KR19990066679A - Panesyl transferase inhibitor having a pyrrole structure and its preparation method - Google Patents

Abstract

The present invention relates to a compound of the formula (1) including a pyrrole structure and capable of inhibiting farnesyl transferase, a method for preparing the same, and an intermediate useful for preparing the compound.

Wherein A, n ₁ , B, C, D and X are as defined in the specification.

Description

Panesyl transferase inhibitor having a pyrrole structure and its preparation method

The present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof, which comprises a pyrrole structure and is capable of inhibiting farnesyl transferase:

Formula 1

In the above formula

n ₁ represents an integer of 1 to 4,

X represents O or S,

A is hydrogen; Straight or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted by C ₃ -C ₇ cycloalkyl or lower alkoxy; Or benzyl unsubstituted or substituted by halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy or lower alkyl,

B is hydrogen; Or lower alkyl unsubstituted or substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,

C represents lower alkyl unsubstituted or substituted by aryl; Any one selected from the group of structural formulas

, , ,

,

Wherein R ₁ and R ₂ each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy,

D represents an amino acid residue or lower alkyl ester of an amino acid residue; Any one selected from the group of structural formulas

, , , ,

,

From here

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Cyano; Lower alkyl; Lower alkoxy; Alkoxyalkyl; Alkylthio; Alkylsulfonyl; Alkylthioalkyl; Alkylthioalkyloxy; Aryl; Or oxy, thio, sulfonyl or lower alkyl substituted by aryl,

Y represents O, S, SO ₂ , C═O, C═S, or CH ₂ or NH unsubstituted or substituted by lower alkyl or hydroxy,

n ₂ represents an integer of 1 to 3,

R ₅ and R ₆ are each independently hydrogen; Aryl; Lower alkyl unsubstituted or substituted by aryl or cyanoaryl; or Wherein n ₃ represents an integer of 2 to 4, Z represents O, S or SO ₂ , and R ₇ represents hydrogen or lower alkyl.

In particular, the compound according to the present invention not only has a specific structure different from the farnesyltransferase inhibitors known to date, but also contains no thiol groups at all.

The present invention also includes a method for preparing the compound of Formula 1, and also includes an intermediate that can be usefully used in the preparation of the compound. Accordingly, these preparation methods and intermediate compounds are also subject of the present invention.

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 protein is produced by mammalian cells by 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 closely related to pancreatic cancer, bladder cancer, lung cancer and skin cancer (see Bos, JL, Cancer Res ., 1989, 49, 4682). It has been reported to be involved in the growth of smooth muscle cells, and is thought to be closely related to atherosclerosis and diabetes mellitus (JP JP H7-112930).

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 with no 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 affinity and adheres to the cell membrane. The panesylated Ras protein is subsequently removed from the carboxy terminus by three AAX peptides removed and methylated so that the panesyl group is formed in the lipid layer or in the cell membrane. It is known to facilitate binding with other 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 developed farnesyl transferase inhibitors include 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 Variant (James, GL et al. , Science, 260, 1937, 1993), which was used as a turn simulation structure of the inhibitor, and inhibitors based on tricyclic organic compounds from the peptide structure (Bishop WR et al. , J. Biol. Chem., 270, 30611, 1995). In addition, since the mechanism by which Panesyl transferase transfers a prenyl group is an electrophilic displacement reaction, it is considered that a positive load is required in the transition state of the reaction, thereby linking the positive load of the transition state to the prenyl group. New types of inhibitors have been proposed (Poulter, CD et al., J. Am. Chem. Soc ., 118, 8761, 1996).

However, K-Ras activation is a major cause in many cases of human cancer, and most prenyl transferase inhibitors developed to date activate K-Ras. Therefore, the inhibition of growth of cells transformed by K-Ras is lower than the growth inhibition of cells transformed by H-Ras and N-Ras, so the study of novel inhibitors that can effectively inhibit K-Ras activity Is getting attention.

Therefore, the present inventors established a new evaluation system for evaluating the enzyme activity inhibitory ability against K-Ras substrate and the inhibitory activity of intracellular K-Ras prenylation, and utilizing the same, thereby identifying the K-Ras as well as H-Ras and N-Ras substrates. Novel compounds that inhibit misfire were synthesized and their inhibitory ability evaluated. As a result, the present inventors have found that the compound of Formula 1 meets the intended purpose of the present invention and that they can be usefully used as an anticancer agent.

Accordingly, the present invention relates to a compound of formula (1) having excellent anticancer effect, a preparation method thereof, and an intermediate that can be usefully used in the preparation of the compound.

The present invention relates to a compound of formula (I), a pharmaceutically acceptable salt or isomer thereof, which comprises a pyrrole structure and is capable of inhibiting farnesyl transferase:

Formula 1

In the above formula

n ₁ represents an integer of 1 to 4,

X represents O or S,

A is hydrogen; Straight or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted by C ₃ -C ₇ cycloalkyl or lower alkoxy; Or benzyl unsubstituted or substituted by halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy or lower alkyl,

B is hydrogen; Or lower alkyl unsubstituted or substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl,

C represents lower alkyl unsubstituted or substituted by aryl; Any one selected from the group of structural formulas

, , ,

,

Wherein R ₁ and R ₂ each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy,

D represents an amino acid residue or lower alkyl ester of an amino acid residue; Any one selected from the group of structural formulas

, , , ,

,

From here

R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Cyano; Lower alkyl; Lower alkoxy; Alkoxyalkyl; Alkylthio; Alkylsulfonyl; Alkylthioalkyl; Alkylthioalkyloxy; Aryl; Or oxy, thio, sulfonyl or lower alkyl substituted by aryl,

Y represents O, S, SO ₂ , C═O, C═S, or CH ₂ or NH unsubstituted or substituted by lower alkyl or hydroxy,

n ₂ represents an integer of 1 to 3,

R ₅ and R ₆ are each independently hydrogen; Aryl; Lower alkyl unsubstituted or substituted by aryl or cyanoaryl; or Wherein n ₃ represents an integer of 2 to 4, Z represents O, S or SO ₂ , and R ₇ represents hydrogen or lower alkyl.

In the substituent definition for the compound of Formula 1, the term "lower alkyl" means straight or branched chain alkyl having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, isobutyl, t-butyl and the like.

The compounds according to the invention may have asymmetric carbon centers and therefore may exist in R or S isomers, racemates, or mixtures thereof. Accordingly, the scope of the present invention includes each of these isomers and mixtures thereof.

Among the compounds of Formula 1, which show excellent anticancer effects, preferred compounds are

n ₁ represents an integer of 1 to 3,

X represents O or S,

A represents straight or branched C ₁ -C ₁₀ alkyl, 4-brobobenzyl, or 4-cyanobenzyl unsubstituted or substituted by hydrogen, C ₅ -C ₆ cycloalkyl or lower alkoxy,

B represents hydrogen, lower alkyl, or benzyl,

C represents any one selected from the group of the following structural formulas,

, , ,

Wherein R ₁ and R ₂ each independently represent hydrogen or lower alkyl,

D represents a methionine or leucine residue or a lower alkylester of these amino acid residues; Any one selected from the group of structural formulas

, , , ,

From here

R ₃ and R ₄ are each independently hydrogen; halogen; Cyano; Lower alkyl; Lower alkoxy; Alkylthioalkyl; Alkylthioalkyloxy; Phenyl; Or oxy or lower alkyl substituted by phenyl,

Y represents O, S, SO ₂ , C═O, or CH ₂ or NH unsubstituted or substituted by lower alkyl or hydroxy,

n ₂ represents 1 or 2,

R ₅ and R ₆ are each independently hydrogen; Phenyl; Lower alkyl unsubstituted or substituted by phenyl or 4-cyanophenyl; Or C ₂ -C ₄ straight alkyl substituted by hydroxy or lower alkoxy.

Representative examples of the compound of formula 1 according to the present invention are as shown in Tables 1a to 1i below.

Compound number Compound structure Compound number Compound structure One 2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20

21 22 23 24 25 26 27 28 29 30

31 32 33 34 35 36 37 38 39 40

41 42 43 44 45 46 47 48 49 50

51 52 53 54 55 56 57 58 59 60

61 62 63 64 65 66 67 68 69 70

71 72 73 74 75 76 77 78 79 80

81

Compound (1) according to the present invention is (a) reacting a compound of formula (2) with a compound of formula (3) in the presence of a base in a solvent and then removing a trityl protecting group in the presence of trifluoroacetic acid To prepare a compound; (b) reacting a compound of formula 4 with a compound of formula 3 in the presence of a base in a solvent to prepare a compound of formula 1b; (c) reacting a compound of formula 5 with a compound of formula 3 in a solvent in the presence of a base and removing a trityl protecting group in the presence of trifluoroacetic acid to produce a compound of formula 6, followed by hydrogenation To prepare a compound of formula 1c; (d) hydrolyzing the compound of Formula 7 to prepare a compound of Formula 8, and then coupling the compound of Formula 9 with a compound of Formula 9 in the presence of a coupling agent to prepare a compound of Formula 1d; (e) converting a carbonyl group of a compound of formula 1e to a thiocarbonyl group in the presence of a sulfiding agent to obtain a compound of formula 1f, which is also obtained. It is an object of the invention.

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

In the above formula

A, n ₁ , B, C, D, R ₅ , R ₆ are as defined above,

A 'is the same as A, except hydrogen

Tr represents trityl.

The compounds of formula (8) used as intermediates in the preparation of the compounds of formula (1d) in the process according to the invention are themselves novel compounds, and the present invention also aims to provide intermediate compounds of formula (8).

In the above methods (a) to (e) of preparing the compound of formula 1 according to the present invention, any solvent which is inert to the reaction may be used. Preferably, dimethylformamide, dimethylacetamide, ethanol, At least one selected from water, methylene chloride, tetrahydrofuran and N-methylpyrrolidinone is used. The base may be one or more selected from sodium hydride, potassium hydroxide, potassium carbonate, potassium t-butoxide, sodium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide, and particularly preferably sodium hydride or Potassium hydroxide is used.

In the reaction between the compound of Formula 8 and compound of Formula 9, as coupling agent, carbodiimide such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) One or more selected from inorganic dehydrating agents such as silicon tetrachloride can be used in a mixed state with 1-hydroxybenzotriazole. Particular preference is given to reacting in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole hydrate.

Sulfurizing agents that can be used to prepare the compound of formula 1f from the compound of formula 1e include 2,4-bis (phenylthio) -1,3-dithia-2,4-diphosphatane-2,4-disulfide, Wesson's Reagent or P ₄ S ₁₀ , including 2,4-bis (phenylthio) -1,3-dithia-2,4-diphosphatane-2,4-disulfide. It is preferably used.

Compounds used as starting materials in the process according to the invention can be prepared according to the methods shown in Schemes 1-4.

First, the compound of Formula 2 may be prepared through a protecting group reaction and a halogenation reaction as shown in Scheme 1 below.

In the compound of Formula 4, A 'is 4-cyanobenzyl, and the compound may be synthesized through protecting group, acetylation, coupling, deprotection group and halogenation reaction as shown in Scheme 2a, wherein A' is C Compounds representing straight or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted by ₃ -C ₇ cycloalkyl or lower alkoxy, or benzyl unsubstituted or substituted by halogen, are shown in Scheme 2b below. Therefore, it can be synthesized through ring closure, desulfurization and halogenation.

In Scheme 2b

A ″ represents straight or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted by C ₃ -C ₇ cycloalkyl or lower alkoxy, or benzyl unsubstituted or substituted by halogen.

The compound of Formula 5 may be synthesized through esterification, protecting group, reduction and halogenation reaction as shown in Scheme 3 below.

In Scheme 3 above

DIBAL stands for diisobutylaluminum hydride.

Meanwhile, the compound of Formula 3 may be synthesized according to the method shown in Scheme 4a or 4b below from 1-naphthaldehydro.

In Schemes 4a and 4b

Ar represents an aromatic group such as phenyl, pyrrole, thienyl, naphthyl,

TosMIC stands for tosylmethyl isocyanide.

In addition, the compound of formula (7) can be easily prepared by appropriately combining the method shown in Scheme 4b and the method shown in Schemes 2a and 2b.

The present invention, in particular the production methods described above will be described in more detail based on the following Preparation Examples, Examples and Experimental Examples. However, these preparation examples, examples and experimental examples are only intended to help the understanding of the present invention, and the scope of the present invention in any sense is not limited thereto.

Preparation Example 1 Synthesis of 4-chloromethyl-1-trityl-1H-imidazole hydrochloride

1-1) Preparation of 4-hydroxymethyl-1-trityl-1H-imidazole

3.99 g (29.6 mmol) of hydroxymethylimidazole hydrochloride was dissolved in a mixture of 30 ml of dimethylformamide and 10 ml of triethylamine, and then 9.35 g (33.5 mmol) of triphenylmethyl chloride was added to 110 ml of dimethylformamide. The solution dissolved in was slowly added. After 2 hours, 500 ml of ice water was added to the reaction solution, and the resulting solid was obtained. This solid was recrystallized from dioxane to give 8.82 g (87% yield) of the title compound.

Melting Point: 227-229 ℃

1-2) Preparation of 4-chloromethyl-1-trityl-1H-imidazole hydrochloride

1.50 g (4.41 mmol) of the compound obtained in Preparation Example 1-1) was dissolved in 50 mL of chloroform, and then 0.94 mL (13.2 mmol) of thionyl chloride was slowly added at 0 ° C. and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure to yield 1.66 g (4.20 mmol, 95% yield) of the title compound which was used for the next reaction without purification.

Preparation Example 2 Synthesis of 4- (5-chloromethyl-1H-imidazol-1-ylmethyl) benzonitrile Hydrochloride

2-1) Preparation of (4-acetoxymethyl-1-trityl) imidazole

To 100 ml of pyridine was added 5.00 g (14.7 mmol) of the compound obtained in Preparation Example 1-1, 1.65 g (16.2 mmol) of acetic anhydride was added thereto, followed by stirring at room temperature for 24 hours. The reaction solution was distilled under reduced pressure to remove pyridine, and the residue was dissolved in 200 ml of ethyl acetate and washed with 100 ml of brine. After distilling off the organic solvent under reduced pressure, column chromatography (eluent: dichloromethane / methanol = 20/1, v / v) was carried out to obtain 5.22 g (13.7 mmol, 93% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.01 (s, 3H), 4.95 (s, 2H), 6.88 (s, 1H), 7.08 (s, 5H), 7.27 (s, 10H), 7.45 (s, 1H).

2-2) Preparation of 4- (4-acetoxymethyl-1-trityl-1H-imidazol-3-ylmethyl) benzonitrile bromide

5.00 g (13.1 mmol) of the compound obtained in Preparation Example 2-1) was dissolved in 20 ml of dichloromethane, and 2.82 g (14.4 mmol) of 4-cyanobenzylbromide was added thereto, followed by stirring at room temperature for 60 hours. The organic solvent was removed by distillation under reduced pressure and the residue was subjected to column chromatography (eluent: dichloromethane / methanol = 5/1, v / v) to give 5.31 g (9.17 mmol, 70% yield) of the title compound. .

¹ H NMR (CDCl ₃ + CD ₃ OD) δ 1.95 (s, 3H), 4.95 (s, 2H), 5.45 (s, 2H), 7.11- 7.40 (m, 18H), 7.65 (d, 2H), 8.21 (s, 1 H).

2-3) Preparation of 4- (5-acetoxymethyl-1H-imidazol-1-ylmethyl) benzonitrile

9.10 g (15.7 mmol) of the compound obtained in Preparation Example 2-2) was dissolved in 500 ml of dichloromethane, and then 6.06 ml (78.7 mmol) of trifluoroacetic acid and 12.5 ml (78.7 mmol) of triethylsilane were slowly added at 0 ° C. It was added and stirred at room temperature for 1 hour. The organic solvent was removed by distillation under reduced pressure, the pH was adjusted to 10 with a saturated aqueous K ₂ CO ₃ solution, and extracted with 300 ml of ethyl acetate. The organic solvent was removed by distillation under reduced pressure, and the residue was subjected to column chromatography using ethyl acetate as an eluent to obtain 3.60 g (14.1 mmol, 90% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.90 (s, 3H), 4.97 (s, 2H), 5.25 (s, 2H), 7.14 (d, 2H), 7.21 (d, 1H), 7.67 (s, 1H), 7.75 (d, 2 H)

2-4) Preparation of 4- (5-hydroxymethyl-1H-imidazol-1-ylmethyl) benzonitrile

4.20 g (16.5 mmol) of the compound obtained in Preparation Example 2-3) was dissolved in 200 ml of methanol, and then 4.50 g (32.9 mmol) of K ₂ CO ₃ was added thereto, followed by stirring at room temperature for 20 minutes. The organic solvent was removed by distillation under reduced pressure, extracted with 300 ml of ethyl acetate, and then subjected to column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) to give 3.19 g (15.0 mmol, 91% yield) of the title compound. ) Was obtained.

¹ H NMR (CDCl ₃ + CD ₃ OD) δ 4.28 (s, 2H), 5.18 (s, 2H), 6.84 (s, 1H), 7.12 (d, 2H), 7.42 (s, 1H), 7.55 (d , 2H)

2-5) Preparation of 4- (5-chloromethyl-1H-imidazol-1-ylmethyl) benzonitrile hydrochloride

3.00 g (14.1 mmol) of the compound obtained in Preparation Example 2-4) was dissolved in 40 mL of chloroform, and then 5.02 mL (70.5 mmol) of thionyl chloride was slowly added at 0 ° C., and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure to yield 3.50 g (13.1 mmol, yield 93%) of the title compound. This compound was used directly in the reaction without purification.

Preparation Example 3 Synthesis of 4- (3-chloro-1-propenyl) -1-trityl-1H-imidazole

3-1) Preparation of methyl 3- (1H-imidazol-4-yl) acrylate

500 mg (3.62 mmol) of 3- (1H-imidazol-4-yl) acrylic acid were added to 20 ml of methanolic HCl and stirred at room temperature for 10 hours. The solvent was removed under reduced pressure, and 30 ml of dichloromethane was added, followed by washing with saturated aqueous NaHCO ₃ solution, brine and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 510 mg (3.35 mmol, 93% yield) of the title compound. This compound was used in the next reaction without purification.

3-2) Methyl 3- (1-trityl-1H-imidazol-4-yl) acrylate

350 mg (2.30 mmol) of the compound obtained in Preparation Example 3-1) and 705 mg (2.53 mmol) of triphenylmethyl chloride were dissolved in 10 ml of dimethylformamide, and 350 µl (2.53 mmol) of triethylamine was added thereto. After 2 hours, 100 ml of ice water was added, and the resulting solid was filtered, washed with diethyl ether, hexane and dried to give 810 mg (2.05 mmol, 87% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 3.75 (s, 3H), 6.35 (d, 1H), 7.05-7.50 (m, 18H)

3-3) Preparation of 1- (1-trityl-1H-imidazol-4-yl) propen-3-ol

800 mg (2.03 mmol) of the compound obtained in Preparation Example 3-2) were added to 20 ml of anhydrous dichloromethane, cooled to −78 ° C., and 6.1 ml (1M hexane solution) of diisobutyl aluminum hydride was added thereto. The temperature was slowly raised to room temperature and 2 ml of water was added to stop the reaction. 3 ml of 1N NaOH was added, followed by 2 ml of water, followed by filtration through celite. The organic layer of the filtrate was separated, the water layer was extracted with dichloromethane, combined and dried over anhydrous magnesium sulfate. The organic solvent was removed under reduced pressure and column chromatography (eluent: dichloromethane / methanol = 20/1, v / v) was performed on the residue to give 671 mg (1.83 mmol, 90% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.25 (s, 2H), 6.45 (s, 2H), 6.78 (s, 1H), 7.10-7.50 (m, 16H)

3-4) Preparation of 4- (3-chloropropenyl) -1-trityl-1H-imidazole

650 mg (1.77 mmol) of the compound obtained in Preparation Example 3-3) were added to 10 ml of chloroform, and 135 µl (1.9 mmol) of thionyl chloride was added at 0 ° C., followed by stirring at room temperature for 2 hours. The organic solvent was removed by distillation under reduced pressure, and the residue was dissolved in 10 ml of ethyl acetate. After washing with saturated aqueous NaHCO ₃ solution, the organic solvent was distilled under reduced pressure to obtain 647 mg (1.68 mmol, yield 95%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.22 (d, 2H), 6.40-6.55 (m, 2H), 6.81 (s, 1H), 7.10-7.50 (m, 16H)

Preparation Example 4 Synthesis of 5-Chloromethyl-1-methylimidazole Hydrochloride

4-1) Preparation of 5-hydroxymethyl-1-methylimidazole

Starting with dihydroxyacetone and methylamine hydrochloride as starting materials (JMDener, LH Zhang, H. Rapoport, J. Org. Chem. , 1993, 58, 1159) in 32% yield The title compound was obtained.

¹ H NMR (CDCl ₃ ) δ 3.67 (s, 3H), 4.58 (s, 2H), 5.37 (brs, 1H), 6.76 (s, 1H), 7.32 (s, 1H)

4-2) Preparation of 5-chloromethyl-1-methylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 4-1) as a starting material, the title compound was obtained in the 95% yield in the same manner as in Preparation Example 1-2).

Preparation Example 5 Synthesis of 1- (4-bromobenzyl) -5-chloromethylimidazole hydrochloride

5-1) Preparation of 1- (4-bromobenzyl) -5-hydroxymethylimidazole

The title compound was obtained in 50% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 4-bromobenzylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ + CD ₃ OD) δ 4.46 (s, 2H), 5.26 (s, 2H), 7.00 (s, 1H), 7.07 (d, 2H), 7.50 (d, 2H), 7.65 (s , 1H)

5-2) Preparation of 1- (4-bromobenzyl) -5-chloromethylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 5-1) as a starting material, to give the title compound in 96% yield in the same manner as in Preparation Example 1-2). This compound was used directly in the next reaction without purification.

Preparation Example 6 Synthesis of 5-chloromethyl-1-isobutylimidazole hydrochloride

6-1) Preparation of 5-hydroxymethyl-1-isobutylimidazole

The title compound was obtained in a yield of 45% by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and isobutylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 0.90 (d, 6H), 1.76 (m, 1H), 3.62 (d, 2H), 4.24 (brs, 1H), 4.60 (s, 2H), 6.85 (s, 1H), 7.45 (s, 1 H)

FAB (M + H): 155

6-2) Preparation of 5-chloromethyl-1-isobutylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 6-1) as a starting material, the title compound was obtained in the same manner as in Preparation Example 1-2) in 95% yield.

Preparation Example 7 Synthesis of 5-chloromethyl-1-cyclohexylmethylimidazole hydrochloride

7-1) Preparation of 5-hydroxymethyl-1-cyclohexylmethylimidazole

The title compound was obtained in 45% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and cyclohexylmethylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 0.94 (m, 2H), 1.16 (m, 3H), 1.50-1.70 (m, 6H), 3.65 (d, 2H), 4.24 (brs, 1H), 4.60 (s, 2H ), 6.85 (s, 1 H), 7.45 (s, 1 H)

FAB (M + H): 195

7-2) Preparation of 5-chloromethyl-1-cyclohexylmethylimidazole hydrochloride

The title compound was obtained in 95% yield in the same manner as in Preparation Example 1-2) except that the compound obtained in Preparation Example 7-1) was used as a starting material.

Preparation Example 8 Synthesis of 5-chloromethyl-1-pentylimidazole hydrochloride

8-1) Preparation of 5-hydroxymethyl-1-pentylimidazole

The title compound was obtained in 50% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and pentylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 0.90 (t, 3H), 1.08 (brs, 2H), 1.30 (m, 4H), 1.45 (m, 2H), 3.64 (t, 2H), 4.24 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1H)

FAB (M + H): 169

8-2) Preparation of 5-chloromethyl-1-pentylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 8-1) as a starting material, to give the title compound in 90% yield in the same manner as in Preparation Example 1-2).

Preparation Example 9 Synthesis of 5-chloromethyl-1-octylimidazole hydrochloride

9-1) Preparation of 5-hydroxymethyl-1-octylimidazole

The title compound was obtained in 52% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and octylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 0.88 (t, 3H), 1.18 (brs, 2H), 1.30 (brs, 10H), 1.42 (m, 2H), 3.67 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1H)

FAB (M + H): 211

9-2) Preparation of 5-chloromethyl-1-octylimidazole hydrochloride

The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except that the compound obtained in Preparation Example 9-1) was used as a starting material.

Preparation Example 10 Synthesis of 5-chloromethyl-1-decylimidazole hydrochloride

10-1) Preparation of 5-hydroxymethyl-1-decylimidazole

The title compound was obtained in 52% yield by carrying out a similar reaction in Preparation Example 4-1) using dihydroxyacetone and decylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 0.88 (t, 3H), 1.04 (brs, 2H), 1.30 (brs, 14H), 1.42 (m, 2H), 3.68 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1H)

FAB (M + H): 239

10-2) Preparation of 5-chloromethyl-1-decylimidazole hydrochloride

The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except for using the compound obtained in Preparation Example 10-1) as a starting material.

Preparation Example 11 Synthesis of 5-chloromethyl-1- (3-methyl) butylimidazole hydrochloride

11-1) Preparation of 5-hydroxymethyl-1- (3-methyl) butylimidazole

The title compound was obtained in 52% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and isoamylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 0.90 (d, 6H), 1.32 (m, 2H), 1.65 (m, 1H), 3.67 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M + H): 169

11-2) Preparation of 5-chloromethyl-1- (3-methyl) butylimidazole hydrochloride

The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except for using the compound obtained in Preparation Example 11-1) as a starting material.

Preparation Example 12 Synthesis of 5-chloromethyl-1- (2-methoxy) ethylimidazole hydrochloride

12-1) Preparation of 5-hydroxymethyl-1- (2-methoxy) ethylimidazole

The title compound was obtained in 60% yield by performing a similar reaction in Preparation Example 4-1) using dihydroxyacetone and 2-methoxyethylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 3.38 (s, 3H), 3.42 (t, 2H), 3.65 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1H), 7.44 (s, 1 H)

FAB (M + H): 157

12-2) Preparation of 5-chloromethyl-1- (2-methoxy) ethylimidazole hydrochloride

The title compound was obtained in 93% yield in the same manner as in Preparation Example 1-2) except that the compound obtained in Preparation Example 12-1) was used as a starting material.

Preparation Example 13 Synthesis of 5-chloromethyl-1- (3-methoxy) propylimidazole hydrochloride

13-1) Preparation of 5-hydroxymethyl-1- (3-methoxy) propylimidazole

The title compound was obtained in 61% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 3-methoxypropylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 1.72 (m, 2H), 3.32 (s, 3H), 3.46 (t, 2H), 3.63 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M + H): 171

13-2) Preparation of 5-chloromethyl-1- (3-methoxy) propylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 13-1) as a starting material, the title compound was obtained in the same manner as in Preparation Example 1-2) in 90% yield.

Preparation Example 14 Synthesis of 5-chloromethyl-1- (3-ethoxy) propylimidazole hydrochloride

14-1) Preparation of 5-hydroxymethyl-1- (3-ethoxy) propylimidazole

The title compound was obtained in 61% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 3-ethoxypropylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 1.20 (t, 3H), 1.72 (m, 2H), 3.50 (s, 4H), 3.63 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M + H): 185

14-2) Preparation of 5-chloromethyl-1- (3-ethoxy) propylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 14-1) as a starting material, the title compound was obtained in a 90% yield in the same manner as in Preparation Example 1-2).

Preparation Example 15 Synthesis of 5-chloromethyl-1- (3-isopropoxy) propylimidazole hydrochloride

15-1) Preparation of 5-hydroxymethyl-1- (3-isopropoxy) propylimidazole

The title compound was obtained in 61% yield by carrying out a similar reaction as in Preparation Example 4-1) using dihydroxyacetone and 3-isopropoxypropylamine hydrochloride as starting materials.

¹ H NMR (CDCl ₃ ) δ 1.15 (d, 6H), 1.71 (m, 2H), 3.45-3.55 (m, 3H), 3.63 (t, 2H), 4.23 (brs, 1H), 4.60 (s, 2H ), 6.84 (s, 1 H), 7.44 (s, 1 H)

FAB (M + H): 199

15-2) Preparation of 5-chloromethyl-1- (3-isopropoxy) propylimidazole hydrochloride

Except for using the compound obtained in Preparation Example 15-1) as a starting material, the title compound was obtained in the same manner as in Preparation Example 1-2) in 90% yield.

Example 1 Synthesis of 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole (1)

1-1) Preparation of 3- (naphthalen-1-yl) -1- (thiophen-2-yl) -prop-2-en-1-one

3.12 g (20 mmol) of 1-naphthalaldehyde and 2.52 g (20 mmol) of 2-acetylthiophene were dissolved in 20 mL of methanol and 800 mg (20 mmol) of sodium hydroxide were slowly added. After reacting for 8 hours at room temperature, the resulting solid was filtered and dried. The pH of the filtrate was adjusted to 4-6 with 1N hydrochloric acid and extracted with ethyl acetate. The organic solvent was removed under reduced pressure and column chromatography (eluent: hexane / ethyl acetate = 4/1, v / v) was carried out to obtain 4.23 g (16 mmol, 80% yield) of the title compound together with the filtered solid. .

¹ H NMR (CDCl ₃ ) δ 7.13-7.31 (m, 2H), 7.55-7.70 (m, 3H), 7.70 (d, 1H), 7.85-7.90 (m, 4H), 8.28 (d, 1H), 8.70 (d, 1H)

1-2) Preparation of 4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole

2.64 g (9.99 mmol) of the compound obtained in Example 1-1) and 2.35 g (12.0 mmol) of tosylmethyl isocyanide were dissolved in 30 ml of tetrahydrofuran. To this was slowly added 1.35 g (12.0 mmol) of potassium t-butoxide and refluxed for 30 minutes. The solvent was removed under reduced pressure, 15 ml of water and 20 ml of ethyl acetate were added thereto, the mixture was shaken well, and the resulting solid was filtered. Washed with diethyl ether and dried to give 1.97 g (6.48 mmol, 65% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 6.90 (s, 1H), 7.12 (s, 1H), 7.20-7.45 (m, 4H), 7.55 (s, 1H), 7.61 (s, 1H), 7.70-8.00 (m , 4H), 11.4 (s, 1H)

1-3) 4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1- (1-trityl-1H-imidazol-4-yl) methyl-1H-pyrrole Produce

200 mg (0.99 mmol) of the compound obtained in Example 1-2) was dissolved in 5 ml of dimethylformamide, 95 mg (4.0 mmol) of sodium hydride (50%) was added at 0 ° C., and the mixture was stirred for 5 minutes. 391 mg (0.99 mmol) of the compound obtained in Preparation Example 1-2) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed by distillation under reduced pressure, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated, followed by column chromatography (eluent: hexane / ethyl acetate = 1/3, v / v) to give 205 mg (0.33 mmol, 33% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.02 (s, 2H), 6.75 (s, 1H), 6.79 (s, 1H), 6.86 (t, 1H), 7.10-7.52 (m, 23H), 7.71 (d, 1H ), 7.78 (d, 1 H), 7.89 (d, 1 H)

1-4) Preparation of 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole

190 mg (0.304 mmol) of the compound obtained in Example 1-3) were dissolved in a mixed solution of trifluoroacetic acid / dichloromethane (0.5 mL / 0.5 mL) and stirred at room temperature for 2 hours. The organic solvent was removed under reduced pressure, dissolved in 10 ml of ethyl acetate, and washed with saturated Na ₂ CO ₃ aqueous solution and water. After drying over anhydrous magnesium sulfate and concentration, column chromatography (eluent: ethyl acetate) was performed to give 103 mg (0.269 mmol, 88% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.87 (s, 2H), 6.55 (s, 1H), 6.72 (s, 1H), 6.88 (t, 1H), 7.11-7.34 (m, 7H), 7.50-7.67 (m , 3H), 7.83 (d, 1H)

FAB MS: 384 (M + 1)

Examples 2 to 29:

The reaction was carried out in a similar manner to Example 1 to obtain the compounds listed in Tables 2A to 2C.

Compound number ¹ H NMR (CDCl ₃ ) δ FAB MS (M + 1) 2 4.85 (s, 2H), 6.51 (s, 1H), 6.67 (s, 1H), 7.06 (s, 1H), 7.14 (s, 1H), 7.21-7.32 (m, 7H), 7.61-7.74 (m, 3H), 7.82 (d, 1H) 384 3 4.95 (s, 2H), 6.58 (s, 1H), 6.76 (s, 1H), 7.13-7.35 (m, 9H), 7.61-7.68 (m, 4H), 7.91 (d, 1H) 378 4 4.92 (s, 2H), 6.61 (s, 1H), 6.70 (s, 1H), 7.02 (d, 2H), 7.17-7.35 (m, 9H), 7.62 (d, 1H), 7.70 (d, 1H) , 7.95 (d, 1 H) 456 5 5.03 (s, 2H), 6.76 (s, 1H), 6.85 (s, 1H), 7.07 (t, 1H), 7.34-7.54 (m, 9H), 7.72-7.79 (m, 3H), 7.94 (d, 1H) 456 6 5.00 (s, 2H), 6.72 (s, 1H), 6.77 (s, 1H), 7.21-7.38 (m, 11H), 7.62 (d, 1H), 7.70 (d, 1H), 7.78 (d, 1H) 456 7 2.23 (s, 3H), 5.02 (s, 2H), 6.74-7.10 (m, 5H), 7.17-7.50 (m, 8H), 7.65 (d, 1H), 7.71 (d, 1H), 7.86 (d, 1H) 392 8 (CDCl ₃ + CD ₃ OD) 2.05 (s, 3H), 5.09 (s, 2H), 6.84 (s, 1H), 6.99-7.05 (m, 8H), 7.23-7.36 (m, 3H), 7.70 (d , 1H), 7.86 (d, 1H) 392 9 2.21 (s, 3H), 4.92 (s, 2H), 6.62 (s, 1H), 6.83 (s, 1H), 7.14-7.35 (m, 8H), 7.61-7.73 (m, 5H), 7.88 (d, 1H) 392 10 3.66 (s, 3H), 5.04 (s, 2H), 6.85 (s, 1H), 6.82 (d, 1H), 6.90 (m, 1H), 7.12-7.17 (m, 2H), 7.26-7.36 (m, 8H), 7.67 (t, 1H), 7.74 (d, 1H), 7.93 (d, 1H) 408 11 3.75 (s, 3H), 5.02 (s, 2H), 6.71 (m, 3H), 6.80 (t, 1H), 7.20-7.35 (m, 6H), 7.60-7.75 (m, 4H), 7.91 (d, 1H) 408 12 4.83 (s, 2H), 6.51 (s, 1H), 6.63 (s, 1H), 6.85 (m, 1H), 7.03-7.29 (m, 10H), 7.61-7.69 (m, 2H), 7.83 (d, 1H) 412 13 5.01 (s, 2H), 6.72 (s, 1H), 6.77 (s, 1H), 7.22-7.35 (m, 11H), 7.61-7.80 (m, 3H) 412 14 4.82 (s, 2H), 6.63 (s, 1H), 6.72 (s, 1H), 7.02-7.24 (m, 10H), 7.56- 7.70 (m, 3H) 446

15 4.91 (s, 2H), 6.65 (s, 1H), 6.77 (m, 1H), 7.20-7.31 (m, 7H), 7.61 (m, 3H), 7.81 (d, 1H) 396 16 4.92 (s, 2H), 6.45 (m, 1H), 6.71 (m, 2H), 7.20-7.32 (m, 9H), 7.63-7.77 (m, 3H) 414 17 5.09 (s, 2H), 6.80-7.20 (m, 4H), 7.15-7.35 (m, 4H), 7.40 (d, 1H), 7.45-7.50 (m, 3H), 7.60 (m, 1H), 7.65 ( d, 1H), 7.75 (d, 1H) 403 18 1.87 (s, 3H), 3.55 (s, 2H), 5.07 (s, 2H), 6.84 (s, 2H), 7.08 (d, 2H), 7.28-7.48 (m, 6H), 7.57 (d, 2H) , 7.63 (t, 1H), 7.71 (d, 1H), 7.90 (d, 1H) 438 19 2.03 (s, 3H), 2.74 (m, 2H), 2.91 (m, 2H), 5.00 (s, 2H), 6.67 (s, 1H), 7.02 (d, 2H), 7.14-7.43 (m, 11H) , 7.72-7.89 (m, 3H) 452 20 1.98 (s, 3H), 2.75 (t, 2H), 3.90 (t, 2H), 4.85 (s, 2H), 6.60-6.72 (m, 4H), 7.11-7.45 (m, 9H), 7.68-7.82 ( m, 3H) 468 21 2.01 (s, 3H), 3.61 (s, 2H), 4.98 (s, 2H), 6.61 (s, 2H), 6.74 (m, 2H), 7.10-7.48 (m, 10H), 7.71-7.88 (m, 3H) 438 22 4.92 (s, 2H), 6.62 (s, 1H), 6.70 (s, 1H), 7.12-7.27 (m, 14H), 7.53- 7.62 (m, 4H), 7.81 (d, 1H) 454 23 4.97 (s, 2H), 6.87 (d, 1H), 7.15-7.46 (m, 15H), 7.55-7.73 (m, 4H), 7.86 (m, 1H) 454 24 5.10 (s, 2H), 6.70 (t, 2H), 6.80-6.95 (m, 4H), 7.15 (t, 1H), 7.21-7.45 (m, 7H), 7.50 (t, 1H), 7.60 (d, 2H), 7.71 (d, 1H), 7.75-7.80 (m, 2H), 7.91 (m, 1H) 470 25 3.82 (s, 2H), 4.95 (s, 2H), 6.57 (s, 1H), 6.63 (s, 1H), 6.92 (d, 2H), 7.04 (d, 2H), 7.20-7.32 (m, 10H) , 7.51-7.68 (m, 4H), 7.82 (d, 1H) 468 26 4.82 (s, 2H), 6.41 (s, 1H), 6.70 (s, 1H), 6.95 (s, 1H), 7.16-7.32 (m, 9H), 7.51 (d, 1H), 7.59 (d, 1H) , 7.67 (m, 3H), 7.90 (d, 1H), 8.05 (d, 1H) 428 27 2.38 (s, 3H), 3.65 (s, 3H), 4.91 (s, 2H), 6.69 (s, 1H), 6.97 (d, 1H), 7.00 (t, 1H), 7.04 (d, 1H), 7.10 -7.16 (m, 3H), 7.19 (d, 1H), 7.34 (s, 1H), 7.42 (s, 1H), 7.57 (d, 1H), 7.67 (s, 2H) 395

28 0.61 (t, 3H), 1.02 (m, 2H), 1.25 (m, 2H), 2.31 (m, 1H), 2.47 (m, 1H), 5.05 (s, 2H), 6.57 (s, 1H), 6.63 (s, 1H), 6.80 (d, 1H), 6.87 (s, 1H), 7.22-7.35 (m, 7H), 7.61-7.72 (m, 3H) 502 29 3.71 (d, 1H), 3.85 (d, 1H), 4.85 (s, 2H), 6.61 (s, 1H), 6.73 (d, 1H), 6.92-7.41 (m, 14H), 7.62-7.73 (m, 3H) 536

Example 30 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl Synthesis of -1H-pyrrole (30)

80 mg (0.3 mmol) of the compound obtained in Preparation Example 2-5) and 90 mg (0.3 mmol) of the compound obtained in Example 1-2) were dissolved in 2 ml of dimethylformamide and 36 mg of 60% sodium hydride was added for 2 hours. Stirred. The solvent was removed by distillation under reduced pressure and column chromatography (eluent: dichloromethane / methanol = 10/1, v / v) was performed to obtain 83 mg (0.17 mmol, yield 56%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.02 (s, 2H), 5.08 (s, 1H), 6.73 (s, 1H), 6.85 (s, 1H), 7.03 (t, 1H), 7.32-7.45 (m, 11H ), 7.63 (s, 1H), 7.75 (d, 1H), 7.82 (d, 1H), 8.02 (d, 1H)

FAB MS: 499 (M + 1)

Examples 31 to 34:

The reaction was carried out in a similar manner to Example 30 to obtain the compounds listed in Table 3 below.

Compound number ¹ H NMR (CDCl ₃ ) δ FAB MS (M + 1) 31 4.82 (s, 2H), 5.12 (s, 1H), 6.30 (s, 1H), 6.41 (s, 1H), 6.77-7.08 (m, 12H), 7.31-7.46 (m, 3H), 7.68 (d, 1H) 499 32 5.00 (s, 2H), 5.05 (s, 2H), 6.76 (s, 1H), 6.82 (s, 1H), 7.23-7.40 (m, 12H), 7.63 (d, 2H), 7.72 (d, 1H) , 7.90 (d, 1 H) 493 33 5.02 (s, 2H), 5.08 (s, 2H), 6.65 (s, 1H), 6.78 (s, 1H), 6.98 (t, 1H), 7.23-7.42 (m, 12H), 7.65-7.73 (m, 3H), 7.82 (d, 1H) 571 34 5.03 (s, 2H), 5.10 (s, 2H), 6.78 (s, 1H), 6.87 (s, 1H), 7.32-7.45 (m, 12H), 7.74 (d, 3H), 7.81 (d, 1H) , 7.88 (d, 1 H) 571

Example 35 Synthesis of 3- (4-fluorobenzoyl) -1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (35)

In Examples 1-3) except that 3- (4-fluorobenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole and the compound obtained in Preparation Example 4-2) are used; In the same manner, the title compound was obtained in 75% yield.

¹ H NMR (CDCl ₃ ) δ 3.42 (s, 3H), 5.01 (s, 2H), 6.73 (m, 3H), 7.11 (s, 1H), 7.24-7.57 (m, 8H), 7.67-7.75 (m , 2H)

FAB MS (M + 1): 410

Example 36 Synthesis of 1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole (36)

In Examples 1-3) except that 4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole and the compound obtained in Preparation Example 4-2) are used; In the same manner, the title compound was obtained in 70% yield.

¹ H NMR (CDCl ₃ ) δ 3.52 (s, 3H), 5.12 (s, 2H), 6.63 (d, 2H), 6.76 (d, 1H), 6.85 (d, 2H), 7.12 (t, 1H), 7.20 (s, 1H), 7.28-7.40 (m, 7H), 7.51 (d, 2H), 7.68 (d, 2H), 7.74 (d, 1H), 7.83 (d, 1H)

FAB MS (M + 1): 484

Example 37: (S) -1- (1H-imidazol-4-yl) methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalene- Synthesis of 1-yl) -1H-pyrrole (37)

37-1) Preparation of ethyl 3- (naphthalen-1-yl) acrylate

22.4 g (0.10 mol) of triethylphosphonoacetate was dissolved in 500 ml of tetrahydrofuran, and then 12.4 g (1.1 mol) of potassium t-butoxide was added slowly. 15.6 g (0.10 mol) of 1-naphthalaldehyde was dissolved in 20 ml of tetrahydrofuran and slowly added to the solution, followed by stirring for 8 hours. The organic solvent was removed by distillation under reduced pressure, and then dissolved in ethyl acetate and washed twice with water. After drying over anhydrous magnesium sulfate and concentration, column chromatography (eluent: hexane / ethyl acetate = 95/5, v / v) was carried out to give 20.3 g (0.090 mol, 90% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.42 (t, 3H), 4.30 (q, 2H), 6.50 (d, 1H), 7.40-7.60 (m, 3H), 7.73 (d, 1H), 7.82 (m, 2H ), 8.20 (d, 1 H), 8.50 (d, 1 H)

37-2) Preparation of 3-ethoxycarbonyl-4- (naphthalen-1-yl) -1H-pyrrole

500 mg (1.89 mmol) of ethyl 3- (naphthalen-1-yl) acrylate obtained in Example 37-1) and 368 mg (1.89 mmol) of tosylmethyl isocyanide were dissolved in 10 ml of tetrahydrofuran. To this was slowly added 255 mg (2.27 mmol) of tetrahydrofuran (10 mL) solution of potassium t-butoxide and refluxed for 30 minutes. 10 ml of water was added to the reaction mixture to stop the reaction, and the solvent was removed under reduced pressure. Extracted with diethyl ether, washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and then column chromatography (eluent: ethyl acetate / hexane = 1/3, v / v) was carried out to give 385 mg (1.45 mmol, 77% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.86 (t, 3H), 4.02 (q, 2H), 6.81 (s, 1H), 7.48-7.61 (m, 5H), 7.90-7.97 (m, 3H), 8.92 (s , 1H)

37-3) Preparation of 3-ethoxycarbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole

The title compound was obtained in 39% yield using the method of Examples 1-3) and 1-4) from the compound obtained in Example 37-2) and the compound obtained in Preparation Example 1-2).

¹ H NMR (CDCl ₃ ) δ 1.11 (t, 3H), 4.20 (q, 2H), 5.05 (s, 2H), 6.78 (s, 1H), 6.89 (s, 1H), 7.38-7.49 (m, 6H ), 7.85-7.97 (m, 3H)

37-4) Preparation of 3-hydroxycarbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole

220 mg (0.64 mmol) of the compound obtained in Example 37-3) was dissolved in 5 ml of 50% ethanol, and 216 mg (3.8 mmol) of potassium hydroxide was added dropwise to reflux for 7 hours. After cooling the reaction solution to room temperature, the pH was adjusted to 4-5 and extracted with ethyl acetate. Drying over anhydrous sodium sulfate and removal of the solvent under reduced pressure yielded 162 mg (0.51 mmol, yield 80%) of the title compound. This compound was used in the next reaction without purification.

¹ H NMR (CD ₃ OD + CDCl ₃ ) δ 5.01 (s, 2H), 6.82 (s, 1H), 6.87 (s, 1H), 7.42-7.70 (m, 7H), 7.82-7.89 (m, 3H)

37-5) (S) -1- (1H-imidazol-4-yl) methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalene- Preparation of 1-yl) -1H-pyrrole

200 mg (0.60 mmol) of the compound obtained in Example 37-4) was dissolved in 2 ml of dimethylformamide, 150 mg (0.78 mmol) of EDC and 105 mg (0.78 mmol) of HOBT were added, followed by stirring at 0 ° C. for 5 minutes. 120 mg (0.60 mmol) of L-methionine methyl ester was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure, 10 ml of saturated aqueous NaHCO ₃ solution was added, and the mixture was extracted with ethyl acetate. Washed with brine and water, dried over anhydrous sodium sulfate and concentrated. Column chromatography on the residue (eluent: dichloromethane / methanol = 20/1, v / v) gave 104 mg (0.225 mmol, 37% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.21 (m, 1H), 1.55 (m, 3H), 1.80 (s, 3H), 3.42 (s, 3H), 4.43 (m, 1H), 5.05 (s, 2H), 5.60 (d, 1H), 6.71 (s, 1H), 6.95 (s, 1H), 7.21-7.45 (m, 7H), 7.75-7.87 (m, 3H)

FAB MS: 463 (M + 1)

Example 38: (S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalene- Synthesis of 1-yl) -1H-pyrrole (38)

70 mg (0.15 mmol) of the compound obtained in Example 37-5) was dissolved in 2 ml of a mixed solvent of tetrahydrofuran / methanol / water (3/2/1, v / v / v), and 10 mg (0.18 mmol) of lithium hydroxide. After the addition, the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give 68 mg (0.15 mmol, yield 99.7%) of the lithium salt of the title compound.

¹ H NMR (CD ₃ OD + CDCl ₃ ) δ 1.25 (m, 1H), 1.49 (m, 3H), 1.85 (s, 3H), 4.41 (m, 1H), 5.11 (s, 2H), 5.58 (d , 1H), 6.70 (s, 1H), 6.89 (s, 1H), 7.15-7.38 (m, 7H), 7.76-7.81 (m, 3H)

FAB MS: 449 (M + 1)

Examples 39-55:

The reaction was carried out in a similar manner to Example 37 to obtain the compounds listed in Tables 4A and 4B below.

Compound number ¹ H NMR (CDCl ₃ ) δ FAB MS (M + 1) 39 5.02 (s, 2H), 6.69 (d, 2H), 6.77 (s, 1H), 6.92-7.18 (m, 5H), 7.40-7.58 (m, 6H), 7.75-7.87 (m, 4H) 393 40 4.06 (d, 2H), 5.01 (s, 2H), 5.57 (t, 1H), 6.46 (d, 1H), 6.71 (s, 1H), 6.83 (s, 1H), 6.92-7.05 (m, 3H) , 7.42-7.55 (m, 7H), 7.74-7.81 (m, 3H) 407 41 0.45 (brs, 2H), 1.22 (brs, 4H), 2.95 (brs, 2H), 3.37 (brs, 2H), 5.04 (s, 2H), 6.65 (s, 1H), 6.92 (s, 1H), 7.08 (s, 1H), 7.31-7.45 (m, 6H), 7.72 (d, 1H), 7.82 (d, 1H), 8.12 (d, 1H) 385 42 2.32 (brs, 2H), 2.22 (brs, 2H), 3.23 (brs, 2H), 3.65 (brs, 2H), 5.06 (s, 2H), 6.72 (s, 1H), 6.95 (s, 1H), 7.12 (s, 1H), 7.31-7.48 (m, 6H), 7.81 (d, 1H), 7.85 (d, 1H), 8.11 (d, 1H) 387 43 1.41 (brs, 2H), 2.86-3.25 (m, 6H), 4.97 (s, 2H), 6.68 (s, 1H), 6.85 (s, 1H), 7.06 (s, 1H), 7.21-7.35 (m, 6H), 7.72 (d, 1H), 7.78 (d, 1H), 7.95 (d, 1H) 403 44 2.04 (brs, 4H), 3.62 (brs, 4H), 5.03 (s, 2H), 6.91 (d, 2H), 7.22- 7.48 (m, 7H), 7.81-7.88 (m, 2H), 8.02 (m, 1H) 435 45 1.46 (brs, 2H), 2.21 (brs, 2H), 3.14 (brs, 4H), 5.11 (s, 2H), 6.88 (s, 1H), 7.02 (s, 1H), 7.11 (s, 1H), 7.32 -7.51 (m, 5H), 7.62 (s, 1H), 7.72-7.80 (m, 2H), 8.05 (d, 1H) 386 46 (CDCl ₃ + CD ₃ OD) 2.05 (s, 3H), 3.33 (brs, 8H), 5.13 (s, 2H), 6.90 (s, 1H), 7.06 (s, 1H), 7.21 (s, 1H), 7.30-7.55 (m, 4H), 7.64 (s, 1H), 7.81 (s, 1H), 7.88 (d, 1H), 8.06 (d, 1H) 400 47 2.62 (brs, 2H), 3.15 (brs, 2H), 3.86 (brs, 1H), 4.35 (brs, 1H), 5.06 (s, 2H), 6.83 (s, 1H), 6.90 (s, 1H), 7.15 -7.60 (m, 6H), 7.73 (d, 1H), 7.82 (d, 1H), 8.06 (d, 1H) 389 48 0.22 (m, 1H), 0.63 (m, 1H), 0.83 (m, 1H), 1.24 (m, 1H), 2.61 (brs, 2H), 3.24 (brs, 2H), 3.65 (brs, 1H), 4.94 (s, 2H), 6.71 (s, 1H), 6.84 (s, 1H), 6.94 (s, 1H), 7.24-7.42 (m, 6H), 7.62-7.70 (m, 2H), 7.94 (d, 1H) ) 401

49 1.37 (brs, 2H), 1.96 (brs, 2H), 3.52 (brs, 4H), 5.21 (s, 2H), 7.08 (s, 1H), 7.20 (s, 1H), 7.37 (s, 1H), 7.54 (m, 5H), 7.70 (s, 1H), 7.94 (m, 2H), 8.23 (d, 1H) 399 50 2.12 (brs, 2H), 3.02 (brs, 2H), 4.98 (s, 2H), 5.24 (m, 1H), 6.82 (s, 1H), 7.03 (s, 1H), 7.20-7.34 (m, 6H) , 7.62-7.71 (m, 3H), 7.93 (d, 1H) 361 51 2.24 (brs, 2H), 3.04 (brs, 4H), 3.11 (s, 3H), 5.03 (s, 2H), 6.77 (s, 1H), 6.89 (s, 1H), 7.14-7.31 (m, 6H) , 7.56-7.63 (m, 3H), 7.87 (d, 1H) 375 52 2.51 (m, 2H), 3.10 (s, 3H), 3.21 (m, 2H), 3.47 (s, 3H), 5.05 (s, 2H), 6.68 (s, 1H), 7.05-7.48 (m, 7H) , 7.74-7.85 (m, 2H), 8.09 (d, 1H) 389 53 2.58-3.50 (brs, 8H), 5.16 (s, 2H), 6.98 (d, 1H), 7.08 (s, 1H), 7.20-7.27 (m, 2H), 7.47 (t, 1H), 7.67 (s, 1H), 7.71 (t, 1H), 8.08 (d, 1H), 8.15 (d, 1H), 8.80 (d, 1H) 388 54 3.40 (m, 4H), 3.70-4.45 (brs, 8H), 3.11 (s, 3H), 5.18 (s, 2H), 6.98 (d, 1H), 7.12 (s, 1H), 7.17-7.22 (m, 2H), 7.25 (d, 1H), 7.30 (d, 1H), 7.35 (t, 1H), 7.62 (d, 1H), 7.90 (s, 1H) 413 55 (CD ₃ OD) 3.86 (s, 2H), 4.83 (s, 2H), 5.58 (t, 1H), 6.37 (d, 1H), 6.52 (s, 2H), 6.81 (s, 1H), 7.05-7.35 (m, 9H), 7.51 (d, 1H), 7.54 (d, 1H), 7.58 (d, 1H) 432

Example 56 1- (1-Methyl-1H-imidazol-5-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (56 ) Synthesis

55% by introducing a trityl protecting group to the compound obtained in Example 42 as in Preparation Example 1-1, and then using methyl iodide in a similar manner to Preparation Examples 2-2) and 2-3) The title compound was obtained in yield.

¹ H NMR (CDCl ₃ ) δ 2.80-3.45 (m, 8H), 3.58 (s, 3H), 5.19 (s, 2H), 6.75 (d, 1H), 7.18 (d, 1H), 7.21 (s, 1H ), 7.35 (d, 1H), 7.40-7.50 (m, 3H), 7.72 (d, 1H), 8.03 (d, 1H)

FAB MS: 401 (M + 1)

Example 57: (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methylthio) Propyl] Synthesis of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (57)

57-1) Preparation of 1- [1- (4-cyanobenzyl) -1H-imidazol-5-ylmethyl] -3-hydroxycarbonyl-4- (naphthalen-1-yl) -1H-pyrrole

From the compound obtained in Example 37-2) and the compound obtained in Preparation Example 2-5), the methods of Example 30 and Example 37-4) were carried out in order to obtain the title compound in 75% yield.

¹ H NMR (CDCl ₃ + CD ₃ OD) δ 5.02 (s, 2H), 5.10 (s, 2H), 6.76 (s, 1H), 7.07 (m, 2H), 7.25-7.82 (m, 12H)

57-2) (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methylthio) Propyl] Preparation of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

Except for using the compound obtained in Example 57-1), the title compound was obtained in the same manner as in Example 37-5) in 35% yield.

¹ H NMR (CDCl ₃ ) δ 1.85 (s, 3H), 2.04 (m, 1H), 2.13 (m, 1H), 2.42 (t, 2H), 3.61 (s, 3H), 4.83 (m, 1H), 5.02 (s, 2H), 5.11 (s, 2H), 6.63 (s, 1H), 7.01 (d, 2H), 7.13 (d, 1H), 7.22-7.43 (m, 7H), 7.65-7.92 (m, 4H)

FAB MS: 578 (M + 1)

Example 58: (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-hydroxycarbonyl-3-methylthio) Propyl] Synthesis of Carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (58)

From the compound obtained in Example 57-2), a lithium salt of the title compound was obtained in 96% yield in the same manner as in Example 38.

¹ H NMR (CDCl ₃ + CD ₃ OD) δ 1.82 (s, 3H), 2.00 (m, 1H), 2.11 (m, 1H), 2.36 (t, 2H), 4.82 (m, 1H), 4.89 (s , 2H), 5.02 (s, 2H), 6.49 (s, 1H), 6.88 (d, 2H), 7.11 (d, 1H), 7.17-7.32 (m, 7H), 7.62-7.83 (m, 4H)

FAB MS: 564 (M + 1)

Examples 59 and 60:

The reaction was carried out in a similar manner to Examples 57 and 58 to afford the compounds listed in Table 5 below.

Compound number ¹ H NMR δ FAB MS (M + 1) 59 (CDCl ₃ ) 0.67 (d, 3H), 0.78 (d, 3H), 0.82 (m, 1H), 0.90 (m, 1H), 1.10 (m, 1H), 3.52 (s, 3H), 4.32 (m, 1H), 5.02 (s, 2H), 5.17 (s, 2H), 6.72 (s, 1H), 6.83 (s, 1H), 7.23-7.34 (m, 3H), 7.41-7.92 (m, 10H) 560 60 (CDCl ₃ + CD ₃ OD) 0.62 (d, 3H), 0.71 (d, 3H), 0.79 (m, 1H), 0.88 (m, 1H), 0.98 (m, 1H), 4.12 (m, 1H), 4.97 (s, 2H), 5.08 (s, 2H), 6.77 (s, 1H), 6.82 (s, 1H), 7.14-7.30 (m, 4H), 7.38-7.84 (m, 9H) 546

Examples 61 and 62:

The reaction was carried out in a similar manner to Example 58 to obtain the compounds listed in Table 6 below.

Compound number ¹ H NMR (CDCl ₃ ) δ FAB MS (M + 1) 61 1.95 (brs, 2H), 2.33 (brs, 1H), 2.95 (brs, 5H), 4.93 (s, 2H), 5.05 (s, 2H), 6.62 (s, 1H), 7.05 (s, 1H), 7.11 (d, 2H), 7.28 (m, 2H), 7.51 (m, 3H), 7.63 (m, 3H), 7.81-7.88 (m, 2H), 7.95 (d, 1H) 502 62 1.12 (brs, 2H), 1.88 (brs, 2H), 1.90 (s, 3H), 2.95 (brs, 2H), 3.34 (brs, 2H), 4.97 (s, 2H), 5.07 (s, 2H), 6.60 (s, 1H), 7.02 (s, 1H), 7.10 (d, 2H), 7.29 (m, 2H), 7.46 (m, 3H), 7.60 (m, 3H), 7.80 (d, 1H), 7.85 ( d, 1H), 7.97 (d, 1H) 515

Example 63 1- [2- (1H-imidazol-1-yl) ethyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (63 ) Synthesis

63-1) Preparation of 2- (1H-imidazol-1-yl) ethyl p-tosylate

0.24 g (2.41 mmol) of 2- (1H-imidazol-1-yl) ethanol and 0.55 g (2.88 mmol) of tosyl chloride were dissolved in 20 ml of dichloromethane, and 0.67 ml of triethylamine was slowly added at 0 ° C, and then at room temperature. Stir for 4 hours. After removing the organic solvent under reduced pressure, it was dissolved in 10 ml of ethyl acetate, and washed sequentially with 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. It was dried over anhydrous magnesium sulfate and then concentrated. Column chromatography (eluent: dichloromethane / methanol = 20/1, v / v) on the residue gave 0.30 g (1.13 mmol, 47% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.42 (s, 3H), 4.17-4.28 (m, 4H), 6.88 (s, 1H), 6.99 (s, 1H), 7.29 (d, 2H), 7.45 (s, 1H ), 7.64 (d, 2 H)

63-2) Preparation of 3-hydroxycarbonyl-4- (naphthalen-1-yl) -1H-pyrrole

The compound obtained in Example 37-2) was hydrolyzed by the method of Example 37-4) to give the title compound in 80% yield.

¹ H NMR (CDCl ₃ + CD ₃ OD) δ 7.12 (m, 3H), 7.20-7.31 (m, 3H), 7.50 (d, 1H), 7.68 (d, 1H), 7.76 (d, 1H)

63-3) Preparation of 3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole

The title compound was obtained in 99% yield from the compound obtained in Example 63-2) and the morpholine by the method of Example 37-5).

¹ H NMR (CDCl ₃ ) δ 2.68-3.62 (brs, 8H), 6.88 (s, 1H), 7.20 (s, 1H), 7.30-7.62 (m, 4H), 7.78 (d, 1H), 7.85 (d , 1H), 8.08 (d, 1H), 10.34 (s, 1H)

63-4) Preparation of 1- [2- (1H-imidazol-1-yl) ethyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole

The compound obtained in Example 63-1) and the compound obtained in Example 63-3) were reacted according to the method of Example 1-3) to obtain the title compound in 51% yield.

¹ H NMR (CDCl ₃ ) δ 2.20-3.72 (brs, 12H), 7.20 (s, 1H), 7.40-7.55 (m, 8H), 7.82 (d, 1H), 7.88 (d, 1H), 8.05 (d , 1H)

FAB MS: 401 (M + 1)

Example 64: (S) -1- [3- (1H-imidazol-4-yl) propyl] -3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4 Synthesis of-(naphthalen-1-yl) -1H-pyrrole (64)

64-1) Preparation of 3-ethoxycarbonyl-4- (naphthalen-1-yl) -1- [3- (1-trityl-1H-imidazol-4-yl) allyl] -1H-pyrrole

The compound obtained in Example 37-2) and the compound obtained in Preparation Example 3-4) were reacted according to the method of Example 1-3) to obtain the title compound in 85% yield.

¹ H NMR (CDCl ₃ ) δ 0.82 (t, 3H), 3.95 (q, 2H), 4.67 (s, 2H), 6.23 (d, 1H), 6.47 (m, 1H), 6.63 (s, 1H), 7.02 (s, 1H), 7.25-7.81 (m, 24H)

64-2) Preparation of 3-ethoxycarbonyl-4- (naphthalen-1-yl) -1- [3- (1-trityl-1H-imidazol-4-yl) propyl] -1H-pyrrole

300 mg (0.49 mmol) of the compound obtained in Example 64-1) was dissolved in 2 ml of methanol, and a catalytic amount of Pd / C was added, followed by stirring for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration to remove the solvent under reduced pressure. Column chromatography on the residue (eluent: dichloromethane / methanol = 98/2, v / v) gave 246 mg (0.40 mmol, yield 82%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.92 (t, 3H), 2.22 (m, 2H), 2.73 (t, 2H), 4.01 (m, 4H), 6.70 (s, 1H), 6.82 (s, 1H), 7.32-7.73 (m, 21 H), 7.91 (m, 3 H)

64-3) (S) -1- [3- (1H-imidazol-4-yl) propyl] -3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4 Preparation of-(naphthalen-1-yl) -1H-pyrrole

The compounds obtained in Example 64-2) were sequentially subjected to the methods of Examples 1-4) and 37-4) to remove trityl groups and subjected to hydrolysis, followed by (L) -methionine methyl ester. Example 37-5) was carried out to give the title compound in 29% yield.

¹ H NMR (CDCl ₃ ) δ 1.65 (m, 2H), 1.90 (s, 3H), 2.12 (m, 2H), 2.31 (m, 2H), 2.73 (m, 2H), 3.54 (s, 3H), 4.02 (m, 2H), 4.56 (m, 1H), 5.77 (d, 1H), 6.72 (s, 1H), 6.90 (s, 1H), 7.42-7.67 (m, 7H), 7.82-8.01 (m, 5H)

FAB MS: 491 (M + 1)

Example 65: (S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- [3- (1H-imidazol-4-yl) propyl] -4 Synthesis of-(naphthalen-1-yl) -1H-pyrrole (65)

The title compound was obtained in 95% yield as in Example 38, except that the compound obtained in Example 64-3) was used.

¹ H NMR (CDCl ₃ ) δ 1.57 (m, 2H), 1.88 (s, 3H), 2.08 (m, 2H), 2.29 (m, 2H), 2.77 (m, 2H), 4.12 (m, 2H), 4.49 (m, 1H), 5.69 (d, 1H), 6.77 (s, 1H), 6.92 (s, 1H), 7.34-7.58 (m, 7H), 7.80-7.89 (m, 5H)

FAB MS: 477 (M + 1)

Example 66 1- [3- (1H-imidazol-4-yl) propyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (66 ) Synthesis

The title compound was obtained in 42% yield using the same method as Example 64-3) except for using morpholine for the compound obtained in Example 64-2).

¹ H NMR (CDCl ₃ ) δ 2.16 (m, 2H), 2.35 (brs, 2H), 2.63 (m, 2H), 2.80-3.50 (brs, 6H), 3.54 (s, 3H), 3.96 (m, 2H ), 6.74 (d, 1H), 6.76 (s, 1H), 7.07 (s, 1H), 7.33 (t, 1H), 7.36-7.50 (m, 4H), 7.76 (d, 1H), 7.84 (d, 1H), 8.08 (d, 1H)

FAB MS: 415 (M + 1)

Example 67 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (67)

67-1) Preparation of 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

Similar method as in Example 37-5) using 100 mg (0.42 mmol) of the compound obtained in Example 63-2) and 38 mg (0.4 mmol) of N- (2-methoxyethyl) -N-methylamine The reaction was carried out to give 110 mg (0.35 mmol, 85% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.21 (s, 3H), 2.64 (brs, 1H), 2.75 (brs, 1H), 3.02 (s, 3H), 3.13 (brs, 1H), 3.32 (brs, 1H), 6.72 (s, 1H), 7.05 (m, 2H), 7.21 (m, 2H), 7.54 (m, 1H), 7.78 (m, 2H), 8.04 (d, 1H), 8.78 (brs, 1H)

67-2) 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Preparation of (Naphthalen-1-yl) -1H-pyrrole

The reaction was carried out in a similar manner to Example 1-3) using 98 mg (0.32 mmol) of the compound obtained in Example 67-1) and 85 mg (0.32 mmol) of the compound obtained in Preparation Example 2-5). 115 mg (0.23 mmol, 72% yield) of the title compound were obtained.

¹ H NMR (CDCl ₃ ) δ 2.41 (s, 3H), 2.75 (brs, 2H), 3.07 (s, 3H), 3.17 (brs, 1H), 3.32 (brs, 1H), 4.91 (s, 2H), 5.11 (s, 2H), 6.71 (s, 1H), 7.05 (s, 1H), 7.17 (d, 1H), 7.40-7.68 (m, 9H), 7.78 (d, 1H), 7.88 (d, 1H) , 8.06 (d, 1 H)

FAB MS: 504 (M + 1)

Example 68: 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (68)

The reaction was carried out in a similar manner to Example 1-3) using 105 mg (0.29 mmol) of the compound obtained in Example 67-1) and 78 mg (0.29 mmol) of the compound obtained in Preparation Example 5-2). 121 mg (0.21 mmol, Yield 75%) of the title compound were obtained.

¹ H NMR (CDCl ₃ ) δ 2.37 (s, 3H), 2.72 (brs, 2H), 3.04 (s, 3H), 3.15 (brs, 1H), 3.31 (brs, 1H), 4.95 (s, 2H), 5.10 (s, 2H), 6.67 (s, 1H), 7.11 (s, 1H), 7.23-7.65 (m, 10H), 7.81 (d, 1H), 7.89 (d, 1H), 8.02 (d, 1H)

FAB MS: 557 (M + 1)

Example 69 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) Synthesis of -1H-pyrrole (69)

The reaction was carried out in a similar manner to Example 1-3) using 100 mg (0.33 mmol) of the compound obtained in Example 63-3) and 105 mg (0.33 mmol) of the compound obtained in Preparation Example 5-2). 130 mg (0.23 mmol, 71% yield) of the title compound were obtained.

¹ H NMR (CDCl ₃ ) δ 2.04 (brs, 2H), 2.25 (brs, 1H), 3.03 (brs, 5H), 4.93 (s, 2H), 5.07 (s, 2H), 6.62 (s, 1H), 7.10 (m, 3H), 7.29 (m, 2H), 7.41 (m, 3H), 7.60 (m, 3H), 7.81 (d, 1H), 7.89 (d, 1H), 8.01 (d, 1H)

FAB MS: 555 (M + 1)

Example 70 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) thiocarbonyl-4- (naphthalen-1-yl Synthesis of) -1H-pyrrole 70

20 mg (0.04 mmol) of the compound obtained in Example 61 and 18 mg of 2,4-bis (phenylthio) -1,3-dithia-2,4-diphosphatane-2,4-disulfide were tetrahydrofuran. It was dissolved in 1ml and stirred at room temperature for 3 hours. 2 ml of saturated aqueous sodium bicarbonate solution was added to the reaction solution, which was then extracted with ethyl acetate. Dry over anhydrous sodium sulfate and remove the organic solvent under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 9/1, v / v) to give 9 mg (0.017 mmol, yield 43%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.88 (brs, 2H), 2.64 (brs, 6H), 4.86 (s, 2H), 5.01 (s, 2H), 6.67 (s, 1H), 7.14 (m, 3H), 7.26-7.58 (m, 8H), 7.81 (m, 2H), 8.03 (d, 1H)

FAB MS: 518 (M + 1)

Example 71: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- (1-methyl-1H-imidazol-5-yl) methyl-4- (naphthalen-1-yl Synthesis of) -1H-pyrrole (71)

71-1) Preparation of 4- (naphthalen-1-yl) -1H-pyrrole-3-carboxylic acid

2.64 g (10 mmol) of the compound of Example 37-2) were dissolved in 50 mL of 50% ethanol, and 2.24 g (40 mmol) of potassium hydroxide was added and refluxed for 7 hours. After cooling the reaction solution to room temperature, the pH was adjusted to 4-5 and extracted with ethyl acetate. Dry over anhydrous sodium sulfate and remove the solvent under reduced pressure to afford 1.62 g (8.1 mmol; yield 81%) of the title compound. This compound was used in the next reaction without purification.

¹ H NMR (CDCl ₃ ) δ 6.60 (s, 1H), 7.32-7.49 (m, 5H), 7.54 (s, 1H), 7.84 (m, 2H), 9.92 (s, 1H)

FAB (M + H): 236

71-2) Preparation of 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole

234 mg (1 mmol) of the compound obtained in Example 71-1) was dissolved in 2 ml of dimethylformamide, 230 mg (1.2 mmol) EDC, 101 mg (1 mmol) triethylamine, and 162 mg (1.7 mmol) HOBT. After the addition was stirred for 5 minutes at 0 ℃. 124 mg (1 mmol) of N- (2-methoxyethyl) -N-methylamine hydrochloride was added thereto, followed by stirring at room temperature for 5 hours. The solvent was removed under reduced pressure, 10 mL of saturated potassium carbonate solution was added thereto, followed by extraction with 20 mL of ethyl acetate, followed by washing with 10 mL of 1N hydrochloric acid solution. Then washed with brine and water, dried over anhydrous sodium sulfate and concentrated to give 246 mg (0.8 mmol) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.46 (s, 2H), 2.80-3.40 (m, 7H), 3.40 (s, 1H), 6.80 (s, 1H), 7.00 (s, 1H), 7.42 (m, 4H ), 7.73 (d, 1H), 7.81 (d, 1H), 8.17 (d, 1H), 10.66 (s, 1H)

FAB (M + H): 309

71-3) 1- (1-methyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl Preparation of 1H-pyrrole

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 367 mg (2.2 mmol) of 5-chloromethyl-1-methylimidazole hydrochloride and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 644 mg (yield 80%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.42 (s, 2H), 2.71 (m, 1H), 3.10 (brs, 6H), 3.30 (brs, 1H), 3.50 (s, 3H), 5.09 (s, 2H), 6.70 (s, 1H), 7.05 (s, 1H), 7.15 (s, 1H), 7.30-7.49 (m, 4H), 7.72 (d, 1H), 7.84 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 403

Example 72: 1- (1-isobutyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1- Synthesis of I) -1H-pyrrole 72

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 459 mg (2.2 mmol) of the compound obtained in Preparation Example 6-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.90 (d, 6H), 1.75 (m, 1H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (d, 2H), 5.13 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.30-7.49 (m, 4H), 7.78 (d, 1H) , 7.84 (d, 2 H), 8.08 d, 1 H)

FAB (M + H): 445

Example 73: 1- (1-cyclohexylmethyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 Synthesis of -yl) -1H-pyrrole (73)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 647 mg (2.2 mmol) of the compound obtained in Preparation Example 2-2 and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 726 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.87 (m, 2H), 1.12 (m, 3H), 1.30 (brs, 1H), 1.40-1.80 (m, 5H), 2.41 (brs, 2H), 2.72 (brs, 1H ), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.63 (d, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H) , 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 485

Example 74: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-pentyl-1H-imidazol-5-yl) Synthesis of Methyl-1H-pyrrole (74)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 429 mg (2.2 mmol) of the compound obtained in Preparation Example 8-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 714 mg (yield 78%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.90 (t, 3H), 1.08 (brs, 2H), 1.30 (m, 2H), 1.45 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 459

Example 75: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-octyl-1H-imidazol-5-yl) Synthesis of Methyl-1H-pyrrole (75)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 508 mg (2.2 mmol) of the compound obtained in Preparation Example 9-2 and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 760 mg (yield 76%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.87 (t, 3H), 1.17 (brs, 2H), 1.30 (brs, 10H), 1.44 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 501

Example 76: 1- (1-decyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl Synthesis of) -1H-pyrrole (76)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 567 mg (2.2 mmol) of the compound obtained in Preparation Example 10-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.87 (t, 3H), 1.17 (brs, 2H), 1.30 (brs, 14H), 1.44 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 529

Example 77: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methylbutyl) -1H-imidazol-5-yl] methyl-4- ( Synthesis of naphthalen-1-yl) -1H-pyrrole (77)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 429 mg (2.2 mmol) of the compound obtained in Preparation Example 11-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 0.91 (d, 6H), 1.31 (q, 2H), 1.67 (m, 1H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.62 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30 -7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 459

Example 78: 1- [1- (2-methoxyethyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (78)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. To this was added 429 mg (2.2 mmol) of the compound obtained in Preparation Example 12-2) and stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 667 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.37 (s, 3H), 3.45 (t, 2H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30-7.49 (m, 3H) , 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 431

Example 79: 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methoxypropyl) -1H-imidazol-5-yl] methyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (79)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. 459 mg (2.2 mmol) of the compound obtained in Preparation Example 13-2 was added thereto, and the resultant was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 683 mg (yield 70%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.71 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.31 (s, 3H), 3.32 (brs, 1H), 3.48 (t, 2H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30 -7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 445

Example 80: 1- [1- (3-ethoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- Synthesis of (naphthalen-1-yl) -1H-pyrrole (80)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. 459 mg (2.2 mmol) of the compound obtained in Preparation Example 14-2 was added thereto, and the resultant was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 712 mg (yield 71%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.20 (t, 3H), 1.70 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.50 (m, 4H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H), 7.30 -7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 457

Example 81 1- [1- (3-isopropoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4 Synthesis of-(naphthalen-1-yl) -1H-pyrrole (81)

618 mg (2.0 mmol) of the compound obtained in Example 71-2) was dissolved in 10 ml of dimethylformamide, and 264 mg (6.6 mmol) of sodium hydride (60%) was added at 0 ° C, followed by stirring for 5 minutes. 459 mg (2.2 mmol) of the compound obtained in Preparation Example 15-2 was added thereto, and the resultant was stirred at room temperature for 5 hours. After distilling off the solvent under reduced pressure, 10 ml of water was added thereto and extracted twice with 20 ml of ethyl acetate. After drying over anhydrous sodium sulfate and concentration, silica gel column chromatography (eluent: dichloromethane / methanol = 90/10, v / v) was carried out to give 751 mg (yield 73%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.16 (d, 6H), 1.70 (m, 2H), 2.41 (brs, 2H), 2.72 (brs, 1H), 3.01 (brs, 6H), 3.32 (brs, 1H), 3.45-3.55 (m, 3H), 3.63 (t, 2H), 5.09 (s, 2H), 6.72 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H), 7.25 (s, 1H) , 7.30-7.49 (m, 3H), 7.78 (d, 1H), 7.83 (d, 2H), 8.08 (d, 1H)

FAB (M + H): 469

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 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).

Enzyme reactions were carried out in 50 μl of 50 mM sodium hippies buffer containing 25 mM potassium chloride, 25 mM magnesium chloride, 10 mM Diti (DTT) and 50 μM zinc chloride, 1.5 μM Ras substrate protein, 0.15 μM tritium-panesyl pyrophosphate And farnesyl transferase 4.5 nM was used. The reaction was stopped by the addition of farnesyl transferase and the reaction was continued at 37 ° C. for 30 minutes, followed by the addition of 1 ml of ethanol solution containing 1 M hydrochloric acid. 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 the state of substrate unsaturation where the concentration of Ras substrate protein and panesyl enzyme showed a quantitative titer relationship. 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. Geranylgeranyl transferase for evaluating the selective inhibitory activity of the test compound was used after purification from the cerebellum by modifying the method of Shaver et al. (Schaber et al. J. Biol Chem., 265, 14701, 1990) Experiments were performed using geranyl geranyl pyrophosphate and Ras-CVIL substrate protein, which are specific substrates of geranylgeranyl transferase under conditions similar to the real transferase reaction. The experimental results are shown in Tables 7a to 7d below.

Experimental Example 2 Analysis of Inhibitory Effect of Intracellular Ras Farnesyl Transferase

In this experiment, a rat2 cell line expressing a C-Harvey-Ras protein having a transforming activity by mutation and a Rat2 cell line transformed with an H-Ras binding protein substituted with a polybasic lysine domain at the K-Ras carboxy terminus (see: Korean Patent Application No. 97-14409) was used, and the experiment was performed by modifying the method of Decrue et al.

The transformed rat2 fibroblast cell line was seeded at a density of 3 × 10 ⁵ cells per dish in a 60 mm cell culture dish, grown to a density of 50% or more by incubating for 48 hours in a 37 ° C. cell culture medium, and then treated with a test compound. . At this time, dimethyl sulfoxide (DMSO) was used as a solvent of the test compound, and dimethyl sulfoxide concentration was used as 1% in both the control group and the test group. After 4 hours of treatment with the test compound, methionine labeled with 150 μCi of radioisotope [35S] per 1 ml of medium was added and incubated for 20 hours, and the cells were washed with physiological saline. 1 ml of cooled cell lysis buffer (Magnesium chloride 5 mM, Dity 1 mM, NP40 1%, EDTA 1 mM, PMSF 1 mM, Lupetin 2 μM, Peptstatin A 2 μM and 50 μM Sodium Hippies buffer solution 2 μM) After the addition of the cells to lysate, the supernatant in which the cells were lysed was obtained by high-speed centrifugation (12,000 gx 5 minutes). The radioisotope labeling amount of the supernatant was measured and normalized to obtain quantitative results in the immunoprecipitation reaction. Subsequently, a monoclonal antibody, Y13-259 (see Furth, ME et al., J. Virol. , 43, 294, 1982), which specifically binds to Ras protein, was added to the reaction solution at Reacted. To this solution was added a protein A-agarose suspension bound to an immunoglobulin antibody from a goth-derived mouse and reacted at 4 ° C for 1 hour, followed by a buffer solution (sodium chloride) to remove the nonspecific binding substance from the immunoreactive precipitate. 50 mM, sodium dioxycholate 0.5%, NP40 0.5% and SDS 0.1% SDS). In order to analyze the precipitate using the electrophoretic method, the precipitate was added to the electrophoretic sample buffer and boiled, followed by electrophoresis using 13.5% SDS polyacrylamide gel. After electrophoresis, the gel was fixed, dried, and then subjected to photo printing by exposing to an X-ray film. The inhibitory effect of intracellular Ras farnesyl transferase was expressed as the concentration of test compound (IC ₅₀ ) in which the farnesyl binding was inhibited by measuring the intensity of the non-bound bands of the farnesyl bound band of the Ras protein. Tables 7a to 7d below show the inhibitory effects of representative compounds according to the invention. Here, IC ₅₀ is data obtained by performing Experimental Example 1 and CIC ₅₀ is data obtained by performing Experimental Example 2.

Compound number H-Ras IC ₅₀ (μM) H-Ras CIC ₅₀ (μM) K-Ras IC ₅₀ (μM) K-Ras CIC ₅₀ (μM) One 0.25 1-50 0.1-10 10-100 2 0.13 1-50 0.1-10 10-100 3 0.12 1-50 0.1-10 10-100 4 0.09 1-50 0.1-10 10-100 5 0.15 1-50 10 10-100 6 0.03 0.7 0.485 <20 7 0.15 1-50 0.1-10 10-100 8 0.27 1-50 0.1-10 10-100 9 0.07 1-50 0.1-10 10-100 10 0.3 1-50 0.1-10 10-100 11 0.39 1-50 0.1-10 10-100 12 0.06 1-50 0.1-10 10-100 13 0.04 1-50 0.1-10 10-100 14 0.038 1-50 0.1-10 10-100

15 0.025 1-50 0.1-10 10-100 16 0.57 1-50 0.1-10 10-100 17 0.2 1-50 0.1-10 10-100 18 0.74 1-50 0.1-10 10-100 19 0.068 1-50 0.1-10 10-100 20 0.23 1-50 0.1-10 10-100 21 0.16 1-50 0.1-10 10-100 22 0.42 1-50 0.1-10 10-100 23 0.12 1-50 0.1-10 10-100 24 0.02 3 0.1-10 ＞ 50 25 0.12 1-50 0.1-10 10-100 26 0.55 1-50 0.1-10 10-100 27 0.21 1-50 0.1-10 10-100 28 0.12 1-50 0.1-10 10-100 29 0.05 1-50 0.1-10 10-100 30 0.002 0.2 0.02 ＞ 10 31 0.01 0.1-1 0.01-0.1 10-100 32 0.005 0.2 0.16 20 33 0.004 0.1-1 0.1-10 10-100 34 0.004 0.1 0.12 20 35 0.0045 0.1 0.2 10-100 36 0.005 0.1 0.1 ＞ 50 37 8.21 1-50 0.1-10 10-100 38 0.68 1-50 0.1-10 10-100 39 0.4 1-50 0.1-10 10-100 40 0.26 1-50 18.5 10-100

41 0.72 1-50 1.83 10-100 42 0.03 4 0.1-10 ＞ 50 43 0.03 2 0.1-10 ＞ 50 44 0.06 1-50 0.1-10 10-100 45 0.6 1-50 0.1-10 10-100 46 0.014 One 0.1-10 10-100 47 0.0425 1-50 0.1-10 10-100 48 2.15 1-50 0.1-10 10-100 49 0.07 1-50 0.1-10 10-100 50 0.32 1-50 0.1-10 10-100 51 0.2 1-50 0.1-10 10-100 52 0.0007 0.01-0.1 0.1-1 10-50 53 0.23 1-50 1-10 10-100 54 12 10-100 10-100 10-100 55 0.90-0.9 1-50 0.1-10 10-100 56 0.0030 0.1 0.1 ＞ 50 57 1.8 ＞ 1 0.1-10 ＞ 20 58 0.01 ＞ 5 0.8 ＞ 50 59 0.45 1-50 22 ＞ 50 60 0.064 0.1-10 1.7 10-100 61 0.0005 <0.05 0.006 <10 62 0.0004 0.05 0.09 ＞ 50 63 0.9 1-50 10-100 10-100 64 10 1-50 0.1-10 10-100 65 0.26 1-50 0.1-10 10-100 66 8.6 1-50 1-50 10-100

67 0.0006 0.008 0.0015 10 68 0.002 0.03 0.002 4 69 0.004 0.015 0.006 10 70 0.004 <0.1 <0.1 10-100 71 0.001 0.015 0.100 <100 72 0.002 0.025 0.035 <50 73 0.004 0.030 0.062 <50 74 - - - <50 75 - - - <40 76 - - - <30 77 - - - <20 78 - - - <40 79 - - - <30 80 - - - <40 81 - - - <20

Claims (5)

A compound of Formula 1, a pharmaceutically acceptable salt or isomer thereof: Formula 1 In the above formula n ₁ represents an integer of 1 to 4, X represents O or S, A is hydrogen; Straight or branched C ₁ -C ₁₀ alkyl unsubstituted or substituted by C ₃ -C ₇ cycloalkyl or lower alkoxy; Or benzyl unsubstituted or substituted by halogen, cyano, nitro, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, lower alkoxy, phenoxy or lower alkyl, B is hydrogen; Or lower alkyl unsubstituted or substituted by hydroxy, mercapto, lower alkoxy, lower alkylthio or aryl, C represents lower alkyl unsubstituted or substituted by aryl; Any one selected from the group of structural formulas , , , , Wherein R ₁ and R ₂ each independently represent hydrogen, lower alkyl, lower alkoxy, halogen, cyano, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, hydroxy, phenyl or phenoxy, D represents an amino acid residue or lower alkyl ester of an amino acid residue; Any one selected from the group of structural formulas , , , , , From here R ₃ and R ₄ are each independently hydrogen; halogen; Hydroxy; Cyano; Lower alkyl; Lower alkoxy; Alkoxyalkyl; Alkylthio; Alkylsulfonyl; Alkylthioalkyl; Alkylthioalkyloxy; Aryl; Or oxy, thio, sulfonyl or lower alkyl substituted by aryl, Y represents O, S, SO ₂ , C═O, C═S, or CH ₂ or NH unsubstituted or substituted by lower alkyl or hydroxy, n ₂ represents an integer of 1 to 3, R ₅ and R ₆ are each independently hydrogen; Aryl; Lower alkyl unsubstituted or substituted by aryl or cyanoaryl; or Wherein n ₃ represents an integer of 2 to 4, Z represents O, S or SO ₂ , and R ₇ represents hydrogen or lower alkyl. The method of claim 1, n ₁ represents an integer of 1 to 3, X represents O or S, A represents straight or branched C ₁ -C ₁₀ alkyl, 4-brobobenzyl, or 4-cyanobenzyl unsubstituted or substituted by hydrogen, C ₅ -C ₆ cycloalkyl or lower alkoxy, B represents hydrogen, lower alkyl, or benzyl, C represents any one selected from the group of the following structural formulas, , , , Wherein R ₁ and R ₂ each independently represent hydrogen or lower alkyl, D represents a methionine or leucine residue or a lower alkylester of these amino acid residues; Any one selected from the group of structural formulas , , , , From here R ₃ and R ₄ are each independently hydrogen; halogen; Cyano; Lower alkyl; Lower alkoxy; Alkylthioalkyl; Alkylthioalkyloxy; Phenyl; Or oxy or lower alkyl substituted by phenyl, Y represents O, S, SO ₂ , C═O, or CH ₂ or NH unsubstituted or substituted by lower alkyl or hydroxy, n ₂ represents 1 or 2, R ₅ and R ₆ are each independently hydrogen; Phenyl; Lower alkyl unsubstituted or substituted by phenyl or 4-cyanophenyl; Or C ₂ -C ₄ linear alkyl substituted by hydroxy or lower alkoxy. The method of claim 2, 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole (1), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiophen-3-yl) carbonyl-1H-pyrrole (2), 3-benzoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (3), 3- (2-bromobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (4), 3- (3-bromobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (5), 3- (4-bromobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (6), 1- (1H-imidazol-4-yl) methyl-3- (2-methylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (7), 1- (1H-imidazol-4-yl) methyl-3- (3-methylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (8), 1- (1H-imidazol-4-yl) methyl-3- (4-methylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (9), 1- (1H-imidazol-4-yl) methyl-3- (3-methoxybenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (10), 1- (1H-imidazol-4-yl) methyl-3- (4-methoxybenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (11), 3- (2-chlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (12), 3- (4-chlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (13), 3- (2,4-dichlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (14), 3- (4-fluorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (15), 3- (2,4-difluorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (16), 3- (4-cyanobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (17), 1- (1H-imidazol-4-yl) methyl-3- (4-methylthiomethylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (18), 1- (1H-imidazol-4-yl) methyl-3- [4- (2-methylthioethyl) benzoyl] -4- (naphthalen-1-yl) -1H-pyrrole (19), 1- (1H-imidazol-4-yl) methyl-3- [4- (2-methylthioethoxy) benzoyl] -4- (naphthalen-1-yl) -1H-pyrrole (20), 1- (1H-imidazol-4-yl) methyl-3- (3-methylthiomethylbenzoyl) -4- (naphthalen-1-yl) -1H-pyrrole (21), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (3-phenylbenzoyl) -1H-pyrrole (22), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenylbenzoyl) -1H-pyrrole (23), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole (24), 3- (4-benzylbenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (25), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (naphthalen-1-yl) carbonyl-1H-pyrrole (26), 1- (1H-imidazol-4-yl) methyl-3- (4-methylbenzoyl) -4- (1-methylindol-3-yl) -1H-pyrrole (27), 5-n-butyl-3- (2,4-dichlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (28), 5-benzyl-3- (2,4-dichlorobenzoyl) -1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (29), 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -3- (thiophen-2-yl) carbonyl-1H-pyrrole 30, 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -3- (thiophen-3-yl) carbonyl-1H-pyrrole (31), 3-benzoyl-1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -1H-pyrrole (32), 3- (3-bromobenzoyl) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -1H-pyrrole (33) , 3- (4-bromobenzoyl) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-4- (naphthalen-1-yl) -1H-pyrrole (34) , 3- (4-fluorobenzoyl) -1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (35), 1- (1-methyl-1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-phenoxybenzoyl) -1H-pyrrole (36), (S) -1- (1H-imidazol-4-yl) methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (37), (S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (38), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (N-phenyl) carbamoyl-1H-pyrrole (39), 3- (N-benzyl) carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (40), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (piperidin-1-yl) carbonyl-1H-pyrrole (41), 1- (1H-imidazol-4-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (42), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiamorpholin-4-yl) carbonyl-1H-pyrrole (43), 3- (1,1-dioxothiamorpholin-4-yl) carbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (44) , 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (piperazin-1-yl) carbonyl-1H-pyrrole (45), 1- (1H-imidazol-4-yl) methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (46), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (thiazolidin-3-yl) carbonyl-1H-pyrrole (47), 3- (4-hydroxypiperidin-1-yl) carbonyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (48), 1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -3- (4-oxopiperidin-1-yl) carbonyl-1H-pyrrole (49), 3- [N- (2-hydroxyethyl)] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (50), 3- [N- (2-hydroxyethyl) -N-methyl] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (51) , 1- (1H-imidazol-4-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H-pyrrole (52) , 1- (1H-imidazol-4-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (quinolin-4-yl) -1H-pyrrole (53), 4- (1,2-dihydroacenaphthalen-5-yl) -1- (1H-imidazol-4-yl) methyl-3- (morpholin-4-yl) carbonyl-1H-pyrrole (54) , 3- [N- (4-cyanobenzyl)] carbamoyl-1- (1H-imidazol-4-yl) methyl-4- (naphthalen-1-yl) -1H-pyrrole (55), 1- (1-methyl-1H-imidazol-5-yl) methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (56), (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl -4- (naphthalen-1-yl) -1 H-pyrrole (57), (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl -4- (naphthalen-l-yl) -lH-pyrrole (58), (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-methoxycarbonyl-3-methyl) butyl] carbamoyl- 4- (naphthalen-1-yl) -1H-pyrrole (59), (S) -1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (1-hydroxycarbonyl-3-methyl) butyl] carbamoyl- 4- (naphthalen-1-yl) -1H-pyrrole (60), 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole 61, 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (4-methylpiperazin-1-yl) carbonyl-4- (naphthalen-1-yl)- 1 H-pyrrole 62, 1- [2- (1H-imidazol-1-yl) ethyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (63), (S) -1- [3- (1H-imidazol-4-yl) propyl] -3- [N- (1-methoxycarbonyl-3-methylthio) propyl] carbamoyl-4- (naphthalene- 1-day) -1H-pyrrole (64), (S) -3- [N- (1-hydroxycarbonyl-3-methylthio) propyl] carbamoyl-1- [3- (1H-imidazol-4-yl) propyl] -4- (naphthalene- 1-day) -1H-pyrrole 65, 1- [3- (1H-imidazol-4-yl) propyl] -3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole (66), 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (67), 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (68), 1- [1- (4-bromobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) carbonyl-4- (naphthalen-1-yl) -1H-pyrrole 69, 1- [1- (4-cyanobenzyl) -1H-imidazol-5-yl] methyl-3- (morpholin-4-yl) thiocarbonyl-4- (naphthalen-1-yl) -1H- Pyrrole 70, 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- (1-methyl-1H-imidazol-5-yl) methyl-4- (naphthalen-1-yl) -1H- Pyrrole (71), 1- (1-isobutyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H Pyrrole 72, 1- (1-cyclohexylmethyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl)- 1 H-pyrrole (73), 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-pentyl-1H-imidazol-5-yl) methyl-1H- Pyrrole (74), 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1- (1-octyl-1H-imidazol-5-yl) methyl-1H- Pyrrole (75), 1- (1-decyl-1H-imidazol-5-yl) methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalen-1-yl) -1H- Pyrrole (76), 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methylbutyl) -1H-imidazol-5-yl] methyl-4- (naphthalene-1- 1) -1H-pyrrole (77), 1- [1- (2-methoxyethyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole (78), 3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-1- [1- (3-methoxypropyl) -1H-imidazol-5-yl] methyl-4- (naphthalene-1 -Yl) -1H-pyrrole (79), 1- [1- (3-ethoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene-1 -Yl) -1H-pyrrole 80, or 1- [1- (3-Isopropoxypropyl) -1H-imidazol-5-yl] methyl-3- [N- (2-methoxyethyl) -N-methyl] carbamoyl-4- (naphthalene- 1-yl) -1H-pyrrole (81). (a) reacting a compound of formula 2 with a compound of formula 3 in a solvent in the presence of a base and then removing a protecting group in the presence of trifluoroacetic acid to prepare a compound of formula 1a; (b) reacting a compound of formula 4 with a compound of formula 3 in the presence of a base in a solvent to prepare a compound of formula 1b; (c) reacting a compound of formula 5 with a compound of formula 3 in a solvent in the presence of a base and removing a protecting group in the presence of trifluoroacetic acid to produce a compound of formula 6, followed by hydrogenation; To prepare the compound of 1c; (d) hydrolyzing the compound of Formula 7 to prepare a compound of Formula 8, and then coupling the compound of Formula 9 with a coupling agent in the presence of a coupling agent to prepare a compound of Formula 1d; (e) A process for preparing the compound of formula 1 as defined in claim 1, characterized by converting the carbonyl group of the compound of formula 1e to a thiocarbonyl group in the presence of a sulfiding agent Formula 2 Formula 3 Formula 1a Formula 4 Formula 1b Formula 5 Formula 6 Formula 1c Formula 7 Formula 8 Formula 9 Formula 1d Formula 1e Formula 1f In the above formula A, n ₁ , B, C, D, R ₅ , R ₆ are as defined in claim 1, A 'is the same as A, except hydrogen Tr represents trityl. A compound of formula Formula 8 Wherein A, n ₁ , B and C are as defined in claim 1.