KR20040083150A - Novel inhibitors of farnesyl transferase and method of preparation thereof - Google Patents

Abstract

PURPOSE: A novel compound having the pyrrole ring and inhibiting farnesyl transferase, its pharmaceutically acceptable salt, hydrate, solvate and isomer are provided. And their preparation method is also provided. The farnesyl transferase inhibitors have anticancer activity, restenosis inhibiting activity, hyperlipidemia inhibiting activity and antiviral activity. CONSTITUTION: The compound as a farnesyl transferase inhibitor is represented by the formula(1), wherein n is 0, 1 or 2; X is C or N; R1 is hydrogen or methyl; R2 is lower alkyl, halogen optionally substituted phenyl, or naphthyl; and R3 is selected from the formula of N-R5-N-R5-R6, N-R5-Y-R6 or N-Y ring in which Y is O, S, S=O or SO2, R5 and R6 are independently hydrogen, hydroxyl, lower alkyl or lower alkoxy, and R4 is lower alkyl, alkoxyalkyl, cycloalkyl, cycloalkyl substituted lower alkyl or hetero aromatic ring substituted lower alkyl, or OR7 in which R7 is lower alkyl, alkoxyalkyl, morpholinyl, morpholinyl substituted lower alkyl, N-methylpiperazinyl substituted lower alkyl or alkenyl. The method for preparing the compound of the formula(1) comprises the steps of: reacting a compound of the formula(2) with (a) L-R4 in which L is halogen, (b) CHO-R4 or ketone compound in the presence of sodium triacetoxy borohydride, or (c) L-C(O)(CH2)n-L in which n is an integer of 1 to 5; and substituting the reaction product with morpholine or piperazine.

Description

Novel inhibitors of farnesyl transferase and method of preparation

The present invention relates to novel compounds of formula (1), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, including pyrrole structures and capable of inhibiting farnesyl transferases.

[Formula 1]

Where

n represents 0, 1 or 2,

X represents C or N,

R 1 represents hydrogen or methyl,

R2 represents lower alkyl, phenyl unsubstituted or substituted by halogen, or naphthyl,

R3 represents any one selected from the group of structural formulas

From here,

Y represents O, S, S = O or SO ₂

R5 and R6 each independently represent hydrogen, hydroxy, lower alkyl or lower alkoxy,

R 4 represents lower alkyl, alkoxyalkyl, cycloalkyl, lower alkyl substituted by cycloalkyl or lower alkyl substituted by heteroaromatic ring, or a group of the following structural formula,

Here, R 7 represents lower alkyl, alkoxyalkyl, morpholinyl group, lower alkyl substituted with morpholinyl group, lower alkyl substituted with N-methylpiperazinyl group, or alkenyl group.

The invention also relates to a process for preparing the compound of formula (1).

The present invention further provides an anticancer composition comprising a compound of Formula 1, a pharmaceutically acceptable salt, a hydrate, a solvate or an isomer thereof as an active ingredient, together with a pharmaceutically acceptable carrier. A composition, an antihyperlipidemic composition, and an antiviral composition.

Farnesyl transferase inhibitors are not only anticancer agents but also anti-vascular stenosis re-epilation agents (Erick E. Brooks, et al. The Journal of Biological Chemistry , 272 (14), 29207-29211, 1997), anti-hyperlipidemic agents (Russell Ross, Nature , 362, 801-809, 1993; Joseph L. Goldstein, et al., Nature , 343, 425-430, 1990) and antiviral agents (James C. Otto, et al., The Journal of Biological Chemistry , 272 (9) , 4569-4572, 1996).

Ras protein is a 21kDa protein that plays an important role in cell growth and differentiation. It binds to guanine nucleotides and hydrolyzes guanosine triphosphate (GTP) to guanosine diphosphate (GDP). It is also known to act as a molecular switch that regulates specific GTPase circuits in cells (Bourne, HR, Sanders, DA, McCormick, F. Nature 1991, 349, 117). Ras proteins are produced in mammalian cells by the three Ras genes as amino acids 188 K-Ras-4B or 189 H-Ras, K-Ras-4A and N-Ras. The amino acids at positions 12, 13, and 61 of the protein are in close proximity to the phosphate groups of GTP, and these amino acid residues affect GTPase activity by affecting the spatial position of water molecules involved in the hydrolysis of GTP. When cancer occurs in the human body, mutations in amino acids at this position are observed, which eventually inhibits Ras protein's intrinsic GTPase activity and maintains GTP binding status, which is known to show carcinogenicity by continuously transmitting abnormal growth signals. have. Such a carcinogenic Ras gene is known to be particularly closely related to pancreatic cancer, bladder cancer, lung cancer and skin cancer (see Bos, JL, Cancer Res ., 1989, 49, 4682). In order for the Ras protein to be biologically active, it must be attached to the cell membrane. This requires a carbon term after protein transfer by Ras farnesyl transferase, three AAX peptide cleavage enzymes at the Ras protein carboxy terminus, methyl transferase and palmitoyl transferase. The modification of is required. The first step, panesylation, is achieved by farnesyl transferase (FTase). The substrate of the farnesyl transferase is four peptides, CA1A2X, at the carboxy terminus of the Ras protein, where A1 and A2 are aliphatic amino acids without an electrical load and X is methionine, alanine or serine. The farnesyl reaction occurs on cysteine to form sulfur ether bonds, and in the case of H-Ras and N-Ras, palmitoylation occurs at another cysteine near the carboxy terminus. As a result of the panesylation, the Ras protein increases in hydrophobicity and adheres to the cell membrane, and the panesylated Ras protein is successively removed from the carboxy terminus by three AAX peptides and is methylated so that the panesyl group is separated from the lipid layer or other in the cell membrane. It is known to facilitate binding with receptors. On the other hand, unlike H-Ras and N-Ras, K-Ras-4B has a site where several lysines, called poly basic domains, are arranged in place of cysteine required for palmitoylation. It is known that binding to lipids is facilitated. In order for Ras protein to adhere well to the cell membrane, all modification steps are required. However, the activation of Ras protein is known to be sufficient for panicylation alone. Therefore, studies are being actively conducted to inhibit Ras carcinogenicity by mutation by blocking this panicylation. (Bus, JE et al ., Chemistry & Biology , 1995, 2, 787). Previous studies have shown that inhibition of farnesyl transferase in Ras-transformed cells inhibits cell growth and improves the cell morphology modified by Ras.

Indeed, several inhibitors of farnesyl transferase have been shown to selectively inhibit the response of Ras oncogenic genes to intracellular prenyl groups (see Kohl, NE et al, Proc. Natl. Acad. Sci. USA , 91, 9141 (1994); Kohl, NE et al., Nature Medicine , 1, 792 (1995).

The farnesyl transferase inhibitors thus far developed are peptide variants containing cysteine thiol groups and similar structures to CAAX, and inhibitors that improve them (see US Patent No. 5,141,851; Kohl, NE et al., Science 260, 1934 (1993); Graham et al., PCT / US95 / 12224), peptides modified with phenyl groups (Sebti, SM, J. Biol. Chem. 270, 26802, 1995), benzodiazepines in the psychotropic pharmaceutical framework And a variant using James as a turn simulation of peptides (James, GL et al. , Science, 260, 1937, 1993). On the other hand, in recent years, development has been focused on the farnesyl transferase inhibitors that do not contain a thiol group, which is limited to be developed as a therapeutic agent in terms of pharmacokinetics and toxicity, and deviated from the peptide structure. Representative examples thereof include inhibitors based on tricyclic organic compounds (see Bishop WR et al. , J. Biol. Chem., 270, 30611, 1995; US Patent No. 6239140; US Patent No.6211193). Inhibitors containing imidazole (see WO 9721701; US Patent No. 5891889; WO 0118006; WO 0052134; WO 0064891).

On the other hand, confirming the interaction between the cytochrome P450 enzyme, which plays an important role in the metabolism of drugs, and the CYP3A4 enzyme, which plays a major role in the drug, as well as drugs intended to be developed as a new anticancer drug, today's elderly drug consumers average 2 In the case of taking ~ 5 different drugs, it is very important to develop a safe drug that can minimize the possibility of drug interaction.

In general, most compounds containing imidazole are known as inhibitors of the CYP3A4 enzyme (Wilkinson, CF et al, Biochem. Pharmacol. 23, 2377, 1974; Halpert, JR. Et al, Annu. Rev. Pharmacol. Toxicol, 35, 29, 1995).

Accordingly, the present inventors have been interested in the study of a new inhibitor having an excellent effect of inhibiting panesyl transferase and at the same time decreasing the inhibitory ability of the CYP3A4 enzyme.

We have already reported a farnesyl transferase inhibitor with a piperidine structure, but did not report results related to CYP3A4 enzyme inhibition of the compounds presented in the examples (WO 9938862).

Therefore, the present inventors re-evaluated the CYP3A4 enzyme inhibitory ability while recognizing the CYP3A4 enzyme inhibitory ability in the development of a farnesyl transferase inhibitor.

In general, CYP3A4 enzyme inhibition is known to correlate with the fat solubility of the compound (Riley R. J. et. Al, Pharmaceutical Research, 18,652, 2001).

The present inventors, by introducing a functional group and a hydrophilic functional group that can increase the action with the farnesyl transferase to reduce the fat solubility of the compound, the effect of inhibiting the farnesyl transferase, while at the same time reduced CYP3A4 enzyme inhibitory ability of the compound of formula (1) New farnesyl transferase inhibitors could be developed, and these compounds have been found to be useful as anticancer agents, antiangiogenic agents, antihyperlipidemic agents and antiviral agents. In addition, the effects of the compounds were investigated through soft agar culture experiments, which are highly correlated with animal experiments. The cell lines used were colon cancer cell lines (HCT116), bladder cancer cell lines (T24), pancreatic cancer cell lines (MiaPaca-2, PANC-1), and the like. As a control drug, 5-FU and gemmcitabin, which are currently used as anticancer drugs, were used.

It is therefore an object of the present invention to contain a compound of formula (1) together with a novel compound of formula (1) comprising a pyrrole structure and capable of inhibiting panesyl transferase, a method for preparing the same, and a pharmaceutically acceptable carrier. It is to provide an anticancer agent composition, a vascular restenosis prevention agent composition, an antihyperlipidemic composition and an antiviral agent composition characterized by.

Hereinafter, the present invention will be described in detail.

The present invention relates to novel compounds of formula (1), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof, including pyrrole structures and capable of inhibiting farnesyl transferases.

[Formula 1]

Where

n represents 0, 1 or 2,

X represents C or N,

R 1 represents hydrogen or methyl,

R2 represents lower alkyl, phenyl unsubstituted or substituted by halogen, or naphthyl,

R3 represents any one selected from the group of structural formulas

From here,

Y represents O, S, S = O or SO ₂

R5 and R6 each independently represent hydrogen, hydroxy, lower alkyl or lower alkoxy,

R 4 represents lower alkyl, alkoxyalkyl, cycloalkyl, lower alkyl substituted with cycloalkyl or lower alkyl substituted with heteroaromatic ring, or represents a group of the formula

Here, R 7 represents lower alkyl, alkoxyalkyl, morpholinyl group, lower alkyl substituted with morpholinyl group, lower alkyl substituted with N-methylpiperazinyl group, or alkenyl group.

Lower alkyl in the compound of Formula 1 according to the present invention means straight or branched chain alkyl having 1 to 6 carbon atoms, lower alkoxy refers to straight or branched chain alkoxy having 1 to 6 carbon atoms, alkyl in the alkoxyalkyl is 1 to 6 carbon atoms Means straight or branched alkyl. In the present invention, cycloalkyl means a saturated hydrocarbon ring having 3 to 6 carbon atoms, and a heteroaromatic ring is a 5- or 6-membered aromatic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. Means. Furthermore, in this invention, an alkenyl group is a C2-C6 linear or branched unsaturated group.

Since the compound of Formula 1 according to the present invention may have an asymmetric carbon center depending on the type of substituents, it may exist as individual enantiomers or diastereomers, or as a mixture thereof including racemates. Such isomers or mixtures thereof are therefore also included within the scope of the present invention.

The compound of formula 1 according to the present invention can be converted into pharmaceutically acceptable salts according to conventional methods known in the art. Such pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbonic acid such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc., sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid Acid addition salts formed by and the like are included.

Among the compounds of the formula (1), preferred compounds are those in which n represents 1 or 2, X represents C, R 1 is H or methyl, R 2 is naphthyl, and R 3 is Wherein R 5 and R 6 are each independently lower alkyl, Y is O, and R 4 is lower alkyl substituted with cycloalkyl, (Wherein R7 is morpholinyl group, lower alkyl substituted with N-methylpiperazinyl group, or lower alkyl substituted with morpholinyl group), alkoxyalkyl, lower alkyl, lower alkyl substituted with heteroaromatic ring, or al It is a compound which shows a kenyl group.

Representative compounds among the compounds of Formula 1 include the following compounds, and the structure of each compound is as shown in Table 1 below, and the numbers in parentheses indicate the example numbers:

1 - [(1- {2- [1- (cyclohexylmethyl) -4-piperidinyl] ethyl} -1 H-imidazol-5-yl) methyl] - N - (2-methoxyethyl) - N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (1);

N- (2-methoxyethyl) -1-[(1-{[1- (2-methoxyethyl) -4-piperidinyl] methyl} -1 H -imidazol-5-yl) methyl]- N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (2);

N- (2-methoxyethyl) -N -methyl-1-{[1-({1- [2- (4-methyl-1-piperazinyl) acetyl] -4-piperidinyl} methyl)- 1 H -imidazol-5-yl] methyl} -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (3);

1 - [(1 - {[1- (cyclopropylmethyl) -4-piperidinyl] methyl} -1 H-imidazol-5-yl) methyl] - N - (2- methoxyethyl) - N - Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (4);

1 - [(1 - {[1- (cyclohexylmethyl) -4-piperidinyl] methyl} -1 H-imidazol-5-yl) methyl] - N - (2- methoxyethyl) - N - Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (5);

1 - ({1 - [(1-cyclohexyl-4-piperidinyl) methyl] -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N-methyl-4 -(1-naphthyl) -1 H -pyrrole-3-carboxamide (6);

1 - [(1- {2- [1- (cyclohexyl) -4-piperidinyl] ethyl} -4-methyl -1 H-imidazol-5-yl) methyl] - N - (2-methoxy Methoxyethyl) -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (7);

N- (2-methoxyethyl) -1-[(1- {2- [1- (2-methoxyethyl) -4-piperidinyl] ethyl} -4-methyl-1 H -imidazole-5 -Yl) methyl] -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (8);

N- (2-methoxyethyl) -N -methyl-1-[(4-methyl-1- {2- [1- (3-methyl-2-butenyl) -4-piperidinyl] ethyl}- 1 H -imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (9);

N- (2-methoxyethyl) -N -methyl-1-({4-methyl-1-[(1-propyl-4-piperidinyl) methyl] -1 H -imidazol-5-yl} methyl ) -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (10);

1 - ({1 - [(1-isopentyl-4-piperidinyl) methyl] -4-methyl -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N -Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (11);

1 - [(1 - {[1- (2-furyl) -4-piperidinyl] methyl} -4-methyl -1 H-imidazol-5-yl) methyl] - N - (2-methoxy Ethyl) -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (12);

1 - [(1 - {[1- (cyclopropylmethyl) -4-piperidinyl] methyl} -4-methyl -1 H-imidazol-5-yl) methyl] - N - (2- methoxyethyl ) -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (13);

1 - ({1 - [(1-cyclohexyl-4-piperidinyl) methyl] -4-methyl -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N -Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (14);

1 - ({1- [1- (cyclopropylmethyl) -4-piperidinyl] -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N-methyl-4 -(1-naphthyl) -1 H -pyrrole-3-carboxamide (15);

1 - ({1- [1- (cyclohexyl) -4-piperidinyl] -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N-methyl-4 -(1-naphthyl) -1 H -pyrrole-3-carboxamide (16);

N- (2-methoxyethyl) -N -methyl-1-[(1- {1- [2- (4-morpholinyl) acetyl] -4-piperidinyl} -1 H -imidazole-5 -Yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (17);

N- (2-methoxyethyl) -N -methyl-1-[(1- {2- [1- (3-methyl-2-butenyl) -4-piperidinyl] ethyl} -1 H -already Dazol-5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (18);

N- (2-methoxyethyl) -N -methyl-1-[(1- {2- [1- (4-morpholinylcarbonyl) -4-piperidinyl] ethyl} -1 H -imidazole -5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (19); And

N- (2-methoxyethyl) -N -methyl-1-[(1-{[1- (3-methyl-2-butenyl) -4-piperidinyl] methyl} -1 H -imidazole- 5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (20).

The invention also relates to a process for the preparation of the novel compounds of formula (1).

The compound of formula 1 according to the present invention can be prepared according to the method as described below. However, the method for preparing the compound according to the present invention, for example, reaction conditions such as a reaction solvent, a base, and the amount of the reactant used, or a reaction sequence, is not limited to those described below, and described herein Various synthesis methods disclosed in the publicly known literature can be easily prepared by combining them, and such combinations are conventional techniques that are generalized to those skilled in the art.

The compound of formula 1 of the present invention may be reacted with a) L-R4, wherein L represents halogen and R4 is as defined above, or b) the presence of sodium triacetoxy borohydride Or reacted with CHO-R4 (where R4 is as defined above) or a ketone compound, or c) LC (O) (CH ₂ ) _n -L where L represents halogen and n is an integer from 1 to 5 And substitution reaction with morpholine or piperazine.

Wherein R1, R2 and R3 are as defined above.

Reaction conditions including the amount of the reactants used, the reaction temperature, the reaction time, etc. in the preparation method according to the present invention can be easily determined by those skilled in the art according to the specific reactants.

On the other hand, the compound of formula (2) used as a starting material in the process of preparing a compound of formula (1) according to the present invention can be prepared by deprotecting the compound of formula (3) and in addition to the method for preparing a compound of formula (1) It can be summarized as in Scheme 1 below.

In the above scheme, PG represents a protecting group such as benzyl or benzyloxycarbonyl, and n, R 1, R 2, R 3 and R 4 are as defined above.

The compound of Formula 3 may be prepared by, for example, a method as shown in Scheme 2 or Scheme 3 below.

In the above scheme, PG represents a protecting group such as benzyl or benzyloxycarbonyl, and n, R 2 and R 3 are as defined above.

First, the compound of Formula 5 is dissolved in N, N-dimethylformamide, and then, based on the compound of Formula 5, about 1-3 equivalents of sodium hydride are added and stirred for about 10 minutes, and then the compound of Formula 4 is added dropwise to room temperature. It is stirred for about 3 to 6 hours to obtain a compound of formula 3.

In the scheme, X 'represents a leaving group such as halogen or O-methanesulfonate, PG represents a protecting group such as benzyl or benzyloxycarbonyl, and n, R2 and R3 are as defined above.

According to Scheme 3, the compound of Formula 7 is dissolved in N, N-dimethylformamide, and then, about 1 to 1.5 equivalents of sodium hydride is added to the compound of Formula 7, and stirred for about 10 minutes. The mixture was added dropwise and stirred at room temperature for about 1-6 hours to complete the reaction. Isomers formed by reacting with nitrogen at position 3 of the imidazole can be removed to obtain a compound of formula 3.

In addition, the compound of Formula 4 shown in Scheme 2 can be prepared by the following Scheme 4.

In the above scheme, PG represents a protecting group such as benzyl or benzyloxycarbonyl, and n is as defined above.

After dissolving the compound of Formula 8 in isopropanol, about 1.5 equivalents of potassium thiocyanate, about 1 to 1.5 equivalents of dihydroxyacetone dipolymer, and about 4 equivalents of acetic acid were added at room temperature. It stirred for 20 to 50 hours to obtain a compound of formula ( 9 ). Subsequently, ethanol is added to dissolve it, and a catalytic amount of vanadium sulfate is added at about 60 ^° C., and an aqueous hydrogen peroxide solution is slowly added dropwise about 4 equivalents based on the compound of Formula 9 to obtain a compound of Formula 10. The compound of formula 10 thus obtained is dissolved in dichloromethane and reacted with about 2 to 5 equivalents of thionyl chloride based on the compound of formula 10 to prepare a compound of formula 4.

On the other hand, the compound of formula 7 in Scheme 3 can be prepared by the method of Scheme 5.

In the above scheme, Tr represents a trityl group, and R 2 and R 3 are as defined above.

Specific reaction conditions of the preparation method may refer to the following Preparation Examples and Examples.

However, the preparation method of the compound according to the present invention is not limited to the one described herein, and can be easily prepared by arbitrarily combining various synthetic methods described in this specification or disclosed in the prior literature, and such combinations can be prepared by the present invention. It is a common technique generalized to those skilled in the art.

After the reaction is completed, the product can be separated and purified by conventional workup methods such as chromatography, recrystallization and the like.

Compounds of formula (I) according to the invention also comprise compounds having a CYP 3A4 enzyme inhibitory capacity (IC ₅₀ ) of at least 0.5 μM, preferably at least 1.0 μM.

The compound of formula 1 according to the present invention has an inhibitory effect on panesyl transferase as described above, and thus may be usefully used as an anticancer agent.

In addition, the compound of the formula (1) according to the present invention also has an effect as an anti-vascular constriction inhibitor, hyperlipidemia and an antiviral agent.

The total daily dose to be administered to the host in a single dose or in separate doses when administering a compound of the present invention for clinical purposes is preferably in the range of 1 to 100 mg per kg of body weight, but the specific dose level for a particular patient will The compound, the weight of the patient, sex, health status, diet, the time of administration of the drug, the method of administration, the rate of excretion, the drug mixture and the severity of the disease can be changed.

The compounds of the present invention can be administered in injectable and oral formulations as desired. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing agents, wetting agents, or suspending agents according to known techniques. Solvents that can be used for this are water, Ringer's solution and isotonic NaCl solution, and sterile fixed oils are also commonly used as solvents or suspending media. Any non-irritating fixed oil may be used for this purpose, including mono- and diglycerides, and fatty acids such as oleic acid may also be used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the active compounds of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and carriers such as lubricants such as magnesium stearate, disintegrants, binders and the like. .

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. In the following preparation example, a method for synthesizing an intermediate for preparing the final compound is described, and the example describes a process for synthesizing the final compound through reaction with the compound obtained in the preparation example. However, these preparation examples and examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Preparation Example 1 Benzyl 4- {2-[(methylsulfonyl) oxy] ethyl} -1-piperidinecarboxylate

20.1 g (0.156 mol) of 2- (4-piperidinyl) -1-ethanol is dissolved in 250 ml of tetrahydrofuran, and 6.85 g (0.171 mol) of caustic soda is added thereto, followed by cooling to 0 ^° C. 25.7 ml (0.171 mol) of benzyl chloroformate is added dropwise for 30 minutes and stirred at room temperature for 2 hours. After completion of the reaction, it is concentrated, 300 ml of water is added, and 150 ml of ethyl acetate is extracted twice. Concentrate, add 200 ml of dichloromethane to dissolve, add 44 ml (0.312 mol) of triethylamine and add 13.2 ml (0.171 mol) of methanesulfonyl chloride dropwise for 30 minutes. Stir for 30 minutes and concentrate. 300 ml of water was added, 150 ml of ethyl acetate was extracted twice, and concentrated to obtain 45.2 g (0.133 mol, yield; 85%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 7.31-7.28 (5H, m), 5.10 (2H, s), 4.28 (2H, t), 4.17-4.14 (2H, m), 3.00 (3H, s), 2.77-2.74 (2H, m), 1.72-1.68 (5H, m), 1.15-1.10 (2H, m)

ESI MS (m / e) = 342 [M + 1]

Preparation Example 2 Benzyl 4- (2-aminoethyl) -1-piperidinecarboxylate

30.3 g (88.9 mmol) of the compound obtained in Preparation Example 1 was dissolved in 150 ml of N, N-dimethylformamide, and 6.35 g (97.7 mmol) of sodium azide was added thereto, followed by stirring at 90 ^° C. for 3 hours. After completion of the reaction, it is concentrated, 250 ml of water is added, 150 ml of ethyl acetate is extracted twice and concentrated again. After dissolving again with 300 ml of methanol, 1 g of Raney-nickel was added thereto, followed by stirring for 10 hours under hydrogen pressure. After completion of the reaction, Raney-Nickel was filtered off and the filtrate was concentrated to give 21.5 g (82.1 mmol, yield; 92%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 7.31-7.27 (5H, m), 5.10 (2H, s), 4.18-4.14 (2H, m), 2.81-2.72 (4H, m), 1.69-1.65 (2H, m), 1.51-1.45 (3H , m), 1.15-1.11 (2H, m)

ESI MS (m / e) = 263 [M + 1]

Preparation Example 3 Benzyl 4- {2- [5- (hydroxymethyl) -2-sulfanyl-1 H -Imidazol-1-yl] ethyl} -1-piperidinecarboxylate

20.1 g (76.7 mmol) of the compound obtained in Preparation Example 2 was dissolved in 200 ml of isopropanol, 11.1 g (115 mmol) of potassium thiocyanide, 16.6 g (92.0 mmol) of 1,3-dihydroxyatetone dimer, and 17.5 ml (307 mmol) of acetic acid Was added and stirred at room temperature for 20 hours. After completion of the reaction, the mixture was concentrated, 200 ml of water, 100 ml of diethyl ether and 50 ml of ethyl acetate were added thereto, and the resultant was stirred for 1 hour to obtain an off-white solid. Filtration, washing with 50 ml of diethyl ether and drying gave 22.5 g (60 mmol, yield; 78%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 7.33-7.25 (5H, m), 6.59 (1H, s), 5.10 (2H, s), 4.49 (2H, d), 4.11-4.07 (4H, m), 2.78-2.74 (2H, m), 1.77-1.71 (4H, m), 1.20-1.16 (2H, m)

ESI MS (m / e) = 376 [M + 1]

Preparation Example 4 Benzyl 4- {2- [5- (hydroxymethyl) -1 H -Imidazol-1-yl] ethyl} -1-piperidinecarboxylate

22.0 g (58.7 mmol) of the compound obtained in Preparation Example 3 was dissolved in 200 ml of ethanol, and then heated to 60 ^° C. After adding 478 mg (2.93 mmol) of vanadium sulfate, 27 ml (235 mmol) of 30% aqueous hydrogen peroxide solution was slowly added dropwise for 1 hour. After stirring for 30 minutes, the mixture is cooled to room temperature and concentrated. 200 ml of water is added to dissolve and washed with 150 ml of ethyl acetate. The water layer is neutralized to pH 8-9 using saturated aqueous sodium hydrogen carbonate solution. 150 ml of ethyl acetate was extracted four times and concentrated again to give 17.5 g (51.0 mmol, yield; 87%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 7.49 (1H, s), 7.35-7.31 (5H, m), 6.92 (1H, s), 5.10 (2H, s), 4.60 (2H, d), 4.16-4.13 (2H, m), 4.04 ( 2H, t), 2.76-2.73 (2H, m), 2.14-2.11 (2H, m), 1.79 (2H, q), 1.51-1.46 (1H, m), 1.21-1.18 (2H, m)

ESI MS (m / e) = 344 [M + 1]

Preparation Example 5 Benzyl 4- [2- (5-{[3-{[(2-methoxyethyl) (methyl) amino] carbonyl} -4- (1-naphthyl) -1 H -Pyrrole-1-yl] methyl} -1 H -Imidazol-1-yl) ethyl] -1-piperidinecarboxylate

After dissolving 17.3 g (50.4 mmol) of the compound obtained in Preparation Example 4 in 100 ml of dichloromethane, 18.3 ml (252 mmol) of thionyl chloride were added thereto, followed by stirring at room temperature for 2 hours. Concentrate after completion of reaction. N- (2-methoxyethyl) -N-methyl-4- (1-naphthyl) -1H-pyrrole-3-carboxamide obtained by the method given in Preparation Example 1 and Preparation Example 2 of Korean Patent KR99 / 001294 Dissolve 13.0 g (42 mmol) in 100 ml of N, N-dimethylformamide, add 3.36 g (84 mmol) of sodium hydride and stir for 15 minutes. The above-concentrated compound was dissolved in this solution in 30 ml of N, N-dimethylformamide dropwise, followed by stirring for 3 hours. After completion of the reaction, 50 ml of water is added and concentrated. 200 ml of water is added, and 150 ml of ethyl acetate is extracted twice. The mixture was concentrated again and separated by column chromatography (eluent; 5% methanol / dichloromethane) to obtain 25.2 g (39.8 mmol, yield; 79%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.51 (1H, s), 7.44-7.40 (3H, m), 7.37-7.33 (5H, m), 7.29 ( 1H, d), 7.17 (1H, s), 7.05 (1H, s), 6.73 (1H, s), 5.30 (2H, s), 5.10 (2H, s), 4.18 (2H, t), 3.31 (3H , s), 3.05-3.01 (7H, m), 2.85 (2H, t), 1.88-1.85 (2H, m), 1.60-1.55 (1H, m), 1.31-1.24 (4H, m), 0.98-0.95 (2H, m)

ESI MS (m / e) = 634 [M + 1]

Preparation Example 6. N- (2-methoxyethyl) -N-methyl-4- (1-naphthyl) -1-({1- [2- (4-piperidinyl) ethyl] -1 H -Imidazol-5-yl} methyl) -1 H -Pyrrole-3-carboxamide

25.0 g (39.5 mmol) of the compound obtained in Preparation Example 5 was dissolved in 200 ml of methanol, 1 g of palladium hydroxide / carbon was added thereto, followed by stirring for 5 hours under hydrogen pressure. After completion of the reaction, the solid was filtered off and the filtrate was concentrated to give 19.1 g (38.3 mmol, yield; 97%) of the title compound.

¹ H NMR (CD ₃ OD, ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.51 (1H, s), 7.44-7.40 (3H, m), 7.30 (1H, d), 7.17 (1H, s), 7.05 (1H, s), 6.73 (1H, s), 5.40 (2H, s), 4.18 (2H, t), 3.31 (3H, s), 3.05-3.01 (7H, m), 2.85 (2H , t), 1.88-1.85 (2H, m), 1.60-1.55 (1H, m), 1.31-1.24 (4H, m), 0.98-0.95 (2H, m)

ESI MS (m / e) = 500 [M + 1]

Example 1. 1-[(1- {2- [1- (cyclohexylmethyl) -4-piperidinyl] ethyl} -1 H Imidazol-5-yl) methyl]- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

100 mg (0.20 mmol) of the compound obtained in Preparation Example 6 was dissolved in 20 ml of 1,2-dichloroethane, followed by addition of 0.097 ml (0.80 mmol) of cyclohexanal and 170 mg (0.80 mmol) of sodium triacetoxy borohydride. Stirred. After completion of the reaction, the mixture was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to obtain 85 mg (0.14 mmol, yield; 71%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.07 (1H, d), 7.83 (1H, d), 7.76 (1H, d), 7.55 (1H, s), 7.46-7.39 (3H, m), 7.30 (1H, d), 7.21 (1H, s), 7.04 (1H, s), 6.75 (1H, s), 5.12 (2H, s), 3.82 (2H, t), 3.32-3.30 (1H, m), 3.18-3.04 (8H, m), 2.45 -2.41 (4H, m), 2.21-2.19 (2H, m), 2.03-2.01 (4H, m), 1.80-1.52 (8H, m), 1.21-1.11 (5H, m), 0.94-0.92 (2H, m)

ESI MS (m / e) = 596 [M + 1]

Preparation Example 7. N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1-{[1- (4-piperidinylmethyl) -1 H -Imidazol-5-yl] methyl} -1 H -Pyrrole-3-carboxamide

Preparation Example 1, Preparation Example 2, Preparation Example 3, Preparation Example 4, Preparation Example using 18.2 g (158 mmol) of 4-piperidinyl methanol instead of 2- (4-piperidinyl) -1-ethanol in Preparation Example 1 It reacted in the order of 5 and the preparation example 6, and obtained 17.8 g (36.7 mmol, total yield; 23%) of target compounds.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.13 (1H, s), 7.02 (1H, s), 6.72 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12-2.19 (4H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-1.17 (2H, m)

ESI MS (m / e) = 486 [M + 1]

Example 2. N -(2-methoxyethyl) -1-[(1-{[1- (2-methoxyethyl) -4-piperidinyl] methyl} -1 H Imidazol-5-yl) methyl]- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

100 mg (0.21 mmol) of the compound obtained in Preparation Example 7 were dissolved in 10 ml of N, N-dimethylformamide, 114 mg (0.82 mmol) of potassium carbonate and 0.077 ml (0.82 mmol) of 2-bromoethyl methyl ether were added thereto, followed by stirring at room temperature for 27 hours. It was. After completion of the reaction, the reaction mixture was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to obtain 45 mg (0.083 mmol, yield; 39%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.13 (1H, s), 7.02 (1H, s), 6.72 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.53-3.51 (2H, m), 3.08-3.00 (9H, m), 2.82 -2.80 (2H, m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12-2.19 (4H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m) , 1.24-1.17 (2H, m)

ESI MS (m / e) = 544 [M + 1]

Example 3. N -(2-methoxyethyl)- N -Methyl-1-{[1-({1- [2- (4-methyl-1-piperazinyl) acetyl] -4-piperidinyl} methyl) -1 H -Imidazol-5-yl] methyl} -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

61 mg (0.126 mmol) of the compound obtained in Preparation Example 7 were dissolved in 5 ml of dichloromethane, 0.026 ml (0.189 mmol) of triethylamine was added and cooled to 0 ^° C. Add 0.013 ml (0.15 mmol) of bromoacetyl bromide and concentrate after stirring for 20 minutes at room temperature. Dissolve with 5 ml of N, N-dimethylformamide, add 0.07 ml (0.63 mmol) of N-methylpiperazine and stir at 80 ^° C for 2 hours. After completion of the reaction was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to give the title compound 52mg (0.083mmol, yield; 66%).

¹ H NMR (CDCl ₃ , ppm); δ) 8.01 (1H, d), 7.82 (1H, d), 7.74 (1H, d), 7.48 (1H, s), 7.43-7.40 (3H, m), 7.30 (1H, d), 7.11 (1H, s), 7.02 (1H, s), 6.72 (1H, s), 5.18 (2H, s), 3.70-3.68 (4H, m), 3.08-3.00 (9H, m), 2.66-2.40 (12H, m) , 2.12-2.19 (4H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-1.17 (2H, m)

ESI MS (m / e) = 626 [M + 1]

Example 4. 1-[(1-{[1- (cyclopropylmethyl) -4-piperidinyl] methyl} -1 H Imidazol-5-yl) methyl]- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

85 mg (0.175 mmol) of the compound obtained in Preparation Example 7 were dissolved in 10 ml of 1,2-dichloroethane, 0.052 ml (0.70 mmol) of cyclopropanal and 148 mg (0.70 mmol) of sodium triacetoxy borohydride were added thereto, followed by stirring at room temperature for 3 hours. It was. After completion of the reaction, the reaction mixture was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to obtain 62 mg (0.115 mmol, yield; 66%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.13 (1H, s), 7.02 (1H, s), 6.72 (1H, s), 5.13 (2H, s), 3.77 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (4H, m), 2.12-2.19 (4H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-1.17 (2H, m), 0.97-0.95 (3H, m) , 0.57-0.54 (2H, m)

ESI MS (m / e) = 540 [M + 1]

Example 5. 1-[(1-{[1- (cyclohexylmethyl) -4-piperidinyl] methyl} -1 H Imidazol-5-yl) methyl]- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

95 mg (0.196 mmol) of the compound obtained in Preparation Example 7 was dissolved in 10 ml of 1,2-dichloroethane, 0.095 ml (0.78 mmol) of cyclohexanal and 166 mg (0.78 mmol) of sodium triacetoxy borohydride were added thereto, followed by stirring at room temperature for 3 hours. It was. After completion of the reaction, the reaction mixture was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to obtain 68 mg (0.117 mmol, yield; 60%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.02 (1H, d), 7.81 (1H, d), 7.73 (1H, d), 7.47 (1H, s), 7.46-7.43 (3H, m), 7.30 (1H, d), 7.12 (1H, s), 7.01 (1H, s), 6.72 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (4H, m), 2.12-2.19 (4H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-0.97 (13H, m)

ESI MS (m / e) = 582 [M + 1]

Example 6. 1-({1-[(1-cyclohexyl-4-piperidinyl) methyl] -1 H Imidazol-5-yl} methyl)- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

125 mg (0.258 mmol) of the compound obtained in Preparation Example 7 was dissolved in 15 ml of 1,2-dichloroethane, 0.11 ml (0.70 mmol) of cyclohexanone and 218 mg (1.03 mmol) of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature for 3 hours. It was. After completion of the reaction, the mixture was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to obtain 54 mg (0.095 mmol, yield; 37%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.13 (1H, s), 7.02 (1H, s), 6.72 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12-2.19 (4H, m), 1.54-1.51 (2H, m), 1.47-1.32 (6H, m), 1.24-1.01 (8H, m)

ESI MS (m / e) = 568 [M + 1]

Preparation Example 8 N-trityl (5-methyl-1 H -Imidazol-4-yl) methanol

4-methyl-5-imidazolmethanol hydrochloride (5 g, 33.6 mmol) and triethylamine (11.7 mL, 83.9 mmol) were added to 150 mL of dimethylformamide and stirred for 5 minutes. Tritylchloride (31 g, 111 mmol) dissolved in 50 mL of dimethylformamide was added over 20 minutes and stirred for 4 hours. The resulting solid was filtered and washed twice with 500 mL of water to give 6.6 g of the title compound in 55% yield. Isomers were not isolated at this time (having a composition ratio of 3: 1).

¹ H NMR (DMSO-d ₆ ); δ) 2.14 (3H, s), 4.28 (2H, s), 6.89 (1H, s), 7.05-7.09 (6H, m), 7.35-7.44 (9H, m)

ESI MS (m / e) = 355 [M + 1]

Preparation Example 9 N-trityl-4- (chloromethyl) -5-methyl-1 H Imidazole

1.6 g (4.5 mmol) of the compound obtained in Preparation Example 8 was dissolved in 40 mL of chloroform, and 0.4 mL (5.5 mmol) of thionyl chloride was added, followed by stirring for 1 hour. Chloroform was removed by distillation under reduced pressure, 100 mL of diethyl ether was added thereto, followed by stirring at 0 ^o C for 30 minutes to form an off-white solid, which was filtered and washed with 200 mL of diethyl ether to give 1.5 g of the title compound in 89% yield. Got it. Isomers were not isolated at this time (having a composition ratio of 3: 1).

¹ H NMR (DMSO-d ₆ ); δ) 2.32 (3H, s), 4.90 (2H, s), 7.13-7.50 (15H, m), 9.04 (1H, s)

ESI MS (m / e) = 373 [M + 1]

Preparation Example 10 N -(2-methoxyethyl)- N -Methyl-1-[(4-methyl-1 H -Imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

N- (2-methoxyethyl) -N-methyl-4- (1-naphthyl) -1H-pyrrole-3-carboxamide obtained by the method given in Preparation Example 1 and Preparation Example 2 of Korean Patent KR99 / 001294 4.3 g (14 mmol) was dissolved in 100 mL of dimethylformamide, sodium hydride (60% purity, 1.7 g, 43 mmol) was added, followed by stirring for 10 minutes. 6.5 g (17 mmol) of the compound obtained in Preparation Example 9 were added at 0 ^° C. over 5 minutes, followed by stirring for 1 hour. The excess sodium hydride was removed by adding 5 mL of water and the solvent was removed by distillation under reduced pressure. Diluted with 100 mL of ethyl acetate and 100 mL of saturated sodium chloride solution, extracted with ethyl acetate (100 mL × 2), dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. Without further purification, it was directly dissolved in 20 mL of dichloromethane, trifluoroacetic acid (4 mL, 52 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The solvent and trifluoroacetic acid were removed by distillation under reduced pressure, and column chromatography (eluent; dichloromethane / methanol = 93/7, v / v) was performed to obtain 2.5 g of the title compound in 49% yield.

¹ H NMR (CDCl ₃ ); δ) 1.88 (2H, s), 2.19 (3H, s), 2.36 (2H, s), 2.71 (1H, s), 3.02 (3H, s), 3.08 (1H, s), 3.32 (1H, s) , 5.05 (2H, s), 6.89 (1H, d), 7.14 (1H, d), 7.35 (1H, dd), 7.38-7.48 (3H, m), 7.78 (1H, d), 7.84 (1H, d ), 8.10 (1 H, d)

ESI MS (m / e) = 403 [M + 1]

Preparation Example 11 Benzyl 4- [2- (5-{[3-{[(2-methoxyethyl) (methyl) amino] carbonyl} -4- (1-naphthyl) -1 H -Pyrrole-1-yl] methyl} -4-methyl-1 H -Imidazol-1-yl) ethyl] -1-piperidinecarboxylate

7.2 g (17.9 mmol) of the compound obtained in Preparation Example 10 were dissolved in 150 ml of N, N-dimethylformamide, and 860 mg (21.4 mmol) of sodium hydride were added and stirred for 10 minutes. 7.32 g (21.5 mmol) of the compound obtained in Preparation Example 1 were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 20 ml of water is added and concentrated. Add 200 ml of water, extract 150 ml twice with ethyl acetate and concentrate again. Separation by column chromatography (eluent; 5% methanol / dichloromethane) gave 6.43 g (9.93 mmol, yield; 56%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.84 (1H, d), 7.75 (1H, d), 7.51 (1H, s), 7.44-7.40 (3H, m), 7.37-7.33 (5H, m), 7.29 ( 1H, d), 7.05 (1H, s), 6.73 (1H, s), 5.30 (2H, s), 5.10 (2H, s), 4.18 (2H, t), 3.31 (3H, s), 3.05-3.01 (7H, m), 2.85 (2H, t), 1.88-1.84 (5H, m), 1.60-1.55 (1H, m), 1.31-1.24 (4H, m), 0.98-0.95 (2H, m)

ESI MS (m / e) = 648 [M + 1]

Preparation Example 12 N -(2-methoxyethyl)- N -Methyl-1-({4-methyl-1- [2- (4-piperidinyl) ethyl] -1 H -Imidazol-5-yl} methyl) -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

6.40 g (9.89 mmol) of the compound obtained in Preparation Example 11 were reacted in the same manner as in Preparation Example 6 to obtain 4.87 g (9.49 mmol, yield; 96%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.11 (1H, d), 7.86 (1H, d), 7.77 (1H, d), 7.52 (1H, s), 7.45-7.40 (3H, m), 7.30 (1H, d), 7.06 (1H, s), 6.75 (1H, s), 5.42 (2H, s), 4.18 (2H, t), 3.31 (3H, s), 3.05-3.01 (7H, m), 2.84 (2H, t), 1.88-1.84 (5H, m), 1.60-1.55 (1H, m), 1.31-1.24 (4H, m), 0.98-0.95 (2H, m)

ESI MS (m / e) = 514 [M + 1]

Example 7. 1-[(1- {2- [1- (cyclohexylmethyl) -4-piperidinyl] ethyl} -4-methyl-1 H Imidazol-5-yl) methyl]- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

150 mg (0.29 mmol) of the compound obtained in Preparation Example 12 were reacted in the same manner as in Example 1, to obtain 125 mg (0.21 mmol, yield; 71%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.11 (1H, d), 7.86 (1H, d), 7.77 (1H, d), 7.52 (1H, s), 7.45-7.40 (3H, m), 7.30 (1H, d), 7.06 (1H, s), 6.75 (1H, s), 5.15 (2H, s), 4.18 (2H, t), 3.31 (3H, s), 3.05-3.01 (7H, m), 2.80-2.74 (4H, m), 1.88 -1.84 (5H, m), 1.60-1.55 (1H, m), 1.31-1.14 (8H, m), 0.98-0.90 (9H, m)

ESI MS (m / e) = 610 [M + 1]

Example 8. N -(2-methoxyethyl) -1-[(1- {2- [1- (2-methoxyethyl) -4-piperidinyl] ethyl} -4-methyl-1 H Imidazol-5-yl) methyl]- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

123 mg (0.24 mmol) of the compound obtained in Preparation Example 12 were reacted in the same manner as in Example 2, to obtain 58 mg of the target compound (0.10 mmol, yield; 42%).

¹ H NMR (CDCl ₃ , ppm); δ) 8.10 (1H, d), 7.84 (1H, d), 7.77 (1H, d), 7.52 (1H, s), 7.45-7.40 (3H, m), 7.30 (1H, d), 7.06 (1H, s), 6.75 (1H, s), 5.08 (2H, s), 4.18 (2H, t), 3.31 (3H, s), 3.19 (3H, s), 3.05-3.01 (7H, m), 2.84 (2H , t), 1.88-1.80 (9H, m), 1.60-1.55 (1H, m), 1.31-1.24 (4H, m), 0.98-0.95 (2H, m)

ESI MS (m / e) = 572 [M + 1]

Example 9. N -(2-methoxyethyl)- N -Methyl-1-[(4-methyl-1- {2- [1- (3-methyl-2-butenyl) -4-piperidinyl] ethyl} -1 H -Imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

162 mg (0.32 mmol) of the compound obtained in Preparation Example 12 were dissolved in 20 ml of dichloromethane, and 0.095 ml (0.54 mmol) of N, N-diisopropylamine was added and cooled to 0 ^° C. 0.075 ml (0.38 mmol) of 3,3-dimethylacryloyl chloride was added to the reaction solution, and the mixture was stirred at room temperature for 20 minutes. After completion of the reaction, the reaction mixture was concentrated and separated by column chromatography (eluent; 10% methanol / dichloromethane) to obtain 145 mg (0.24 mmol, yield; 76%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.10 (1H, d), 7.84 (1H, d), 7.77 (1H, d), 7.52 (1H, s), 7.45-7.40 (3H, m), 7.30 (1H, d), 7.06 (1H, s), 6.75 (1H, s), 5.70 (1H, s), 5.08 (2H, s), 4.18 (2H, t), 3.31 (3H, s), 3.05-3.01 (7H, m), 2.84 (2H , t), 1.82 (3H, s), 1.80 (3H, s), 1.65-1.55 (7H, m), 1.31-1.24 (4H, m), 0.98-0.95 (2H, m)

ESI MS (m / e) = 596 [M + 1]

Preparation Example 13 Benzyl 4-[(5-{[3-{[(2-methoxyethyl) (methyl) amino] carbonyl} -4- (1-naphthyl) -1 H -Pyrrole-1-yl] methyl} -4-methyl-1 H -Imidazol-1-yl) methyl] -1-piperidinecarboxylate

6.3 g (15.7 mmol) of the compound obtained in Preparation Example 10 were dissolved in 150 ml of N, N-dimethylformamide, and 690 mg (17.2 mmol) of sodium hydride were added and stirred for 10 minutes. The same procedure as the procedure for synthesizing the compound of Preparation Example 1, except for using 2- (4-piperidinyl) -1-methanol in place of 2- (4-piperidinyl) -1-ethanol in the reaction solution. 6.15 g (18.8 mmol) of benzyl 4-{[(methylsulfonyl) oxy] methyl} -1-piperidinecarboxylate is added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, 20 ml of water is added and concentrated. Add 200 ml of water, extract 150 ml twice with ethyl acetate and concentrate again. Separation by column chromatography (eluent; 5% methanol / dichloromethane) gave 4.35 g (6.87 mmol, yield; 44%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.08 (1H, d), 7.81 (1H, d), 7.74 (1H, d), 7.47 (1H, s), 7.45-7.42 (3H, m), 7.30 (1H, d), 7.15-7.12 ( 5H, m), 7.01 (1H, s), 6.78 (1H, s), 5.21 (2H, s), 5.13 (2H, s), 3.71 (2H, d), 3.08-3.00 (6H, m), 2.54 (2H, t), 2.42-2.39 (2H, m), 2.12-2.07 (7H, m), 1.54-1.50 (2H, m), 1.42-1.39 (1H, m), 1.24-1.17 (2H, m)

ESI MS (m / e) = 634 [M + 1]

Preparation Example 14. N -(2-methoxyethyl)- N -Methyl-1-{[4-methyl-1- (4-piperidinylmethyl) -1 H -Imidazol-5-yl] methyl} -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

4.32 g (6.82 mmol) of the compound obtained in Preparation Example 13 were reacted in the same manner as in Preparation Example 6, to obtain 3.25 g (6.51 mmol, Yield; 95%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.07 (1H, d), 7.82 (1H, d), 7.75 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.02 (1H, s), 6.77 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12 -2.07 (7H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-1.17 (2H, m)

ESI MS (m / e) = 500 [M + 1]

Example 10. N -(2-methoxyethyl)- N -Methyl-1-({4-methyl-1-[(1-propyl-4-piperidinyl) methyl] -1 H -Imidazol-5-yl} methyl) -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

95 mg (0.19 mmol) of the compound obtained in Preparation Example 14 and 0.055 ml (0.76 mmol) of propionaldehyde were reacted by the method of Example 1 to obtain 82 mg (0.15 mmol, yield; 80%) of the target compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.03 (1H, d), 7.80 (1H, d), 7.71 (1H, d), 7.45 (1H, s), 7.41-7.37 (3H, m), 7.30 (1H, d), 7.02 (1H, s), 6.75 (1H, s), 5.12 (2H, s), 3.71 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12 -2.05 (9H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-1.17 (7H, m)

ESI MS (m / e) = 542 [M + 1]

Example 11. 1-({1-[(1-isopentyl-4-piperidinyl) methyl] -4-methyl-1 H Imidazol-5-yl} methyl)- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

105 mg (0.21 mmol) of the compound obtained in Preparation Example 14 and 72 mg (0.84 mmol) of isoamyl aldehyde were reacted by the method of Example 1 to obtain 74 mg (0.13 mmol, Yield; 62%) of the target compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.07 (1H, d), 7.82 (1H, d), 7.75 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.02 (1H, s), 6.77 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.08-3.00 (6H, m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12 -2.07 (9H, m), 1.54-1.49 (4H, m), 1.42-1.38 (2H, m), 1.24-1.17 (2H, m), 1.01-0.99 (6H, m)

ESI MS (m / e) = 570 [M + 1]

Example 12. 1-[(1-{[1- (2-furylmethyl) -4-piperidinyl] methyl} -4-methyl-1 H Imidazol-5-yl) methyl]- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

101 mg (0.20 mmol) of the compound obtained in Preparation Example 14 and 0.067 ml (0.80 mmol) of perfural were reacted in the same manner as in Example 1, to obtain 65 mg (0.11 mmol, yield; 56%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.05 (1H, d), 7.81 (1H, d), 7.72 (1H, d), 7.51 (1H, s), 7.46-7.43 (3H, m), 7.31 (1H, d), 7.21 (1H, d), 7.12 (1H, d), 7.02 (1H, s), 6.92 (1H, t), 6.77 (1H, s), 5.13 (2H, s), 3.70 (2H, d), 3.08-2.97 (8H , m), 2.55 (2H, t), 2.43-2.40 (2H, m), 2.12-2.07 (7H, m), 1.54-1.51 (2H, m), 1.42-1.38 (1H, m), 1.24-1.17 (2H, m)

ESI MS (m / e) = 580 [M + 1]

Example 13. 1-[(1-{[1- (cyclopropylmethyl) -4-piperidinyl] methyl} -4-methyl-1 H Imidazol-5-yl) methyl]- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

93 mg (0.19 mmol) of the compound obtained in Preparation Example 14 and 0.056 ml (0.74 mmol) of cyclopropanecarboxyaldehyde were reacted by the method of Example 1 to obtain 62 mg (0.11 mmol, yield; 59%) of the target compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.11 (1H, d), 7.87 (1H, d), 7.79 (1H, d), 7.52 (1H, s), 7.46-7.43 (3H, m), 7.37 (1H, d), 7.12 (1H, s), 6.87 (1H, s), 5.17 (2H, s), 3.72 (2H, d), 3.08-3.00 (6H, m), 2.58 (2H, t), 2.43-2.40 (2H, m), 2.12 -2.07 (9H, m), 1.54-1.51 (2H, m), 1.42-1.38 (2H, m), 1.24-1.17 (2H, m), 0.98-0.95 (4H, m)

ESI MS (m / e) = 554 [M + 1]

Example 14 1-({1-[(1-cyclohexyl-4-piperidinyl) methyl] -4-methyl-1 H Imidazol-5-yl} methyl)- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

112 mg (0.22 mmol) of the compound obtained in Preparation Example 14 and 0.093 ml (0.89 mmol) of cyclohexanone were reacted by the method of Example 1 to obtain 42 mg (0.072 mmol, yield; 33%) of the target compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.08 (1H, d), 7.85 (1H, d), 7.74 (1H, d), 7.49 (1H, s), 7.46-7.43 (3H, m), 7.32 (1H, d), 7.03 (1H, s), 6.78 (1H, s), 5.14 (2H, s), 3.71 (2H, d), 3.08-3.00 (6H, m), 2.59 (2H, t), 2.43-2.40 (2H, m), 2.12 -2.07 (8H, m), 1.54-1.51 (2H, m), 1.34-1.32 (1H, m), 1.24-1.15 (6H, m), 1.00-0.85 (6H, m)

ESI MS (m / e) = 582 [M + 1]

Preparation Example 15 Benzyl 4-hydroxy-1-piperidinecarboxylate

Dissolve 1.57 g (11.4 mmol) of 4-hydroxypiperidine in 40 mL of tetrahydrofuran, add 23 mL (22.8 mmol) of 1N aqueous sodium hydroxide solution, and then add 1.30 mL (9.12 mmol) of chlorobenzylformate for 3 hours. Stirred. 160 mL of ethyl acetate was added to the mixture, and the mixture was diluted with water, washed with 100 mL of water, 100 mL of 1N hydrochloric acid solution, and 100 mL of sodium chloride saturated solution, followed by removing water with anhydrous magnesium sulfate and distilling under reduced pressure to remove the solvent. Without further purification 2.58 g (11.0 mmol) of the title compound were obtained in a yield of 96.5%.

¹ H NMR (CDCl ₃ , ppm); δ 1.42-1.54 (br m, 2H), 1.79-1.91 (br m, 2H), 3.06-3.19 (br m, 2H), 3.79-3.99 (br m, 3H), 5.12 (s, 2H), 7.23- 7.44 (m, 5 H)

ESI MS (m / e) = 235 [M + 1]

Preparation Example 16 Benzyl 4-Amino-1-piperidinecarboxylate

2.58 g (11.0 mmol) of the compound obtained in Preparation Example 15 were dissolved in 100 mL of dichloromethane, and 1.99 mL (14.3 mmol) of triethylamine and 0.934 mL (12.1 mmol) of methanesulfonyl chloride were sequentially added at 0 ^° C. After stirring for 2 hours at room temperature, 150 mL of dichloromethane was added thereto, diluted, washed with 100 mL of water, 100 mL of 1N hydrochloric acid solution and 100 mL of saturated sodium chloride solution, water was removed with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. 2.24 g (7.15 mmol) of the obtained compound was dissolved in 70 mL of dimethylformamide, and 2.32 g (35.8 mmol) of sodium azide were added, followed by stirring at 120 ^° C. for 4 hours. After distilling off the solvent under reduced pressure, the solvent was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water and 100 mL of saturated sodium chloride solution. Water was removed with anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained compound was purified by column chromatography (n-hexane / ethyl acetate = 4/1). 1.52 g (5.84 mmol) of the obtained compound was dissolved in 50 mL of methanol, and an excess of Raney-Ni was added thereto, followed by stirring for 4 hours under hydrogen at 1 atmosphere. Raney-nickel was removed using celite, and the solvent was removed by distillation under reduced pressure. Then, 2.7 M hydrogen chloride ethylacetate solution was added to form a salt, followed by distillation under reduced pressure to remove 1.19 g (4.41 mmol) of the title compound. Obtained in a yield of 40%.

¹ H NMR (DMSO, ppm); δ) 1.42 (dq, 2H), 1.92 (br d, 2H), 2.89 (br s, 2H), 3.21 (m, 1H), 4.02 (br d, 2H), 7.30-7.41 (m, 5H), 8.19 (br s, 2H)

ESI MS (m / e) = 234 [M + 1]

Preparation 17. Benzyl 4- [5- (hydroxymethyl) -2-sulfanyl-1 H -Imidazol-1-yl] -1-piperidinecarboxylate

1.19 g (4.41 mmol) of the compound obtained in Preparation Example 16 was added to 100 mL of isopropanol, followed by stirring, followed by stirring of dihydroxyacetone dipolymer 794 mg (4.41 mmol), potassium thiocyanate 643 mg (6.62 mmol), and acetic acid 1.00 mL (17.6 mmol) in this order. After the addition, the mixture was stirred at room temperature for 48 hours. After the solvent was removed under reduced pressure distillation, 200 mL of water was added thereto, stirred for 30 minutes to form a solid, and then filtered to remove the solvent. The obtained solid material was washed with 200 mL of an ethyl acetate / diethyl ether (1/5) mixed solution to obtain 990 mg (2.85 mmol; 65%) of the title compound.

¹ H NMR (DMSO, ppm); δ) 1.68 (br d, 2H), 2.87 (br s, 2H), 3.32 (br d, 2H), 4.15 (br d, 2H), 4.35 (d, 2H), 5.10 (s, 2H), 5.27 ( t, 1H), 6.81 (s, 1H), 7.29-7.38 (m, 5H), 12.02 (s, 1H)

ESI MS (m / e) = 348 [M + 1]

Preparation Example 18 Benzyl 4- [5- (Hydroxymethyl) -1 H -Imidazol-1-yl] -1-piperidinecarboxylate

990 mg (2.85 mmol) of the compound obtained in Preparation Example 17 were dissolved in 40 mL of ethanol and heated to 55 ^° C. After adding vanadium sulfate by the amount of catalyst, 1.3% (11.4 mmol) of 30% aqueous hydrogen peroxide solution was slowly added and stirred for 2 hours. 1N sodium hydroxide (11.4 mL) was added, ethanol was removed under reduced pressure distillation, diluted with 100 mL of ethyl acetate, washed with 50 mL of water and 50 mL of saturated sodium chloride solution. Water was removed with anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to obtain 513 mg (1.63 mmol) of the title compound in a yield of 57%.

¹ H NMR (DMSO, ppm); δ 1.68 (br d, 2H), 2.84 (br s, 2H), 3.21 (br d, 2H), 4.15 (br d, 2H), 4.35 (d, 2H), 5.50 (s, 2H), 5.27 (t , 1H), 7.12 (s, 1H), 7.29-7.38 (m, 5H), 7.57 (s, 1H)

ESI MS (m / e) = 316 [M + 1]

Preparation Example 19 Benzyl 4- (5-{[3-{[(2-methoxyethyl) (methyl) amino] carbonyl} -4- (1-naphthyl) -1 H -Pyrrole-1-yl] methyl} -1 H -Imidazol-1-yl) -1-piperidinecarboxylate

513 mg (1.63 mmol) of the compound obtained in Preparation Example 18 were dissolved in dichloromethane, and 0.24 mL (3.26 mmol) of thionyl chloride was added at room temperature, followed by stirring for 2 hours. The solvent was distilled off under reduced pressure to obtain 603 mg (1.63 mmol) of the product. N- (2-methoxyethyl) -N-methyl-4- (1-naphthyl) -1H-pyrrole-3-carboxamide obtained by the method given in Preparation Example 1 and Preparation Example 2 of Korean Patent KR99 / 001294 Dissolve 400 mg (1.30 mmol) in 25 mL of N, N-dimethylformamide, add 1.55 mg (24%, 3.90 mmol) of sodium hydride, and after 10 minutes, add 603 mg (1.63 mmol) of the previously obtained product and stir at room temperature for 3 hours. It was. The residual sodium hydride was removed with water and the solvent was removed under reduced pressure distillation. Dilute with 150 mL of ethyl acetate, wash with 100 mL of water and 100 mL of saturated aqueous sodium chloride solution, remove water with anhydrous magnesium sulfate, and remove the solvent by distillation under reduced pressure. The obtained compound was purified by column chromatography (dichloromethane / methanol = 98/2) to give 610 mg (1.01 mmol) of the title compound in a yield of 62.0%.

¹ H NMR (CDCl ₃ , ppm); δ) 1.42-1.67 (br m, 7H), 2.39 (br s, 1H), 2.51-2.80 (br m, 3H), 2.91-3.11 (br m, 4H), 3.30 (br s, 1H), 3.83 ( m, 1H), 4.32 (br s, 2H), 5.12 (s, 2H), 5.16 (s, 2H) 6.72 (d, 1H), 7.11 (br s, 1H), 7.18 (s, 1H), 7.28- 7.48 (m, 9H), 7.58 (s, 1H), 7.77 (d, 1H), 7.84 (d, 1H), 7.98 (d, 1H)

ESI MS (m / e) = 606 [M + 1]

Preparation Example 20 N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1-{[1- (4-piperidinyl) -1 H -Imidazol-5-yl] methyl} -1 H -Pyrrole-3-carboxamide

605 mg (1.0 mmol) of the compound obtained in Preparation Example 19 were reacted by the method of Preparation Example 6, to obtain 460 mg (0.98 mmol, yield; 98%) of the target compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.00 (1H, d), 7.82 (1H, d), 7.78 (1H, d), 7.54 (1H, s), 7.46-7.38 (3H, m), 7.30 (1H, d), 7.17 (1H, s), 7.09 (1H, s), 6.72 (1H, s), 5.15 (2H, s), 4.08-4.02 (1H, m), 3.08-2.97 (7H, m), 2.40-2.32 (7H, m) , 1.82-1.67 (4H, m)

ESI MS (m / e) = 472 [M + 1]

Example 15. 1-({1- [1- (cyclopropylmethyl) -4-piperidinyl] -1 H Imidazol-5-yl} methyl)- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

78 mg (0.17 mmol) of the compound obtained in Preparation Example 20 were reacted in the same manner as in Example 4, to obtain 63 mg (0.12 mmol, yield; 71%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.01 (1H, d), 7.83 (1H, d), 7.79 (1H, d), 7.55 (1H, s), 7.46-7.38 (3H, m), 7.30 (1H, d), 7.16 (1H, s), 7.09 (1H, s), 6.72 (1H, s), 5.15 (2H, s), 4.08-4.02 (1H, m), 3.08-2.97 (9H, m), 2.40-2.32 (8H, m) , 1.82-1.67 (4H, m), 1.01-0.92 (4H, m)

ESI MS (m / e) = 526 [M + 1]

Example 16. 1-({1- [1- (cyclohexylmethyl) -4-piperidinyl] -1 H Imidazol-5-yl} methyl)- N -(2-methoxyethyl)- N -Methyl-4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

65 mg (0.14 mmol) of the compound obtained in Preparation Example 20 were reacted by the method of Example 1 to obtain 48 mg (0.085 mmol, yield; 60%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 7.98 (1H, d), 7.80 (1H, d), 7.76 (1H, d), 7.52 (1H, s), 7.44-7.38 (3H, m), 7.31 (1H, d), 7.15 (1H, s), 7.07 (1H, s), 6.71 (1H, s), 5.13 (2H, s), 4.08-4.02 (1H, m), 3.08-2.97 (9H, m), 2.40-2.32 (8H, m) , 1.82-1.67 (4H, m), 1.30-1.21 (4H, m), 1.05-0.89 (6H, m)

ESI MS (m / e) = 568 [M + 1]

Example 17. N -(2-methoxyethyl)- N -Methyl-1-[(1- {1- [2- (4-morpholinyl) acetyl] -4-piperidinyl} -1 H -Imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

101 mg (0.21 mmol) of the compound obtained in Preparation Example 20 are dissolved in 5 ml of dichloromethane, 0.060 ml (0.43 mmol) of triethylamine is added, and the mixture is cooled to 0 ^° C. Add 0.022 ml (0.25 mmol) of bromoacetyl bromide and concentrate after 20 min stirring at room temperature. Dissolve with 5 ml of N, N-dimethylformamide, add 0.073 ml (0.84 mmol) of morpholine and stir at 80 ^° C for 2 hours. After completion of the reaction, the reaction mixture was concentrated and separated by column chromatography (eluent; 20% methanol / dichloromethane) to obtain 54 mg (0.090 mmol, yield; 43%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.01 (1H, d), 7.84 (1H, d), 7.77 (1H, d), 7.55 (1H, s), 7.46-7.39 (3H, m), 7.31 (1H, d), 7.18 (1H, s), 7.10 (1H, s), 6.73 (1H, s), 5.17 (2H, s), 4.08-4.02 (1H, m), 3.30 (2H, s), 3.08-2.97 (7H, m), 2.68 -2.55 (8H, m), 2.40-2.32 (7H, m), 1.82-1.67 (4H, m)

ESI MS (m / e) = 599 [M + 1]

Example 18. N -(2-methoxyethyl)- N -Methyl-1-[(1- {2- [1- (3-methyl-2-butenoyl) -4-piperidinyl] ethyl} -1 H -Imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

After dissolving 130 mg (0.26 mmol) of the compound obtained in Preparation Example 6 in 5 ml of dichloromethane, 0.054 ml (0.39 mmol) of triethylamine was added thereto, and 0.035 ml (0.31 mmol) of 3,3-dimethylacryloyl chloride was added thereto for 30 minutes at room temperature. Stirred. Concentrate, dissolve with 30 ml of ethyl acetate and wash twice with 20 ml of water. Concentrated again and separated by tube chromatography (eluent; ethyl acetate: normalhexane = 2: 1) to give 128 mg (0.22 mmol, yield; 85%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.05 (1H, d), 7.82 (1H, d), 7.75 (1H, d), 7.59 (1H, s), 7.47-7.37 (3H, m), 7.31 (1H, d), 7.18 (1H, s), 7.07 (1H, s), 6.72 (1H, s), 5.69 (1H, s), 5.12 (2H, s), 4.60-4.58 (1H, m), 3.84-3.82 (3H, m), 3.32 -2.72 (9H, m), 2.45-2.41 (3H, m), 1.83 (3H, s), 1.79 (3H, s), 1.62-1.55 (2H, m), 1.45-1.32 (3H, m), 1.06 -0.97 (2H, m)

ESI MS (m / e) = 582 [M + 1]

Example 19. N -(2-methoxyethyl)- N -Methyl-1-[(1- {2- [1- (4-morpholinylcarbonyl) -4-piperidinyl] ethyl} -1 H -Imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

240 mg (0.48 mmol) of the compound obtained in Preparation Example 6 was dissolved in 10 ml of dichloromethane, and 0.10 ml (0.72 mmol) of triethylamine was added thereto and cooled to 0 ^° C. Triphosgene 142 mg (0.48 mmol) is added and stirred for 30 minutes. Add 0.12 ml (1.44 mmol) of morpholine, raise the temperature to room temperature and stir for 30 minutes. Concentrate, add 50 ml of ethyl acetate, and wash twice with 30 ml of water. Concentration and separation by column chromatography (eluent; 10% methanol / ditlomethane) gave 159 mg (0.26 mmol, yield; 54%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.07 (1H, d), 7.82 (1H, d), 7.75 (1H, d), 7.57 (1H, s), 7.42-7.37 (3H, m), 7.31 (1H, d), 7.18 (1H, s), 7.07 (1H, s), 6.72 (1H, s), 5.12 (2H, s), 3.84 (2H, t), 3.62-3.60 (6H, m), 3.31-2.98 (9H, m), 2.67 -2.64 (3H, m), 2.41-2.39 (2H, m), 2.06-2.01 (2H, m), 1.59-1.56 (2H, m), 1.50-1.46 (2H, m), 1.40-1.36 (1H, m), 1.12-1.07 (2H, m)

ESI MS (m / e) = 613 [M + 1]

Example 20. N -(2-methoxyethyl)- N -Methyl-1-[(1-{[1- (3-methyl-2-butenyl) -4-piperidinyl] methyl} -1 H -Imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -Pyrrole-3-carboxamide

After dissolving 120 mg (0.25 mmol) of the compound obtained in Preparation Example 7 in 5 ml of dichloromethane, 0.051 ml (0.37 mmol) of triethylamine was added thereto, and 0.033 ml (0.30 mmol) of 3,3-dimethylacryloyl chloride was added thereto for 30 minutes at room temperature. Stirred. Concentrate, dissolve with 30 ml of ethyl acetate and wash twice with 20 ml of water. Concentrated again and separated by column chromatography (eluent; ethyl acetate: normal hexane = 2: 1) to give 115 mg (0.20 mmol, yield; 81%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ) 8.09 (1H, d), 7.82 (1H, d), 7.75 (1H, d), 7.50 (1H, s), 7.42-7.31 (3H, m), 7.27 (1H, d), 7.23 (1H, s), 7.06 (1H, s), 6.73 (1H, s), 5.70 (1H, s), 5.12 (2H, s), 4.60-4.58 (1H, m), 3.91-3.88 (1H, m), 3.70 -3.67 (2H, m), 3.32-2.72 (9H, m), 2.45-2.41 (3H, m), 1.83 (3H, s), 1.79 (3H, s), 1.54-1.51 (2H, m), 1.35 -1.32 (1H, m), 1.06-0.97 (2H, m)

ESI MS (m / e) = 568 [M + 1]

Experimental Example 1: Analysis of Ras farnesyl transferase inhibitory activity

In this experiment, the improved method of Pompiano et al. (Pompliano et al., Biochemistry 31, 3800, 1992) was used. In other words, Ras farnesyl transferase prepared by genetic recombination technology was used, and H-Ras (H-Ras-CVLS) as a substrate and H- which substituted the polybasic lysine domain present at the carboxy terminus of K-Ras. The binding protein with Ras (see Korean Patent Application No. 97-14409) was purified and used according to the previously reported method (Chung et al., Bichimica et Biophysica Acta 1129, 278, 1992).

Enzymatic reactions were carried out in 50 μl of 50 mM sodium hippies buffer containing 25 mM potassium chloride, 2.5 mM magnesium chloride, 10 mM Diti (DTT) and 50 μM zinc chloride, and 2-4 μM Ras substrate protein (4 μM for H-Ras). , K-Ras 2 μM), tritium-panesyl pyrophosphate 0.1 μM and panesyl transferase 5 nM were used. Panesyl transferase was added and the reaction was continued for 30 minutes at 37 ° C., and then 1 mL of ethanol solution containing 1M hydrochloric acid was added to stop the reaction. The resulting precipitate was adsorbed onto a GF / B filter using a hopper harvester (hopper #FH 225V) for filter binding, washed with ethanol, and the radioactivity of the dried filter was measured using an LKB beta counter. The enzyme titer was measured in a substrate unsaturated state in which the concentration of Ras substrate protein and panesyl enzyme showed a quantitative titer relationship, and the compound synthesized according to the present invention was dissolved in dimethyl sulfoxide (DMSO) solvent to obtain 5 The enzyme inhibition was assessed by addition within%. The enzyme inhibitory activity was expressed as a percentage of the amount of farnesyl introduced in the presence of the test compound relative to the amount of farnesyl introduced into the Ras substrate protein in the absence of the test compound, and the concentration that inhibited the enzyme activity of 50% was determined by IC ₅₀ of each test compound. Determined.

Experimental Example 2: Analysis of Cell Growth Inhibition of Cancer Cell Lines

This experiment was performed based on the method developed by the National Cancer Institute's In Vitro Cell Line Screening Project (http://dtp.nci.nih.gov/branches/ btb / ivclsp.html? pagestyle = pp).

Human cancer cell lines were grown in RPMI1640 medium containing 5% fetal bovine serum and antibiotics. The cancer cell lines used are EJ cancer cell lines (bladder cancer) with H-Ras mutations and HCT116 cell lines (colon cancer) with K-Ras mutations. Cancer cells were dispensed into 96-well microplates at a cell concentration of 3000 cells / 100 μL medium and allowed to grow at 37 ^° C., 5% carbon dioxide for 24 hours prior to treatment with the synthesized compounds. After 24 hours, 1 plate for each cell line fixed cells in 1.3% formaldehyde solvent to use the cell number at the time of compound treatment as a reference. The compound synthesized according to the present invention was dissolved in dimethyl sulfoxide (DMSO) solvent, diluted sequentially, and finally added to 0.1% of the total medium. Only the dimethyl sulfoxide solvent was treated as a control. After treatment with the compounds, the cancer cells were allowed to grow at 37 ^° C., 5% carbon dioxide for 48 hours. After 48 hours, the cancer cells were treated with formaldehyde solvent and left at room temperature for a minimum of 16 hours. The supernatant of each plate was discarded, washed five times with running water, and completely dried in air. Sulfurhodamine B (SRB) staining solution of 0.4% in 1% acetic acid was added to each well 50 ul and left at room temperature for 2 hours. After dyeing, washing 5 times with 1% acetic acid solution to remove undyed dye and drying in air. The dye stained in the cancer cell line was dissolved in 10 mM Tris buffer and the absorbance was measured at 530 nm and 650 nm and the difference was obtained. Each condition was tested in three sets. The percentage of cancer cell growth inhibition at each compound concentration was calculated as follows.

Growth inhibition% = (Ti-Tz) / (C-Tz) δ100

Ti = absorbance obtained from cell growth at each compound treatment concentration

Tz = absorbance obtained from cell growth immediately before compound treatment

C = absorbance obtained from cell growth in the control group

The concentration that induces 50% growth inhibition of cancer cells was determined by the GI ₅₀ of each test compound. Table 2 shows the inhibitory effect of the representative compounds according to the present invention.

Example H-Ras IC ₅₀ (nM) EJ GI ₅₀ (μM) K-Ras IC ₅₀ (nM) HCT116 GI ₅₀ (μM) number One 1.5 1.0 12 9.0 2 2.5 4.0 20 2.0 3 1.5 3.0 12 8.0 4 2.2 5.0 9.0 40 5 5.0 1.0 20 9.0 6 4.2 9.0 20 40 7 25 0.4 45 7.0 8 10 7.0 80 7.0 9 3.2 5.0 15 9.0 10 2.5 2.2 12 8.0 11 3.5 1.0 2.5 4.0 12 2.0 1.0 8.0 3.0 13 4.5 5.0 22 16 14 8.0 5.0 22 13 15 15 2.0 30 2.0 16 9.0 1.6 40 1.4 17 0.9 6.0 8.0 16.0 18 << 1.0 0.4 9.0 20 19 1.5 5.0 8.0 55 20 << 1.0 <0.3 5.0 26

Experimental Example 3: Determination of Inhibitory Activity on Cytochrome P450 (CYP 3A4) Enzyme

This experiment uses the nifedipine oxidation reaction, one of the enzyme reactions selectively caused by the cytochrome P450 3A4 enzyme, reported in many papers (Drug Metabolism and Disposition, 25 (2) 168-174, 1997). The inhibitory activity of these compounds against cytochrome P450 3A4 enzyme was evaluated. The purpose of this evaluation is to describe the cytochrome P450 3A4 enzyme, which is a representative drug metabolizing enzyme present in humans, but is involved in drug metabolism of about 50% of existing drugs. Therefore, drugs with high inhibitory ability against this enzyme may cause pharmacokinetic changes of the drug when co-administered with other drugs, and furthermore, may cause unwanted toxicity or interaction with weak enzyme chambers.

Cytochrome P450 3A4 enzymatic reaction was performed in 100 mM potassium phosphate buffer (pH 7.4), 5 mM magnesium chloride (MgCl ₂ ), 3 mM glucose-6-phosphate, 1 mM beta nicotinamide adenine di 1 mg of microsomes containing this enzyme in nucleotide phosphate (β-Nicotnamide Adenine Dinucleotide Phosphate), 0.2 unit / ml glucose-6-phosphate-dehydrogenase and human liver fraction The reaction mixture was added to / ml at 37 ° C for 10 minutes, and then added to 50 μM of nifedipine, which is a substrate of the reaction enzyme, followed by another 10 minutes. At this time, in order to determine the inhibitory capacity (IC ₅₀ ) for the enzymatic reaction of each compound (No. 1-18), each compound was reacted with nifedipine to have 6-7 concentrations within a concentration range of 0.02-50 μM. The reaction was stopped by adding a volume of methanol / 10% zinc sulfide (ZnSO ₄ ) (2: 1) mixture that was three times the volume of the reaction mixture, mixed, centrifuged at 13,000 rpm for 10 minutes, and then the supernatant was subjected to high performance liquid chromatography. (High Pressure Liquid Chromatography) method. At this time, the assay quantifies the nifedipine-oxide body produced by the enzyme and the remaining nifedipine, and the enzyme inhibitory ability is determined by the percentage of nifedipine-oxide body produced in the absence of the test compound in the presence of compounds of each concentration. From the concentration-inhibition rate curve obtained by calculating how much oxide production was inhibited, a value (IC ₅₀ ) of 50% inhibition was obtained, and the enzymatic reaction inhibitory ability of each compound was evaluated and the results are shown in Table 3. On the other hand, using the compound of Example 1 and Example 3 of WO9928315 filed by the company as a compound for comparing the CYP3A4 enzyme inhibitory ability, the experimental results of Comparative Example 1 and Comparative Example 2 are shown in Table 3.

Experimental Example 4: Analysis of Cell Growth Inhibition of Cancer Cell Line Using Soft Agar

Human cancer cells to be used in the soft agar assay are prepared by culturing in DMEM (DMEM, Gibco-BRL) medium containing 10% FBS (FBS, Gibco). Mix 5 ml of 1% agar, 5 ml of 2-fold concentrated DMEM medium (2x DMEM / 20% FBS), and 50 µl of 200-fold concentrated test compound. Dispense 3 ml of each well of a 6-well plate for 1 hour at room temperature. Harden to make 0.5% bottom agar. Next, a 2-fold concentrated medium DMEM (2x DMEM / 20% FBS) 1% agar into the 1.5㎖ the 1.5㎖, 200 times a test compound 23㎕ concentration in the liquid phase after cooling to 30 ℃ 2 ~ 5 x10 ³ cells / ㎖ Mix 1.5 ml of human cancer cells at the concentration. Dispense 1.2 ml each on top of the hardened lower agar to make 0.33% top agar. Incubate for 2 weeks in a CO ₂ incubator and count the colonies formed under a microscope. A growth curve of log ₁₀ of the number of colonies per compound concentration is drawn from which the GI ₅₀ value is calculated.

Claims (9)

Compounds of Formula 1 below, pharmaceutically acceptable salts, hydrates, solvates and isomers thereof: [Formula 1] Where n represents 0, 1 or 2, X represents C or N, R 1 represents hydrogen or methyl, R2 represents lower alkyl, phenyl unsubstituted or substituted by halogen, or naphthyl, R3 represents any one selected from the group of structural formulas From here, Y represents O, S, S = O or SO ₂ R5 and R6 each independently represent hydrogen, hydroxy, lower alkyl or lower alkoxy, R 4 represents lower alkyl, alkoxyalkyl, cycloalkyl, lower alkyl substituted by cycloalkyl or lower alkyl substituted by heteroaromatic ring, or a group of the following structural formula, Here, R 7 represents lower alkyl, alkoxyalkyl, morpholinyl group, lower alkyl substituted with morpholinyl group, lower alkyl or alkenyl group substituted with N-methylpiperazinyl group. The compound of claim 1, wherein the CYP 3A4 enzyme inhibitory capacity (IC 50) is at least 1.0 μM. The compound of claim 1, wherein n represents 1 or 2, X represents C, R 1 is H or a methyl group, R 2 is naphthyl, and R 3 is Wherein R 5 and R 6 are each independently lower alkyl, Y is O, and R 4 is lower alkyl substituted with cycloalkyl, (Wherein R7 is morpholinyl group, lower alkyl substituted with N-methylpiperazinyl group, or lower alkyl substituted with morpholinyl group), alkoxyalkyl, lower alkyl, lower alkyl substituted with heteroaromatic ring, or al A compound which shows a kenyl group. The method of claim 1, 1 - [(1- {2- [1- (cyclohexylmethyl) -4-piperidinyl] ethyl} -1 H-imidazol-5-yl) methyl] - N - (2-methoxyethyl) - N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (1); N- (2-methoxyethyl) -1-[(1-{[1- (2-methoxyethyl) -4-piperidinyl] methyl} -1 H -imidazol-5-yl) methyl]- N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (2); N- (2-methoxyethyl) -N -methyl-1-{[1-({1- [2- (4-methyl-1-piperazinyl) acetyl] -4-piperidinyl} methyl)- 1 H -imidazol-5-yl] methyl} -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (3); 1 - [(1 - {[1- (cyclopropylmethyl) -4-piperidinyl] methyl} -1 H-imidazol-5-yl) methyl] - N - (2- methoxyethyl) - N - Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (4); 1 - [(1 - {[1- (cyclohexylmethyl) -4-piperidinyl] methyl} -1 H-imidazol-5-yl) methyl] - N - (2- methoxyethyl) - N - Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (5); 1 - ({1 - [(1-cyclohexyl 4-piperidinyl) methyl] -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N-methyl-4 -(1-naphthyl) -1 H -pyrrole-3-carboxamide (6); 1 - [(1- {2- [1- (cyclohexyl) -4-piperidinyl] ethyl} -4-methyl -1 H-imidazol-5-yl) methyl] - N - (2-methoxy Methoxyethyl) -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (7); N- (2-methoxyethyl) -1-[(1- {2- [1- (2-methoxyethyl) -4-piperidinyl] ethyl} -4-methyl-1 H -imidazole-5 -Yl) methyl] -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (8); N- (2-methoxyethyl) -N -methyl-1-[(4-methyl-1- {2- [1- (3-methyl-2-butenyl) -4-piperidinyl] ethyl}- 1 H -imidazol-5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (9); N- (2-methoxyethyl) -N -methyl-1-({4-methyl-1-[(1-propyl-4-piperidinyl) methyl] -1 H -imidazol-5-yl} methyl ) -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (10); 1 - ({1 - [(1-isopentyl-4-piperidinyl) methyl] -4-methyl -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N -Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (11); 1 - [(1 - {[1- (2-furyl) -4-piperidinyl] methyl} -4-methyl -1 H-imidazol-5-yl) methyl] - N - (2-methoxy Ethyl) -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (12); 1 - [(1 - {[1- (cyclopropylmethyl) -4-piperidinyl] methyl} -4-methyl -1 H-imidazol-5-yl) methyl] - N - (2- methoxyethyl ) -N -methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (13); 1 - ({1 - [(1-cyclohexyl-4-piperidinyl) methyl] -4-methyl -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N -Methyl-4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (14); 1 - ({1- [1- (cyclopropylmethyl) -4-piperidinyl] -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N-methyl-4 -(1-naphthyl) -1 H -pyrrole-3-carboxamide (15); 1 - ({1- [1- (cyclohexyl) -4-piperidinyl] -1 H-imidazol-5-yl} methyl) - N - (2- methoxyethyl) - N-methyl-4 -(1-naphthyl) -1 H -pyrrole-3-carboxamide (16); N- (2-methoxyethyl) -N -methyl-1-[(1- {1- [2- (4-morpholinyl) acetyl] -4-piperidinyl} -1 H -imidazole-5 -Yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (17); N- (2-methoxyethyl) -N -methyl-1-[(1- {2- [1- (3-methyl-2-butenyl) -4-piperidinyl] ethyl} -1 H -already Dazol-5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (18); N- (2-methoxyethyl) -N -methyl-1-[(1- {2- [1- (4-morpholinylcarbonyl) -4-piperidinyl] ethyl} -1 H -imidazole -5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (19); And N- (2-methoxyethyl) -N -methyl-1-[(1-{[1- (3-methyl-2-butenyl) -4-piperidinyl] methyl} -1 H -imidazole- 5-yl) methyl] -4- (1-naphthyl) -1 H -pyrrole-3-carboxamide (20). Or reacting a compound of formula (2) with a) L-R4, wherein L represents halogen and R4 is as defined in claim 1, or b) CHO-R4 (in the presence of sodium triacetoxy borohydride) Wherein R4 is as defined in claim 1) or a ketone compound, or c) LC (O) (CH ₂ ) _n -L where L represents a halogen and n represents an integer from 1 to 5 And a substitution reaction with morpholine or piperazine to prepare a compound of formula 1 as defined in claim 1 [Formula 2] Wherein R 1, R 2 and R 3 are as defined in claim 1. An anticancer composition comprising a compound of formula (1) as defined in claim 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. An anti-vascular constriction re-exposure composition containing a compound of formula (1) as defined in claim 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. An antihyperlipidemic composition comprising a compound of formula (1) as defined in claim 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier. An antiviral composition comprising a compound of formula (1) as defined in claim 1, a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient together with a pharmaceutically acceptable carrier.