IMIDAZOLE DERIVATIVES HAVING ARYL PIPERIDINE SUBSTITUENT, METHOD FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

FIELD OF THE INVENTION

The present invention relates to a novel imidazole derivative having an aryl piperidine substituent, a method for preparation thereof, and a pharmaceutical composition containing same.

BACKGROUND OF THE INVENTION

The occurrence of obesity in adults as well as children has rapidly increased over the last ten years, which has raised the risk of associated health problems including Type 2 diabetes, heart diseases, cancer, hypertension. Accordingly, many studies for obesity treatment have been performed.

Melanine-concentrating hormone (MCH) is a cyclic 19 amino acid peptide that has been implicated to be involved in the regulation of feeding behavior of a mammal. Studies with MCH-administered rat models have shown an increase in food intake, while MCH-deficient mice undergo weight loss due to a significant decrease in the food intake and an increase in the metabolic rate (see D. Qu et al., Nature, 380 (6571), 243-247, 1996). Also, the effect of MCH in regulating the feeding behavior is known to be attributed to MCH receptor-1 which stimulates feeding, and obesity in MCH receptor-1 knock-out mice does not take place even after MCH administration (see A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-4022, 2006).

Meanwhile, the effect of MCH is mediated by an MCH receptor-1 antagonist which is one of G-protein-coupled receptors. Such a MCH receptor-1 antagonist is also reported to be useful in treating depression and anxiety (see B. Borowsky et al., Nature Medicine, 8(8), 825-830, 2002), and also diabetes and metabolic disturbance (see D. S. Ludwig et al., J. Clin. Invest. 107, 379-386, 2001).

A specific MCH receptor-1 antagonist, GW3430, developed by Amgen and GlaxoSmithKline is currently undergoing clinical evaluation for the treatment of obesity (see Dyck et al, Bioorg. Med. Chem, Lett. 2006, 16, 4237-4242).

Also, Xenical® and Reductil®, the structures of which are shown below, are marketed as drugs for obesity treatment. However, they show unsatisfactory therapeutic effects and cause undesirable side effects (see Trisha Gura, Science 2003, 299, 849-852).

Accordingly, the present inventors have endeavored to develop a novel MCH receptor-1 antagonist and found that an imidazole derivative having a specific structure is capable of acting as an effective MCH receptor-1 antagonist to be useful for preventing or treating MCH-related diseases including obesity.

SUMMARY OF THE INVENTION

It is a primary object of the present invention to provide a novel imidazole derivative having an aryl piperidine substituent and a method for preparing the same.

It is another object of the present application to provide a pharmaceutical composition containing said imidazole derivative as an active ingredient for preventing or treating MCH-related diseases.

In accordance with one aspect of the present invention, there is provided an imidazole derivative having aryl piperidine substituents of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

R¹is

C_1-4alkyl,

in which X is H, halogen, OR⁵, C_1-4alkyl, CF₃, phenyl, CN, NO₂, —CO₂R⁶, or —CONR⁷R⁸, R⁵, R⁶, R⁷and R⁸being each independently H, halogen, C_1-3alkyl, or phenyl;

R⁴is H, halogen, C_1-3alkyl, C_1-3alkoxy, phenyl, or phenyl having at least one halogen or methyl substituent;

W is CH or N;

Y is O, S, or NR⁹, R⁹being H or C_1-3alkyl;

m is 1 or 2;

R²is at least one selected from the group consisting of H, halogen, C_1-3alkyl

phenyl, OR⁵, NO₂, CN, pyridyl, CHO, and —CONR⁷R⁸, in which X¹is H, halogen, C_1-3alkyl, OR⁵, or NO₂, and R⁵, R⁷, and R⁸are the same as defined above;

R³is C_1-3alkyl, phenyl, or phenyl having at least one halogen or methyl substituent;

A is CH or N, with the proviso that the number of N representing A does not exceed 2; and

n is an integer of 2 to 5.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel compound of formula (I) or a pharmaceutically acceptable salt thereof as a MCH receptor-1 antagonist.

Among the compounds of formula (I) of the present invention, preferred are those wherein

R¹is

in which X is H, halogen, OR⁵, C_1-4alkyl, CF₃, phenyl, CN, NO₂, —CO₂R⁶, or —CONR⁷R⁸, R⁵, R⁶, R⁷and R⁸being each independently H, halogen, C_1-3alkyl, or phenyl; and

R²is at least one selected from the group consisting of H, halogen, C_1-3alkyl, phenyl, OR⁵, NO₂, CN, pyridyl, and —CONR⁷R⁸, in which R³, R⁵, R⁷, R⁸, A and n are the same as defined above.

In another embodiment of the compounds of formula (I), preferred are those wherein

R¹is C_1-4alkyl;

R²is at least one selected from the group consisting of H, halogen, C_1-3alkyl,

OR⁵, NO₂, CN, pyridyl, CHO, and —CONR⁷R⁸, in which X¹is H, halogen, C_1-3alkyl, OR⁵, or NO₂, and R⁵, R⁷and R⁸are each independently H, C_1-3alkyl, or phenyl; and

R³, A and n are the same as defined above.

In another embodiment of the compounds of formula (I), preferred are those wherein

R¹is

in which R⁴is H, halogen, C_1-3alkyl, C_1-3alkoxy, phenyl, or phenyl having at least one halogen or methyl substituent;

W is CH or N;

Y is O, S or NR⁹, in which R⁹is H or C_1-3alkyl;

m is 1 or 2;

R²is at least one selected from the group consisting of H, halogen, C_1-3alkyl, phenyl, OR⁵, NO₂, CN, pyridyl, and —CONR⁷R⁸, R⁵, R⁷and R⁸being each independently H, C_1-3alkyl, or phenyl; and

R³, A and n are the same as defined above.

The inventive compound of formula (I) may be used in the form of a pharmaceutically acceptable addition salt formed with a free acid such as an organic or inorganic acid. Examples of such inorganic acid include hydrochloric, bromic, sulfuric, sulfurous and phosphoric acids, preferably hydrochloric acid, while the organic acid may be citric, acetic, maleic, fumaric, gluconic, methanesulfonic, glycolic, succinic, tartaric, 4-toluenesulfonic, galacturonic, embonic, glutamic and aspartic acids, preferably methanesulfonic acid.

The addition salt according to the present invention may be prepared by a conventional method, e.g., by dissolving the compound of formula (I) in a water-miscible organic solvent (e.g., acetone, methanol, ethanol and acetonitrile) and adding thereto an organic or inorganic acid specified above in an equivalent or excessive amount, followed by isolating the salt transformed.

The present invention also includes a solvate, hydrate and stereoisomer of the compound of formula (I).

Exemplary compounds of formula (I) according to the present invention are as follows and each structure thereof is shown in Table 1:

1) 2-phenyl-1-{2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethyl}-1H-benzimidazole;
2) 2-(4-chlorophenyl)-1-{2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethyl}-1H-benzimidazole;
3) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
4) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
5) 2-phenyl-1-{4-[4-(3-acetylaminophenyl)piperidin-1-yl]butyl}-1H-benzimidazole;
6) 2-(4-chlorophenyl)-1-{4-[4-(3-acetylaminophenyl)piperidin-1-yl]butyl}-1H-benzimidazole;
7) 2-phenyl-1-{5-[4-(3-acetylaminophenyl)piperidin-1-yl]pentyl}-1H-benzimidazole;
8) 2-(4-chlorophenyl)-1-{5-[4-(3-acetylaminophenyl)piperidin-1-yl]pentyl}-1H-benzimidazole;
9) 2-(2-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
10) 2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
11) 2-(4-bromophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
12) 2-(3,4-dichlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
13) 2-(3-bromophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
14) 2-(2-iodophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
15) 2-(2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
16) 2-(2,4-dichlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
17) 2-(2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
18) 2-(3-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
19) 2-(4-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-yl]propyl}-1H-benzimidazole;
20) 2-(4-isopropylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
21) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
22) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
23) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methyl-1H-benzimidazole;
24) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methyl-1H-benzimidazole;
25) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole;
26) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-fluoro-1H-benzimidazole;
27) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methoxy-1H-benzimidazole;
28) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methoxy-1H-benzimidazole;
29) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole;
30) 2-(4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)-piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole;
31) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-fluoro-1H-benzimidazole;
32) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-nitro-1H-benzimidazole;
33) 2-(2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole;
34) 2-(3-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole;
35) 2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole;
36) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-bromo-1H-benzimidazole;
37) 2-(2-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
38) 2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
39) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-4,5-dimethyl-1H-benzimidazole;
40) 2-(2-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-nitro-1H-benzimidazole;
41) 2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-nitro-1H-benzimidazole;
42) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-nitro-1H-benzimidazole;
43) 2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-bromo-1H-benzimidazole;
44) 2-(2,3,4,5-tetrafluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
45) 2-(4-trifluoromethylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
46) 2-(4-biphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
47) 2-(4-phenoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
48) 2-(4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
49) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,7-dimethyl-1H-benzimidazole;
50) 2-(3,4-difluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
51) 2-(4-cyanophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
52) 2-(3-cyanophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
53) 2-(4-chloro-2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
54) 2-(2-chloro-4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
55) 2-(3-nitrophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
56) 2-(5-chloro-2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
57) 2-(2-chloro-4-nitrophenyl)-1-{2-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
58) 2-(2,4-dimethoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
59) 2-(4-chloro-2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
60) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-carbamoyl-1H-benzimidazole;
61) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-carbamoyl-1H-benzimidazole;
62) 2-(3-carbamoylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
63) 2-(2-hydroxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
64) 2-(4-chlorophenyl)-1-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
65) 2-(4-chlorophenyl)-1-{3-[4-(3-benzoylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
66) 2-(4-chlorophenyl)-1-{3-[4-(3-(3-chlorobenzoylamino)phenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
67) 2-(4-chlorophenyl)-1-{3-[4-(3-(4-methylbenzoylamino)phenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
68) 6-bromo-5-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
69) 5-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
70) 2-(benzo[1,3]dioxol-5-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
71) 2-(4-chlorophenyl)-1-{2-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]ethyl}-1H-benzimidazole;
72) 2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-c]pyridine;
73) 2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-d]pyridine;
74) 5-bromo-6-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-e]pyridine;
75) 6-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-e]pyridine;
76) 2-(3-methoxycarbonylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
77) 2-(4-ethylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
78) 2-(4-cyanophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
79) 2-(m-tolyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
80) 2-(2-chloro-4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
81) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-cyano-1H-benzimidazole;
82) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-cyano-1H-benzimidazole;
83) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-fluoro-1H-benzimidazole;
84) 2-(4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-chloro-1H-benzimidazole;
85) 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-nitro-1H-benzimidazole;
86) 2-(4-chloro-2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
87) 2-(5-chloro-2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
88) 2-methyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
89) 2-methyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole;
90) 2-methyl-1-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
91) 2,5-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
92) 6-bromo-2,5-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
93) 6-bromo-2-ethyl-5-methyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
94) 6-bromo-2-butyl-5-methyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
95) 2-butyl-5,7-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
96) 2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
97) 2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
98) 6-bromo-2-butyl-5-methyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
99) 2-butyl-5,7-dimethyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
100) 2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
101) 2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
102) 2-butyl-5-formyl-6-phenyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
103) 2-butyl-5-methyl-6-(4-nitrophenyl)-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine;
104) 2-(pyridin-2-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
105) 2-(pyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
106) 2-(pyridin-4-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
107) 2-(furan-3-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
108) 2-(5-bromofuran-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
109) 2-(thiophen-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
110) 2-(5-methylthiophen-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
111) 2-(1-methyl-1H-pyrrol-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
112) 2-(5-bromopyridin-3-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
113) 2-(6-chloropyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
114) 2-(6-methylpyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
115) 2-(2-methoxypyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
116) 5-chloro-2-(pyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
117) 5-nitro-2-(pyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
118) 5-chloro-2-(5-bromofuran-2-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
119) 2-(furan-2-yl)-5-methoxy-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
120) 5-methyl-2-(thiophen-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
121) 5,6-dimethyl-2-(1-methylpyrrol-2-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
122) 2-(thiazol-4-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
123) 2-(4-methyloxazol-5-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
124) 2-(1-methyl-1H-imidazol-5-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
125) 2-(pyridin-2-ylmethyl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole;
126) 2-(pyridin-3-ylmethyl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole; and
127) 2-[2-(pyridin-3-yl)ethyl]-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole.

TABLE 1

Compound
Structure

1

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

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

Further, the present invention provides a method for preparing the compound of formula (I).

The inventive compound of formula (I) can be prepared by subjecting a compound of formula (II) to a reaction with a compound of formula (III) in a solvent in the presence of a base:

wherein, R¹, R², R³, A and n are the same as defined in formula (I) and L is a leaving group such as methanesulfonyloxy (OMs), toluenesulfonyloxy (OTs) and halogen.

Alternatively, the compound of formula (I) can be prepared by subjecting a compound of formula (IV) to a reaction with a compound of formula (V) in a solvent in the presence of a base:

wherein, R¹, R², R³, A and n are the same as defined in formula (I) and L is a leaving group such as OMs, OTs and halogen.

Examples of the base which may be used in the present invention include an organic base such as pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), and a mixture thereof; and an inorganic base such as NaOH, Na₂CO₃, K₂CO₃, Cs₂CO₃, and a mixture thereof. The base may be used in an equivalent or excessive amount.

Examples of the solvent which may be used in the present invention include an ether solvent such as tetrahydrofuran, dioxane, dichloromethane, and 1,2-dimethoxyethane; dimethyl formamide (DMF); dimethyl sulfoxide; acetonitrile; and a mixture thereof. The reaction may be conducted at a temperature ranging from room temperature to the boiling point of the solvent used.

The compound of formula (III) used as a starting material in the inventive method may be prepared by subjecting the compound of formula (V) to alkylation with

to obtain a compound of formula (V-1) and subjecting the compound of formula (V-1) to an acylation reaction with methanesulfonyl chloride (MsCl) or toluenesulfonyl chloride (TsCl); or by subjecting the compound of formula (V) to alkylation with

as shown in Reaction Scheme 1. The aryl piperidine compound of formula (V) may be prepared by the method disclosed in PCT Publication No. WO 03/004027.

wherein, R³and n are the same as defined in formula (I), X is halogen, and L is a leaving group such as OMs, OTs and halogen.

In Reaction Scheme 1, the alkylation step may be conducted in a suitable solvent in the presence of a base, and

may be used in an equivalent or excessive amount.

Examples of the base which may be used in the alkylation include an organic base such as pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and a mixture thereof; and an inorganic base such as NaOH, Na₂CO₃, K₂CO₃, Cs₂CO₃, and a mixture thereof. The base may be used in an equivalent or excessive amount.

Examples of the solvent which may be used in the alkylation include an ether such as tetrahydrofuran, dioxane, dichloromethane, and 1,2-dimethoxyethane; dimethyl formamide (DMF); dimethyl sulfoxide; acetonitrile; and a mixture thereof. The reaction may be conducted at a temperature ranging from 0° C. to the boiling point of the solvent used.

In Reaction Scheme 1, the acylation step may be conducted in a proper solvent in the presence of a base, and MsCl or TsCl may be used in an equivalent or excessive amount. The solvent and base may be the same as those used in the alkylation step. The reaction may be conducted at a temperature ranging from 0° C. to the boiling point of the solvent used.

Also, the compound of formula (IV) used as a starting material in the inventive method may be prepared by subjecting an imidazole compound to alkylation with

as shown in Reaction Scheme 2. The imidazole compound is commercially available, but it may be prepared by a conventionally known method (see PCT Publication No. WO 07/43943, Korean Patent No. 303944, and Oguchi et al., J. Med. Chem., 43(16), 3052, 2000).

wherein, R¹, R², A and n are the same as defined in formula (I), X is halogen, and L is a leaving group such as OMs, OTs and halogen.

In Reaction Scheme 2, the alkylation may be conducted in a proper solvent in the presence of a base. The solvent and base may be the same as those used in the alkylation step of Reaction Scheme 1. The reaction may be conducted at a temperature ranging from room temperature to the boiling point of the solvent used.

The compound of formula (I) having various R³may be prepared by deacetylating the compound of formula (I) in the presence of an acid or base to obtain an aniline derivative and subjecting the aniline derivative to a reaction with one of various acyl chloride or carboxylic acid compounds to form an amide compound, as shown in Reaction Scheme 3.

wherein, R¹, R², A and n are the same as defined in formula (I) and R^3′ represents R³of formula (I) excluding methyl.

In Reaction Scheme 3, the deacetylation step may be conducted in a suitable solvent in the presence of an acid or base. Examples of the acid include an inorganic acid such as hydrochloric acid and sulfuric acid in the form of an aqueous solution and an organic acid such as trifluoroacetic acid and methanesulfonic acid, in which the base may be used in an equivalent or excess amount. Examples of the base include NaOH, KOH, NaOMe, and NaOEt. Examples of the solvent include water, alcohol such as methanol, tetrahydrofuran, dioxane, acetonitrile, and a mixture thereof. Optionally, the solvent is not used. The reaction may be conducted at a temperature ranging from room temperature to the boiling point of the solvent used.

In Reaction Scheme 3, the amide forming step may be conducted by subjecting the aniline compound to a reaction with an acyl chloride in the presence of a base, or with a carboxylic acid derivative in the presence of a condensing agent, in a suitable solvent. Examples of the base include pyridine, triethylamine and N,N-diisopropylethylamine. Examples of the condensing agent include 1,3-dicyclohexylcarbodimide (DCC), 1,3-diisopropylcarbodimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,1-carbonyldiimidazole (CDI). Also, the condensing agent may be used in the form of a mixture with an organic base such as 1-hydroxybenzotriazole (HOBT), 4-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). Examples of the solvent include dichloromethane, chloroform, tetrahydrofuran, N,N-dimethyl formamide (DMF), acetonitrile, dimethyl sulfoxide (DMSO) and a mixture thereof. The reaction is preferably conducted at room temperature.

The present invention further provides a pharmaceutical composition for preventing or treating an MCH-related disease, comprising the inventive compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Examples of the MCH-related disease include obesity, depression, anxiety, diabete, metabolic disturbance, and schizophrenia.

The pharmaceutical composition of the present invention may be orally or parenterally administered and it may be formulated using conventional pharmaceutically acceptable diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants.

The solid formulation for oral administration may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose and gelatin, and lubricants such as magnesium stearate and talc. The liquid formulation for oral administration may take various forms such as suspension, solution, emulsion and syrup, which may contain diluents such as water and liquid paraffin, and various excipients such as wetting agents, sweetening agents, odorants and preservatives.

The formulation for parenteral administration may be in the form of steriled aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried product, and suppository. The non-aqueous solution or suspension form may contain propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethylolate. The suppository may be prepared by using a base such as witepsol, macrogol, Tween 61, cacao butter, laurin butter, and glycerol gelatin.

The amount of the inventive compound of formula (I) or a pharmaceutically salt thereof actually administered will be determined depending on various factors including the age, body weight, sex and condition of the patient and the chosen route of administration. The typical daily dosage of the compound of formula (I) is 0.1 to 1,000 mg, preferably 1 to 500 mg for an average 70 kg adult patient, and can be administered in a single dose or in divided doses.

The present invention will be described in further detail with reference to Examples. However, it should be understood that the present is not restricted by the specific Examples.

The molecular structures of the subject invention were confirmed by infrared spectrometry, NMR spectroscopy, mass spectroscopy, liquid chromatography, X-ray crystallography, rotation measurement, or comparison of ultimate analysis values for a representative compound with a real measurement values.

Preparation of Formula (V-1)
PREPARATION EXAMPLES 1 to 3

Preparation Example 1
Preparation of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propan-1-ol (Formula (V-1); n=2, Y=Me)

5.3 g (20.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 50 ml of N,N-dimethylformamide, and then 3.8 g (27.0 mmol) of 3-bromo-1-propanol and 8.6 g (62 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 150 ml of water and extracted with ethylacetate (100 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH₂Cl₂) to obtain 4.8 g (yield 85%) of the title compound.

¹H-NMR (300 MHz, CDCl₃) δ 1.76-1.86 (m, 6H), 2.13 (m, 2H), 2.17 (s, 3H), 2.55 (m, 1H), 2.71 (t, 2H), 3.25 (brd, 2H), 3.84 (t, 2H), 6.95 (d, 1H), 7.19-7.31 (m, 3H), 7.43 (s, 1H, NH); MS (m/e, M⁺): 276

Preparation Example 2
Preparation of 3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propan-1-ol (Formula (V-1); n=2, Y=i-Pr)

3.05 g (yield 81%) of the title compound was obtained by repeating the procedure of Preparation Example 1 except for using 3.5 g (12.4 mmol) of 3-[4-(3-isobutyrylaminophenyl)piperidine]hydrochloride.

¹H-NMR (300 MHz, CDCl₃) δ 1.25 (d, 6H), 1.69-1.78 (m, 4H), 1.83 (brd, 2H), 2.05 (t, 2H), 2.50 (m, 1H), 2.55 (m, 1H), 2.66 (t, 2H), 3.17 (brd, 2H), 3.83 (t, 2H), 6.92 (d, 1H), 7.23 (dd, 1H), 7.35-7.38 (m, 2H), 7.40 (s, 1H, NH); MS (m/e, M⁺): 304

Preparation Example 3
Preparation of 2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethanol (Formula (V-1); n=1, Y=Me)

2.0 g (7.8 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 20 ml of N,N-dimethylformamide, and then 1.3 g (10.2 mmol) of 2-bromoethanol and 3.2 g (23.4 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 60° C. for 5 hours. The reaction mixture was combined with 100 ml of water and extracted with ethylacetate (70 ml×5), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% methanol/CH₂Cl₂) to obtain 1.14 g (yield 56%) of the title compound.

¹H-NMR (300 MHz, CDCl₃) δ 1.73-1.82 (m, 4H), 2.09 (m, 2H), 2.18 (s, 3H), 2.40 (m, 1H), 2.57 (m, 2H), 3.05 (brd, 2H), 3.63 (t, 2H), 6.62 (d, 1H), 6.96-7.40 (m, 4H; MS (m/e, M⁺): 262

Preparation of Formula (III)
PREPARATION EXAMPLES 4 to 6

Preparation Example 4
Preparation of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl methanesulfonate (Formula (III); n=2, Y=Me)

4.5 g (16.3 mmol) of the compound obtained in Preparation Example 1 was dissolved in 70 ml of dichloromethane, and then cooled to 0° C. and 6.7 ml (48.0 mmol) of triethylamine was added to the resulting solution. Subsequently, 1.15 ml (19.5 mmol) of methanesulfonyl chloride, which was diluted in 10 ml of CH₂Cl₂, was slowly added to the solution, followed by mixing at 0° C. for 3 hours. The reaction mixture was combined with a mixture of 100 ml of water and saturated solution 30 ml of NaHCO₃and extracted with CH₂Cl₂(100 ml×2), and then a combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure to obtain 5.2 g (yield 90%) of the title compound. The resulting compound was used in a next reaction without further being refined.

¹H-NMR (300 MHz, CDCl₃) δ 1.90-2.03 (m, 4H), 2.21 (s, 3H), 2.39 (m, 1H), 2.43 (m, 2H), 2.80 (s, 3H), 2.82 (m, 2H), 3.07 (m, 2H), 3.58 (m, 2H), 4.40 (t, 2H), 6.93 (d, 1H), 7.20 (dd, 1H), 7.42 (brs, 1H, NH), 7.58 (d, 1H), 8.48 (s, 1H, NH); MS (m/e, M⁺): 354

Preparation Example 5
Preparation of 3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl methanesulfonate (Formula (III); n=2, Y=i-Pr)

3.5 g (yield 93%) of the title compound was obtained by repeating the procedure of Preparation Example 4 except for using 3.0 g (9.87 mmol) of the compound obtained by Preparation Example 2.

¹H-NMR (300 MHz, CDCl₃) δ 1.23 (d, 6H), 1.77-1.94 (m, 4H), 2.62 (m, 2H), 2.65 (m, 1H), 2.76 (m, 1H), 2.79 (s, 3H), 3.38 (m, 2H), 3.83 (brd, 2H), 4.32 (t, 2H), 4.40 (t, 2H), 6.74 (d, 1H), 7.17 (dd, 1H), 7.51 (s, 1H), 7.86 (d, 1H), 9.34 (s, 1H, NH); MS (m/e, M⁺): 382

Preparation Example 6
Preparation of 2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethyl methanesulfonate (Formula (III); n=1, Y=Me)

0.78 g (yield 75%) of the title compound was obtained by repeating the procedure of Preparation Example 4 except for using 0.8 g (3.05 mmol) of the compound obtained by Preparation Example 3. The resulting compound was used in a next reaction without further being refined.

¹H-NMR (300 MHz, CDCl₃) δ 1.75-1.86 (m, 4H), 2.19 (s, 3H), 2.45 (m, 1H), 2.76 (s, 3H), 3.01 (m, 2H), 3.14 (t, 2H), 3.40 (t, 2H), 3.48 (t, 2H), 6.88 (d, 1H), 7.17-7.49 (m, 4H); MS (m/e, M⁺): 340

Preparation of Formula (IV)
PREPARATION EXAMPLES 7 to 10

Preparation Example 7
Preparation of 1-(4-chlorobutyl)-2-phenyl-1H-benzimidazole (Formula (IV); n=3, X=H)

2.5 g (12.88 mmol) of 2-phenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) of K₂CO₃and 2.0 ml (16.7 mmol) of 1-chloro-4-iodobutane were added to the resulting solution, followed by mixing the mixture at a room temperature for 10 hours. The reactant was combined with 100 ml of water and extracted with ethylacetate (70 ml×5) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=2/1) to obtain 3.5 g (yield 96%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.69 (m, 2H), 2.00 (m, 2H), 3.43 (t, 2H), 4.29 (t, 2H), 7.30-7.50 (m, 3H), 7.55 (m, 3H), 7.72 (m, 2H), 7.83 (m, 1H); MS (m/e, M⁺): 285

Preparation Example 8
Preparation of 1-(4-chlorobutyl)-2-(4-chlorophenyl)-1H-benzimidazole (Formula (IV); n=3, X=Cl)

2.6 g (yield 93%) of the title compound was obtained by repeating the procedure of Preparation Example 7 except for using 2.0 g (8.73 mmol) of 2-(4-chlorophenyl)benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.69 (m, 2H), 2.00 (m, 2H), 3.46 (t, 2H), 4.27 (t, 2H), 7.34 (m, 2H), 7.41 (m, 1H), 7.51 (d, 2H), 7.66 (d, 2H), 7.81 (m, 1H); MS (m/e, M⁺): 319, 283, 255, 206

Preparation Example 9
Preparation of 1-(5-chloropentyl)-2-phenyl-1H-benzimidazole (Formula (IV); n=4, X═H)

2.5 g (12.88 mmol) of 2-phenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) of K₂CO₃and 2.3 ml (16.7 mmol) of 1-chloro-5-iodopetane were added to the resulting solution, followed by mixing the solution at a room temperature for 10 hours. The reaction mixture was combined with 100 ml of water and extracted with ethylacetate (70 ml×5) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=3/1) to obtain 3.16 g (yield 82%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.35 (m, 2H), 1.67-1.87 (m, 4H), 3.41 (t, 2H), 4.25 (t, 2H), 7.31 (m, 2H), 7.39 (m, 1H), 7.51-7.55 (m, 3H), 7.70 (m, 2H), 7.81 (m, 1H); MS (m/e, M⁺): 298

Preparation Example 10
Preparation of 1-(5-chloropentyl)-2-(4-chlorophenyl)-1H-benzimidazole (Formula (IV); n=4, X=Cl)

2.9 g (yield 80%) of the title compound was obtained by repeating the procedure of Preparation Example 8 except for using 2.5 g (10.92 mmol) of 2-(4-chlorophenyl)benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.35 (m, 2H), 1.68-1.87 (m, 4H), 3.43 (t, 2H), 4.24 (t, 2H), 7.29-7.41 (m, 3H), 7.50 (d, 2H), 7.64 (d, 2H), 7.82 (m, 1H); MS (m/e, M⁺): 333

Preparation of Imidazole Derivative
Examples 1 to 4

Example 1
2-phenyl-1-{2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethyl}-1H-benzimidazole

70 mg (0.36 mmol) of 2-phenylbenzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 122 mg (0.36 mmol) of 2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethylmethanesulfonate obtained by Preparation Example 6 and 150 mg (1.08 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 56 mg (yield 36%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.55 (−1.77 (m, 6H), 2.06 (m, 2H), 2.16 (m, 3H), 2.43 (m, 1H), 2.78 (t, 2H), 2.85 (br-d, 2H), 4.39 (t, 2H), 6.92 (d, 1H), 7.23-7.38 (m, 5H), 7.50-7.54 (m, 4H), 7.79-7.83 (m, 3H); MS (m/e, M⁺): 438, 231, 207, 188, 160, 146

Example 2
2-(4-chlorophenyl)-1-{2-[4-(3-acetylaminophenyl)piperidin-1-yl]ethyl}-1H-benzimidazole

45 mg (yield 31%) of the title compound was obtained by repeating the procedure of Example 1 except for using 70 mg (0.31 mmol) of 2-(4-chlorophenyl)benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.50 (−1.79 (m, 6H), 2.08 (m, 2H), 2.17 (m, 3H), 2.45 (m, 1H), 2.78 (t, 2H), 2.85 (br-d, 2H), 4.37 (t, 2H), 6.92 (d, 1H), 7.24-7.37 (m, 5H), 7.45 (m, 1H), 7.50 (d, 2H, J=8.4 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.84 (m, 1H); MS (m/e, M⁺): 472, 231, 188, 160, 146

Example 3
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (0.36 mmol) of 2-phenylbenzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 127 mg (0.36 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propylmethanesulfonate obtained by Preparation Example 4 and 150 mg (1.08 mmol) of K₂CO₃were added to the resulting solution, followed by mixing the solution at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 75 mg (yield 46%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.61-1.77 (m, 4H), 1.89-2.01 (m, 4H), 2.15 (s, 3H), 2.28 (t, 2H), 2.42 (m, 1H), 2.83 (brd, 2H), 4.37 (t, 2H), 6.94 (d, 1H, J=7.3 Hz), 7.24-7.32 (m, 4H), 7.46 (m, 2H), 7.47-7.53 (m, 4H), 7.73 (m, 2H), 7.80 (m, 1H); MS (m/e, M⁺): 452, 424, 367, 257, 231

Example 4
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

77 mg (yield 51%) of the title compound was obtained by repeating the procedure of Example 3 except for using 70 mg (0.31 mmol) of 2-(4-chlorophenyl)benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.79 (m, 4H), 1.90-2.01 (m, 4H), 2.16 (s, 3H), 2.26 (t, 2H), 2.43 (m, 1H), 2.82 (brd, 2H), 4.37 (t, 2H), 6.95 (d, 1H, J=7.5 Hz), 7.24-7.37 (m, 5H), 7.46 (m, 1H), 7.52 (d, 2H, J=8.4 Hz), 7.71 (d, 2H, J=8.4 Hz), 7.80 (m, 1H); MS (m/e, M⁺): 486, 458, 311, 270, 257, 231

Preparation of Imidazole Derivative
Examples 5 to 8

Example 5
2-phenyl-1-{4-[4-(3-acetylaminophenyl)piperidin-1-yl]butyl}-1H-benzimidazole

100 mg (0.39 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride was dissolved in 5 ml of N,N-dimethylformamide, and 112 mg (0.39 mmol) of 1-(4-chlorobutyl)-2-phenyl-1H-benzimidazole obtained by Preparation Example 7, 163 mg (1.17 mmol) of K₂CO₃and 20 mg (0.12 mmol) of KI were added to the resulting solution, followed by mixing the solution at 100° C. for 5 hours. The reaction mixture was combined in 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% MeOH/CH₂Cl₂) to obtain 104 mg (yield 57%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.48 (m, 2H), 1.69-1.99 (m, 8H), 2.15 (s, 3H), 2.30 (t, 2H), 2.45 (m, 1H), 2.90 (br, 2H), 4.28 (t, 2H), 7.23-7.38 (m, 6H), 7.45-7.53 (m, 4H), 7.72 (m, 2H), 7.81 (m, 1H); MS (m/e, M⁺): 467

Example 6
2-(4-chlorophenyl)-1-{4-[4-(3-acetylaminophenyl)piperidin-1-yl]butyl}-1H-benzimidazole

127 mg (yield 65%) of the title compound was obtained by repeating the procedure of Example 5 except for using 100 mg (0.39 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride, and 90 mg (0.39 mmol) of 1-(4-chlorobutyl)-2-(4-chlorophenyl)-1H-benzimidazole resulting from Preparation Example 8.

¹H NMR (300 MHz, CDCl₃) δ 1.48 (m, 2H), 1.71-2.00 (m, 8H), 2.15 (s, 3H), 2.30 (t, 2H), 2.42 (m, 1H), 2.91 (br, 2H), 4.26 (t, 2H), 6.95 (d, 1H), 7.23-7.38 (m, 6H), 7.45-7.52 (m, 3H), 7.67 (d, 2H), 7.80 (m, 1H); MS (m/e, M⁺): 500, 458, 324, 284,

Example 7
2-phenyl-1-{5-[4-(3-acetylaminophenyl)piperidin-1-yl]pentyl}-1H-benzimidazole

120 mg (yield 55%) of the title compound was obtained by repeating the procedure of Example 5 except for using 100 mg (0.39 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride, and 103 mg (0.39 mmol) of 1-(5-chloropentyl)-2-phenyl-1H-benzimidazole resulting from Preparation Example 9.

5 g: ¹H NMR (300 MHz, CDCl₃) δ 1.26 (m, 2H), 1.47 (m, 2H), 1.73-1.96 (m, 8H), 2.16 (s, 3H), 2.27 (t, 2H), 2.45 (m, 1H), 2.93 (brd, 2H), 4.25 (t, 2H), 6.95 (d, 1H), 7.26-7.41 (m, 7H), 7.51 (m, 3H), 7.70 (m, 2H), 7.80 (m, 1H); MS (m/e, M⁺): 480

Example 8
2-(4-chlorophenyl)-1-{5-[4-(3-acetylaminophenyl)piperidin-1-yl]pentyl}-1H-benzimidazole

118 mg (yield 59%) of the title compound was obtained by repeating the procedure of Example 5 except for using 100 mg (0.39 mmol) of 4-(3-acetylaminophenyl)piperidine hydrochloride, and 130 mg (0.39 mmol) of 1-(5-chloropentyl)-2-(4-chlorophenyl)-1H-benzimidazole resulting from Preparation Example 10.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (m, 2H), 1.48 (m, 2H), 1.72-1.86 (m, 6H), 1.99 (m, 2H), 2.16 (s, 3H), 2.28 (t, 2H), 2.46 (m, 1H), 2.94 (brd, 2H), 4.24 (t, 2H), 6.97 (d, 1H), 7.23-7.41 (m, 7H), 7.50 (d, 2H), 7.66 (d, 2H), 7.68 (m, 1H); MS (m/e, M⁺): 515

Preparation of Imidazole Derivative
Examples 9 to 63

Example 9
2-(2-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (0.31 mmol) of 2-(2-chlorophenyl)-1H-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 110 mg (0.31 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl methanesulfonate obtained by Preparation Example 4 and 130 mg (0.93 mmol) of K₂CO₃were added to the resulting solution, followed by mixing the solution at 80° C. for 5 hours. The reaction mixture was combined in 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 87 mg (yield 58%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.75 (m, 4H), 1.85-1.90 (m, 4H), 2.16 (s, 3H), 2.23 (t, 2H), 2.38 (m, 1H), 2.78 (brd, 2H), 4.17 (t, 2H), 6.93 (d, 1H, J=7.5 Hz), 7.24-7.56 (m, 11H), 7.83 (m, 1H); MS (m/e, M⁺): 486, 451, 375, 346, 269, 257

Example 10
2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

83 mg (yield 55%) of the title compound was obtained by repeating the procedure of Example 9 except for using 70 mg (0.31 mmol) of 2-(3-chlorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.59 (−1.78 (m, 4H), 1.89-1.99 (m, 4H), 2.16 (m, 3H), 2.27 (t, 2H), 2.46 (m, 1H), 2.82 (br-d, 2H), 4.38 (t, 2H), 6.94 (d, 1H), 7.24-7.50 (m, 9H), 7.65 (d, 1H), 7.78 (s, 1H, NH), 7.83 (d, 1H); MS (m/e, M⁺): 487

Example 11
2-(4-bromophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (yield 51%) of the title compound was obtained by repeating the procedure of Example 9 except for using 70 mg (0.25 mmol) of 2-(4-bromophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.74 (m, 2H), 1.93 (m, 4H), 2.16 (s, 3H), 2.26 (t, 2H), 2.43 (m, 1H), 2.79 (brd, 2H), 4.36 (t, 2H), 6.94 (d, 1H), 7.25-7.37 (m, 6H), 7.46 (m, 1H), 7.66 (m, 4H), 7.81 (m, 1H); MS (m/e, M⁺): 531

Example 12
2-(3,4-dichlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

67 mg (yield 48%) of the title compound was obtained by repeating the procedure of Example 9 except for using 70 mg (0.27 mmol) of 2-(3,4-dichlorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.55-1.64 (m, 2H), 1.76 (m, 2H), 1.89-1.99 (m, 4H), 2.17 (m, 3H), 2.26 (t, 2H), 2.42 (m, 1H), 2.80 (br-d, 2H), 4.39 (t, 2H), 6.94 (d, 1H), 7.24-7.35 (m, 6H), 7.48 (m, 1H), 7.50 (m, 2H) 7.82 (d, 1H), 7.92 (s, 1H); MS (m/e, M⁺): 521, 479, 345, 304, 289, 257, 231

Example 13
2-(3-bromophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

67 mg (yield 50%) of the title compound was obtained by repeating the procedure of Example 9 except for using 70 mg (0.25 mmol) of 2-(3-bromophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.78 (m, 4H), 1.89-1.99 (m, 4H), 2.16 (m, 3H), 2.27 (t, 2H), 2.46 (m, 1H), 2.83 (br-d, 2H), 4.38 (t, 2H), 6.96 (d, 1H), 7.24-7.47 (m, 8H), 7.62-7.71 (m, 2H), 7.80 (d, 1H), 7.94 (s, 1H); MS (m/e, M⁺): 531, 451, 357, 316, 257, 231

Example 14
2-(2-iodophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

88 mg (yield 49%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.31 mmol) of 2-(2-iodophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.65-1.82 (m, 4H), 1.92-2.05 (m, 4H), 2.15 (m, 3H), 2.37 (m, 2H), 2.45 (m, 1H), 2.92 (br-d, 2H), 4.16 (t, 2H), 6.91 (d, 1H, J=6.7 Hz), 7.20-7.53 (m, 10H), 7.83 (d, 1H, J=7.3 Hz), 7.98 (d, 1H); MS (m/e, M⁺): 578, 451, 347, 256, 231

Example 15
2-(2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

103 mg (yield 47%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.47 mmol) of 2-(2-fluorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58 (m, 2H), 1.72 (m, 2H), 1.91 (m, 4H), 2.17 (s, 3H), 2.23 (t, 2H), 2.37 (m, 1H), 2.81 (brd, 2H), 4.24 (t, 2H), 6.92 (d, 1H), 7.21-7.34 (m, 7H), 7.39 (s, 1H), 7.48 (m, 2H), 7.66 (t, 1H), 7.82 (dd, 1H); MS (m/e, M⁺): 470

Example 16
2-(2,4-dichlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

110 mg (yield 56%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.38 mmol) of 2-(2,4-dichlorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.57 (m, 2H), 1.65 (m, 2H), 1.91 (m, 4H), 2.17 (s, 3H), 2.25 (t, 2H), 2.43 (m, 1H), 2.84 (brd, 2H), 4.16 (t, 2H), 6.93 (d, 1H), 7.25-7.37 (m, 8H), 7.43 (d, 1H), 7.49 (d, 1H), 7.59 (d, 1H), 7.82 (d, 1H); MS (m/e, M⁺): 521

Example 17
2-(2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

98 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.44 mmol) of 2-(2-methoxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.66-1.83 (m, 4H), 1.84-2.04 (m, 4H), 2.17 (s, 3H), 2.35 (t, 2H), 2.37 (m, 1H), 2.89 (br, 2H), 3.69 (s, 3H), 4.07 (t, 2H), 6.90 (d, 1H), 7.05 (d, 1H), 7.13 (dd, 1H), 7.23-7.37 (m, 4H), 7.42-7.45 (m, 2H), 7.50 (dd, 1H), 7.57 (d, 1H), 7.79 (d, 1H); MS (m/e, M⁺): 482

Example 18
2-(3-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

102 mg (yield 48%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.44 mmol) of 2-(3-methoxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58 (m, 2H), 1.71 (m, 2H), 1.90 (m, 4H), 2.12 (s, 3H), 2.26 (t, 2H), 2.39 (m, 1H), 2.78 (d, 2H), 3.84 (s, 3H), 4.37 (t, 2H), 6.94 (d, 1H), 7.04 (d, 1H), 7.21-7.45 (m, 9H), 7.79 (dd, 1H), 7.98 (s, 1H); MS (m/e, M⁺): 482

Example 19
2-(4-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

98 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.44 mmol) of 2-(4-methoxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.61 (m, 2H), 1.72 (m, 2H), 1.96 (m, 4H), 2.15 (s, 3H), 2.24 (t, 2H), 2.37 (m, 1H), 2.79 (d, 2H), 3.85 (s, 3H), 4.36 (t, 2H), 6.92 (d, 1H), 7.02 (d, 2H), 7.23-7.43 (m, 6H), 7.68 (d, 2H), 7.71 (dd, 1H); MS (m/e, M⁺): 482

Example 20
2-(4-isopropylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

114 mg (yield 55%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.42 mmol) of 2-(4-isopropylphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (d, 3H), 1.29 (d, 3H), 1.63 (m, 2H), 1.74 (m, 2H), 1.94 (m, 4H), 2.14 (s, 3H), 2.30 (t, 2H), 2.54 (m, 1H), 2.84 (brd, 2H), 2.97 (m, 1H), 4.36 (t, 2H), 6.93 (d, 1H), 7.23-7.38 (m, 6H), 7.44 (m, 1H), 7.47 (s, 1H), 7.65 (d, 2H), 7.80 (m, 1H); MS (m/e, M⁺): 492

Example 21
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

123 mg (yield 57%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.45 mmol) of 2-phenyl-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.65 (m, 2H), 1.70 (m, 2H), 1.91 (m, 4H), 2.10 (s, 3H), 2.26 (t, 2H), 2.38 (s, 3H), 2.40 (s, 3H), 2.45 (m, 1H), 2.80 (brd, 2H), 4.29 (t, 2H), 6.92 (d, 1H), 7.19 (dd, 2H), 7.32 (d, 1H), 7.41 (s, 1H), 7.47 (m, 3H), 7.56 (s, 1H), 7.71 (dd, 2H), 7.95 (s, 1H); MS (m/e, M⁺): 480

Example 22
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

118 mg (yield 59%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(4-chlorophenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58 (m, 2H), 1.74 (m, 2H), 1.92 (m, 4H), 2.13 (s, 3H), 2.24 (t, 2H), 2.38 (s, 3H), 2.40 (s, 3H), 2.46 (m, 1H), 2.79 (brd, 2H), 4.30 (t, 2H), 6.93 (d, 1H), 7.22 (d, 2H), 7.33 (s, 1H), 7.35 (d, 1H), 7.46 (s, 2H), 7.55 (s, 1H), 7.66 (d, 3H): MS (m/e, M⁺): 515

Example 23
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methyl-1H-benzimidazole

103 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.48 mmol) of 2-phenyl-5-methyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.60-1.74 (m, 4H), 1.89-1.98 (m, 4H), 2.14 (m, 3H), 2.27 (t, 2H), 2.42 (m, 1H), 2.49 (s, 3H), 2.84 (br-d, 2H), 4.32 (t, 2H), 6.95 (d, 1H), 7.13 (m, 1H), 7.23-7.40 (m, 5H), 7.49-7.59 (m, 4H), 7.70-7.74 (m, 3H); MS (m/e, M⁺): 466, 438, 360, 291, 250, 231

Example 24
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methyl-1H-benzimidazole

101 mg (yield 49%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.41 mmol) of 2-(4-chlorophenyl)-5-methyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.61 (m, 2H), 1.73 (m, 2H), 1.92 (m, 4H), 2.14 (s, 3H), 2.23 (t, 2H), 2.45 (m, 1H), 2.49 (s, 3H), 2.51 (s, 3H), 2.81 (brd, 2H), 4.31 (t, 2H), 6.92 (brd, 1H), 7.13 (dd, 1H), 7.23 (d, 2H), 7.35 (dd, 2H), 7.48 (d, 2H), 7.59 (s, 1H), 7.67 (d, 3H): MS (m/e, M⁺): 501

Example 25
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole

109 mg (yield 55%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.38 mmol) of 2-(4-chlorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.55 (m, 2H), 1.74 (m, 2H), 1.92 (m, 4H), 2.16 (s, 3H), 2.23 (t, 2H), 2.42 (m, 1H), 2.76 (d, 2H), 4.35 (t, 2H), 6.95 (d, 1H), 7.24-7.41 (m, 6H), 7.50 (d, 2H), 7.69 (d, 2H), 7.77 (d, 1H): MS (m/e, M⁺): 521

Example 26
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-fluoro-1H-benzimidazole

121 mg (yield 55%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.47 mmol) of 2-phenyl-5-fluoro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.74 (m, 2H), 1.92 (m, 4H), 2.15 (s, 3H), 2.26 (t, 2H), 2.42 (d, 2H), 4.34 (t, 2H), 6.87 (d, 1H), 7.03 (dd, 1H), 7.21-7.53 (m, 9H), 7.70-7.74 (m, 2H): MS (m/e, M⁺): 470

Example 27
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methoxy-1H-benzimidazole

114 mg (yield 53%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.45 mmol) of 2-phenyl-5-methoxy-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 4H), 1.91 (m, 4H), 2.18 (s, 3H), 2.25 (t, 2H), 2.39 (m, 1H), 2.82 (brd, 2H), 3.88 (d, 3H), 4.33 (t, 2H), 6.90-6.94 (m, 2H), 7.22-7.33 (m, 4H), 7.49 (m, 3H), 7.67-7.73 (m, 3H): MS (m/e, M⁺): 482

Example 28
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-methoxy-1H-benzimidazole

108 mg (yield 54%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.38 mmol) of 2-(4-chlorophenyl)-5-methoxy-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.76 (m, 4H), 1.91 (m, 4H), 2.18 (s, 3H), 2.25 (t, 2H), 2.39 (m, 1H), 2.82 (brd, 2H), 3.89 (d, 3H), 4.33 (t, 2H), 6.93-6.98 (m, 2H), 7.28-7.38 (m, 5H), 7.51 (d, 2H), 7.71 (m, 2H): MS (m/e, M⁺): 517

Example 29
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole

106 mg (yield 51%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.43 mmol) of 2-phenyl-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ NMR (300 MHz, CDCl₃) δ 1.65-1.81 (m, 4H), 1.90-2.00 (m, 4H), 2.15 (s, 3H), 2.25 (t, 2H), 2.45 (m, 1H), 2.82 (br-d, 2H), 4.30 (t, 2H), 6.92 (d, 1H, J=6.8 Hz), 7.24-7.53 (m, 9H), 7.69-7.79 (m, 3H); MS (m/e, M+): 487

Example 30
2-(4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole

70 mg (yield 35%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(4-fluorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.61 (m, 2H), 1.75 (m, 2H), 1.89-1.97 (m, 4H), 2.17 (s, 3H), 2.26 (t, 2H), 2.45 (m, 1H), 2.80 (br-d, 2H), 4.32 (t, 2H), 6.95 (d, 1H), 7.21-7.38 (m, 7H), 7.69-7.78 (m, 3H); MS (m/e, M⁺): 504

Example 31
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-fluoro-1H-benzimidazole

67 mg (yield 33%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(4-chlorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.60 (m, 2H), 1.75 (m, 2H), 1.89-1.97 (m, 4H), 2.17 (s, 3H), 2.25 (t, 2H), 2.44 (m, 1H), 2.80 (br-d, 2H), 4.32 (t, 2H), 6.97 (d, 1H), 7.05 (m, 1H), 7.15-7.40 (m, 5H), 7.51 (d, 2H), 7.68 (d, 2H); MS (m/e, M+): 505

Example 32
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-nitro-1H-benzimidazole

86 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.42 mmol) of 2-phenyl-5-nitro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.55 (m, 2H), 1.72 (m, 2H), 1.87-1.97 (m, 4H), 2.19 (s, 3H), 2.26 (t, 2H), 2.41 (m, 1H), 2.76 (br-d, 2H), 4.45 (t, 2H), 6.92 (d, 1H), 7.24-7.32 (m, 3H), 7.38 (s, 1H, NH), 7.57-7.59 (m, 4H), 7.76 (m, 2H), 8.25 (dd, 1H), 8.72 (d, 1H); MS (m/e, M+): 483

Example 33
2-(2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole

110 mg (yield 56%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(2-s fluorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.71 (m, 2H), 1.85-1.93 (m, 4H), 2.15 (s, 3H), 2.20 (t, 2H), 2.42 (m, 1H), 2.76 (br, 2H), 4.23 (t, 2H), 6.94 (d, 1H), 7.24-7.80 (m, 11H); MS (m/e, M+): 504, 288, 257, 231

Example 34
2-(3-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole

108 mg (yield 54%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(3-fluorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.64 (m, 2H), 1.77 (m, 2H), 1.87-1.95 (m, 4H), 2.17 (s, 3H), 2.26 (t, 2H), 2.42 (m, 1H), 2.82 (br, 2H), 4.35 (t, 2H), 6.94 (d, 1H), 7.25-7.79 (m, 11H); MS (m/e, M+): 504, 476, 380, 329, 288, 257, 231

Example 35
2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-chloro-1H-benzimidazole

100 mg (yield 51%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.38 mmol) of 2-(3-chlorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.61-1.75 (m, 4H), 1.88-1.96 (m, 4H), 2.17 (s, 3H), 2.26 (t, 2H), 2.42 (m, 1H), 2.81 (brd, 2H), 4.35 (t, 2H), 6.96 (d, 1H), 7.25-7.79 (m, 11H); MS (m/e, M+): 520, 492, 409, 380, 302, 257, 231

Example 36
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-bromo-1H-benzimidazole

92 mg (yield 50%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.32 mmol) of 2-(4-chlorophenyl)-5-bromo-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.60-1.77 (m, 4H), 1.88-1.98 (m, 4H), 2.16 (s, 3H), 2.23 (t, 2H), 2.42 (m, 1H), 2.80 (brd, 2H), 4.34 (t, 2H), 6.96 (d, 1H), 7.23-7.43 (m, 6H), 7.50 (d, 2H), 7.64 (m, 1H), 7.69 (d, 2H); MS (m/e, M+): 566, 536, 485, 348, 257, 231

Example 37
2-(2-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

106 mg (yield 53%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(2-chlorophenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58-1.75 (m, 4H), 1.82-1.91 (m, 4H), 2.14 (s, 3H), 2.21 (t, 2H), 2.38 (m, 1H), 2.39 (s, 3H), 2.42 (s, 3H), 2.76 (br, 2H), 4.10 (t, 2H), 6.94 (d, 1H), 7.22-7.30 (m, 3H), 7.39-7.58 (m, 7H); MS (m/e, M+): 514, 499, 479, 374, 339, 283, 231

Example 38
2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

110 mg (yield 55%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(3-chlorophenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62-1.78 (m, 4H), 1.90-1.98 (m, 4H), 2.16 (s, 3H), 2.27 (t, 2H), 2.38 (m, 1H), 2.39 (s, 3H), 2.42 (s, 3H), 2.84 (br, 2H), 4.32 (t, 2H), 6.94 (d, 1H), 7.23-7.46 (m, 7H), 7.56 (s, 1H), 7.61 (m, 1H), 7.76 (s, 1H); MS (m/e, M+): 514

Example 39
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-4,5-dimethyl-1H-benzimidazole

90 mg (yield 45%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(3-chlorophenyl)-4,5-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58-1.78 (m, 4H), 1.88-1.96 (m, 4H), 2.16 (s, 3H), 2.24 (t, 2H), 2.41 (s, 3H), 2.43 (m, 1H), 2.62 (s, 3H), 2.82 (br, 2H), 4.28 (t, 2H), 6.94 (d, 1H), 7.11-7.35 (m, 6H), 7.48 (d, 2H), 7.68 (d, 2H); MS (m/e, M+): 514, 486, 403, 339, 298, 257, 231

Example 40
2-(2-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-nitro-1H-benzimidazole

83 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(2-chlorophenyl)-5-nitro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.60-1.80 (m, 4H), 1.83-1.92 (m, 4H), 2.19 (s, 3H), 2.23 (t, 2H), 2.40 (m, 1H), 2.74 (brd, 2H), 4.27 (t, 2H), 6.94 (d, 1H), 7.23-7.63 (m, 8H), 7.63 (d, 1H), 8.28 (dd, 1H), 8.58 (d, 1H); MS (m/e, M+): 532

Example 41
2-(3-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-nitro-1H-benzimidazole

80 mg (yield 41%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(3-chlorophenyl)-5-nitro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, 1H), 8.29 (dd, 1H), 7.63˜7.23 (m, 8H), 7.15 (d, 1H), 6.94 (dd, 1H), 4.27 (t, 2H), 2.74 (brd, 2H), 2.41 (m, 1H), 2.22 (t, 2H), 2.19 (s, 3H), 1.89˜1.96 (m, 4H), 1.57˜1.80 (m, 4H); MS (m/e, M+): 532

Example 42
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-nitro-1H-benzimidazole

57 mg (yield 30%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(4-chlorophenyl)-5-nitro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 8.73 (d, 1H), 8.29 (dd, 1H), 8.03 (d, 1H), 7.73˜7.51 (m, 4H), 7.34˜7.20 (m, 4H), 6.94 (dd, 1H), 4.27 (t, 2H), 2.74 (brd, 2H), 2.41 (m, 1H), 2.22 (t, 2H), 2.19 (s, 3H), 1.89˜1.96 (m, 4H), 1.57˜1.80 (m, 4H); MS (m/e, M+): 532

Example 43
2-phenyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-bromo-1H-benzimidazole

97 mg (yield 50%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-phenyl-5-bromo-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 7.75 (m, 3H), 7.68 (m, 3H), 7.22˜7.43 (m, 6H), 6.96 (d, 1H), 4.35 (t, 2H), 2.81 (brd, 2H), 2.43 (m, 1H), 2.25 (t, 2H), 2.19 (s, 3H), 1.89˜1.96 (m, 4H), 1.66˜1.80 (m, 4H); MS (m/e, M+): 531

Example 44
2-(2,3,4,5-tetrafluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

92 mg (yield 47%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.37 mmol) of 2-(2,3,4,5-tetrafluorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 7.85 (m, 1H), 7.53 (m, 1H), 7.19-7.51 (m, 7H), 6.94 (d, 1H), 4.27 (t, 2H), 2.80 (brd, 2H), 2.42 (m, 1H), 2.22 (t, 2H), 2.19 (s, 3H), 1.89˜1.96 (m, 4H), 1.57˜1.80 (m, 4H); MS (m/e, M+): 524

Example 45
2-(4-trifluoromethylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

103 mg (yield 52%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.38 mmol) of 2-(4-trifluoromethylphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.53-1.64 (m, 2H), 1.75 (m, 2H), 1.89-2.02 (m, 4H), 2.14 (s, 3H), 2.26 (br t, 2H, J=6.4 Hz), 2.41 (m, 1H), 2.80 (m, 2H), 4.39 (br t, 2H, J=7.1 Hz), 6.92 (m, 1H), 7.22 (t, 1H, J=7.7 Hz), 7.32-7.38 (m, 4H), 7.50 (m, 1H), 7.68 (br s, 1H), 7.79 (d, 2H, J=8.0 Hz), 7.83 (m, 1H), 7.91 (d, 2H, J=8.2 Hz); MS (m/e, M⁺): 520 (M⁺), 231

Example 46
2-(4-biphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

105 mg (yield 54%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.37 mmol) of 2-(4-biphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.75 (m, 4H), 1.89-2.03 (m, 4H), 2.21 (s, 3H), 2.30 (m, 2H), 2.40 (m, 1H), 2.83 (m, 2H), 4.42 (m, 2H), 6.89 (m, 1H), 7.17 (m, 1H), 7.26-7.47 (m, 8H), 7.57 (br s, 1H), 7.63 (m, 2H), 7.75 (m, 2H), 7.83 (m, 3H); MS (m/e, M⁺): 528 (M⁺), 297, 231, 70

Example 47
2-(4-phenoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

95 mg (yield 50%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.35 mmol) of 2-(4-phenoxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.67 (m, 2H), 1.76 (m, 2H), 1.90-2.03 (m, 4H), 2.12 (s, 3H), 2.28 (br t, 2H, J=6.6 Hz), 2.43 (m, 1H), 2.84 (m, 2H), 4.38 (br t, 2H, J=7.2 Hz), 6.95 (m, 1H), 7.04-7.40 (m, 12H), 7.47 (m, 1H), 7.53 (m, 1H), 7.72 (m, 2H), 7.81 (m, 1H); MS (m/e, M⁺): 544 (M⁺), 327, 231, 70

Example 48
2-(4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

98 mg (yield 44%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.47 mmol) of 2-(4-fluorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 7.73˜7.83 (m, 2H), 7.20˜7.73 (m, 10H), 6.96 (d, 1H), 4.35 (t, 2H), 2.81 (brd, 2H), 2.43 (m, 1H), 2.25 (t, 2H), 2.19 (s, 3H), 1.88˜1.96 (m, 4H), 1.55˜1.78 (m, 4H); MS (m/e, M+): 470

Example 49
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-4,6-dimethyl-1H-benzimidazole

100 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.45 mmol) of 2-(3-chlorophenyl)-4,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58-1.79 (m, 4H), 1.87-1.96 (m, 4H), 2.16 (s, 3H), 2.24 (t, 2H), 2.43 (m, 1H), 2.48 (s, 3H), 2.65 (s, 3H), 2.80 (br, 2H), 4.27 (t, 2H), 6.93 (s, 1H), 6.94 (d, 1H), 7.08 (s, 1H), 7.24-7.37 (m, 4H), 7.47 (d, 2H), 7.47 (d, 2H); MS (m/e, M⁺): 514

Example 50
2-(3,4-difluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

107 mg (yield 51%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.43 mmol) of 2-(3,4-difluorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.64 (m, 2H), 1.76 (brd, 2H), 1.90-2.04 (m, 4H), 2.17 (s, 3H), 2.27 (t, 2H), 2.44 (m, 1H), 2.82 (br, 2H), 4.38 (t, 2H), 6.94 (d, 1H), 7.24-7.38 (m, 7H), 7.45-7.59 (m, 2H), 7.65 (m, 1H), 7.80 (m, 1H); MS (m/e, M+): 488

Example 51
2-(4-cyanophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

103 mg (yield 48%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.45 mmol) of 2-(4-cyanophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.43 (m, 2H), 1.71 (brd, 2H), 1.85-2.01 (m, 4H), 2.18 (s, 3H), 2.16 (t, 2H), 2.41 (m, 1H), 2.72 (br, 2H), 4.44 (t, 2H), 6.91 (d, 1H), 7.23-7.32 (m, 4H), 7.49-7.53 (m, 3H), 7.83 (m, 1H), 7.85 (d, 2H), 7.94 (d, 2H); MS (m/e, M+): 477

Example 52
2-(3-cyanophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

96 mg (yield 45%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.45 mmol) of 2-(3-cyanophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.55 (m, 2H), 1.71 (brd, 2H), 1.86-1.99 (m, 4H), 2.17 (s, 3H), 2.24 (t, 2H), 2.41 (m, 1H), 2.72 (br, 2H), 4.43 (t, 2H), 6.92 (d, 1H), 7.24-7.49 (m, 7H), 7.67 (dd, 1H), 7.80 (m, 2H), 8.05-8.11 (m, 2H); MS (m/e, M⁺): 477

Example 53
2-(4-chloro-2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

93 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(4-chloro-2-fluorohenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.60 (m, 2H), 1.74 (brd, 2H), 1.85-1.96 (m, 4H), 2.16 (s, 3H), 2.21 (t, 2H), 2.41 (m, 1H), 2.77 (br, 2H), 4.24 (t, 2H), 6.94 (d, 1H), 7.24-7.37 (m, 8H), 7.49 (d, 1H), 7.60 (dd, 1H), 7.82 (d, 1H); MS (m/e, M⁺): 505

Example 54
2-(2-chloro-4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

86 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(2-chloro-4-fluorophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.74 (brd, 2H), 1.84-1.94 (m, 4H), 2.16 (s, 3H), 2.23 (t, 2H), 2.42 (m, 1H), 2.78 (br, 2H), 4.16 (t, 2H), 6.95 (d, 1H), 7.16-7.37 (m, 8H), 7.52 (m, 2H), 7.82 (d, 1H); MS (m/e, M⁺): 505

Example 55
2-(3-nitrophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

97 mg (yield 47%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.42 mmol) of 2-(3-nitrophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.48 (m, 2H), 1.72 (brd, 2H), 1.88-2.04 (m, 4H), 2.19 (s, 3H), 2.27 (t, 2H), 2.41 (m, 1H), 2.78 (br, 2H), 4.45 (t, 2H), 6.89 (d, 1H), 7.24-7.39 (m, 5H), 7.51 (d, 1H), 7.75 (dd, 1H), 7.84 (d, 1H), 8.19 (d, 1H), 8.37 (d, 1H), 8.66 (s, 1H); MS (m/e, M⁺): 497

Example 56
2-(5-chloro-2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

62 mg (yield 31%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.38 mmol) of 2-(5-chloro-2-methoxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.68-1.82 (m, 4H), 1.84-2.03 (m, 4H), 2.17 (s, 3H), 2.35 (t, 2H), 2.38 (m, 1H), 2.88 (br, 2H), 3.70 (s, 3H), 4.06 (t, 2H), 6.95 (d, 1H), 6.99 (d, 1H), 7.23-7.47 (m, 7H), 7.58 (s, 1H), 7.80 (d, 1H); MS (m/e, M⁺): 517

Example 57
2-(2-chloro-4-nitrophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

96 mg (yield 50%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(2-chloro-4-nitrophenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.46 (m, 2H), 1.72 (brd, 2H), 1.84-1.94 (m, 4H), 2.17 (s, 3H), 2.18 (t, 2H), 2.41 (m, 1H), 2.88 (br, 2H), 4.20 (t, 2H), 6.87 (d, 1H), 7.16 (s, 1H), 7.23 (d, 1H), 7.35-7.42 (m, 4H) 7.52 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 8.30 (dd, 1H), 8.47 (s, 1H); MS (m/e, M⁺): 532

Example 58
2-(2,4-dimethoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

54 mg (yield 27%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(2,4-dimethoxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.66-1.82 (m, 4H), 1.84-1.99 (m, 4H), 2.16 (s, 3H), 2.34 (t, 2H), 2.36 (m, 1H), 2.89 (br, 2H), 3.67 (s, 3H), 3.87 (s, 3H), 4.04 (t, 2H), 6.60 (d, 1H, J=2.1 Hz), 6.64 (dd, 1H, J=8.4 Hz, 2.1 Hz), 6.97 (d, 1H), 7.21-7.42 (m, 6H), 7.50 (d, 1H, J=8.4 Hz), 7.78 (m, 1H); MS (m/e, M⁺): 512

Example 59
2-(4-chloro-2-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

92 mg (yield 48%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(4-chloro-2-fluorophenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.59 (m, 2H), 1.75 (brd, 2H), 1.86-1.94 (m, 4H), 2.16 (s, 3H), 2.20 (t, 2H), 2.39 (s, 3H), 2.41 (m, 1H), 2.42 (s, 3H), 2.80 (br, 2H), 4.18 (t, 2H), 6.92 (d, 1H), 7.16-7.34 (m, 4H), 7.37 (s, 1H), 7.46 (s, 1H), 7.57-7.63 (m, 2H); MS (m/e, M⁺): 533

Example 60
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-4-carbamoyl-1H-benzimidazole

46 mg (yield 24%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.37 mmol) of 2-(4-chlorophenyl)-4-carbamoyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.28 (m, 2H), 1.62 (brd, 2H), 1.72-1.91 (m, 4H), 2.21 (s, 3H), 2.22 (t, 2H), 2.33 (m, 1H), 2.65 (brd, 2H) 4.43 (t, 2H), 4.84 (brs, 1H, NH₂), 5.70 (brs, 1H, NH₂), 6.88 (d, 1H, J=7.8 Hz), 7.24 (m, 2H), 7.48 (d, 1H), 7.53 (d, 2H, J=8.7 Hz), 7.57 (m, 1H), 7.71 (d, 2H, J=8.7 Hz), 7.80 (s, 1H), 7.90 (dd, 1H, J=8.7 Hz, 1.5 Hz), 8.32 (d, 1H, J=1.5 Hz); MS (m/e, M⁺): 530

Example 61
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-carbamoyl-1H-benzimidazole

49 mg (yield 25%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.37 mmol) of 2-(4-chlorophenyl)-5-carbamoyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.61 (m, 2H), 1.72 (brd, 2H), 1.86-2.04 (m, 4H), 2.18 (s, 3H), 2.22 (t, 2H), 2.41 (m, 1H), 2.74 (br, 2H) 4.44 (t, 2H), 4.83 (brs, 1H, NH₂), 5.85 (brs, 1H, NH₂), 6.92 (d, 1H, J=7.4 Hz), 7.23 (dd, 1H), 7.36 (s, 1H), 7.43 (d, 1H, J=7.8 Hz), 7.54 (d, 2H, J=8.7 Hz), 7.69 (m, 2H), 7.49 (d, 2H, J=8.7 Hz), 7.80 (d, 1H, J=8.6 Hz), 8.30 (s, 1H); MS (m/e, M⁺): 530

Example 62
2-(3-carbamoylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

95 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.42 mmol) of 2-(3-carbamoylphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.05 (m, 2H), 1.51 (brd, 2H), 1.68-1.82 (m, 4H), 1.97 (m, 2H), 2.23 (m, 1H), 2.25 (s, 3H), 2.51 (brd, 2H) 4.05 (t, 2H), 5.98 (brs, 1H, NH₂), 6.79 (d, 1H, J=7.5 Hz), 6.87 (s, 1H), 7.18 (dd, 1H), 7.35-7.37 (m, 3H), 7.55 (dd, 1H), 7.48 (d, 1H), 7.83-7.88 (m, 2H), 7.99 (s, 1H), 8.01 (d, 1H, J=8.1 Hz), 8.78 (s, 1H); MS (m/e, M⁺): 495

Example 63
242-hydroxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

50 mg (yield 23%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.47 mmol) of 2-(2-hydroxyphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.84 (m, 4H), 2.04 (m, 2H), 2.18 (s, 3H), 2.24 (t, 2H), 2.51 (m, 1H), 2.70 (m, 2H), 3.13 (brd, 2H), 4.38 (t, 2H), 6.93 (d, 1H, J=8.4 Hz), 7.07-7.29 (m, 7H), 7.36-7.42 (m, 2H), 7.71 (m, 2H), 8.55 (d, 1H); MS (m/e, M⁺): 468

Preparation of Imidazole Derivative
Examples 64 to 67

Example 64
2-(4-chlorophenyl)-1-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole
Step 1) 2-(4-chlorophenyl)-1-{3-[4-(3-aminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

1.5 g (3.08 mmol) of 2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole obtained in Example 4 was dissolved in 30 ml of methanol, and 10 ml of 5N-HCl aqueous solution was added to the resulting solution, followed by mixing the solution at 50° C. for 3 hours. The resulting solution was concentrated under a reduced pressure and 60 ml of water was added thereto. Then, pH of the solution was adjusted to 8 or more. The reaction mixture was extracted with ethylacetate (80 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (n-hexane/ethylacetate=1/3) to obtain 1.19 g (yield 87%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.74 (m, 2H), 1.88-1.99 (m, 4H), 2.25 (t, 2H), 2.35 (m, 1H), 2.82 (brs, 2H), 3.63 (brs, 2H, NH₂), 4.36 (t, 2H), 6.53 (m, 2H), 6.60 (d, 1H), 7.07 (dd, 1H), 7.29-7.33 (m, 2H), 7.47 (m, 1H), 7.52 (d, 2H), 7.71 (d, 1H), 7.81 (m, 1H); MS (m/e, M⁺): 445

Step 2) 2-(4-chlorophenyl)-1-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 g (0.157 mmol) of 2-(4-chlorophenyl)-1-{3-[4-(3-aminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole obtained in the above step 1) was dissolved in 5 ml of dichloromethane, and 0.044 ml (0.31 mmol) of triethylamine and 0.02 ml (0.19 mmol) of isobutyrylchloride were slowly added to the resulting solution, followed by mixing the solution at room temperature for 1 hour. The reaction mixture was combined with 30 ml of water and extracted with dichloromethane (30 ml×2), and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5%-MeOH/CH₂Cl₂) to obtain 70 mg (yield 86%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.71-1.85 (m, 4H), 1.97-2.06 (m, 4H), 2.17 (s, 3H), 2.34 (t, 2H), 2.48 (m, 1H), 2.65 (s, 3H), 2.95 (brd, 2H), 4.22 (t, 2H), 6.97 (d, 1H, J=7.5 Hz), 7.20-7.38 (m, 6H), 7.43 (brs, 1H, NH), 7.67 (m, 1H); MS (m/e, M⁺): 515

Example 65
2-(4-chlorophenyl)-1-{3-[4-(3-benzoylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

77 mg (yield 90%) of the title compound was obtained by repeating the procedure of Example 64 except for using 70 mg (0.157 mmol) of 2-(4-chlorophenyl)-1-{3-[4-(3-aminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole obtained in step 1) of Example 64, and 0.022 ml (0.19 mmol) of benzoylchloride.

¹H NMR (300 MHz, CDCl₃) δ 1.71 (t, 2H), 1.80 (d, 2H), 1.96 (m, 2H), 2.01 (m, 2H), 2.27 (t, 2H), 2.48 (m, 1H), 2.84 (br-d, 2H), 4.37 (t, J=14.4, 2H), 7.01 (d, J=7.5, 1H) 7.31 (m, 3H), 7.51 (m, 7H), 7.72 (d, 2H), 7.86 (m, 4H); MS (m/e, M⁺): 549, 490, 443, 408

Example 66
2-(4-chlorophenyl)-1-{3-[4-(3-(3-chlorobenzoylamino)phenyl)piperidin-1-yl]propyl}-1H-benzimidazole

84 mg (yield 92%) of the title compound was obtained by repeating the procedure of Example 64 except for using 70 mg (0.157 mmol) of 2-(4-chlorophenyl)-1-{3-[4-(3-aminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole obtained in step 1) of Example 64, and 0.024 ml (0.19 mmol) of 4-chlorobenzoylchloride.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.78 (d, 2H), 1.91 (m, 2H), 1.96 (m, 2H), 2.04 (s, 3H) 2.26 (t, 2H), 2.47 (m, 1H) 2.85 (br-d, 2H), 4.37 (t, J=14.7, 2H), 7.00 (d, J=37.8 Hz, 1H) 7.33 (m, 5H), 7.52 (m, 5H), 7.85 (m, 6H); MS (m/e, M⁺): 584, 529, 475, 441

Example 67
2-(4-chlorophenyl)-1-{3-[4-(3-(4-methylbenzoylamino)phenyl)piperidin-1-yl]propyl}-1H-benzimidazole

77 mg (yield 87%) of the title compound was obtained by repeating the procedure of Example 64 except for using 70 mg (0.157 mmol) of 2-(4-chlorophenyl)-1-{3-[4-(3-aminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole obtained in step 1) of Example 64, and 0.025 ml (0.19 mmol) of p-toluoylchloride.

¹H NMR (300 MHz, CDCl₃) δ 1.71 (m, 2H), 1.80 (m, 2H), 1.98 (m, 2H), 2.03 (m, 2H), 2.31 (t, 2H), 2.42 (s, 3H) 2.47 (m, 1H) 2.89 (br-d, 2H), 4.37 (t, J=14.7, 2H), 7.00 (d, 1H) 7.32 (m, 5H), 7.50 (m, 5H), 7.80 (m, 6H); MS (m/e, M⁺): 563, 532, 499, 458

Preparation of Imidazole Derivative
Examples 68 to 70

Example 68
6-bromo-5-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

100 mg (0.35 mmol) of 6-bromo-5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine was dissolved in 5 ml of N,N-dimethyl formamide, and 240 mg (0.68 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propylmethanesulfonate obtained in Preparation Example 4 and 282 mg (2.04 mmol) of K₂CO₃were added to the resulting solution, followed by mixing the solution at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5%-MeOH/CH₂Cl₂) to obtain 90 mg (yield 47%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.57 (m, 2H), 1.72 (m, 2H), 2.01 (m, 2H), 2.17 (s, 3H), 2.35 (t, 2H), 2.37 (m, 1H), 2.77 (s, 3H), 2.84 (brd, 2H), 4.47 (t, 2H), 6.92 (d, 1H), 7.21-7.36 (m, 3H), 7.54 (t, 3H), 7.77 (t, 2H), 8.17 (s, 1H): MS (m/e, M⁺): 546

Example 69
5-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

98 mg (yield 45%) of the title compound was obtained by repeating the procedure of Example 68 except for using 100 mg (0.47 mmol) of 5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.75 (m, 4H), 1.90 (brt, 2H), 2.02 (m, 2H) 2.16 (s, 3H), 2.32 (t, 2H), 2.42 (m, 1H), 2.67 (s, 3H), 2.84 (br, 2H), 4.50 (t, 2H), 6.92 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=8.1 Hz), 7.23-7.39 (m, 3H), 7.50-7.54 (m, 3H), 7.78 (m, 2H), 7.93 (d, 1H, J=8.1 Hz); MS (m/e, M⁺): 467

Example 70
2-(benzo[1,3]dioxol-5-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

46 mg (yield 84%) of the title compound was obtained by repeating the procedure of Example 9 except for using 26.1 mg (0.11 mmol) of 2-(benzo[1,3]dioxol-5-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.61-1.78 (m, 4H), 1.89-2.01 (m, 4H), 2.15 (s, 3H), 2.28 (br t, 2H, J=6.6 Hz), 2.42 (m, 1H), 2.83 (m, 2H), 4.36 (br t, 2H, J=7.4 Hz), 6.02 (s, 2H), 6.95 (m, 2H), 7.20-7.38 (m, 7H), 7.45 (m, 1H), 7.71 (br s, 1H), 7.79 (m, 1H); MS (m/e, M⁺): 496 (M⁺), 265, 231, 70.

Preparation of Imidazole Derivative
Examples 71 and 87

Example 71
2-(4-chlorophenyl)-1-{2-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]ethyl}-1H-benzimidazole

45 mg (yield 31%) of the title compound was obtained by repeating the procedure of Example 1 except for using 115 mg (0.31 mmol) of 3-[4-(3-isoburyrylaminophenyl)piperidin-1-yl]ethylmethanesulfonate obtained by the procedure similar to Preparation Example 5, and 70 mg (0.31 mmol) of 2-(4-chlorophenyl)benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.25 (d, 6H), 1.52-1.86 (m, 4H), 2.12 (m, 2H), 2.46 (m, 1H), 2.52 (m, 1H), 2.79 (t, 2H), 2.86 (brd, 2H), 4.38 (t, 2H), 6.92 (d, 1H, J=7.2 Hz), 7.10 (s, 1H), 7.22-7.35 (m, 3H), 7.47 (m, 2H), 7.52 (d, 2H, J=8.4 Hz), 7.79 (d, 2H, J=8.4 Hz), 7.84 (m, 1H); MS (m/e, M⁺): 500

Example 72
2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-c]pyridine

74 mg (yield 32%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.51 mmol) of 2-phenyl-3H-imidazo[4,5-c]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.64 (m, 2H), 1.78 (brd, 2H), 1.99 (brt, 2H), 2.17 (s, 3H), 2.36 (m, 1H), 2.37-2.48 (m, 4H), 2.94 (brd, 2H), 4.80 (t, 2H), 6.94 (d, 1H, J=7.6 Hz), 7.05 (dd, 1H), 7.25 (m, 1H), 7.35-7.50 (m, 5H), 7.74 (d, 2H, J=6.0 Hz), 8.18 (d, 1H, J=7.5 Hz), 8.50 (d, 2H); MS (m/e, M⁺): 453

Example 73
2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-d]pyridine

30 mg (yield 13%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.51 mmol) of 2-phenyl-3H-imidazo[4,5-d]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.57-1.75 (m, 4H), 1.93 (m, 2H), 2.07 (m, 2H), 2.17 (s, 3H), 2.34 (m, 1H), 2.41 (m, 2H), 2.83 (brd, 2H), 4.53 (t, 2H), 6.95 (d, 1H, J=7.6 Hz), 7.21-7.35 (m, 4H), 7.55 (m, 4H), 7.80 (m, 2H), 8.06 (d, 1H, J=8.1 Hz), 8.40 (d, 1H, J=4.8 Hz), 8.50 (d, 2H); MS (m/e, M⁺): 453

Example 74
5-bromo-6-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-e]pyridine

15 mg (yield 8%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.35 mmol) of 6-bromo-5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.61 (m, 2H), 1.73 (brd, 2H), 1.86-2.03 (m, 4H), 2.16 (s, 3H), 2.22 (t, 2H), 2.39 (m, 1H), 2.78 (s, 3H), 2.83 (brd, 2H), 4.37 (t, 2H), 6.93 (d, 1H, J=7.5 Hz), 7.21-7.37 (m, 3H), 7.51-7.55 (m, 4H), 7.78 (m, 2H), 8.02 (s, 1H); MS (m/e, M⁺): 546

Example 75
6-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-e]pyridine

13 mg (yield 6%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.47 mmol) of 5-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.75 (m, 4H), 1.90 (brt, 2H), 2.02 (m, 2H) 2.16 (s, 3H), 2.32 (t, 2H), 2.42 (m, 1H), 2.68 (s, 3H), 2.84 (br, 2H), 4.39 (t, 2H), 6.92 (d, 1H, J=7.2 Hz), 7.23-7.39 (m, 3H), 7.50-7.54 (m, 4H), 7.70 (d, 1H, J=8.1 Hz), 7.78 (m, 2H); MS (m/e, M⁺): 467

Example 76
2-(3-methoxycarbonylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

85 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(3-methoxycarbonylphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.41 (m, 2H), 1.66 (brd, 2H), 1.82-2.00 (m, 4H), 2.20 (t, 2H), 2.21 (s, 3H), 2.35 (m, 1H), 2.72 (brd, 2H), 3.95 (s, 3H), 4.44 (t, 2H), 6.89 (d, 1H, J=7.5 Hz), 7.10 (s, 1H), 7.23-7.35 (m, 3H), 7.48 (m, 2H), 7.63 (dd, 1H, J=7.5 Hz, 7.8 Hz), 7.78 (brs, 1H, NH), 7.82 (m, 1H), 8.00 (d, 1H, J=7.5 Hz), 8.20 (d, 1H, J=7.8 Hz), 8.44 (d, 1H, J=1.6 Hz); MS (m/e, M⁺): 510

Example 77
2-(4-ethylphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

117 mg (yield 54%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.45 mmol) of 2-(4-ethylphenyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.27 (t, 3H), 1.68 (m, 4H), 1.98 (m, 4H), 2.16 (s, 3H), 2.30 (t, 2H), 2.40 (m, 1H), 2.72 (q, 2H), 2.83 (brd, 2H), 4.36 (t, 2H), 6.95 (d, 1H, J=7.5 Hz), 7.24-7.39 (m, 7H), 7.45 (m, 1H), 7.67 (d, 2H, J=8.1 Hz), 7.80 (m, 1H); MS (m/e, M⁺): 480

Example 78
2-(4-cyanophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

113 mg (yield 56%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(4-cyanophenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.40-1.45 (m, 2H), 1.72 (m, 2H), 1.85-2.04 (m, 4H), 2.14 (t, 2H), 2.17 (s, 3H), 2.35 (m, 1H), 2.40 (s, 3H), 2.43 (s, 3H), 2.74 (brd, 2H), 4.38 (t, 2H), 6.91 (d, 1H, J=7.6 Hz), 7.17-7.28 (m, 2H), 7.47 (d, 1H, J=7.8 Hz), 7.60 (d, 2H, J=10.9 Hz), 7.78-7.85 (m, 2H), 7.92 (d, 2H, J=8.1 Hz); MS (m/e, M⁺): 505

Example 79
2-(m-tolyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

132 mg (yield 59%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.48 mmol) of 2-(m-tolyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.67 (m, 4H), 1.96 (m, 4H), 2.15 (s, 3H), 2.29 (t, 2H), 2.43 (s, 3H) 2.84 (brd, 2H), 4.36 (t, 2H), 6.94 (d, 1H, J=7.5 Hz), 7.24 (m, 2H), 7.29-7.51 (m, 7H) 7.58 (s, 1H), 7.80 (d, 1H, J=4.2 Hz); MS (m/e, M⁺): 505

Example 80
2-(2-chloro-4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

86 mg (yield 45%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(2-chloro-4-fluorophenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.66-1.80 (m, 4H), 1.89-1.95 (m, 4H), 2.17 (s, 3H), 2.23 (t, 2H), 2.40 (s, 3H), 2.43 (s, 3H), 2.47 (m, 1H), 2.82 (brd, 2H), 4.10 (t, 2H), 6.96 (d, 1H, J=7.5 Hz), 7.16 (m, 1H), 7.24-7.32 (m, 4H), 7.37 (s, 1H), 7.51-7.58 (m, 2H); MS (m/e, M⁺): 533

Example 81
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-cyano-1H-benzimidazole

30 mg (yield 15%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(4-chlorophenyl)-5-cyano-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.57-1.73 (m, 4H), 1.80-2.03 (m, 4H), 2.18 (s, 3H), 2.20 (t, 2H), 2.44 (m, 1H), 2.78 (brd, 2H), 4.44 (t, 2H), 6.94 (d, 1H, J=7.2 Hz), 7.24 (m, 1H), 7.33 (s, 1H), 7.60 (m, 4H), 7.74 (d, 2H, J=8.4 Hz), 7.87 (d, 1H, J=8.4 Hz), 8.04 (s, 1H); MS (m/e, M⁺): 512

Example 82
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-6-cyano-1H-benzimidazole

60 mg (yield 30%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.39 mmol) of 2-(4-chlorophenyl)-6-cyano-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.57 (m, 2H), 1.75 (m, 2H), 1.88-1.95 (m, 4H), 2.19 (s, 3H), 2.21 (t, 2H), 2.41 (m, 1H), 2.78 (brd, 2H), 4.43 (t, 2H), 6.94 (d, 1H, J=7.2 Hz), 7.24 (m, 1H), 7.29 (m, 1H), 7.40 (s, 1H), 7.56 (m, 4H), 7.72 (d, 2H, J=8.4 Hz), 8.14 (s, 1H); MS (m/e, M⁺): 512

Example 83
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-fluoro-1H-benzimidazole

32 mg (yield 16%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(4-chlorophenyl)-5-fluoro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.60-1.80 (m, 4H), 1.90-1.98 (m, 4H), 2.18 (s, 3H), 2.24 (t, 2H), 2.45 (m, 1H), 2.81 (brd, 2H), 4.33 (t, 2H), 6.96 (d, 1H, J=7.5 Hz), 7.06 (m, 1H), 7.19-7.36 (m, 4H), 7.53 (m, 2H), 7.69-7.77 (m, 3H); MS (m/e, M⁺): 505

Example 84
2-(4-fluorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-chloro-1H-benzimidazole

28 mg (yield 14%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.40 mmol) of 2-(4-fluorophenyl)-5-chloro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.65-1.81 (m, 4H), 1.88-1.99 (m, 4H), 2.18 (s, 3H), 2.24 (t, 2H), 2.44 (m, 1H), 2.83 (brd, 2H), 4.33 (t, 2H), 6.96 (d, 1H, J=7.5 Hz), 7.21-7.28 (m, 5H), 7.36 (d, 1H, 7.8 Hz), 7.53 (m, 2H), 7.69-7.77 (m, 3H); MS (m/e, M+): 505

Example 85
2-(4-chlorophenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5-nitro-1H-benzimidazole

21 mg (yield 11%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.36 mmol) of 2-(4-chlorophenyl)-5-nitro-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.64 (m, 2H), 1.78 (m, 2H), 1.96-2.04 (m, 4H), 2.20 (s, 3H), 2.24 (t, 2H), 2.43 (m, 1H), 2.78 (brd, 2H), 4.50 (t, 2H), 6.96 (d, 1H, J=7.8 Hz), 7.24-7.33 (m, 2H), 7.42 (d, 1H, J=7.8 Hz), 7.58 (d, 2H, J=8.4 Hz), 7.77 (d, 2H, J=8.4 Hz), 7.86 (d 1H, J=8.7 Hz), 8.24 (d,d 1H, J=8.7 Hz, 2.1 Hz), 8.54 (d, 1H, J=2.1 Hz); MS (m/e, M+): 532

Example 86
2-(4-chloro-2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

52 mg (yield 28%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.34 mmol) of 2-(4-chloro-2-methoxyphenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58-1.67 (m, 2H), 1.74 (brd, 2H), 1.82-1.88 (m, 4H), 2.16 (s, 3H), 2.19 (t, 2H), 2.38 (s, 3H), 2.40 (s, 3H), 2.41 (m, 1H), 2.78 (brd, 2H), 3.83 (s, 3H), 4.07 (t, 2H), 6.94 (d, 1H, J=7.2 Hz), 7.02 (d, 1H, J=1.8 Hz), 7.07 (dd, 1H, J=8.1, 1.8 Hz), 7.21-7.30 (m, 4H), 7.38 (s, 1H), 7.42 (d, 1H, J=8.1 Hz), 7.55 (s, 1H); MS (m/e, M+): 545

Example 87
2-(5-chloro-2-methoxyphenyl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

59 mg (yield 32%) of the title compound was obtained by repeating the procedure of Example 9 except for using 100 mg (0.34 mmol) of 2-(5-chloro-2-methoxyphenyl)-5,6-dimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.64 (m, 2H), 1.76 (brd, 2H), 1.84-1.90 (m, 4H), 2.16 (s, 3H), 2.21 (t, 2H), 2.39 (s, 3H), 2.41 (s, 3H), 2.42 (m, 1H), 2.80 (brd, 2H), 3.77 (s, 3H), 4.09 (t, 2H), 6.94-6.97 (m, 2H), 7.21-7.31 (m, 2H), 7.36 (s, 1H), 7.40-7.44 (m, 2H), 7.49 (d, 1H, J=2.7 Hz), 7.55 (s, 1H); MS (m/e, M+): 545

Preparation of Imidazole Derivative
Examples 88 to 90

Example 88
2-methyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

100 mg (0.75 mmol) of 2-methyl-1H-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 265 mg (0.75 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propylmethanesulfonate obtained by Preparation Example 4 and 310 mg (2.25 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 160 mg (yield 55%) of the title compound.

Example 89
2-methyl-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-5,6-dimethyl-1H-benzimidazole

145 mg (yield 56%) of the title compound was obtained by repeating the procedure of Example 88 except for using 100 mg (0.62 mmol) of 2,5,6-trimethyl-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.70-1.85 (m, 4H), 1.96-2.04 (m, 4H), 2.17 (s, 3H), 2.33 (t, 2H), 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (m, 1H), 2.60 (s, 3H), 2.94 (brd, 2H), 4.16 (t, 2H), 6.91 (d, 1H, J=7.5 Hz), 7.12 (s, 1H), 7.21-7.37 (m, 2H), 7.43 (m, 2H), 7.62 (brs, 1H, NH); MS (m/e, M⁺): 418, 403, 376, 257, 245, 231, 187, 174

Example 90
2-methyl-1-{3-[4-(3 sobutyrylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

100 mg (0.75 mmol) of 2-methyl-1H-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 286 mg (0.75 mmol) of 3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propylmethanesulfonate and 310 mg (2.25 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 159 mg (yield 51%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.25 (d, 6H), 1.74-1.83 (m, 4H), 1.97-2.05 (m, 4H), 2.33 (t, 2H), 2.46 (m, 1H), 2.53 (m, 1H), 2.65 (s, 3H), 2.95 (brd, 2H), 4.22 (t, 2H), 6.97 (d, 1H), 7.09 (m, 1H), 7.20-7.38 (m, 5H), 7.53 (brs, 1H, NH), 7.70 (m, 1H); MS (m/e, M⁺): 418

Preparation of Imidazole Derivative
Examples 91 to 97

Example 91
2,5-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

100 mg (0.68 mmol) of 2,5-dimethyl-3H-imidazo[4,5-b]pyridine was dissolved in 5 ml of N,N-dimethylformamide, and 240 mg (0.68 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propylmethanesulfonate obtained by Preparation Example 4 and 282 mg (2.04 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 124 mg (yield 45%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.67-1.81 (m, 4H), 1.96-2.05 (m, 4H), 2.17 (m, 3H), 2.38 (t, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 2.65 (s, 3H), 2.96 (br-d, 2H), 4.30 (t, 2H), 6.52 (m, 1H), 6.95 (m, 1H), 6.98 (d, 1H, J=8.1 Hz), 7.21-7.38 (m, 3H), 7.76 (d, 1H, J=8.1 Hz); MS (m/e, M⁺): 405

Example 92
6-bromo-2,5-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

100 mg (yield 47%) of the title compound was obtained by repeating the procedure of Example 91 except for using 100 mg (0.44 mmol) of 6-bromo-2,5-demethyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.67-1.83 (m, 4H), 1.96-2.06 (m, 4H), 2.17 (m, 3H), 2.36 (t, 2H), 2.46 (m, 1H), 2.65 (s, 3H), 2.72 (s, 3H), 2.94 (br-d, 2H), 4.27 (t, 2H), 6.95 (d, 1H, J=6.8 Hz), 7.21-7.42 (m, 4H), 8.02 (s, 1H); MS (m/e, M⁺): 484, 469, 267, 245, 231

Example 93
6-bromo-2-ethyl-5-methyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

94 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 91 except for using 100 mg (0.41 mmol) of 6-bromo-2-ethyl-5-methyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 1.47 (t, 3H), 1.68-1.83 (m, 4H), 1.96-2.07 (m, 4H), 2.16 (m, 3H), 2.38 (t, 2H), 2.46 (m, 1H), 2.72 (s, 3H), 2.94 (br-d, 2H), 2.99 (q, 2H), 4.27 (t, 2H), 6.95 (d, 1H, J=6.9 Hz), 7.21-7.43 (m, 4H), 8.06 (s, 1H); MS (m/e, M⁺): 499, 497, 468, 280, 245, 231

Example 94
6-bromo-2-butyl-5-methyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

87 mg (yield 45%) of the title compound was obtained by repeating the procedure of Example 91 except for using 100 mg (0.37 mmol) of 6-bromo-2-butyl-5-methyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (m, 3H), 1.25 (m, 3H), 1.84 (m, 6H), 1.97 (m, 3H), 2.16 (s, 3H), 2.37 (m, 2H), 2.96 (m, 5H), 4.25 (t, 2H), 6.96 (d, 1H), 7.32 (m, 2H), 7.62 (s, 1H), 8.05 (s, 1H): MS (m/e, M⁺): 526, 468, 447

Example 95
2-butyl-5,7-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

106 mg (yield 47%) of the title compound was obtained by repeating the procedure of Example 91 except for using 100 mg (0.49 mmol) of 2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (m, 3H), 1.45 (m, 2H), 1.82 (m, 6H), 2.04 (m, 4H), 2.12 (s, 3H), 2.42 (m, 3H), 2.59 (s, 6H), 2.96 (m, 4H), 4.31 (t, 2H), 6.97 (d, 1H), 7.23 (m, 1H), 7.35 (m, 2H), 7.55 (s, 1H): MS (m/e, M⁺): 461, 432, 404

Example 96
2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

83 mg (yield 44%) of the title compound was obtained by repeating the procedure of Example 91 except for using 100 mg (0.35 mmol) of 2-butyl-5,7-dimethyl-6-phenyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.97 (m, 3H), 1.46 (m, 2H), 1.86 (m, 6H), 2.04 (m, 4H), 2.11 (s, 3H), 2.32 (s, 6H), 2.48 (m, 3H), 2.99 (m, 6H), 4.35 (t, 2H), 6.95 (d, 1H), 7.15 (m, 2H), 7.38 (m, 5H), 7.44 (s, 1H): MS (m/e, M⁺): 537, 508, 482

Example 97
2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

83 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 91 except for using 100 mg (0.37 mmol) of 2-butyl-5-methyl-6-pyridin-2-yl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (m, 3H), 1.46 (m, 2H), 1.78 (m, 4H), 1.95 (m, 3H), 2.10 (m, 5H), 2.44 (m, 3H), 2.63 (s, 2H), 3.03 (m, 4H), 4.35 (t, 2H), 6.96 (d, 1H), 7.22 (m, 4H), 7.75 (m, 4H), 7.92 (s, 1H): MS (m/e, M⁺): 524, 509, 495

Preparation of Imidazole Derivative
Examples 98 to 103

Example 98
6-bromo-2-butyl-5-methyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

100 mg (0.37 mmol) of 6-bromo-2-butyl-5-methyl-3H-imidazo[4,5-b]pyridine was dissolved in 5 ml of N,N-dimethylformamide, and 140 mg (0.37 mmol) of 3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propylmethanesulfonate obtained by Preparation Example 5 and 155 mg (1.11 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (5% MeOH/CH₂Cl₂) to obtain 94 mg (yield 46%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, 3H), 1.24 (m, 9H), 1.50 (m, 3H), 1.82 (m, 10H), 2.50 (m, 5H), 2.89 (m, 4H), 3.01 (m, 5H), 4.30 (t, 2H), 6.97 (d, 1H), 7.30 (m, 2H), 7.53 (d, 1H), 8.05 (s, 1H): MS (m/e, M⁺): 554

Example 99
2-butyl-5,7-dimethyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

108 mg (yield 45%) of the title compound was obtained by repeating the procedure of Example 98 except for using 100 mg (0.49 mmol) of 2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (m, 3H), 1.23 (m, 7H), 1.50 (m, 2H), 1.84 (m, 7H), 2.06 (m, 5H), 2.57 (m, 7H), 3.03 (m, 4H), 4.31 (t, 2H), 6.83 (s, 1H), 6.96 (d, 1H), 7.25 (m, 2H), 7.36 (d, 1H), 7.46 (s, 1H): MS (m/e, M⁺): 489, 460, 432

Example 100
2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

91 mg (yield 46%) of the title compound was obtained by repeating the procedure of Example 98 except for using 100 mg (0.35 mmol) of 2-butyl-5,7-dimethyl-6-phenyl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, 3H), 1.23 (m, 7H), 1.54 (m, 2H), 1.86 (m, 6H), 2.04 (m, 4H), 2.32 (s, 6H), 2.43 (m, 4H), 2.99 (m, 3H), 4.35 (t, 2H), 6.94 (d, 1H), 7.20 (m, 2H), 7.38 (m, 6H): MS (m/e, M⁺): 565, 536, 508

Example 101
2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

84 mg (yield 41%) of the title compound was obtained by repeating the procedure of Example 98 except for using 100 mg (0.37 mmol) of 2-butyl-5-methyl-6-pyridin-2-yl-3H-imidazo[4,5-b]pyridine.

¹H NMR (300 MHz, CDCl₃) δ 0.97 (m, 3H), 1.23 (m, 6H), 1.52 (m, 2H), 1.93 (m, 8H), 2.45 (m, 4H), 2.67 (s, 3H), 2.96 (m, 5H), 4.36 (t, 2H), 6.96 (d, 1H), 7.29 (m, 2H), 7.38 (m, 4H), 7.48 (m, 1H), 7.91 (s, 1H), 8.71 (m 1H); MS (m/e, M⁺): 552, 523, 509

Example 102
2-butyl-5-formyl-6-phenyl-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

95 mg (yield 47%) of the title compound was obtained by repeating the procedure of Example 98 except for using 100 mg (0.36 mmol) of 2-butyl-6-phenyl-3H-imidazo[4,5-b]pyridine-5-carb aldehyde.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, 3H), 1.23 (d, 6H), 1.28 (m, 2H), 1.52 (m, 2H), 1.81-2.04 (m, 8H), 2.16 (m, 1H), 2.45 (m, 2H), 2.52 (m, 1H), 3.01 (m, 2H), 3.04 (t, 2H), 4.47 (t, 2H), 6.94 (d, 1H), 7.21-7.48 (m, 8H), 7.95 (s, 1H), 10.07 (s, 1H): MS (m/e, M⁺): 565

Example 103
2-butyl-5-methyl-6-(4-nitrophenyl)-3-{3-[4-(3-isobutyrylaminophenyl)piperidin-1-yl]propyl}-3H-imidazo[4,5-b]pyridine

82 mg (yield 43%) of the title compound was obtained by repeating the procedure of Example 98 except for using 100 mg (0.32 mmol) of 2-butyl-5-methyl-6-(4-nitrophenyl)-3H-imidazo[4,5-b]pyridine-5-carb aldehyde.

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, 3H), 1.23 (d, 6H), 1.28 (m, 2H), 1.50 (m, 2H), 1.70-2.04 (m, 8H), 2.12 (m, 1H), 2.44 (m, 1H), 2.49 (t, 2H), 2.51 (s, 3H), 2.97 ((t, 2H), 3.00 (m, 2H), 4.36 (t, 2H), 6.95 (d, 1H), 7.16-7.27 (m, 2H), 7.35 (brs, 1H, NH), 7.50 (d, 2H), 7.53 (m, 1H), 7.75 (s, 1H), 8.28 (d, 2H): MS (m/e, M⁺): 596

Preparation of Imidazole Derivative
Examples 104 to 127
Example 104
2-(pyridin-2-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (0.36 mmol) of 2-(pyridin-2-yl)-1H-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 128 mg (0.31 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-1-yl]propylmethanesulfonate obtained by Preparation Example 4 and 150 mg (1.08 mmol) of K₂CO₃were added to the resulting solution, followed by treating the mixture at 80° C. for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml×2) being washed with water and a sodium hydroxide solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under a reduced pressure, and the resulting residue was refined by silica gel column chromatography (10% MeOH/CH₂Cl₂) to obtain 87 mg (yield 53%) of the title compound.

¹H NMR (300 MHz, CDCl₃) δ 1.65-1.80 (m, 4H), 2.15 (s, 3H), 1.93-2.24 (m, 4H), 2.43 (br t, 2H, J=6.8 Hz), 2.48 (m, 1H), 2.98 (m, 2H), 4.90 (br t, 2H, J=7.3 Hz), 6.95 (m, 1H), 7.21-7.39 (m, 6H), 7.52 (m, 1H), 7.67 (br s, 1H), 7.84 (m, 2H), 8.40 (d, 1H, J=7.9 Hz), 8.86 (br d, 1H J=4.1 Hz); MS (m/e, M⁺): 453 (M⁺), 258, 209, 196

Example 105
2-(pyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

83 mg (yield 51%) of the title compound was obtained by repeating the procedure of Example 104 except for using 70 mg (0.36 mmol) of 2-(pyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.58-1.77 (m, 4H), 1.89-2.04 (m, 4H), 2.17 (s, 3H), 2.27 (br t, 2H, J=6.6 Hz), 2.42 (m, 1H), 2.80 (m, 2H), 4.41 (br t, 2H, J=7.2 Hz), 6.95 (m, 1H), 7.21-7.40 (m, 5H), 7.48-7.53 (m, 2H), 7.65 (br s, 1H), 7.84 (m, 1H), 8.14 (dt, 1H, J=7.9, 1.8 Hz), 8.76 (dd, 1H, J=4.9, 1.5 Hz), 9.03 (m, 1H); MS (m/e, M⁺): 453 (M⁺), 257, 231, 70.

Example 106
2-(pyridin-4-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

92 mg (yield 56%) of the title compound was obtained by repeating the procedure of Example 104 except for using 70 mg (0.36 mmol) of 2-(pyridin-4-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.55 (m, 2H), 1.74 (m, 2H), 1.90-2.02 (m, 4H), 2.20 (s, 3H), 2.25 (t, 2H), 2.42 (m, 1H), 2.79 (br-d, 2H), 4.47 (t, 2H), 6.91 (d, 1H), 7.21-7.50 (m, 6H), 7.76 (d, 2H), 7.85 (m, 1H), 7.82 (d, 2H); MS (m/e, M⁺): 453 (M⁺), 257, 231, 70.

Example 107
2-(furan-3-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

38 mg (yield 61%) of the title compound was obtained by repeating the procedure of Example 104 except for using 25.8 mg (0.14 mmol) of 2-(furan-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.80 (m, 4H), 2.03 (m, 4H), 2.17 (s, 3H), 2.39 (br t, 2H J=6.3 Hz), 2.48 (m, 1H), 2.94 (m, 2H), 4.41 (br t, 2H, J=7.3 Hz), 6.99 (m, 1H), 7.06 (m, 1H), 7.25-7.36 (m, 4H), 7.45 (m, 2H), 7.59 (m, 1H), 7.63 (br s, 1H), 7.74 (m, 1H), 8.21 (br s, 1H); MS (m/e, M⁺): 442 (M⁺), 413, 231, 70.

Example 108
2-(5-bromofuran-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (yield 58%) of the title compound was obtained by repeating the procedure of Example 104 except for using 60.5 mg (0.23 mmol) of 2-(5-bromofuran-2-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.71-1.78 (m, 4H), 1.97-2.12 (m, 4H), 2.17 (s, 3H), 2.44 (m, 3H), 2.96 (m, 2H), 4.55 (br t, 2H, J=6.9 Hz), 6.55 (br d, 1H, J=3.4 Hz), 6.97 (br d, 1H, J=7.3 Hz), 7.20-7.54 (m, 8H), 7.77 (m, 1H); MS (m/e, M⁺): 521 (M⁺), 441, 231.

Example 109
2-(thiophen-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

54 mg (yield 84%) of the title compound was obtained by repeating the procedure of Example 104 except for using 28.1 mg (0.14 mmol) of 2-(thiophen-2-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.70-1.83 (m, 4H), 1.97-2.09 (m, 4H), 2.16 (s, 3H), 2.40 (br t, 2H J=6.6 Hz), 2.47 (m, 1H), 2.93 (m, 2H), 4.51 (br t, 2H, J=7.3 Hz), 6.97 (br, d, 1H, J=7.4 Hz), 7.19 (dd, 1H, J=5.0, 3.8 Hz), 7.22-7.35 (m, 4H), 7.45 (m, 2H), 7.51 (dd, 1H, J=5.0, 0.9 Hz), 7.64 (br s, 1H), 7.67 (m, 1H), 7.77-7.80 (m, 1H); MS (m/e, M⁺): 458 (M⁺), 425, 231, 70.

Example 110
2-(5-methylthiophen-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (yield 64%) of the title compound was obtained by repeating the procedure of Example 104 except for using 49.3 mg (0.23 mmol) of 2-(5-methylthiophen-2-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.80 (m, 4H), 1.97-2.04 (m, 4H), 2.14 (s, 3H), 2.38 (br t, 2H, J=6.6 Hz), 2.47 (m, 1H), 2.94 (m, 2H), 3.88 (s, 3H), 4.37 (br t, 2H, J=7.2 Hz), 6.26 (m, 1H), 6.55 (m, 1H), 6.84 (br s, 1H), 6.97 (m, 1H), 7.21-7.50 (m, 6H), 7.78 (m, 1H), MS (m/e, M⁺): 457 (M⁺-15), 231, 209.

Example 111
2-(1-methylpyrrol-2-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (yield 67%) of the title compound was obtained by repeating the procedure of Example 104 except for using 45.4 mg (0.23 mmol) of 2-(1-methylpyrrol-2-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.71-1.83 (m, 4H), 1.97-2.11 (m, 4H), 2.16 (s, 3H), 2.41 (t, 2H, J=6.5 Hz), 2.47 (m, 1H), 2.55 (s, 3H), 2.95 (m, 2H), 4.48 (br t, 2H, J=7.2 Hz), 6.84 (m, 1H), 6.97 (m, 1H), 7.22-7.36 (m, 5H), 7.41-7.47 (m, 3H), 7.68 (br s, 1H), 7.75 (m, 1H), MS (m/e, M⁺): 455 (M⁺), 257, 231.

Example 112
2-(5-bromopyridin-3-yl)-1-{3-[4-(3-acetylaminophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

47 mg (yield 80%) of the title compound was obtained by repeating the procedure of Example 104 except for using 30.2 mg (0.11 mmol) of 2-(5-bromopyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.63 (m, 2H), 1.77 (m, 2H), 1.91-2.05 (m, 4H), 2.18 (s, 3H), 2.28 (br t, 2H, J=6.5 Hz), 2.43 (m, 1H), 2.82 (m, 2H), 4.42 (br t, 2H, J=7.2 Hz), 6.97 (m, 1H), 7.22-7.40 (m, 6H), 7.52 (m, 1H), 7.84 (m, 1H), 8.35 (t, 1H, J=2.1 Hz), 8.82 (d, 1H, J=2.2 Hz), 8.96 (d, 1H, J=1.8 Hz); MS (m/e, M⁺): 532 (M⁺), 257, 231, 70.

Example 113
2-(6-chloropyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

40 mg (yield 75%) of the title compound was obtained by repeating the procedure of Example 104 except for using 25.3 mg (0.11 mmol) of 2-(6-chloropyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.65 (m, 2H), 1.77 (m, 2H), 1.92-2.06 (m, 4H), 2.18 (s, 3H), 2.27 (br t, 2H, J=6.3 Hz), 2.44 (m, 1H), 2.82 (m, 2H), 4.41 (br t, 2H, J=7.4 Hz), 6.99 (m, 1H), 7.23-7.40 (m, 6H), 7.51 (m, 2H), 7.83 (m, 1H), 8.16 (dd, 1H, J=8.3, 2.5 Hz), 8.90 (m, 1H); MS (m/e, M⁺): 488 (M⁺), 257, 231, 70.

Example 114
2-(6-methylpyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

46 mg (yield 89%) of the title compound was obtained by repeating the procedure of Example 104 except for using 23.0 mg (0.11 mmol) of 2-(6-methylpyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.56-1.68 (m, 2H), 1.76 (m, 2H), 1.90-2.03 (m, 4H), 2.17 (s, 3H), 2.27 (br t, 2H, J=6.6 Hz), 2.43 (m, 1H), 2.65 (s, 3H), 2.82 (m, 2H), 4.39 (br t, 2H, J=7.3 Hz), 6.96 (m, 1H), 7.23 (m, 1H), 7.31-7.36 (m, 4H), 7.40 (br s, 1H), 7.50 (m, 2H), 7.83 (m, 1H), 8.02 (dd, 1H, J=8.0, 2.3 Hz), 8.90 (d, 1H, J=2.1 Hz); MS (m/e, M⁺): 467 (M⁺), 250, 231, 70.

Example 115
2-(2-methoxypyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

53 mg (yield 78%) of the title compound was obtained by repeating the procedure of Example 104 except for using 31.5 mg (0.14 mmol) of 2-(2-methoxypyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.62 (m, 2H), 1.73 (m, 2H), 1.90 (m, 4H), 2.16 (s, 3H), 2.23 (br t, 2H, J=6.8 Hz), 2.47 (m, 1H), 2.80 (m, 2H), 3.98 (s, 3H), 4.19 (t, 2H, J=7.2 Hz), 6.94 (m, 1H), 7.06 (dd, 1H, J=7.2, 5.1 Hz), 7.21-7.39 (m, 6H), 7.50 (m, 1H), 7.82 (m, 1H), 7.88 (dd, 1H, J=7.3, 1.8 Hz), 8.34 (dd, 1H, J=5.0, 1.8 Hz); MS (m/e, M⁺): 483 (M⁺), 468, 252, 231, 70.

Example 116
5-chloro-2-(pyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

40 mg (yield 59%) of the title compound was obtained by repeating the procedure of Example 104 except for using 32.2 mg (0.14 mmol) of 5-chloro-2-(pyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.57-1.77 (m, 4H), 1.91-2.00 (m, 4H), 2.18 (s, 3H), 2.26 (br t, 2H, J=6.3 Hz), 2.43 (m, 1H), 2.80 (m, 2H), 4.39 (m, 2H), 6.97 (m, 1H), 7.22-7.41 (m, 5H), 7.50 (dd, 1H, J=7.8, 4.9 Hz) 7.57 (d, 1H, J=1.8 Hz), 7.74 (d, 1H, J=8.6 Hz), 8.13 (dt, 1H, J=7.9, 1.8 Hz), 8.78 (m, 1H), 9.03 (m, 1H); MS (m/e, M⁺): 488 (M⁺), 257, 231, 70.

Example 117
5-nitro-2-(pyridin-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

70 mg (yield 44%) of the title compound was obtained by repeating the procedure of Example 104 except for using 76.9 mg (0.32 mmol) of 5-nitro-2-(pyridin-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.47-1.76 (m, 4H), 1.89-1.99 (m, 4H), 2.20 (s, 3H), 2.27 (m, 2H), 2.43 (m, 1H), 2.77 (m, 2H), 4.51 (m, 2H), 6.95 (m, 1H), 7.22-7.40 (m, 4H), 7.56 (dd, 1H, J=7.8, 4.9 Hz), 7.63 (d, 1H, J=9.0 Hz), 8.16 (m, 1H), 8.30 (dd, 1H, J=9.1, 2.1 Hz), 8.75 (d, 1H, J=2.0 Hz), 8.83 (m, 1H), 9.06 (d, 1H, J=1.9 Hz); MS (m/e, M⁺): 498 (M⁺), 481, 231, 70.

Example 118
5-chloro-2-(5-bromofuran-2-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

25 mg (yield 64%) of the title compound was obtained by repeating the procedure of Example 104 except for using 20.8 mg (0.07 mmol) of 5-chloro-2-(5-bromofuran-2-yl)-1H-benzimidazole.

¹H NMR (300 MHz, MeOH-d₄) δ 1.66-1.81 (m, 4H), 2.03-2.13 (m, 4H), 2.14 (s, 3H), 2.45 (m, 2H), 2.96 (m, 2H), 4.63 (m, 2H), 6.58 (m, 1H), 6.78 (m, 1H), 7.00 (m, 1H), 7.24 (t, 1H, J=7.8 Hz), 7.30-7.44 (m, 3H), 7.63-7.81 (m, 3H); MS (m/e, M⁺): 475 (M⁺-Br), 257, 231.

Example 119
2-(furan-2-yl)-5-methoxy-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

30 mg (yield 68%) of the title compound was obtained by repeating the procedure of Example 104 except for using 19.9 mg (0.09 mmol) of 2-(furan-2-yl)-5-methoxy-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.77-1.84 (m, 4H), 1.99-2.12 (m, 4H), 2.17 (s, 3H), 2.45 (m, 3H), 3.00 (m, 2H), 3.89 (s, 3H), 4.54 (q, 2H, J=7.1 Hz), 6.60 (m, 1H), 6.94 (m, 2H), 7.17-7.41 (m, 7H), 7.60 (m, 1H); MS (m/e, M⁺): 472 (M⁺), 257, 231, 120.

Example 120
5-methyl-2-(thiophen-3-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

27 mg (yield 61%) of the title compound was obtained by repeating the procedure of Example 104 except for using 19.9 mg (0.09 mmol) of 5-methyl-2-(thiophen-3-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.80 (m, 4H), 2.04 (m, 4H), 2.16 (s, 3H), 2.38 (m, 2H), 2.46 (m, 1H), 2.49 (s, 3H), 2.94 (m, 2H), 4.41 (br t, 2H, J=6.8 Hz), 6.98 (m, 1H), 7.12 (m, 1H), 7.22-7.34 (m, 3H), 7.43-7.48 (m, 2H), 7.56-7.67 (m, 3H), 7.91 (br s, 1H); MS (m/e, M⁺): 472 (M⁺), 256, 231, 70.

Example 121
5,6-dimethyl-2-(1-methylpyrrol-2-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

42 mg (yield 62%) of the title compound was obtained by repeating the procedure of Example 104 except for using 31.5 mg (0.14 mmol) of 5,6-dimethyl-2-(1-methylpyrrol-2-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.81 (m, 4H), 2.00 (m, 4H), 2.14 (s, 3H), 2.37 (m, 2H), 2.39 (s, 3H), 2.40 (s, 3H), 2.48 (m, 1H), 2.97 (m, 2H), 3.85 (s, 3H), 4.31 (br t, 2H, J=7.4 Hz), 6.24 (br t, 1H, J=2.9 Hz), 6.50 (m, 1H), 6.81 (br s, 1H), 6.97 (m, 1H), 7.20-7.27 (m, 2H), 7.35 (m, 1H), 7.43 (m, 2H), 7.55 (br s, 1H); MS (m/e, M⁺): 483 (M⁺), 252, 231, 70.

Example 122
2-(thiazol-4-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

34 mg (yield 80%) of the title compound was obtained by repeating the procedure of Example 104 except for using 18.7 mg (0.09 mmol) of 2-(4-thiazolyl)-1H-benzimidazole.

¹H NMR (300 MHz, MeOH-d₄) δ 1.74-1.90 (m, 4H), 2.10 (s, 3H), 2.24 (m, 2H), 2.44 (m, 2H), 2.61 (m, 1H), 2.76 (br t, 2H, J=7.5 Hz), 3.22 (m, 2H), 4.86 (m, 2H), 6.94 (m, 1H), 7.21 (br t, 1H, J=7.7 Hz), 7.30-7.40 (m, 3H), 7.48 (br s, 1H), 7.69 (br t, 2H, J=7.4 Hz), 8.38 (d, 1H, J=1.8 Hz), 9.21 (d, 1H, J=1.9 Hz); MS (m/e, M⁺): 459 (M⁺), 257, 231, 70.

Example 123
2-(4-methyloxazol-5-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

45 mg (yield 70%) of the title compound was obtained by repeating the procedure of Example 104 except for using 27.9 mg (0.14 mmol) of 2-(4-methyloxazol-5-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.68-1.83 (m, 4H), 1.94-2.10 (m, 4H), 2.17 (s, 3H), 2.36 (br t, 2H, J=6.8 Hz), 2.47 (m, 1H), 2.64 (s, 3H), 2.93 (m, 2H), 4.50 (br t, 2H, J=7.1 Hz), 6.97 (m, 1H), 7.21-7.34 (m, 4H), 7.42 (m, 2H), 7.49 (m, 1H), 7.82 (m, 1H), 7.99 (s, 1H); MS (m/e, M⁺): 457 (M⁺), 257, 231, 120.

Example 124
2-(1-methyl-1H-imidazol-5-yl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

66 mg (yield 85%) of the title compound was obtained by repeating the procedure of Example 104 except for using 33.7 mg (0.17 mmol) of 2-(1-methyl-1H-imidazol-5-yl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.72-1.84 (m, 4H), 2.04 (m, 4H), 2.18 (s, 3H), 2.40 (t, 2H, J=6.7 Hz), 2.48 (m, 1H), 2.96 (m, 2H), 3.98 (s, 3H), 4.42 (t, 2H, J=7.4 Hz), 6.97 (d, 1H, J=7.6 Hz), 7.24 (m, 1H), 7.32 (m, 2H), 7.37 (m, 1H), 7.43 (m, 1H), 7.50 (m, 1H), 7.54 (br s, 1H), 7.67 (br s, 1H), 7.70 (br s, 1H), 7.80 (m, 1H): MS (m/e, M⁺): 456 (M⁺), 231.

Example 125
2-(pyridin-2-ylmethyl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

140 mg (yield 52%) of the title compound was obtained by repeating the procedure of Example 104 except for using 121.4 mg (0.58 mmol) of 2-(pyridin-2-ylmethyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.70-1.99 (m, 8H), 2.16 (s, 3H), 2.30 (t, 2H, J=6.8 Hz), 2.46 (m, 1H), 2.89 (m, 2H), 4.27 (t, 2H, J=7.1 Hz), 4.58 (s, 2H), 6.98 (m, 1H), 7.15 (m, 1H), 7.21-7.40 (m, 8H), 7.59 (dt, 1H, J=7.7, 1.8 Hz), 7.75 (m, 1H), 8.54 (m, 1H); MS (m/e, M⁺): 467 (M⁺), 375, 223.

Example 126
2-(pyridin-3-ylmethyl)-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

60 mg (yield 71%) of the title compound was obtained by repeating the procedure of Example 104 except for using 37.7 mg (0.18 mmol) of 2-(pyridin-3-ylmethyl)-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.72-2.04 (m, 8H), 2.19 (s, 3H), 2.28 (t, 2H, J=6.3 Hz), 2.50 (m, 1H), 2.95 (m, 2H), 4.16 (t, 2H, J=6.8 Hz), 4.47 (s, 2H), 6.96 (m, 1H), 7.22-7.30 (m, 4H), 7.37 (m, 2H), 7.49 (br d, 1H, J=7.8 Hz), 7.57 (m 1H), 7.77 (m, 1H), 8.03 (br s, 1H), 8.51 (dd, 1H, J=4.7, 1.4 Hz), 8.68 (m, 1H); MS (m/e, M⁺): 467 (M⁺), 375, 245.

Example 127
2-[2-(pyridin-3-yl)ethyl]-1-{3-[4-(3-acetamidophenyl)piperidin-1-yl]propyl}-1H-benzimidazole

75 mg (yield 87%) of the title compound was obtained by repeating the procedure of Example 104 except for using 40.2 mg (0.18 mmol) of 2-[2-(pyridin-3-yl)ethyl]-1H-benzimidazole.

¹H NMR (300 MHz, CDCl₃) δ 1.59 (m, 2H), 1.74 (m, 2H), 1.91-2.03 (m, 4H), 2.18 (t, 2H, J=6.0 Hz), 2.27 (s, 3H), 2.44 (m, 1H), 2.87 (m, 2H), 3.30 (m, 2H), 3.40 (m, 2H), 4.29 (t, 2H, J=6.4 Hz), 6.87 (m, 1H), 7.05 (s, 1H), 7.21-7.32 (m 4H), 7.38 (m, 1H), 7.71 (dt, 1H, J=7.8, 1.8 Hz), 7.77 (m, 1H), 7.89 (br dd, 1H, J=8.2, 1.2 Hz), 8.51 (dd, 1H, J=4.8, 1.6 Hz), 8.76 (d, 1H, J=1.8 Hz), 9.37 (br s, 1H); MS (m/e, M⁺): 481 (M⁺), 245, 159, 70.

The substituents of the compounds described in Examples among imidazole derivatives of formula (I) of the present invention were shown in Table 2.

TABLE 2

Example
R¹
R²
R³
A
n

1
Ph
H
Me
CH
2

2
4-Cl-Ph
H
Me
CH
2

3
Ph
H
Me
CH
3

4
4-Cl-Ph
H
Me
CH
3

5
Ph
H
Me
CH
4

6
4-Cl-Ph
H
Me
CH
4

7
Ph
H
Me
CH
5

8
4-Cl-Ph
H
Me
CH
5

9
2-Cl-Ph
H
Me
CH
3

10
3-Cl-Ph
H
Me
CH
3

11
4-Br-Ph
H
Me
CH
3

12
3,4-di-Cl-Ph
H
Me
CH
3

13
3-Br-Ph
H
Me
CH
3

14
2-I-Ph
H
Me
CH
3

15
2-F-Ph
H
Me
CH
3

16
2,4-di-Cl-Ph
H
Me
CH
3

17
2-OMe-Ph
H
Me
CH
3

18
3-OMe-Ph
H
Me
CH
3

19
4-OMe-Ph
H
Me
CH
3

20
4-iPr-Ph
H
Me
CH
3

21
Ph
5,6-di-Me
Me
CH
3

22
4-Cl-Ph
5,6-di-Me
Me
CH
3

23
Ph
6-Me
Me
CH
3

24
4-Cl-Ph
6-Me
Me
CH
3

25
4-Cl-Ph
6-Cl
Me
CH
3

26
Ph
6-F
Me
CH
3

27
Ph
6-OMe
Me
CH
3

28
4-Cl-Ph
6-OMe
Me
CH
3

29
Ph
6-Cl
Me
CH
3

30
4-F-Ph
6-Cl
Me
CH
3

31
4-Cl-Ph
6-F
Me
CH
3

32
Ph
6-NO₂
Me
CH
3

33
2-F-Ph
6-Cl
Me
CH
3

34
3-F-Ph
6-Cl
Me
CH
3

35
3-Cl-Ph
6-Cl
Me
CH
3

36
4-Cl-Ph
6-Br
Me
CH
3

37
2-Cl-Ph
5,6-di-Me
Me
CH
3

38
3-Cl-Ph
5,6-di-Me
Me
CH
3

39
4-Cl-Ph
4,5-di-Me
Me
CH
3

40
2-Cl-Ph
6-NO₂
Me
CH
3

41
3-Cl-Ph
6-NO₂
Me
CH
3

42
4-Cl-Ph
6-NO₂
Me
CH
3

43
Ph
6-Br
Me
CH
3

44
2,3,4,5-tet-F-Ph
H
Me
CH
3

45
4-CF₃-Ph
H
Me
CH
3

46
4-Ph-Ph
H
Me
CH
3

47
4-OPh-Ph
H
Me
CH
3

48
4-F-Ph
H
Me
CH
3

49
4-Cl-Ph
5,7-di-Me
Me
CH
3

50
3,4-di-F-Ph
H
Me
CH
3

51
4-CN-Ph
H
Me
CH
3

52
3-CN-Ph
H
Me
CH
3

53
2-F, 4-Cl-Ph
H
Me
CH
3

54
2-Cl, 4-F-Ph
H
Me
CH
3

55
3-NO₂-Ph
H
Me
CH
3

56
2-OMe, 5-Cl-Ph
H
Me
CH
3

57
2-Cl, 4-NO₂-Ph
H
Me
CH
3

58
2,4-di-OMe-Ph
H
Me
CH
3

59
2-F, 4-Cl-Ph
5,6-di-Me
Me
CH
3

60
Ph
6-Me
Me
CH
3

61
4-Cl-Ph
6-CONH₂
Me
CH
3

62
3-CONH₂-Ph
H
Me
CH
3

63
2-OH-Ph
H
Me
CH
3

64
4-Cl-Ph
H
i-Pr
CH
3

65
4-Cl-Ph
H
Ph
CH
3

66
4-Cl-Ph
H
3-Cl-Ph
CH
3

67
4-Cl-Ph
H
4-Me-Ph
CH
3

68
Ph
5-Br, 6-Me
Me
7-N
3

69
Ph
6-Me
Me
7-N
3

70

H
Me
CH
3

71
4-Cl-Ph
H
i-Pr
CH
2

72
Ph
H
Me
6-N
3

73
Ph
H
Me
5-N
3

74
Ph
6-Br, 5-Me
Me
4-N
3

75
Ph
5-Me
Me
4-N
3

76
3-CO₂Me-Ph
H
Me
CH
3

77
4-Et-Ph
H
Me
CH
3

78
4-CN-Ph
5,6-di-Me
Me
CH
3

79
3-Me-Ph
H
Me
CH
3

80
2-Cl, 4-F-Ph
5,6-di-Me
Me
CH
3

81
4-Cl-Ph
5-CN
Me
CH
3

82
4-Cl-Ph
6-CN
Me
CH
3

83
4-Cl-Ph
5-F
Me
CH
3

84
4-F-Ph
5-Cl
Me
CH
3

85
4-Cl-Ph
5-NO₂
Me
CH
3

86
2-OMe, 4-Cl-Ph
5,6-di-Me
Me
CH
3

87
2-OMe, 5-Cl-Ph
5,6-di-Me
Me
CH
3

88
Me
H
Me
CH
3

89
Me
5,6-di-Me
Me
CH
3

90
Me
H
i-Pr
CH
3

91
Me
6-Me
Me
7-N
3

92
Me
5-Br, 6-Me
Me
7-N
3

93
Et
5-Br, 6-Me
Me
7-N
3

94
n-Bu
5-Br, 6-Me
Me
7-N
3

95
n-Bu
4,6-di-Me
Me
7-N
3

96
n-Bu
4,6-di-Me, 5-Ph
Me
7-N
3

97
n-Bu
5-(2-pyridyl),
Me
7-N
3

6-Me

98
n-Bu
5-Br, 6-Me
i-Pr
7-N
3

99
n-Bu
4,6-di-Me
i-Pr
7-N
3

100
n-Bu
4,6-di-Me, 5-Ph
i-Pr
7-N
3

101
nBu
5-(2-Pyridyl),
i-Pr
7-N
3

6-Me

102
n-Bu
5-Ph, 6-CHO
i-Pr
7-N
3

103
n-Bu
5-(4-NO₂-Ph),
i-Pr
7-N
3

6-Me

104
2-pyridyl
H
Me
CH
3

105
3-pyridyl
H
Me
CH
3

106
4-pyridyl
H
Me
CH
3

107

H
Me
CH
3

108

H
Me
CH
3

109

H
Me
CH
3

110

H
Me
CH
3

111

H
Me
CH
3

112

H
Me
CH
3

113

H
Me
CH
3

114

H
Me
CH
3

115

H
Me
CH
3

116
2-pyridyl
6-Cl
Me
CH
3

117
2-pyridyl
6-NO₂
Me
CH
3

118

6-Cl
Me
CH
3

119

6-OMe
Me
CH
3

120

5-Me
Me
CH
3

121

5,6-di-Me
Me
CH
3

122

H
Me
CH
3

123

H
Me
CH
3

124

H
Me
CH
3

125

H
Me
CH
3

126

H
Me
CH
3

127

H
Me
CH
3

Test Example 1
Inhibitory Effects on MCH R1 Binding of Aryl Piperidine Group-Containing Imidazole Derivatives

First, MCH R1 (melanine-concentrating hormone receptor-1; Euroscreen, Gosselies, Belgium), 1 μM Europium-labeled melanine-concentrating hormone (Eu-MCH, PerkinElmer, Turku, Finland) and 1 mM melanine-concentrating hormone (MCH, #070-47, Phoenix, Belmont Calif., USA) were kept at 4° C. for ready use. 1 μM Eu-MCH and 1 mM MCH were diluted with an experimental solution (25 mM HEPES pH 7.4, 5 mM MgCl₂, 1 mM CaCl₂and 0.5% (w/w) BSA) to 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. The compounds prepared in the Examples (“Test compounds”) were dissolved in the experimental solution in concentration of 4 nM to 40 μM (final reaction concentration: 1 nM to 10 μM). MCH R1 (200 assays/vial) was homogeneously dispersed in the experimental solution.

Then, 100 μl/well of the following reaction mixture was added to the wells of a microplate (Multiwell 96 well filter plates PN5020, Pall Co., Ann Arbor, Mich., USA) equipped with a filter paper, with an 8-channel pipette (multi 8-channel, Eppendorf, Hamburg, Germany). Specifically, to the wells of a non-specific binding control group, 25 μl of Eu-MCH, 50 μl of MCH R1 and 25 μl of MCH were added. Further, 25 μl of the experimental solution supplemented with 10% (w/w) of DMSO, 25 μl of Eu-MCH and 50 μl of MCH R1 were added to the wells of a total binding control group, while 25 μl of the test compounds, 25 μl Eu-MCH and 50 μl of MCH R1 were added to the wells of an experimental group. Subsequently, the microplate was shaken gently for 15 seconds and kept at room temperature for 90 minutes to allow the reaction to take place. Then, the plate was washed with a microplate washer (EMBLA, Molecular Devices) by washing three times with 300 μl of a washing solution (25 mM HEPES pH 7.4, 5 mM MgCl₂, 1 mM CaCl₂) to remove the residual unreacted Eu-MCH. Moisture was removed from the bottom of the wells and 150 μl of dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland) was added to each well, followed by keeping the plate at room temperature for 2 to 4 hours. Subsequently, time-resolved fluorescence (TRF) values were measured with a multilabel counter (Victor2, PerkinElmer, Turku, Finland) (emission wave length: 615 nm, excitation wave length: 340 nm). The inhibition rate based on the time-resolved fluorescence data was calculated using the following Equation (I).

Inhibition rate of time-resolved fluorescence (%)=[(Average TRF value of the total binding group−Time-resolved fluorescence value of the test compound)/(Average TRF value of the total binding group−Average TRF value of the non-specific binding group)]×100 (I)

Table 3 shows the IC₅₀values of the test compounds, which represents the concentration of the test compounds inhibiting the binding of MCH to MCH R1 by 50% in vitro.

TABLE 3

Compound
IC₅₀(nM)

Example 1
>10,000

Example 2
6,000

Example 3
2

Example 4
1

Example 5
29

Example 6
1

Example 7
74

Example 8
32

Example 9
10

Example 10
5

Example 11
5

Example 12
24

Example 13
1

Example 14
>10,000

Example 15
10

Example 16
3

Example 17
747

Example 18
7

Example 19
9

Example 20
19

Example 21
5

Example 22
200

Example 23
16

Example 24
10

Example 25
13

Example 26
7

Example 27
11

Example 28
55

Example 29
10

Example 30
13

Example 31
11

Example 32
10

Example 33
148

Example 34
8

Example 35
7

Example 36
17

Example 37
39

Example 38
3

Example 39
7

Example 40
82

Example 41
635

Example 42
111

Example 43
3

Example 44
77

Example 45
3

Example 46
8

Example 47
42

Example 48
56

Example 49
197

Example 50
4

Example 51
16

Example 52
15

Example 53
1

Example 54
4

Example 55
8

Example 56
66

Example 57
37

Example 58
22

Example 59
239

Example 60
8

Example 61
199

Example 62
11

Example 63
94

Example 64
5

Example 65
19

Example 66
213

Example 67
>10,000

Example 68
110

Example 69
22

Example 70
12

Example 71
>10,000

Example 72
260

Example 73
5

Example 74
680

Example 75
23

Example 76
60

Example 77
60

Example 78
100

Example 79
20

Example 80
80

Example 81
70

Example 82
70

Example 83
70

Example 84
50

Example 85
70

Example 86
110

Example 87
70

Example 88
>10,000

Example 89
60

Example 90
80

Example 91
2800

Example 92
188

Example 93
98

Example 94
3

Example 95
90

Example 96
60

Example 97
70

Example 98
1

Example 99
40

Example 100
320

Example 101
40

Example 102
260

Example 103
20

Example 104
33

Example 105
60

Example 106
150

Example 107
25

Example 108
3

Example 109
15

Example 110
14

Example 111
9

Example 112
5

Example 113
1

Example 114
42

Example 115
67

Example 116
48

Example 117
3

Example 118
20

Example 119
249

Example 120
1

Example 121
5

Example 122
306

Example 123
3

Example 124
44

Example 125
2

Example 126
47

Example 127
1

As shown in Table 3, the compounds of the present invention exhibit an improved antagonism against MCH receptor. These results confirm that the imidazole derivative of the present invention is effective as an antagonist against a MCH receptor and can be used for the treatment of MCH-related diseases.

As described above, imidazole derivatives having aryl piperidine substituents are effective as an antagonist against a MCH receptor and compositions containing the imidazole derivatives as an active ingredient are useful for preventing and treating for MCH-related diseases.

Number	Date	Country	Kind
10-2007-0046064	May 2007	KR	national
10-2007-0046073	May 2007	KR	national
10-2007-0046077	May 2007	KR	national

IMIDAZOLE DERIVATIVES HAVING ARYL PIPERIDINE SUBSTITUENT, METHOD FOR PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

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