KR102611617B1 - A novel GSK3 inhibiting compound, a process for producing the same, and a usage comprising the same - Google Patents

Abstract

It relates to a novel GSK3 inhibitory compound, a method for producing the same, and a pharmaceutical composition for preventing or treating GSK3-related diseases containing the same as an active ingredient.
The GSK-3β inhibitory compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt has excellent selective inhibitory activity against GSK-3β, and can therefore be usefully used in the prevention or treatment of GSK-3-related diseases.

Description

A novel GSK3 inhibiting compound, a process for producing the same, and a usage comprising the same}

It relates to a novel GSK3 inhibitory compound, a method for producing the same, and a pharmaceutical composition for preventing or treating GSK3-related diseases containing the same as an active ingredient.

Glycogen synthase kinase (GSK-3) is a serine/threonine protein kinase that includes α and β isoforms, and these isoforms are each encoded by separate genes (Non-patent Documents 1 and 2).

Threonine/serine kinase GSK-3 plays a central role in various receptor-linked signaling pathways (Non-patent Document 3).

Dysregulation of lipid metabolism, insulin, and growth factors within these pathways is responsible for several prevalent human diseases, such as type II diabetes (non-patent document 4), Alzheimer's disease (non-patent document 5), manic-depressive disorder, and neurodegenerative diseases. It is considered a critical case in the occurrence of central nervous system (CNS) diseases such as diseases and chronic inflammatory symptoms (Non-Patent Document 6). These diseases may be caused by, or may cause, abnormal operation of specific cell signaling pathways in which GSK-3 plays a role.

GSK-3 has been found to regulate the activity of multiple regulatory proteins through phosphorylation. These proteins include glycogen synthase, the rate-limiting enzyme required for glycogen synthesis, microtubule-associated protein Tau, gene transcription factor β-catenin, translation initiation factor e1F2B, and ATP citrate lyase, axin, heat shock factor-1, and c. -Jun, c-Myc, c-Myb, CREB, and CEPBa. These various protein targets are associated with GSK-3 in several aspects of cell metabolism, proliferation, differentiation and development.

That is, to develop new pharmaceutical entities for the treatment of diseases in which inhibition of GSK-3 is not resolved through insulin mimicry, tau dephosphorylation, and amyloid processing or transcriptional regulation, respectively (Non-patent Document 7). It appears to present a practical strategy.

It has been reported that inhibition of GSK-3 triggers neuronal differentiation of embryonic stem cells (ESCs) and helps regeneration of human and mouse ESCs and maintenance of their pluripotency, which makes inhibitors of GSK-3 applicable to regenerative medicine. This suggests that there is (Non-patent Document 8).

The types of GSK-3 inhibitors proposed to date can be classified into seven types depending on their binding site and method, and into three types depending on whether they compete with the substrate ATP. By applying these two criteria, existing GSK-3 inhibitors can be classified into 25 inhibitor types such as 'AR-A014418', 'Hepes', 'GS-2', and 'VP0.7'.

Classifying them again by use, they were clinically tested as anti-cancer drugs like '9-ING-41', or clinical trials were attempted for cranial nerve diseases such as Alzheimer's disease, degenerative brain disease, or bipolar disorder like 'NP031112' or 'Lithium'.

To date, there are no GSK3 inhibitors that have successfully received clinical approval.

Considering its regulatory mechanism and binding site suitability, its development is necessary for metabolic abnormalities such as lipid metabolism and insulin, growth factor abnormalities, central nervous system (CNS) diseases, chronic inflammatory diseases, and anticancer drugs.

Chemistry & Biology, 7, 793-803 (2000). Curr. Opinion Genetics Dev., 10, 508-514 (2000). J. Cell Sci. 116, 1175 (2003). ExpertOpin. Ther. Targets, 2002, 6:555. Prog. Neurobiol. 2001, 65:391. Nature 2000, 406:86-90. Med. Res. Rev., 2002, 22:373. PLoS One, 6, 2237-2247, 2008.

The purpose of one aspect of the present invention is to provide a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for producing the novel GSK-3 inhibitory compound.

The object of another aspect of the present invention is to mediate GSK-3 (Glycogen synthase kinase-3) containing a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a pharmaceutical composition for preventing or treating diseases.

The purpose of another aspect of the present invention is to treat GSK-3 (Glycogen synthase kinase-3)-mediated diseases containing a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a health functional food composition for preventing or improving.

The object of another aspect of the present invention is to administer a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to a subject and/or patient in need thereof. Provides a treatment method for GSK-3 (Glycogen synthase kinase-3)-mediated diseases including the following steps:

The purpose of another aspect of the present invention is to treat GSK-3 (Glycogen synthase kinase-3)-mediated diseases containing a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Provides a diagnostic composition.

In order to achieve the above purpose,

One aspect of the present invention provides a compound represented by the following formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof.

[Formula I]

(In Formula I above,

A is or ego;

X ¹ and X ² are independently carbon or nitrogen atoms;

R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or one or more halogen-substituted C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy , C _1-10 straight or branched alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched alkyl, unsubstituted or C _1-10 straight or branched alkyl substituted with one or more halogens. Sulfonyl, or C _1-10 straight or branched alkylcarbonylamino,

R ² and R ³ are linked together with the atoms to which they are bonded to form a heterocycle of an unsubstituted or substituted 5- to 6-membered ring containing one or more heteroatoms selected from the group consisting of N, O and S, ,

The substituted 5- to 6-membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, and oxo group. It is a heterocyclic ring of 5 to 6 rings,

However, if X ¹ is a nitrogen atom, R ¹ is absent, and if X ² is a nitrogen atom, R ³ is absent; and

where n is an integer from 0 to 2).

In addition, another aspect of the present invention is as shown in Scheme 1 below,

Preparing a compound represented by Formula 3 from a compound represented by Formula 2 (Step 1); and

Preparing a compound represented by Formula I below by reacting the compound represented by Formula 3 prepared in Step 1 with the compound represented by Formula 4 below (Step 2); It provides a method for producing a compound represented by Formula I, including.

[Scheme 1]

(In Scheme 1 above,

A is as defined in Formula 1 above).

Furthermore, another aspect of the present invention is to use the compound represented by Formula (I), its racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof as an active ingredient. Provided is a pharmaceutical composition for preventing or treating GSK-3 (Glycogen synthase kinase-3)-mediated diseases containing.

In addition, another aspect of the present invention is a compound represented by the formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof as an active ingredient. Provided is a health functional food composition for preventing or improving GSK-3 (Glycogen synthase kinase-3)-mediated diseases.

Furthermore, another aspect of the present invention requires a compound represented by the formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof. Provided is a method of treating GSK-3 (Glycogen synthase kinase-3)-mediated diseases, including the step of administering to a subject and/or patient.

In addition, another aspect of the present invention provides the use of the compound represented by Formula I for producing a medicament used for the prevention or treatment of GSK-3 (Glycogen synthase kinase-3)-mediated diseases.

Furthermore, another aspect of the present invention is to use the compound represented by Formula (I), its racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof as an active ingredient. Provided is a composition for diagnosing GSK-3 (Glycogen synthase kinase-3)-mediated diseases containing.

In addition, another aspect of the present invention is to use the compound represented by Formula (I), its racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof as an effective treatment ingredient. Provides a cell composition comprising:

The GSK-3β inhibitory compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt has excellent selective inhibitory activity against GSK-3β, and can therefore be usefully used in the prevention or treatment of GSK-3-related diseases.

Figure 1 is a diagram showing the kinase inhibition efficacy (%) of the compound of Example 3 of the present invention, and it can be seen that the high selectivity for GSK-3β, which was not derived from the existing prior patent material, was confirmed.
Figure 2 is a diagram showing that the GSK-3β inhibitory effect of the compound of Example 3 of the present invention is concentration (30, 10, 3.3, 1, 0.3, 0.1, 0.04, 0.004, 0.0015 uM) dependent.
Figure 3 is a diagram showing that the GSK-3β inhibitory effect of the compound of Example 9 of the present invention is concentration dependent.

Hereinafter, the present invention will be described in detail.

Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, the embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field. Furthermore, “including” a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless specifically stated to the contrary.

One aspect of the present invention provides a compound represented by the following formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof.

[Formula I]

In Formula I above,

A is or ego;

X ¹ and X ² are independently carbon or nitrogen atoms;

R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or one or more halogen-substituted C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy , C _1-10 straight or branched alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched alkyl, unsubstituted or C _1-10 straight or branched alkyl substituted with one or more halogens. Sulfonyl, or C _1-10 straight or branched alkylcarbonylamino,

R ² and R ³ are linked together with the atoms to which they are bonded to form a heterocycle of an unsubstituted or substituted 5- to 6-membered ring containing one or more heteroatoms selected from the group consisting of N, O and S, ,

The substituted 5- to 6-membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, and oxo group. It is a heterocyclic ring of 5 to 6 rings,

However, if X ¹ is a nitrogen atom, R ¹ is absent, and if X ² is a nitrogen atom, R ³ is absent; and

The n may be an integer from 0 to 2.

On the other side,

R ¹ , R ² and R ³ are independently -H, -F, -Cl, -Br, -CN, unsubstituted or one or more halogen-substituted C _1-5 straight or branched alkyl, C _{1- 5} straight or branched alkoxy, C _1-5 straight or branched alkylsulfanyl, C ₆ aryl, C _1-3 straight or branched alkyl, unsubstituted or substituted with one or more halogens, C _1-5 It is straight or branched chain alkylsulfonyl, or C _1-5 straight or branched chain alkylcarbonylamino,

R ² and R ³ are linked together with the atoms to which they are bonded to form a heterocycle of an unsubstituted or substituted 5- to 6-membered ring containing one or more heteroatoms selected from the group consisting of N, O and S, ,

The substituted 5- to 6-membered ring heterocycle is a 5- to 6-membered ring heterocycle substituted with one or more substituents selected from the group consisting of C _1-3 straight or branched alkyl and oxo groups,

However, if X ¹ is a nitrogen atom, R ¹ is absent, and if X ² is a nitrogen atom, R ³ is absent; and

The n may be an integer of 0 or 1.

From another aspect,

R ¹ and R ³ are independently -H, -F, -Cl, -Br, -CN, unsubstituted or one or more halogen-substituted C _1-5 straight or branched alkyl, C _1-5 straight chain or branched alkoxy, straight or branched chain alkylsulfanyl of C _1-5 , aryl of C ₆ straight or branched chain alkyl of C _1-3 , unsubstituted or substituted by one or more halogens, straight or branched chain of C _1-5 chain alkylsulfonyl, or C _1-5 straight or branched chain alkylcarbonylamino,

R ² is -H, -F, -Cl, -Br, -CN, straight or branched C _1-5 alkyl unsubstituted or substituted with one or more halogens, straight or branched C _1-5 alkyl sulpha Nyl, C ₆ aryl, C _1-3 straight or branched alkyl, unsubstituted or C _1-5 straight or branched alkylsulfonyl substituted with one or more halogens, or C _1-5 straight or branched alkyl Carbonylamino, or

R ² and R ³ are linked together with the atoms to which they are bonded to form a heterocycle of an unsubstituted or substituted 5- to 6-membered ring containing one or more heteroatoms selected from the group consisting of N, O and S, ,

The substituted 5- to 6-membered ring heterocycle is a 5- to 6-membered ring heterocycle substituted with one or more substituents selected from the group consisting of C _1-3 straight or branched alkyl and oxo groups,

However, when X ¹ is a nitrogen atom, R ¹ is absent, when X ² is a nitrogen atom, R ³ is absent, and when both X ¹ and X ² are carbon atoms simultaneously, among R ¹ , R ² and R ³ Neither -H; and

The n may be an integer of 0.

On the other side,

Wherein R ¹ is -H, benzyl, or -OCH ₃ ego,

The R ² is -H, -F, -Br, -CF ₃ , -SCH ₃ , -S(=O) ₂ CF ₃ , or -NHC(=O)CH ₃ ego,

The R ³ is -H, -Cl, -CN, or -OCH ₃ This is,

The R ² and R ³ are connected together with the atoms to which they are bonded. or forming;

When both X ¹ and X ² are carbon atoms at the same time, any one of R ¹ , R ² and R ³ is not -H; and

The n may be an integer of 0.

From another aspect,

The compound represented by the formula (I) may be any one compound selected from the following compound group.

(1) 5-phenyl-3-((1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;

(2) 3-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;

(3) 3-((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5]unde car-7,10-diene-4,9-dione;

(4) 3-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;

(5) 5-phenyl-3-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-5-aza spiro[5.5]undeca-7,10-diene-4,9-dione;

(6) 3-(4-((4,9-dioxo-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-dien-3-yl)methyl)-1H- 1,2,3-triazol-1-yl)benzonitrile;

(7) 3-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;

(8) 3-((1-(4-(methylthio)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[ 5.5]undeca-7,10-diene-4,9-dione;

(9) 3-((1-(3-benzylphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5]unde car-7,10-diene-4,9-dione;

(10) 5-phenyl-3-((1-(4-((trifluoromethyl)sulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa -5-azaspiro[5.5]undeca-7,10-diene-4,9-dione;

(11) N-(4-(4-((4,9-dioxo-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-dien-3-yl)methyl) -1H-1,2,3-triazol-1-yl)phenyl)acetamide;

(12) 3-((1-(3,5-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[ 5.5]undeca-7,10-diene-4,9-dione;

(13) 3-((1-(4-fluoro-3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5- Azaspiro[5.5]undeca-7,10-diene-4,9-dione;

(14) 3-((1-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl- 1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione;

(15) 3-((1-(4-methyl-2-oxo-2H-chromen-7-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl- 1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione;

(16) 3-((1-((3R,5S)-adamantan-1-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa -5-azaspiro[5.5]undeca-7,10-diene-4,9-dione;

(17) 3-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10 -diene-4,9-dione; and

(18) 5-phenyl-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-5-azaspiro[5.5]undeca-7,10 -Diene-4,9-dione.

The compound represented by the formula (I) of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Includes glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

The acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of formula (I) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. Additionally, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (e.g., silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula (I) and its pharmaceutically acceptable salts, but also solvates, optical isomers, hydrates, etc. that can be prepared therefrom.

Another aspect of the present invention is as shown in Scheme 1 below,

Preparing a compound represented by Formula 3 from a compound represented by Formula 2 (Step 1); and

Preparing a compound represented by Formula I below by reacting the compound represented by Formula 3 prepared in Step 1 with the compound represented by Formula 4 below (Step 2); It provides a method for producing a compound represented by Formula I, including.

[Scheme 1]

In Scheme 1 above,

A is as defined in Formula I above.

In the above production method, the terminal amine group of the formula 2 is reacted with NaN ₃ to convert it into a -N ₃ group, and the -N ₃ group is reacted with the C≡C bond represented by the formula 4, finally represented by the formula I. It consists of the step of manufacturing a compound.

Reagents used in Step 1: NaNO ₂ , NaN ₃ , 6N HCl

Reagents used in Step 2: CuSO ₄ , THF:H ₂ O, Sodium Ascorbate

Another aspect of the present invention contains the compound represented by Formula I, its racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof as an active ingredient. Provided is a pharmaceutical composition for preventing or treating GSK-3 (Glycogen synthase kinase-3)-mediated diseases.

The disease may be caused by overexpression of GSK-3 (Glycogen synthase kinase-3), and the compound may prevent or treat the disease by inhibiting the expression of GSK-3.

The above diseases include diabetes, Alzheimer's disease, Parkinson's disease, pugilistic encephalitis, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntington's disease, AIDS-related dementia, amyotrophic lateral sclerosis, multiple sclerosis, stroke, epilepsy, depression, and mental illness. Schizophrenia, bipolar disorder, hair loss, obesity, cardiovascular atherosclerosis, hypertension, polycystic ovary syndrome, syndrome It may be any one or more diseases selected from the group consisting of, but can be applied without limitation as long as it is a known disease related to GSK-3.

The compound represented by Formula I or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations contain one or more compounds and at least one excipient, such as starch, calcium carbonate, sucrose, or lactose ( It is prepared by mixing lactose, gelatin, etc. Additionally, in addition to simple excipients, lubricants such as magnesium stearate, talc, etc. are also used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate.

A pharmaceutical composition containing the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be done by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. It depends on how you do it.

At this time, in order to formulate a formulation for parenteral administration, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is mixed with water along with a stabilizer or buffer to prepare a solution or suspension, which is administered in ampoule or vial unit dosage form. It can be manufactured with The composition may be sterilized and/or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be mixed, granulated, etc. using conventional methods. It can be formulated according to the coating or coating method.

The dosage of the pharmaceutical composition to the human body may vary depending on the patient's age, weight, gender, dosage form, health condition, and degree of disease, and is preferably administered in an amount of 0.01 to 1000 mg/kg/day by a doctor or Depending on the pharmacist's judgment, it can be administered through oral or parenteral routes at certain time intervals, divided into several times a day, preferably once to three times a day.

Dosage forms for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. These dosage forms contain a diluent (e.g. lactose) in addition to the active ingredient. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron agents such as starch, agar, alginic acid or its sodium salt, etc. The releasing or boiling mixture may contain absorbents, colorants, flavors, and sweeteners.

Another aspect of the present invention is a compound containing the compound represented by Formula I, its racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof as an active ingredient. Provides a health functional food composition for preventing or improving GSK-3 (Glycogen synthase kinase-3)-mediated diseases.

The compound represented by the formula (I) according to the present invention can be added directly to food or used together with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention or improvement). Generally, the amount of the above compound in health food can be 0.1 to 90 parts by weight of the total weight of the food. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

In addition, the health functional beverage composition of the present invention has no particular restrictions on other ingredients other than containing the above compounds as essential ingredients in the indicated proportions, and may contain various flavoring agents or natural carbohydrates as additional ingredients like ordinary drinks. there is. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the composition of the present invention.

Furthermore, in addition to the above, the compound represented by Formula I according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, colorants and thickening agents (cheese, chocolate, etc.), and pects. It may contain acids and their salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the compound represented by Formula 1 of the present invention may contain pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages.

Another aspect of the present invention is a compound represented by the formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof. Provided is a method of treating a GSK-3 (Glycogen synthase kinase-3)-mediated disease comprising administering to a subject and/or patient.

Another aspect of the present invention provides the use of the compound represented by Formula I for producing a medicament used for the prevention or treatment of GSK-3 (Glycogen synthase kinase-3)-mediated diseases. .

Another aspect of the present invention contains the compound represented by Formula I, its racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or pharmaceutically acceptable salt thereof as an active ingredient. Provides a composition for diagnosing GSK-3 (Glycogen synthase kinase-3)-mediated diseases.

Another aspect of the present invention is a compound represented by the formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof. Methods for inhibiting the enzymatic activity of GSK-3 (Glycogen synthase kinase-3), uses for inhibiting them, and industrial uses including these are provided.

Another aspect of the present invention is a compound represented by the formula (I), a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate, or a pharmaceutically acceptable salt thereof as an effective treatment ingredient. Provided is a cell composition that

The GSK-3β inhibitory compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt has excellent selective inhibitory activity against GSK-3β, and can be usefully used in the prevention or treatment of GSK-3-related diseases. This is directly supported by the examples and experimental examples described later.

Hereinafter, the present invention will be described in detail through examples and experimental examples described below.

However, the examples and experimental examples described below only partially illustrate the present invention, and the present invention is not limited thereto.

< Example 1> 5-phenyl-3-((1-(pyridin-3-yl)-1H-1,2,3- Triazole -4-day) methyl )-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

3-(2-propynyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione compound represented by the following formula A, Korea It was prepared with reference to Example 38 of Publication Patent No. 10-2018-0028391.

[Formula A]

3-(2-propynyl)-5-phenyl-1-oxa-5-azaspiro[5,5]undeca-7,10-diene-4,9-dione compound represented by Formula A (1 mmol ) was dissolved in a solvent mixed with tetrahydrofuran (THF) and distilled water (H ₂ O) at 5°C in a 1:1 (v/v) ratio, and then 3-azidopyridine (NaNO from pyridin-3-amine) ₂ , NaN ₃ , prepared using 6N HCl) (1.5 mmol) and CuSO ₄ ·5H ₂ O (2 mmol) were added. Afterwards, sodium ascorbate (1 mmol) was added and the temperature was gradually raised to room temperature (about 20-23°C) while stirring.

After confirming the consumption of the starting material by TLC, extraction was performed with ethyl acetate, and the organic layer was washed with brine solution and dried over sodium sulfate. The pressure was lowered to remove the solvent, and then purified through flash column chromatography on silica gel to obtain the title compound.

Dark brown liquid; 92% yield; IR (neat): 2972, 2854, 2760, 1708, 1697 1619,, 1535, 1479, 1260, 867, 715 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 8.12 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.51 (dd, J = 24.5, 6.8 Hz, 2H), 7.28 (dd, J = 4.8, 2.5 Hz, 4H), 7.19 (dd, J = 10.3, 3.2 Hz, 1H), 7.01 - 6.96 (m, 2H), 6.83 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.61 (dd, J = 12.1, 9.6 Hz, 1H), 4.40 (dd, J = 12.2, 6.4 Hz, 1H) , 3.43 (dd, J = 15.0, 6.8 Hz, 1H), 3.38 - 3.32 (m, 1H), 3.20 (dd, J = 15.0, 4.0 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.87, 169.46, 144.56, 142.76, 136.28, 129.80 (2 C), 129.77 (2 C), 129.67 (2 C), 129.03 (3 C), 128.97, 128.8 9, 127.79 , 120.80, 119.83, 83.40, 63.65, 41.41, 23.53 ppm.

Based on the synthesis script of Example 1, the compounds of Examples 2 to 18 below were prepared.

< Example 2> 3-((1-(4- fluorophenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Yellow liquid; 88% yield; IR (neat): 2980, 2935, 2719, 1720, 1673 1640, 1538, 1261, 882, 705 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.75 - 7.69 (m, 2H), 7.34 - 7.27 (m, 3H), 7.27 - 7.22 (m, 2H), 7.20 (dd, J = 10.3, 3.2 Hz, 1H), 6.98 (d, J = 6.3 Hz, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.13 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.65 (dd, J = 12.1, 9.6 Hz, 1H), 4.40 (dd, J = 12.2, 6.5 Hz, 1H), 3.43 (dd, J = 15.0, 6.9 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.19 (dd, J = 14.9, 3.8 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.76, 169.34, 163.01, 161.36, 145.01, 144.49, 142.67, 136.20, 133.02, 129.63, 129.60, 129.56, 128.8 6 (2 C), 128.79, 122.16, 122.10, 120.91, 116.63 , 116.47, 83.23, 63.52, 41.31, 23.40 ppm.

< Example 3> 3-((1-(3- Chlorophenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Light yellow liquid; 90% yield; IR (neat): 2930, 2926, 2836, 2738, 1738, 1671 1646, 1478, 715 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.80 (t, J = 2.0 Hz, 1H), 7.64 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.53 - 7.42 ( m, 2H), 7.35 - 7.28 (m, 3H), 7.17 (dd, J = 10.3, 3.2 Hz, 1H), 7.03 - 6.94 (m, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H) , 6.13 (dd, J = 10.3, 2.0 Hz, 1H), 6.04 (dd, J = 10.2, 2.0 Hz, 1H), 4.62 (dd, J = 12.2, 9.6 Hz, 1H), 4.40 (dd, J = 12.2 , 6.5 Hz, 1H), 3.44 (dd, J = 15.0, 6.8 Hz, 1H), 3.38 - 3.30 (m, 1H), 3.19 (dd, J = 15.0, 3.9 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.96, 169.56, 145.37, 144.68, 142.82, 137.77, 136.37, 135.65, 130.87, 129.86, 129.84, 129.77 (2 C), 1 29.10 (2 C), 129.04, 128.83, 120.91 , 120.64, 118.29, 83.45, 63.68, 41.51, 23.62 ppm.

< Example 4> 3-((1-(4- bromophenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Light brown liquid; 95% yield; IR (neat): 2932, 2864, 2736, 1728, 1680, 1578, 1439, 705 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.71 - 7.66 (m, 2H), 7.66 - 7.61 (m, 2H), 7.28-7.28 (m, 3H), 7.18 (dd, J = 10.3, 3.2 Hz, 1H), 6.98 (d, J = 6.4 Hz, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.13 (dd, J = 10.3, 2.0 Hz, 1H), 6.04 (dd, J = 10.2, 2.0 Hz, 1H), 4.64 (dd, J = 12.1, 9.7 Hz, 1H), 4.40 (dd, J = 12.2, 6.5 Hz, 1H), 3.43 (dd, J = 15.0, 6.8 Hz, 1H), 3.39 - 3.32 (m, 1H), 3.18 (dd, J = 15.0, 3.9 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.95, 169.54, 144.68, 142.83, 136.39, 135.91, 132.94, 129.86, 129.82, 129.76 (3 C), 129.09 (4 C), 129.0 2, 122.40, 121.73, 120.79, 83.45 , 63.71, 41.52, 23.61 ppm.

< Example 5> 5-phenyl-3-((1-(4-( trifluoromethyl )phenyl)-1H-1,2,3- Triazole -4-yl)methyl)-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Pale yellow liquid; 89% yield; IR (neat): 2920, 2860, 2698, 1718, 1678, 1568, 1438, 715 cm ^-1 ;

^1H NMR (600 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.28-7.34 (m, 3H) , 7.19 (dd, J = 10.3, 3.2 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.13 (dd, J = 10.3, 2.0 Hz, 1H) ), 6.04 (dd, J = 10.2, 2.0 Hz, 1H), 4.64 (dd, J = 12.2, 9.7 Hz, 1H), 4.42 (dd, J = 12.2, 6.5 Hz, 1H), 3.45 (dd, J = 15.0, 6.7 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.21 (dd, J = 15.0, 3.9 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.93, 169.52, 145.69, 144.65, 142.77, 129.90, 129.86, 129.75 (2 C), 129.12 (4 C), 129.06, 127.16, 127.1 4, 124.42, 120.82, 120.77, 120.28 (2 C), 83.48, 63.73, 41.53, 23.61 ppm.

< Example 6> 3-(4-((4,9- dioxo -5-phenyl-1-oxa-5- Azaspiro [5.5] Undeka -7,10-dien-3-yl)methyl)-1H-1,2,3-triazol-1-yl)benzonitrile

Brown liquid; 87% yield; IR (neat): 2932, 2867, 2678, 1715, 1658, 1430, 715 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.09 - 8.05 (m, 1H), 8.03 - 7.97 (m, 1H), 7.93 (s, 1H), 7.75 - 7.70 (m, 1H), 7.66 (dd, J = 12.9, 4.9 Hz, 1H), 7.31-7.26 (m, 3H), 7.17 (dd, J = 10.3, 3.2 Hz, 1H), 6.99 - 6.95 (m, 2H), 6.82 (dd, J = 10.2, 3.2 Hz, 1H), 6.11 (dd, J = 10.3, 2.0 Hz, 1H), 6.02 (dd, J = 10.2, 2.0 Hz, 1H), 4.59 (dd, J = 12.1, 9.6 Hz, 1H), 4.39 (dd , J = 12.2, 6.4 Hz, 1H), 3.41 (dd, J = 15.0, 6.7 Hz, 1H), 3.38 - 3.32 (m, 1H), 3.18 (dd, J = 15.0, 4.1 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.72, 169.37, 144.39, 142.54, 136.12, 131.84, 130.71, 129.72, 129.69 (2 C), 129.54, 128.93 (4 C), 128.9 0, 128.79, 124.01, 123.30, 119.70 , 114.06, 83.31, 63.53, 41.30, 23.43 ppm.

< Example 7> 3-((1-(4- Methoxyphenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Yellow liquid; 93% yield; IR (neat): 2920, 2851, 1728, 1678, 1518, 1392, 1094, 698 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.80 (s, 1H), 7.64 (d, J = 9.0 Hz, 2H), 7.32 - 7.28 (m, 3H), 7.19 (dd, J = 10.3, 3.2 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 6.98 (dd, J = 7.7, 1.5 Hz, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3) , 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.67 (dd, J = 12.2, 9.7 Hz, 1H), 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.90 (s, 3H), 3.44 (dd, J = 15.0, 6.9 Hz, 1H), 3.40 - 3.31 (m, 1H), 3.18 (dd, J = 15.0, 3.7 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 184.02, 169.59, 159.83, 144.78, 142.96, 136.47, 130.44, 129.83, 129.80 (3 C), 129.07 (2 C), 128.97 (2 C), 1 22.02 (2 C) , 121.11, 114.80 (2 C), 83.43, 63.74, 55.65, 41.54, 31.94 ppm.

< Example 8> 3-((1-(4-( methylthio )phenyl)-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Dark yellow liquid; 92% yield; IR (neat): 2996, 2838, 2748, 1718, 1680, 1520, 1379, 715 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.97 - 7.94 (m, 1H), 7.85 (s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.7 Hz, 1H) , 7.34 - 7.29 (m, 3H), 7.18 (dd, J = 10.3, 3.3 Hz, 1H), 6.98 (t, J = 6.1 Hz, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.65 (dd, J = 12.1, 9.6 Hz, 1H), 4.43 - 4.33 (m, 1H) , 3.44 (ddd, J = 15.0, 6.7, 3.2 Hz, 1H), 3.39 - 3.32 (m, 1H), 3.18 (dd, J = 15.1, 3.7 Hz, 1H); 2.66 (s, 3H) ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.81, 169.39, 144.55, 142.71, 139.79, 136.24, 129.65, 129.62, 129.59, 129.57 (2 C), 128.9 2, 128.89 (4 C), 128.81 , 126.97, 120.56, 83.25, 63.53, 41.34, 31.75, 22.51, 13.94 ppm.

< Example 9> 3-((1-(3- Benzylphenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Pale brown liquid; 84% yield; IR (neat): 2960, 2920, 2836, 2789, 2672, 1715, 1587, 1314, 697 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.82 (s, 1H), 7.57 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.28 (d, J = 7.2 Hz, 2H), 7.25-7.19 (m, 5H), 7.15 (dd, J = 10.3, 3.2 Hz, 1H), 6.95 (d, J = 7.1 Hz, 2H), 6.81 (dd, J = 10.2, 3.2 Hz, 1H), 6.09 (dd, J = 10.3, 2.0 Hz, 1H), 6.01 (dd, J = 10.2, 2.0 Hz, 1H), 4.62 (dd , J = 12.2, 9.7 Hz, 1H), 4.37 (dd, J = 12.2, 6.6 Hz, 1H), 4.06 (s, 2H), 3.41 (dd, J = 15.0, 6.9 Hz, 1H), 3.35 - 3.27 ( m, 1H), 3.15 (dd, J = 14.9, 3.7 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 184.01, 169.58, 144.95, 144.75, 143.37, 142.93, 139.96, 137.12, 136.43, 129.85, 129.83, 129.80, 129.7 9 (2 C), 129.40, 129.07 (2 C), 128.98 , 128.91 (2 C), 128.71 (2 C), 126.54, 121.05, 120.92, 118.21, 83.43, 63.70, 41.75, 41.54, 23.63.

< Example 10> 5-phenyl-3-((1-(4-(( trifluoromethyl ) Sulfonyl )phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Light yellow liquid; 80% yield; IR (neat): 2960, 2951, 2852, 2790, 2672, 1720, 1687, 1214, 790 cm ^{-1 1} H NMR (600 MHz, CDCl ₃ ) δ 8.22 (d, J = 8.7 Hz, 2H), 8.10 ( d, J = 8.8 Hz, 2H), 8.05 (s, 1H), 7.33 - 7.27 (m, 4H), 7.16 (dd, J = 10.3, 3.2 Hz, 1H), 6.98 (d, J = 6.6 Hz, 2H) ), 6.83 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.58 (dd, J = 12.1, 9.6 Hz, 1H), 4.40 (dd, J = 12.1, 6.4 Hz, 1H), 3.42 (dd, J = 15.0, 6.6 Hz, 1H), 3.38 - 3.33 (m, 1H), 3.21 (dd, J = 15.0, 4.2 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.95, 169.59, 146.49, 144.59, 142.73, 142.70, 136.35, 133.00, 130.90, 130.03, 129.99, 129.80 (3 C), 1 29.22 (4 C), 129.08, 120.77, 83.60 , 63.80, 41.58, 23.70 ppm.

< Example 11> N-(4-(4-((4,9- dioxo -5-phenyl-1-oxa-5- Azaspiro [5.5] Undeka -7,10-dien-3-yl)methyl)-1H-1,2,3-triazol-1-yl)phenyl)acetamide

Brown gummy liquid; 78% yield; IR (neat): 3246, 2989, 2942, 2780, 2670, 1720, 1688, 1314, 710 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.82 (s, 1H), 7.69-7.63 (m, 3H), 7.47 (s, 1H), 7.33 - 7.28 (m, 4H), 7.24 (dd, J = 10.3 , 3.1 Hz, 1H), 7.00 (d, J = 6.3 Hz, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.14 (dd, J = 10.3, 2.0 Hz, 1H), 6.04 (dd , J = 10.2, 2.0 Hz, 1H), 4.68 (dd, J = 12.1, 9.8 Hz, 1H), 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.45 (dd, J = 15.1, 6.8 Hz, 1H), 3.39-3.33 (m, 1H), 3.17 (dd, J = 15.1, 3.7 Hz, 1H), 2.22 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 181.77, 169.46, 168.20, 144.75, 144.53 (2 C), 142.71, 136.22, 129.70, 129.66 (2 C), 129.63, 129.58, 128.8 8 (4 C), 128.82, 120.84 , 120.60, 120.30, 83.26, 63.52, 41.21, 23.36, 22.50 ppm.

< Example 12> 3-((1-(3,5- Dimethoxyphenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Pale yellow liquid; 74% yield; IR (neat): 2980, 2842, 2765, 2679, 1708, 1687, 1414, 710 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.83 (s, 1H), 7.33 - 7.27 (m, 4H), 7.15 (dd, J = 10.3, 3.2 Hz, 1H), 6.97 (dd, J = 8.8, 2.8 Hz, 2H), 6.88 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 10.2, 3.2 Hz, 1H), 6.52 (t, J = 2.2 Hz, 1H), 6.11 (dd, J = 10.3 , 2.0 Hz, 1H), 6.02 (dd, J = 10.2, 2.0 Hz, 1H), 4.63 (dd, J = 12.2, 9.7 Hz, 1H), 4.38 (dd, J = 12.2, 6.6 Hz, 1H), 3.86 (s, 6H), 3.46 - 3.39 (m, 1H), 3.34 (ddd, J = 12.8, 6.6, 3.3 Hz, 1H), 3.17 (dd, J = 15.0, 3.8 Hz, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 182.95, 168.54, 147.10, 147.03, 143.69, 141.85, 135.39, 128.82 (2 C), 128.79 (2 C), 128.75 (2 C), 128.06, 1 27.98, 119.96, 115.09 (2 C), 112.69, 108.43, 82.42, 62.70, 55.51 (2 C), 40.49, 22.58 ppm.

< Example 13> 3-((1-(4- fluoro -3- Methoxyphenyl )-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Dark yellow liquid; 74% yield; IR (neat): 2984, 2832, 2865, 2568, 1718, 1584, 1320, 697 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.81 (s, 1H), 7.55 (dd, J = 11.3, 2.5 Hz, 1H), 7.46 - 7.41 (m, 1H), 7.31 (dd, J = 11.9, 6.9 Hz, 3H), 7.19 (dd, J = 10.3, 3.2 Hz, 1H), 7.09 (t, J = 8.7 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.84 (dd, J = 10.2, 3.2 Hz) , 1H), 6.13 (dd, J = 10.3, 1.9 Hz, 1H), 6.04 (dd, J = 10.2, 2.0 Hz, 1H), 4.64 (dd, J = 12.1, 9.7 Hz, 1H), 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.98 (s, 3H), 3.43 (dd, J = 14.9, 6.8 Hz, 1H), 3.38-3.32 (m, 1H), 3.18 (dd, J = 14.9, 3.7 Hz) , 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 183.93, 169.52, 148.08, 148.00, 144.67, 142.83, 136.37, 129.80, 129.77, 129.73 (2 C), 129.04 (4 C), 128.9 6, 120.94, 116.06, 113.67, 109.41 , 83.40, 63.68, 56.49, 41.47, 22.65 ppm.

< Example 14> 3-((1-( Benzo[d][1,3]dioxol -5-day)-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Pale dark liquid; 96% yield; IR (neat): 2918, 2852, 2825, 1715, 1679, 1584, 1320, 697 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.78 (s, 1H), 7.34 - 7.29 (m, 3H), 7.26 (d, J = 2.2 Hz, 1H), 7.19 (dd, J = 10.3, 3.2 Hz, 1H), 7.13 (dd, J = 8.3, 2.2 Hz, 1H), 7.01 - 6.96 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H) ), 6.13 (dd, J = 10.3, 2.0 Hz, 1H), 6.10 (s, 2H), 6.04 (dd, J = 10.2, 2.0 Hz, 1H), 4.65 (dd, J = 12.2, 9.6 Hz, 1H) , 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.43 (dd, J = 15.0, 6.9 Hz, 1H), 3.38 - 3.32 (m, 1H), 3.17 (dd, J = 14.9, 3.7 Hz, 1H) ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 180.08, 169.59, 144.84, 144.75, 144.28, 142.92, 136.43, 129.83, 129.80, 129.79 (2 C), 129.08 (4 C), 128.9 9, 121.24, 114.04, 108.52, 102.59 , 102.13, 83.43, 63.72, 41.51, 22.70 ppm.

< Example 15> 3-((1-(4- methyl -2-oxo-2H- chromen -7-day)-1H-1,2,3- Triazole -4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Brown gummy liquid; 85% yield; IR (neat): 2988, 2862, 2718, 1740, 1710, 1689, 1489, 1270, 1098, 733 cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.78 - 7.73 (m, 2H), 7.71 (d, J = 1.1 Hz, 1H), 7.33 - 7.27 (m, 3H), 7.19 ( dd, J = 10.3, 3.2 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.83 (dd, J = 10.2, 3.2 Hz, 1H), 6.37 (d, J = 1.1 Hz, 1H), 6.12 (dd , J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.62 (dd, J = 12.1, 9.5 Hz, 1H), 4.40 (dd, J = 12.2, 6.4 Hz, 1H), 3.43 (dd, J = 15.0, 6.8 Hz, 1H), 3.38-3.32 (m, 1H), 3.20 (dd, J = 15.0, 3.9 Hz, 1H), 2.49 (d, J = 1.1 Hz, 3H) ); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 184.00, 169.59, 159.96, 151.51, 144.68, 142.89, 136.41, 133.40, 129.94, 129.90, 129.81 (3 C), 129.17 (4 C) ), 129.11, 126.29, 120.81, 115.78 , 115.74, 108.40, 83.53, 63.80, 41.51, 23.67, 18.76 ppm.

< Example 16> 3-((1-(( 3R, 5S )- Adamantane -1-day)-1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione

Light brown liquid; 89% yield; IR (neat): 2957, 2922, 2852, 1708, 1690, 1592, 1486, 1356, 760, 697 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 7.30 (d, J = 6.0 Hz, 3H), 7.09 (dd, J = 10.3, 3.1 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.81 (dd, J = 10.2, 3.1 Hz, 1H), 6.11 (dd, J = 10.3, 1.8 Hz, 1H), 6.01 (dd, J = 10.2, 1.9 Hz, 1H), 4.65 (dd, J = 12.1, 9.8 Hz, 1H), 4.35 (dd, J = 12.2, 6.8 Hz, 1H), 3.37 (dd, J = 14.8, 6.9 Hz, 1H), 3.32-3.25 (m, 1H), 3.08 (dd, J = 14.8, 3.3 Hz, 1H), 2.29 (s, 3H), 2.25 (s, 6H), 1.82 (q, J = 12.5 Hz, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 184.08, 169.66, 144.86, 143.08, 136.57, 129.78 (2 C), 129.74, 129.70, 129.01 (2 C), 128.92, 123.98, 119.1 9, 83.32, 63.71, 59.50, 43.06 (2 C), 41.50, 35.91 (2 C), 31.94, 29.67, 29.44 (2 C), 29.37, 22.70 ppm.

< Example 17> 3-((1- benzyl -1H-1,2,3- Triazole -4-day) methyl )-5-phenyl-1-oxa-5- Azaspiro [5.5] Undeka -7,10-diene-4,9-dione

Brown liquid; 82% yield; IR (neat): 2989, 2939, 2852, 1715, 1590, 1448, 1378, 1170, 715, cm ^-1 ; ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.43 - 7.37 (m, 4H), 7.34 - 7.29 (m, 3H), 7.25 (t, J = 7.4 Hz, 2H), 6.92 (dd, J = 10.3, 3.2 Hz, 1H), 6.83 (d, J = 7.3 Hz, 2H), 6.78 (dd, J = 10.2, 3.2 Hz, 1H), 6.06 (dd, J = 10.3, 2.0 Hz, 1H), 5.99 (dd, J = 10.2, 2.0 Hz, 1H), 5.59 (d, J = 14.8 Hz, 1H), 5.46 (d, J = 14.8 Hz, 1H), 4.49 (dd, J = 12.1, 9.8 Hz, 1H), 4.33 (dd , J = 12.2, 6.7 Hz, 1H), 3.38 (dd, J = 15.0, 6.5 Hz, 1H), 3.33 - 3.23 (m, 1H), 3.06 (dd, J = 15.0, 3.7 Hz, 1H); ¹³ C NMR (151 MHz, CDCl ₃ ) δ 183.99, 177.33, 169.45, 144.71, 142.85, 136.39, 134.79, 130.50, 129.73, 129.67 (3 C), 129.18 (2 C), 129.0 4 (2 C), 128.90, 128.86 , 128.06 (2 C), 83.27, 63.60, 54.20, 41.29, 23.61 ppm.

< Example 18> 5-phenyl-3-((1-phenyl-1H-1,2,3- Triazole -4-day) methyl )-1-oxa-5- Azaspiro [5.5] Undeka -7,10-diene-4,9-dione

Light brown liquid; 94% yield; IR (neat): 2978, 2940, 2856, 2758, 1710, 1686, 1538, 1518, 1489, 1358, 1260, 868, 705 cm ^-1 ; ^1H NMR (600 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.74 (dd, J = 8.6, 1.1 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.49 - 7.45 (m, 1H), 7.33 - 7.26 (m, 3H), 7.18 (dd, J = 10.3, 3.2 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.84 (dd, J = 10.2, 3.2 Hz, 1H), 6.12 (dd, J = 10.3, 2.0 Hz, 1H), 6.03 (dd, J = 10.2, 2.0 Hz, 1H), 4.65 (dd, J = 12.2, 9.6 Hz, 1H), 4.40 (dd, J = 12.2, 6.6 Hz, 1H), 3.45 (dd, J = 15.0, 6.9 Hz, 1H), 3.41 - 3.31 (m, 1H), 3.19 (dd, J = 15.0, 3.8 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ 184.02, 169.61, 144.74, 142.93, 136.97, 136.43, 129.84, 129.81 (4 C), 129.08 (3 C), 128.99, 128.80 (2 C), 1 21.00, 120.40 (2 C), 83.44, 63.71, 41.55, 23.65 ppm.

The chemical structures of the compounds prepared in Examples 1 to 18 are summarized and shown in Table 1 below.

Example structure Example structure One 10 2 11 3 12 4 13 5 14 6 15 7 16 8 17 9 18

<Experimental Example 1> Enzyme inhibitory activity selectivity evaluation

In order to evaluate the selectivity of the example compounds according to the present invention for various enzyme inhibitory activities, the following experiment was performed.

The selectivity of the example compounds of the invention against a panel of kinases (Reaction Biology Corp) was investigated. Using radiolabeled ATP ([γ- ³³ P] ATP), the extent to which the substrate is replaced by the ³³ P-phosphorylated substrate was measured, and changes in the activity of the kinase were measured from the measurement of the radiolabeled phosphorylated substrate. Example compounds were tested at 30 μM for an ATP concentration of 10 μM and a substrate concentration of 10 μM.

As control compounds, Staurosporine or PI-103, NH125, GSK-2606414, JNKi VIII, SB202190, GW5074 were tested in 10-dose IC ₅₀ mode at 4-fold serial dilutions starting at 20 or 100 μM. Example compounds were tested in 10 dose IC ₅₀ mode with 3- or 4-fold serial dilutions starting at 10, 20 or 100 μM. Curve fitting of control compounds with enzyme activity less than 65% of the compound at the highest concentration was performed, the concentration of DMSO was adjusted, and based on the raw data, enzyme activity relative to the DMSO control was calculated, and each of the 369 enzymes calculated. Among the inhibitory activities of the example compounds, the enzymes showing significant results and their inhibitory activity (%) are shown in Table 2 below.

Kinase
Residual enzyme activity (%)
(Calculated value compared to DMSO control group) 1st round 2nd round GSK3β 2.81 1.64 AMPK(A2/B1/G1) 50.81 47.50 CDK2/cyclin O 54.36 54.15 CDK1/cyclin B 59.28 58.64 AMPK(A1/B1/G1) 60.89 60.04 CDK3/cyclin E 61.64 59.02 PKCa 62.98 62.24 STK25/YSK1 63.29 61.07 PDK2/PDHK2 64.28 63.30 TRPM7/CHAK1 67.49 63.76 AMPK(A1/B1/G2) 68.01 66.48 EIF2AK3 70.78 70.64 Haspin 71.58 70.31 DAPK1 75.82 73.41 JNK2 80.30 79.67 TLK1 82.06 81.34 JNK1 82.70 82.67 PDK1/PDHK1 85.62 85.01 PDK3/PDHK3 85.93 82.28 RIPK5 86.12 83.85 ZIPK/DAPK3 88.84 86.95 EIF2AK1 91.72 87.95 TRKC (G623R) 92.10 90.32 ARK5/NUAK1 93.57 84.16 AMPK(A2/B2/G1) 94.05 89.86 MST3/STK24 94.20 89.43 JNK3 95.45 95.42 AMPK(A2/B2/G3) 95.82 88.96 TRKC (G623R/L686M) 96.00 95.31 TRKA-TPM3 98.17 95.56 ROCK2 100.46 98.38 AMPK(A1/B1/G3) 101.13 100.85 EIF2AK2 101.35 100.73 PKN2/PRK2 101.83 97.21 TRKA (G595R) 102.66 99.08 DNA-PK 102.84 101.60 EEF2K 103.09 101.96 TRKB 103.12 101.29 mTOR/FRAP1 103.16 96.09 TRKA (G667C) 103.46 101.95 EIF2AK4 103.68 102.49 ROCK1 105.45 101.05 TRKA-TPR 105.68 101.99 TRKC (L686M) 107.04 106.77 TRKC 108.18 102.60 TRKA-TFG (TRK-T3) 109.31 102.82 AMPK(A1/B2/G1) 109.51 107.43 P38b/MAPK11 110.21 109.52 DAPK2 110.63 109.81 PDK4/PDHK4 111.00 105.05 AMPK(A2/B2/G2) 113.71 111.36 TRKC (G623E) 117.78 114.78 TRKA 119.15 115.47

As confirmed in Table 2 and Figure 1 above,

Despite the commonality of the parent nucleus, the compound of Example 3 of the present invention contains JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, and TLK1 of prior patent materials (corresponding to Examples 7, 17, and 18). , JNK2, RIPK5, CDK3/cyclin E, PKN2/PRK2, Haspin, STK25/YSK1, ARK5/NUAK1, PKCb2, and JNK3, and did not show any significant enzyme inhibitory activity, and showed high target selectivity against GSK3β. , it can be seen that it can be appropriately applied to therapeutic, diagnostic, and pharmaceutical compositions that require selectivity for GSK3β.

Table 3 below shows the inhibitory activity values of the compounds of Examples 1 to 18 of the present invention against GSK3β.

Example GSK3β residual enzyme activity (%)
(Calculated value compared to DMSO control group) Whether prior material is patented 1st round 2nd round Example 1 87.05 87.86 Example 2 81.03 88.50 Example 3 46.74 55.42 Example 4 66.04 73.19 Example 5 84.57 107.94 Example 6 42.45 41.22 Example 7 114.87 108.52 Preceding substance Example 8 58.86 75.00 Example 9 11.90 9.07 Example 10 32.14 38.08 Example 11 123.88 120.67 Example 12 117.58 111.24 Example 13 84.18 86.97 Example 14 75.51 74.48 Example 15 38.37 33.08 Example 16 72.66 70.62 Example 17 71.51 51.98 Preceding substance Example 18 63.92 60.62 Preceding substance

As shown in Table 3 above,

The compounds of Examples 3, 6, 8, 9, 10, and 15 of the present invention were found to have relatively excellent inhibitory activity against GSK3β compared to the prior patented substances (corresponding to Examples 7, 17, and 18).

From this, the GSK-3β inhibitory compound of the present invention, its stereoisomer, or its pharmaceutically acceptable salt has excellent selective inhibitory activity against GSK-3β, and can be usefully used in the prevention or treatment of GSK-3-related diseases. It is directly supported that it can be done.

< example 1> Preparation of pharmaceutical preparations

1-1. manufacture of powders

500 mg of GSK-3 inhibitor of the present invention

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled into an airtight bubble to prepare a powder.

1-2. manufacture of tablets

500 mg of GSK-3 inhibitor of the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

After mixing the above ingredients, tablets are manufactured by compressing them according to a typical tablet manufacturing method.

1-3. Manufacturing of capsules

500 mg of GSK-3 inhibitor of the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2 mg

Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a typical capsule manufacturing method.

1-4. Manufacturing of injectable drugs

500 mg of GSK-3 inhibitor of the present invention

Proper amount of sterile distilled water for injection

Appropriate amount of pH adjuster

It is prepared with the above ingredients per ampoule (2 ml) according to the usual manufacturing method for injections.

1-5. Manufacture of liquid

100 mg of GSK-3 inhibitor of the present invention

10 g isomerized sugar

5 g mannitol

Proper amount of purified water

According to the usual liquid preparation method, add and dissolve each ingredient in purified water, add an appropriate amount of lemon flavor, mix the above ingredients, add purified water, adjust the total to 100 ml by adding purified water, and fill it into a brown bottle. Sterilize to prepare the liquid.

Above, the present invention has been described in detail through preferred embodiments and experimental examples, but the scope of the present invention is not limited to specific embodiments and should be interpreted in accordance with the appended claims. Additionally, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (14)

delete delete delete delete delete delete delete GSK-3 (Glycogen synthase kinase) containing a compound represented by the following formula (I), racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. -3) Pharmaceutical composition for preventing or treating vector diseases:
wherein the disease is selected from the group consisting of diabetes, hair loss, obesity, cardiovascular atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, cancer, leukopenia, and Down syndrome;
[Formula I]

In Formula I above,
A is or ego;
X ¹ and X ² are independently carbon or nitrogen atoms;
R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or one or more halogen-substituted C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy , C _1-10 straight or branched alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched alkyl, unsubstituted or C _1-10 straight or branched alkyl substituted with one or more halogens. sulfonyl, or C _1-10 straight or branched alkylcarbonylamino,
R ² and R ³ are linked together with the atoms to which they are bonded to form a heterocycle of an unsubstituted or substituted 5- to 6-membered ring containing one or more heteroatoms selected from the group consisting of N, O and S, ,
The substituted 5- to 6-membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, and oxo group. It is a heterocyclic ring of 5 to 6 rings,
However, if X ¹ is a nitrogen atom, R ¹ is absent, and if X ² is a nitrogen atom, R ³ is absent; and
The n is an integer from 0 to 2.
According to clause 8,
The compound is
(1) 5-phenyl-3-((1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;
(2) 3-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;
(3) 3-((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5]unde car-7,10-diene-4,9-dione;
(4) 3-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5] Undeca-7,10-diene-4,9-dione;
(5) 5-phenyl-3-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-5-aza spiro[5.5]undeca-7,10-diene-4,9-dione;
(6) 3-(4-((4,9-dioxo-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-dien-3-yl)methyl)-1H- 1,2,3-triazol-1-yl)benzonitrile;
(8) 3-((1-(4-(methylthio)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[ 5.5]undeca-7,10-diene-4,9-dione;
(9) 3-((1-(3-benzylphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[5.5]unde car-7,10-diene-4,9-dione;
(10) 5-phenyl-3-((1-(4-((trifluoromethyl)sulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa -5-azaspiro[5.5]undeca-7,10-diene-4,9-dione;
(11) N-(4-(4-((4,9-dioxo-5-phenyl-1-oxa-5-azaspiro[5.5]undeca-7,10-dien-3-yl)methyl) -1H-1,2,3-triazol-1-yl)phenyl)acetamide;
(12) 3-((1-(3,5-dimethoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5-azaspiro[ 5.5]undeca-7,10-diene-4,9-dione;
(13) 3-((1-(4-fluoro-3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa-5- Azaspiro[5.5]undeca-7,10-diene-4,9-dione;
(14) 3-((1-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl- 1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione;
(15) 3-((1-(4-methyl-2-oxo-2H-chromen-7-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl- 1-oxa-5-azaspiro[5.5]undeca-7,10-diene-4,9-dione; and
(16) 3-((1-((3R,5S)-adamantan-1-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-phenyl-1-oxa -5-Azaspiro[5.5]undeca-7,10-diene-4,9-dione is a compound selected from the group consisting of compounds,
A pharmaceutical composition, characterized in that the disease is caused by overexpression of GSK-3 (Glycogen synthase kinase-3).
According to clause 8,
The compound is a pharmaceutical composition that prevents or treats the disease by inhibiting the expression of GSK-3 (Glycogen synthase kinase-3).
delete GSK-3 (Glycogen synthase kinase) containing a compound represented by the following formula (I), racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate, or pharmaceutically acceptable salt thereof as an active ingredient. -3) Health functional food composition for preventing or improving vector diseases:
wherein the disease is selected from the group consisting of diabetes, hair loss, obesity, cardiovascular atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, cancer, leukopenia, and Down syndrome,
[Formula I]

In Formula I above,
A is or ego;

X ¹ and X ² are independently carbon or nitrogen atoms;
R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or one or more halogen-substituted C _1-10 straight or branched alkyl, C _1-10 straight or branched alkoxy , C _1-10 straight or branched alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched alkyl, unsubstituted or C _1-10 straight or branched alkyl substituted with one or more halogens. Sulfonyl, or C _1-10 straight or branched alkylcarbonylamino,
R ² and R ³ are linked together with the atoms to which they are bonded to form a heterocycle of an unsubstituted or substituted 5- to 6-membered ring containing one or more heteroatoms selected from the group consisting of N, O and S, ,
The substituted 5- to 6-membered heterocyclic ring is substituted with one or more substituents selected from the group consisting of C _1-5 straight or branched alkyl, C _1-5 straight or branched alkoxy, and oxo group. It is a heterocyclic ring of 5 to 6 rings,
However, if X ¹ is a nitrogen atom, R ¹ is absent, and if X ² is a nitrogen atom, R ³ is absent; and
The n is an integer from 0 to 2.
delete delete