NOVEL IMIDAZOLE DERIVATIVES AND THERAPEUTIC USE THEREOF

The present invention relates to a novel imidazole derivative, a pharmaceutical acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating cancer. The imidazole derivative of the present invention has excellent apoptosis activity, and thus can be useful for treating various hyperproliferative diseases including cancer.

TECHNICAL FIELD

The present invention relates to novel imidazole derivatives and anticancer compositions with apoptotic activity thereof.

BACKGROUND ART

Apoptosis or programmed cell death is a key biological process for normal function and development in multicellular organisms. Damaged or undesirable cells are removed by intrinsic apoptosis occurring in the mitochondria or extrinsic apoptosis triggered by binding of a death ligand (e.g., Fas ligand) to a corresponding receptor (Cell,2003, 112, 481-490; Science1998, 281, 1305-1308; Cell,1999, 96, 245-254). Apoptosis is involved in many biological processes necessary for the normal growth of organisms. However, when this process abnormally occurs, various diseases are caused (Science1995, 267, 1456-1462; Nat. Rev. Drug Dis. 2002, 1, 111-121; Nat. Rev. Mol. Cell. Biol.2000, 1, 120-129). For example, when apoptosis is suppressed, a variety of cancers are generated or autoimmune diseases are caused by the failure of the elimination of autoreactive lymphocytes. On the contrary, when apoptosis excessively occurs, neurodegenerative and cardiovascular diseases are caused. For these reasons, apoptosis is closely related to various human diseases, and thus the research on this topic is a very important core field in the medical research.

Various proteins including the families of B cell lymphoma-2 (Bcl-2) and inhibitor of apoptosis proteins (IAP) are known to be involved in apoptosis. Caspases (cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases) are critical enzymes that induce apoptosis. Interestingly, members of Hsp70 family are known to block apoptosis via multiple anti-apoptotic processes. For example, Hsp70 directly binds to several proteins, for example, an apoptosis-inducing factor (AIF) and Apaf-1 to inhibit apoptosis. Accordingly, inhibitors of an Hsp70 protein can induce apoptosis and thus have potential to be used as anticancer agents (Genes Dev.2005, 19, 570-582; Proc. Natl. Acad. Sci. USA2000, 97, 7871-7876).

Throughout this specification, a number of theses and patent documents are provided as references and cited references thereof are represented. The disclosure of the cited theses and patent documents are incorporated herein by reference in its entirety, and thus the level of the field of art including the present invention and the scope of the present invention are more fully described.

DISCLOSURE

Technical Problem

The inventors have conducted research to discover compounds with excellent therapeutic efficacy to treat various hyperproliferative diseases occurring by inhibiting normal apoptosis, more specifically, to treat cancers by inducing effective apoptosis. As a result, a novel imidazole derivative represented by Formula 1 with excellent cancer cell death activity was discovered, and thus the inventors completed the present invention.

Accordingly, the purpose of present invention includes providing novel imidazole derivatives or pharmaceutically acceptable salts thereof.

Other purpose of present invention also includes providing pharmaceutical compositions for preventing or treating cancer, which includes the imidazole derivatives of the present invention, pharmaceutically acceptable salts thereof or a solvate thereof as an active ingredient.

Other objectives and advantages of the present invention are more apparent by the detailed description, claims and drawings of the present invention, as described below.

Technical Solution

In one aspect of the present invention, the present invention provides an imidazole derivative represented by Formula 1, or a pharmaceutically acceptable salt thereof:

(B1is C1-C5alkoxy), hydroxy, cyano, phenyl, phenyl C1-C5alkyl or phenyl C1-C5alkoxy; R3and R4are each independently 5- to 10-membered aryl or heteroaryl which is unsubstituted or substituted by halogen, C1-C5alkyl, C1-C5alkoxy or amine that is unsubstituted or substituted by C1-C5alkyl, and n is an integer from 0 to 2.

The inventors conducted investigations aiming at discovery of compounds with excellent therapeutic efficacy for various hyperproliferative diseases occurring by inhibiting normal apoptosis, in particular, cancers. In this effort, they found that the novel imidazole derivative represented by Formula 1 has excellent cancer cell death activity.

According to the present invention, compounds of the present invention exhibit high death activity of various cancer cells including lung cancer cells, colorectal cancer cells, uterine cervical cancer cells, liver cancer cells, leukemia cells and breast cancer cells, and can be used as effective anticancer compositions.

The term “alkyl” used herein refers to a linear or branched saturated hydrocarbon group, for example, methyl, ethyl, propyl, isobutyl, pentyl or hexyl. C1-C5alkyl is an alkyl group having an alkyl unit possessing 1 to 5 carbon atoms, and when C1-C5alkyl is substituted, the number of carbon atoms of the substituent is not included.

The term “alkoxy” used herein refers to a radical formed by eliminating hydrogen from an alcohol, and when a C1-C5alkoxy is substituted, the number of carbon atoms of the substituent is not included.

The term “halogen” used herein is a halogen atom, for example, fluorine, chlorine, bromine and iodine.

The term “aryl” used herein refers to a monocyclic or polycyclic aromatic ring containing substituents.

The term “heteroaryl” used herein refers to a heterocyclic aromatic group including a heteroatom such as oxygen, sulfur or nitrogen in a ring. Preferably, the heteroatom is oxygen, nitrogen, or sulfur. The number of the heteroatoms is 1 to 4, and preferably 1 to 2. In the heteroaryl, an aryl may be a monoaryl or a biaryl.

The term “aminoalkoxyalkoxy” refers to an amine-bonded alkoxy group, which is a substituted alkoxy group, and for example, the term “amino C1-C5alkoxy C1-C5alkoxy” is a substituent to which an amine group, a C1-C5alkoxy group and a C1-C5alkoxy group sequentially bond from the outermost to a backbone.

The term “phenylalkyl” used herein refers to a phenyl-substituted alkyl group, and for example, the “phenyl C1-C5alkyl” refers to a phenyl bonded alkyl group containing 1 to 5 carbon atoms.

In the specification, the term “phenylalkoxy” refers to a phenyl-substituted alkoxy group, and for example, the “phenyl C1-C5alkoxy” refers to a phenyl bonded alkoxy group having 1 to 5 carbon atoms.

According to an exemplary embodiment of the present invention, R1of Formula 1 of the present invention is

According to an exemplary embodiment of the present invention, R2of Formula 1 of the present invention is phenyl, furan, pyridine or indole, which is unsubstituted or substituted by halogen, C1-C3alkoxy, unsubstituted or halogen-substituted C1-C3alkyl,

According to an exemplary embodiment of the present invention, R3and R4of Formula 1 of the present invention are each independently phenyl, benzimidazole, naphthalene or quinoline, which is unsubstituted or substituted by halogen, C1-C3alkyl, C1-C3alkoxy, or unsubstituted or C1-C3alkyl-substituted amine, and n is 1. More specifically, R3and R4are each independently phenyl, benzimidazole, naphthalene or quinoline, which is unsubstituted or substituted by F, Br, Cl, methyl, methoxy or an unsubstituted or methyl-substituted amine.

According to an exemplary embodiment of the present invention, the imidazole derivative represented by Formula 1 of the present invention is selected from the group consisting of the compounds represented by Formulas 2 to 201:

According to a further exemplary embodiment of the present invention, the imidazole derivatives of the present invention are selected from the group consisting of the compounds represented by Formulas 2, 11, 27, 35, 43 to 48, 68, 100, 102, 105 to 107, 117 to 123, 128, 181 to 185, 187 to 195 and 197 to 201.

As shown in Table 1, the compounds of the present invention exhibited cancer cell death activity. Therefore, they can be used as effective therapeutic compositions for various hyperproliferative diseases caused by suppression of normal apoptosis.

The term “hyperproliferative disease” used herein refers to a pathological state triggered by the excessive growth, division and migration of cells which are not controlled by a general inhibitory means in a normally growing animal body. The hyperproliferative diseases prevented or treated by the composition of the present invention include cancer, diabetic retinopathy, retinopathy of prematurity, keratoplasty rejection, neovascular glaucoma, erythrosis, proliferative retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, autoimmune disease, Crohn's disease, restenosis, atherosclerosis, intestinal stenosis, ulcer, cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, organ transplantation rejection and glomerulopathy, but the present invention is not limited thereto. Such hyperproliferative diseases include all of the hyperproliferative diseases caused by abnormal proliferation of cells and excessive angiogenesis. More specifically, the hyperproliferative disease treated by the composition of the present invention is cancer.

In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, which includes the imidazole derivative of the present invention, pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. More specifically, the cancer treated by the composition of the present invention is selected from the group consisting of lung cancer, colorectal cancer, uterine cervical cancer, liver cancer, leukemia, and breast cancer.

The composition of the present invention may be provided as a pharmaceutical composition for preventing or treating hyperproliferative diseases including cancer. When the composition of the present invention is prepared as the pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention is conventionally used in the preparation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc., but the present invention is not limited thereto. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc. in addition to the above-described ingredients. Suitable pharmaceutically acceptable carriers and preparations are described in detail inRemington's Pharmaceutical Sciences(19th ed., 1995).

The pharmaceutical composition of the present invention may be orally or parenterally administered, and the parenteral administration includes intravenous injection, subcutaneous injection, muscular injection, abdominal injection, subcutaneous administration, etc.

Suitable prescribed doses of the pharmaceutical composition of the present invention may vary depending on parameters such as preparation method, administration method, patient age, body weight, sex, pathological state, diet, duration of administration, administration route, excretion rate and reaction sensitivity. A daily dose of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg/kg.

The pharmaceutical composition of the present invention may be prepared by a unit dose packaging or multi-dose packaging after being prepared in a conventional dosage form using a pharmaceutically acceptable carrier and/or excipient according to a method capable of being performed by those of ordinary skill in the art. A conventional dosage form may be, for example, a dosage form for oral (tablet, capsule or powder), intra-oral, sublingual, rectal, intravaginal, intranasal, topical or parenteral (including intravenous, intracavernous, intramuscular, subcutaneous and intraluminal) administration. For example, the compounds of the present invention are formed in a tablet containing starch or lactose, a capsule alone or containing an excipient, an elixir containing a chemical for enhancing a flavor or color or a suspension, and may be orally, intra-orally or sublingually administered. A liquid preparation is prepared with a pharmaceutically acceptable additive such as a suspending agent (e.g., methylcellulose, a semi-synthetic glyceride such as Witepsol, a mixture of apricot kernel oil and a PEG-6 ester, or a glyceride mixture such as a mixture of PEG-8 and caprylic/capric glyceride). Also, for parenteral injection, for example, intravenous, intracavernous, intramuscular, subcutaneous or intraluminal injection, the compounds are most preferably used in an aseptic aqueous solution, here, the solution may contain other materials (e.g., salt, mannitol, or a monosaccharide such as glucose) to have isotonicity with blood.

The acid salts of the present invention are prepared by using a conventional method, for example, by dissolving the derivative of Formula 1 in an organic solvent, for example, methanol, ethanol, acetone, methylene chloride or acetonitrile, filtering precipitates produced after addition of an organic acid or inorganic acid, and drying the resultant products, or performing distillation under reduced pressure to remove residual solvent and an excessive acid, and then drying the resultant products or recrystallizing the resultant products in an organic solvent.

Advantageous Effects

Characteristics and advantages of the present invention are summarized below:

(a) The present invention provides novel imidazole derivatives or pharmaceutically acceptable salts thereof; and pharmaceutical compositions for preventing or treating cancer, which include the same as an active ingredient.

(b) The imidazole derivatives of the present invention have excellent apoptotic activity, and may be used to treat various hyperproliferative diseases including cancer.

Modes of the Invention

Hereinafter, the present invention is described in further detail with reference to examples. The examples are merely provided to more fully describe the present invention, and it will be obvious to those of ordinary skill in the art that the scope of the present invention is not limited to the following examples.

EXAMPLES

Throughout the specification, unless particularly described otherwise, “%” used to express the concentration of a specific material is (wt/wt) % for solid/solid, (wt/vol) % for solid/liquid, and (vol/vol) % for liquid/liquid.

Preparation Methods for Compounds

EXAMPLES

The above-prepared amine resin (30 μmol) was reacted with 3,5-bis(trifluoromethyl)benzaldehyde (40 μl, 10 equiv), ammonium acetate (60 mg, 40 equiv) and 4,4′-dibromobenzyl (110 mg, 10 equiv) in acetic acid (400 μl) in a heat block on a stirrer at 100° C. for 8 hours. The resin was filtered, and washed with DMF, MeOH and CH2Cl2several times. A product was treated with trifluoroacetic acid (TFA) for 1.5 hours to remove from the resin.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-dihydroxyphenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide. 1,3-dihydroxybenzaldehyde (50 mg, 362 μmol), 4-aminomethyl benzoic acid (72 mg, 470 μmol), 4,4′-dimethoxybenzyl (127 mg, 470 μmol) and ammonium acetate (167 mg, 2.2 mmol) were dissolved in acetic acid, heated at 100° C. and stirred for 12 hours. The temperature was decreased to room temperature, and a reaction mixture was diluted with ethyl acetate and then washed with water and a saline solution. An organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The mixture obtained thereby was purified by flash column chromatography (CH2Cl2:MeOH=10:1), thereby obtaining a compound with a yield of 73%.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(2-chlorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H33Cl2F6N4O3[M+H]+765.1756 was 765.4510.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(2-chlorophenyl)-2-(3-(trifluoromethyl)phenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C36H34Cl2F3N4O3[M+H]+697.1882 was 697.5340.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(2-chlorophenyl)-2-(9H-fluorene-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C42H39Cl2N4O3[M+H]+717.2321 was 717.5688.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(2-chlorophenyl)-2-phenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C35H35Cl2N4O3[M+H]+629.2008 was 629.4283.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H35F6N4O3[M+H]+697.2535 was 697.5340.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-diphenyl-2-(4-(trifluoromethyl)phenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C36H36F3N4O3[M+H]+629.2661 was 629.4913.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(2,4-bis(trifluoromethyl)phenyl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H35F6N4O3[M+H]+697.2535 was 697.4710.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-dimethylphenyl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H41N4O3[M+H]+589.3100 was 589.3590.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2,4,5-triphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C35H37N4O3[M+H]+561.2787 was 561.5751.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-bromophenyl)-2-phenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C35H35Br2N4O3[M+H]+717.0998 was 717.3168.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-fluorophenyl)-2-phenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C35H35F2N4O3[M+H]+597.2599 was 597.2343.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-phenyl-4,5-ditolyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H41N4O3[M+H]+589.3100 was 589.5480.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-(dimethylamino)phenyl)-2-phenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C39H47N6O3[M+H]+647.3631 was 647.5100.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-methoxyphenyl)-2-phenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H41N4O5[M+H]+621.2999 was 621.5100.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3-bromo-4,5-dimethoxyphenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H38BrF2N4O5[M+H]+735.1915 was 735.4498.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3-bromo-4,5-dimethoxyphenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C39H44BrN4O7[M+H]+759.2315 was 759.7061.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3-bromo-4,5-dimethoxyphenyl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H40BrN4O5[M+H]+699.2104 was 699.4750.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-fluoro phenyl)-2-(furan-2-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C33H33F2N4O4[M+H]+587.2392 was 587.5184.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(furan-2-yl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C35H39N4O6[M+H]+611.2791 was 611.7117.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(furan-2-yl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C33H35N4O4[M+H]+551.258 was 551.5436.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-fluorophenyl)-2-(pyridine-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C34H34F2N5O3[M+H]+598.2551 was 598.3550.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-methoxyphenyl)-2-(pyridine-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C36H40N5O5[M+H]+622.2951 was 622.3591.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-diphenyl-2-(pyridine-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C34H36N5O3[M+H]+562.2740 was 562.3171.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-fluorophenyl)-2-(1-methyl-1H-indole-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C38H38F2N5O3[M+H]+650.2864 was 650.5846.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((4,5-bis(4-methoxyphenyl)-2-(1-methyl-1H-indole-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C40H44N5O5[M+H]+674.3264 was 674.5258.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(1-methyl-1H-indole-3-yl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C38H40N5O3[M+H]+614.3053 was 614.6281.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(benzo[d][1,3]dioxol-5-yl)-4,5-bis(4-fluorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C36H35F2N4O5[M+H]+641.2497 was 641.5751.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(benzo[d][1,3]dioxol-5-yl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C38H41N4O7[M+H]665.2897 was 665.5164.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(4-(benzyloxy)phenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C42H41F2N4O4[M+H]+703.3018 was 703.6613.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(4-(benzyloxy)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C43H47N4O6[M+H]+727.3417 was 727.7313.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(4-(benzyloxy)phenyl)-4,5-diphenyl-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C42H43N4O4[M+H]+667.3206 was 667.6196.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(4-(benzyloxy)phenyl)-4,5-bis(2-chlorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C42H41Cl2N4O4[M+H]+735.2427 was 735.7335.

4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(2-chlorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 155: The obtained value of LC-MS calculated for C31H20Cl2F6N3O [M+H]+634.0809 was 634.5352.

4-((4,5-bis(2-chlorophenyl)-2-(9H-fluorene-3-yl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 155: The obtained value of LC-MS calculated for C36H26Cl2N3[M+H]+586.1375 was 586.2860.

2-(2-(2-(2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole-1-yl)ethoxy)ethoxy)ethaneamine was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C31H32F6N3O4[M+H]+624.2219 was 624.2267.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-fluorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H33F8N4O3[M+H]+733.2347 was 733.5911.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-((2-(3,5-bis(trifluoromethyl)phenyl)-4,5-bis(4-chlorophenyl)-1H-imidazole-1-yl)methyl)benzamide was synthesized by the same method as used in Example 1: The obtained value of LC-MS calculated for C37H33Cl2F6N4O3[M+H]+765.1756 was 765.4890.

Experimental Example

Detection of Apoptotic Activity

Lung cancer cells (A549), colorectal cancer cells (HCT116), HeLa cells, liver cancer cells (HepG2), T-cell leukemia cells (Jurkat), myeloid leukemia cells (K562), breast cancer cells (MCF-7 and MDA-MB-231) and myelocytic leukemia cells (K562) were obtained from the American Type Culture Collection (ATCC), and cultured in 10% fetal bovine serum (FBS), 50 units/mL penicillin and 50 units/mL streptomycin-added RPMI 1640 (Invitrogen). The cells were maintained in a humidified 37° C., 5% CO2atmosphere. The anticancer activity was detected by MTT analysis. Each type of cancer cells were plated in triplicate in a 96-well microtiter plate, and cultured at 37° C. for 24 hours. The cells were treated with each of the compounds prepared above at 37° C. for 12 hours. After the culturing of the cells, 10 μL of an MTT reagent ((3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazoliumbromide) was added to each well, and cultured for 3.5 hours. The absorbance of each sample was detected using a UV microplate reader (SpectraMax 340PC 384, Molecular Devices) at 570 nm. The detection results were measured as a mean value. The effect of each compound on apoptosis is shown in Table 1.

The A549 and HeLa cells were treated with 15 μM of the compound for 12 hours. The apoptosis was detected using MTT (mean±standard deviation).

From above, specific parts of the present invention have been described in detail. However, it will be apparent to those of ordinary skill in the art that such detailed descriptions are just exemplary embodiments, and thus the scope of the present invention is not limited thereto. Therefore, the actual range of the present invention will be defined by the accompanying claims and equivalents thereof.