WO2010104306A2 - Pharmaceutical compositions for treating or preventing diseases caused by the translocation of gsk3 from the cell nucleus to the cytoplasm, containing compounds for inhibiting the translocation of gsk3 from the cell nucleus to the cytoplasm - Google Patents

Abstract

The present invention relates to pharmaceutical compositions for treating or preventing diseases caused by the translocation of GSK3 from the cell nucleus to the cytoplasm, containing compounds for inhibiting the translocation of GSK3 from the cell nucleus to the cytoplasm. More particularly, the present invention relates to pharmaceutical compositions for inhibiting the growth or the metastatis of cancer cells and pharmaceutical compositions for treating autoimmune diseases, containing novel compounds for inhibiting the translocation of GSK3 from the cell nucleus to the cytoplasm. The present invention provides compositions for inhibiting the outbreak and progression of diseases caused by a decrease in the concentration of GSK3 in the nucleus and the translocation of GSK from the cell nucleus to the cytoplasm. The compounds according to the present invention inhibit the nuclear export function of GSK3 performed by Axin, and increase the concentration of GSK3 in the nucleus, and can thus be valuably used in treating or preventing a variety of diseases caused by a decrease in the concentration of GSK3 in the nucleus.

Description

Pharmaceutical composition for the treatment or prophylaxis of diseases caused by the shift of the VS3 from the cell nucleus to the cytoplasm containing a compound that inhibits the shift of the VS3 from the cell nucleus to the cytoplasm

The present invention relates to a pharmaceutical composition for treating or preventing a disease caused by GSK3 migration from a cell nucleus to a cytoplasm containing a compound that inhibits the migration of GSK3 from the nucleus to the cytoplasm, and more particularly, to the cytoplasm in the nucleus. The present invention relates to a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells and a pharmaceutical composition for treating immunological diseases, which contain a novel compound that inhibits the migration of GSK3 to the stratum.

Glycogen synthase kinase-3 (GSK3) is a serine / threonine kinase and has a molecular weight of about 47 kD and phosphorylates 50 proteins. GSK3 has two isoforms, GSK3α and GSK3β, and these genes are known to be very similar and very similar in function (Double BW & Woodgett. JR, J. Cell Sci., 116: 1175, 2003). .

GSK3 has numerous proteins, especially β-catenin or (1) in the course of (1) onset, (2) cancer development and progression, and (3) development of immune and chronic inflammatory diseases such as rheumatoid arthritis or It regulates the phosphorylation of proteins such as snail. In other words, abnormality in signaling systems such as Wnt signaling promotes the development and progression of various diseases by increasing the half-life by inhibiting the phosphorylation of cancer-causing and metastatic activators such as β-catenin and snail by GSK3.

Thus, substances that promote the activity of GSK3 in cells or in the nucleus may be helpful in suppressing disease occurrence and progression by Wnt signaling. In particular, increasing the activity of GSK3 can reduce the inhibition of GSK3 in the nucleus by Wnt signaling and effectively inhibit the onset and progression of many diseases caused by Wnt signaling.

However, little is known about the precise phosphorylation process of substrate proteins by GSK3, and little is known about the diseases caused by inhibition of GSK3 activity in the nucleus. This is because the mechanisms leading to GSK3 by Wnt signaling are not clear.

In addition, the Axin gene has two isoforms, Axin1 and Axin2 (conductin). The Axin1 and Axin2 genes are known to regulate protein phosphorylation through different transcriptional regulation processes. The Axin gene acts as a negative regulator of Wnt signaling by promoting the phosphorylation of β-catenin by GSK3 and reducing its half-life (US Patent 2001 / 0052137A1).

In addition, there are FRAT-1 and FRAT-2 genes that bind to GSK3 to perform the nuclear export function of GSK3. However, FRAT was found to be a GSK3 inhibitor, unlike Axin, which is known to promote β-catenin phosphorylation (Ciani, L. et al. , J. Cell Biol. , 164: 243, 2004; Yost, C. et al. ., Cell, 93: 1031, 1998), as well as GSK3 is different from the binding point and a binding form. In particular, it is not related to Wnt at all, but knock-out of either Axin-1 or Axin-2 genes does not normally occur (Chia, IV & Costatini, F., Mol. Cell Biol. , 25: 4371, 2005), FRAT-1, -2, -3 can be knocked out in the normal occurrence (van Amerongen, R. et al. , Genes De., 19: 425, 2005) FRAT It is not yet clear what role genes play in Wnt signaling.

Until now, many drugs have been developed to inhibit GSK3 activity, but concepts and substances that inhibit the onset and progression of diseases caused by Wnt signaling by increasing GSK3 activity are not known. The inventors have developed a polypeptide that inhibits the onset and progression of diseases caused by Wnt signaling based on the newly identified nuclear export function of GSK3 by Axin, and specifically, glycogen synthase kinase 3 (glycogen synthase kinase 3, Polypeptides have been developed that include a GD3 binding domain (GSK3) or ABD (Axin binding domain) that binds Axin and a PTD that can permeate cell membranes without the help of cell membrane receptors. It has been shown to be useful for treating various diseases caused by decreasing GSK3 concentrations (WO 2008/051048).

The present inventors have made diligent efforts to develop new compounds for treating diseases caused by a decrease in GSK3 concentration in the nucleus, resulting in novel compounds that inhibit GSK3 migration from the nucleus to the cytoplasm, and the compounds in the nucleus. The present invention has been found to be useful in treating various diseases caused by decreasing GSK3 concentration.

Summary of the Invention

It is a primary object of the present invention to provide a novel compound of formula 1 which inhibits GSK3 migration from the cell nucleus to the cytoplasm by binding to Axin.

Another object of the present invention to provide a pharmaceutical composition for the treatment or prevention of diseases caused by GSK3 migration from the cell nucleus to the cytoplasm containing the compound as an active ingredient.

Still another object of the present invention is to provide a pharmaceutical composition for inhibiting growth or metastasis of cancer cells containing the compound as an active ingredient.

Still another object of the present invention is to provide a pharmaceutical composition for treating an immunological disease containing the compound as an active ingredient.

In order to achieve the above object, the present invention provides a method for treating diseases caused by GSK3 migration from the cell nucleus to the cytoplasm containing the compound represented by the following formula (I), a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient. Provided are pharmaceutical compositions for treatment or prophylaxis:

Formula 1

A is CR _a or N;

D is CR _d or N;

G is CR _g or N;

J is CR _j or N;

Y is Y ¹ (

) Or Y ² (

);

When Y is Y ¹ , W is C; Or Y ² , W is CR _w or N;

M is CR _m or N;

Q is CR _q or N;

When Y is Y ¹ , Z is C (R _z ) ₂ , C═O, C = S, NR _z , O, S, S (O) ₂ ; Or, when Y ² , Z is CR _z or N; And

R _a , R _d , R _g , R _j , R _w , R _m , R _q and R _z are each independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O ) H, -OH, substituted or unsubstituted -C (O) O-alkyl, substituted or unsubstituted -C (O) O-aryl, substituted or unsubstituted -C (O) O-hetero Aryl, substituted or unsubstituted -C (O) -alkyl, substituted or unsubstituted -C (O) -aryl, substituted or unsubstituted -C (O) -heteroaryl, substituted or unsubstituted Substituted carboxamido, substituted or unsubstituted carbonylamino, substituted or unsubstituted sulfonamido, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl Alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, halogen substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Arylalkenyl, substituted or unsubstituted he Roarylalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxy, substituted or unsubstituted arylalkoxy, substituted or Unsubstituted heteroarylalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted amino Alkenyl, substituted or unsubstituted aminoaryl, substituted or unsubstituted amido group, substituted or unsubstituted urea, substituted or unsubstituted alkylurea, substituted or unsubstituted arylurea, substituted Or unsubstituted heteroarylurea, substituted or unsubstituted thiourea, substituted or unsubstituted alkylthiourea, substituted or unsubstituted arylthiourea, substituted or unsubstituted hete Roarylthiourea, substituted or unsubstituted -S (O) ₂ -alkyl, substituted or unsubstituted -S (O) ₂ -aryl, substituted or unsubstituted -S (O) ₂ -heteroaryl , Substituted or unsubstituted -S (O) -alkyl, substituted or unsubstituted -S (O) -aryl, substituted or unsubstituted -S (O) -heteroaryl, substituted or unsubstituted -S-alkyl, substituted or unsubstituted -S-aryl, substituted or unsubstituted -S-heteroaryl, substituted or unsubstituted nonaromatic ring, substituted or unsubstituted ester, substituted or unsubstituted Substituted ethers, substituted or unsubstituted acyl, substituted or unsubstituted primary, secondary, tertiary amines, substituted or unsubstituted oxime groups, substituted or unsubstituted carbonates, substituted or unsubstituted Boron, substituted or unsubstituted silicone and substituted or unsubstituted phosphine.

The present invention also provides a pharmaceutical composition for inhibiting the growth or metastasis of cancer cells containing the compound represented by Formula 1, a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient.

Other features and embodiments of the present invention will become more apparent from the following detailed description and the appended claims.

1 is a schematic diagram showing the activation of β-catenin, increased Axin2 expression, and GSK3 regulation in the nucleus by Wnt signaling.

Figure 2 is a schematic diagram of the process of concentration control of nuclear GSK3 by nuclear signaling by Wnt signaling.

3 is a schematic diagram of the binding structure of Axin and GSK3.

Figure 4 shows the results of analyzing the activity of the compounds represented by 41, 45, 78, 80, 81, 82, 95, 147 and 149 according to the present invention Axin2 through the expression of GSK3β.

Detailed Description of the Invention and Specific Embodiments

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

Hereinafter, the present invention will be described in detail.

1. Definition of terms

As used herein, "comprising", "containing" and "including" are used herein in an open, non-limiting sense.

Unless otherwise specified, the term "alkyl" as used herein refers to a saturated straight or branched ratio having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, most preferably 1 to 4 carbon atoms. -Means a cyclic hydrocarbon. Representative saturated straight chain alkyls include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl, and saturated branched alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, tert-butyl, -isopentyl, 2- Methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3 , 3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2 -Ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2 , 2-diethylpentyl, 3,3-diethylhexyl, 2,2- And the like-ethylhexyl, 3,3-diethylhexyl. Alkyl groups may be unsubstituted or substituted. Alkyl groups can be specified as having a certain number of carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms may be specified as a C1-C8 alkyl group, while an alkyl group having 1 to 6 carbon atoms may be specified as a C1-C6 alkyl group. When used in conjunction with other terms, such as in the term "-(C1-C6 alkyl) aryl", the symbol "-" denotes the point of attachment to the rest of the molecule, wherein one of the hydrogens of the alkyl group is associated with an aryl group. It is substituted with a bond. For example,-(C 1 -C ₂ alkyl) aryl includes groups such as —CH ₂ Ph, —CH ₂ CH ₂ Ph and —CH (Ph) CH ₃ .

Unless otherwise specified, the term "alkenyl" as used herein refers to an unsaturated straight or branched non-cyclic hydrocarbon having 2 to 20 carbon atoms and one or more carbon-carbon double bonds. Preferably alkenyl has 2 to 10 carbon atoms. Exemplary straight-chain alkenyls include, but are not limited to, -but-3-ene, -hex-4-ene and -oct-1-ene. Exemplary branched alkenyls include, but are not limited to, 2-methyl-but-2-ene, -1-methyl-hex-4-ene and -4-ethyl-oct-1-ene Can be. Alkenyl groups may be substituted or unsubstituted. Alkenyl groups can be specified as having a certain number of carbon atoms. For example, alkenyl groups having 2 to 8 carbon atoms can be specified as C 2 -C 8 alkenyl groups, while alkenyl groups with 2 to 6 carbon atoms can be specified as C 2 -C 6 alkenyl groups.

Unless otherwise specified, the term "alkynyl" as used herein, means an alkyl group wherein one or more carbon-carbon single bonds are replaced with the same number of carbon-carbon triple bonds. Alkynyl groups must contain two or more carbon atoms and can be substituted or unsubstituted. Alkynyl groups can be specified as having a certain number of carbon atoms. For example, an alkynyl group having 2 to 8 carbon atoms may be specified as a C 2 -C 8 alkynyl group, while an alkynyl group having 2 to 6 carbon atoms may be specified as a C 2 -C 6 alkynyl group.

As used herein, the term “oxo” means a ═O group. As used herein, the terms "hydroxy" and "hydroxyl" refer to an -OH group. Unless otherwise specified, the term "hydroxyalkyl" as used herein, means an alkyl group wherein at least one hydrogen is substituted with a hydroxyl group. Unless otherwise specified, the term "hydroxyalkenyl" as used herein refers to an alkenyl group in which one or more hydrogens are substituted with hydroxyl groups. Unless otherwise specified, the term "hydroxyalkynyl" as used herein, means an alkynyl group in which one or more hydrogens are substituted with a hydroxyl group.

"Alkoxy" means the structure of formula -O-alkyl, wherein alkyl has the meanings described above. "Haloalkoxy" means an alkoxy group wherein at least one hydrogen has been replaced with a halogen atom. "Hydroxyalkoxy" means an alkoxy key in which at least one hydrogen is substituted with a hydroxy group. "Alkylsulfonyl" means the structure of the formula -S (O) ₂ -alkyl. "Amino" refers to the -NH ₂ group. "Alkylamino" and "dialkylamino" refer to the structures of the formula -NH-alkyl and -N (alkyl) alkyl, respectively, wherein alkyl is as defined above. The alkyl groups in the dialkylamino groups can be the same or different. "Alkylsulfonyl amino" refers to the structure of the formula -NHS (O) ₂ -alkyl.

"Carbocyclic ring system" and "carbocyclic" refer to ring systems in which all ring members are carbon atoms. Carbocyclic ring systems typically contain 3 to 14 ring atoms. Carbocyclic ring systems may be aromatic or non-aromatic. Carbocyclic ring systems include cycloalkyl rings and may also include fused ring systems. Examples of fused ring carbocyclic ring systems include, but are not limited to, decalin, norbornane, tetrahydronaphthalene, naphthalene, indene and adamantane. Ring atoms in the carbocyclic ring system may be substituted or unsubstituted.

As used herein, the terms “heterocyclic ring”, “heterocyclic” and “heterocyclyl” refer to a carbocyclic ring system in which one or more ring atoms is a hetero atom such as N, O, S or Si. In some embodiments, the heterocyclic ring system includes 1 to 4 hetero atoms. In some embodiments, the hetero atom is selected from N, O or S. Heterocyclic ring systems can include one ring or a fused ring system. By way of non-limiting example, the heterocyclic ring system may comprise two six membered rings fused to each other, or may comprise one five membered ring and one six membered ring fused to each other. Heterocyclic ring systems can be aromatic or non-aromatic, and can be unsaturated, partially unsaturated or saturated. Ring atoms in the heterocyclic ring system may be substituted or unsubstituted.

Unless otherwise specified, the term "aryl" as used herein refers to a carbocyclic ring or ring system containing 6 to 14 ring atoms wherein at least one ring is aromatic. The ring atoms of the carbocyclic aryl group are all carbon atoms. Aryl groups include mono-, bi- and tricyclic groups, as well as benzo-fused carbocyclic moieties such as, but not limited to, 5,6,7,8-tetrahydronaphthyl and the like. . In some embodiments, the aryl group is a monocyclic ring or bicyclic ring. Representative aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and naphthyl. The aryl group can be unsubstituted or substituted.

The term "heteroaryl" means an aryl group in which one or more, but not all, ring carbon atoms in any ring that is aromatic or non-aromatic is substituted with a hetero atom. For example, pyridine is a heteroaryl group, such as a compound in which benzene is fused to a non-aromatic ring containing one or more hetero atoms. Exemplary hetero atoms are N, O, S and Si. In some embodiments, the hetero atom is N, O or S. Heteroaryl groups can be unsubstituted or substituted. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3- Pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-iso Sazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, dibenzofuryl, 2-thienyl (2 -Thiophenyl), 3-thienyl (3-thiophenyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3 -Pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzo [c] [1,2,5] oxadiazolyl, furinyl, 2-benz Imidazolyl, 5-indolyl, 1H-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2- Quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3- Quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, there may be mentioned 7-quinolyl and 8-quinolyl. Non-limiting examples of other heteroaryl groups include pyridyl, indazolyl, isoquinolinyl, thiazolopyridinyl, benzothiazolonyl, dihydroquinolinonyl, benzoisoxazolyl, benzooxazoloyl, indolinonyl, Benzoimidazolonyl, phthalazinyl, naphthyridinyl, thienopyridinyl, benzodioxolyl, isoindolinonyl, quinazolinyl or cinnaolinyl. Non-aromatic rings in aryl and heteroaryl groups comprising non-aromatic rings are, for example, but not limited to, oxo (=) in groups such as benzo [d] thiazole-2 (3H) -onyl groups. O) can be substituted with a variety of groups described herein, including groups.

The term "cycloalkyl" refers to an unsaturated or saturated hydrocarbon that forms one or more rings having 3 to 20 ring carbon atoms, and in some embodiments 3 to 10, 3 to 8 or 3 to 6 ring carbon atoms do. The ring in the cycloalkyl group is non-aromatic. Cycloalkyl groups can be unsubstituted or substituted.

As described herein, a compound of the present invention may be optionally substituted with one or more substituents, such as those generally exemplified above or exemplified by certain classes, subclasses and species of the present invention. In general, the term "substituted" refers to the substitution of a hydrogen radical in a given structure with a radical of a specified substituent, whether or not preceded by "optionally". Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from the specified group, such substituents May be the same or different at all positions. Combinations of substituents contemplated in the present invention are preferably combinations which lead to the formation of stable or chemically suitable compounds.

In the present invention, "for inhibiting the growth or metastasis of cancer cells" means "anticancer". That is, it means the action of inhibiting or killing the proliferation of cancer cells and the action of inhibiting or blocking the metastasis of cancer cells, and means both prevention and treatment of cancer. As used herein, "prevention" refers to any action that inhibits cancer formation or delays the onset of administration of the composition, and "treatment" refers to any action that improves or advantageously changes the symptoms of the disease by administration of the composition. It means.

In particular, “treatment” includes (i) preventing the disease, disorder or symptom in a mammal that may be susceptible to disease, disorder and / or symptom but cannot yet be diagnosed with it; (ii) inhibiting a disease, disorder or symptom, ie, arresting their onset; And (iii) alleviating a disease, disorder or symptom, ie, causing regression of one or more of the disease, disorder and / or symptoms, or signs thereof. "Prevention" also specifically refers to the ability of a compound or composition of the invention to prevent such a disease in a mammal diagnosed with or at risk of developing the disease identified herein. The term also includes preventing further progression of the disease in a mammal already suffering from or having signs of the disease.

In the present invention, "containing as an active ingredient" is meant to contain a "therapeutically effective amount" or "prophylactically effective amount" of a compound represented by the formula (1) according to the present invention, a pharmaceutically acceptable salt, prodrug or isomer thereof.

A "therapeutically effective amount" is a compound of the invention sufficient to provide an advantage in the treatment or prevention of a symptom or disease, such as cancer, to delay or minimize a symptom associated with the symptom or disease, or to treat or ameliorate a disease or cause thereof. Or the amount of a prodrug thereof. In particular, a therapeutically effective amount means an amount sufficient to provide a therapeutic benefit in vivo. The term “preferably” when used in conjunction with the amount of a compound of the present invention, improves the overall therapy, reduces or avoids the signs or causes of the disease, or enhances or synergizes with the therapeutic efficacy of another therapeutic agent. Contains non-toxic amounts.

As used herein, “prophylactically effective amount” refers to an amount of a compound of the present invention or other active ingredient sufficient to prevent a symptom or disease, such as cancer, or recurrence or metastasis of the cancer. A prophylactically effective amount refers to an amount sufficient to prevent the initial disease, or recurrence or spread of the disease. The term “preferably” includes non-toxic amounts that improve overall prophylaxis or enhance or synergize with the prophylactic efficacy of another prophylactic or therapeutic agent.

As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic and organic acids and bases. If the compound of formula 1 is a base, any suitable method available in the art, for example, treatment of the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, or organic acids such as acetic acid, male Acids, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid such as glucuronic acid or galacturonic acid, alpha-hydroxy acid such as citric acid or tartaric acid, amino acids such as aspartic acid Or by treating with glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid and the like to produce the desired pharmaceutically acceptable salts. When the compound of formula 1 is an acid, any suitable method is preferred, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide or the like. Phase acceptable salts can be prepared. Examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and sodium, calcium, Inorganic salts derived from potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The salt can be contacted with a base or an acid in a conventional manner and the parent compound can be isolated to regenerate the neutral form of the compound from the salt. Although the parent form of the compound differs from some physical properties, such as various salt forms, solubility in polar solvents, for the purposes of the present invention, the salt is equivalent to the parent form of the compound.

In addition to salt forms, the present invention provides compounds in prodrug form. The term “prodrug” means any chemical that is converted to various therapeutically effective chemicals after administration. Prodrugs of the compounds described herein are compounds that readily change chemically under physiological conditions to provide the compounds of the present invention. Prodrugs may also be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, if a prodrug is present with a suitable enzyme or chemical reagent in a transdermal patch reservoir, it may be slowly converted to a compound of the present invention. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, prodrugs are available in vivo by oral administration, while parent drugs are not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Various prodrug derivatives, such as derivatives based on hydrolytic or oxidative activation of prodrugs, are known in the art. Non-limiting examples of prodrugs will be compounds of the invention that are administered as esters ("prodrugs"), but then metabolically hydrolyzed with an active substance called carboxylic acid. Further examples include peptidyl derivatives of the compounds.

The compounds of the present invention may contain one or more asymmetric centers and may therefore exist in racemic and racemic mixtures, scalemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. have. All such isomeric forms of these compounds are expressly included in the present invention.

Unless indicated otherwise, as used herein, the term “optically pure” or “stereoisomericly pure” means a composition comprising one stereoisomer of a compound and substantially free of other stereoisomers of that compound.

For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomers of the compound. A typical stereoisomerically pure compound is greater than about 80 weight percent of one isomer of the compound, less than about 20 weight percent of the other stereoisomer of the compound, more preferably greater than about 90 weight percent of one stereoisomer of the compound, Less than about 10 weight percent of stereoisomers, even more preferably more than about 95 weight percent of one stereoisomer of the compound, less than about 5 weight percent of the other stereoisomers of the compound, most preferably about 97 weight of one stereoisomer of the compound Greater than weight percent and less than about 3 weight percent of other stereoisomers of the compound. The present invention encompasses the use of stereoisomericly pure forms of such compounds as well as the use of mixtures of these forms. For example, mixtures comprising the same or non-equivalent amounts of enantiomers of certain compounds of the invention can be used in the methods and compositions of the invention. These isomers can be synthesized asymmetrically or cleaved using standard techniques such as chiral columns or chiral splitting agents (see, eg, Jacques, J., et al, Enantiomers, Racemates and Resolution (Wiley-lnterscience). , New York, 1981); Wilen, SH, et al. (1997) Tetrahedron 33: 2725; Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN, 1972)).

Compounds of the present invention may exhibit tautomerization. Although Formula 1 described herein does not explicitly depict all possible tautomeric forms, it will be understood that these structures represent all tautomeric forms of the depicted compounds and are not limited to the specific compound forms depicted in the formulas.

Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are within the scope of the present invention.

In the present invention, synonyms of GSK3 are tau protein kinase (TPK I), FA factor (Factor A) kinase, kinase FA and ATP-citrate lyase kinase (ACLK).

Glycogen synthase kinase 3 (GSK3), present in two isotypes, GSK3α and GSK3β, is a proline-associated serine / threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase. However, GSK3 is a glycogen synthase, phosphatase inhibitor I-2, type II subunit of cAMP-dependent protein kinase, G-subunit of phosphatase-1, acetyl coenzyme A carboxylase, myelin basic protein, microtubule- Related protein, neurofibrillary protein, M-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous It has been demonstrated to phosphorylate many proteins in vitro, such as polyposis tumor suppressor protein, tau protein and β-catenin. The various proteins described above that can be phosphorylated by GSK3 mean that GSK3 is involved in a number of metabolic and regulatory processes in the cell.

Thus, in the present invention, the "disease caused by GSK3 migration from the cell nucleus to the cytoplasm" is a disease mediated through GSK3, for example, cancer, diabetes mellitus, Niemann Pick's disease type C , Bipolar disorder (particularly manic depression), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple systemic atrophy atrophy, Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, post-inflammation Parkinson Postencephalic Parkinsonism, frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dysfunction Myotonic dystrophy, subacute sclerotizing panencephalitis, prion disease, Down's syndrome, allergy or asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease Inflammatory diseases, skin diseases such as baldness, pain, especially neuropathic pain, osteoarthritis, leukopenia and the like.

2. Specific contents of the present invention

Most anticancer drugs and β-catenin-targeted therapeutic agents to date have been developed as substances that induce apoptosis of cancer cells. Therefore, the signaling mechanism proposed by the present invention suggests a new therapeutic effect and concept of the β-catenin targeted therapeutic agent that has been developed or developed in the future. As a method of inhibiting the activity of β-catenin, it is known to inhibit the β-catenin transcriptional regulation by competitively binding to β-catenin transcription complexes, that is, LEF / TCF, CBP300 and the like. In this case, most of the drugs developed so far have been expected to induce apoptosis of cells by targeting β-catenin.

However, the present inventors have proposed a novel function and regulatory mechanism of β-catenin (Giles, RH et al. , Biochim . Biophys . Acta, 1653: 1,2003), which is known to be the most important factor in cancer development . In addition to cancer development, it has been shown to play a role in inducing invasive growth and metastasis of cancer cells (WO 2008/051048). Genetic mutations or other abnormalities of the Wnt signaling system are generally observed in more than 90% of cancers in humans. Therefore, the Wnt signaling system is considered to be very important in the development of cancer. The mechanism is not well known. However, the genetic abnormalities of Wnt signaling activate the β-catenin gene in common and the cancer development process proceeds.

Wnt signaling reduces the expression of E-cadherin, increases the expression of β-catenin and Snail, and invades growth or metastasis of cancer cells. Snail phosphorylation control process by β-catenin is as shown in FIG. Briefly, the expression of Axin is increased by β-catenin, and Axin binds to GSK3 inside the nucleus and transfers GSK3 into the cytoplasm. This increases the expression of Snail and metastasis of cancer cells occurs. 2 is a schematic diagram illustrating the GSK3 concentration control process in the nucleus by Wnt signaling. That is, the activation of β-catenin gene induces Axin2 gene expression, and the Axin2 gene binds to GSK3 present in the cell nucleus to perform the nuclear export function of GSK3, thereby reducing the concentration of GSK3 in the nucleus. As a result, the expression of the Snail gene, which is phosphorylated and degraded by GSK3, is increased. Eventually, increased expression of the Snail gene by Wnt signaling induces invasive growth and metastasis of cancer cells, and clinically causes continuous recurrence and distant metastasis.

Therefore, when a compound having the same or similar structure as the binding site of Axin to GSK3 is used, the development and progression of various diseases caused by Wnt signaling and β-catenin activation by inhibiting the nuclear export function of GSK3 by Axin, etc. Can be suppressed. In particular, in the treatment of cancer patients, if the existing β-catenin-targeted therapeutic agent or the compound of the present invention is inhibited or controlled, the recurrence and distant metastasis of cancer can be increased by at least 2 times. It is expected to change the concept of cancer treatment that has lasted for more than 30 years.

Figure 3 shows the binding structure of Axin and GSK3, it can be seen that Axin binds to GSK3 by Axin-derived peptide fragment (370-390 amino acid sequence of hAxin2) (Dajani et al. , EMBOJ ., 22: 494, At this time, Axin and FRAT proteins have α-helix structure, and the intermediate hydrophobic residues bind to the groove structure of GSK3, and the compound that can competitively bind is the nuclear export function of GSK3 by Axin or FRAT. It was first identified by the present inventors that the amino acids 383-401 of Axin1, which are known to bind GSK3 so far, are the helix (262-273) and extended loop (amino acid 285) of GSK3β. 299), it was found to bind to a groove formed. In particular, hydrophobic ridges consisting of residues of phenylalanine 388 (Phe388), leucine 392 (Leu392), leucine 396 (Leu396) and valine 399 (Val399) play a crucial role in binding to GSK3β. Axin1 and Axin2 have very similar structures and similar functions to transfer GSK3 into the cytoplasm inside the nucleus. In addition, Axin1 and Axin2 seem to have the same function, ie very similar structure, because Axin1 and Axin2 can be replaced in the developmental process (Chia, IV & Cos tantini, F., Mol. Cell Biol. , 25: 4371,2005). After the trial and error, the present inventors induce the expression of Axin1 or Axin2 in cells, and the expression of the Snail protein, which is phosphorylated and degraded by GSK3, is strongly reduced. We have seen an increase.

Until now, the development of drugs that specifically bind to the kinase domain to which ATP (Adenosin triphosphate) binds has been mostly developed. However, the present invention has a fundamentally different concept from the development of various compounds for inhibiting existing phosphatase. That is, the compound described in the present invention is fundamentally different from the conventional phosphatase inhibition in that it increases the GSK3 kinase activity inside the cell nucleus by inhibiting the nuclear export function of GSK3 by Axin, rather than inhibiting the kinase domain. The concept is different.

Specifically, the present inventors first analyzed the X-ray structure of GSK3-Axin2 to develop a new inhibitor that inhibits the binding of GSK3 and Axin2, and through this, the structural and functional pharmacophore of Axin2 binding to GSK3 Obtained new information on On the basis of this, 32 compounds of the final product obtained through various stages of organic chemical reaction were obtained, and their structure was confirmed through NMR and Mass experiment equipment. The compounds with high fitness scores were selected for the pharmacophore, and the expected pharmacological activity of the selected compounds was predicted through docking studies. The actual pharmacological activity of the compounds was confirmed by in vitro screeening experiments.

In one aspect, the present invention provides a composition for inhibiting GSK3 migration from the nucleus to the cytoplasm comprising a compound represented by the following Chemical Formula 1, a pharmaceutically acceptable salt, a prodrug, or an isomer thereof, in other words, from the nucleus to the cytoplasm. A pharmaceutical composition for treating or preventing a disease caused by GSK3 migration:

Formula 1

A is CR _a or N;

D is CR _d or N;

G is CR _g or N;

J is CR _j or N;

Y is Y ¹ (

) Or Y ² (

);

When Y is Y ¹ , W is C; Or Y ² , W is CR _w or N;

M is CR _m or N;

Q is CR _q or N;

When Y is Y ¹ , Z is C (R _z ) ₂ , C═O, C = S, NR _z , O, S, S (O) ₂ ; Or, when Y ² , Z is CR _z or N;

R _a , R _d , R _g , R _j , R _w , R _m , R _q and R _z are each independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O ) H, -OH, substituted or unsubstituted -C (O) O-alkyl, substituted or unsubstituted -C (O) O-aryl, substituted or unsubstituted -C (O) O-hetero Aryl, substituted or unsubstituted -C (O) -alkyl, substituted or unsubstituted -C (O) -aryl, substituted or unsubstituted -C (O) -heteroaryl, substituted or unsubstituted Substituted carboxamido, substituted or unsubstituted carbonylamino, substituted or unsubstituted sulfonamido, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl Alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, halogen substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Arylalkenyl, substituted or unsubstituted he Roarylalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxy, substituted or unsubstituted arylalkoxy, substituted or Unsubstituted heteroarylalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted amino Alkenyl, substituted or unsubstituted aminoaryl, substituted or unsubstituted amido group, substituted or unsubstituted urea, substituted or unsubstituted alkylurea, substituted or unsubstituted arylurea, substituted Or unsubstituted heteroarylurea, substituted or unsubstituted thiourea, substituted or unsubstituted alkylthiourea, substituted or unsubstituted arylthiourea, substituted or unsubstituted hete Roarylthiourea, substituted or unsubstituted -S (O) ₂ -alkyl, substituted or unsubstituted -S (O) ₂ -aryl, substituted or unsubstituted -S (O) ₂ -heteroaryl , Substituted or unsubstituted -S (O) -alkyl, substituted or unsubstituted -S (O) -aryl, substituted or unsubstituted -S (O) -heteroaryl, substituted or unsubstituted -S-alkyl, substituted or unsubstituted -S-aryl, substituted or unsubstituted -S-heteroaryl, substituted or unsubstituted nonaromatic ring, substituted or unsubstituted ester, substituted or unsubstituted Substituted ethers, substituted or unsubstituted acyl, substituted or unsubstituted primary, secondary, tertiary amines, substituted or unsubstituted oxime groups, substituted or unsubstituted carbonates, substituted or unsubstituted Boron, substituted or unsubstituted silicone and substituted or unsubstituted phosphine.

In the present invention, R _a is hydrogen, halogen, substituted or unsubstituted alkyl, halogen substituted alkyl, including -CF ₃ ,

Substituted or unsubstituted-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -alkoxy;

N is each independently an integer of 0 to 6;

Each R is independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O) H, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl Or substituted or unsubstituted aryl and substituted or unsubstituted amino.

In the present invention, R _a is-(CH ₂ ) _n -C (O) OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted morpholinyl, substituted Or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -Aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -heteroaryl, substituted or unsubstituted -Z ^a -alkyl, substituted or unsubstituted- Z ^a -cycloalkyl, substituted or unsubstituted -Z ^a -heterocycloalkyl, substituted or unsubstituted -Z ^a -cycloalkylalkyl, substituted or unsubstituted -Z ^a -arylalkyl, substituted or Unsubstituted -Z ^a -aryl or substituted or unsubstituted -Z ^a -heteroaryl and substituted or unsubstituted-(CH ₂ ) _n alkoxy;

Z ^a is each independently-(CH ₂ ) _n- C (O) N (R)-(CH ₂ ) _n or-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n Can be.

In the present invention, R _a is _{- (CH 2) n- CN,} - (CH 2) n -NO 2, - (CH 2) n -C (O) H, - (CH 2) n -OH, Substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -heteroaryl, substituted or unsubstituted primary, secondary, tertiary amine, or substituted or unsubstituted heterocyclic nonaromatic ring.

In the present invention, R _d may be hydrogen or halogen.

In the present invention, R _d is-(CH ₂ ) _n -NO ₂ ,-(CH ₂ ) _n -SO ₃ H, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted Alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted -Z ^a -alkyl, substituted or unsubstituted -Z ^a -cycloalkyl, substituted or unsubstituted -Z ^a -heterocycloalkyl, substituted or unsubstituted -Z ^a -cycloalkylalkyl, substituted or unsubstituted -Z ^a -arylalkyl, substituted or unsubstituted -Z ^a -aryl, substituted Or unsubstituted -Z ^a -heteroaryl, substituted or unsubstituted -Z ^b -alkyl, substituted or unsubstituted -Z ^b -heterocycloalkyl, substituted or unsubstituted -Z ^b -arylalkyl, Substituted or unsubstituted -Z ^b -aryl, substituted or unsubstituted -Z ^b -heteroaryl, substituted or unsubstituted -Z ^a -N (R)-(CH ₂ ) _n -aryl, or substituted an unsubstituted or ^{-Z a -N (R) - (} CH 2) n - hete Aryl;

Z ^a is each independently-(CH ₂ ) _n- C (O) N (R)-(CH ₂ ) _n or-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n ego;

Z ^b are each independently — (CH ₂ ) _N —S (O) ₂ N (R) — (CH ₂ ) _n — or — (CH ₂ ) _n —N (R) S (O) ₂ — (CH ₂ ) _n -may be.

In the present invention, R _d is-(CH ₂ ) _n -CN,-(CH ₂ ) _n -C (O) OH,-(CH ₂ ) _n -C (O) H,-(CH ₂ ) _n -OH, substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted- (CH ₂ ) _n -C (O) -heteroaryl, substituted or unsubstituted primary, secondary, tertiary amine, or substituted or unsubstituted heterocyclic nonaromatic ring.

In the present invention, R _g is hydrogen, substituted or unsubstituted-(CH ₂ ) _n -pyridyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted Heteroaryl.

In the present invention, the R_gIs halogen,-(CH₂)_n-NO₂,-(CH₂)_n-C (O) OH,-(CH₂)_n-C (O) -N (R)₂, Substituted or unsubstituted alkyl- (CH₂)_n-NO₂, Substituted or unsubstituted aryl- (CH₂)_n-NO₂, Substituted or unsubstituted heteroaryl- (CH₂)_n-NO_2,Substituted or unsubstituted alkyl- (CH₂)_n-C (O) OH, substituted or unsubstituted aryl- (CH₂)_n-C (O) OH, substituted or unsubstituted heteroaryl- (CH₂)_n-C (O) OH, substituted or unsubstituted alkyl- (CH₂)_n-C (O) -N (R)₂, Substituted or unsubstituted aryl- (CH₂)_n-C (O) -N (R)_2,Substituted or unsubstituted heteroaryl- (CH₂)_n-C (O) -N (R)₂, Substituted or unsubstituted-(CH₂)_n-C (O) O- (CH₂)_n-Alkyl, substituted or unsubstituted-(CH₂)_n-C (O) O- (CH₂)_n-Aryl, substituted or unsubstituted-(CH₂)_n-C (O) O- (CH₂)_n-Heteroaryl, substituted or unsubstituted -Z^a-Alkyl, substituted or unsubstituted -Z^a-Cycloalkyl, substituted or unsubstituted -Z^a-Heterocycloalkyl, substituted or unsubstituted -Z^a-Cycloalkylalkyl, substituted or unsubstituted -Z^a-Arylalkyl, substituted or unsubstituted -Z^a-Aryl, substituted or unsubstituted -Z^a-Heteroaryl, substituted or unsubstituted -Z^bAlkyl, Substituted or unsubstituted -Z^b-Heterocycloalkyl, substituted or unsubstituted -Z^b-Arylalkyl, substituted or unsubstituted -Z^b-Aryl, substituted or unsubstituted -Z^bHeteroaryl, substituted or unsubstituted-(CH₂)_n-Aryl-Z^a-Aryl, substituted or unsubstituted-(CH₂)_n-Aryl-Z^aHeteroaryl, substituted or unsubstituted-(CH₂)_nHeteroaryl-Z^a-Aryl, substituted or unsubstituted-(CH₂)_nHeteroaryl-Z^aHeteroaryl, substituted or unsubstituted-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_n-Aryl, substituted or unsubstituted-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_nHeteroaryl, substituted or unsubstituted-(CH₂)_n-N (R)-(CH₂)_n-(Z^C= Z^C)_m-(CH₂)_n-Aryl, substituted or unsubstituted-(CH₂)_n-N (R)-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_nHeteroaryl, substituted or unsubstituted-(CH₂)_n-N (R) -Z^cAryl, substituted or unsubstituted-(CH₂)_n-N (R) -Z^cHeteroaryl, substituted or unsubstituted-(CH₂)_n-Alkoxy or substituted or unsubstituted primary, secondary, tertiary amines;

Z ^a is each independently-(CH ₂ ) _n- C (O) N (R)-(CH ₂ ) _n or-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n ego;

Z ^b are each independently — (CH ₂ ) _n —S (O) ₂ N (R) — (CH ₂ ) _n — or — (CH ₂ ) _n —N (R) S (O) ₂ — (CH ₂ ) _n- ;

Z ^c are each independently C (R) or N;

M may be each independently 0, 1 or 2.

In the present invention, R _g is-(CH ₂ ) _n- CN,-(CH ₂ ) _n C (O) H,-(CH ₂ ) _n -OH, substituted or unsubstituted-(CH ₂ ) _n- C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -heteroaryl, Or a substituted or unsubstituted heterocyclic nonaromatic ring.

In the present invention, R _j is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted (CH ₂ ) _n -N (R)-(CH ₂ ) _n -aryl, or substituted or unsubstituted-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -heteroarylyl Can be.

In the present invention, R _j is-(CH ₂ ) _n -CN,-(CH ₂ ) _n -NO ₂ ,-(CH ₂ ) _n -C (O) OH,-(CH ₂ ) _n -C ( O) H,-(CH ₂ ) _n -OH, substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -Aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -heteroaryl, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted primary, secondary , Tertiary amine or substituted or unsubstituted heterocyclic nonaromatic ring.

In the present invention, R _w is hydrogen, halogen,-(CH ₂ ) _n -CN,-(CH ₂ ) _n -NO ₂ ,-(CH ₂ ) _n -C (O) OH,-(CH ₂ ) _n- C (O) H,-(CH ₂ ) _n -OH, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl , Substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted-(CH ₂ ) _n- C (O) -heteroaryl, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted primary, secondary, tertiary amine or substituted or unsubstituted hetero It may be a cyclic non-aromatic ring.

In the present invention, R _m , R _q and R _z are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -T ¹ -T ² -T ³ -T ⁴ or

ego;

Each T ¹ is independently a covalent bond,-(CH ₂ ) _n -,-(CH ₂ ) _n -O- (CH ₂ ) _n -,-(CH ₂ ) _n -S- (CH ₂ ) _n- , -(CH ₂ ) _n -N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -S (O) _p- (CH ₂ ) _n -,-(CH ₂ ) _n -C (O) -(CH ₂ ) _n -,-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -,-(CH ₂ ) _n -OC (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n- S (O) _p N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R) S (O) _p- (CH ₂ ) _n -,-(CH ₂ ) _n -OC ( O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R) C (O) O- (CH ₂ ) _n -,-(CH ₂ ) _n -C (O)- (CH ₂ ) _n -N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -C (O)-(CH ₂ ) _n -,-( CH ₂ ) _n -O- (C (R) ₂ ) _n -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (O)-(C (R) ₂ ) _n -O -(CH ₂ ) _n -,-(CH ₂ ) _n -O- (C (R) ₂ ) _n -O- (CH ₂ ) _n -,-(CH ₂ ) _n -C (O) N (R) -(CH ₂ ) _n -O-,-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n -O-,-(CH ₂ ) _n -C (O) N (R) -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -S (O) _p N (R) -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (R) ₂ -C (O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (R) ₂ -N (R) C (O)-(CH ₂ ) _n- , -(CH ₂ ) _n -SC (R) ₂ -C (O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _{n -SC (R) 2 -N (R} ) C (O) - (CH 2) n -, or - (CH _{2) n} - aryl _{- (CH 2) n -N (} R) C (O) N (R )-(CH ₂ ) _n- ;

Each T ² is independently a covalent bond,-(Z ^c = Z ^c ) _m- (CH ₂ ) _n- , or halogen, alkyl, -C (O) OH, -C (O) H, -CN,- NO ₂ ,-(CH ₂ ) _n -cycloalkyl- (CH ₂ ) _n -substituted or unsubstituted or substituted or unsubstituted amino or substituted or unsubstituted phenyl;

Each of T ³ is independently covalently substituted, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic non-aromatic ring, quinolinyl, quinoxalinyl, quinazolinyl, iso Bicyclic aromatic, aromatic rings containing substituted or unsubstituted nitrogen-containing heterocycles having six atoms in each ring, including quinolinyl, phthalazinyl, each having five atoms, or imidazopyrimidinyl Different orientations with six atoms, including imidazoimidazolyl, imidazothiazolyl, naphthyl, tetrahydronaphthyl, benzothienyl, benzoxazolyl, benzoisoxazolyl and benzothiazolyl Nitrogen-containing heterocyclic substituted or unsubstituted bicyclic aromatic with rings, or furanyl, phenyl, pyridinyl, benzimidazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydratriazolopyra Genyl, tetrahydropyridopyrimidinone, thiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, isoxazolyl, tetrahydropyranyl, pyrazolyl, pyrrolyl, pyrrolopyridinyl, H -Pyridinone, oxazolyl, isothiazolyl, oxdiazolyl, thiadiazolyl, indolinyl, indazolyl, imidazopyridinyl, benzoisothiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl, thienyl , Imidazolyl,

,

,

,

, And

Single or multiple substituted or unsubstituted aromatic or non-aromatic rings, including;

Each of T ⁴ is independently hydrogen, halogen, — (CH ₂ ) _n —CN, — (CH ₂ ) _n —NO ₂ , — (CH ₂ ) _n —C (O) OH, — (CH ₂ ) _n − C (O) H,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -C (O) -N (R) ₂ , substituted or unsubstituted alkyl, halogen substituted alkyl, substituted or non- Single or polysubstituted or unsubstituted, including substituted cycloalkyl, single or polysubstituted or unsubstituted aryl, piperidinyl, piperazinyl, tetrazolyl, furanyl, pyridinyl, oxdiazolyl and isoxoxazolyl Aromatic or non-aromatic ring, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted-(CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n -O-alkyl, substituted or unsubstituted-(CH ₂ ) _n -O-alkenyl, substituted or unsubstituted-(CH ₂ ) _n -O- (CH ₂ ) _n -aryl, substituted or unsubstituted Substituted-(CH ₂ ) _n -N (R) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -aryl, substituted or unsubstituted-( CH ₂ ) _n- C (O) O-alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n -OC ( O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -OC (O)-(CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl , Substituted or unsubstituted-(CH ₂ ) _n -C (O)-(CH ₂ ) _n -aryl, substituted or unsubstituted -Z ^a -alkyl, substituted or unsubstituted -Z ^a -aryl , Substituted or unsubstituted-(CH ₂ ) _n -S-alkyl, substituted or unsubstituted-(CH ₂ ) _n -S- (CH ₂ ) _n -aryl, or substituted or unsubstituted amino;

L ₁ is C (R) or N;

Each L ₂ is independently C═O, C═S, N, O, S, S (O) _p , CHOR _L , C (R _L ) _p , or N (R _L ), wherein each R _L is Independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O) H, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or Unsubstituted aryl, or substituted or unsubstituted amino;

Each of p may be 1 or 2 independently.

In the present invention, the compound is 4- (3-((tetrahydrofuran-2-yl) methylamino) imidazo [1,2-a] pyrazin-2-yl) benzene-1,2-diol, N Cinnamil-4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, N- (1- (3-isopropyl-3H-imidazo [4,5-b] pyridine 2-yl) -3-methylbutyl) cyclopropanecarboxamide, 4,6-dimethyl-N- (3- (trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridine- 3-amine, N- (4-ethoxybenzyl) -4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, 4,6-dimethyl-N-((1-propyl -1H-benzo [d] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, (E) -N- (3- (furan-2-yl) Allyl) -6-methyl-4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 1- (2- (1H-benzo [d] imidazol-2- Yl) pyrrolidin-1-yl) -2- (4-methoxyphenyl) ethanone, 1- (3-cyclopropyl-5,6-dihydro- [1,2,4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) -4- (1H-indol-3-yl) butan-1-one, 1- (2- (5-fluoro-1H-benzo [d] imidazole -2- days) blood Ferridin-1-yl) -2- (3-methoxyphenyl) ethanone, (4,6-dimethyl-3-((5-methylfuran-2-yl) methylamino) -1H-pyrazolo [3 , 4-b] pyridin-1-yl) (isoxazol-5-yl) methanone, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (pyridin-3- 1) piperidine-4-carboxamide, N-cyclopentyl-1- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide, ethyl 2- (1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamido) acetate, 1- (1-methyl-1H-benzo [d] imidazole- 2-yl) -N- (2- (vinyloxy) ethyl) piperidine-4-carboxamide, N- (4-fluorobenzyl) -4,6-dimethyl-1H-pyrazolo [3,4 -b] pyridin-3-amine, 6-methyl-N- (pyridin-2-ylmethyl) -4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, Methyl 2- (3-((2-methyl-4-oxo-3,4,5,6-tetrahydropyrido [3,4-d] pyrimidin-7 (8H) -yl) methyl) -1H- Indol-1-yl) acetate, 7-((5-fluoro-3-methyl-1H-indol-2-yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6 , 7,8-tet Lahydropyrido [3,4-d] pyrimidin-4 (3H) -one, 1- (1-ethyl-1H-benzo [d] imidazol-2-yl) -N- (pyridin-3-yl Methyl) piperidine-4-carboxamide, N- (2- (5- (pyridin-4-yl) pyrazolo [1,5-a] pyrimidin-2-yl) ethyl) picolinamide, 3 -(1- (2-ethoxybenzyl) piperidin-4-yl) -1-methyl-1H-pyrazolo [3,4-b] pyridine, N- (4-((6-methyl-4- (Trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-ylamino) methyl) phenyl) acetamide, N- (2-methoxyethyl) -2,5-dimethyl-3- p-tolylpyrazolo [1,5-a] pyrimidin-7-amine, N-((1-ethyl-1H-benzo [d] imidazol-2-yl) methyl) -6-methyl-4- ( Trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 2- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidine- 1-yl) -N- (2-ethoxyphenyl) acetamide, 2- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -1 -(4-methylpiperidin-1-yl) ethanone, 1- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -2- (2,5-dimethoxyphenyl) ethanone, 2-methoxy -N- (3-methyl-1- (3-methyl-3H-imidazo [4,5-b] pyridin-2-yl) butyl) acetamide, N- (3-methoxyphenyl) -1- ( 1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (3-phenylpropyl) piperidine-4-carboxamide, or 1- (4- (1H-pyrazolo [3,4-b] pyridin-3-yl) piperidin-1-yl) -2 It may be-(2-fluorophenyl) ethanone.

In the present invention, preferably, the compound is N-cinamyl-4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, 4,6-dimethyl-N- (3 -(Trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (Pyridin-3-yl) piperidine-4-carboxamide, N-cyclopentyl-1- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carbox Amide, ethyl 2- (1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamido) acetate, 1- (1-methyl-1H-benzo [ d] imidazol-2-yl) -N- (2- (vinyloxy) ethyl) piperidine-4-carboxamide, 7-((5-fluoro-3-methyl-1H-indole-2- Yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, N -(3-methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide or 1- (1-methyl-1H-benzo [ d] imidazol-2-yl) -N- (3-phenylpropyl) piperidine-4-carboxamide , More preferably, 4,6-dimethyl-N- (3- (trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 7-((5-fluoro Rho-3-methyl-1H-indol-2-yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d ] Pyrimidin-4 (3H) -one, or N- (3-methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carbox Amide.

In the present invention, specifically, the compound may be a compound according to the following examples.

Example 1 (Compound 39): 4- (3-((tetrahydrofuran-2-yl) methylamino) imidazo [1,2-a] pyrazin-2-yl) benzene-1,2-diol

Example 2 (Compound 41): N-cinamyl-4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine

Example 3 (Compound 42): N- (1- (3-isopropyl-3H-imidazo [4,5-b] pyridin-2-yl) -3-methylbutyl) cyclopropanecarboxamide

Example 4 (Compound 45): 4,6-dimethyl-N- (3- (trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine

Example 5 (Compound 50): N- (4-ethoxybenzyl) -4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine

Example 6 (Compound 52): 4,6-dimethyl-N-((1-propyl-1H-benzo [d] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-b] pyridine -3-amine

Example 7 (Compound 55): (E) -N- (3- (furan-2-yl) allyl) -6-methyl-4- (trifluoromethyl) -1H-pyrazolo [3,4-b ] Pyridin-3-amine

Example 8 (Compound 57): 1- (2- (1H-Benzo [d] imidazol-2-yl) pyrrolidin-1-yl) -2- (4-methoxyphenyl) ethanone

Example 9 (Compound 59): 1- (3-cyclopropyl-5,6-dihydro- [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl) -4 -(1H-indol-3-yl) butan-1-one

Example 10 (Compound 71): 1- (2- (5-fluoro-1H-benzo [d] imidazol-2-yl) piperidin-1-yl) -2- (3-methoxyphenyl) Ethanon

Example 11 (Compound 72): (4,6-dimethyl-3-((5-methylfuran-2-yl) methylamino) -1H-pyrazolo [3,4-b] pyridin-1-yl) ( Isoxazol-5-yl) methanone

Example 12 (Compound 78): 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (pyridin-3-yl) piperidine-4-carboxamide

Example 13 (Compound 80): N-cyclopentyl-1- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide

Example 14 (Compound 81): ethyl 2- (1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamido) acetate

Example 15 (Compound 82): 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (2- (vinyloxy) ethyl) piperidine-4-carboxamide

Example 16 (Compound 86): N- (4-fluorobenzyl) -4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine

Example 17 (Compound 87): 6-Methyl-N- (pyridin-2-ylmethyl) -4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine

Example 18 (Compound 94): Methyl 2- (3-((2-methyl-4-oxo-3,4,5,6-tetrahydropyrido [3,4-d] pyrimidine-7 (8H) -Yl) methyl) -1H-indol-1-yl) acetate

Example 19 (Compound 95): 7-((5-fluoro-3-methyl-1H-indol-2-yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6 , 7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one

Example 20 (Compound 125): 1- (1-ethyl-1H-benzo [d] imidazol-2-yl) -N- (pyridin-3-ylmethyl) piperidine-4-carboxamide

Example 21 (Compound 126): N- (2- (5- (pyridin-4-yl) pyrazolo [1,5-a] pyrimidin-2-yl) ethyl) picolinamide

Example 22 (Compound 128): 3- (1- (2-ethoxybenzyl) piperidin-4-yl) -1-methyl-1H-pyrazolo [3,4-b] pyridine

Example 23 (Compound 137): N- (4-((6-methyl-4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-ylamino) methyl) phenyl) Acetamide

Example 24 (Compound 138): N- (2-methoxyethyl) -2,5-dimethyl-3-p-tolylpyrazolo [1,5-a] pyrimidin-7-amine

Example 25 (Compound 139): N-((1-ethyl-1H-benzo [d] imidazol-2-yl) methyl) -6-methyl-4- (trifluoromethyl) -1H-pyrazolo [ 3,4-b] pyridin-3-amine

Example 26 (Compound 140): 2- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -N- (2-ethoxyphenyl) acet amides

Example 27 (Compound 141): 2- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -1- (4-methylpiperidine- Ethanone

Example 28 (Compound 142): 1- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -2- (2,5-dimethoxyphenyl Ethanone

Example 29 (Compound 145): 2-methoxy-N- (3-methyl-1- (3-methyl-3H-imidazo [4,5-b] pyridin-2-yl) butyl) acetamide

Example 30 (Compound 147): N- (3-methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide

Example 31 (Compound 149): 1- (1-Methyl-1H-benzo [d] imidazol-2-yl) -N- (3-phenylpropyl) piperidine-4-carboxamide

Example 32 (Compound 152): 1- (4- (1H-pyrazolo [3,4-b] pyridin-3-yl) piperidin-1-yl) -2- (2-fluorophenyl) ethane On

The compounds according to the present invention are available from commercial compound library vendors such as LeadQuest, Asinex, or can be synthesized through known synthetic methods.

In the present invention, it was confirmed that the compounds inhibit the nuclear export function of GSK3 by binding GSK3 competitively with Axin. That is, the compounds according to the present invention inhibit GSK3 migration from the cell nucleus to the cytoplasm by binding to Axin, thereby promoting intracellular activity of GSK, or inhibiting or maintaining and increasing GSK3 concentration or activity decrease in the cell nucleus. It is useful for the treatment of diseases caused by decreasing GSK3 concentration.

The "diseases caused by GSK3 migration from the cell nucleus to the cytoplasm" include diseases mediated through GSK3, such as cancer, diabetes, Niemann Pick's disease type C, bipolar disorder (especially manic depression). ), Alzheimer's disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, and peak disease ( Pick's disease, dementia Pugilistica, AIDS associated dementia, dementia, stroke, Guam parkinsonism-dementia complex, postencephalic Parkinsonism, Frontal lobe degeneration, argyrophilic grains disease, depression, Schizophrenia, Huntington's disease, myotonic dystrophy , Inflammatory diseases such as suvacute sclerotizing panencephalitis, prion disease, Down syndrome, allergy or asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, baldness, etc. Among the skin diseases, pain, especially neuropathic pain, osteoarthritis, leukopenia, and the like, the compound according to the present invention by inhibiting the movement of the GSK3 from the cell nucleus to the cytoplasm, GSK function is inhibited to prevent and treat the disease This can be useful. It can also be used to inhibit sperm movement and thus can be used as a male contraceptive. In particular, the compounds of the present invention are useful for the prevention or treatment of cancer.

In view of the above pharmacological properties, the compound of formula 1 or a pharmaceutically acceptable salt, prodrug, or isomer thereof may be used as a medicament. In particular, the compounds can be used to prepare a medicament for treating or preventing diseases caused by GSK3 migration from the cell nucleus to the cytoplasm.

 Accordingly, the present invention, in another aspect, the pharmaceutical composition for inhibiting the growth or metastasis of cancer cells and the immune disease treatment containing the compound represented by the formula (1), a pharmaceutically acceptable salt, prodrug or isomer thereof as an active ingredient It relates to a pharmaceutical composition. Specifically, the composition is the compound 39, 41, 42, 45, 50, 52, 55, 57, 59, 71, 72, 78, 80 to 82, 86, 87, 94, 95, 125, 126, 128, 137-142, 145, 147, 149, 152.

The compounds according to the present invention can be usefully used to inhibit the development and progression of autoimmune and degenerative diseases such as rheumatoid arthritis as well as metastasis of cancer cells promoted by Wnt signal transduction.

The compounds according to the invention can be used by themselves or in the form of pharmaceutically acceptable acid addition salts or salts of metal complexes such as zinc, iron and the like. More specifically, the acid addition salt may be selected from the group consisting of hydrogen chloride, hydrogen bromide, sulfate, phosphate, maleate, acetic salt, citralate, benzoate, succinate, dried salt, ascorbate and tartalate. It is preferable.

Pharmaceutical compositions containing a compound according to the invention as an active ingredient, in other words a therapeutically effective amount or a prophylactically effective amount, may contain a pharmaceutically acceptable excipient or matrix according to conventional administration methods, dosage forms and therapeutic purposes. Mixing and dilution with a phosphorus carrier or encapsulation in a carrier in the form of a container is preferred. It can also be used in combination with other medicines that are beneficial for the treatment of other bone defects. At this time, the preparation of a physiologically acceptable protein composition having a desired pH, isotonicity, stability and the like can be used within the conventional technical scope in the field of the present invention. In the present invention, the matrix is a biodegradable and chemical substance such as calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, or polyanhydride, depending on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and contact properties; Biodegradable and biological substances such as bone or skin collagen, other pure proteins or matrix components of cells; Non-biodegradable and chemical materials such as sintered hydroxyapatite, bioglass, aluminate or other ceramics; Preference is given to using combinations of the foregoing materials such as polylactic acid, hydroxyapatite, collagen and tricalcium phosphate. However, the present invention is not limited to the carrier.

Excipients in the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, magnesium styrate, water, methylhydroxy Benzoate (methylhydroxybenzoate), propylhydroxybenzoate (propylhydroxybenzoate), talc (talc), mineral oil and the like can be used.

When used as a medicament in preventing or treating cancer, the compound of formula 1 may be used in other conventional drugs used to treat cancer, such as platinum coordination compounds such as cisplatin or carboplatin; Taxane compounds such as paclitaxel or docetaxel; Camptothecin compounds such as irinotecan or topotecan; Anti-tumor vinca alkaloids such as vinblastine, vincristine or vinorelbine; Anti-tumor nucleoside derivatives such as 5-fluorouracil, gemcitabine or capecitabine; Nitrogen mustard or nitrosourea alkylating agents such as cyclophosphamide, chlorambucil, carmustine or romustine; Anti-tumor anthracycline derivatives such as daunorubicin, doxorubicin or idarubicin; HER2 antibodies such as trastuzumab; And anti-tumor grapephytotoxin derivatives such as etoposide or teniposide; And antiestrogenic agents including estrogen receptor antagonists or selective estrogen receptor modulators, preferably tamoxifen or separately toremifene, droroxifene, parslodex and raloxifene; Aromatase inhibitors such as exemestane, anastrozole, retrazole and borosol; Differentiating agents such as retinoids, vitamin D and DNA methyl transferase inhibitors such as azacytidine; It can be used in combination with kinase inhibitors such as flaboferridol and imatinib mesylate or farnesyltransferase inhibitors such as R115777. Accordingly, the present invention also relates to a combination of a compound of formula 1 and another agent capable of preventing or treating cancer. The combination can be used as a medicament. The invention also relates to a product containing (a) Formula (1) and another agent capable of preventing or treating cancer as a combination formulation for simultaneous, separate or continuous use in the prevention or treatment of cancer. Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.

When used as a medicament in preventing or treating an inflammatory disease, the compound of formula 1 may be used in other conventional drugs used to treat inflammatory diseases, such as steroids, cyclooxygenase-2 inhibitors, nonsteroidal-anti-inflammatory drugs, TNF -α antibodies, for example acetyl salicylic acid, bufexamac, diclofenac potassium, schlindax, diclofenac sodium, ketorolac tromethamol, tolmethine, ibuprofen, naproxen, naproxen sodium, triaprofenic acid, flubiprofen, mefenamic acid , Niflumic acid, meclofenamate, indomethacin, proglumetacin, ketoprofen, nabumethone, paracetamol, pyricampam, tenoxycam, nimesulide, phenylbutazone, tramadol, beclomethasone Dipropionate, betamethasone, beclomethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, predney Ron, prednisone, triamcinolone, celecoxib, rofecoxib to

It can be used in combination with sieve, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine.

Accordingly, the present invention also relates to a combination of a compound of formula (1), a pharmaceutically acceptable salt, prodrug, or isomer and another agent capable of preventing or treating an inflammatory disease. The combination can be used as a medicament. The present invention also provides a combination formulation for use simultaneously, separately or continuously in the prevention or treatment of an inflammatory disease, comprising (a) a compound of formula 1, a pharmaceutically acceptable salt, a prodrug, or an isomer thereof and (b The present invention relates to a product containing another agent capable of preventing or treating an inflammatory disease. Different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.

In another aspect, the present invention provides methods for treating or preventing mammals, including humans suffering from diseases caused by GSK3 migration from the cell nucleus to the cytoplasm, more particularly immune diseases including cancer, arthritis, Alzheimer's disease, Methods of treating or preventing diabetes, particularly type 2 diabetes, or bipolar disorder are provided. The method comprises administering to a mammal, including a human, an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, prodrug, or isomer thereof.

On the other hand, the pharmaceutical composition containing the compound according to the present invention can be prepared in a variety of formulations, it is preferable to use injectable or capsulated in a viscous form for injection into the site where the therapeutic effect is expected. The dosage of the composition according to the present invention can be adjusted in consideration of the type of carrier such as the excipient or matrix used, the treatment site of the patient, the age, sex and diet of the patient, the severity of infection, the time of administration and other clinical factors. Although not limited thereto, a conventionally known effective amount can be administered continuously or dividedly, in consideration of weight, to observe the therapeutic effect and to determine further administration.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

Experimental Example 1: Confirmation of the in vitro binding inhibitory effect of Axin2 and GSK3β on the compounds according to the present invention

In order to determine the in vitro binding inhibitory effect of Axin2 and GSK3β on the compounds 41, 45, 78, 80, 81, 82, 95, 147 and 149 of the compound according to the present invention was carried out as follows. .

(1) Preparation of Axin2 Overexpressing Cells

In order to obtain the pcDNA3.1-Axin2-His expression vector, the Axin2 expression vector, Axin2-His cDNA was obtained by PCR amplification in A549 cells and amplified at the HindIII and BamHI sites of the pcDNA3.1-hyg (+) (invitrogen) vector. Axin2-His cDNA was prepared and amplified in E. coli DH5α to obtain pcDNA3.1-Axin2-His expression vector.

After transfection of the episomal Axin2-His expression vector, pcDNA3.1-Axin2-His expression vector, to MCF7 cells (ATCC HTB-26), 200 μg / ml of hygromycin (hygromycin) ) Was treated to obtain Axin2-His overexpressing cells.

(2) immunoprecipitation

Triton X-100 lysis buffer was added to the obtained Axin2-His overexpressing cells to obtain cell lysate. To neutralize the Ni-NTA bead, 1000 µl of Triton X-100 lysis buffer was added to 20 µl of beads, and the procedure of precipitation for 1 minute at 2000 rpm was repeated three times. 10 μM of each of the cell lysate and compounds 41, 45, 78, 80, 81, 82, 95, 147 and 149 (obtained from Asinex) were added to the neutralized bead, and Triton X-100 The total volume was adjusted to 1000 μl with lysis buffer. After shaking for 5 hours at 4 ℃, it was precipitated at 2000 rpm for 1 minute. After washing twice with the addition of 1000 μl of Triton X-100 lysis buffer, it was washed twice with 1000 μl of 1 × TBS. 20 μl of a 2 × sample buffer (50 mM Tris-Hcl, pH6.8, 4% SDS, 25% glycerol, 14.1 mM 2-mercaptoetanol, 0.1% bromophenol blue) containing 500 mM immidazole was added to the beads. It was boiled and 10 μl was loaded onto the SDS-PAGE gel.

(3) immunoblot analysis

In order to confirm the inhibition of the in vitro binding effect of Axin2 and GSK3β according to the treatment of each compound, GSK3β expression was examined using immunoblotting.

After performing the immunoprecipitation method, it was transferred to a nitrocellulose membrane (Pall Corp., NY), and the membrane was blocked for 1 hour in 5% fat-free dry milk, and then reacted for 3 hours with a primary antibody. The primary antibodies were anti-conductin (Sigma) and anti-GSK3β (BD Bioscience), and the protein expression level was horseradish peroxidase (HRP) -conjugated secondary antibody and enhanced chemiluminescence (ECL) detection kit ( Intron, Korea) was used to sensitize the x-ray film.

As shown in the above experiment, in the cells overexpressing Axin2, Axin2 and GSK3β bound lysates were bound to Ni-NTA bead, and immunoprecipitation was performed on Axin2, and GSK3β bound to Axin2 was immunoblotted. Confirmed by lotting.

As a result, as shown in Table 1 and Figure 4, the expression of GSK3β was suppressed by the compound treatment according to the present invention, it was shown that the binding of Axin2 and GSK3β by the compound. In FIG. 4, CTL is a control and compounds 41, 45, 78, 80, 81, 82, 95, 147 and 149 all showed activity, among which compounds 45, 95, 147 were particularly strong.

Table 1

Example	Compound no.	Biological activity
2	41	+
4	45	+++
12	78	+
13	80	+
14	81	+
15	82	+
19	95	+++
30	147	+++
31	149	+

As described above, the present invention has an effect of providing a composition for inhibiting the development and progression of a disease caused by the GSK3 migration from the cell nucleus to the cytoplasm, which occurs due to the decrease in GSK3 concentration in the nucleus. The compounds according to the present invention are useful for the treatment or prevention of various diseases caused by a decrease in the GSK3 concentration in the nucleus by inhibiting the nuclear export function of GSK3 by Axin and increasing the GSK3 concentration in the nucleus.

Having described the specific part of the present invention in detail, it is obvious to those skilled in the art that such a specific description is only a preferred embodiment, thereby not limiting the scope of the present invention. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (21)

1. A pharmaceutical composition for the treatment or prevention of diseases caused by GSK3 migration from the cell nucleus to the cytoplasm containing the compound represented by the following formula (1), a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient:

   Formula 1

   

   A is CR _a or N;

   D is CR _d or N;

   G is CR _g or N;

   J is CR _j or N;

   Y is Y ¹ (

   

   ) Or Y ² (

   

   );

   When Y is Y ¹ , W is C; Or Y ² , W is CR _w or N;

   M is CR _m or N;

   Q is CR _q or N;

   When Y is Y ¹ , Z is C (R _z ) ₂ , C═O, C = S, NR _z , O, S, S (O) ₂ ; Or, when Y ² , Z is CR _z or N; And

   R _a , R _d , R _g , R _j , R _w , R _m , R _q and R _z are each independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O ) H, -OH, substituted or unsubstituted -C (O) O-alkyl, substituted or unsubstituted -C (O) O-aryl, substituted or unsubstituted -C (O) O-hetero Aryl, substituted or unsubstituted -C (O) -alkyl, substituted or unsubstituted -C (O) -aryl, substituted or unsubstituted -C (O) -heteroaryl, substituted or unsubstituted Substituted carboxamido, substituted or unsubstituted carbonylamino, substituted or unsubstituted sulfonamido, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl Alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, halogen substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Arylalkenyl, substituted or unsubstituted he Roarylalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxy, substituted or unsubstituted arylalkoxy, substituted or Unsubstituted heteroarylalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted amino Alkenyl, substituted or unsubstituted aminoaryl, substituted or unsubstituted amido group, substituted or unsubstituted urea, substituted or unsubstituted alkylurea, substituted or unsubstituted arylurea, substituted Or unsubstituted heteroarylurea, substituted or unsubstituted thiourea, substituted or unsubstituted alkylthiourea, substituted or unsubstituted arylthiourea, substituted or unsubstituted hete Roarylthiourea, substituted or unsubstituted -S (O) ₂ -alkyl, substituted or unsubstituted -S (O) ₂ -aryl, substituted or unsubstituted -S (O) ₂ -heteroaryl , Substituted or unsubstituted -S (O) -alkyl, substituted or unsubstituted -S (O) -aryl, substituted or unsubstituted -S (O) -heteroaryl, substituted or unsubstituted -S-alkyl, substituted or unsubstituted -S-aryl, substituted or unsubstituted -S-heteroaryl, substituted or unsubstituted nonaromatic ring, substituted or unsubstituted ester, substituted or unsubstituted Substituted ethers, substituted or unsubstituted acyl, substituted or unsubstituted primary, secondary, tertiary amines, substituted or unsubstituted oxime groups, substituted or unsubstituted carbonates, substituted or unsubstituted Boron, substituted or unsubstituted silicone and substituted or unsubstituted phosphine.
2. The compound of claim 1, wherein R _a is hydrogen, halogen, substituted or unsubstituted alkyl, halogen substituted alkyl including —CF ₃ ,

   

   Substituted or unsubstituted-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -alkoxy;

   N is each independently an integer of 0 to 6; And

   Each R is independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O) H, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl Or substituted or unsubstituted aryl or substituted or unsubstituted amino.
3. The compound of claim 1, wherein R _a is — (CH ₂ ) _n —C (O) OH, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted morpholinyl, Substituted or unsubstituted-(CH ₂ ) _N -C (O) O- (CH ₂ ) _n -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -heteroaryl, substituted or unsubstituted -Z ^a -alkyl, substituted or unsubstituted -Z ^a -cycloalkyl, substituted or unsubstituted -Z ^a -heterocycloalkyl, substituted or unsubstituted -Z ^a -cycloalkylalkyl, substituted or unsubstituted -Z ^a -arylalkyl, substituted or unsubstituted -Z ^a - aryl, or a substituted or unsubstituted -Z ^a - heteroaryl or substituted or unsubstituted - (CH _{2) n-alkoxy;}

   Z ^a is each independently-(CH ₂ ) _n- C (O) N (R)-(CH ₂ ) _n or-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n The composition characterized in that the.
4. 2. The method of claim 1, wherein R _a is _{- (CH 2) n- CN,} - (CH 2) n -NO 2, - (CH 2) n -C (O) H, - (CH 2) n -OH , Substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted-(CH ₂ ) _n- C (O) -heteroaryl, substituted or unsubstituted primary, secondary, tertiary amine, or substituted or unsubstituted heterocyclic non-aromatic ring.
5. The composition of claim 1, wherein R _d is hydrogen or halogen.
6. The compound of claim 1, wherein R _d is — (CH ₂ ) _n —NO ₂ , — (CH ₂ ) _n —SO ₃ H, substituted or unsubstituted — (CH ₂ ) _n -alkoxy, substituted or unsubstituted Substituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted -Z ^a -alkyl, substituted or unsubstituted -Z ^a -cycloalkyl, substituted or unsubstituted Substituted -Z ^a -heterocycloalkyl, substituted or unsubstituted -Z ^a -cycloalkylalkyl, substituted or unsubstituted -Z ^a -arylalkyl, substituted or unsubstituted -Z ^a -aryl, substituted Or unsubstituted -Z ^a -heteroaryl, substituted or unsubstituted -Z ^b -alkyl, substituted or unsubstituted -Z ^b -heterocycloalkyl, substituted or unsubstituted -Z ^b -arylalkyl , Substituted or unsubstituted -Z ^b -aryl, substituted or unsubstituted -Z ^b -heteroaryl, substituted or unsubstituted -Z ^a -N (R)-(CH ₂ ) _n -aryl, or a substituted or unsubstituted ^{-Z a -N (R) - (} CH 2) n - heteroaryl A reel;

   Z ^a is each independently-(CH ₂ ) _n- C (O) N (R)-(CH ₂ ) _n or-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n ego;

   Z ^b are each independently — (CH ₂ ) _N —S (O) ₂ N (R) — (CH ₂ ) _n — or — (CH ₂ ) _n —N (R) S (O) ₂ — (CH ₂ ) _n -composition.
7. The method of claim 1, wherein R _d is-(CH ₂ ) _n -CN,-(CH ₂ ) _n -C (O) OH,-(CH ₂ ) _n -C (O) H,-(CH ₂ ) _n- OH, substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted -(CH ₂ ) _n -C (O) -heteroaryl, substituted or unsubstituted primary, secondary, tertiary amine, or substituted or unsubstituted heterocyclic nonaromatic ring .
8. The compound of claim 1, wherein R _g is hydrogen, substituted or unsubstituted-(CH ₂ ) _n -pyridyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted And heteroaryl.
9. According to claim 1, wherein R_gIs halogen,-(CH₂)_n-NO₂,-(CH₂)_n-C (O) OH,-(CH₂)_n-C (O) -N (R)₂, Substituted or unsubstituted alkyl- (CH₂)_n-NO₂, Substituted or unsubstituted aryl- (CH₂)_n-NO₂, Substituted or unsubstituted heteroaryl- (CH₂)_n-NO_2,Substituted or unsubstituted alkyl- (CH₂)_n-C (O) OH, substituted or unsubstituted aryl- (CH₂)_n-C (O) OH, substituted or unsubstituted heteroaryl- (CH₂)_n-C (O) OH, substituted or unsubstituted alkyl- (CH₂)_n-C (O) -N (R)₂, Substituted or unsubstituted aryl- (CH₂)_n-C (O) -N (R)_2,Substituted or unsubstituted heteroaryl- (CH₂)_n-C (O) -N (R)₂, Substituted or unsubstituted-(CH₂)_n-C (O) O- (CH₂)_n-Alkyl, substituted or unsubstituted-(CH₂)_n-C (O) O- (CH₂)_n-Aryl, substituted or unsubstituted-(CH₂)_n-C (O) O- (CH₂)_n-Heteroaryl, substituted or unsubstituted -Z^a-Alkyl, substituted or unsubstituted -Z^a-Cycloalkyl, substituted or unsubstituted -Z^a-Heterocycloalkyl, substituted or unsubstituted -Z^a-Cycloalkylalkyl, substituted or unsubstituted -Z^a-Arylalkyl, substituted or unsubstituted -Z^a-Aryl, substituted or unsubstituted -Z^a-Heteroaryl, substituted or unsubstituted -Z^bAlkyl, Substituted or unsubstituted -Z^b-Heterocycloalkyl, substituted or unsubstituted -Z^b-Arylalkyl, substituted or unsubstituted -Z^b-Aryl, substituted or unsubstituted -Z^bHeteroaryl, substituted or unsubstituted-(CH₂)_n-Aryl-Z^a-Aryl, substituted or unsubstituted-(CH₂)_n-Aryl-Z^aHeteroaryl, substituted or unsubstituted-(CH₂)_nHeteroaryl-Z^a-Aryl, substituted or unsubstituted-(CH₂)_nHeteroaryl-Z^aHeteroaryl, substituted or unsubstituted-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_n-Aryl, substituted or unsubstituted-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_nHeteroaryl, substituted or unsubstituted-(CH₂)_n-N (R)-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_n-Aryl, substituted or unsubstituted-(CH₂)_n-N (R)-(CH₂)_n-(Z^c= Z^c)_m-(CH₂)_nHeteroaryl, substituted or unsubstituted-(CH₂)_n-N (R) -Z^cAryl, substituted or unsubstituted-(CH₂)_n-N (R) -Z^cHeteroaryl, substituted or unsubstituted-(CH₂)_n-Alkoxy or substituted or unsubstituted primary, secondary, tertiary amines;

   Z ^a is each independently-(CH ₂ ) _n- C (O) N (R)-(CH ₂ ) _n or-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n ego;

   Z ^b are each independently — (CH ₂ ) _n —S (O) ₂ N (R) — (CH ₂ ) _n — or — (CH ₂ ) _n —N (R) S (O) ₂ — (CH ₂ ) _n- ;

   Each Z ^C is independently C (R) or N; And

   M is each independently 0, 1 or 2;

   The composition characterized in that the.
10. The compound of claim 1, wherein R _g is — (CH ₂ ) _n— CN, — (CH ₂ ) _n C (O) H, — (CH ₂ ) _n —OH, substituted or unsubstituted — (CH ₂₎ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -heteroaryl Or a substituted or unsubstituted heterocyclic non-aromatic ring.
11. The compound of claim 1, wherein R _j is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted (CH ₂ ) _n -N (R)-(CH ₂ ) _n -aryl, or substituted or unsubstituted-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -heteroaryl The composition characterized in that the.
12. The method of claim 1, wherein R _j is-(CH ₂ ) _n -CN,-(CH ₂ ) _n -NO ₂ ,-(CH ₂ ) _n -C (O) OH,-(CH ₂ ) _n -C (O) H,-(CH ₂ ) _n -OH, substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O ) -Aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -heteroaryl, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted primary, 2 Tea, tertiary amine or substituted or unsubstituted heterocyclic non-aromatic ring.
13. The method of claim 1, wherein R _w is hydrogen, halogen,-(CH ₂ ) _n -CN,-(CH ₂ ) _n -NO ₂ ,-(CH ₂ ) _n -C (O) OH,-(CH ₂ ) _n -C (O) H,-(CH ₂ ) _n -OH, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetero Aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) -aryl, substituted or unsubstituted-( CH ₂ ) _n- C (O) -heteroaryl, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted primary, secondary, tertiary amine or substituted or unsubstituted A composition characterized in that the heterocyclic non-aromatic ring.
14. The compound of claim 1, wherein R _m , R _q and R _z are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -T ¹ -T ² -T ³ -T ⁴ or

    

    ego;

    Each T ¹ is independently a covalent bond,-(CH ₂ ) _n -,-(CH ₂ ) _n -O- (CH ₂ ) _n -,-(CH ₂ ) _n -S- (CH ₂ ) _n- , -(CH ₂ ) _n -N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -S (O) _p- (CH ₂ ) _n -,-(CH ₂ ) _n -C (O) -(CH ₂ ) _n -,-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -,-(CH ₂ ) _n -OC (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n- S (O) _p N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R) S (O) _p- (CH ₂ ) _n -,-(CH ₂ ) _n -OC ( O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R) C (O) O- (CH ₂ ) _n -,-(CH ₂ ) _n -C (O)- (CH ₂ ) _n -N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -C (O)-(CH ₂ ) _n -,-( CH ₂ ) _n -O- (C (R) ₂ ) _n -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (O)-(C (R) ₂ ) _n -O -(CH ₂ ) _n -,-(CH ₂ ) _n -O- (C (R) ₂ ) _n -O- (CH ₂ ) _n -,-(CH ₂ ) _n -C (O) N (R) -(CH ₂ ) _n -O-,-(CH ₂ ) _n -N (R) C (O)-(CH ₂ ) _n -O-,-(CH ₂ ) _n -C (O) N (R) -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -S (O) _p N (R) -C (O)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (R) ₂ -C (O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _n -C (R) ₂ -N (R) C (O)-(CH ₂ ) _n- , -(CH ₂ ) _n -SC (R) ₂ -C (O) N (R)-(CH ₂ ) _n -,-(CH ₂ ) _{n -SC (R) 2 -N (R} ) C (O) - (CH 2) n -, or - (CH _{2) n} - aryl _{- (CH 2) n -N (} R) C (O) N (R )-(CH ₂ ) _n- ;

    Each T ² is independently a covalent bond,-(Z ^c = Z ^c ) _m- (CH ₂ ) _n- , or halogen, alkyl, -C (O) OH, -C (O) H, -CN,- NO ₂ ,-(CH ₂ ) _n -cycloalkyl- (CH ₂ ) _n -substituted or unsubstituted or substituted or unsubstituted amino or substituted or unsubstituted phenyl;

    Each of T ³ is independently covalently substituted, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic non-aromatic ring, quinolinyl, quinoxalinyl, quinazolinyl, iso Bicyclic aromatic, aromatic rings containing substituted or unsubstituted nitrogen-containing heterocycles having six atoms in each ring, including quinolinyl, phthalazinyl, have five atoms, or imidazopyrimides Other having six atoms, including nil, imidazoimidazolyl, imidazothiazolyl, naphthyl, tetrahydronaphthyl, benzothienyl, benzoxazolyl, benzoisoxazolyl and benzothiazolyl Nitrogen-containing heterocycle substituted or unsubstituted bicyclic aromatic with aromatic rings, or furanyl, phenyl, pyridinyl, benzimidazolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydratriazolo Pyrazinyl, tetrahydropyridopyrimidinone, thiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, isoxazolyl, tetrahydropyranyl, pyrazolyl, pyrrolyl, pyrrolopyridinyl, H-pyridinone, oxazolyl, isothiazolyl, oxdiazolyl, thiadiazolyl, indolinyl, indazolyl, imidazopyridinyl, benzoisothiazolyl, pyrimido-oxazolyl, pyrimido-thiazolyl, tier Neal, imidazolyl,

    

    ,

    

    ,

    

    ,

    

    

    , or

    

    Single or multiple substituted or unsubstituted aromatic or non-aromatic rings comprising;

    Each of T ⁴ is independently hydrogen, halogen, — (CH ₂ ) _n —CN, — (CH ₂ ) _n —NO ₂ , — (CH ₂ ) _n —C (O) OH, — (CH ₂ ) _n − C (O) H,-(CH ₂ ) _n -OH,-(CH ₂ ) _n -C (O) -N (R) ₂ , substituted or unsubstituted alkyl, halogen substituted alkyl, substituted or non- Single or polysubstituted or unsubstituted, including ringed cycloalkyl, single or polysubstituted or unsubstituted aryl, piperidinyl, piperazinyl, tetrazolyl, furanyl, pyridinyl, oxadiazolyl and isoxoxazolyl Substituted aromatic or non-aromatic rings, substituted or unsubstituted-(CH ₂ ) _n -alkoxy, substituted or unsubstituted-(CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n- O-alkyl, substituted or unsubstituted-(CH ₂ ) _n -O-alkenyl, substituted or unsubstituted-(CH ₂ ) _n -O- (CH ₂ ) _n -aryl, substituted or Unsubstituted-(CH ₂ ) _n -N (R) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -N (R)-(CH ₂ ) _n -aryl, substituted or unsubstituted- (CH ₂ ) _n -C (O) O-alkyl, substituted or unsubstituted-(CH ₂ ) _n -C (O) O- (CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n -OC (O) -alkyl, substituted or unsubstituted-(CH ₂ ) _n -OC (O)-(CH ₂ ) _n -aryl, substituted or unsubstituted-(CH ₂ ) _n -C (O)- alkyl, substituted or unsubstituted _{- (CH 2) n -C (} O) - (CH 2) n - aryl, a substituted or unsubstituted -Z ^a - alkyl, a substituted or unsubstituted -Z ^a - Aryl, substituted or unsubstituted-(CH ₂ ) _n -S-alkyl, substituted or unsubstituted-(CH ₂ ) _n -S- (CH ₂ ) _n -aryl, or substituted or unsubstituted amino ;

    L ₁ is C (R) or N;

    Each L ₂ is independently C═O, C═S, N, O, S, S (O) _p , CHOR _L , C (R _L ) _p , or N (R _L ), wherein each R _L is Independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O) H, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or Unsubstituted aryl, or substituted or unsubstituted amino; And

    Each of p is independently 1 or 2;

    The composition characterized in that the.
15. The compound of claim 1, wherein the compound is 4- (3-((tetrahydrofuran-2-yl) methylamino) imidazo [1,2-a] pyrazin-2-yl) benzene-1,2-diol, N-cinamyl-4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, N- (1- (3-isopropyl-3H-imidazo [4,5-b] Pyridin-2-yl) -3-methylbutyl) cyclopropanecarboxamide, 4,6-dimethyl-N- (3- (trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridine -3-amine, N- (4-ethoxybenzyl) -4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, 4,6-dimethyl-N-((1- Propyl-1H-benzo [d] imidazol-2-yl) methyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, (E) -N- (3- (furan-2-yl ) Allyl) -6-methyl-4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 1- (2- (1H-benzo [d] imidazol-2 -Yl) pyrrolidin-1-yl) -2- (4-methoxyphenyl) ethanone, 1- (3-cyclopropyl-5,6-dihydro- [1,2,4] triazolo [4 , 3-a] pyrazin-7 (8H) -yl) -4- (1H-indol-3-yl) butan-1-one, 1- (2- (5-fluoro-1H-benzo [d] Dazol-2-yl) Pipe Ridin-1-yl) -2- (3-methoxyphenyl) ethanone, (4,6-dimethyl-3-((5-methylfuran-2-yl) methylamino) -1H-pyrazolo [3, 4-b] pyridin-1-yl) (isoxazol-5-yl) methanone, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (pyridin-3-yl Piperidine-4-carboxamide, N-cyclopentyl-1- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide, ethyl 2- ( 1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamido) acetate, 1- (1-methyl-1H-benzo [d] imidazole-2 -Yl) -N- (2- (vinyloxy) ethyl) piperidine-4-carboxamide, N- (4-fluorobenzyl) -4,6-dimethyl-1H-pyrazolo [3,4- b] pyridin-3-amine, 6-methyl-N- (pyridin-2-ylmethyl) -4- (trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, methyl 2- (3-((2-methyl-4-oxo-3,4,5,6-tetrahydropyrido [3,4-d] pyrimidin-7 (8H) -yl) methyl) -1H-indole -1-yl) acetate, 7-((5-fluoro-3-methyl-1H-indol-2-yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6, 7,8-tetra Hydropyrido [3,4-d] pyrimidin-4 (3H) -one, 1- (1-ethyl-1H-benzo [d] imidazol-2-yl) -N- (pyridin-3-ylmethyl ) Piperidine-4-carboxamide, N- (2- (5- (pyridin-4-yl) pyrazolo [1,5-a] pyrimidin-2-yl) ethyl) picolinamide, 3- (1- (2-ethoxybenzyl) piperidin-4-yl) -1-methyl-1H-pyrazolo [3,4-b] pyridine, N- (4-((6-methyl-4- ( Trifluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-ylamino) methyl) phenyl) acetamide, N- (2-methoxyethyl) -2,5-dimethyl-3-p -Tolylpyrazolo [1,5-a] pyrimidin-7-amine, N-((1-ethyl-1H-benzo [d] imidazol-2-yl) methyl) -6-methyl-4- (tri Fluoromethyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 2- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidine-1 -Yl) -N- (2-ethoxyphenyl) acetamide, 2- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -1- (4-methylpiperidin-1-yl) ethanone, 1- (4- (3H-imidazo [4,5-b] pyridin-3-yl) piperidin-1-yl) -2- ( 2,5-dimethoxyphenyl) ethanone, 2-methoxy- N- (3-methyl-1- (3-methyl-3H-imidazo [4,5-b] pyridin-2-yl) butyl) acetamide, N- (3-methoxyphenyl) -1- (1 -Methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- ( 3-phenylpropyl) piperidine-4-carboxamide, or 1- (4- (1H-pyrazolo [3,4-b] pyridin-3-yl) piperidin-1-yl) -2- (2-fluorophenyl) ethanone.
16. 16. The compound of claim 15, wherein the compound is N-cinamyl-4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, 4,6-dimethyl-N- (3- (tri Fluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (pyridine- 3-yl) piperidine-4-carboxamide, N-cyclopentyl-1- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide, ethyl 2- (1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamido) acetate, 1- (1-methyl-1H-benzo [d] imide Dazol-2-yl) -N- (2- (vinyloxy) ethyl) piperidine-4-carboxamide, 7-((5-fluoro-3-methyl-1H-indol-2-yl) methyl ) -2- (3-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, N- (3 -Methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide or 1- (1-methyl-1H-benzo [d] Dazol-2-yl) -N- (3-phenylpropyl) piperidine-4-carboxamide .
17. The compound of claim 16, wherein the compound is 4,6-dimethyl-N- (3- (trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 7-(( 5-fluoro-3-methyl-1H-indol-2-yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [3, 4-d] pyrimidin-4 (3H) -one or N- (3-methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4 Carboxamide.
18. 18. The disease according to any one of claims 1 to 17, wherein the disease caused by GSK3 migration from the cell nucleus to the cytoplasm is cancer, diabetes, Niemann Pick's disease type C, bipolar disorder, Alzheimer's disease. Disease, FTDP-17 (frontal temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease Dementia Pugilistica, AIDS associated dementia, Dementia, Stroke, Guam parkinsonism-dementia complex, Postencephalic Parkinsonism, Frontal lobe degeneration frontal lobe degeneration, argyrophilic grains disease, depression, schizophrenia, Huntington's disease, myotonic dystrophy, subacute Cute sclerotizing panencephalitis, prion disease, Down's syndrome, allergy, asthma, multiple sclerosis, rheumatoid arthritis, arteriosclerosis, inflammatory bowel disease, inflammatory disease, skin disease, pain, osteoarthritis And leukopenia is a composition, characterized in that at least one selected from the group consisting of.
19. A pharmaceutical composition for inhibiting the growth or metastasis of cancer cells containing a compound represented by the following Formula 1, a pharmaceutically acceptable salt, prodrug, or isomer thereof as an active ingredient:

    Formula 1

    

    A is CR _a or N;

    D is CR _d or N;

    G is CR _g or N;

    J is CR _j or N;

    Y is Y ¹ (

    

    ) Or Y ² (

    

    );

    When Y is Y ¹ , W is C; Or Y ² , W is CR _w or N;

    M is CR _m or N;

    Q is CR _q or N;

    When Y is Y ¹ , Z is C (R _z ) ₂ , C═O, C = S, NR _z , O, S, S (O) ₂ ; Or, when Y ² , Z is CR _z or N; And

    R _a , R _d , R _g , R _j , R _w , R _m , R _q and R _z are each independently hydrogen, halogen, -CN, -NO ₂ , -C (O) OH, -C (O ) H, -OH, substituted or unsubstituted -C (O) O-alkyl, substituted or unsubstituted -C (O) O-aryl, substituted or unsubstituted -C (O) O-hetero Aryl, substituted or unsubstituted -C (O) -alkyl, substituted or unsubstituted -C (O) -aryl, substituted or unsubstituted -C (O) -heteroaryl, substituted or unsubstituted Substituted carboxamido, substituted or unsubstituted carbonylamino, substituted or unsubstituted sulfonamido, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl Alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, halogen substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Arylalkenyl, substituted or unsubstituted he Roarylalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxy, substituted or unsubstituted arylalkoxy, substituted or Unsubstituted heteroarylalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted amino, substituted or unsubstituted aminoalkyl, substituted or unsubstituted amino Alkenyl, substituted or unsubstituted aminoaryl, substituted or unsubstituted amido group, substituted or unsubstituted urea, substituted or unsubstituted alkylurea, substituted or unsubstituted arylurea, substituted Or unsubstituted heteroarylurea, substituted or unsubstituted thiourea, substituted or unsubstituted alkylthiourea, substituted or unsubstituted arylthiourea, substituted or unsubstituted hete Roarylthiourea, substituted or unsubstituted -S (O) ₂ -alkyl, substituted or unsubstituted -S (O) ₂ -aryl, substituted or unsubstituted -S (O) ₂ -heteroaryl , Substituted or unsubstituted -S (O) -alkyl, substituted or unsubstituted -S (O) -aryl, substituted or unsubstituted -S (O) -heteroaryl, substituted or unsubstituted -S-alkyl, substituted or unsubstituted -S-aryl, substituted or unsubstituted -S-heteroaryl, substituted or unsubstituted nonaromatic ring, substituted or unsubstituted ester, substituted or unsubstituted Substituted ethers, substituted or unsubstituted acyl, substituted or unsubstituted primary, secondary, tertiary amines, substituted or unsubstituted oxime groups, substituted or unsubstituted carbonates, substituted or unsubstituted Boron, substituted or unsubstituted silicone or substituted or unsubstituted phosphine.
20. 20. The compound of claim 19, wherein the compound is N-cinamyl-4,6-dimethyl-1H-pyrazolo [3,4-b] pyridin-3-amine, 4,6-dimethyl-N- (3- (tri Fluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 1- (1-methyl-1H-benzo [d] imidazol-2-yl) -N- (pyridine- 3-yl) piperidine-4-carboxamide, N-cyclopentyl-1- (1-ethyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide, ethyl 2- (1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamido) acetate, 1- (1-methyl-1H-benzo [d] imide Dazol-2-yl) -N- (2- (vinyloxy) ethyl) piperidine-4-carboxamide, 7-((5-fluoro-3-methyl-1H-indol-2-yl) methyl ) -2- (3-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidin-4 (3H) -one, N- (3 -Methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4-carboxamide or 1- (1-methyl-1H-benzo [d] Dazol-2-yl) -N- (3-phenylpropyl) piperidine-4-carboxamide .
21. The compound of claim 20, wherein the compound is 4,6-dimethyl-N- (3- (trifluoromethyl) benzyl) -1H-pyrazolo [3,4-b] pyridin-3-amine, 7-(( 5-fluoro-3-methyl-1H-indol-2-yl) methyl) -2- (3-methylpiperidin-1-yl) -5,6,7,8-tetrahydropyrido [3, 4-d] pyrimidin-4 (3H) -one or N- (3-methoxyphenyl) -1- (1-methyl-1H-benzo [d] imidazol-2-yl) piperidine-4 Carboxamide.

Images