KR20150131484A - Chemical compound for inhibiting protein tyrosin kinase and pharmaceutical composition for treating or preventing cancer comprising the same - Google Patents

Abstract

The present invention relates to a novel compound and a manufacturing method thereof and, particularly, to a pharmaceutical composition for treating or preventing diseases associated with abnormal activation of protein tyrosine kinase, wherein the compound is represented by chemical formula 1.

Description

TECHNICAL FIELD [0001] The present invention relates to a compound for inhibiting protein tyrosine kinase, and a pharmaceutical composition for the treatment or prevention of cancer comprising the compound. [0002] The present invention relates to a compound for inhibiting protein tyrosine kinase,

The present invention relates to a novel compound and a method for producing the same, and more particularly, to a pharmaceutical composition capable of treating or preventing a disease associated with an abnormal activity of a protein kinase.

Protein kinase (PK) is an enzyme that catalyzes the phosphorylation of hydroxyl groups in the tyrosine, serine, and threonine residues of proteins by the terminal phosphate transport of ATP. These enzymes regulate cell growth, differentiation, and proliferation, that is, virtually all aspects of cell life through signal transduction pathways, in one way, or by another method that is dependent on PK activity. In particular, abnormal protein phosphorylation and / or expression is often reported as one of the causes of abnormal cell proliferation, metastasis and cell survival in cancer. In particular, abnormal regulation and / or expression of various kinases including Akt, VEGF, ILK, ROCK, p70S6K, Bcl, PKA, Raf, Src, PDK1, ErbB2, MEK, IKK, Cdk, EGFR, BAD, CHK1, CHK2 and GSK3 Have a special relationship with cancer.

Protein tyrosine kinase (PTK) is an enzyme that can phosphorylate the phosphate group of intracellular ATP by transferring it to the tyrosine residue of the substrate protein, and can control various intracellular functions on and off. Protein phosphorylation by kinase plays an important role in intracellular signal transduction and regulates cell activity such as cell division.

PTK6 is not expressed in normal mammary epithelial tissues or benign lesions of mammals, but is overexpressed in breast cancer tissues. In particular, the mutation of p53 in breast cancer is found in about 20% of the cases, and overexpression of c-erbB-2 is found in a frequency of 25-30%, which is about 65% Cancer target molecule. PTK6 is overexpressed not only in breast cancer but also in colorectal cancer, ovarian cancer, and head and neck squamous cell carcimoma.

Expression of PTK6 improves the cell division potential of mammary epithelial cells and promotes cell migration and invasion. Proteins that interact with various substrates involved in the carcinogenesis of PTK6 have already been reported. For example, signal transducing adapter protein-2 (STAP-2), paxillin, AKT, p130 CRK-binding substrate (p130CAS) and p190RhoGAP-A. Recently, we have reported that Arf-GAP, Rho-GAP, ankyrin repeat, and pleckstrin homology (PH) domain-containing protein 1 (ARAP1) are novel interacting proteins and substrates for PTK6. ARAP1 promotes the down-regulation of EGF receptor. When ARAP1 is phosphorylated by PTK6, it does not down-regulate the EGF receptor, thus enhancing carcinogenic signaling by the EGF receptor. Moreover, since PTK6 overexpresses in various cancers and exhibits carcinogenic activity, inhibition of PTK6 has been suggested as a target for chemotherapy or prevention since it may delay or terminate tumor growth. Therefore, in the present invention, a new compound assay for inhibiting tyrosine kinase by targeting PTK6 was performed.

The present invention seeks to provide a novel compound that inhibits protein tyrosine kinase. The present invention also provides a therapeutic agent for diseases that can be treated by inhibition of protein tyrosine kinases.

In order to solve the above-mentioned problems,

As one embodiment of the present invention, there is provided a compound represented by the following general formula (1).

[Chemical Formula 1]

R < ₁ > is H or OH;

R ₂ is alkoxy or halogen;

R ₃ is H, OH, OCH ₃ ;

R ₄ and R ₅ are independently selected and are H or halogen;

And R < ₆ > is a heterocyclic compound containing a hetero atom of S or N.

Preferably R < ₁ > is OH.

Preferably R < _{2 >} is methoxy or ethoxy or Br.

Preferably, R ₃ is a hydroxy group or a methoxy group.

Preferably, R < ₄ > is Br.

,

,

,

,

및

로 구성된 군에서 선택될 수 있다.Preferably R < ₆ >

,

,

,

,

And

≪ / RTI >

이다.Preferably, R ₁ is OH, R ₂ is OCH ₃ , OCH ₂ CH ₃ or Br, R ₃ is H or OH, R ₄ is Br, Cl or I and R ₅ is H, Br or Cl And R < ₆ >

to be.

이다.Preferably, R ₁ is OH, R ₂ is OCH ₃ , or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

to be.

이다.Preferably, R1 is OH, R2 is OCH3, or OCH2CH3, R3 is H, R4 is Br, R5 is Br, and R6 is

to be.

이다.Preferably, R ₁ is OH and R ₂ is OCH ₃ Or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

to be.

이다.
Preferably, R ₁ is OH, R ₂ is OCH ₃ , or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

to be.

Preferably, the compound represented by formula (1) of the present invention is selected from the group consisting of the following compounds:

(E) -5 - ((5-Bromo-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5- (Benzylideneamino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Bromo-2-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Bromo-2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Bromo-2,3-dimethoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Chloro-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Chloro-2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2-Hydroxy-5-ureido-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Bromo-3-ethoxy-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((3-ethoxy-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((5-Chloro-3-ethoxy-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((3,5-dibromo-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2,4-dihydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2-hydroxy-4-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2-Bromo-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((6-Bromo-2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2,3,5-tribromo-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2,3-dibromo-6-hydroxy-5-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2,3-dibromo-5-ethoxy-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -5 - ((2,3-Dichloro-5-ethoxy-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;

5 - ((2,3-dibromo-6-hydroxy-5-methoxybenzyl) amino) -1H-benzo [d] imidazol-2 (3H) -one;

5 - ((2,3-dibromo-5-ethoxy-6-hydroxybenzyl) amino) -1H-benzo [d] imidazol-2 (3H) -one;

(E) -2 - ((( 1H -indol-5-yl) imino) methyl) -3,4-dibromo-6-methoxyphenol;

(E) -2 - (((1H-indol-5-yl) imino) methyl) -3,4-dibromo-6-ethoxyphenol;

(E) -2 - (((1H-benzo [d] imidazol-5-yl) imino) methyl) -3,4-dibromo-6-methoxyphenol;

(E) -2 - (((1H-benzo [d] imidazol-5-yl) imino) methyl) -3,4-dibromo-6-ethoxyphenol;

(E) -2 - ((benzo [d] thiazol-5-ylimino) methyl) -3,4-dibromo-6-methoxyphenol;

(E) -2 - ((benzo [d] thiazol-5-ylimino) methyl) -3,4-dibromo-6-ethoxyphenol.

In another aspect of the present invention, there can be provided a pharmaceutical composition comprising a compound represented by the general formula (1), or a pharmaceutically acceptable salt thereof, and a diluent, carrier or excipient. Herein, the additional therapeutic agent may include at least one selected from the group consisting of an anti-cancer compound, an analgesic agent, an anti-vomiting agent, an antidepressant, and an anti-inflammatory agent.

The pharmaceutical composition can treat or prevent diseases caused by overexpression of PTK.

Preferably, the PTK is Protein tyrosine kinase 6 (PTK6).

The diseases caused by overexpression of PTK include not only various cancers but also psoriasis, papilloma, gliomas, glioblastomas, restenosis, atherosclerosis and the like .

The cancer is selected from the group consisting of gastric cancer, colorectal cancer, lung cancer, liver cancer, prostate cancer, thyroid cancer, bladder cancer, pancreatic cancer, renal cancer, biliary cancer, breast cancer, uterine cancer, ovarian cancer, brain tumor, esophageal cancer, skin cancer, lymphoma, .

The present invention relates to a novel compound which inhibits protein tyrosine kinase (PTK), and can provide a composition for treating or preventing cancer comprising the compound as an active ingredient. In particular, the present invention provides a cancer therapeutic agent that inhibits the proliferation of cancer cells and the metastasis of cancer by regulating the signal transduction mechanism in cancer cells with active cell division.

1 is a graph for analyzing cell viability of a compound according to the present invention. This graph is a graph showing the viability of fibroblasts after treating Compound 1 , Compound 20 , and Compound 21 with AG808, a known PTK inhibitor, as a control.
Fig. 2 shows the result of Western blotting to observe the effect of PTK inhibitor on substrate phosphorylation by PTK6. Fig. 2 (A) shows the results obtained when PTK6-phosphorylated cell protein was treated with PTK inhibitor Compound 20 and Compound 21 Dependent phosphorylation was observed in a concentration-dependent manner. 2 (B) and 2 (C) show that STAT3 and paxillin, which are known as PTK6 substrate proteins, were phosphorylated by PTK6, but the degree of phosphorylation was decreased in a concentration-dependent manner by compound 20 and compound 21 Results.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel compound which inhibits protein tyrosine kinase (PTK), and can provide a composition for treating or preventing cancer comprising the compound as an active ingredient. The novel compounds according to the present invention were developed targeting the kinase domain of PTK and were designed to inhibit the activity of PTK through interaction with this domain.

The definitions of the terms used in the present invention are as follows:

&Quot; Protein tyrosine kinase " exists in 90 human species and can be divided into receptor type tyrosine kinase and cytosolic tyrosine kinase (also called non-water body tyrosine kinase). Receptor tyrosine kinases include EGF receptor, VEGF receptor (FLT1 and KDR), and intracellular tyrosine kinases include PTK6, SRC, Abl, Jak2, Fyn, Bmx and the like.

&Quot; Alkoxy " means an alkyl group associated with oxygen, and C 1-4 alkoxy includes methoxy, ethoxy, and the like.

&Quot; Halogen " refers to chloro (Cl), fluoro (F), bromo (Br) or iodo (I).

Means a mono-cyclic or fused bi-cyclic aromatic ring structure containing from 6 to 10 carbon atoms, for example, as the (C1-C10) heteroaryl, pyridyl, indolyl , Indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo [1,3] dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl , Oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, and the like.

&Quot; Heteroaryl " means aryl in which one or more of the ring members is a heteroatom.

&Quot; Compound of the present invention " means a compound represented by any one of formulas 1 to 6, a precursor thereof, a pharmaceutically acceptable salt thereof, all stereoisomers (including left and right isomers and enantiomers) and Means tautomers.

Hereinafter, the present invention will be described in more detail with reference to examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

As one embodiment of the present invention, there is provided a compound represented by the following general formula (1).

[Chemical Formula 1]

R < ₁ > is H or OH,

R ₂ is C ₁ -C ₄ alkoxy or halogen,

R ₃ is H, OH, OCH ₃ ,

R ₄ And R < ₅ > are independently selected from H or halogen,

And R < ₆ > is a heterocyclic compound containing a hetero atom of S or N.

As specific examples of the compound represented by the formula (1) of the present invention, there may be mentioned the compounds represented by the following formulas (2) to (6):

(Compounds 1 to 22 of Tables 1 and 2)

Wherein R ₁ is OH, OCH ₃ , R ₂ is OCH ₃ , OCH ₂ CH ₃ , Br, R ₃ is H or OH, R ₄ is Br, Cl, I and R ₅ is H, Br , Cl.

[Chemical Formula 3] (Compounds 23 and 24 )

Wherein R ₁ is OH, R ₂ is OCH ₃ , OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, and R ₅ is Br.

[Chemical Formula 4] (Compounds 26 and 29 )

Wherein R ₁ is OH, R ₂ is OCH ₃ , OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, and R ₅ is Br.

[Chemical Formula 5] (Compounds 27 and 30 )

Wherein R ₁ is OH, R ₂ is OCH ₃ , OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, and R ₅ is Br.

[Chemical Formula 6] (Compounds 28 and 31 )

Wherein R ₁ is OH, R ₂ is OCH ₃ , OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, and R ₅ is Br.

Hereinafter, various derivatives of the compounds represented by formulas (2) and (6) show inhibition levels of PTK activity in vitro and in vivo as shown in the following Tables 1 to 4, We will compare and compare these values:

[Table 1]

The present inventors purified PTK6 phosphorylation catalytic domain [PTK6 linker (ΔN) -kinase] in the "in vitro" analysis of the PTK inhibitor and used it as an enzyme, using a non-isotopic poly (4: 1 Glu-Tyr) And analyzed by ELISA (Kim and Lee, 2005 J. Biol. Chem. 280: 28973-28980). This assay is based on the detection of tyrosine residues phosphorylated with monoclonal antibodies to phosphotyrosine. Using this in vitro assay system, we have screened chemical libraries to obtain several compounds that inhibit the catalytic activity of PTK6. Among them, Compound 1 (IC ₅₀ = 1.90 μM in vitro) is Lipinski? rule and was a lead compound with a novel chemical scaffold.

[Compound 1]

The present inventors analyzed the inhibitory activity of PTK activity in " cellular level " In a basic experiment, PTK6 overexpression in HEK293 cells was analyzed by western blotting using phosphotyrosine antibody to determine whether substrate phosphorylation by PTK6 was decreased by the compound. Compound 1 showed inhibition of PTK6 in vitro, but did not inhibit PTK6-dependent phosphorylation at a concentration of 100 uM at the cellular level.

The present inventors synthesized derivatives thereof based on compound 1 to analyze whether hydroxyl and bromine groups in benzylidene of compound 1 are important for inhibition of PTK6 in vitro and at the cellular level (Table 1). Compound 2 was a compound without side chain in benzylidene and did not inhibit PTK6 in vitro. Compound 3 having a hydroxy group at the R1 position showed PTK6 inhibitory activity (IC50 = 1.74 [mu] M in vitro). Replacing the hydroxy group with a methoxy group at the R1 position reduced the inhibitory activity of PTK6 (Compound 3 vs. Compound 4; and Compound 5 vs. Compound 6) . From these results, it was confirmed that the hydroxyl group in compound 1 is an essential constituent for inhibiting the activity of PTK6.

Removal of the Br group at the R4 position of Compound 1 does not change the PTK6 inhibitory activity (Compound 3 vs. Compound 1 ). However, in other compounds the Br group is beneficial to PTK6 inhibitory activity (compound 5 vs. compound 8; and compound 11 vs. compound 12 ). In addition, the compound having Cl or I instead of Br at the position R4 showed activity to inhibit PTK6 (Compound 7 , Compound 9, Compound 10 and Compound 13 ). Thus, in the presence of chloride, iodine, or bromine at the R4 position, the in vitro PTK6 inhibition tended to be enhanced.

The present inventors analyzed the effect of the side chain present at the R2 position of the compound 1. Addition of a bromine, methoxy or ethoxy group at the R2 position reduces PTK6 activity in vitro, but does not enhance inhibition at the cellular level ( 14 , 5 and 11 ).

Next, the present inventors analyzed the effect when side chains were present at the R3 or R5 position. Compounds 15 and 16 having a hydroxy or methoxy group at the R3 position of the compound 3 could not inhibit the PTK6 catalytic activity. The Br group at the R5 position not only enhanced PTK6 inhibitory activity in vitro (Compound 3 vs. Compound 17 vs. Compound 8 vs. Compound 18 ), but also enhanced PTK6 activity inhibition at the cellular level (Compound 8 vs. Compound 18 ).

Based on the effect of the side chain on the benzylidene of Compound 1, we synthesized compounds that enhance the inhibition of PTK6 in vitro and at the cellular level (Table 2). Among them, Compounds 20 and 21 , when compared to Compound 1, showed a significant improvement in inhibition of PTK6 in vitro and at the cellular level. Tyrphostin AG808, used as a control in the PTK6 in vitro assay, was developed as an inhibitor of PDGF and EGFR and is also known as PTK6 inhibitor (Gazit A et al., J Med Chem , 1996). In the present assay, AG808 inhibited PTK6 in vitro (IC ₅₀ = 2.33 μM) and at the cellular level (IC ₅₀ = 53.24 μM), but this inhibitory activity is much weaker than compounds 20 and 21 .

[Table 2]

The present inventors analyzed the effect of inhibiting the binding of benzylidene and benzimidazoline ring on PTK6 activity inhibition. Compounds 23 and 24 showed lower inhibition rates than Compounds 20 and 21 , respectively (Table 3).

[Table 3]

The present inventors made variants of the benzimidazoline structure to analyze whether the benzimidazoline ring structure is important for PTK6 inhibition. Compounds 25 , 26 , 28 and 29 have in vitro inhibitory activity similar to compounds 20 and 21 . However, inhibition at the cellular level was reduced (Table 4). Compounds 30 and 27 decreased the activity of PTK6 in vitro, as NH was changed to S in benzimidazoline (Table 4).

[Table 4]

We have found that compounds 20 (IC ₅₀ = 0.52 μM in vitro and IC ₅₀ = 1.60 μM at cellular level) and 21 (IC ₅₀ ) are candidates for PTK inhibitors based on the structure-activity relationship (SAR) = 0.12 μM in vitro and IC ₅₀ = 1.46 μM at cellular level).

The present inventors analyzed the effect of selected PTK inhibitors, 20 and 21, on cell proliferation using human foreskin fibroblast (Fig. 1). Compound 21 decreased fibroblast proliferation only at concentrations of 100 μM or higher. Compound 20 affected cell proliferation in a dose-dependent manner at < RTI ID = 0.0 > 10 < / RTI > However, IC ₅₀ of the compound 20 (1.60 μM) and 21 (1.46 μM) for PTK6 inhibition at the cellular level is much lower than the concentration that shows a decrease in cell proliferation. Therefore, cytotoxicity seems not to be a concern in using these compounds as PTK inhibitors.

We further analyzed whether compounds 20 and 21 could inhibit PTK6 substrate phosphorylation in HEK293 cells expressing PTK6 (Figure 2). As expected, expression of PTK6 increased the phosphorylation of STAT3 and paclcillin tyrosine phosphorylation, known as PTK6 specific substrates, as well as increased tyrosine phosphorylation of cellular proteins. Both PTK inhibitors decreased the tyrosine-phosphorylation levels of cellular proteins, STAT3 and paxiline in a dose-dependent manner.

In order to analyze the PTK selectivity of compounds 20 and 21, the inhibitory effect of compounds on intracellular tyrosine kinases PTK6, Src, Fyn, Bmx and EGF receptor belonging to receptor tyrosine kinases was analyzed (Table 5). Compounds 20 and 21 were found to be inferior to PTKs except for Src (Fyn, Bmx and EGF receptor), but the inhibition against PTK6 was the most excellent.

In summary, we screened leading compounds that inhibit PTK6 catalytic activity by ELISA. Through analysis of the derivatives of compound 1 and SAR analysis, compounds 20 and 21 were selected as PTK inhibitors. These compounds showed improved PTK6 inhibitory activity and low cytotoxicity at both in vitro and cellular levels. Thus, compounds 20 and 21 may be valuable therapeutic tools for the treatment of PTK6-positive malignancies such as breast cancer.

When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like.

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, .

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited thereto.

Synthesis of Compound Represented by Formula (1)

[Synthesis of compound 1 ]

Benzo [d] imidazol-2 (3H) -one (Compound 1 ) was added to a solution of (5-

5-bromo-2-hydroxybenzaldehyde (0.1g, 0.50mmol), 5- amino-2-benzimidazolyl stirred at room temperature for BBIT (0.05g, 0.33mmol) and isopropyl alcohol (2mL) under N ₂ Respectively. Acetic acid (0.7 mL) was then added dropwise and the mixture was refluxed overnight. The mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and dried to give compound 1 (0.09 g, 0.28 mmol, 84.8%) as a thick yellow powder.

^{1 H NMR (DMSO, 300MHz)} δ 13.84 (s, 1H), 11.27 (s, 1H), 11.21 (s, 1H), 9.36 (s, 1H), 8.27 (s, 1H), 7.93 (d, 1H, J = 8.7 Hz), 7.39 (d, 1H, J = 8.7 Hz), 7.51-7.32 (m, 3H); ¹³ C NMR (DMSO, 500 MHz)? 159.95, 156.27, 141.50, 135.56, 134.57, 131.30, 130.21, 122.02, 119.62, 116.17, 110.44, 109.51, 101.55, 31.39. R _f = 0.39 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 2 ]

(E) -5- (benzylideneamino) -1H-benzo [d] imidazol-2 (3H)

(1.4 g, 9.42 mmol) and isoamyl alcohol (60 mL) were stirred at room temperature under N ₂ . Acetic acid (2.1 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with EA, CH ₂ Cl ₂ , MeOH and dried to give compound 2 (4.67 g, 19.66 mmol, 47.9%) as a light brown powder.

^{1 H NMR (DMSO, 300MHz)} δ 10.72 (s, 1H), 10.68 (s, 1H), 8.64 (s, 1H), 7.99-7.84 (m, 2H), 7.58-7.45 (m, 3H), 6.98- 6.85 (m, 3 H); ¹³ C NMR (DMSO, 500 MHz) δ 158.67, 156.27, 145.32, 137.05, 131.66, 131.10, 129.43, 129.23, 129.07, 115.39, 109.34, 101.80. R _f = 0.50 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 3 ]

Benzo [d] imidazol-2 (3H) -one ( 3 ) ( 5 )

2-Benzimidazolinone (0.42 g, 3.41 mmol) and isopropyl alcohol (10 mL) were stirred at room temperature under N ₂ . Acetic acid (0.63 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 3 as a yellow powder (1.44 g, 5.69 mmol, 59.9%).

^{1 H NMR (DMSO, 300MHz)} δ 13.39 (bs, 1H), 10.80 (bs, 2H), 8.95 (s, 1H), 7.63 (d, 1H, J = 7.5Hz), 7.42-7.34 (m, 1H) , 7.06 (d, 1H, J = 1.8 Hz), 7.04 (d, 1H, J = 1.8 Hz), 6.99 (s, 1H), 6.76-6.19 (m, 2H); ¹³ C NMR (DMSO, 500 MHz) δ 161.56, 160.85, 156.29, 141.89, 133.36, 133.01, 131.28, 129.89, 120.15, 119.69, 117.16, 115.77, 109.51, 101.69. R _f = 0.45 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 4 ]

Benzo [d] imidazol-2 (3H) -one ( 4 ) To a solution of (5-bromo-

Amino-2-benzimidazolidinone (0.06 g, 0.39 mmol) and isopropyl alcohol (2 mL) were stirred at room temperature under N ₂ , Respectively. Acetic acid (0.07 mL) was then added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 4 as a light brown powder (0.12 g, 0.35 mmol, 90.3%).

^{1 H NMR (DMSO, 300MHz)} δ 10.69 (s, 2H), 8.79 (s, 1H), 8.07 (s, 1H), 7.65 (d, 1H, J = 7.8Hz), 7.15 (d, 1H, J = 7.8 Hz), 6.93 (s, 1H), 6.99-6.83 (m, 2H), 3.90 (s, 3H); ¹³ C NMR (DMSO, 500 MHz) δ 158.86, 156.24, 151.83, 145.29, 135.39, 131.17, 129.55, 129.27, 126.92, 115.51, 115.35, 113.21, 109.42, 101.79, 56.92. R _f = 0.44 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 5 ]

Benzo [d] imidazol-2 (3H) -one ( 5 ) was obtained as colorless crystals from (E) -5- (5-bromo-2-

Amino-2-benzimidazolidinone (0.04 g, 0.28 mmol) and isoamyl alcohol (2 mL) were dissolved in N (5 mL) ₂ < / RTI > at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 5 (0.05 g, 0.15 mmol, 53.6%) as a light orange powder.

¹ H NMR (DMSO, 300 MHz) [delta] 13.64 (s, IH), 10.84 (s, IH), 10.78 , 7.05 (s, 1 H), 7.07 - 6.95 (m, 2 H), 3.83 (s, 3 H); ¹³ C NMR (DMSO, 500 MHz)? 160.18, 156.27, 150.67, 149.81, 141.21, 131.28, 130.18, 125.81, 121.10, 118.02, 115.95, 109.78, 109.59, 101.69, 56.95. R _f = 0.34 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 6 ]

Benzo [d] imidazol-2 (3H) -one ( 6 ) ( 5 )

5-bromo-2,3-dimethoxy-benzaldehyde (0.1g, 0.41mmol), 5- amino-2-benzimidazolyl BBIT (0.04g, 0.27mmol) and isoamyl alcohol (2mL) N ₂ At room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 6 as a dark yellow powder (0.06 g, 0.16 mmol, 59.3%).

^{1 H NMR (DMSO, 300MHz)} δ 10.70 (s, 2H), 8.73 (s, 1H), 7.70 (s, 1H), 7.36 (s, 1H), 6.96 (s, 1H), 7.18-6.83 (m, 2H), 3.88 (s, 3H), 3.84 (s, 3H); ¹³ C NMR (DMSO, 500 MHz) δ 156.23, 154.55, 152.02, 149.38, 145.03, 131.59, 131.16, 129.69, 120.85, 118.55, 116.95, 115.60, 109.39, 101.88, 62.21, 57.10. R _f = 0.44 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 7 ]

Benzo [d] imidazol-2 (3H) -one ( 7 ) ( 5 )

The 5-chloro-2-hydroxybenzaldehyde (0.1g, 0.64mmol), 5- amino-2-benzimidazolyl BBIT (0.06g, 0.42mmol) and isoamyl alcohol (2mL) N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 7 (0.11 g, 0.38 mmol, 89.6%) as a thick yellow powder.

^{1 H NMR (DMSO, 300MHz)} δ 13.39 (s, 1H), 10.84 (s, 1H), 10.78 (s, 1H), 8.93 (s, 1H), 7.72 (s, 1H), 7.48-7.36 (m, 1H), < / RTI > 7.17-6.94 (m, 4H); ¹³ C NMR (DMSO, 500 MHz)? 159.85, 159.32 156.05, 141.29, 132.59, 131.40, 131.07, 129.99, 122.85, 121.17, 118.96, 115.96, 109.31, 101.34. R _f = 0.56 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 8]

(E) -5 - ((2- hydroxy-3-methoxy-benzylidene) amino) -1H- benzo [d] imidazol -2 (3H) - one (8)

The 2-chloro-3-methoxybenzaldehyde (0.1g, 0.64mmol), 5- amino-2-benzimidazolyl BBIT (0.06g, 0.42mmol) and isoamyl alcohol (2mL) N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 8 (0.09 g, 0.32 mmol, 74.4%) as a pale orange powder.

^{1 H NMR (DMSO, 300MHz,} ) δ 13.56 (bs, 1H), 10.80 (bs, 2H), 8.95 (s, 1H), 7.21 (d, 1H, J = 7.5Hz), 7.12-6.84 (m, 5H ), 3.81 (s, 3H); ¹³ C NMR (DMSO, 500 MHz) δ 161.69, 156.27, 151.15, 148.57, 141.68, 131.30, 129.92, 124.49, 120.06, 119.12, 115.91, 115.71, 109.50, 101.67, 56.59. R _f = 0.41 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 9 ]

Benzo [d] imidazol-2 (3H) -one ( 9 ) (5-chloro-2-

Of 5-chloro-2-hydroxy-3-methoxy benzaldehyde (0.1g, 0.54mmol), 5- amino-2-benzimidazolyl BBIT (0.05g, 0.35 mmol) and isoamyl alcohol (2mL) N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 9 as an orange powder

 (0.10 g, 0.31 mmol, 88.9%).

¹ H NMR (DMSO, 300 MHz) 隆 13.64 (s, IH), 10.87 (s, IH), 10.81 (s, IH), 8.94 ), 7.08-6. 94 (m, 3H), 3.83 (s, 3H); ¹³ C NMR (DMSO, 500 MHz) δ 169.57, 160.33, 156.26, 150.25, 149.68, 141.25, 131.32, 130.21, 122.74, 120.44, 116.00, 115.44, 109.52, 101.57, 54.97. R _f = 0.28 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 10 ]

( 10 ) -benzo [d] imidazol-2 (3H) -one ( 10 )

2-hydroxy-5-urethra-3-methoxy-benzaldehyde (0.1g, 0.36mmol), the 5-amino-2-benzimidazolyl BBIT (0.06g, 0.43 mmol) and isoamyl alcohol (2mL) N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 10 (0.12 g, 0.29 mmol, 66.4%) as a pale orange powder.

¹ H NMR (DMSO, 300 MHz) [delta] 13.67 (s, IH), 10.85 (s, IH), 10.78 , 7.14 - 6.95 (m, 3 H), 3.82 (s, 3 H); ¹³ C NMR (DMSO, 500 MHz)? 160.18, 156.27, 151.21, 149.71, 141.18, 132.17, 131.28, 130.16, 123.22, 121.91, 116.08, 109.53, 101.53, 80.25, 56.84. R _f = 0.38 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 11 ]

Benzo [d] imidazol-2 (3H) -one ( 11 ) (5-bromo-3-ethoxy-2-hydroxybenzylidene)

(0.29 g, 1.17 mmol), 5-amino-2-benzimidazolidinone (0.09 g, 0.59 mmol) and isoamyl alcohol (5.8 mL) were added to a solution of 5-bromo-3-ethoxy- N ₂ Followed by stirring at room temperature. Acetic acid (0.2 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 11 as a dark orange powder (0.21 g, 0.56 mmol, 94.9%).

^{1 H NMR (DMSO, 300MHz)} δ 13.74 (s, 1H), 10.87 (s, 1H), 10.81 (s, 1H), 8.93 (s, 1H), 7.42 (d, 1H, J = 1.8Hz), 7.20 (d, 1H, J = 1.8Hz ), 7.07 (s, 1H), 7.08-6.95 (m, 2H), 4.08 (q, 2H, J = 6.9Hz), 1.34 (t, 3H, J = 6.9Hz) ; ¹³ C NMR (DMSO, 500 MHz)? 160.29, 156.27, 150.91, 148.98, 141.13, 131.32, 130.24, 125.98, 121.17, 119.10, 116.00, 109.71, 109.53, 101.57, 65.20, 15.31. R _f = 0.60 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 12 ]

(E) -5 - ((3-ethoxy-2-hydroxy-benzylidene) amino) -1H- benzo [d] imidazol -2 (3H) - one (12)

Ethoxy-2-hydroxybenzaldehyde (0.1g, 0.60 mmol), 5- amino-2-benzimidazolyl BBIT (0.06g, 0.39 mmol) and isoamyl alcohol (2mL) in ₂ N 3- Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 12 as an orange powder (0.10 g, 0.35 mmol, 89.7%).

^{1 H NMR (DMSO, 300MHz)} δ 13.60 (bs, 1H), 10.80 (bs, 2H), 8.94 (s, 1H), 7.20 (d, 1H, J = 7.2Hz), 7.12-6.82 (m, 5H) , 4.06 (q, 2H, J = 6.9 Hz), 1.34 (t, 3H, J = 6.9 Hz); ¹³ C NMR (DMSO, 500 MHz) δ 161.72, 156.27, 151.45, 147.67, 141.63, 131.29, 129.92, 124.67, 120.16, 119.12, 117.31, 115.68, 109.52, 101.69, 64.81, 15.50. R _f = 0.41 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 13 ]

Benzo [d] imidazol-2 (3H) -one ( 13 ) ( 5 )

Of 5-chloro-3-ethoxy-2-hydroxybenzaldehyde (0.15g, 0.75 mmol), 5- amino-2-benzimidazolyl BBIT (0.08g, 0.56 mmol) and isoamyl alcohol (3mL) in N ₂ Followed by stirring at room temperature. Acetic acid (0.11 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 13 (0.15 g, 0.46 mmol, 82.1%) as an orange powder.

^{1 H NMR (DMSO, 300MHz)} δ 13.70 (s, 1H), 10.87 (s, 1H), 10.81 (s, 1H), 6.93 (s, 1H), 7.29 (d, 1H, J = 1.8Hz), 7.11 (d, 1H, J = 1.8Hz ), 7.06 (s, 1H), 7.08-6.96 (m, 2H), 4.08 (q, 2H, J = 7.0Hz), 1.35 (t, 3H, J = 7.0Hz) ; ¹³ C NMR (DMSO, 500 MHz)? 160.39, 156.26, 150.47, 148.82, 141.16, 131.32, 130.23, 122.88, 122.47, 120.48, 116.49, 115.98, 109.53, 101.58, 65.17, 15.29. R _f = 0.55 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 14 ]

Benzo [d] imidazol-2 (3H) -one ( 14 ) ( 5 )

3,5-dibromo-2-hydroxybenzaldehyde (0.1g, 0.36 mmol), 5- amino-2-benzimidazolyl BBIT (0.03g, 0.23 mmol) and isoamyl alcohol ₍₂ mL) N 2 Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 14 (0.08 g, 0.20 mmol, 88.9%) as a pale brown powder.

^{1 H NMR (DMSO, 300MHz)} δ 14.96 (bs, 1H), 10.91 (s, 1H), 10.83 (s, 1H), 8.99 (s, 1H), 7.88 (d, 1H, J = 2.3Hz), 7.85 (d, 1H, J = 2.3 Hz), 7.13 (s, 1H), 7.12 (d, 1H, J = 8.3 Hz), 7.04 (d, 1H, J = 8.3 Hz); ¹³ C NMR (DMSO, 700 MHz)? 159.50, 157.85, 156.05, 139.40, 137.32, 134.38, 131.13, 130.46, 121.52, 116.20, 111.93, 109.57, 109.37, 101.31. R _f = 0.50 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 15 ]

Benzo [d] imidazol-2 (3H) -one ( 15 ) ( 5 )

Of 2,4-dihydroxy-benzaldehyde (0.1g, 0.72 mmol), 5- amino-2-benzimidazolyl BBIT (0.07g, 0.47 mmol) and isoamyl alcohol (3 mL) N ₂ Followed by stirring at room temperature. Acetic acid (0.11 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 15 (0.12 g, 0.44 mmol, 94.4%) as a yellow powder.

^{1 H NMR (DMSO, 300MHz)} δ 13.76 (s, 1H), 10.75 (s, 1H), 10.69 (s, 1H), 10.19 (bs, 1H), 8.77 (s, 1H), 7.40 (d, 1H, J = 8.4 Hz), 7.21-6.88 (m, 3H), 6.37 (dd, 1H, J = 8.6 Hz, 2.0 Hz), 6.27 (s, 1H); ¹³ C NMR (DMSO, 500 MHz) δ 163.52, 162.66, 161.02, 156.28, 142.16, 134.76, 131.25, 129.21, 115.12, 112.89, 109.51, 108.33, 103.07, 101.47. R _f = 0.31 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 16 ]

Benzo [d] imidazol-2 (3H) -one ( 16 ) was obtained as colorless crystals from (E) -5-

2-hydroxy-4-methoxybenzaldehyde (0.1g, 0.66 mmol), 5- amino-2-benzimidazolyl BBIT (0.64g, 0.43 mmol) and isoamyl alcohol (2 mL) with N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 16 (0.12 g, 0.42 mmol, 98.0%) as a yellow powder.

^{1 H NMR (DMSO, 300MHz)} δ 13.88 (s, 1H), 10.77 (s, 1H), 10.70 (s, 1H), 8.85 (s, 1H), 7.52 (d, 1H, J = 8.4Hz), 7.02 -6.97 (m, 2H), 6.95 (d, 1H, J = 8.4Hz), 6.54 (d, 1H, J = 1.8Hz), 6.47 (d, 1H, J = 1.8Hz), 3.80 (s, 3H) ; ¹³ C NMR (DMSO, 700 MHz)? 163.67, 163.39, 160.72, 156.06, 141.58, 134.26, 131.04, 129.19, 115.15, 113.61, 109.28, 107.02, 101.28, 101.20, 55.90. R _f = 0.50 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 17 ]

Benzo [d] imidazol-2 (3H) -one ( 17 ) (2-bromo-6-hydroxybenzylidene)

2-bromo-6-hydroxybenzaldehyde (0.26g, 1.04 mmol), 5- amino-2-benzimidazolyl BBIT (0.08g, 0.52 mmol) and isoamyl alcohol (5.1 mL) with N ₂ Followed by stirring at room temperature. Acetic acid (0.18 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 17 (0.15 g, 0.45 mmol, 85.3%) as a yellow powder.

^{1 H NMR (DMSO, 300MHz)} δ 14.59 (s, 1H), 10.83 (bs, 2H), 9.07 (s, 1H), 7.14-7.22 (m, 2H), 7.10-7.07 (m, 2H), 7.12- 6.96 (m, 2H); ¹³ C NMR (DMSO, 500 MHz) δ 163.01, 160.03, 156.19, 140.84, 134.63, 131.41, 130.53, 126.16, 124.10, 117.80, 117.48, 116.00, 109.68, 101.67. R _f = 0.53 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 18 ]

( 18 ) -benzo [d] imidazol-2 (3H) -one ( 18 )

(0.02 g, 0.27 mmol), 5-amino-2-benzimidazolidinone (0.02 g, 0.14 mmol) and isoamyl alcohol (1.2 mL) were added to a solution of 6-bromo-2-hydroxy-3-methoxybenzaldehyde N ₂ Followed by stirring at room temperature. Acetic acid (0.04 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 18 (0.02 g, 0.06 mmol, 42.9%) as an orange powder.

¹ H NMR (DMSO, 300 MHz) δ 14.95 (s, 1H), 10.82 (s, 1H), 10.78 (s, 1H), 9.01 (s, 1H), 7.14-6.98 (m, 3.80 (s, 3 H); ¹³ C NMR (DMSO, 700 MHz)? 160.17, 155.98, 153.99, 148.73, 140.13, 131.16, 130.26, 122.47, 116.40, 116.27, 115.65, 115.44, 109.52, 101.41, 56.41. R _f = 0.36 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 19 ]

(E) -5 - ((2,3,5- tribromo-6-hydroxy-benzylidene) amino) -1H- benzo [d] imidazol -2 (3H) - one (19)

6-hydroxybenzaldehyde (0.17 g, 0.48 mmol), 5-amino-2-benzimidazolidinone (0.04 g, 0.24 mmol) and isoamyl alcohol (3.4 mL) N ₂ Followed by stirring at room temperature. Acetic acid (0.13 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 19 (0.07 g, 0.14 mmol, 58.3%) as a red powder.

¹ H NMR (DMSO, 300 MHz) [delta] 16.59 (s, IH), 10.91 (s, IH), 10.90 (s, IH), 9.09 , 7.22-7.00 (m, 2H); ¹³ C NMR (DMSO, 500 MHz) δ 161.71, 160.19, 156.17, 139.14, 137.55, 131.45, 131.11, 127.71, 118.88, 116.26, 113.29, 113.13, 109.75, 101.61. R _f = 0.50 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 20 ]

Benzo [d] imidazol-2 (3H) -one ( 20 ) To a solution of (E) -5-

5-methoxybenzaldehyde (1.39 g, 4.48 mmol), 5-amino-2-benzimidazolidinone (0.67 g, 4.48 mmol) and isoamyl alcohol (30 mL) was dissolved in N ₂ Followed by stirring at room temperature. Acetic acid (1 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 20 (1.88 g, 4.26 mmol, 95.2%) as a dark orange powder.

¹ H NMR (DMSO, 300 MHz) [delta] 15.49 (s, IH), 10.83 (s, IH), 10.80 (s, IH), 9.09 , 7.18-6.98 (m, 2 H), 3.84 (s, 3 H); ¹³ C NMR (DMSO, 500 MHz) δ 161.20, 156.17, 154.65, 149.60, 139.41, 131.45, 130.71, 119.00, 117.88, 117.56, 115.92, 113.08, 109.71, 101.56, R _f = 0.52 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 21 ]

( 21 ) -benzo [d] imidazol-2 (3H) -one ( 21 )

Hydroxybenzaldehyde (0.1 g, 0.31 mmol), 5-amino-2-benzimidazolidinone (0.03 g, 0.20 mmol) and isoamyl alcohol (3 mL) was dissolved in N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 21 (0.08 g, 0.18 mmol, 90.0%) as an orange powder.

¹ H NMR (DMSO, 300 MHz) [delta] 15.51 (s, IH), 10.83 (s, IH), 10.81 (s, IH), 9.09 , 7.15-6.92 (m, 2H), 4.08 (q, 2H, J = 6.6Hz), 1.34 (t, 3H, J = 6.6Hz); ¹³ C NMR (DMSO, 700 MHz)? 159.87, 154.87, 153.39, 147.46, 138.11, 130.13, 129.39, 118.57, 116.65, 116.25, 114.66, 111.80, 108.42, 100.25, 63.91, R _f = 0.70 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 22 ]

Benzo [d] imidazol-2 (3H) -one ( 22 ) was obtained as colorless crystals from (E) -5 - ((2,3-

6-hydroxybenzaldehyde (0.30 g, 1.26 mmol), 5-amino-2-benzimidazolidinone (0.09 g, 0.63 mmol) and isoamyl alcohol (5.9 mL) To N ₂ Followed by stirring at room temperature. Acetic acid (0.2 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 22 (0.20 g, 0.55 mmol, 87.5%) as an orange powder

^{1 H NMR (DMSO, 300MHz)} δ 15.38 (s, 1H), 10.82 (s, 1H), 10.80 (s, 1H), 9.11 (s, 1H), 7.27 (s, 1H), 7.15-7.10 (m, 2H), 7.01 (d, 1H, J = 8.7 Hz), 4.09 (q, 2H, J = 6.6 Hz), 1.35 (t, 3H, J = 6.6 Hz); ¹³ C NMR (DMSO, 500 MHz) δ 157.74, 156.19, 154.45, 148.07, 139.54, 131.42, 130.72, 123.50, 120.73, 117.10, 116.24, 115.96, 109.67, 101.73, 65.30, 15.20. R _f = 0.50 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 23 ]

Benzo [d] imidazol-2 (3H) -one ( 23 ) was obtained as colorless crystals from 5-

Benzo [d] imidazol-2 (3H) -one ( 20 ) ((E) -5- ((2,3- dibromo-5-ethoxy-6-hydroxybenzylidene) amino) 0.07g, 0.16mmol) was dissolved in EtOH (1.5mL), then stirred under N ₂ the reaction mixture from 0 ℃. Sodium borohydride (0.009 g, 0.23 mmol) was added dropwise at 0 占 and the reaction mixture was stirred at room temperature for 20 minutes. The resulting mixture was evaporated and the residue was extracted with EtOAc. The organic layer was washed with H ₂ O and NaHCO ₃ , dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (CH ₂ Cl ₂ / MeOH) to give compound 23 as a pale brown powder (0.014 g, 0.03 mmol, 18.8%).

^{1 H NMR (DMSO, 300MHz)} δ 10.25 (s, 1H), 10.09 (s, 1H), 9.73 (bs, 1H), 7.29 (s, 1H), 6.65 (d, 1H, J = 8.4Hz), 6.35 (s, IH), 6.32 (dd, IH, J = 8.1 Hz, 1.8 Hz), 5.16 (bs, IH), 4.29 (s, 2H), 3.83 (s, 3H); ¹³ C NMR (DMSO, 700 MHz) δ 155.97, 148.14, 145.94, 144.14, 131.07, 127.40, 121.59, 118.07, 115.69, 113.35, 109.20, 105.84, 94.78, 56.83, 45.25. R _f = 0.39 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 24 ]

Benzo [d] imidazol-2 (3H) -one ( 24 ) was prepared in accordance with the general method of example 1 from 5 - ((2,3- dibromo-5-ethoxy-

Benzo [d] imidazol-2 (3H) -one ( 20 ) ((E) -5- ((2,3- dibromo-5-ethoxy-6-hydroxybenzylidene) amino) 0.05g, 0.11mmol) was dissolved in EtOH (1.3mL), then stirred under N ₂ the reaction mixture from 0 ℃. Sodium borohydride (0.006 g, 0.17 mmol) was added dropwise at 0 < 0 > C and the reaction mixture was stirred at room temperature for 20 minutes. The resulting mixture was evaporated and the residue was extracted with EtOAc. The organic layer was washed with H ₂ O and NaHCO ₃ , dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (CH ₂ Cl ₂ / MeOH) to give compound 24 as a pale orange powder (0.023 g, 0.05 mmol, 45.5%).

^{1 H NMR (DMSO, 300MHz)} δ 10.24 (s, 1H), 10.08 (s, 1H), 9.47 (bs, 1H), 7.15 (s, 1H), 6.64 (d, 1H, J = 8.4Hz), 6.35 (s, 1H), 6.32 (dd, 1H, J = 8.1 Hz, 1.8 Hz), 5.22 (bs, 1H), 4.25 (s, 2H), 4.08 (q, 2H, J = 4.8 Hz), 1.33 , 3H, J = 4.8 Hz); ¹³ C NMR (DMSO, 500 MHz) δ 156.19, 146.82, 146.13, 144.28, 131.33, 125.79, 124.09, 121.94, 121.55, 113.83, 109.40, 106.12, 95.12, 65.43, 42.45, 15.12. R _f = 0.42 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 25 ]

(E) -2 - ((( 1 H - indol-5-yl) imino) methyl) -3,4-dibromo-6-methoxy-phenol 25

5-methoxybenzaldehyde (0.1 g, 0.32 mmol), 5-aminoindole (0.03 g, 0.21 mmol) and isoamyl alcohol (2 mL) were dissolved in N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 25 (0.05 g, 0.11 mmol, 50.0%) as an orange powder.

^{1 H NMR (DMSO, 300MHz)} δ 10.25 (s, 1H), 10.09 (s, 1H), 9.73 (bs, 1H), 7.29 (s, 1H), 6.65 (d, 1H, J = 8.4Hz), 6.35 (s, IH), 6.32 (dd, IH, J = 8.1 Hz, 1.8 Hz), 5.16 (bs, IH), 4.29 (s, 2H), 3.83 (s, 3H); ¹³ C NMR (DMSO, 700 MHz) δ 155.97, 148.14, 145.94, 144.14, 131.07, 127.40, 121.59, 118.07, 115.69, 113.35, 109.20, 105.84, 94.78, 56.83, 45.25. R _f = 0.39 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of Compound 26 ]

Yl) imino) methyl) -3,4-dibromo-6-methoxyphenol ( 26 )

Of 2,3-dibromo-6-hydroxy-5-methoxybenzaldehyde (0.1g, 0.32 mmol), 5- amino-benzimidazole (0.03g, 0.21 mmol) and isoamyl alcohol ₍₂ mL) N 2 Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 26 (0.06 g, 0.14 mmol, 65.4%) as an orange powder.

^{1 H NMR (DMSO, 300MHz)} δ 15.54 (s, 1H), 9.20 (s, 1H), 8.34 (s, 1H), 7.76-7.68 (m, 2H), 7.43 (s, 1H), 7.38 (s, 1H), 3.86 (s, 3H); ¹³ C NMR (DMSO, 700 MHz) δ 162.30, 154.74, 149.45, 144.27, 140.84, 120.42, 118.82, 118.46, 117.60, 117.43, 117.10, 113.95, 112.87, 56.78. R _f = 0.48 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 27 ]

(E) -2 - ((benzo [d] thiazol-5-yl-butylimino) methyl) -3,4-dibromo-6-methoxy-phenol 27

5-methoxybenzaldehyde (0.1 g, 0.32 mmol), 5-benzothiazolamine (0.03 g, 0.21 mmol) and isoamyl alcohol (2 mL) were dissolved in N ₂ Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 27 (0.08 g, 0.18 mmol, 87.5%) as an orange powder.

^{1 H NMR (DMSO, 300MHz)} δ 15.12 (s, 1H), 9.49 (s, 1H), 9.25 (s, 1H), 8.29 (d, 1H, J = 8.4Hz), 8.22 (d, 1H, J = 1.8 Hz), 7.65 (dd, 1H, J = 8.4 Hz, 1.8 Hz), 7.42 (s, 1H), 3.86 (s, 3H); ¹³ C NMR (DMSO, 700 MHz) δ 164.89, 158.70, 154.49, 154.33, 149.34, 145.16, 133.37, 124.00, 121.49, 120.28, 119.30, 117.71, 115.64, 113.35, 57.07. _{R f = 0.59 (Hexane / EtOAc} 2: 1)

[Synthesis of compound 28 ]

Yl) imino) methyl) -3,4-dibromo-6-ethoxyphenol ( 28 )

2,3-di-bromo-5-ethoxy-6-hydroxybenzaldehyde (0.1g, 0.31 mmol), 5-aminoindole (0.03g, 0.20 mmol) and isoamyl alcohol ₍₂ mL) N 2 Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction was denoted H2O and the aqueous layer was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO _4, and concentrated under vacuum. The residue was purified by column chromatography (hexane / EtOAc) to give compound 28 as a yellow powder (0.06 g, 0.13 mmol, 65.2%).

_{^{1 H NMR (CDCl 3, 300MHz}} ) δ 15.96 (s, 1H), 11.34 (s, 1H), 9.18 (s, 1H), 7.71 (s, 1H), 7.51 (dd, 1H, J = 8.7Hz, 1.8 Hz), 7.46-7.42 (m, 1H ), 7.32 (s, 1H), 7.28 (dd, 1H, J = 8.7Hz, 1.8Hz), 6.53 (s, 1H), 4.08 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz); ¹³ C NMR (CDCl _3, 700 MHz)? 160.15, 155.38, 148.76, 137.43, 136.15, 128.71, 127.73, 119.41, 117.64, 117.19, 115.37, 113.31, 112.99, 112.43, 102.53, 64.96, 14.56. _{R f = 0.26 (Hexane / EtOAc} 3: 1)

[Synthesis of compound 29 ]

Yl) imino) methyl) -3,4-dibromo-6-ethoxyphenol ( 29 )

A 2,3-di-bromo-5-ethoxy-6 in the parent-hydroxybenzaldehyde (0.1g, 0.31 mmol), 5- amino-benzimidazole (0.03g, 0.20 mmol) and isoamyl alcohol ₍₂ mL) N 2 Followed by stirring at room temperature. Acetic acid (0.07 L) was added dropwise and the mixture was refluxed overnight. The reaction mixture was filtered, washed with CH ₂ Cl ₂ , MeOH and then dried to give compound 29 (0.06 g, 0.13 mmol, 65.4%) as an orange powder.

^{1 H NMR (DMSO, 300MHz)} δ 15.57 (s, 1H), 12.50 (bs, 1H), 9.20 (s, 1H), 8.31 (s, 1H), 7.81-7.68 (m, 2H), 7.38 (s, 1H), 7.35 (s, 1H), 4.10 (q, 2H, J = 6.9 Hz), 1.36 (t, 3H, J = 6.9 Hz); ¹³ C NMR (DMSO, 700 MHz) δ 162.36, 154.82, 148.63, 144.23, 140.92, 120.40, 119.77, 117.69, 117.42, 117.30, 116.15, 113.00, 111.88, 104.91, 65.01, 15.00. R _f = 0.48 (CH ₂ Cl ₂ / MeOH 9: 1)

[Synthesis of compound 30 ]

(E) -2 - ((benzo [d] thiazol-5-ylimino) methyl) -3,4-dibromo-6-ethoxyphenol ( 30 )

A 2,3-di-bromo-5-ethoxy-6 in the parent-hydroxybenzaldehyde (0.1g, 0.31 mmol), 5- benzothiazolyl asleep Min (0.03g, 0.20 mmol) and isoamyl alcohol ₍₂ mL) N 2 Followed by stirring at room temperature. Acetic acid (0.07 mL) was added dropwise and the mixture was refluxed overnight. The reaction was denoted H2O and the aqueous layer was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO _4, and concentrated under vacuum. The residue was purified by column chromatography (hexane / EtOAc) to give compound 30 as a yellow powder (0.08 g, 0.18 mmol, 91.3%).

¹ H NMR (CDCl _3, 300MHz,) δ 15.41 (s, 1H), 9.31 (d, 1H, J = 1.5Hz), 9.08 (s, 1H), 8.10 (d, 1H, J = 2.1Hz), 8.02 (d, 1H, J = 2H, J = 6.9 Hz), 1.52 (t, 3H, J = 6.9 Hz); 7.47 (dd, 1H, J = 8.4 Hz, 2.1 Hz), 7.16 (s, ¹³ C NMR (CDCl ₃ , 700 MHz) δ 164.05, 155.84, 154.84, 154.32, 148.42, 145.18, 132.95, 122.79, 120.06, 119.57, 117.74, 117.54, 115.19, 113.32, 64.99, 14.64. _{R f = 0.50 (Hexane / EtOAc} 2: 1)

PTK  Inhibitors inhibit cell viability ( cell viability )

The effect of PTK inhibitor on cell viability was analyzed using human foreskin fibroblasts (Fig. 1). The cells were incubated for 24 hours with various concentrations of compounds 20 and 21 in complete medium containing 5% fetal bovine serum (FBS). The medium was removed and fresh medium containing 0.5 mg / ml MTT was added. After incubation for 4 hours, the medium was removed, the dye was dissolved in DMSO and the absorbance was measured at a wavelength of 565 nm. The relative survival rate of the control (DMSO treatment) was 100%. All data were performed in duplicate and expressed as mean ± standard deviation of three independent experiments (* p <0.05; *** p <0.001 vs. no compound). Compound 20 showed cytotoxicity when treated in a concentration dependent manner, but the toxic concentration was higher than that in the cells. Compound 21 was analyzed to show no cytotoxicity even after treatment up to 100 uM.

PTK  At the cellular level by inhibitor PTK6 Of substrate phosphorylation inhibition

Compound 20 and compound 21 were assayed for inhibition of substrate phosphorylation by PTK6 at the cellular level. HEK293 cells expressing PTK6 were incubated with compound 20 or compound 21 at a specific concentration. The cell lysate was Western blotted with anti-phosphotyrosine antibody to analyze the degree of tyrosine phosphorylation of the whole cell protein, Western blotting with anti-phospho STAT3 antibody to analyze the phosphorylation of STAT3, known as substrate of PTK6, -Phacillin antibody followed by Western blotting with anti-phosphotyrosine antibody to analyze the phosphorylation of paxilin, which is known as the substrate of PTK6 (Fig. 2). The expression of PTK6 in HEK293 cells increased the phosphorylation of cellular proteins and increased the phosphorylation of PTK6 substrate proteins STAT3 and paxillin. Treatment of compound 20 and compound 21 showed that the degree of phosphorylation of these substrates decreased. Thus, it was found that Compound 20 and Compound 21 according to the present invention inhibited PTK6 activity at the cell level and inhibited substrate phosphorylation of PTK6.

PTK  Inhibitor PTK  Selectivity analysis

For the analysis of selective PTK PTK inhibitors, by measuring the degree PTK inhibitor to inhibit the phosphorylation of cell proteins by several PTK determined the IC ₅₀ (μM). In this assay, PTK6, Src, Fyn, Bmx belonging to the intracellular tyrosine kinase and the EGF receptor belonging to the receptor tyrosine kinase were used. After expressing these PTKs in HEK293 cells, Compound 20 or Compound 21 was incubated at a specific concentration. Phosphorylation of cellular proteins by each PTK was analyzed by Western blotting method using anti-phosphotyrosine antibody (Table 5). When PTKs were expressed in HEK293 cells, phosphorylation of substrate protein was increased. Compound 20, this time the IC ₅₀ values for inhibition of substrate phosphorylation by PTK6 was 1.46 μM, Fyn, respectively the IC ₅₀ value for the EGF receptor Bmx and 38.67 μM, 38.57 μM and 88.67 μM. And when the IC ₅₀ values for the compound 21 inhibits substrate phosphorylation by PTK6 was 1.60 μM, IC ₅₀ values for Fyn, Bmx and EGF receptor were respectively 68.54 μM, 42.29 μM and 76.70 μM. Genistein, known to inhibit several PTKs, had IC ₅₀ values of 43.46 μM, 58.18 μM, 67.99 μM and 25.12 μM for PTK6, Fyn, Bmx and EGF receptors, respectively. Compound 20 , compound 21 and genistein did not inhibit Src up to 100 μM. These results indicate that compounds 20 and 21 inhibit PTK6 most effectively, but inhibit other PTKs.

[Table 5]

PTK Selectivity Analysis of PTK Inhibitors by IC ₅₀ (μM) Crystallization of PTK-Dependent Cell Protein Phosphorylation by PTK Inhibitors at the Cellular Level

The degree of cellular protein phosphorylation in the absence of PTK inhibitor was determined as 100% in HEK293 cells expressing PTK6, Src, Fyn, Bmx, or EGFR. When Compound 20 or 21 was treated, the degree of relative cellular protein phosphorylation was measured to determine the IC ₅₀ ([mu] M) value. Genistein, known to inhibit several PTKs, was used as a control.

Claims (19)

A compound represented by the following formula (1):
[Chemical Formula 1]

R &lt; ₁ &gt; is H or a hydroxy group;
R ₂ is C _{1 -4} alkoxy or halogen;
R ₃ is H, hydroxy or C _{1 -4} alkoxy;
R ₄ And R &lt; ₅ &gt; are independently selected H or halogen;
And R &lt; ₆ &gt; is a heterocyclic compound containing a hetero atom of S or N. 2. The compound according to claim 1, wherein R &lt; ₁ &gt; is OH. 2. The compound according to claim 1, wherein R &lt; _{2 &gt;} is methoxy or ethoxy or Br. The compound according to claim 1, wherein R ₃ is preferably a hydroxy group or a methoxy group. 2. The compound according to claim 1, wherein R &lt; ₄ &gt; is Br. The compound according to claim 1, wherein R &lt; ₆ &gt;

,

,

,

,

,

&Lt; / RTI &gt;
The compound according to claim 1, wherein R ₁ is OH and R ₂ is OCH ₃ or OCH ₂ CH ₃ Or Br, R ₃ is H or OH, R ₄ is Br, Cl or I, R ₅ is H, Br or Cl, and R ₆ is

&Lt; / RTI &gt;
The compound of claim 1, wherein R ₁ is OH, R ₂ is OCH ₃ , or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

&Lt; / RTI &gt;
The compound of claim 1, wherein R ₁ is OH, R ₂ is OCH ₃ , or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

&Lt; / RTI &gt;
The compound according to claim 1, wherein R ₁ is OH and R ₂ is OCH ₃ Or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

&Lt; / RTI &gt;
The compound of claim 1, wherein R ₁ is OH, R ₂ is OCH ₃ , or OCH ₂ CH ₃ , R ₃ is H, R ₄ is Br, R ₅ is Br, and R ₆ is

&Lt; / RTI &gt;
The compound according to claim 1, wherein the compound represented by the formula (1)
(E) -5 - ((5-Bromo-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5- (Benzylideneamino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Bromo-2-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Bromo-2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Bromo-2,3-dimethoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Chloro-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Chloro-2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2-Hydroxy-5-ureido-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Bromo-3-ethoxy-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((3-ethoxy-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((5-Chloro-3-ethoxy-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((3,5-dibromo-2-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2,4-dihydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2-hydroxy-4-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2-Bromo-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((6-Bromo-2-hydroxy-3-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2,3,5-tribromo-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2,3-dibromo-6-hydroxy-5-methoxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2,3-dibromo-5-ethoxy-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -5 - ((2,3-Dichloro-5-ethoxy-6-hydroxybenzylidene) amino) -1H-benzo [d] imidazol-2 (3H) -one;
5 - ((2,3-dibromo-6-hydroxy-5-methoxybenzyl) amino) -1H-benzo [d] imidazol-2 (3H) -one;
5 - ((2,3-dibromo-5-ethoxy-6-hydroxybenzyl) amino) -1H-benzo [d] imidazol-2 (3H) -one;
(E) -2 - ((( 1H -indol-5-yl) imino) methyl) -3,4-dibromo-6-methoxyphenol;
(E) -2 - (((1H-indol-5-yl) imino) methyl) -3,4-dibromo-6-ethoxyphenol;
(E) -2 - (((1H-benzo [d] imidazol-5-yl) imino) methyl) -3,4-dibromo-6-methoxyphenol;
(E) -2 - (((1H-benzo [d] imidazol-5-yl) imino) methyl) -3,4-dibromo-6-ethoxyphenol;
(E) -2 - ((benzo [d] thiazol-5-ylimino) methyl) -3,4-dibromo-6-methoxyphenol;
(E) -2 - ((benzo [d] thiazol-5-ylimino) methyl) -3,4-dibromo-6-ethoxyphenol.
&Lt; / RTI &gt;
2. The compound of claim 1, wherein said compound binds to the kinase domain of a protein tyrosine kinase (PTK).
A pharmaceutical composition for treating or preventing a disease caused by overexpression of a compound represented by the formula (1) according to claim 1, or a pharmaceutically acceptable salt thereof, and a protein tyrosine kinase comprising a diluent, carrier or excipient.
15. The pharmaceutical composition according to claim 14, wherein the additional therapeutic agent comprises at least one selected from the group consisting of an anti-cancer compound, an analgesic agent, an antipruritic agent, an antidepressant, and an anti-inflammatory agent.
15. The pharmaceutical composition according to claim 14, wherein the protein tyrosine kinase is Protein tyrosine kinase.
15. The method of claim 14, wherein the PTK overexpression disease is selected from the group consisting of psoriasis, papilloma, gliomas, glioblastomas, restenosis, arteriosclerosis, atherosclerosis, and the like.
18. The method of claim 17, wherein the cancer is selected from the group consisting of gastric cancer, colorectal cancer, lung cancer, liver cancer, prostate cancer, thyroid cancer, bladder cancer, pancreatic cancer, renal cancer, biliary cancer, breast cancer, uterine cancer, &Lt; / RTI &gt; and the like.
2. The pharmaceutical composition according to claim 1, wherein said compound binds to the kinase domain of protein tyrosine kinase 6 (PTK6).

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