KR101627602B1 - 2-Methyl-2H-chromene-2-carboxamide compounds - Google Patents

Abstract

The present invention relates to the use of a 2-methyl-2 H -chromene-2-carboxamide compound and a selective inhibitory activity of the compound on 11? -HSD1 enzyme to prevent, control and prevent diseases associated with the regulation of sugar corticoid Medicinal uses for use as therapeutic agents.

The 2-methyl-2 H -chromene-2-carboxamide compound of the present invention is useful as a medicament for the treatment of diseases associated with the regulation of glucocorticoids involving human-derived 11? -HSD1 enzymes such as type 1 and type 2 diabetes, Prevention of metabolic syndrome diseases such as adult type latent autoimmune diabetes (LADA), insulin resistance, obesity, IGT, fasting glucose deficiency (IFG), impaired glucose tolerance, dyslipidemia, arteriosclerosis and hypertension , ≪ / RTI >

2-methyl-2H-chromene-2-carboxamide compound, sugar corticoid, 11? -HSD1, 11? -HSD2, diabetes, obesity, metabolic syndrome

Description

2-methyl-2H-chromene-2-carboxamide compounds <

The present invention relates to the use of a 2-methyl-2H - chromene-2-carboxamide compound and a selective inhibitory activity of the compound on the 11? -HSD1 enzyme to prevent, control and prevent diseases associated with the regulation of sugar corticoid Medicinal uses for use as therapeutic agents.

Glucocorticoid (cortisol in humans) plays an important role in glucose homeostasis, lipid and protein metabolism in the body. In particular, excessive sugar corticosteroids in liver and adipose tissue cause metabolic syndrome such as insulin resistance, visceral obesity, hypertension and dyslipidemia.

11β-hydroxysteroid dehydrogenase (11β-HSD) is known to be two types of isozymes, type 1 and type 2, 11β-hydroxysteroid dehydrogenase. The first type, llbeta-HSD1, is an NADPH-dependent reductase, an important enzyme that converts the inactive corticoid cortisone to the active corticoid cortisol in liver, fat and brain tissue, 11 [beta] -HSD2 shows opposite activity to 11 [beta] -HSDl and is mainly expressed in the kidney.

In a transgenic mouse experiment in which 11β-HSD1 was overexpressed, it was reported that cortisol levels were normal in blood, but cortisol levels were increased in adipocytes, resulting in insulin resistance, visceral fat obesity, hyperlipidemia and hypertension. And the rate of increase in body weight is high. [Masuzaki H. Science 2001 , 294 , 2166-2170; Masuzaki H. J. Clin. Invest. 2003 , 112 , 83-90] Furthermore, 11β-HSD1 knockout mice have been reported to exhibit improved glucose tolerance, lowered triglycerides in blood, and elevated HDL-cholesterol. [Morton NM J. Biol. Chem. 2001 , 276 , 41293-41300]

Carbenoxolone (CBX), a non-selective inhibitor of 11β-HSD, improves insulin sensitivity in healthy volunteers and type 2 diabetics. [Andrew, RC J. Clin. Endocrionl. Metab. 2003 , 88 , 285-291). However, it has been reported that CBX can induce hypokalemia and hypertension due to nonselective inhibition of 11? -HSD1 and 11? -HSD2, and its development as a therapeutic agent is limited. [Kotelevtsev, Y. J. Clin. Invest. 1999, 103, 683-689;

Thus, a selective inhibitor of effective ll [beta] -HSDl activity inhibits the conversion to active glucocorticoids in tissues, thereby inhibiting the action of glucocorticoids, resulting in the formation of type 2 diabetes mellitus, obesity, non-insulin dependent diabetes mellitus , Hyperlipidemia, hypertension, and glucose tolerance.

The present inventors have found that obesity and effectively for the purpose of control and treatment of the metabolic syndrome, diabetes, diseases of the result of search of a compound having a selective inhibitory activity for 11β-HSD1 enzyme, a novel 2-methyl -2 H-chromen- 2-carboxamide compound was synthesized, and these novel compounds showed selective inhibitory activity of 11? -HSD1 enzyme, thereby completing the present invention.

It is an object of the present invention to provide a 2-methyl- 2H -chromene-2-carboxamide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a racemate thereof, or a stereoisomer thereof .

Another object of the present invention is to provide a pharmaceutical composition comprising the 2-methyl- 2H -chromene-2-carboxamide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a racemate thereof or a stereoisomer thereof And a pharmaceutical composition for inhibiting human-derived 11? -HSD1 enzyme.

It is a further object of the present invention to provide a method for the treatment of diseases associated with the modulation of glucocorticoids involving human-derived 1? -HSD1 enzymes, such as type 1 and type 2 diabetes, late diabetes complications, adult latent autoimmune diabetes mellitus (LADA) The present invention provides a preventive, regulatory, and therapeutic agent for metabolic syndrome diseases such as obesity, impaired glucose tolerance (IGT), fasting glucose tolerance (IFG), impaired glucose tolerance, dyslipidemia, arteriosclerosis and hypertension.

In order to achieve the above object, the present invention provides a 2-methyl- 2H -chromene-2-carboxamide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a racemate thereof, Lt; / RTI >

In Formula 1,

R ¹ is a hydrogen atom; A halogen atom; A hydroxyl group; Cyano; A nitro group; An amino group; A C _{1 to} C ₁₀ linear or branched or cyclic alkyl group; A C _{1 to} C ₁₀ alkoxy group; A haloalkyl group of C ₁ ~C _10; And a haloalkoxy group of C ₁ ~C _10; And R < 4 >

R ² is a hydrogen atom; Or a linear or branched or cyclic alkyl group of _{1 to 10} carbon atoms,

R ³ is a halo, cyano, hydroxy, amino, C ₁ ~C ₁₀ straight or branched chain or a high polycyclic alkyl, C ₁ ~C ₁₀ alkoxy, C ₁ ~C ₁₀ haloalkyl, C ₁ ~C ₁₀ of the haloalkoxy, C ₂ ~C ₁₀ of the alkoxycarbonyl, carboxylic acid, carboxamide, sulfonic acid, and from 1 to 3 substituents selected from the group consisting of a sulfonamide substituted or unsubstituted C ₁ ~C ₁₀ straight or branched chain Or a cyclic alkyl group; Halo, cyano, hydroxy, amino, haloalkoxy of C ₁ ~C ₁₀ straight or branched chain or cyclic alkyl, C ₁ ~C ₁₀ alkoxy, C ₁ ~C ₁₀ haloalkyl, C ₁ ~C ₁₀ of the, An adamantyl group in which 1 to 3 substituents selected from the group consisting of C _{2 to} C ₁₀ alkoxycarbonyl, carboxylic acid, carboxamide, sulfonic acid, and sulfonamide are substituted or unsubstituted; Or - (CH ₂ ) _n -R ⁴ , wherein n is 0 or an integer of 1 to 6,

R ⁴ is a halo, cyano, hydroxy, amino, C ₁ ~C ₁₀ straight or branched chain or cyclic alkyl, C ₁ ~C ₁₀ alkoxy, C ₁ ~C ₁₀ haloalkyl, C ₁ ~C ₁₀ of the Wherein the aromatic group is a substituted or unsubstituted aromatic group having 1 to 4 substituents selected from the group consisting of halogen, haloalkoxy, C _{2 to} C ₁₀ alkoxycarbonyl, carboxylic acid, carboxamide, sulfonic acid, and sulfonamide, A benzooxol group, a naphthyl group, a pyridinyl group, a thiophenyl group, or a furanyl group,

Or R < ² > and R < ³ > are a saturated or unsaturated 4- or 10-membered heterocyclic ring formed by further including a nitrogen atom to which they are bonded and another hetero atom selected from N, Wherein the heterocyclic group is selected from the group consisting of halo, cyano, hydroxy, amino, C _{1 -} C (lower alkyl) ₁₀ alkyl, C ₁ ~C ₁₀ of alkoxy, C ₁ ~C ₁₀ of haloalkyl, alkoxycarbonyl, carboxylic acid of the C ₁ ~C ₁₀ haloalkoxy, C ₂ ~C ₁₀ of, carboxamide, sulfonic acid, and Sulfone amide can be substituted or unsubstituted.

The 2-methyl- 2H -chromene-2-carboxamide compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a racemate thereof or Its stereoisomer has a selective inhibitory activity against human-derived 11? -HSD1 enzyme. Thus, the compounds of the present invention are useful for the treatment of diseases associated with the modulation of glucocorticoids induced by 11? -HSD1 enzyme activity, such as Type 1 and Type 2 diabetes, post-diabetes complications, adult latent autoimmune diabetes mellitus (LADA) And is effective as a preventive, regulating and treating agent for diseases such as obesity, impaired glucose tolerance (IGT), fasting glucose insufficiency (IFG), impaired glucose tolerance, dyslipidemia, arteriosclerosis and hypertension.

The pharmaceutically acceptable salts of the 2-methyl- 2H -chromene-2-carboxamide compounds represented by Formula 1 according to the present invention can be prepared by a conventional method in the art. The pharmaceutically acceptable salts of the present invention include salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogenphosphate, phosphoric acid, and carbonic acid, or organic acids such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, With an organic acid such as salicylic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin), or by reacting with an alkali metal ion such as sodium or potassium, Or may react with ammonium ions to form another type of salt.

The 2-methyl- 2H -chromene-2-carboxamide compound represented by Formula 1 according to the present invention may be crystallized or recrystallized from a solvent such as aqueous and organic solvents. In such cases, solvates (especially hydrates) may be formed. Thus, compounds of the present invention also include stoichiometric solvates, including hydrates, in addition to varying amounts of water-containing compounds that can be prepared by methods such as lyophilization.

The 2-methyl-2 H -chromene-2-carboxamide compound represented by the formula (1) according to the present invention has a structural characteristic comprising a chiral carbon in which different substituents are substituted at the C-2 position of benzopyran And exhibits optical activity. Thus, the compounds of the present invention may be enantiomers, stereoisomers or tautomers. In addition, the isomer can be separated or decomposed by a conventional method. In addition, any desired isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

The 2-methyl- 2H -chromene-2-carboxamide compound represented by the above formula (1) according to the present invention includes a radioactive derivative, and these radioactive compounds are useful in the field of biological research.

The 2-methyl-2 H -chromene-2-carboxamide compound represented by the above formula (1) according to the present invention is preferably as follows. R ¹ represents a hydrogen atom, a halogen atom, a fluorine atom, a bromine atom, a hydroxyl group, a cyano group, a nitro group, an amino group, a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, n-butyl group, tert- butyl group, a cyclopentyl group, a cyclopropyl group, cyclopentyl group, n-hexyl group, a cyclohexyl group, a cyclohexyl group, cyclohexyl group, methoxy group, ethoxy group, normal propoxy group, isopropoxy A phenoxy group, a fluorine atom, a chlorine atom, a chlorine atom, a chlorine atom, a chlorine atom, a chlorine atom, a chloro group, a chloro group, a dichloroethyl group, a trifluoromethyl group and a trifluoromethoxy group; R ² represents a hydrogen atom, a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a normal butyl group, a tert- butyl group, a cyclopentyl group, a cyclopropylethyl group, a cyclopentylmethyl group, A cyclohexyl group, a cyclohexylmethyl group, and a cyclohexylethyl group; R ³ is a group selected from the group consisting of a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a normal butyl group, a tert- butyl group, a cyclopentyl group, a cyclopropylethyl group, a cyclopentylmethyl group, A phenyl group, a phenyl group, a phenyl group, a phenyl group, a benzooxolyl group, a benzooxolylmethyl group, a pyridinyl group, a pyridylmethyl group, a furanylmethyl group, a furanylmethyl group, ≪ / RTI > Wherein ring is a ring of substituents consisting of cyclohexyl, adamantyl, phenyl, benzyl, phenylethyl, phenylpropyl, benzoxoyl, benzooxoylmethyl, pyridinyl, pyridinylmethyl, furanyl, is halo, cyano, hydroxy, amino, haloalkoxy, C ₂ ~C ₁₀ of the C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ alkoxy, C ₁ ~C ₁₀ haloalkyl, C ₁ ~C ₁₀ of the 1 to 3 substituents selected from the group consisting of alkoxycarbonyl, carboxylic acid, carboxamide, sulfonic acid, and sulfonamide can be substituted or unsubstituted; Or R ² and R ³ together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, piperazine, azepane, azabicyclooctane, octahydroindole, octahydroisoindole, dehydroquinoline, tetra tetrahydroquinoline, tetrahydroisoquinoline, indoline, or a heterocyclic group selected from a isoindoline, wherein the heterocyclic groups of halo, cyano, hydroxy, amino, C ₁ ~C ₁₀ alkyl, C ₁ ~C ₁₀ Selected from the group consisting of alkyl, alkoxy, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ haloalkoxy, C ₂ -C ₁₀ alkoxycarbonyl, carboxylic acid, carboxamide, sulfonic acid, and sulfonamide. Or a compound in which three substituents are substituted or unsubstituted.

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, 페닐기, 2-클로로페닐기, 3-클로로페닐기, 4-클로로페닐기, 2-플루오로페닐기, 3-플루오로페닐기, 4-플루오로페닐기, 2-메틸페닐기, 3-메틸페닐기, 4-메틸페닐기, 2-시아노페닐기, 3-시아노페닐기, 4-시아노페닐기, 2-메톡시페닐기, 3-메톡시페닐기, 4-메톡시페닐기, 벤질기, 2-클로로벤질기, 3-클로로벤질기, 4-클로로벤질기, 2-플루오로벤질기, 3-플루오로벤질기, 4-플루오로벤질기, 2-메틸벤질기, 3-메틸벤질기, 4-메틸벤질기, 2-트리플루오로메틸벤질기, 3-트리플루오로메틸벤질기, 4-트리플루오로메틸벤질기, 2-메톡시벤질기, 3-메톡시벤질기, 4-메톡시벤질기, 2,3-다이메톡시벤질기, 3,4-다이메톡시벤질기, 2,6-다이메톡시벤질기, 2-메톡시카르보벤질기, 3-메톡시카르보벤질기, 4-메톡시카르보벤질기, 페닐에틸기, (2-플루오로페닐)-에틸기, (3-플루오로페닐)-에틸기, (4-플루오로페닐)-에틸기, (2-메틸페닐)-에틸기, (3-메틸페닐)-에틸기, (4-메틸페닐)-에틸기, (3-메톡시페닐)-에틸기, (4-메톡시페닐)-에틸기, (3,4-다이메톡시페닐)-에틸기, 벤조옥솔-4-일기, 벤조옥솔-5-일기, 벤조옥솔-4-일메틸기, 벤조옥솔-5-일메틸기, 피리딘-2-일기, 피리딘-3-일기, 피리딘-4-일기, 피리딘-2-일메틸기, 피리딘-3-일메틸기, 피리딘-4-일메틸기, 퓨란-2-일기, 및 퓨란-2-일메틸기로 이루어진 군으로부터 선택된 치환기를 나타내고; 또는, 상기 R² 및 R³은 이들이 결합된 질소원자와 함께 피롤리딘, 피페리딘, 4-하이드록시-피페리딘, 4-하이드록시-4-트리플루오로메틸-피페리딘, 피페라진, 아제판, 아자바이사이클로옥탄, 옥타하이드로인돌, 옥타하이드로이소인돌, 데하이드로퀴놀린, 테트라하이드로퀴놀린, 테트라하이드로이소퀴놀린, 인돌린, 또는 이소인돌린으로부터 선택되는 헤테로고리기를 형성하는 화합물의 경우이다.The 2-methyl-2 H -chromene-2-carboxamide compound represented by Formula 1 according to the present invention is more preferably as follows. Wherein R ¹ represents 1 to 2 substituents selected from the group consisting of a chloro atom, a fluorine atom, a nitro group, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a trifluoromethyl group, and a trifluoromethoxy group; R ² represents a substituent selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a cyclopropyl group, and a cyclopropylmethyl group; R ³ is a group selected from the group consisting of a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a normal butyl group, a tert- butyl group, a cyclopentyl group, a cyclopropylethyl group, a cyclopentylmethyl group, Hydroxy-4-methyl-cyclohexyl group, 4-hydroxy-4-trifluoromethyl-cyclohexyl group, cyclohexylmethyl group,

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, A phenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, , 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, benzyl, 2-chlorobenzyl, Fluorobenzyl group, a 4-fluorobenzyl group, a 2-methylbenzyl group, a 3-methylbenzyl group, a 4-methylbenzyl group, a 2-trifluoromethyl group, Benzyl group, 3-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, Dimethoxybenzyl group, a 2-methoxycarbonylbenzyl group, a 3-methoxycarbonylbenzyl group, a 4-methoxycarbonylbenzyl group, a phenyl (2-fluorophenyl) ethyl group, (3-fluorophenyl) -ethyl group, (4- (3-methoxyphenyl) -ethyl group, (4-methoxyphenyl) -ethyl group, Yl group, a benzooxazol-4-ylmethyl group, a benzooxol-5-ylmethyl group, a pyridin-2-yl group, From the group consisting of a pyridin-3-yl group, a pyridin-4-yl group, a pyridin-2-ylmethyl group, a pyridin- Selected substituent; Or R ² and R ³ together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, 4-hydroxy-piperidine, 4-hydroxy-4-trifluoromethyl- In the case of a compound which forms a heterocyclic group selected from razine, azepan, azabicyclooctane, octahydroindole, octahydroisoindole, dehydroquinoline, tetrahydroquinoline, tetrahydroisoquinoline, indoline, or isoindoline, to be.

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, 벤질기, 4-클로로벤질기, 또는 3-플루오로벤질기이고; 또는, 상기 R² 및 R³은 이들이 결합된 질소원자와 함께 형성된 4-하이드록시-4-트리플루오로메틸-피페리딘, 또는 1,2,3,4-테트라하이드로이소퀴놀린기인 화합물의 경우이다.The 2-methyl-2 H -chromene-2-carboxamide compound represented by the general formula (1) according to the present invention is particularly preferably as follows. Wherein R < ¹ > is a fluorine atom, a nitro group, a methyl group, or a methoxy group; R ² is a hydrogen atom, a methyl group or a cyclopropyl group; R ³ is a cyclohexyl group, a 4-hydroxy-cyclohexyl group, a cyclohexylmethyl group,

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, A benzyl group, a 4-chlorobenzyl group, or a 3-fluorobenzyl group; Or R ² and R ³ are 4-hydroxy-4-trifluoromethyl-piperidine formed together with the nitrogen atom to which they are bonded, or a 1,2,3,4-tetrahydroisoquinoline group to be.

The 2-methyl- 2H -chromene-2-carboxamide compound represented by the general formula (1) according to the present invention is particularly preferable as follows.

N- (2-adamantyl) -2,6-dimethyl- 2H -chromene-2-carboxamide,

N- (2-adamantyl) -6-methoxy-2-methyl- 2H -chromene-

N- (5- hydroxy-2-adamantyl) -6-methoxy-2-methyl -2 H - chromen-2-carboxamide Id,

N- (2-adamantyl) -6-fluoro-2-methyl- 2H -chromene-

N- (2-adamantyl) -2-methyl-6-nitro- 2H -chromene-2-carboxamide, or

N- (5-Carbamoyl-2-adamantyl) -2-methyl-6-nitro- 2H -chromene-2-carboxamide.

The present invention also provides a process for preparing a 2-methyl-2 H -chromene-2-carboxamide compound represented by the above formula (1), wherein the process of the present invention is briefly described below.

In the above Reaction Scheme 1, R ¹ , R ² , and R ³ are as defined above.

The method for producing the 2-methyl-2 H -chromene-2-carboxamide compound represented by the above formula (1) as shown in the above-mentioned Scheme 1 will be described in more detail. the two R ¹ represented a substituted 2-methyl -2 H - chromen-2-carboxyl acid amine compound represented by the compound with the formula (3) performing the condensation of (NHR ² R ³⁾ to an amide are introduced into the general formula 2-methyl- 2H -chromene-2-carboxamide compound represented by the formula (1).

Examples of the reaction solvent include dichloromethane (CH ₂ Cl ₂ ), acetonitrile (MeCN), dichloroethane (ClCH ₂ CH ₂ Cl), dioxane, tetrahydrofuran (THF), or dimethylformamide (DMF) Is used as a solvent, and dichloromethane is preferably used. The amine compound represented by the formula (3) is used in an amount of 1 to 3 equivalents, preferably 1.2 to 1.5 equivalents, based on the compound represented by the formula (2). Further, it is better to use dimethylaminopyridine (DMAP) in a catalytic amount (0.5 equivalent or less). The coupling agent may be 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), N, N -dicyclohexylcarbodiimide (DCC), or N, N -diisopropylcarbodiimide DIC), and the like, and it is most preferable to use eddy (EDC). The binder used in the condensation reaction is used in an amount of 1 to 3 equivalents, preferably 1.2 to 1.5 equivalents, based on the compound represented by the formula (2).

Further, in the process of producing the compound represented by Formula 1, the degree of progress of the reaction was confirmed by TLC method in the middle of the reaction, and the compound represented by Formula 1 was separately purified and analyzed by NMR or Mass spectroscopy.

The 2-methyl- 2H -chromene-2-carboxamide compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a racemate thereof, or a stereoisomer thereof, The present invention can be used as a modulator or therapeutic agent for diseases caused by 11? -HSD1 enzyme, since it exhibits selective inhibitory activity against human-derived 11? -HSD1 enzyme. The diseases caused by the activity of the 11? -HSD1 enzyme are specifically classified into type 1 and type 2 diabetes, late complications of diabetes, adult latent autoimmune diabetes (LADA), insulin resistance, obesity, metabolic syndrome, impaired glucose tolerance (IGT) Fasting glucose tolerance (IFG), impaired glucose tolerance, dyslipidemia, arteriosclerosis, hypertension, and the like.

Accordingly, the present invention provides a method for the treatment of type 1 and type 2 diabetes, late diabetes complications, adult latent autoimmune diabetes (LADA), insulin resistance, obesity, metabolic syndrome, impaired glucose tolerance (IGT) Characterized by a pharmaceutical composition for the prevention, control and treatment of glucose tolerance, dyslipidemia, arteriosclerosis, hypertension.

The pharmaceutical composition of the present invention is a 2-methyl- 2H -chromene-2-carboxamide compound represented by the above formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, A pharmaceutically acceptable carrier, an adjuvant, and an excipient, to prepare a pharmaceutical preparation, for example, a tablet, a capsule, a troche, a liquid, a suspensions And the like can be formulated into preparations for oral administration or parenteral administration.

Examples of excipients which can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonizing agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, perfumes and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

The dose of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally 0.01 To 1,000 mg / day. Depending on the judgment of a doctor or a pharmacist, it may be administered once to several times a day at a predetermined interval.

The present invention will now be described in more detail with reference to the following examples, experimental examples and preparation examples. It should be noted that the following examples, experimental examples and formulation examples are merely illustrative of the present invention, And the like.

[Example]

Example 1 Synthesis of N- (4-methoxybenzyl) -2,6-dimethyl- 2H -chromene-2-carboxamide (Compound 1)

2,6-dimethyl -2 H - chromen-2-carboxylic acid (20 mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), at 0 ℃ 4- methoxybenzylamine (0.021 mg, 0.15 mmol), 1 (EDC; 30 mg, 0.15 mmol) and a catalytic amount of dimethylaminopyridine (DMAP) were added to the solution, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate (10 mL) and washed with brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The concentrated mixture was separated and purified by column chromatography on silica gel in a mixed solvent of hexane / ethyl acetate (7/1, v / v) to give the title compound (31 mg, yield 96%) as an oil.

^{1 H NMR (500 MHz, CDCl} 3) δ 1.56 (s, 3H), 3.78 (s, 3H), 4.33 (dd, J = 5.9, 14.9 Hz, 1H), 4.37 (dd, J = 6.0, 14.8 Hz, 1H), 6.16 (d, J = 9.9 Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 6.75 (m, 1H), 6.79 (d, J = 8.7 Hz, 2H), 6.89 (br s , ≪ / RTI > 1H), 7.00 (d, J = 8.7 Hz, 2H), 7.04-7.06 (m, 2H); LC-MS (ESI) m / z 324 ([M + 1] < ⁺ >).

The structure and analytical results of the 2-methyl-2 H -chromene-2-carboxamide compound synthesized in the same manner as in Example 1 are summarized in Table 1 below.

Example R ¹ R ² R ³ Structural analysis data [ ¹ H NMR (500 MHz, CDCl ₃ ) and LC / MS (ESI)] One 6-Me H 4-OMe-Bn ^{1 H NMR δ 1.57 (s,} 3H), 3.78 (s, 3H), 4.33 (dd, J = 5.9, 14.9 Hz, 1H), 4.37 (dd, J = 6.0, 14.8 Hz, 1H), 6.16 (d, J = 9.9 Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 6.75 (m, 1H), 6.79 (d, J = 8.7 Hz, 2H), 6.89 (br s, 1H), 7.00 (d , ≪ / RTI > J = 8.7 Hz, 2H), 7.04-7.06 (m, 2H); m / z 324 ([M + 1] < ⁺ >) [ 2 6-Me H

^{1 H NMR δ 1.57 (s,} 3H), 2.28 (s, 3H), 4.35 (m, 2H), 5.91 (s, 2H), 6.00 (d, J = 10.0 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.53-6.54 ( m, 2H), 6.68 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.81 (br s, 1H), 6.89 (s , ≪ / RTI > 1H), 6.92 (dd, J = 1.6,8.2 Hz, 1H); m / z 338 ([M + 1] < ⁺ >) [ 3 6-Me H 4-Me-Bn m / z 308 ([M + 1] < ⁺ >) [ 4 6-Me H 4-F-Bn ^{1 H NMR δ 1.59 (s,} 3H), 2.28 (s, 3H), 4.38 (dd, J = 6.0, 15.2 Hz, 1H), 4.43 (dd, J = 6.3, 15.2 Hz, 1H), 5.99 (d, J = 9.9 Hz, 1H), 6.41 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.87-6.94 (m, 5H), 7.03 (dd, J = 5.5, 8.7 Hz, 2H); m / z 312 ([M + l] ⁺ ) 5 6-Me H 3-F-Bn ^{1 H NMR δ 1.58 (s,} 3H), 2.28 (s, 3H), 4.42 (m, 2H), 6.01 (d, J = 10.0 Hz, 1H), 6.41 (d, J = 9.9 Hz, 1H), 6.70 (m, 1H), 6.75 (d, J = 8.2Hz, 1H), 6.84-6.94 (m, 5H), 7.20 (m, 1H); m / z 312 ([M + l] ⁺ ) 6 6-Me H 4-Cl-Bn ^{1 H NMR δ 1.66 (s,} 3H), 2.29 (s, 3H), 4.35 (dd, J = 5.9, 15.2 Hz, 1H), 4.44 (dd, J = 6.4, 15.2 Hz, 1H), 6.02 (d, J = 9.9 Hz, 1H), 6.41 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.84 (br s, 1H), 6.89 (d, J = 1.6 Hz, 1H ), 6.93-6.97 (m, 3H), 7.22 (d, J = 8.5 Hz, 2H); m / z 328 ([M + 1] < ⁺ >).

7 6-Me H 3-Cl-Bn ^{1 H NMR δ 1.58 (s,} 3H), 2.28 (s, 3H), 4.38-4.44 (m, 2H), 6.01 (d, J = 10.0 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H) , 6.76 (d, J = 8.1 Hz, 1H), 6.88-6.94 (m, 4H), 7.01 (m, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.21 (m, 1H); m / z 328 ([M + 1] < ⁺ >). 8 6-Me H 4-CF ₃ -Bn ^{1 H NMR δ 1.59 (s,} 3H), 2.28 (s, 3H), 4.43 (dd, J = 5.9, 15.6 Hz, 1H), 4.53 (dd, J = 6.4, 15.6 Hz, 1H), 6.00 (d, J = 9.9 Hz, 1H), 6.42 (d, J = 9.9 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.90-6.96 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H); m / z 362 ([M + 1] < ⁺ >). 9 6-Me H 3-CF ₃ -Bn ^{1 H NMR δ 1.59 (s,} 3H), 2.27 (s, 3H), 4.45-4.53 (m, 2H), 5.99 (d, J = 10.0 Hz, 1H), 6.42 (d, J = 10.0 Hz, 1H) , 6.76 (d, J = 8.1 Hz, 1H), 6.90-6.94 (m, 3H), 7.23 (d, J = 7.7 Hz, 1H), 7.32 (s, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1 H); m / z 362 ([M + 1] < ⁺ >). 10 6-Me H 4-CO ₂ Me-Bn ^{1 H NMR δ 1.58 (s,} 3H), 2.27 (s, 3H), 3.91 (s, 3H), 4.43 (dd, J = 5.9, 15.6 Hz, 1H), 4.53 (dd, J = 6.5, 15.6 Hz, 1H), 6.76 (d, J = 8.2 Hz, 2H), 6.01 (d, J = 10.0 Hz, 1H), 6.42 (d, J = 10.0 Hz, 1H), 6.89-6.93 (m, 3H), 7.11 ( d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H); m / z 352 ([M + 1] < ⁺ >). 11 6-Me H

^{1 H NMR δ 1.58 (s,} 3H), 2.28 (s, 3H), 4.53 (m, 2H), 6.00 (d, J = 9.9 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.93 (m, 1H), 7.06-7.12 (m, 2H), 7.51-7.57 dd, J = 1.7, 4.9 Hz, 1 H); m / z 295 ([M + 1] < ⁺ >) [ 12 6-Me H

^{1 H NMR δ 1.59 (s,} 3H), 2.28 (s, 3H), 4.36 (m, 1H), 4.51 (dd, J = 6.4, 15.6 Hz, 1H), 6.00 (d, J = 10.0 Hz, 1H) , 6.42 (d, J = 10.0 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.88-6.96 (m, 5H), 8.45 (d, J = 3.4 Hz, 2H); m / z 295 ([M + 1] < ⁺ >) [ 13 6-Me H

^{1 H NMR δ 1.57 (s,} 3H), 2.28 (s, 3H), 4.39-4.46 (m, 2H), 6.00-6.05 (m, 2H), 6.28 (dd, J = 1.9, 3.2 Hz, 1H), 6.41 (d, J = 10.0 Hz , 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.82 (br s, 1H), 6.87 (d, J = 1.6 Hz, 1H), 6.94 (dd, J = 1.6, 8.3 Hz, 1 H), 7.32 (d, J = 1.8 Hz, 1 H); m / z 284 ([M + 1] < ⁺ >) [

14 6-Me H 3,4-di-OMe-Ph- CH 2 CH 2 - ^{1 H NMR δ 1.54 (s,} 3H), 2.27 (s, 3H), 2.69 (m, 2H), 3.43-3.49 (m, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 6.01 ( d, J = 10.0 Hz, 1H ), 6.41 (d, J = 10.0 Hz, 1H), 6.54 (dd, J = 2.0, 8.2 Hz, 1H), 6.64 (m, 2H), 6.71 (d, J = 8.2 1H), 6.73 (br s, 1H), 6.85 (d, J = 1.6 Hz, 1H), 6.92 (dd, J = 1.6, 8.3 Hz, 1H). m / z 368 ([M + 1] < ⁺ >) [ 15 6-Me H _{4-F-Ph-CH 2} CH 2 - m / z 326 ([M + 1] < ⁺ >) [ 16 6-Me H

^{1 H NMR δ 0.76 (m,} 2H), 1.00-1.18 (m, 3H), 1.31 (m, 1H), 1.47 (m, 2H), 1.55 (s, 3H), 1.57-1.63 (m, 3H), (D, J = 9.9 Hz, 1H), 6.42 (d, J = 9.9 Hz, 1H), 6.62 (br s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 1.6 Hz, 1H), 6.93 (m, 1H); m / z 300 ([M + 1] ⁺ ) 17 6-Me H

¹ H NMR? 1.15-1.38 (m, 2H), 1.54 (s, 3H), 1.60 (m, 2H), 1.66 (m, 3H), 1.72-1.78 J = 10.0 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H) ), 6.86-6.89 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H); m / z 338 ([M + 1] < ⁺ >) [ 18 6-Me H

^{1 H NMR δ 1.51 (s,} 3H), 1.64 (m, 6H), 1.91 (m, 6H), 2.03 (m, 3H), 2.27 (s, 3H), 6.01 (d, J = 10.0 Hz, 1H) , 6.41 (d, J = 10.0 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 6.63 (br s, 1H), 6.88 (d, J = 1.0 Hz, 1H), 6.93 (dd, J = 1.6, 8.2 Hz, 1 H); m / z 338 ([M + 1] < ⁺ >) [ 19 6-Me H

^{1 H NMR δ 1.46-1.64 (m,} 4H), 1.52 (s, 3H), 1.86-2.04 (m, 6H), 2.26 (s, 3H), 2.34 (m, 1H), 2.68 (m, 2H), 5.99 (d, J = 10.0 Hz , 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.69 (br s, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.88 (s, 1H) , 6.93 (dd, J = 1.5, 8.2 Hz, 1 H); m / z 324 ([M + 1] < ⁺ >) [ 20 6-Me H

m / z 308 ([M + 1] < ⁺ >) [ 21 6-Me H 4-OMe-Ph ¹ H NMR 隆; m / z 310 ([M + l] ⁺ ) 22 6-Me H 3-OMe-Ph ¹ H NMR 隆; m / z 310 ([M + l] ⁺ ) 23 6-Me H 4-Me-Ph ¹ H NMR 隆; m / z 294 ([M + 1] < ⁺ >) [ 24 6-Me H 4-Cl-Ph ¹ H NMR 隆; m / z 314 ([M + 1] < ⁺ >) [ 25 6-Me H 4-F-Ph ¹ H NMR 隆; m / z 298 ([M + 1] < ⁺ >) [ 26 6-Me H 4-CN-Ph ¹ H NMR 隆; m / z 305 ([M + l] ⁺ ) 27 6-Me H n-Bu ¹ H NMR 隆; m / z 260 ([M + l] ⁺ ) 28 6-Me H t-Bu ¹ H NMR 隆; m / z 260 ([M + l] ⁺ )

29 6-Me H

¹ H NMR 隆; m / z 286 ([M + 1] < ⁺ >) [ 30 6-Me Me Bn ^{1 H NMR (two rotamers in a} 3: 1 ratio) major rotamer δ 1.65 (s, 3H), 2.31 (s, 3H), 3.21 (s, 3H), 4.32 (d, J = 15.0 Hz, 1H), 4.66 (d, J = 15.0 Hz, 1H), 6.00 (d, J = 9.9 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.84 (m 2H), 6.88 (m, 1H), 6.95 (s, 1H), 7.12-7.19 (m, 3H), minor rotamer? 1.63 (s, 3H) , 4.91 (d, J = 15.2 Hz, 1H), 4.99 (d, J = 15.2 Hz, 1H), 5.96 (d, J = 9.9 Hz, 1H), 6.45 (d, J = 10.0 Hz, 1H), 6.43 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.91 (m, 1H), 7.09 (m, 2H), 7.25-7.29 (m, 3H); m / z 308 ([M + 1] < ⁺ >) [ 31 6-Me Me 3-F-Bn m / z 326 ([M + 1] < ⁺ >) [ 32 6-Me Me

¹ H NMR 隆; m / z 322 ([M + 1] < ⁺ >). 33 6-Me NR ¹ R ² =

¹ H NMR 隆; m / z 272 ([M + 1] < ⁺ >). 34 6-Me NR ¹ R ² =

m / z 306 ([M + l] ⁺ ) 35 6-Me NR ¹ R ² =

^{1 H NMR (two rotamers in a} 3: 2 ratio) δ 1.58 and 1.66 (each s, total 3H in a 3: 2 ratio), 2.25 (s, 3H), 2.81-2.93 (m, 2H), 3.25 (m , 0.4H), 3.92 (m, 0.6H), 4.12 (m, 0.4H), 4.50 (m, 0.6H), 4.57 (m, 0.6H), 4.75 (m, 1H), 5.49 (d, J = 15.6 Hz, 0.4H), 5.99 ( d, J = 10.0 Hz, 0.4H), 6.01 (d, J = 10.0 Hz, 0.6H), 6.43 (d, J = 10.0 Hz, 0.6H), 6.47 (d, J = 10.0 Hz, 0.4H), 6.78 (d, J = 8.4 Hz, 1H), 6.83-6.93 (m, 2H), 7.07-7.21 (m, 4H); m / z < / RTI > 320 ([M + 1] ⁺ ) 36 6-Me Meat Meat ¹ H NMR 隆; m / z 260 ([M + l] ⁺ ) 37 6-Me

Ph ¹ H NMR 隆; m / z < / RTI > 320 ([M + 1] ⁺ ) 38 6-Me

Bn ¹ H NMR 隆; m / z 334 ([M + 1] < ⁺ >) [

39 6-OMe H

^{1 H NMR δ 1.57 (s,} 3H), 3.76 (s, 3H), 4.36 (dd, J = 5.9, 14.7 Hz, 1H), 4.41 (dd, J = 5.9, 14.7 Hz, 1H), 5.94 (s, 2H), 6.04 (d, J = 9.8 Hz, 1H), 6.39 (d, J = 9.8 Hz, 1H), 6.58 (d, J = 2.9 Hz, 1H), 6.68-6.76 br s, 1 H); m / z 354 < ^{RTI ID} = 0.0 > ([M + 1] ⁺ ) 40 6-OMe H 4-F-Bn ^{1 H NMR δ 1.58 (s,} 3H), 3.76 (s, 3H), 4.43 (dd, J = 6.0, 15.0 Hz, 1H), 4.47 (dd, J = 5.9, 15.0 Hz, 1H), 6.04 (d, J = 9.8 Hz, 1H), 6.40 (d, J = 9.8 Hz, 1H), 6.59 (d, J = 2.9 Hz, 1H), 6.69 (dd, J = 3.0, 8.8 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 7.00 (tt, J = 2.3, 9.0 Hz, 2H), 7.02 (br s, 1H), 7.20 (dd, J = 5.4, 8.6 Hz, 2H); m / z 328 ([M + 1] < ⁺ >). 41 6-OMe H 3-F-Bn ^{1 H NMR δ 1.59 (s,} 3H), 3.76 (s, 3H), 4.48 (d, J = 6.1 Hz, 2H), 6.04 (d, J = 9.8 Hz, 1H), 6.41 (d, J = 9.8 Hz , 1H), 6.60 (d, J = 3.0 Hz, 1H), 6.70 (dd, J = 3.0, 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.92 (m, 1H), 6.95 (dt, J = 2.2, 8.6 Hz, 1H), 7.01 (dd, J = 0.7, 7.7 Hz, 1H), 7.06 (br s, 1H), 7.28 (dt, J = 5.9, 7.9 Hz, 1H); m / z 328 ([M + 1] < ⁺ >). 42 6-OMe H 4-Cl-Bn ^{1 H NMR δ 1.58 (s,} 3H), 3.76 (s, 3H), 4.45 (d, J = 6.1 Hz, 2H), 6.03 (d, J = 9.9 Hz, 1H), 6.40 (d, J = 9.8 Hz , 1H), 6.59 (d, J = 2.9 Hz, 1H), 6.69 (dd, J = 3.0, 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 7.03 (br s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H); m / z 344 ([M + 1] < ⁺ >) [ 43 6-OMe H 3-Cl-Bn ^{1 H NMR δ 1.59 (s,} 3H), 3.76 (s, 3H), 4.46 (d, J = 6.1 Hz, 2H), 6.04 (d, J = 9.9 Hz, 1H), 6.41 (d, J = 9.8 Hz , 1H), 6.60 (d, J = 3.0 Hz, 1H), 6.70 (dd, J = 3.0, 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 7.05 (br s, 1H), 7.11 (m, 1 H), 7.20 (m, 1 H), 7.23 - 7.25 (m, 2H); m / z 344 ([M + 1] < ⁺ >) [ 44 6-OMe H 4-CF ₃ -Bn ^{1 H NMR δ 1.59 (s,} 3H), 3.76 (s, 3H), 4.54 (d, J = 6.2 Hz, 2H), 6.03 (d, J = 9.8 Hz, 1H), 6.41 (d, J = 9.8 Hz , 1H), 6.60 (d, J = 3.0 Hz, 1H), 6.70 (dd, J = 3.0, 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 7.12 (br s, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H); m / z 378 ([M + 1] < ⁺ >) [

45 6-OMe H 3-CF ₃ -Bn ^{1 H NMR δ 1.60 (s,} 3H), 3.76 (s, 3H), 4.54 (d, J = 6.2 Hz, 2H), 6.04 (d, J = 9.8 Hz, 1H), 6.41 (d, J = 9.8 Hz , 1H), 6.60 (d, J = 3.0 Hz, 1H), 6.70 (dd, J = 3.0, 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 7.11 (br s, 1H), 7.41-7.45 (m, 2H), 7.47 (s, 1 H), 7.52 (m, 1 H); m / z 378 ([M + 1] < ⁺ >) [ 46 6-OMe H

^{1 H NMR δ 1.60 (s,} 3H), 3.77 (s, 3H), 4.48 (dd, J = 6.2, 16.0 Hz, 1H), 4.52 (dd, J = 6.4, 16.1 Hz, 1H), 6.03 (d, J = 9.8 Hz, 1H), 6.42 (d, J = 9.8 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1H), 6.71 (dd, J = 3.0, 8.8 Hz, 1H), 6.78 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 6.0 Hz, 2H), 7.14 (br s, 1H), 8.53 (d, J = 6.0 Hz, 2H); m / z 311 ([M + 1] < ⁺ >) [ 47 6-OMe H _{4-F-Ph-CH 2} CH 2 - ^{1 H NMR δ 1.53 (s,} 3H), 2.79 (t, J = 7.0 Hz, 2H), 3.45-3.57 (m, 2H), 3.77 (s, 3H), 5.97 (d, J = 9.8 Hz, 1H) , 6.36 (d, J = 9.8 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.69 (dd, J = 2.6, 8.8 Hz, 1H) , 6.70 (br s, 1 H), 6.94 (tt, J = 2.2, 8.9 Hz, 2H), 7.09 (dd, J = 5.4, 8.6 Hz, 2H); m / z 342 ([M + 1] < ⁺ >) [ 48 6-OMe H

^{1 H NMR δ 0.77 (m,} 2H), 1.07 (m, 3H), 1.32 (m, 1H), 1.47 (m, 2H), 1.54 (s, 3H), 1.61 (m, 3H), 2.97 (ddd, J = 5.6,6.6, 13.3 Hz, 1H), 3.14 (ddd, J = 6.7,6.7, 13.4 Hz, 1H), 3.74 (s, 3H), 6.04 (d, J = 9.8 Hz, 1H), 6.41 , J = 9.8 Hz, 1H) , 6.59 (d, J = 3.0 Hz, 1H), 6.69 (dd, J = 3.0, 8.9 Hz, 1H), 6.72 (br s, 1H), 6.87 (d, J = 8.9 Hz, 1H); m / z 316 ([M + 1] < ⁺ >) [ 49 6-OMe H

¹ H NMR? 1.56 (m, 1H), 1.58 (s, 3H), 1.60-1.68 (m, 2H), 1.73 1.96 (m, 1H), 3.77 (s, 3H), 4.01 (m, 1H), 6.02 (d, J = 9.8 Hz, 1H), 6.37 (d, J = 9.8 Hz, 1H), 6.59 (d, J = 3.0 Hz, 1H), 6.71 (dd, J = 3.0, 8.7 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 7.06 (br d, J = 6.9 Hz, 1H); m / z 354 < ^{RTI ID} = 0.0 > ([M + 1] ⁺ ) 50 6-OMe H

m / z 354 < ^{RTI ID} = 0.0 > ([M + 1] ⁺ ) 51 6-OMe H

m / z 340 ([M + 1] < ⁺ >) [

52 6-OMe H

^{1 H NMR δ 1.51 (m,} 1H), 1.55 (s, 3H), 1.58-1.63 (m, 2H), 1.65-1.76 (m, 8H), 2.11 (m, 2H), 2.23 (s, 1H), J = 9.8 Hz, 1H), 6.37 (d, J = 9.8 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H) 6.72 (dd, J = 3.0,8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 6.96 (br d, J = 7.3 Hz, 1H); m / z 370 ([M + 1] < ⁺ >). 53 6-OMe H

¹ H NMR? 1.49 (m, 1 H), 1.52 (m, 1 H), 1.54 (m, 1.89 (m, 2H), 2.05 (m, 1H), 2.10 (m, 1H), 2.16 (s, 1H), 3.76 (s, 3H), 3.97 (m, 1H), 6.01 (d, J = 9.8 Hz , 1H), 6.38 (d, J = 9.8 Hz, 1H), 6.58 (d, J = 3.0 Hz, 1H), 6.72 (dd, J = 3.0, 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz , ≪ / RTI > 1H), 6.96 (br d, J = 7.7 Hz, 1H); m / z 370 ([M + 1] < ⁺ >). 54 6-OMe H

m / z 386 ([M + 1] < ⁺ >) [ 55 6-OMe H

m / z 386 ([M + 1] < ⁺ >) [ 56 6-OMe

m / z 358 ([M + 1] < ⁺ >). 57 6-OMe

m / z 358 ([M + 1] < ⁺ >). 58 6-OMe

m / z 372 ([M + 1] ⁺ ) 59 6-OMe

m / z 372 ([M + 1] ⁺ ) 60 6-OMe

m / z 426 ([M + 1] < ⁺ >) [ 61 6-OMe

m / z 426 ([M + 1] < ⁺ >) [ 62 6-OMe NR ¹ R ² =

m / z 372 ([M + 1] ⁺ ) 63 6-OMe Me 3-F-Bn ^{1 H NMR (two rotamers in a} 2: 1 ratio) δ 1.61 and 1.68 (each s, total 3H in a 2: 1 ratio), 2.87 and 3.17 (each s, total 3H in a 2: 1 ratio), 3.76 ( s, 3H), 4.44 (d , J = 14.8 Hz, 2 / 3H), 4.63 (d, J = 16.6 Hz, 1 / 3H), 4.70 (d, J = 14.8 Hz, 2 / 3H), 5.03 (d J = 15.8 Hz, 1H), 5.88 (d, J = 9.8 Hz, 1H), 6.37-6.84 (m, 5H), 6.93 (m, 2H), 7.25 (m, 1H); m / z 342 ([M + 1] < ⁺ >) [

64 6-F H 4-OMe-Bn ^{1 H NMR δ 1.58 (s,} 3H), 3.77 (s, 3H), 4.32 (dd, J = 6.0, 15.2 Hz, 1H), 4.39 (dd, J = 6.2, 15.1 Hz, 1H), 6.03 (d, J = 9.9 Hz, 1H), 6.44 (d, J = 9.9 Hz, 1H), 6.73-6.83 (m, 5H), 6.87 (br s, 1H), 7.00 (d, J = 8.7 Hz, 2H); m / z 328 ([M + 1] < ⁺ >). 65 6-F H

^{1 H NMR δ 1.56 (s,} 3H), 4.29 (dd, J = 5.7, 14.8 Hz, 1H), 4.35 (dd, J = 6.2, 14.8 Hz, 1H), 5.92 (s, 2H), 6.05 (d, J = 10.1 Hz, 1H), 6.44 (d, J = 10.1 Hz, 1H), 6.52-6.56 (m, 2H), 6.69 (d, J = 8.6Hz, 1H), 6.75-6.82 6.86 (br s, 1 H); m / z 342 ([M + 1] < ⁺ >) [ 66 6-F H 4-F-Bn ^{1 H NMR δ 1.57 (s,} 3H), 4.35 (dd, J = 5.8, 15.1 Hz, 1H), 4.42 (dd, J = 6.2, 15.1 Hz, 1H), 6.02 (d, J = 10.0 Hz, 1H) , 6.46 (d, J = 10.0 Hz, 1H), 6.75-6.84 (m, 4H), 6.94 (m, 2H), 7.03 (m, 2H); m / z 316 ([M + 1] < ⁺ >) [ 67 6-F H 3-F-Bn ^{1 H NMR δ 1.58 (s,} 3H), 4.37 (dd, J = 5.8, 15.2 Hz, 1H), 4.48 (dd, J = 6.2, 15.2 Hz, 1H), 6.08 (d, J = 10.0 Hz, 1H) , 6.48 (d, J = 10.0 Hz, IH), 6.75-6.86 (m, 6H), 6.92 (m, IH), 7.22 (m, IH); m / z 316 ([M + 1] < ⁺ >) [ 68 6-F H 4-Cl-Bn ^{1 H NMR δ 1.57 (s,} 3H), 4.38 (dd, J = 5.9, 15.2 Hz, 1H), 4.41 (dd, J = 6.2, 15.3 Hz, 1H), 6.09 (d, J = 9.9 Hz, 1H) , 6.46 (d, J = 9.9 Hz, 1H), 6.76-6.83 (m, 4H), 6.97 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H); m / z 332 ([M + 1] < ⁺ >). 69 6-F H 3-Cl-Bn ^{1 H NMR δ 1.58 (s,} 3H), 4.31 (m, 1H), 4.43 (m, 1H), 6.04 (d, J = 10.0 Hz, 1H), 6.47 (d, J = 10.0 Hz, 1H), 6.77 J = 1.8, 8.0 Hz, 1H), 6.84 (m, 4H), 6.94 (m, 1H), 7.00 (m, 1H), 7.18 (t, J = 7.7 Hz, 1H). m / z 332 ([M + 1] < ⁺ >). 70 6-F H 4-CF ₃ -Bn ^{1 H NMR δ 1.58 (s,} 3H), 4.43 (dd, J = 5.9, 15.3 Hz, 1H), 4.53 (dd, J = 6.2, 15.3 Hz, 1H), 6.11 (d, J = 10.0 Hz, 1H) , 6.49 (d, J = 10.0 Hz, 1H), 6.76-6.85 (m, 3H), 6.87 (br s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.1 Hz , 2H); m / z 366 ([M + 1] ⁺ ) 71 6-F H 3-CF ₃ -Bn ^{1 H NMR δ 1.58 (s,} 3H), 4.34 (dd, J = 6.0, 15.5 Hz, 1H), 4.51 (dd, J = 6.1, 15.5 Hz, 1H), 6.13 (d, J = 10.1 Hz, 1H) , 6.49 (d, J = 10.1 Hz, 1H), 6.77-6.81 (m, 3H), 6.89 (br s, 1H), 7.22 (d, J = 7.7 Hz, 1H), 7.32 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H); m / z 366 ([M + 1] ⁺ )

72 6-F H

^{1 H NMR δ 1.58 (s,} 3H), 4.38 (dd, J = 5.9, 15.6 Hz, 1H), 4.49 (dd, J = 6.4, 15.6 Hz, 1H), 6.03 (d, J = 10.1 Hz, 1H) , 6.48 (d, J = 10.1 Hz, 1H), 6.77-6.85 (m, 3H), 6.93-6.96 (m, 3H), 8.45 (d, J = 6.0 Hz, 2H); m / z 299 ([M + 1] < ⁺ >) [ 73 6-F H _{4-F-Ph-CH 2} -CH 2 - ^{1 H NMR δ 1.52 (s,} 3H), 2.61-2.73 (m, 2H), 3.35 (m, 1H), 3.61 (m, 1H), 6.02 (d, J = 10.0 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.64 (br s, 1H), 6.70 (m, 1H), 6.76 (dd, J = 3.0, 8.6 Hz, 1H), 6.82 (dt, J = 3.0, 8.5 Hz, 1H) , 6.88 (m, 2 H), 6.94 (m, 2 H); m / z 330 ([M + 1] ⁺ ) 74 6-F H

^{1 H NMR δ 0.76 (m,} 2H), 0.97-1.18 (m, 3H), 1.34 (m, 1H), 1.48 (m, 2H), 1.55 (s, 3H), 1.58-1.66 (m, 3H), 2.96 (m, 1H), 3.18 (td, J = 6.7, 13.4 Hz, 1H), 5.93 (d, J = 10.0 Hz, 1H), 6.41 (d, J = 10.0 Hz, 1H), 6.67 (br s, 1H), 6.76 (m, 1H), 6.81 - 6.83 (m, 2H); m / z 304 ([M + l] ⁺ ) 75 6-F H

^{1 H NMR δ 1.11 (d,} J = 13.2 Hz, 1H), 1.38 (m, 1H), 1.56 (s, 3H), 1.59 (m, 2H), 1.67 (m, 3H), 1.72-1.76 (m, 3H), 1.78-1.84 (m, 4H ), 3.95 (m, 1H), 5.91 (d, J = 10.0 Hz, 1H), 6.39 (d, J = 10.0 Hz, 1H), 6.76 (dd, J = 2.8 , 8.9 Hz, 1 H), 6.79 - 6.84 (m, 2 H), 6.85 (dd, J = 5.0, 8.9 Hz, 1 H); m / z 342 ([M + 1] < ⁺ >) [ 76 6-F Me 3-F-Bn m / z 330 ([M + 1] ⁺ ) 77 6-Cl H 4-OMe-Bn ^{1 H NMR δ 1.58 (s,} 3H), 3.77 (s, 3H), 4.36 (m, 2H), 6.01 (d, J = 10.0 Hz, 1H), 6.46 (d, J = 10.0 Hz, 1H), 6.74 2H), 7.05 (m, 2H), 7.01 (d, J = 8.8 Hz, 2H). m / z 344 ([M + 1] < ⁺ >) [ 78 6-Cl H 4-F-Bn m / z 332 ([M + 1] < ⁺ >). 79 6-Cl H 3-CF ₃ -Bn m / z 382 ([M + 1] ⁺ ) 80 6-Cl H

m / z 315 ([M + 1] < ⁺ >) [ 81 6-Cl H

¹ H NMR? 0.77 (m, 2H), 1.06 (m, 3H), 1.31-1.49 (m, 3H), 1.55 (s, 3H), 1.58-1.65 3.15 (m, 1H), 6.00 (d, J = 10.0 Hz, 1H), 6.46 (d, J = 10.0 Hz, 1H), 6.62 (br s, 1H), 6.82 (d, J = 8.7 Hz, 1H) , 7.02 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 2.6, 8.6 Hz, 1H); m / z < / RTI > 320 ([M + 1] ⁺ )

82 6-Cl H

^{1 H NMR δ 1.18 (d,} J = 13.1 Hz, 1H), 1.42 (d, J = 14.4 Hz, 1H), 1.57 (s, 3H), 1.59-1.69 (m, 5H), 1.72-1.85 (m, 7H), 3.95 (m, 1H ), 6.02 (d, J = 10.0 Hz, 1H), 6.45 (d, J = 10.0 Hz, 1H), 6.78 (br s, 1H), 6.86 (d, J = 8.7 Hz , ≪ / RTI > 1H), 7.06 (d, J = 2.5 Hz, 1H), 7.11 (m, 1H); m / z 358 ([M + 1] < ⁺ >). 83 6-NO ₂ H 4-Cl-Bn ^{1 H NMR δ 1.62 (s,} 3H), 4.38-4.42 (m, 2H), 6.03 (d, J = 10.0 Hz, 1H), 6.47 (d, J = 10.0 Hz, 1H), 6.83 (br s, 1H ), 6.93 (d, J = 8.7 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 8.00-8.04 (m, 2H); m / z 359 ([M + 1] < ⁺ >) [ 84 6-NO ₂ H 3-CF ₃ -Bn ^{1 H NMR δ 1.63 (s,} 3H), 4.46 (dd, J = 6.1, 15.2 Hz, 1H), 4.52 (dd, J = 6.3, 15.2 Hz, 1H), 6.02 (d, J = 10.2 Hz, 1H) , 6.52 (d, J = 10.2 Hz, 1H), 6.89 (br s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.35 (s, 1H ), 7.39 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 8.01 (m, 1H), 8.03 (d, J = 2.6 Hz, 1H); m / z 393 ([M + 1] < ⁺ >) [ 85 6-NO ₂ H 4-CF ₃ -Bn ^{1 H NMR δ 1.61 (s,} 3H), 4.50 (m, 2H), 6.01 (m, 1H), 6.44 (d, J = 10.0 Hz, 1H), 6.87 (br s, 1H), 6.96 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 8.01 (m, 1H), 8.04 (d, J = 2.4 Hz, 1H); m / z 393 ([M + 1] < ⁺ >) [ 86 6-NO ₂ H 3-F-Bn ^{1 H NMR δ 1.62 (s,} 3H), 4.45 (m, 2H), 6.00 (d, J = 10.1 Hz, 1H), 6.48 (d, J = 10.0 Hz, 1H), 6.76 (m, 1H), 6.81 (br s, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.94 (m, 1H), 6.97 (d, J = 8.8 Hz, 1H), 7.22 (m, 1H), 8.02 (dd, J = 2.7, 8.9 Hz, 1 H), 8.04 (d, J = 2.5 Hz, 1 H); m / z 343 ([M + 1] < ⁺ >) [ 87 6-NO ₂ Me 3-F-Bn ^{1 H NMR (for major rotamor)} δ 1.67 (s, 3H), 3.17 (s, 3H), 4.32 (d, J = 15.2 Hz, 1H), 4.59 (d, J = 15.2 Hz, 1H), 6.01 (d , J = 10.0 Hz, 1H) , 6.47 (d, J = 10.0 Hz, 1H), 6.55 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 6.7 Hz, 1H), 6.86-6.92 (m , ≪ / RTI > 2H), 7.14 (m, 1H), 7.97-8.05 (m, 2H); m / z 357 ([M + 1] < ⁺ >) [

88 6-NO ₂ H

¹ H NMR? 1.60 (m, 2H), 1.65 (s, 3H), 1.68-1.77 (m, 4H), 1.82-1.86 6.19 (d, J = 10.0 Hz , 1H), 6.47 (d, J = 10.0 Hz, 1H), 6.90 (br d, J = 7.3 Hz, 1H), 6.99 (dd, J = 0.5, 8.9 Hz, 1H) , 7.95 (d, J = 2.7 Hz, 1H), 8.09 (dd, J = 2.7, 8.9 Hz, 1H); m / z 369 ([M + 1] < ⁺ >) [ 89 6-NO ₂ H

^{1 H NMR δ 1.58 (s,} 3H), 1.69 (m, 6H), 2.01 (m, 6H), 2.10 (m, 3H), 6.16 (d, J = 10.0 Hz, 1H), 6.23 (br s, 1H ), 6.45 (d, J = 10.0 Hz, 1H), 6.94 (dd, J = 0.4, 8.9 Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 2.7, 8.9 Hz , 1H); m / z 369 ([M + 1] < ⁺ >) [ 90 6-NO ₂ H

^{1 H NMR δ 1.60 (s,} 3H), 1.52-1.65 (m, 4H), 1.92 (m, 2H), 2.01-2.10 (m, 4H), 2.30 (m, 2H), 2.43 (m, 1H), 6.18 (d, J = 10.0 Hz , 1H), 6.46 (d, J = 10.0 Hz, 1H), 6.66 (br s, 1H), 6.97 (dd, J = 0.4, 8.9 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 8.08 (dd, J = 2.7, 8.9 Hz, 1H); m / z 355 ([M + 1] < ⁺ >). 91 6-NO ₂ H

m / z 413 ([M + 1] < ⁺ >) [ 92 6-NO ₂ H

m / z 413 ([M + 1] < ⁺ >) [ 93 6-NO ₂ H

m / z 428 ([M + 1] < ⁺ >) [ 94 6-NO ₂ H

m / z 428 ([M + 1] < ⁺ >) [ 95 6-NO ₂ NR ¹ R ² =

m / z 319 ([M + 1] < ⁺ >) [ 96 6-CF ₃ H 4-OMe-Bn m / z 378 ([M + 1] < ⁺ >) [ 97 6-CF ₃ H 4-F-Bn m / z 366 ([M + 1] ⁺ ) 98 6-CF ₃ H 3-CF ₃ -Bn m / z 416 ([M + 1] < ⁺ >) [ 99 6-OCF ₃ H 4-OMe-Bn m / z 394 < ^{RTI ID} = 0.0 > ([M + 1] ⁺ ) 100 6-OCF ₃ H 4-F-Bn m / z 382 ([M + 1] ⁺ )

[Experimental Example]

Experimental Example 1. Enzyme detection for 11? - HSD1

In order to confirm the effect of inhibiting the activity of the human-derived 11? -HSD1 (h11? -HSD1) enzyme on the compound of the present invention, the following experiment was conducted.

In order to measure the 11? -HSD1 enzyme activity, recombinant DNA having the h11? -HSD1 gene was introduced into animal cells to express and isolate the protein [Arampatzis, S. J Mol Endocrinol. 2005 , 35 , 89-101]. First, HEK-293 cells were grown to 70-80% of the surface of the container using a cell incubator. The recombinant DNA having the h11β-HSD1 gene was mixed with Fugene 6, reacted at room temperature for 1 hour, and then treated with cells to inject DNA into cells. The next day, the cell supernatant was removed, fresh medium was added, and then the protein was further cultured in a cell culture incubator for 24 hours. Cells expressing the protein were dissolved well in phosphate-buffered saline containing 1 mM DTT and protease inhibitor, followed by sonication to break down the cells. The pulverized cells were centrifuged at 1500 rpm for 10 minutes at 1500 rpm to remove cell debris and the supernatant was centrifuged again at 100,000 g for 1 hour to separate microsomes containing h11 [beta] -HSD1. The separated microfilaments were dissolved in phosphate buffered saline containing 10% glycerol, stored at -70 ° C, and used for enzyme activity measurement.

The measurement of hl [beta] -HSD1 enzyme activity was used by modifying the conditions reported in the literature [Walker, EA J Biol Chem. 2001 , 276 , 21343-21350]. For the assay, four solutions, 0.5 M sodium phosphate buffer, 2 μM cortisone, 5 mM NADPH and NADPH regeneration system solutions were prepared. An enzyme substrate solution (16 μL / well) was prepared by mixing 4 μL of the above four reagents. 6.7 μL of the test compound dissolved in 0.5 mM DMSO was diluted with 93.3 μL of distilled water to prepare a compound solution. Next, the microcellular membrane containing h11β-HSD1 was diluted with 25 mM sodium phosphate buffer solution to prepare an enzyme solution. First, an enzyme substrate solution (16 [mu] L / well) was added to the 384 well microtiter plate, followed by the diluted compound solution (12 [mu] L / well) and finally the diluted enzyme solution The reaction was started. The reaction was allowed to react at 37 ° C for 1 hour. At this time, a dark condition was maintained so that no light would enter. After 1 hour reaction, the reaction was reacted in an oven at 80 ° C for 5 minutes to inactivate the enzyme. 18 [beta] -glyceritinic acid was added thereto so that the final concentration was 100 [mu] M. Quantitation of cortisol in the reaction was performed using the system provided by AssayDesigns. An enzyme reaction product was added to a plate coated with anti-mouse IgG, and a specific antibody for binding to cortisol and cortisol combined with alkaline phosphatase were added thereto, followed by reaction at room temperature for 2 hours. After the reaction, the contents in the wells were discarded and washed three times with buffer solution consisting of surfactant and Tris-saline solution. After that, a solution of p-nitrophenyl phosphate, which is a substrate of alkaline phosphatase, was added for the color reaction, and after 40 minutes of reaction, the absorbance at 405 nm was measured using a plate reader. The measurement results are shown in Table 2 below.

Experimental Example 2. Enzyme search for h-11 ? -HSD2

The activity of h-11 [beta] -HSD2 enzyme was measured by the following method. Three reagents (0.5 M sodium phosphate buffer 150 nM cortisol, 5 mM NAD) were prepared to make the enzyme substrate solution. 16 μL of enzyme substrate solution was prepared by mixing 4 μL of the above three reagents and 4 μL of distilled water. 6.7 μL of the 0.5 mM compound was diluted with 93.3 μL of distilled water, and 12 μL of the solution was added to the enzyme substrate solution. The reaction was initiated by adding 12 μL of the diluted 11β-HSD2 enzyme to the active assay solution. The subsequent reaction conditions and cortisol quantitation method were the same as those used for the measurement of 11? -HSD1 enzyme activity. The measurement results are shown in Table 2 below.

Experimental compound Inhibitory activity (IC ₅₀ , nM) h-11 [beta] -HSD18 h-11 [beta] -HSD2 > 10 Example 16 22 > 10 Example 17 8 > 10 Example 30 160 > 10 Example 35 50 > 10 Example 42 > 1000 Example 49 5 > 10 Example 63 > 1000 Example 75 7 > 10 Example 88 12 > 10 Example 89 90 > 10

[Formulation Example]

Preparation Example 1. Preparation of tablets (pressurized system)

As the active ingredient, 5.0 mg of the compound represented by the formula (1) of the present invention was sieved, and 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressed to prepare tablets.

Formulation Example 2. Preparation of tablets (wet granulation)

As an active ingredient, 5.0 mg of the compound represented by the formula (1) of the present invention was sieved, and 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation Example 3. Preparation of powders and capsules

As an active ingredient, 5.0 mg of the compound represented by the formula (1) of the present invention was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation Example 4. Preparation of injection

As an active ingredient, 100 mg of the compound represented by the formula (1) of the present invention was contained. In addition, injections were prepared by adding 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2,974 mg of distilled water.

As described above, the 2-methyl-2 H -chromene-2-carboxamide compound of the present invention has selective inhibitory activity against 11? -HSD1 enzyme. Thus, diseases associated with the modulation of glucocorticoids involving 11? -HSD1 enzymes, such as type 1 and type 2 diabetes, late diabetes complications, adult latent autoimmune diabetes mellitus (LADA), insulin resistance, obesity, impaired glucose tolerance IGT), fasting insulin resistance (IFG), impaired glucose tolerance, dyslipidemia, atherosclerosis, hypertension, and the like.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims. .

Claims (7)

2-methyl- 2H -chromene-2-carboxamide compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a racemate thereof, Lt; / RTI > isomer. [Chemical Formula 1]

In Formula 1, R ¹ represents 1 to 4 substituents selected from the group consisting of a halogen atom, a nitro group, a C _{1 to} C ₁₀ linear or branched or cyclic alkyl group, and a C _{1 to} C ₁₀ alkoxy group, R ² is a hydrogen atom; Or a linear or branched or cyclic alkyl group of _{1 to 10} carbon atoms, R ³ is A C ₁ -C ₁₀ linear or branched or cyclic alkyl group substituted or unsubstituted with hydroxy; An adamantyl group in which a substituent selected from the group consisting of hydroxy and carboxamide is substituted or unsubstituted; Or - (CH ₂ ) _n -R ⁴ , wherein n is 1 and R ⁴ is a halo-substituted or unsubstituted phenyl group, Or R ² and R ³ are 4-hydroxy-4-trifluoromethyl-piperidine or 1,2,3,4-tetrahydroisoquinoline group formed together with the nitrogen atom to which they are bonded. delete delete The method according to claim 1, Wherein R ¹ is a fluorine atom, a nitro group, a methyl group, or a methoxy group, R ² is a hydrogen atom, a methyl group or a cyclopropyl group, Wherein R ³ is hydroxy substituted or unsubstituted of C ₁ ~C ₁₀ straight or branched chain or cyclic alkyl group; An adamantyl group in which a substituent selected from the group consisting of hydroxy and carboxamide is substituted or unsubstituted; Or - (CH ₂ ) _n -R ⁴ , wherein n is 1 and R ⁴ is a halo-substituted or unsubstituted phenyl group, Or R ² and R ³ are 4-hydroxy-4-trifluoromethyl-piperidine or 1,2,3,4-tetrahydroisoquinoline group formed together with the nitrogen atom to which they are bonded. The method according to claim 1, N- (2-adamantyl) -2,6-dimethyl- 2H -chromene-2-carboxamide, N- (2-adamantyl) -6-methoxy-2-methyl- 2H -chromene- N- (5- hydroxy-2-adamantyl) -6-methoxy-2-methyl -2 H - chromen-2-carboxamide Id, N- (2-adamantyl) -6-fluoro-2-methyl- 2H -chromene- N- (2-adamantyl) -2-methyl-6-nitro- 2H -chromene-2-carboxamide, or N- (5-carbamoyl-2-adamantyl) -2-methyl-6-nitro- 2H -chromene-2-carboxamide. A method for the treatment of type 1 and type 2 diabetes, late diabetes complication, adult latent autoimmune diabetes mellitus (LADA), insulin resistance syndrome, A pharmaceutical composition for the control, prevention, or treatment of obesity, impaired glucose tolerance (IGT), fasting glucose deficiency (IFG), impaired glucose tolerance, dyslipidemia, or hypertension. The method according to claim 6, A pharmaceutical composition for use as an inhibitor of 11 [beta] -HSD1 activity.