KR20190063746A - NEW COMPOUNDS FOR INHIBITING BINDING BETWEEN p34 PROTEIN AND NEDD4-1 PROTEIN AND USE THEREOF - Google Patents

Abstract

The present invention relates to a novel compound having an inhibitory effect on binding between p34 protein and NEDD4-1 protein. A pharmaceutical composition containing the compound of the present invention as an active component can be usefully used for treating and/or preventing cancer. In addition, the novel compound according to the present invention can selectively or simultaneously inhibit various diseases mediated by simultaneous expression of p34 and NEDD4-1.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel compounds as inhibitors of binding of p34 protein and NEDD4-1 protein,

The present invention relates to a novel compound and its use, and more particularly, to a novel compound having a binding inhibitory effect of p34 protein and NEDD4-1 protein, or a pharmaceutically acceptable salt or solvate thereof, ≪ / RTI > and their use.

Cancer is one of the greatest threats to human health, a disease that occurs when cells undergo a series of mutagenic processes that multiply and are immortalized in an unlimited, unregulated way. The causes of cancer are environmental or external factors such as chemicals, viruses, bacteria, and ionizing radiation, and internal factors such as congenital mutations (Klaunig & Kamendulis, Annu Rev Pharmacol Toxicol., 44: 239-267, 2004 ). In the early stage of cancer, there are treatments such as surgery, radiation therapy, and chemotherapy, but the side effects are becoming a serious problem. In the case of terminal cancer or metastatic cancer, life is terminated without any special treatment.

As of 2011, the death rate for colorectal cancer is 15.4% per 100,000 cancer patients. The incidence of colorectal cancer per 100,000 population is increasing from 21.8% to 50.3%. More specifically, it was confirmed that expression of PTEN decreases when colon cancer develops and metastasis progresses, and the role of PTEN in this process is very important. Taking this into consideration, it can be said that PTEN needs to be used as an endpoint in the development of anticancer drugs. Activation of PTEN inhibits the cell cycle and induces apoptosis.

In addition, tumor growth is inhibited when PTEN is overexpressed in an animal model derived from a colon cancer cell line. The overexpression of PTEN in the animal models derived from the colorectal cancer cell lines SW480 and HT29 indicates that tumor growth is remarkably inhibited.

It has been reported that PTEN expression, which is a tumor suppressor in PI3K / PTEN signal transduction in colorectal cancer, is rarely expressed in colorectal cancer, and 75.4% of patients with liver metastases have almost no expression of PTEN Year survival rate has been reported to decrease significantly.

More specifically, 50 to 60% of patients, including patients with metastatic colorectal cancer recurring at 20 to 50% after curative resection of colorectal cancer, are candidates for chemotherapeutic treatment. Recently, biologically targeted therapeutic agents have been applied to colorectal cancer chemotherapy, which shows a therapeutic effect in some patients with metastatic colorectal cancer.

Korean Patent No. 10-1652010

One of the objects of the present invention is to provide a compound capable of selectively and effectively inhibiting the binding of p34 protein and NEDD4-1 protein, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition comprising the compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition capable of preventing or treating various diseases mediated by selectively and effectively inhibiting the binding of p34 protein and NEDD4-1 protein by including the above compound as an active ingredient do.

In order to accomplish the above object, the present invention provides a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

here,

n is an integer of 1 to 10,

X ₁ and X ₄ are the same or different and are each independently selected from the group consisting of S, O, N (R ₂ ) and C (R ₃ ) (R ₄ )

X ₂ and X ₃ are each independently N or C (R ₅ ), at least one is N,

L ₁ and L ₂ are the same or different and each independently represents a single bond, a carbonyl group, an unsubstituted or substituted alkylene group having 1 to 10 carbon atoms or an unsubstituted or substituted arylene group having 6 to 30 carbon atoms,

Ar ₁ and Ar ₂ are the same or different and each independently represents an unsubstituted or substituted C 6 -C 30 aryl group, an unsubstituted or substituted C 6 -C 30 aralkyl group, an unsubstituted or substituted C 3 -C 30 A substituted or unsubstituted heteroaryl group, an unsubstituted or substituted C 6 -C 30 heteroarylalkyl group, an unsubstituted or substituted C 3 -C 40 cycloalkyl group, and an unsubstituted or substituted C 3 -C 40 heterocycloalkyl group And,

R ₁ to R ₅ are the same or different from each other and each independently represents hydrogen, deuterium, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, An aralkyl group having 7 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms and may be bonded to adjacent groups to form a substituted or unsubstituted ring,

The substituted alkylene group, the substituted arylene group, the substituted aryl group, the substituted aralkyl group, the substituted heteroaryl group, the substituted heteroarylalkyl group, the substituted cycloalkyl group, and the substituted heterocycloalkyl group are each independently hydrogen, deuterium A halogen atom, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms , An aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms , An aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 40 carbon atoms, An arylsilyl group having 6 to 60 carbon atoms and an aryloxy group having 6 to 30 carbon atoms, and when they are substituted with a plurality of substituents, they may be the same or different from each other And may be bonded to adjacent groups to form a substituted or unsubstituted ring.

According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, wherein said medicament is for the prevention or treatment of a disease mediated by the simultaneous expression of p34 and NEDD4-1 Purpose.

It is particularly preferred that the disease is selected from tumor cells (e. G., Breast, colon and colon carcinoma).

The novel compounds according to the present invention can selectively or simultaneously inhibit various diseases mediated by the coexpression of p34 and NEDD4-1. Therefore, the novel derivatives according to the present invention can be usefully used for the treatment or prevention of tumor cells (for example, breast, colon and colon carcinoma).

FIG. 1 is a graph comparing the growth of a tumor of a mouse group administered with p34 activity inhibitor and a control group by subcutaneously injecting SW620, a human colon cancer cell line, into a Balb / c nude mouse to form a xenograft tumor.
FIG. 2 shows the expression of PTEN and NEDD4-1 in the mouse group treated with p34 activity inhibitor and the control group by subcutaneously injecting SW620, a human colon cancer cell line, into Balb / c nude mice to form xenograft tumors This is a comparative photograph.
FIG. 3 is a graph comparing the growth of a tumor of a mouse group administered with p34 activity inhibitor and a control group by subcutaneously injecting SW620, a human colon cancer cell line, into a Balb / c nude mouse to form xenograft tumors.
4a to 4d are graphs showing the results of performing NMR titration to determine the site of NEDD4-1 protein binding to p34.

The definitions listed below are definitions of various terms used to describe the present invention. These definitions apply throughout this specification, either individually or as part of a term including them, unless the context otherwise requires.

The term " halogen ", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine or both.

The term " alkyl ", as used herein, unless otherwise indicated, refers to saturated, straight or branched hydrocarbon radicals represented by C _n H _{2n +} 1, specifically between 1 and 6, Refers to saturated, straight or branched hydrocarbon radicals containing between 8, 1 to 10, or between 1 and 20 carbon atoms. Examples of these radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.

The term " alkenyl ", as used herein, unless otherwise indicated, refers to monovalent groups derived from unsaturated, linear, or branched hydrocarbon moieties having at least one carbon-carbon double bond, Refers to an unsaturated, straight chain or branched monovalent group comprising between 2 and 6, between 2 and 8, between 2 and 10, or between 2 and 20 carbon atoms. Examples thereof include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, and octenyl radicals.

The term " cycloalkyl ", as used herein, unless otherwise indicated, refers to a monovalent radical derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, examples of C3-C8-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl; Examples of C3-C12-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Monovalent radicals derived from monocyclic or polycyclic carbocyclic ring compounds having at least one carbon-carbon double bond by the removal of a single hydrogen atom are also contemplated. Examples of such groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, cyclooctenyl, and the like.

Unless otherwise stated, the term " cycloalkenyl ", as used herein, unless otherwise indicated, refers to a partially unsaturated carbocyclic ring containing 3 to 6 carbon atoms and having a carbon-carbon double bond in the ring . Examples of such groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.

The term " aryl ", as used herein, unless otherwise indicated, refers to a mono- or poly-cyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including, but not limited to, Phenyl, naphthyl, tetrahydronaphthyl, indenyl, indenyl, and the like.

The term " heterocycloalkyl ", as used herein, unless otherwise indicated, includes saturated or partially unsaturated 3-10 membered rings containing one or more heteroatoms selected from N, O and S, Quot; means a monocyclic or polycyclic substituent of < / RTI > Examples of monocyclic heterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups. It is not.

The term " heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic 5- to 12-membered ring containing one or more heteroatoms selected from O, N and S, Refers to an aromatic group that is more than a click. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrroyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine Pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, Isoquinolinyl, purine, furopyridinyl and similar groups, but is not limited thereto.

The term " non-aromatic condensed heterocyclic ring " as used herein refers to a heterocyclic ring having two or more rings condensed with each other and containing heteroatoms selected from N, O and S in addition to carbon as a ring- Refers to a group having a non-aromacity (e.g., having 5 to 10 nucleus atoms). Examples of such non-aromatic fused heterocyclic rings include, but are not limited to, benzo [d] [1,3] dioxole and the like.

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

The present invention provides a compound of the formula 1: < EMI ID = 2.1 > or a pharmaceutically acceptable salt thereof, wherein:

[Chemical Formula 1]

here,

n is an integer of 1 to 10,

X ₁ and X ₄ are the same or different and are each independently selected from the group consisting of S, O, N (R ₂ ) and C (R ₃ ) (R ₄ )

X ₂ and X ₃ are each independently N or C (R ₅ ), at least one is N,

L ₁ and L ₂ are the same or different and each independently represents a single bond, a carbonyl group, an unsubstituted or substituted alkylene group having 1 to 10 carbon atoms or an unsubstituted or substituted arylene group having 6 to 30 carbon atoms,

Ar ₁ and Ar ₂ are the same or different and each independently represents an unsubstituted or substituted C 6 -C 30 aryl group, an unsubstituted or substituted C 6 -C 30 aralkyl group, an unsubstituted or substituted C 3 -C 30 A substituted or unsubstituted heteroaryl group, an unsubstituted or substituted C 6 -C 30 heteroarylalkyl group, an unsubstituted or substituted C 3 -C 40 cycloalkyl group, and an unsubstituted or substituted C 3 -C 40 heterocycloalkyl group And,

R ₁ to R ₅ are the same or different from each other and each independently represents hydrogen, deuterium, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, An aralkyl group having 7 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms and may be bonded to adjacent groups to form a substituted or unsubstituted ring,

The substituted alkylene group, the substituted arylene group, the substituted aryl group, the substituted aralkyl group, the substituted heteroaryl group, the substituted heteroarylalkyl group, the substituted cycloalkyl group, and the substituted heterocycloalkyl group are each independently hydrogen, deuterium A halogen atom, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms , An aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms , An aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 40 carbon atoms, An arylsilyl group having 6 to 60 carbon atoms and an aryloxy group having 6 to 30 carbon atoms, and when they are substituted with a plurality of substituents, they may be the same or different from each other And may be bonded to adjacent groups to form a substituted or unsubstituted ring.

In one specific embodiment of the present invention, Ar ₁ may be a compound represented by the following formula (2):

(2)

here,

* Denotes the part where the combination is made,

m is an integer of 0 to 2,

X ₅ is selected from the group consisting of _{N (R 6), S,} O and _{C (R 7) (R 8} ),

R ₆ to R ₈ are the same or different from each other and each independently represent a hydrogen atom, a hydrogen atom, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, An alkenyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, An alkoxy group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, A cycloalkyl group having 3 to 40 carbon atoms, a heterocycloalkyl group having 3 to 40 carbon atoms, an arylsilyl group having 6 to 60 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms.

In one specific embodiment of the present invention, Ar ₂ may be selected from the group consisting of compounds represented by the following formulas (3) to (5):

(3)

[Chemical Formula 4]

[Chemical Formula 5]

here,

* Denotes the part where the combination is made,

o is an integer from 0 to 4,

p and q are the same as or different from each other, each independently an integer of 0 to 2,

X ₆ , X ₉ and X ₁₀ are the same or different and are each independently selected from the group consisting of N, O, S and C (R ₁₁ )

X ₇ and X ₈ are the same or different and are each independently selected from the group consisting of N (R ₁₂ ), O, S and C (R ₁₃ ) (R ₁₄ )

R ₉ to R ₁₄ are the same or different from each other and each independently represents hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, alkyl group having 1 to 30 carbon atoms, cycloalkyl group having 1 to 20 carbon atoms, An alkenyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, An alkoxy group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, A cycloalkyl group having 3 to 40 carbon atoms, a heterocycloalkyl group having 3 to 40 carbon atoms, an arylsilyl group having 6 to 60 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms.

In a specific embodiment of the present invention, L ₂ is a single bond, and adjacent R ₁ and Ar ₂ may bond to each other to form a condensed ring.

In one specific embodiment of the present invention, the condensed ring formed by combining R ₁ and Ar ₂ with each other is a compound represented by the following formula 6:

[Chemical Formula 6]

here,

r is an integer of 1 to 4,

X ₈ , R ₁₀ and p are as defined in formula (4).

In one embodiment of the present invention, the compound of Formula 1 may be selected from the group consisting of the following compounds, but not limited thereto:

The compound of formula 1 according to the present invention can be prepared by a method represented by the following schemes 1 to 8:

<Reaction Scheme 1>

The intermediate compound (2) containing a carboxylic acid group is synthesized by reacting a commercially available oxadiazole compound (1) as a starting material with chloroacetic acid and coupling reaction with various amines (3) to obtain the final compound (4) were synthesized.

The compound of formula (I) according to the present invention may be prepared in the form of a pharmaceutically acceptable salt to which an inorganic acid or an organic acid is added. Preferred salts thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, , Pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, , Salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

Specifically, the pharmaceutically acceptable salt according to the present invention is prepared by dissolving the compound of the formula (1) in an organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding crystals precipitated by adding an organic acid or an inorganic acid, can do. Or by reducing the solvent or excess acid in a reaction mixture to which acid has been added and drying the residue, or by adding a different organic solvent to the precipitated salt.

The compounds of formula (I) according to the invention, or pharmaceutically acceptable salts thereof, may be in the form of hydrates or solvates, and such compounds are also included in the present invention.

The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention can effectively inhibit protein kinase. In one embodiment, the compounds of the present invention can effectively prevent or treat diseases mediated by the coexpression of p34 and NEDD4-1. That is, binding to a part of the p34 protein and binding to a part of the NEDD4-1 protein can inhibit binding of the p34 protein and the NEDD4-1 protein. Specifically, the disease may be selected from, but not limited to, metastatic growth of the tumor.

In one specific embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof can effectively prevent or treat cancer or tumor, and further effectively inhibit the metastasis of cancer cells. Wherein the cancer is selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, cancer of the head and neck, colorectal cancer, bladder cancer, ovarian cancer, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, pancreatic cancer, gastric cancer, Breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, Lung cancer, colorectal cancer, colon cancer, and other solid tumors. It is selected from the group, but is not limited to this.

In one specific embodiment of the present invention, the compound of formula 1 or a pharmaceutically acceptable salt thereof can effectively prevent or treat the carcinoma mediated by the simultaneous expression of p34 and NEDD4-1. Herein, the carcinoma can be selected from the group consisting of lung, liver, bile duct, gastrointestinal tract, head and neck, pancreas, prostate, cervix, breast, colon and colon.

The compound of the formula (1) according to the present invention or a pharmaceutically acceptable salt thereof and the like can be administered to a specimen to prevent or treat the above-mentioned diseases. The dosage of the compound of formula (I) is usually 0.1 to 2,000 mg per day on a weight basis of 70 kg as an active ingredient to a human, although the dosage thereof may vary depending on the subject to be treated, the severity of the disease or condition, , Preferably from 1 to 1,000 mg per day, or via an oral or parenteral route, with an on / off schedule of one to four times per day. In some cases, doses less than the above-mentioned ranges may be more suitable, more doses may be used without causing harmful side effects, and more doses may be dispensed with several smaller doses per day do.

The pharmaceutical composition according to the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions, or by intramuscular, intravenous or subcutaneous administration Can be prepared in parenteral dosage forms.

When the pharmaceutical composition according to the present invention is prepared in the form of an oral dosage form, examples of the carrier to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, Calcium, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents and the like. When the pharmaceutical composition according to the present invention is prepared in the form of an injection, the carrier includes water, saline solution, glucose aqueous solution, pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, Glyceride, a surfactant, a suspending agent, an emulsifying agent and the like can be used.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example

[ Manufacturing Example 1] 2- {5- (2,3-Dimethyl-1H-indol-5-yl) -1,3,4-oxadiazol-

5- (2,3-dimethyl- 1H -indol-5-yl) -1,3,4-oxadiazole-2-thione (2.45 g, 10 mmol) was dissolved in anhydrous ethanol (100 mL) , Then triethylamine (2.1 mL, 15 mmol, 1.5 eq) is added. To this solution was slowly added chloroacetic acid (1.42 g, 12 mmol), the temperature of the solution was raised to 70 ° C, and the mixture was stirred for 12 hours. When the starting materials were all reacted, the solvent was removed under reduced pressure, and the reaction mixture was dissolved in anhydrous ethanol (30 mL), and 1N HCl was added little by little to acidify (pH 2-3). The resulting solid was filtered to obtain the desired compound %).

_{^{1 H NMR (DMSO-d 6}} , 400 MHz): δ (ppm) 11.15 (1H, s, -NH), 7.97 (1H, s, ArH), 7.58 (1H, d, J = 8.8, ArH), 7.38 (1H, d, J = 8.8 , ArH), 4.16 (2H, s, s-CH 2 -COOH), 2.33 (3H, s), 2.20 (3H, s)

MS (ESI) m / z 304 (M ^&lt; + & gt ^; +1).

[ Manufacturing Example 2] 2- {5- (1H-Indol-5-yl) -1,3,4-oxadiazol-2-yl} acetic acid

In Preparative Example 1 5- (2,3-dimethyl -1 H - indol-5-yl) -1,3,4-oxadiazol-2-thione in place of 5- (1 H - indol-5-yl ) -1,3,4-oxadiazole-2-thione, the title compound was obtained in the same manner and used directly in the next reaction without purification.

Example 1 2 - ((5-2,3- dimethyl -1H- indol-5-yl) -1,3,4-oxadiazol-2-yl) thio) -N- (thiazole -2 Ylmethyl) acetamide &lt; / RTI &gt;

Yl) acetic acid (2.60 g, 8.57 mmol) obtained in Preparative Example 1 and 5 (3-dimethyl-lH-indol- Hydroxybenzotriazole (HOBT, 1.27 g, 9.40 mmol, 1.1 eq.), Dimethylaminopropyl) carbodiimide hydrochloride was added to a DMF (120 mL) solution of 1- (aminomethyl) thiazolidine hydrochloride (1.60 g, 8.57 mmol) N-ethylcarbodiimide hydrochloride (EDC, 1.80 g, 1.1 eq) and diisopropylethylamine (DIPEA, 15 mL, 94.0 mmol, 10 eq) were added and stirred at room temperature for 16 hours. After the starting materials were reacted, a saturated aqueous solution of NaHCO ₃ (60 mL) was added, and the mixture was extracted with ethyl acetate (200 mL, twice), dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure to obtain 2.24 g . The crude pale yellow solid (1.78 g, 52%, HPLC purity) was prepared by slurrying the crude product with ethyl acetate / MeOH (2: 1, v / 98%).

_{^{1 H NMR (DMSO-d 6}} , 400 MHz): δ (ppm) 11.15 (1H, s, -NH), 9.01 (1H, t, J = 5.8 Hz, -NH), 8.93 (1H, s, ArH) , 7.96 (1H, s, ArH), 7.78 (1H, s, ArH), 7.58 (1H, dd, J = 8.4 & (3H, s), 2.12 (3H, s), 4.12 (2H, s,

MS (ESI) m / z 400 (M ^&lt; + & gt ^; +1).

The compounds of Examples 3 to 6 were synthesized in the same manner except for the amine used in Example 1, and the results are shown in Table 1. (5-2,3-dimethyl-1H-indol-5-yl) -1,3,4-oxadiazol-2-yl) acetic acid obtained in Preparation Example 1 instead of 2- The compound of Example 2 was synthesized using 2- {5- (1H-indol-5-yl) -1,3,4-oxadiazol-2-yl} acetic acid obtained in 2 .

Example Chemical structure NMR spectrum data One

_{^{1 H NMR (DMSO-d 6}} ) δ 11.15 (1H, s, -NH), 9.01 (1H, t, J = 5.8 Hz, -NH), 8.93 (1H, s, ArH), 7.96 (1H, s, ArH), 7.78 (1H, s, ArH), 7.58 (1H, dd, J = 8.4 & 1.2, ArH), 7.37 (1H, d, J = 8.4, ArH), 4.54 (3H, s), 2.12 (3H, s), 4.12 (2H, s, 2

^{1 H NMR (DMSO-d6)} δ 0.85 (s, 1H), 1.06 (s, 1H), 1.34 (d, 1H), 1.82 (s, 1H), 2.32 (s, 1H), 4.52 (d, 3H) , 4.68 (d, IH), 5.13 (s, 3H), 6.52 (s, IH), 7.40-7.48 (m, 3H), 7.58-7.60 2H), 9.01-9. 07 (m, 3H), 8.04 (d, IH) 3

_{^{1 H NMR (DMSO-d 6}} ) δ 2.20 (s, 3H), 2.33 (s, 3H), 4.17 (s, 2H), 4.62 (d, 2H), 7.39 (d, 1H), 7.58-7.61 (m 2H), 7.70 (d, IH), 7.97 (s, IH), 9.23 4

_{^{1 H NMR (DMSO-d 6}} ) δ 2.15 (s, 3H), 2.29 (s, 3H), 3.93 (t, 1H), 4.00 (t, 2H), 4.17 (t, 1H), 4.68 (s, 3H ), 7.34 (s, IH), 7.55-7.58 (m, IH), 7.80 5

_{^{1 H NMR (DMSO-d 6}} ) δ 2.15 (s, 3H), 2.28 (s, 3H), 3.90 (s, 1H), 4.23 (d, 2H), 4.61 (d, 2H), 7.27-7.33 (m (S, 3H), 7.55-7.58 (m, 3H), 7.93 (d, 6

_{^{1 H NMR (DMSO-d 6}} ) δ 2.20 (s, 3H), 2.33 (s, 3H), 3.33 (s, 5H), 4.20 (s, 2H), 4.49 (d, 2H), 7.38 (d, 1H ), 7.59 (d, 1 H), 7.97 (s, 1 H), 8.51-8.62 (m, 3H), 9.03

Test Example

The results of evaluating the efficacy of the compounds prepared in the above examples were as follows.

Test Example  1: Using the fluorescence resonance energy transfer (FRET) assay, NEDD4 -1 binding inhibition activity

The inhibitory activity of the compound against p34 and NEDD4-1 was evaluated using the p34 protein and the NEDD4-1 protein based on HTRF technology developed by CISBio. This assay measures the FRET (fluorescence resonance energy transfer) signal in the presence of Terbium-labeled Anti-FLAG antibody and d2-labeled Anti-6XHis antibody. Experiments were performed in 384-well plates, 1X PBS pH 7.4, 0.1% BSA and 2% DMSO. After the background signal was measured in the absence of p34-NEDD4-1 protein and only the solvent (2% DMSO) was added as a non-inhibitory signal, the compound to be evaluated was treated to a final concentration of 10 uM The p34-NEDD4-1 inhibitory activity of the compound after the preparation was calculated as%. The results are shown in Table 2 below.

Compound_ID FRET result
( Inhibition%  @ 10? M) Example 1 45.8 Example 2 65.8 Example 3 59.4 Example 4 54.6 Example 5 58.9 Example 6 46.6 control 0

Test Example  2: of the p34 activity inhibitor PTEN  Evaluation of activity through induction of reactivation

The human colon cancer cell line, SW620, was treated with 5 uM of p34 activity inhibitor for 48 hours. The cell lysate was collected and immunoprecipitated with PTEN antibody. After incubation at 37 ° C for 40 minutes with reaction buffer (100 mM tris-HCl pH 8.0, 10 mM DTT) containing water-soluble diC8-phosphatidylinositol 3, 4 and 5 triphosphate, Solution for 30 minutes at room temperature, and the PTEN lipid phosphatase activity was measured at CD650 nm. The activity of the phospholipase by PTEN reactivation of the compound was calculated as%. The results are shown in Table 3 below.

Compound_ID PTEN  activity
(relative fold @ 5νΝ ) Example 1 1.8 Example 2 1.0 Example 3 2.1 Example 4 2.2 Example 5 2.2 Example 6 1.8 control 1.0

Test Example  3: of the p34 activity inhibitor xenograft  Evaluation of tumor growth inhibitory activity in mouse animal models

Human colon cancer cell line SW620 was injected subcutaneously into Balb / c nude mice to form xenograft tumors. Tumor size was monitored every 3 days and the size of the tumor was continuously monitored by oral administration of p34 activity inhibitor daily (the control group was administered only the solvent) with 0 day when the tumor size reached 100 mm ³ . The p34 activity inhibitor was completely dissolved in the phosphate buffer (pH 4.0): 10% PVP: Tween 80 = 47.5: 47.5: 5 and administered at a concentration of 10, 30, 100 mg / kg or 50 mg / kg (BID). As shown in Fig. 1 and Fig. 3, tumor growth was significantly reduced in the mouse group to which the p34 activity inhibitor was administered, as compared with the control group. As shown in Fig. 2, PTEN expression was increased and NEDD4-1 expression was decreased in the group to which p34 activity inhibitor was administered.

Test Example  4: Coupled with p34 NEDD4 -1 binding site

NMR titration was performed to determine the site of NEDD4-1 protein binding to p34. 0.5 mM recombinant ¹⁴ N-labeled NEDD4-1 ^WW1 domain and 0.8 mM unlabed p34 protein were prepared. Two proteins are 137 mM NaCl, 2.7 mM KCl, 8.1 mM Na 2 HPO 4 and 1.5 mM KH 2 PO 4, It was prepared by dissolving in PBS buffer for the _{pH 7.4 in 10% D 2 O} . Unlabed p34 increased the concentration of ¹⁴ N-labeled NEDD4-1 ratios with the ^WW1 domain to 1: 0. 1: 0.25, and 1: 0.5, respectively. All NMR experiments were performed with Bruker DRX 850 MHz and the results were analyzed by XWINNMR program and NMRpipe / NMRDraw software.

Figures 4a-4d illustrate the molecular interaction and backbone dynamics of the WW1 domain of NEDD4-1 after interaction with p34SEI-1. Figure 4a is a superposition of the 2D 1H-15N HSQC spectrum of the 15N WW1 domain of NEDD4-1 (Red) titrated with increasing concentrations of unlabeled p34SEI-1 (1e120). Figure 4b is an enlargement of the overlapping 1H-15N HSQC spectrum of the WW1 domain of NEDD4-1 titrated with increasing concentrations of unlabeled p34SEI-1 (1e120). The asterisk [*] denotes residues that have disappeared due to peak broadening. Figure 4c shows the average heteronuclear NOE value for the NEDD4-1 WW1 domain and the corresponding secondary structure (shown on the panel) as a result of the 1H-15N heteronuclear NOE experiment. FIG. 4D is a depiction of a sausage form showing the dynamic region of the NEDD4-1 WW1 domain (SWISS-MODEL).

As shown in Figures 4a to 4d, it binds to the p34 protein through the G196, E198, I203, Y209, V210, N211, H212, K220 and R221 amino acids located in the core region of the NEDD4-1WW1 domain.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (15)

Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; (1) &lt; / RTI &
[Chemical Formula 1]

here,
n is an integer of 1 to 10,
X ₁ and X ₄ are the same or different and are each independently selected from the group consisting of S, O, N (R ₂ ) and C (R ₃ ) (R ₄ )
X ₂ and X ₃ are each independently N or C (R ₅ ), at least one is N,
L ₁ and L ₂ are the same or different and each independently represents a single bond, a carbonyl group, an unsubstituted or substituted alkylene group having 1 to 10 carbon atoms or an unsubstituted or substituted arylene group having 6 to 30 carbon atoms,
Ar ₁ and Ar ₂ are the same or different and each independently represents an unsubstituted or substituted C 6 -C 30 aryl group, an unsubstituted or substituted C 6 -C 30 aralkyl group, an unsubstituted or substituted C 3 -C 30 A substituted or unsubstituted heteroaryl group, an unsubstituted or substituted C 6 -C 30 heteroarylalkyl group, an unsubstituted or substituted C 3 -C 40 cycloalkyl group, and an unsubstituted or substituted C 3 -C 40 heterocycloalkyl group And,
R ₁ to R ₅ are the same or different from each other and each independently represents hydrogen, deuterium, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, An aralkyl group having 7 to 30 carbon atoms and an aryl group having 6 to 30 carbon atoms and may be bonded to adjacent groups to form a substituted or unsubstituted ring,
The substituted alkylene group, the substituted arylene group, the substituted aryl group, the substituted aralkyl group, the substituted heteroaryl group, the substituted heteroarylalkyl group, the substituted cycloalkyl group, and the substituted heterocycloalkyl group are each independently hydrogen, deuterium A halogen atom, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms , An aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms , An aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, a cycloalkyl group having 3 to 40 carbon atoms, An arylsilyl group having 6 to 60 carbon atoms and an aryloxy group having 6 to 30 carbon atoms, and when they are substituted with a plurality of substituents, they may be the same or different from each other And may be bonded to adjacent groups to form a substituted or unsubstituted ring. The method according to claim 1,
Wherein Ar &lt; ₁ &gt; is a compound represented by the following formula (2): &lt; EMI ID =
(2)

here,
* Denotes the part where the combination is made,
m is an integer of 0 to 2,
X ₅ is selected from the group consisting of _{N (R 6), S,} O and _{C (R 7) (R 8} ),
R ₆ to R ₈ are the same or different from each other and each independently represent a hydrogen atom, a hydrogen atom, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, a cycloalkyl group having 1 to 20 carbon atoms, An alkenyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, An alkoxy group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, A cycloalkyl group having 3 to 40 carbon atoms, a heterocycloalkyl group having 3 to 40 carbon atoms, an arylsilyl group having 6 to 60 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms. The method according to claim 1,
Wherein Ar &lt; ₂ &gt; is selected from the group consisting of compounds represented by the following formulas (3) to (5): &lt; EMI ID =
(3)

[Chemical Formula 4]

[Chemical Formula 5]

here,
* Denotes the part where the combination is made,
o is an integer from 0 to 4,
p and q are the same as or different from each other, each independently an integer of 0 to 2,
X ₆ , X ₉ and X ₁₀ are the same or different and are each independently selected from the group consisting of N, O, S and C (R ₁₁ )
X ₇ and X ₈ are the same or different and are each independently selected from the group consisting of N (R ₁₂ ), O, S and C (R ₁₃ ) (R ₁₄ )
R ₉ to R ₁₄ are the same or different from each other and each independently represents hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, alkyl group having 1 to 30 carbon atoms, cycloalkyl group having 1 to 20 carbon atoms, An alkenyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 6 to 30 carbon atoms, a heteroaralkyl group having 3 to 30 carbon atoms, An alkoxy group, an alkylamino group having 1 to 30 carbon atoms, an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, a heteroarylamino group having 6 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, A cycloalkyl group having 3 to 40 carbon atoms, a heterocycloalkyl group having 3 to 40 carbon atoms, an arylsilyl group having 6 to 60 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms.
The method according to claim 1,
Wherein L ₂ is a single bond, and adjacent R ₁ and Ar ₂ may be bonded to each other to form a condensed ring.
5. The method of claim 4,
Wherein the condensed ring formed by combining R ₁ and Ar ₂ with each other is a compound represented by the following formula 6:
[Chemical Formula 6]

here,
r is an integer of 1 to 4,
X ₈ , R ₁₀ and p are as defined in claim 3. The method according to claim 1,
Wherein the compound of Formula 1 is a compound selected from the group consisting of the following compounds:

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount. A pharmaceutical composition comprising a compound of claim 6 or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount. A method for inhibiting the binding of p34 and NEDD4-1 (Neuronal precursor cell-expressed developmentally down-regulated 4-1) protein in a sample or a cell, comprising administering a pharmaceutically effective amount of the compound of claim 1 to a sample. 10. The method of claim 9, wherein the compound is selected from the group consisting of: G196, E198, I203, Y209, V210, N211, H212, K220 and R221 amino acid residues located in the core region of the NEDD4-1WW1 domain To inhibit the binding of p34 and NEDD4-1 protein in a sample or a cell. A method for inhibiting the metastasis of cancer cells in a sample, comprising administering a pharmaceutically effective amount of the compound of claim 1 to the sample. comprising administering to a subject in need of treatment of a carcinoma mediated by the simultaneous expression of p34 and NEDD4-1 a therapeutically effective amount of a compound of claim 1, Treatment method. 13. The method of claim 12,
Wherein said carcinoma is selected from the group consisting of lung, breast, colon, colon, liver, biliary tract, gastrointestinal tract, head and neck, pancreas, prostate and carcinoma of the cervix, multiple myeloma, melanoma, glioma and glioblastoma . 9. The method according to claim 7 or 8,
Wherein said pharmaceutical composition is for preventing or treating cancer or a tumor. 15. The method of claim 14, wherein the cancer is selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, ), Basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, pancreatic cancer, lung cancer, skin cancer, colorectal cancer, colon cancer, Pharmaceutical compositions characterized in that other solid tumor is selected from the group consisting of.

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