KR20200081617A - A novel GSK3 inhibiting compound, a process for producing the same, and a usage comprising the same - Google Patents

Abstract

The present invention relates to a novel GSK-3 inhibitory compound, a manufacturing method thereof, and a pharmaceutical composition for preventing or treating GSK-3-related diseases containing the same as an active component. A GSK-3β inhibitory compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has excellent selective inhibitory activity on GSK-3β, thereby being able to be usefully used for preventing or treating GSK-3 related diseases.

Description

A novel GSK-3 inhibitory compound, a process for producing the same, and a usage comprising the same}

The present invention relates to a novel GSK3 inhibitory compound, a method for manufacturing 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 comprising α and β isoforms, which are encoded by distinct genes, respectively (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).

Lipid metabolism, insulin, and growth factor dysregulation within these pathways are prevalent in some humans, such as type II diabetes (Non-patent Document 4), Alzheimer's disease (Non-Patent Document 5), manic depressive disease and neurodegenerative diseases It is considered to be a critical case in the development of central nervous system (CNS) diseases such as diseases and chronic inflammatory symptoms (Non-Patent Document 6). These diseases are caused by the abnormal activation of specific cellular signaling pathways in which GSK-3 plays a role, or can cause such abnormal operation.

GSK-3 has been found to modulate the activity of a number of regulatory proteins by phosphorylation. These proteins are glycogen synthase, a 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, thermal shock factor-1, c -Jun, c-Myc, c-Myb, CREB, and CEPBa. These various protein targets are related to GSK-3 in many aspects of cell metabolism, proliferation, differentiation and development.

That is, to develop a novel medicinal entity for the treatment of diseases (non-patent document 7) where the inhibition of GSK-3 is not resolved through insulin imitation, tau dephosphorylation and amyloid processing or transcriptional adjustment, respectively. It seems to suggest a viable strategy.

It has been reported that inhibition of GSK-3 causes neuronal differentiation of embryonic stem cells (ESC) and helps regeneration of human and mouse ESCs and maintains their pluripotency, which can be applied to regenerative medicine. It suggests that there is (non-patent document 8).

The types of GSK-3 inhibitors proposed so far can be classified into seven types according to their binding sites and methods, and can be classified 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'.

If this is classified by use again, clinical trials were conducted with anticancer drugs such as '9-ING-41', or brain neurological diseases such as Alzheimer's, degenerative brain disease, or bipolar disorder, such as'NP031112' or'Lithium'.

There are no GSK3 inhibitors that have been successful in clinical approval to date,

Considering its regulation mechanism and binding site suitability, it is necessary to develop metabolic abnormalities such as lipid metabolism and insulin, growth factor abnormalities, central nervous system (CNS) disease, chronic inflammatory disease, and anticancer drugs.

Chemistry & Biology, 7, 793-803 (2000). Curr. Opinion Genetics Dev., 10, 508-514 (2000). J. Cell Sci. 116, 1175 (2003). Expert Opin. 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.

An object in one aspect of the invention is to provide a novel GSK-3 inhibitory compound, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof.

An object in another aspect of the present invention is to provide a method for preparing the novel GSK-3 inhibitory compound.

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

An object of another aspect of the present invention is a GSK-3 (Glycogen synthase kinase-3) mediated disease containing a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a health functional food composition for the prevention or improvement of.

The object of another aspect of the invention is to administer a new GSK-3 inhibitory compound, its stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof, to a subject and/or patient in need thereof It provides a method for treating GSK-3 (Glycogen synthase kinase-3) mediated disease comprising a step.

An object of another aspect of the present invention is a GSK-3 (Glycogen synthase kinase-3) mediated disease containing a novel GSK-3 inhibitory compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a diagnostic composition.

In order to achieve the above object,

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

[Formula I]

(In the above formula I,

또는

이고;A is

or

ego;

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

R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or substituted C _1-10 linear or branched alkyl of _{1 to 10} , C _1-10 linear or branched alkoxy of C _1-10 , C _1-10 straight or branched chain alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _1-10 straight or branched chain alkyl Sulfonyl, or C _1-10 straight or branched chain alkylcarbonylamino, or

The R ² and R ³ are linked together with the atoms to which they are attached to form an unsubstituted or substituted 5- to 6-membered heterocycle 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 linear or branched alkyl, C _1-5 linear or branched alkoxy and oxo groups. Heterocyclic ring of 5 to 6,

Provided that when X ¹ is a nitrogen atom, R ¹ is absent, and when X ² is a nitrogen atom, R ³ is absent; And

N is an integer from 0 to 2).

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

Preparing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2 (step 1); And

Reacting the compound represented by the formula (3) prepared in step 1 with the compound represented by the formula (4) to prepare a compound represented by the formula (I) (step 2); It provides a method for producing a compound represented by the formula (I) comprising a.

[Scheme 1]

(In Scheme 1 above,

A is as defined in Formula 1).

Furthermore, another aspect of the present invention, the compound represented by the formula (I), racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof as an active ingredient It provides a pharmaceutical composition for the prevention or treatment of GSK-3 (Glycogen synthase kinase-3) mediated diseases containing.

In addition, another aspect of the present invention, the compound represented by the formula (I), racemic compounds thereof, diastereomers, tautomers, geometric isomers, stereoisomers, hydrates thereof, or a pharmaceutically acceptable salt thereof as an active ingredient It provides a health functional food composition for the prevention or improvement of GSK-3 (Glycogen synthase kinase-3) mediated disease containing.

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

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

Furthermore, another aspect of the present invention, the compound represented by the formula (I), racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, its hydrate, or a pharmaceutically acceptable salt thereof as an active ingredient It provides a composition for the diagnosis of GSK-3 (Glycogen synthase kinase-3) mediated disease containing.

In addition, another aspect of the present invention, the compound represented by the formula (I), racemic compounds thereof, diastereomers, tautomers, geometric isomers, stereoisomers, hydrates thereof, or a pharmaceutically acceptable salt thereof as an effective treatment component To provide a cell composition.

The GSK-3β inhibitory compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of the present invention has excellent selective inhibitory activity against GSK-3β, and thus may be useful for the prevention or treatment of GSK-3 related diseases.

1 is a diagram showing the kinase inhibitory efficacy (%) of the compound of Example 3 of the present invention, and it is possible to confirm high selectivity for GSK-3β, which has not been derived from existing prior patent materials.
FIG. 2 is a graph showing that GSK-3β inhibitory efficacy 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.
3 is a view showing that the inhibitory effect of GSK-3β 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 in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art. Furthermore, "including" a component throughout the specification means that other components may be further included, rather than excluding other components, unless otherwise specified.

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

[Formula I]

In the formula (I),

또는

이고;A is

or

ego;

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

R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or substituted C _1-10 linear or branched alkyl of _{1 to 10} , C _1-10 linear or branched alkoxy of C _1-10 , C _1-10 straight or branched chain alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _1-10 straight or branched chain alkyl Sulfonyl, or C _1-10 straight or branched chain alkylcarbonylamino, or

The R ² and R ³ are linked together with the atoms to which they are attached to form an unsubstituted or substituted 5- to 6-membered heterocycle 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 linear or branched alkyl, C _1-5 linear or branched alkoxy and oxo groups. Heterocyclic ring of 5 to 6,

Provided that when X ¹ is a nitrogen atom, R ¹ is absent, and when 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 substituted C _1-5 linear or branched alkyl of one or more halogens, C _1- Straight or branched chain alkoxy of ₅ , straight or branched chain alkylsulfanyl of C _1-5 , straight or branched chain alkyl of aryl C _1-3 of C ₆ , unsubstituted or substituted C _1-5 of one or more halogens Straight or branched chain alkylsulfonyl, or C _1-5 straight or branched chain alkylcarbonylamino,

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

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

Provided that when X ¹ is a nitrogen atom, R ¹ is absent, and when X ² is a nitrogen atom, R ³ is absent; And

The n may be an integer of 0 or 1.

In another aspect,

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

R ² is -H, -F, -Cl, -Br, -CN, unsubstituted or substituted C _1-5 linear or branched alkyl of one or more halogens, C _1-5 linear or branched alkyl sulfa Neil, C ₆ Aryl C _1-3 Linear or branched chain alkyl, unsubstituted or substituted C _1-5 linear or branched alkylsulfonyl, or C _1-5 linear or branched chain alkyl Carbonylamino, or

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

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

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

The n may be an integer of 0.

On the other side,

R ¹ is -H, benzyl, or -OCH ₃ ego,

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

R ³ is -H, -Cl, -CN, or -OCH ₃ Or

또는

를 형성하고;R ² and R ³ are linked together with the atoms to which they are attached

or

To form;

When X ¹ and X ² are both 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.

In another aspect,

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

(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] Ka-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] Ka-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 -Den-4,9-Dion.

The compound represented by the formula (I) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. 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, trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. Get from The types of pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, 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, Glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving a 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 filtration and drying, or by distilling the solvent and excess acid under reduced pressure and drying to crystallize under an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and evaporating and drying the filtrate. At this time, it is suitable to manufacture sodium, potassium or calcium salts as metal salts. Further, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

Furthermore, the present invention includes all the compounds represented by the formula (I) and pharmaceutically acceptable salts thereof, as well as solvates, optical isomers, hydrates, and the like, which can be prepared therefrom.

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

Preparing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2 (step 1); And

Reacting the compound represented by the formula (3) prepared in step 1 with the compound represented by the formula (4) to prepare a compound represented by the formula (I) (step 2); It provides a method for producing a compound represented by the formula (I) comprising a.

[Scheme 1]

In Reaction Scheme 1,

A is as defined in the above formula (I).

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

Step 1 Reagent: NaNO ₂ , NaN ₃ , 6N HCl

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

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

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

These diseases include diabetes, Alzheimer's disease, Parkinson's disease, projection encephalitis, peak disease, cortical basal degeneration, frontotemporal dementia, Huntington's disease, AIDS-related dementia, amyotrophic lateral sclerosis, multiple sclerosis, stroke, epilepsy, depression, mental illness Schizophrenia, bipolar disorder, hair loss, obesity, cardiovascular atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy's disease, hyperproliferative disease and immunodeficiency It may be any one or more diseases selected from the group consisting of, but any known disease related to GSK-3 may be applied without limitation.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may be administered in various dosage forms, oral and parenteral, during clinical administration. In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient in one or more compounds such as starch, calcium carbonate, sucrose or lactose ( lactose) and gelatin. In addition, lubricants such as magnesium stearate, talc and the like are used in addition to simple excipients. Liquid preparations for oral administration include suspending agents, intravenous solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used as diluents, various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, can be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, and emulsions. As a non-aqueous solvent and a suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable estero such as ethyl oleate may be used.

The pharmaceutical composition using the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration may be administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. How to do.

At this time, in order to formulate a formulation for parenteral administration, a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is mixed with water with a stabilizer or a buffer to prepare a solution or suspension, and it is administered in ampoules or vials. Can be produced. The composition may be sterile and/or contain preservatives, stabilizers, hydrating or emulsifying accelerators, adjuvants such as salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, conventional methods of mixing, granulation It can be formulated according to the chemical or coating method.

The dosage of the pharmaceutical composition to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease level, preferably in the amount of 0.01 to 1000 mg/kg/day. Depending on the pharmacist's judgment, the predetermined time interval may be divided into several times a day, preferably once to three times a day, and administered through an oral or parenteral route.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, liquids, suspensions, emulsifiers, syrups, granules, elixirs, troches, etc. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycols). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and, if desired, a boron such as starch, agar, alginic acid or its sodium salt, etc. It may contain an releasing or boiling mixture and/or absorbent, colorant, flavoring agent, and sweetening agent.

Another aspect of the present invention, the compound represented by the formula (I), racemic compounds thereof, diastereomers, tautomers, geometric isomers, stereoisomers, hydrates thereof, or a pharmaceutically acceptable salt thereof containing as an active ingredient Provides a health functional food composition for preventing or improving GSK-3 (Glycogen synthase kinase-3) mediated disease.

The compound represented by the formula (I) according to the present invention may be added to food as it is or used with other foods or food ingredients, and may be suitably used according to conventional methods. The mixing amount of the active ingredient can be appropriately determined according to its purpose of use (for prevention or improvement). In general, the amount of the compound in the health food can be added to 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene purposes or for health control purposes, 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 limitation on other components except for containing the compound as an essential component in the indicated proportions, and may contain various flavors or natural carbohydrates, etc., as additional components, such as ordinary beverages. have. Examples of the natural carbohydrates described above include monosaccharides, such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, etc.; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (for example, rebaudioside A, glycyrrhizine, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g per 100 g of the composition of the present invention, preferably about 5 to 12 g.

Furthermore, in addition to the above, the compound represented by the formula (I) according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate, etc.), pect Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like. In addition, the compound represented by Chemical Formula 1 of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.

Another aspect of the present invention, the compound represented by the formula (I), racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof Provided is a method of treating 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 the formula (I) for preparing a medicament for use in the prevention or treatment of GSK-3 (Glycogen synthase kinase-3) mediated disease. .

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

Another aspect of the present invention, the compound represented by the formula (I), racemic compounds thereof, diastereomers, tautomers, geometric isomers, stereoisomers, hydrates thereof, or previously expressed using a pharmaceutically acceptable salt thereof It provides a method for inhibiting the enzyme activity of GSK-3 (Glycogen synthase kinase-3), an inhibitory use, and an industrial use including the same.

Another aspect of the present invention, the compound represented by the formula (I), racemic compounds thereof, diastereomers, tautomers, geometric isomers, stereoisomers, hydrates thereof, or a pharmaceutically acceptable salt thereof as an effective treatment component To provide a cell composition.

Since the GSK-3β inhibitory compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of the present invention has excellent selective inhibitory activity against GSK-3β, it can be useful for the prevention or treatment of GSK-3 related diseases, This is directly supported by the examples and experimental examples described below.

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

However, the examples and experimental examples to be described later are merely examples of 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 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 Chemical Formula A (1 mmol ) Was dissolved in a solvent in which 5°C tetrahydrofuran (THF) and distilled water (H ₂ O) were mixed at a ratio of 1:1 (v/v), and then 3-azidopyridine (NaNO from pyridin-3-amine) ₂ , NaN ₃ , 6N HCl prepared) (1.5 mmol) and CuSO ₄ ·5H ₂ O (2 mmol) were added. Then, sodium ascorbate (1 mmol) was added and stirred, while gradually raising the temperature to room temperature (about 20 to 23°C).

After confirming the consumption of the starting material by TLC, after extracting with ethyl acetate, the organic layer was washed with brine solution and dried over sodium sulfate. The solvent was removed by lowering the pressure, 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 ; ¹ H 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, 128.89, 127.79 , 120.80, 119.83, 83.40, 63.65, 41.41, 23.53 ppm.

Based on the synthetic script of Example 1, the following Examples 2 to 18 compounds 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, 128.86 (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 ; ¹ H 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), 129.10 (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), 129.02, 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 ;

¹ H 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, 127.14, 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- Azafiro[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), 128.90, 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 ; ¹ H 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), 122.02 (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), 128.92, 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 ; ¹ H 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, 129.79 (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), 129.22 (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- Azafiro[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 ; ¹ H 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, 128.88 (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 ; ¹ H 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, 127.98, 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 ; ¹ H 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), 128.96, 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]dioxo l -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 ; ¹ H 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), 128.99, 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- Cromen -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-yl)-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 ; ¹ H 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, 119.19, 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- Azafiro[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), 129.04 (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- Azafiro[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 ; ¹ H 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), 121.00, 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 in Table 1 below.

Example rescue Example rescue One

10

2

11

3

12

4

13

5

14

6

15

7

16

8

17

9

18

<Experimental Example 1> Evaluation of enzyme inhibitory activity selectivity

In order to evaluate the selectivity for various enzyme inhibitory activities of the example compounds according to the present invention, experiments were conducted as follows.

The selectivity of the inventive compounds for the Kinase panel (Reaction Biology Corp) was investigated. Using radiolabeled ATP ([γ- ³³ P] ATP), the degree of substitution of the substrate with a ³³ P-phosphorylated substrate was measured for the activity change of the kinase from the measurement of the radiolabeled phosphorylated substrate. The ATP concentration of 10 μM and the substrate concentration of 10 μM were tested by treating the example compound with 30 μM.

As a control compound, Staurosporine or PI-103, NH125, GSK-2606414, JNKi VIII, SB202190, GW5074 were tested in 10 dose IC ₅₀ mode with a 4-fold dilution 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 a control compound with an enzyme activity of less than 65% at the highest concentration of compound was performed, the concentration of DMSO was adjusted, and based on the raw data, the enzyme activity for the DMSO control was calculated, and each of the calculated 369 enzymes Among the inhibitory activities of the Example compounds for, enzymes showing significant results and inhibitory activities (%) thereof are shown in Table 2 below.

Kinase
Residual enzyme activity (%)
(Calculated value compared to DMSO control) 1st round 2nd 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 shown in Table 2 and Figure 1 above,

In spite of the commonality of the parent nuclei, Example 3 compounds of the present invention, JNK1, CDK2/cyclin O, DAPK1, PKCa, CDK1/cyclin B, MST3/STK24, 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. , It can be seen that it can be appropriately applied to therapeutic, diagnostic and pharmaceutical compositions requiring selectivity for GSK3β.

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

Example GSK3β residual enzyme activity (%)
(Calculated value compared to DMSO control) Prior material patent availability 1st round 2nd 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 substances 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 substances Example 18 63.92 60.62 Preceding substances

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 superior inhibitory activity values for GSK3β compared to prior patent materials (corresponding to Examples 7, 17, and 18).

From this, the GSK-3β inhibitor compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof of the present invention has excellent selective inhibitory activity against GSK-3β, and thus is useful for the prevention or treatment of GSK-3 related diseases. It is directly supported.

< Formulation example 1> Preparation of pharmaceutical preparations

1-1. Preparation of powder

500 mg GSK-3 inhibitor of the present invention

Lactose 100 mg

Talc 10 mg

The above ingredients are mixed and filled in an airtight fabric to prepare a powder.

1-2. Preparation of tablets

500 mg GSK-3 inhibitor of the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2mg

After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.

1-3. Preparation of capsules

500 mg GSK-3 inhibitor of the present invention

Corn starch 100 mg

Lactose 100 mg

Magnesium stearate 2mg

According to a conventional capsule preparation method, the above ingredients are mixed and filled into a gelatin capsule to prepare a capsule.

1-4. Preparation of injection

500 mg GSK-3 inhibitor of the present invention

Suitable amount of sterile distilled water for injection

pH Adjuster

It is prepared with the above-mentioned ingredient content per ampoule (2 ml) according to the preparation method of a conventional injection.

1-5. Preparation of liquid

GSK-3 inhibitor 100 mg of the present invention

Isomerized sugar 10 g

5 g of mannitol

Purified water

Each component was added to purified water to dissolve it according to the method of preparing a conventional liquid formulation, lemon scent was added in an appropriate amount, and then the above components were mixed, and then purified water was added to adjust the total to 100 ml, followed by filling into a brown bottle. Sterilize to prepare liquid.

Above, the present invention has been described in detail through preferred examples and experimental examples, but the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, 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)

A compound represented by the formula (I), racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula I]

(In the above formula I,
A is

or

ego;

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

R ¹ , R ² and R ³ are independently -H, halogen, -CN, unsubstituted or substituted C _1-10 linear or branched alkyl of _{1 to 10} , C _1-10 linear or branched alkoxy of C _1-10 , C _1-10 straight or branched chain alkylsulfanyl, C _6-10 aryl C _1-5 straight or branched chain alkyl, unsubstituted or substituted C _1-10 straight or branched chain alkyl Sulfonyl, or C _1-10 straight or branched chain alkylcarbonylamino, or
The R ² and R ³ are linked together with the atoms to which they are attached to form an unsubstituted or substituted 5- to 6-membered heterocycle 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 linear or branched alkyl, C _1-5 linear or branched alkoxy and oxo groups. Heterocyclic ring of 5 to 6,
Provided that when X ¹ is a nitrogen atom, R ¹ is absent, and when X ² is a nitrogen atom, R ³ is absent; And

N is an integer from 0 to 2).
According to claim 1,
R ¹ , R ² and R ³ are independently —H, —F, —Cl, —Br, —CN, unsubstituted or substituted C _1-5 linear or branched alkyl of one or more halogens, C _1- Straight or branched chain alkoxy of ₅ , straight or branched chain alkylsulfanyl of C _1-5 , straight or branched chain alkyl of aryl C _1-3 of C ₆ , unsubstituted or substituted C _1-5 of one or more halogens Straight or branched chain alkylsulfonyl, or C _1-5 straight or branched chain alkylcarbonylamino,
The R ² and R ³ are linked together with the atoms to which they are attached to form an unsubstituted or substituted 5- to 6-membered heterocycle containing one or more heteroatoms selected from the group consisting of N, O and S, ,
The substituted 5- to 6-membered heterocyclic ring is a 5- to 6-membered heterocyclic ring in which one or more substituents selected from the group consisting of C _1-3 straight or branched chain alkyl and oxo groups are substituted,
Provided that when X ¹ is a nitrogen atom, R ¹ is absent, and when X ² is a nitrogen atom, R ³ is absent; And

N is an integer of 0 or 1, a racemic compound thereof, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
Wherein R ¹ and R ³ are independently -H, -F, -Cl, -Br, -CN, straight-chain or branched unsubstituted or at least one halogen-substituted C _1-5 alkyl, C _1-5 straight-chain of Or branched chain alkoxy, C _1-5 straight or branched chain alkylsulfanyl, C ₆ aryl C _1-3 straight or branched chain alkyl, unsubstituted or straight chained or branched C _1-5 substituted with one or more halogens Chain alkylsulfonyl, or C _1-5 straight or branched chain alkylcarbonylamino,
R ² is -H, -F, -Cl, -Br, -CN, unsubstituted or substituted C _1-5 linear or branched alkyl of one or more halogens, C _1-5 linear or branched alkyl sulfa Neil, C ₆ Aryl C _1-3 Linear or branched chain alkyl, unsubstituted or substituted C _1-5 linear or branched alkylsulfonyl, or C _1-5 linear or branched chain alkyl Carbonylamino, or
The R ² and R ³ are linked together with the atoms to which they are attached to form an unsubstituted or substituted 5- to 6-membered heterocycle containing one or more heteroatoms selected from the group consisting of N, O and S, ,
The substituted 5- to 6-membered heterocyclic ring is a 5- to 6-membered heterocyclic ring in which one or more substituents selected from the group consisting of C _1-3 straight or branched chain alkyl and oxo groups are substituted,
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 X ¹ and X ² are both carbon atoms at the same time, R ¹ , R ² and R ³ are Which one is not -H; And

Wherein n is an integer of 0, a compound thereof, a racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
R ¹ is -H, benzyl, or -OCH ₃ ego,
R ² is -H, -F, -Br, -CF ₃ , -SCH ₃ , -S(=O) ₂ CF ₃ , or -NHC(=O)CH ₃ ego,
R ³ is -H, -Cl, -CN, or -OCH ₃ Or
R ² and R ³ are linked together with the atoms to which they are attached

or

To form;

When X ¹ and X ² are both carbon atoms at the same time, any one of R ¹ , R ² and R ³ is not -H; And
Wherein n is an integer of 0, a compound thereof, a racemic compound, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof.
According to claim 1,
The compound represented by the formula (I) is a compound, a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate thereof, or a pharmaceutical thereof, characterized in that it is any one selected from the following group of compounds: Acceptable salt:
(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] Ka-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] Ka-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 -Den-4,9-Dion.
According to claim 1,
The compound represented by the formula (I) is a compound, a racemic compound, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate thereof, or a pharmaceutical thereof, characterized in that it is any one selected from the following group of compounds: Acceptable salt:
(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] Ka-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] Ka-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.
As shown in Scheme 1 below,
Preparing a compound represented by Chemical Formula 3 from a compound represented by Chemical Formula 2 (step 1); And
Preparing a compound represented by the following formula (I) by reacting the compound represented by the formula (3) prepared in step 1 with a compound represented by the following formula (4); A method of preparing a compound represented by Formula I of claim 1 comprising:
[Scheme 1]

(In Scheme 1 above,
A is as defined in formula I of claim 1).
GSK-3 (Glycogen) containing the compound represented by the formula (I) of claim 1, racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient synthase kinase-3) Pharmaceutical composition for the prevention or treatment of mediated diseases.
The method of claim 8,
The disease is a pharmaceutical composition characterized in that the disease caused by overexpression of GSK-3 (Glycogen synthase kinase-3).
The method of claim 8,
The compound is a pharmaceutical composition characterized in that to prevent or treat the disease by inhibiting the expression of GSK-3 (Glycogen synthase kinase-3).
The method of claim 8,
These diseases include diabetes, Alzheimer's disease, Parkinson's disease, projectile encephalitis, peak disease, cortical basal degeneration, frontotemporal dementia, Huntington's disease, AIDS-related dementia, amyotrophic lateral sclerosis, multiple sclerosis, stroke, epilepsy, depression, mental illness Schizophrenia, bipolar disorder, hair loss, obesity, cardiovascular atherosclerosis, hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy's disease, hyperproliferative disease and immunodeficiency Pharmaceutical composition, characterized in that any one or more diseases selected from the group consisting of.
GSK-3 (Glycogen) containing the compound represented by the formula (I) of claim 1, racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient synthase kinase-3) Health functional food composition for preventing or improving mediated diseases.
GSK-3 (Glycogen) containing the compound represented by the formula (I) of claim 1, racemic compound thereof, diastereomer, tautomer, geometric isomer, stereoisomer, hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient synthase kinase-3) Composition for the diagnosis of mediated diseases.
A cell composition comprising a compound represented by the formula (I) of claim 1, a racemic compound thereof, a diastereomer, a tautomer, a geometric isomer, a stereoisomer, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an effective treatment component.

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