WO2008140239A1 - Imidazole derivatives having aryl piperidine substituent, method for preparation thereof and pharmaceutical compositions containing same - Google Patents

Imidazole derivatives having aryl piperidine substituent, method for preparation thereof and pharmaceutical compositions containing same Download PDF

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Publication number
WO2008140239A1
WO2008140239A1 PCT/KR2008/002653 KR2008002653W WO2008140239A1 WO 2008140239 A1 WO2008140239 A1 WO 2008140239A1 KR 2008002653 W KR2008002653 W KR 2008002653W WO 2008140239 A1 WO2008140239 A1 WO 2008140239A1
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Prior art keywords
benzimidazole
propyl
piperidin
acetylaminophenyl
phenyl
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PCT/KR2008/002653
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French (fr)
Inventor
Jee Hee Suh
Kyu Yang Yi
Nack Jeong Kim
Sung Eun Yoo
Kwang-Seok Oh
Hyae Gyeong Cheon
Mija Ahn
Byung Ho Lee
Won Hoon Jung
Sang Dal Rhee
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Korea Research Institute Of Chemical Technology
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Priority claimed from KR1020070046064A external-priority patent/KR100895998B1/en
Priority claimed from KR1020070046077A external-priority patent/KR100871077B1/en
Priority claimed from KR1020070046073A external-priority patent/KR100893394B1/en
Application filed by Korea Research Institute Of Chemical Technology filed Critical Korea Research Institute Of Chemical Technology
Priority to US12/599,005 priority Critical patent/US8198307B2/en
Priority to JP2010508296A priority patent/JP5514716B2/en
Publication of WO2008140239A1 publication Critical patent/WO2008140239A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention is directed to a novel imidazole derivative having an aryl piperidine substituent of formula (I) and a method for preparation thereof, and a pharmaceutical composition containing said imidazole derivative as an active ingredient for preventing or treating a MCH (melanine-concentrating hormone)-related disease.

Description

IMIDAZOLE DERIVATIVES HAVING ARYL PIPERIDINE
SϋBSTITUENT, 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 diabete, heart diseases, cancer, hypertension. Accordingly, many studies for obesity treatment have been performed.
Melanine-concentrating hormone (MCBT) 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. CHn. 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).
Figure imgf000003_0001
Xenical Rediictil
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, mere is provided an imidazole derivative having aryl piperidine substituents of formula (T) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
wherein
R> is ^ , " v , C1, alky,, <V \ V ,
or N 5 in which X is H, halogen, OR5, C1-4 alkyl, CF3, phenyl, CN, NO2, -CO2R6, or -CONR7R8, R5, R6, R7 and R8 being each independently H, halogen, C1-3 alkyl, or phenyl;
R4 is H5 halogen, Q-3 alkyl, C1-3 alkoxy, phenyl, or phenyl having at least one halogen or methyl substituent;
W is CH or N; Y is O, S, or NR9, R9 being H or C1-3 alkyl; m is 1 or 2; R2 is at least one selected from the group consisting of H, halogen, C1-3
alkyl,
Figure imgf000004_0002
, phenyl, OR5, NO2, CN, pyridyl, CHO, and -CONR7R8, in which X1 is H, halogen, C1-3 alkyl, OR5, or NO2, and R5, R7, and R8 are the same as defined above;
R3 is Ci.3 alkyl, 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
R1 is
Figure imgf000005_0001
, in which X is H5 halogen, OR5, C1. 4 alkyl, CF3, phenyl, CN, NO2, -CO2R6, or -CONR7R8, R5, R6, R7 and R8 being each independently H5 halogen, Ci_3 alkyl, or phenyl; and
R2 is at least one selected from the group consisting of H, halogen, Ci-3 alkyl, 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
R1 is Ci.4 alkyl; R2 is at least one selected from the group consisting of H, halogen, Ci-3
alkyl,
Figure imgf000005_0002
is H, halogen, Cw alkyl, OR5, or NO2, and R5, R7 and R8 are each independently H, Ci-3 alkyl, 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
R1 is
Figure imgf000005_0003
, in which R4 is H, halogen, C 1.3 alkyl, C 1.3 alkoxy, phenyl, or phenyl having at least one halogen or methyl substituent; W is CH or N;
Y is O, S or NR9, in which R9 is H or Ci-3 alkyl; m is 1 or 2;
R2 is at least one selected from the group consisting of H, halogen, C1-3 alkyl, phenyl, OR5, NO2, CN, pyridyl, and -CONR7R8, R5, R7 and R8 being each independently H, Ci_3 alkyl, 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 -acetylaminophenytypiperidin- 1 - yl]ethyl}- lH-benzimidazole;
2) 2-(4-chlorophenyl)-l-{2-[4-(3-acetylaminophenyl)piperidin- 1-yl] ethyl}- 177-benzimidazole; 3) 2-phenyl- 1- {3-[4-(3-acetylaminophenyl)piperidin-l- yl]propyl} - 1 //-benzimidazole;
4) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl} -l//"-benzimidazole;
5) 2-phenyl- 1 - {4-[4-(3-acetylaminophenyl)piperidin- 1 - yl]butyl}-li-T-benzimidazole;
6) 2-(4-chlorophenyl)-l-{4-[4-(3-acetylaminophenyl)piperidin- 1-yl] butyl} -lH-benzimidazole;
7) 2-phenyl- 1 - { 5-[4-(3-acetylaminoρhenyl)piρeridin- 1 - yl]pentyl} - lif-benzimidazole;
8) 2-(4-chlorophenyl)- 1 - { 5- [4-(3 -acetylaminophenyl)piperidin- 1-yl] pentyl}-lH-benzimidazole;
9) 2-(2-chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1-yl] propylj-lif-benzimidazole;
10) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl}- lϋT-benzimidazole;
11) 2-(4-bromophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piρeridin- 1-yl] propyl} -lH-benzimidazole; 12) 2-(3,4-dichlorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl} - 1 i7-benzimidazole;
13) 2-(3 -bromophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl}-l#-benzimidazole;
14) 2-(2-iodophenyl)- 1 - { 3 - [4-(3 -acetylaminopheny^piperidin- 1 - yl] propyl} -lif-benzimidazole;
15) 2-(2-fluorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin- 1-yl] propyl} -lH-benzimidazole;
16) 2-(254-dichlorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl} - l//-benzimidazole; 17) 2-(2-methoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)pipeπdin-l-yl] propyl}- l//-benzimidazole;
18) 2-(3-methoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin-l-yl] propyl}-l//-benzimidazole;
19) 2-(4-methoxyphenyl)- 1 - {3-[4-(3- acetylaminophenyl)piperidin-yl] propyl} -lϋ/-benzimidazole;
20) 2-(4-isopropylphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl} - Ii7-benzimidazole;
21) 2-phenyl- 1 - {3-[4-(3-acetylaminoρhenyl)ρiρeridin- 1 - yl]propyl} -5,6-dimethyl- lif-benzimidazole; 22) 2-(4-chloroρhenyl)-l-{3-[4-(3-acetylaminoρhenyl)piρeridin-
1 -yl] propyl} -5,6-dimethyl- lϋZ-benzimidazole;
23) 2-ρhenyl-l-{3-[4-(3-acetylaminoρhenyl)ρiρeridin-l- yl]propyl} -6-methyl- lif-benzimidazole; 24) 2-(4-chlorophenyl)- 1 - {3-[4-(3-acetylaminoρhenyl)piρeridin- 1 -yl] propyl} -6-methyl- li/-benzimidazole;
25) 2-(4-chloroρhenyl)- 1 - {3- [4-(3-acetylaminophenyl)ρiρeridin- 1 -yl] propyl} -6-chloro- lf/-benzimidazole; 26) 2-phenyl-l-{3-[4-(3-acetylaminoρhenyl)ρiρeridin-l- yljpropyl} -6-fluoro- 1 if-benzimidazole;
27) 2-phenyl- 1-{3-[4-(3 -acetylaminophenytypiperidin- 1 - yljpropyl} -6-methoxy- lH-benzimidazole;
28) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl} -6-methoxy- liϊ-benzimidazole;
29) 2-phenyl-l-{3-[4-(3-acetylaminophenyl)piperidin-l- yl]propyl}-6-chloro-li7-benzimidazole;
30) 2-(4-fluorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)-piperidin- 1 -yl] propyl} -6-chloro- l//-benzimidazole; 31) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin-
1 -yl] propyl} -6-fluoro- Ii7-benzimidazole;
32) 2-phenyl- 1 - {3 - [4-(3 -acetylaminopheny^piperidin- 1 - yl]propyl} -6- nitro- liT-benzimidazole;
33) 2-(2-fluorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piρeridin- 1-yl] propyl} -6-chloro- li/-benzimidazole;
34) 2-(3 -fluorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -6-chloro- liT-benzimidazole;
35) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -6-chloro- l//-benzimidazole; 36) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin-
1 -yl] propyl} -6-bromo- li-T-benzimidazole;
37) 2-(2-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -5,6-dimethyl- Ii7-benzimidazole;
38) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3 -acerylaminophenyl)piperidin- 1-yl] propyl} -5,6-dimethyl- li-T-benzimidazole;
39) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl}-4,5-dimethyl-l//-benzimidazole;
40) 2-(2-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -6-nitro- l/Z-benzimidazole;
41) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -6-nitro- li/-benzimidazole;
42) 2-(4-chlorophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl} -6-nitro- l//-benzimidazole;
43) 2-phenyl- 1 - {3-[4-(3-acetylaminophenyl)piperidin- 1 - yl]propyl} -6-bromo- l//-benzimidazole;
44) 2-(2,3,455-tetrafluorophenyl)- 1 - {3-[4-(3- acetylaminopheny^piperidin-l-yypropy^-l/f-benzimidazole; 45) 2-(4-trifluoromethylρhenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- l-yl]propyl}-177-benzimidazole;
46) 2-(4-biphenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 - yljpropyl} - lif-benzimidazole;
47) 2-(4-phenoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin-l-yl] propyl} -liiT-benzimidazole;
48) 2-(4-fluorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl} -l//-benzimidazole;
49) 2-(4-chlorophenyl)- l-{3-[4-(3-acetylaminoρhenyl)piperidin- 1 -yl] propyl} -5,7-dimethyl- lii/-benzimidazole; 50) 2-(3,4-difluorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl} - 1,/i-benzimidazole;
51) 2-(4-cyanophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl}- l//-benzimidazole;
52) 2-(3-cyanophenyl)- 1 - {3-[4-(3-acetylaminophenyl)piperidin- 1-yl] propyl} -l#-benzimidazole;
53) 2-(4-chloro-2-fluorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- l-yl]propyl}-li/-benzimidazole;
54) 2-(2-chloro-4-fluorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} - Ii7-benzimidazole; 55) 2-(3-nitrophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l- yl] propyl}- l//-benzimidazole;
56) 2-(5-chloro-2-methoxyρhenyl)-l-{3-[4-(3- acetylaminoρhenyl)ρipeπdin -l-yl]propyl}-l//-benzimidazole; 57) 2-(2-chloro-4-nitrophenyl)-l-{2-[4-(3- acetamidophenyl)piperidin- 1 -yl]propyl} - l//-benzimidazole;
58) 2-(2,4-dimethoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin-l-yl]propyl}-lϋ/-benzimidazole; 59) 2-(4-chloro-2-fluoroρhenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} -5,6-dimethyl- 177-benzimidazole;
60) 2-(4-chlorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -5-carbamoyl- li-T-benzimidazole;
61) 2-(4-chlorophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1-yl] propyl} -ό-carbamoyl-l-H-benzimidazole;
62) 2-(3-carbamoylphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl} - l//-benzimidazole;
63) 2-(2-hydroxyphenyl)-l-{3-[4-(3- acetylaminoplienyl)piperidin- 1 -yl] propyl}- l//-benzimidazole; 64) 2-(4-chlorophenyl)-l-{3-[4-(3- isobutyrylaminophenyl)piperidin- 1 -yl] propyl} - l//-benzimidazole;
65) 2-(4-chlorophenyl)-l-{3-[4-(3- benzoylammophenyl)piperidin-l-yl] propyl}- Ii7-benzimidazole;
66) 2-(4-chlorophenyl)-l-{3-[4-(3-(3- chloiObenzoylamino)phenyl) piperidin- 1 -yl]propyl} - 1 //-benzimidazole;
67) 2-(4-chlorophenyl)-l-{3-[4-(3-(4- methylbenzoylamino)phenyl) piperidin- 1 -yl]propyl} - 177-benzimidazole;
68) 6-bromo-5-methyl-2-phenyl-3-{3-[4-(3- acetylaminopheny^piperidin-l-yypropylJ-Sϋr-imidazo^^-bJpyridine; 69) 5-methyl-2-prienyl-3-{3-[4-(3-acetylaminophenyl)piρeridin-
1 -yl] propyl}-3i7-imidazo[4,5-b]pyridine;
70) 2-(benzo[l,3]dioxol-5-yl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl}- liT-benzimidazole;
71) 2-(4-chlorophenyl)-l-{2-[4-(3- isobutyrylaminophenyl)piperidin-l-yl] ethyl} -177-benzimidazole;
72) 2-phenyl-3 - {3 - [4-(3 -acetylaininopheny^piperidin- 1 - yl]propyl}-3i7-imidazo[455-c]pyridine;
73) 2-phenyl-3- {3-[4-(3-acetylaminophenyl)piperidin- 1 - yl]ρroρyl}-3#-midazo[455-d]ρyridine;
74) 5-bromo-6-methyl-2-phenyl-3- {3-[4-(3- acetylaminopheny^piperidin-l-yypropyll-S/f-imidazo^jS-eJpyridine;
75) 6-methyl-2-phenyl-3 - { 3 -[4-(3 -acetylaminophenyl)piρeridin- 1-yl] propyl} -3/Z"-imidazo[4,5-e]pyridine;
76) 2-(3-methoxycarbonylρhenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yljpropyl} - li/-benzimidazole;
77) 2-(4-ethylphenyl)- 1 -{3-[4-(3-acetylaminophenyl)piperidin- 1 - yl] propyl} -li/-benzimidazole; 78) 2-(4-cyaiiophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-
1 -yl] propyl} -5 ,6-dimethyl- lJϊ-benzimidazole;
79) 2-(m-tolyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l - yl]ρropyl}-lif-benzimidazole;
80) 2-(2-chloro-4-fluorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin-l-yl]propyl}-5,6-dimethyl-177-benzimidazole;
81) 2-(4-chlorophenyl)~ 1 - { 3 -[4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -5-cyano- l/f-benzimidazole;
82) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -o-cyano-lif-benzimidazole; 83) 2-(4-chlorophenyl)- 1 -{3-[4-(3-acetylaminophenyl)piperidin-
1 -yl] propyl} -5-fluoro- li/-benzimidazole;
84) 2-(4-fluorophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -5-chloro- lif-benzirnidazole;
85) 2-(4-chlorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -5-nitro- lϋ/-benzimidazole;
86) 2-(4-chloro-2-methoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin - 1 -yl]propyl} -5,6-dimethyl- 177-benzimidazole;
87) 2-(5-chloro-2-methoxyphenyl)- 1 - {3-[4-(3- acetylaminophenyl)piperidin - 1 -yl]propyl}-5,6-dimethyl- lT-T-benzimidazole; 88) 2-methyl-l-{3-[4-(3-acetylaminophenyl)ρiperidin-l- yl]propyl} - l/z'-benzimidazole;
89) 2-methyl- 1 -{3-[4-(3-acetylaminophenyl)piperidin- 1 - yl]propyl} -5, 6-dimethyl- l//-benzimidazole; 90) 2-methyl- 1 - {3-[4-(3-isobutyrylaminophenyl)ρiperidin- 1 - yljpropyl} - lTY-benzimidazole;
91) 2,5-dimethyl-3 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 - yl]propyl}-3i:/-imidazo[4,5-b]pyridine; 92) 6-bromo-2,5-dimethyl-3-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl] propyl} -3//-imidazo[4,5-b]pyridine;
93) 6-bromo-2-ethyl-5-methyl-3-{3-[4-(3- acetylaminophenyl)piperidin-l-yl] propyl}-3i7-imidazo[4,5-b]pyridine;
94) 6-bromo-2-butyl-5-methyl-3- {3-[4-(3- acetylaminophenyl)piperidin-l-yl] propyl}-3//-imidazo[455-b]pyridine;
95) 2-butyl-557-dimethyl-3-{3-[4-(3- acetylaminoρhenyl)piperidin- 1 -yl] propyl}-3i?-imidazo[4,5-b]ρyridine;
96) 2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3- acetylaminophenyl)piperidin -l-yl]propyl}-3//-imidazo[4,5-b]pyridine; 97) 2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3- acetylaminophenyl) piperidin-l-yl]propyl}-3i¥-imidazo[4,5-b]ρyridine;
98) 6-bromo-2-butyl-5-methyl-3- {3-[4-(3- isobutyrylaminophenyl)piperidin - 1 -yljpropyl} -3H-imidazo [4,5-b]pyridine;
99) 2-butyl-537-dimethyl-3-{3-[4-(3- isobutyrylaminophenyl)piperidin-l-yl] propyl}-3H-imidazo[4,5-b]pyridine;
100) 2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3- isobutyrylaminophenyl) piperidin-l-yl]piOpyl}-3i7-imidazo[4,5-b]pyridine;
101) 2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3- isobutyrylaminophenyl) piperidin-l-yl]propyl}-3i7-imidazo[4,5-b]pyridine; 102) 2-butyl-5-formyl-6-phenyl-3-{3-[4-(3- isobutyiylaminoplienyl)piperidin -l-yl]propyl}-3H-imidazo[4:,5-b]pyridine;
103) 2-butyl-5-methyl-6-(4-nitrophenyl)-3- {3-[4-(3- isobutyrylaminophenyl) piperidin-l-yl]propyl}-3H-imidazo[455-b]pyridine;
104) 2-(pyridin-2-yl)-l -{3-[4-(3-acetamidoρhenyl)piperidin- 1- yljpropyl} -lH-benzimidazole;
105) 2-(ρyridin-3-yl)- 1 -{3-[4-(3-acetamidophenyl)piρeridin- 1 - yljpropyl}- lH-benzimidazole;
106) 2-(pyridin-4-yl)- 1 - {3-[4-(3-acetamidophenyl)ρiperidin- 1 - yl]propyl}-l#-benzimidazole;
107) 2-(ftιran-3-yl)- 1 - {3-[4-(3-acetylaminoρhenyl)piρeridin-l - yl]propyl}-l#-benzimidazole;
108) 2-(5-bromofuran-2-yl)-l-{3-[4-(3- acetylaminophenyl)piperidin-l-yl] propyl}- lH-benzimidazole;
109) 2-(thiophen-2-yl)- 1 - { 3 - [4-(3 -acetylaminopheny^piperidin- 1 ■ yl] propyl} -l//-benzimidazole;
110) 2-(5-methylthiophen-2-yl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} - Ii7-benzimidazole; 111) 2-(l-methyl-l#-pyrrol-2-yl)-l-{3-[4-(3- acetylaminophenyl)piρeridin- 1 -yl]propyl} - lH-benzimidazole;
112) 2-(5-bromopyridin-3-yl)-l-{3-[4-(3- acetylaminophenyl)piperidin-l -yl] propyl} -lH-benzimidazole;
113) 2-(6-chloropyridin-3-yl)-l-{3-[4-(3- acetamidophenyl)piperidin-l-yl] propyl} -lϋT-benzimidazole;
114) 2-(6-methylpyridin-3-yl)-l-{3-[4-(3- acetamidophenyl)piperidin- 1 -yl] propyl} - lif-benzimidazole;
115) 2-(2-methoxypyridin-3-yl)- 1 - {3-[4-(3- acetamidophenyl)piperidin- 1 -yl] propyl} - Ii7-benzimidazole; 116) 5-chloro-2-(pyridin-3-yl)-l-{3-[4-(3- acetamidophenyl)piperidin- 1 -yl] propyl} - lif-benzimidazole;
117) 5-nitro-2-(pyridin-3-yl)-l-{3-[4-(3- acetamidophenyl)piperidin- 1 -yl] propyl}- lH-benzimidazole;
118) 5-chloro-2-(5-biOmofuran-2-yl)-l-{3-[4-(3- acetamidopheny^piperidin-l-y^propy^-liϊ-benzimidazole;
119) 2-(ruran-2-yl)-5-methoxy-l-{3-[4-(3-acetamidoρhenyl) piperidin- 1 -yl]propyl} - liϊ-benzimidazole;
120) 5-methyl-2-(thiophen-3-yl)-l-{3-[4-(3- acetamidophenyl)piperidin-l -yl]propyl} - liT-benzimidazole; 121) 5,6-dimethyl-2-(l-methylpyrrol-2-yl)-l-{3-[4-(3- acetamidophenyl) piperidin- 1 -yl]propyl}- l#-benzimidazole;
122) 2-(thiazol-4-yl)-l-{3-[4-(3-acetamidoρhenyl)piρeridin-l- yl]propyl } - li/"-benzimidazole; 123) 2-(4-methyloxazol-5-yl)-l-{3-[4-(3- acetamidophenyl)ρiperidin-l-yl] propyl}-li7-benzimidazole;
124) 2-(l-methyl-lif-imidazol-5-yl)-l-{3-[4-(3- acetamidophenyl)piperidin- 1 -yl]propyl} - l//-benzimidazole;
5 125) 2-(pyridin-2-ylmethyl)-l-{3-[4-(3- acetamidophenyl)piperidin- 1 -yl]propyl} - lH-benzimidazole;
126) 2-(pyridin-3-ylmethyl)-l-{3-[4-(3- acetamidophenyl)piperidin-l-yl] propyl} -liϊ-benzimidazole; and
127) 2-[2-(pyridin-3-yl)ethyl]-l-{3-[4-(3- l o acetamidophenyl)piperidin- 1 -yl] propyl} - lif-benzimidazole.
Table 1
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
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:
Figure imgf000020_0001
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:
Figure imgf000021_0001
wherein, R1, R2, R3, A and n are the same as defined in formula (I) and
L is a leaving group such as OMs5 OTs and halogen.
Examples of the base which may be used in the present invention include an organic base such as pyridine, triethylamine, N5N- diisopropylethylamine, l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), and a mixture thereof; and an inorganic base such as NaOH5 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
X^OH (V) to alkylation with n to obtain a compound of formula (V-I) and subjecting the compound of formula (V-I) 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.
Reaction Scheme 1
Figure imgf000022_0001
V 1 1 1
V-I
Figure imgf000022_0002
wherein, R3 and n are the same as defined in formula (I)5 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 n 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-diisoproρylethylamine, l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and a mixture thereof; and an inorganic base such as NaOH5 Na2CO35 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 0C to the boiling point of the solvent used.
In Reaction Scheme I5 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 0C 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).
Reaction Scheme 2
Figure imgf000023_0001
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 R3 may be prepared by deacerylating 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.
Reaction Scheme 3
Figure imgf000024_0001
wherein, R1, R2, A and n are the same as defined in formula (I) and R3' represents R3 of 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), l-(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, N5N- diisopropylethylamine and l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). Examples of the solvent include dichlorornethane, chloroform, tetrahydrofuran, N,N-dimethyl formamide (DMF)5 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-I) (Preparation Examples 1 to 3)
Figure imgf000026_0001
Preparation Example 1
Preparation of 3-[4-(3 -acetylaminophenvDpiperidin- 1 -yllpropan- 1 -ol (formula (V-I); 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-l-proρanol and 8.6 g (62 mmol) Of K2CO3 were 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 X 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-N]VlR(SOOMHz, CDC13)5 1.76-1.86(m, 6H), 2.13(m, 2H), 2.17(s, 3H), 2.55(m, IH), 2.71(t, 2H), 3.25(brd, 2H), 3.84(t, 2H), 6.95(d, IH), 7.19- 7.31(m, 3H), 7.43(s, IH, NH) ; MS(m/e, M+): 276
Preparation Example 2 Preparation of 3 - F4-C3 -isobutyrylaminophenvDpiperidin- 1 -vl]propan- 1 -ol (formula (V-I); n=2, Y=J-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) of3-[4-(3-isobutyrylaminophenyl)piperidine]hydrochloride. 1H-NMR(SOOMHz, CDCl3)δ 1.25(d, 6H), 1.69-1.78(m, 4H), 1.83(brd,
2H), 2.05(t, 2H), 2.50(m, IH), 2.55(m, IH), 2.66(t, 2H), 3.17(brd, 2H), 3.83(t, 2H), 6.92(d, IH)5 7.23(dd, IH), 7.35-7.38(m, 2H), 7.40(s, IH, NH); MS(m/e, M+): 304
Preparation Example 3
Preparation of 2-[4-(3-acetylaminoρhenyl)piperidin-l-yl1ethanol (formula
(V-I): n=l, 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) OfK2CO3 were 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 X 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(SOOMHz5 CDCl3)δ 1.73-1.82(m, 4H), 2.09(m, 2H), 2.18(s,
3H)5 2.40(m, IH), 2.57(m, 2H), 3.05(brd, 2H), 3.63(t, 2H), 6.62(d, IH), 6.96-7.40(m, 4H; MS(m/e, M+): 262
Preparation of formula (III) (Preparation Examples 4 to 6)
Figure imgf000028_0001
Preparation Example 4 Preparation of 3-["4-C3-acetylaminophenyl)piperidin-l-yllpropyl 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, 1.15ml (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 NaHCO3 and extracted with CH2Cl2 (100 ml X 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(SOOMHz, CDCl3)δ 1.90-2.03(m, 4H), 2.21(s, 3H), 2.39(m, IH), 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, IH), 7.20(dd, IH), 7.42(brs, IH, NH), 7.58(d, IH), 8.48(s, IH, NH); MS(m/e, M+): 354
Preparation Example 5
Preparation of 344-(34sobutyrylammophenyl)piperidin-l-yl1propyl methanesulfonate ("formula (III); n=2. Y=J-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(SOOMHz, CDCl3)δ 1.23(d, 6H)5 1.77-1.94(m, 4H), 2.62(m5 2H)5 2.65(m, IH), 2.76(m, IH), 2.79(s, 3H), 3.38(m, 2H)5 3.83(brd, 2H), 4.32(t5 2H), 4.40(t, 2H), 6.74(d, IH), 7.17(dd, IH)5 7.51(s, IH), 7.86(d, IH)5 9.34(s, IH5 NH); MS(m/e, M+): 382
Preparation Example 6
Preparation of 2-f4-(3-acetylammophenyl)piρeridin-l-yl]ethyl methanesulfonate (formula (HI); n=l, 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(SOOMHz5 CDCl3)δ 1.75-1.86(m, 4H)5 2.19(s, 3H)5 2.45(m, IH), 2.76(s, 3H), 3.01(m, 2H)5 3.14(t5 2H), 3.40(t, 2H), 3.48(t, 2H)5 6.88(d,
IH), 7.17-7.49(m, 4H); MS(m/e, M+): 340
Preparation of formula (IV) (Preparation Examples 7 to 10)
Cl
Figure imgf000029_0001
Preparation Example 7
Preparation of l-f4-chlorobuM)-2-phenyl-lH-benzimidazole (formula (IV); n=3. X=H) 2.5 g (12.88 mmol) of 2-ρhenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) Of K2CO3 and 2.0 ml (16.7 mmol) of l-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 X 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/l) to obtain 3.5 g (yield 96%) of the title compound.
1H NMR (300MHz, 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, IH); MS(m/e, M+): 285
Preparation Example 8
Preparation of 1 -(4-chlorobutyl)-2-(4-chlorophenyD- l./7-benzimidazole (formula TIV); 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 (300MHz5 CDCl3) δ 1.69(m, 2H), 2.00(m, 2H)5 3.46(t5 2H), 4.27(t, 2H), 7.34(m, 2H), 7.41(m, IH), 7.51(d, 2H), 7.66(d, 2H), 7.81(m, IH); MS(m/e, M+): 319, 283, 255, 206
Preparation Example 9
Preparation of l-f5-cMoroρentyl)-2-phenvπ#-benzimidazole fformula (IV); n=4, X=H)
2.5 g (12.88 mmol) of 2-ρhenyl-benzimidazole was dissolved in 30 ml of N,N-dimethylformamide, and 5.3 g (38.6 mmol) Of K2CO3 and 2.3 ml (16.7 mmol) of l-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 X 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/l) to obtain 3.16 g (yield 82%) of the title compound. 1H NMR (SOOMHZ5 CDCl3) δ 1.35(m, 2H), 1.67-1.87(m, 4H)5 3.41 (t, 2H)5 4.25(t, 2H)5 7.31(m3 2H), 7.39(m5 IH)5 7.51-7.55(m5 3H), 7.70(m, 2H)5 7.81(m, IH); MS(m/e5 M+): 298
5 Preparation Example 10
Preparation of 1 -(5-chloroρentylV 2-(4-chloroυhenyr)- Iffi-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) i o of 2-(4-chlorophenyl) benzimidazole.
1H NMR (SOOMHZ, CDCl3) δ 1.35(m, 2H), 1.68-1.87(m, 4H)5 3.43(t, 2H)5 4.24(t5 2H)5 7.29-7.41(m5 3H), 7.50(d, 2H)5 7.64(d, 2H), 7.82(m, IH); MS(m/e, M+): 333
15 Preparaion of Imidazole Derivative (Examples 1 to 4)
Figure imgf000031_0001
Example 1 0 2-phenyl- 1 - f 2- [4-(3 -acetylaminophenvDpiperidin- 1 -yl] ethyl I - 1 H- benzimidazole
70 mg (0.36 mmol) of 2-phenylbenzimidazole was dissolved in 5 ml of N5N-dimethylformamide, and 122 mg (0.36 mmol) of 2-[4-(3- acetylaminophenyl)piρeridin-l -yl]ethylmethanesulfonate obtained by5 Preparation Example 6 and 150 mg (1.08 mmol) OfK2CO3 were 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 X 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 NMRPOOMHZ, CDCl3)δ 1.55(-1.77(m, 6H), 2.06(m, 2H), 2.16(m, 3H), 2.43(m, IH), 2.78(t, 2H), 2.85(br-d, 2H), 4.39(t, 2H), 6.92(d, IH), 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-chlorophenylVl-{2-r4-(3-acetylaminoρhenyl)piperidin-l-yllethyl}-l/jr- 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.
1HNMR(300MHz, CDCl3)δ 1.50(-1.79(m, 6H), 2.08(m, 2H), 2.17(m,
3H), 2.45(m, IH), 2.78(t, 2H), 2.85(br-d, 2H), 4.37(t, 2H), 6.92(d, IH), 7.24-
7.37(m, 5H), 7.45(m, IH), 7.50(d, 2H, J=8.4 Hz), 7.78(d5 2H, J=SA Hz), 7.84(m, IH); MS(m/e, M+): 472, 231, 188, 160, 146
Example 3
2-phenyl- 1 - { 3 - F4-C3 -acetylammophenvDpiperidin- 1 -yllpropyll - IH- 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) OfK2CO3 were added to the resulting solution, followed by mixing the solution at 800C for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml X 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(300MHz, CDCl3)δ 1.61-1.77(m, 4H), 1.89-2.01(m, 4H), 2.15(s, 3H)5 2.28(1, 2H), 2.42(m, IH), 2.83(brd, 2H)5 4.37(t, 2H), 6.94(d, IH5 J=7.3 Hz), 7.24-7.32(m, 4H)5 7.46(m, 2H)5 7.47-7.53(m, 4H), 7.73(m, 2H)5 7.80(m5 IH) ; MS(m/e5 M+): 452, 424, 367, 257, 231
Example 4 2-f 4-chlorophenylV 1 - ( 3 -F4-(3 -acetylaminophenvDpiperidin- 1 -ylipropyll - lij-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(300MHz5 CDCl3)δ 1.59-1.79(m5 4H), 1.90-2.01(m, 4H)5
2.16(s5 3H)5 2.26(t5 2H)5 2.43(m, IH), 2.82(brd5 2H)5 4.37(t5 2H)5 6.95(d, IH,
/=7.5 Hz), 7.24-7.37(m, 5H)5 7.46(m, IH)5 7.52(d5 2H, J=SA Hz)5 7.71(d5
2H5 J=SA Hz), 7.80(m, IH) ; MS(m/e, M+): 486, 458, 311, 270, 257, 231
Preparation of Imidazole Derivative (Examples 5 to 8)
Figure imgf000033_0001
Example 5 2-phenyl- 1 - (4- f 4-(3 -acetylaminophenvDpiperidin- 1 -ylibutyll - IH- benzimidazole
100 mg (0.39 mmol) of 4-(3-acetylaminoρhenyl) piperidine hydrochloride was dissolved in 5 ml of N,N-dimethylformamide, and 112 mg (0.39 mmol) of l-(4-chlorobutyl)-2-phenyl-li:/"-benzimidazole obtained by Preparation Example 7, 163 mg (1.17 mmol) Of K2CO3 and 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 X 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% MeOHZCH2Cl2) to obtain 104 mg (yield 57%) of the title compound. 1H NMR(300MHz, CDCl3)δ 1.48(m, 2H), 1.69-1.99(m, 8H)5 2.15(s,
3H), 2.30(t, 2H), 2.45(m, IH), 2.90(br, 2H), 4.28(t, 2H), 7.23-7.38(m, 6H), 7.45-7.53(m, 4H), 7.72(m, 2H), 7.8 l(m, IH) ; MS(m/e, M+): 467
Example 6 2-(4-chlorophenyl)- 1 - {4- [4-(3-acetylaminophenyl)piperidin- 1 -yljbutyl} - 1 H- 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)-lH-benzimidazole resulting from
Preparation Example 8.
1H NMR(SOOMHZ, CDCl3)δ 1.48(m, 2H), 1.71~2.00(m, 8H), 2.15(s,
3H), 2.30(t, 2H), 2.42(m, IH), 2.91(br, 2H), 4.26(t, 2H), 6.95(d, IH), 7.23-
7.38(m, 6H), 7.45-7.52(m, 3H), 7.67(d, 2H), 7.80(m, IH) ; MS(m/e, M+): 500, 458, 324, 284,
Example 7
2-phenyl-l-(5-["4-C3-acetylaminophenyl)piperidin-l-yl]pentyl>-lϋ/- 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-l#-benzimidazole resulting from Preparation Example 9.
5g :!H NMR(300MHz5 CDCl3)δ 1.26(m, 2H), 1.47(m, 2H), 1.73- 1.96(m, 8H)5 2.16(s, 3H), 2.27(t, 2H), 2.45(m, IH)5 2.93(brd, 2H)5 4.25(t, 2H), 6.95(d, IH), 7.26-7.41(m, 7H)5 7.51(m, 3H)5 7.70(m, 2H), 7.80(m, IH); MS(m/e, M+): 480
Example 8
2-(4-chlorophenylVl-{5-r4-r3-acetylaminophenyl)piperidin-l-yl1pentvU- lH-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)-177-benzimidazole resulting from
Preparation Example 10. 1H NMR(300MHz, CDC13)5 1.27(m, 2H)5 1 ,48(m, 2H)5 1.72-1.86(m,
6H)5 1.99(m5 2H)5 2.16(s, 3H), 2.28(t5 2H), 2.46(m, IH), 2.94(brd, 2H),
4.24(t, 2H)5 6.97(d, IH), 7.23-7.4 l(m, 7H), 7.50(d5 2H), 7.66(d, 2H)5 7.68(m,
IH); MS(m/e5 M+): 515
Preparation of Imidazole Derivative (Examples 9 to 63)
Figure imgf000035_0001
Example 9 2-C2-chlorophenyD- 1 - ( 3 - r4-(3-acetylaminophenyl)ρiperidin- 1 -yllpropyU -
Ii7-benzimidazole
70 mg (0.31 mmol) of 2-(2-chlorophenyl)-liϊ-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 110 mg (0.31 mmol) of 3-
[4-(3-acetylaminophenyl)piperidin- 1 -yljpropyl methanesulfonate obtained by Preparation Example 4 and 130 mg (0.93 mmol) OfK2CO3 were 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 X 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% MeOHZCH2Cl2) to obtain 87 mg (yield 58%) of the title compound.
1H NMR(300MHz, CDCl3)δ 1.59-1.75(m, 4H), 1.85-1.90(m, 4H), 2.16(s, 3H)5 2.23(t, 2H)5 2.38(m, IH), 2.78(brd5 2H)5 4.17(t, 2H), 6.93(d, IH5 J=7.5 Hz)5 7.24-7.56(m, 11H)5 7.83(m, IH) ; MS(m/e, M+): 486, 451, 375, 346, 269, 257
Example 10 2-(3 -chloropheny I)- 1 - { 3 - [4-(3 -acety laminophenvDpiperidin- 1 -y l]propyl } - lffi-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)- lif-benzimidazole. 1H NMR(300MHz, CDCl3)δ 1.59(-1.78(m, 4H)5 1.89-1.99(m5 4H),
2.16(m, 3H), 2.27(t, 2H)5 2.46(m5 IH)5 2.82(br-d, 2H), 4.38(t, 2H), 6.94(d,
IH), 7.24-7.50(m, 9H), 7.65(d, IH), 7.78(s, IH, NH), 7.83(d, IH); MS(m/e,
M+): 487
Example 11
2-(4-bromophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l-yllpropyU- lff-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)-l#-benzimidazole.
Η NMR(300MHz, CDCl3)δ 1.62(m5 2H), 1.74(m, 2H)5 1.93(m5 4H), 2.16(s, 3H)5 2.26(t, 2H)5 2.43(m, IH)5 2.79(brd, 2H), 4.36(t, 2H), 6.94(d5 IH)5 7.25-7.37(m, 6H), 7.46(m, IH)5 7.66(m, 4H), 7.81(m5 IH); MS(m/e, M+): 531
Example 12
2-(3.4-dichlorophenylV 1 - (3- F4-(3 -acetylaminophenyβpiperidin- 1 - yljpropyl} - l//-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)~lH-benzimidazole.
1H NMR(SOOMHZ5 CDCl3)δ 1.55-1.64(m, 2H), 1.76(m9 2H)5 1.89- 1.99(m, 4H), 2.17(m, 3H)3 2.26(t5 2H)5 2.42(m, IH)5 2.80(br-d, 2H)5 4.39(t5 2H)5 6.94(d5 IH)5 7.24-7.35(m, 6H)5 7.48(m5 IH)5 7.50(m, 2H) 7.82(d, IH)5 7.92(s5 IH); MS(m/e5 M+): 52I5 479, 345, 304, 289, 257, 231
Example 13 2-(3 -bromophenyiy 1 - { 3 -[4-f 3 -acetylaminopheny Dpiperidin- 1 -yljpropyl} - lff-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)- li/~benzimidazole. 1H NMR(300MHz5 CDCl3)δ 1.59-1.78(m5 4H), 1.89-1.99(m5 4H),
2.16(m, 3H)5 2.27(t5 2H)5 2.46(m5 IH), 2.83(br-d, 2H), 4.38(t, 2H)5 6.96(d,
IH), 7.24-7.47(m, 8H)5 7.62-7.71(m, 2H)5 7.80(d, IH), 7.94(s, IH); MS(m/e5
M+): 53I5 45I5 357, 316, 257, 231
Example 14
2-f2-iodophenyD- 1 - (3-f4-(3-acetylaminophenyr)piρeridin- 1 -yl~|propyll- IH- 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- iodoρhenyl)-lϋ/-benzimidazole.
1H NMR(3Q0MHz, CDCl3)δ 1.65-1.82(m, 4H)5 1.92-2.05(m, 4H), 2.15(m, 3H), 2.37(m, 2H)5 2.45(m, IH)5 2.92(br-d5 2H)5 4.16(t5 2H)5 6.91(d, IH5 J=6.7 Hz)5 7.20-7.53(m, 10H)5 7.83(d5 IH5 /=7.3 Hz), 7.98(d, IH); MS(m/e, M+): 578, 451, 347, 256, 231
Example 15
2-(2-fluorophenyl)-l-(3-[4-(3-acetylaminophenyl)piperidin-l-yllproρyll- lij-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)- l//-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.58(m, 2H), 1.72(m, 2H), 1.91(m, 4H), 2.17(s, 3H)5 2.23(t, 2H), 2.37(m, IH), 2.81(brd, 2H), 4.24(t, 2H), 6.92(d, IH), 7.21-7.34(m, 7H), 7.39(s, IH), 7.48(m, 2H), 7.66(t5 IH), 7.82(dd, IH); MS(m/e, M+): 470
Example 16 2-(2.,4-dichloroρhenylVl-(3-r4-C3-acetylaminophenvπpiperidin-l- yllpropyl} - Ii7-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- dichloroρhenyl)-lJ7-benzimidazole. 1H NMR(300MHz, CDCl3)δ 1.57(m, 2H), 1.65(m, 2H), 1.91 (m, 4H)5
2.17(s5 3H), 2.25(t, 2H), 2.43(m, IH), 2.84(brd, 2H)5 4.16(t, 2H), 6.93(d, IH),
7.25-7.37(m, 8H), 7.43(d5 IH), 7.49(d, IH), 7.59(d, IH), 7.82(d, IH);
MS(m/e, M+): 521
Example 17
2-f 2-methoχyphenyr)- 1 - (3- r4-(3-acetylaminophenvDpiperidin- 1 -yllpropyll - lff-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)-lf/-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.66-1.83(m5 4H), 1.84-2.04(m, 4H), 2.17(s, 3H), 2.35(t, 2H), 2.37(m, IH), 2.89(br, 2H), 3.69(s, 3H), 4.07(t, 2H), 6.90(d, IH), 7.05(d, IH), 7.13(dd, IH)5 7.23-7.37(m, 4H), 7.42-7.45(m, 2H), 7.50(dd, IH), 7.57(d5 IH), 7.79(d, IH) ; MS(m/e, M+): 482
Example 18
2-(3 -methoxyphenyl V 1 - { 3 - [4-(3 -acetylaminophenvBpiperidin- 1 - vllpropyU - 5 lJT-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)- l//-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.58(m, 2H), 1.71(m, 2H)5 1.90(m, 4H),o 2.12(s, 3H), 2.26(t, 2H), 2.39(m, IH), 2.78(d, 2H), 3.84(s, 3H), 4.37(t, 2H), 6.94(d, IH), 7.04(d, IH), 7.21-7.45(m, 9H), 7.79(dd, IH)5 7.98(s, IH) ; MS(m/e, M+): 482
Example 19 5 2-(4-methoxyρhenylV 1 - { 3 -f 4-(3 -acetylaminophenyOpiperidin- 1 -yl~[ρropyll - lif-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)- l//-benzimidazole. 0 1H NMR(300MHz5 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, IH), 2.79(d, 2H), 3.85(s, 3H), 4.36(t, 2H),
6.92(d, IH), 7.02(d, 2H), 7.23-7.43(m, 6H), 7.68(d, 2H), 7.71(dd, IH) ;
MS(m/e, M+): 482 5 Example 20
2-r4-isopropylphenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l-yl]propyl}- lff-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- o isopropylphenyl)- 1 iϊ-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.27(d, 3H), 1.29(d5 3H)5 1.63(m, 2H)5 1.74(m, 2H), 1.94(m, 4H), 2.14(s, 3H), 2.30(t, 2H), 2.54(m, IH)5 2.84(brd, 2H)5 2.97(m, IH)5 4.36(t, 2H)5 6.93(d, IH)5 7.23-7.38(m, 6H)5 7.44(m5 IH), 7.47(s, IH), 7.65(d, 2H), 7.80(m, IH) ; MS(m/e, M+): 492
Example 21
2-phenyl-l-{3-r4-r3-acetylaminophenyl)piperidin-l-vnpropyl>-5,6- dimethyl- l//"-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-536-dimemyl-li/-benzimidazole.
1H NMR(300MHz, CDCl3)O 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)5 2.45(m, IH), 2.80(brd, 2H), 4.29(t, 2H), 6.92(d, IH), 7.19(dd, 2H), 7.32(d, IH), 7.41(s, IH), 7.47(m, 3H), 7.56(s, IH), 7.71(dd, 2H), 7.95(s, IH); MS(m/e, M+): 480
Example 22 2-r4-chlorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l-yl]propyl}-
5,6-dimethyl- Ii7-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-177-benzimidazole. 1H NMR(300MHz, CDCl3)δ 1.58(m, 2H), 1.74(m, 2H)3 1.92(m, 4H),
2.13(s, 3H), 2.24(t, 2H), 2.38(s, 3H), 2.40(s, 3H)3 2.46(m, IH), 2.79(brd, 2H)3
4.30(t, 2H), 6.93(d, IH)3 7.22(d, 2H)3 7.33(s3 IH)3 7.35(d, IH), 7.46(s, 2H),
7.55(s, IH), 7.66(d, 3H) : MS(m/e, M+): 515
Example 23
2-phenyl-l-{3-r4-D-acetylaminophenyl)ρiperidin-l-yllproρyll-6-methyl- lffi-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- l//-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.60-1.74(m, 4H)3 1.89-1.98(m, 4H), 2.14(m, 3H), 2.27(t, 2H), 2.42(m, IH)3 2.49(s, 3H), 2.84(br-d3 2H)3 4.32(t, 2H)3 6.95(d, IH)3 7.13(m3 IH)3 7.23-7.40(m3 5H)3 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-chlorophenylV 1 - (3 -\4-( 3-acetylaminophenyDpiperidin- 1 -ylipropyl) -6- methyl- liZ-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-l/zr-benzimidazole.
1H NMR^OOMHZ, 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, IH), 2.49(s, 3H), 2.5 l(s, 3H), 2.81(brd, 2H), 4.3 l(t, 2H), 6.92(brd, IH), 7.13(dd, IH), 7.23(d, 2H), 7.35(dd, 2H), 7.48(d, 2H), 7.59(s, IH), 7.67(d, 3H) : MS(m/e, M+): 501
Example 25 2-(4-chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -ylipropyll -6- chloro- li/-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-li/-benzimidazole. 1H NMR(300MHz, 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, IH), 2.76(d, 2H), 4.35(t, 2H), 6.95(d, IH),
7.24-7.41(m, 6H), 7.50(d, 2H), 7.69(d, 2H), 7.77(d, IH) : MS(m/e, M+): 521
Example 26 2-phenyl- 1 - (3-r4-(3-acetylaminophenyl)piperidin- 1 -ylipropyll -6-fluoro- IH- 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- liT-benzimidazole. 1H NMR(300MHz, 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, IH), 7.03(dd, IH),
7.21 -7.53 (m, 9H), 7.70-7.74(m, 2H) : MS(m/e, M+): 470 Example 27
2-phenyl-l--{'3-r4-r3-acetylaminophenyl>)piperidin-l-vnproρyll-6-metlioxy- lff-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-li7-benzimidazole.
1H NMR(SOOMHZ5 CDC13)6 1.62(m, 4H), 1.91(m, 4H), 2.18(s, 3H)5 2.25(t, 2H), 2.39(m, IH), 2.82(brd, 2H), 3.88(d5 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-chlorophenvπ-l-l3-r4-r3-acetylaminophenyl)piperidin-l-yllpropyU-6- methoxy- 1 //"-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- l//-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.76(m, 4H), 1.91(m, 4H), 2.18(s, 3H),
2.25(t, 2H), 2.39(m, IH), 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) I MS(HVe5 M+):
517
Example 29
2-phenyl- 1 - ( 3 - F4-(3 -acetylaminophenvDpiperidin- 1 -ylipropyl } -6-chloro- IH- 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-l#-benzimidazole.
!H NMR(300MHz, CDC13)5 NMR(300MHz, CDC13 )δ 1.65-1.81(m, 4H), 1.90-2.00(m, 4H), 2.15(s, 3H)5 2.25(t, 2H)5 2.45(m, IH), 2.82(br-d,
2H), 4.30(t, 2H)5 6.92(d, IH, J=6.8 Hz)5 7.24-7.53(m, 9H),7.69-7.79(m5
3H) ; MS(m/e, M+): 487 Example 30
2-C4-fluorophenylV 1 -(3-r4-C3-acetylaminophenyl)ρiperidin- 1 -yllproρyll-6- chloro- l//-benzirnidazole
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-lif-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.61(m, 2H), 1.75(m5 2H), 1.89-1.97(m, 4H), 2.17(s, 3H), 2.26(t, 2H)5 2.45(m5 IH), 2.80(br-d5 2H), 4.32(t, 2H), 6.95(d, IH), 7.21 -7.38(m, 7H), 7.69-7.78(m, 3H) ; MS(m/e, M+): 504
Example 31
2-(4-ChIQrOPhCnVlV 1 -{3-[4-(3-acetylarninophenyl)piperidm- 1 -yl]propyl) -6- fluoro- lff-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- l//-benzimidazole.
1H NMR(SOOMHZ, 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, IH), 2.80(br-d, 2H), 4.32(t, 2H)5 6.97(d, IH), 7.05(m, IH), 7.15-7.40 (m, 5H), 7.5 l(d, 2H), 7.68(d, 2H) ; MS(m/e, M+): 505
Example 32
2-phenyl- 1 - { 3 - [4-(3 -acetylaminopheny Dpiperidin- 1 -yllpropyl } -6-nitro- 1 H- 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- l//-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.55(m, 2H)5 1.72(m, 2H), 1.87-1.97(m,
4H)5 2.19(s5 3H), 2.26(t, 2H), 2.41(m, IH)5 2.76(br-d, 2H)5 4.45(t, 2H)5 6.92(d5 IH)5 7.24-7.32(m5 3H)5 7.38(s5 IH5 NH)5 7.57-7.59 (m5 4H)5 7.76(m5
2H)5 8.25(dd, IH)5 8.72(d, IH) ; MS(m/e, M+): 483
Example 33 2-f2-fluoiOphenylVl-(3-|'4-D-acetylaminoρhenylv)piperidin-l-yl1ρroρvU-6- chloro- liT-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~ fluorophenyl)-5-chloro- 1 if-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.62(m5 2H)5 1.71(m, 2H), 1.85-1.93(m, 4H), 2.15(s, 3H), 2.20(t, 2H), 2.42(m, IH), 2.76(br, 2H), 4.23(t, 2H), 6.94(d, IH), 7.24-7.80(m, 1 IH), ; MS(m/e, M+): 504, 288, 257, 231
Example 34
2-(3 -fluorophenyl)- 1 - { 3 -[4-f 3 -acetylaminophenyl)piperidin- 1 -yTjpropyl} -6- chloro- l#-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-li!/-ben2;imidazole.
1H NMR(SOOMHZ5 CDCl3)δ 1.64(m, 2H), 1.77(m, 2H)5 1.87-1.95(m, 4H), 2.17(s, 3H), 2.26(t, 2H), 2.42(m, IH), 2.82(br, 2H)5 4.35(t5 2H), 6.94(d5 IH)5 7.25-7.79(m, HH)5 ; MS(m/e, M+): 504, 476, 380, 329, 2885 257,231
Example 35
2-(3 -chlorophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl]propyU -6- chloro- l//-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- Ii7-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.61-1.75(m, 4H), 1.88-1.96(m, 4H), 2.17(s, 3H)5 2.26(t, 2H), 2.42(m, IH)5 2.81(brd5 2H), 4.35(t, 2H)5 6.96(d, IH)5 7.25-7.79(m5 HH)5 ; MS(m/e, M+): 520, 492, 409, 380, 302, 257, 231
Example 36
2-f 4-chlorophenvD- 1 - {344-O-acetylaminophenvDpiperidin- 1 -yllpropyll -6- bromo- lJZ-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-bromo4iY-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.60-1.77(m, 4H)5 1.88-1.98(m, 4H), 2.16(s, 3H)5 2.23(t, 2H), 2.42(m, IH), 2.80(brd, 2H), 4.34(t, 2H), 6.96(d, IH), 7.23-7.43(m, 6H), 7.50(d, 2H), 7.64(m, IH), 7.69(d, 2H) ; MS(m/e, M+): 566, 536, 485, 348, 257, 231
Example 37
2-f2-chlorophenyl)-l-(3-r4-r3-acetylaminophenvDρiperidin-l-yllpropyU- 5,6-dimemyl-li7-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-177-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.58-1.75(m, 4H)5 1.82-1.91(m, 4H), 2.14(s, 3H)5 2.21(t, 2H)5 2.38(m, IH), 2.39(s, 3H), 2.42(s, 3H), 2.76(br, 2H)5
4.10(t, 2H), 6.94(d, IH), 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 2-0 -chlorophenylV 1 - (3 - [4-f 3 -acetylaminophenvDpiperidin- 1 -yljpropyl} -
5,6-dimethyl- l/f-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-lH-benzimidazole. 1H NMR(300MHz, CDCl3)δ 1.62-1.78(m, 4H)5 1.90-1.98(m, 4H),
2.16(s, 3H)5 2.27(t, 2H)5 2.38(m, IH), 2.39(s, 3H)5 2.42(s, 3H)5 2.84(br5 2H),
4.32(t5 2H)5 6.94(d, IH)5 7.23-7.46(m, 7H), 7.56(s, IH)5 7.61(m5 IH), 7.76(s,
IH) ; MS(m/e, M+): 514
Example 39
2-C4-chloiOphenylVl-(3-r4-(3-acetylaminophenvDpiperidin-l-yl]propyll- 4,5-dimethyl- liT-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- chloroρhenyl)-4,5-dimethyl-l#-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.58-1.78(m, 4H), 1.88-1.96(m, 4H)3 2.16(s, 3H), 2.24(t, 2H), 2.41(s, 3H), 2.43(m, IH), 2.62(s,3H), 2.82(br, 2H), 4.28(t, 2H), 6.94(d, IH), 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 - ["4-0 -acetylaminophenyDpiperidin- 1 -yljpropyl} -5 - nitro- 1/Z-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-li7-benzimidazole.
1H NMR(300MHz, 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, IH), 2.74(brd, 2H), 4.27(t, 2H), 6.94(d, IH),
7.23-7.63(m, 8H), 7.63(d, IH), 8.28(dd, IH), 8.58(d, IH) ; MS(m/e, M+):
532
Example 41 2-(3 -chlorophenyl)- 1 - (3 - \4-( 3 -acetylaminophenyDpiperidin- 1 -yljpropyl} -5 - nitro- l//-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-hitro-lH-benzimidazole. 1H NMR(300MHz, CDCl3)δ 8.75(d. IH), 8.29(dd, IH),
7.63 ~7.23(m, 8H), 7.15(d, IH), 6.94(dd, IH), 4.27(t, 2H), 2.74(brd, 2H)5
2.41(m, IH), 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-r4-chlorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l-vnpropyl|-5- nitro- lffi-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-lif-benzimidazole.
1H NMR(SOO]VDH-Z5 CDCl3)δ 8.73(d. IH)5 8.29(dd, IH)5 8.03(d5 IH)5 7.73 - 7.5 l(m, 4H)5 7.34~7.20(m5 4H), 6.94(dd5 IH)5 4.27(t, 2H)5 2.74(brd, 2H)5 2.41(m5 IH)5 2.22(t, 2H)5 2.19(s, 3H)5 1.89~ 1.96(m, 4H)5 1.57- 1.80(Da9 4H) ; MS(m/e, M+): 532
Example 43
2-phenyl-l-{3-[4-f3-acetylaminophenyl)piperidm-l-yllpropyl}-5-bromo-l./7- 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- l//-benzimidazole.
1H NMR(300MHz, CDCl3)S 7.75(m. 3H)5 7.68(m, 3H)5 7.22~7.43(m, 6H)5 6.96(d, IH)5 4.35(t5 2H)5 2.81(brd, 2H)5 2.43(m5 IH)5
2.25(t5 2H)5 2.19(s5 3H)5 1.89~ 1.96(m, 4H)5 1.66 ~ 1.80(m5 4H) ; MS(m/e,
M+): 531
Example 44 2-(2,3 A 5-tetrafluorophenyD- 1 - (3 - [4-(3 -acetylaminophenyppiperidin- 1 - yllpropyll - 1/7-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)- li/-benzimidazole. 1H NMR(300MHz, CDCl3)δ 7.85(m. IH), 7.53(m, IH)5
7.19~7.51(m5 7H)5 6.94(d,. IH), 4.27(t, 2H)5 2.80(brd, 2H), 2.42(m, IH),
2.22(t, 2H)5 2.19(s, 3H), 1.89~ 1.96(m, 4H), 1.57~ 1.80(m, 4H); MS(m/e,
M+): 524
Example 45
2-r4-trifluoromethylphenylV 1 - (3 - [4-C3 -acetylaminophenyDpiperidin- 1 - ylipropyU- l/T-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- Mfluoromethylphenyl)4i7-benzimidazole.
1H ]SIMR(SOO]VIHZ, CDC13)5 1.53-1.64(m, 2H), 1.75(m, 2H)5 1.89- 2.02(m, 4H)5 2.14(s5 3H)5 2.26(br t, 2H, J=6.4 Hz^2.41(m, IH), 2.80(m, 2H), 4.39(br t, 2H, J=IA Hz)5 6.92(m, IH)5 7.22(t, IH, J=7.7 Hz), 7.32-7.38(m, 4H)5 7.50(m5 IH)5 7.68(br S5 IH)5 7.79(d, 2H5 J=8.0 Hz)5 7.83(m, IH)5 7.91(d, 2H5 J=8.2 Hz); MS(m/e, M+): 520 (M+), 231
Example 46 2-f 4-biphenvD- 1 - ( 3 - f4-("3 -acetylaminophenvDpiperidin- 1 -ylipropyll - IH- 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)- lff-benzimidazole. 1H NMR(300MHz, CDCl3)S 1.59-1.75(m5 4H)5 1.89-2.03(m, 4H),
2.21(s5 3H)5 2.30(m5 2H)5 2.40(m5 IH)5 2.83(m, 2H)5 4.42(m, 2H)5 6.89(m,
IH), 7.17(m, IH)5 7.26-7.47(m5 8H)5 7.57(br s, IH), 7.63(m, 2H)5 7.75(m5
2H)5 7.83(m, 3H); MS(m/e, M+): 528 (M+), 297, 23I5 70
Example 47
2-(4-phenoxyphenyr)- 1 - (3 - \4-( 3 -acetylaminophenvDpiperidin- 1 -yllpropyll - l/Z-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)- lif-benzimidazole.
1H NMR(SOOMHZ5 CDCl3)δ 1.67(m5 2H), 1.76(m, 2H), 1.90-2.03(m, 4H)5 2.12(s5 3H)5 2.28( br t, 2H, J=6.6 Hz)5 2.43(m, IH)5 2.84(m5 2H)5 4.38(br t5 2H, J=7.2 Hz)5 6.95(m, IH)5 7.04-7.40(m5 12H)5 7.47(m5 IH), 7.53(m5 IH), 7.72(m5 2H), 7.81(m5 IH); MS(m/e, M+): 544 (M+), 327, 23I5 70
Example 48 2-C4-fluoroρhenylVl-(3-r4-('3-acetylaminoϋhenvDρiρeridin-l-vnproρvU- lffi-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)- lif-benzimidazole. 1H NMR(300MHz5 CDCl3) δ 7.73 ~7.83(m. 2H)5 7.20~7.73(m,
10H)5 6.96(d, IH)5 4.35(t, 2H)5 2.81(brd5 2H)5 2.43(m, IH)5 2.25(t5 2H)5 2.19(s, 3H)5 1.88 - 1.96(m, 4H)5 1.55 - 1.78(m, 4H) ; MS(m/e5 M+): 470
Example 49 2-("4-chlorophenylVl-{3-[4-(3-acetylaminophenyl)piperidin-l-yl]propyl}-
4,6-dimethyl- liJ-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-li/-benzimidazole. 1H NMR(300MHz5 CDCl3)δ 1.58-1.79(m5 4H)5 1.87-1.96(m, 4H)5
2.16(s, 3H)5 2.24(t5 2H)5 2.43(m5 IH)5 2.48(s, 3H)5 2.65(s5 3H)5 2.80(br5 2H)5
4.27(t5 2H)5 6.93(s5 IH)5 6.94(d, IH)3 7.08(s5 IH)5 7.24-7.37(m5 4H)5 7.47(d,
2H)5 7.47(d5 2H) ; MS(m/e5 M+): 514
Example 50
2-f 3 ,4-difluorophenvD- 1 -(3 - F4-C3 -acetylaminophenvDpiperidin- 1 - yl1propyl}-l//-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-(354- difluorophenyl)- 177-benzimidazole.
1H MMR(300MHz, CDCl3)δ 1.64(m, 2H)5 1.76(brd5 2H)5 1.90-
2.04(m5 4H)5 2.17(s, 3H)5 2.27(t5 2H)5 2.44(m, IH)5 2.82(br5 2H)5 4.38(t, 2H)5
6.94(d5 IH)5 7.24-7.38(m, 7H)5 7.45-7.59(m, 2H)5 7.65(m5 IH)5 7.80(m5
IH) ; MS(m/e, M+): 488
Example 51
2-f 4-cvanophenylV 1-13- 1"4-("3 -acetylaminophenvDpiperidin- 1 -yllpropyU - liT-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)- li/"-benzimidazole.
1H NMR(300MHz, CDCl3)O 1.43(m5 2H)5 1.71(brd, 2H)5 1.85- 2.0Km9 4H)5 2.18(s, 3H)5 2.16(t, 2H)5 2.4 l(m, IH), 2.72(br, 2H)5 4.44(t, 2H)5 6.91(d5 IH)5 7.23-7.32(m5 4H)5 7.49-7.53(m, 3H)5 7.83(m5 IH)5 7.85(d5 2H)5 7.94(d, 2H) ; MS(m/e5 M+): 477
Example 52 2-C3 -cyanophenyp- 1 - {3 - [4-(3-acetylaminophenyl)piperidin- 1 -ylipropyl } - l//-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)- Ii7-benzimidazole. 1H NMR(300MHz5 CDCl3)δ 1.55(m, 2H)5 1.71(brd, 2H)5 1.86-
1.99(m, 4H)5 2.17(s, 3H)5 2.24(t5 2H)5 2.41(m, IH)5 2.72(br, 2H)5 4.43(t, 2H),
6.92(d5 IH)5 7.24-7.49(m, 7H)5 7.67(dd5 IH)5 7.80(m5 2H)5 8.05-8. ll(m,
2H) ; MS(m/e, M+): 477
Example 53
2-( 4-chloro-2-fluorophenyl)- 1-13- F4-f 3 -acetylaminophenvDpiperidin- 1 - yllpropyU - l/Z-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)- lϋT-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.60(m5 2H)5 1.74(brd, 2H)5 1.85-
1.96(m, 4H), 2.16(s5 3H)5 2.21(t, 2H), 2.41(m, IH)5 2.77(br, 2H), 4.24(t, 2H)5
6.94(d5 IH), 7.24-7.37(m, 8H)5 7.49(d, IH)5 7.60(dd, IH)5 7.82(d5 IH) ;
MS(m/e, M+): 505
Example 54
2-f 2-chloro-4-fluorophenyr)- 1 - (3 - F4-(3 -acetylaminophenvDpiperidin- 1 - yllpropyl) - Ii7-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)-li7-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.62(m, 2H)5 1.74(brd, 2H), 1.84- 1.94(m, 4H), 2.16(s, 3H)5 2.23(t, 2H)5 2.42(m, IH), 2.78(br, 2H)5 4.16(t, 2H)5
6.95(d, IH), 7.16-7.37(m, 8H)5 7.52(m, 2H)5 7.82(d, IH) ; MS(m/e, M+): 505
Example 55
2-f3-nitrophenylVl-(3-r4-(3-acetylaminophenyl)piperidin-l-yl]propyl|-l/zr- 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)- l//-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.48(m, 2H)5 1.72(brd5 2H)5 1.88- 2.04(m, 4H)5 2.19(s, 3H)5 2.27(t, 2H), 2.41(m, IH), 2.78(br, 2H), 4.45(t, 2H),
6.89(d, IH)5 7.24-7.39(m, 5H), 7.51(d, IH), 7.75(dd, IH), 7.84(d, IH),
8.19(d, IH), 8.37(d, IH)5 8.66(s5 IH) ; MS(m/e, M+): 497
Example 56 2-("5-chloiO-2-methoxyphenyl)-l-(3-r4-O-acetylaminophenyl)piperidin-l- yllpropyll - 1/f-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)-lϋ/-benzimidazole. 1H NMR(300MHz, CDCl3 )δ 1.68-1.82(m, 4H)5 1.84-2.03(m5 4H)5
2.17(s, 3H)5 2.35(1, 2H), 2.38(m5 IH), 2.88(br, 2H), 3.70(s, 3H), 4.06(t, 2H),
6.95(d, IH), 6.99(d, IH), 7.23-7.47(m, 7H)5 7.58(s, IH), 7.80(d5 IH) ;
MS(m/e5 M+): 517
Example 57
2-(2-chloro-4-nitrophenylV 1-13- F4-C3 -acetylaminophenvDpiperidin- 1 - ylipropyU - lϋT-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- ch.loro-4-nitrophenyl)-li/-benzimidazole.
1H NMR(300MHz, 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, IH), 2.88(br, 2H), 4.20(t, 2H), 6.87(d, IH), 7.16(s, IH), 7.23(d, IH), 7.35-7.42(m, 4H) 7.52(d, IH), 7.79(d, IH), 7.85(d, IH), 8.30(dd, IH), 8.47(s, IH) ; MS(m/e, M1"): 532
Example 58
2-C2,4-dimethoxyphenyl)- 1 - (3 - F4-D -acetylaminophenvDpiperidin- 1 - ylipropyl ) - l//-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)-liϊ-benzimidazole.
1H NMR(300MHz, 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, IH), 2.89(br, 2H), 3.67(s, 3H), 3.87(s, 3H),
4.04(t, 2H), 6.60(d, IH, J=2.1 Hz), 6.64(dd, IH, J=8.4 Hz, 2.1 Hz), 6.97(d,
IH), 7.21-7.42(m, 6H), 7.50(d, IH, J=8.4 Hz), 7.78(m, IH) ; MS(m/e, M+):
512
Example 59
2-f 4-chloro-2-fluorophenyl)- 1 - (3 - F4-0 -acetylaminophenyppiperidin- 1 - yl]propyU-5,6-dimethyl-li/-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- lif-benzimidazole.
1H NMR(300MHz, 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, IH), 2.42(s,
3H)5 2.80(br, 2H), 4.18(t, 2H), 6.92(d, IH), 7.16-7.34(m, 4H), 7.37(s, IH),
7.46(s, IH), 7.57-7.63(m, 2H); MS(m/e, M+): 533
Example 60
2-(4-chloroρhenyl> 1 -(3-r4-r3-acetylaminophenvDpiperidin- 1 -ylipropylM- carbamoyl- li^-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-liJ-benzimidazole.
1H NMR(300MHz, CDCl3)O 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, IH), 2.65(brd, 2H) 4.43(t, 2H), 4.84(brs, IH, NH2), 5.70(brs, IH, NH2), 6.8δ(d, IH, J=7.8Hz), 7.24(m, 2H), 7.48(d, IH), 7.53(d, 2H, J=8.7Hz), 7.57(m, IH), 7.71(d, 2H, J=8.7Hz), 7.80(s, IH), 7.90(dd, IH, J=8.7Hz, 1.5Hz), 8.32(d, IH5 J=I.5Hz) ; MS(m/e, M1"): 530
Example 61
2-(4-chlorophenyl')-l-(3-r4-(3-acetylaminoρhenyl)pipeπdm-l-yllρroρvU-5- carbamoyl- Ii7-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-li.T-berizimidazole.
1H NMR(300MHz, 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, IH), 2.74(br, 2H) 4.44(t, 2H),
4.83(brs, IH, NH2), 5.85(brs, IH, NH2), 6.92(d, IH, J=7.4Hz), 7.23(dd, IH), 7.36(s, IH), 7.43(d, IH, J=7.8Hz), 7.54(d, 2H, J=8.7Hz), 7.69(m, 2H),
7.49(d, 2H, J=8.7Hz), 7.80(d, IH, J=8.6Hz), 8.30(s, IH) ; MS(m/e, M+): 530
Example 62
2-(3 -carbamoylphenyP)- 1 - (3 - F4-f 3 -acetylaminophenyppiperidin- 1 - yllpropyl) - lffi-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- carbamoylρhenyl)-l#-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.05(m, 2H), 1.51(brd, 2H), 1.68- 1.82(m, 4H)5 1.97(m5 2H), 2.23(m5 IH)5 2.25(s, 3H), 2.51(brd5 2H) 4.05(t5
'2H), 5.98(brs, IH5 NH2), 6.79(d, IH, J=7.5 Hz), 6.87(s, IH), 7.18(dd, IH),
7.35-7.37(m5 3H), 7.55(dd, IH), 7.48(d, IH)5 7.83-7.88(m, 2H), 7.99(s, IH),
8.01(d, IH, 7=8.1 Hz), 8.78(s, IH) ; MS(m/e, M+): 495 Example 63
2-r2-hvdroxyphenyl)-l-(3-[4-r3-acetylaminophenvDρiρeridin-l-yllproρyll- liT-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)- l//-benzimidazole.
1H NMR(SOOMHZ, CDCl3) δ 1.72-1.84(m, 4H), 2.04(m, 2H), 2.18(s, 3H), 2.24(t, 2H)5 2.51(m5 IH), 2.70(m, 2H), 3.13(brd, 2H), 4.38(t, 2H), 6.93(d, IH, J=8.4Hz), 7.07-7.29(m, 7H), 7.36-7.42(m, 2H), 7.71(m, 2H), 8.55(d, IH) ; MS(m/e, M+): 468
Preparation of Imidazole Derivative (Examples 64 to 67)
Figure imgf000054_0001
Example 64
2-f 4-chlorophenyl)- 1 - { 3 - 1~4-(3 -isobutyrylaminophenyDpiperidin- 1 - yljpropyl) - l//-benzimidazole
Step 1) 2-(4-chlorophenyl)-l-{3-[4-(3-aminophenyl)piperidin-l- yl]propyl} - Ii7-benzimidazole
Figure imgf000054_0002
1.5 g (3.08 mmol) of 2-(4-chlorophenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} - Ii7-benzimidazole obtained in Example 4 was dissolved in 30 ml of methanol, and 10 ml of 5N-HC1 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 60ml 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 X 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^l/S) to obtain 1.19 g (yield 87%) of the title compound.
1H ΝMR(300MHz, CDCl3)O 1.62(m, 2H), 1.74(m, 2H), 1.88-1.99(m, 4H), 2.25(t, 2H), 2.35(m, IH), 2.82(brs, 2H)5 3.63(brs, 2H, ΝH2), 4.36(t, 2H), 6.53(m, 2H), 6.60(6, IH), 7.07(dd, IH), 7.29-7.33(m, 2H), 7.47(m, IH), 7.52(d, 2H), 7.71(d, IH)5 7.81(m, IH) ; MS(m/e, M+): 445
Step 2) 2-(4-chlorophenyl)-l-{3-[4-(3- isobutyrylaminophenyl)piperidin-l-yl]piOpyl}-l//-benzimidazole
70 g (0.157 mmol) of 2-(4-chlorophenyl)-l-{3-[4-(3- aminophenyl)ρiperidin-l-yl]propyl}-li7-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 X 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(300MHz, 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, IH), 2.65(s, 3H), 2.95(brd, 2H), 4.22(t, 2H)5 6.97(d5 IH, J=I.5 Hz), 7.20-7.38(m, 6H)5 7.43(brs, IH3 NH), 7.67(m, IH) ; MS(m/e, M+): 515
Example 65 2-(4-chlorophenyl)- 1 - { 3 - [4-f 3-benzoylammophenγr)piρeridin- 1 -yl]propyl| - lH-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} - IH- benzimidazole obtained in step 1) of Example 64, and 0.022 ml (0.19 mmol) of benzoylchloride.
1H NMR(300MHz, CDCl3)δ 1.71(t, 2H), 1.80(d, 2H), 1.96(m, 2H), 2.01(m, 2H), 2.27(t, 2H)5 2.48(m, IH)5 2.84(br-d, 2H), 4.37(t, J=14.4, 2H), 7.01(d, J=7.5, IH) 7.31(m, 3H), 7.51 (m5 7H)5 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^phenvDpiperidin- 1 - yl1propyll-l/Z-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 -yljpropyl} - IH- benzimidazole obtained in step 1) of Example 64, and 0.024 ml (0.19 mmol) of 4-chlorobenzoylchloride. 1H NMR(300MHz, CDCl3)δ 1.62(m, 2H)5 1.78(d5 2H), 1.91(m, 2H)5
1.96(m, 2H), 2.04(s, 3H) 2.26(t, 2H), 2.47(m, IH) 2.85(br-d, 2H)5 4.37(t,
J=14.7, 2H), 7.00(d5 J=37.8Hz, IH) 7.33(m, 5H), 7.52 (m, 5H)5 7.85(m5
6H) ; MS(m/e, M+): 584, 529, 475, 441
Example 67
2-( 4-chloroρhenyl V 1 - ( 3 - F4-(3 -(4-methylbenzoylamino)phenyl)ρiρeridin- 1 - yllpropyl}- 1/f-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)-l-{3-[4-(3-aminophenyl)piperidin-l-yl]propyl}-lH- benzimidazole obtained in step 1) of Example 64, and 0.025 ml (0.19 mmol) of p-toluoylchloride. 1H NMR(300MHz5 CDCl3)δ 1.71(m, 2H)5 1.80(m5 2H)5 1.98(m5 2H)5
2.03(m, 2H)5 2.31(t, 2H)5 2.42(s, 3H) 2.47(m, IH) 2.89(br-d, 2H)5 4.37(t, J=UJ, 2H)5 7.00(d5 IH) 7.32(m5 5H)5 7.50 (m, 5H)5 7.80(m5 6H) ; MS(m/e5 M+): 563, 532, 499, 458
Preparation of Imidazole Derivative (Examples 68 to 70)
Figure imgf000057_0001
Example 68 6-biOmo-5-meth.yl-2-phenyl-3-(3-r4-(3-acetylaminoplienyl)ρiρeridin-l- vl1piOpyl|-3//-imidazo[4,5-blρyridine
100 mg (0.35 mmol) of 6-bromo-5-methyl-2-phenyl-3#- imidazo[455-b]pyridine was dissolved in 5 ml of N5N-dimethyl formamide, and 240 mg (0.68 mmol) of 3-[4-(3-acetylaminophenyl)piperidin-l- yl]propylmethanesulfonate obtained in Preparation Example 4 and 282 mg (2.04 mmol) of K2CO3 were 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 X 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%- MeOHZCH2Cl2) to obtain 90 mg (yield 47%) of the title compound.
1H NMR(SOOMHZ, CDCl3)δ 1.57(m, 2H), 1.72(m, 2H), 2.01(m, 2H)5 2.17(s, 3H)3 2.35(t, 2H)5 2.37(m, IH)5 2.77(s5 3H)5 2.84(brd5 2H)5 4.47(t5 2H)5 6.92(d5 IH)5 7.21-7.36(m5 3H)5 7.54(t5 3H)5 7.77(t5 2H)5 8.17(s, IH): MS(m/e5 M+): 546
Example 69
5-methyl-2-phenyl-3 - ( 3 - f4-(3 -acetylaminophenvDpiperidin- 1 -ylipropyll - 3ϋ/-imidazo[4.,5-blpyridine
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-3if-imidazo[455-b]pyτidine.
1H NMR(SOOMHZ5 CDCl3)δ 1.59-1.75(m5 4H)5 1.90(brt, 2H)5 2.02(m5 2H) 2.16(s5 3H)5 2.32(t5 2H)5 2.42(m5 IH)5 2.67(s, 3H)5 2.84(br, 2H)5 4.50(t5 2H)5 6.92(d5 IH5 J=7.2Hz), 7.10(d, IH5 J=8. IHz)5 7.23-7.39(m5 3H)5 7.50- 7.54(m, 3H)5 7.78(m5 2H)5 7.93(d5 IH5 J=8.1Hz); MS(m/e, M+): 467
Example 70
2-(benzo[l,3]dioxol-5-yl)-l-{3-[4-f3-acetylaminophenyl)piperidin-l- yllpropyl} - Ii7-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[l53]dioxol-5-yl)-li7-benzimidazole.
1H NMR(300MHz5 CDCl3) δ 1.61-1.78(m5 4H)5 1.89-2.01(m5 4H),
2.15(s5 3H)5 2.28(br t, 2H5 J=6.6 Hz)5 2.42(m5 IH)5 2.83(m5 2H)5 4.36(br t5
2H5 J=7.4 Hz)5 6.02(s, 2H)5 6.95(m5 2H)5 7.20-7.38(m5 7H)5 7.45(m5 IH)5 7.71(br S5 IH)5 7.79(m5 IH); MS(m/e5 M+): 496 (M+), 265, 231, 70.
Preparation of Imidazole Derivative (Examples 71 and 87)
Figure imgf000059_0001
ti = 1 or 2 A-. CH' or N Y = Me orW
Example 71
2-(4-chlorophenyl)-l-(2-[4-(3-isobutyrylaminophenyl)piperidin-l-yl]ethyl}- Ii7-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 mrnol) of 3-[4-(3- isoburyrylaminophenyl)piperidin- 1 -yljethylmethanesulfonate obtained by the procedure similar to Preparation Example 5, and 70 mg (0.31 mmol) of 2-(4-chlorophenyl)benzimidazole.
1H NMR(SOOMHZ, CDCl3 )δ 1.25(d5 6H), 1.52-1.86(m, 4H)5 2.12(m, 2H)5 2.46(m, IH)5 2.52(m, IH), 2.79(t, 2H), 2.86(brd, 2H)5 4.38(t5 2H), 6.92(d5 IH5 J=7.2 Hz)5 7.10(s, IH)5 7.22-7.35(m, 3H)5 7.47(m5 2H), 7.52(d, 2H, /=8.4 Hz), 7.79(d5 2H, J=8.4 Hz)5 7.84(m, IH) ; MS(m/e, M+): 500
Example 72
2-phenyl-3 - {3 - [4-(3 -acetylaminophenyppiperidin- 1 -yljpropyll -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-3//-imidazo[4,5-c]ρyridine.
1H NMR(SOOMHZ5 CDCl3 )δ 1.64(m, 2H)5 1.78(brd5 2H)5 1.99(brt,
2H), 2.17(s, 3H)5 2.36(m5 IH)5 2.37-2.48(m5 4H)5 2.94(brd, 2H), 4.80(t, 2H),
6.94(d, IH, J=I.6 Hz)5 7.05(dd, IH), 7.25(m5 IH), 7.35-7.50(m, 5H)5 7.74(d, 2H, J=6.0 Hz), 8.18(d, IH5 J=7.5Hz), 8.50(d, 2H) ; MS(m/e, M+): 453
Example 73 2-phenyl-3 - ( 3 - [4-f 3 -acetylaminophenvDpiperidin- 1 -yllpropyl I -3H- imidazo [4, 5-dlpyridine
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(SOOMHZ3 CDCl3 )δ 1.57-1.75(m, 4H), 1.93(m, 2H)5 2.07(m, 2H), 2.17(s, 3H), 2.34(m5 IH), 2.41(m, 2H), 2.83(brd, 2H), 4.53(t, 2H), 6.95(d, IH, J=I.6 Hz), 7.21-7.35(m, 4H)5 7.55(m, 4H)5 7.80(m5 2H)5 8.06(d, IH, J=8.1 Hz), 8.40(d, IH5 J=4.8Hz)5 8.50(d, 2H) ; MS(m/e, M+): 453
Example 74
5-bromo-6-methyl-2-phenyl-3-(3-r4-(3-acetylaminophenyl)piperidin-l- yl]propyl)-3jy-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-3//-imidazo[4,5-b]pyridine.
1H NMR(300MHz, CDCl3 )δ 1.61(m5 2H), 1.73(brd, 2H), 1.86- 2.03(m, 4H)5 2.16(s, 3H), 2.22(t, 2H)5 2.39(m, IH), 2.78(s, 3H), 2.83(brd5 2H)5 4.37(t, 2H)5 6.93(d, IH5 J=7.5 Hz)5 7.21-7.37(m, 3H)5 7.51-7.55(m5 4H)5 7.78(m5 2H), 8.02(s5 IH) ; MS(m/e5 M+): 546
Example 75
6-methyl-2-phenyl-3-(3-r4-r3-acetylaminophenyl)piperidin-l-vnpropyll-
3.H-imidazor4,5-e1pyridine 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-3//-imidazo[4,5-b]pyridine.
1H NMR(300MHz, CDCl3 )δ 1.59-1.75(m5 4H)5 1.90(brt, 2H),
2.02(m, 2H) 2.16(s, 3H), 2.32(t, 2H)5 2.42(m5 IH)5 2.68(s5 3H), 2.84(br5 2H)5 4.39(t5 2H), 6.92(d, IH5 J=7.2Hz)5 7.23-7.39(m, 3H)5 7.50-7.54(m5 4H),
7.70(d, IH5 J=8.1Hz)5 7.78(m5 2H) ; MS(m/e, M+): 467
Example 76 2-C3 -methoxycarbonylphenyl)- 1 - (3 -[4-f 3-aceMammophenyl)piperidin- 1 - yllpropylMTT-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)- 177-benzimidazole.
1H NMR(300MHz5 CDC13)6 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, IH), 2.72(brd, 2H), 3.95(s, 3H), 4.44(t, 2H), 6.89(d, IH, J=I '.5 Hz), 7.10(s, IH), 7.23-7.35(m, 3H), 7.48(m, 2H), 7.63(dd, IH, J=7.5 Hz, 7.8 Hz), 7.78(brs, IH, NH), 7.82(m, IH), 8.00(d, IH, /=7.5 Hz), 8.20(d, IH, J=7.8 Hz), 8.44(d, IH, J=I.6 Hz) ; MS(m/e, M+): 510
Example 77
2-(4-ethylphenvD- 1 - (3 -r4-O-acetylaminophenyl)piperidin- 1 -yllpropyll - 177- 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)- 177-benzimidazole.
1H NMR(SOOMHZ, 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, IH), 2.72(q, 2H), 2.83(brd, 2H), 4.36(t, 2H),
6.95(d, IH, J=7.5 Hz), 7.24-7.39(m, 7H), 7.45(m, IH), 7.67(d, 2H, J=8.1
Hz), 7.80(m, IH) ; MS(m/e, M+): 480
Example 78 2-(4-cyanophenyD- 1 - (3 - [~4-(3 -acetylaminophenvDpiperidin- 1 -yl]propyl| -
5,6-dimethyl- 177-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- 177-benzimidazole. 1H NMR(300MHz, 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, IH), 2.40(s, 3H), 2.43(s, 3H),
2.74(brd, 2H), 4.38(t, 2H), 6.91(d, IH, J=7.6 Hz), 7.17-7.28(m, 2H), 7.47(d,
IH, /=7.8Hz), 7.60(d, 2H, J=10.9 Hz), 7.78-7.85(m, 2H), 7.92(d, 2H, 7=8.1 Hz) ; MS(m/e5 M+): 505
Example 79
2-Cm-tolyl)- 1 - (3 - [4-G -acetylaminophenvDpiperidin- 1 -yllpropyll -IH- 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)- liiZ-benzimidazole.
1H NMR(SOOMHZ, CDCl3)δ 1.67(m, 4H)3 1.96(m, 4H)5 2.15(s, 3H), 2.29(t, 2H)5 2.43(s, 3H) 2.84(brd, 2H)5 4.36(t, 2H), 6.94(d5 IH5 J=7.5Hz), 7.24(m, 2H), 7.29-7.51(m, 7H) 7.58(s, IH), 7.80(d, IH5 J=4.2Hz) ; MS(m/e5 M+): 505
Example 80 2-(2-chloro-4-fluorophenyl)- 1 - ( 3 -|~4-(3 -acetylaminophenvDpiperidin- 1 - yllpropyl)-5,6-dimethγl-liJr-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-li7-benzimidazole. 1H NMR(300MHz, CDCl3)δ 1.66-1.80(m, 4H)5 1.89-1.95(m, 4H)5
2.17(s, 3H)5 2.23(t, 2H), 2.40(s, 3H)5 2.43(s, 3H)5 2.47(m5 IH), 2.82(brd, 2H)5
4.10(t5 2H), 6.96(d, IH5 /=7.5 Hz)5 7.16(m, IH)5 7.24-7.32(m, 4H), 7.37(s5
IH)5 7.51-7.58(m5 2H) ; MS(m/e, M+): 533
Example 81
2-(4-chloroτ>henviy 1 - ( 3 -[4-f 3-acetylaminophenyr)piperidin- 1 -ylipropyl) -5- cyano- Ii7-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- lH-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.57-1.73(m, 4H)5 1.80-2.03(m, 4H), 2.18(s, 3H)5 2.20(t5 2H)5 2.44(m5 IH), 2.78(brd5 2H)5 4.44(t5 2H)5 6.94(d5 IH5 J=7.2 Hz), 7.24(m, IH), 7.33(s, IH), 7.60(m5 4H), 7.74(d, 2H, J=8.4Hz), 7.87(d, IH5 J=SA Hz), 8.04(s, IH) ; MS(m/e, M+): 512
Example 82
2-f4-chlorophenylV 1 - ( 3 - [4-G -acetylaminophenvDpiperidin- 1 -yllpropyll -6- cyano- Ii7-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-li/-benzimidazole.
1H NMR(SOOMHZ5 CDCl3)δ 1.57(m5 2H)5 1.75(m5 2H)5 1.88-1.95(m, 4H)5 2.19(s5 3H)5 2.21(t, 2H)5 2.41(m, IH)5 2.78(brd, 2H), 4.43(t, 2H)5 6.94(d, IH5 J=7.2 Hz)5 7.24(m5 IH)5 7.29(m, IH), 7.40(s, IH)5 7.56(m5 4H)5 7.72(d5 2H, J=8.4Hz), 8.14(s5 IH) ; MS(m/e5 M+): 512
Example 83 2-(4-chloroρhenyl)- 1 -(3-[4-(3-acetylaminophenyl)piperidin- 1 -yl~|ρropyl}-5- fluoro- lif-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-l//-benzimidazole. 1H NMR(300MHz, CDCl3)δ 1.60-1.80(m, 4H)5 1.90-1.98(m, 4H),
2.18(s, 3H), 2.24(t, 2H)5 2.45(m, IH)5 2.81(brd5 2H)5 4.33(t, 2H)5 6.96(d5 IH5
J=7.5 Hz), 7.06(m, IH), 7.19-7.36(m, 4H), 7.53(m, 2H)5 1.69-1.11 {m, 3H) ;
MS(m/e, M+): 505
Example 84
2-(4-fluorophenyl )- 1 - 13 - F4-C3 -acetylaminophenvDpiperidin- 1 -yllpropyl 1-5- chloro- liT-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- li/-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.65-1.81(m5 4H), 1.88-1.99(m, 4H)5 2.18(s, 3H), 2.24(t, 2H), 2.44(m5 IH), 2.83(brd, 2H), 4.33(t, 2H)5 6.96(d5 IH5 J=7.5 Hz)5 7.21-7.28(m, 5H), 7.36(d, IH5 7.8 Hz)5 7.53(m, 2H)5 7.69-7.77(m, 3H) ; MS(We5 M+): 505
Example 85
2-r4-chloroρhenylVl-(3-r4-('3-acetylaininophenyl)piperidin-l-yllρroρyll-5- nitro- li/-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-lJ7-benzimidazole.
1H NMR(SOOMHZ5 CDCl3)δ 1.64(m, 2H)5 1.78(m5 2H)5 1.96-2.04(m, 4H)5 2.20(s5 3H), 2.24(t, 2H)5 2.43(m, IH)5 2.78(brd5 2H)5 4.50(t, 2H)5 6.96(d5 IH, J=7.S Hz)5 7.24-7.33(m, 2H)5 7.42(d, IH5 J=7.8 Hz)5 7.58(d5 2H5 J=8.4 Hz)5 7.77(d, 2H5 J=8.4 Hz)5 7.86(d IH5 J=8.7 Hz), 8.24(d,d IH5 J=8.7 Hz5 2.1 Hz)5 8.54(d5 IH5 J=2.1 Hz) ; MS(m/e, M+): 532
Example 86
2-( 4-chloro-2-methoxyphenylV 1 - (3 - F4-f 3 -acetylaminophenvDpiperidin- 1 - yl1propyU-5,6-dimethyHi7-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- Ii7-benzimidazole.
1H NMR(SOOMHZ5 CDCl3)δ 1.58-1.67(m, 2H)5 1.74(brd5 2H), 1.82- 1.88(m, 4H), 2.16(s, 3H)5 2.19(t, 2H), 2.38(s, 3H)5 2.40(s5 3H), 2.4 l(m, IH)5 2.78(brd5 2H)5 3.83(s5 3H)5 4.07(t, 2H)5 6.94(d, IH5 J=7.2 Hz)5 7.02(d, IH5 j=1.8 Hz)5 7.07(dd5 IH, J=S Λ, 1.8 Hz)5 7.21-7.30(m5 4H), 7.38(s, IH)5 7.42(d5 IH5 J=8.1 Hz)5 7.55(s, IH) ; MS(m/e5 M+): 545
Example 87
2-(5-chloro-2-methoxyphenylVl-(3-r4-r3-acetylaminophenyl)piperidin-l- vnpropyll-5,6-dimethyl-l//-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-l/i-benzimidazole.
1H NMR(300MHz, CDCl3)δ 1.64(m, 2H)5 1.76(brd5 2H)5 1.84- 1.90(m, 4H)5 2.16(s5 3H)5 2.21 (t, 2H)5 2.39(s5 3H)5 2.41 (s, 3H)5 2.42(m, IH)5 2.80(brd, 2H)5 3.77(s5 3H)5 4.09(t, 2H)5 6.94-6.97(m, 2H)5 7.21-7.3 l(m5 2H)5 7.36(s, IH)5 7.40-7.44(m5 2H)5 7.49(d5 IH5 J=2.7 Hz)5 7.55(s5 IH) ; MS(m/e, M+): 545
Preparation of Imidazole Derivative (Examples 88 to 90)
Figure imgf000065_0001
Example 88
2-methyl- 1 - { 3 - [4-(3 -acetylaminophenvDpiperidin- 1 -ylipropyl) - IH- benzimidazole
100 mg (0.75 mmol) of 2-methyl- lH-benzimidazole was dissolved in 5 ml of N,N-dimethylfoπnamide, and 265 mg (0.75 mmol) of 3-[4-(3- acetylaminophenyl)piperidin-l-yl]propylmethanesulfonate obtained by Preparation Example 4 and 310 mg (2.25 mmol) OfK2CO3 were 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 X 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% MeOHZCH2Cl2) to obtain 160 mg (yield 55%) of the title compound. 1H NMR(300MHz5 CDCl3)O 1.71-1.85(m, 4H)5 1.97-2.06(m, 4H)5
2.17(s5 3H), 2.34(t, 2H)5 2.48(m, IH), 2.65(s, 3H)5 2.95(brd5 2H)5 4.22(t, 2H)5 6.97(d5 IH5 J=7.5 Hz)5 7.20-7.38(m5 6H)5 7.43(brs, IH5 NH)5 7.67(m, IH) ; MS(m/e, M+): 390, 375, 348, 257, 245, 23I5 159 Example 89
2-methyl- 1 - { 3 -F4-(3 -acetylaminophenvDpiperidin- 1 -yllpropyll -5.6- dimethyl- li/-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- lϋf-benzimidazole.
1H NMR(300MHz, CDCl3)O 1.70-1.85(m, 4H)3 1.96-2.04(m, 4H),
2.17(s, 3H), 2.33(t, 2H)5 2.35(s, 3H), 2.37(s, 3H), 2.48(m, IH), 2.60(s, 3H),
2.94(brd, 2H), 4.16(t, 2H), 6.91(d, IH, J-7.5 Hz), 7.12(s, IH), 7.21-7.37(m, 2H), 7.43(m, 2H), 7.62(brs, IH, NH) ; MS(m/e, M+): 418, 403, 376, 257,
245,231,187,174
Example 90
2-methyl- 1 - { 3-[4-(3-isobutyrylaminophenyl)piperidin- 1 -ylipropyl) - IH- benzimidazole
100 mg (0.75 mmol) of 2-methyl- lH-benzimidazole was dissolved in 5 ml of N,N-dimethylformamide, and 286 mg (0.75 mmol) of 3-[4-(3- isobutyrylaminophenyl)piperidin-l-yl]propylmethanesulfonate and 310 mg (2.25 mmol) of K2CO3 were 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 X 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% MeOHZCH2Cl2) to obtain 159 mg (yield 51%) of the title compound.
1H NMR(300MHz, 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, IH), 2.53(m, IH), 2.65(s, 3H)5 2.95(brd, 2H), 4.22(t, 2H), 6.97(d5 IH)5 7.09(m, IH), 7.20-7.38(m, 5H), 7.53(brs, IH, NH)5 7.70(m, IH) ; MS(m/e, M+): 418
Preparation of Imidazole Derivative (Examples 91 to 97)
Figure imgf000067_0001
Example 91 2,5-dimethyl-3 - { 3 - \4-( 3 -acetylaminophenvDpiperidin- 1 -yllpropyl j -3H- imidazo[4,5-b1pyridine
100 mg (0.68 mmol) of 255-dimethyl-3i7-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) OfK2CO3 were 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 X 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(300MHz, CDCl3)δ 1.67-1.81(m, 4H), 1.96-2.05(m, 4H)5 2.17(m, 3H)3 2.38(t, 2H), 2.46(m, IH)5 2.62(s5 3H), 2.65(s, 3H), 2.96(br-d,
2H), 4.30(t, 2H), 6.52(m5 IH), 6.95(m, IH)5 6.98(d, IH5 J=8.1Hz)5 7.21-
7.38(m, 3H)5 7.76(d5 IH, J=8.1Hz) ; MS(m/e, M+): 405
Example 92 6-bromo-2, 5-dimethyl-3 - (3 - r4-(3-acetylaminoρhenyl)piperidin- 1 -yllpropyl ) - Sffi-imidazo F4.5-biρyridine
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-255-demethyl-3#-imidazo[4,5-b]pyridine. 1H NMR(300MHz, CDCl3)δ 1.67-1.83(m5 4H)5 1.96-2.06(m, 4H)5 2.17(m, 3H)5 2.36(t5 2H)5 2.46(m, IH)5 2.65(s, 3H)5 2.72(s, 3H)5 2.94(br-d, 2H)5 4.27(t, 2H)5 6.95(d5 IH5 J=6.8 Hz)5 7.21-7.42(m5 4H)5 8.02(s5 IH); MS(m/e5 M+): 484, 469, 267, 245, 231
Example 93
6-bromo-2-ethyl-5-methyl-3-(3-[4-π-acetylaminophenvπpiperidin-l- yllpropyll-3ijr-imidazor4.,5-blpyridine
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-377-imidazo[4,5-b]pyridine.
1H NMR(300MHz, CDCl3)δ 1.47(t, 3H), 1.68-1.83(m, 4H)5 1.96-
2.07(m, 4H), 2.16(m, 3H)5 2.38(t, 2H)5 2.46(m5 IH)5 2.72(s, 3H), 2.94(br-d,
2H), 2.99(q, 2H)5 4.27(t, 2H)5 6.95(d, IH, J=6.9 Hz), 7.21-7.43(m, 4H)5 8.06(s, IH); MS(m/e, M+): 499, 497, 468, 28O5 245, 231
Example 94
6-bromo-2-butyl-5-methyl-3 - { 3 - ["4-D -acetylaminophenyDpiperidin- 1 - yllpropyl}-3iJ-imidazo[4,5-b'lpyridine 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-3//-imidazo[4,5-b]pyridine.
1H NMR(SOOMHZ, CDCl3)δ 0.98(m, 3H)5 1.25(m, 3H)5 1.84(m, 6H)5
1.97(m5 3H)5 2.16(s5 3H)5 2.37(m5 2H)5 2.96(m, 5H), 4.25(t, 2H)5 6.96(d, IH), 7.32(m, 2H)5 7.62(s, IH)5 8.05(s5 IH): MS(m/e5 M+): 526, 468, 447
Example 95
2-butyl-5,7-dimethyl-3-{3-r4-r3-acetylaminophenvπpiperidin-l-yllpropyU- 3ij"-imidazo ["4.5-blpyridine 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-3i7'-imidazo[455-b]ρyridine.
1H NMR(SOOMHZ5 CDCl3)S 0.98(m, 3H), 1.45(m, 2H)5 1.82(m5 6H)5 2.04(m, 4H), 2.12(s, 3H)5 2.42(m5 3H), 2.59(s5 6H)5 2.96(m, 4H)5 4.31(t, 2H)5 6.97(d, IH)5 7.23(m, IH)5 7.35(m5 2H)5 7.55(s5 IH): MS(m/e, M+): 461, 432, 404
Example 96
2-butyl-5J-dimethyl-6-phenyl-3 - ( 3 - F4-f 3 -acetylaminophenvDpiperidin- 1 - yllpropyl}-3//"-imidazor4,5-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.
!H NMR(300MHz5 CDCl3)O 0.97(m, 3H)5 1.46(m, 2H), 1.86(m, 6H), 2.04(m5 4H)5 2.11(s, 3H)5 2.32(s5 6H)5 2.48(m, 3H)5 2.99(m, 6H)5 4.35(t, 2H)5 6.95(d, IH)5 7.15(m5 2H)5 7.38(m5 5H)5 7.44(s, IH): MS(m/e, M+): 537, 508, 482
Example 97
2-butyl-5-methyl-6-pyridin-2-yl-3 - ( 3 - [4-(3 -acetylaminophenyl)piperidin- 1 - yllpropyU-3/-r-imidazor4,5-blpyridine
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(SOOMHZ, CDCl3)δ 0.98(m, 3H), 1.46(m, 2H)5 1.78(m5 4H)5
1.95(m5 3H)5 2.10(m5 5H)5 2.44(m, 3H)5 2.63(s, 2H)5 3.03(m, 4H)5 4.35(t5
2H)5 6.96(d5 IH)5 7.22(m5 4H)5 7.75(m5 4H), 7.92(s5 IH): MS(m/e5 M+): 524, 509, 495
Preparation of Imidazole Derivative (Examples 98 to 103)
Figure imgf000069_0001
Example 98
6-bromo-2-butyl-5-methyl-3- (3-r4-r3-isobutyrylaminophenvπpiperidin- 1 - yllpropyl)-377-imidazor4,5-b1pyridine 100 mg (0.37 mmol) of 6-bromo-2-butyl-5-methyl-3H-imidazo[4,5- bjpyridine was dissolved in 5 ml of N.N-dimethylformamide, and 140 mg (0.37 mmol) of 3-[4-(3-isobutyrylaminophenyl)piρeridin-l- yl]propylmethanesulfonate obtained by Preparation Example 5 and 155 mg (1.11 mmol) of K2CO3 were added to the resulting solution, followed by treating the mixture at 800C for 5 hours. The reaction mixture was combined with 50 ml of water and extracted with ethylacetate (50 ml X 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% MeOHZCH2Cl2) to obtain 94 mg (yield 46%) of the title compound.
1H NMR(SOOMHZ, CDCl3)δ 0.97(t, 3H), 1.24(m, 9H), 1.50(m, 3H), 1.82(m, 10H), 2.50(m5 5H), 2.89(m, 4H), 3.01(m, 5H), 4.30(t, 2H), 6.97(d, IH), 7.30(m, 2H), 7.53(d, IH), 8.05(s, IH) : MS(m/e, M+): 554
Example 99
2-butyl-5,7-dimethyl-3-{3-r4-(3-isobutyrylaminophenyl')piperidin-l- vllρropyl)-3//-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-3//'-imidazo[4,5-b]pyridine.
1H NMR(SOOMHZ, CDCl3 )δ 0.98(m, 3H), 1.23(m, 7H), 1.50(m, 2H),
1.84(m, 7H), 2.06(m, 5H)5 2.57(m, 7H), 3.03(m, 4H), 4.3 l(t, 2H), 6.83(s, IH), 6.96(d, IH), 7.25(m, 2H), 736(6, IH), 7.46(s, IH): MS(m/e, M+): 489,
460, 432
Example 100 2-bu1^l-5J-dimethyl-6-phenyl-3-l3-r4-G-isobutyrylaminophenyl)ρiperidin- l-vnpropyll-3i/-imidazor4.,5-blp'yridine
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-557-dimethyl-6-phenyl-3//-imidazo[4,5-b]pyridine.
1H NMR(SOOMHZ, CDCl3 )δ 0.97(t, 3H)5 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, IH), 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-r4-r3- isobutyrylaminophenvDpiperidin- 1 -yl]propyl} -3ϋ/-imidazo [4,5 -blpyridine
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-3i7-imidazo[4,5-b]pyridine.
1H NMR(SOOMHZ, 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, IH),
7.29(m, 2H), 7.38(m, 4H), 7.48(m, IH), 7.91(s, IH), 8.71(m IH); MS(m/e,
M+): 552, 523, 509
Example 102
2-butyl-5-formyl-6-phenyl-3-(3-f4-f3-isobutyrylaminoρhenyl)piperidm-l- yllpropyl>-3i/-imidazor4.5-blρyridine
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-3ϋ/-imidazo[4,5-b]pyridine-5-carbaldehyde.
1H NMR(SOOMHZ, 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, IH), 2.45(m, 2H), 2.52(m, IH),
3.01(m, 2H), 3.04(t, 2H), 4.47(t, 2H), 6.94(d, IH), 7.21-7.48(m, 8H), 7.95(s, IH), 10.07(s, IH) : MS(m/e, M+): 565
Example 103 2-butvl-5-methvl-6-r4-nitrophenvlV3-(3-r4-('3- isobutyrylaminophenvDpiperidin- 1 -ylipropyl) -3i7-imidazo r4,5-b1pyridine
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-carbaldehyde. 1H NMR(300MHz, CDCl3 )δ 0.99(t, 3H), 1.23(d, 6H), 1.28(m, 2H)5
1.50(m5 2H), 1.70-2.04(m, 8H), 2.12(m, IH), 2.44(m, IH)5 2.49(t, 2H), 2.51(s, 3H), 2.97((t, 2H), 3.00(m, 2H)5 4.36(t, 2H)5 6.95(d, IH), 7.16-7.27(m, 2H), 7.35(brs, IH5 NH), 7.50(d, 2H), 7.53(m, IH), 7.75(s5 IH)5 8.28(d5 2H) : MS(m/e5 M+): 596
Preparation of Imidazole Derivative (Examples 104 to 127)
Example 104 2-rpyridm-2-ylVl-{3-r4-(3-acetamidophenyl')piperidin-l-yllpropyll-l//- benzimidazole
70 mg (0.36 mmol) of 2-(pyridin-2-yl)-l//-benzimidazole was dissolved in 5 ml of N5N-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) OfK2CO3 were 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 X 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(300MHz, CDCl3 )δ 1.65-1.80(m, 4H), 2.15(s, 3H), 1.93- 2.24(m5 4H)5 2.43(br t, 2H, J=6.8 Hz), 2.48(m5 IH), 2.98(m, 2H), 4.90(br t, 2H, 7=7.3 Hz), 6.95(m, IH)5 7.21-7.39(m, 6H), 7.52(m, IH)5 7.67(br s, IH), 7.84(m, 2H)5 8.40(d5 IH5 J=7.9 Hz)5 8.86(br d5 IH J=4.1 Hz); MS(m/e, M+): 453 ^, 258, 209, 196 Example 105
2-(pyridin-3-yD-l - (3-r4-C3-acetamidophenvDpiperidin- 1 -ylipropyll- IH- 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)- l//-benzimidazole.
1H NMR(300MHz, CDCl3 )δ 1.58-1.77(m, 4H), 1.89-2.04(m5 4H)5
2.17(s5 3H), 2.27(br t, 2H, J=6.6 Hz), 2.42(m, IH)5 2.80(m, 2H)5 4.41(br t,
2H, J=7.2 Hz)5 6.95(m5 IH)5 7.21-7.40(m5 5H)5 7.48-7.53(m, 2H), 7.65(br S5 IH), 7.84(m, IH)5 8.14(dt, IH5 J=7.9, 1.8 Hz)5 8.76(dd5 IH, J=4.9, 1.5 Hz),
9.03(m, IH); MS(m/e, M+): 453 (M+), 257, 231, 70.
Example 106
2-(pyridin-4-vD- 1 -(3-r4-f3-acetamidophenyl)piperidin- 1 -yllpropyl) - \H- 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)- lif-benzimidazole.
1H NMR(SOOMHZ5 CDCl3 )δ 1.55(m5 2H)5 1.74(m5 2H)5 1.90-2.02(m, 4H)5 2.20(s5 3H)5 2.25(t, 2H), 2.42(m, IH), 2.79(br-d, 2H), 4.47(t, 2H)5 6.91(d5 IH)5 7.21-7.50(m5 6H)5 7.76(d, 2H), 7.85(m, IH), 7.82(d, 2H) ; MS(m/e, M+): 453 (M+), 257, 231, 70.
Example 107 2-(furan-3-ylVl-l3-r4-("3-acetylaminoρhenyl)piperidin-l-yllρropyll-li7- 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)- liT-benzimidazole. 1H NMR(300MHz, 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, IH), 2.94(m5 2H), 4.41(br t5 2H5 J=7.3 Hz)5
6.99(m, IH)5 7.06(m, IH)5 7.25-7.36(m, 4H), 7.45(m5 2H), 7.59(m, IH)5
7.63(br S5 IH)5 7.74(m5 IH), 8.21(br S5 IH); MS(m/e, M+): 442 (M+), 413, 231, 70.
Example 108
2-( 5-bromofuran-2-ylV 1 - (3 -[4-f3-acetylaminophenyls)ρiperidin- 1 - ylipropylj - 1 //"-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)- l//-benzimidazole.
1H NMR(300MHz, 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, JM5.9 Hz), 6.55(br d, IH, J=3.4 Hz)5 6.97(br d, IH, J=7.3 Hz), 7.20-7.54(m, 8H), 7.77(m, IH); MS(m/e, M+): 521 (M+), 441, 231..
Example 109 2-(tmOphen-2-yl)- 1 - { 3 - [4-(3 -acetylaminophenvDpiperidin- 1 -yljpropyl} - IH- 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)-l#-benzimidazole. 1H NMR(300MHz, 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, IH), 2.93(m, 2H), 4.51(br t, 2H, J=7.3 Hz), 6.97(br, d, IH, J=7.4 Hz), 7.19(dd, IH, J=5.0, 3.8 Hz), 7.22- 7.35(m, 4H), 7.45(m, 2H), 7.51(dd, IH, J=5.0, 0.9 Hz), 7.64(br s, IH), 7.67(m, IH), 7.77-7.80(m, IH); MS(m/e, M+): 458 (M+), 425, 231, 70.
Example 110
2-f 5-methylthiophen-2-ylV 1 - ( 3 - [4-(3 -acetylaminophenvπpiperidin- 1 - yl]propyl 1-1 /7-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)-li7-benzimidazole.
1H NMR(300MHz, CDCl3) δ 1.72-1.80(m, 4H), 1.97-2.04(m, 4H)5 2.14(s, 3H), 2.38(br t, 2H, J=6.6 Hz), 2.47(m, IH), 2.94(m, 2H), 3.88(s, 3H), 4.37(br t, 2H, J=I.2 Hz)5 6.26(m, IH)5 6.55(m5 IH), 6.84(br s, IH)5 6.97(m5 IH)5 7.21-7.50(m, 6H)5 7.78(m, IH)5 MS(m/e, M+): 457 (M+-IS)5 231, 209.
Example 111 2-d -methylpyrrol-2-ylV 1 - (3 - [4-0 -acetylaminophenyDpiperidin- 1 - ylipropyll-lTT-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-(l- methylpyrrol-2-yl)-lizr-benzimidazole. 1H NMR(300MHz, CDCl3) δ 1.71-1.83(m, 4H)5 1.97-2.11(m, 4H),
2.16(s5 3H)5 2.41(t, 2H5 J=6.5 Hz)5 2.47(m, IH)5 2.55(s, 3H), 2.95(m5 2H), 4.48(br t, 2H, /=7.2 Hz), 6.84(m, IH), 6.97(m, IH), 7.22-7.36(m, 5H), 7.41- 7.47(m, 3H), 7.68(br S5 IH), 7.75(m, IH), MS(m/e5 M+): 455 (M+), 257, 231.
Example 112
2-f 5-bromopyridin-3 -yp- 1 - (3 -r4-D-acetylaminophenyl)piperidin- 1 - yljpropyl} - lffi-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)- l//-benzimidazole.
1H NMR(SOOMHZ, CDCl3) δ 1.63(m, 2H), 1.77(m, 2H), 1.91-2.05(m, 4H), 2.18(s, 3H), 2.28(br t, 2H5 J=6.5 Hz), 2.43(m, IH), 2.82(m, 2H), 4.42(br t, 2H, J=7.2 Hz), 6.97(m, IH), 7.22-7.40(m, 6H), 7.52(m, IH)5 7.84(m5 IH), 8.35(t, IH, J=2.1 Hz)5 8.82(d, IH5 J=2.2 Hz), 8.96(d, IH, 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 - ylipropyll-lif-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)- Ii7-benzimidazole.
1H NMR(SOOMHZ, CDCl3) δ 1.65(m, 2H)5 1.77(m5 2H)5 1.92-2.06(m, 4H)5 2.18(s, 3H)5 2.27(br t, 2H5 J=6.3 Hz)5 2.44(m5 IH)5 2.82(m, 2H)5 4.41(br t, 2H5 J=7.4 Hz)5 6.99(m5 IH)5 7.23-7.40(m5 6H)5 7.51(m, 2H)5 7.83(m, IH)5 8.16(dd5 IH5 J=8.3, 2.5 Hz)5 8.90(m5 IH); MS(m/e, M-+): 488 (M+), 257, 231, 70.
Example 114
2-f 6-methylpyridin-3 -vD- 1 -(3 - [4-(3 -acetamidophenyDpiperidin- 1 - yljpropylj- liiT-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)- lϋf-benzimidazole.
1H NMR(SOOMHZ5 CDCl3) δ 1.56-1.68(m5 2H)5 1.76(m, 2H)5 1.90-
2.03(m, 4H)5 2.17(s, 3H)5 2.27(br t, 2H5 J=6.6 Hz)5 2.43(m5 IH), 2.65(s, 3H),
2.82(m, 2H)5 4.39(br t5 2H5 J=7.3 Hz)5 6.96(m5 IH)5 7.23(m, IH), 7.31- 7.36(m, 4H), 7.40(br s, IH), 7.50(m, 2H), 7.83(m, IH), 8.02(dd, IH5 J-8.0,
2.3 Hz), 8.90(d, IH5 J=2.1 Hz); MS(m/e5 M+): 467 (M+), 250, 231, 70.
Example 115
2-(2-methoxypyridin-3-yiy 1 - (3-F4-f 3-acetamidophenyDpiperidin- 1 - yljpropyl} - lTT-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)- liT-benzimidazole.
1H NMR(SOOMHZ, CDCl3) δ 1.62(m, 2H)5 1.73(m, 2H)5 1.90(m, 4H), 2.16(s, 3H), 2.23(br t, 2H, J=6.8 Hz), 2.47(m, IH), 2.80(m, 2H)5 3.98(s, 3H)5
4.19(t5 2H, J=7.2 Hz), 6.94(m, IH), 7.06(dd, IH, J=7.2, 5.1Hz), 7.21-
7.39(m, 6H), 7.50(m, .lH)5 7.82(m5 IH)5 7.88(dd, IH, J=7.3, 1.8 Hz), 8.34(dd,
IH5 J=5.05 1.8 Hz); MS(m/e5 M+): 483 (M+), 468, 252, 231, 70.
Example 116
5-chloro-2-(pyridin-3-viy 1 - B-K-O-acetamidophenyDpiperidin-l - ylipropyli- 177-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)- lif-benzimidazole.
1H NMR(300MHz, 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, IH), 2.80(m, 2H), 4.39(m, 2H), 6.97(m, IH), 7.22-7.41(m, 5H), 7.50(dd, IH, J=7.8, 4.9 Hz) 7.57(d, IH, J=I.8 Hz), 7.74(d, IH5 J=8.6 Hz), 8.13(dt, IH, J=7.9, 1.8 Hz), 8.78(m, IH), 9.03(m, IH); MS(m/e, M+): 488 (M+), 257, 231, 70.
Example 117 5-nitro-2-(pyridin-3-yl)- 1 - J3-f4-(3 -acetamidophenyppiperidin- 1 -ylipropyll - liT-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)-lH-benzimidazole. 1H NMR(300MHz, 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, IH), 2.77(m, 2H), 4.51(m, 2H), 6.95(m, IH), 7.22-7.40(m, 4H), 7.56(dd, IH, J=7.8, 4.9 Hz), 7.63(d, IH, J"=9.0 Hz), 8.16(m, IH), 8.30(dd, IH, J=9Λ, 2.1 Hz), 8.75(d, IH, J=2.0 Hz), 8.83(m, IH), 9.06(d, IH, JE=I .9 Hz); MS(m/e, M+): 498 (M+), 481, 231, 70.
Example 118
5-chloro-2-r5-bromofuran-2-vD- 1 - {3-[4-(3-acetamidophenyl)piperidin- 1 - vnpropyll-li/-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)-li:/-benzimidazole.
1H NMR(SOOMHZ, MeCWFW4) 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, IH), 6.78(m.
IH), 7.00(m, IH)3 7.24(t, IH, 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-rfuran-2-vlV5-methoxv- 1 - (3 -^-(θ-acetamidophenvDpiperidin- 1 - yllpropyU-liZ-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-li7-benzimidazole. 1H NMR(300MHz5 CDCl3) δ 1.77-1.84(m, 4H), 1.99-2.12(m5 4H)5
2.17(s5 3H)5 2.45(m5 3H), 3.00(m5 2H), 3.89(s, 3H)5 4.54(q, 2H5 J=7.1 Hz)5 6.60(m, IH)5 6.94(m5 2H)5 7.17-7.41(m, 7H)5 7.60(m, IH); MS(m/e, M+): 472 (M+), 257, 23I5 120.
Example 120
5-memyl-2-(thiophen-3-yl)- 1 -(3-r4-(3-acetamidophenvDpiperidin- 1 - yllpropyl) - l-fl-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)- l//-benzimidazole.
1H NMR(300MHz5 CDCl3) δ 1.80(m5 4H), 2.04(m, 4H), 2.16(s, 3H)5 2.38(m, 2H)5 2.46(m, IH)5 2.49(s, 3H)5 2.94(m5 2H), 4.41 (br t, 2H, J=6.8 Hz)5 6.98(m5 IH)5 7.12(m, IH)5 7.22-7.34(m, 3H)5 7.43-7.48(m5 2H), 7.56-7.67(m5 3H)5 7.91(br s, IH); MS(m/e, M+): 472 (M+), 256, 231, 70.
Example 121
5.6-dimethyl-2-(l-methylpyrrol-2-ylVl-(3-r4-r3-acetamidophenyl)piperidin-
1 -ylipropyU - l//"-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)- 1 if-benzimidazole.
1H NMR(SOOMHZ5 CDCl3) δ 1.81(m5 4H)5 2.00(m, 4H)5 2.14(s5 3H)5
2.37(m5 2H)5 2.39(s5 3H), 2.40(s5 3H)5 2.48(m5 IH), 2.97(m, 2H), 3.85(s, 3H),
4.31(br t5 2H5 J=7.4 Hz)5 6.24(br t5 IH5 ./=2.9 Hz), 6.50(m, IH), 6.81(br s, IH), 6.97(m5 IH), 7.20-7.27(m, 2H)5 7.35(m, IH)5 7.43(m, 2H), 7.55(br s,
IH); MS(m/e, M+): 483 (M+), 252, 231, 70.
Example 122 '2-rthiazol-4-ylVl-(3-r4-r3-acetamidophenyl')piperidin-l-yllproρyl)-li7- 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)-lif-benzimidazole.
1H NMR(300MHz, MeOH-J4) δ 1.74-1.90(m, 4H), 2.10(s, 3H),
2.24(m5 2H), 2.44(m, 2H), 2.61(m, IH), 2.76(br t, 2H, J=I.5 Hz)5 3.22(m,
2H)5 4.86(m, 2H)5 6.94(m, IH), 7.21(br t, IH5 /=7.7 Hz), 7.30-7.40(m, 3H),
7.48(br S5 IH)5 7.69(br t, 2H5 J=7.4 Hz)5 8.38(d, IH5 7=1.8 Hz)5 9.21(d, IH5 J=I.9 Hz); MS(m/e, M+): 459 (M+), 257, 23I5 70.
Example 123
2-(4-methyloxazol-5-yl)- 1 - (3 -[4-f3-acetamidophenyl)piperidin- 1 - yllpropyl) - Ii7-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)-l//-benzimidazole.
1H NMR(300MHz5 CDCl3) δ 1.68-1.83(m, 4H)5 1.94-2.10(m, 4H),
2.17(s, 3H)5 2.36(br t, 2H5 J=6.8 Hz)5 2.47(m, IH), 2.64(s, 3H), 2.93(m, 2H)5 4.50(br t, 2H, J=IA Hz)5 6.97(m5 IH), 7.21-7.34(m, 4H), 7.42(m, 2H)5
7.49(m5 IH)5 7.82(m, IH), 7.99(s, IH); MS(m/e, M+): 457 (M+), 257, 231,
120.
Example 124 2-Cl -methyl- l//-imidazol-5-ylV 1 -!'3-r4-('3-acetamidophenyl)piperidin- 1 - yllpropyll - 177-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-(l- methyl- l.ff-imidazol-5-yl)- l//-benzimidazole. 1H NMR(300MHz, CDCl3) δ 1.72- 1.84(m, 4H)5 2.04(m5 4H)5 2.18(s,
3H), 2.40(t, 2H, /=6.7 Hz)5 2.48(m5 IH)5 2.96(m5 2H), 3.98(s, 3H), 4.42(t,
2H5 /=7.4 Hz), 6.97(d5 IH5 /=7.6 Hz)5 7.24(m, IH)5 7.32(m5 2H), 7.37(m,
IH), 7.43(m, IH)5 7.50(m, IH), 7.54(br s, IH)5 7.67(br S5 IH), 7.70(br s, IH)5 7.80(m, IH): MS(m/e, M+): 456 (M+), 231.
Example 125
2-('pyridin-2-ylmethylVl-{3-['4-(3-acetamidophenvπpiρeridin-l-yllpropyl)- lffi-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- (ρyridin-2-ylmethyl)-lϋ/-benzimidazole.
1H NMR(300MHz, CDCl3) δ 1.70-1.99(m, 8H)5 2.16(s, 3H), 2.30(t, 2H, J = 6.8 Hz), 2.46(m, IH), 2.89(m, 2H), 4.27(t, 2H, J=7.1 Hz)5 4.58(s, 2H)5 6.98(m, IH), 7.15(m5 IH), 7.21-7.40(m, 8H), 7.59(dt, IH, J=IJ3 1.8 Hz), 7.75(m, IH), 8.54(m, IH); MS(m/e, M+): 467 (M+), 375, 223.
Example 126 2-(pyridin-3 -ylmethyl)- 1 - (3 - [4-(3 -acetamidophenvDpiperidin- 1 -ylipropyl} -
177-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)-li7-benzimidazole. 1H NMR(300MHz, CDCl3) δ 1.72-2.04(m, 8H), 2.19(s, 3H), 2.28(t,
2H, J=6.3 Hz)5 2.50(m, IH)5 2.95(m5 2H)5 4.16(t, 2H, JM5.8 Hz), 4.47(s, 2H),
6.96(m, IH)5 7.22-7.30(m, 4H)5 7.37(m, 2H), 7.49(br d, IH5 J=7.8 Hz)5
7.57(m IH), 7.77(m, IH), 8.03(br s, IH), 8.51(dd5 IH5 7=4.7, 1.4 Hz),
8.68(m, IH); MS(m/e, M+): 467 (M+), 375, 245.
Example 127
2-r2-fpyridin-3-vDethyπ- 1 - (3-F4-C 3-acetamidophenvDpiperidin- 1 - yl]propyll - lH-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] - liT-benzimidazole.
1H NMR(SOOMHZ, 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, IH), 2.87(m, 2H), 3.30(m, 2H)5 3.40(m, 2H)5 4.29(t, 2H5 J=6A Hz)5 6.87(m5 IH), 7.05(s, IH)5 7.21- 7.32(m 4H)5 7.38(m, IH)5 7.71(dt5 IH5 .7=7.8, 1.8 Hz)5 7.77(m, IH)5 7.89(br dd, IH5 J=8.25 1.2 Hz)5 8.51(dd5 IH5 J=4.85 1.6 Hz)5 8.76(d, IH5 J=I .8 Hz)5 9.37(br S5 IH); MS(m/e5 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
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Test Example 1 : Inhibitory effects on MCH Rl binding of aryl piperidine group-containing imidazole derivatives
First, MCH Rl (melanine-concentrating hormone receptor- 1; Euroscreen, Gosselies, Belgium), 1 μ M Europium-labeled melanine- concentrating hormone (Eu-MCH, PerkinElmer, Turku, Finland) and 1 niM melanine-concentrating hormone (MCH, #070-47, Phoenix, Belmont CA, USA) were kept at 4°C for ready use. 1 μ M Eu-MCH and 1 niM MCH were diluted with an experimental solution (25 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2 and 0.5%(w/w) BSA) to 8 nM (final reaction concentration: 2 nM) and 2 μ M (final reaction concentration: 0.5 μ M), respectively. The compounds prepared in the Examples ("Test compounds") were dissolved in the experimental solution in concentration of 4 nM to 40 μ M (final reaction concentration: 1 nM to 10 μ M). MCH Rl (200 assays/vial) was homogeniously dispersed in the experimental solution.
Then, 100 μ I/well of the following reaction mixture was added to the wells of a microplate (Multiwell 96 well filter plates PN5020, Pall Co., Ann Arbor, MI, 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 μ 1 of Eu-MCH, 50 μ 1 of MCH Rl and 25 μ 1 of MCH were added. Further, 25 μ 1 of the experimental solution supplemented with 10% (w/w) of DMSO, 25 μ l of Eu-MCH and 50 μ 1 of MCH Rl were added to the wells of a total binding control group, while 25 μ 1 of the test compounds, 25 μ 1 Eu-MCH and 50 μ 1 of MCH Rl 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 μ 1 of a washing solution (25 niM 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 μ 1 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)] X 100 (I)
Table 3 shows the IC50 values of the test compounds, which represents the concentration of the test compounds inhibiting the binding of MCH to MCH Rl by 50% in vitro. Table 3
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
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.

Claims

WHAT IS CLAIMED IS :
1. An imidazole derivative of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000091_0001
wherein
R1 is
Figure imgf000091_0002
C1-4 alkyl,
Figure imgf000091_0003
or rfC "N.J' , in which X is H, halogen, OR5, C1-4 alkyl, CF3, phenyl, CN, NO2, -CO2R6, or -CONR7R8, R5, R6, R7 and R8 being each independently H, halogen, C 1.3 alkyl, or phenyl;
R4 is H, halogen, C1.3 alkyl, C1-3 alkoxy, phenyl, or phenyl having at least one halogen or methyl substituent;
W is CH or N; Y is O, S, or NR9, R9 being H or C1-3 alkyl; m is 1 or 2;
R2 is at least one selected from the group consisting of H, halogen, C1-3
alkyl,
Figure imgf000091_0004
, phenyl, OR5, NO2, CN, pyridyl, CHO, and - CONR7R8, in which X1 is H, halogen, C1-3 alkyl, OR5, or NO2, and R5, R7, and R8 are the same as defined above;
R3 is C1-3 alkyl, 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.
;
2. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim I5 wherein
R i is
Figure imgf000092_0001
in which X is H, halogen, OR5, C1-4 alkyl, CF3, phenyl, CN5 NO2, -CO2R6, or -CONR7R8, R5, R6, R7 and R8 being each independently H, halogen, Ci_3 alkyl, or phenyl; and R2 is at least one selected from the group consisting of H, halogen, C 1.3 alkyl, phenyl, OR5, NO2, CN, pyridyl, and -CONR7R8.
3. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is C 1.4 alkyl; and
R2 is at least one selected from the group consisting of H, halogen, C1-3
alkyl,
Figure imgf000092_0002
, OR5, NO2, CN, pyridyl, CHO, and -CONR7R8, in which X1 is H, halogen, C1-3 alkyl, OR5, or NO2, and R5, R7 and R8 are each independently H, Q.3 alkyl, or phenyl.
4. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein
R1 is
Figure imgf000092_0003
, in which R4 is H, halogen, Ci_3 alkyl, Ci_3 alkoxy, phenyl, or phenyl having at least one halogen or methyl substituent;
W is CH or N;
Y is O, S or NR9, in which R9 is H or d_3 alkyl; m is 1 or 2; and
R2 is at least one selected from the group consisting of H, halogen, C1-3 alkyl, phenyl, OR5, NO2, CN, pyridyl, and -CONR7R8, R5, R7 and R8 being each independently H, C 1.3 alkyl, or phenyl.
5. The Imidazole derivative or pharmaceutically acceptable salt thereof according to claim 2, wherein R5 is H5 methyl, or phenyl;
R6 is H or methyl;
R7 and R8 are each H; and the number of N representing A is 1.
6. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 2, being selected from the group consisting of:
1 ) 2-phenyl- 1 - {2-[4-(3 -acetylaminophenyi)piperidin- 1 -yl] ethyl} -IH- benzimidazole;
2) 2-(4-chlorophenyl)- 1 - {2-[4-(3-acetylaminophenyl)piperidin- 1 -yl] ethyl} -1/f-benzimidazole;
3 ) 2-phenyl- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yljpropyl} - IH- benzimidazole;
4) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -y 1] propyl}-li7-benzimidazole; 5) 2-phenyl- 1 - {4- [4-(3 -acetylaminophenyl)piperidin- 1 -yljbutyl } - IH- benzimidazole;
6) 2-(4-chlorophenyl)- 1 - {4-[4-(3-acetylaminophenyl)piperidin- 1 -yl] butyl} - 1 /f-benzimidazole;
7) 2-ρhenyl- 1 - { 5-[4-(3-acetylaminophenyl)piperidin- 1 -yl]pentyl} - IH- benzimidazole;
8) 2-(4-chloroρhenyl)- 1 - { 5-[4-(3-acetylaminoρhenyl)piρeridin- 1 -yl] pentyl} - lii/-benzimidazole;
9) 2-(2-chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piρeridin- 1 -yl] propyl} - 1 H-benzimidazole; 10) 2-(3 -chlorophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl}-liϊ-benzimidazole;
11 ) 2-(4-bromophenyl)- 1 - {3 -[4-(3-acetylaminoρhenyl)piperidin- 1 -yl] propyl}- liϊ-benzimidazole; 12) 2-(3 ,4-dichloroρhenyl)- 1 - { 3 - [4-(3 -acetylaminophenytypiperidin- 1 -yl] propyl} - liZ-benzimidazole;
13) 2-(3-bromophenyl)-l-{3-[4-(3-acetylaminophenyl)ρiperidin-l-yl] propyl} - liT-benzimidazole; 14) 2-(2-iodophenyl)-l-{3-[4-(3-acetylaminophenyl)piρeridin-l-yl] propyl} - 177-benzimidazole;
15) 2-(2-fluorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} - l//-benzimidazole;
16) 2-(2,4-dichlorophenyl)- 1 - {3 - [4-(3 -acetylaminopheny^piperidin- 1 -yl] propyl} -177-benzimidazole;
17) 2-(2-methoxyphenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl}- Ii7-benzimidazole;
18) 2-(3 -methoxyphenyl)- 1 - { 3 - [4-(3 -acetylaminopheny^piperidin- 1 -yl] propyl}- lif-benzimidazole; 19) 2-(4-methoxyphenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin-yl] propyl}- liT-benzimidazole;
20) 2-(4-isopropylphenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} - l/Z-benzimidazole;
21) 2-phenyl- 1 - {3-[4-(3-acetylaminophenyl)piperidin- 1 -yl]propyl} -5,6- dimethyl- l//-benzimidazole;
22) 2-(4-chlorophenyl)- 1 - {3 -[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl}-5,6-dimethyl-l/7-benzimidazole;
23) 2-phenyl- 1 - {3-[4-(3-acetylaminophenyl)piperidin- 1 -yl]propyl}-6- methyl- liT-benzimidazole; 24) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -6-methyl- lH-benzimidazole;
25) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piρeridin- 1 -yl] propyl}-6-chloro- lH-benzimidazole;
26) 2-ρhenyl-l-{3-[4-(3-acetylaminoρhenyl)ρiρeridin-l-yl]ρroρyl}-6- fluoro-li/-benzimidazole;
27) 2-ρhenyl-l-{3-[4-(3-acetylaminoρhenyl)ρiρeridin-l-yl]proρyl}-6- methoxy- 1 i7-benzimidazole;
28) 2-(4-chlorophenyl)-l-{3-[4-(3-acetylaminophenyl)ρiperidin-l-yl] propyl}-6-methoxy-li/-benzimidazole;
29) 2-ρhenyl-l-{3-[4-(3-acetylaminoρhenyl)piρeridin-l-yl]propyl}-6- chloro- lϋf-benzimidazole;
30) 2-(4-fluorophenyl)-l-{3-[4-(3-acetylaminophenyl)-piperidin-l-yl] ProPyl} -6-chloro- 1 /7-benzimidazole;
31) 2-(4-chlorophenyl)- 1 -{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl } -6-fluoro- liT-benzimidazole;
32) 2-phenyl- 1 -{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl]propyl} -6- nitro- 1/7-benzimidazole; 33) 2-(2-fluorophenyl)- 1 - {3 - [4-(3 -acetylaminophenytypiperidin- 1 -yl] propyl} -6-chloro- liT-benzimidazole;
34) 2-(3 -fluorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -6-chloro- l#-benzimidazole;
35) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -6-chloro- liT-benzimidazole;
36) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl}-6-bromo-lizr-benzimidazole;
37) 2-(2-chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -5,6-dimethyl- lϋ/-benzimidazole; 38) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl}-5,6-dimethyl-li7-benzimidazole;
39) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -4,5-dimethyl- li/-benzimidazole;
40) 2-(2-chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -6-nitro- lϋ/'-benzimidazole;
41) 2-(3 -chlorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} -6-nitro- 1/7-benzimidazole;
42) 2-(4-chlorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -6-nitro- 177-benzimidazole; 43) 2-phenyl- 1 - {3-[4-(3-acetylaminophenyl)ρiperidin- 1 -yl]propyl}-6- bromo- Ii7-benzimidazole;
44) 2-(253,4,5-tetrafluorophenyl)-l-{3-[4-(3-acetylaminoρhenyl)piρeridin- 1 -yl]proρyl} - liT-benzimidazole; 45) 2-(4-trifluoromethylphenyl)-l-{3-[4-(3-acetylaminophenyl)piρeridin- 1 -yl]propyl} - liϊ-benzimidazole;
46) 2-(4-biphenyl)- 1 - {3 - [4-(3 -acetylaminophenytypiperidin- 1 -yl]ρropyl} - lϋT-benzimidazole; 47) 2-(4-phenoxyphenyl)- 1 - {3 - [4~(3 -acetylaminophenytypiperidin- 1 -yl] propyl}- li/-benzimidazole;
48) 2-(4-fluorophenyl)- 1 - { 3 - [4-(3 -acetylaminophenytypiperidin- 1 -yl] propyl}-lif-benzimidazole;
49) 2-(4-chloroρhenyl)- 1 - {3 -[4-(3-acetylaminoρhenyl)piρeridin- 1 -yl] propyl}-5,7-dimethyl-li/-benzimidazole;
50) 2-(3,4-difluorophenyl)-l-{3-[4-(3-acetylaminophenyl)ρiperidin-l-yl] propyl} - 1 H-benzimidazole;
51) 2-(4-cyanophenyl)- 1 - {3 - [4-(3 -acetylaminophenyOpiperidin- 1 -yl] propyl} - lif-benzimidazole; 52) 2-(3 -cyanophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl} - lif-benzimidazole;
53) 2-(4-chloro-2-fluorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl]propyl} - liϊ-benzimidazole;
54) 2-(2-chloro-4-fluoroρhenyl)-l-{3-[4-(3-acetylaminoρhenyl)ρiperidin- l-yl]propyl}-li7-benzimidazole;
55) 2-(3 -nitrophenyl)- 1 - { 3 - [4-(3 -acetylaminopheny^piperidin- 1 -yl] propyl} - lϋf-benzimidazole;
56) 2-(5-chloro-2-methoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piρeridin - 1 -yl]propyl} - Ii7-benzimidazole; 57) 2-(2-chloro-4-nitrophenyl)- 1 - {2- [4-(3 -acetamidopheny^piperidin- 1 - yl]ρropyl}-liϊ-benzimidazole;
58) 2-(254-dimethoxyρhenyl)- 1 - {3 - [4-(3 -acetylaminopheny^piperidin- 1 - yl]propyl}-lif-benzimidazole;
59) 2-(4-chloro-2-fluorophenyl)-l-{3-[4-(3-acetylaminoρhenyl)ρiρeridin- l-yl]ρropyl}-5,6-dimethyl-liϊ-benzimidazole;
60) 2-(4-chlorophenyl)- 1 - { 3 -[4-(3 -acetylaminopheny^piperidin- 1 -yl] propyl}-5-carbamoyl-lH-benzimidazole;
61) 2-(4-chloroρhenyl)- 1 - {3 -[4-(3 -acetylaminopheny^piperidin- 1 -yl] propyl} -6-carbamoyl- lH-benzimidazole;
62) 2-(3 -carbamoylphenyl)- 1 - {3 - [4-(3 -acetylaminophenytypiperidin- 1 -yl] propyl} - Ii7-benzimidazole;
63) 2-(2-hydroxyphenyl)-l-{3-[4-(3-acetylaminoρhenyl)piperidin-l-yl] propyl}- liJ-benzimidazole;
64) 2-(4-chloroρhenyl)-l - {3-[4-(3-isobutyrylaminoρhenyl)ρiρeridin- 1 -yl] propyl}-l//-benzimidazole;
65) 2-(4-chlorophenyl)-l-{3-[4-(3-benzoylaminophenyl)piperidin-l-yl] propyl}- lif-benzimidazole; 66) 2-(4-chloroρhenyl)-l-{3-[4-(3-(3-chlorobenzoylamino)ρhenyl) piperidin-l-yl]propyl}-liϊ-benzimidazole;
67) 2-(4-chlorophenyl)-l-{3-[4-(3-(4-methylbenzoylamino)phenyl) piperidin- 1 -yl]propyl} - l#-benzimidazole;
68) 6-bromo-5-methyl-2-phenyl-3-{3-[4-(3-acetylaminoplienyl)piperidiri- 1 -yl]propyl}-3i7-imidazo[4,5-b]pyridine;
69) 5-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-l-yl] propyl}-3i/-imidazo[4,5-b]pyridine;
70) 2-(benzo[l,3]dioxol-5-yl)-l-{3-[4-(3-acetylaminoplienyl)piperidin-l- yl] propyl} -lϋZ-benzimidazole; 71) 2-(4-chlorophenyl)- 1 - {2-[4-(3-isobutyrylaminoplienyl)piperidin- 1 -yl] ethyl} - Ii7-benzimidazole;
72) 2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidiri-l-yl]propyl}-3iir- imidazo[4,5-c]pyridine;
73) 2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-l-yl]ρroρyl}-3//- imidazo[4,5-d]pyridine;
74) 5-bromo-6-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin- l-yypropylj^if-imidazo^^-ejpyridine;
75) 6-methyl-2-phenyl-3-{3-[4-(3-acetylaminophenyl)piperidin-l-yl] propyl}-3i/-imidazo[455-e]pyridine; 76) 2-(3-methoxycai-bonylρhenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} - l/f-benzimidazole; 77) 2-(4-ethylρhenyl)-l - {3-[4-(3-aceτylaminophenyl)ρiperidin- 1 -yl] propyl} -l//-benzimidazole; 78) 2-(4-cyanophenyl)- 1 -{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl}-5,6-dimethyl-l#-benzimidazole;
79) 2-(m-tolyl)- 1 - {3 - [4-(3 -acetylaminophenytypiperidin- 1 -yl]ρroρyl} - IH- benzimidazole; 80) 2-(2-chloro-4-fluorophenyl)- 1 - {3-[4-(3-acetylaminophenyl)piperidin- 1 -yl]propyl} -5,6-dimethyl- liiZ-benzimidazole;
81) 2-(4-chlorophenyl)-l-{3-[4-(3-acetylaminophenyl)piperidin-l-yl] propyl}-5-cyano-l/7"-benzimidazole;
82) 2-(4-chlorophenyl)- 1 - {3-[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl} -ό-cyano-liT-benzimidazole;
83) 2-(4-chlorophenyl)~ 1 -{3-[4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl}-5-fluoro-l//"-benzimidazole;
84) 2-(4-fluorophenyl)- 1 - { 3 - [4-(3-acetylaminophenyl)piperidin- 1 -yl] propyl}-5-chloro-li/-benzimidazole; 85) 2-(4-chlorophenyl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl}-5-nitro-l//-benzimidazole; 86) 2-(4-chloro-2-methoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} -5,6-dimethyl- IH- benzimidazole; and 87) 2-(5-chloro-2-methoxyphenyl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} -5,6-dimethyl- IH- benzimidazole.
7. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 3, wherein R5 is H, methyl, or phenyl; R7 and R8 are each H; R2 is at least one selected from the group consisting of H, halogen, Ci-3
alkyl, K^ , OR5, NO2, CN, pyridyl, and -CONR7R8, X1 being H, halogen, methyl, OrNO2; and the number of N representing A is 1.
8. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 3, being selected from the group consisting of:
I ) 2-methyl- 1 - { 3 -[4-(3 -acetylaminophenytypiperidin- 1 -yl]propyl} - IH- benzimidazole; 2) 2-methyl- 1 - { 3 - [4-(3 -acetylaminopheny^piperidin- 1 -yl]propyl} -5,6- dimethyl- liϊ-benzimidazole;
3) 2-methyl-l-{3-[4-(3-isobutyrylaminophenyl)piρeridin-l-yl]proρyl}- 177-benzimidazole;
4) 2,5-dimethyl-3-{3-[4-(3-acetylaminoρhenyl)piperidin-l-yl]propyl}-
Figure imgf000099_0001
5) 6-bromo-2,5-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-l-yl] propyl}-3i/-imidazo[4,5-b]pyridine;
6) 6-bromo-2-ethyl-5-methyl-3 - { 3 - [4-(3 -acetylaminophenyl)piperidin- 1 - yl] propyl}-3#-imidazo[4,5-b]pyridine; 7) 6-bromo-2-butyl-5-methyl-3- {3-[4-(3-acetylaminophenyl)piperidin- 1 - yl] propyl}-3i7-imidazo[4,5-b]pyridine;
8) 2-butyl-5,7-dimethyl-3-{3-[4-(3-acetylaminophenyl)piperidin-l-yl] propyl}-3i/-imidazo[4,5-b]pyridine;
9) 2-butyl-5,7-dimethyl-6-phenyl-3- {3-[4-(3- acetylaminophenyl)piperidin- 1 -yljpropyl} -3i7-imidazo[4,5-b]pyridine;
10) 2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3-acetylaminophenyl) piperidin- 1 -yl]propyl}-3//-imidazo[455-b]pyridine;
I 1) 6-bromo-2-butyl-5-methyl-3-{3-[4-(3- isobutyrylaminophenyl)piperidin-l-yl]propyl}-3H-imidazo[4,5- b]pyridine;
12) 2-butyl-5,7-dimethyl-3- {3-[4-(3-isobutyrylaminoρhenyl)piperidin- 1 - yl] propyl}-3/-r-imidazo[4,5-b]pyridine;
13) 2-butyl-5,7-dimethyl-6-phenyl-3-{3-[4-(3-isobutyrylaminophenyl) piperidin- 1 -yl]propyl} -3H-imidazo[4,5-b]pyridine; 14) 2-butyl-5-methyl-6-pyridin-2-yl-3-{3-[4-(3-isobutyrylaminophenyl) piperidin-l-yl]propyl}-3ϋZ-imidazo[4.5-b]pyridine; 15) 2-butyl-5-formyl-6-phenyl-3-{3-[4-(3- isobutyrylaminophenyl)piρeridin-l-yl]piOpyl}-3H-imidazo[4,5- b]ρyridine; and 16) 2-butyl-5-methyl-6-(4-nitrophenyl)-3-{3-[4-(3- isobutyrylaminoρhenyl)ρiperidin-l-yl]proρyl}-3/f-imidazo[4,5- b]pyridine.
9. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 4, wherein
R4 is halogen, OCH3, or methyl;
R5 is H, methyl, or phenyl; R7 and R8 are each H;
R9 is H or methyl;
R3 is Cu alkyl; and
A is CH.
10. The imidazole derivative or pharmaceutically acceptable salt thereof according to claim 4, being selected from the group consisting of:
128) 2-(pyridin-2-yl)- 1 - {3-[4-(3-acetamidophenyl)piperidin- 1 -yl]proρyl}- l//-benzimidazole;
129) 2-(pyridin-3-yl)- 1 - {3-[4-(3-acetamidophenyl)piperidin- 1 -yl]propyl}~ Ii7-benzimidazole;
130) 2-(pyridin-4-yl)-l-{3-[4-(3-acetamidophenyl)piperidin-l-yl]ρroρyl}-
1/7-benzimidazole; 131) 2-(furan-3 -yl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yljpropyl} -
Ii7-benzimidazole; 132) 2-(5-bromofuran-2-yl)-l-{3-[4-(3-acetylaminoρhenyl)ρiρeridin-l-yl] propyl} - 1 H-benzimidazole;
133) 2-(thiophen-2-yl)- 1 - {3 - [4-(3 -acetylaminophenyl)piperidin- 1 -yl] propyl}- li?-benzimidazole;
134) 2-(5-methylthiophen-2-yl)- 1 - {3-[4-(3-acetylaminophenyl)piperidin- l-yl]propyl}-li/-benzimidazole;
135) 2-(l-methyl-li7-pyriOl-2-yl)-l-{3-[4-(3- acetylaminophenyl)piperidin- 1 -yl]propyl} - Ii7-benzimidazole; 136) 2-(5-bromopyridin-3 -yl)- 1 - {3 -[4-(3 -acetylaminopheny^piperidin- 1 - yl] propyl}- lif-benzimidazole;
137) 2-(6-chloropyτidin-3 -yl)- 1 - {3 -[4-(3 -acetamidophenytypiperidin- 1 -yl] propyl} - IH-benzwύdazole;
138) 2-(6-methylpyridin-3 -yl)- 1 - { 3- [4-(3 -acetamidophenyl)piperidin- 1 -yl] propyl} -1/Z-benzimidazole;
139) 2-(2-methoxypyridin-3-yl)-l-{3-[4-(3-acetamidophenyl)piperidin-l- yl] proρyl}-lH-benzimidazole; 140) 5-chloro-2-(pyridin-3-yl)- 1 -{3-[4-(3-acetamidophenyl)piperidin- 1 - yl] propyl}- l//-benzimidazole; 141) 5-nitro-2-(pyridin-3-yl)- 1 - {3-[4-(3-acetamidophenyl)piperidin- 1 -yl] propyl} - 1 //-benzimidazole;
142) 5-chloro-2-(5-bromofuran-2-yl)- 1 -{3-[4-(3- acetamidophenyl)piperidin- 1 -yl]propyl} - l//-benzimidazole;
143) 2-(furan-2-yl)-5-methoxy- 1 - {3-[4-(3-acetamidophenyl) piperidin- 1 - yl]propyl} - liϊ-benzimidazole;
144) 5 -methyl-2-(thiophen-3 -yl)- 1 - {3 - [4-(3 -acetamidopheny^piperidin- 1 - yl]propyl} - 1 //-benzimidazole;
145) 556-dimethyl-2-( 1 -methylρyrrol-2-yl)- 1 - { 3 - [4-(3 -acetamidophenyl) piperidin- 1 -yl]propyl}- li^-benzimidazole; 146) 2-(thiazol-4-yl)- 1 - {3 - [4-(3 -acetamidophenyl)piperidin- 1 -yl]propyl} - lH-benzimidazole;
147) 2-(4-methyloxazol-5-yl)- 1- {3-[4-(3-acetamidoρhenyl)ρiperidin- 1 -yl] propyl} - l//-benzimidazole;
148) 2-(l -methyl-l#-imidazol-5-yl)- 1 - {3-[4-(3- acetamidophenyl)ρiperidin- 1 -yl]ρropyl} - l//-benzimidazole;
149) 2-(pyridin-2-ylmethyl)- 1 - { 3 - [4-(3 -acetamidopheny^piperidin- 1 - yl]propyl} - li¥-benzimidazole;
150) 2-(pyridin-3-ylmethyl)- 1 - {3-[4-(3-acetamidophenyl)piperidin- 1 -yl] propyl}- l//-benzimidazole; and 151) 2-[2-(ρyridin-3-yl)ethyl]- 1 - {3-[4-(3-acetamidoρhenyl)ρiperidin- 1 -yl] propyl} - l//-benzimidazole.
11. A process for preparing the imidazole derivative of formula (I) according to claim 1 comprising subjecting an imidazole derivative of formula (II) to a reaction with a compound of formula (III) in a solvent in the presence of a base:
Figure imgf000102_0001
wherein
R1, R2, R3, A and n are the same as defined in claim 1, and L is halogen, OMs or OTs.
12. A process for preparing an imidazole derivative of formula (I) comprising subjecting an imidazole derivative of formula (IV) to a reaction with a compound of formula (V) in a solvent in the presence of a base:
Figure imgf000103_0001
wherein
R1, R2, R3, A and n are the same as defined in claim 1, and L is halogen,
OMs or OTs.
13. The process for preparing imidazole derivative according to claim 11 or 12, wherein the base is an organic base selected from pyridine, triethylamine, N,N-diisopropylethylamine, 1 , 8-diazabicyclo- [5.4.0]undec-7-ene (DBU), and a mixture thereof; or an inorganic base selected from NaOH, Na2CO3, K2CO3, Cs2CO3, and a mixture thereof.
14. The process for preparing the imidazole derivative according to claim 11 or 12, wherein the solvent is an ether-based solvent, dimethylformamide (DMF)5 dimethylsulfoxide, acetonitrile, or a mixture thereof.
15. An antagonist of melanin-concentrating hormone (MCH) receptor, containing as an active ingredient the imidazole derivative according to any one of claims 1 to 4 or pharmaceutically acceptable salt thereof.
16. A composition for the prevention or treatment of an MCH-related disease, comprising the imidazole derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.
17. The composition of claim 16, wherein the disease is selected from the group consisting of obesity, depression, anxiety, diabetes, metabolic disturbance, and schizophrenia.
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