipient and a diluent, which have been well known in the art.

The compound of Chemical Formula <NUM> according to the present invention is used as a substrate for NQO1, by which it can inhibit expressions and activities of inflammatory cytokines, and thus, it can be used for prevention or treatment of diseases which relate to NQO1 activities.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the examples are provided only for illustration of the present invention, and should not be construed as limiting the scope of the present invention.

Benzaldehyde (282mmol) and dimethyl succinate (<NUM>. 2mmol) were put into a round bottom flask, and dissolved in methanol (<NUM>). When the reactants were well dissolved, <NUM>% Sodium methoxide solution (<NUM>. 6mmol) was slowly added, and reaction mixture was stirred under reflux for <NUM> hours. The reaction mixture was acidified with <NUM> HCl to pH <NUM>, transferred to a separatory funnel, and then extracted three times with dichloromethane. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure to give crude product. The crude product was dissolved in THF (<NUM>), to which trifluoroacetic anhydride (282mmol) was slowly added, and the reaction mixture was stirred under reflux until the completion of the reaction was observed. After confirming the completion of the reaction with TLC, the reaction mixture was cooled to room temperature, moved into an ice bath, and then neutralized to pH <NUM>-<NUM> with slow addition of sat. NaHCO<NUM> solution. When neutralization was completed, the reaction mixture was extracted three times with ethyl acetate, and combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was recrystallized with ethyl acetate and n-hexane, and mother liquor was purified by column chromatography.

Methyl <NUM>-hydroxy-<NUM>-naphthoate (<NUM>. 54mmol) and K<NUM>CO<NUM> (<NUM>. 08mmol) were put into a round bottom flask and dissolved in anhydrous DMF (<NUM>). Methyl iodide (<NUM>. 54mmol) was added and then the reaction mixture was stirred at room temperature for <NUM> hours. The reaction mixture was transferred to a separatory funnel, to which water was added, and then extracted three times with dichloromethane. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was used for the next step without further purification.

Methyl-<NUM>-hydroxy-<NUM>-naphthoate (<NUM>. 7mmol) was put into a round bottom flask and dissolved in acetonitrile (<NUM>), to which N-bromosuccinimide (<NUM>. 7mmol) was added portion-wise over <NUM> minutes. The reaction mixture was stirred for <NUM> hours. The solvent was removed under reduced pressure. The crude mixture was dissolved in ethyl acetate, transferred to a separatory funnel, and then washed with saturated aq. NaHCO<NUM> solution twice. Organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was recrystallized with ethyl acetate and n-hexane, and mother liquor was purified by column chromatography.

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

Methyl <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoate (<NUM>. 8mmol, <NUM>) was put into a round bottom flask and dissolved in THF, methanol and water (<NUM>:<NUM>:<NUM> v/v). When sufficiently dissolved, KOH (<NUM>. 4mmol) was added, and then the reaction mixture was stirred under reflux for <NUM> hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and then acidified with <NUM> HCl to pH <NUM>. The mixture was extracted four times with ethyl acetate, and combined organic layer was dried over MgSO<NUM>. The solvent was removed under reduced pressure. The crude product was recrystallized from dichloromethane.

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

<NUM>-Bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 2mmol, Intermediate <NUM>) and phenyl hydrazine hydrochloride (<NUM>. 64mmol) were put into a round bottom flask and dissolved in dichloromethane (<NUM>). To the reaction mixture, triethylamine (<NUM>. 3mmol) was added. When it is observed that the color of the reaction solution becomes transparent after stirring at room temperature for <NUM> minutes, bis(<NUM>-oxo-<NUM>-oxazolidinyl)phosphinic chloride (<NUM>. 64mmol) was added. The reaction mixture was stirred at room temperature for <NUM> hours. The reaction was quenched with addition of sat. NaHCO<NUM> solution, and the reaction mixture was transferred to a separatory funnel and extracted three times with dichloromethane. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was recrystallized with ethyl acetate and n-hexane.

<NUM>-Bromo-<NUM>-methoxy-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 4mmol), CuI (<NUM> mol%), <NUM>,<NUM>-phenanthroline (<NUM> mol%) and Cs<NUM>CO<NUM> (<NUM>. 1mml) were put into a round bottom flask, and stirred with slow addition of anhydrous DMSO (<NUM>). After then, the reaction mixture was stirred at room temperature for <NUM> hours. The reaction was quenched by addition of <NUM> HCl (<NUM>), water was added to the reaction mixture, and precipitate was filtered. Filter cake was dried and recrystallized from methanol.

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

Using <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 6mmol, Intermediate <NUM>) and tert-butyl <NUM>-(isopropyl)carbazate (<NUM>. 9mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

Using tert-butyl <NUM>-(<NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoyl)-<NUM>-isopropylhydrazinecarboxylate (<NUM>. 4mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>).

tert-Butyl <NUM>-isopropyl-<NUM>-methoxy-<NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>H-benzo[g]indazole-<NUM>-carboxylate (<NUM>. 1mmol) was put into a round bottom flask and dissolved in anhydrous dichloromethane. Trifluoroacetic acid (<NUM> mmol) was carefully added and the reaction mixture was then reacted at room temperature for <NUM> hours. The reaction mixture was neutralized with slow addition of sat. NaHCO<NUM> solution, and then water was added. The reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was purified by column chromatography.

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

tert-Butyl <NUM>-(isopropyl)carbazate (10mmol), CuI (<NUM> mol%), <NUM>,<NUM>-phenanthroline (<NUM> mol%) and Cs<NUM>CO<NUM> (12mmol) were put into a round bottom flask and dissolved with slow addition of anhydrous DMF (<NUM>). Iodobenzene (12mmol) was added, and the reaction mixture was then stirred at <NUM> for <NUM> hours. The reaction was quenched with addition of water, and the reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was purified by column chromatography.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

tert-Butyl <NUM>-isopropyl-<NUM>-phenylhydrazinecarboxylate (<NUM>. 998mmol) was put into a round bottom flask and dissolved in anhydrous dichloromethane (<NUM>). Trifluoroacetic acid (<NUM>. 94mmol) was added at room temperature, and the reaction mixture was reacted with stirring for <NUM> hours. The reaction mixture was neutralized with slow addition of sat. NaHCO<NUM> solution, transferred to a separatory funnel and then extracted three times with dichloromethane. Combined organic layer was washed with brine. To the resulting yellow solution, <NUM> HCl in <NUM>,<NUM>-dioxane (<NUM> mmol) was slowly added by syringe and stirred for <NUM> minutes, and then concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate.

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

<NUM>-Bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 59mmol, Intermediate <NUM>) was put into a round bottom flask and suspended in anhydrous toluene (<NUM>). To the reaction mixture, trimethylamine (<NUM>. 75mmol) was added and stirred for <NUM> minutes. After then, diphenyl phosphoryl azide (<NUM>. 45mmol) was added, followed by t-BuOH (<NUM>. 13mmol) was added. The reaction mixture was stirred at <NUM> for <NUM> hours. The reaction was quenched by addition of water, and the reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was purified by column chromatography.

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

tert-Butyl (<NUM>-bromo-<NUM>-methoxynaphthalen-<NUM>-yl)carbamate (<NUM>. 33mmol) was put into a round bottom flask and dissolved in anhydrous diethyl ether (<NUM>). After the reaction mixture was cooled to - <NUM>, <NUM> n-butyl lithium solution was slowly added dropwise by syringe. After stirring for <NUM> hours, ethyl chloroformate (<NUM>. 33mmol) was slowly added dropwise by syringe, and the reaction mixture was stirred for additional <NUM> hours. The reaction was quenched with slow addition of sat. NH<NUM>Cl solution, and water was poured into the reaction mixture. The reaction mixture was transferred to a separatory funnel and extracted three times with ethyl acetate. Combined organic layer was washed with brine and dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was purified by column chromatography.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Ethyl <NUM>-(tert-butoxycarbonylamino)-<NUM>-methoxy-<NUM>-naphthoate (<NUM>. 93mmol) was put into a round bottom flask and dissolved in anhydrous dichloromethane (<NUM>). Trifluoroacetic acid (<NUM>. 5mmol) was added, and the reaction mixture was stirred at room temperature for <NUM> hours. The reaction mixture was neutralized with sat. NaHCO<NUM> solution and water was added. The reaction mixture was transferred to a separatory funnel and extracted three times with dichloromethane. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was purified by column chromatography.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Ethyl <NUM>-amino-<NUM>-methoxy-<NUM>-naphthoate (<NUM>. 02mmol) was put into a round bottom flask and dissolved in acetic acid (<NUM>). <NUM>% Hydrobromic acid (<NUM>) was added, and the reaction mixture was moved into an ice bath to lower the temperature to <NUM>, to which sodium nitrite (<NUM>. 02mmol) in <NUM> of H<NUM>O was slowly added dropwise over <NUM> minutes by syringe, and then stirred for <NUM> hours. After <NUM> hours, CuBr (<NUM>. 02mmol) in <NUM> of <NUM>% Hydrobromic acid solution was slowly added by pipette, and stirred for additional <NUM> hours while slowly raising the temperature to room temperature. The reaction was quenched with addition of water, and the reaction mixture was transferred to a separatory funnel and extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM> and concentrated under reduced pressure. The crude product was purified by column chromatography.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Ethyl <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoate (<NUM>. 57mmol) and LiOH (<NUM>. 38mmol) were put into a round bottom flask and dissolved in THF, methanol and water (<NUM>:<NUM>:<NUM> v/v). After raising the temperature to <NUM>, the reaction mixture was stirred under reflux for <NUM> hours. The reaction mixture was transferred to a separatory funnel and acidified with <NUM> HCl to pH <NUM>-<NUM>. The mixture was extracted three times with ethyl acetate, and combined organic layer was washed with water and brine in order, and dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was recrystallized with ethyl acetate and n-hexane.

Pale-Yellowish white solid, Yield: <NUM>%.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>-Bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 60mmol) was put into a round bottom flask and dissolved in catalytic amount of DMF and anhydrous dichloromethane (<NUM>). After slowly adding oxalyl chloride (<NUM>. 21mmol) dropwise by syringe, reacted with stirring at room temperature for <NUM> hours. After <NUM> hours, residual oxalyl chloride and dichloromethane were removed under reduced pressure. After drying the reaction mixture in vacuo for <NUM> minutes, residue was dissolved in anhydrous dichloromethane (<NUM>), and then phenyl hydrazine (<NUM>. 33mmol) and pyridine were slowly added by syringe. The reaction mixture was stirred at room temperature for <NUM> hours. The reaction was quenched with <NUM> HCl, and the reaction mixture was transferred to a separatory funnel and then extracted three times with dichloromethane. Combined organic layer was washed with brine and dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was purified by column chromatography.

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

Using the previously prepared <NUM>-bromo-<NUM>-methoxy-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 42mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

Benzyl carbazate (<NUM>. 1mmol) was put into a round bottom flask and dissolved in acetone (18mmol) and diethyl ether (<NUM>). The reaction mixture was stirred for <NUM> hours. Concentration was conducted under reduced pressure to obtain white solid, to which NaBH<NUM>CN (18mmol) was added, followed by methanol (<NUM>) and acetic acid (<NUM>) were added, and then stirred at room temperature for <NUM> hours. After completion of the reaction, methanol was removed under reduced pressure, and residue was dissolved in ethyl acetate, washed with <NUM>% aq. NaHCO<NUM> solution and brine, and dried over MgSO<NUM>. After filtering under reduced pressure, filtrate was concentrated under reduced pressure, and resulting product was used for the next step without further purification.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (d, J = <NUM>, <NUM>).

Benzyl <NUM>-isopropylhydrazinecarboxylate (<NUM>. 7mmol) and <NUM>-dimethylaminopyridine (<NUM> mol%) were put into a round bottom flask and dissolved in acetonitrile (<NUM>). To the reaction mixture was slowly added di-tert-butyl dicarbonate (BoC<NUM>O, <NUM>. 3mmol) dropwise by syringe, and stirred at room temperature for <NUM> hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give a yellowish oil mixture and used for the next step without further purification.

<NUM>-Benzyl <NUM>-tert-butyl <NUM>-isopropylhydrazine-<NUM>,<NUM>-dicarboxylate (<NUM>. 3mmol) and 10wt% Pd on carbon were put into a round bottom flask and dissolved in methanol (<NUM>). The reaction mixture was replaced under reduced pressure with hydrogen gas <NUM> times, and stirred for <NUM> hours under a hydrogen balloon. The reaction mixture was filtered through Celite pad and filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (d, J = <NUM>, <NUM>).

Using <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 38mmol) and tert-butyl <NUM>-isopropylhydrazinecarboxylate (<NUM>. 5mmol, Intermediate <NUM>) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

tert-Butyl <NUM>-(<NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoyl)-<NUM>-isopropylhydrazinecarboxylate (<NUM>. 56mmol) was put into a round bottom flask and dissolved in dichloromethane (<NUM>). Trifluoroacetic acid (<NUM>. 14mmol) was added, and the reaction mixture was stirred at room temperature for <NUM> hours. When the reaction was completed, the reaction mixture was neutralized with sat. NaHCO<NUM> solution, transferred to a separatory funnel and then extracted with dichloromethane. Combined organic layer was washed with brine and dried over MgSO<NUM>. After filtering under reduced pressure, filtrate was concentrated under reduced pressure. The resulting product was used for the next step without further purification.

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

Using the previously prepared <NUM>-bromo-N'-isopropyl-<NUM>-methoxy-<NUM>-naphthohydrazide as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

Using <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 01mmol, Intermediate <NUM>) and (<NUM>-(trifluoromethyl)phenyl)hydrazine (<NUM>. 3mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-bromo-<NUM>-methoxy-N'-(<NUM>-(trifluoromethyl)phenyl)-<NUM>-naphthohydrazide as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

Using <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 0mmol, Intermediate <NUM>) and (<NUM>-fluorophenyl)hydrazine hydrochloride (<NUM>. 2mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-bromo-N'-(<NUM>-fluorophenyl)-<NUM>-methoxy-<NUM>-naphthohydrazide as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

Using the previously prepared <NUM>-bromo-<NUM>-methxy-<NUM>-naphthoic acid (<NUM>. 0mmol, Intermediate <NUM>) and <NUM>-Boc-<NUM>-phenylhydrazine (<NUM>. 6mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM> and resulting white solid was used for next step without further purification.

Using the previously prepared tert-butyl <NUM>-(<NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoyl)-<NUM>-phenylhydrazinecarboxylate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared tert-butyl <NUM>-methoxy-<NUM>-oxo-<NUM>-phenyl-<NUM>,<NUM>-dihydro-<NUM>H-benzo[g]indazole-<NUM>-carboxylate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

Using <NUM>-fluorobenzaldehyde (<NUM>. 3mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared methyl <NUM>-fluoro-<NUM>-hydroxy-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM> and resulting compound was used for next step without further purification.

Using the previously prepared methyl <NUM>-fluoro-<NUM>-methoxy-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared methyl <NUM>-bromo-<NUM>-fluoro-<NUM>-methoxy-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using <NUM>-bromo-<NUM>-fluoro-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 34mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-bromo-<NUM>-fluoro-<NUM>-methoxy-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 3mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

Using <NUM>-nitrobenzaldehyde (150mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared methyl <NUM>-hydroxy-<NUM>-nitro-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>, as a yellow solid, which was used the next step without further purification.

Using the previously prepared methyl <NUM>-methoxy-<NUM>-nitro-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

Using the previously prepared methyl <NUM>-bromo-<NUM>-methoxy-<NUM>-nitro-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using <NUM>-bromo-<NUM>-methoxy-<NUM>-nitro-<NUM>-naphthoic acid (<NUM>. 14mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-bromo-<NUM>-methoxy-<NUM>-nitro-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 4mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using <NUM>-bromobenzaldehyde (150mmol) and diethyl succinate (165mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

Pale-brown solid, Yield: overall <NUM>%.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Using the previously prepared ethyl <NUM>-bromo-<NUM>-hydroxy-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM> and used for next step without further purification.

Using the previously prepared ethyl <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Using the previously prepared ethyl-<NUM>,<NUM>-dibromo-<NUM>-methoxy-<NUM>-naphthoate as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using <NUM>,<NUM>-dibromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 39mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>,<NUM>-dibromo-<NUM>-methoxy-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 1mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

Methyl <NUM>-hydroxy-<NUM>-naphthoate (<NUM> mmol) was dissolved in DMF (<NUM>), and K<NUM>CO<NUM> (<NUM> mmol) and benzyl bromide (<NUM> mmol) were added at room temperature. After stirring for <NUM> hours, the reaction was quenched by adding water. The resulting mixture was extracted with ethyl acetate, and separated organic layer was washed with brine and dried over MgSO<NUM>. Obtained crude product was used for the next step without further purification.

Methyl <NUM>-(benzyloxy)-<NUM>-naphthoate (<NUM> mmol) was dissolved in acetonitrile (<NUM>). N-Bromosuccinimide (<NUM> mmol) was then added in one-portion, and the reaction mixture was stirred at room temperature for <NUM> days. When the reaction was completed, solvent was removed under reduced pressure, and purification was conducted by column chromatography.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Methyl <NUM>-(benzyloxy)-<NUM>-bromo-<NUM>-naphthoate (<NUM> mmol) was dissolved in a mixture of THF (<NUM>), methanol (<NUM>) and water (<NUM>). NaOH (<NUM> mmol) was then added, and the reaction mixture was stirred at room temperature for <NUM> day. When the reaction was completed, organic solvent was removed under reduced pressure, and water was added and then conc. HCl was added so as to lower pH. Aqueous layer was extracted with ethyl acetate and dried over MgSO<NUM>. Obtained compound was recrystallized with dichloromethane.

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

<NUM>-(Benzyloxy)-<NUM>-bromo-<NUM>-naphthoic acid (<NUM> mmol, Intermediate <NUM>) was dissolved in dichloromethane (<NUM>) and <NUM> drops of DMF was added. Oxalyl chloride (<NUM>. 9mmol) was added at room temperature under argon atmosphere, and reacted for <NUM> hours. After the reaction was completed, the solvent was removed under reduced pressure, the resulting acid chloride intermediate was dissolved in dichloromethane (<NUM>), to which a mixture of phenyl hydrazine (<NUM>. 7mmol), pyridine (<NUM>. 9mmol) and dichloromethane (<NUM>) was added. After reacting at room temperature for <NUM> hours, the reaction was quenched by adding water. Aqueous layer was extracted with dichloromethane, and organic layer was dried over MgSO<NUM>. Resulting compound was recrystallized with ethyl acetate and hexane.

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

<NUM>-(Benzyloxy)-<NUM>-bromo-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 2mmol), CuI (<NUM>. 12mmol), L-proline (<NUM>. 24mmol) and K<NUM>CO<NUM> (<NUM>. 4mmol) were put into a round bottom flask and dissolved in DMSO (<NUM>). The reaction mixture was stirred at room temperature for <NUM> hours, and the reaction was quenched by adding water. The resulting mixture was neutralized with conc. HCl and extracted with ethyl acetate. Organic layer was dried over MgSO<NUM>. The crude product was purified by column chromatography.

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

<NUM>-Methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 75mmol, Intermediate <NUM>) was put into a round bottom flask and suspended in dichloromethane (<NUM>), to which <NUM> BBr<NUM> in CH<NUM>Cl<NUM> (<NUM>. 88mmol) was slowly added. After reacting for <NUM> hours, water was slowly added to quench the reaction. The reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was washed with brine and dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was purified by column chromatography.

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

<NUM>-Hydroxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>)-one (<NUM>. 38mmol) was put into a round bottom flask and dissolved in DMF (<NUM>). IBX (<NUM> mmol) was added in one-portion, and the reaction mixture was stirred for <NUM> hours. When the reaction was completed, the reaction was quenched with sat. NaHCO<NUM>. The reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was purified by column chromatography.

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

<NUM>-Phenyl-<NUM>H-benzo[g]indazol-<NUM>,<NUM>,<NUM>(<NUM>H)-trione (<NUM>. 27mmol, Compound <NUM>) and K<NUM>CO<NUM> (<NUM>. 80mmol) were put into a round bottom flask and dissolved in anhydrous DMSO (<NUM>). <NUM>-Bromopropane (<NUM>. 48mmol) was added, and the reaction mixture was stirred at <NUM> for <NUM> hours. After confirming the completion of the reaction with TLC, the reaction was quenched by adding water. The reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was purified by column chromatography.

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

<NUM>-Isopropyl-<NUM>-methoxy-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 90mmol, Intermediate <NUM>) and K<NUM>CO<NUM> (<NUM>. 80mmol) were put into a round bottom flask and dissolved in anhydrous DMSO (<NUM>). When reactants were well dissolved, iodomethane (<NUM>. 80mmol) was added, and the resulting mixture was stirred at room temperature for <NUM> hours. The reaction was quenched with addition of water, and the reaction mixture was transferred to a separatory funnel and then extracted three times with ethyl acetate. Combined organic layer was dried over MgSO<NUM>. After concentrated under reduced pressure, the crude product was purified by column chromatography.

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

Using the previously prepared <NUM>-isopropyl-<NUM>-methoxy-<NUM>-methyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 64mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-hydroxy-<NUM>-isopropyl-<NUM>-methyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 63mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using <NUM>-isopropyl-<NUM>-methoxy-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 90mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-isopropyl-<NUM>,<NUM>-dimethoxy-<NUM>H-benzo[g]indazole (<NUM>. 28mmol, <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-isopropyl-<NUM>-methoxy-<NUM>H-benzo[g]indazol-<NUM>-ol (<NUM>. 25mmol, <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using <NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 41mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-hydroxy-<NUM>-methyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using Intermediate <NUM> as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>,<NUM>-dimethoxy-<NUM>-phenyl-<NUM>-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using <NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>-benzo[g]indazol-<NUM>(<NUM>)-one (<NUM>. 09mmol, Intermediate <NUM>) and iodoethane (<NUM>. 43mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-methoxy-<NUM>-ethyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Using the previously prepared <NUM>-hydroxy-<NUM>-ethyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Using the previously prepared <NUM>-ethoxy-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Using the previously prepared <NUM>-ethoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

Using <NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>-benzo[g]indazol-<NUM>(<NUM>)-one (<NUM>. 00mmol, Intermediate <NUM>) and <NUM>-iodo-<NUM>-methylpropane (<NUM>. 01mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-isobutyl-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-hydroxy-<NUM>-isobutyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-isobutoxy-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-isobutoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using <NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>-benzo[g]indazol-<NUM>(<NUM>)-one (<NUM>. 0mmol, Intermediate <NUM>) and <NUM>-iodo-<NUM>-methylbutane (<NUM>. 01mmol) as a starting material and a reactant, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-isopentyl-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-hydroxy-<NUM>-isopentyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Using the previously prepared <NUM>-(isopentyloxy)-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-(isopentyloxy)-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using <NUM>-bromo-<NUM>-methoxy-<NUM>-naphthoic acid (<NUM>. 70mmol, Intermediate <NUM>) and <NUM>-isopropyl-<NUM>-phenylhydrazine hydrochloride (<NUM>. 75mmol, Intermediate <NUM>) as a starting material and a reactant in a dried round bottom flask under argon atmosphere, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>).

Using the previously prepared <NUM>-bromo-N-isopropyl-<NUM>-methoxy-N'-phenyl-<NUM>-naphthohydrazide (<NUM>. 16mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Preparation Example <NUM>.

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

Using the previously prepared <NUM>-isopropyl-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-hydroxy-<NUM>-isopropyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>)-one (<NUM>. 52mmol) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

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

Using the previously prepared <NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>,<NUM>-dihydro-<NUM>H-benzo[e]indazol-<NUM>-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-hydroxy-<NUM>-methyl-<NUM>-phenyl-<NUM>,<NUM>-dihydro-<NUM>H-benzo[e]indazol-<NUM>-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>,<NUM>-dimethoxy-<NUM>-phenyl-<NUM>H-benzo[e]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>. The resulting pale-yellow product was used for the next step without column chromatography purification.

Using the previously prepared <NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[e]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using <NUM>-isopropyl-<NUM>-methoxy-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 00mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-isopropyl-<NUM>-methoxy-<NUM>-methyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-hydroxy-<NUM>-isopropyl-<NUM>-methyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

Using the previously prepared <NUM>-isopropyl-<NUM>,<NUM>-dimethoxy-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-isopropyl-<NUM>-methoxy-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>,<NUM>-dimethoxy-<NUM>-(<NUM>-(trifluoromethyl)phenyl)-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethyl)phenyl)-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-(<NUM>-fluorophenyl)-<NUM>,<NUM>-dimethoxy-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-(<NUM>-fluorophenyl)-<NUM>-methoxy-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using <NUM>-fluoro-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one (<NUM>. 5mmol, Intermediate <NUM>) as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-fluoro-<NUM>-methoxy-<NUM>-methyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-fluoro-<NUM>-hydroxy-<NUM>-methyl-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>(<NUM>H)-one as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-fluoro-<NUM>,<NUM>-dimethoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-fluoro-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>,<NUM>-dimethoxy-<NUM>-nitro-<NUM>-phenyl-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-methoxy-<NUM>-nitro-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

<NUM>-Methoxy-<NUM>-nitro-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>,<NUM>-dione (<NUM>. 29mmol, Compound <NUM>) was put into a round bottom flask and replaced under reduced pressure with hydrogen gas, to which <NUM>% Pd/C (<NUM> wt%) was added, and then methanol (<NUM>) and dichloromethane (<NUM>) were added to dissolve the reaction mixture. After reacting under a hydrogen atmosphere for <NUM> hours, the reaction mixture was filtered through Celite pad, and filtrate was concentrated under reduced pressure. The crude product was recrystallized with ethyl acetate to yield the title compound.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ: <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM> (s, <NUM>).

Using the previously prepared <NUM>-bromo-<NUM>,<NUM>-dimethoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazole as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

Using the previously prepared <NUM>-bromo-<NUM>-methoxy-<NUM>-phenyl-<NUM>H-benzo[g]indazol-<NUM>-ol as a starting material, the title compound was synthesized according to the procedure described in (<NUM>) of Example <NUM>.

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

In order to evaluate the activity of synthesized compound in NQO1, the experiments were conducted as follows:.

The results are shown in Tables <NUM> to <NUM>.

Claim 1:
A compound represented by the following Chemical Formula <NUM>, or a pharmaceutically acceptable salt, hydrate, solvate, enantiomer, diasteromer or tautomer thereof:
<CHM>
wherein,
R<NUM> is selected from the group consisting of H, C<NUM>-<NUM> alkyl, C<NUM>-<NUM> alkoxy, substituted or unsubstituted C<NUM>-<NUM> aryl, substituted or unsubstituted heteroaryl, halo, cyano, nitro and NR<NUM>R<NUM>;
R<NUM> and R<NUM> are each independently not present, or selected from the group consisting of H, O, C<NUM>-<NUM> alkyl, substituted or unsubstituted C<NUM>-<NUM> aryl and C<NUM>-<NUM> alkoxy; and R<NUM> is selected from the group consisting of O, unsubstituted C<NUM>-<NUM> aryl and C<NUM>-<NUM> alkoxy, wherein at least one of R<NUM> and R<NUM> are O or C<NUM>-<NUM> alkoxy;
R<NUM> and R<NUM> are each independently H, C<NUM>-<NUM> alkyl or C<NUM>-<NUM> alkyl carbonyl, or R<NUM> and R<NUM> may be joined together to form a heterocyclyl containing at least one nitrogen atom in ring structure;
X<NUM>, X<NUM>, X<NUM> and X<NUM> are each independently selected from C and N, wherein two of X<NUM>, X<NUM>, X<NUM> and X<NUM> are N, provided that X<NUM> and X<NUM> cannot simultaneously be N, and X<NUM> and X<NUM> cannot simultaneously be N;
- - - is a single bond or a double bond depending on R<NUM>, R<NUM>, R<NUM>, X<NUM>, X<NUM>, X<NUM> and X<NUM>;
wherein the alkyl is a linear, branched or cyclic alkyl, the heteroaryl is a <NUM>- to <NUM>-membered aromatic ring containing at least one hetero atom selected from the group consisting of N, O and S in the ring, wherein when the aryl or heteroaryl is substituted, a substituent thereof is C<NUM>-<NUM> alkyl, halo, or C<NUM>-<NUM> alkyl substituted with <NUM> to <NUM> halos.