EP1200430A1

EP1200430A1 - Thiourea and isothiourea derivatives for inhibiting ras-transformed cell growth

Info

Publication number: EP1200430A1
Application number: EP00948382A
Authority: EP
Inventors: Bong Yong Lee; Jae Gyu Kim; Soon Ho Hwang; Won Hui Yi; Young Hwan Jung; Jae Young Shim; Yoo Hoi Park; Woo Jeon Shim
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 1999-07-30
Filing date: 2000-07-31
Publication date: 2002-05-02
Also published as: AU765433B2; WO2001009128A1; KR100683418B1; KR20010011698A; AU6186700A; JP2003506372A; EP1200430A4; CA2380371A1; CN1376155A; KR20020030084A

Abstract

The present invention relates to thiourea and isothiourea derivatives of formula (I) or pharmaceutically acceptable salt thereof which possess excellent activity for inhibiting ras-transformed cell growth wherein, A, B, R?1, R2, R3, R4, R5 and R6¿ have the same meaning as defined in the specification.

Description

THIOUREA AND ISOTHIOUREA DERIVATIVES FOR INHIBITING RAS-TRANSFORMED CELL GROWTH

Field of the Invention

The present invention relates to novel thiourea and isothiourea derivatives or pharmaceutically acceptable salts thereof which possess excellent activity for inhibiting ras-transformed cell growth, to processes for the preparation thereof, and to a pharmaceutical composition for the inhibition of ras-transformed cell growth comprising the same as an active ingredient.

Background of the Invention

A ras protein is farnesylated or geranylgeranylated by famesyltransferases [farnesyl protein transferase (hereinafter referred to as "FPTase") or geranylgeranyl protein transferase (hereinafter referred to as "GGPTase"), respectively], and then, translocated into an intracelluar membrane, in which the ras protein is activated by GTP or inactivated by GDP. The activated, GTP -bound ras protein triggers the stepwise transmission of the outside signal into nucleus, which, in turn, activates translational factors of cells such as myc, jun and fos, thereby leading to cell growth or nucleus division, (see M. Barbacid, Annu. Rev. Biochem., 56, 779, 1987, P J. Casey et al., Natl. Acad. Sci. U.S.A. 86, 8323, 1989).

When a transformed ras protein variant such as H-Ras, N-Ras, K-RasA and K-RasB derived from mutated ras genes is activated, it remains activated, and causes cell tumorization as the result of unregulated cell growth. The mutated ras genes are found in various cancer cases, e.g., colon cancer (about 50%), pancreas cancer (about 90%), lung cancer (about 50%), and thyroid gland cancer (about 30%) (see S. Rodenhuis, Semin. Cancer Biol. 3, 241, 1992). A number of researches have attempted to develop inhibitors of ras protein variants, focusing mostly on FPTase inhibitors which inhibit the translocation of ras proteins into an intracellular membrane. For example, Cys-Val-Phe-Met, a sequence similar to the C-terminal sequence of ras protein(Cys-Al-A2-Met), has been reported (see J. L. Goldstein et al., J. Biol. Chem., 266, 15575, 1991; A. M. Garcia et al., J. Biol. Chem., 268, 18415, 1993; S. L. Graham et al., J. Med. Chem., 37, 725, 1994).

Further, various derivatives mimicking Cys-Ile-Phe-Met as a prototype inhibitor have been developed. For example, aromatic alkylamine derivatives wherein the Phe-Met moiety is displaced by an aromatic alkylaminefsee S. J. Desolms et al., J. Med. Chem., 38, 3967, 1995) and carbonylamide derivatives wherein aminomethylnaphthalene is combined with cysteine and trans-3(S)- ethylproline(see WO9606609, 1996) have been reported to have FPTase inhibitory activity. And pseudopeptide derivatives containing substituted imidazolethyl group in place of cysteine have been reported to have FPTase inhibitory activity (see J. H. Hunt et al., J. Med. chem., 39, 353, 1996; WO9610035, 1996; WO9610034, 1996; WO9609836, 1996). Further, W09639173 discloses that compounds containing p-cyanobenzyl- imidazolacetate in place of cysteine and N-naphthylmethyl in place of phenylalanine, respectively, in the structure of Cys-Ile-Phe-Met, have FPTase inhibitory activity.

However, it has been pointed out that the above FPTase inhibitors can not effectively inhibit the geranylgeranylation of the K-ras protein, i.e., the most frequently found ras-protein variant in human cancer. Therefore, FPTase inhibitors fail to inhibit the prenylation of the K-ras protein in cells (see G. L. James et al, J. Biol. Chem. 270, 6221, 1995).

The present inventors have endeavored to develop ras-transformed cell growth inhibitors which is capable of blocking the prenylation of the K-ras protein more effectively; and have discovered that novel thiourea or isothiourea derivatives exhibit excellent activity for inhibiting K-ras prenylation as well as ras-transformed cell (per se) growth.

Summary of the Invention

Accordingly, it is a primary object of the present invention to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein,

A is -(CH₂)_n- or -(CH₂) _n-C(=0)-_: , n being an integer from 1 to 4;

R¹ is Cι_-4 alkyl, or benzyl optionally having one or more ring substituents selected from the group consisting of cyano, nitro and methylenedioxy; R² is Cι_-5 alkyl, C_2-5 alkenyl; C_5-7 cycloalkylmethyl; Cι_-3 alkylphenyl; a ring containing group selected from the group consisting of benzyl, α

-methylbenzyl, naphthy lmethyl, pyrrolymethyl, pyridylmethyl, indolylmethyl, and quinolylmethyl, each optionally having one or more ring substituents selected from the group consisting of C_l-3 alkyl, halogen, C_1-3 alkoxy, and trifluoromethyl; . R³ is Ci.io alkyl; C_2-5 alkenyl; C_3-8 cycloalkyl; adamantyl; C_1-5-alkoxy-C_1-5-alkyl; mono- or di- C_1-5-alkylamino-C_1-5-alkyl; Cι_-5 alkoxylcarbonyl; phenyl-C_1-5-alkyl; tetrahydrofuranyl-Cι_-5-alkyl; a nitrogen-containing heterocycle group selected from the group consisting of pyridyl, pyrimidyl, piperidyl, piperazyl, morphorinyl, and morphorinyl-Cι_-5-alkyl, each heterocyclo being optionally substituted with C[.₃ alkyl or Cι_-3 alkoxy; an aromatic ring containing group selected from the group consisting of phenyl, naphthyl, and benzoyl, each optionally having one or more ring substituents selected from the group consisting of Cι_-5 alkyl, Cι_-5 alkoxy, Cι_-5 alkylthio, mono- or di-Ci.s-alkylamino, trifluoromethyl, benzyloxy, hydroxy, halogen, cyano, nitro, Cι_-5 alkoxycarbonyl, acetyl, and phenyl;

R⁴ is hydrogen or C[_-4 alkyl;

R⁵ is phenyl optionally having one or more substituents selected from the group consisting of halogen, Cι_-5 alkyl, C₁.₅ alkoxy, and trifluoromethyl; benzyl; or pyridyl optionally substituted with hydroxy or methoxy; and

R⁶ is C_1-10 alkyl, C_2-5 alkenyl, or benzyl with one or more optional ring substituents selected from the group consisting of Cι_₅ alkoxy, cyano and nitro. It is another object of the present invention to provide processes for preparing the compound of formula (I).

It is a further object of the present invention to provide a pharmaceutical composition for the inhibition of ras-transformed cell growth comprising a therapeutically effective amount of a compound or salt of formula(I) as an active ingredient together with a pharmaceutically acceptable carrier.

Detailed Description of the Invention

The pharmaceutically acceptable salt of the thiourea or isothiourea derivative of the present invention is a non-toxic salt generated from an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, or an organic acid e.g., acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, citric acid, maleic acid, malonic acid, methanesulfonic acid, tartaric acid, malic acid, hydroxymalic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, oxalic acid or trifluoroacetic acid.

Among the compound of formula (I) of the present invention, the preferred are those wherein R¹ is benzyl optionally substituted with cyano, nitro or methylenedioxy; R² is benzyl optionally substituted with halogen, Cι_-5 alkyl or trifluoromethyl; R³ is Cι_-3 alkoxypyridyl; or phenyl optionally substituted with halogen, Cι_-5 alkyl, C₁-₅ alkoxy, trifluoromethyl, hydroxy, C_1-5 alkylthio, or Cι_-5 alkoxycarbonyl; and R⁶ is .₁₀ alkyl. The present invention also provides processes for preparing thiourea and isothiourea derivatives of formula(I).

For example, a thiourea compound of formula(I-l), corresponding to

R⁴

I ₃ the compound of formula(I) wherein B is " , may be prepared by the process which comprises reacting a compound of formula (XXXII) with a compound of formula (XXXIII) or (XXXIV) :

N ^A (XXXII)

R¹

(R³)-N=C=S (XXXIII)

(R³)(R⁴)-N-C(=S)-C1 (XXXIV) wherein A, R¹, R , R and R⁴ have the same meaning as defined above.

Further, an isothiourea compound of formula(I-2), corresponding to the

R⁵-N . ,S-R° compound of formula(I) wherein B is ^ , may be prepared by the process which comprises reacting a compound of formula (If) with a compound of formula (XXXV):

R⁶-X (XXX> wherein R and A have the same meaning as defined above.

The processes for preparing the compound of formula(I) may be conducted in accordance with Reaction Schemes 1 to 6 as described below :

Reaction Scheme 1

(M)

(111) (IV)

(VII) (la)

(VIII) (IX) (X)

Step 2 _0H SteplO (XI) (XII)

Step 11 Step 3

Tr-N OMs Tr-N

\=N \=N -N

"R (XIII) (XIV) (XV)

(XVI) (lb) Reaction Scheme 3

(XVII) (XVIII) (XIX)

Reaction Scheme 4

(XVIII) (XXV) (XXVI)

(XXVII) (XXVIII) (XXIX)

(1d) Reaction Scheme 5

Reaction Scheme 6

R⁶

(if) (ig)

In the above Reaction Schemes, R , R , R , R , R , R , and A have the same meanings as defined previously, and Tr is triphenylmethyl. The processes summarized in the above Reaction Schemes may be conducted in a conventional manner and typical procedures thereof are described below.

Step 1. Amine protection The compound of formula(II) is reacted with N-ethoxycarbonyl phthalimide to give the compound of formula(III) to protect the primary amine group.

Step 2. Imidazole protection The compounds of formula(III), (X) and (XVII) are each dissolved in an appropriate organic solvent and then reacted with triphenylmethyl chloride to give the compounds of formula (IV), (XI) and (XVIII), respectively. Step 3. Addition

The compound of formula(IV), (XIV), (XXI) and (XXV) are each dissolved in an appropriate organic solvent and then reacted with R'-X (X is halogen) to give compounds of formula(V), (XV), (XXII) and (XXVI) , respectively.

The organic solvent may be selected from dichloromethane, dimethylformamide, acetonitrile, methanol, ethyl acetate or a mixture thereof. To facilitate the reaction, the reaction mixture can be heated.

Step 4. Deprotection

Compounds of formula(V) and (XXII) are each reacted with hydrazine to remove the amino-protecting group giving compounds of formula(VI) and (XXIII) , respectively.

Step 5. Reductive alkylation

Compounds of formula(VI) and (XXIII) are each reacted with an aldehyde capable of providing R moiety in the presence of sodium cyanoborohydride or other conventional reducing agent, to give compounds of formula(VII) and (XXIV), respectively. This reaction can be facilitated by the addition of potassium acetate or acetic acid and 3 A molecular sieve. The compound of formula(XXVIII) may be reacted with an amine of R² -NH₂ under the same condition as described in the above to give the compound of formula(XXLX).

Step 6. Addition

Compounds of formula(VII), (XVI), (XXIV) and (XXIX) are each reacted with (R³)-N=C=S or (R³)(R )-N-C(=S)-C1 in dimethylformamide, dichloromethane or acetonitrile to give compounds of formula(Ia), (lb), (Ic) and (Id) , respectively. Step 7. Esterification

The compound of formula (VIII) is reacted with an alcohol under an acidic condition to give the compound of formula(IX).

Step 8. Hydrogenation

The compounds of formula(IX) and (XX) are each reacted with hydrogen in the presence of a catalyst(e.g.: palladium and rhodium) to give the compounds of formula(X) and (XXI), respectively. The preferred solvent for this reaction is dimethylformamide, ethanol or ethyl acetate.

Step 9. Reduction

The compound of formula(XI) is reacted with lithium aluminium hydride in tetrahydrofuran or diethyl ether, to give the compound of formula(XII).

Steps 10, 11, and 15. Substitution

The compound of formula(XII) is reacted with methanesulfonyl chloride in the presence of an organic bases, to give the compound of formula(XIII). The compound of formula(XIII) is reacted with sodium azide in dimethylformamide or hexamethylphosphoramide to give the compound of formula(XIV).

The compound of formula(XVIII) is reacted with acetic anhydride or acetyl halide in the presence of an organic base to give the compound of formula(XXV).

Step 12. Reductive alkylation

A compound of formula(XV) is reacted with an aldehyde capable of providing R² moiety in the presence of triphenylphosphine and sodium borohydride or other conventional reducing agent to give the compound of formula(XVI).

Step 13. Oxidation

The compound of formula(XVIII) or a compound of formula(XXVII) is reacted with pyridine-sulfur trioxide complex or other conventional oxidizing agent to give the compound of formula(XIX) or a compound of formula(XXVIII), respectively.

Step 14. Olefination The compound of formula(XIX) is reacted with a ylide prepared from the reaction of 3-halophthalimide with triphenylphosphine in the presence of a base such as potassium t-butoxide, to give the compound of formιιla(XX).

Step 16. Hydrolysis A compound of formula(XXVI) is hydrolyzed in water, or in a mixture of tetrahydrofuran and water in the presence of an alkali or acid condition to give a compound of formula(XXVII).

Step 17. Amide formation A compound of formula(XXX) is reacted with an amine R²-NH₂ in the presence of an appropriate coupling agent to give a compound of formula(XXXI). The coupling agent may be hydroxybenzotriazole or dialkylcarbodiimidate. A suitable solvent may be dimethylformamide, dichloromethane or a mixture thereof.

Step 18. Addition

A compound of formula(XXXI) is reacted with with (R³)-N=C=S or (R³)(R⁴)-N-C(=S)-C1 in the presence of an appropriate base such as sodium hydride and potassium carbonate to give a compounds of formula(Ie). A suitable solvents for this reaction is dimethylformamide, dimethylsulfoxide or hexamethylphosphoamide.

Step 19. Alkylation

A compound of formula(If) may be reacted with R⁶-X (X is halogen) in dichloromethane, methanol, ethanol, acetonitrile, acetone or dimethylformamide, optionally in the presence of a base such as sodium hydroxide, potassium carbonate or triethylamine, to give a compound of formula(Ig).

The non-toxic pharmaceutically acceptable salts of the compound(I) may be prepared according to conventional methods known per se in the art, by reacting the compound in an appropriate solvent with a stoichiometric or excess amount of an inorganic or organic acid.

The present invention also includes within its scope a pharmaceutical composition for the inhibition of ras-transformed cell growth comprising a therapeutically effective amount of the novel compounds of formula(I), as defined above, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.

The composition of the present invention may include additives such as lactose or com starch, lubricant such as magnesium stearate, or conventional emulsifier, suspending agent, stabilizer, isotonic agent. If necessary, sweetener and/or flavoring agent may be added.

The composition of the present invention may be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions. In case of tablets for oral use, carriers such as lactose, com starch, and lubricating agents, e.g. magnesium stearate, are commonly added. For oral administration in capsule form, lactose and/or dried com starch can be used as a diluent. When an aqueous suspension are required for oral use, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweeteners and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic. The composition of the present invention may be in the form of aqueous solution containing pharmaceutically acceptable carriers, e.g., saline, at a pH level of 7.4. The solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.

The compounds of the present invention may be administered in an effective amount ranging from about 0.1 mg/kg to about 20mg/kg, preferably from about 0.5mg/kg to about lOmg/kg, per day into a subject patient suffered from various cancers, e.g., colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Of course, the dosage may be changed according to patient's age, weight, susceptibility, or symptom.

The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention.

Preparation Example 1

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-trifluoromethyl-benzylam ine

N-[2-(lH-Imidazol-4-yl)]ethyl phthalimide

To a solution of histamine 2HCl(21.5g, 0.12mol) in distilled water(300ml) was added sodium carbonate(37.1g 0.35mol). N-ethoxy carbony lphthalimide(25.6g, 0.12mol) was added dropwise to above solution and the reaction mixture was stirred for 24hr at room temperature. The resulting solid was filtered, washed with water(50ml) and n-hexane(50ml). The title compound(20g) as a white solid to give after dried under in vacuo. Η-NMR(DMSO-d₆ + TFA-di) δ 8.95(s, IH), 7.78(m, 4H), 7.43(s, IH), 3.85(t, 2H), 2.98(t, 2H),

N-[2-(l-Triphenylmethyl-imidazol-4-yl)]ethyl phthalimide

To a solution of N-[2-(lH-imidazol-4-yl)]ethyl phthalimide(20.0g, 82.9mmol) and triethylamine(23.0ml, 166mmol) in co-solvent of DMF(50ml) and dichloromethane(200ml) was added dropwise triphenylmethyl chloride(27.7g, 99.5mmol) under ice-water bath. After the stirring for 24hr at room temperature, dichloromethane(200ml) was added to the reaction mixture. The mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give an oily material. The residue was recrystallized from n-hexane to provide a white solid of the title compound(40g). Η-NMR(DMSO-d₆) δ 7.8(m, 4H), 7.3(m, 9H), 7.2(s, IH), 7.0(m, 6H), 6.6(s, IH), 3.8(t, 2H), 2.8(t, 2H)

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl phthalimide HBr

A suspension of N-[2-(l-triphenylmethyl-imidazol-4-yl)]ethyl phthalimide(40g, 82.7mmol) and 4-cyanobenzyl bromide(19.7g, 91.2mmol) in acetonitile(250ml) were stirred for 24hr at 50-60°C. The reaction mixture was concentrated in vacuo to give an oily material. After the addition of methanol(200ml), the reaction mixture was refluxed for 3hr. The solution was concentrated in vacuo to the volume of 50 ml. Ethyl acetate(200ml) was added, and the solution was stirred for lhr under ice-water bath. The collected solid by filtration was dried in vacuo to give a white solid of the title compound(30.9g). 1H-NMR(DMSO-d₆) δ 9.32(s, IH) 7.8(m, 6H), 7.65(s, IH), 7.5(d, 2H), 5.65(s, 2H), 3.75(t, 2H), 2.90(t, 2H),

N- {2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HC1

To a solution of N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethyl phthalimide HBr(30g, 65.6mmol) in methanol( 100ml) was added hydrazine hydrate(6.4ml, 131.2mmol). The reaction mixture was refluxed for 1.5hr and then HC1 gas was passed the reaction mixture under ice-water bath. The resulting insoluble material was filtered off. The resulting filtrate was concentrated in vacuo and the solid residue was washed with ethyl acetate(50ml), dried in vacuo to give a pale yellow solid of the title compound(25g).

<Step 5> N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-trifluoromethylbenzylami ne

To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(8.5g, 28.4mmol) and 2-(trifluoromethyl)benzaldehyde(3.7ml, 28.4mmol) in methanol( 100ml) were added molecular sieve(3 A , 30g), and acetic acid(0.5ml). The reaction mixture was stirred for 30 minute at room temperature, and sodium cyanoborohydride(2.7g, 42.6mmol) was added dropwise under ice-water bath. The reaction mixture was stirred for 2hr at room temperature. After the removal of insoluble material by filtration, the filtrate was concentrated in vacuo to give a pale yellow liquid. The residue was dissolved in ethyl acetate(200ml), washed with water and saturated NaHC0₃ solution. The organic layer was dried over anhydrous MgS0₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give a liquid of the title compound(4.0g).

1H-NMR(CDC1₃) δ 7.51-7.65(m, 6H), 7.35-7.39(m, IH), 7.09(d, 2H) 6.92(s, IH), 5.17(s, 2H), 3.89(s, 2H), 2.82(t, 2H), 2.60(t, 2H)

Preparation Example 2 Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichlorobenzyl-amine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethylamine 2HCl(900mg, 3.01 mmol) prepared from <Step 4> of Preparation Example 1 and 2,3-dichlorobenzaldehyde(526mg, 3.01mmol) in methanol(20ml) were added molecular sieve(3 A, 3.0g), and acetic acid(0.5ml). The reaction mixture was stirred for 30 minute at room temperature, and sodium cyanoborohydride(378mg, 6.02mmol) was added dropwise under ice-water bath. The reaction mixture was stirred for 4hr at room temperature. After the removal of insoluble material by filtration, the filtrate was concentrated in vacuo to give a pale yellow liquid. The residue was dissolved in ethyl acetate(200ml), washed with water and saturated NaHC0₃ solution. The organic layer was dried over anhydrous Na₂S0 , and concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol= 0/l, v/v) to give a liquid of the title compound(334mg, 49%). R_f=0.3(dichloromethane/methanol = 20/1, v/v)

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.49(s, IH), 7.35-7.40(m, IH), 7.20-7.26(m, 2H), 7.07(d, 2H), 6.91(s, IH), 5.15(s, 2H), 3.84(s, 2H), 2.81(t, 2H), 2.59(t, 2H)

Preparation Example 3

Synthesis of

N- {2-[ 1 -(4-Cyanobenzy 1)- 1 H-imidazol-5-yl] } ethyl-2-chlorobenzylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(2.05g,

6.12mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(769mg, 12.2mmol) and replacing

2-(trifluoromethyl)benzaldehyde with 2-chlorobenzaldehyde(1.03g, 7.33mmol), to give the title compound(462mg, 20%).

R_f=0.2(dichloromethane/methanol = 20/1, v/v)

1H-NMR(CDC1₃) δ 7.59(d, 2H), 7.50(s, IH), 7.32-7.37(m, IH), 7.18-7.30(m, 3H), 7.07(d, 2H), 6.90(s, IH), 5.15(s, 2H), 3.82(s, 2H), 2.78(t, 2H), 2.59(t, 2H)

Preparation Example 4

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-3 -chlorobenzylamine The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethylamine 2HCl(2.05g,

2-(trifluoromethyl)benzaldehyde with 3-chlorobenzaldehyde(1.03g, 7.33mmol), to give the title compound(580mg, 27%). R_f=0.2(dichloromethane/methanol = 20/1, v/v)

Η-NMR(CDC1₃) δ 7.6 l(d, 2H), 7.50(s, IH), 7.22-7.27(m, 3H), 7.05-7.13(m, 3H), 6.91(s, IH), 5.15(s, 2H), 3.71(s, 2H), 2.77(t, 2H), 2.58(t, 2H)

Preparation Example 5

Synthesis of

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -y 1] } ethyl-2-fluorobenzylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(1.88g,

5.61mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(769mg, 12.2mmoι) and replacing

2-(trifluoromethyl)benzaldehyde with 2-fluorobenzaldehyde(694mg,

5.61mmol), to give the title compound(868mg, 46%).

R_f=0.2(dichloromethane/methanol = 20/1, v/v)

Η-NMR(CDC1₃) δ 7.61(d, 2H), 7.49(s, IH), 7.13-7.28(m, 2H), 6.98-7.17(m, 4H), 6.89(s, IH), 5.15(s, 2H), 3.78(s, 2H), 2.78(t, 2H), 2.59(t, 2H)

Preparation Example 6

Synthesis of

N- {2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-3-fluorobenzylamine The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethylamine 2HCl(2.05g,

2-(trifluoromethyl)benzaldehy de with 3 -fluorobenzaldehyde(0.78ml,

6.12mmol), to give the title compound(419mg, 21%). R_f=0.2(dichloromethane/methanol = 20/1, v/v)

Η-NMR(CDC1₃) δ 7.61(d, 2H), 7.49(s, IH), 7.24-7.27(m, IH), 7.07(d, 2H), 6.90-7.05(m, 4H), 5.15(s, 2H), 3.72(s, 2H), 2.77(t, 2H), 2.58(t, 2H)

Preparation Example 7

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-2-methylbenzylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(2.05g,

2-(trifluoromethyl)benzaldehyde with o-tolualdehyde(0.85ml, 6.12mmol), to give the title compound(222mg, 11%).

R =0.2(dichloromethane/methanol = 20/1, v/v)

'H-NMRCCDCls) δ 7.59(d, 2H), 7.48(s, IH), 7.13-7.17(m, 4H), 7.07(d, 2H), 6.91(s, IH), 5.15(s, 2H), 3.71(s, 2H), 2.84(t, 2H), 2.59(t, 2H), 2.28(s, 3H)

Preparation Example 8

Synthesis of

N- {2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-difluorobenzylamine The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethylamine 2HCl(2.05g,

2-(trifluoromethyl)benzaldehyde with 2,3-difluorobenzaldehyde(0.80ml, 6.12mmol), to give the title compound(898mg, 42%). R_f=0.2(dichloromethane/methanol = 20/1, v/v)

Η-NMR(CDC1₃) δ 7.6 l(d, 2H), 7.49(s, IH), 7.09(d, 2H), 7.00-7.06(m, 3H), 6.69(s, IH), 5.16(s, 2H), 3.80(s, 2H), 2.77(t, 2H), 2.58(t, 2H)

Preparation Example 9

Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,6-difluorobenzyl-amine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(2.05g,

2-(trifluoromethyl)benzaldehyde with 2,6-difluorobenzaldehyde(0.80ml,

6.12mmol), to give the title compound(950mg, 44%).

R_f=0.2(dichloromethane/methanol = 20/1, v/v)

1H-NMR(CDC1₃) δ 7.59(d, 2H), 7.48(s, IH), 7.18-7.26(m, IH), 7.07(d, 2H), 6.82-6.90(m, 3H), 5.15(s, 2H), 3.82(s, 2H), 2.73(t, 2H), 2.57(t, 2H)

Preparation Example 10

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-4-trifluoromethyl-benzylam ine The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethylamine 2HCl(4.52g, 13.5mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(1.70g, 27.0mmol) and replacing

2-(trifluoromethyl)benzaldehyde with a , a , a -trifluorp-/?-tolualdehyde(2.35g, 13.5mmol), to give the title compound(2.38g, 46%).

Preparation Example 11

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 -methyl- 1 H-pyrrol-2yl)m ethylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethylamine 2HCl(900mg,

4.0mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(300mg, 4.8mmol) and replacing 2-(trifluoromethyl)benzaldehyde with l-methyl-2-pyrrolecarboxaldehyde(430ul, 4.0mmol), to give the title compound(260mg, 20%). R =0.25(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.62(d, 2H), 7.50(s, IH), 7.10(d, 2H), 6.90(s, IH), 6.60(s, IH), 6.05(t, IH), 5.97(s, IH), 5.20(s, 2H), 3.70(s, 2H), 3.60(s, 3H), 2.82(t, 2H), 2.60(t, 2H)

Preparation Example 12

Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(lH-indol-3-yl)-methylami ne The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using

N- {2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethylamine 2HCl(900mg, 4.0mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(300mg, 4.8mmol) and replacing

2-(trifluoromethyl)benzaldehyde with indole-3-carboxaldehyde(0.58ml, 4.0mmol), to give the title compound(330mg, 23%). Rr=0.05(dichloromethane/methanol = 10/1, v/v) 1H-NMR(CDC1₃) δ 8.20(bs, IH), 7.45-7.62(m, 3H), 7.40(d, IH), 7.10-7.20(m, 2H), 7.00(t, 3H), 6.90(s, IH), 5.10(s, 2H), 4.00(s, 2H), 2.82(t, 2H), 2.60(t, 2H)

Preparation Example 13 Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 -methyl- 1 H-indol-3-yl)m ethylamine

The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethylamine 2HCl(790mg,

3.5mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(260mg, 4.2mmol) and replacing

2-(trifluoromethyl)benzaldehyde with l-methylindole-3-carboxaldehyde(0.56g, 3.5mmol), to give the title compound(260mg, 20%). R_f=0.05(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.60(m, 2H), 7.50(d, 2H), 7.30(m, 2H), 7.13(m, IH), 7.00(d, 2H), 6.92(d, 2H), 5.10(s, 2H), 4.00(s, 2H), 3.80(s, 3H), 2.85(t, 2H), 2.60(t, 2H) Preparation Example 14

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(2-methyl- 1 H-indol-3-yl)m ethylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- 1 H-imidazol-5 -yl]} ethylamine 2HCl(1000mg,

4.5mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(340mg, 5.4mmol) and replacing

2-(trifluoromethyl)benzaldehyde with

2-methylindole-3-carboxaldehyde(720mg, 4.5mmol), to give the title compound(570mg, 34%).

R_f=0.05(dichloromethane/methanol = 10/1, v/v) Η-NMR(CDC1₃) δ 7.52(d, 2H), 7.48(s, IH), 7.40(d, IH), 7.30(m, IH),

7.10(m, 2H), 7.00(d, 2H), 6.78(s, IH), 5.02(s, 2H), 3.85(s, 2H), 2.78(t, 2H),

2.60(t, 2H), 2.35(s, 3H)

Preparation Example 15 Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(5-methoxy-lH-indol-3-yl) methylamine

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethylamine 2HC1( 1 OOOmg,

4.5 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(340mg, 5.4mmol) and replacing

2-(trifluoromethyl)benzaldehyde with 5-methoxyindole-3-carboxaldehyde(720mg, 4.5mmol), to give the title compound(330mg, 19%).

R_f=0.05(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 7.60(s, IH), 7.50(d, 2H), 7.30(d, IH), 7.00(m, 4H),

5.10(s, 2H), 4.00(s, 2H), 3.85(s, 3H), 2.78(t, 2H), 2.60(t, 2H)

Preparation Example 16

Synthesis of

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(6-methyl-pyridin-2-yl)met hylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethylamine 2HCl(790mg,

2-(trifluoromethyl)benzaldehyde with

6-methyl-2-pyridinecarboxaldehyde(420mg, 3.5mmol), to give the title compound(140mg, 12%).

R_f=0.20(dichloromethane/methanol = 10/1, v/v) 1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.50(s, IH), 7.15(d, 2H), 7.05(d, 2H), 6.92(s,

IH), 5.20(s, 2H), 3.82(s, 2H), 2.85(t, 2H), 2.65(t, 2H), 2.55(s, 3H)

Preparation Example 17

Synthesis of N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(2,6-dichloro-pyridin-3-yl) methylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(1.0g, 4.5mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanobόrohydride(0.34g, 5.4mmol) and replacing

2-(trifluoromethyl)benzaldehyde with

2,6-dichloropyridine-3-carboxaldehyde(0.79g, 4.5mmol), to give the title compound(l . lg, 63%).

R_f=0.15(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.65(m, 3H), 7.52(s, IH), 7.22(d, IH), 7.10(d, 2H),

6.92(s, IH), 5.20(s, 2H), 3.80(s, 2H), 2.80(t, 2H), 2.60(t, 2H)

Preparation Example 18

Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(2-chloro-pyridin-3-yl)meth ylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HC1(1.4g, 6.2mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(0.47g, 7.4mmol) and replacing 2-(trifluoromethyl)benzaldehyde with

2-chloropyridine-3-carboxaldehyde(0.88g, 6.2mmol), to give the title compound(1.0g, 46%).

R_f=0.25(dichloromethane/methanol = 10/1, v/v) Η-NMR(CDC1₃) δ 8.28(dd, IH), 7.65(dd, IH), 7.60(d, 2H), 7.50(s, IH), 7.20(m, IH), 7.05(d, 2H), 6.92(s, IH), 5.20(s, 2H), 3.80(s, 2H), 2.80(t, 2H), 2.60(t, 2H)

Preparation Example 19

Synthesis of N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(6-chloro-pyridin-2-yl)meth ylamine

The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethylamine 2HCl(1.2g, 5.3mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(0.4g, 6.4mmol) and replacing

2-(trifluoromethyl)benzaldehyde with

6-chloropyridine-2-carboxaldehyde(0.75g, 5.3mmol), to give the title compound( 1.1 g, 59%).

R_f=0.25(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 7.65(m, 3H), 7.52(s, IH), 7.20(t, 2H), 7.10(d, 2H), 6.92(s,

IH), 5.20(s, 2H), 3.80(s, 2H), 2.80(t, 2H), 2.60(t, 2H)

Preparation Example 20

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(3-chloro-pyridin-4-yl)meth ylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(1.0g, 4.5mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(0.34g, 5.4mmol) and replacing 2-(trifluoromethyl)benzaldehyde with

3-chloropyridine-4-carboxaldehyde(0.64g, 4.5mmol), to give the title compound(0.82g, 52%). R_f=0.25(dichloromethane/methanol = 10/1, v/v) 1H-NMR(CDC1₃) δ 8.50(s, IH), 8.40(d, 2H), 7.60(d, 2H), 7.52(s, IH), 7.30(d, IH), 7.10(d, 2H), 6.92(s, IH), 5.20(s, 2H), 3.82(s, 2H), 2.85(t, 2H), 2.62(t, 2H) Preparation Example 21

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-(quinolin-4-yl)methylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(1.0g, 4.5mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(0.34g, 5.4mmol) and replacing

2-(trifluoromethyl)benzaldehyde with 4-quinolinecarboxaldehyde(0.71 g,

4.5mmol), to give the title compound(0.81g, 49%).

R_f=0.25(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 8.85(d, IH), 8.15(d, IH), 8.05(d, IH), 7.75(t, IH), 7.60(d, 2H), 7.52(s, IH), 7.40(d, IH), 7.10(d, 2H), 6.98(s, IH), 5.20(s, 2H), 4.25(s, 2H),

3.00(t, 2H), 2.65(t, 2H)

Preparation Example 22

Synthesis of N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(naphthyl- 1 -yl)methylamin

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(0.70g,

3.1 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(0.23g, 3.7mmol) and replacing 2-(trifluoromethyl)benzaldehyde with l-naphthaldehyde(0.48g, 3.1 mmol), to give the title compound(0.58g, 51%). R_f=0.25(dichloromethane/methanol = 10/1, v/v) 1H-NMR(CDC1₃) δ 8.03(dd, IH), 7.86(dd, IH), 7.78(dd, IH), 7.50(d, 4H), 7.42(d, 2H), 7.38(s, IH), 7.00(d, 2H), 6.90(s, IH), 5.08(s, 2H), 4.20(s, 2H), 2.90(t, 2H), 2.60(t, 2H)

Preparation Example 23

Synthesis of

N-[2-(l-Methyl-lH-imidazol-5-yl)]ethyl-2-trifluoromethylbenzylamine

<Step 1> 2-( 1 -Methyl- 1 H-imidazol-5-yl)ethyl phthalimide

To a solution of N-[2-(l-triphenylmethyl-imidazol-4-yl)] ethyl ρhthalimide(10.0g, 20.7mmol) prepared from <Step 2> of Preparation Example 1 in acetone( 100ml) was added dimethyl sulfate(2.2ml, 22.7mmol). The reaction mixture was stirred for overnight at room temperature. The solid of reaction mixture was filtered and washed by ethyl ether(50ml) to give the title compound(4.8g, 90%)

R_f=0.20(dichloromethane/methanol = 20/1, v/v) 1H-NMR(DMSO-d₆) δ 9.00(s, IH), 7.85(s, 4H), 7.50(s, IH), 3.90(s, 6H), 3.40(s, 2H), 3.05(t, 2H)

2-( 1 -Methyl- 1 H-imidazol-5 -yl)ethylamine

Hydrazine 2H₂0(1.5ml, 30.0mmol) was added to a solution of

2-(l-methyl-lH-imidazol-5-yl)ethyl phthalimide(4.8g, 15.0mmol) in 50ml of methanol. The reaction mixture was refluxed for 3hr. The reaction mixture was concentrated in vacuo, crystallized with ethyl alcohol(5ml) to give the title compound(1.8g, 95%) as a solid. 1H-NMR(DMSO-d₆) δ 7.50(s, IH), 6.70(s, IH), 3.55(s, 3H), 2.85(t, 2H), 2.70(t, 2H)

N-[2-(l -Methyl- lH-imidazol-5-yl)]ethyl-2-trifluoromethylbenzylamine

To a solution of 2-( 1 -methyl- lH-imidazol-5-yl)ethylamine(630mg, 5.0mmol) in methanol(lθml) were added

2-(trifluoromethyl)benzaldehyde(870mg, 5.0mmol), AcOH(O. lml) and molecular sieve(3 A, lg). The reaction mixture was stirred for lhr at room temperature. Sodium cyanoborohydride(380mg, 6.0mmol) was added dropwise under ice-water bath. The reaction mixture was stirred for 8hr at room temperature. The insoluble material was filtered off by filtration, and the mother liquid was concentrated in vacuo. The residue was dissolved in 20ml of ethyl acetate, and washed with water, saturated NaHC0₃ solution. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol = 10/1, v/v) to give the title compound(320mg, 22.6%). R_f=0.20(dichloromethane/methanol = 10/1, v/v) 1H-NMR(CDC1₃) δ 7.45-7.65(m, 3H), 7.38(s, IH), 7.34(t, IH), 6.80(s, IH), 4.00(s, 2H), 3.58(s, 3H), 2.90(t, 2H), 2.70(t, 2H)

Preparation Example 24

Synthesis of N- [2-( 1 -Methyl- 1 H-imidazol-5 -yl)] ethy 1-2 ,3 -dichlorobenzylamine

The reaction was carried out under the same condition as described in <Step 3> of Preparation Example 23, using

2-(l-methyl- 1 H-imidazol-5 -yl)ethylamine(630mg, 5.0mmol) prepared from <Step 2> of Preparation Example 23 and sodium cyanoborohydride(380mg, 6.0mmol) and replacing 2-(trifluoromethyl)benzaldehyde with 2,3 -dichlorobenzaldehyde(870mg, 5.0mmol), to give the title compound(320mg, 23%). R_f=0.20(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.28-7.40(m, 4H), 6.80(s, IH), 3.96(s, 2H), 3.58(s, 3H), 2.90(t, 2H), 2.75(t, 2H)

Preparation Example 25

Synthesis of

N- { 2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethy 1-2-trifluor omethylbenzylamine

N- { 2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethyl phthalimide

To a solution of N-[2-(l-triphenylmethyl-imidazol-4-yl)]ethyl phthalimide(16.2g 33.5mmol) prepared from <Step 2> of Preparation Example

1 in 150ml of acetonitrile was added piperonyl bromide(7.2g, 33.5mmol). The reaction mixture was stirred at 60 ^°C for overnight. The reaction mixture was concentrated in vacuo and dissolved with 150ml of methanol. The reaction mixture was refluxed for 2hr, cooled to room temperature. The resulting solid was filtered and washed by ethyl ether to give the title compound(9.1g, 72%) as a white solid.

R_f=0.30(dichloromethane/methanol = 20/1, v/v) Η-NMR(DMSO-d₆) δ 9.20(s, IH), 7.85(s, 4H), 7.60(s, IH), 7.00(s, IH),

6.90(s, 2H), 6.00(s, 2H), 5.40(s, 2H), 3.80(t, 2H), 2.95(t, 2H)

N- {2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethylamine To a solution of

N- { 2- [ 1 -(3 ,4-methy lenedioxypheny lmethy 1)- 1 H-imidazol-5 -yl] } ethyl phthalimide(9.1g, 24.2mmol) in methanol(50ml) was added hydrazine hydrate(2.4ml, 48.5mmol). The reaction mixture was refluxed for 3hr. The reaction mixture was concentrated in vacuo to give the title compound(5.38g, 98%) as a solid.

Η-NMR(DMSO-d₆) δ 7.72(s, IH), 6.90(d, IH), 6.75(d, 2H), 6.60(d, IH), 6.60(s, 2H), 5.05(s, 2H), 2.87(t, 2H), 2.70(t, 2H)

N-{2-[l-(3,4-Methylenedioxyphenylmethyl)-lH-imidazol-5-yl]}ethyl-2-trifluor omethylbenzylamine

N-{2-[l-(3,4-Methylenedioxyphenylmethyl)-lH-imidazol-5-yl]}ethyla mine(700mg, 2.8mmol) was reacted with

2-(trifluoromethyl)benzaldehyde(500mg, 2.8mmol) under the same condition as described in <Step 5> of Preparation Example 1 to give the title compound(400mg, 35%).

R_f=0.20(dichloromethane/methanol = 10/1, v/v) Η-NMR^DCla) δ 7.60(d, IH), 7.55(m, 2H), 7.35(m, IH), 6.88(s, IH),

6.75(d, IH), 6.55(s, 2H), 6.00(s, 2H), 5.00(s, 2H), 3.95(s, 2H), 2.85(t, 2H),

2.65(t, 2H)

Preparation Example 26 Synthesis of

N-{2-[l-(3,4-Methylenedioxyphenylmethyl)-lH-imidazol-5-yl]}ethyl-2,3-dichl orobenzylamine

The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, but N- {2-[ 1 -(3,4-methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethylamine(70 Omg, 2.8mmol) prepared from <Step 2> of Preparation Example 25 reacting with 2,3-dichlorobenzaldehyde(500mg, 2.8mmol) instead of

2-(trifluoromethyl)benzaldehyde, to give the title compound(350mg, 31%). R_f=0.20(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.50(s, IH), 7.40(dd, IH), 7.20(m, 2H), 6.90(s, IH), 6.75(d, IH), 6.50(s, 2H), 5.98(s, 2H), 5.00(s, 2H), 3.85(s, 2H), 2.80(t, 2H), 2.65(t, 2H)

Preparation Example 27

Synthesis of N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl -butylamine

The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, using N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(700mg,

3.1 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(230mg, 3.7mmol) and replacing

2-(trifluoromethyl)benzaldehyde with butyraldehyde(230mg, 3.7mmol), to give the title compound(240mg, 27%). R_f=0.10(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.55(s, IH), 7.15(d, 2H), 6.90(s, IH), 5.20(s, 2H), 2.80(m, 2H), 2.60(t, 2H), 2.50(d, IH), 2.00(t, IH), 1.35(m, 2H), 0.90(m, 5H)

Preparation Example 28

Synthesis of N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-isobutylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using N- {2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]} ethylamine 2HCl(700mg, 3.1mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(230mg, 3.7mmol) and replacing

2-(trifluoromethyl)benzaldehyde with isobutyraldehyde(0.28ml, 3.1mmol), to give the title compound(170mg, 19%). R_f=0.10(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.62(d, 2H), 7.48(s, IH), 7.10(d, 2H), 6.86(s, IH), 5.20(s, 2H), 2.82(t, 2H), 2.60(t, 2H), 2.38(d, 2H), 1.70(m, IH), 0.85(d, 6H)

Preparation Example 29 Synthesis of N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-pentylamine

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethylamine 2HCl(700mg, 3.1 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(230mg, 3.7mmol) and replacing

2-(trifluoromethyl)benzaldehyde with valeraldehyde(0.33ml, 3.1mmol), to give the title compound(630mg, 69%). 1H-NMR(CDC1₃) δ 7.60(d, 2H0, 7.50(s, IH), 7.10(d, 2H), 6.90(s, IH), 5.20(s, 2H), 2.80(m, 3H), 2.60(m, 3H), 1.30(m, 4H), 0.90(m, 5H)

Preparation Example 30

Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2-butenylamine

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethylamine 2HCl(700mg,

3.1 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(230mg, 3.7mmol) and replacing 2-(trifluoromethyl)benzaldehyde with crotonaldehyde(0.26ml, 3.1mmol), to give the title compound(420mg, 48%).

Η-NMRCCDCb) δ 7.65(d, 2H), 7.50(d, IH), 7.10(d, 2H), 6.90(d, IH), 5.20(s, 2H), 3.25(m, 2H), 2.40-2.65(m, 6H), 1.10(t, 3H)

Preparation Example 31

Synthesis of

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-cyclohexylmethylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethylamine 2HCl(700mg,

3.1 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(230mg, 3.7mmol) and replacing 2-(trifluoromethyl)benzaldehyde with cyclohexanecarboxaldehyde(0.38ml, 3.1mmol), to give the title compound(750mg, 75%). R_f=0.10(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 7.70(d, 2H), 7.58(s, IH), 7.20(d, 2H), 7.00(s, IH), 5.25(s, 2H), 2.85(t, 2H), 2.65(t, 2H), 2.50(d, 2H)1.80(m, 5H), 1.25(m, 4H), 0.95(m, 2H)

Preparation Example 32

Synthesis of N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-propylamine

The reaction was carried out under the same condition as described in

<Step 5> of Preparation Example 1, using

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethylamine 2HCl(700mg,

3.1 mmol) prepared from <Step 4> of Preparation Example 1 and sodium cyanoborohydride(230mg, 3.7mmol) and replacing 2-(trifluoromethyl)benzaldehyde with propionaldehyde(0.22ml, 3.1mmol), to give the title compound(440mg, 53%). R_f=0.05(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.40(s, IH), 7.05(d, 2H), 6.90(s, IH), 5.18(s, 2H), 2.70(m, 2H), 2.50(m, 2H), 2.25(m, IH), 1.95(m, IH), 1.20(m, 2H), 0.80(t, 3H)

Preparation Example 33

Synthesis of

N-{2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-2-trifluoromethyl-benzylami ne

N- {2-[ 1 -(4-Nitrobenzyl)- 1 H-imidazol-5-yl] } ethyl phthalimide

The reaction was carried out under the same condition as described in

<Step 1> of Preparation Example 25, but

N- [2-( 1 -tripheny lmethyl-imidazol-4-yl)] ethyl phthalimide( 15.5 g 32.1 mmol) prepared from <Step 2> of Preparation Example 1 reacting with 4-nitrobenzyl bromide(6.9g, 32.1mmol) instead of piperonyl bromide, to give the title compound(8.3g, 69%).

R_f=0.30(dichloromethane/methanol = 20/1, v/v)

1H-NMR(DMSO-d₆) δ 9.30(s, IH), 8.23(d, 2H), 7.85(s, 4H), 7.70(s, IH),

7.60(d, 2H), 5.75(s, 2H), 3.80(t, 2H), 2.95(t, 2H)

2-[ 1 -(4-Nitrobenzyl)- 1 H-imidazol-5 -yl] ethylamine

Using the same method as described in <Step 2> of Preparation

Example 25, N-{2-[l-(4-nitrobenzyl)-lH-imidazol-5-yl]}ethyl phthalimide(8.3g, 22.1mmol) was transformed to the title compound(5.4g, 99%).

1H-NMR(DMSO-d₆) δ 8.20(d, 2H), 7.80(s, IH), 7.30(d, 2H), 6.85(s, IH),

5.40(s, 2H), 2.83(t, 2H), 2.63(t, 2H)

N- {2-[ 1 -(4-Nitrobenzyl)- lH-imidazol-5-yl] } ethyl-2-trifluoromethylbenzylamin

2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]ethylamine(700mg, 2.8mmol) was reacted with 2-(trifluoromethyl)benzaldehyde(500mg, 2.8mmol) under the same condition as described in <Step 5> of Preparation Example 1 to give the title compound(440mg, 39%).

R_f=0.20(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.63(d, IH), 7.55(m, 3H), 7.37(m, IH), 7.16(d, IH), 6.95(s, IH), 5.20(s, 2H), 3.92(s, 2H), 2.85(t, 2H), 2.60(t, 2H)

Preparation Example 34

Synthesis of

N-{2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichloro-benzylamine

The reaction was carried out under the same condition as described in <Step 5> of Preparation Example 1, but

2-[ 1 -(4-nitrobenzyl)- lH-imidazol-5-yl]ethylamine(700mg, 2.8mmol) prepared from <Step 2> of Preparation Example 33 reacting with 2,3-dichlorobenzaldehyde(500mg, 2.8mmol) instead of

2-(trifluoromethyl)benzaldehyde, to give the title compound(400mg, 35%). R_f=0.20(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.57(s, IH), 7.40(dd, IH), 7.12-7.22(m, 4H), 6.95(s, IH), 5.20(s, 2H), 3.85(s, 2H), 2.80(t, 2H), 2.60(t, 2H) Preparation Example 35

Synthesis of N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-(α

-methy 1-3 -chloro)benzy lamine

To a solution of

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethylamine 2HCl(0.5g,

2.21mmol) prepared from <Step 4> of Preparation Example 1, AcOH(O. lml), sodium cyanoborohydride(0.21g, 3.32mmol) and molecular sieve(3 A, lg) in 30ml of methanol was added 3'-chloroacetophenone(0.34g, 2.21mmol) at 0^°C . The reaction mixture was stirred for 3hr at room temperature. The reaction mixture was filtered through celite, and mother liquid was concentrated in vacuo. The residue was dissolved in 50ml of dichloromethane and washed with water(50ml). The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(56mg, 7%).

1H-NMR(CDC1₃) δ 6.88-7.63(m, 10H), 5.12(s, 2H), 3.65(dd, IH), 2.47-2.73(m, 4H), 1.28(dd, 3H)

Preparation Example 36

Synthesis of N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(α

-methyl-3-fluoro)benzylamine

The reaction was carried out under the same condition as described in Preparation Example 35, but

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]} ethylamine 2HCl(0.5g,

2.21 mmol) prepared from <Step 4> of Preparation Example 1 reacting with 3'-fluoroacetophenone(0.27g, 2.21mmol) instead of 3'-chloroacetophenone, to give the title compound(87mg, 11%). 1H-NMR(CDC1₃) δ 6.92-7.63(m, 10H), 5.12(s, 2H), 3.65(dd, IH), 2.47-2.73(m, 4H), 1.28(dd, 3H).

Preparation Example 37

Synthesis of N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy 1-2-trifluoromethy Ibenzy la mine

3-(lH-Imidazol-4-yl)-acrylic acid methyl ester HC1

The suspension of urocanic acid(lθθg) in 1000ml of absolute methanol was bubbled by HC1 gas for 30minute under ice-water bath. The reaction mixture was refluxed for lhr and poured into 2000ml of ethyl ether. The resulting solid was filtered and dried in vacuo to give the title compound(140g) as a white solid.

R_f=0.3(dichloromethane/methanol = 20/1, v/v)

1H-NMR(DMSO-d₆) δ 9.24(s, IH), 8.06(s, IH), 7.58(d, IH), 6.94(d, IH),

3.72(s, 3H)

3-(lH-Imidazol-4-yl)-propionic acid methyl ester HC1

To a suspension of 3-(lH-imidazol-4-yl)-acrylic acid methyl ester HCl(140g) and Pd-C(10%, 3g) in MeOH(1500ml) was hydrogenated for 48hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound(152g).

1H-NMR(DMSO-d₆) δ 9.03(s, IH), 7.41(s, IH), 3.60(s, 3H), 2.94(t, 2H), 2.75(t, 2H)

<Step 3> 3 -(1 -Triphenylmethyl- lH-imidazol-4-yl)-propionic acid methyl ester

To a solution of 3-(lH-imidazol-4-yl)-propionic acid methyl ester HCl(152.4g, 0.80mol) and triethylamine(234ml, 1.68mol) in dimethylformamide(760ml) was added a solution of triphenylmethyl chloride(234g, 0.84mol) in dimethylformamide(990ml) under ice-water bath. After stirring for 18hr at room temperature, water(lOL) was added to reaction mixture. The resulting solid was filtered and washed with ethyl ether(2L), dried in vacuo to give the title compound(257g, 81%). R_f=0.4(dichloromethane/methanol = 20/1, v/v)

Η-NMR(DMSO-d₆) δ 7.30-7.36(m, 10H), 7.25(s, IH), 7.11-7.18(m, 5H), 6.56(s, IH), 3.63(s, 3H), 2.89(t, 2H), 2.67(s, 2H)

<Step 4> 3-( 1 -Triphenylmethyl- lH-imidazol-4-yl)-propanol

To a suspension of lithium aluminium hydride(49.2g, 1.30mol) in absolute tetrahydrofuran(2000ml) was added

3 -(1 -triphenylmethyl- lH-imidazol-4-yι)-propionic acid methyl ester(257g, 0.65mol) under ice-water bath. The reaction mixture was stirred for lhr at same temperature and added 100ml of water. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The resulting residue was diluted with ethyl acetate(500ml), and washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give the title compound(202g, 85%).

R_f=0.3(dichloromethane/methanol = 20/1, v/v)

1H-NMR(CDC1₃) δ 7.27-7.36(m, 10H), 7.11-7.18(m, 6H), 6.56(s, IH), 3.74(t,

2H), 2.69(t, 2H), 1.84-1.94(m, 2H)

<Step 5> 3-(l -Triphenylmethyl- lH-imidazol-4-yl)-propyl methanesulfonate

To a solution of 3-(l -triphenylmethyl- lH-imidazol-4-yl)-propanol(202g, 0.55mol) and triethylamine(82.2ml, 0.60mol) in dichloromethane( 1000ml) was added dropwise methanesulfonyl chloride(42.3ml, 0.55mol) in dichloromethane(50ml) under ice- water bath. The reaction mixture was stirred for 18hr at room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to give the title compound(250g). R_f=0.4(dichloromethane/methanol = 20/1, v/v)

Η-NMR(CDC1₃) δ 7.27-7.40(m, 10H), 7.12-7.19(m, 6H), 6.59(s, IH), 4.25(t, 2H), 2.96(s, 3H), 2.67(t, 2H), 2.13-2.02(m, 2H)

<Step 6> 4-(3-Azido-propyl)- 1 -triphenylmethyl- 1 H-imidazole

To a solution of 3-(l-triphenylmethyl-lH-imidazol-4-yl)-propyl methane-sulfonate(250g, 0.56mol) in HMPA(700ml) was added sodium azide(72.8g, 1.12mol). The reaction mixture was heated for 20hr at 60 °C . The reaction mixture was extracted with ethyl acetate, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to give the title compound(206g, 94%). R_f=0.4(dichloromethane/methanol = 20/1, v/v) 1H-NMR(CDC1₃) δ 7.27-7.40(m, 10H), 7.15-7.22(m, 6H), 6.58(s, IH), 3.24(s, 3H), 2.64(t, 2H), 1.87-1.98(m, 2H)

<Step 7> 5-(3-Azido-propyl)-l-(4-cyanobenzyl)-lH-imidazole

To a solution of 4-(3 -azido-propy 1)- 1 -triphenylmethyl- 1 H-imidazole(206g, 0.52mol) in acetonitrile( 1000ml) was added 4-cyanobenzyl bromide(91.9g, 0.47mol). The reaction mixture was heated for 18hr at 65 °C . The solvent was concentrated in vacuo and the resulting residue was diluted with methanol( 1000ml). The reaction mixture was heated for 2hr at 80 °C .

The solution was concentrated in vacuo to the volume of 500 ml and the insoluble material was filtered off. The filtrate was concentrated in vacuo and the solid was washed with ethyl acetate, dried in vacuo to give the title compound as a solid(147.8g, 81%). R_f=0.3(dichloromethane/methanol = 20/1, v/v)

1H-NMR(DMSO-d₆) δ 9.28(s, IH), 7.9 l(d, 2H), 7.64(s, IH), 7.48(α\ 2H), 5.61(s, 2H), 3.35(t, 2H), 2.55(t, 2H), 1.65-1.77(m, 2H)

<Steρ 8> N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-2-trifluoromethylbenzyla mine

To a solution of

5 -(3 -azido-propy 1)- 1 -(4-cyanobenzyl)- 1 H-imidazole( 1.0g, 3.76mmol) and 2-(trifluoromethyl)benzaldehyde(0.51ml, 3.76mmol) in anhydrous tetrahydrofuran(50ml) was added triphenylphosphine(1.0g, 3.76mmol) at 0^°C . The reaction was stirred for overnight at room temperature, concentrated in vacuo and dissolved in methanol(50ml). Sodium borohydride(0.17g, 4.51 mmol) was added dropwise at 0^°C . The reaction mixture was stirred for 30 minute at room temperature, concentrated in vacuo and partitioned with dichloromethane(50ml) and water(50ml). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(1.04g, 69%). Η-NMR(CDC1₃) δ 6.88-7.65(m, 10H), 5.17(s, 2H), 3.89(s, 2H), 2.66(t, 2H), 2,45(t, 2H), 1.78(m, 2H).

Preparation Example 38

Synthesis of N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy 1-2 ,3 -dichlorobenzy 1-amine

The reaction was carried out under the same condition as described in <Step 8> of Preparation Example 37, but

5-(3-azido-propyl)-l-(4-cyanobenzyl)-lH-imidazole(l .0g, 3.76mmol) prepared from <Step 7> of Preparation Example 37 reacting with 2,3-dichlorobenzaldehyde(0.67ml, 3.76mmol) instead of

2-(trifluoromethyl)benzaldehyde, to give the title compound(1.0g, 67%). Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.49(s, IH), 7.35-7.40(m, IH), 7.20-7.26(m, 2H),7.07(d, 2H), 6.9 l(s, IH), 5.18(s, 2H), 3.87(s, 2H), 2.66(t, 2H), 2,39(t, 2H), 1.73-1.81(m, 2H)

Preparation Example 39

Synthesis of

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-3 -chlorobenzyl-amine

5-(3-azido-propyl)-l-(4-cyanobenzyl)-lH-imidazole(1.0g, 3.76mmol) prepared from <Step 7> of Preparation Example 37 reacting with 3-chlorobenzaldehyde(0.44ml, 3.76mmol) instead of

2-(trifluoromethyl)benzaldehyde, to give the title compound(0.76g, 55%). 1H-NMR(CDC1₃) δ 7.6 l(d, 2H), 7.50(s, IH), 7.22-7.27(m, 3H), 7.05-7.13(m, 3H), 6.91(s, IH), 5.19(s, 2H), 3.91(s, 2H), 2.62(t, 2H), 2,44(t, 2H), 1.71-1.82(m, 2H) Preparation Example 40

Synthesis of

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-2-methylbenzylamine

The reaction was carried out under the same condition as described in

<Step 8> of Preparation Example 37, but

5-(3-azido-propyl)-l -(4-cyanobenzyl)- lH-imidazole(1.0g, 3.76mmol) prepared from <Step 7> of Preparation Example 37 reacting with o-tolualdehyde(0.45ml, 3.76mmol) instead of 2-(trifluoromethyl)benzaldehyde, to give the title compound(0.40g, 31%).

1H-NMR(CDC1₃) δ 7.61(d, 2H), 7.49(s, IH), 7.36-7.41(m, IH), 7.20-7.26(m, 2H),7.07(d, 2H), 6.91(s, IH), 5.17(s, 2H), 3.89(s, 2H), 2.66(t, 2H), 2,45(t, 2H), 2.29(s, 3H), 1.74-1.82(m, 2H)

Preparation Example 41

Synthesis of

N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] }propyl-(l -naphthyl)methylamine

5-(3-azido-propyl)-l-(4-cyanobenzyl)-lH-imidazole(1.0g, 3.76mmol) prepared from <Step 7> of Preparation Example 37 reacting with l-naphthaldehyde(0.52ml, 3.76mmol) instead of

2-(trifluoromethyl)benzaldehyde, to give the title compound(0.63g, 44%). 1H-NMR(CDC1₃) δ 8.02(dd, IH), 7.83(dd, IH), 7.79(dd, IH), 7.50(d, 4H), 7.42(d, 2H), 7.38(s, IH), 7.00(d, 2H), 6.68(s, IH), 5.20(s, 2H), 3.88(s, 2H), 2.67(t, 2H), 2,45(t, 2H), 1.74-1.82(m, 2H)

Preparation Example 42 Synthesis of N-{4-[ l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}butyl-2-trifluoromethylbenzylami ne

<Step 1> (1 -Triphenylmethyl- lH-imidazol-4-yl)carboxaldehyde

To a solution of 4-(hydroxymethyl)imidazole HCl(5.0g, 37.2mmol) and triethylamine( 11.4ml, 81.7mmol) in dimethylformamide(50ml) was added triphenylmethyl chloride(11.4g, 40.9mmol) in dimethy lformamide(50ml) under ice- water bath. After stirring for 36hr at room temperature, water( 1500ml) was added to the reaction mixture. The resulting solid was filtered and suspended with ethyl acetate(200ml) for lhr. The resulting solid was filtered and dried in vacuo to give l-(triphenylmethyl)-4-(hydroxymethyl)-imidazole(12.2g, 97%) as a white solid. To a solution of l-(triphenylmethyl)-4-(hydroxymethyl)-imidazole(6.0g, 14.7mmol) in dimethylsulfoxide(75ml) was added sulfur trioxide pyridine complex(5.85g, 36.7mmol) under ice-water bath. After stirring for 3hr at room temperature, water and ethyl acetate were added to the reaction mixture and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was washed with ethyl ether, dried in vacuo to give the title compound(4.02g, 81%). R_f=0.6(dichloromethane/methanol = 20/1, v/v)

1H-NMR(CDC1₃) δ 9.87(s, IH), 7.61(s, IH), 7.53(s, IH), 7.35-7.38(m, 10H), 7.08-7.13(m, 5H)

N- [4-( 1 -Triphenylmethyl- 1 H-imidazol-4-y 1)] -3 -butenyl-phthalimide

To a solution of N-(3-bromopropyl)-phthalimide(10.7g, 40mmol) in acetonitrile( 100ml) was added triphenylphosphine(10.5g, 40mmol), and the reaction mixture was refluxed for 20hr. The reaction mixture was concentrated in vacuo. The resulting solid was washed with water and ethyl ether, dried in vacuo to give the 3-(N-phthalimido)propyl-triphenylphosphonium bromide(18.3g, 86%). To a solution of (l-triphenylmethyl-lH-imidazol-4-yl)carboxaldehyde(4.49g, 13.3mmol) prepared from <Step 1> and 3-(N-phthalimido)propyl-triphenylphosphonium bromide(7.77g, 14.6mmol) in anhydrous tetrahytrofuran( 100ml) was added potassium t-butoxide(1.79g, 15.9mmol). The reaction mixture was stirred for 3hr at 60 °C . The solvent was concentrated in vacuo and the resulting solid was washed with ethyl acetate, dried in vacuo to give the title compound(6.65g, 98%).

R_f=0.3(EtOAc/n-hexane= 2/1, v/v)

1H-NMR(CDC1₃) δ 7.80-7.86(m, 2H), 7.70-7.76(m, 2H), 7.31-7.39(m, 10H), 7.13-7.18(m, 6H), 6.78(s, IH), 6.32(d, IH), 5.50-5.63(m, IH), 3.86(t, 2H), 2.88-2.99(m, 2H)

N-[4-( 1 -Triphenylmethyl- 1 H-imidazol-4-yl)]butyl phthalimide

To a suspension of

N- [4-( 1 -triphenylmethyl- 1 H-imidazol-4-y 1)] -3 -butenyl-phthalimide(3. Og, 5.89mmol) and Pd-C(10%. 0.3g) in tetrahydrofuran/MeOH( 120ml, tetrahydrofuran/MeOH=5/l, v/v) was hydrogenated for 3.5hr. The reaction mixture was filtered and filtrate was concentrated in vacuo to give the title compound(2.8g, 93%).

1H-NMR(CDC1₃) δ 7.81-7.86(m, 2H), 7.68-7.73(m, 2H), 7.29-7.34(m, 10H), 7.11-7.16(m, 6H), 6.52(s, IH), 3.68(t, 2H), 2.58(t. 2H), 1.67-1.70(m, 4H)

<Step 4> N-{4-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}butyl phthalimide A suspension of N-[2-(l-triphenylmethyl-imidazol-4-yl)]butyl phthalimide(2.80g, 5.47mmol) and 4-cyanobenzyl bromide(1.07g, 5.47mmol) in acetonitile(30ml) was stirred for 5hr at 65°C. The reaction mixture was concentrated in vacuo to give an oily material. After the addition of methanol(40ml), the reaction mixture was heated for 1.5hr at 80 °C . The solution was concentrated in vacuo and the residue was dissolved dichloromethane. The mixture was washed with saturated solution of sodium bicarbonate and dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give a white solid of the title compound(1.38g, 66%).

Η-NMR(CDC1₃) δ 7.56-7.67(m, 4H), 7.50-7.53(m, 2H), 7.58(d, 2H), 7.47(s, IH), 7.09(d, 2H), 6.87(s, IH), 5.14(s, 2H), 3.63(t, 2H), 2.42(t, 2H), 1.52-1.73(m, 4H)

<Step 5> l-(4-Cyanobenzyl)-5-(4-aminobutyl)imidazole

To a solution of N-{4-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}butyl phthalimide(1.38g, 3.59mmol)) in ethanol(30ml) was added hydrazine hydrate(0.52g, 10.8mmol). After refluxing for 3hr, the insoluble material was filtered off by filtration. The filtrate was concentrated in vacuo and dichloromethane(40ml) was added. The insoluble material was filtered off and the filtrate was concentrated in vacuo to give a solid of the title compound(0.86g, 95%). R_f=0.1(dichloromethane/methanol = 10/1, v/v)

Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.47(s, IH), 7.07(d, 2H), 6.86(s, IH), 5.12(s, 2H), 2.63(t, 2H), 2.33(t, 2H), 1.42-1.61(m, 6H) <Step 6>

N- {4-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } butyl-2-trifluoromethylbenzylami ne

l-(4-Cyanobenzyl)-5-(4-aminobutyl)imidazole(864mg, 3.4mmol) was reacted with 2-(trifluoromethyl)benzaldehyde(0.45ml, 3.40mmol) under the same condition as described in <Step 5> of Preparation Example 1 to give the title compound(150mg, 11%). R_f=0.2(dichloromethane/methanol= 20/1, v/v) 1H-NMR(CDC1₃) δ 7.56-7.67(m, 4H), 7.50-7.53(m, 2H), 7.58(d, 2H), 7.47(s, IH), 7.09d, 2H), 6.87(s, IH), 5.14(s, 2H), 3.63(t, 2H), 2.42(t, 2H), 1.52-1.73(m, 4H)

Preparation Example 43 Synthesis of

N- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -y l]methyl-2-trifluoromethy 1-benzy lamin e

<Step 1> 1 -(Triphenylmethyl)-4-hydroxymethyl- 1 H-imidazole

Using the same method as described in <Step 2> of Preparation Example 1, 4-(hydroxymethyl)imidazole HCl(5.0g) was transformed to the title compound(12g) as a white solid. 1H-NMR(CDC1₃) δ 7.4(s, IH), 7.3-7.4(m, 9H), 7.1-7.2(m, 6H), 6.8(s, IH), 4.6(s, 2H)

1 -(Triphenylmethyl)-4-acetoxymethyl- 1 H-imidazole To a solution of l-(triphenylmethyl)-4-hydroxymethyl-lH-imidazole(12g, 35.25mmol) in pyridine(50ml) was added acetic anhydride(10ml, 105.75mmol) and the reaction mixture was stirred for overnight at room temperature. The reaction mixture was diluted with ethyl acetate(400ml) and washed with water(300ml X 3), 10% solution of HCl(50ml) and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give a white solid of the title compound(6.5g).

1H-NMR(CDC1₃) δ 7.4(s, IH), 7.3-7.4(m, 9H), 7.1-7.2(m, 6H), 6.7(s, IH), 5.0(s, 2H), 2.1(s, 3H)

<Step 3> l-(4-Cyanobenzyl)-5-acetoxymethyl-l H-imidazole

A suspension of

1 -(triphenylmethyl)-4-acetoxymethyl- 1 H-imidazole(6.5g, 17mmol) and 4-cyanobenzyl bromide(3.7g, 17mmol) in acetonitrile(50ml) were stirred at 50°C for overnight. After the reaction mixture was concentrated in vacuo, and methanol(20ml) was added. The reaction mixture was refluxed for 2hr. The solution was concentrated in vacuo to give a solid of the title compound(5g).

1 -(4-Cyanobenzyl)-5-hydroxymethyl- 1 H-imidazole

To a solution of l-(4-cyanobenzyl)-5-acetoxymethyl-lH-imidazole(5g,

14.9mmol) in tetrahydrofuran(30ml) was added lithium hydroxide monohydrate(1.88g, 44.7mmol) under ice-water bath. After stirring for lhr at room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate( 100ml) and washed with saturated solution of sodium bicarbonate, water and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound(2.35g, 74%). R_f=0.1(dichloromethane/methanol = 20/1, v/v)

1H-NMR(CDC1₃) δ 7.65(d, 2H), 7.52(s, IH), 7.23(d, 2H), 6.98(s, IH), 5.35(s, 2H), 4.42(s, 2H)

<Step 5> l-(4-Cyanobenzyl)-lH-imidzol-5-carboxaldehyde

To a solution of l-(4-cyanobenzyl)-5-hydroxymethyl-lH-imidazole(0.95g, 4.5mmol) in dimethyl sulfoxide(20ml) were added triethylamine(2.5ml, 18.0mmol) and sulfur trioxide pyridine complex(1.80g, 11.3mmol). After stirring for lhr at room temperature, the reaction mixture was diluted with ethyl acetate(50ml) and washed with water, brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound. The title compound was used to next step without further purification. R_f=0.3(dichloromethane/methanol = 20/1, v/v) 1H-NMR(CDC1₃) δ 9.74(s, IH), 7.87(s, IH), 7.78(s, IH), 7.64(d, 2H), 7.26(d, 2H), 5.58(s, 2H)

N-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]-methyl-2-trifluoromethylbenzylamin e

Molecular sieve(3 A, 0.5g) was added to a solution of 1 -(4-cyanobenzyl)- lH-imidzol-5-carboxaldehyde(200mg, 0.95mmol),

2-(trifluoromethyl)benzylamine (170mg, 0.95mmol) and acetic acid(O. lml) in methanol(lθml). After addition of sodium cyanoborohydride(72mg, 1.2mmol) to above solution, the reaction mixture was stirred for overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was diluted in ethyl acetate(lθml), washed with saturated sodium bicarbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(221mg, 63%). R=0.25(dichloromethane/methanol = 20/1, v/v)

Η-NMR^DC ) δ 7.25-7.65(m, 7H), 7.08(d, 2H), 6.98(s, IH), 5.35(s, 2H), 3.85(s, 2H), 3.60(s, 2H)

Preparation Example 44

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } acetyl-2-trifluoromethyl-benzyla mine

<Step 1> lH-Imidazol-4-ylacetic acid methyl ester HC1

Hydrogen chloride gas was bubbled through a solution of 4-imidazoleacetic acid HCl(lOg) in methanol(200 ml) until saturated. The solution was allowed to stand for 18h at room temperature and then concentrated in vacuo to give the title compound(l 1.6g) as a white solid. 1H-NMR(DMSO-d₆) δ 9.05(s, IH), 7.50(s, IH), 3.90(s, 2H), 3.60(s, 3H).

<Steρ 2>

1 -(Triphenylmethyl)- lH-imidazol-4-ylacetic acid methyl ester

To a suspension of lH-imidazol-4-ylacetic acid methyl ester HC1(11.6 g, 65.6 mmol) in dichloromethane(350 ml) and DMF(50 ml) were added triethylamine(27.4 ml, 196.6 mmol) and triphenylmethyl chloride(21.9 g, 78.6 mmol). The mixture was stirred for 15hr. The reaction mixture was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo The residue was purified by silica gel column chromatography(eluent: EtOAc/n-hexane=4/l, v/v) to provide a white solid of the title compound(7.4g). R_f=0.2(EtOAc/n-hexane = 1/1, v/v) 1H-NMR(CDC1₃) δ 7.45(s, IH), 7.05-7.45(m, 15H), 6.75(s, IH), 3.70(s, 2H)

<Step 3> 1 -(4-Cyanobenzyl)- lH-imidazol-5-ylacetic acid methyl ester

To a solution of 1 -triphenylmethyl- lH-imidazol-4-ylacetic acid methyl ester(1.43g, 3.74mmol) in acetonitrile(50 ml) was added 4-cyanobenzyl bromide(0.81g, 4.11mmol) and the mixture was heated to 65°C for 24hr. The reaction mixture was cooled to room temperature and solvent was concentrated in vacuo. Methanol( 100ml) was added to above residue and heated to reflux temperature for lhr. The solution was concentrated in vacuo to the volume of 10 ml. Crystallization from methanol gave the title compound(0.89g, 93%) as a white solid. 1H-NMR(DMSO-d₆) δ 9.30(s, IH), 7.95(d, 2H), 7.70(s, IH), 7.52(d, 2H), 5.65(s, 2H), 3.92(s, 2H), 3.50(s, 3H)

1 -(4-Cyanobenzyl)- lH-imidazol-5-ylacetic acid HC1

A solution of 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -ylacetic acid methyl ester(3.3g) in 1.0N HC1(25 ml) was heated at 60°C for 4hr and concentrated in vacuo to dryness. The title compound was obtained as a white solid.

1H-NMR(DMSO-d₆) δ 14.60(br, IH), 12.95(br, IH), 9.35(s, IH), 7.95(d, 2H), 7.65(s, IH), 5.60(s, 2H), 3.80(s, 2H) <Step 5>

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } acetyl-2-trifluoromethylbenzylam ine

To a solution of 1 -(4-cyanobenzyl)- lH-imidazol-5-ylacetic acid HCl(3.33g, 0.012mol) and 2-(trifluoromethyl)benzylamine(1.75g, O.Olmol) in dichloromethane(40ml) were added l-hydroxybenzotriazole(1.62g, 0.012mol), EDAC(2.30g, 0.012mol) and triethylamine(3.51ml, 0.025mol). The reaction mixture was stirred for 18hr at room temperature and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methano 1=40/1, v/v) to give the title compound(1.90g, 47%). R_f=0.3 (dichloromethane/methanol = 20/ 1 , v/v)

'H-NMR CDCl- δ 7.45-7.71(m, 7H), 7.16(d, 2H), 7.03(s, IH), 6.18(br, IH), 5.25(s, 2H), 4.53(d, IH), 3.44(s, 2H)

Preparation Example 45 Synthesis of

N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] }propionyl-2-trifluoromethylbenzy lamine

<Step 1> 3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]propionic acid methyl ester

4-Cyanobenzyl bromide(1.63g, 8.32mmol) was added to a solution of

3 -(1 -triphenylmethyl- lH-imidazol-4-yl)-propionic acid methyl ester(3.00g,

7.56mmol) prepared from <Step 3> of Preparation Example 37 in ethyl acetate(20ml). The reaction mixture was stirred at 60 °C for 20hr and concentrated in vacuo. Methanol(30ml) was added to the residue and the mixture was stirred for lhr at 80 ^°C . The reaction mixture was concentrated in vacuo to give the title compound(2.32g, 88%). R_f=0.3(dichloromethane/methanol = 20/1, v/v) 1H-NMR(CDC1₃) δ 9.49(s, IH), 7.70(d, 2H), 7.67(s, IH), 7.41(d, 2H), 7.33(s, IH), 5.66(s, 2H), 3.59(s, 3H), 2.76(t, 2H), 2.58(t, 2H)

3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]propionic acid HC1

The reaction mixture of

3-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl]propionic acid methyl ester HBr(1.32g,

3.77mmol) and 4N-HCl(10ml) were stirred for 3hr at 100^°C . The solution was concentrated in vacuo and the residue was washed with ethyl ether. The solid was dried to give the title compound( 1.16g) .

R_f=0.3(dichloromethane/methanol = 20/1, v/v)

Η-NMR CDC ) δ 9.38(s, IH), 7.91(d, 2H), 7.59(s, IH), 7.49(d, 2H), 5.69(s,

2H), 2.69(t, 2H), 2.56(t, 2H)

N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] }propionyl-2-trifluoromethy Ibenzy lamine

To a solution of 3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]propionic acid HCl(1.16g 3.97mmol), triethylamine( 1.22ml, 8.73mmol), EDAC(0.91g, 4.76mmol) and l-hydroxybenzotriazole(0.64g, 4.76mmol) in dichloromethane(30ml) was added 2-(trifluoromethyl)benzylamine(0.63g, 3.57mmol). The reaction mixture was stirred for 18hr at room temperature and washed with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(930mg, 57%). Η-NMR(CDC1₃) δ 7.72(s, IH), 7.66(d, 2H), 7.40-7.60(m, 4H), 7.16(d, 2H), 6.90(s, IH), 6.18(t, IH), 5.23(s, 2H), 4.63(d, 2H), 2.79(t, 2H), 2.54(t, 2H)

Preparation Example 46

Synthesis of

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-2-methylphenylamine

The reaction mixture of

N- { 2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy lamine( 1.33 g, 5.OOmmol), 2-bromotoluene(0.86g, 5.00mmol), sodium t-butoxide(0.67g, 7.00mmol), tris(dibenzylideneacetone)dipalladium(0)( 11.5mg, 0.013mmol) and

(S)-(-)-2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl(23.4mg, 0.036mmol) in toluene(25ml) were stirred for overnight at 90°C through sealed tube reaction. The reaction mixture was poured into ethyl ether( 100ml) and the insoluble material was filtered off. The filtrate was concentrated in vacuo to give the title compound(684mg, 43%).

Example 1

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

To a solution of N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethyl-2-trifluoromethylbenzylami ne(120mg, 0.312mmol) prepared from Preparation Example 1 in dichloromethane(lθml) was added 4-methoxyphenyl isothiocyanate(62mg, 0.375mmol). The mixture was stirred for 3hr at room temperature. After concentration in vacuo, the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give a solid(165mg, 96%) of the title compound. R_f=0.3(dichloromethane/methanol=40/l , v/v)

1H-NMR(CDC1₃) δ 7.75(d, IH), 7.57-7.64(m, 3H), 7.48-7.52(m, 2H), 7.35(d, IH), 7.13(d, 2H), 7.03(d, 2H), 6.92(s, 2H), 6.84(d, 2H), 5.44(s, 2H), 4.97(s, 2H), 3.98-4.02(m, 2H), 3.78(s, 3H), 2.99(t, 2H)

Example 2

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethyl-2-trifluoromethylbenzylami ne(120mg, 0.312mmol) prepared from Preparation Example 1 in dichloromethane(lθml) was added 2-methoxypyridin-5-yl isothiocyanate(62.3mg, 0.375mmol). The mixture was stirred for 3hr at room temperature. After concentration in vacuo, the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give a solid(122mg, 71%) of the title compound.

R_f=0.3 (dichloromethane/methanol=40/ 1 , v/v) 1H-NMR(CDC1₃) δ 7.34-7.80(m, 2H), 7.57-7.61 (m, 3H), 7.47-7.53(m, 2H),

7.35(d, IH), 7.14-7.27(m, 3H), 6.89(s, IH), 6.71(d, 2H), 5.41(s, 2H), 5.00(s,

2H), 4.00(t, 2H), 3.90(s, 3H), 2.98(t, 2H)

Example 3 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-2-trifluoromethylbenzylamine HC1

To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-2-trifluoromethylbenzylamine(675mg) prepared from Example 2 in ethyl acetate(20ml) was bubbled by HC1 gas at ice bath. The mixture was diluted with diethyl ether(50ml) and the resulting solid was filtered. The solid was dried in vacuo to give the title compound(592mg, 77%). Η-NMR(CD₃OD) δ 9.04(s, IH), 8.10-8.18(m, 2H), 7.63-7.80(m, 4H), 7.52-7.59(m, 2H), 7.17-7.43(m, 4H), 5.68(s, 2H), 5.16(s, 2H) 4.07(s, 3H), 4.0 l(t, 2H), 3.10(t, 2H)

Example 4-39

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-trifluoromethyl-b enzylamine prepared from Preparation Example 1 was reacted with the corresponding isothiocyanates under the same condition as described in Example 1 to give the title compounds.

Example 4

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-allylthiocarbamoyl-2-trif luoromethylbenzylamine

LC/MS(MH⁺) 484

Example 5

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-isobutylthiocarbamoyl-2- trifluoromethylbenzylamine

LC/MS(MH⁺) 500

Example 6

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxyethyl)thio-car bamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 7.7(d, IH), 7.5-7.7(d+m, 3H), 7.5(m, IH), 7.1-7.2(m,

3H), 6.9(s, IH), 5.4(s, 2H), 4.8(s, 2H), 4.0(m, 2H), 3.7(q, 2H), 3.4(t, 2H), 3.1(s, 3H), 2.9(m, 2H) LC/MS(MH⁺) 502

Example 7

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-ethoxypropyl)thio-car bamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 529

Example 8

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(n-butyl)thiocarbamoyl-2 -trifluoromethy Ibenzy lamine LC/MS(MH⁺) 514

Example 9

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-cyclopentylthio-carbamo yl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 512

Example 10

N-{2-[l -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl]}ethyl-N-cyclohexylthio-carbamo yl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 526

Example 11

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)thio-car bamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.8(d, IH), 7.6(d, 2H), 7.5(m, 2H), 7.3-7.3(m, 3H), 7.0-7.2(m, 3H), 6.9(m, 3H), 5.4(s, 2H), 5.0(s, 2H), 4.0(m, 2H), 3.0(m, 2H) LC/MS(MH⁺) 538

Example 12 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxyphenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 8.3(d, IH), 7.6(d+m, 3H), 7.4-7.5(m, 2H), 7.3(m, IH), 7.2(d, 2H), 7.1(d, IH), 7.0(m, 2H), 6.8(d, IH), 5.5(s, 2H), 5.0(s, 2H), 4.0(m, 2H), 3.5(s, 3H), 3.0(m, 2H) LC/MS(MH⁺) 550

Example 13

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 7.8(d, IH), 7.5-7.6(m, 5H), 7.4(d, IH), 7.1-7.2(m, 4H),

7.0(s, IH), 6.9-7.0(m, 2H), 5.4(s, 2H), 5.0(s, 2H), 4.0(m, 2H), 3.0(m, 2H), 2.3(s,

3H)

LC/MS(MH⁺) 534

Example 14

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-nitrophenyl)thio-carba moyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 8.2(d, 2H), 7.8(d, IH), 7.5-7.6(m, 5H), 7.4(d, 2H), 7.3(d, IH), 7.2(d, 2H), 7.0(s, IH), 5.4(s, 2H), 5.0(s, 2H), 4.0(m, 2H), 3.0(t, 2H)

LC/MS(MH⁺) 565

Example 15

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-trifluoromethyl-pheny l)thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 588

Example 16

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methyl-phen yl)thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 568

Example 17

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-benzylthiocarbamoyl-2-t rifluoromethylbenzylamine LC/MS(MH⁺) 534

Example 18

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-phenylphenyl)thio-car bamoy 1-2-trifluoromethy Ibenzy lamine LC/MS(MH⁺) 596

Example 19

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-chlorophenyl)thio-car bamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 554

Example 20

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[2-(N",N"-dimethyl-ami no)ethyl]thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 515

Example 21

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-trifluoromethoxy-phe nyl)-thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 604

Example 22

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-hydroxy-4-methoxyph eny l)-thiocarbamoy 1-2-trifluoromethy Ibenzy lamine 1H-NMR(CDC1₃) δ 7.7(d, IH), 7.5-7.6(m, 4H), 7.3(d, IH), 7.1(d, 2H), 6.9(d, 2H), 6.8(d, lH), 6.6-6.7(m, 2H), 5.4(s, 2H), 5.0(s, 2H), 4.0(m, 2H), 3.9(s, 3H), 3.0(m, 2H) LC/MS(MH⁺) 566

Example 23

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methylthiophenyl)-thi ocarbamoyl-2-trifluoromethylbenzylamine

LC/MS(MH⁺) 566

Example 24

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(naphthyl- 1 -yl)thio-carba moyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.7-7.8(m, 4H), 7.5-7.6(m, 5H), 7.3-7.5(m, 4H), 7.3(s, IH), 7.1(d, 2H), 7.0(s, IH), 5.4(s, 2H), 5.0(s, 2H), 4.0(m, 2H), 3.0(m, 2H)

LC/MS(MH⁺) 570

Example 25

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2,2-dimethyl-3,3-dimeth yl-butyl)thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 556

Example 26

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-phenylethyl)thio-carb amoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 548

Example 27

N- {2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-phenylthiocarbamoyl-2-t rifluoromethylbenzylamine LC/MS(MH⁺) 520

Example 28

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(t-butyl)thiocarbamoyl-2 -trifluoromethylbenzylamine LC/MS(MH⁺) 500

Example 29

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(n-buty l)thiocarbamoy 1-2 -trifluoromethylbenzylamine LC/MS(MH⁺) 500

Example 30

N- {2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(n-propyl)thio-carbamoy 1-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.7(d, IH), 7.5-7.6(d+m, 4H), 7.4(d, IH), 7.3(s, IH),

7.2(d, 2H), 6.9(s, IH), 5.5(s, 2H), 4.8(s, 2H), 4.0(m, 2H), 3.5(q, 2H), 2.9(m,

2H), 1.4(q, 2H), 0.7(t, 3H)

LC/MS(MH⁺) 486

Example 31

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-ethylthiocarbamoyl-2-trif luoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.7(d, IH), 7.5-7.6(d+m, 4H), 7.5(d, IH), 7.1-7.3(d+m, 3H), 6.9(s, IH), 5.5(s, 2H), 4.8(s, 2H), 3.9(dd, 2H), 3.5(q, 2H), 2.9(m, 2H),

1.0(t, 3H)

LC/MS(MH) 472

Example 32 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-adamantylthio-carbamoy 1-2-trifluoromethylbenzylamine LC/MS(MH⁺) 578

Example 33 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-methylthiocarbamoyl-2-t rifluoromethylbenzylamine LC/MS(MH⁺) 458

Example 34 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-hydroxyphenyl)-thioc arbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 536

Example 35 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-benzoylthiocarbamoyl-2- trifluoromethylbenzylamine LC/MS(MH⁺) 548

Example 36 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-pyrimidyl)thio-carba moyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 522

Example 37 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-( 1 -piperidino)thio-carba moyl-2-trifluoromethylbenzylamine

R_f=0.3(dichloromethane/methanol=40/l , v/v)

1H-NMR(CDC1₃) δ 7.0-7.6(m, 9H), 6.8(s, IH), 5.4(s, 2H), 4.9(s, 2H), 3.7(t,

2H), 3.2(t, 2H), 2.8(m, 4H), 1.6-2.0(m, 6H) LC/MS(MH⁺) 527 Example 38

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(4-mo holino)thio-carb amoyl-2-trifluoromethylbenzylamine R_f=0.3 (dichloromethane/methanol=20/ 1 , v/v)

Η-NMR(CDC1₃) δ 7.1-7.8(m, 9H), 6.9(s, IH), 5.4(s, 2H), 4.9(s, 2H), 3.6-4.0(m, 4H), 3.0-3.4(m, 4H), 2.4-2.9(m, 4H) LC/MS(MH⁺) 529

Example 39

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(4-methyl- 1 -piperazino)- thiocarbamoyl-2-trifluoromethylbenzylamine

R_f=0.2(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.0-7.8(m, 9H), 6.8(s, IH), 5.4(m, 2H), 4.9(s, 2H), 3.7(m, 2H), 2.4-3.3(m, 6H), 2.0-2.2(m, 3H)

LC/MS(MH⁺) 542

Example 40

N- {2-[ I -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(2-trifluoromethyl-benzy l)moφholin-4-carbothioamide

To a solution of morpholine( 1.57ml, lδmmol) in chloroform(21.9ml) was added triethylamine(5.17ml, 36mmol) and the reaction mixture was stirred for 30minute at room temperature. A solution of N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-2-trifluoromethylbenzylami ne(500mg, 1.30mmol) prepared from Preparation Example 1 in chloroform(lθml) was added dropwise to the reaction mixture and the mixture was heated at 60 ^°C for 24hr. After concentration in vacuo, the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound. R_f=0.3 (dichloromethane/methanol=20/ 1 , v/v)

Η-NMR(CDC1₃) δ 7.18-7.78(m, 10H), 5.78(s, 2H), 4.78(s, 2H), 3.42-3.83(m,

10H), 2.84(t, 2H)

LC/MS(MH⁺) 514

Example 41

N- {2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-methoxy-phenyl)thioc arbamoyl-2,3-dichlorobenzylamine

To a solution of

N- {2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichlorobenzylamine(l l 5mg, 0.32mmol) prepared from Preparation Example 2 in dichloromethane(lθml) was added 4-methoxyphenyl isothiocyanate(58mg, 0.35mmol). The mixture was stirred for 3hr at room temperature. After concentration in vacuo, the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give a solid(164mg, 99%) of the title compound.

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.50-7.53(m, 2H), 7.27-7.34(m, 2H), 7.04-7.18(m, 5H), 6.90(d, 2H), 6.84(s, IH), 5.46(s, 2H), 4.84(s, 2H), 3.95-4.03(m, 2H), 3.8 l(s, 3H), 2.97-3.05(m, 2H) LC/MS(MH⁺) 550

Example 42

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-2,3-dichlorobenzylamine

To a solution of

N- {2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichlorobenzylamine(l l 5mg, 0.32mmol) prepared from Preparation Example 2 in dichloromethane(lθml) was added 2-methoxypyridin-5-yl isothiocyanate(60mg, 0.35mmol). The mixture was stirred for 3hr at room temperature. After concentration in vacuo, the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l , v/v) to give a solid(154mg, 94%) of the title compound. Η-NMR(CDC1₃) δ 7.83(d, IH), 7.60(d, 2H), 7.46-7.52(m, 2H), 7.34(t, IH), 7.06-7.26(m, 3H), 6.9 l(s, IH), 6.72(d, 2H), 5.43(s, 2H), 4.85(s, 2H), 3.94-4.03(m, 2H), 3.91(s, 3H), 2.95-3.03(m, 2H) LC/MS(MH⁺) 551

Example 43-55

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichlorobenzyl- amine prepared from Preparation Example 2 was reacted with the corresponding isothiocyanates under the same condition as described in Example 41 to give the title compounds.

Example 43

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)thio-car bamoyl-2,3-dichlorobenzylamine Η-NMR(CDC1₃) δ 7.63-7.54(m, 2H), 7.38-7.50(m, 3H), 7.22-7.38(m, 2H), 6.99-7.18(1X1, 4H), 6.85-6.96(m, 2H), 5.41(s, 2H), 4.81(s, 2H), 3.94(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 538

Example 44

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-chlorophenyl)thio-car bamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.43-7.59(m, 3H), 7.24-7.33(m, 4H), 7.07-7. l l(m, 5H),

6.84(s, IH), 5.39(s, 2H), 4.8 l(s, 2H), 3.93(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 554 Example 45

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methylphenyl)thio-car bamoyl-2,3-dichlorobenzylamine Η-NMR(CDC1₃) δ 7.31-7.59(m, 4H), 7.24-7.3 l(m, 2H), 6.99-7.14(m, 6H), 6.89(s, IH), 5.42(s, 2H), 4.81(s, 2H), 3.95(t, 2H), 2.97(t, 2H), 2.31(s, 3H) LC/MS(MH⁺) 534

Example 46 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-nitrophenyl)thio-carba moyl-2,3-dichlorobenzylamine LC/MS(MH⁺) 565

Example 47 N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -chloro-4-methyl-phen yl)thiocarbamoyl-2,3-dichlorobenzylamine LC/MS(MH⁺) 568

Example 48 N-{2-[l -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl]} ethy l-N-(3-chlorophenyl)-thiocar bamoyl-2,3-dichlorobenzylamine

Η-NMR(CDC1₃) δ 7.46-7.59(m, 4H), 7.24-7.32(m, 2H), 6.94-7.17(m, 5H), 6.85(s, IH), 5.40(s, 2H), 4.8 l(s, 2H), 3.93(t, 2H), 2.96(t, 2H), 2.3 l(s, 3H) LC/MS(MH⁺) 554

Example 49

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylthiophenyl)-thi ocarbamoyl-2,3-dichlorobenzylamine

LC/MS(MH⁺) 566 Example 50

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-cyclohexylthio-carbamo yl-2,3-dichlorobenzylamine LC/MS(MH⁺) 526

Example 51

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl -N-ethoxycarbonyl-thiocarb amoyl-2,3-dichlorobenzylamine

LC/MS(MH⁺) 516

Example 52

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(naphthyl-2-yl)thio-carba moyl-2,3-dichlorobenzylamine

LC/MS(MH⁺) 570

Example 53

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-phenylthiocarbamoyl-2,3

-dichlorobenzylamine

LC/MS(MH⁺) 520

Example 54

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(2-methylphenyl)thio-car bamoyl-2,3-dichlorobenzylamine

LC/MS(MH⁺) 534

Example 55

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(4-fluoropheny l)thio-car bamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.46-7.60(m, 4H), 7.21-7.32(m, 2H), 6.94-7.13(m, 6H), 6.86(s, IH), 5.40(s, 2H), 4.8 l(s, 2H), 3.93(t, 2H), 2.96(t, 2H) LC/MS(MH⁺) 535

Example 56

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-chlorophenyl)thio-car bamoyl-2-chlorobenzylamine

To a solution of

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethyl-2-chlorobenzylamine(0.02M solution in dichloromethane, 1ml, 0.02mmol) prepared from Preparation Example 3 was added a solution of 4-chlorophenyl isothiocyanate(0.1M in dichloromethame, 0.2ml, 0.02mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound as a white foam. Η-NMR(CDC1₃) δ 7.58(d, 2H), 7.43-7.47(m, 2H), 7.18-7.36(m, 4H), 7.08-7.14(m, 4H), 6.88(s, IH), 5.41(s, 2H), 4.81(s, 2H), 3.97(t, 2H), 2.96(t, 2H) LC/MS(MH⁺) 520

Example 57-59

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-2-chlorobenzyl-ami ne prepared from Preparation Example 3 was reacted with the corresponding isothiocyanates under the same condition as described in Example 56 to give the title compounds.

Example 57

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methyl-phen yl)thio-carbamoyl-2-chlorobenzylamine

Η-NMR(CDC1₃) δ 7.51-7.63(m, 4H), 7.26-7.34(m, 2H), 7.12-7.18(m,4H), 6.91-6.99(m, 3H), 5.43(s, 2H), 4.80(s, 2H), 3.93(t, 2H), 2.98(t, 2H), 2.32(s, 3H) LC/MS(MH⁺) 534

Example 58

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c i arbamoyl-2-chlorobenzylamine

1H-NMR(CDC1₃) δ 7.59(s, IH), 7.57(d, 2H), 7.42-7.47(m, 2H), 7.25-7.35(m, 3H), 7.01-7.07(m, 3H), 6.81-6.91(m, 3H), 5.41 (s, 2H), 4.81(s, 2H), 3.98(t, 2H), 3.77(s, 3H), 2.98(t, 2H) LC/MS(MH⁺) 516

Example 59

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-2-chlorobenzylamine

Η-NMR(CDC1₃) δ 7.8 l(s, IH), 7.58(d, 2H), 7.42-7.52(m, 3H), 7.31-7.36(m, 2H), 7.11-7.27(m, 3H), 6.89(s, IH), 6.90(d, IH), 5.43(s, 2H), 4.83(s, 2H),

4.0 l(t, 2H), 3.89(s, 3H), 2.96(t, 2H)

LC/MS(MH⁺) 517

Example 60 N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -fluorophenyl)thio-car bamoy 1-3 -chlorobenzy lamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethyl-3-chlorobenzylamine(0.02M solution in dichloromethane, 2ml, 0.04mmol) prepared from Preparation Example 4 was added a solution of 3 -fluorophenyl isothiocyanate(0.1M solution in dichloromethane, 0.4ml, 0.04mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound as a white foam. Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.50(s, IH), 7.35(m, 2H), 7.18-7.30(m, 3H), 7.00-7.16(m, 4H), 6.80-6.97(m, 3H), 5.40(s, 2H), 4.79(s, 2H), 4.00(dd, 2H), 2.95(dd, 2H) LC/MS(MH⁺) 504

Example 61-67

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-3-chlorobenzyl-ami ne prepared from Preparation Example 4 was reacted with the corresponding isothiocyanates under the same condition as described in Example 60 to give the title compounds.

Example 61

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(4-bromophenyl)thio-car bamoy 1-3 -chlorobenzy lamine LC/MS(MH⁺) 564

Example 62

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methylphenyl)thio-car bamoy 1-3 -chlorobenzy lamine

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.50(s, IH), 7.35(m, IH), 7.26(s, IH),

6.98-7.22(m, 9H), 6.91(s, IH), 5.41(s, 2H), 4.78(s, 2H), 4.00(dd, 2H), 2.95(dd,

2H), 2.32(s, 3H)

LC/MS(MH⁺) 500

Example 63

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-chloro-4-methyl-phen yl)-thiocarbamoyl-3-chlorobenzylamine

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.52(s, IH), 7.35(m, 2H), 7.06-7.22(m, 6H), 6.91-7.02(m, 3H), 5.41(s, 2H), 4.78(s, 2H), 4.00(dd, 2H), 2.95(dd, 2H), 2.32(s, 3H) LC/MS(MH⁺) 534

Example 64 N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3 -chlorophenyl)thiocarb amoyl-3 -chlorobenzylamine

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.50(s, IH), 7.35(m, 2H), 7.01-7.27(m, 9H), 6.90(s, IH), 5.39(s, 2H), 4.79(s, 2H), 4.00(dd, 2H), 2.95(dd, 2H) LC/MS(MH⁺) 520

Example 65

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-trifluoromethyl -pheny l)-thiocarbamoyl-3-chlorobenzylamine

Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.50(s, IH), 7.35(m, 2H), 7.1 l-7.25(m, 9H), 6.92(s, IH), 5.40(s, 2H), 4.80(s, 2H), 4.02(dd, 2H), 2.95(dd, 2H)

LC/MS(MH⁺) 570

Example 66

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-3 -chlorobenzylamine

Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.52(s, IH), 7.34(m, 2H), 7.00-7.26(m, 7H), 6.86(t, 3H), 5.41(s, 2H), 4.78(s, 2H), 4.00(dd, 2H), 3.78(s, 3H), 2.95(dd, 2H) LC/MS(MH⁺) 516

Example 67

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hiocaιbamoyl-3-chlorobenzylamine

1H-NMR(CDC1₃) δ 7.78(d, IH), 7.60(d, 2H), 7.50(m, 2H), 7.36(m, 2H),

7.2 l(s, IH), 7.09-7.16(m, 4H), 6.9 l(s, IH), 6.70(d, IH), 5.40(s, 2H), 4.80(s, 2H), 4.03(dd, 2H), 3.90(s, 3H), 2.95(dd, 2H) LC/MS(MH⁺) 517

Example 68

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)thio-car bamoyl-2-fluorobenzylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-fluorobenzylamine(0.02M solution in dichloromethane, 1ml, 0.02mmol) prepared from Preparation Example 5 was added a solution of 3 -fluorophenyl isothiocyanate(0.1M solution in dichloromethane, 0.2ml, 0.02mmol). After stirring for 3hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound as a white foam. Η-NMR(CDC1₃) δ 7.61(s, IH), 7.53(d, 2H), 7.03-7.38(m, 7H), 6.89-6.91(m, 4H), 5.41(s, 2H), 4.80(s, 2H), 3.99(t, 2H), 2.94(t, 2H) LC/MS(MH⁺) 488

Example 69-73

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-fTuorobenzyl-ami ne prepared from Preparation Example 5 was reacted with the corresponding isothiocyanates under the same condition as described in Example 68 to give the title compounds.

Example 69

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl-2-fluorobenzylamine

1H-NMR(CDC1₃) δ 7.59(s, IH), 7.53(d, 2H), 7.32-7.38(m, IH), 7.06-7.22(m, 9H), 5.42(s, 2H), 4.80(s, 2H), 3.99(t, 2H), 2.94(t, 2H), 2.45(s, 3H) LC/MS(MH⁺) 484

Example 70

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(3 -chloro-4-methy 1-phen yl)thiocarbamoyl-2-fluorobenzylamine LC/MS(MH⁺) 518

Example 71

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methylthiophenyl)-thi ocarbamoyl-2-fluorobenzylamine LC/MS(MH⁺) 516

Example 72

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-2-fluorobenzylamine

1H-NMR(CDC1₃) δ 7.60(s, IH), 7.54(d, 2H), 7.31-7.37(m, IH), 7.04-7.21(m,

7H), 6.88(d, 2H), 6.82(s, IH), 5.43(s, 2H), 4.80(s, 2H), 4.00(t, 2H), 3.78(s, 3H),

2.95(t, 2H)

LC/MS(MH⁺) 500

Example 73

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-2-fluorobenzylamine

Η-NMR(CDC1₃) δ 7.82(s, IH), 7.48-7.60(m, 4H), 7.34-7.37(m, IH), 7.10-7.27(m, 5H), 6.89(s, IH), 6.70(d, IH), 5.40(s, 2H), 4.81(s, 2H), 4.00(t,

2H), 3.89(s, 3H), 2.93(t, 2H)

LC/MS(MH⁺) 501

Example 74 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-fluorophenyl)thio-car bamoy 1-3 -fluorobenzy lamine

To a solution of

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethyl-3-fluorobenzylamine(0.02M solution in dichloromethane, 2ml, 0.04mmol) prepared from Preparation Example 6 was added a solution of 4-fluorophenyl isothiocyanate(0.1M solution in dichloromethane, 0.4ml, 0.04mmol). The mixture was stirred for 2hr at room temperature. The reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound as a white foam.

Η-NMR(CDC1₃) δ 7.62(d, 2H), 7.54(s, IH), 7.34-7.48(m, IH), 7.18(s, IH), 6.98-7.14(m, 8H), 6.95(s, IH), 5.45(s, 2H), 4.83(s, 2H), 4.06(t, 2H), 3.00(t, 2H) LC/MS(MH⁺) 488

Example 75-81

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-3 -fluorobenzyl-ami ne prepared from Preparation Example 6 was reacted with the corresponding isothiocyanates under the same condition as described in Example 74 to give the title compounds.

Example 75

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl-3 -fluorobenzylamine 1H-NMR(CDC1₃) δ 7.62(s, IH), 7.55(d, 2H), 7.35-7.42(m, IH), 7.12-7.17(m, 5H), 6.99-7.05(m, 4H), 6.93(s, IH), 5.44(s, 2H), 4.81(s, 2H), 4.05(t, 2H), 2.98(t, 2H), 2.34(s, 3H) LC/MS(MH⁺) 484

Example 76 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methylpheny l)-thiocarbamoyl-3-fluorobenzylamine

Η-NMR(CDC1₃) δ 7.62(s, IH), 7.54(d, 2H), 7.34-7.41(m, IH), 7.05-7.17(m, 4H), 6.92-7.00(1X1, 5H), 6.93(s, IH), 5.41(s, 2H), 4.78(s, 2H), 4.00(t, 2H), 2.97(t, 2H), 2.32(s, 3H) LC/MS(MH⁺) 518

Example 77

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chlorophenyl)thio-car bamoyl-3-fluorobenzylamine

Η-NMR(CDC1₃) δ 7.62(s, IH), 7.53(d, 2H), 7.36-7.41(m, IH), 6.98-7.23(m, 9H), 6.92(s, IH), 5.40(s, 2H), 4.79(s, 2H), 4.02(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 504

Example 78

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methoxypheny l)thio-c arbamoyl-3-fluorobenzylamine

1H-NMR(CDC1₃) δ 7.6 l(s, IH), 7.53(d, 2H), 7.34-7.45(m, IH), 6.99-7.16(m,

4H), 6.81-6.92(m, 3H), 5.43(s, 2H), 4.80(s, 2H), 4.04(t, 2H), 3.81(s, 3H), 2.97(t, 2H)

LC/MS(MH⁺) 500

Example 79

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-3-fluorobenzylamine

1H-NMR(CDC1₃) δ 7.77(d, IH), 7.60(d, 2H), 7.35-7.50(m, 3H), 6.97-7.15(m,

5H), 6.73(s, IH), 6.71(d, IH), 5.41(s, 2H), 4.82(s, 2H), 4.05(t, 2H), 3.90(s, 3H),

2.96(t, 2H)

LC/MS(MH⁺) 501 Example 80

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylthiophenyl)-thi ocarbamoyl-3-fluorobenzylamine

Η-NMR(CDC1₃) δ 7.60(s, IH), 7.53(d, 2H), 7.34-7.41(m, IH), 7.10-7.19(m, 9H), 6.90(s, IH), 5.40(s, 2H), 4.78(s, 2H), 4.01(t, 2H), 2.90(t, 2H), 2.44(s, 3H) LC/MS(MH⁺) 516

Example 81

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-trifluoromethyl-pheny l)thiocarbamoyl-3 -fluorobenzy lamine

1H-NMR(CDC1₃) δ 7.60(s, IH), 7.52(d, 2H), 7.37-7.43(m, 5H), 6.97-7.14(m, 5H), 6.90(s, IH), 5.39(s, 2H), 4.82(s, 2H), 4.03(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 538

Example 82

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methylpheny l)-thiocarbamoyl-2-methylbenzylamine

To a solution of N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2-methylbenzylamine(0.02 M solution in dichloromethane, 1ml, 0.02mmol) prepared from Preparation Example 7 was added a solution of 3-chloro-4-methylphenyl isothiocyanate(0.1M solution in dichloromethane, 0.2ml, 0.02mmol). The mixture was stirred for 2hr at room temperature. The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound. Η-NMR(CDC1₃) δ 7.61(s, IH), 7.53(d, 2H), 7.26-7.28(m, 3H), 7.07-7.16(m, 4H), 6.90-6.96(m, 3H), 5.46(s, 2H), 4.66(s, 2H), 4.02(t, 2H), 2.98(t, 2H), 2.3 l(s, 3H), 2.28(s, 3H) LC/MS(MH⁺) 514 Example 83-89

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-2-methylbenzyl-am ine prepared from Preparation Example 7 was reacted with the corresponding isothiocyanates under the same condition as described in Example 82 to give the title compounds.

Example 83 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-fluorophenyl)thio-car bamoyl-2-methylbenzylamine LC/MS(MH⁺) 484

Example 84 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-fluorophenyl)thio-car bamoyl-2-methylbenzylamine LC/MS(MH⁺) 484

Example 85 N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl-2-methylbenzylamine LC/MS(MH⁺) 480

Example 86 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3-trifluoromethyl-pheny l)thiocarbamoyl-2-methylbenzylamine LC/MS(MH⁺) 534

Example 87 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chlorophenyl)-thiocar bamoyl-2-methylbenzylamine

Η-NMR(CDC1₃) δ 7.59(d, IH), 7.49(s, IH), 7.26-7.3 l(m, 3H), 7.00-7.22(m, 7H), 6.89(s, IH), 5.44(s, 2H), 4.67(s, 2H), 4.01(t, 2H), 2.98(t, 2H), 2.28(s, 3H) LC/MS(MH⁺) 500

Example 88

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-2-methylbenzylamine

Η-NMR(CDC1₃) δ 7.57(d, IH), 7.52(s, IH), 7.25(s, 3H), 7.00-7.16(m, 5H), 6.80-6.91(m, 3H), 5.46(s, 2H), 4.67(s, 2H), 4.03(t, 2H), 3.77(s, 3H), 2.99(t, 2H), 2.28(s, 3H) LC/MS(MH⁺) 496

Example 89 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-2-methylbenzylamine

1H-NMR(CDC1₃) δ 7.76(d, IH), 7.58(d, 2H), 7.44-7.49(m, 2H), 7.25-7.29(m,

2H), 7.06-7.14(m, 5H), 6.87(s, IH), 6.69(d, IH), 5.44(s, 2H), 4.70(s, 2H),

4.03(t, 2H), 3.88(s, 3H), 2.97(t, 2H), 2.28(s, 3H) LC/MS(MH⁺) 497

Example 90

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -fluoropheny l)thio-car bamoyl-2,3-difluorobenzylamine

To a solution of

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethyl-2,3-difluorobenzylamine(0.

02M solution in dichloromethane, 2ml, 0.04mmol) prepared from Preparation

Example 8 was added a solution of 3 -fluorophenyl isothiocyanate(0.1M solution in dichloromethane, 0.4ml, 0.04mmol). The mixture was stirred for 3hr at room temperature and purified by short silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound as a white foam.

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.5 l(s, IH), 7.36(s, IH), 7.02-7.20(m, 8H), 6.92(s, IH), 5.39(s, 2H), 4.87(s, 2H), 3.96(t, 2H), 2.94(t, 2H) LC/MS(MH⁺) 506

Example 91-97

N- { 2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-2,3 -difluorobenzyl- amine prepared from Preparation Example 8 was reacted with the corresponding isothiocyanates under the same condition as described in Example 90 to give the title compounds.

Example 91

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-fluorophenyl)thio-car bamoyl-2 ,3 -difluorobenzylamine lH-NMR(CDCl₃) δ 7.59(d, 2H), 7.50(s, IH), 7.32(s, IH), 7.00-7.16(m, 8H),

6.90(s, IH), 5.39(s, 2H), 4.87(s, 2H), 3.96(t, 2H), 2.94(t, 2H) LC/MS(MH⁺) 506

Example 92

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methylphenyl)thio-car bamoy 1-2 , 3 -difluorobenzylamine 1H-NMR(CDC1₃) δ 7.53-7.61(m, 3H), 7.26(s, IH), 7.01-7.15(m, 8H), 6.93(s, IH), 5.41(s, 2H), 4.86(s, 2H), 3.97(t, 2H), 2.95(t, 2H), 2.33(s, 3H) LC/MS(MH⁺) 502

Example 93 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methyl-phen yl)thiocarbamoyl-2,3-difluorobenzylamine

1H-NMR(CDC1₃) δ 7.59(d, 2H), 7.53(s, IH), 7.27(s, IH), 7.12-7.18(m, 4H), 6.94-7.01(1X1, 4H), 5.41(s, 2H), 4.86(s, 2H), 3.96(t, 2H), 2.94(t, 2H), 2.34(s, 3H) LC/MS(MH⁺) 536

Example 94

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-chlorophenyl)-thiocar bamoyl-2, 3 -difluorobenzylamine

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.5 l(s, IH), 7.3 l(s, 3H), 6.99-7.27(m, 8H), 6.92(s, IH), 5.39(s, 2H), 4.87(s, 2H), 3.95(t, 2H), 2.94(t, 2H) LC/MS(MH⁺) 522

Example 95

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-trifluoromethyl-pheny l)thio-carbamoyl-2,3-difluorobenzylamine

1H-NMR(CDC1₃) δ 7.6 l(d, 2H), 7.54(s, IH), 7.00-7.27(m, 9H), 6.95(s, IH), 5.40(s, 2H), 4.88(s, 2H), 3.98(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 572

Example 96

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-2,3-difluorobenzylamine

1H-NMR(CDC1₃) δ 7.59(d, 2H), 7.5 l(s, IH), 7.00-7.22(m, 7H), 6.89(d, 2H),

6.83(s, IH), 5.41(s, 2H), 4.87(s, 2H), 3.96(t, 2H), 3.79(s, 3H), 2.95(t, 2H) LC/MS(MH⁺) 518

Example 97

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-2,3-difluorobenzylamine 1H-NMR(CDC1₃) δ 8.84(d, IH), 7.61(d, 2H), 7.48-7.53(m, 2H), 7.39(s, IH), 6.99-7.22(m, 4H), 6.89(s, IH), 6.72(d, IH), 5.40(s, 2H), 4.89(s, 2H), 3.98(t,

2H), 3.91(s, 3H), 2.95(t, 2H)

LC/MS(MH⁺) 519

Example 98

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] }ethyl-N-(4-methylphenyl)thio-car bamoy 1-2 ,6-difluorobenzy lamine

To a solution of N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2,6-difluorobenzylamine(0. 02M solution in dichloromethane, 2ml, 0.04mmol) prepared from Preparation Example 9 was added a solution of 4-methylphenyl isothiocyanate(0.1M solution in dichloromethane, 0.4ml, 0.04mmol). The mixture was stirred for 4hr at room temperature and purified by short silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound as a white foam.

Η-NMR(CDC1₃) δ 7.53-7.66(m, 4H), 7.37-7.40(m, IH), 6.95-7.17(m, 9H), 5.44(s, 2H), 4.76(s, 2H), 3.98(t, 2H), 2.91(t, 2H), 2.36(s, IH) LC/MS(MH⁺) 502

Example 99-102

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2,6-difluorobenzyl- amine prepared from Preparation Example 9 was reacted with the corresponding isothiocyanates under the same condition as described in Example 98 to give the title compounds.

Example 99

N- {2-[l -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl]} ethy l-N-(4-fluorophenyl)thio-car bamoyl-2,6-difluorobenzylamine LC/MS(MH⁺) 506

Example 100

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(3 -chloro-4-methy 1-phen yl)thiocarbamoyl-2,6-difluorobenzylamine

Η-NMR(CDC1₃) δ 7.63(s, IH), 7.56(d, 2H), 7.39-7.43(m, IH), 7.25-7.32(m,

2H), 7.01-7.2 l(m, 5H), 6.97(s, IH), 5.44(s, 2H), 4.77(s, 2H), 4.00(t, 2H), 2.92(t,

2H), 2.38(s, 3H)

LC/MS(MH⁺) 536

Example 101

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-2,6-difluorobenzylamine lH-NMR(CDCl₃) δ 7.62(s, IH), 7.55(d, 2H), 7.37-7.44(m, IH), 6.89-7.28(m, 8H), 6.89(s, IH), 5.45(s, 2H), 4.76(s, 2H), 4.01(t, 2H), 3.83(s, 3H), 2.93(t, 2H) LC/MS(MH⁺) 518

Example 102

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-2,6-difluorobenzylamine

1H-NMR(CDC1₃) δ 7.95(d, IH), 7.48-7.68(m, 5H), 7.32-7.44(m, IH),

6.94-7.27(m, 4H), 6.74(d, IH), 5.41(s, 2H), 4.77(s, 2H), 4.00(t, 2H), 3.92(s,

3H), 2.9 l(t, 2H)

LC/MS(MH⁺) 519

Example 103

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-fluorophenyl)-thiocar bamoyl-4-trifluoromethylbenzylamine

To a solution of N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-4-trifluoromethylbenzylami ne(20mg, 0.05mmol) prepared from Preparation Example 10 in dichloromethane(lml) was added a solution of 4-fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 0.1ml, 0.05mmoι). The mixture was stirred for 4hr at room temperature, and the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(25mg, 94%). 1H-NMR(CDC1₃) δ 7.69(d, 2H), 7.59(d, 2H), 7.35-7.47(m, 4H), 6.96-7.13(m, 5H), 6.83(s, IH), 5.41(s, 2H), 4.93(s, 2H), 4.02(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 538

Example 104-109

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-4-trifluoromethyl-b enzylamine prepared from Preparation Example 10 was reacted with the corresponding isothiocyanates under the same condition as described in Example 103 to give the title compounds.

Example 104 N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(4-chloroρhenyl)-thiocar bamoyl-4-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.72(d, 2H), 7.60(d, 2H), 7.35-7.49(m, 3H), 7.26-7.30(m,

3H), 7.07-7.13(m, 3H), 6.84(s, IH), 5.41(s, 2H), 4.93(s, 2H), 4.01(t, 2H), 2.95(t,

2H) LC/MS(MH⁺) 554

Example 105

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-chloro-4-methyl-phen yl)thio-carbamoyl-4-trifluoromethylbenzylamine Η-NMR(CDC1₃) δ 7.71(d, 2H), 7.62(d, 2H), 7.53(s, IH), 7.38(d, 2H), 7.11-7.21(m, 4H), 6.94-6.98(m, IH), 6.93(s, IH), 5.44(s, 2H), 4.91(s, 2H), 4.03(t, 2H), 2.98(t, 2H) LC/MS(MH⁺) 568

Example 106

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-chlorophenyl)-thiocar bamoyl-4-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.69(d, 2H), 7.58-7.62(m, 3H), 7.43(s, IH), 7.36(d, 2H), 7.04-7.25(m, 5H), 6.83(s, IH), 5.40(s, 2H), 4.93(s, 2H), 4.00(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 554

Example 107

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-4-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 7.69(d, 2H), 7.60(d, 2H), 7.50(s, IH), 7.38(d, 2H), 7.13(d, 3H), 7.04(d, 2H), 6.84-6.89(m, 3H), 5.44(s, 2H), 4.91(s, 2H), 4.03(t, 2H), 3.80(s, 3H), 2.98(t, 2H) LC/MS(MH⁺) 550

Example 108

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-4-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 7.80(d, IH), 7.71(d, 2H), 7.62(d, 2H), 7.46-7.5 l(m, 2H),

7.39(d, 2H), 7.11-7.19(m, 3H), 6.90(s, IH), 6.73(d, IH), 5.43(s, 2H), 4.94(s, 2H), 4.05(t, 2H), 3.92(s, 3H), 2.98(t, 2H)

LC/MS(MH⁺) 551

Example 109

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)-thiocar bamoy 1-4-trifluoromethylbenzy lamine H-NMR(CDC1₃) δ 7.72(d, 2H), 7.56-7.62(m, 3H), 7.46(s, IH), 7.24-7.39(m, 2H), 7.12(d, 2H), 6.99-7.04(m, IH), 6.73(d, IH), 6.86-6.91(m, 3H), 5.41(s, 2H), 4.93(s, 2H), 4.0 l(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 538

Example 110

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)-thiocar bamoyl-(l -methyl- lH-pyrrol-2-yl)methy lamine

To a solution of

N- {2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 -methyl- 1 H-pyrrol-2-yl)m ethylamine(15mg, 0.05mmol) prepared from Preparation Example 11 in dichloromethane(lmι) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 0.1ml, 0.05mmol). The mixture was stirred for lhr at room temperature and purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(19mg, 90%).

1H-NMR(CDC1₃) δ 7.85(s, IH), 7.60(d, 2H), 7.48(s, IH), 7.25(d, IH), 7.15(d, 2H), 7.02(t, IH), 6.80-6.92(m, 3H), 6.70(t, IH), 6.12(s, 2H), 5.40(s, 2H), 4.75(s, 2H), 4.00(dd, 2H), 3.60(s, 3H), 2.85(dd, 2H) LC/MS(MH⁺) 473

Example 111-114

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 -methyl- 1 H-pyrr ol-2-yl)methylamine prepared from Preparation Example 11 was reacted with the corresponding isothiocyanates under the same condition as described in Example 110 to give the title compounds.

Example 111 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-chlorophenyl)thio-car bamoy l-( 1 -methyl- 1 H-pyrrol-2-yl)methy lamine

Η-NMR(CDC1₃) δ 7.80(s, IH), 7.60(d, 2H), 7.48(s,^' IH), 7.25(d, 2H), 7.06-7.20(m, 4H), 6.88(s, IH), 6.70(t, IH), 6.12(s, 2H), 5.40(s, 2H), 4.75(s, 2H), 4.00(dd, 2H), 3.60(s, 3H), 2.85(dd, 2H) LC/MS(MH⁺) 489

Example 112

N- {2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chlorophenyl)thio-car bamoyl-( 1 -methyl- 1 H-pyrrol-2-yl)methylamine

1H-NMR(CDC1₃) δ 7.83(s, IH), 7.60(d, 3H), 7.48(s, IH), 7.00-7.25(m, 6H),

6.88(s, IH), 6.70(t, IH), 6.12(s, 2H), 5.40(s, 2H), 4.76(s, 2H), 4.00(dd, 2H),

3.60(s, 3H), 2.85(dd, 2H)

LC/MS(MH⁺) 489

Example 113

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-( 1 -methyl- 1 H-pyrrol-2-yl)methylamine

1H-NMR(CDC1₃) δ 7.60(d, 3H), 7.45(s, IH), 7.00-7.20(m, 4H), 6.85(m, 3H), 6.67(t, IH), 6.10(s, 2H), 5.40(s, 2H), 4.75(s, 2H), 3.98(dd, 2H), 3.80(s, 3H),

3.58(s, 3H), 2.83(dd, 2H)

LC/MS(MH⁺) 485

Example 114 N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(2-methoxypyridin-5 -yl)t hio-carbamoyl-( 1 -methyl- 1 H-pyrrol-2-yl)methylamine

1H-NMR(CDC1₃) δ 7.82(d, IH), 7.78(s, IH), 7.60(d, 2H), 7.52(dd, IH), 7.47(s, IH), 7.15(d, 2H), 6.87(s, IH), 6.70(d, 2H), 6.10(d, 2H), 5.40(s, 2H), 4.78(s, 2H), 3.98(dd, 2H), 3.92(s, 3H), 3.58(s, 3H), 2.83(dd, 2H) LC/MS(MH⁺) 486 Example 115

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-fluorophenyl)thio-car bamoyl-(lH-indol-3-yl)methylamine

To a solution of

N- {2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 H-indol-3-yl)methy lamine

(15mg, 0.04mmol) prepared from Preparation Example 12 in dichloromethane(lml) was added a solution of 4-fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 0.1ml, 0.05mmol). The reaction mixture was stirred for 2hr at room temperature and purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(21mg, 97%).

Η-NMR(CDC1₃) δ 9.00(s, IH), 7.50-7.60(m, 5H), 7.45(d, IH), 7.18-7.33(m, 2H), 7.02-7.17(m, 5H), 6.98(d, 2H), 6.90(s, IH), 5.40(s, 2H), 4.97(s, 2H),

4.10(dd, 2H), 3.00(dd, 2H)

LC/MS(MH⁺) 509

Example 116-119

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(lH-indol-3-yl)met hylamine prepared from Preparation Example 12 was reacted with the corresponding isothiocyanates under the same condition as described in Example 115 to give the title compounds.

Example 116

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3-chlorophenyl)thio-car bamoyl-(lH-indol-3-yl)methylamine

Η-NMR(CDC1₃) δ 9.07(s, IH), 7.70(s, IH), 7.40-7.60(m, 5H), 7.20-7.32(m, 3H), 7.00-7.17(m, 6H), 6.90(s, IH), 5.40(s, 2H), 4.97(s, 2H), 4.10(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 525

Example 117 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-phenylethyl)thio-carb amoyl-(lH-indol-3-yl)methylamine

1H-NMR(CDC1₃) δ 7.60(s, IH), 7.66(d, 2H), 7.45(d, 2H), 7.25(t, IH), 7.10-7.20(m, 6H), 7.05(m, 2H), 6.82(d, 2H), 6.15(t, IH), 5.40(s, 2H), 4.67(s, 2H), 4.00(dd, 2H), 3.82(m, 2H), 2.85(m, 4H) LC/MS(MH⁺) 519

Example 118

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(lH-indol-3-yl)methylamine 1H-NMR(CDC1₃) δ 9.00(s, IH), 7.40-7.60(m, 6H), 7.00-7.32(m, 7H), 6.90(s, IH), 6.80(d, 2H), 5.40(s, 2H), 4.97(s, 2H), 4.10(dd, 2H), 3.78(s, 3H), 3.00(dd, 2H) LC/MS(MH⁺) 521

Example 119

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-(lH-indol-3-yl)methylamine

1H-NMR(CDC1₃) δ 9.18(s, IH), 7.78(d, IH), 7.65(s, IH), 7.40-7.60(m, 6H),

7.00-7.32(m, 5H), 6.86(s, IH), 6.78(d, IH), 5.40(s, 2H), 4.97(s, 2H), 4.10(dd, 2H), 3.85(s, 3H), 3.00(dd, 2H)

LC/MS(MH⁺) 522

Example 120

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-fluoroρhenyl)thio-car bamoyl-(6-methyl-pyridin-2-yl)methylamine To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(6-methyl-pyridin-2-yl)meth ylamine(10mg, 0.03mmol) prepared from Preparation Example 16 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 72ul, 0.036mmol). The mixture was stirred for 3hr at room temperature. The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(14mg, 96%). 1H-NMR(CDC1₃) δ 11.72(s, IH), 7.65(t, IH), 7.60(d, 2H), 7.56(s, IH), 7.10-7.40(m, 7H), 6.96(s, IH), 6.85(m, IH), 5.50(s, 2H), 4.60(s, 2H), 3.90(q, 2H), 2.96(q, 2H), 2.60(s, 3H) LC/MS(MH⁺) 485

Example 121-125

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-(6-methyl-pyridin-2-yl)met hyl-amine prepared from Preparation Example 16 was reacted with the corresponding isothiocyanates under the same condition as described in Example 120 to give the title compounds.

Example 121

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methyl-phen yl)thiocarbamoyl-(6-methyl-pyridin-2-yl)methylamine 1H-NMR(CDC1₃) δ 11.58(s, IH), 7.65(t, IH), 7.60(d, 2H), 7.50(m, 2H), 7.10-7.50(m, 6H), 6.96(s, IH), 5.50(s, 2H), 4.60(s, 2H), 3.90(q, 2H), 2.96(q, 2H), 2.60(s, 3H), 2.40(s, 3H) LC/MS(MH⁺) 515

Example 122 N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3 -chlorophenyl)-thiocar bamoyl-(6-methyl-pyridin-2-yl)methylamine

1H-NMR(CDC1₃) δ 11.72(s, IH), 7.65(t, IH), 7.60(d, 2H), 7.56(m, 2H), 7.40(m, IH), 7.10-7.30(m, 6H), 6.96(s, IH), 5.50(s, 2H), 4.60(s, 2H), 3.90(q, 2H), 2.96(q, 2H), 2.60(s, 3H) LC/MS(MH⁺) 501

Example 123

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylthio-phenyl)thi o-carbamoyl-(6-methyl-pyridin-2-yl)methy lamine

Η-NMR(CDC1₃) δ 11.55(s, IH), 7.65(t, IH), 7.60(d, 2H), 7.56(s, IH),

7.40(m, 2H), 7.40(xn, 2H), 7.15(q, 4H), 6.96(s, IH), 5.50(s, 2H), 4.60(s, 2H),

3.90(q, 2H), 2.96(q, 2H), 2.60(s, 3H), 2.45(s, 3H)

LC/MS(MH⁺) 513

Example 124

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(6-methyl-pyridin-2-yl)methylamine

1H-NMR(CDC1₃) δ 11.30(s, IH), 7.65(t, IH), 7.60(d, 2H), 7.56(s, IH), 7.26(d, 2H), 7.18(q, 4H), 6.98(s, 2H), 6.90(s, IH), 5.50(s, 2H), 4.60(s, 2H),

3.95(q, 2H), 3.80(s, 3H), 3.00(q, 2H), 2.60(s, 3H)

LC/MS(MH⁺) 497

Example 125 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-(6-methyl-pyridin-2-yl)methylamine

1H-NMR(CDC1₃) δ 11.45(s, IH), 8.10(d, IH), 7.80(dd, IH), 7.65(t, IH), 7.60(d, 2H), 7.56(s, IH), 7.15(q, 7H), 6.96(s, IH), 6.80(d, IH), 5.45(s, 2H), 4.62(s, 2H), 4.00(s, 3H), 3.94(q, 2H), 2.98(q, 2H), 2.60(s, 3H) LC/MS(MH⁺) 498 Example 126

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)-thiocar bamoyl-(2-chloro-pyridin-3-yl)methylamine

To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(2-chloro-pyridin-3-yl)meth ylamine(15mg, 0.043mmol) prepared from Preparation Example 18 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 102ul, 0.051mmol). The mixture was stirred for lhr at room temperature. The reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methano 1=20/1, v/v) to give the title compound(19mg). 1H-NMR(CDC1₃) δ 8.40(dd, IH), 7.95(s, IH), 7.60(m, 3H), 7.42(s, IH), 7.20-7.40(m, 2H), 7.12(d, 2H), 6.85-7.08(m, 3H), 6.80(s, IH), 5.40(s, 2H),4.85(s, 2H), 3.95(q, 2H), 2.96(q, 2H) LC/MS(MH⁺) 505

Example 127-128

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(2-chloro-pyridin-3 -yl)methylamine prepared from Preparation Example 18 was reacted with the corresponding isothiocyanates under the same condition as described in Example 126 to give the title compounds.

Example 127

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methyl-phen yl)thio-carbamoyl-(2-chloro-pyridin-3-yl)methylamine 1H-NMR(CDC1₃) δ 8.36(dd, IH), 7.90(s, IH), 7.56(m, 3H), 7.40(s, IH), 7.30(m, IH), 7.12(m, 4H), 7.00(dd, IH), 6.80(s, IH), 5.40(s, 2H), 4.85(s, 2H), 3.90(q, 2H), 2.96(q, 2H), 2.30(s, 3H) LC/MS(MH⁺) 535

Example 128 N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethy l-N-(3 -trifluoromethyl-pheny l)thiocarbamoyl-(2-chloro-pyridin-3-yl)methylamine

1H-NMR(CDC1₃) δ 8.38(dd, IH), 8.22(s, IH), 7.80(s, IH), 7.56(m, 3H), 7.42(s, 4H), 7.32(m, 2H), 7.10(d, 2H), 6.80(s, IH), 5.40(s, 2H), 4.90(s, 2H), 3.95(q, 2H), 2.96(q, 2H) LC/MS(MH⁺) 555

Example 129

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)-thiocar bamoyl-( 1 -methyl- lH-indol-3-yl)methylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 -methyl- 1 H-indol-3-y l)me thylamine(15mg, 0.041mmol) prepared from Preparation Example 13 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 97ul, 0.05mmol). The reaction mixture was stirred for lhr at room temperature and purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(20mg).

1H-NMR(CDC1₃) δ 7.56(m, 5H), 7.36(m, 2H), 7.20(d, IH), 7.10(m, 4H), 7.00(s, IH), 6.90(s, IH), 6.85(m, 2H), 5.40(s, 2H), 4.92(s, 2H), 4.08(dd, 2H),

3.80(s, 3H), 3.00(dd, 2H)

LC/MS(MH⁺) 523

Example 130-131 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-( 1 -methyl- 1 H-indol -3 -yl)methy lamine prepared from Preparation Example 13 was reacted with the corresponding isothiocyanates under the same condition as described in Example 129 to give the title compounds.

Example 130

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(3 -chloro-4-methy lpheny l)thio-carbamoyl-( 1 -methyl- 1 H-indol-3-yι)methylamine

1H-NMR(CDC1₃) δ 7.55(m, 5H), 7.35(m, 2H), 7.20(m, IH), 7.10(m, 4H), 6.95(m, 2H), 6.87(s, IH), 5.40(s, 2H), 4.92(s, 2H), 4.08(dd, 2H), 3.80(s, 3H), 3.00(dd, 2H), 2.30(s, 3H) LC/MS(MH⁺) 553

Example 131 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3 -chlorophenyl)-thiocar bamoyl-(l -methyl- lH-indo 1-3 -yl)methylamine

1H-NMR(CDC1₃) δ 7.55(m, 5H), 7.35(m, 2H), 7.18(m, 6H), 7.00(m, 2H),

6.90(s, IH), 5.40(s, 2H), 4.92(s, 2H), 4.08(dd, 2H), 3.80(s, 3H), 3.00(dd, 2H)

LC/MS(MH⁺) 539

Example 132

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-chlorophenyl)-thiocar bamoyl-(3-chloro-pyridin-4-yl)methylamine

To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(3-chloro-pyridin-4-yl)meth ylamine(12mg, 0.035mmol) prepared from Preparation Example 20 in dichloromethane(lml) was added a solution of 4-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 80ul, 0.04mmol). After stirring for lhr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(16mg).

1H-NMR(CDC1₃) δ 8.60(s, IH), 8.55(d, IH), 7.65(s, IH), 7.60(d, 2H), 7.45(s, IH), 7.25(m, 2H), 7.10(m, 5H), 6.84(s, IH), 5.40(s, 2H), 4.90(s, 2H), 3.96(dd, 2H), 2.96(dd, 2H) LC/MS(MH⁺) 521

Example 133-134

N-{2-[l -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl]}ethyl-(3-chloro-pyridin-4

-yl)methylamine prepared from Preparation Example 20 was reacted with the corresponding isothiocyanates under the same condition as described in Example 132 to give the title compounds.

Example 133

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -chloro-4-methylpheny l)thio-carbamoyl-(3-chloro-pyridin-4-yl)methylamine

1H-NMR(CDC1₃) δ 8.60(s, IH), 8.55(d, IH), 7.65(s, IH), 7.60(d, 2H), 7.42(s,

IH), 7.15(m, 5H), 7.00(m, IH), 6.84(s, IH), 5.40(s, 2H), 4.90(s, 2H), 3.96(dd, 2H), 2.96(dd, 2H), 2.35(s, 3H)

LC/MS(MH⁺) 535

Example 134

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoy l-(3 -chloro-pyridin-4-yl)methy lamine

1H-NMR(CDC1₃) δ 8.55(s, IH), 8.50(d, IH), 8.00(s, IH), 7.80(d, IH), 7.60(d,

2H), 7.48(dd, IH), 7.40(s, IH), 7.10(m, 3H), 6.80(s, IH), 6.70(d, IH), 5.40(s,

2H), 4.90(s, 2H), 3.96(dd, 2H), 3.85(s, 3H), 2.96(dd, 2H)

LC/MS(MH⁺) 518 Example 135

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)thio-car bamoy l-(2 ,6-dichloro-py ridin-3 -yl)methylamine

To a solution of

N- { 2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-(2,6-dichloro-py ridin-3 -yl) methylamine(13.5mg, 0.035mmol) prepared from Preparation Example 17 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 80ul, 0.04mmol). The mixture was stirred for lhr at room temperature and purified by short silica gel column chromatography(eluent: dichloromethane/methano 1=20/1, v/v) to give the title compound(19mg).

1H-NMR(CDC1₃) δ 8.02(s, IH), 7.60(t, 3H), 7.45(s, IH), 7.35(d, lH),7.25(m, IH), 7.15(d, 2H), 6.89-7.08(m, 3H), 6.82(s, IH), 5.38(s, 2H), 4.86(s, 2H), 3.95(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 539

Example 136-139

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-(2,6-dichloro-pyridi n-3-yl)methy lamine prepared from Preparation Example 17 was reacted with the corresponding isothiocyanates under the same condition as described in Example 135 to give the title compounds.

Example 136

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3 -chloro-4-methylpheny l)thio-carbamoyl-(2,6-dichloro-pyridin-3-yl)methylamine

1H-NMR(CDC1₃) δ 8.00(s, IH), 7.60(t, 3H), 7.42(s, IH), 7.35(d, IH), 7.15(m,

4H), 7.00(dd, IH), 6.80(s, IH), 5.38(s, 2H), 4.86(s, 2H), 3.92(t, 2H), 2.95(t, 2H), 2.35(s, 3H) LC/MS(MH⁺) 569

Example 137

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -y 1] } ethy l-N-(3 -trifluoromethyl-pheny l)thiocarbamoyl-(2,6-dichloro-pyridin-3-yl)methylamine

1H-NMR(CDC1₃) δ 8.30(s, IH), 7.60(t, 3H), 7.43(s, 5H), 7.35(d, IH), 7.10(d, 2H), 6.80(s, IH), 5.38(s, 2H), 4.92(s, 2H), 3.95(t, 2H), 2.95(t, 2H) LC/MS(MH⁺) 589

Example 138

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(2,6-dichloro-pyridin-3-yl)methylamine

1H-NMR(CDC1₃) δ 7.60(q, 3H), 7.45(s, IH), 7.35(d, IH), 7.10(m, 4H),

6.83(d, 3H), 5.38(s, 2H), 4.86(s, 2H), 3.95(t, 2H), 3.80(s, 3H), 2.95(t, 2H) LC/MS(MH⁺) 551

Example 139

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-(2,6-dichloro-pyridin-3-yl)methylamine 1H-NMR(CDC1₃) δ 8.22(s, IH), 7.82(d, IH), 7.60(d, 2H), 7.50(t, 2H), 7.40(s, IH), 7.35(d, IH), 7.10(d, 2H), 6.78(d, IH), 6.72(d, IH), 5.38(s, 2H), 4.86(s, 2H), 3.95(t, 2H), 3.88(s, 3H), 2.95(t, 2H) LC/MS(MH⁺) 552

Example 140

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-fluorophenyl)thio-car bamoyl-(5-methoxy-lH-indol-3-yl)methy lamine

To a solution of N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(5-methoxy-lH-indol-3-yl) methylamine(13.5mg, 0.035mmol) prepared from Preparation Example 15 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 80ul, 0.04mmol). The mixture was stirred for 3hr at room temperature. And the reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(15mg). 1H-NMR(CDC1₃) δ 8.80(s, IH), 7.62(s, IH), 7.55(m, 3H), 7.35(d, IH), 7.00-7.18(m, 5H), 6.95(d, 3H), 6.82(m, 2H), 5.40(s, 2H), 4.89(s, 2H), 4.08(t, 2H), 3.80(s, 3H), 2.97(t, 2H) LC/MS(MH⁺) 539

Example 141-144

N- { 2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-(5 -methoxy- 1 H-ind ol-3-yl)methylamine prepared from Preparation Example 15 was reacted with the corresponding isothiocyanates under the same condition as described in Example 140 to give the title compounds.

Example 141 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-methylphenyl)thio-car bamoyl(5-methoxy-lH-indol-3-yl)methylamine

1H-NMR(CDC1₃) δ 8.78(s, IH), 7.50(t, 4H), 7.31(d, IH), 7.10(m, 5H),

6.96(d, 4H), 6.90(s, IH), 5.40(s, 2H), 4.89(s, 2H), 4.08(t, 2H), 3.80(s, 3H),

2.97(t, 2H), 2.27(s, 3H) LC/MS(MH⁺) 535

Example 142

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-chlorophenyl)thio-car bamoyl-(5-methoxy-lH-indol-3-yl)methylamine Η-NMR(CDC1₃) δ 8.80(s, IH), 7.60(d, 2H), 7.52(d, 2H), 7.35(d, IH), 7.00-7.20(m, 7H), 6.92(d, 3H), 5.40(s, 2H), 4.90(s, 2H), 4.07(t, 2H), 3.80(s, 3H), 2.98(t, 2H) LC/MS(MH⁺) 555

Example 143

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(5-methoxy-lH-indol-3-yl)methylamine

Η-NMR(CDC1₃) δ 8.75(s, IH), 7.55(m, 3H), 7.42(s, IH), 7.35(d, IH), 6.92-7.12(ixi, 7H), 6.90(s, IH), 6.80(d, 2H), 5.40(s, 2H), 4.90(s, 2H), 4.07(t, 2H), 3.82(s, 3H), 3.76(s, 3H), 2.98(t, 2H) LC/MS(MH⁺) 551

Example 144

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoy l-(5 -methoxy- 1 H-indol-3 -yl)methylamine

1H-NMR(CDC1₃) δ 8.90(s, IH), 7.75(d, IH), 7.55(m, 5H), 7.30(d, IH),

7.08(d, 3H), 6.90(d, 3H), 6.65(d, IH), 5.40(s, 2H), 4.90(s, 2H), 4.07(t, 2H),

3.85(s, 3H), 3.80(s, 3H), 2.98(t, 2H)

LC/MS(MH⁺) 552

Example 145

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)thio-car bamoyl-(2-methyl-lH-indol-3-yl)methylamine

To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(2-methyl-lH-indol-3-yl)me thylamine(13mg, 0.035mmol) prepared from Preparation Example 14 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 80ul, 0.04mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(14mg).

1H-NMR(CDC1₃) δ 8.62(s, IH), 7.75(s, IH), 7.55(d, 2H), 7.48(s, IH), 7.43(d, IH), 7.35(d, IH), 7.05-7.22(m, 5H), 6.95(m, IH), 6.80(m, 3H), 5.38(s, 2H), 4.83(s, 2H), 4.00(t, 2H), 2.85(t, 2H), 2.40(s, 3H) LC/MS(MH⁺) 523

Example 146

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(3 -chloro-4-methyl-phen yl)thiocarbamoyl-(quinolin-4-yl)methylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(quinolin-4-yl)methylamine (13mg, 0.035mmol) prepared from Preparation Example 21 in dichloromethane(lml) was added a solution of 3-chloro-4-methylphenyl isothiocyanate(0.5M solution in dichloromethane, 80ul, 0.04mmol). The mixture was stirred for 2hr at room temperature. The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(17mg). 1H-NMR(CDC1₃) δ 8.95(d, IH), 8.20(d, IH), 7.80(t, 2H), 7.72(s, IH), 7.62(d, IH), 7.58(d, 2H), 7.40(s, IH), 7.20(s, 3H), 7.05(m, 3H), 6.80(s, IH), 5.39(s, 2H), 5.30(s, 2H), 4.00(t, 2H), 3.00(t, 2H), 2.35(s, 3H) LC/MS(MH⁺) 551

Example 147-148

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(quinolin-4-yl)-met hylamine prepared from Preparation Example 21 was reacted with the corresponding isothiocyanates under the same condition as described in Example 146 to give the title compounds. Example 147

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(2-pheny lethy l)thiocarba moyl-(quinolin-4-yl)methylamine lH-NMR(CDCl₃) δ 8.80(d, IH), 8.20(d, IH), 7.82(t, IH), 7.64(m, 2H), 7.59(d, 2H), 7.45(s, IH), 7.15(d, 2H), 6.90-7.00(m, 7H), 5.43(s, 2H), 4.95(s, 2H), 3.98(t, 2H), 3.85(q, 2H), 2.95(t, 2H), 2.80(t, 2H) LC/MS(MH⁺) 531

Example 148

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-(quinolin-4-yl)methylamine

1H-NMR(CDC1₃) δ 8.92(d, IH), 8.18(d, IH), 7.92(s, IH), 7.87(d, IH), 7.80(t,

2H), 7.62(m, IH), 7.57(d, 3H), 7.40(s, IH), 7.22(d, IH), 7.10(d, 2H), 6.80(s, IH), 6.72(d, IH), 5.38(s, 2H), 5.3 l(s, 2H), 4.05(t, 2H), 3.85(s, 3H), 3.00(t, 2H)

LC/MS(MH⁺) 534

Example 149

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3-chloro-4-methyl-phen yl)thiocarbamoyl-(6-chloro-pyridin-2-yl)methylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(6-chloro-pyridin-2-yl)meth ylamine(190mg, 0.55mmol) prepared from Preparation Example 19 in dichloromethane(lml) was added 3-chloro-4-methylphenyl isothiocyanate(110mg, 0.6mmol). The mixture was stirred for 4hr at room temperature, and concentrated in vacuo. The residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(270mg). Η-NMR(CDC1₃) δ 10.60(s, IH), 7.80(t, IH), 7.60(m, 3H), 7.48(s, IH), 7.40(d, IH), 7.20-7.40(m, 3H), 7.15(d, 2H), 6.95(s, IH), 5.42(s, 2H), 4.64(s, 2H), 3.90(dd, 2H), 2.96(dd, 2H), 2.38(s, 3H) LC/MS(MH⁺) 535

Example 150

N- {2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-fluorophenyl)thio-car bamoyl-(naphthyl- 1 -yl)methylamine

To a solution of N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(naphthyl- 1 -yl)methylamin e(13mg, 0.035mmol) prepared from Preparation Example 22 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 80ul, 0.04mmol). The mixture was stirred for 2hr at room temperature. The mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(16mg). 1H-NMR(CDC1₃) δ 7.80-8.00(m, 3H), 7.60(m, 2H), 7.50(d, 3H), 7.42(s, IH), 7.35(s, IH), 7.25(d, IH), 7.18(d, IH), 7.08(d, 2H), 7.00(m, IH), 6.85(d, 2H), 6.80(s, IH), 5.40(s, 2H), 5.20(s, 2H), 4.00(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 520

Example 151-155

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(naphthyl- 1 -yl)met hyl-amine prepared from Preparation Example 22 was reacted with the corresponding isothiocyanates under the same condition as described in Example 150 to give the title compounds.

Example 151 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methylphenyl)thio-car bamoy l-(naphthyl- 1 -y l)methy lamine

Η-NMR(CDC1₃) δ 7.80-8.00(m, 3H), 7.60(m, 2H), 7.50(d, 3H), 7.45(s, IH), 7.25(d, IH), 7.10(p, 7H), 6.82(s, IH), 5.40(s, 2H), 5.20(s, 2H), 4.00(dd, 2H), 3.00(dd, 2H), 2.30(s, 3H) LC/MS(MH⁺) 516

Example 152

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy l-N-(3 -chloro-4-methy 1-phen yl)thio-carbamoyl-(naphthyl- 1 -yl)methylamine 1H-NMR(CDC1₃) δ 7.80-8.00(m, 3H), 7.60(m, 2H), 7.50(m, 3H), 7.40(s, IH), 7.25(m, 2H), 7.10(m, 7H), 6.97(dd, IH), 6.80(s, IH), 5.40(s, 2H), 5.20(s, 2H), 4.00(dd, 2H), 3.00(dd, 2H), 2.30(s, 3H) LC/MS(MH⁺) 550

Example 153

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -chlorophenyl)thiocarb amoyl- (naphthyl- 1 -yl)methy lamine

1H-NMR(CDC1₃) δ 7.80-8.00(m, 3H), 7.60(m, 2H), 7.50(m, 3H), 7.40(s, IH),

7.36(s, IH), 7.25(d, 2H), 7.15(m, 2H), 7.05(d, 3H), 6.80(s, IH), 5.40(s, 2H), 5.20(s, 2H), 4.00(dd, 2H), 3.00(dd, 2H)

LC/MS(MH⁺) 536

Example 154

N- {2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(naphthyl- 1 -yl)methylamine

1H-NMR(CDC1₃) δ 7.80-8.00(m, 3H), 7.60(m, 2H), 7.50(d, 3H), 7.42(s, IH),

7.30(d, IH), 7.12(d, 2H), 7.05(m, 3H), 6.80(d+s, 3H), 5.40(s, 2H), 5.20(s, 2H),

4.05(dd, 2H), 3.77(s, 3H), 3.00(dd, 2H)

LC/MS(MH⁺) 532 Example 155

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-(naphthy 1- 1 -yl)methy lamine

Η-NMR(CDC1₃) δ 7.80-8.00(m, 4H), 7.60(m, 2H), 7.50(m, 4H), 7.25(d, 2H), 6.80(s, IH), 6.67(d, IH), 5.40(s, 2H), 5.20(s, 2H), 4.03(dd, 2H), 3.82(s, 3H), 3.00(dd, 2H) LC/MS(MH⁺) 533

Example 156 N-[2-(l-Methyl-lH-imidazol-5-yl)]ethyl-N-(3-chloro-4-methylphenyl)thio-carb amoyl-2-trifluoromethylbenzylamine

To a solution of

N- [2-( 1 -methyl- 1 H-imidazol-5 -yl)] ethyl-2-trifluoromethyl-benzylamine( 11 mg, 0.04mmol) prepared from Preparation Example 23 in dichloromethane(lml) was added a solution of 3-chloro-4-methylphenyl isothiocyanate(0.5M solution in dichloromethane, 88ul, 0.04mmol). The mixture was stirred for lhr at room temperature. The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound.

Η-NMR(CDC1₃) δ 7.75(d, IH), 7.61(m, IH), 7.40-7.60(m, 3H), 7.30(s, IH), 7.10-7.20(m, 2H), 7.00(dd, IH), 6.79(s, IH), 5.12(s, 2H), 4.03(dd, 2H), 3.62(s, 3H), 3.09(dd, 2H), 2.32(s, 3H) LC/MS(MH⁺) 467

Example 157

N-[2-(l-Methyl-lH-imidazol-5-yl)]ethyl-N-(3-fluorophenyl)thiocarbamoyl-2,3- dichlorobenzylamine

To a solution of N-[2-(l-methyl-lH-imidazol-5-yl)]ethyl-2,3-dichlorobenzyl-amine(l lmg, 0.04mmol) prepared from Preparation Example 24 in dichloromethane(lml) was added a solution of 3 -fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 88ul, 0.04mmol). The mixture was stirred for 2hr at room temperature. And the mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound.

1H-NMR(CDC1₃) δ 7.69(s, IH), 7.47(d, IH), 7.30(m, 3H), 7.20(t, IH), 7.07(d, 2H), 6.90(m, 2H), 6.77(s, IH), 4.97(s, 2H), 4.03(dd, 2H), 3.62(s, 3H), 3.09(dd, 2H)

LC/MS(MH⁺) 437

Example 158-159

N- [2-( 1 -Methyl- 1 H-imidazol-5 -yl)] ethyl-2,3 -dichlorobenzylamine prepared from Preparation Example 24 was reacted with the corresponding isothiocyanates under the same condition as described in Example 157 to give the title compounds.

Example 158

N-[2-( 1 -Methyl- 1 H-imidazol-5 -yl)]ethyl-N-(4-trifluoromethylphenyl)thio-carba moyl-2,3 -dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.72(s, IH), 7.47(d, IH), 7.25(m, 3H), 7.15(m, 4H),

6.72(s, IH), 4.97(s, 2H), 4.03(dd, 2H), 3.62(s, 3H), 3.09(dd, 2H) LC/MS(MH⁺) 503

Example 159

N-[2-(l -Methyl- lH-imidazol-5-yl)]ethyl-N-(2-methoxypyridin-5-yl)thiocarbam oyl-2,3 -dichlorobenzylamine 1H-NMR(CDC1₃) δ 7.78(d, IH), 7.50(dd, IH), 7.35(d, IH), 7.30(s, IH), 7.20(t, 2H), 7.05(d, IH), 6.65(m, 2H), 4.87(s, 2H), 3.97(dd, 2H), 3.80(s, 3H), 3.60(s, 3H), 3.00(dd, 2H) LC/MS(MH⁺) 450

Example 160

N-{2-[l -(3 ,4-Methylenedioxyphenylmethyl)- lH-imidazol-5-yl]}ethyl-N-(3-chl oro-4-methylphenyl)thiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of N- {2-[ 1 -(3,4-methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethyl-2-trifluor omethylbenzylamine(12mg, 0.03 mmol) prepared from Preparation Example 25 in dichloromethane(lml) was added a solution of 3 -chloro-4-me thylphenyl isothiocyanate(0.5M solution in dichloromethane, 60ul, 0.03mmol). The mixture was stirred for 3hr at room temperature. The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(16mg). Η-NMR(CDC1₃) δ 7.75(d, IH), 7.60(m, IH), 7.47(d, IH), 7.40(m, 3H), 7.17(d, 2H), 7.00(dd, IH), 6.82(s, IH), 6.70(d, IH), 6.55(m, 2H), 5.90(s, 2H), 5.12(s, 2H), 5.02(s, 2H), 3.97(dd, 2H), 3.00(dd, 2H), 2.35(s, 3H) LC/MS(MH⁺) 587

Example 161-163

N-{2-[l-(3,4-Methylenedioxyphenylmethyl)-lH-imidazol-5-yl]}ethyl- 2-trifluoromethylbenzylamine prepared from Preparation Example 25 was reacted with the corresponding isothiocyanates under the same condition as described in Example 160 to give the title compounds.

Example 161 N- {2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-flu oro-phenyl)thiocarbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 7.75(d, IH), 7.60(m, IH), 7.47(d, IH), 7.40(m, 3H), 7.35(s, IH), 7.15(m, 2H), 7.00(t, 2H), 6.82(s, IH), 6.70(d, IH), 6.55(ιxι, 2H), 5.90(s, 2H), 5.12(s, 2H), 5.02(s, 2H), 3.97(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 557

Example 162

N- {2-[ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-met hyl-phenyl)thiocarbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 7.75(d, IH), 7.60(m, IH), 7.45(m, 3H), 7.00-7.20(m, 5H), 6.87(s, IH), 6.70(d, IH), 6.55(m, 2H), 5.90(s, 2H), 5.15(s, 2H), 5.02(s, 2H), 3.98(dd, 2H), 3.00(dd;.2H), 2.32(s, 3H) LC/MS(MH⁺) 553

Example 163

N- {2-[ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-trifl uoro-methylphenyl)thiocarbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 7.75(d, IH), 7.60(m, IH), 7.50(m, 3H), 7.45(m, 2H), 7.35(d, 3H), 6.84(s, IH), 6.70(d, IH), 6.55(m, 2H), 5.90(s, 2H), 5.10(s, 2H), 5.05(s, 2H), 3.98(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 607

Example 164

N- {2-[ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-chl oro-phenyl)thiocarbamoy 1-2, 3 -dichlorobenzy lamine

To a solution of

N-{2-[l-(3,4-methylenedioxyphenylmethyl)-lH-imidazol-5-yl]}ethyl-2,3-dichl orobenzylamine(12mg, 0.03mmol) prepared from Preparation Example 26 in dichloromethane(lml) was added a solution of 4-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 60ul, 0.03mmol). After stirring for lhr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(14mg). 1H-NMR(CDC1₃) δ 7.60(s, IH), 7.45(d, IH), 7.40(s, IH), 7.25(m, 3H), 7.10(m, 3H), 6.80(s, IH), 6.70(d, IH), 6.55(m, 2H), 5.90(s, 2H), 5.10(s, 2H), 4.80(s, 2H), 3.90(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 573

Example 165-169

N- {2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethy 1- 2,3-dichlorobenzylamine prepared from Preparation Example 26 was reacted with the corresponding isothiocyanates under the same condition as described in Example 164 to give the title compounds.

Example 165

N- {2-[ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-flu oro-phenyl)thiocarbamoyl-2,3-dichlorobenzylamine 1H-NMR(CDC1₃) δ 7.40(s, IH), 7.35(d, IH), 7.15(m, 2H), 6.90(m, 3H), 6.77(d, IH), 6.70(s, IH), 6.55(d, IH), 6.42(m, 2H), 5.80(s, 2H), 5.00(s, 2H), 4.70(s, 2H), 3.77(dd, 2H), 2.85(dd, 2H) LC/MS(MH⁺) 557

Example 166

N- {2-[ l-(3,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-flu oro-phenyl)thiocarbamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.50(m, 2H), 7.40(s, IH), 7.30(t, IH), 7.15(m, 3H),

7.02(t, IH), 6.82(s, IH), 6.70(d, IH), 6.55(m, 2H), 5.90(s, 2H), 5.10(s, 2H), 4.80(s, 2H), 3.90(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 557

Example 167

N- { 2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethy l-N-(3 -hy d roxy-4-methoxyphenyl)thiocarbamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.47(m, 2H), 7.27(t, 2H), 7.10(d, IH), 6.87(s, IH),

6.80(d, IH), 6.70(m, 3H), 6.80(m, 2H), 5.92(s, 2H), 5.12(s, 2H), 4.80(s, 2H),

3.95(dd, 2H), 3.87(s, 3H), 3.00(dd, 2H)

LC/MS(MH⁺) 585

Example 168

N- { 2- [ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5 -yl] } ethyl-N-(4-met hyl-phenyl)thiocarbamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.50(d, IH), 7.47(s, IH), 7.30(m, 2H), 7.10(q, 5H), 6.85(s, IH), 6.70(d, IH), 6.70(m, 2H), 5.90(s, 2H), 5.17(s, 2H), 4.80(s, 2H),

3.98(dd, 2H), 3.05(dd, 2H), 2.35(s, 3H)

LC/MS(MH⁺) 553

Example 169 N- {2-[ 1 -(3 ,4-Methylenedioxyphenylmethyl)- 1 H-imidazol-5-yl] } ethyl-N-pheny lthio-carbamoyl-2,3-dichlorobenzylamine

Η-NMR^DCls) δ 7.50(d, IH), 7.47(s, IH), 7.10-7.40(m, 8H), 6.85(s, IH),

6.70(d, IH), 6.70(m, 2H), 5.90(s, 2H), 5.17(s, 2H), 4.80(s, 2H), 3.98(dd, 2H),

3.05(dd, 2H) LC/MS(MH⁺) 539

Example 170

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3 -chloro-4-methylpheny l)thio-carbamoyl-butylamine To a solution of

N- {2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethyl-butylamine(12mg, 0.043mmol) prepared from Preparation Example 27 in dichloromethane(lml) was added a solution of 3-chloro-4-methylphenyl isothiocyanate(0.5M solution in dichloromethane, 86ul, 0.043mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(12mg).

1H-NMR(CDC1₃) δ 7.57-7.70(m, 3H), 7.10-7.40(m, 6H), 7.00(d, IH), 5.50(s, 2H), 3.97(dd, 2H), 3.55(m, 2H), 3.00(dd, 2H), 2.40(s, 3H), 1.40(m, 3H), 1.00(m, 4H) LC/MS(MH⁺) 466

Example 171-172

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-butylamine prepared from Preparation Example 27 was reacted with the corresponding isothiocyanates under the same condition as described in Example 170 to give the title compounds.

Example 171 ^'

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2,4-dimethoxyphenyl)-t hiocarbamoyl-butylamine

1H-NMR(CDC1₃) δ 8.00(m, IH), 7.65(d, 2H), 7.57(s, IH), 7.00(d, IH), 6.55(m, 2H), 5.60(s, 2H), 3.97(dd, 2H), 3.87(s, 6H), 3.55(m, 2H), 3.00(dd, 2H), 1.40(m, 3H), 1.00(m, 4H) LC/MS(MH⁺) 478

Example 172 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-butylamine

Η-NMR(CDC1₃) δ 7.95(ixi, IH), 7.65(d, 3H), 7.57(s, IH), 7.20(m, 3H), 7.00(s, lH),6.80(d, IH), 5.52(s, 2H), 3.97(dd+s, 5H), 3.55(m, 2H), 3.00(dd, 2H), 1.40(ixi, 3H), 1.00(m, 4H) LC/MS(MH⁺) 449

Example 173

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl-2-butenylamine

To a solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2-butenylamine(12mg,

0.043mmol) prepared from Preparation Example 30 in dichloromethane(lml) was added a solution of 4-methylphenyl isothiocyanate(0.5M solution in dichloromethane, 86ul, 0.043mmol). After stirring for 4hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(6mg).

1H-NMR(CDC1₃) δ 7.57-7.70(m, 3H), 7.15-7.30(m, 6H), 7.00(m, 2H), 5.57(ixi, 2H), 3.97(dd, 2H), 3.55(m, 2H), 3.00(dd, 2H), 2.40(s, 3H), 1.80(m, 2H),

1.30(1X1, 3H)

LC/MS(MH⁺) 430

Example 174-175

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2-butenylamine prepared from Preparation Example 30 was reacted with the corresponding isothiocyanates under the same condition as described in Example 173 to give the title compounds. Example 174

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)-thioc arbamoyl-2-butenylamine

1H-NMR(CDC1₃) δ 7.67(d, 2H), 7.57(s, IH), 7.17-7.40(m, 4H), 6.90-7.05(m, 4H), 5.57(m, 2H), 3.98(dd, 2H), 3.85(s, 3H), 3.55(m, 2H), 3.00(dd, 2H), 1.80(m, 2H), 1.30(m, 3H) LC/MS(MH⁺) 446

Example 175 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-2-butenylamine

Η-NMR(CDC1₃) δ 8.00(m, IH), 7.67(d, 2H), 7.57(s, IH), 7.20(d, 2H),

7.05(s, IH), 6.80(d, IH), 5.57(d, 2H), 3.98(dd+s, 5H), 3.55(m, 2H), 3.00(dd,

2H), 1.80(m, 2H), 1.30(m, 3H) LC/MS(MH⁺) 447

Example 176

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-fluorophenyl)thio-car bamoylcyclohexylmethylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-cyclohexylmethylamine( 14 mg, 0.043mmol) prepared from Preparation Example 31 in dichloromethane(lml) was added a solution of 4-fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 86ul, 0.043mmol). After stirring for 6hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(14mg).

Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.50(s, IH), 7.23(m, 3H), 7.00-7.20(m, 4H), 6.95(s, IH), 5.45(s, 2H), 3.95(dd, 2H), 3.35(d, 2H), 2.92(dd, 2H), 1.80(m, 5H), 1.25(m, 4H), 1.00(1X1, 2H) LC/MS(MH⁺) 476

Example 177-179

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-cyclohexylmethyl-a mine prepared from Preparation Example 31 was reacted with the corresponding isothiocyanates under the same condition as described in Example 176 to give the title compounds.

Example 177

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl-cyclohexylmethylamine

1H-NMR(CDCl₃) δ 7.60(d, 2H), 7.50(m, 2H), 7.07-7.24(m, 7H), 6.95(s, IH), 5.45(s, 2H), 3.95(dd, 2H), 3.35(d, 2H), 2.92(dd, 2H), 2.37(s, 3H), 1.80(m, 5H),

1.25(m, 4H), 1.00(m, 2H)

LC/MS(MH⁺) 472

Example 178 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -trifluoromethyl-pheny l)thiocarbamoyl-cyclohexylmethylamine

1H-NMR(CDC1₃) δ 7.50-7.65(m, 7H), 7.40(s, IH), 7.15(d, 2H), 6.95(s, IH),

5.45(s, 2H), 3.95(dd, 2H), 3.40(d, 2H), 2.92(dd, 2H), 2.37(s, 3H), 1.80(m, 5H),

1.25(1X1, 4H), 1.00(m, 2H) LC/MS(MH⁺) 526

Example 179

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-phenylethyl)thio-carb amoyl-cyclohexylmethylamine Η-NMR(CDC1₃) δ 7.65(d, 2H), 7.55(s, IH), 7.15-7.40(m, 7H), 6.95(s, IH), 5.50(s, 2H), 5.30(t, IH), 3.95(q, 2H), 3.82(dd, 2H), 2.97(t, 4H), 2.82(dd, 2H), 1.70(m, 3H), 1.50(m, 2H), 1.25(m, 2H), 1.10(m, 2H), 0.70(m, 2H) LC/MS(MH⁺) 486

Example 180

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chlorophenyl)thiocarb amoyl-isobutylamine

To a solution of N- {2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-isobutylamine(12mg,

0.043mmol)prepared from Preparation Example 28 in dichloromethane(lml) was added a solution of 3-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 86ul, 0.043mmol). The mixture was stirred for 3hr at room temperature. The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(13mg).

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.42(s, IH), 7.10-7.30(m, 7H), 6.95(s, IH), 5.47(s, 2H), 3.95(dd, 2H), 3.37(d, 2H), 2.95(dd, 2H), 2.10(m, IH), 1.05(d, 6H) LC/MS(MH⁺) 452

Example 181

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(2-phenylethyl)thiocarba moyl-isobutylamine

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-isobutylamine prepared from Preparation Example 28 was reacted with phenethyl isothiocyanate under the same condition as described in Example 180 to give the title compound. 1H-NMR(CDC1₃) δ 7.61(d, 2H), 7.50(s, IH), 7.10-7.40(m, 6H), 6.95(s, IH), 5.47(s, 2H), 3.77-3.98(m, 4H), 2.95(t, 4H), 2.80(dd, 2H), 1.80(m, IH), 0.75(d, 6H) LC/MS(MH⁺) 446

Example 182 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-chlorophenyl)thio-car bamoylpropylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-propylamine( 12mg, 0.044mmoι)prepared from Preparation Example 32 in dichloromethane(lml) was added a solution of 4-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 86ul, 0.043mmol). After stirring for 3hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(12mg).

Η-NMR(CDC1₃) δ 7.62(dd, 2H), 7.55(s, IH), 7.10-7.40(m, 7H), 6.97(m, IH), 5.50(m, 2H), 3.97(dd, 2H), 3.37(m, IH), 2.95(dd, 2H), 2.15(m, IH), 1.00(m, 5H) LC/MS(MH⁺) 438

Example 183-184

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-propy lamine prepared from Preparation Example 32 was reacted with the corresponding isothiocyanates under the same condition as described in Example 182 to give the title compounds.

Example 183

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methylpheny l)thio-carbamoyl-propylamine 1H-NMR(CDC1₃) δ 7.50-7.70(m, 8H), 7.15(m, 2H), 6.97(s, IH), 5.50(m, 2H), 3.97(dd, 2H), 3.37(m, IH), 2.95(dd, 2H), 2.15(m, IH), 1.00(m, 5H) LC/MS(MH⁺) 472

Example 184

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-trifluoromethyl-pheny l)thiocarbamoyl-propylamine

1H-NMR(CDC1₃) δ 7.65(d, 2H), 7.55(s, IH), 7.10-7.40(m, 7H), 6.97(s, IH), 5.50(m, 2H), 3.97(dd, 2H), 3.37(m, IH), 2.95(dd, 2H), 2.15(m, IH), 1.00(m, 5H)

LC/MS(MH⁺) 488

Example 185

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3-chlorophenyl)thio-car bamoylpentylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-pentylamine( 13mg, 0.043mmol) prepared from Preparation Example 29 in dichloromethane(lml) was added a solution of 3-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 86ul, 0.043mmol). After stirring for lhr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(13mg). 1H-NMR(CDC1₃) δ 7.65(d, 2H), 7.55(s, IH), 7.10-7.40(m, 7H), 6.97(s, IH), 5.50(s, 2H), 3.95(dd, 2H), 3.50(t, 2H), 2.95(dd, 2H), 1.40(m, 4H), 0.95(m, 5H) LC/MS(MH⁺) 466

Example 186 N- {2-[ l-(4-Nitrobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-chlorophenyl)thio-carb amoyl-2-trifluoromethylbenzylamine

To a solution of

N- {2-[ 1 -(4-nitrobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-trifluoromethy Ibenzy lamin e(12mg, 0.03mmol) prepared from Preparation Example 33 in dichloromethane(lml) was added a solution of 3-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 60ul, 0.03mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(15mg).

Η-NMR(CDC1₃) δ 8.18(d, 2H), 7.80(d, IH), 7.65(t, IH), 7.50(m, 2H), 7.32(t, 2H), 7.20(m, 5H), 7.08(d, IH), 6.92(s, IH), 5.50(s, 2H), 5.00(s, 2H), 4.00(dd, 2H), 3.00(dd, 2H) LC/MS(MH⁺) 574

Example 187-188

N-{2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-2-trifluoromethyl-be nzyl-amine prepared from Preparation Example 33 was reacted with the corresponding isothiocyanates under the same condition as described in Example 186 to give the title compounds.

Example 187

N- {2- [ 1 -(4-Nitrobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methoxyphenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 8.18(d, 2H), 7.78(d, IH), 7.62(t, IH), 7.50(m, 2H),

7.35(d, IH), 7.20(d, 2H), 7.08(d, 3H), 6.80(t, 3H), 5.50(s, 2H), 5.00(s, 2H),

4.01(dd, 2H), 3.80(s, 3H), 3.01(dd, 2H)

LC/MS(MH⁺) 570 Example 188

N- {2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)th io-carbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 8.18(d, 2H), 7.82(d, IH), 7.78(d, IH), 7.62(t, IH), 7.50(m, 3H), 7.35(d, 2H), 7.20(d, 2H), 6.90(s, IH), 6.72(d, IH), 5.50(s, 2H), 5.00(s, 2H), 4.01(dd, 2H), 3.90(s, 3H), 3.01(dd, 2H) LC/MS(MH⁺) 571

Example 189 N-{2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methyl-pheny l)thiocarbamoyl-2,3-dichlorobenzylamine

To a solution of

N-{2-[l-(4-nitrobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichlorobenzylamine(12 mg, 0.03mmol) prepared from Preparation Example 34 in dichloromethane(lmι) was added a solution of 3-chloro-4-methylphenyl isothiocyanate(0.5M solution in dichloromethane, 60ul, 0.03mmol). The mixture was stirred for 2hr at room temperature. And the mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(17mg).

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.55(m, 3H), 7.35(t, IH), 7.22(d, 4H), 7.00-7.15(m, 2H), 6.91(s, IH), 5.55(s, 2H), 4.95(s, 2H), 4.00(dd, 2H), 3.03(dd, 2H), 2.40(s, 3H) LC/MS(MH⁺) 588

Example 190-194

N-{2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-2,3-dichlorobenzyl-a mine prepared from Preparation Example 34 was reacted with the corresponding isothiocyanates under the same condition as described in Example 189 to give the title compounds.

Example 190

N- {2-[ 1 -(4-Nitrobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-chlorophenyl)thio-carb amoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.60(m, IH), 7.52(s, IH), 7.35(m, 2H),

7.22(m, 5H), 7.15(t, 2H), 6.91(s, IH), 5.55(s, 2H), 4.90(s, 2H), 4.00(dd, 2H),

3.03(dd, 2H)

LC/MS(MH⁺) 574

Example 191

N- {2-[ 1 -(4-Nitrobenzyl)- lH-imidazol-5-yl] } ethyl-N-(4-chlorophenyl)thio-carb amoyl-2,3 -dichlorobenzylamine

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.55(m, 3H), 7.35(m, 3H), 7.10-7.25(m, 5H), 6.91(s, IH), 5.55(s, 2H), 4.90(s, 2H), 4.00(dd, 2H), 3.03(dd, 2H)

LC/MS(MH⁺) 574

Example 192

N- {2- [ 1 -(4-Nitrobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -fluorophenyl)thio-carb amoyl-2,3 -dichlorobenzylamine

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.55(s, 3H), 7.20-7.40(m, 4H), 7.10(m, 2H), 6.95(d, 2H), 6.91(s, IH), 5.55(s, 2H), 4.90(s, 2H), 4.00(dd, 2H), 3.03(dd, 2H) LC/MS(MH⁺) 558

Example 193

N-{2-[l-(4-Nitrobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-methoxyphenyl)thio-ca rbamoyl-2,3 -dichlorobenzylamine

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.55(d+s, 2H), 7.20-7.35(m, 4H), 7.20(d,

2H), 7.12(1X1, 3H), 6.91(m, 3H), 5.55(s, 2H), 4.90(s, 2H), 4.00(dd, 2H), 3.80(s, 3H), 3.03(dd, 2H) LC/MS(MH⁺) 570

Example 194

N-{2-[l -(4-Nitrobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)-t hio-carbamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 8.20(d, 2H), 7.85(d, IH), 7.70(s, IH), 7.55(m, 2H),

7.48(s, IH), 7.35(t, IH), 7.22(d, 2H), 7.12(d, IH), 6.85(s, IH), 6.76(d, IH),

5.55(s, 2H), 4.90(s, 2H), 4.03(dd, 2H), 3.90(s, 3H), 3.03(dd, 2H)

LC/MS(MH⁺) 571

Example 195

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(α -methyl-3 -chloro)benzylamine

To a solution of N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(α

-methyl-3 -chloro)benzylamine(10mg, 0.027mmol) prepared from Preparation Example 35 in dichloromethane(lml) was added a solution of 4-methoxyphenyl isothiocyanate(0.5M solution in dichloromethane, 54ul, 0.027mmol). After stirring for 6hr at room temperature, the reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(13mg, 91%).

Η-NMR^DCy δ 6.81-7.60(m, 14H), 5.84(dd, IH), 5.28(s, 2H), 3.80(s, 3H), 3.67(m, 2H), 2.76(m, 2H), 1.66(d, 3H) LC/MS(MH⁺) 530

Example 196-197

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(α -methyl-3 -chloro)benzy lamine prepared from Preparation Example 35 was reacted with the corresponding isothiocyanates under the same condition as described in Example 195 to give the title compounds.

Example 196

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)- thiocarbamoyl-(α -methyl-3 -chloro)benzy lamine

H-NMR(CDC1₃) δ 6.71-7.88(1X1, 13H), 5.82(dd, IH), 5.28(s, 2H), 3.91(s, 3H),

3.79(1X1, 2H), 2.77(m, 2H), 1.67(d, 3H)

LC/MS(MH⁺) 531

Example 197

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-fluorophenyl)thio-car bamoyl(α -methyl-3 -chloro)benzylamine

H-NMR(CDC1₃) δ 6.80-7.60(m, 14H), 5.81(dd, IH), 5.29(s, 2H), 3.78(m,

2H), 2.77(m, 2H), 1.65(d, 3H) LC/MS(MH⁺) 518

Example 198

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-methoxyphenyl)thio-c arbamoyl-(α -methyl-3-fluoro)benzylamine

To a solution of N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-(α

-methyl-3 -fluoro)benzylamine(10mg, 0.026mmol) prepared from Preparation

Example 36 in dichloromethane(lml) was added a solution of 4-methoxyphenyl isothiocyanate(0.5M solution in dichloromethane, 54ul, 0.027mmol). After stirring for 6hr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(lθmg).

1H-NMR(CDC1₃) δ 6.81-7.60(m 14H), 5.79(dd, IH), 5.3 l(s, 2H), 3.80(s,

3H), 3.74(m, 2H), 2.78(m, 2H), 1.67(d, 3H). LC/MS(MH⁺) 514 Example 199-201

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-(α -methyl-3 -fluoro)-benzy lamine prepared from Preparation Example 36 was reacted with the corresponding isothiocyanates under the same condition as described in Example 198 to give the title compounds.

Example 199 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-(α -methyl-3 -fluoro)benzy lamine

1H-NMR(CDC1₃) δ 6.69-7.73(m, 13H), 5.79(dd, IH), 5.33(s, 2H), 3.92(s,

3H), 3.81(m, 2H), 2.79(m, 2H), 1.68(d, 3H)

LC/MS(MH⁺) 515

Example 200

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-chlorophenyl)thio-car bamoyl(α -methyl-3 -fluoro)benzylamine

1H-NMR(CDC1₃) δ 6.81-7.58(m, 14H), 5.77(dd, IH), 5.28(s, 2H), 3.79(m, 2H), 2.79(m, 2H), 1.65(d, 3H)

LC/MS(MH⁺) 518

Example 201

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylphenyl)thio-car bamoyl(α -methyl-3 -fluoro)benzylamine

Η-NMR(CDC1₃) δ 6.79-7.59(m, 14H), 5.80(dd, IH), 5.34(s, 2H), 3.79(m, 2H), 2.79(m, 2H), 2.35(s, 3H), 1.66(d, 3H) LC/MS(MH⁺) 498

Example 202 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethy 1-N- [(4-methoxyphenyl)-N^*- methyl]thiocarbamoyl-2-trifluoromethylbenzylamine

<Step 1> N-(4-Methoxyphenyl)-N-methylthiocarbamoyl chloride

A suspension of N-methyl-p-anisidine(5.13g, 37.4mmol) and NaH(60%, 1.65g, 41.1 mmol) in anhydrous tetrahydrofuran( 100ml) was refluxed for 5hr. To the reaction mixture was added dropwise trimethylsilyl chloride(4.06g, 37.4mmol) at room temperature and then the mixture was refluxed for lhr. The insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was distillated in vacuo to give(4-methoxyphenyl)-methyl-trimethylsilanylamine(5.95g, 76%) as an yellow oil. To a solution of thiophosgen(1.61ml, 21.1mmol) in anhydrous n-hexane(40ml) was added(4-methoxyphenyl)-methyl-trimethylsilanylamine (5.95g, 76%) at -100°C and the reaction mixture was stirred for lhr. The insoluble material was filtered off and the filtrate was concentrated in vacuo to give the title compound. R_f=0.5(Ethyl acetate/n-Hexane=l/3, v/v)

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-[(4-methoxyρhenyl)-N'- methyl]thiocarbamoyl-2-trifluoromethylbenzylamine

A solution of

N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-2-trifluoromethylbenzylami ne prepared from Preparation Example 1 and

N-(4-methoxyphenyl)-N-methylthiocarbamoyl chloride in dichloromethane was refluxed for 24hr. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the title compound as white yellow.

R_f=0.5(dichloromethane/methanol = 10/1, v/v)

1H-NMR(CDC1₃) δ 6.76-7.60(m, 14H), 5.08(s, 2H), 4.65(s, 2H), 3.77(s, 3H),

3.65(m, 2H), 3.42(s, 3H), 2.66(m, 2H)

Example 203

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(3 -chlorophenyl)thio-car bamoyl-2-methylphenylamine

To a solution of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-2-methylphenylamine(20m g, 0.063mmol) prepared from Preparation Example 46 in dichloromethane(lml) was added a solution of 3-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, 126ul). The mixture was heated for 24hr at 35 °C . The reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(14.7mg).

1H-NMR(CDC1₃) δ 7.57-7.66(m, 3H), 7.45-7.48(m, 3H), 7.15-7.42(m, 6H), 6.90(s, IH), 6.82(s, IH), 5.54(dd, 2H), 4.59-4.74(m, IH), 3.63-3.78(m, IH), 2.96-3.08(m, 2H), 2.28(s, 3H) LC/MS(MH⁺) 486

Example 204-205

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-2-methylpheny 1-am ine prepared from Preparation Example 46 was reacted with the corresponding isothiocyanates under the same condition as described in Example 203 to give the title compounds.

Example 204 N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(4-chlorophenyl)thiocarb amoyl-2-methylphenylamine

1H-NMR(CDC1₃) δ 7.57-7.65(m, 3H), 7.39-7.49(m, 3H), 7.15-7.37(m, 6H), 6.90(s, IH), 6.79(s, IH), 5.54(dd, 2H), 4.59-4.74(m, IH), 3.63-3.78(m, IH), 2.96-3.07(m, 2H), 2.28(s, 3H) LC/MS(MH⁺) 486

Example 205

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(4-methylphenyl)thio-car bamoy 1-2 -methy lpheny lamine

1H-NMR(CDC1₃) δ 7.59-7.65(m, 4H), 7.36-7.46(m, 3H), 7.16-7.28(m, 6H),

6.91(s, IH), 6.76(s, IH), 5.56(dd, 2H), 4.59-4.74(m, IH), 3.65-3.80(m, IH),

2.98-3.09(m, 2H), 2.36(s, 3H), 2.30(s, 3H)

LC/MS(MH⁺) 466

Example 206

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(3 -chloro-4-methyl-phe nyl)thiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of N- {3-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] }propyl-2-trifluoromethylbenzylam ine(264mg, 0.66mmol) prepared from Preparation Example 37 in dichloromethane(lθml) was added 3-chloro-4-methylphenyl isothiocyanate(110mg, 0.66mmol) in dichloromethane. After stirring for lhr at room temperature, the solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(364mg, 95%).

1H-NMR(CDC1₃) δ 6.83-7.76(m, 13H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H),

2.42(t, 2H), 2.13(s, 3H), 2.06(m, 2H)

LC/MS(MH⁺) 582 Example 207-241

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-2-trifluoromethyl- benzy lamine prepared from Preparation Example 37 was reacted with the corresponding isothiocyanates under the same condition as described in Example 206 to give the title compounds.

Example 207

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-chlorophenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 568

Example 208

N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-(4-chlorophenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H),

2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 568

Example 209

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2,4-dichlorophenyl)-th iocarbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 6.83-7.90(m, 13H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 602

Example 210 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-fluorophenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.06(1X1, 2H) LC/MS(MH⁺) 552

Example 211

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-fluorophenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 552

Example 212

N- {3-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } propy l-N-(3-hy droxy-4-methoxy- phenyl)thiocarbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.70-7.77(m, 13H), 5.20(s, 2H), 5.01(s, 2H), 3.90(t, 2H), 3.87(s, 3H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 580

Example 213

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-methoxyphenyl)-thi ocarbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H),

3.79(s, 3H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 564

Example 214

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(2-methoxypyridin-5 -y 1 )thio-carbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 6.70-7.81(m, 13H), 5.17(s, 2H), 5.03(s, 2H), 3.88(s, 3H), 3.87(t, 2H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 565

Example 215 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methylphenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H),

2.42(t, 2H), 2.09( m, 2H), 2.04(s, 3H)

LC/MS(MH⁺) 548

Example 216

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-methylphenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.32(s, 3H), 2.06(m, 2H)

LC/MS(MH⁺) 548

Example 217

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-phenylthiocarbamoyl-2 -trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 6.83-7.76(m, 15H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.08(m, 2H) LC/MS(MH⁺) 534

Example 218

N- {3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-N-(3 -trifluoromethyl-phen yl)thiocarbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H),

2.42(t, 2H), 2.06(xn, 2H) LC/MS(MH⁺) 602 Example 219

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(4-trifluoromethy 1-phen yl)thiocarbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 6.83-7.76(m, 14H), 5.17(s, 2H), 5.03(s, 2H), 3.85(t, 2H), 2.42(t, 2H), 2.06(m, 2H) LC/MS(MH⁺) 602

Example 220 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(4-acetylphenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 576

Example 221 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-benzyloxyphenyl)-th iocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 640

Example 222 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-bromophenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 612

Example 223 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-bromophenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.75-7.35(m, 9H), 7.1(m, 5H), 6.85(s, IH), 5.15(s, IH),

5.05(s, IH), 3.85(t, 2H), 2.4(t, 2H), 2.1(m, 2H)

LC/MS(MH⁺) 612 Example 224

N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] }propyl-N-(3-chloro-6-methoxy-p henyl)thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 598

Example 225

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(3 -nitro-4-chloro-pheny l)thiocarbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC13) δ 7.90-7.40(m, 11H), 7.10(dd, 2H), 6.80(s, IH), 5.15(s, 2H), 5.10(s 2H), 3.85(t, 2H), 2.45(t, 2H), 2.05(m, 2H) LC/MS(MH⁺) 612

Example 226

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(4-cyanophenyl)thio-ca rbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 559

Example 227

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(n-pentyl)thio-carbamo yl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 528

Example 228

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-N",N"-dimethyl-ami nonaphthyl- 1 -yl)thiocarbamoyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 627

Example 229

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-ethoxycarbonyl-phe nyl)thiocarbamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 8.00(dd, 2H), 7.80-7.30(m, 10), 7.10(dd, 2H), 6.85(s, IH), 5.15(s, 2H), 5.05(s, 2H), 4.35(m, 2H), 3.85(t, 2H), 2.45(t, 2H), 2.10(m, 2H) 1.35(t, 3H) LC/MS(MH⁺) 606

Example 230

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(4-methylthio-phenyl)t hiocarbamoyl-2-trifluoromethylbenzylamine

LC/MS(MH⁺) 580

Example 231

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(naphthyl- 1 -yl)thiocarb amoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.85-7.25(m, 17H), 7.05(dd, 2H), 6.85(s, IH), 5.15(s, 2H), 3.95(t, 2H), 2.45(t, 2H), 2.15(m, 2H)

LC/MS(MH⁺) 584

Example 232

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(tetrahydrofuran-2-ylm ethyl)-thiocarbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.65-7.15(m, 9H), 6.90(s, IH), 5.8(m, IH), 5.15(s, 2H), 4.95(s, IH), 3.90-3.50(m, 7H), 2.40(t, 2H), 2.00-1.80(m, 6H) LC/MS(MH⁺) 542

Example 233

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-phenylpropyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.70-7.05(m, 14H), 6.90(s, IH), 5.25(m, IH), 5.20(s, IH),

4.90(s, IH), 3.75(t, 2H), 3.6(m, 2H), 2.5-2.35(m, 4H), 2.00-1.80(m, 4H) LC/MS(MH⁺) 576 Example 234

N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] }propyl-N-(n-butyl)thio-carbamoy 1-2-trifluoromethylbenzylamine LC/MS(MH⁺) 514

Example 235

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-cyclohexylthio-carbam oyl-2-trifluoromethylbenzylamine LC/MS(MH⁺) 540

Example 236

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-cycloocty lthio-carbamo yl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 7.70-7.40(m, 8H), 7.25-7.15(m, 2H), 6.90(s, IH), 5.20(s, 2H), 4.80(s, 2H), 4.50(m, IH), 3.90(t, 2H), 2.45(t, 2H), 2.05(m, 2H), 1.80(m, 4H), 1.45(m, 10H) LC/MS(MH⁺) 568

Example 237

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-cyclopropy lthio-carba moyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.75-7.40(m, 7H), 7.15(dd, IH), 6.90(s, IH), 5.45(s, IH),

5.20(s, 2H), 4.80(s, 2H), 3.80(t, 2H), 3.00(m, IH), 2.40(t, 2H), 2.00(m, 2H), 0.80(m, 2H), 0.40(m, 2H)

LC/MS(MH⁺) 498

Example 238

N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-ethoxycarbonylthio-car bamoyl-2-trifluoromethylbenzylamine Η-NMR(CDC1₃) δ 7.70-7.30(m, 8H), 7.15(dd, 2H), 6.90(s, IH), 5.60(s, 2H), 5.20(s, 2H), 4.90(s, 2H), 3.85(t, 2H), 2.25(t, 2H), 2.00(m, 2H), 1.70(t, 3H) LC/MS(MH⁺) 530

Example 239

N- { 3 -[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-N-isobutylthiocarbamoyl-

2-trifluoromethylbenzylamine

LC/MS(MH⁺) 514

Example 240

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-methoxypropyl)thio- carbamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 7.70-7.35(m, 6H), 7.15(dd, 2H), 6.9(s, IH), 6.65(m, IH),

5.15(s, IH), 4.9(s, IH), 3.70(m, 2H), 3.40(t, 2H), 2.95(s, 3H), 2.40(t, 2H), 2.00(m, 2H), 1.75(m, 2H)

LC/MS(MH⁺) 530

Example 241

N- { 3 -[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-morpholin-4-y l)-eth yl]thio-carbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.75-7.15(m, 8H), 6.90(s, IH), 6.30(br, IH), 5.20(s, 2H),

4.80(s, 2H), 3.90(t, 2H), 3.55(m, 2H), 3.20(m, 4H), 2.25(m, 4H), 2.20(m, 4H),

2.05(1X1, 2H)

LC/MS(MH⁺) 571

Example 242

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-fluorophenyl)thio-ca rbamoyl-2,3 -dichlorobenzylamine

To a solution of N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-2,3-dichlorobenzylamine(l Omg, 0.025mmol) prepared from Preparation Example 38 in dichloromethane(lml) was added a solution of 4-fluorophenyl isothiocyanate(0.5M solution in dichloromethane, 50ul, 0.025mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(13mg, 96%).

1H-NMR(CDC1₃) δ 7.65(dd, 2H), 7.50(m, 2H), 7.25(m, 2H), 7.20-6.95(m, 7H), 6.85(s, IH), 5.15(s, 2H), 4.90(s, 2H), 3.90(t, 2H), 2.45(t, 2H), 2.05(m, 2H) LC/MS(MH⁺) 552

Example 243-249

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-2,3-dichloro-benz ylamine prepared from Preparation Example 38 was reacted with the corresponding isothiocyanates under the same condition as described in Example 242 to give the title compounds.

Example 243 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(3 -chloro-4-methyl-phe nyl)thiocarbamoyl-2,3-dichlorobenzylamine LC/MS(MH⁺) 582

Example 244 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(3 -chlorophenyl)thio-ca rbamoyl-2,3-dichlorobenzylamine LC/MS(MH⁺) 568

Example 245 N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]}propyl-N-(3-fluorophenyl)thio-ca rbamoyl-2,3 -dichlorobenzylamine LC/MS(MH⁺) 552

Example 246 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(4-methoxyphenyl)-thi ocarbamoy 1-2, 3 -dichlorobenzylamine LC/MS(MH⁺) 564

Example 247 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thio-carbamoyl-2,3-dichlorobenzylamine LC/MS(MH⁺) 565

Example 248 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-methylphenyl)thio-c arbamoyl-2, 3 -dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.60(dd, 2H), 7.50(dd, 2H), 7.30-7.00(m, 9H), 6.85(s,

IH), 5.20(s, 2H), 4.90(s, 2H), 3.90(t, 2H), 2.45(t, 2H), 2.35(s, 3H), 2.10(m, 2H)

LC/MS(MH⁺) 548

Example 249

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(3 -trifluoromethyl-phen yl)thiocarbamoyl-2,3-dichlorobenzylamine

1H-NMR(CDC1₃) δ 7.62(dd, 2H), 7.45(m, 7H), 7.25(m, IH), 7.15(m, 3H), 6.85(s, IH), 5.15(s, 2H), 4.95(s, 2H), 3.90(t, 2H), 2.45(t, 2H), 2.10(m, 2H)

LC/MS(MH⁺) 602

Example 250-256

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-3-chlorobenzyl-a mine prepared from Preparation Example 39 was reacted with the corresponding isothiocyanates under the same condition as described in Example 242 to give the title compounds.

Example 250

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-chlorophenyl)thio-ca rbamoyl-3-chlorobenzylamine

Η-NMR(CDC1₃) δ 7.60(d+s, 3H), 7.32(s, 2H), 7.02-7.28(m, 9H), 6.9 l(s, IH), 5.20(s, 2H), 4.82(s, 2H), 3.85(t, 2H), 2.43(t, 2H), 2.07(m, 2H) LC/MS(MH⁺) 534

Example 251

N- {3-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] }propyl-N-(4-chlorophenyl)thio-ca rbamoy 1-3 -chlorobenzylamine 1H-NMR(CDC1₃) δ 7.60(dd, 2H), 7.50(s, IH), 7.35-7.25(m, 5H), 7.10(m, 6H), 6.90(s, IH), 5.15(s, 2H), 4.85(s, 2H), 3.90(t, 2H), 2.42(t, 2H), 2.05(m, 2H) LC/MS(MH⁺) 534

Example 252 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(4-methoxyphenyl)-thi ocarbamoy 1-3 -chlorobenzylamine LC/MS(MH⁺) 530

Example 253 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thio-carbamoyl-3-chlorobenzylamine LC/MS(MH⁺) 531

Example 254 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(2-methylpheny l)thio-c arbamoy 1-3 -chlorobenzylamine

1H-NMR(CDC1₃) δ 7.62(dd, 2H), 7.50(s, IH), 7.35-7.10(m, 10H), 6.90(s, IH), 6.80(s, IH), 5.15(s, 2H), 4.82(s, 2H), 3.95(t, 2H), 2.45(t, 2H), 2.05(m, 2H), 2.00(s, 3H) LC/MS(MH⁺) 514

Example 255

N-{3-[ l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-chloro-4-methyl-phe nyl)thiocarbamoyl-3-chlorobenzylamine LC/MS(MH⁺) 548

Example 256

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(3 -fluorophenyl)thio-ca rbamoy 1-3 -chlorobenzylamine LC/MS(MH⁺) 518

Example 257-262

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-2-methylbenzyl-a mine prepared from Preparation Example 40 was reacted with the corresponding isothiocyanates under the same condition as described in Example 242 to give the title compounds.

Example 257 N- {3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-chloro-4-methyl-phe nyl)thiocarbamoyl-2-methylbenzylamine

1H-NMR(CDC1₃) δ 7.60(d+s, 3H), 7.28(m, 3H), 7.02-7.20(m, 5H),

6.85-7.00(m, 3H), 5.20(s, 2H), 4.70(s, 2H), 3.95(t, 2H), 2.45(t, 2H), 2.30(d, 6H),

2.07(m, 2H) LC/MS(MH⁺) 528 Example 258

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(4-fluorophenyl)thio-ca rbamoyl-2-methylbenzylamine Η-NMR(CDC1₃) δ 7.60(d, 3H), 7.28(m, 4H), 6.80-7.20(m, 8H), 5.20(s, 2H), 4.70(s, 2H), 3.97(t, 2H), 2.45(t, 2H), 2.30(s, 3H), 2.07(m, 2H) LC/MS(MH⁺) 498

Example 259 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(4-methylphenyl)thio-c arbamoyl-2-methylbenzylamine

1H-NMR(CDC1₃) δ 7.60(d, 3H), 7.24(d, 4H), 7.10(m, 4H), 6.85-7.02(m, 4H), 5.20(s, 2H), 4.67(s, 2H), 3.95(t, 2H), 2.45(t, 2H), 2.30(d, 6H), 2.07(m, 2H) LC/MS(MH⁺) 494

Example 260

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propy l-N-(3 -chloropheny l)thio-ca rbamoyl-2-methylbenzylamine

LC/MS(MH⁺) 514

Example 261

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(3 -fluorophenyl)thio-ca rbamoyl-2-methylbenzylamine

LC/MS(MH⁺) 498

Example 262

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl

)thio-carbamoyl-2-methylbenzylamine

LC/MS(MH⁺) 511 Example 263-266

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-(naphthy 1- 1 -yl)-m ethyl-amine prepared from Preparation Example 41 was reacted with the corresponding isothiocyanates under the same condition as described in Example 242 to give the title compounds.

Example 263

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol- 5 -yl] } propy l-N-(3 -fluoropheny l)thio-ca rbamoyl-(naphthyl- 1 -yl)methylamine

1H-NMR(CDC1₃) δ 7.90(xn, 3H), 7.60-7.45(m, 6H), 7.30-7.00(m, 6H), 6.85(m, 3H), 5.25(s, 2H), 5.15(s, 2H), 3.95(t, 2H), 2.45(t, 2H), 2.10(m, 2H) LC/MS(MH⁺) 534

Example 264

N- {3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(2-methoxypyridin-5 -y 1 )thio-carbamoyl(naphthy 1- 1 -yl)methylamine LC/MS(MH⁺) 547

Example 265

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(3-chloro-4-methyl-phe nyl)thiocarbamoyl-(naphthyl- 1 -yl)methylamine LC/MS(MH⁺) 564

Example 266

N- {3-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] }propyl-N-(4-methoxyphenyl)-thi ocarbamoyl-(naphthyl- 1 -yl)methylamine

1H-NMR(CDC1₃) δ 7.82-8.00(m, 3H), 7.45-7.68(m, 6H), 7.24-7.38(m, 2H),

7.02-7.18(m, 5H), 6.80-6.95(m, 2H), 5.28(s, 2H), 5.17(s, 2H), 4.00(t, 2H), 3.80(s, 3H), 2.45(t, 2H), 2.30(d, 6H), 2.10(m, 2H) LC/MS(MH⁺) 546

Example 267

N- {4- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } butyl-N-(4-chlorophenyl)thio-car bamoyl-2-trifluoromethylbenzylamine

To a solution of

N- {4-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] }butyl-2-trifluoromethylbenzylami ne(15mg, 0.036mmol) prepared from Preparation Example 42 in dichloromethane(lmι) was added a solution of 4-chlorophenyl isothiocyanate(0.5M solution in dichloromethane, lOOul, 0.05mmol). After stirring for 2hr at room temperature, the reaction mixture was purified by short silica gel column chromatography (eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(18.3mg). 1H-NMR(CDC1₃) δ 7.74(d, IH), 7.60-7.64(m, 3H), 7.41-7.5 l(m, 3H), 7.24-7.30(m, 2H), 7.07-7.18(m, 4H), 6.83(s, IH), 5.13(s, 2H), 5.09(s, 2H), 3.81(t, 2H), 2.43(t, 2H), 1.78-1.86(m, 2H), 1.56-1.63(m, 2H) LC/MS(MH⁺) 582

Example 268-270

N-{4-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}butyl-2-trifluoromethyl-b enzylamine prepared from Preparation Example 42 was reacted with the corresponding isothiocyanates under the same condition as described in Example 267 to give the title compounds.

Example 268

N- {4- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } butyl-N-(4-fluorophenyl)thio-car bamoyl-2-trifluoromethylbenzylamine 1H-NMR(CDC1₃) δ 7.74(d, IH), 7.60-7.67(m, 3H), 7.42-7.5 l(m, 3H), 6.96-7.20(m, 6H), 6.84(s, IH), 5.14(s, 2H), 5.09(s, 2H), 3.82(t, 2H), 2.43(t, 2H), 1.75-1.86(m, 2H), 1.56-1.67(m, 2H) LC/MS(MH⁺) 566

Example 269

N-{4-[l -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl]} buty l-N-(4-methoxyphenyl)thio-c arbamoyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 7.71(d, IH), 7.58-7.65(m, 3H), 7.42-7.46(m, 3H), 7.03-7.10(1X1, 5H), 6.82-6.86(m, 2H), 5.12(s, 2H), 5.08(s, 2H), 3.83-3.75(m, 5H), 2.41(t, 2H), 1.73-1.88(xn, 2H), 1.55-1.65(m, 2H) LC/MS(MH⁺) 578

Example 270

N- {4-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] }butyl-N-(2-methoxypyridin-5-yl)t hio-carbamoyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.83(d, IH), 7.73(d, IH), 7.59-7.66(m, 3H), 7.42-7.5 l(m,

3H), 7.22(s, IH), 7.09(d, 2H), 6.81(s, IH), 6.7 l(d, IH), 5.13(s, 4H),3.90(s, 3H),

3.82(t, 2H), 2.42(t, 2H), 1.75-1.89(m, 2H), 1.56-1.67(m, 2H)

LC/MS(MH⁺) 579

Example 271

N-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]methyl-N-(4-methoxyphenyl)thio-car bamoyl-2-trifluoromethylbenzylamine

To a solution of

N-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]methyl-2-trifluoromethylbenzylamine (lOmg, 0.027mmol) prepared from Preparation Example 43 in dichloromethane(lmι) was added a solution of 4-methoxyphenyl isothiocyanate(0.5M solution in dichloromethane, 65ul). After stirring for lhr at room temperature, the reaction mixture was purified by short silica gel column chromatography(eluent: dichloromethane/methanol=20/l, v/v) to give the title compound(14mg).

1H-NMR(CDC1₃) δ 7.40-7.80(m, 6H), 7.20(d, IH), 7.05(m, 3H), 6.85(m, 5H), 5.60(s, 2H), 5.40(s, 2H), 4.55(s, 2H), 3.80(s, 3H) LC/MS(MH⁺) 536

Example 272-273

N-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]methyl-2-trifluoromethyl-ben zylamine prepared from Preparation Example 43 was reacted with the corresponding isothiocyanates under the same condition as described in Example 271 to give the title compounds.

Example 272 N-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]methyl-N-(4-nitrophenyl)thio-carbam oyl-2-trifluoromethylbenzylamine

Η-NMR(CDC1₃) δ 8.10(d, 2H), 7.50-7.70(m, 5H), 7.35(m, 3H), 6.95-7.15(m,

5H), 5.45(s, 2H), 5.20(s, 2H), 4.75(s, 2H)

LC/MS(MH⁺) 551

Example 273

N-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]methyl-N-(2-chlorophenyl)thio-carba moyl-2-trifluoromethylbenzylamine

1H-NMR(CDC1₃) δ 7.40-7.75(m, 6H), 7.20(m, 3H), 7.05(m, 5H), 6.85(d, IH), 5.60(s, 2H), 5.40(s, 2H), 4.60(s, 2H)

LC/MS(MH⁺) 540

Example 274

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } acetyl-N-(4-methoxyphenyl)thio- carbamoyl-2-trifluoromethylbenzylamine To a suspension of NaH(24.1mg, 0.6mmol) in dimethylformamide(5ml) was added

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } acetyl-2-trifluoromethylbenzyl-a mine (200mg, 0.5mmol) prepared from Preparation Example 44 at -78 ^°C . After stirring for lOminute at the same temperature, 4-methoxyphenyl isothiocyanate(81mg, 0.5mmol) was added to the mixture. The reaction mixture was standed for 24hr at room temperature and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was recrystallized with ethanol to give the title compound(109mg, 38%). R_f=0.4(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.46-7.74(m, 7H), 6.91-7.10(m, 6H), 6.83(s, IH), 5.06-5.11(xn, 4H), 3.87(s, 3H), 3.25(s, 2H) LC/MS(MH⁺) 564

Example 275

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}acetyl-N-(2-methoxypyridin-5-yl

)thio-carbamoyl-2-trifluoromethylbenzylamine

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } acetyl-2-trifluoromethyl-b enzylamine prepared from Preparation Example 44 was reacted with

2-methoxypyridin-5-yl isothiocyanates under the same condition as described in Example 274 to give the title compound. R_f=0.4(dichloromethane/methanol=20/l, v/v)

Η-NMR(CDC1₃) δ 11.52(s, IH), 7.88(s, IH), 7.45-7.72(m, 7H), 7.26-7.3 l(m,

2H), 7.07(d, 2H), 6.82(s, IH), 5.09(s, 2H), 5.05(d, 2H), 3.98(s, 3H), 3.26(s, 2H)

LC/MS(MH⁺) 565

Example 276 N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] }propionyl-N-(4-methoxyphenyl)- thio-carbamoyl-2-trifluoromethylbenzylamine

To a suspension of NaH(60%, 40.1mg, l .OOmmol) in dimethylformamide(8ml) was added

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propionyl-2-trifluoromethylbenzy lamine(345mg, 0.84mmol) prepared from Preparation Example 45 at -40 ^°C . To the reaction mixture was added a solution of 4-methoxyphenyl isothiocyanate(136mg, 0.84mmol) in dimethylformamide(lml) and stirred for 30min at the same temperature. After stirring for 3hr at room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was recrystallized with ethanol to give the title compound(l 15mg, 24%). Η-NMR(CDC1₃) δ 7.48-7.66(m, 6H), 7.33-7.37(m, IH), 7.06(d, 2H), 6.86(d, 2H), 6.68(s, IH), 5.23(s, 2H), 5.15(s, 2H), 3.76(s, 3H), 2.84(t, 2H), 2.67(t, 2H) LC/MS(MH⁺) 578

Example 277 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(3-chloro-4-methyl-phe nyl)-S-methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of

N- { 2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-(3 -chloro-4-methylpheny 1 )thiocarbamoyl-2-trifluoromethylbenzylamine(173mg, 0.304mmol) prepared from Example 16 in dichloromethane(2ml) was added iodomethane(129mg, 0.912mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(64mg, 36%). R_f=0.3(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.74(d, IH), 7.50(m, 4H), 7.40(m, 2H), 7.12(d, IH), 6.90(ixi, 4H), 6.72(dd, IH), 5.26(s, 2H), 5.00(s, 2H), 3.52(dd, 2H), 2.92(dd, 2H), 2.40(s, 3H), 1.90(s, 3H) LC/MS(MH⁺) 582

Example 278-281

The compounds prepared from Example 17, Example 1, Example 2, Example 3 were reacted with iodomethane under the same condition as described in Example 277 to give the title compounds.

Example 278

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(benzyl-S-methyl)-isothi ocarbamoyl-2-trifluoromethylbenzylamine R_f=0.35(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 548

Example 279 N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-[(4-methoxyphenyl)-S-m ethyl]isothiocarbamoyl-2-trifluoromethylbenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.88(d, IH), 7.33-7.72(m, 6H), 7.23(s, IH), 6.88-7.07(m,

4H), 6.82(s, IH), 5.26(s, 2H), 4.97(s, 2H), 3.83(s, 3H), 3.45(t, 3H), 2.83(t, 2H), 1.82(s, 3H)

LC/MS(MH⁺) 564

Example 280

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine R_f=0.30(dichloromethane/methanol=20/ 1 , v/v)

1H-NMR(CDC1₃) δ 7.72-7.76(m, 2H), 7.43-7.61(m, 5H), 7.19-7.38(m, 3H), 6.96(d, 2H), 6.72(d, IH), 5.24(s, 2H), 5.02(s, 2H), 3.94(s, 3H), 3.53(t, 3H), 2.79(t, 2H), 1.82(s, 3H) LC/MS(MH⁺) 565

Example 281

N- {2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(4-methylphenyl)-S-met hyl]isothiocarbamoyl-2-trifluoromethylbenzylamine R_f=0.35(dichloromethane/methanol=20/l, v/v)

Η-NMR(CDC1₃) δ 7.68(d, IH), 7.34-7.68(m, 6H), 7.06(d, 2H), 6.88-6.92(m,

2H), 6.77(d, 2H), 5.23(s, 2H), 4.98(s, 2H), 3.47(t, 3H), 2.82(t, 2H), 2.34(s,

3H),1.82(s, 3H)

LC/MS(MH⁺) 548

Example 282

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-[(3-chloro-4-methyl-phe nyl)-S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] }ethyl-N-(3-chloro-4-methylphenyl )thiocarbamoyl-2,3-dichlorobenzylamine(24.9mg, 0.048mmol) prepared from Example 47 in dichloromethane(lml) was added iodomethane(34.1mg, 0.24mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(9.8mg, 36%). R_f=0.3(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 582 Example 283-284

The compounds prepared from Example 55, Example 41 were reacted with iodomethane under the same condition as described in Example 282 to give the title compounds.

Example 283

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(4-fluorophenyl)-S-met hyl]isothiocarbamoyl-2,3-dichlorobenzylamine R{=0.35(dichloromethane/methanol=20/l, v/v)

Η-NMR(CDC1₃) δ 7.41-7.54(1X1, 3H), 7.19-7.26(m, 2H), 7.01-7.09(m, 2H),

6.90-6.99(m, 4H), 6.76-6.82(m, 2H), 5.25(s, 2H), 4.84(s, 2H), 3.52(t, 2H),

2.81(m, 2H), 1.81(s.3H)

LC/MS(MH⁺) 552

Example 284

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(4-methoxyphenyl)-S-m ethyl] isothiocarbamoyl-2 ,3 -dichlorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.48-7.52(m, 3H), 7.40-7.47(m, lh), 7.19-7.27(m, 2H),

7.07-7. l l(m, IH), 6.86-6.92(m, 3H), 6.75-6.82(m, 4H), 5.27(s, 2H), 4.85(s, 2H),

3.82(s, 3H), 3.52(t, 2H), 2.82(t, 2H), 1.82(s, 3H)

LC/MS(MH⁺) 563

Example 285

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-[(3-chloro-4-methyl-phe nyl)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine

To a solution of N-{2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methylphenyl )thiocarbamoyl-3-chlorobenzylamine(24.9mg, 0.048mmol) prepared from Example 63 in dichloromethane(lml) was added iodomethane(34.1mg, 0.24mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(9.8mg, 36%). R =0.3(dichloromethane/methanol=20/ 1 , v/v) LC/MS(MH⁺) 548

Example 286-288

The compounds prepared from Example 60, Example 66, Example 67 were reacted with iodomethane under the same condition as described in

Example 285 to give the title compounds.

Example 286

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(3-fluorophenyl)-S-met hy 1] isothiocarbamoy 1-3 -chlorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.52-7.57(m, 2H), 7.13-7.34(m, 5H), 6.92-6.96(m, 3H),

6.57-6.77(m, 4H), 5.24(s, 2H), 4.79(s, 2H), 3.58(t, 2H), 2.78(t, 2H), 1.86(s, 3H)

LC/MS(MH⁺) 518

Example 287 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(4-methoxyphenyl)-S-m ethyl] isothiocarbamoyl-3 -chlorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.49-7.53(m, 3H), 7.24-7.35(m, 4H), 7.12-7.16(m, IH),

6.79-6.96(m, 6H), 5.23(s, 2H), 4.77(s, 2H), 3.82(s, 3H), 3.54(t, 2H), 2.73(t, 2H), 1.85(s, 3H) LC/MS(MH⁺) 530

Example 288

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy 1-N- [(2-methoxypyridin-5 -y 1) -S-methyl]isothiocarbamoyl-3-chlorobenzylamine R_f=0.30(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 531

Example 289 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(3-chloro-4-methylphen yl)-S-methyl]isothiocarbamoyl-3-fluorobenzylamine

To a solution of

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methylphenyl )thiocarbamoyl-3-fluorobenzylamine(38.3mg, 0.27mmol) prepared from Example 76 in dichloromethane(lml) was added iodomethane(38.3mg, 0.27mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(10.9mg, 38%).

R_f=0.3(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 532

Example 290-292

The compounds prepared from Example 77, Example 78, Example 81 were reacted with iodomethane under the same condition as described in Example 289 to give the title compounds.

Example 290 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(3-chlorophenyl)-S-met hyl] isothiocarbamoy 1-3 -fluorobenzy lamine R_f=0.35(dichloromethane/methanol=20/l, v/v)

1H-NMR(CDC1₃) δ 7.49-7.56(m, 3H), 7.17-7.33(m, 3H), 6.92-7.01(m, 3H), 6.74-6.89(m, 5H), 5.24(s, 2H), 4.78(s, 2H), 3.52(t, 2H), 2.71(t, 2H), 1.83(s, 3H) LC/MS(MH⁺) 518

Example 291

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(4-methoxyphenyl)-S-m ethyl] isothiocarbamoyl-3 -fluorobenzy lamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.51-7.54(m, 3H), 7.16-7.19(xn, 2H), 6.79-7.05(m, 9H),

5.26(s, 2H), 4.77(s, 2H), 3.83(s, 3H), 3.53(t, 2H), 2.74(t, 2H), 1.82(s, 3H)

LC/MS(MH⁺) 514

Example 292

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N- [(3 -trifluoromethyl-phen yl)-S-methyl] isothiocarbamoyl-3 -fluorobenzy lamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 552

Example 293

N- {2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N- [(3 -chloro-4-methyl-phe nyl)-S-methyl]isothiocarbamoyl-2,3-difluorobenzylamine

To a solution of

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-(3-chloro-4-methylphenyl )thiocarbamoyl-2,3-difluorobenzylamine(28.0mg, 0.052mmol) prepared from Example 47 in dichloromethane(lml) was added iodomethane(36.9mg, 0.26mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(9.15mg, 32%). R_f=0.3 (dichloromethane/methanol=20/ 1 , v/v) LC/MS(MH⁺) 550

Example 294-297

The compounds prepared from Example 94, Example 92, Example 96, Example 97 were reacted with iodomethane under the same condition as described in Example 293 to give the title compounds.

Example 294

N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-[(3-chlorophenyl)-S-met hyl]-isothiocarbamoyl-2,3-difluorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.48-7.58(m, 3H), 6.72-7.23(m, 10H), 5.24(s, 2H), 4.83(s,

2H), 3.53(t, 2H), 2.76(t, 2H), 1.86(s, 3H)

LC/MS(MH⁺) 536

Example 295

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(3-fluorophenyl)-S-met hyl]isothiocarbamoyl-2,3-difluorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.50-7.57(m, 3H), 6.92-7.22(m, 6H), 6.52-6.75(m, 4H),

5.23(s, 2H), 4.84(s, 2H), 3.53(t, 2H), 2.77(t, 2H), 1.86(s, 3H)

LC/MS(MH⁺) 520

Example 296 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(4-methoxyphenyl)-S-m ethyl]isothiocarbamoyl-2,3-difluorobenzylamine R_f=0.35(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 532

Example 297

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]isothiocarbamoyl-2,3-difluorobenzylamine R_f=0.30(dichloromethane/methanol=20/l , v/v)

Η-NMR(CDC1₃) δ 7.68(d, IH), 7.55(d, 2H), 7.50(s, IH), 6.92-7.18(m, 7H), 6.68(d, IH), 5.2 l(s, 2H), 4.83(s, 2H), 3.96(s, 3H), 3.56(t, 2H), 2.76(t, 2H), 1.84(s, 3H) LC/MS(MH⁺) 533

Example 298 N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(3-chloro-4-methyl-phe nyl)-S-methyl]isothiocarbamoyl-4-trifluoromethylbenzylamine

To a solution of

N- {2-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-(3-chloro-4-methylphenyl )thiocarbamoyl-4-trifluoromethylbenzylamine(27.8mg, 0.049mmol) prepared from Example 105 in dichloromethane(lml) was added iodomethane(34.8mg, 0.25mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(10.5mg, 37%).

R_f=0.3(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 582

Example 299-301 The compounds prepared from Example 109, Example 103, Example 107 were reacted with iodomethane under the same condition as described in Example 298 to give the title compounds.

Example 299

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(3-fluorophenyl)-S-met hyl]isothiocarbamoyl-4-trifluoromethylbenzylamine R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.62(d, 2H), 7.50-7.58(m, 3H), 7.37(d, 2H), 7.17-7.28(m, 2H), 6.88-7.83(m, 2H), 6.54-6.73(m, 3H), 5.21(s, 2H), 4.83(s, 2H), 3.52(t, 2H), 2.74(t, 2H), 1.86(s, 3H) LC/MS(MH⁺) 552

Example 300 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-[(4-fluorophenyl)-S-met hyl]isothiocarbamoyl-4-trifluoromethylbenzylamine R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v) LC/MS(MH⁺) 552

Example 301

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(4-methoxyphenyl)-S-m ethyl]isothiocarbamoyl-4-trifluoromethylbenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.60(d, 2H), 7.51-7.53(m, 3H), 7.38(d, 2H), 6.79-7.92(m, 7H), 5.23(s, 2H), 4.82(s, 2H), 3.83(s, 3H), 3.55(t, 2H), 2.75(t, 2H), 1.86(s, 3H)

LC/MS(MH⁺) 564

Example 302

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]thiocarbamoyl-(naphthyl- 1 -yl)methylamine To a solution of

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-(2-methoxypyridin-5-yl)t hiocarbamoyl-(naphthyl-l-yl)methylamine(27.0mg, 0.051mmol) prepared from Example 108 in dichloromethane(lml) was added iodomethane(36.0mg, 0.25mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(10.0mg, 36%). R_f=0.3(dichloromethane/methanol=20/l, v/v)

1H-NMR(CDC1₃) δ 7.85(ixi, 2H), 7.76(m, 2H), 7.50(m, 2H), 7.40(m, 4H), 7.20(m, 2H), 6.75(m, 4H), 5.20(s, 2H), 5.06(s, 2H), 3.90(s, 3H), 3.50(dd, 2H), 2.60(dd, 2H), 1.82(s, 3H) LC/MS(MH⁺) 547

Example 303

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]thiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of

N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(2-methoxypyridin-5 -y 1 )thiocarbamoyl-2-trifluoromethylbenzylamine( 150mg, 0.27mmol) prepared from Example 214 in dichloromethane(lml) was added iodomethane(156mg, l. lOmmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(60mg, 38%). R_f=0.3(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.75(d, IH), 7.60(m, 4H), 7.48(s, IH), 7.38(t, 3H), 7.22(dd, IH), 7.05(d, 2H), 6.87(s, IH), 6.67(d, IH), 5.12(s, 2H), 4.98(s, 2H), 3.90(s, 3H), 3.45(t, 2H), 2.35(t, 2H), 1.95(m, 2H), 1.86(s, 3H) LC/MS(MH⁺) 579

Example 304-306

The compounds prepared from Example 213, Example 207, Example 210 were reacted with iodomethane under the same condition as described in Example 303 to give the title compounds.

Example 304

N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] }propyl-N-[(4-methoxyphenyl)-S- methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

Η-NMR(CDC1₃) δ 7.32-7.70(m, 6H), 7.04(d, 2H), 6.85(m, 5H), 5.12(s, 2H), 4.98(s, 2H), 3.80(s, 3H), 3.45(t, 2H), 2.35(t, 2H), 1.95(m, 2H), 1.86(s, 3H)

LC/MS(MH⁺) 578

Example 305

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-chlorophenyl)-S-me thyl]isothiocarbamoyl-2-trifluoromethylbenzylamine

R_f=0.35(dichloromethane/methanol=20/l, v/v)

Η-NMR^DC^) δ 7,51-7.64(m, 4H), 7.28-7.45(m, 3H), 7.14-7.23(m, IH),

7.04(d, 2H), 6.80-6.96(m, 4H), 5.13(s, 2H), 4.96(s, 2H), 3.43(t, 2H), 2.14(t, 2H),

1.95-2.03(m, 2H), 1.84(s, 3H) LC/MS(MH⁺) 582

Example 306

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-fluorophenyl)-S-me thyl]isothiocarbamoyl-2-trifluoromethylbenzylamine R_f=0.35(dichloromethane/methanol=20/l, v/v) Η-NMR(CDC1₃) δ 7,50-7.68(m, 4H), 7.36-7.42(m, 3H), 7.16-7.24(m, IH), 7.03(d, 2H), 6.84(s, IH), 6.62-6.73(m, 3H), 5.08(s, 2H), 4.94(s, 2H), 3.46(t, 2H), 2.16(t, 2H), 1.93-1.97(m, 2H), 1.87(s, 3H) LC/MS(MH⁺) 566

Example 307

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy 1-N- [(3 -chloro-4-methy lphe nyl)-S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine

To a solution of

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-N-(3 -chloro-4-methylphe nyl)thiocarbamoyl-2,3-dichlorobenzylamine(26.5mg, 0.046mmol) prepared from Example 243 in dichloromethane(lml) was added iodomethane(32.6mg, 0.230mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(8.5mg, 31%). R_f=0.3(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 596

Example 308-311

The compounds prepared from Example 244, Example 245, Example 247 were reacted with iodomethane under the same condition as described in Example 307 to give the title compounds.

Example 308

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-chlorophenyl)-S-me thyl]isothiocarbamoyl-2,3-dichlorobenzylamine R_f=0.35(dichloromethane/methanol=20/l, v/v) 1H-NMR(CDC1₃) δ 7.62(d, 2H), 7.54(s, IH), 7.08-7.28(m, 6H), 6.90-6.97(m, 2H), 6.89(dd, IH), 5.15(s, 2H), 4.92(s, 2H), 3.49(t, 2H), 2.16(t, 2H), 1.90-1.97(m, 2H), 1.84(s, 3H) LC/MS(MH⁺) 582

Example 309

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-fluorophenyl)-S-me thyl]isothiocarbamoyl-2,3-dichlorobenzylamine R_f=0.35(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 566

Example 310

N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-[(4-methoxyphenyl)-S- methyl]isothiocarbamoyl-2,3-dichlorobenzylamine R =0.35(dichloromethane/methanol=20/l, v/v)

1H-NMR(CDC1₃) δ 7.62(d, 2H), 7.57(s, IH), 7.44(d, IH), 7.06-7.13(m, 4H),

6.83-6.95(m, 5H), 5.13(s, 2H), 4.92(s, 2H), 3.79(s, 3H),3.47(t, 2H), 2.17(t, 2H),

1.91-1.98(m, 2H), 1.84(s, 3H)

LC/MS(MH⁺) 578

Example 311

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.7 l(s, IH), 7.73(d, 2H), 7.57(s, IH), 7.42(d, IH),

7.06-7.30(m, 5H), 6.95(s, IH), 6.68(dd, IH), 5.14(s, 2H), 4.92(s, 2H), 3.91(s,

3H), 3.52(t, 2H), 2.18(t, 2H), 1.91-1.98(m, 2H), 1.83(s, 3H)

LC/MS(MH⁺) 579

Example 312 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-chloro-4-methylphe nyl)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine

To a solution of N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(3 -chloro-4-methylphen yl)thiocarbamoyl-3-chlorobenzylamine(27.2mg, 0.049mmol) prepared from Example 255 in dichloromethane(lml) was added iodomethane(35.1mg, 0.248mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(10.6mg, 38%). R_f=0.3(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 562

Example 313-317

The compounds prepared from Example 250, Example 251, Example

256, Example 252, Example 253 were reacted with iodomethane under the same condition as described in Example 312 to give the title compounds.

Example 313

N- {3-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] }propyl-N-[(3-chlorophenyl)-S-me thyl] isothiocarbamoyl-3 -chlorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.62(d, 2H), 7.54(d, 2H), 7.23-7.32(m, 3H), 7.03-7.18(m,

4H), 6.76-6.95(m, 4H), 5.08(s, 2H), 4.69(s, 2H), 3.44(t, 2H), 2.09(t, 2H), 1.83(s,

3H), 1.81-1.87(ixi, 2H)

LC/MS(MH⁺) 548

Example 314 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(4-chlorophenyl)-S-me thyl] isothiocarbamoyl-3 -chlorobenzy lamine R_f=0.35(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 548

Example 315

N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-[(3-fluorophenyl)-S-me thyl] isothiocarbamoyl-3 -chlorobenzylamine R_f=0.35(dichloromethane/methanol=20/l , v/v) Η-NMR(CDC1₃) δ 7.62(d, 2H), 7.53(d, 2H), 7.24-7.30(m, 3H), 7.03-7.2 l(m, 4H), 6.96(s, IH), 6.59-6.70(m, 3H), 5.07(s, 2H), 4.71(s, 2H), 3.43(t, 2H), 2.23(t, 2H), 1.83(s, 3H), 1.81-1.86(m, 2H) LC/MS(MH⁺) 532

Example 316

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(4-methoxyphenyl)-S- methyl] isothiocarbamoyl-3 -chlorobenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

Η-NMR(CDC1₃) δ 7.6 l(d, 2H), 7.52(d, 2H), 7.26-7.3 l(m, 3H), 7.10-7.16(m, IH), 7.07(d, 2H), 6.83-6.91(m, 5H), 5.06(s, 2H), 4.70(s, 2H), 3.79(s, 3H),

3.43(t, 2H), 2.30(t, 2H), 1.83(s, 3H), 1.78-1.81(m, 2H)

LC/MS(MH⁺) 544

Example 317 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine

R =0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.75(d, IH), 7.62(d, 2H), 7.50(s, IH), 7.19-7.29(m, 4H),

7.06-7.15(m, 3H), 6.90(s, IH), 6.69(d, IH), 5.10(s, 2H), 4.73(s, 2H), 3.93(s, 3H), 3.49(t, 2H), 2.34(t, 2H), 1.94(s, 3H), 1.62-1.90(m, 2H) LC/MS(MH⁺) 545

Example 318

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-chloro-4-methylphe nyl)-S-methyl]isothiocarbamoyl-2-methylbenzylamine

To a solution of

N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(3 -chloro-4-methy lphen yl)thiocarbamoyl-2-methylbenzylamine(29.1mg, 0.055mmol) prepared from Example 257 in dichloromethane(lml) was added iodomethane(39mg, 0.275mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(9.5mg, 32%). R_f=0.3(dichloromethane/methanol=20/l, v/v) LC/MS(MH⁺) 542

Example 319-321

The compounds prepared from Example 260, Example 261, Example

262 were reacted with iodomethane under the same condition as described in Example 318 to give the title compounds.

Example 319 N- {3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(3 -chloropheny l)-S-me thyl]isothiocarbamoyl-2-methylbenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.62(d, 2H), 7.53(s, IH), 7.04-7.3 l(m, 7H), 6.91-6.95(m,

4H), 5.10(s, 2H), 4.74(s, 2H), 3.43(t, 2H), 2.24-2.33(m, 5H), 1.86(s, 3H), 1.81-1.85(m, 2H) LC/MS(MH⁺) 528

Example 320

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-fluorophenyl)-S-me thyl] isothiocarbamoy 1-2-methylbenzylamine R_f=0.35(dichloromethane/methanol=20/l, v/v)

1H-NMR(CDC1₃) δ 7.62(d, 2H), 7.52(s, IH), 7.05-7.23(m, 7H), 6.88(s, IH), 6.62-6.72(m, 3H), 5.08(s, 2H), 4.72(s, 2H), 3.42(t, 2H), 2.25-2.31(m, 5H), 1.88(s, 3H), 1.82-1.87(m, 2H) LC/MS(MH⁺) 512

Example 321

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-2-methylbenzylamine R_f=0.35(dichloromethane/methanol=20/l, v/v) LC/MS(MH⁺) 525

Example 322

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(4-methoxyphenyl)-S- methyl] isothiocarbamoyl-2-methylbenzy lamine

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(4-methoxyphenyl)thio

-carbamoyl-2-methylbenzylamine

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-2-methylbenzyla mine prepared from Preparation Example 40 was reacted with 4-methoxyphenyl isothiocyanate under the same condition as described in Example 242 to give the title compound. <Step 2>

N- {3-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] }propyl-N-[(4-methoxyphenyl)-S- methyl]isothiocarbamoyl-2-methylbenzylamine

The compound prepared from <Step 1> was reacted with iodomethane under the same condition as described in Example 318 to give the title compound.

R_f=0.35(dichloromethane/methanol=20/l , v/v)

Η-NMR(CDC1₃) δ 7.60(d, 2H), 7.52(s, IH), 7.12-7.22(m, 4H), 7.05(d, 2H), 6.85-6.91(m, 5H), 5.06(s, 2H), 4.73(s, 2H), 3.79(s, 3H), 3.43(t, 2H), 2.26-2.33(m, 5H), 1.80-1.87(m, 5H) LC/MS(MH⁺) 524

Example 323 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(3-chloro-4-methylphe nyl)-S-methyl] isothiocarbamoyl-(naphthyl- 1 -yl)methylamine

To a solution of

N- {3-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } propy l-N-(3-chloro-4-methylphen yl)thiocarbamoyl-(naphthyl-l-yl)methylamine(30mg, 0.053mmol) prepared from Example 265 in dichloromethane(lmι) was added iodomethane(60mg, 0.43mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methano 1=40/1, v/v) to give the title compound(l lmg, 37%).

R_f=0.3(dichloromethane/methanol=20/l , v/v) LC/MS(MH⁺) 578

Example 324-326 The compounds prepared from Example 263, Example 266, Example 264 were reacted with iodomethane under the same condition as described in Example 323 to give the title compounds.

Example 324

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy 1-N- [(3 -fluoropheny l)-S-me thyl]isothiocarbamoyl-(naphthyl- 1 -yl)methylamine

R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v)

LC/MS(MH⁺) 548

Example 325

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(4-methoxyphenyl)-S- methyl]isothiocarbamoyl-(naphthyl- 1 -yl)methylamine

1H-NMR(CDC1₃) δ 7.81-8.06(m, 3H), 7.43-7.62(m, 5H), 7.30-7.38(m, 3H), 6.83-7.07(m, 6H), 5.23(s, 2H), 5.03(s, 2H), 3.93(s, 3H), 3.43(t, 2H), 2.24(t, 2H),

1.87(s, 3H), 1.78-1.85(1X1, 2H)

LC/MS(MH⁺) 560

Example 326 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-(naphthyl- 1 -yl)methylamine

Rf=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.81-8.03(m, 3H), 7.42-7.62(m, 6H), 7.28-7.35(m, 3H),

7.03(d, 2H), 6.84(s, IH), 6.72(d, IH), 5.22(s, 2H), 5.01(s, 2H), 3.92(s, 3H), 3.46(t, 2H), 2.24(t, 2H), 1.91(s, 3H), 1.781-1.89(m, 2H)

LC/MS(MH⁺) 561

Example 327

N- { 2- [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethy 1-N- [(3 -chloro-4-methylphen yl)-S-methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine HC1 A solution of

N-{2-[l -(4-cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(3-chloro-4-methylphen yl)-S-methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine(200mg, 0.34mmol) prepared from Example 277 in ethyl acetate(lθml) was bubbled with HC1 gas at ice bath for 3 minute. The reaction mixture was poured into diethyl ether( 100ml) and the resulting solid was filtered to give the title compound(200mg, 95.1%). R_f=0.35(dichloromethane/methanol=20/l , v/v) Η-NMR(CD₃OD-d₄) δ 9.12(s, IH), 7.60-7.90(m, 6H), 7.55(m, 2H), 7.40(q, 4H), 5.65(s, 2H), 5.20(s, 2H), 4.10(dd, 2H), 3.10(dd, 2H), 2.40(s, 3H), 2.20(s, 3H)

Example 328 N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine 2HCl

A solution of

N- {2-[ 1 -(4-cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]isothiocarbamoyl-2-trifluoromethylbenzylamine(1.20g, 2.10mmol) prepared from Example 280 in ethyl acetate(lθml) was bubbled with HC1 gas at ice bath for 3 minute. The reaction mixture was poured into diethyl ether( 100ml) and the resulting solid was filtered to give the title compound(1.15g). R=0.35(dichloromethane/methanol=20/l, v/v)

1H-NMR(CD₃OD-d₄) δ 9.10(s, IH), 8.25(m, IH), 8.07(dd, IH), 7.80(d, IH), 7.59-7.79(m, 4H), 7.55(d, IH), 7.40(d, 2H), 7.22(d, IH), 5.68(s, 2H), 5.20(s, 2H), 4.12(s, 3H), 4.05(dd, 2H), 3.15(dd, 2H), 2.18(s, 3H)

Example 329 N- {2-[ 1 -(4-Cyanobenzyl)- lH-imidazol-5-yl] } ethyl-N-[(4-fluorophenyl)-S-met hyl]isothiocarbamoyl-2,3-dichlorobenzylamine HC1

A solution of N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(4-fluorophenyl)-S-met hyl]isothiocarbamoyl-2,3-dichlorobenzylamine(455mg, 0.824mmol) prepared from Example 283 in dichloromethane(30ml) was bubbled with HC1 gas at ice bath for 3 minute. The reaction mixture was concentrated in vacuo and the residue was recrystallized with dichloromethane to give the title compound(356mg, 75%).

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆ + TFA-d) δ 7.76-8.12(m, 3H), 7.62-7.68(m, 2H), 7.41-7.45(m,3H), 7.25-7.39(m, 4H), 5.66(s, 2H), 5.04(s, 2H), 3.91(t, 2H), 3.07(t, 2H), 1.98(s, 3H)

Example 330

N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-[(4-methoxyphenyl)-S-m ethyl]isothiocarbamoyl-2,3-dichlorobenzylamine HC1

A solution of

N- {2- [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N-[(4-methoxyphenyl)-S-m ethyl] isothiocarbamoyl-2,3-dichlorobenzylamine(226mg, 0.400mmoι) prepared from Example 284 in dichloromethane(20ml) was bubbled with HC1 gas at ice bath for 5 minute. The reaction mixture was concentrated in vacuo and the residue was solidified with dichloromethane to give the title compound(216mg, 90%).

R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v)

1H-NMR(DMSO-d₆ + TFA-d) δ 9.29(s, IH), 7.74-7.8 l(m, 3H), 7.65(d, IH), 7.38-7.45(m, 4H), 7.03-7.36(m, 2H), 7.00(d, 2H), 5.63(s, 2H), 5.05(s, 2H), 3.92(t, 2H), 3.77(s, 3H), 3.05(t, 2H), 2.03(s, 3H) Example 331

N-{2-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine 2HCl

N-{2-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}ethyl-N-[(2-methoxypyridin-5-yl)

-S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine

The compound prepared from Example 42 was reacted with iodomethane under the same condition as described in Example 282 to give the title compound.

<Step 2> N- {2-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } ethyl-N- [(2-methoxypyridin-5 -yl) -S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine 2HCl

A solution of

N- {2-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } ethyl-N-[(2-methoxypyridin-5-yl) -S-methyl]isothiocarbamoyl-2,3-dichlorobenzylamine(325mg, 0.547mmol) prepared from <Step 1> in dichloromethane(25mι) was bubbled with HC1 gas at ice bath for 3 minute. The reaction mixture was concentrated in vacuo and the residue was washed with dichloromethane. The resulting solid was dissolved in methanol(4ml) and the solution was poured into diethyl ether( 100ml). The resulting solid was filtered to give the title compound(304mg, 89%).

R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v)

1H-NMR(DMSO-d₆ + TFA-d) δ 9.31(s, IH), 8.08(d, IH), 7.71-7.81(m, 3H), 7.63-7.68(m, 2H), 7.32-7.45(m, 4H), 6.94(d, IH), 5.66(s, 2H), 5.04(s, 2H), 3.88(s, 3H), 3.82-3.87(m, 2H), 3.08(t, 2H), 2.03(s, 3H) Example 332

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(4-methoxyphenyl)-S- methyl]isothiocarbamoyl-3-chlorobenzylamine HCl

A solution of

N- {3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(4-methoxyphenyl)-S- methyl] isothiocarbamoyl-3 -chlorobenzy lamine(5 OOmg, 0.919mmol) prepared from Example 316 in dichloromethane(25ml) was bubbled with HCl gas at ice bath for 5 minute. The reaction mixture was concentrated in vacuo to give the title compound(532mg, 95%).

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 6.98-9.38(m, 14H), 5.65(s, 2H), 5.10(s, 2H), 3.80(m,

2H), 3.75(s, 3H), 2.60(m, 2H), 2.09(s, 3H), 2.0 l(m, 2H)

Example 333

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2HC1

A solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine(500mg, 0.917mmol) prepared from Example 317 in dichloromethane(25ml) was bubbled with HCl gas at ice bath for 5 minute. The reaction mixture was concentrated in vacuo to give the title compound(566mg, 98%).

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 6.92-9.38(m, 13H), 5.66(s, 2H), 5.17(s, 2H), 3.94(s,

3H), 3.82(m, 2H), 2.60(m, 2H), 2.13(s, 3H), 2.02(m, 2H)

Example 334 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2oxalic acid

To a solution of N- {3-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-N- [(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine(500mg, 0.92mmol) prepared from Example 317 in ethanol(lθml) was added oxalic acid(230mg, 1.84mmol) and the reaction mixture was stirred for 2hr at room temperature. Diethyl ether( 100ml) was added and the resulting solid was filtered to give the title compound(570mg, 85.4%).

R_f=0.35(dichloromethane/methanol=20/l , v/v)

Η-NMR(DMSO-d₆) δ 8.60(s, IH), 7.95(d, 2H), 7.60(s, IH), 7.10-7.40(m, 8H), 6.75(d, IH), 5.45(s, 2H), 4.73(s, 2H), 3.80(s, 3H), 3.45(t, 2H), 2.45(t, 2H), 1.95(s, 3H), 1.80(t, 2H)

Example 335

N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2methanesulfonic acid

To a solution of

N- {3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } propy 1-N- [(2-methoxypyridin-5 -y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine(500mg, 0.92mmol) prepared from Example 317 in ethanol(lθml) was added methanesulfonic acid(119ul, 1.84mmol) and the reaction mixture was stirred for 2hr at room temperature. Diethyl ether( 100ml) was added and the resulting solid was recrystallized with dichloromethane to give the title compound(370mg, 50.9%). R =0.35(dichloromethane/methanol=20/l , v/v)

Η-NMR(DMSO-d₆) δ 9.20(s, IH), 8.05(s, IH), 7.88(d, 2H), 7.65(m, 2H), 7.40(m, 5H), 7.25(m, IH), 6.92(d, IH), 5.60(s, 2H), 5.00(s, 2H), 3.85(s, 3H), 3.65(t, 2H), 2.55(t, 2H), 2.35(s, 6H), 2.15(s, 3H), 1.98(t, 2H) Example 336

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2maleic acid

To a solution of

N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-methyl] isothiocarbamoyl-3 -chlorobenzy lamine(100mg, 0.18mmol) prepared from Example 317 in ethanol(lml) was added maleic acid(43mg, 0.36mmol) and the reaction mixture was stirred for 2hr at room temperature.

The reaction solution was concentrated in vacuo and the solid was washed with diethyl ether to give the title compound(100mg, 71.5%).

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 9.10(bs, IH), 7.90(d, 2H), 7.60(s, IH), 7.30-7.50(m, 5H), 7.20(t, 2H), 6.75(d, IH), 6.20(s, 4H), 5.60(s, 2H), 4.70(s, 2H), 3.80(s, 3H),

3.45(t, 2H), 2.50(t, 2H), 1.95(s, 3H), 1.85(t, 2H)

Example 337

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2malic acid

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine(100mg, 0.18mmol) prepared from Example 317 in ethanol(lml) was added malic acid(50mg, 0.36mmol), and the reaction mixture was stirred for 2hr at room temperature. The reaction solution was concentrated in vacuo and the solid was washed with diethyl ether to give the title compound(100mg, 68.3%). R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v) Η-NMR(DMSO-d₆) δ 7.95(s, IH), 7.85(d, 2H), 7.60(s, IH), 7.10-7.40(m, 7H), 6.90(s, IH), 6.75(d, IH), 5.35(s, 2H), 4.70(s, 2H), 4.25(t, 2H), 3.80(s, 3H), 3.40(t, 2H), 2.35-2.70(m, 6H), 1.95(s, 3H), 1.80(t, 2H)

Example 338 N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2malonic acid

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl] isothiocarbamoyl-3 -chlorobenzylamine(100mg, O.lδmmol) prepared from Example 317 in ethanol(lml) was added malonic acid(36mg, 0.36mmol) and the reaction mixture was stirred for 2hr at room temperature. The reaction solution was concentrated in vacuo and the solid was washed with diethyl ether to give the title compound(100mg, 73.8%). R_f=0.35(dichloromethane/methanol=20/l, v/v)

1H-NMR(DMSO-d₆) δ 8.20(s, IH), 7.85(d, 2H), 7.60(d, IH), 7.10-7.40(m, 7H), 7.05(s, IH), 6.75(d, IH), 5.40(s, 2H), 4.70(s, 2H), 3.80(s, 3H), 3.45(t, 2H), 3.20(s, 4H), 2.40(t, 2H), 1.95(s, 3H), 1.80(t, 2H)

Example 339

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2tartaric acid

To a solution of N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine(100mg, O.lδmmol) prepared from Example 317 in ethanol(lml) was added tartaric acid(53mg, 0.36mmol) and the reaction mixture was stirred for 2hr at room temperature. The reaction solution was concentrated in vacuo and the solid was washed with diethyl ether to give the title compound(100mg, 65.7%). R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v)

Η-NMR(CD₃OD-d₄) δ 8.50(s, IH), 7.78(d, 2H), 7.60(d, IH), 7.20-7.40(m, 8H), 6.78(d, IH), 5.45(s, 2H), 4.78(s, 2H), 4.48(s, 4H), 3.87(s, 3H), 3.55(t, 2H), 2.50(t, 2H), 1.90(s, 5H)

Example 340

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy 1-N- [(2-methoxypyridin-5 -y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2citric acid

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine(100mg, O. lδmmol) prepared from Example 317 in ethanol(lml) was added citric acid(62mg, 0.36mmol) and the reaction mixture was stirred for 2hr at room temperature. The reaction solution was concentrated in vacuo and the solid was washed with diethyl ether to give the title compound(100mg, 58.9%). R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 8.05(s, IH), 7.82(d, 2H), 7.58(d, IH), 7.10-7.40(m, 7H), 6.95(s, IH), 6.70(d, IH), 5.38(s, 2H), 4.70(s, 2H), 3.80(s, 3H), 3.55(t, 2H), 2.70(q, 8H), 2.40(t, 2H), 1.95(s, 3H), 1.80(t, 2H)

Example 341

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-hydroxypyridin-5 -y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine

A solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-methyl]isothiocarbamoyl-3-chlorobenzylamine 2HCl(2.93g, 4.74mmol) prepared from Example 333 in 6N-HCl(20ml) was stirred for 24hr at room temperature. The reaction mixture was neutralized with a solution of saturated NaHC0₃ and the organic layer was dried over anhydrous sodium sulfate. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(135mg). 1H-NMR(DMSO-d₆) δ 7.60(d, IH), 7.48(s, IH), 7.17-7.35(m, 4H), 6.99-7.08(m, 4H), 6.87(s, IH), 6.55(d, IH), 5.08(s, 2H), 4.67(s, 2H), 3.44(t, 2H), 2.30(t, 2H), 2.02(s, 3H), 1.85(m, 2H)

Example 342 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-( 1 -propyl)] isothiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine(30mg, 0.053mmol) prepared from Example 214 in methanol(lml) was added l-iodopropane(45.2mg, 0.266mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(10mg, 31%). R=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.75-7.76(m, IH), 7.49-7.70(m, 5H), 7.35-7.43(m, 2H), 7.21-7.27( m, IH), 7.08(d, 2H), 6.90(s, IH), 6.68(d, IH), 5.1 l(s, 2H), 5.00(s, 2H), 3.93(s, 3H), 3.51(t, 2H), 2.32-2.40(m, 2H), 2.26(t, 2H), 1.91-1.98(m, 2H), 1.23- 1.44(m, 2H), 0.77(t, 3H)

Example 343-346

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyri din-5-yl)thiocarbamoyl-2-trifluoromethylbenzylamine prepared from Example 214 was reacted with the corresponding alkyl or allyl iodide derivatives under the same condition as described in Example 342 to give the title compounds.

Example 343 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propy 1-N- [(2-methoxypyridin-5 -y l)-S-( 1 -butyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine Yield=26%

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.75-7.76(m, IH), 7.49-7.69(m, 5H), 7.35-7.42(m, 2H), 7.19-7.27( m, IH), 7.07(d, 2H), 6.90(s, IH), 6.67(d, IH), 5.10(s, 2H), 4.99(s, 2H), 3.92(s, 3H), 3.5 l(t, 2H), 2.24-2.39(m, 4H), 1.90-1.97(m, 2H), 1.25-1.36(m, 2H), 1.13-1.20(m, 2H), 0.77(t, 3H)

Example 344 N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-( 1 -pentyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine

Yield=32%

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.75-7.76(m, IH), 7.49-7.69(m, 5H), 7.35-7.42(m, 2H), 7.20-7.27( m, IH), 7.07(d, 2H), 6.89(s, IH), 6.68(d, IH), 5.1 l(s, 2H), 5.00(s,

2H), 3.92(s, 3H), 3.5 l(t, 2H), 2.24-2.39(m, 4H), 1.90-1.97(m, 2H), 1.26-1.37(m,

2H), 1.12-1.14(m, 4H), 0.8 l(t, 3H)

Example 345 N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-( 1 -hexyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine

Yield=26%

R_f=0.35(dichloromethane/methanol=20/l, v/v)

Η-NMR(CDC1₃) δ 7.74-7.75(m, IH), 7.49-7.69(m, 5H), 7.34-7.41(m, 2H), 7.20-7.27( m, IH), 7.06(d, 2H), 6.88(s, IH), 6.67(d, IH), 5.10(s, 2H), 4.99(s, 2H), 3.92(s, 3H), 3.50(t, 2H), 2.23-2.38(m, 4H), 1.90-1.97(m, 2H), 1.21-1.32(m, 4H), 1.12-1.17(1X1, 4H), 0.83(t, 3H)

Example 346 N- {3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-allyl]isothiocarbamoyl-2-trifluoromethylbenzylamine Yield=29%

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.77-7.79(m, IH), 7.51-7.69(m, 5H), 7.36-7.42(m, 2H), 7.23-7.29( m, IH), 7.07(d, 2H), 6.90(s, IH), 6.70(d, IH), 5.45-5.68(m, IH), 5.1 l(s, 2H), 5.04(s, 2H), 4.99(s, 2H), 3.93(s, 3H), 3.50(t, 2H), 2.94(d, 2H), 2.35(t, 2H), 1.90-1.97(ixi, 2H)

Example 347 N- {3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-benzyl]isothiocarbamoyl-2-trifluoromethylbenzylamine

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine(30mg, 0.053mmol) prepared from Example 214 in methanol(lmι) was added benzyl bromide(45.5mg, 0.266mmol). The mixture was stirred for 24hr at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography(eluent: dichloromethane/methanol=40/l, v/v) to give the title compound(3.3mg).

R=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.83(s, IH), 7.53-7.61(m, IH), 7.19-7.46(m, 7H), 6.99-7.03(m, 5H), 6.82(s, IH), 6.69(d, IH), 5.04(s, 2H), 4.78(s, 2H), 3.91(s, 3H), 3.45(s, 2H), 3.32(t, 2H), 2.23(t, 2H), 1.72-1.78(m, 2H) Example 348-352

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyri din-5-yl)thiocarbamoyl-2-trifluoromethy Ibenzy lamine prepared from Example 214 was reacted with the corresponding benzyl bromide derivatives under the same condition as described in Example 347 to give the title compounds.

Example 348

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-(2-cyanobenzyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine R_f=0.35(dichloromethane/methanol=20/l , v/v)

Η-NMR(CDC1₃) δ 7.80(s, IH), 7.51-7.62(m, 4H), 7.40-7.45(m, 2H), 7.21-7.33(m, 3H), 7.02-7.15(m, 4H), 6.78(s, IH), 6.68(dd, IH), 5.07(s, 2H), 4.81(s, 2H), 3.90(s, 3H), 3.67(s, 2H), 3.37(t, 2H), 2.28(t, 2H), 1.75-1.83(m, 2H)

Example 349

N- {3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-(3-cyanobenzyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine

R_f=0.35(dichloromethane/methanol=20/l , v/v) 1H-NMR(CDC1₃) δ 7.84(d, IH), 7.58-7.68(m, 2H), 7.42-7.52(m, 2H), 7.24-7.38(m, 6H), 7.05-7.09(m, 4H), 6.87(s, IH), 6.73(d, IH), 5.10(s, 2H), 4.82(s, 2H), 3.96(s, 3H), 3.48(s, 2H), 3.40(t, 2H), 2.30(t, 2H), 1.79-1.85(m, 2H)

Example 350 N-{3-[l -(4-Cyanobenzyl)- lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-(4-cyanobenzyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine

R_f=0.35 (dichloromethane/methanol=20/ 1 , v/v)

1H-NMR(CDC1₃) δ 7.85(s, IH), 7.26-7.68(m, 8H), 7.00-7.14(m, 6H), 6.89(s,

IH), 6.73(d, IH), 5.09(s, 2H), 4.83(s, 2H), 3.96(s, 3H), 3.49(s, 2H), 3.39(t, 2H), 2.29(t, 2H), 1.79-1.86(m, 2H) Example 351

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-[(2-methoxypyridin-5-y l)-S-(4-nitrobenzyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine Yield=30%

R_f=0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 8.03(d, 2H), 7.85(d, IH), 7.66(s, IH), 7.61(d, 2H), 7.50(s, IH), 7.30-7.39(m, 3H), 7.16(d, 2H), 7.05(d, 2H), 6.93-7.00(m, IH), 6.87(s, IH), 6.73(d, IH), 5.08(s, 2H), 4.83(s, 2H), 3.95(s, 3H), 3.53(s, 2H), 3.40(t, 2H), 2.29(t, 2H), 1.78-1.86(m, 2H)

Example 352

N- {3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N- [(2-methoxypyridin-5 -y l)-S-(3-methoxybenzyl)]isothiocarbamoyl-2-trifluoromethylbenzylamine Yield=26%

R 0.35(dichloromethane/methanol=20/l , v/v)

1H-NMR(CDC1₃) δ 7.86(d, IH), 7.57-7.65(m, 3H), 7.26-7.49(m, 4H),

7.03-7.19(m, 4H), 6.86(s, IH), 6.61-6.75(m, 4H), 5.08(s, 2H), 4.83(s, 2H),

3.96(s, 3H), 3.74(s, 3H), 3.46(s, 2H), 3.38(t, 2H), 2.27(t, 2H), 1.75-1.84(m, 2H)

Example 353

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl

)thiocarbamoyl-2-trifluoromethylbenzylamine 2HC1

A solution of

N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(2-methoxypyridin-5 -yl )thiocarbamoyl-2-trifluoromethylbenzylamine(500mg, 0.90mmol) prepared from Example 214 in dichloromethane(5ml) was bubbled HCl gas at ice bath for 3 minute. The reaction solution was poured into diethyl ether(50ml) and the resulting solid was filtered to give the title compound(150mg, 97%). R(=0.30(dichloromethane/methanol=20/ 1 , v/v)

Η-NMR(CD₃OD) δ 7.39-9.05(m, 13H), 5.60(s, 2H), 5.29(s, 2H), 4.11(s,

3H),3.80(t, 2H), 2.64(t, 2H), 2.07(m, 2H)

Example 354

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine citric acid

To a solution of N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(2-methoxypyridin-5 -yl )thiocarbamoyl-2-trifluoromethylbenzylamine(100mg, 0. lδmmol) prepared from Example 214 in ethanol(lml) was added citric acid(69mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. Diethyl ether(5ml) was added and the resulting solid was filtered to give the title compound(100mg, 58.7%).

R_f=0.30(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 9.38(s, IH), 8.00(m, 2H), 7.50-7.80(m, 6H), 7.35(d, IH), 7.7.27(d, 2H), 6.90(s, IH), 6.83(d, IH), 5.38(s, 2H), 5.24(s, 2H), 3.90(s, 3H), 3.65(t, 2H), 2.75(q, 4H), 2.42(t, 2H), 1.95(p, 2H)

Example 355

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine maleic acid

To a solution of

N- {3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propy l-N-(2-methoxypyridin-5 -yl )thiocarbamoyl-2-trifluoromethylbenzylamine( 1 OOmg, 0.18mmol) prepared from Example 214 in ethanol(lml) was added maleic acid(42mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. Diethyl ether(5ml) was added and the resulting solid was filtered to give the title compound(100mg, 58.9%). R_f=0.30(dichloromethane/methanol=20/ 1 , v/v)

1H-NMR(DMSO-d₆) δ 9.38(s, IH), 8.85(s, IH), 8.00(s, IH), 7.50-7.80(m, 6H), 7.45(s, 2H), 7.41(s, IH), 7.37(d, IH), 6.83(d, IH), 6.15(s, 2H), 5.52(s, 2H), 5.24(s, 2H), 3.90(s, 3H), 3.70(t, 2H), 2.50(t, 2H), 2.00(p, 2H)

Example 356

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl] } propy l-N-(2-methoxypyridin-5 -yl

)thiocarbamoyl-2-trifluoromethylbenzylamine malic acid

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl

)thiocarbamoyl-2-trifluoromethylbenzylamine(100mg, 0.18mmol) prepared from Example 214 in ethanol(lml) was added malic acid(49mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. Diethyl ether(5ml) was added and the resulting solid was filtered to give the title compound(100mg, 58.9%).

R_f=0.30(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 9.38(s, IH), 8.00(s, IH), 7.50-7.80(m, 7H), 7.35(d, IH), 7.25(d, 2H), 6.82(d+s, 2H), 5.35(s, 2H), 5.24(s, 2H), 4.30(t, IH), 3.90(s,

3H), 3.70(t, 2H), 2.50-2.70(m, 4H), 2.43(t, 2H), 1.97(p, 2H)

Example 357

N- { 3 - [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(2-methoxypyridin-5 -y 1 )thiocarbamoyl-2-trifluoromethylbenzylamine malonic acid

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine( 1 OOmg, 0.18mmol) prepared from Example 214 in ethanol(lml) was added malonic acid(37mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. Diethyl ether(5ml) was added and the resulting solid was filtered to give the title compound(100mg, 59.9%). R_f=0.30(dichloromethane/methanol=20/l , v/v) Η-NMR(DMSO-d₆) δ 9.38(s, IH), 8.00(m, 2H), 7.50-7.80(m, 6H), 7.35(d, IH), 7.27(d, 2H), 6.92(s, IH), 6.82(d, IH), 5.38(s, 2H), 5.24(s, 2H), 3.90(s, 3H), 3.70(t, 2H), 3.20(s, 2H), 2.43(t, 2H), 1.97(p, 2H)

Example 358 N- {3-[ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5 -yl] }propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine 2methanesulfonic acid

To a solution of

N- {3-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl] }propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine(100mg, O. lδmmol) prepared from Example 214 in ethanol(lml) was added methanesulfonic acid(23ul, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature, diethyl ether(5ml) was added and the resulting solid was filtered to give the title compound(100mg, 60.9%). R_f=0.30(dichloromethane/methanol=20/l, v/v)

1H-NMR(DMSO-d₆) δ 9.42(s, IH), 9.26(s, IH), 8.05(s, IH), 7.90(d, 2H), 7.62-7.82(m, 4H), 7.42-7.62(m, 3H), 7.35(d, IH), 6.90(d, IH), 5.60(s, 2H), 5.24(s, 2H), 3.90(s, 3H), 3.70(t, 2H), 2.43(t, 2H), 2.61(s, 6H), 2.00(p, 2H)

Example 359

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine oxalic acid

To a solution of N- { 3 - [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] } propyl-N-(2-methoxypyridin-5 -y 1 )thiocarbamoyl-2-trifluoromethylbenzylamine( 1 OOmg, 0.18mmol) prepared from Example 214 in ethanol(lml) was added oxalic acid(45mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. The reaction solution was treated with diethyl ether(5ml) and the resulting solid was filtered to give the title compound(100mg, 59.9%). R_f=0.30(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 9.40(s, IH), 8.43(m, IH), 8.00(s, IH), 7.50-7.90(m, 6H), 7.35(d, 3H), 7.20(d, IH), 6.82(d, IH), 5.45(s, 2H), 5.24(s, 2H), 3.90(s, 3H), 3.70(t, 2H), 2.43(t, 2H), 2.00(p, 2H)

Example 360

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine tartaric acid

To a solution of

N-{3-[l-(4-cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethy lbenzylamine( 1 OOmg, 0.18mmol) prepared from Example 214 in ethanol(lml) was added tartaric acid(54mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. The reaction solution was treated with diethyl ether(5ml) and the resulting solid was filtered to give the title compound(100mg, 58.9%). R_f=0.30(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 9.40(s, IH), 8.02(s, IH), 7.50-7.90(m, 7H), 7.35(d, IH), 7.25(d, 2H), 6.82(s+d, 2H), 5.38(s, 2H), 5.27(s, 2H), 4.38(s, 2H), 3.90(s, 3H), 3.70(t, 2H), 2.43(t, 2H), 2.00(p, 2H)

Example 361

N-{3-[l-(4-Cyanobenzyl)-lH-imidazol-5-yl]}propyl-N-(2-methoxypyridin-5-yl )thiocarbamoyl-2-trifluoromethylbenzylamine 2acetic acid To a solution of

N- {3-[ 1 -(4-cyanobenzyl)- 1 H-imidazol-5 -yl] }propyl-N-(2-methoxypyridin-5-yl )thiocarbamoy l-2-trifluoromethylbenzylamine( 1 OOmg, 0.18mmol) prepared from Example 214 in ethanol(lml) was added acetic acid(21mg, 0.36mmol) and the reaction mixture was stirred for 4hr at room temperature. The reaction solution was diluted with diethyl ether(5ml) and the resulting solid was filtered to give the title compound(100mg, 61.4%). R_f=0.30(dichloromethane/methanol=20/l , v/v)

1H-NMR(DMSO-d₆) δ 9.40(s, IH), 8.02(s, IH), 7.50-7.90(m, 7H), 7.35(d, IH), 7.25(d, 2H), 6.82(s+d, 2H), 5.38(s, 2H), 5.27(s, 2H), 4.38(s, 2H), 3.90(s, 3H), 3.70(t, 2H), 2.43(t, 2H), 2.00(p, 2H), 1.98(s, 6H)

The structures of the compouds prepared in Examples are shown in Tables I to III.

Table I. (Thiocarbamoyl derivatives)

Table I. (continued)

Table. II (Isothiocarbamoyl derivatives)

Table. II (continued) Table III

Structure of the compound of Example 202.

Assay 1 : In Vitro Cell Growth Inhibition Assay

The viability of K-ras transformed cells was measured by using MTT colorimetric assay which is based on the conversion of MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) to MTT- formazan by mitochondrial enzyme. In brief, cells were dispensed within 96-well culture plate in 100 μ 1 culture medium at a density of 200 cells/well. Following 24 hours incubation at 37 ^°C , 5% C0₂, 100% relative humidity, 100 μ 1 of culture medium containing compound or culture medium containing compound vehicle was dispensed within appropriate wells. Culture plates were then incubated for 4 days prior to addition of MTT reagent. MTT solution(5 mg/ml PBS) was added to the well in a concentration of 0.5 mg/ml. After incubation for 4 hours, mixed culture medium and MTT solution were carefully removed, then 100 μ 1 DMSO was added to the well to solubilize formazan. The absorbance of each well was measured using microculture plate reader at 570 nm. Measurements were performed in triplicate. Growth inhibition of 50%(IC₅₀) is calculated in terms of %T/C [(absorbance of treated cells/absorbance of control cells)x 100].

The results of the compounds shown in Table IV reflects their ability to inhibit K-ras transformed cell growth in vitro.

Assay 2 : In vitro inhibition of FPTase

Bovine brain cytosol was fractionated with ammonium sulfate and subjected the active fraction to ion exchange chromatography on a Mono Q column followed by gel filtration on sephacryl S-200. The Ras protein substrate, K-ras4B, is expressed in Escherichia coll The donor of farnesyl residues to ras protein is [³H] farnesyl pyrophosphate (FPP). The standard reaction mixture contained the following concentrations of components in a final volume of 50 μi ; 50 mM HEPES pH7.5, 5 mM MgCl₂, 5mM dithiothreitol (DTT), 10 μ M ZnCl₂, 0.2% n-Octyl-β -D-glucopyranoside and 0.6 μg K-ras4B. The mixture also contained 0.15 μ Ci of [³H]FPP (16.0 Ci/mmol; Amersham Life Science) and 1.5 μg of partially purified farnesyl-protein transferase.

Test compounds were dissolved in 99.9% ethyl alcohol (EtOH). After incubation for 1 hr at 37 ^°C in 1.5 ml effendorf tubes, the reaction was stopped by the addition of 90 μl of 4% sodium dodecyl sulfate (SDS) and then 90 μl of 30% trichloroacetic acid (TCA). The tubes were left on ice for 45-60 minute and then the precipitates were transferred to Millipore multiscreen filtration 96-well plate with glass fiber C membrane (Millipore Corp.).

Following filtration using the multiscreen vacuum manifold, the wells were washed once with 200 μl of 4%SDS/6%TCA and five times with 200 μl of 6% TCA. Following removal of the bottom seal, excess washing fluid was blotted and the plates were allowed to dry before the filters were punched into 6 ml vials using the multiscreen punch. After punching, 5 ml of scintillation fluid (Packard) was added and radioactivity was determined by scintillation counting (Beckman LS5801). Dose-response curves for inhibitors used were duplicated at each drug concentration, and the IC₅₀ estimations were made from Litchfield-Wilcoxon method.

The data presented below in Table IV reflects the ability of the test compound to inhibit ras farnesylation.

Table IV. Inhibition of K-ras transformed cell growth and In vitro FPTase a : Inhibition of K-ras transformed cell growth b : Inhibition of In vitro FPTase NT : Not Tested Table IV. (continued) a : Inhibition of K-ras transformed cell growth b : Inhibition of In vitro FPTase NT : Not Tested Table IV. (continued) a : Inhibition of K-ras transformed cell growth b : Inhibition of In vitro FPTase NT : Not Tested Table IV. (continued) a : Inhibition of K-ras transformed cell growth b : Inhibition of In vitro FPTase NT : Not Tested Table IV. (continued) a : Inhibition of K-ras transformed cell growth b : Inhibition of In vitro FPTase NT : Not Tested Table 1. (continued) a : Inhibition of K-ras transformed cell growth b : Inhibition of In vitro FPTase NT : Not Tested

From results of Table IV, the compound of formula (I) according to the present invention were identified as having a potent inhibitory activity against K-ras transformed cell growth and an ability to inhibit FPTase effectively. Assay 3 : Inhibition of K-ras4B processing

NIH3T3 cells transfected with oncogenic human K-ras4B were plated in 6-well plate and cultured until the cell concentration reached at 10⁵ per well. The cells were treated for 48 hours with either vehicle or the test compounds (0.1, 1, lOμ M). Cells were washed and lysed in 1 ml of lysis buffer (lx PBS(phosphate buffer saline), 1% Triton X-100, 1 mM phenylmethyl- sulfonyl fluoride, 25 g/ml leupeptin, 16 g/ml benzamidine HCl, 1 mg/ml Sigma- 104 phosphate substrate) at 4^°C for 1 hour. Lysates were cleared (10,000 φm, 4^°C , 15 min), and equal amounts of protein were immunoprecipitated with the anti-ras antibody-agarose beads (OP01A, Oncogene Science) at 4^°C for 2 hours. The immunoprecipitated proteins were separated on a 15% SDS-PAGE, transferred to Hybond-ECL (Amersham Coφ.), and immunoblotted using an anti-K-ras antibody (OP24, Oncogene Science). Antibody reactions were visualized using peroxidase-conjugated goat anti-mouse IgG and an enhanced chemiluminescence detection system (ECL, Amersham Coφ.).

Posttranslational modifications have different effects on electro-phoretic mobility. Processed ras protein migrate slightly faster than their unprocessed counteφarts. Therefore, the intensities of the bands corresponding to prenylated and nonprenylated K-ras proteins were compared to determine the inhibition of prenyl transfer to protein. The results of effective compounds presented in Table V reflects the ability to inhibit K-ras4B processing. Table V. Inhibition of K-ras4B processing by compounds of this invention. a : IC₅₀; b : inhibitory effect at lOuM

From the results of Table V, the compound of formula (I) according to the present invention were identified as having an ability to inhibit K-ras4B processing.

While the embodiments of the subject invention have been described and illustrated, it is obvious that various changes and modifications can be made therein without departing from the spirit of the present invention which should be limited only by the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

A is -(CH₂)_n- or -(CH₂) _n-C(=0)-, n being an integer from 1 to 4;

R¹ is Cι_-4 alkyl, or benzyl optionally having one or more ring substituents selected from the group consisting of cyano, nitro and methylenedioxy;

R is Ci_₅ alkyl, C_2-5 alkenyl; C_5-7 cycloalkylmethyl; C_1-3 alkylphenyl; a ring containing group selected from the group consisting of benzyl, α -methylbenzyl, naphthy lmethyl, pyrrolymethyl, pyridylmethyl, indolylmethyl, and quinolylmethyl, each optionally having one or more ring substituents selected from the group consisting of C_1-3 alkyl, halogen, Cι_-3 alkoxy, and trifluoromethyl;

R³ is Ci-io alkyl; C_2-5 alkenyl; C_3-8 cycloalkyl; adamantyl; Cι_-5-alkoxy-C_1-5-alkyl; mono- or di- C_1-5-alkylamino-Cι_-5-alkyl; Cι_-5 alkoxylcarbonyl; phenyl- .s-alkyl; tetrahydrofuranyl-C_1-5-alkyl; a nitrogen-containing heterocycle group selected from the group consisting of pyridyl, pyrimidyl, piperidyl, piperazyl, moφhorinyl, and moφhorinyl-Cι.₅-alkyl, each heterocyclo being optionally substituted with Cι_-3 alkyl or Cι_-3 alkoxy; an aromatic ring containing group selected from the group consisting of phenyl, naphthyl, and benzoyl, each optionally having one or more ring substituents selected from the group consisting of _-5 alkyl, Cι_-5 alkoxy, Cι_-5 alkylthio, mono- or di-Cι.₅-alkylamino, trifluoromethyl, benzyloxy, hydroxy, halogen, cyano, nitro, Cι_-5 alkoxycarbonyl, acetyl, and phenyl;

R⁴ is hydrogen or C_[- alkyl;

R⁵ is phenyl optionally having one or more substituents selected from the group consisting of halogen, C_1-5 alkyl, C_1-5 alkoxy, and trifluoromethyl; benzyl; or pyridyl optionally substituted with hydroxy or methoxy; and

R⁶ is .io alkyl, C_2-5 alkenyl, or benzyl with one or more optional ring substituents selected from the group consisting of Cι_-5 alkoxy, cyano and nitro.

2. The compound of claim 1, wherein

R¹ is benzyl optionally substituted with cyano, nitro or methylenedioxy;

R is benzyl optionally substituted with halogen, C_1-5 alkyl or trifluoromethyl;

R is Cu₃ alkoxypyridyl; or phenyl optionally substituted with halogen, Cι_-5 alkyl, Cι_-5 alkoxy, trifluoromethyl, hydroxy, C_1-5 alkylthio or Cι_₅ alkoxycarbonyl; and

R⁶ is C _O alkyl.

3. A process for preparing a compound of formula (1-1) which comprises reacting a compound of formula (XXXII) with a compound of formula (XXXIII) or (XXXIV): (XXXII)

(R³)-N=C=S (XXXIII)

(R³)(R⁴)-N-C(=S)-C1 (XXXIV)

wherein A, R , R » 2 , r R» 3 and R have the same meaning as defined in claim 1.

4. A process for preparing the compound of formula (1-2) which comprises reacting a compound of formula (If) with a compound of formula

(XXXV):

R⁶-X (XXXV) wherein R¹, R², R⁵, R⁶ and A have the same meaning as defined in claim 1; and X is halogen.

5. A pharmaceutical composition for the inhibition of ras-transformed cell growth comprising a therapeutically effective amount of the compound or salt defined in claim 1 as an active ingredient together with a pharmaceutically acceptable carrier.