KR101746199B1 - GSK3 Nitrogen-Containing Heteroaryl Derivatives and Their Use as GSK3 Inhibitors - Google Patents

Abstract

상기 화학식 1에서,
X는 탄소(C) 또는 질소(N)이고;
Y는 탄소(C) 또는 산소(O)이며;
R₁은 수소, 아릴, -CO-아릴 또는 헤테로아릴이며, 이때 상기 아릴 또는 헤테로아릴은 치환되지 않거나 또는 치환될 수 있고;
R₂는 -CO-NH-(CH₂)_n-CO-NH-, -CO-O-(CH₂)_n-, -CH=CH-(CH₂)_m-CO-NH- 또는 -(CH₂)_n-CO-NH-이며, 이때 n은 1 내지 3의 정수이고 m은 0 내지 3의 정수이며;
R₃는 C_1-6 알킬, -(CH₂)_n-아릴, -(CH₂)_n-헤테로아릴 또는 -(CH₂)_n-헤테로사이클릴이고, 이때 상기 아릴, 헤테로아릴 또는 헤테로사이클릴은 치환되지 않거나 또는 치환될 수 있다.
상기 화학식 1의 화합물은 GSK3β와 연관된 질환, 즉 증식성 질환, 신경 변성 또는 신경성 질환, 염증성 자가면역질환, 심혈관 질환, 내분비 질환, 및 바이러스 감염 질환을 예방 또는 치료하는데 유용하다.The present invention provides a novel compound of formula (I) or a pharmaceutically acceptable salt thereof having GSK3? Inhibitory activity.
[Chemical Formula 1]

In Formula 1,
X is carbon (C) or nitrogen (N);
Y is carbon (C) or oxygen (O);
R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or substituted;
R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2) m -CO-NH- or - (CH ₂ ) _n- CO-NH-, wherein n is an integer from 1 to 3 and m is an integer from 0 to 3;
R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl wherein the aryl, heteroaryl or heterocyclyl May be unsubstituted or substituted.
The compound of Formula 1 is useful for preventing or treating a disease associated with GSK3 [beta], i.e., a proliferative disease, a neurodegenerative or neurodegenerative disease, an inflammatory autoimmune disease, a cardiovascular disease, an endocrine disease, and a viral infectious disease.

Description

Nitrogen-containing heteroaryl derivatives and uses thereof as GSK3? Inhibitors (Nitrogen-Containing Heteroaryl Derivatives and Their Use as GSK3? Inhibitors)

The present invention relates to a novel nitrogen-containing heteroaryl derivative having the activity of inhibiting glycogen synthase kinase 3β (hereinafter abbreviated as "GSK3β"), a process for producing the same, and a method for preventing or treating a disease associated with GSK3β Lt; / RTI >

GSK3β is known to undergo "priming phosphorylation" which phosphorylates a serine or threonine residue located at the 4th position of the N-terminus in serine, which is already specifically phosphorylated by a serine / threonine kinase. Phosphorylation by GSK3β can form multiple phosphorylated domains because it can form priming sites for additional phosphorylation by gsk3.

This phosphorylation of GSK3β can alter the inherent physiological activity of the substrate. As can be deduced from the name of kinase, the glycogen-forming enzyme is one of its substrates. GSK3β is known to be involved in the regulation of insulin metabolism associated with glucose regulation, as glycogenesis enzyme is involved in the regulation of glucose, which is influenced by the ratio of glucose to glycogen. In particular, GSK3β has been reported to be a target for the treatment of type 2 diabetes with insulin resistance and relative insulin deficiency. It has been reported that the expression of GSK3β is increased in diabetic muscle. In overexpression studies, GSK3β phosphorylates insulin receptor substrate 1 (IRS1) And insulin signaling system weakens as it controls.

In addition, GSK3β, also called "tau" phosphorylated kinase, a microtubule-binding protein, is abundant in the brain and is located predominantly in neurons. GSK3β generally phosphorylates serine 199 and 396 of the tau, which in Alzheimer's disease is known to phosphorylate the abnormally hyperphosphorylated site of tau. Abnormal tau phosphorylation of GSK3β desorbs tau from microtubules and causes accumulation in the neuronal sensory area. It has been reported that desorption and accumulation of tau lead to the formation of twisted filament, causing nerve fiber knot and neuronal death.

Recent studies have also shown that GSK3 [beta] can be applied to the neuropathologic consequences associated with Alzheimer ' s disease, and other acute and chronic neurodegenerative diseases as well as cognitive and attention deficits, and other pathologies in which GSK3 [beta] is deregulated. Such neurodegenerative diseases include Parkinson's disease, other dementias including tauopathy (for example, frontotemporal dementia, cortical basal degeneration, peak disease, progressive supranuclear palsy), Wilson's disease, Huntington's disease, prion disease and vascular dementia; Acute stroke and other traumatic injuries; Brain and spinal trauma; Amyotrophic lateral sclerosis); Bipolar disorder (manic depression); And mental illness. For example, Parkinson's disease is a neuropathic disorder characterized by a decrease in certain dopamine-containing neurons, which may be induced by the control of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) . It is known that MPP + (1-methyl-4-phenylpyridinium), an active metabolite of MPTP, induces neuronal cell death through caspase-3 dependent cell death. This phenomenon is facilitated by overexpression of GSK3 beta, It was observed that treatment with GSK3 beta inhibitor was attenuated. Huntington's disease is characterized by decreased levels of vetecanine in the cells and decreased expression of the mutated huntingtin, which indicates that GSK3 can regulate cytotoxicity. In fact, overexpression experiments or inhibitor experiments have been observed to protect cells from the toxicity of mutant huntingtin. In the case of prion diseases caused by the accumulation of insoluble forms of prion proteins, neuronal cell death by pathological prion proteins was significantly reduced in lithium or insulin treatment inhibiting GSK. In addition, a decrease in the concentration of AKT1 and an increase in the activity of GSK3beta due to a decrease in phosphorylation of GSK3beta at Serine 9 is observed in the brain of schizophrenic patients. Continuous stimulation of dopamine receptors leads to activation of GSK3, and some GSK3 inhibitors As opposed to dopamine dependence and activity.

In addition, GSK3β plays a crucial role in cell signaling, stem cell regeneration and growth, cell apoptosis, cadmium rhythm, transcription, neuronal plasticity, and cell differentiation in a variety of proteins such as beta-catenin, c-MYC, elF2B, CREB, , And are known to act as important regulators of tumorigenesis. Specifically, it has been reported that inhibition of GSK3 beta induces neuronal differentiation of embryonic stem cells (ESCs), helps regenerate human and mouse ESCs and maintain their pluripotency, which can be applied to regenerative medicine . Inhibition of GSK3 [beta] may be useful in the treatment of cancer, such as colorectal cancer, prostate cancer, breast cancer, non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia and various viral induced tumors. For example, the active form of GSK3β has been shown to be elevated in tumors of colorectal cancer patients, and inhibition of GSK3β in colorectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth. Inhibition of GSK3 [beta] also promotes TRAIL-induced apoptosis in prostate cancer cell lines. GSK3 [beta] also plays a role in the dynamics of mitotic spindle whilst inhibitors of GSK3 [beta] inhibit chromosomal transfer and induce microtubule stabilization and hoop-like quiescence similar to those observed in low doses of Taxol.

Therefore, GSK3 [beta] may be a target for the treatment of not only Type 2 diabetes and Alzheimer's, but also central nervous disorders such as bipolar disorder and neurodegenerative diseases, proliferative diseases, and a selective inhibitor thereof is studied as a therapeutic agent for various diseases mentioned above have.

Despite numerous studies, however, no selective low molecular inhibitors have been approved by the FDA for GSK3β, and the development of such inhibitors has been desired.

Accordingly, the inventors of the present invention confirmed that the benzisoxazole, indole, and 7-azaindole derivatives of the present invention effectively inhibited GSK3?

It is an object of the present invention to provide a nitrogen-containing heteroaryl derivative, such as benzoisooxazole, indole or 7-azaindole derivative, which can treat diseases related to GSK3? Such as type 2 diabetes, Alzheimer's by inhibiting GSK3? Kinase, To provide an acceptable salt.

In order to achieve the above object, the present invention provides a nitrogen-containing heteroaryl derivative represented by the following general formula (I): or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

X is carbon (C) or nitrogen (N);

Y is carbon (C) or oxygen (O);

R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or substituted;

R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2) m -CO-NH- or - (CH ₂ ) _n- CO-NH-, wherein n is an integer from 1 to 3 and m is an integer from 0 to 3;

R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl wherein the aryl, heteroaryl or heterocyclyl May be unsubstituted or substituted.

The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:

(a) reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4); And

(2)

In this formula,

X and Y are the same as defined in Formula 1,

R is R ₁ defined in the above formula (1) or I, wherein R- ₁ is as defined in the above formula (1).

(3)

NH ₂ - (CH ₂ ) _n -CO ₂ H

In the above formula, n is an integer of 1 to 3.

[Chemical Formula 4]

Wherein X and Y are as defined in Formula 1,

R is R ₁ defined in the above formula (1) or I, wherein R- ₁ is as defined in the above formula (1)

n is an integer of 1 to 3;

(b) reacting a compound of formula (4) obtained in step (a) with R ₃ -NH ₂ , wherein R ₃ is as defined in formula (1); Or X and Y are carbon in the compound of formula (IV), when R is I and then form a compound of formula (VI) by reacting a compound of formula 4 with R ₃ -NH ₂ R a formula 6 compound ₄ B (OH) ₂ with Suzuki coupling with R < ₂ > wherein R < ₄ > is aryl or heteroaryl;

[Chemical Formula 5]

In this formula,

R is R ₁ defined in the above formula (1) or I, wherein R- ₁ is as defined in the above formula (1)

n is an integer of 1 to 3,

X, Y and R < ₃ > are as defined in the above formula (1).

[Chemical Formula 6]

In this formula,

n is an integer of 1 to 3,

X, Y and R < ₃ > are as defined in the above formula (1).

(7)

In the above formula

R < ₄ > is aryl or heteroaryl,

n is an integer of 1 to 3,

R ₃ is the same as defined in the above formula (1).

In addition, the present invention provides a process for preparing a compound of formula 8, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[Chemical Formula 8]

In this formula,

R ₁ and R ₃ are the same as defined in Formula 1,

m is an integer of 0 to 3

(a) a compound of formula 9 CH = CH-COOCH ₃ Or heck coupling with CH = CH- (CH ₂ ) _n -COOCH ₃ , wherein n is an integer from 1 to 3, to prepare a compound of formula (10); And

[Chemical Formula 9]

In this formula,

R ₁ is the same as defined in the above formula (1).

[Chemical formula 10]

In this formula,

R ₁ is the same as defined in Formula 1,

Z is SO ₂ Ph or H,

and m is an integer of 0 to 3.

(b) coupling the compound of formula (10) with an amide of R ₃ -NH ₂ wherein R ₃ is as defined in formula (1), and optionally removing the sulfone protecting group of 7- ≪ / RTI >

In addition, the present invention provides GSK3 [beta] kinase inhibiting uses of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, , Inflammatory autoimmune diseases, cardiovascular diseases, endocrine diseases, and viral infectious diseases.

The compounds of formula (I) according to the present invention and their pharmaceutically acceptable salts exhibit inhibitory activity against GSK3 [beta] kinase, and thus can be used for the treatment of diseases associated with GSK3 [beta], such as proliferative diseases, neurodegeneration or Neurodegenerative diseases, inflammatory autoimmune diseases, cardiovascular diseases, endocrine diseases, and viral infectious diseases.

Hereinafter, the present invention will be described in more detail.

The terms used to define the compounds according to the invention have the following meanings.

Specific examples of the term "halogen " include fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), in particular fluorine (F) and chlorine (Cl).

The term "cyano ", which can be represented by -CN, has a triple bond at an atomic group where one atom of carbon and nitrogen is bonded, and another atom or group is bonded to a carbon atom to form a cyanohydrogen, metal cyanide or nitrile have.

The term "nitro" means a functional group represented by -NO ₂ .

The term " C _1-6 alkyl " means a monovalent linear or branched, saturated hydrocarbon moiety consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl and the like. Examples of "branched alkyl" are isopropyl, isobutyl, tert-butyl and the like.

The term "C _1-6 alkoxy" means a radical of the formula -OC _1-6 alkyl, including but not limited to methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

The term "aryl" includes at least one ring having a covalent pi electron system and includes, for example, a group of monocyclic or fused ring polycyclic (i. E., Rings dividing adjacent pairs of carbon atoms) groups . That is, in the present specification, aryl may include phenyl, naphthyl, etc., and a biaryl, unless otherwise defined. In one embodiment of the present invention, aryl refers to an aromatic ring having 6 to 10 carbon atoms.

The term "heteroaryl ", unless otherwise defined, is an aromatic ring of five or six ring atoms containing one to four heteroatoms selected from the group consisting of N, O and S, or wherein said heteroaryl ring is a benzene ring or Refers to a bicyclic ring fused to another heteroaryl ring. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, triazolyl, triazinyl, thiadiazolyl, tetrazolyl , Oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryls include indolyl, azaindolyl, indolinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, But are not limited to, pyridyl, quinolinyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, and similar groups.

The term "heterocyclyl" denotes a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms containing from 1 to 3 heteroatoms selected from N, O and S in addition to the carbon atom. For example, heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isooxazolidinyl, Thiomorpholin-4-yl, azepanyl, diazepanyl, cyclohexyl, thiomorpholinyl, thiomorpholinyl, Dihydroimidazolinyl, dihydrooxazolyl, tetrahydropyridinyl, dihydropyranyl, dihydrobenzofuranyl, benzodioxolyl, or benzothiophenol, or a pharmaceutically acceptable salt thereof. Benzodioxanyl.

The term "treatment" refers to stopping or delaying the progression of a disease when used in an object exhibiting an onset symptom.

The term "pharmaceutical composition" may include, where appropriate, a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, together with the compound of the present invention.

The term "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of the compound.

The term "carrier" means a substance that facilitates the addition of a compound into a cell or tissue.

The term "diluent" is defined as a substance that not only stabilizes the biologically active form of the compound of interest, but also dilutes it in water to dissolve the compound.

Other terms and abbreviations used herein can be interpreted as commonly understood by one of ordinary skill in the art to which the present invention belongs, unless otherwise defined.

In one aspect, the present invention relates to a derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

X is carbon (C) or nitrogen (N);

Y is carbon (C) or oxygen (O);

R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or substituted;

R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2) m -CO-NH- or - (CH ₂ ) _n- CO-NH-, wherein n is an integer from 1 to 3 and m is an integer from 0 to 3;

R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl wherein the aryl, heteroaryl or heterocyclyl May be unsubstituted or substituted;

Wherein said aryl refers to an aromatic ring having 6 to 10 carbon atoms;

Wherein said heteroaryl is an aromatic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms selected from N, O and S, or a bicyclic ring wherein said heteroaryl ring is fused to a benzene ring or another heteroaryl ring Lt; / RTI >

The heterocyclyl refers to a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms containing from 1 to 4 heteroatoms selected from N, O and S.

According to a more specific embodiment of the present invention, the compound of Chemical Formula 1 may be a benzoisoxazole derivative represented by Chemical Formula 1-1, an indole derivative represented by Chemical Formula 1-2 or an azo compound represented by Chemical Formula 1-3 Indole derivatives.

In the above Chemical Formulas 1-1 to 1-3,

R ₁ , R ₂ and R ₃ are the same as defined in the above formula (1).

According to one embodiment of the present invention, R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein the aryl or heteroaryl can be unsubstituted or substituted. Specifically, the aryl or heteroaryl are halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, -CO-C _1-6 alkyl, -CO-NH _2, -SO ₂ -C _1-6 alkyl, -SO ₂ -NH _2, and aryl.

According to another embodiment of the present invention, when R ₁ is an aryl group, it may be phenyl.

According to another embodiment of the present invention, when R < ₁ > is a heteroaryl group, it may be a pyridine such as 2-, 3- or 4-pyridine.

According to another embodiment of the present invention, R ₁ may be any one selected from the group represented by the following structural formula (1).

[Structural formula 1]

According to another embodiment of the invention, wherein R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2 ) _m -CO-NH- or - (CH ₂ ) _n -CO-NH-, wherein n is an integer of 1 to 3 and m is an integer of 0 to 3.

Specifically, according to one embodiment of the present invention, R ₂ may be any one selected from the group represented by the following structural formula (2).

[Structural formula 2]

According to one embodiment of the present invention, R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl, The aryl, heteroaryl or heterocyclyl can be unsubstituted or substituted. Specifically, the aryl, heteroaryl or heterocyclyl are halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, -CO-C _1-6 alkyl, -CO-NH ₂ , -SO ₂ -C _1-6 alkyl, -SO ₂ -NH _2, and aryl. More specifically, said aryl or heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and aryl.

According to another embodiment of the present invention, when R ₃ is - (CH ₂ ) _n -aryl, the aryl group may be phenyl.

According to another embodiment of the present invention, when R ₃ is - (CH ₂ ) _n -heteroaryl, the heteroaryl group may be indolyl, azaindolyl (eg, 7-azaindolyl), imidazolyl, Pyridinyl, thiophenyl, furanyl, and benzimidazolyl.

According to another embodiment of the present invention, when R ₃ is - (CH ₂ ) _n -heterocyclyl, said heterocyclyl group is selected from morpholinyl, dihydrobenzofuranyl, benzodioxolyl and benzodioxanyl And may be one or more substituents selected.

According to another embodiment of the present invention, R ₃ may be any one selected from the group represented by the following structural formula (3).

[Structural Formula 3]

The benzoisooxazole, indole or 7-azaindole derivative compound of Formula 1 according to the present invention may be prepared more exclusively from the group consisting of the following Formulas (2) to (67), although the scope of the present invention is not limited thereto. It can be one.

According to one embodiment of the present invention, the benzisoxazole, indole or 7-azaindole compound may form a pharmaceutically acceptable salt. In the present invention, pharmaceutically acceptable salts are formed with acids which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, Examples of the organic acid include organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, The acid moiety formed by sulfonic acid such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like may be a salt, and the acid addition salt represented by the formula The indole derivative compound may be an acid addition salt as described above and a salt of sodium, calcium and ammonium, and a pharmaceutically acceptable salt addition salt, For example, an alkali metal or alkaline earth metal salt formed by lithium, sodium, potassium, calcium, magnesium or the like, an amino acid salt such as lysine, arginine or guanidine and an amino acid salt such as dicyclohexylamine, N-methyl- (Hydroxymethyl) methylamine, diethanolamine, choline, triethylamine, and the like.

The benzisoxazole, indole and 7-azaindole compounds of formula (I) according to the present invention can be converted into their salts by conventional methods. The preparation of the salts can be carried out according to the structure of the above formula As shown in FIG.

Unless otherwise specified hereinafter, the benzisoxazole, indole and 7-azaindole compounds of formula (I) include pharmaceutically acceptable salts thereof, all of which should be construed as being included within the scope of the present invention. For convenience of explanation, they are simply represented by the compound of the formula (1) in the present specification.

In another aspect, the present invention relates to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:

(a) reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4); And

(2)

In this formula,

X and Y are the same as defined in Formula 1,

R is R ₁ defined in the above formula (1) or I, wherein R- ₁ is as defined in the above formula (1).

(3)

NH ₂ - (CH ₂ ) _n -CO ₂ H

In the above formula, n is an integer of 1 to 3.

[Chemical Formula 4]

Wherein X and Y are as defined in Formula 1,

R is R ₁ defined in the above formula (1) or I, wherein R- ₁ is as defined in the above formula (1)

n is an integer of 1 to 3;

(b) reacting a compound of formula (4) obtained in step (a) with R ₃ -NH ₂ , wherein R ₃ is as defined in formula (1); Or X and Y are carbon in the compound of formula (IV), when R is I and then form a compound of formula (VI) by reacting a compound of formula 4 with R ₃ -NH ₂ R a formula 6 compound ₄ B (OH) ₂ with Suzuki coupling with R < ₂ > wherein R < ₄ > is aryl or heteroaryl;

 [Chemical Formula 5]

In this formula,

R is R ₁ defined in the above formula (1) or I, wherein R- ₁ is as defined in the above formula (1)

n is an integer of 1 to 3,

X, Y and R < ₃ > are as defined in the above formula (1).

[Chemical Formula 6]

In this formula,

n is an integer of 1 to 3,

X, Y and R < ₃ > are as defined in the above formula (1).

(7)

In the above formula

R < ₄ > is aryl or heteroaryl,

n is an integer of 1 to 3,

R ₃ is the same as defined in the above formula (1).

According to one embodiment of the present invention, R ₄ in Formula 7 may be any one selected from the group represented by the following Formula 1-1.

[Structural formula 1-1]

According to one embodiment of the present invention, n in the above formula (7) is an integer of 1 to 2.

According to one embodiment of the present invention, R ₃ in the general formula (7) is - (CH ₂ ) _n -heteroaryl.

According to another embodiment of the present invention, R ₃ in Formula 5 is represented by the following Formula 3-1.

[Structural Formula 3-1]

The above production method can be summarized as follows.

[Reaction Scheme A]

The starting material, a compound of Formula 2 of Scheme A is for example 3-phenyl-benzo [c] -isoxazol-5-carboxylic acid, 3-iodo-1- (phenylsulfonyl) -1 H - indole-5 Carboxylic acid and 3-aryl-1 H -pyrrolo [2,3- b ] pyridine-5-carboxylic acid.

The C5 carboxylic acid functional group of the starting material is subjected to an amide coupling reaction with glycine to obtain a compound of formula (4). Subsequently, an amide coupling reaction may be further carried out to the carboxylic acid of the compound of Formula 4 to prepare the benzisoxazole derivative of Formula 1-1 and the azaindole derivative of Formula 1-3.

Further, the indole derivatives of the general formula (1-2) can be synthesized through Suzuki coupling, in which the compound of the general formula (6) is further subjected to palladium catalyzed at the C3 position of the indole.

More specifically, the synthesis of the benzisoxazole derivative of formula (1-1), the indole derivative of formula (1-2) and the 7-azaindole derivative of formula (1-3) according to Scheme A is carried out by reacting N-hydroxysuccinimide (NHS) Using an amide coupling reaction using dicyclohexylcarbodiimide (DCC) as the first step and R < ₃ > through a second amide coupling using hydroxybenzotriazole (HOBt) and dicyclohexylcarbodiimide Can be introduced.

Particularly, in the case of the indole derivatives of the general formula (1-2), after the above-mentioned two amide coupling reactions according to Scheme A, a coupling reaction of Suzuki type using various arylboronic acids and a palladium catalyst (II) (Ratio 3: 1) heated to 100 < 0 > C under solvent conditions and stirred to displace the aryl group in the iodo substituent. An aqueous potassium hydroxide solution is added without further purification and the benzenesulfonic group is removed by heating for 1 hour to obtain an indole derivative in which C3 is substituted with various aryl groups.

In addition, the present invention provides a process for preparing a compound of formula 8, or a pharmaceutically acceptable salt thereof, comprising the steps of:

[Chemical Formula 8]

In this formula,

R ₁ and R ₃ are the same as defined in Formula 1,

m is an integer of 0 to 3

(a) a compound of formula 9 CH = CH-COOCH ₃ Or heck coupling with CH = CH- (CH ₂ ) _n -COOCH ₃ , wherein n is an integer from 1 to 3, to prepare a compound of formula (10); And

[Chemical Formula 9]

In this formula,

R ₁ is the same as defined in the above formula (1).

[Chemical formula 10]

In this formula,

R ₁ is the same as defined in Formula 1,

Z is SO ₂ Ph or H,

and m is an integer of 0 to 3.

(b) coupling the compound of formula (10) with an amide of R ₃ -NH ₂ wherein R ₃ is as defined in formula (1), and optionally removing the sulfone protecting group of 7- ≪ / RTI >

According to an embodiment of the present invention, R ₁ in Formula 9 may be any one selected from the group represented by Formula 1-2.

[Structural formula 1-2]

The production process for the 7-azaindole derivative represented by the formula (1-3b) wherein R ₂ is CH = CH- (CH ₂ ) _m -CO-NH- is summarized in the following reaction scheme.

[Scheme B]

The starting material, compounds of formula 9 of Scheme B is, for example 5-bromo-3-aryl-1- (phenylsulfonyl) -1 H - may be a pyrrolo [2,3- b] pyridine. The compound of formula (10) is obtained by introducing an acrylate or vinyl acetate group into the C5 position of the compound of formula (9) with heck coupling catalyzed by palladium. The ester group of the compound of formula (10) can be hydrolyzed under acid or base conditions to give O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate A 7-azaindole compound represented by the general formula 1-3 can be prepared by introducing an amine group represented by R ₃ through an amide coupling with a phenate (HBTU).

The azaindole derivative of formula 1-3 of Scheme B can be prepared according to Scheme B using a Heck-type reaction using acrylate or vinyl acetate and a palladium catalyst (II), triethylamine base as the first step And heated to 140 DEG C with anhydrous DMF as a solvent and stirred to replace acrylate or vinyl acetate in the bromine site. The resulting ester group of the intermediate can be converted into a carboxylic acid by heating to 100 ° C in an aqueous hydrochloric acid solution and a dioxane solvent. The carboxylic acid of Intermediate B is stirred at room temperature under a dimethylformamide solvent at various conditions of the amide coupling reaction using various amines and HBTU and diisopropylethylamine (DIPEA), and further, in a base condition using potassium hydroxide, .

Specifically, when R < ₁ > In the case of a non-phenyl substituted aryl or heteroaryl, after the hexetype reaction, the ester group is converted to a carboxylic acid and the benzenesulfonyl group is removed at the same time in the presence of potassium hydroxide and dioxane to obtain the intermediate of formula (10). The resulting compound of formula 10 is stirred at room temperature under an amide coupling reaction using various amines, HBTU and DIPEA to obtain a 7-azaindole derivative of the formula 1-3.

However, those skilled in the art will appreciate that compounds of formula (I) may be prepared by a variety of methods based on the structure of formula (I), and these methods are all included in the scope of the present invention .

That is, various synthetic methods described in the present specification or disclosed in the prior art can be arbitrarily combined to produce the compound of formula (1), which is understood to fall within the scope of the present invention, and the method of producing the compound of formula It is not.

In another aspect, the present invention relates to GSK3 [beta] kinase inhibiting uses of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

Specifically, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, , Inflammatory autoimmune diseases, cardiovascular diseases, endocrine diseases, and viral infectious diseases. Specifically, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent for a proliferative disease, a neurodegenerative or neurodegenerative disease, an inflammatory autoimmune disease, a cardiovascular disease, an endocrine disease and a viral infectious disease caused by GSK3? Can be used.

The proliferative disease is, for example, cancer, and the cancer is selected from the group consisting of leukemia, brain tumor, kidney cancer, gastric cancer, skin cancer, bladder cancer, breast cancer, uterine cancer, lung cancer, colon cancer, prostate cancer, ovarian cancer, liver cancer, , Pancreatic cancer, and the like, but are not limited thereto.

The neurodegenerative or neurological disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, mild cognitive impairment, frontotemporal dementia, frontotemporal lobar degeneration associated with Pick bodies, peak disease, progressive supranuclear palsy, Parkinson's disease, AIDS-related dementia, Huntington's disease, senile dementia, Parkinson's disease, Parkinson's disease, encephalitis, dementia, Amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis, depression, depression, epilepsy, epilepsy, mood disorders, autism, attention deficit hyperactivity disorder, Down syndrome, fragile X syndrome, ischemia reperfusion, Cerebral hemorrhage, Lou Gehrig's disease, prune disease, degenerative diseases of the cerebral basal ganglia, myotonic dystrophy. Guam parkinsonism-dementia complex of Guam, Gerstman-Straussler-Scheinker disease, and the like.

The inflammatory autoimmune disease is selected from the group consisting of rheumatoid arthritis, colitis, psoriasis, arthritis, peritonitis, systemic inflammation, renal dysfunction, hepatotoxicity of endotoxemia, inflammatory organ damage due to asthma, And the like, but are not limited thereto.

The cardiovascular diseases include, but are not limited to, myocardial infarction, hypertension, angina atherosclerosis, restenosis, leukopenia, and the like.

The endocrine disorder may be diabetes, and the viral infection diseases include, but are not limited to, AIDS, avian influenza, swine flu and the like.

In one embodiment, the disease associated with GSK3 [beta] activity may be Type 2 diabetes, Alzheimer's and an abnormal cell growth disorder.

In the present invention, the benzoisooxazole derivative of Formula 1-1, the indole derivative of Formula 1-2, and the azaindole derivative of Formula 1-3 or a pharmaceutically acceptable salt thereof have an activity of inhibiting GSK3β kinase.

The inhibitory activity of the benzoisooxazole derivative of the formula 1-1, the indole derivative of the formula 1-2 and the azaindole derivative of the formula 1-3 or the pharmaceutically acceptable salt thereof according to the present invention is inhibited by GSK3β kinase, The activity of a known kinase inhibitor, Staurosporine, was measured together. To confirm competitive inhibition against ATP, 1 μM of ATP was treated, and the reaction buffer and the compound according to the present invention were co-cultured in the medium to determine the IC ₅₀ value as the enzyme activity. The IC ₅₀ value is the concentration of the compound capable of inhibiting the activity of the enzyme by 50%, and the smaller the value, the more effective it is. This will be described later in the following experimental examples.

According to one embodiment of the present invention, a salt dissolved in a buffer solution is used as a diluent, and a buffer solution that is usually used may be phosphate buffer saline that mimics the salt form of a human solution. Since buffer salts can control the pH of the solution at low concentrations, the buffer diluent does not alter the biological activity of the compound.

The compounds of the present invention may be formulated for use as pharmaceutical or veterinary compositions also containing a pharmaceutically or veterinarily acceptable carrier or diluent. The composition according to the present invention can be generally prepared according to a conventional method, and can be administered in a pharmaceutically or veterinarily appropriate form.

The pharmaceutical compositions of the present invention may be administered orally in the form of tablets, capsules, sugar-coated tablets, film-coated tablets, liquid solutions or suspensions, or parenterally, either by injection or infusion into the blood, Lt; / RTI >

The dosage can be determined according to various factors including the patient's age, body weight and condition and administration route. The daily dose can vary within wide limits and can be tailored to individual requirements in each individual case. In general, however, when the present compound is administered alone to an adult, the dosage administered by route of administration is 0.0001 to 50 mg / kg body weight, for example in the range of 0.001 to 10 mg / kg body weight, for example, 0.01 to 1 mg / kg You can lose weight.

Such dosage can be provided, for example, 1 to 5 times per day. For intravenous injection, the appropriate daily dose is 0.0001 to 1 mg / kg body weight, preferably 0.0001 to 0.1 mg / kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the preferred embodiments of the present invention and the GSK3? Inhibition activity will be described in detail. It will be apparent to those skilled in the art, however, that these examples are provided to further illustrate the present invention, and the scope of the present invention is not limited thereto.

<Production Example>

According to the present invention, the benzisoxazole derivative represented by the formula (1-1a), the indole derivative represented by the formula (1-2a) or the 7-azaindole derivative represented by the following formula (1-3a) were prepared according to the following general preparation procedure.

<General Manufacturing Procedure 1>

The starting material (1 eq.) And NHS (1 eq.) Were dissolved in dichloromethane according to the following Schemes A-1 to A-3 and DCC (1.1 eq.) Was added and stirred at room temperature for 30 min. The precipitate formed in the reaction solution was filtered, and the filtrate was reduced in pressure to remove the solvent to obtain a carboxylic acid-activated intermediate. After dissolving it in acetone again, glycine (1 eq) dissolved in water and sodium bicarbonate (2 eq) were added. The reaction solution was stirred at room temperature overnight, then the solvent was removed by reducing the pressure, and the reaction solution was dissolved again in water. The insoluble solids were filtered and the filtrate was adjusted to pH 3 with 10% aqueous hydrochloric acid solution to cause the product to fall to solid. The obtained solid was filtered and washed with water, and then the water was removed by vacuum to obtain intermediate B.

<General Manufacturing Procedure 2>

According to Scheme A, the material (1 eq), amine (1 eq) and HOBt (1 eq) from the general preparation procedure 1 were placed in a round bottom flask and dissolved in dichloromethane under nitrogen. DCC (1.1 equivalents) dissolved in dichloromethane was slowly added to the reaction solution, and the mixture was stirred at room temperature overnight. The precipitate of the reaction solution was filtered, and R ₂ is _{-CO-NH- (CH 2) n} -CO-NH- and the filtrate was concentrated under reduced pressure and subjected to column chromatography through a benjeuyi sook Sasol, 7-azaindole and indole intermediate compound .

<General Manufacturing Procedure 3>

(1 eq.), Arylboronic acid (1.1 eq.), Potassium carbonate (3 eq.), Bis (diphenylphosphine) ferrocene-palladium (0.1 eq.) According to Scheme A- Was placed in a round bottom flask and the mixture was heated at 100 for 4 hours under a solution of 3: 1 ratio of 1,4-dioxane to water. After completion of the reaction, 4N aqueous potassium hydroxide solution was added to the reaction mixture and the mixture was heated for another 1 hour. After cooling to room temperature, the mixture was neutralized with aqueous hydrochloric acid, extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Then, an indole compound wherein R ₂ is -CO-NH- (CH ₂ ) _n -CO-NH- is obtained by column chromatography.

<General Manufacturing Procedure 4>

To follow the reaction scheme B-1 1- (benzenesulfonyl) -5-bromo-3-phenyl-pyrrolo [2,3- b] pyridine (1 equivalent), the alkene (5.0 equiv), triethylamine (3.0 And Pd (PPh ₃ ) ₂ Cl ₂ (0.2 eq.) Were dissolved in DMF under N ₂ conditions and stirred at 140 ^° C for 1 hour. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic solvent layers were dried with magnesium sulfate and concentrated. This was purified through column chromatography to methyl (E) -4- (1-phenyl-3- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylate was obtained . This intermediate (269 mg, 0.064 mmol) was dissolved in dioxane, 1N hydrochloric acid aqueous solution was added, and the mixture was stirred at 105 ° C for 10 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate, and washed with saturated aqueous sodium chloride solution. The combined organic solvent layers were dried over magnesium sulfate and concentrated to give an intermediate for the preparation of the 7-azaindole derivatives of formula 1-3 wherein R ₂ is -CH = CH- (CH ₂ ) _m -CO-NH-.

<General Manufacturing Procedure 5>

To follow the reaction scheme B-1 (E) -3- ( 3- aryl -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid (1.0 eq.), Amine (2.5 eq), DIPEA (3.0 eq.) And HBTU (2.2 eq.) Were dissolved in DMF and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate and saturated aqueous sodium chloride solution, concentrated under reduced pressure. The residue was subjected to column chromatography to obtain a 7-azaindole derivative compound protected with a sulfonyl group. This intermediate and potassium hydroxide (4.0 eq.) Were dissolved in a 3: 1 mixture of dioxane and water and stirred at room temperature for 19 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The organic layer was concentrated under reduced pressure, and a desired amine-introduced 7-azaindole derivative was obtained by column chromatography.

[Reaction Scheme B-1]

<General Manufacturing Procedure 6>

Pyrrolo [2,3- b ] pyridine (118 mg, 0.261 mmol), methyl acrylate (5.0 eq.) In accordance with Reaction Scheme B-2, the mixture was stirred at Lai ethylamine (3.0 equiv), and _{Pd (PPh 3) 2 Cl 2} 140 ℃ for 1 hour and dissolved in DMF under a N ₂ conditions (0.2 eq.). The reaction solution was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The combined organic solvent layers were dried with magnesium sulfate and concentrated. This was purified through column chromatography to methyl (E) -4- (3- aryl-1- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylate was obtained . This intermediate (74 mg, 0.190 mmol) and lithium hydroxide (1.5 eq.) Were dissolved in THF / H ₂ O = 1: 1 and stirred at room temperature for 19 hours. The reaction mixture was extracted with 1N hydrochloric acid aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated to obtain an intermediate for obtaining a 7-azaindole derivative in which R ₂ is -CH = CH-CO-NH-.

<General Manufacturing Procedure 7>

According to the following reaction scheme B-2, (E) -3- (3- aryl -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid (1.0 eq.), Amine (2.5 equiv), DIPEA (3.0 eq.) And HBTU (2.2 eq.) Were dissolved in DMF and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was extracted with ethyl acetate and saturated aqueous sodium chloride solution, concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the desired R ₃ -introduced 7-azaindole derivative.

[Reaction Scheme B-2]

Example 1 Synthesis of (3-phenylbenzo [ c ] isoxazole-5-carbonyl) glycine

According to the following scheme 1, 3-phenyl-benzo [c] this sook Sasol-5-carboxylic acid (39 mg, 0.2 mmol), NHS (23 mg, 0.2 mmol), DCC (45.4 mg, 0.22 mmol), glycine ( 15 mg, 0.2 mmol) and NaHCO ₃ (23.6 mg, 0.4 mmol) were reacted according to the general preparation procedure 1 above. The obtained solid was filtered, washed with water, and then the water was removed by vacuum to obtain (3-phenylbenzo [ c ] isoxazole-5-carbonyl) glycine. (36.2 mg, yield 61%).

[Reaction Scheme 1]

The obtained compound corresponds to an intermediate of benzoisooxazole compounds A1, A3 and A5 according to the present invention.

^{1 H NMR (300 MHz, DMSO-} d 6) δ 12.68 (br, 1H), 9.13 (br, 1H), 8.64 (s, 1H), 8.20 (dd, J = 7.9, 1.7 Hz, 2H), 7.88 ( dd, J = 9.5, 1.4 Hz, 1H), 7.80-7.60 (m, 4H), 3.99 (d, J = 5.9 Hz, 2H).

Example 2 Synthesis of N - (2 - ((2- (1 H -indol-3-yl) ethyl) amino) -2-oxoethyl) -3-phenylbenzo [ c ] isoxazole- Mide

According to the following scheme 2, (3-phenyl-benzo [c] -isoxazol-5-carbonyl) glycine (20 mg, 0.068 mmol), 2- - ethane-1-amine (1 H-indol-3-yl) ( 10.9 mg, 0.068 mmol), HOBt (9.2 mg, 0.068 mmol), DCC (15.4 mg, 0.075 mmol) were reacted according to the general preparation procedure 2 above. The precipitate of the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain N - (2 - ((2- (1 H -indol-3-yl) ethyl) amino) -2- -Phenylbenzo [ c ] isoxazole-5-carboxamide. (15.5 mg, 52% yield)

[Reaction Scheme 2]

The compound thus obtained corresponds to the above-mentioned specific benzisoxazole compound (A1), [Formula 2], which is different from the present ringgene.

^{1 H NMR (400 MHz, DMSO-} d 6) δ 10.82 (br, 1H), 9.08 (t, J = 5.9 Hz, 1H), 8.67 (t, J = 1.4 Hz, 1H), 8.25 - 8.17 (m, 2H), 8.12 (t, J = 5.7 Hz, 1H), 7.91 (dd, J = 9.4, 1.4 Hz, 1H), 7.79 - 7.62 (m, 4H), 7.54 (dd, J = 7.3, 0.7 Hz, 1H ), 7.32 (dt, J = 8.1, 0.9 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.05 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.97 (ddd, J = 1H), 3.93 (d, J = 5.9 Hz, 2H), 3.42-3.35 (m, 2H), 2.89-2.80 (m, 2H).

Example 3: Synthesis of 3-iodo-l-phenylsulfonyl-lH-indole-5-carboxylic acid

Potassium hydroxide (1.6 g, 28.6 mmmol) was added to a solution of methyl 1 H -indole-5-carboxylate (2.0 g, 11.4 mmol) in dimethylformamide according to the following reaction scheme 3 and stirred at room temperature for 20 minutes. Was added iodine (2.9 g, 11.4 mmol) dissolved in dimethylformamide and stirred for an additional 45 min. The reaction solution was poured into ice water and the precipitate was filtered. The precipitate was washed with water and dried to obtain methyl 3-iodo-1H-indole-5-carboxylate. (3.41 g, 99% yield)

(730 mg, 2.42 mmol) and tetrabutylammonium hydrogen sulfate (165 mg, 0.48 mmol) were dissolved in dichloromethane, and 1 mL of a 50% aqueous solution of sodium hydroxide at 0 ° C. was added thereto. And benzenesulfonyl chloride (0.68 mL, 5.33 mmol) were added. The reaction solution was stirred at room temperature, extracted with distilled water, dichloromethane and distilled water to obtain methyl 3-iodo-1-phenylsulfonyl-1H-indole-5-carboxylate. (921 mg, yield 86%).

Methyl 3-iodo-l-phenylsulfonyl-lH-indole-5-carboxylate (100 mg, 0.23 mmol) was dissolved in dioxane: water (3: 1) and 0.2 mL of 35% hydrochloric acid was added. The reaction solution was stirred overnight at 110 ° C and cooled to room temperature. Water was added thereto and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and then subjected to column chromatography to obtain 3-iodo-1-phenylsulfonyl-1H-indole-5-carboxylic acid. (72 mg, yield 74%).

[Reaction Scheme 3]

The obtained compounds correspond to the starting materials of the specific indole compounds B1, B2, B3, B4, B5, B6, B7 and B8 according to the present invention.

<Example 4> iodo-1- (phenylsulfonyl) -1 H - indole-5-carbonyl) glycine

According to the Scheme 4 from 3-iodo-1- (phenylsulfonyl) -1 H-indole-5-carboxylic acid (245 mg, 0.573 mmol) to a carrying out a reaction in accordance with the general preparation procedure 1 iodo- 1- (phenylsulfonyl) -1 H - indole-5-carbonyl) glycine to give the. (221 mg, yield 79%).

[Reaction Scheme 4]

The compound obtained above corresponds to an intermediate of the specific indole compounds B1, B2, B3, B4, B5, B6, B7 and B8 according to the present invention.

<Example 5> N - (2 - ( (2- (1 H - indol-3-yl) ethyl) amino) -2-oxoethyl) -3-iodo-1- (phenylsulfonyl) -1 H - indole-5-carboxamide

To In accordance with Scheme 5, the iodo-1- (phenylsulfonyl) -1 H-indole-5-carbonyl) glycine (221 mg, 0.46 mmol) and 2- (1 H-indol-3-yl) ethane- 1 -amine (73 mg, 0.46 mmol) was reacted according to the general preparation procedure 2 to obtain N - (2 - ((2- (1 H -indol-3- yl) ethyl) ) -3-iodo-1- (phenylsulfonyl) -1 H - indole-5-carboxamide was obtained. (164 mg, 57% yield)

[Reaction Scheme 5]

The compound obtained above corresponds to an intermediate of the specific indole compounds B1, B2, B3, B4, B5, B6, B7 and B8 according to the present invention.

<Example 6> N - (2 - ((2- (1 H-indol-3-yl) ethyl) amino) -2-oxoethyl) -3- (pyridin-4-yl) -1 H-indole- 5-carboxamide

According to Scheme 6 below. N - (2 - ((2- (1 H - indol-3-yl) ethyl) amino) -2-oxoethyl) -3-iodo-1- (phenylsulfonyl) -1 H - indole-5 (20 mg, 0.14 mmol), bis (diphenylphosphine) ferrocene-palladium (II) (3.9 g, 0.10 mmol), 4- pyridinylboronic acid mg, 0.0048 mmol), and the reaction was carried out according to the general preparation procedure 3. Then, column chromatography using dichloromethane and methanol gave N - (2 - ((2- (1 H -indol-3-yl) ethyl) amino) -2-oxoethyl) -3- -yl) -1 H-indole-5-carboxamide was obtained. (7.5 mg, 36% yield)

[Reaction Scheme 6]

The obtained compound corresponds to the specific indole compound B3 according to the present invention (Formula 9).

^{1 H NMR (400 MHz, DMSO-} d 6) δ 11.93 (d, J = 2.7 Hz, 1H), 10.82 (br, 1H), 8.82 (t, J = 5.9 Hz, 1H), 8.59-8.57 (m, 3H), 8.13 (d, J = 2.7 Hz, 1H), 8.06 (t, J = 5.7 Hz, 1H), 7.87 - 7.75 (m, 3H), 7.54 (d, J = 8.3 Hz, 2H), 7.33 ( d, J = 8.0 Hz, 1H ), 7.17 (d, J = 2.4 Hz, 1H), 7.05 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.96 (ddd, J = 8.1, 7.0, 1.2 Hz , 3.91 (d, J = 5.9 Hz, 2H), 3.44-3.34 (m, 2H), 2.84 (t, J = 7.6 Hz, 2H).

<Example 7> 3- (pyridin-4-yl) -1 H - pyrrolo [2,3- b] pyridine-5-carboxylic acid

To In accordance with Scheme 7, 3-iodo-1- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridine (100 mg, 0.244 mmol) 4- pyridinyl boronic acid (34 mg, 0.269 mmol) and bis (diphenylphosphine) ferrocene-palladium (II) (10 mg, 0.0122 mmol) and cesium carbonate (239 mg, 0.732 mmol) . Then, through the 3-dichloromethane and column chromatography with methanol (pyridin-4-yl) -1 H - pyrrolo [2,3- b] pyridine-5-carbonitrile. (26 mg, yield ^{48%) 1 H NMR (300} MHz, DMSO- d 6) δ 12.46 (br, 1H), 8.87 (d, J = 2.0 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H ), 8.63-8.54 (m, 2H), 8.30 (s, 1H), 7.87-7.77 (m, 2H).

To In accordance with Scheme 7, the 4- (pyridin-4-yl) -1 H - pyrrolo [2,3- b] pyridine (22 mg, 0.1 mmol) were dissolved in dioxane / water = 3: 1 And 35% hydrochloric acid aqueous solution was added thereto, followed by heating under reflux for 3 hours. After cooling the reaction solution to room temperature, neutralized with 4 n aqueous potassium hydroxide solution and pulling the solvent without further purification 4- (pyridin-4-yl) -1 H - pyrrolo [2,3- b] pyridine-5-carboxylic acid &Lt; / RTI &gt;

[Reaction Scheme 7]

The obtained compound corresponds to the starting material of the specific 7-azaindole compound C7 according to the present invention.

<Example 8> N - (2 - ( (2- (1 H - indol-3-yl) ethyl) amino) -2-oxoethyl) -3- (pyridin-4-yl) -1 H - pyrrolo [2,3- b ] pyridine-5-carboxamide

To In accordance with Scheme 8, the 3- (pyridin-4-yl) -1 H - pyrrolo [2,3- b] pyridine-5-carboxylic acid and N - (2- (1 H - indol-3-yl) ethyl ) -2-aminoacetamide (22 mg, 0.1 mmol) was reacted according to the general preparation procedure 2 under DMF solvent conditions. After completion of the reaction, the residue was purified by column chromatography using methanol and dichloromethane to obtain N - (2 - ((2- (1 H -indol-3-yl) ethyl) amino) -2- 4-yl) -1 H - pyrrolo [2,3- b] pyridine-5-carboxamide was obtained. (12 mg, 27% yield)

[Reaction Scheme 8]

The compound obtained above corresponds to the specific 7-azaindole compound C7 (Formula 21) according to the present invention.

^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.51 (br, 1H), 10.82 (br, 1H), 9.02 (t, J = 5.9 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H) , 8.86 (d, J = 2.0 Hz, 1H), 8.66 - 8.53 (m, 2H), 8.33 (d, J = 2.6 Hz, 1H), 8.11 (t, J = 5.8 Hz, 1H), 7.89 - 7.79 ( m, 2H), 7.54 (d , J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.05 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H ), 6.96 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 3.94 (d, J = 5.9 Hz, 2H), 3.43 - 3.33 (m, 2H), 2.84 (t, J = 7.6 Hz, 2H) .

<Example 9> (E) -4- (3- phenyl-l- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid

Pyrrolo [2,3- b ] pyridine (300 mg, 0.73 mmol), methyl acrylate (0.327 mL, 3.63 mmol) and triethylamine ), Triethylamine (0.306 mL, 2.18 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (102 mg, 0.145 mmol) were reacted in 7.5 mL of DMF under N ₂ conditions according to General Preparation Procedure 4. Finally, through the extraction with ethyl acetate (E) -4- (1-phenyl-3- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid . (2-step yield: 72%)

[Reaction Scheme 9]

C12, C15, C19, C20, C21, C22, C24, C25, C26, C27, C28, C29, C30, C31, C32, C33, C34, C35 and C36.

<Example 10> (E) - N - (2- (1 H - indol-3-yl) ethyl) -3- (3-phenyl -1 H - pyrrolo [2,3- b] pyridin-5 Yl) acrylamide

To according to scheme 10, (E) -4- (3- phenyl-l- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid (100mg, 0.248 mmol ) and 2- (1 H-indol-3-yl) ethane-1-amine (100 mg, were reacted according to the 0.620 mmol), the general manufacturing process 5 (E) - N - ( 2- (1 H - indol - 3-yl) ethyl) -3- (3-phenyl -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylamide was obtained. (56 mg, 45% yield)

[Reaction Scheme 10]

The obtained compound corresponds to the specific 7-azaindole compound C14 (Formula 28) according to the present invention.

^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.10 (d, J = 2.5 Hz, 1H), 10.82 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.15 (t, J = 5.7 Hz, 1H), 7.92 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 8.3, 1.2 Hz, 2H), 7.63 (d, J = 15.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.19 ( d, J = 2.4 Hz, 1H), 7.07 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.99 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 6.75 (d, J = 15.8 Hz, 1H), 3.55-3.44 (m, 2H), 2.90 (t, J = 7.3 Hz, 2H).

<Example 11> N - (2- (1 H - indol-3-yl) ethyl) -3- (3-phenyl -1 H - pyrrolo [2,3- b] pyridin-5-yl) propanoic amide

Based on the following scheme 11, (E) - N - (2- (1 H - indol-3-yl) ethyl) -3- (3-phenyl -1 H - pyrrolo [2,3- b] pyridine-5 (25 mg, 0.062 mmol) was dissolved in methanol, 10% palladium / charcoal (6 mg) was added, and the mixture was stirred at room temperature overnight under hydrogen ballooning conditions. The reaction solution was filtered using a Celite filter, and the filtrate was concentrated. Via the residue was purified by column chromatography obtained N - (2- (1 H - indol-3-yl) ethyl) -3- (3-phenyl -1 H - pyrrolo [2,3- b] pyridin-5-yl ) Propanamide. &Lt; / RTI &gt; (6 mg, 24% yield)

[Reaction Scheme 11]

The obtained compound corresponds to the specific 7-azaindole compound C17 (Formula 31) according to the present invention.

^{1 H NMR (400 MHz, DMSO-} d 6) δ 11.79 (d, J = 2.4 Hz, 1H), 10.78 (s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.95 ( t, J = 5.7 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 8.3, 1.3 Hz, 2H), 7.48 (dd, J = 7.8, 1.1 Hz, 1H), 7.42 (dd, J = 8.3, 7.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.3 Hz, 1H), 7.11 - 7.00 ( J = 7.6 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 6.95 (ddd, J = , 2H), 2.45 (dd, J = 7.6 Hz, 2H).

<Example 12> (E) -4- (3- phenyl-l- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) -3-butene acid

Pyrrolo [2,3- b ] pyridine (569 mg, 1.379 mmol), methyl vinyl acetate (0.327 mL, 3.63 mmol) and 1- (benzenesulfonyl) ), Triethylamine (0.306 mL, 2.18 mmol) and Pd (PPh ₃ ) ₂ Cl ₂ (102 mg, 0.145 mmol) were added to the reaction mixture. After completion of the reaction, ethyl acetate was used to extract ( E ) -4- (3-phenyl-1- (phenylsulfonyl) -1 H- pyrrolo [2,3- b ] pyridin- - butene acid. (264 mg, yield 78%).

[Reaction Scheme 12]

The obtained compound corresponds to an intermediate of the specific 7-azaindole compounds C18 (Formula 32) and C23 (Formula 37) according to the present invention.

^{1 H NMR (300 MHz, Methanol-} d 4) δ 8.41 (d, J = 2.0 Hz, 1H), 8.22 - 8.10 (m, 3H), 7.98 (s, 1H), 7.71 - 7.57 (m, 3H), 7.60 - 7.41 (m, 4H) , 7.36 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.42 (dt, J = 16.0, 7.0 Hz, 1H), 3.25 (d , &Lt; / RTI &gt; J = 7.0 Hz, 2H).

<Example 13> (E) - N - phenyl-4-ethyl (3-phenyl -1 H - pyrrolo [2,3- b] pyridin-5-yl) -3-butene amide

To according to scheme 13, (E) -4- (3- phenyl-l- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) -3-section tenik acid ( 79 mg, 0.190 mmol) and 2-phenyl ethanamine (reacted in accordance with 60 uL, 0.474 mmol) prepared in general procedure 5 (E) - N - phenyl-4-ethyl (3-phenyl -1 H - pyrrolo [ 2,3- b ] pyridin-5-yl) -3-butenamide. (6 mg, yield 7%).

[Reaction Scheme 13]

The obtained compound corresponds to the specific 7-azaindole compound C23 according to the present invention (Formula 37).

^{1 H NMR (500 MHz, DMSO-} d 6) δ 11.92 (s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.27 (br, 1H), 7.99 (m, 1H), 7.86 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.28-7.24 (m, 3H), 7.20 (d, J = 6.7 Hz, 2H), 7.15 ( m, 1H), 6.60 (d , J = 15.8 Hz, 1H), 6.40-6.36 (m, 1H), 3.29 (m, 2H), 3.05 (d, J = 7.2 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H).

<Example 14> (E) -3- (3- (4- acetyl-phenyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid

To In accordance with Scheme 14, l- (4- (5-bromo-1- (phenylsulfonyl) -1 H - pyrrolo [2,3- b] pyridin-3-yl) phenyl) ethanone (118 mg , 0.261 mmol), methyl acrylate (0.118 mL, 1.305 mmol), triethylamine (0.117 mL, 0.834 mmol), and _{Pd (PPh 3) 2 Cl 2} (40 mg, 0.056 mmol) the according to the general preparation procedure 6 Respectively. The reaction mixture was extracted with a 1 normal aqueous solution of hydrochloric acid and ethyl acetate and concentrated after drying the organic layer over magnesium sulfate (E) -3- (3- (4- acetyl-phenyl) -1 H - pyrrolo [2,3- b ] pyridin-5-yl) acrylic acid. (90 mg, 62% yield)

[Reaction Scheme 14]

The obtained compound corresponds to an intermediate of the specific 7-azaindole compounds C46 (Formula 60) and C53 (Formula 67) according to the present invention.

<Example 15> (E) -3- (3- (4- acetyl-phenyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) - N - (2- (2- Yl) ethyl) acrylamide

To according to scheme 15, (E) -3- (3- (4- acetyl-phenyl) -1 H - pyrrolo [2,3- b] pyridin-5-yl) acrylic acid (84 mg, 0.274 mmol), (82 μL, 0.685 mmol), DIPEA (143 μL, 0.822 mmol) and HBTU (229 mg, 0.603 mmol) were reacted according to the general procedure for preparation 7, using 2- (2-pyridyl) ethanamine. The reaction mixture was purified by column chromatography (E) -3- (3- (4- acetyl-phenyl) -1 H-pyrrolo [2,3- b] pyridin-5-yl) - N - (2- (pyridin- Yl) ethyl) acrylamide. (30 mg, 27% yield)

[Reaction Scheme 15]

The obtained compound corresponds to the specific 7-azaindole compound C53 (formula 67) according to the present invention.

^{1 H NMR (500 MHz, DMSO-} d 6) δ 12.30 (s, 1H), 8.56-8.52 (m, 3H), 8.14 (s, 2H), 8.02 (m, 2H), 7.94 (m, 2H), 7.72 (m, 1H), 7.62 (d, J = 15.8 Hz, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.74 (d, J = 15.8 Hz, 1H), 3.58 (m, 2H ), 2.95 (t, J = 7.3 Hz, 2H), 2.61 (s, 3H).

<Example 16> 4- (1 H - indol-3-yl) butyl-3-phenyl -1 H - pyrrolo [2,3- b] pyridine-5-carboxylate

To In accordance with Scheme 16, the 3-phenyl -1 H - pyrrolo [2,3- b] pyridine-5-carboxylic acid (26 mg, 0.11mmol) and 4- (1 H - indol-3-yl) -1-butane (21 mg, 0.11 mmol) triphenylphosphine (58 mg, 0.22 mmol) was dissolved in anhydrous THF and cooled to 2 &lt; 0 &gt; C. Diisopropyl azodicarboxylate (DIAD) (0.043 mL, 0.22 mmol) was slowly added while stirring the reaction solution, and after 1 hour, the temperature was raised to room temperature and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 4- ( 1H -indol-3-yl) butyl 3-phenyl- 1H -pyrrolo [2,3- b ] pyridine-5-carboxylate. (Yield 60%)

[Reaction Scheme 16]

The obtained compound corresponds to the specific 7-azaindole compound C5 according to the present invention (Formula 19).

^{1 H NMR (400 MHz, DMSO-} d 6) δ 12.39 (s, 1H), 10.76 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H) , 8.01 (s, 1H), 7.75 - 7.66 (m, 2H), 7.54 - 7.41 (m, 3H), 7.35 - 7.26 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 7.03 (ddd , J = 8.1, 7.0, 1.2 Hz, 1H), 6.91 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 4.42 - 4.30 (m, 2H), 2.83 - 2.71 (m, 2H), 1.89 - 1.73 (m, 4H).

<Example 17> 3-benzoyl -1 H - pyrrolo [2,3- b] pyridine-5-carboxylic acid

5-Bromo-7-azaindole (100 mg, 0.507 mmol) was added to a solution of aluminum chloride (338 mg, 2.54 mmol) in dichloromethane according to Reaction Scheme 17 and stirred at room temperature for 45 minutes. To the reaction solution was added benzoyl chloride (0.3 mL, 2.54 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 ° C and methanol was added to terminate the reaction, and the solvent was removed under reduced pressure. The pH was adjusted to 4 with 1N aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and then (5-bromo-1 H -pyrrolo [2,3- b ] pyridin-3-yl) (phenyl) methanone was obtained by column chromatography. (51 mg, yield: 24%).

(47 mg, 0.156 mmol), (18.5 mg, 0.157 mmol) and tetrakis triphenylphosphine (2-bromo-1 H- pyrrolo [2,3- b ] pyridin- Fins palladium (9.0 mg, 0.0078 mmol) was dissolved in dimethylformamide and stirred at 150 ° C for 30 minutes using microwave. Distilled water was added to the reaction solution and extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated using a back column chromatography to give 3-benzoyl -1 H - pyrrolo [2,3- b] pyridine-5-carbonitrile. (23 mg, yield 59%).

3-benzoyl -1 H - pyrrolo [2,3- b] pyridine-5-carbonitrile (20 mg, 0.081 mmol) was added 35% hydrochloric acid solution 0.06 mL dissolved in dioxane of 0.5 mL. The reaction solution was heated to 110 ° C, stirred, and then extracted with ethyl acetate to obtain 3-benzoyl-1 H -pyrrolo [2,3- b ] pyridine-5-carboxylic acid. (6.5 mg, 31% yield)

[Reaction Scheme 17]

The obtained compound corresponds to the intermediate of the above-mentioned concrete 7-azaindole compound C4 according to the present invention (Formula 18).

<Example 18> N - (2 - ( (2- (1 H - indol-3-yl) ethyl) amino) -2-oxoethyl) -3-benzoyl -1 H - pyrrolo [2,3- b ] Pyridine-5-carboxamide

To In accordance with Scheme 18, the 3-benzoyl -1 H - pyrrolo [2,3- b] pyridine-5-carboxylic acid (6 mg, 0.023 mmol) and N - (2- (1 H - indol-3 Yl) ethyl) -2-aminoacetamide (5 mg, 0.023 mmol) was reacted according to the general preparation procedure 2 under DMF solvent conditions. After completion of the reaction, the residue was purified by column chromatography using methanol and dichloromethane to obtain N - (2 - ((2- ( 1H -indol-3-yl) ethyl) amino) -2-oxoethyl) 1 H- pyrrolo [2,3- b ] pyridine-5-carboxamide. (6.6 mg, 60% yield)

[Reaction Scheme 18]

The obtained compound corresponds to the specific 7-azaindole compound C4 according to the present invention (Formula 18).

^{1 H NMR (300 MHz, Methanol-} d 4) δ 9.12 (d, J = 2.2 Hz, 1H), 8.86 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.90 - 7.80 (m, 2H), 7.70-7.88 (m, 1H), 7.62-7.49 (m, 3H), 7.32-7.22 2H), 3.55 (t, J = 7.3 Hz, 2H), 2.98 (t, J = 7.3 Hz, 2H).

Although there are differences in the structure and physical properties of the substituents depending on the kind of the substituent, the reaction principle and conditions of the above-mentioned examples according to the present invention are nonetheless applicable to the compounds containing substituents not described in the above- It will be apparent to those of ordinary skill in the art that compounds containing these substituents can be easily carried out based on the disclosure of the examples and common sense in the art.

Further, the synthesis of the specific benzimidazole derivative, the benzothiazole derivative, and the imidazopyridine derivative compound according to the present invention will be described in detail with reference to each of the final compounds or their respective intermediates by the above examples. It will be apparent to those skilled in the art that the above-mentioned specific indole compounds can be easily applied to the whole.

In the present invention, benzisoxazole, indole and 7-azaindole derivative compounds specifically represented by the formulas (2) to (67) are shown in the following table.

EXPERIMENTAL EXAMPLE 1 Measurement of GSK3? Inhibitory Activity.

The GSK3? Inhibitory activity of the specific compound represented by the formula (1) according to the present invention was measured as follows.

To determine a measure of the biological, biochemical GSK3β inhibitory activity of the inhibitor according to the present invention, Reaction Biology Corp. (Malvern, PA, USA) were measured result of the request by the activity measurement of the concentration in the IC ₅₀ in Table 2 below Respectively.

The IC ₅₀ value is the molar concentration of the compound used when the activity of the enzyme or cell is inhibited to 50%.

Compound No. IC ₅₀ values for GSK3β (μM) A4 17.3 B3 33.8 C1 1.45 C7 0.994 C10 0.049 C11 0.0457 C12 0.18 C15 0.0435 C19 0.0317 C20 0.0190 C21 0.248 C24 0.064 C25 0.167 C26 0.0281 C27 0.156 C28 0.103 C29 0.101 C31 0.062 C32 0.0341 C33 0.0771 C34 0.111 C37 0.00275 C38 0.0165 C39 0.0228 C40 0.00772 C41 0.032 C42 0.0631 C43 0.113 C44 0.104 C45 0.025 C48 0.55 C49 0.22 C50 0.508 C51 0.0249 C52 0.474 C53 0.00153

As shown in <Experimental Example 1> and Table 2, according to the present invention, it can be confirmed that benzisoxazole, indole and 7-azaindole compounds represented by Formula 1 can effectively inhibit the activity of GSK3β kinase .

Claims (10)

A compound of the following general formula (1-2) or (1-3): or a pharmaceutically acceptable salt thereof:

In Formulas 1-2 or 1-3,
R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or substituted;
R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2) m -CO-NH- or - (CH ₂ ) _n- CO-NH-, wherein n is an integer from 1 to 3 and m is an integer from 0 to 3;
R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl wherein the aryl, heteroaryl or heterocyclyl is optionally substituted with halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, -CO-C _{1-6 alkyl, -CO-NH 2, -SO 2} -C 1 _-6 alkyl, -SO ₂ -NH _2, and aryl can be optionally substituted with 1 to 3 substituents, selected from the group consisting of;
Wherein said aryl refers to an aromatic ring having 6 to 10 carbon atoms;
Wherein said heteroaryl is an aromatic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms selected from N, O and S, or a bicyclic ring wherein said heteroaryl ring is fused to a benzene ring or another heteroaryl ring Lt; / RTI &gt;
The heterocyclyl refers to a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms containing from 1 to 4 heteroatoms selected from N, O and S.
delete The method according to claim 1,
Wherein R &lt; ₁ &gt; is any one selected from the group consisting of the following substituents:

The method according to claim 1,
R ₂ is any one selected from the group consisting of the following substituents:

The method according to claim 1,
R ₃ is any one selected from the group consisting of the following substituents:

The method according to claim 1,
A compound selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof.

A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the steps of:
(a) reacting a compound of formula (2) with a compound of formula (3) to produce a compound of formula (4); And
[Chemical Formula 1]

In Formula 1,
X is carbon (C) or nitrogen (N);
Y is carbon (C) or oxygen (O);
R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or substituted;
R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2) m -CO-NH- or - (CH ₂ ) _n- CO-NH-, wherein n is an integer from 1 to 3 and m is an integer from 0 to 3;
R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl wherein the aryl, heteroaryl or heterocyclyl is optionally substituted with halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, -CO-C _{1-6 alkyl, -CO-NH 2, -SO 2} -C 1 _-6 alkyl, -SO ₂ -NH _2, and aryl can be optionally substituted with 1 to 3 substituents, selected from the group consisting of;
Wherein said aryl refers to an aromatic ring having 6 to 10 carbon atoms;
Wherein said heteroaryl is an aromatic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms selected from N, O and S, or a bicyclic ring wherein said heteroaryl ring is fused to a benzene ring or another heteroaryl ring Lt; / RTI &gt;
The heterocyclyl refers to a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms containing from 1 to 4 heteroatoms selected from N, O and S.
(2)

In this formula,
X and Y are the same as defined in Formula 1,
R is R ₁ defined in the above formula (1) or I, wherein R ₁ is the same as defined in the above formula (1).
(3)
NH ₂ - (CH ₂ ) _n -CO ₂ H
In the above formula, n is an integer of 1 to 3.
[Chemical Formula 4]

Wherein X and Y are as defined in Formula 1,
R is R ₁ defined in the above formula (1) or I, wherein R ₁ is the same as defined in the above formula (1)
n is an integer of 1 to 3;
(b) reacting a compound of formula (4) obtained in step (a) with R ₃ -NH ₂ , wherein R ₃ is as defined in formula (1); Or X and Y are carbon in the compound of formula (IV), when R is I and then form a compound of formula (VI) by reacting a compound of formula 4 with R ₃ -NH ₂ R a formula 6 compound ₄ B (OH) ₂ with Suzuki coupling with R &lt; ₂ &gt; wherein R &lt; ₄ &gt; is aryl or heteroaryl;
[Chemical Formula 5]

In this formula,
R is R ₁ defined in the above formula (1) or I, wherein R ₁ is the same as defined in the above formula (1)
n is an integer of 1 to 3,
X, Y and R &lt; ₃ &gt; are as defined in the above formula (1).
[Chemical Formula 6]

In this formula,
n is an integer of 1 to 3,
X, Y and R &lt; ₃ &gt; are as defined in the above formula (1).
(7)

In the above formula
R &lt; ₄ &gt; is aryl or heteroaryl,
n is an integer of 1 to 3,
R ₃ is the same as defined in the above formula (1).
8. The method of claim 7, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
(a) reacting a compound of formula (9) with heck coupling with CH = CH-COOCH ₃ or CH = CH- (CH ₂ ) _n -COOCH ₃ wherein n is an integer from 1 to 3 Preparing a compound of formula 10; And
(b) coupling the compound of formula 10 with an amide of R ₃ -NH ₂ , wherein R ₃ is as defined in formula 1, and removing the sulfone protecting group of 7-azaindole to obtain a compound of formula 8 Manufacturing steps.
[Chemical Formula 8]

In this formula,
R ₁ and R ₃ are the same as defined in Formula 1,
m is an integer of 0 to 3
[Chemical Formula 9]

In this formula,
R ₁ is the same as defined in the above formula (1).
[Chemical formula 10]

In this formula,
R ₁ is the same as defined in Formula 1,
Z is SO ₂ Ph or H,
and m is an integer of 0 to 3.
A pharmaceutical composition capable of treating or preventing type 2 diabetes or Alzheimer's, comprising a compound of formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[Chemical Formula 1]

In Formula 1,
X is carbon (C) or nitrogen (N);
Y is carbon (C) or oxygen (O);
R ₁ is hydrogen, aryl, -CO-aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or substituted;
R ₂ is _{-CO-NH- (CH 2) n} -CO-NH-, -CO-O- (CH 2) n -, -CH = CH- (CH 2) m -CO-NH- or - (CH ₂ ) _n- CO-NH-, wherein n is an integer from 1 to 3 and m is an integer from 0 to 3;
R ₃ is C _1-6 alkyl, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -heteroaryl or - (CH ₂ ) _n -heterocyclyl wherein the aryl, heteroaryl or heterocyclyl is optionally substituted with halogen, hydroxy, cyano, nitro, amino, C _1-6 alkyl, C _1-6 alkoxy, -CO-C _{1-6 alkyl, -CO-NH 2, -SO 2} -C 1 _-6 alkyl, -SO ₂ -NH _2, and aryl can be optionally substituted with 1 to 3 substituents, selected from the group consisting of;
Wherein said aryl refers to an aromatic ring having 6 to 10 carbon atoms;
Wherein said heteroaryl is an aromatic ring of 5 or 6 ring atoms containing 1 to 4 heteroatoms selected from N, O and S, or a bicyclic ring wherein said heteroaryl ring is fused to a benzene ring or another heteroaryl ring Lt; / RTI &gt;
The heterocyclyl refers to a saturated or partially unsaturated carbocyclic ring of 5 to 9 ring atoms containing from 1 to 4 heteroatoms selected from N, O and S. delete