JP5782234B2 - Benzimidazole compounds and uses thereof - Google Patents

Description

Microtubules are intracellular tubes composed of α- and β-tubulin. As important components of the cytoskeleton, they play a particularly important role in cell division, which is essential for cancer development. Therefore, microtubules / tubulin has received much attention as a target for cancer treatment.

DNA is another therapeutic target for the treatment of cancer. DNA damage is known to induce cell death by apoptosis. Therefore, an agent that induces DNA damage can function as an anticancer agent.

Vitale I et al. Combretastatin CA-4 and combretastatin derivative induce mitotic catastrophe dependent on spindle checkpoint and caspase-3 activation in non-small cell lung cancer cells. Apoptosis 12: 155-166. Critchley et al. Albendazole for lymphatic filariasis (Review). The Cochrane Library 2009, Issue 1.

The present invention is an unexpected discovery that certain benzimidazole compounds have potent anticancer activity, antiplatelet activity, and antithrombotic activity, and have therapeutic effects in the treatment of cardiovascular and cerebrovascular diseases. Based.

The present invention therefore relates to benzimidazole compounds and their use in the treatment of cardiovascular and cerebrovascular diseases as well as cancer. In addition, these compounds are
It was found to have antiplatelet activity and antithrombotic activity.

  In one aspect, the present invention provides a compound of formula (I):

It is characterized by the following benzimidazole compound. In formula (I), each

Is a single bond or a double bond, provided that one

Next to it is a double bond

Is not a double bond and X is CR ′, NR ″, N, O, or S where R ′ is H,
Alkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, R ″ is arylsulfonyl) and Y is (
CH ₂ ) _n (where n is 1, 2, 3, or 4), C (O), SO, SO ₂ , or NR ′ ″ (where R ′ ″ is H or Is Z) and Z ₁ and Z ₂
Each is CH or deleted, except that at most _one of Z ₁ and Z ₂ is deleted, each of R ¹ and R ² is independently H, halo, Alkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R ₁ and R ₂ are aryl or heteroaryl with the C atom to which they are attached, R ³ and R Each of ⁴ is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, cyano, amino, hydroxy, alkoxy, aryloxy , SR _a , C (O) R _a , or C (O
) OR _{a where} R _a is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, provided that R ³ and At most one of R ⁴ is H and R
⁵ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

One subset of the above-mentioned benzimidazole compound include those Y is is CH _2. In these compounds, X may be CR ′ and each of Z ₁ and Z ₂ is C
X may be NR ″, _one of Z ₁ and Z ₂ may be CH and the other may be deleted; X may be N Z ₁ and Z ₂ may be C
May be H; each of R ′, R ¹ , and R ² is alkoxy (eg, methoxy)
One of R ³ and R ⁴ may be H and the other may be alkyl, halo, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ⁵ may be cycloalkyl, heterocycloalkyl, aryl (eg phenyl), or heteroaryl (eg furyl or thiophenyl); or R ₁ and R ₂ are aryl together with the C atom to which they are attached. It may be.

Another subset of the benzimidazole compounds described above includes those where Y is CO. In these compounds, X may be CR ′, Z ₁ and Z ₂ may be CH; X may be O or S, and _one of Z ₁ and Z ₂ is CH Or the other may be deleted; or R ⁵ may be alkyl or aryl.

Still another subset of the above-mentioned benzimidazole compound include those wherein Y is SO _2.

The term “alkyl” refers to a straight or branched monovalent hydrocarbon containing ₁ to 20 carbon atoms (eg, C _{1 to} C ₁₀ ), unless otherwise stated. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-
Examples include but are not limited to butyl. The term “alkenyl” refers to a straight or branched monovalent hydrocarbon containing 2 to 20 carbon atoms (eg, C ₂ -C ₁₀ ) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, allyl, and 1,4-butadienyl. The term “alkynyl” refers to a straight or branched monovalent hydrocarbon containing 2 to 20 carbon atoms (eg, C ₂ -C ₁₀ ) and one or more triple bonds. Examples of alkynyl include ethynyl, 1-
This includes, but is not limited to, propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl. The term “alkoxy” refers to an —O-alkyl group. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. The term “acyloxy” refers to the group —O—C (O) —R, wherein R is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or hetero May be aryl). The term “amino” refers to NH ₂ , alkylamino, or arylamino. The term “alkylamino” refers to the group —N (R) -alkyl where R is H
, Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. The terms “amide” and “carbamide” are each —NRC (O) R ′.
A group and a —C (O) NRR ′ group wherein each of R and R ′ is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, Or it may be heteroaryl.

The term “cycloalkyl” refers to a monovalent saturated hydrocarbon ring system having _{3 to} 30 carbon atoms (eg, C ₃ -C ₁₂ ). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,4-cyclohexylene, cycloheptyl,
Examples include, but are not limited to, cyclooctyl and adamantyl. The term “cycloalkenyl” refers to a monovalent non-aromatic hydrocarbon ring system having 3 to 30 carbons (eg, C ₃ -C ₁₂ ) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term “heterocycloalkyl” is a monovalent non-aromatic 5-8 membered monocyclic, 8-12 membered bicyclic having one or more heteroatoms (eg, O, N, S, or Se). Or a 11-14 membered tricyclic ring system. Examples of heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl. The term “heterocycloalkenyl” is a monovalent non-aromatic 5-8 membered monocycle having one or more heteroatoms (eg, O, N, S, or Se) and one or more double bonds. Formula, 8-1
Refers to a 2-membered bicyclic or 11-14 membered tricyclic ring system.

The term “aryl” refers to a monovalent 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The term “aryloxyl” refers to —O-aryl. The term “arylamino” refers to —N (R) -aryl where R is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. May be). The term “arylsulfonyl” refers to —SO ₂ -aryl. The term “heteroaryl” refers to a monovalent aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, having one or more heteroatoms (eg, O, N, S, or Se), or Refers to a 11-14 membered tricyclic ring system. Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.

Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl as described above,
Cycloalkenyl, heterocycloalkenyl, amino, aryl, and heteroaryl include both substituted and unsubstituted moieties. Amino, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and the substituents can be on the _heteroaryl, C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10
Alkynyl,} C 3 _{-C 20 cycloalkyl,} C 3 _{-C 20 cycloalkenyl,} C 1 -C _2
0 heterocycloalkyl, C ₁ -C ₂₀ heterocycloalkenyl, C ₁ -C ₁₀ alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C ₁
-C ₁₀ alkylamino, arylamino, hydroxy, halo, oxo (O =), thioxo (S =), thio, _silyl, C 1 _{-C 10} alkylthio, _arylthio, C 1 _{-C 10} alkylsulfonyl, arylsulfonyl, acylamino , aminoacyl, Aminothioacyl, amidino, mercapto, amido, thioureido, thiocyanato, sulfonamido, guanidine, ureido, cyano, nitro, acyl, thioacyl, acyloxy, carbamide, carbamyl _{(-C (O) NH 2)} , carboxyl (- COOH), and carboxylic acid esters. On the other hand, alkyl, alkenyl, alkynyl, or the possible substituents on the alkylene, include all of the listed substituents on except C ₁ -C ₁₀ alkyl. Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl may also be fused to each other.

The benzimidazole compounds described herein include not only the compound itself, but also its salts, solvates, and prodrugs where applicable. For example, a salt can be formed between an anion and a positively charged group (eg, amino) on a benzimidazole compound. Suitable anions include chloride ion, bromide ion, iodide ion, sulfate ion,
Bisulfate ion, sulfamate ion, nitrate ion, phosphate ion, citrate ion, methanesulfonate ion, trifluoroacetate ion, glutamate ion, glucuronic acid ion, glutarate ion, malate ion, maleate ion, succinic acid Ions, fumarate ions, tartrate ions, tosylate ions, salicylate ions, lactate ions, naphthalene sulfonate ions, and acetate ions. Similarly, a salt can also be formed between a cation and a negatively charged group (eg, a carboxylate) on the benzimidazole compound. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. Benzimidazole compounds also include salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that can provide an active benzimidazole compound after administration to a subject.

  In another embodiment, the present invention provides a subject in need thereof with formula (I):

It relates to a method for treating cancer by administering an effective amount of a benzimidazole compound. In this formula, each

Is a single bond or a double bond, provided that one

Next to it is a double bond

Is not a double bond, X is CR ′, NR ″, N, O, or S, where R ′ is H, alkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl,
Or is heteroaryl, R ″ is arylsulfonyl) and Y is (C
H ₂ ) _n (where n is 1, 2, 3, or 4), C (O), SO, SO ₂ , or NR ″ ′ (where R ′ ″ is H or Each of Z ₁ and Z ₂ is CH or deleted, but at least _one of Z ₁ and Z ₂ is deleted, and R ¹ and R ² Each independently is H, halo, alkyl, hydroxy, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or R ₁ and R ₂ are the C atoms to which they are attached. Each of R ³ and R ⁴ is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl. Ru, aryl, heteroaryl, halo, nitro, cyano, amino, hydroxy, alkoxy, aryloxy, SR _a , C (O) R _a , or C (O)
OR _{a where} R _a is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, and R ⁵ is alkyl, alkenyl , Alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.

Referring to formula (I), a subset of the above benzimidazole compounds include those Y is is CH _2. In these compounds, X may be CR ′ and Z ₁ and Z ₂
Each of can be CH; X can be NR ″, _one of Z ₁ and Z ₂ can be CH, and the other can be deleted; N may be Z ₁
And Z ₂ may be CH; each of R ′, R ¹ , and R ² may be alkoxy (eg, methoxy); one of R ³ and R ⁴ may be H , The other may be alkyl, halo, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ⁵ is cycloalkyl, heterocycloalkyl,
It may be aryl (eg phenyl) or heteroaryl (eg furyl or thiophenyl); alternatively, R ₁ and R ₂ may be aryl with the C atom to which they are attached.

Another subset of these benzimidazole compounds includes those where Y is CO.
In these compounds, X may be CR ′, Z ₁ and Z ₂ may be CH; X may be O or S, and _one of Z ₁ and Z ₂ is CH Or the other may be deleted; or R ⁵ may be alkyl or aryl.

Yet another subset of compounds of formula (I) include those where Y is SO ₂ .

Also, a pharmaceutical composition containing one or more of the above-mentioned benzimidazole compounds for use as an antiplatelet agent or antithrombotic agent, or for use in the treatment of cancer, cardiovascular disease or cerebrovascular disease, Also within the scope of this invention are the therapeutic use and use of antiplatelet or antithrombotic agents or compounds for the manufacture of a medicament for treating cancer, cardiovascular or cerebrovascular disease. .

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

  Exemplary compounds described herein are shown below.

The benzimidazole compounds described herein can be prepared by conventional chemical transformations (including methods with protecting groups), such as R.I. Larock, Comprehensive Organic
Transformations, VCH Publishers (1989); W
. Greene and P.M. G. M.M. Wuts, Protective Groups i
n Organic Synthesis, 3rd edition, John Wiley and S
ons (1999); Fieser and M.M. Fieser, Fieser and
Fieser's Reagents for Organic Synthesis
John Wiley and Sons (1994); Paquett
eEdit, Encyclopedia of Reagents for Organic
Synthesis, John Wiley and Sons (1995) and subsequent editions can be used.

The pathway shown in Scheme 1 illustrates the synthesis of certain benzimidazole compounds of the present invention (R ³ and R ⁵ are defined above). 5-Substituted 2-nitroaniline 1 reacts with acyl chloride 2 to produce compound 3. The nitro group in compound 3 is reduced (iron powder, NH
₄ Cl, 100 ° C. or sodium dithionite in ethanol, reflux) to produce aniline 4. The Schiff base 5 formed by reacting compound 4 and 3,4,5-trimethoxybenzaldehyde in methanol is treated with sodium borohydride at room temperature to produce compound 6. Cyclization of compound 6 in the presence of 4N HCl in methanol then gives final compound 7.

Reagents and conditions: (i) pyridine, CH ₂ Cl ₂ , room temperature; (ii) Fe, NH ₄ Cl,
IPA, 100 ° C .; or Na ₂ S ₂ O ₄ , ethanol, reflux (iii) 3,4,5-trimethoxybenzaldehyde, MeOH, room temperature; (iv) NaBH ₄ , MeOH; (v)
MeOH / 4N HCl (2: 1), 50 ° C.

The benzimidazole compound thus synthesized can be further purified by flash column chromatography, high performance liquid chromatography, crystallization, or any other suitable method.

The benzimidazole compounds described herein can contain non-aromatic double bonds and one or more asymmetric centers. They are therefore racemates and racemic mixtures,
Single enantiomers, individual diastereomers, diastereomeric mixtures, and cis-
Or it can occur as a trans-isomer form. All such isomeric forms are contemplated.

Also, (1) a pharmaceutical composition containing an effective amount of at least one benzimidazole compound of the present invention and a pharmaceutically acceptable carrier, and (2) a subject in need of such treatment, such as Also within the scope of the invention is a method for treating cancer by administering an effective amount of any benzimidazole compound.

As used herein, the term “treat” refers to the prevention, cure, treatment, alleviation, alleviation, modification, treatment, improvement, enhancement of a disorder, symptoms of cancer or a predisposition to it, or It refers to administering a benzimidazole compound to a subject who has cancer, or who is prone to cancer symptoms, or who is prone to suffer, for the purpose of affecting it.
The term “effective amount” refers to the amount of active agent required to provide the intended therapeutic effect to the subject. Effective amounts can vary depending on the route of administration, the use of excipients, and the possibility of co-usage with other agents, as will be appreciated by those skilled in the art.

Cancers that can be treated by the methods of the present invention include both solid organs and hematological tumors. Examples of solid tumors include pancreatic cancer; bladder cancer; colorectal cancer; breast cancer including metastatic breast cancer; prostate cancer including androgen-dependent and androgen-independent prostate cancer; metastatic kidney cells Kidney cancer including cancer; hepatocellular carcinoma; non-small cell lung cancer (NSC)
LC), bronchioloalveolar carcinoma (BAC), and lung cancer including adenocarcinoma of the lung; ovarian cancer including advanced epithelial cancer or primary peritoneal cancer; cervical cancer; gastric cancer Esophageal cancer; head and neck cancer including squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer including metastatic neuroendocrine tumor; glioma, anaplastic oligodendroglioma, many adults Examples include brain tumors including glioblastoma and adult anaplastic astrocytoma; osteosarcoma; and soft tissue sarcoma. Examples of hematologic malignancies include acute myeloid leukemia (AML); CML including accelerated phase chronic myeloid leukemia (CML) and CML blast crisis (CML-BP); acute lymphoblastic leukemia (ALL); Spherical leukemia (CLL); Hodgkin's disease (HD); Non-Hodgkin's lymphoma (NHL), including follicular and mantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; Multiple myeloma (
MM); Waldenstrom's macroglobulinemia; refractory anemia (RA), refractory anemia with cyclic iron blasts (RARS), refractory anemia with increased blasts (RAEB), and further increase in blasts Myelodysplastic syndromes (MDS) including RAEB (RAEB-T); and myeloproliferative syndromes.

For practicing the method of the present invention, the above-described pharmaceutical composition can be administered orally, parenterally, by inhalation spray,
It can be administered topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term “parenteral” refers to subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and skull Includes internal injection or infusion techniques.

Sterile injectable compositions, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents. Can be The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium (eg, synthetic monoglycerides or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, and natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylenated forms are also useful. is there. These oily solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants such as Tween or Span, or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms Can also be used for formulation purposes.

Compositions for oral administration may be any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Typically, a lubricant such as magnesium stearate is also added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase in combination with emulsifying or suspending agents. As desired
Certain sweetening, flavoring, or coloring agents can be added. Nasal aerosol or inhalation compositions can be prepared according to techniques well known in the pharmaceutical formulation art. The benzimidazole compound-containing composition can also be administered in the form of suppositories for rectal administration.

A carrier in a pharmaceutical composition must be “acceptable” in the sense of being compatible with the active ingredient of the formulation (and preferably being able to stabilize it) and detrimental to the subject being treated. Must not. One or more solubilizers (eg, cyclodextrins) that form a more soluble complex with the active benzimidazole compound can be used as a pharmaceutical carrier for delivery of the active compound. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, sodium lauryl sulfate, and D & C Yellow #
10 is included.

A suitable in vitro assay can be used to assess in advance the efficacy of a benzimidazole compound in anti-cancer activity such as inhibition of tumor cell growth. The compound can be further tested for its effect in treating cancer. For example, a compound can be administered to an animal with cancer (eg, a mouse model) and then its therapeutic effect is evaluated. Based on the results, an appropriate dosage range and administration route can also be determined.

Without giving further details, it is believed that the above description has provided a thorough understanding of the present invention. Accordingly, the following examples are to be construed as merely illustrative and not limiting the remainder of the disclosure in any manner. All publications cited herein are hereby incorporated by reference in their entirety.

[Example 1]
Synthesis of 5-methyl-2-phenyl-1- (3,4,5-trimethoxybenzyl) -1H-benzo [d] imidazole (compound 5) N- (5-methyl-2-nitrophenyl) benzamide: dried Dichloromethane (15m
L) 5-methyl-2-nitroaniline (4 mmol) and pyridine (8 mmol)
To the stirred solution of benzoyl chloride (8 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 8 hours. The solvent was evaporated under vacuum and the residue was subjected to flash chromatography on silica gel using a mixture of hexane and CH ₂ Cl ₂ (7: 3) as eluent.
-(5-Methyl-2-nitrophenyl) benzamide was obtained as a solid.

N- (2-amino-5-methylphenyl) benzamide: isopropanol (150 m
To a suspension of N- (5-methyl-2-nitrophenyl) benzamide (3 mmol) in L) was added iron powder (2 g) and ammonium chloride (0.3 mmol). The reaction mixture was heated at 100 ° C. for 12 hours. The hot mixture was filtered and the filtrate was evaporated. The residue hexanes and _{CH 2 Cl 2 (9: 1} ) mixture when subjected to flash chromatography on silica gel using as eluent, N-(2-amino-5-methylphenyl) benzamide is obtained as an off-white solid It was.

(E) -N- (5-methyl-2- (3,4,5-trimethoxybenzylideneamino) phenyl) benzamide: N- (2-amino-5-methylphenyl) benzamide (2 mmol) and 3 in methanol , 4,5-Trimethoxybenzaldehyde (3 mmol)
Was stirred at room temperature for 12 hours. The suspension was filtered and the solid was washed with methanol to give (E) -N- (5-methyl-2- (3,4,5-trimethoxybenzylideneamino) phenyl) benzamide as a yellow solid.

N- (5-methyl-2- (3,4,5-trimethoxybenzylamino) phenyl) benzamide: Compound (E) -N- (5-methyl-2- (3,4,5-trimethyl) in methanol A suspension of methoxybenzylideneamino) phenyl) benzamide (3 mmol) was cooled in an ice bath. Sodium borohydride was added until the color changed to white. Excess sodium borohydride was quenched by the addition of distilled water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give N- (5-methyl-2- (3,4,5-trimethoxybenzylamino) phenyl) benzamide as a solid As obtained.

5-methyl-2-phenyl-1- (3,4,5-trimethoxybenzyl) -1H-benzo [d] imidazole: N- (5-methyl-2- (3,4,5) in ethanol (20 mL)
To a suspension of 5-trimethoxybenzylamino) phenyl) benzamide, 4N HCl was added. The reaction mixture was heated at 50 ° C. for 5 hours and then cooled to room temperature. Excess acid was neutralized with ammonium hydroxide, and the resulting mixture was extracted with ethyl acetate (3 × 50 mL).
The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ and concentrated under vacuum.
The residue was subjected to flash chromatography on silica gel to give 5-methyl-2-phenyl-1- (3,4,5-trimethoxybenzyl) -1H-benzo [d] imidazole as a solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.83-7.79 (m, 3H, 4, 2 ', 6'-H), 7.48-7.37
(m, 4H, 7, 3 ', 4', 5'-H), 7.07 (dd, J = 8, 2 Hz, 1H, 6H), 6.29 (s, 2H, 2``, 6 ''-
H), 5.34 (s, 2H, CH ₂ ), 3.57 (s, 9H, OCH ₃ ), 2.40 (s, 3H, CH ₃ ); ¹³ C NMR (100 MHz,
DMSO-d ₆ ) δ (ppm): 164.6, 162.1, 153.5, 153.5, 152.8, 143.4, 137.1, 134.5, 133.0
, 131.9, 131.9, 127.4, 124.6, 119.5, 116.3, 119.6, 111.2, 104.1, 104.1, 60.4, 56
.2, 56.2, 48.0, 21.6; EIMS: m / z 388 (M ⁺ ).

[Example 2]
Synthesis of 2- (2-fluorophenyl) -5-methyl-1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 30) Compound 30 was prepared in a manner similar to that described in Example 1. did.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.68-7.62 (m, 2H, 4, 6'-H), 7.52-7.37 (m,
4H, 7, 3 ', 4', 5'-H), 7.10 (dd, J = 8, 2 Hz, 1H, 6-H), 6.25 (s, 2H, 2``, 6 ''-H) ,
5.27 (s, 2H, CH ₂ ), 3.57 (s, 3H, OCH ₃ ), 3.55 (s, 6H, OCH ₃ ), 2.41 (s, 3H, CH ₃ ); ^1
3 C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 161.3, 158.9, 153.3, 153.3, 148.6, 143.6, 13
7.3, 133.7, 132.9, 132.8, 131.8, 125.5, 124.5, 119.6, 116.8, 116.6, 111.3, 104.7
, 104.7, 60.2, 56.5, 56.5, 47.9, 21.6; EIMS: m / z 406 (M ⁺ ).

[Example 3]
2- (2-Chlorophenyl) -5-methyl-1- (3,4,5-trimethoxybenzyl)
Synthesis of benzimidazole (Compound 45) Compound 45 was prepared in a manner similar to that described in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.67-7.60 (m, 2H, 4, 7-H), 7.54-7.48 (m, 4
H, 3 ', 4', 5 ', 6'-H), 7.10 (dd, J = 8, 2 Hz, 1H, 6H), 6.26 (s, 2H, 2``, 6''-H),
5.19 (s, 2H, CH ₂ ), 3.58 (s, 3H, OCH ₃ ), 3.54 (s, 3H, OCH ₃ ), 2.41 (s, 3H, CH ₃ ); ¹³
C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 153.3, 153.3, 150.7, 143.4, 137.2, 133.7, 133
.3, 133.1, 132.4, 132.4, 132.3, 131.7, 130.3, 127.9, 124.7, 119.6, 111.3, 104.8,
104.8, 60.3, 56.2, 56.2, 47.9, 21.6; EIMS: m / z 422 (M ⁺ ).

[Example 4]
Synthesis of 2- (2-ethoxyphenyl) -5-methyl-1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 48) Compound 48 was prepared in a manner similar to that described in Example 1. did.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.52-7.44 (m, 5H, 4, 7, 3 ', 4, 5', 6'-H),
7.20 (d, J = 8 Hz, 1H, 4'H), 7.10 (t, J = 7 Hz, 1H, 5'-H), 7.05 (d, J = 8 Hz, 1H
, 3'H), 6.25 (s, 2H, 2``, 6 ''-H), 5.19 (s, 2H, CH ₂ ), 4.10 (q, J = 7 Hz, 3H, OCH ₂
) 3.59 (s, 6H, OCH ₃ ), 3.56 (s, 3H, OCH ₃ ), 2.40 (s, 3H, CH ₃ ), 1.20 (t, J = 7 Hz,
3H, OCH ₂ CH ₃ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 156.6, 153.2, 153.2, 151.9, 1
43.8, 137.2, 133.6, 132.9, 132.9, 132.1, 131.1, 124.1, 121.1, 120.4, 119.3, 113.
1, 111.0, 105.0, 105.0, 64.1, 60.4, 56.2, 56.2, 48.0, 21.6, 14.9; EIMS: m / z 432
(M ⁺ ).

[Example 5]
Synthesis of 2- (2-hydroxyphenyl) -5-methyl-1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 53) Compound 53 was prepared in a manner similar to that described in Example 1. did.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.62 (s, 1H, 4-H), 7.41 (d, J = 8 Hz, 1H,
6-H), 7.28-7.13 (m, 4H, 7, 3 ', 4', 6'-H), 6.82 (t, J = 6 Hz, 1H, 5'-H), 6.34 (s
, 2H, 2 ", 6" -H), 5.45 (s, 2H.CH ₂ ) 3.81 (s, 3H, OCH ₃ ), 3.7 (s, 6H, OCH ₃ ), 2.5 (s,
3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 159.1, 154.6, 154.6, 152.3, 140.
5, 138.2, 134.3, 134.0, 132.6, 131.9, 127.9, 126.1, 119.6, 119.0,, 118.6, 113.0
, 110.5, 103.6, 103.6, 61.5, 56.8, 56.8, 50.1, 22.2; EIMS: m / z 404 (M ⁺ ).

[Example 6]
5-Methyl-2- (pyridin-4-yl) -1- (3,4,5-trimethoxybenzyl)
Synthesis of Benzimidazole (Compound 70) Compound 70 was prepared in a manner similar to that described in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.74 (d, J = 6 Hz, 1H, 2 ', 6'-H), 7.76 (d,
J = 6 Hz, 1H, 3 ', 5'-H), 7.54-7.51 (m, 2H, 4, 7-H), 7.13 (d, J = 8 Hz, 1H, 6-H)
, 6.28 (s, 2H, 2``, 6 ''-H), 5.52 (s, 2H, CH ₂ ) 3.57 (s, 9H, OCH ₃ ), 2.42 (s, 3H, C
H ₃ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 153.0, 153.0, 150.5, 150.2, 150.2, 14
2.8, 137.7, 136.7, 134.3, 132.3, 131.7, 124.9, 123.2, 123.2, 119.3, 110.9, 103.7
, 103.7, 59.9, 55.7, 55.7, 47.6, 21.1; EIMS: m / z 389.0 (M ⁺ ).

[Example 7]
Synthesis of 5-methyl-2-propyl-1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 71) Compound 71 was prepared in a manner similar to that described in Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.35 (d, J = 2 Hz, 1H, 4-H), 7.31 (d, J =
8 Hz, 1H, 7-H), 6.96 (dd, J = 8, 2 Hz, 1H, 6-H), 6.40 (s, 2H, 2``, 6 ''-H), 5.33
(s, 2H, CH ₂ ), 3.63 (s, 6H, OCH ₃ ), 3.60 (s, 3H, OCH ₃ ), 2.81 (t, J = 7 Hz, 2H, CH ₂
), 2.36 (s, 3H, CH ₃ ), 1.78-1.72 (m, 2H, CH ₂ ), 0.94 (t, J = 7 Hz, 3H, CH ₃ ); ¹³ CN
MR (100 MHz, DMSO-d ₆ ) δ (ppm): 154.8, 153.0, 153.0, 142.7, 136.7, 133.3, 132.8,
130.1, 122.9, 122.9, 118.3, 118.3, 115.3, 111.4, 109.6, 109.6, 105.3, 103.9, 10
3.9, 59.9, 55.8, 55.8, 46.1, 28.4, 21.1, 20.4, 13.7; EIMS: m / z 354.0 (M ⁺ ).

[Example 8]
Synthesis of 2- (1-adamantyl) -5-methyl-1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 72) Compound 72 was prepared in a manner similar to that described in Example 1. .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 7.36 (s, 1H, 4-H), 6.99 (d, J = 8 Hz, 1H,
6-H), 6.90 (d, J = 8 Hz, 1H, 7-H), 6.25 (s, 2H, 2``, 6 ''-H), 5.61 (s, 2H, CH ₂ ),
3.58 (s, 9H, OCH ₃ ), 2.35 (s, 3H, CH ₃ ), 2.13 (br s, 6H, CH ₂ ), 2.02 (br s, 3H, CH)
, 1.79-1.69 (m, 6H, CH ₂ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 171.0, 171.0, 154
.7, 139.2, 139.2, 126.1, 126.1, 125.5, 125.5, 124.7, 124.7, 123.6, 122.3, 116.0,
116.0, 35.4, 35.4, 29.6, 28.1, 27.4, 27.4, 21.8, 21.8, 21.8, 21.2, 21.2, 13.7,
13.7; EIMS: m / z 446.0 (M ⁺ ).

[Example 9]
Synthesis of 5-methyl-2- (1′-naphthyl) -1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 73) Compound 73 was prepared in a manner similar to that described in Example 1. did.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.13 (d, J = 8 Hz, 1H, 8'-H), 8.04 (d, J =
8 Hz, 1H, 2'-H), 7.76 (t, J = 8 Hz, 2H, 7 ', 6'-H), 7.67 (t, J = 8 Hz, 1H, 3'-H)
, 7.58-7.50 (m, 4H, 4, 7, 4 ', 5'-H), 7.12 (d, J = 8 Hz, 1H, 6-H), 6.10 (s, 2H, 2
'', 6 ''-H), 5.22 (s, 2H, CH ₂ ), 3.47 (s, 3H, OCH ₃ ), 3.41 (s, 6H, OCH ₃ ), 2.44 (s,
3H, CH ₃ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 153.2, 153.2, 152.1, 143.6, 137.1
, 133.7, 132.5, 132.2, 131.7, 130.6, 129.2, 128.9, 128.2, 127.6, 127.0, 125.8, 1
25.7, 124.6, 119.6, 111.3, 104.8, 104.8, 60.3, 56.0, 56.0, 47.9, 21.7; EIMS: m / z
438 (M ⁺ ).

[Example 10]
Synthesis of 5-methyl-2- (2′-naphthyl) -1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 74) Compound 74 was prepared in a manner similar to that described in Example 1. did.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.33 (d, J = 2 Hz, 1H, 1'-H), 8.07 (d, J =
8 Hz, 1H, 4-H), 8.00-7.79 (m, 2H, 5, 8-H), 7.89 (dd, J = 8, 2 Hz, 1H, 3'-H), 7.
61-7.52 (m, 4H, 4, 7, 6 ', 7'-H), 7,11 (d, J = 8 Hz, 1H, 6-H) 6.30 (s, 2H, 2``, 6
'' -H), 5.54 (s, 2H, CH ₂ ), 3.55 (s, 6H, OCH ₃ ), 3.50 (s, 3H, OCH ₃ ), 2.43 (s, 3H, C
H ₃ ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ (ppm): 153.1, 152.9, 152.9, 143.1, 136.7, 134
.2, 133.0, 132.6, 132.5, 131.3, 128.8, 128.3, 128.3, 127.9, 127.6, 127.3, 126.8,
126.3, 124.2, 118.9, 110.7, 103.9, 103.9, 59.9, 55.6, 55.6, 47.6, 21.2; EIMS: m
/ z 455 (M ⁺ ).

[Example 11]
Synthesis of 2-phenyl-5- (pyrrolidin-1-yl) -1- (3,4,5-trimethoxybenzyl) -1H-benzo [d] imidazole (Compound 55) 2-Nitro-5- (pyrrolidine- 1-yl) benzenamine: 5-chloro-2-nitroaniline (1.73 g, 10 mmol) and pyrrolidine (1.42 g, 20 mmol)
Was refluxed in a pressure vessel for 6 hours. The solvent was evaporated and the residue was diluted with ethyl acetate. The resulting mixture was washed with aqueous NaHCO ₃ (5%) and distilled water, dried over MgSO ₄ and concentrated to give 2-nitro-5- (pyrrolidin-1-yl) benzenamine as a solid. (Yield 93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.80 (d, J =
8 Hz, 1H, 3-H), 7.22 (s, 2H, NH ₂ ), 6.05 (dd, J = 8, 2 Hz, 1H, 4-H), 5.81 (d, J
= 2 Hz, 1H, 6-H), 3.30-3.27 (m, 4H, 2 ', 5'-H), 1.97-1.91 (m, 4H, 3', 4'-H). ¹³ C NM
R (100 MHz, CDCl ₃ -d ₁ ) δ (ppm): 151.9, 148.3, 127.4, 122.1, 104.7, 94.5, 47.3, 4
7.3, 24.8, 24.8; EIMS: m / z 207 (M ⁺ ).
N- (2-nitro-5- (pyrrolidin-1-yl) phenyl) benzamide: 2-nitro-5- (pyrrolidin-1-yl) benzenamine (4 mmol) and pyridine (8 mmol) in dry dichloromethane (15 mL) To a stirred solution of benzoyl chloride (8 mmo)
l) was added dropwise. The reaction mixture was stirred at room temperature for 8 hours. The solvent was evaporated under vacuum and subjecting the residue of a mixture of hexane and _CH 2 Cl ₂ flash chromatographed on silica gel using as eluent, N-(2-nitro-5- (pyrrolidin-1-yl) Phenyl) benzamide was obtained as a solid.

N- (2-amino-5- (pyrrolidin-1-yl) phenyl) benzamide: N- (2-nitro-5- (pyrrolidin-1-yl) phenyl) benzamide and sodium dithionite in ethanol (150 mL) A mixture of (9 mmol) (3 mmol) was refluxed for 1 hour. After cooling to room temperature, the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give
Crude N- (2-amino-5- (pyrrolidin-1-yl) phenyl) benzamide was obtained.

(E) -N- (5- (pyrrolidin-1-yl) -2- (3,4,5-trimethoxybenzylideneamino) phenyl) benzamide: N- (2-amino-5- (pyrrolidine-) in methanol A mixture of 1-yl) phenyl) benzamide (2 mmol) and 3,4,5-trimethoxybenzaldehyde (3 mmol) was stirred at room temperature for 12 hours. The suspension was filtered and the solid was washed with methanol to give (E) -N- (5- (pyrrolidin-1-yl)
-2- (3,4,5-trimethoxybenzylideneamino) phenyl) benzamide was obtained as a yellow solid.

N- (5- (pyrrolidin-1-yl) -2- (3,4,5-trimethoxybenzylamino) phenyl) benzamide: Compound (E) -N- (5- (pyrrolidine-) in methanol
A suspension of 1-yl) -2- (3,4,5-trimethoxybenzylideneamino) phenyl) benzamide (3 mmol) was cooled in an ice bath. Sodium borohydride was added until the color changed to white. Excess sodium borohydride was quenched by the addition of distilled water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo to give N- (5- (pyrrolidin-1-yl) -2- (3,4,5-trimethoxybenzylamino). ) Phenyl) benzamide was obtained as a solid.

2-Phenyl-5- (pyrrolidin-1-yl) -1- (3,4,5-trimethoxybenzyl) -1H-benzo [d] imidazole: N- (5- (pyrrolidin-) in ethanol (20 mL) To a suspension of 1-yl) -2- (3,4,5-trimethoxybenzylamino) phenyl) benzamide, 4N HCl was added. The reaction mixture is heated at 50 ° C. for 5 hours,
It was then cooled to room temperature. Excess acid was neutralized with ammonium hydroxide, and the resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases are washed with brine and anhydrous MgS
Dried over O ₄ and concentrated under vacuum. The residue was subjected to flash chromatography on silica gel to give 2-phenyl-5- (pyrrolidin-1-yl) -1- (3,4,5-trimethoxybenzyl) -1H-benzo [d] imidazole as a solid. Obtained. ¹ H NMR
(400 MHz, DMSO-d ₆ ) δ (ppm): 7.75-7.72 (m, 2H, 2 ', 6'-H), 7.55-7.50 (m, 3H, 3',
4 ', 5'-H), 7.34 (d, J = 8 Hz, 1H, 7-H), 7.75 (d, J = 2 Hz, 1H, 4-H), 6.60 (dd,
J = 8, 2 Hz, 1H, 6-H), 6.29 (s, 2H, 2``, 6 ''-H), 5.38 (s, 2H, CH ₂ ), 3.56 (s, 9H,
OCH ₃ ), 3.25-3.22 (m, 4H, 2 ', 5'-H), 1.97-1.94 (m, 4H, 3', 4'-H); ¹³ C NMR (100 M
Hz, DMSO-d ₆ ) δ (ppm): 152.9, 152.9, 152.5, 144.8, 144.0, 136.6, 132.7, 130.7, 1
29.4, 128.9, 128.9, 128.7, 128.7, 127.9, 111.1, 109.9, 103.7, 103.7, 99.9, 59.8,
55.7, 55.7, 47.9, 47.9, 47.7, 24.8, 24.8; EIMS: m / z 443 (M ⁺ ).

[Example 12]
Synthesis of 2- (2-ethoxyphenyl) -5- (pyrrolidin-1-yl) -1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 64) Similar to that described in Example 11 Compound 64 was prepared in a manner.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.58-7.44 (m, 2H, 4, 7-H), 7.13-7.08 (m,
4H, 3 ', 4', 5 ', 6'-H), 6.64 (d, J = 9 Hz, 1H, 6-H), 6.18 (s, 2H, 2 ", 6" -H), 5.16
(s, 2H, CH ₂ ), 4.08-3.85 (m, 2H, OCH ₂ ), 3.76 (s, 3H, OCH ₃ ), 3.69 (s, 6H, OCH ₃ ),
3.34-3.28 (m, 4H, CH ₂ ), 2.04-1.97 (m, 4H, CH ₂ ), 1.27-1.18 (m, 3H, OCH ₂ OCH ₃ ); ¹³ C
-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 156.5, 153.2, 153.2, 150.5, 145.3, 142.9, 137.
2, 132.5, 131.7, 126.6, 120.8, 119.0, 112.3, 110.8, 110.1, 103.9, 103.9, 99.8, 6
4.5, 64.1, 60.7, 55.9, 55.9, 48.5, 48.3, 48.3, 25.3, 25.3, 14.1; EIMS: m / z 487 (M ⁺
).

[Example 13]
Synthesis of 2- (furan-2-yl) -5- (pyrrolidin-1-yl) -1- (3,4,5-trimethoxybenzyl) benzimidazole (Compound 77) Similar to that described in Example 11 Compound 77 was prepared in the following manner.

¹ H-NMR (400 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.56 (s, 1H, 4-H), 7.50 (d, J = 9 Hz, 1H,
3'-H), 7.14 (s, J = 9 Hz, 1H, 7-H), 6.90 (s, 1H, 5'-H), 6.6 (dd, J = 9, 2Hz, 1H
, 6-H), 6.56-6.55 (m, 1H, 4'-H), 6.40 (s, 2H, 2 ", 6" -H), 5.57 (s, 2H, CH ₂ ), 3.78
(s, 3H, OCH ₃ ), 3.69 (s, 6H, OCH ₃ ), 3.30-3.27 (m, 5H, CH ₂ ), 1.99-1.97 (m, 3H, CH
₂ ); ¹³ C-NMR (100 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 159.1, 154.6, 154.6, 152.3, 140.5, 138.
2, 134.3, 134.0, 132.6, 131.9, 127.9, 126.1, 119.6, 119.0, 118.6, 113.0, 110.5,
103.6, 103.6, 61.5, 56.8, 56.8, 50.1, 22.2; EIMS: m / z 433 (M ⁺ ).

[Example 14]
Synthesis of 5- (pyrrolidin-1-yl) -1- (3,4,5-trimethoxybenzyl) -2- (thiophen-2-yl) benzimidazole (Compound 78) Similar to that described in Example 11 Compound 78 was prepared in the following manner.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.87-7.83 (m, 1H, 3'-H), 7.47-7.42 (m, 2H
, 4 ', 5'-H), 7.07 (s, 1H, 7-H), 7.06-7.03 (m, 1H, 4-H), 6.63 (dd, J = 9, 2, 1H, 6
-H), 6.31 (s, 2H, 2 ", 6" -H), 5.43 (s, 2H, CH ₂ ), 3.80 (s, 3H, OCH ₃ ), 3.69 (s, 6H,
OCH ₃ ), 3.29-3.09 (m, 5H, CH ₂ ), 2.02-1.98 (m, 3H, CH ₂ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁
) δ (ppm): 153.8, 147.4, 145.6, 144.3, 137.3, 132.4, 132.1, 128.4, 127.8, 127.2
, 116.9, 110.5, 110.1, 102.7, 100.4, 93.8, 60.8, 56.1, 56.1, 48.3, 48.3, 29.7, 2
5.4, 25.4, 14.2; EIMS: m / z 449 (M ⁺ ).

[Example 15]
Synthesis of 5,6-dimethyl-2-phenyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 105) Compound 105 was prepared in a manner similar to that described in Example 1. did.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.00 (d, J = 8 Hz, 1H, ArH), 7.70-7.58 (m
, 5H, ArH), 7.47-7.34 (m, 5H, ArH), 7.24-7.13 (m, 4H, ArH), 7.00 (s, 1H, ArH), 5
.48 (s, 2H, CH ₂ ), 2.38 (s, 3H, CH ₃ ), 2.32 (s, 3H, CH ₃ ), 2.31 (s, 3H, CH ₃ ); ¹³ CN
MR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 151.6, 145.1, 138.4, 135.5, 134.7, 133.5, 133.4,
133.2, 130.6, 129.9, 129.9, 129.1, 129.1, 129.0, 129.0, 128.3, 127.8, 126.7, 12
6.7, 125.5, 123.9, 123.7, 118.9, 118.9, 117.9, 114.1, 110.6, 41.6, 21.5, 20.6, 2
0.2; ESI: m / z 506 (M + 1) ⁺ .

[Example 16]
Synthesis of 6-methyl-2-phenyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 106) Compound 106 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.01 (d, J = 8 Hz, 1H, ArH), 7.76 (d, J =
8 Hz, 1H, ArH), 7.66 (dd, J = 8, 1 Hz, 2H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7
.48-7.21 (m, 6H, ArH), 7.16-7.13 (m, 4H, ArH), 6.98 (s, 1H, ArH), 5.44 (s, 2H, C
H ₂ ), 2.41 (s, 3H, CH ₃ ), 2.32 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm):
152.9, 145.1, 140.6, 135.9, 134.8, 133.4, 130.0, 129.8, 129.5, 129.5, 129.0, 129
.0, 128.8, 128.8, 128.4, 126.7, 126.7, 125.5, 125.5, 124.7, 123.9, 123.6, 119.5,
119.0, 118.6, 114.1, 110.0, 41.3, 21.8, 21.5; ESI: m / z 492 (M + 1) ⁺ .

[Example 17]
2- (2-methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl)
Synthesis of benzimidazole (Compound 107) Compound 107 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.93 (d, J = 8 Hz, 1H, ArH), 7.85 (d, J =
8 Hz, 1H, ArH), 7.59-7.47 (m, 4H, ArH), 7.31-7.24 (m, 2H, ArH), 7.16-7.09 (m, 7
H, ArH), 7.04-6.95 (m, 2H, ArH), 5.30 (s, 2H, CH ₂ ), 3.61 (s, 3H, OCH ₃ ), 2.32 (s,
3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 157.5, 151.6, 145.0, 142.8, 135.1
, 134.8, 134.8, 132.3, 132.3, 131.9, 129.8, 129.8, 128.9, 126.7, 126.7, 125.1, 1
24.5, 123.4, 122.7, 122.4, 121.0, 119.9, 119.0, 117.8, 113.8, 111.1, 110.4, 55.4
, 40.6, 21.5; ESI: m / z 508 (M + 1) ⁺ .

[Example 18]
Synthesis of 2- (2-methoxyphenyl) -5-methyl-1-((1-tosylindol-3-yl) methyl) benzimidazole (Compound 108) Compound 108 in a manner similar to that described in Example 1. Was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.92 (d, J = 8Hz, 1H, ArH), 7.60-7.51 (m,
3H, ArH), 7.46-7.38 (m, 2H, ArH), 7.33-7.20 (m, 2H, ArH), 7.15-7.06 (m, 4H, ArH
), 7.03-6.90 (m, 4H, ArH), 5.24 (s, 2H, CH ₂ ), 3.56 (s, 3H, O CH ₃ ), 2.45 (s, 3H,
CH ₃ ), 2.29 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 157.3, 156.8, 151.
6, 144.9, 143.4, 135.0, 134.7, 133.0, 132.0, 131.6, 129.7, 129.7, 128.9, 126.5,
126.5, 124.9, 124.3, 123.9, 123.3, 120.8, 119.6, 119.2, 119.0, 118.0, 113.7, 110
.9, 109.7, 55.2, 40.4, 21.4, 21.4; ESI: m / z 522 (M + 1) ⁺ .

[Example 19]
2- (2-Ethoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl)
Synthesis of benzimidazole (Compound 109) Compound 109 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.92-7.82 (m, 2H, ArH), 7.59-7.53 (m, 3H,
ArH), 7.50-7.41 (m, 2H, ArH), 7.29-7.21 (m, 2H, ArH), 7.16-7.06 (m, 7H, ArH), 7.
03-6.96 (m, 1H, ArH), 5.34 (d, J = 1 Hz, 2H, CH ₂ ), 3.99 (q, J = 7 Hz, 2H, OCH ₂ CH ₃
), 2.32 (s, 3H, CH ₃ ), 1.18 (t, J = 7 Hz, 3H, OCH ₂ CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁
) δ (ppm): 156.8, 151.5, 145.0, 141.7, 135.1, 134.8, 134.4, 132.4, 132.2, 129.8
, 129.8, 128.8, 126.7, 126.7, 125.1, 124.6, 123.4, 122.9, 122.7, 121.0, 119.6, 1
18.9, 118,5, 117.4, 113.8, 112.2, 110.5,64.2, 40.7, 21.5, 14.5; ESI: m / z 522 (M +
1) ⁺ .

[Example 20]
2- (3-methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl)
Synthesis of benzimidazole (Compound 110) Compound 110 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.99 (d, J = 8 Hz, 1H, ArH), 7.88 (d, J =
8 Hz, 1H, ArH), 7.56 (d, J = 8Hz, 2H, ArH), 7.37-7.28 (m, 3H, ArH), 7.26-7.18 (
m, 6H, ArH), 7.14-7.18 (m, 3H, ArH), 7.02-6.96 (m, 1H, ArH), 5.50 (d, J = 1Hz, 2
H, CH ₂ ), 2.32 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 159.8, 153.4, 1
45.1, 142.6, 135.6, 135.4, 134.6, 130.7, 129.8, 129.8, 129.8, 128.4, 126.7, 126.
7, 125.4, 124.0, 123.6, 123.2, 122.9, 121.1, 120.0, 119.0, 118.5, 116.7, 114.1,
113.9, 110.2, 55.1, 41.2, 21.5; ESI: m / z 508 (M + 1) ⁺ .

[Example 21]
Synthesis of 2- (2-chlorophenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 111) Compound 111 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.93-7.84 (m, 2H, ArH), 7.58 (d, J = 8 Hz
, 2H, ArH), 7.45-7.36 (m, 4H, ArH), 7.32-7.22 (m, 4H, ArH), 7.17-7.06 (m, 5H, Ar
H), 5.33 (s, 2H, CH ₂ ), 2.31 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 1
50.9, 145.0, 142.6, 135.1, 134.7, 134.1, 134.1, 132.0, 131.5, 129.8, 129.8, 129.
8, 129.5, 128.6, 126.9, 126.6, 126.6, 125.1, 124.3, 123.4, 123.2, 122.7, 120.2,
118.8, 117.3, 113.8, 110.4, 40.3, 21.5; ESI: m / z 512 M ⁺ .

[Example 22]
Synthesis of 2- (3-chlorophenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 112) Compound 112 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.00 (d, J = 8 Hz, 1H, ArH), 7.88 (d, J =
8 Hz, 1H, ArH), 7.73-7.71 (m, 1H, ArH), 7.59-7.49 (m, 3H, ArH), 7.45-7.24 (m, 6
H, ArH), 7.21 (d, J = 1 Hz, 2H, ArH), 7.17 (s, 1H, ArH), 7.13 (d, J = 1 Hz, 2H,
ArH), 5.48 (d, J = 1 Hz, 2H, CH ₂ ), 2.32 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ )
δ (ppm): 151.6, 145.2, 141.6, 135.5, 135.4, 135.1, 134.6, 130.5, 130.2, 129.9,
129.9, 129.3, 128.3, 127.1, 126.7, 126.7, 125.6, 124.9, 124.0, 123.9, 123.7, 12
3.6, 119.9, 118.9, 117.9, 114.2, 110.5, 41.4, 21.6; ESI: m / z 512 M ⁺ .

[Example 23]
Synthesis of 2- (4-chlorophenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 113) Compound 113 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.01 (d, J = 8 Hz, 1H, ArH), 7.88 (d, J =
8 Hz, 1H, ArH), 7.63-7.55 (m, 4H, ArH), 7.44-7.28 (m. 5H, ArH), 7.26-7.12 (m, 6
H, ArH), 5.46 (s, 2H, CH ₂ ), 2.34 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (pp
m): 152.2, 145.2, 142.2, 136.6, 135.6, 134.7, 130.3, 129.9, 129.9, 129.2, 129.2,
128.3, 128.3, 127.7, 126.7, 126.7, 125.6, 124.0, 123.7, 123.7, 123.4, 119.9, 11
8.9, 118.9, 118.2, 114.2, 110.3, 41.4, 21.5; ESI: m / z 512 M ⁺ .

[Example 24]
2- (4-Methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl)
Synthesis of benzimidazole (Compound 114) Compound 114 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.00 (d, J = 8 Hz, 1H, ArH), 7.90 (d, J =
8 Hz, 1H, ArH), 7.68-7.56 (m, 4H, ArH), 7.37-7.26 (m, 4H, ArH), 7.24-7.13 (m, 5
H, ArH), 6.93 (d, J = 2 Hz, 1H, ArH), 6.90 (d, J = 2 Hz, 1H, ArH), 5.49 (d, J =
1 Hz, 2H, CH ₂ ), 3.82 (s, 3H, OCH ₃ ), 2.33 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁
) δ (ppm): 161.5, 153.1, 145.1, 141.0, 135.6, 135.1, 134.7, 130.8, 130.8, 130.3
, 129.9, 129.9, 128.4, 126.8, 126.8, 125.6, 124.1, 123.7, 123.5, 120.5, 119.3, 1
18.9, 118.1, 114.5, 114.5, 114.2, 110.3, 55.4, 41.6, 21.6; ESI: m / z 508 (M + 1) ⁺ .

[Example 25]
Synthesis of 2- (3-methoxyphenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 115) Compound in a manner similar to that described in Example 1 115 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.99 (d, J = 8 Hz, 1H, ArH), 7.68 (s, 1H,
ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.37-7.08 (m, 9H, ArH), 7.08-6.97 (m, 3H, Ar
H), 5.49 (s, 2H, CH ₂ ), 3.60 (s, 3H, OCH ₃ ), 2.50 (s, 3H, CH ₃ ), 2.33 (s, 3H, CH ₃ );
¹³ C-NMR (100 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 159.8, 153.3, 145.1, 142.8, 135.5, 134.7,
133.7, 132.8, 130.8, 129.8, 129.8, 129.8 128.5, 126.7, 126.7, 125.4, 124.8, 124
.1, 123.6, 121.1, 119.7, 119.0, 118.6, 116.6, 114.1, 114.0, 109.9, 55.1, 41.3, 2
1.5, 21.5; ESI: m / z 522 (M + 1) ⁺ .

[Example 26]
Synthesis of 2- (4-methoxyphenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 116) Compound in a manner similar to that described in Example 1. 116 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.99 (d, J = 8 Hz, 1H, ArH), 7.67-7.57 (m
, 6H, ArH), 7.38 -7.31 (m, 1H, ArH), 7.19-7.13 (m, 4H, ArH), 7.05 (s, 2H, ArH),
6.89 (d, J = 8 Hz, 2H, ArH), 5.47 (s, 2H, CH ₂ ), 2.48 (s, 3H, CH ₃ ), 2.33 (s, 3H,
CH ₃ ); ESI: m / z 522 (M + 1) ⁺ .

[Example 27]
Synthesis of 2- (2-ethoxyphenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 117) Compound in a manner similar to that described in Example 1 117 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.90 (d, J = 8 Hz, 1H, ArH), 7.6 (s, 1H,
ArH), 7.60-7.49 (m, 3H, ArH), 7.45-7.41 (m, 2H, ArH), 7.22-7.13 (m, 3H, ArH), 7.
09-6.96 (m, 6H, ArH), 5.32 (s, 2H, CH ₂ ), 3.99 (q, J = 7 Hz, 2H, OCH ₂ CH ₃ ), 2.47 (
s, 3H, CH ₃ ), 2.33 (s, 3H, CH ₃ ), 1.18 (t, J = 7 Hz, 3H, OCH ₂ CH ₃ ); ESI: m / z 536 (M
+1) ⁺ .

[Example 28]
Synthesis of 5-chloro-2- (2-methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 118) Compound in a manner similar to that described in Example 1 118 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.95 (d, J = 8 Hz, 1H, ArH), 7.85 (d, J =
2 Hz, 1H, ArH), 7.59-7.46 (m, 4H, ArH), 7.33-7.26 (m, 1H, ArH), 7.17-7.07 (m, 5
H, ArH), 7.06-6.94 (m, 4H, ArH), 5.29 (s, 2H, CH ₂ ), 3.65 (s, 3H, OCH ₃ ), 2.35 (s,
3H, CH ₃ ); ¹³ C-NMR (100 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 157.5, 152.8, 145.2, 143.1, 135
.2, 134.9, 133.3, 132.4, 132.4, 132.2, 129.9, 129.9, 128.8, 128.3, 126.7, 126.7,
125.3, 124.6, 123.6, 123.3, 121.2, 119.5, 118.9, 117.3, 114.0, 111.2, 111.2, 55
.5, 41.0, 21.6; ESI: m / z 543 (M + 1) ⁺ .

[Example 29]
Synthesis of 2- (4-chlorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 119) Compound 119 in a manner similar to that described in Example 1. Was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.08 (d, J = 8 Hz, 1H, ArH), 7.22-7.62 (m
, 5H, ArH), 7.47-7.37 (m, 3H, ArH), 7.35-7.26 (m, 3H, ArH), 7.20-7.18 (m, 2H, Ar
H), 7.14 (d, J = 1 Hz, 1H, ArH), 5.45 (d, J = 1 Hz, 2H, CH ₂ ), 2.49 (s, 3H. CH ₃ ),
2.34 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 151.7, 145.2, 141.6, 13
6.7, 135.6, 134.7, 133.5, 130.4, 130.4, 129.9, 129.9, 129.9, 129.2, 129.2, 128.2
, 127.2, 127.2, 126.7, 125.6, 125.4, 124.0, 123.7, 119.3, 118.1, 118.9, 114.2, 1
09.9, 41.5, 21.6, 21.6; ESI: m / z 549 (M + 23) ⁺ .

[Example 30]
Synthesis of 2- (3-chlorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 120) Compound 120 in a manner similar to that described in Example 1. Was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.99 (d, J = 8 Hz, 1H, ArH), 7.69-7.66 (m
, 2H, ArH), 7.58 (d, J = 8 Hz, 3H, ArH), 7.52-7.39 (m, 3H, ArH), 7.35-7.29 (m, 2
H, ArH), 7.20-7.13 (m, 3H, ArH), 7.08 (s, 2H, ArH), 5.44 (s, 2H, CH ₂ ), 2.50 (s,
3H, CH ₃ ), 2.22 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 151.9, 145.1,
143.0, 135.5, 134.9, 134.6, 132.8, 132.2, 131.5, 130.0, 130.0, 129.8, 129.8, 129
.2, 128.3, 126.8, 126.8, 126.6, 125.5, 125.0, 124.0, 123.6, 119.9, 118.9, 118.4,
114.1, 109.8, 41.2, 21.5, 21.5; ESI: m / z 526 (M + 1) ⁺ .

[Example 31]
Synthesis of 5-methyl-2- (4-methylphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 121) Compound in a manner similar to that described in Example 1 121 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.00 (d, J = 8 Hz, 1H, ArH), 7.65-7.53 (m
, 6H, ArH), 7.38-7.34 (m, 1H, ArH), 7.24-7.14 (m, 6H, ArH), 7.03 (s, 2H, ArH), 5
.44 (s, 2H, CH ₂ ), 2.49 (s, 3H, CH ₃ ), 2.37 (s, 3H, CH ₃ ), 2.33 (s, 3H, CH ₃ ); ¹³ CN
MR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 153.6, 145.0, 142.7, 140.3, 135.6, 134.7, 133.6,
132.7, 129.8, 129.8, 129.6, 129.6, 128.9, 128.9, 128.5, 126.7, 126.7, 126.5, 12
5.4, 124.6, 124.0, 123.6, 119.6, 119.0, 118.6, 114.1, 109.7, 41.3, 22.0, 21.6, 2
1.4; ESI: m / z 506 (M + 1) ⁺ .

[Example 32]
Synthesis of 5-methyl-2- (2-methylphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 122) Compound in a manner similar to that described in Example 1 122 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.93 (d, J = 8 Hz, 1H, ArH), 7.58 (d, J =
8 Hz, 2H, ArH), 7.47-7.32 (m, 3H, ArH), 7.30-7.24 (m, 2H, ArH), 7.18-7.07 (m, 6
H, ArH), 7.02-7.00 (m, 2H, ArH), 5.24 (s, 2H, CH ₂ ), 2.47 (s, 3H, CH ₃ ), 2.33 (s,
3H, CH ₃ ), 2.09 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 153.2, 151.0,
145.0, 138.1, 134.7, 132.2, 130.6, 130.1, 130,1, 130.0, 129.8, 129.8, 129.4, 128
.6, 126.7, 126.7, 125.9, 125.7, 125.2, 124.4, 124.1, 123.4, 119.6, 118.9, 117.8,
113.8, 109.8, 40.0, 21.5, 21.5, 19.6; ESI: m / z 506 (M + 1) ⁺ .

[Example 33]
Synthesis of 5-methyl-2- (2-methylphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 123) Compound in a manner similar to that described in Example 1 123 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.00 (d, J = 8 Hz, 1H, ArH), 7.67 (s, 1H,
ArH), 7.60-7.56 (m, 2H, ArH), 7.52 (s, 1H, ArH), 7.41-7.33 (m, 2H, ArH), 7.31-7
.22 (m, 4H, ArH), 7.19-7.12 (m, 4H, ArH), 7.05 (s, 2H, ArH), 5.46 (s, 2H, CH ₂ ),
2.50 (s, 3H, CH ₃ ), 2.32 (s, 3H, CH ₃ ), 2.20 (s, 3H, CH ₃ ); ESI: m / z 506 (M + 1) ⁺ .

[Example 34]
Synthesis of 2- (2-chlorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 124) Compound 124 in a manner similar to that described in Example 1. Was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.91 (d, J = 8 Hz, 1H, ArH), 7.67-7.57 (m
, 3H, ArH), 7.51-7.38 (m, 3H, ArH), 7.31-7.22 (m, 2H, ArH), 7.18-7.12 (m, 2H, Ar
H), 7.14-7.03 (m, 5H, ArH), 5.31 (s, 2H, CH ₂ ), 2.49 (s, 3H, CH ₃ ), 2.33 (s, 3H, C
H ₃ ); ESI: m / z 526 (M + 1) ⁺ .

[Example 35]
Synthesis of 5-carbonitrile-2-phenyl-3-((1-tosyl-1H-indol-3-yl) methyl) benzimidazole (Compound 125) Compound 125 was prepared in a manner similar to that described in Example 1. Prepared.

¹ H-NMR (400 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.04 (d, J = 8 Hz, 1H, ArH), 7.97 (d, J =
8 Hz, 1H, ArH), 7.76-7.75 (m, 2H, ArH), 7.60-7.54 (m, 5H, ArH), 7.48-7.37 (m, 4
H, ArH), 7.26-7.24 (m, 3H, ArH), 7.16 (s, 1H, ArH), 5.56 (s, 2H, CH ₂ ), 2.37 (s,
3H.CH ₃ ); ESI: m / z 503 (M + 1) ⁺ .

[Example 36]
Synthesis of 2- (2-fluorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 126) Compound in a manner similar to that described in Example 1 126 was prepared.

¹ H-NMR (400 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.91 (d, J = 8 Hz, 1H, ArH), 7.65 (s, 1H,
ArH), 7.62-7.57 (m, 3H, ArH), 7.48-7.44 (m, 2H, ArH), 7.28-7.19 (m, 1H, ArH), 7
.17-7.14 (m, 4H, ArH), 7.11-7.08 (m, 2H, ArH), 7.08 (s, 1H, ArH), 7.01-6.99 (m,
1H, ArH), 5.36 (s, 2H, CH ₂ ), 2.47 (s, 3H, CH ₃ ), 2.32 (s, 3H, CH ₃ ); ¹³ C-NMR (100
MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 161.5, 161.3, 158.8, 148.4, 145.0, 143.2, 142.7, 135.1,
134.7, 133.0, 132.7, 132.4, 132.2, 129.9, 129.8, 128.6, 126.7, 125.2, 124.9, 12
4.8, 124.4, 123.5, 119.7, 118.8, 117.4, 113.8, 110.1, 408, 21.5, 21.5; ESI: m / z
510 (M + 1) ⁺ .

[Example 37]
5-Methyl-2-phenyl-1-((1-phenylsulfonyl-indol-3-yl)
Synthesis of methyl) benzimidazole (Compound 127) Compound 127 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.02 (d, J = 8 Hz, 1H, ArH), 7.78 (s, 1H,
ArH), 7.74-7.70 (m, 4H, ArH), 7.58-7.50 (m, 2H, ArH), 7.48-7.46 (m, 2H, ArH), 7
.42-7.32 (m, 5H, ArH), 7.22 (s, 2H, ArH), 7.19 (d, J = 7 Hz, 2H, ArH), 7.11 (s,
2H, ArH), 5.52 (s, 2H, CH ₂ ), 2.49 (s, 3H, CH ₃ ); ¹³ C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (p
pm): 152.4, 137.6, 135.5, 134.0, 134.0, 132.8, 130.9, 129.3, 129.3, 129.3, 129.3
, 129.1, 129.1, 129.1, 128.3, 127.6, 126.7, 126.7, 126.7, 125.7, 125.7, 124.1, 1
23.8, 118.9, 118.0, 114.1, 110.1, 41.7, 21.6; ESI: m / z 478 (M + 1) ⁺ .

[Example 38]
Synthesis of 5-methyl-2-phenyl-1-((1-methylsulfonyl-indol-3-yl) methyl) benzimidazole (Compound 128) Compound 128 was prepared in a manner similar to that described in Example 1. .

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.87 (d, J = 8 Hz, 1H, ArH), 7.27-7.66 (m
, 2H, ArH), 7.64 (d, J = 1 Hz, 1H, ArH), 7.45-7.44 (m, 2H, ArH), 7.43-7.37 (m, 2
H, ArH), 7.34-7.28 (m, 2H, ArH), 7.24-7.17 (m, 1H, ArH), 7.09 (d, J = 1 Hz, ArH)
, 7.04 (s, 1H, ArH), 5.51 (s, 2H, CH ₂ ), 2.97 (s, 3H, CH ₃ ), 2.47 (s, 3H, CH ₃ ); ¹³
C-NMR (50 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 153.4, 143.0, 135.2, 133.7, 132.6, 130.0, 129
.8, 129.0, 129.0,128.8, 128.8, 128.3, 125.6, 124.7, 123.7, 123.7, 119.7, 119.2,
117.9, 113.3, 109.6, 40.9, 40.7, 21.5; ESI: m / z 416 (M + 1) ⁺ .

[Example 39]
2- (Furan-2-yl) -5-methyl-1-((1-tosyl-indol-3-yl)
Synthesis of methyl) benzimidazole (Compound 129) Compound 129 was prepared in a manner similar to that described in Example 1.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.94 (d, J = 8 Hz, 1H, ArH), 7.60-7.51 (m
, 4H, ArH), 7.36-7.31 (m, 2H, ArH), 7.21-7.12 (m, 5H, ArH), 7.07-7.02 (m, 2H, Ar
H), 6.54-6.52 (m, 1H, ArH), 5.72 (S, 2H, CH ₂ ), 2.47 (s, 3H, CH ₃ ), 2.30 (s, 3H, C
H ₃ ); ESI: m / z 482 (M + 1) ⁺ .

[Example 40]
Synthesis of 5-methyl-2- (thiophen-2-yl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 130) In a manner similar to that described in Example 1. Compound 130 was prepared.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.03-7.99 (m, 1H, ArH), 7.90-7.86 (m, 1H,
ArH), 7.54 (d, J = 8 Hz, ArH), 7.48-7.37 (m, 3H, ArH), 7.35-7.21 (m, 5H, ArH),
7.10 (d, J = 8 Hz, 3H, ArH), 7.03-6.97 (m, 1H, ArH), 5.61 (s, 2H, CH ₂ ), 2.31 (s,
3H, CH ₃ ); ESI: m / z 484 (M + 1) ⁺ .

[Example 41]
Synthesis of 2- (furan-2-yl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 131) Compound 131 was prepared in a manner similar to that described in Example 1. did.

¹ H-NMR (200 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 7.94 (d, J = 8Hz, 1H, ArH), 7.86 (d, J =
8 Hz, 1H, ArH), 7.53 (d, J = 8Hz, 3H, ArH), 7.35-7.24 (m, 5H, ArH), 7.21-7.18 (m
, 2H, ArH), 7.14-7.08 (m, 2H, ArH), 6.57 (dd, J = 3, 2 Hz, 1H, ArH), 5.78 (s, 2H,
CH ₂ ), 2.30 (s, 3H, CH ₃ ); ¹³ C-NMR (100 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 145.0, 144.5, 14
4.2, 143.4, 135.4, 135.0, 134.7, 129.8, 129.8, 129.8, 128.7, 126.7, 126.7, 126.7
, 125.3, 124.3, 123.7, 123.6, 119.5, 119.0, 117.9, 114.3, 114.1, 112.3, 110.0, 4
1.0, 21.5; ESI: m / z 468 (M + 1) ⁺ .

[Example 42]
Synthesis of 2- (4- (diethylamino) phenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 132) Compound 132 was prepared in a manner similar to that described in Example 1. Prepared.

¹ H-NMR (400 MH _Z , CDCl ₃ -d ₁ ) δ (ppm): 8.19 (d, J = 8 Hz, 1H, ArH), 7.76-7.68 (m
, 2H, ArH), 7.63 (d, J = 8 Hz, 1H, ArH), 7.60-7.56 (m, 2H, ArH), 7.48-7.33 (m, 5
H, ArH), 7.26-7.25 (m, 1H, ArH), 7.24-7.19 (m, 2H, ArH), 7.10 (d, J = 8 Hz, 1H,
ArH), 7.05-7.01 (m, 1H, ArH), 6.72 (s, 1H, ArH), 3.45 (q, J = 7 Hz, 4H, NCH ₂ CH ₃
), 2.33 (s, 3H, CH ₃ ), 1.24 (t, J = 7 Hz, NCH ₂ CH ₃ ); ESI: m / z 599 (M + 1) ⁺ .

[Example 43]
Effect on Cell Proliferation and Cell Cycle Progression The anticancer activity of benzimidazole compounds was evaluated by examining its effect on mammalian cancer cell growth and cell cycle progression.

i) SRB assay The NCI / ADR-RES cell line is a DTP Human Tumor Cell Li
ne Screen (Developmental Therapeutics Pro
gram, NCI). Other cancer cell lines (A549, Hep G2, Hep
3B, DU-145, LNCaP, and PC-3) are American Type Culture Collection (American Type Culture Collection).
n) (from Rockville, MD). These cancer cells are 10% (v /
v) Cultured in RPMI 1640 medium containing fetal bovine serum (FBS) and penicillin (100 units / mL) / streptomycin (100 μg / mL). The culture is at 37 ° C.
Maintained in a humidified incubator with 5% CO ₂ /95% air.

Cells were seeded in 96 well plates for 24 hours in medium containing 5% FBS. They were then incubated for an additional 48 or 72 hours with vehicle (0.1% DMSO) or test compound as a control. Cells treated with control or compound were treated with 10
Fixed with% TCA and stained with 0.4% (w / v) SRB in 1% acetic acid. Unbound SRB was washed away with 1% acetic acid, and SRB-bound cells were solubilized with 10 mM Trizma base.

Absorbance (515 nm) measurements were used to obtain the amount of cellular protein indicating cell number at zero time (T ₀ ) in the control (C) and in the presence of the test compound (Tx). The percentage of proliferation at each of the compound concentration levels was calculated. The growth inhibition rate is 100-[(Tx-T ₀
) / (C−T ₀ )] × 100. 50% growth inhibition by test compound (IC
₅₀ ) is defined as the concentration of compound that results in a 50% reduction in the amount of total protein in cells treated with the control.

Compounds 1-63, 68-77, 88-93, 107-114, and 129 were tested. Unexpectedly, of the compounds tested, 23 had an IC ₅₀ value of less than 10 μM in human non-small cell lung cancer A549 cells and 10 was 10 μM in hepatocellular carcinoma HepG2 cells.
An IC ₅₀ value of less than 10 and 10 is less than 10 μM I in hepatocellular carcinoma Hep3B cells
Having a C ₅₀ value, 42 have _{IC 50} values of less than 20μM in prostate cancer PC-3 cells (of which 20 have _{IC 50} values of less than 10 [mu] M). Unexpectedly, Compound 5
IC ₅₀ value of 5 is A549, HepG2, Hep3B, PC-3, DU-145, LN
In breast cancer NCI / ADR-RES cells rich in CaP and P-glycoprotein (P-gp), 2.4, 3.3, 2.4, 2.3, 2.3, 1.7 and 3. 7μM
It is.

ii) FACScan flow cytometric analysis PC-3 cells were treated with Compound 55 (1 μM, 3 μM, and 10 μM different concentrations) at 0, 6, 12, 18, 24, 36, and 48 hours. . After treatment, the cells were washed twice with ice-cold PBS, collected by centrifugation, and fixed in 70% (v / v) ethanol at 4 ° C. for 30 minutes. Cells are then treated with 0.2 ml of buffer (containing 0.2 M Na ₂ HPO ₄ and 0.1 M citrate buffer, pH 7.8) for 30 minutes, centrifuged, and then propidium iodide (PI) staining Buffer (0.1% Triton X in PBS
-100, 100 μg / mL RNase A, 80 μg / mL propidium iodide) 1
Incubated for 30 minutes at 37 ° C. in mL. Cells are detected using a cytofluorometer and the FACScan and CellQuest programs (Becton Dic
Kinson)).

Unexpectedly, compound 55 induced an increase in the G2 / M phase cell population, followed by an increase in the cell cycle hypodiploid (sub-G1, apoptosis) population.

iii) Western blotting analysis for cell cycle regulator expression / activation PC-3 cells were treated with vehicle (0.1% DMSO) or compound 55 (10
μM), 30 min, 45 min, 60 min, and 120 in the Ras test
Minutes; or in the Raf-1, Phospho-MEK, MEK, and GAPDH tests, incubated for 6, 12, 18, and 24 hours. After treatment,
Cells were washed twice with ice-cold PBS and then lysis buffer (20 mM Tris, pH 7.5, 1 m
_{M MgCl 2, 125mM NaCl, 1} % Triton X-100,1mM phenylmethylsulfonyl fluoride, 10 [mu] g / mL leupeptin, 10 [mu] g / mL aprotinin, 25 mM beta-glycerophosphate, 50 mM NaF, and 100μM sodium orthovanadate) dissolved in 100μL I let you. Subsequently, the expression of the protein was detected by Western blotting. Unexpectedly, the results show that compound 55 is Ras,
Raf-1 and MEK were shown to be upregulated.

Cell cycle regulators were also examined by Western blot analysis. The protein (40 μg) in the lysate is separated by electrophoresis in a 10% or 15% polyacrylamide gel, transferred to a nitrocellulose membrane, cyclin E, cyclin A, cyclin B1, Cd.
Immunoreacted with respective antibodies against k1, Cdk2, p27, MPM2, and GAPDH. The results demonstrated that compound 55 upregulates cyclin B1 and downregulated cyclin E and cyclin A. Furthermore, the expression of p27 (Cdk inhibitor) was also decreased by compound 55. These data suggested that Compound 55 induced Cdk1 activation and PC-3 cell mitotic arrest.

[Example 44]
Inhibition of Tubulin Polymerization i) In Vitro Tubulin Turbidity Assay The effect of benzimidazole compounds on tubulin polymerization was determined by CytoDYNAMI.
Detection was performed using an X Screen 03 kit (Cytoskeleton, Inc., Denver, CO).

Tubulin protein (purity> 99%), 80 mM PIPES, 2 mM MgC
l _2, 0.5 mM EDTA, and containing 1.0 mM GTP (pH 6.9) and 5% glycerol, suspended in G-PEM buffer with or without test compound. The mixture was then transferred to a 96 well plate and the absorbance was measured at 340 nm (37 ° C.) for 60 minutes (SpectraMAX Plus, Molecular Devices).
Inc. Made by Sunnyvale, California).

The level of tubulin polymerization was determined by examining the turbidity of the tubulin suspension. The absorbance of the suspension at 340 nm was plotted as a function of time. Accordingly, the rate and extent of tubulin polymerization was determined.

Compound 55 was tested. Unexpectedly, compound 55 inhibited tubulin polymerization in a dose-dependent manner.

ii) In situ tubulin assay Microtubule organization and formation in PC-3 cells was detected by immunofluorescence microscopy.

PC-3 cells were seeded on 8-well chamber slides and vehicle (0.1% DMSO,
Control), compound 55 (10 μM), taxol (0.1 μM), or vincristine (
0.1 μM) and incubated for 18-24 hours. The cells were then fixed with 100% methanol at -20 ° C for 5 minutes and 1% containing 0.1% Triton X-100.
Incubated in bovine serum albumin (BSA) at 37 ° C. for 30 minutes. The cells are then P
The plate was washed twice with BS for 5 minutes and stained with a primary antibody specific for β-tubulin for 1 hour at 37 ° C. Thereafter, FITC-labeled secondary antibody was used (staining was performed at 37 ° C. for 40 minutes, green fluorescence), and protein was detected using a confocal laser microscope system (Leica TCS SP2). Nuclei were visualized by DAPI staining (1 mg / mL DAPI, blue fluorescence).

Tubulin and chromosomal in situ labeling demonstrated that multipolar spindles and nuclei were formed in taxol-treated cells, while multipolar spindles and chromosome condensation were observed in vincristine-treated cells. In contrast, unexpectedly, the major spindle formed in Compound 55 treated cells was unipolar.

[Example 45]
Effects on apoptosis induction The effects of benzimidazole compounds on apoptosis induction were assessed by examining their effects on the expression / activation of Bcl-2 family member proteins, caspases, and c-Jun N-terminal kinase (JNK). Protein Bcl-2
The family is the most important regulator of apoptotic cell death involving mitochondria. Proapoptotic members, Bax, Bak and Bad are required for mitochondrial division, while anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 are
Apoptosis can be prevented by antagonizing proapoptotic members.

PC-3 cells were incubated with vehicle (0.1% DMSO) or compound 55 (10 μM) at 0 hours, 6 hours, 12 hours, 18 hours, 24 hours, and 36 hours. Cells were then harvested and lysed for detection of protein expression with specific antibodies by Western blot analysis. For Western blotting, the lysate (Phosph
o-Bcl-2, Bcl-2, Phospho-Bcl-xL, Bcl-xL, Mcl-
1, Bax, Bak, Bad, GAPDH, cleaved Bad, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, poly- (ADP-ribose) polymerase (PARP), cleaved PARP, and GAPDH ) Protein (40 μg)
Were separated by electrophoresis in 10-15% polyacrylamide gel, transferred to a nitrocellulose membrane and immunoreacted with specific antibodies.

Both anti-apoptotic and pro-apoptotic members of the Bcl-2 family were detected and the results indicated that compound 55 unexpectedly reduced Bcl-2 and Bcl-xL phosphorylation and degradation, and decreased Mcl-1 expression. Indicates that it has been induced. In addition, unexpectedly, compound 55 induced cleavage of proapoptotic Bad into a 15 kDa fragment. This suggested that Compound 55 induced apoptosis of PC-3 cells. Next, the levels of various caspases in Compound 55 treated cells were determined by Western blot analysis. The results show that caspase-9, caspase-3 and PA
It indicates that RP was cleaved to produce catalytically active fragments, suggesting activation of these caspases.

Furthermore, the effect of benzimidazole compounds on JNK activation was evaluated. PC-3
Cells were treated with vehicle (0.1% DMSO), compound 55 (10 μM), or a mixture of compound 55 and SP600125 (20 μM, specific JNK inhibitor) for 12 hours, 24 hours, and 36 hours. The cells are then fixed and stained with propidium iodide,
DNA content was analyzed by FACScan flow cytometer.

The results show that SP600125 significantly inhibited apoptosis induced by compound 55 in PC-3 cells, indicating that apoptosis induced by compound 55 is mediated by JNK. The SP600125 reversible cell population also shifted to the G2 / M phase of the cell cycle, indicating that JNK-mediated apoptosis occurred after checkpoint arrest in the G2 / M phase.
Other Embodiments All of the features disclosed herein can be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

From the above description, those skilled in the art can easily confirm the essential characteristics of the present invention,
Various changes and modifications may be made to the invention to adapt to various uses and conditions without departing from the spirit and scope of the invention. Thus, other embodiments are also
Within the scope of the following claims.

Claims (8)

The following formula:

(Where
R ₁ is Cl, H or CH ₃ ;
R ₂ is H, CN or CH ₃ ;
R ₃ is Cl, F, H, CH ₃ , OCH ₃ , or OC ₂ H ₅ ;
R ₄ is Cl, H, CH ₃ , or OCH ₃ ;
R ₅ is Cl, H, CH ₃ , or OCH ₃ ;
R ₆ and R ₇ are H;
R ₁₀ is 4-methylbenzenesulfonyl)
Or a salt thereof. 5,6-dimethyl-2-phenyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 105),
6-methyl-2-phenyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 106),
2- (2-methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 107),
2- (2-methoxyphenyl) -5-methyl-1-((1-tosylindol-3-yl) methyl) benzimidazole (Compound 108),
2- (2-ethoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 109),
2- (3-methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (compound 110),
2- (2-Chlorophenyl) -1-((1-tosyl-indol-3-yl) methyl)
Benzimidazole (compound 111),
2- (3-Chlorophenyl) -1-((1-tosyl-indol-3-yl) methyl)
Benzimidazole (compound 112),
2- (4-Chlorophenyl) -1-((1-tosyl-indol-3-yl) methyl)
Benzimidazole (compound 113),
2- (4-methoxyphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (compound 114),
2- (3-Methoxyphenyl) -5-methyl-1-((1-tosyl-indole-3-
Yl) methyl) benzimidazole (compound 115),
2- (4-Methoxyphenyl) -5-methyl-1-((1-tosyl-indole-3-
Yl) methyl) benzimidazole (compound 116),
2- (2-Ethoxyphenyl) -5-methyl-1-((1-tosyl-indole-3-
Yl) methyl) benzimidazole (compound 117),
5-Chloro-2- (2-methoxyphenyl) -1-((1-tosyl-indole-3-
Yl) methyl) benzimidazole (compound 118),
2- (4-chlorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 119),
2- (3-chlorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (compound 120),
5-methyl-2- (4-methylphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 121),
5-methyl-2- (2-methylphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 122),
5-methyl-2- (2-methylphenyl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 123),
2- (2-chlorophenyl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (compound 124),
5-carbonitrile-2-phenyl-3-((1-tosyl-1H-indol-3-yl) methyl) benzimidazole (Compound 125),
2- (2-Fluorophenyl) -5-methyl-1-((1-tosyl-indole-3-
Yl) methyl) benzimidazole (compound 126),
5-methyl-2-phenyl-1-((1-phenylsulfonyl-indol-3-yl) methyl) benzimidazole (compound 127), and 5-methyl-2-phenyl-1-((1-methylsulfonyl- Indol-3-yl)
Methyl) benzimidazole (Compound 128)
The compound of claim 1 selected from. The following formula:

(Where
W is CH ₂ or SO ₂ ,
R ₁ is H or CH ₃
R ₂ is H;
R ₁₁ is 2-furyl, 2-thiophenyl, 4-diethylaminophenyl, 3-pyridinyl or 4-pyridinyl;
R ₁₂ is 4-methylbenzenesulfonyl)
Or a salt thereof. 2- (furan-2-yl) -5-methyl-1-((1-tosyl-indol-3-yl) methyl) benzimidazole (Compound 129),
5-Methyl-2- (thiophen-2-yl) -1-((1-tosyl-indole-3-
Yl) methyl) benzimidazole (compound 130),
2- (furan-2-yl) -1-((1-tosyl-indol-3-yl) methyl) benzimidazole (compound 131), and 2- (4- (diethylamino) phenyl) -1-((1 -Tosyl-indol-3-yl) methyl) benzimidazole (compound 132)
3. A compound according to claim 2 selected from.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.   6. A pharmaceutical composition according to claim 5 for use in the treatment of cancer.   The pharmaceutical composition according to claim 5, for use as an antiplatelet agent or an antithrombotic agent. 6. A pharmaceutical composition according to claim 5 for use in the treatment of cardiovascular and cerebrovascular diseases.