Abstract:
Provided is a therapeutic agent for diseases associated with a cholinergic property of the central nervous system (CNS) and/or the peripheral nervous system (PNS), diseases associated with the contraction of smooth muscle, incretion disease, diseases associated with neuronal degeneration and the like, said therapeutic agent comprising a compound represented by Formula (I): 
     
       
                 
         
             
             
         
       
     
     [wherein X—Y—Z represents N—CO—NR 4A R 4B  or the like; R 1  represents a phenyl group or the like; R 2A  and R 2B  may be the same as or different from each other and independently represent a hydrogen atom or the like; R 3A  to R 3D  and R 6  may be the same as or different from one another and independently represent a hydrogen atom or the like; R 4A  and R 4B  may be the same as or different from each other and independently represent an aryl group or the like; and n represents 1 or 2]
 
or a pharmaceutically acceptable salt thereof and having a potent activity of regulating an α7 nicotinic acetylcholine receptor (an α7 nAChR).

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to a novel imidazole derivative which is a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR). On the basis of such pharmacological properties, the present compound can be useful for treating, for example, diseases related to cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders, diseases such as inflammation and pain, and diseases associated with withdrawal symptoms caused by addictive drug abuse. 
       BACKGROUND ART 
       [0002]    Recently, potential neuroprotective-effects of nicotine have been shown, and meanwhile various neurodegenerative-models in animals and cultured cells suffering from excitotoxic injury, athrepsia, ischemia, injury, neuronal cell death induced by amyloid beta (Aβ) or neurodegeneration induced by protein aggregation have been proposed. In many cases where nicotine shows neuroprotective effects, it has been found that nicotinic acetylcholine receptors containing α7 subtype are activated. These findings suggest that nicotine is useful in providing neuroprotective effects, and indicate that receptors containing α7-subtype are directly related with the effects. These data suggest that α7 nicotinic acetylcholine receptor is typically a suitable molecular-target for neuroprotection. In other words, the neuroprotection may be accomplished by developing an active agonist/positive modulator (i.e. positive allosteric modulator: PAM) of the receptor. In fact, α7 nicotinic acetylcholine receptor agonist has already been identified, and is expected to provide a possible clue to the development of neuroprotective drugs. In addition, it has recently been reported that α7 nicotinic acetylcholine receptor is also involved in inflammation. Thus, the development of a novel modulator of the receptor is expected to lead to a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases. 
         [0003]    In the past, there were some disclosures about modulators of α7 nicotinic acetylcholine receptor (α7 nAChR), but the chemical structures thereof are different from that of the present compound (see, Patent Reference 1 and Patent Reference 2). 
       CONVENTIONAL ART REFERENCES 
     Patent References 
       [0004]    [Patent reference 1]WO 2003/093250 
         [0005]    [Patent reference 2]WO 2006/138510 
       SUMMARY OF INVENTION 
     Problems to be Solved by the Invention 
       [0006]    A problem to be solved by the present invention is to provide a novel compound which has potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR), and can be useful as a novel medicament for treating and/or preventing nervous system diseases, psychiatric diseases and inflammatory diseases. 
         [0007]    In addition, WO 2012/133509 and WO 2012/176763 are applications related to the present application, which have already been published. The compounds therein have similar but different structures from that of the present compound. Further, the priority date of the present application is earlier than the published dates of the related applications, and they are not thus conventional art references for the present application. 
       Means of Solving the Problems 
       [0008]    The present inventors have extensively studied to solve the problem and then have found that a novel compound of the following Formula (I) exhibits potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR). On the basis of the new findings, the present invention has been completed. The present invention provides an imidazole derivative of the following Formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, optionally referred to as “the present compound”). 
         [0000]    [Item 1]A compound of Formula (I): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein X—Y—Z is N—CO—NR 4A R 4B , N—COR 5 , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —COR 5 , CR 6 —NR 7 —CONR 4A R 4B  or CR 6 —NR 7 -Q, 
         [0009]    R 1  is phenyl or heteroaryl in which the phenyl and the heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms, cyano, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9  and —NR 8 COR 9 , 
         [0010]    R 2A  and R 2B  are the same or different and are hydrogen atom; halogen; cyano; —COOR 10 ; —CONR 10 R 11 ; —NR 10 R 11 ; —NR 10 COR 11 ; C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, cyano, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11  and —NR 10 COR 11 ; or C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 1-6  alkoxy, cyano, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11  and —NR 10 COR 11 ; provided that when X—Y—Z is N—CO—NHEt and n=1, R 2A  is C 1-4  alkyl which may be optionally substituted with the above substituents, 
         [0011]    R 3A , R 3B , R 3C , R 3D  and R 6  are the same or different and are hydrogen atom; fluorine atom; hydroxyl group; C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; or C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms; provided that when any two of R 3A , R 3B , R 3C , R 3D  and R 6  are independently selected from C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, the two alkyl groups may be combined each other together with the ring to which the alkyl groups attach to form another ring, 
         [0012]    R 4A , R 4B , R 5  and R 7  are the same or different and are C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl or heteroaryl (in which the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms), halogen, hydroxyl group, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, C 3-10  cycloalkyl and —NR 12 R 13 ; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl or heteroaryl (in which the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms), halogen, hydroxyl group, C 1-6  alkoxy, C 1-6  alkyl and —NR 12 R 13 ; 4- to 10-membered saturated heterocycle which may be optionally substituted with C 1-6  alkyl; aryl or heteroaryl in which the aryl and the heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; or hydrogen atom; provided that R 5  is not hydrogen atom, and R 4A  and R 4B  are not concurrently hydrogen atom, and that when both R 4A  and R 4B  are independently selected from C 1-6  alkyl, they may be combined each other to form 4- to 10-membered nitrogen-containing saturated heterocycle which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, C 1-6  alkyl and C 1-6  alkoxy, 
         [0013]    Q is 6-membered heteroaryl containing one or two nitrogen atoms [in which the heteroaryl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkoxy, C 3-6  cycloalkyl, —NR 10 R 11 , —CONR 10 R 11  and —NR 10 COR 11 ; C 3-10  cycloalkyl, C 3-10  cycloalkoxy or 4- to 10-membered saturated heterocycle (in which the cycloalkyl, the cycloalkoxy and the saturated heterocycle may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkyl, C 1-6  alkoxy, —NR 14 R 15 , —CONR 14 R 15  and —NR 14 COR 15 ); C 1-6  alkoxy which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkoxy, —NR 14 R 15 , —CONR 14 R 15  and —NR 14 COR 15 ; halogen; cyano; —CONR 14 R 15 ; —NR 14 COR 15 ; and —NR 14 R 15 ], 
         [0014]    R 8  to R 15  are the same or different, and independent each other when the same substituent symbol exists plurally, and are hydrogen atom, or C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms; provided that in each combination of R 8  and R 9 , R 10  and R 11 , R 12  and R 13 , or R 14  and R 15 , (1) when one is hydrogen atom, the other is not hydrogen atom, and (2) when both of them are independently selected from C 1-6  alkyl, they may be combined each other to form 4- to 10-membered nitrogen-containing saturated heterocycle, and 
         [0015]    n is 1 or 2, 
         [0000]    or a pharmaceutically acceptable salt thereof.
 
[Item 2]A compound of Formula (I):
 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein X—Y—Z is N—CO—NR 4A R 4B , N—COR 5 , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —COR 5 , CR 6 —NR 7 —CONR 4A R 4B  or CR 6 —NR 7 -Q, 
         [0016]    R 1  is phenyl or monocyclic heteroaryl in which the phenyl and the monocyclic heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms, cyano, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9  and —NR 8 COR 9 , 
         [0017]    R 2A  and R 2B  are the same or different and are hydrogen atom; halogen; cyano; —COOR 10 ; —CONR 10 R 11 ; —NR 10 R 11 ; —NR 10 COR 11 ; C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, cyano, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11 , and —NR 10 COR 11 ; or C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 1-6  alkoxy, cyano, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11  and —NR 10 COR 11 ; provided that when X—Y—Z is N—CO—NHEt and n=1, R 2A  is hydrogen atom; halogen; cyano: or C 1-4  alkyl which may be optionally substituted with the above substituents, 
         [0018]    R 3A , R 3B , R 3C , R 3D  and R 6  are the same or different and are hydrogen atom; fluorine atom; hydroxyl group; C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; or C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms; provided that when any two of R 3A , R 3B , R 3C , R 3D  and R 6  are independently selected from C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, the two alkyl groups may be combined each other together with the ring to which the alkyl groups attach to form another ring, 
         [0019]    R 4A , R 4B , R 5  and R 7  are the same or different and are C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl or heteroaryl (in which the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms), halogen, hydroxyl group, C 1-6  alkoxy 4- to 10-membered saturated heterocyle, C 3-10  cycloalkyl and —NR 12 R 13 , C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl or heteroaryl (in which the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms), halogen, hydroxyl group, C 1-6  alkoxy, C 1-6  alkyl, and —NR 12 R 13 ; 4 to 10-membered saturated heterocycle which may be optionally substituted with C 1-6  alkyl; aryl or heteroaryl in which the aryl and the heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; or hydrogen atom; provided that R 5  is not hydrogen atom and R 4A  and R 4B  are not concurrently hydrogen atom, and that when both R 4A  and R 4B  are independently selected from C 1-6  alkyl, they may be combined each other to form 4- to 10-membered nitrogen-containing saturated heterocycle which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, C 1-6  alkyl and C 1-6  alkoxy, 
         [0020]    Q is 6-membered heteroaryl containing one or two nitrogen atoms [in which the heteroaryl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkoxy, C 3-6  cycloalkyl, —NR 10 R 11 , —CONR 10 R 11  and —NR 10 COR 11 ; C 3-10  cycloalkyl, C 3-10  cycloalkoxy or 4- to 10-membered saturated heterocycle (in which the cycloalkyl, the cycloalkoxy and the saturated heterocycle may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkyl, C 1-6  alkoxy, —NR 14 R 15 , —CONR 14 R 15  and —NR 14 COR 15 ); C 1-6  alkoxy which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkoxy, —NR 14 R 15 , —CONR 14 R 15  and —NR 14 COR 15 ; halogen; cyano; —CONR 14 R 15 ; —NR 14 COR 15 ; and —NR 14 R 15 ], 
         [0021]    R 8  to R 15  are the same or different, and independent each other when the same substituent symbol exists plurally, and are hydrogen atom, or C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms; provided that in each combination of R 8  and R 9 , R 10  and R 11 , R 12  and R 13 , or R 14  and R 15 , (1) when one is hydrogen atom, the other is not hydrogen atom, and (2) when both of them are independently selected from C 1-6  alkyl, they may be combined each other to form 4- to 10-membered nitrogen-containing saturated heterocycle, and 
         [0022]    n is 1 or 2, 
         [0000]    or a pharmaceutically acceptable salt thereof.
 
[Item 3] The compound of Item 1 or 2 wherein n is 1, or a pharmaceutically acceptable salt thereof.
 
[Item 4] The compound of any one of Items 1 to 3 wherein X—Y—Z is N—CO—NR 4A R 4B , N—COR 5 , CR 6 —CO—NR 4A R 4B  or CR 6 —NR—COR 5 , or a pharmaceutically acceptable salt thereof.
 
[Item 5] The compound of any one of Items 1 to 4 wherein R 1  is phenyl or monocyclic heteroaryl in which the phenyl and the monocyclic heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms, and cyano, or a pharmaceutically acceptable salt thereof.
 
[Item 6] The compound of any one of Items 1 to 4 wherein R 1  is phenyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms, cyano, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , and —NR 8 COR 9 , or a pharmaceutically acceptable salt thereof.
 
[Item 7] The compound of any one of Items 1 to 4 wherein R 1  is phenyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms, or a pharmaceutically acceptable salt thereof.
 
[Item 8] The compound of any one of Items 1 to 7 wherein R 2A  and R 2B  are the same or different and are hydrogen atom; halogen; cyano; C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, cyano, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11 , and —NR 10 COR 11 ; or C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 1-6  alkoxy, cyano, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11  and —NR 10 COR 11 ; provided that when X—Y—Z is N—CO—NHEt and n=1, R 2A  is hydrogen atom, halogen, cyano, or C 1-4  alkyl which may be optionally substituted with the above substituents, or a pharmaceutically acceptable salt thereof.
 
[Item 9] The compound of any one of Items 1 to 7 wherein R 2A  and R 2B  are the same or different and are hydrogen atom; halogen; cyano; or C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy and 4- to 10-membered saturated heterocycle; provided that when X—Y—Z is N—CO—NHEt and n=1 R 2A  is hydrogen atom, halogen, cyano, or C 1-4  alkyl which may be optionally substituted with the above substituents, or a pharmaceutically acceptable salt thereof.
 
[Item 10] The compound of any one of Items 1 to 7 wherein R 2A  and R 2B  are the same or different and are hydrogen atom, halogen or cyano, or a pharmaceutically acceptable salt thereof.
 
[Item 11] The compound of any one of Items 1 to 7 wherein R 2A  is halogen or cyano, and R 2B  is hydrogen atom, or a pharmaceutically acceptable salt thereof.
 
[Item 12] The compound of any one of Items 1 to 10 wherein R 2B  is hydrogen atom, or a pharmaceutically acceptable salt thereof.
 
[Item 13] The compound of any one of Items 1 to 12 wherein R 3A , R 3B , R 3C , R 3D  and R 6  are the same or different and are hydrogen atom, or C 1-6  alkyl; provided that when any two of R 3A , R 3B , R 3C  and R 3D  are independently selected from C 1-6  alkyl, the two alkyl groups may be combined each other together with the carbon atoms to which the alkyl groups attach or the ring containing the carbon atoms to form another ring, or a pharmaceutically acceptable salt thereof.
 
[Item 14] The compound of any one of Items 1 to 12 wherein all of R 3A , R 3B , R 3C , R 3D  and R 6  are hydrogen atom, or a pharmaceutically acceptable salt thereof.
 
[Item 15] The compound of any one of Items 1 to 14 wherein R 4A , R 4B , R 5  and R 7  are the same or different and are C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl or heteroaryl (in which the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms), halogen, hydroxyl group, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, C 3-10  cycloalkyl and —NR 12 R 13 ; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of aryl or heteroaryl (in which the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms), halogen, hydroxyl group, C 1-6  alkoxy, C 1-6  alkyl and —NR 12 R 13 ; or hydrogen atom; provided that R 5  is not hydrogen atom and both R 4A  and R 4B  are not concurrently hydrogen atom, and that when both R 4A  and R 4B  are independently selected from C 1-6  alkyl, they may be combined with each other to form 4- to 10-membered nitrogen-containing saturated heterocycle which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, C 1-6  alkyl and C 1-6  alkoxy, or a pharmaceutically acceptable salt thereof.
 
[Item 16] The compound of any one of Items 1 to 14 wherein R 4A , R 4B , R 5  and R 7  are the same or different and are C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, C 3-10  cycloalkyl and —NR 12 R 13 ; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkoxy, C 1-6  alkyl and —NR 12 R 13 ; aryl or heteroaryl (in which the aryl and the heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms); or hydrogen atom; provided that R 3  is not hydrogen atom, and that when both R 4A  and R 4B  are independently selected from C 1-6  alkyl they may be combined each other to form 4- to 10-membered nitrogen-containing saturated heterocycle which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, C 1-6  alkyl and C 1-6  alkoxy, or a pharmaceutically acceptable salt thereof.
 
[Item 17] The compound of any one of Items 1 to 14 wherein R 4A , R 4B , R 5  and R 7  are the same or different and are C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, C 3-10  cycloalkyl and —NR 12 R 13 ; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkoxy, C 1-6  alkyl or —NR 12 R 13 ; or hydrogen atom; provided that R 5  is not hydrogen atom, or a pharmaceutically acceptable salt thereof.
 
[Item 18] The compound of any one of Items 1 to 17 wherein R 4B  and R 7  are hydrogen atom, or a pharmaceutically acceptable salt thereof.
 
[Item 19] The compound of any one of Items 1 to 18 wherein X—Y—Z is N—CO—NR 4A R 4B , or a pharmaceutically acceptable salt thereof.
 
[Item 20] The compound of any one of Items 1 to 18 wherein X—Y—Z is N—COR 5 , or a pharmaceutically acceptable salt thereof.
 
[Item 21] The compound of any one of Items 1 to 18 wherein X—Y—Z is CR 6 —CO—NR 4A R 4B , or a pharmaceutically acceptable salt thereof.
 
[Item 22] The compound of any one of Items 1 to 18 wherein X—Y—Z is CR 6 —NR 7 —COR 5 , or a pharmaceutically acceptable salt thereof.
 
[Item 23] The compound of any one of Items 1 to 18 wherein X—Y—Z is CR 6 —NR 7 -Q, or a pharmaceutically acceptable salt thereof.
 
[Item 24] The compound of any one of Items 1, 2, or 4 to 18, wherein X—Y—Z is CR 6 —NR 7 -Q, and Q is pyrimidinyl in which the pyrimidinyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms, or a pharmaceutically acceptable salt thereof.
 
[Item 25] The compound of Item 1 selected from the following compounds:
   N-cyclohexyl-4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 1),   1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-4-phenyl-1H-imidazole-5-carbonitrile (Example 7),   N-cyclohexyl-4-[4-(2-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 66),   4-{5-chloro-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 94),   N-(4,4-difluorocyclohexyl)-4-(5-methyl-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxamide (Example 105),   1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-4-(4-fluorophenyl)-1H-imidazole-5-carbonitrile (Example 154),   1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-4-(2-fluorophenyl)-1H-imidazole-5-carbonitrile (Example 156),   N-{cis-4-[5-chloro-4-(4-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-fluoro-2-methylpropanamide (Example 183),   N-[cis-4-(5-cyano-4-phenyl-1H-imidazol-1-yl)cyclohexyl]-2-fluoro-2-methylpropanamide (Example 197),   N-(cis-4-{5-cyano-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}cyclohexyl)-2-fluoro-2-methylpropanamide (Example 201),   cis-4-{5-chloro-4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}-N-(tetrahydro-2H-pyran-4-yl)cyclohexanecarboxamide (Example 224),   N-{cis-4-[4-(4-chlorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-fluoro-2-methylpropanamide (Example 280),   N-{cis-4-[4-(4-chloro-2-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-fluoro-2-methylpropanamide (Example 283),   N-{cis-4-[4-(2,4-difluorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-fluoro-2-methylpropanamide (Example 300),   N-{cis-4-[5-cyano-4-(4-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-fluoro-2-methylpropanamide (Example 332),   cis-4-[5-chloro-4-(3,4-difluorophenyl)-1H-imidazol-1-yl]-(tetrahydro-2H-pyran-4-yl)cyclohexanecarboxamide (Example 370), and   {(3-exo)-3-[5-chloro-4-(4-fluorophenyl)-1H-imidazol-1-yl]-8-azabicyclo[3.2.1]oct-8-yl}(4,4-difluorocyclohexyl)methanone (Example 452),   or a pharmaceutically acceptable salt thereof.
 
[Item 26] The compound of Item 1 selected from the following compounds:
   N-cyclohexyl-4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 1),   1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-4-phenyl-1H-imidazole-5-carbonitrile (Example 7),   N-cyclohexyl-4-[4-(2-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 66),   1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-4-(4-fluorophenyl)-1H-imidazole-5-carbonitrile (Example 154),   N-{cis-4-[5-chloro-4-(4-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-fluoro-2-methylpropanamide (Example 183),   cis-4-[5-chloro-4-(3,4-difluorophenyl)-1H-imidazol-1-yl]-(tetrahydro-2H-pyran-4-yl)cyclohexanecarboxamide (Example 370), and   {(3-exo)-3-[5-chloro-4-(4-fluorophenyl)-1H-imidazol-1-yl]-8-azabicyclo[3.2.1]oct-8-yl}(4,4-difluorocyclohexyl)methanone (Example 452),   or a pharmaceutically acceptable salt thereof.
 
[Item 27]A pharmaceutical composition comprising the compound of any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof.
 
[Item 28]A medicament for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine, comprising as an active ingredient the compound of any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof.
 
[Item 29] The medicament of Item 28 wherein the disease due to an abnormality of the intracellular signaling mediated by acetylcholine is CIAS (cognitive impairment associated with schizophrenia), Alzheimer&#39;s disease, Down&#39;s syndrome, cognitive disorder, mild cognitive disorder, memory disorder/learning disorder, attention deficit/hyperactivity disorder or cerebral angiopathy.
 
[Item 30]A drug comprising the combination use of the compound of any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof and at least one drug selected from atypical antipsychotics.
 
[Item 31]A method for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine, comprising administering a therapeutically effective amount of the compound of any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
 
[Item 32] Use of the compound of any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine.
 
[Item 33]A pharmaceutical composition comprising the compound of any one of Items 1 to 26 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease due to an abnormality of the intracellular signaling mediated by acetylcholine.
   
 
       Effect of the Invention 
       [0049]    The present compound is useful as a novel medicament for treating nervous system disease, psychiatric disease, and inflammatory disease (e.g. senile dementia, attentional deficit disorder, Alzheimer&#39;s disease, and schizophrenia). The present compound is also useful as a combination drug with an atypical antipsychotic for treating nervous system disease, psychiatric disease such as schizophrenia. 
     
    
     DESCRIPTION OF EMBODIMENTS 
       [0050]    The present compound may exist in a form of hydrates and/or solvates, and thus such hydrates and/or solvates are also included in the present compound. 
         [0051]    Since the compound of Formula (I) may contain one or possibly more asymmetric carbon atoms, or may have geometrical isomerism or an axial chirality, the compound may exist as several stereoisomers. Such stereoisomers, mixtures thereof, and racemates are also included in the present compound of Formula (I). 
         [0052]    The compound of Formula (I) wherein one or more of  1 H are substituted with  2 H (D) (i.e. its deuterated form) is also included in the present compound of Formula (I). 
         [0053]    In the present invention, hydrates and solvates such as an ethanolate of the compound of Formula (I) or a pharmaceutically acceptable salt thereof are also included in the present compound of Formula (I). 
         [0054]    The terms used herein are explained hereinafter. 
         [0055]    The term “alkyl” refers to a straight or branched chain saturated hydrocarbon group, and for example, “C 1-4  alkyl” or “C 1-6  alkyl” refers to an alkyl wherein the number of the carbon atoms is 1 to 4, or 1 to 6, respectively. In the case where the alkyl is “C 1-4  alkyl”, its specific example includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. In the case where the alkyl is “C 1-6  alkyl”, it includes, for example, pentyl, isopentyl, neopentyl, hexyl, etc. in addition to those mentioned above. 
         [0056]    The term “cycloalkyl” refers to a monocyclic or polycyclic saturated hydrocarbon, and for example, “C 3-10  cycloalkyl” refers to a cyclic alkyl wherein the number of the carbon atoms is 3 to 10, and also includes a group which has a partially-cross-linked structure or forms a fused ring with aryl or heteroaryl. In the case where the cycloalkyl is “C 3-10  cycloalkyl”, its specific example includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc. 
         [0057]    The term “alkoxy” refers to a group wherein its straight or branched chain saturated hydrocarbon group attaches through its oxygen atom to a parent molecular moiety, and for example, “C 1-6  alkoxy” refers to an alkoxy wherein the number of the carbon atoms is 1 to 6. In the case where the alkoxy is “C 1-6  alkoxy”, its specific example includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. 
         [0058]    The term “halogen” refers to fluorine atom, chlorine atom, bromine atom or iodine atom. The preferable one among them is fluorine atom or chlorine atom. 
         [0059]    The term “aryl” specifically includes, for example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, etc. The preferable one among them includes phenyl. 
         [0060]    The term “heteroaryl” includes a monocyclic 5- to 7-membered ring aromatic heterocyclic group, a bicyclic 8- to 11-membered aromatic heterocyclic group or a tricyclic 12 to 16-membered aromatic heterocyclic group, containing 1 to 4 atoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom. It includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzisooxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, thioxanthene, 6,11-dihydrodibenzo[B,E]thiepinyl, etc. The preferable heteroaryl includes pyridyl, pyrimidinyl, quinolyl, and isoquinolyl. 
         [0061]    The term “monocyclic heteroaryl” includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, etc. The preferable one among them includes pyridyl, pyridazinyl, thienyl, imidazolyl, pyrimidinyl, etc. The most preferable one includes pyridyl and thienyl. 
         [0062]    The term “6-membered heteroaryl which contains 1 or 2 nitrogen atoms” includes, for example, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The preferable one among them includes pyrimidinyl. 
         [0063]    The term “4- to 10-membered saturated heterocycle” refers to a saturated heterocycle consisting of 4 to 10 atoms comprising 1 to 2 atoms independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as well as carbon atoms. For example, it includes azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran, etc. 
         [0064]    The term “4- to 10-membered nitrogen-containing saturated heterocycle” refers to a saturated heterocycle consisting of 4 to 10 atoms comprising at least 1 to 2 nitrogen atoms as well as carbon atoms. For example, it includes azetidine, pyrrolidine, piperidine, piperazine, homopiperidine, etc. 
         [0065]    In the present compound of Formula (I), X—Y—Z, Q, R 1 , R 2A , R 2 , R 3A  to R 3D , R 4A , R 4B , R 5  to R 15 , and n are preferably those shown below, but the technical scope of the present invention should not be limited to the following compounds. 
         [0066]    X—Y—Z preferably includes N—CO—NR 4A R 4B , N—COR 5 , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —COR 5 . 
         [0067]    Q preferably includes 6-membered heteroaryl which contains 1 or 2 nitrogen atoms [in which the heteroaryl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6  alkoxy; C 3-8  cycloalkyl or C 3-8  cycloalkoxy (in which the cycloalkyl and the cycloalkoxy may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group, C 1-6  alkyl and C 1-6  alkoxy); C 1-6  alkoxy which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, hydroxyl group and C 1-6  alkoxy; or halogen]. It more preferably includes 6-membered heteroaryl which contains two nitrogen atoms in which the heteroaryl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom and C 1-6  alkoxy; C 3-8  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms; C 3-8  cycloalkoxy; C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; chlorine atom; or fluorine atom. It furthermore preferably includes pyrimidinyl in which the pyrimidinyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom and C 1-6  alkoxy; C 3-8  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms; C 3-8  cycloalkoxy; C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; chlorine atom; or fluorine atom. It furthermore preferably includes pyrimidinyl in which the pyrimidinyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms; or C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms. 
         [0068]    R 1  preferably includes phenyl or monocyclic heteroaryl in which the phenyl and the monocyclic heteroaryl may be each optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms. It more preferably includes phenyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy which may be optionally substituted with 1 to 5 fluorine atoms. It furthermore preferably includes phenyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, chlorine atom, C 1-6  alkyl which may be optionally substituted with 1 to 3 fluorine atoms, and C 1-6  alkoxy. It most preferably includes phenyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, and C 1-6  alkoxy. 
         [0069]    R 2A  and R 2B  are the same or different and preferably include hydrogen atom; halogen; cyano; C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkyl, C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms, C 1-6  alkoxy or 4- to 10-membered saturated heterocycle. More preferably, R 2A  and R 2B  are the same or different and include hydrogen atom, halogen or cyano. Furthermore preferably, R 2A  includes halogen or cyano, and R 2B  includes hydrogen atom. Most preferably, R 2A  includes chlorine atom or cyano, and R 2B  includes hydrogen atom. 
         [0070]    R 3A , R 3B , R 3C , R 3D  and R 6  are the same or different and preferably include hydrogen atom, fluorine atom, hydroxyl group or C 1-6  alkyl. More preferable ones include hydrogen atom. 
         [0071]    In the case where any two of R 3A , R 3B , R 3C , R 3D  and R 6  are independently selected from C 1-6  alkyl, the two alkyl groups may be combined each other together with the ring to which the alkyl groups attach to form another ring, which in particular includes the following rings. The carbon atoms on the newly formed ring may be optionally substituted with 1 to 5 fluorine atoms. It more preferably includes r 3 -1 and r 3 -2. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0072]    R 4A , R 4B , R 5  and R 7  are the same or different and preferably include C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkoxy, 4- to 10-membered saturated heterocycle, C 3-10  cycloalkyl and —NR 12 R 13 ; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6  alkoxy, C 1-6  alkyl and —NR 12 R 13 ; 4- to 10-membered saturated heterocycle which may be optionally substituted with C 1-6  alkyl; or hydrogen atom. More preferably, they are the same or different and include C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkoxy, 4 to 10-membered saturated heterocycle and C 3-10  cycloalkyl; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6  alkoxy, C 1-6  alkyl; or hydrogen atom. Furthermore preferably, they are the same or different and include C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, 4- to 10-membered saturated heterocycle and C 3-10  cycloalkyl; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom, C 1-6  alkoxy and C 1-6  alkyl; or hydrogen atom. Most preferably, they are the same or different and include C 1-6  alkyl which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atom and 4- to 10-membered saturated heterocycle; C 3-10  cycloalkyl which may be optionally substituted with 1 to 5 fluorine atoms; or hydrogen atom. 
         [0073]    R 8  to R 15  are the same or different and preferably include hydrogen atom or C 1-6  alkyl. More preferable ones include C 1-6  alkyl. 
         [0074]    n includes 1 or 2, preferably 1. 
         [0075]    The pharmaceutically acceptable salt of the compound of Formula (I) refers to a salt which is formed with the compound of Formula (I) and a pharmaceutically acceptable acid or base. The present compound of Formula (I) which has a basic functional group such as an amino group may form salts with various kinds of acids. Specific examples of the acid addition salt include an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, hydrosulfate, perchlorate, and phosphate; an organic acid salt such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate; and an amino acid salt such as glutamate, aspartate. 
         [0076]    The present compound of Formula (I) which has an acidic functional group such as a carboxyl group may form salts with various kinds of bases. Such pharmaceutically acceptable salts include an alkali metal salt such as sodium and potassium salt, an alkaline earth metal salt such as calcium salt, and ammonium salt. These salts can be prepared by mixing the present compound of Formula (I) with the above-mentioned base, followed by isolating it according to conventional methods such as recrystallization. 
         [0077]    For the purpose of simplifying expressions, the following abbreviations may be used herein. o-: ortho-, m-: meta-, p-: para-, t-: tert-, s-: sec-, THF: tetrahydrofuran, DMF: N,N-dimethylformamide, NMP: N-methylpyrrolidone, DMSO: dimethylsulfoxide, d 6 -DMSO: deuterated dimethylsulfoxide, HEPES: N-2-hydroxyethylpiperazin-N′-2-ethanesulfonic acid, BSA: bovine serum albumin, FDSS: Functional Drug Screening System, Boc: tert-butoxycarbonyl, c-Hex: cyclohexyl, EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt: 1-hydroxybenzotriazole, HBTU: 2-(1H-7-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, TFA: trifluoroacetic acid 
         [0078]    Hereinafter, processes for preparing the present compound are explained. The present compound of Formula (I) can be prepared by, for example, the following Preparation Processes A to G. 
       Preparation Process A 
     Process for Preparing Synthetic Intermediates 
       [0079]    Synthetic intermediates a3 to a5 for the compound of Formula (I) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, R 1 , R 3A  to R 3D , R 6 , R 7  and n are as defined in Item 1, P is a protecting group for the amino group, and R is alkyl or phenyl.) 
         [0080]    Compound a1 can be synthesized by known methods such as an oxidation reaction of the corresponding alcohol and a reduction reaction of the corresponding ester, or is commercially available. 
       [Step A-1] 
       [0081]    In this step, Compound a1 is reacted with Compound a6 to give Compound a2. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably ethanol or tetrahydrofuran. The reaction temperature herein is preferably −78° C. to 100° C., and the reaction time herein is preferably several minutes to several days. The process as described in, for example, Heterocycles, 1994, Vol. 39, 139-154 is known as a similar reaction and can similarly give the compound. 
       [Step A-2] 
       [0082]    In this step, Compound a2 which is obtained in the above Step A-1 can be reacted with Compound a7 to give Compound a3. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably xylene or toluene. The reaction temperature herein is preferably room temperature to 150° C., and the reaction time herein is preferably several minutes to several days. The process as described in, for example, Heterocycles, 1994, Vol. 39, 139-154 is known as a similar reaction and can similarly give the compound. 
       [Step A-3] 
       [0083]    In this step, Compound a2 which is obtained in the above Step A-1 is reacted with Compound a8 according to the above Step A-2 to give Compound a4. 
       [Step A-4] 
       [0084]    In this step, Compound a2 which is obtained in the above Step A-1 is reacted with Compound a9 according to the above Step A-2 to give Compound a5. 
       Preparation Process B 
     Process for Preparing Synthetic Intermediates 
       [0085]    Synthetic intermediates b2 to b4 for the compound of Formula (I) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, R 1 , R 2A , R 3A  to R 3D , R 6 , R 7  and n are as defined in Item 1, P is a protecting group for the amino group, and R is alkyl or phenyl.) 
         [0086]    Compound b1 can be synthesized by known methods such as an oxidation reaction of the corresponding alcohol and a reduction reaction of the corresponding ester, or is commercially available. 
         [0087]    Compound b5 can be synthesized by the method as desribed in, for example, Tetrahedron. Lett. 1996, 37, 8113-8116, Organic Synthesis, 2000, 77, 198, or is commercially available. 
       [Step B-1] 
       [0088]    In this step, Compound b1 can be reacted with Compound a7 and Compound b5 in an appropriate solvent in the presence of an appropriate base to give Compound b2. The base used in this step is selected from the bases as illustrated hereinafter, and is preferably potassium carbonate or piperazine. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably dimethylformamide or tetrahydrofuran. The reaction temperature herein is preferably −78° C. to 150° C., and the reaction time herein is preferably several minutes to several days. The process as described in, for example, J. Org. Chem. 2000, 65, 1516-1524 is known as a similar reaction and can similarly give the compound. 
       [Step B-2] 
       [0089]    In this step, Compound b1 is reacted with Compound a8 and Compound b5 according to the above Step B-1 to give Compound b3. 
       [Step B-3] 
       [0090]    In this step, Compound b1 is reacted with Compound a9 and Compound b5 according to the above Step B-1 to give Compound b4. 
       Preparation Process C 
       [0091]    Among the compounds of Formula (I), compounds of formulae [C1], [C2] and [C3] wherein X—Y—Z is N—CO—NR 4A R 4B  (also referred to hereinafter as Compound C1, C2, and C3, respectively) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, R 1 , R 2A , R 3A  to R 3D , R 4A , R 4B  and n are as defined in Item 1, R and R are hydrogen atom, nitro, fluorine atom or trifluoromethyl, R 2AX  is chlorine atom, bromine atom or iodine atom, and P is a protecting group of the amino group.) 
       [Step C-1] 
       [0092]    In this step, a protecting group, P, of the amino group in Compound a3 which is obtained in the above Preparation Process A is deprotected to give Compound c1. This step can be carried out according to the process described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley &amp;#38; Sons, Inc., 1999), etc. 
       [Step C-2] 
       [0093]    In this step, Compound c1 which is obtained in the above Step C-1 is reacted with Compound c3 or c4 in the presence of an appropriate base in an appropriate solvent to give Compound C1. The base used in this step is selected from the bases as illustrated hereinafter, and is preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably tetrahydrofuran or methylene chloride. The reaction temperature herein is preferably −78° C. to 100° C., and the reaction time is preferably several minutes to several days. The processes as described in, for example, J. Org. Chem. 1995, 60(25), 8262-8266, Bioorg. Med. Chem. Lett. 2004, 14(3), 727-779, Tetrahedron Lett. 2001, 42(8), 1445-1447, etc. are known as a similar reaction and can similarly give the compound. 
       [Step C-3] 
       [0094]    In this step, Compound C1 which is obtained in the above Step C-2 is reacted with various halogenating agents in an appropriate solvent in the presence of an appropriate acid to give Compound C2. The halogenating agent used in this step is preferably N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably methylene chloride or dichloroethane. The acid used in this step is selected from the acids as illustrated hereinafter, and is preferably trifluoroacetic acid or hydrochloric acid. The reaction temperature herein is preferably −78° C. to 100° C., and the reaction time is preferably several minutes to several days. The processes as described in, for example, Bioorg. Med. Chem. Lett. 2008, 18(5), 1702-1707, J. Org. Chem. 2002, 67(17), 5913-5918, etc. are known as a similar reaction and can similarly give the compound. 
       [Step C-4] 
       [0095]    In this step, Compound C2 which is obtained in the above Step C-3 is reacted in an appropriate solvent in the presence of an appropriate metal reagent to give Compound C3. The reaction temperature herein is preferably −78° C. to 150° C., and the reaction time is preferably several minutes to several days. The processes as described in, for example, Tetrahedron Lett. 2003, 44(7), 1379-1382, J. Med. Chem. 2009, 52(14), 4370-4379, Bioorg. Med. Chem. Lett. 2012, 20(9), 3009-3015, J. Org. Chem. 2002, 67(10), 3365-3373, Tetrahedron Lett. 2007, 48(13), 2339-2343, etc. are known as a similar reaction and can similarly give the compound. 
       [Step C-5] 
       [0096]    In this step, Compound b2 which is obtained in the above Preparation Process B is reacted under the condition according to the above Step C-1 to give Compound c2. 
       [Step C-6] 
       [0097]    In this step, Compound c2 which is obtained in the above Step C-5 is reacted with Compound c3 or c4 under the condition according to the above Step C-2 to give Compound C3. 
       Preparation Process D 
       [0098]    Among the compounds of Formula (I), compounds of formulae [D1], [D2], and [D3] wherein X—Y—Z is N—COR 5  (also referred to hereinafter as Compound D1, D2, and D3, respectively) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, R 1 , R 2A , R 3A  to R 3D , R 5 , and n are as defined in Item 1, and R 2AX  is chlorine atom, bromine atom or iodine atom.) 
       [Step D-1] 
       [0099]    In this step, Compound c1 which is obtained in the Preparation Process C is reacted with Compound d1 or d2 in the presence or absence of an appropriate condensing agent in the presence of an appropriate base in an appropriate solvent to give Compound D1. The condensing agent used in this step is preferably EDCI (including its hydrochloride) or HBTU. The base used in this step is selected from the bases as illustrated hereinafter, and is preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably dimethylformamide, tetrahydrofuran or methylene chloride. The reaction temperature herein is preferably −78° C. to 100° C., and the reaction time is preferably several minutes to several days. 
       [Step D-2] 
       [0100]    In this step, Compound D1 which is obtained in the above Step D-1 is reacted under the condition according to the above Step C-3 to give Compound D2. 
       [Step D-3] 
       [0101]    In this step, Compound D2 which is obtained in the above Step D-2 is reacted under the condition according to the above Step C-4 to give Compound D3. 
       [Step D-4] 
       [0102]    In this step, Compound c2 which is obtained in the Preparation Process C is reacted with Compound d1 or d2 under the condition according to the above Step D-1 to give Compound D3. 
       Preparation Process E 
       [0103]    Among the compounds of Formula (I), compounds of formulae [E1], [E2], and [E3] wherein X—Y—Z is CR 6 —NR 7 —COR 5  or CR 6 —NR 7 -Q (also referred to hereinafter as Compound E1, E2, and E3, respectively) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, Q, R 1 , R 2A , R 3A  to R 3D , R 5 , R 6 , R 7 , and n are as defined in Item 1, and R 2AX  is chlorine atom, bromine atom or iodine atom, P is a protecting group of the amino group, and LG is a leaving group such as halogen.) 
         [0104]    Compound Q-LG can be prepared by the processes described in, for example, EP1333029 (A1), European Journal of Organic Chemistry, 6, 1593-1598 (2006), US2004/2507 A1, 2004, Tetrahedron Letters, 46, 3977-3979 (2005), WO 2011/063272 pamphlet, etc., or is commercially available. 
       [Step E-1] 
       [0105]    In this step, Compound a4 which is obtained in the Preparation Process A is reacted under the condition according to the above Step C-3 to give Compound e1. 
       [Step E-2] 
       [0106]    In this step, Compound e1 which is obtained in the above Step E-1 is reacted under the condition according to the above Step C-1 to give Compound e2. 
       [Step E-3] 
       [0107]    In this step, Compound e2 which is obtained in the above Step E-2 is reacted with Compound d1 or d2 under the condition according to the above Step D-1 to give Compound E1. 
       [Step E-4] 
       [0108]    In this step, Compound E1 which is obtained in the above Step E-3 is reacted under the condition according to the above Step C-4 to give Compound E2. 
       [Step E-5] 
       [0109]    In this step, Compound b3 which is obtained in the Preparation Process B is reacted under the condition according to the above Step C-1 to give Compound e3. 
       [Step E-6] 
       [0110]    In this step, Compound e3 which is obtained in the above Step E-5 is reacted with Compound d1 or d2 under the condition according to the above Step D-1 to give Compound E2. 
       [Step E-7] 
       [0111]    In this step, Compound e2 which is obtained in the above Step E-2 is coupled with Compound Q-LG in the presence or absence of a catalyst in the presence of a base, under neat or in an appropriate solvent, to give Compound E3. The catalyst used herein includes a transition metal (e.g. palladium) or its salt, a complex thereof, or those which are supported on a carrier such as polymer. The base used in this step is selected from the bases as illustrated hereinafter, and is preferably diisopropylethylamine, triethylamine or potassium carbonate. The solvent used in this step should be selected depending on the types of starting compounds, etc., and includes, for example, N,N-dimethylformamide, 1-methylpyrrolidin-2-one, dimethylsulfoxide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methylene chloride, ethyl acetate, acetone, acetonitrile or water. These solvents each may be used alone, or in combination with two or more of them. The reaction temperature is preferably room temperature to 200° C., the reaction time is preferably several minutes to several days, and a reaction under microwave exposure can be also carried out. 
       [Step E-8] 
       [0112]    In this step, Compound e3 which is obtained in the above Step E-5 is reacted with Compound Q-LG under the condition according to the above Step E-7 to give Compound E3. 
       Preparation Process F 
       [0113]    Among the compounds of Formula (I), compounds of formulae [F1], and [F2] wherein X—Y—Z is CR 6 —CO—NR 4A R 4B  (also referred to hereinafter as Compounds F1 and F2, respectively) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, R 1 , R 2A , R 3A  to R 3D , R 4A , R 4B , R 6 , and n are as defined in Item 1, R 2AX  is chlorine atom, bromine atom or iodine atom, and R is alkyl, phenyl or benzyl.) 
       [Step F-1] 
       [0114]    In this step, Compound a5 which is obtained in the Preparation Process A is reacted under the condition according to the above Step C-3 to give Compound f1. 
       [Step F-2] 
       [0115]    In this step, the ester compound f1 which is obtained in the above Step F-1 is converted into the corresponding carboxylic acid compound f2. This step can be carried out according to the process described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley &amp;#38; Sons, Inc., 1999), etc. 
       [Step F-3] 
       [0116]    In this step, Compound f2 which is obtained in the above Step F-2 is reacted with Compound f4 in the presence of an appropriate condensing agent and an appropriate base in an appropriate solvent to give Compound F1. The condensing agent used in this step is preferably EDCI (including its hydrochloride) or HBTU. The base used in this step is selected from the bases as illustrated hereinafter, and is preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents as illustrated hereinafter, and is preferably dimethylformamide, tetrahydrofuran or methylene chloride. The reaction temperature herein is preferably −78° C. to 100° C., and the reaction time is preferably several minutes to several days. 
       [Step F-4] 
       [0117]    In this step, Compound F1 which is obtained in the above Step F-3 is reacted under the condition according to the above Step C-4 to give Compound F2. 
       [Step F-5] 
       [0118]    In this step, Compound b4 which is obtained in the Preparation Process B is reacted under the condition according to the above Step F-2 to give Compound f3. 
       [Step F-6] 
       [0119]    In this step, Compound f3 which is obtained in the above Step F-5 is reacted with Compound f4 under the condition according to the above Step F-3 to give Compound F2. 
       Preparation Process G 
       [0120]    Among the compounds of Formula (I), the compounds of formulae [G1] and [G2] wherein X—Y—Z is CR 6 —NR 7 —CONR 4A R 4B  (also referred to hereinafter as Compound G1 and G2, respectively) can be prepared by, for example, the following processes. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    (In the scheme, R 1 , R 2A , R 3A  to R 3D , R 4A , R 4B , R 6 , R 7 , and n are as defined in Item 1, R and R x  are hydrogen atom, nitro, fluorine atom or trifluoromethyl, and R 2AX  is chlorine atom, bromine atom or iodine atom.) 
       [Step G-1] 
       [0121]    In this step, Compound e2 which is obtained in the Preparation Process E is reacted with Compound c3 or c4 under the condition according to the above Step C-2 to give Compound G1. 
       [Step G-2] 
       [0122]    In this step, Compound G1 which is obtained in the above Step G-1 is reacted under the condition according to the above Step C-4 to give Compound G2. 
       [Step G-3] 
       [0123]    In this step, Compound e3 which is obtained in the Preparation Process E is reacted with Compound c3 or c4 under the condition according to the above Step C-2 to give Compound G2. 
         [0124]    The imidazole derivatives wherein R 2B  is hydrogen atom prepared in the Preparation Processes A to G can be subject to a conventional nucleophilic substitution reaction to give compounds of Formula (I) wherein R 2B  has a substituent other than hydrogen atom. 
         [0125]    The base used in each step in the above processes can be optionally selected depending on the type of reactions and starting compounds, etc.; and includes, for example, alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkaline carbonates such as sodium carbonate and potassium carbonate; metal hydrides such as sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide and sodium t-butoxide; organometallic bases such as butyllithium and lithium diisopropylamide; and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). 
         [0126]    The solvent used in each step in the above processes can be optionally selected depending on the type of reactions and starting compounds, etc.; and includes, for example, alcohols such as methanol, ethanol and isopropanol; ketones such as acetone and methyl ketone; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as tetrahydrofuran (THF) and dioxane; aromatic hydrocarbons such as toluene and benzene; aliphatic hydrocarbons such as hexane and heptane; esters such as ethyl acetate and propyl acetate; amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); and nitriles such as acetonitrile. These solvents can be used alone or in combination with two or more of them. In addition, organic bases may be also used as the solvent depending on the type of reactions. 
         [0127]    The present compound of Formula (I) or an intermediate thereof can be isolated and purified by well-known methods for one skilled in the art. For example, such methods include extraction, partition, reprecipitation, column chromatography (e.g. silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization, etc. The recrystallization solvent used herein includes, for example, alcohol solvents such as methanol, ethanol or 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as benzene and toluene; ketone solvents such as acetone; halogen solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane; aprotic solvents such as dimethylformamide and acetonitrile; water, or a mixed solvent of the above-listed solvents. Other purification methods including, for example, those described in Experimental Chemistry Textbook Vol. 1 (the Chemical Society of Japan, ed., Maruzen) can be also used herein. The molecular structure of the present compound can be readily determined by spectrographic methods such as nuclear magnetic resonance method, infrared absorption spectroscopy, or circular dichroism spectroscopy, and mass spectrometry in view of each structure derived from each starting compound. 
         [0128]    The present compound of Formula (I) or a pharmaceutically acceptable salt thereof may exhibit chirality or contain a substituent having an asymmetric carbon, which can exist as optical isomers. The present compound includes a mixture of each of the isomers and a single isomer isolated therefrom, which can be prepared according to a conventional method. Such a conventional method includes, for example, using a starting material having an asymmetric center, or introducing chirality during the process. For example, in order to obtain an optical isomer, it can be prepared by using optically active compounds as a starting material, or carrying out an optical resolution at an appropriate stage during the process. In the case where the compound of Formula (I) or an intermediate thereof has a basic functional group, the optical resolution method includes, for example, a diastereomeric method which forms a salt using an optically active acid (e.g. a monocarboxylic acid such as mandelic acid, N-benzyloxyalanine or lactic acid, a dicarboxylic acid such as tartaric acid, o-diisopropylidene tartaric acid or malic acid, a sulfonic acid such as camphor sulfonic acid or bromocamphor sulfonic acid) in an inert solvent (e.g. an alcoholic solvent such as methanol, ethanol and 2-propanol; an ether solvent such as diethylether; an ester solvent such as ethyl acetate; a hydrocarbon solvent such as toluene; an aprotic solvent such as acetonitrile; or a mixed solvent thereof). In the case where the compound of Formula (I) or an intermediate thereof has an acidic functional group such as carboxyl group, the optical resolution method can be also carried out by using an optically active amine (e.g. an organic amine such as 1-phenylethylamine, kinin, quinidine, cinchonidine, cinchonine and strychnine) to form its salt. 
         [0129]    The temperature for forming the salt is selected from the range of −50° C. to a boiling point of a solvent as used, more preferably the range of room temperature to a boiling point of the solvent. In order to improve the optical purity, it is desirable that the temperature is once raised to around a boiling point of the solvent. When a precipitated salt is collected on a filter, the filtration may be, if necessary, carried out under a cooled condition to improve the yield. The appropriate amount of an optically active acid or amine used herein is about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, per mole of the reactant. If necessary, the crystal may be recrystallized from an inert solvent (e.g. an alcoholic solvent such as methanol, ethanol and 2-propanol; an ether solvent such as diethylether; an ester solvent such as ethyl acetate; a hydrocarbon solvent such as toluene; an aprotic solvent such as acetonitrile; or a mixed solvent thereof) to give the optically active salt in a high purity. In addition, if necessary, it is also possible to treat the optically-resolved salt with an acid or a base by a conventional method to give a free form thereof. 
         [0130]    Alternatively, in the case where the compound of Formula (I) or an intermediate thereof has carboxyl group, the optical resolution method can be also carried out by using an optically active amine (e.g. 1-phenylethylamine, etc.) to form its amide. 
         [0131]    The present compound can be a novel medicament for treating and/or preventing a disease due to an abnormality of the intracellular signaling mediated by acetylcholine, in particular, CIAS (cognitive impairment associated with schizophrenia), Alzheimer&#39;s disease, Down&#39;s syndrome, cognitive disorder, mild cognitive disorder, memory disorder/learning disorder, attention deficit/hyperactivity disorder or cerebral angiopathy, for example. 
         [0132]    The present compound can be also a novel medicament for treating nervous system disease, psychiatric disease, and inflammatory disease (e.g. senile dementia, attentional deficit disorder, Alzheimer&#39;s disease, and schizophrenia). The administration route of the present compound may be any of oral, parenteral or rectal administration; and the daily dosage thereof may vary depending on the type of the compound, the administration method, conditions/age of the patient, and other factors. For example, in the case of an oral administration, the present compound can be administered to human beings or mammals at typically about 0.01 to 1000 mg and more preferably about 0.1 to 500 mg per kg of body weight as a single or multiple doses. In the case of a parenteral administration such as an intravenous injection, the present compound can be administered to human beings or mammals at typically about 0.01 mg to 300 mg and more preferably about 1 mg to 100 mg per kg of body weight. The term “treating” used herein also includes a prophylactic administration. 
         [0133]    The dosage forms of the present compound include, for example, tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, embrocations, adhesive skin patches, and inhalants. These formulations can be prepared according to conventional methods. In addition, liquid formulations may be in a form wherein the present compound is dissolved or suspended in water, appropriate aqueous solutions, or other appropriate media at the time of use. Tablets and granules may be coated according to known methods. Furthermore, these formulations may comprise additional ingredients which are useful for the treatment. 
         [0134]    The present compound can be used in combination with an atypical antipsychotic drug. The atypical antipsychotic drug includes, for example, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone. 
       EXAMPLES 
       [0135]    Hereinafter, details are further explained in particular in Reference Examples, Examples and Test Examples, but the present invention is not intended to be limited thereto. In addition, compounds were identified by, for example, elementary analysis, mass spectra, high performance liquid chromatograph-mass spectrometer, LCMS, IR spectra, NMR spectra, and high performance liquid chromatography (HPLC). 
         [0136]    For the purpose of simplifying expressions herein, the following abbreviations may be optionally used in Reference Examples, Examples and the tables in Examples. When referring to substituents in abbreviation, Me is methyl group, Et is ethyl group, Ph is phenyl group, Ts is tosyl group. TFA is trifluoroacetic acid. The following abbreviations are used in NMR data: s: singlet; d: doublet; dd: doublet of doublet; t: triplet; td: triplet of doublet; q: quartet; m: multiplet; br: broad; brs: broad singlet; brd: broad doublet; brt: broad triplet; and J: a coupling constant. 
         [0137]    High performance liquid chromatograph-mass spectrometer: The measurement conditions of LCMS are shown below; the observed value of mass spectrometry [MS(m/z)] is shown as MH+, and the retention time is shown as Rt (minutes, min). In addition, the conditions used in measuring each of observed values are shown as A to G. 
         [0138]    Measurement Condition A 
       Detector: Waters ACQUITY UPLC 
       [0139]    Column: ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column 
       Solvent: Solution A: 0.05% HCOOH/H 2 O, Solution B: CH 3 CN 
     Gradient Condition: 
       [0140]    0.0-1.3 min; A/B=90:10 to 1:99 (linear gradient) 
         [0141]    1.35-1.5 min; A/B=1:99 
         [0142]    1.5-2 min; A/B=90:10 
         [0000]    Flow Rate: 0.75 mL/min 
       UV: 220 nm, 254 nm 
       [0143]    Column temperature: 50° C. 
       Measurement Condition B 
     Detector: Shimadzu LCMS-2020 
       [0144]    Column: Phenomenex Kinetex 1.7 μm C18 2.1 mm×50 mm 
       Solvent: Solution A: MeOH, Solution B: 0.05% TFA/H 2 O 
       [0145]    Gradient condition: 
         [0146]    0 min: A/B=30:70 
         [0147]    0-1.90 min: A/B=99:1 
         [0148]    1.91-3.00 min: A/B=30:70 
         [0000]    Flow Rate: 0.5 ml/min. 
       UV: 220 nm 
       [0149]    Column temperature: 40° C. 
       Measurement Condition C 
       [0150]    Detector: A series of Agilent 1100 for a series of API (manufactured by Applied Biosystems)
 
HPLC: API 150EX LC/MS system (manufactured by Applied Biosystems)
 
       Column: YMC CombiScreen Hydrosphere C18 (S-5 μM, 12 nm, 4.6×50 mm) 
     Solvent: Solution A: 0.05% TFA/H 2 O, Solution B: 0.05% TFA/MeOH 
     Gradient Condition: 
       [0151]    0.0-6.0 min; A/B=75:25 to 1:99 (linear gradient) 
         [0000]    Flow rate: 3.5 mL/min 
       UV: 254 nm 
     Measurement Condition D 
     Detector: Shimadzu, LC: 20A, MS: 2010 
     Column: Xtimate C18 2.1*30 mm, 3 μm 
       [0152]    Solvent: Solution A: 1.5 mL/4 L TFA/H 2 O, Solution B: 0.75 mL/4 L TFA/MeCN 
       Gradient Condition: 
       [0153]    Using the elution gradient 10%-80% (solvent B) over 2.2 minutes and holding at 80% for 0.3 minutes 
         [0000]    Flow rate: 0.8 mL/min 
       UV: 220 nm 
     Measurement Condition E 
     Detector: Shimadzu, LC: 20A, MS: 2010 
     Column: Xtimate C18 2.1*30 mm, 3 μm 
       [0154]    Solvent: Solution A: 1.5 mL/4 L TFA/H 2 O, Solution B: 0.75 mL/4 L TFA/MeCN 
       Gradient Condition: 
       [0155]    Using the elution gradient 30%-90% (solvent B) over 2.2 minutes and holding at 90% for 0.3 minutes 
         [0000]    Flow rate: 0.8 mL/min 
       UV: 220 nm 
     Measurement Condition F 
     Detector: Shimadzu, LC: 20A, MS: 2010 
     Column: Xtimate C18 2.1*30 mm, 3 μm 
       [0156]    Solvent: Solution A: 1.5 mL/4 L TFA/H 2 O, Solution B: 0.75 mL/4 L TFA/MeCN 
       Gradient Condition: 
       [0157]    Using the elution gradient 0%-60% (solvent B) over 2.2 minutes and holding at 60% for 0.3 minutes 
         [0000]    Flow rate: 0.8 mL/min 
       UV: 220 nm 
     Measurement Condition G 
     Detector: Agilent, LC: 1200, MS: 6110 
     Column: Xbrige RP-18 2.1*50 mm, 5 μm 
       [0158]    Solvent: Solution A: 0.5 mL/1 L NH 3 .H 2 O/H 2 O, Solution B: MeCN 
       Gradient Condition: 
       [0159]    Using the elution gradient 10%-80% (solvent B) over 2.0 minutes and holding at 80% for 0.5 minutes 
         [0160]    Flow rate: 1.0 mL/min 
         [0161]    UV: 220 nm 
       Reference Example 1 
     tert-Butyl 4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxylate (Reference Example 1) 
       [0162]    
       
                 
         
             
             
         
       
     
       a) Preparation of 5-(3-fluorophenyl)-4-[(4-methylphenyl)sulfonyl]-4,5-dihydro-1,3-oxazole (Compound cmp-1) 
       [0163]    To a solution of 3-fluorobenzaldehyde (6.68 g) in ethanol (200 ml) and tetrahydrofuran (60 ml) was added p-toluenesulfonylmethylisocyanide (10 g) at room temperature, and sodium cyanide (252 mg) dissolved in a small amount of water was added dropwise thereto, and then the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then to the resulting residue was added ethyl acetate. The mixture was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Compound cmp-1 (15.8 g). 
         [0164]    LCMS; [M+H] + /Rt (min): Measurement Condition (320/1.02: A) 
       b) Preparation of tert-butyl 4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxylate (Reference Example 1) 
       [0165]    To Compound cmp-1 (15.8 g) were added tert-butyl 4-aminopiperidine-1-carboxylate (15.4 g) and xylene (100 ml) at room temperature, and the mixture was stirred under nitrogen atmosphere for 13 hours with heating at 135° C. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give Reference Example 1 (5.63 g). 
         [0166]    LCMS; [M+H] + /Rt (min): Measurement Condition (346/0.70: A) 
       Reference Example 2 
     4-(5-Bromo-4-phenyl-1H-imidazol-1-yl)piperidine (Reference Example 2) 
       [0167]    
       
                 
         
             
             
         
       
     
         [0168]    To a solution of tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (1 g) obtained in a similar manner to Reference Example 1 in methylene chloride (10 ml) were added N-bromosuccinimide (816 mg) and trifluoroacetic acid (1.18 ml) at room temperature, and then the mixture was heated to reflux at 50° C. for 3 hours. The reaction was quenched by adding aqueous saturated sodium hydrogen carbonate to the reaction solution under ice cooling, which was then extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Reference Example 2 (900 mg). 
         [0169]    LCMS; [M+1H] + /Rt (min): Measurement Condition (306/0.18: A) 
       Reference Example 3 
     tert-Butyl 4-(5-cyano-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (Reference Example 3 
       [0170]    
       
                 
         
             
             
         
       
     
       a) Preparation of tert-butyl 4-(5-formyl-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (Compound cmp-2) 
       [0171]    To a solution of 40% aqueous glyoxal solution (1.52 g) in dimethylformamide (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (2.8 g) at room temperature, and the mixture was stirred at room temperature for 8 hours, and then thereto were added (1-phenyl-1-tosyl)methylisocyanide (2 g) and potassium carbonate (2.41 g), and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by adding 1 mol/L hydrochloric acid to the reaction solution, which was then extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Compound cmp-2 (549 mg). 
         [0172]    LCMS; [M+H] + /Rt (min): Measurement Condition (356/1.58: B) 
       b) Preparation of tert-butyl 4-(5-cyano-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (Reference Example 3) 
       [0173]    To an aqueous solution (10 ml) of hydroxylamine hydrochloride (754 mg) was added sodium hydrogen carbonate (916 mg) at room temperature, and then thereto was added a solution of Compound cmp-2 (549 mg) in ethanol (5 ml), and the mixture was stirred at room temperature for 15 hours. Then, the precipitated solid was collected on a filter and washed with water, and then dried at 60° C. to give a solid (298 mg). Then, thereto was added acetic anhydride (15 ml) at room temperature, and the mixture was stirred under reflux for 15 hours. The reaction solution was concentrated under reduced pressure, and then extracted with chloroform, and the organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Reference Example 3 (254 mg). 
         [0174]      1 H-NMR (300 MHz, CDCl 3 ) δ: 8.03-7.99 (m, 2H), 7.69 (s, 1H), 7.50-7.40 (m, 3H), 4.38-4.24 (m, 3H), 2.94-2.86 (m, 2H), 2.24-2.20 (m, 2H), 2.01-1.88 (m, 2H), 1.49 (s, 9H). 
       Reference Example 4 
     tert-Butyl 4-(5-fluoro-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (Reference Example 4) 
       [0175]    
       
                 
         
             
             
         
       
     
         [0176]    A solution of tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (250 mg) obtained in a similar manner to Reference Example 1 in tetrahydrofuran (5 ml) was cooled to −78° C., and then thereto was added n-butyllithium/hexane solution (2.69 mol/l: 0.30 ml), and the mixture was stirred at −78° C. for 20 minutes. Then, to the reaction mixture was added a solution of tert-butyldimethylchlorosilane (121 mg) in tetrahydrofuran (5 ml) dropwise at −78° C., and then the mixture was warmed to room temperature and stirred for 4 hours. The mixture was cooled again to −78° C., and then thereto was added n-butyllithium/hexane solution (2.69 mol/l: 0.30 ml), and the mixture was stirred at −78° C. for 1 hour. Then, to the reaction mixture was added a solution of N-fluorobenzenesulfonimide (252 mg) in tetrahydrofuran (5 ml) at −78° C., and then the mixture was stirred at −78° C. for 1 hour and at room temperature for 1 hour. The reaction was quenched by adding 1 mol/L hydrochloric acid to the reaction solution under ice cooling, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Reference Example 4 (18 mg). 
         [0177]      1 H-NMR (300 MHz, CDCl 3 ) δ: 7.78-7.76 (m, 2H), 7.43-7.38 (m, 2H), 7.30 (s, 1H), 7.27-7.22 (m, 1H), 4.35-4.31 (m, 2H), 4.1.4-4.03 (m, 1H), 2.90-2.82 (m, 2H), 2.13-2.08 (m, 2H), 1.96-1.83 (m, 211), 1.49 (s, 9H). 
       Reference Example 5 
     tert-Butyl 4-(2-fluoro-4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (Reference Example 5) 
       [0178]    
       
                 
         
             
             
         
       
     
         [0179]    A solution of tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (160 mg) obtained in a similar manner to Reference Example 1 in tetrahydrofuran (5 ml) was cooled to −78° C., and then n-butyllithium/hexane solution (2.69 mol/l: 0.19 ml) was added thereto, and the mixture was stirred at −78° C. for 30 minutes. Then, to the mixture was added a solution of N-fluorobenzenesulfonimide (161 mg) in tetrahydrofuran (5 ml) dropwise at −78° C., and then the mixture was stirred at −78° C. for 1 hour and at room temperature for 15 hours. The reaction was quenched by adding aqueous saturated ammonium chloride to the reaction solution under ice cooling, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Reference Example 5 (10 mg). 
         [0180]      1 H-NMR (300 MHz, CDCl 3 ) δ: 7.90-7.76 (m, 2H), 7.42-7.36 (m, 3H), 7.23 (s, 1H), 4.35-4.31 (m, 2H), 4.13-4.02 (m, 1H), 2.90-2.82 (m, 2H), 2.13-2.09 (m, 2H), 1.96-1.82 (m, 2H), 1.49 (s, 9H). 
       Reference Example 6 
     cis-4-(4-Phenyl-1H-imidazol-1-yl)cyclohexanecarboxylic acid (Reference Example 6) 
       [0181]    
       
                 
         
             
             
         
       
     
         [0182]    To a solution of methyl cis-4-(4-phenyl-11H-imidazol-1-yl)cyclohexanecarboxylate (280 mg) obtained in a similar manner to Reference Example 1 in methanol/tetrahydrofuran (2.5 ml/5 ml) was added 2 mol/1 aqueous sodium hydroxide (2.5 ml) at room temperature, and then the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and then to the resulting residue were added chloroform and 1 mol/1 hydrochloric acid. The mixture was extracted with chloroform five times, and then the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give Reference Example 6 (146 mg). 
         [0183]    LCMS; [M+H] + /Rt (min): Measurement Condition (271/0.39: B) 
       Example 1 
     N-Cyclohexyl-4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 1) 
       [0184]    
       
                 
         
             
             
         
       
     
       a) Preparation of 4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine hydrochloride (Compound cmp-3) 
       [0185]    To Reference Example 1 (5.63 g) was added 4 mol/L hydrogen chloride/ethyl acetate solution (50 ml) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to give Compound cmp-3 (4.06 g). 
         [0186]    LCMS; [M+H] + /Rt (min): Measurement Condition (246/0.18: A) 
       b) Preparation of N-cyclohexyl-4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 1) 
       [0187]    To a solution of Compound cmp-3 (1 g) in tetrahydrofuran (15 ml) were added cyclohexyl isocyanate (0.48 ml) and triethylamine (1.3 ml) at room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Example 1 (960 mg). 
         [0188]    LCMS; [M+H] + /Rt (min): Measurement Condition (371/0.63: A) 
         [0189]      1 H-NMR (400 MHz, MeOD) δ: 7.62 (s, 1H), 7.52-7.45 (m, 2H), 7.33 (s, 1H), 6.93 (s, 1H), 6.73 (s, 1H), 4.36 (s, 1H), 4.15-4.11 (m, 3H), 3.67 (s, 1H), 2.96-2.89 (m, 2H), 2.15-2.13 (m, 2H), 1.97-1.90 (m, 2H), 1.71-1.62 (m, 41H), 1.40-1.37 (m, 2H), 1.14-1.11 (m, 4H) 
       Example 2 
     N-(Bicyclo[2.2.1]hept-2-yl)-4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide Example 2) 
       [0190]    
       
                 
         
             
             
         
       
     
         [0191]    To a solution of exo-2-aminonorbornene (0.027 ml) in tetrahydrofuran (0.5 ml) were added triphosgene (27 mg) and triethylamine (0.064 ml) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Then, to the reaction mixture were added a solution of Compound cmp-3 (53 mg) in tetrahydrofuran (0.5 ml) and triethylamine (0.082 ml) under ice cooling, followed by adding a small amount of water thereto so as to be homogenized, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give Example 2 (14 mg). 
         [0192]    LCMS; [M+H] + /Rt (min): Measurement Condition (383/0.65: A) 
       Example 3 
     4-[4-(3-Fluorophenyl)-1H-imidazol-1-yl]-N-[trans-4-(trifluoromethyl)cyclohexyl]piperidine-1-carboxamide (Example 3) 
       [0193]    
       
                 
         
             
             
         
       
     
         [0194]    To a solution of trans-4-trifluoromethylcyclohexanecarboxylic acid (0.045 ml) in toluene (5 ml) were added diphenylphosphoryl azide (0.137 ml) and triethylamine (0.096 ml), and the mixture was stirred for 3 hours with heating at 95° C. Then, the mixture was cooled to room temperature, and thereto were added a solution of Compound cmp-3 (53 mg) in tetrahydrofuran and triethylamine (0.082 ml), followed by adding a small amount of water so as to be homogenized, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give Example 3 (22 mg). 
         [0195]    LCMS; [M+H] + /Rt (min): Measurement Condition (439/0.70: A) 
       Example 4 
     N-(trans-4-Methoxycyclohexyl)-4-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}piperidine-1-carboxamide (Example 4) 
       [0196]    
       
                 
         
             
             
         
       
     
         [0197]    To a solution of 4-{4-[4-(trifluoromethyl)phenyl]-1H-imidazol-1-yl}piperidine hydrochloride (200 mg) obtained in a similar manner to Reference Example 1, Example 1a) in dimethylformamide (6 ml) were added diisopropylethylamine (0.47 ml) and phenyl(trans-4-methoxycyclohexyl)carbamate (136 mg) at room temperature, and the mixture was stirred for 60 hours with heating at 70° C. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Example 4 (11 mg). 
         [0198]    LCMS; [M+H] + /Rt (min): Measurement Condition (451/1.27: B) 
       Example 5 
     N-tert-Butyl-4-[5-chloro-4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (Example 5) 
       [0199]    
       
                 
         
             
             
         
       
     
         [0200]    To a solution of N-tert-butyl-4-[4-(3-fluorophenyl)-1H-imidazol-1-yl]piperidine-1-carboxamide (48 mg) obtained in a similar manner to Example 1 in methylene chloride (3 ml) were added N-chlorosuccinimide (29 mg) and trifluoroacetic acid (0.06 ml) at room temperature, and then the mixture was heated to reflux at 50° C. for 40 hours. The reaction was quenched by adding aqueous saturated sodium hydrogen carbonate to the reaction solution under ice cooling, which was then extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Example 5 (9 mg). 
         [0201]    LCMS; [M+H] + /Rt (min): Measurement Condition (379/1.59: B) 
         [0202]      1 H-NMR (300 MHz, CDCl 3 ) δ: 7.76-7.73 (m, 1H), 7.70-7.65 (m, 1H), 7.61 (s, 1H), 7.41-7.34 (m, 1H), 7.02-6.98 (m, 1H), 4.37 (brs, 1H), 4.26-4.09 (m, 3H), 2.96-2.87 (m, 2H), 2.18-2.13 (m, 2H), 1.96-1.83 (m, 2H), 1.38 (s, 9H). 
       Example 6 
     [4-(4-Phenyl-1H-imidazol-1-yl)piperidin-1-yl](4,4-difluorocyclohexyl)methanone (Example 6) 
       [0203]    
       
                 
         
             
             
         
       
     
         [0204]    To a solution of 4-(4-phenyl-1H-imidazol-1-yl)piperidine dihydrochloride (300 mg) obtained in a similar manner to Reference Example 1, Example 1a) in methylene chloride (10 ml) were added 4,4-difluorocyclohexylcarboxylic acid (246 mg) and diisopropylethylamine (0.87 ml), HBTU (569 mg) at room temperature, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Example 6 (370 mg). 
         [0205]    LCMS; [M+H] + /Rt (min): Measurement Condition (374/0.54: A) 
       Example 7 
     1-{1-[(4,4-Difluorocyclohexyl)carbonyl]piperidin-4-yl}-4-phenyl-1H-imidazole-5-carbonitrile (Example 7) 
       [0206]    
       
                 
         
             
             
         
       
     
         [0207]    To a solution of Example 6 (370 mg) in methylene chloride (12 ml) were added N-iodosuccinimide (391 mg) and trifluoroacetic acid (0.52 ml) at room temperature, and then the mixture was stirred at room temperature under protecting from light for 18 hours. The reaction was quenched by adding aqueous sodium thiosulfate to the reaction solution, which was then extracted with chloroform. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, and then to the residue were added dimethylformamide (6 ml), copper iodide (67 mg), and potassium cyanide (113 mg) at room temperature, and the mixture was stirred for 15 hours with heating at 150° C. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Example 7 (269 mg). 
         [0208]    LCMS; [M+H] + /Rt (min): Measurement Condition (399/1.49: B) 
         [0209]      1 H-NMR (300 MHz, CDCl 3 ) δ: 8.03-7.99 (m, 2H), 7.68 (s, 1H), 7.50-7.38 (m, 3H), 4.92-4.89 (m, 1H), 4.41-4.36 (m, 1H), 4.11-4.07 (m, 1H), 3.30-3.26 (m, 1H), 2.69-2.60 (m, 2H), 2.30-1.67 (m, 12H). 
       Example 8 
     2-Fluoro-N-{cis-4-[4-(4-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}-2-methylpropanamide (Example 8) 
       [0210]    
       
                 
         
             
             
         
       
     
         [0211]    To a solution of tert-butyl {cis-4-[4-(4-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}carbamate (2.89 g) obtained in a similar manner to Reference Example 1 in methanol (20 ml) was added 4 mol/L hydrogen chloride/dioxane solution (5 m) at room temperature, and then the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and then to the residue were added dichloromethane (40.2 ml), diisopropylethylamine (7.00 ml), HBTU (4.57 g), and 2-fluoro-2-methylpropionic acid (1.28 g) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and then the resulting residue was purified by aminosilica gel column chromatography (Eluting solvent; hexane:chloroform=20:80 to 0:100) to give Example 8 (2.86 g). 
         [0212]      1 H-NMR (400 MHz, CDCl 3 ) δ: 7.70 (dd, J=9, 5.5 Hz, 2H), 7.56 (s, 1H), 7.19 (s, 1H), 7.03 (t, J=9 Hz, 2H), 6.46 (br, 1H), 4.00-4.12 (m, 2H), 2.01-2.10 (m, 2H), 1.74-1.98 (m, 6H), 1.58 (s, 3H), 1.52 (s, 3H). 
       Example 9 
     cis-N-Cyclohexyl-4-(4-phenyl-1H-imidazol-1-yl)cyclohexanecarboxamide (Example 9) 
       [0213]    
       
                 
         
             
             
         
       
     
         [0214]    To a solution of Reference Example 6 (49 mg) in dimethylformamide (3 ml) were added cyclohexylamine (41 mg), WSC.HCl (69 mg), HOBt (49 mg), and triethylamine (0.15 ml) at room temperature, and then the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (Eluting solvent; chloroform:methanol=100:0 to 90:10) to give Example 9 (23 mg). 
         [0215]      1 H-NMR (300 MHz, CDCl 3 ) δ: 7.78-7.75 (m, 2H), 7.59-7.58 (m, 1H), 7.39-7.19 (m, 4H), 5.35-5.32 (m, 1H), 4.06-3.97 (m, 1H), 3.84-3.73 (m, 1H), 2.44-2.42 (m, 1H), 2.31-2.18 (m, 2H), 2.13-1.06 (m, 16H). 
       Examples 10 to 137 
       [0216]    Compounds listed in Table 1 were obtained by using corresponding starting compounds according to the methods of Reference Examples 1 to 5 and Examples 1 to 5 or 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                   
                 (min): Measurement 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 2B   
                 R 4A   
                 Condition 
               
               
                   
               
             
          
           
               
                 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.58: A 
               
               
                   
               
               
                 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403/0.65: A 
               
               
                   
               
               
                 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401/0.54: A 
               
               
                   
               
               
                 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379/0.56: A 
               
               
                   
               
               
                 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.58: A 
               
               
                   
               
               
                 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371/0.60: A 
               
               
                   
               
               
                 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/0.57: A 
               
               
                   
               
               
                 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.60: A 
               
               
                   
               
               
                 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.60: A 
               
               
                   
               
               
                 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 402/0.61: A 
               
               
                   
               
               
                 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387/0.67: A 
               
               
                   
               
               
                 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 399/0.64: A 
               
               
                   
               
               
                 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/0.65: A 
               
               
                   
               
               
                 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421/0.78: A 
               
               
                   
               
               
                 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433/0.75: A 
               
               
                   
               
               
                 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/0.75: A 
               
               
                   
               
               
                 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.69: A 
               
               
                   
               
               
                 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401/0.66: A 
               
               
                   
               
               
                 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425/0.67: A 
               
               
                   
               
               
                 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/0.59: A 
               
               
                   
               
               
                 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357/0.61: A 
               
               
                   
               
               
                 31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357/0.61: A 
               
               
                   
               
               
                 32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/0.64: A 
               
               
                   
               
               
                 33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401/0.51: A 
               
               
                   
               
               
                 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.76: A 
               
               
                   
               
               
                 35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 425/0.74: A 
               
               
                   
               
               
                 36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 339/0.50: A 
               
               
                   
               
               
                 37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 353/0.54: A 
               
               
                   
               
               
                 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 365/0.57: A 
               
               
                   
               
               
                 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.53: A 
               
               
                   
               
               
                 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383/0.48: A 
               
               
                   
               
               
                 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421/0.62: A 
               
               
                   
               
               
                 42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421/0.61: A 
               
               
                   
               
               
                 43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 395/0.56: A 
               
               
                   
               
               
                 44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431/0.54: A 
               
               
                   
               
               
                 45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/0.68: A 
               
               
                   
               
               
                 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/0.70: A 
               
               
                   
               
               
                 47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439/0.69: A 
               
               
                   
               
               
                 48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.53: A 
               
               
                   
               
               
                 49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.53: A 
               
               
                   
               
               
                 50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/0.59: A 
               
               
                   
               
               
                 51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.60: A 
               
               
                   
               
               
                 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/0.66, 0.67: A 
               
               
                   
               
               
                 53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419 /0.67: A 
               
               
                   
               
               
                 54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419/0.64: A 
               
               
                   
               
               
                 55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/0.61: A 
               
               
                   
               
               
                 56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431/0.69: A 
               
               
                   
               
               
                 57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431/0.66: A 
               
               
                   
               
               
                 58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409/0.62: A 
               
               
                   
               
               
                 59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455/0.66: A 
               
               
                   
               
               
                 60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 455/0.62: A 
               
               
                   
               
               
                 61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433/0.59: A 
               
               
                   
               
               
                 62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 328/2.68: C 
               
               
                   
               
               
                 63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345/0.55: B 
               
               
                   
               
               
                 64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345/0.67: B 
               
               
                   
               
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401/0.77: B 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371/1.30: B 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345/0.80: B 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 401/0.61: B 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.20: B 
               
               
                   
               
               
                 70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357/0.65: A 
               
               
                   
               
               
                 71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383/0.66: A 
               
               
                   
               
               
                 72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417/0.73: A 
               
               
                   
               
               
                 73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387/0.93: A 
               
               
                   
               
               
                 74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403/0.59: A 
               
               
                   
               
               
                 75 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 453/0.88: A 
               
               
                   
               
               
                 76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/0.88: A 
               
               
                   
               
               
                 77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/0.91: A 
               
               
                   
               
               
                 78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417/0.83: A 
               
               
                   
               
               
                 79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359/0.52: A 
               
               
                   
               
               
                 80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/0.94: A 
               
               
                   
               
               
                 81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405/0.97: A 
               
               
                   
               
               
                 82 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/0.86: A 
               
               
                   
               
               
                 83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/0.97: A 
               
               
                   
               
               
                 84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405/1.03: A 
               
               
                   
               
               
                 85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362/3.58: C 
               
               
                   
               
               
                 86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379/1.63: B 
               
               
                   
               
               
                 87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/1.55: B 
               
               
                   
               
               
                 88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 447/1.52: B 
               
               
                   
               
               
                 89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417/1.43: B 
               
               
                   
               
               
                 90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/1.51: B 
               
               
                   
               
               
                 91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 405/1.63: B 
               
               
                   
               
               
                 92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379/1.47: B 
               
               
                   
               
               
                 93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/1.64: B 
               
               
                   
               
               
                 94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/1.63: B 
               
               
                   
               
               
                 95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/1.56: B 
               
               
                   
               
               
                 96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/1.68: B 
               
               
                   
               
               
                 97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/1.67: B 
               
               
                   
               
               
                 98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379/4.36: C 
               
               
                   
               
               
                 99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414/0.87: A 
               
               
                   
               
               
                 100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352/1.50: C 
               
               
                   
               
               
                 101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Br 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/0.92: A 
               
               
                   
               
               
                 102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.53: A 
               
               
                   
               
               
                 103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Et 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 381/0.88: A 
               
               
                   
               
               
                 104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Br 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 468/0.89: A 
               
               
                   
               
               
                 105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403/0.51: A 
               
               
                   
               
               
                 106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 F 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372/3.89: C 
               
               
                   
               
               
                 107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438/2.93: C 
               
               
                   
               
               
                 108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393/0.63: B 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.41: B 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 383/0.54: B 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 357/0.40: B 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/0.76: B 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429/0.54: B 
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 367/0.56: A 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 F 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371/3.90: C 
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387/4.37:C 
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 393/0.80: A 
               
               
                   
               
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429/0.77: A 
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388/0.66: A 
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/0.66: A 
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 345/0.55: A 
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359/0.59: A 
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359/0.61: A 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/0.65: A 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 395/0.58: A 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409/0.62: A 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/0.51: A 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 403/0.55: A 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359/0.52: A 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394/0.64: A 
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/0.79: A 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 354/0.85: B 
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 354/0.58: B 
               
               
                   
               
               
                 134 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388/1.07: B 
               
               
                   
               
               
                 135 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388/1.25: B 
               
               
                   
               
               
                 136 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/0.73: B 
               
               
                   
               
               
                 137 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/0.98: B 
               
               
                   
               
             
          
         
       
     
       Examples 138 to 160 
       [0217]    Compounds listed in Table 2 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 3, and Examples 5 to 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                 (min): Measurement 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Condition 
               
               
                   
               
               
                 138 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442/0.78: A 
               
               
                   
               
               
                 139 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410/0.68: A 
               
               
                   
               
               
                 140 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387/0.57: A 
               
               
                   
               
               
                 141 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/0.58: A 
               
               
                   
               
               
                 142 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 368/0.47, 0.49: A 
               
               
                   
               
               
                 143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/0.64: A 
               
               
                   
               
               
                 144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/0.63: A 
               
               
                   
               
               
                 145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440/0.68: A 
               
               
                   
               
               
                 146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440/0.68: A 
               
               
                   
               
               
                 147 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418/0.60: A 
               
               
                   
               
               
                 148 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 438/0.91: A 
               
               
                   
               
               
                 149 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426/0.98: A 
               
               
                   
               
               
                 150 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/0.86: A 
               
               
                   
               
               
                 151 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/0.80: A 
               
               
                   
               
               
                 152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 408/0.95: A 
               
               
                   
               
               
                 153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 363/1.62: B 
               
               
                   
               
               
                 154 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417/1.57: B 
               
               
                   
               
               
                 155 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417/1.47: B 
               
               
                   
               
               
                 156 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 417/1.31: B 
               
               
                   
               
               
                 157 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 467/1.69: B 
               
               
                   
               
               
                 158 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 467/1.62: B 
               
               
                   
               
               
                 159 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433/1.64: B 
               
               
                   
               
               
                 160 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433/1.59: B 
               
               
                   
               
             
          
         
       
     
       Examples 161 to 203 
       [0218]    Compounds listed in Table 3 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 5, and Example 5, 7 or 8. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                 (min): Measurement 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Condition 
               
               
                   
               
               
                 161 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394/0.76: A 
               
               
                   
               
               
                 162 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 456/0.77: A 
               
               
                   
               
               
                 163 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 488/0.87: A 
               
               
                   
               
               
                 164 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 327/2.96: C 
               
               
                   
               
               
                 165 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 353/3.32: C 
               
               
                   
               
               
                 166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/1.20: C 
               
               
                   
               
               
                 167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360/3.84: C 
               
               
                   
               
               
                 168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386/4.19: C 
               
               
                   
               
               
                 169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/3.40: C 
               
               
                   
               
               
                 170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372/1.75: B 
               
               
                   
               
               
                 171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358/1.60: B 
               
               
                   
               
               
                 172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364/1.64: B 
               
               
                   
               
               
                 173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416/1.68: B 
               
               
                   
               
               
                 174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412/1.69: B 
               
               
                   
               
               
                 175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382/1.70: B 
               
               
                   
               
               
                 176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376/0.99: A 
               
               
                   
               
               
                 177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390/1.05: A 
               
               
                   
               
               
                 178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428/1.74: B 
               
               
                   
               
               
                 179 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/1.00: A 
               
               
                   
               
               
                 180 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.05: A 
               
               
                   
               
               
                 181 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 376/0.96: A 
               
               
                   
               
               
                 182 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390/1.01: A 
               
               
                   
               
               
                 183 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382/1.65: B 
               
               
                   
               
               
                 184 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 416/1.71: B 
               
               
                   
               
               
                 185 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382/0.91: A 
               
               
                   
               
               
                 186 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 412/0.99: A 
               
               
                   
               
               
                 187 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434/0.94: A 
               
               
                   
               
               
                 188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394/1.68: B 
               
               
                   
               
               
                 189 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434/1.62: B 
               
               
                   
               
               
                 190 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 464/1.70: B 
               
               
                   
               
               
                 191 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/1.68: B 
               
               
                   
               
               
                 192 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440/1.74: B 
               
               
                   
               
               
                 193 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/1.83: B 
               
               
                   
               
               
                 194 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/1.84: B 
               
               
                   
               
               
                 195 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426/1.86: B 
               
               
                   
               
               
                 196 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 426/1.91: B 
               
               
                   
               
               
                 197 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 355/1.52: B 
               
               
                   
               
               
                 198 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 349/1.54: B 
               
               
                   
               
               
                 199 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419/1.80: B 
               
               
                   
               
               
                 200 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419/1.79: B 
               
               
                   
               
               
                 201 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/1.73: B 
               
               
                   
               
               
                 202 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/1.68: B 
               
               
                   
               
               
                 203 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/1.54: B 
               
               
                   
               
             
          
         
       
     
       Examples 204 to 207 
       [0219]    Compounds listed in Table 4 were obtained by using corresponding starting compounds according to the methods of Reference Example 1, and Example 5 or 8. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; 
               
               
                   
                   
                   
                   
                 [M + H] + /Rt 
               
               
                   
                   
                   
                   
                 (min):  
               
               
                 Ex- 
                   
                   
                   
                 Measurement 
               
               
                 ample 
                 R 1   
                 R 2A   
                 R 5   
                 Condition 
               
               
                   
               
               
                 204 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352/0.75: B 
               
               
                   
               
               
                 205 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 388/0.47: B 
               
               
                   
               
               
                 206 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386/1.75: B 
               
               
                   
               
               
                 207 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/1.60: B 
               
               
                   
               
             
          
         
       
     
       Examples 208 to 230 
       [0220]    Compounds listed in Table 5 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 6, and Example 5, 7 or 9. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                   
                 (min): Measurement 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 R 4B   
                 Condition 
               
               
                   
               
               
                 208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 366/0.64: A 
               
               
                   
               
               
                 209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 370/0.62: A 
               
               
                   
               
               
                 210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 344/0.56: A 
               
               
                   
               
               
                 211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 372/0.46: A 
               
               
                   
               
               
                 212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 406/0.59: A 
               
               
                   
               
             
          
           
               
                 213 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/0.57: A 
               
               
                   
               
             
          
           
               
                 214 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 456/0.72: A 
               
               
                   
               
             
          
           
               
                 215 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442/0.73: A 
               
               
                   
               
             
          
           
               
                 216 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 388/0.84: B 
               
               
                   
               
               
                 217 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 360/0.92: A 
               
               
                   
               
               
                 218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 386/4.02: C 
               
               
                   
               
               
                 219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 434/1.64: B 
               
               
                   
               
               
                 220 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 416/1.58: B 
               
               
                   
               
               
                 221 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 388/1.48: B 
               
               
                   
               
               
                 222 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 386/1.55: B 
               
               
                   
               
               
                 223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 484/1.85: B 
               
               
                   
               
               
                 224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 456/1.74: B 
               
               
                   
               
               
                 225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 484/1.81:B 
               
               
                   
               
               
                 226 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 456/1.72: B 
               
               
                   
               
               
                 227 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 406/1.55: B 
               
               
                   
               
               
                 228 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 351/1.59: B 
               
               
                   
               
               
                 229 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 377/1.66: B 
               
               
                   
               
               
                 230 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 413/1.56: B 
               
               
                   
               
             
          
         
       
     
       Examples 231 to 234 
       [0221]    Compounds listed in Table 6 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 6, and Example 5 or 9. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 Measurement Condition 
               
               
                   
               
               
                 231 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352/0.60:B 
               
               
                   
               
               
                 232 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 326/0.50:B 
               
               
                   
               
               
                 233 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386/1.78:B 
               
               
                   
               
               
                 234 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360/1.66:B 
               
               
                   
               
             
          
         
       
     
       Example 235 
     N-[cis-4-(4-Phenyl-1H-imidazol-1-yl)cyclohexyl]-6-(trifluoromethyl)pyrimidin-4-amine (Example 235) 
       [0222]    
       
                 
         
             
             
         
       
     
         [0223]    To a solution of cis-4-(4-phenyl-1H-imidazol-1yl)cyclohexaneamine hydrochloride (55 mg) obtained in a similar manner to Reference Example 1, Example 1a) and diisopropylethylamine (122 μl) in NMP (2 ml) was added 4-chloro-6-trifluoromethylpyrimidine (35 mg), and the mixture was stirred at 50° C. for 4 hours. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (80 ml×twice). The organic layer was dried over anhydrous magnesium sulfate, and then passed through a filter, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (Eluting solution: hexane/ethyl acetate=50:50 to 0:100) to give the titled compound 39 mg. 
         [0224]    LCMS; [M+H] + /Rt (min): Measurement Condition (388/0.62: A) 
         [0225]      1 H-NMR (CDCl 3 ) δ: 1.71-2.37 (8H, m), 3.20-3.54 (1H, m), 3.85-4.42 (1H, m), 5.58-5.89 (1H, m), 6.65 (1H, s), 7.09-7.39 (3H, m), 7.53 (1H, s), 7.60-7.80 (3H, m), 8.61 (1H, s) 
       Examples 236 to 239 
       [0226]    Compounds listed in Table 7 were obtained by using corresponding starting compounds according to the method of Example 235. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 LCMS; [M + H] + / 
               
               
                   
                   
                   
                 Rt (min): 
               
               
                   
                   
                   
                 Measurement  
               
               
                 Example 
                 R 1   
                 R 2A   
                 Condition 
               
               
                   
               
               
                 236 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 407/0.65:A 
               
               
                   
               
               
                 237 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 440/0.81:A 
               
               
                   
               
               
                 238 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 432/1.12:A 
               
               
                   
               
               
                 239 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 420/0.74:A 
               
               
                   
               
             
          
         
       
     
       Examples 240 and 241 
       [0227]    Compounds listed in Table 8 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 and Examples 1 to 5. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 Measurement Condition 
               
               
                   
               
               
                 240 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/1.14:B 
               
               
                   
               
               
                 241 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 419/1.90:B 
               
               
                   
               
             
          
         
       
     
       Examples 242 to 243 
       [0228]    Compounds listed in Table 9 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 and Example 5 or 6. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Measurement Condition 
               
               
                   
               
               
                 242 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/1.18:B 
               
               
                   
               
               
                 243 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 440/1.79:B 
               
               
                   
               
             
          
         
       
     
       Examples 244 to 259 
       [0229]    Compounds listed in Table 10 were obtained by using corresponding starting compounds according to the methods of Reference Examples 1 to 5 and Examples 1 to 5 or 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                 (min):Measurement 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 Condition 
               
               
                   
               
               
                 244 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/0.54:B 
               
               
                   
               
               
                 245 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/0.52:B 
               
               
                   
               
               
                 246 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/1.47:B 
               
               
                   
               
               
                 247 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 423/1.41:B 
               
               
                   
               
               
                 248 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/1.30:B 
               
               
                   
               
               
                 249 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/1.19:B 
               
               
                   
               
               
                 250 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441/1.71:B 
               
               
                   
               
               
                 251 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 441/1.62:B 
               
               
                   
               
               
                 252 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/1.38:B 
               
               
                   
               
               
                 253 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 407/1.58:B 
               
               
                   
               
               
                 254 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 408/1.08:B 
               
               
                   
               
               
                 255 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 396/0.98:A 
               
               
                   
               
               
                 256 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 421/1.10:B 
               
               
                   
               
               
                 257 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359/0.96:B 
               
               
                   
               
               
                 258 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/1.25:B 
               
               
                   
               
               
                 259 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 387/0.45:B 
               
               
                   
               
             
          
         
       
     
       Examples 260 to 276 
       [0230]    Compounds listed in Table 11 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 3 and Examples 5 to 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                 (min):Measurement 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Condition 
               
               
                   
               
               
                 260 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 334/1.11:B 
               
               
                   
               
               
                 261 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/1.42:B 
               
               
                   
               
               
                 262 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 442/1.60:B 
               
               
                   
               
               
                 263 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 368/1.78:B 
               
               
                   
               
               
                 264 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 408/1.69:B 
               
               
                   
               
               
                 265 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 429/0.97:A 
               
               
                   
               
               
                 266 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 359/1.81:B 
               
               
                   
               
               
                 267 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/1.72:B 
               
               
                   
               
               
                 268 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 371/1.40:B 
               
               
                   
               
               
                 269 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/1.45:B 
               
               
                   
               
               
                 270 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/1.20:B 
               
               
                   
               
               
                 271 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/1.60:B 
               
               
                   
               
               
                 272 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/0.92:B 
               
               
                   
               
               
                 273 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/1.77:B 
               
               
                   
               
               
                 274 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 435/2.05:B 
               
               
                   
               
               
                 275 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/1.04:B 
               
               
                   
               
               
                 276 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372/0.45:B 
               
               
                   
               
             
          
         
       
     
       Examples 277 to 354 
       [0231]    Compounds listed in Table 12 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 and Example 5, 7 or 8. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt 
               
               
                   
                   
                   
                   
                 (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Measurement Condition 
               
               
                   
               
               
                 277 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348/1.23:B 
               
               
                   
               
               
                 278 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414/1.46:B 
               
               
                   
               
               
                 279 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 410/0.86:B 
               
               
                   
               
               
                 280 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364/0.96:B 
               
               
                   
               
               
                 281 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360/0.94:B 
               
               
                   
               
               
                 282 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372/0.52:B 
               
               
                   
               
               
                 283 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382/1.43:B 
               
               
                   
               
               
                 284 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382/0.97:B 
               
               
                   
               
               
                 285 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 360/0.51:B 
               
               
                   
               
               
                 286 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364/0.95:B 
               
               
                   
               
               
                 287 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378/0.53:B 
               
               
                   
               
               
                 288 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 352/0.51:B 
               
               
                   
               
               
                 289 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 338/0.43:B 
               
               
                   
               
               
                 290 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 398/0.65:B 
               
               
                   
               
               
                 291 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 368/0.66:B 
               
               
                   
               
               
                 292 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 354/0.49:B 
               
               
                   
               
               
                 293 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414/1.02:B 
               
               
                   
               
               
                 294 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348/0.57:B 
               
               
                   
               
               
                 295 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/1.15:B 
               
               
                   
               
               
                 296 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/1.14:B 
               
               
                   
               
               
                 297 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 348/0.50:B 
               
               
                   
               
               
                 298 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414/0.92:B 
               
               
                   
               
               
                 299 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/0.92:B 
               
               
                   
               
               
                 300 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/0.59:B 
               
               
                   
               
               
                 301 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/0.62:B 
               
               
                   
               
               
                 302 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/0.73:B 
               
               
                   
               
               
                 303 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/1.23:B 
               
               
                   
               
               
                 304 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 432/1.26:B 
               
               
                   
               
               
                 305 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 364/0.55:B 
               
               
                   
               
               
                 306 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 382/0.94:B 
               
               
                   
               
               
                 307 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378/0.88:B 
               
               
                   
               
               
                 308 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394/0.61:B 
               
               
                   
               
               
                 309 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394/0.68:B 
               
               
                   
               
               
                 310 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/1.59:D 
               
               
                   
               
               
                 311 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 414/1.60:D 
               
               
                   
               
               
                 312 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384/1.57:D 
               
               
                   
               
               
                 313 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384/1.53:D 
               
               
                   
               
               
                 314 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 384/1.44:D 
               
               
                   
               
               
                 315 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 366/1.33:D 
               
               
                   
               
               
                 316 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400/1.68:D 
               
               
                   
               
               
                 317 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400/1.55:D 
               
               
                   
               
               
                 318 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400/1.62:D 
               
               
                   
               
               
                 319 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 396/1.41:D 
               
               
                   
               
               
                 320 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448/1.89:B 
               
               
                   
               
               
                 321 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 444/1.91:B 
               
               
                   
               
               
                 322 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 394/1.84:B 
               
               
                   
               
               
                 323 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/1.77:B 
               
               
                   
               
               
                 324 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466/1.96:B 
               
               
                   
               
               
                 325 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448/1.86:B 
               
               
                   
               
               
                 326 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400/1.47:B 
               
               
                   
               
               
                 327 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466/1.86:B 
               
               
                   
               
               
                 328 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466/1.80:B 
               
               
                   
               
               
                 329 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400/1.50:B 
               
               
                   
               
               
                 330 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 466/1.87:E 
               
               
                   
               
               
                 331 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 448/1.96:D 
               
               
                   
               
               
                 332 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/1.54:B 
               
               
                   
               
               
                 333 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 389/1.71:B 
               
               
                   
               
               
                 334 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 385/1.78:B 
               
               
                   
               
               
                 335 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431/1.91:B 
               
               
                   
               
               
                 336 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/1.41:B 
               
               
                   
               
               
                 337 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/1.13:E 
               
               
                   
               
               
                 338 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 373/1.56:E 
               
               
                   
               
               
                 339 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/2.11:D 
               
               
                   
               
               
                 340 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/2.12:D 
               
               
                   
               
               
                 341 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/2.11:D 
               
               
                   
               
               
                 342 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/2.19:D 
               
               
                   
               
               
                 343 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 391/2.28:D 
               
               
                   
               
               
                 344 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439/2.14:D 
               
               
                   
               
               
                 345 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439/1.87:E 
               
               
                   
               
               
                 346 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 439/2.36:D 
               
               
                   
               
               
                 347 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/2.36:D 
               
               
                   
               
               
                 348 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/1.77:E 
               
               
                   
               
               
                 349 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/2.37:D 
               
               
                   
               
               
                 350 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 457/1.75:E 
               
               
                   
               
               
                 351 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 362/1.07:B 
               
               
                   
               
               
                 352 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386/0.49:B 
               
               
                   
               
               
                 353 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 420/1.12:B 
               
               
                   
               
               
                 354 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 358/0.85:B 
               
               
                   
               
             
          
         
       
     
       Examples 355 to 381 
       [0232]    Compounds listed in Table 13 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 6 and Example 5, 7 or 9. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 Measurement Condition 
               
               
                   
               
               
                 355 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372/0.85:B 
               
               
                   
               
               
                 356 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 372/0.70:B 
               
               
                   
               
               
                 357 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390/1.10:B 
               
               
                   
               
               
                 358 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 390/1.10:B 
               
               
                   
               
               
                 359 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/0.68:B 
               
               
                   
               
               
                 360 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 406/0.67:B 
               
               
                   
               
               
                 361 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 428/1.43:B 
               
               
                   
               
               
                 362 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/1.70:B 
               
               
                   
               
               
                 363 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/1.74:B 
               
               
                   
               
               
                 364 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 378/1.76:B 
               
               
                   
               
               
                 365 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/1.76:B 
               
               
                   
               
               
                 366 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 392/1.77:B 
               
               
                   
               
               
                 367 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/1.83:B 
               
               
                   
               
               
                 368 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/1.81:B 
               
               
                   
               
               
                 369 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/2.00:B 
               
               
                   
               
               
                 370 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/1.80:B 
               
               
                   
               
               
                 371 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/1.68:B 
               
               
                   
               
               
                 372 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 472/1.95:B 
               
               
                   
               
               
                 373 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/1.41:B 
               
               
                   
               
               
                 374 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.66:B 
               
               
                   
               
               
                 375 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.65:B 
               
               
                   
               
               
                 376 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.86:B 
               
               
                   
               
               
                 377 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 447/1.92:B 
               
               
                   
               
               
                 378 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.80:B 
               
               
                   
               
               
                 379 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.62:B 
               
               
                   
               
               
                 380 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 463/1.72:B 
               
               
                   
               
               
                 381 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Me 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 386/0.83:B 
               
               
                   
               
             
          
         
       
     
       Examples 382 to 404 
       [0233]    Compounds listed in Table 14 were obtained by using corresponding starting compounds according to the methods of Reference Examples 1 to 5 and Examples 1 to 5 or 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 Measurement Condition 
               
               
                   
               
               
                 382 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/0.68:A 
               
               
                   
               
               
                 383 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379/1.30:B 
               
               
                   
               
               
                 384 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/0.76:B 
               
               
                   
               
               
                 385 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/2.13:F 
               
               
                   
               
               
                 386 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.90:G 
               
               
                   
               
               
                 387 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/2.16:F 
               
               
                   
               
               
                 388 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.60:D 
               
               
                   
               
               
                 389 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.65:D 
               
               
                   
               
               
                 390 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431/2.00:B 
               
               
                   
               
               
                 391 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 467/1.93:B 
               
               
                   
               
               
                 392 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 433/1.71:B 
               
               
                   
               
               
                 393 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413/0.72:B 
               
               
                   
               
               
                 394 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/1.57:B 
               
               
                   
               
               
                 395 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/2.13:F 
               
               
                   
               
               
                 396 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/2.02:D 
               
               
                   
               
               
                 397 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.69:D 
               
               
                   
               
               
                 398 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/1.95:D 
               
               
                   
               
               
                 399 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.63:G 
               
               
                   
               
               
                 400 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 458/1.63:B 
               
               
                   
               
               
                 401 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 424/1.39:B 
               
               
                   
               
               
                 402 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476/2.08:D 
               
               
                   
               
               
                 403 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476/1.47:E 
               
               
                   
               
               
                 404 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476/2.07:D 
               
               
                   
               
             
          
         
       
     
       Examples 405 to 424 
       [0234]    Compounds listed in Table 15 were obtained by using corresponding starting compounds according to the methods of Reference Examples 1 to 5 and Examples 1 to 5 or 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 4A   
                 Measurement Condition 
               
               
                   
               
               
                 405 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 397/0.67:A 
               
               
                   
               
               
                 406 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 379/1.32:A 
               
               
                   
               
               
                 407 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/0.70:B 
               
               
                   
               
               
                 408 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.00:B 
               
               
                   
               
               
                 409 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/2.09:B 
               
               
                   
               
               
                 410 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/2.15:B 
               
               
                   
               
               
                 411 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 415/1.66:D 
               
               
                   
               
               
                 412 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.60:D 
               
               
                   
               
               
                 413 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 431/1.97:B 
               
               
                   
               
               
                 414 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 413/0.72:B 
               
               
                   
               
               
                 415 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/1.98:D 
               
               
                   
               
               
                 416 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.71:D 
               
               
                   
               
               
                 417 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/2.04:D 
               
               
                   
               
               
                 418 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.77:D 
               
               
                   
               
               
                 419 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 485/2.03:D 
               
               
                   
               
               
                 420 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 451/1.75:D 
               
               
                   
               
               
                 421 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 422/1.97:B 
               
               
                   
               
               
                 422 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476/2.10:D 
               
               
                   
               
               
                 423 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476/1.46:E 
               
               
                   
               
               
                 424 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 476/1.86:G 
               
               
                   
               
             
          
         
       
     
       Examples 425 to 445 
       [0235]    Compounds listed in Table 16 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 3 and Examples 5 to 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Measurement Condition 
               
               
                   
               
               
                 425 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418/1.18:B 
               
               
                   
               
               
                 426 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.60:B 
               
               
                   
               
               
                 427 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418/1.25:B 
               
               
                   
               
               
                 428 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400 /1.13:B 
               
               
                   
               
               
                 429 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.91:G 
               
               
                   
               
               
                 430 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.63:D 
               
               
                   
               
               
                 431 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452/1.88:B 
               
               
                   
               
               
                 432 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470/1.88:B 
               
               
                   
               
               
                 433 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418/1.69:B 
               
               
                   
               
               
                 434 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452/1.74:B 
               
               
                   
               
               
                 435 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434/0.70:B 
               
               
                   
               
               
                 436 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/2.19:F 
               
               
                   
               
               
                 437 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470/2.01:D 
               
               
                   
               
               
                 438 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.74:D 
               
               
                   
               
               
                 439 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470/2.00:D 
               
               
                   
               
               
                 440 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.70:D 
               
               
                   
               
               
                 441 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 409/1.35:B 
               
               
                   
               
               
                 442 (TFA salt) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443/1.60:B 
               
               
                   
               
               
                 443 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461/2.17:D 
               
               
                   
               
               
                 444 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461/1.43:E 
               
               
                   
               
               
                 445 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461/1.91:G 
               
               
                   
               
             
          
         
       
     
       Examples 446 to 464 
       [0236]    Compounds listed in Table 17 were obtained by using corresponding starting compounds according to the methods of Reference Example 1 or 3 and Examples 5 to 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 LCMS; [M + H] + /Rt (min): 
               
               
                 Example 
                 R 1   
                 R 2A   
                 R 5   
                 Measurement Condition 
               
               
                   
               
               
                 446 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418/1.12:B 
               
               
                   
               
               
                 447 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.59:B 
               
               
                   
               
               
                 448 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 418/1.39:B 
               
               
                   
               
               
                 449 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 400/1.07:B 
               
               
                   
               
               
                 450 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/2.11:B 
               
               
                   
               
               
                 451 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.61:D 
               
               
                   
               
               
                 452 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452/1.80:B 
               
               
                   
               
               
                 453 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470/1.88:B 
               
               
                   
               
               
                 454 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 452/1.82:B 
               
               
                   
               
               
                 455 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 434/1.74:B 
               
               
                   
               
               
                 456 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.76:D 
               
               
                   
               
               
                 457 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470/2.09:D 
               
               
                   
               
               
                 458 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.83:D 
               
               
                   
               
               
                 459 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 470/2.08:D 
               
               
                   
               
               
                 460 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 Cl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 436/1.81:D 
               
               
                   
               
               
                 461 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 443/1.80:B 
               
               
                   
               
               
                 462 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461/2.13:D 
               
               
                   
               
               
                 463 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461/2.05:D 
               
               
                   
               
               
                 464 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CN 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 461/2.12:D 
               
               
                   
               
             
          
         
       
     
       Test Example 
       [0237]    Hereinafter, pharmacological test results of the representative compounds of the present invention are demonstrated and pharmacological actions of such compounds are explained, but the present invention should not be limited thereto. 
       Test Example 1 
     Evaluation of PAM activity with human α7 nACh receptor stably expressing cells 
       [0238]    (1) Human α7 nAChR stably expressing cells 
         [0239]    Human α7 nAChR stably expressing cells were generated and cultured. In particular, GH4C1 cells derived from rat pituitary (cat#CCL-82.2, ATCC, USA) were used as a host cell. pcDNA3.1Zeo vector containing a nucleotide sequence encoding a protein GenBank BAC81731 and pcDNA3.1 vector containing human α7 nAChR gene (cat#V790-20, invitrogen, Carlsbad, Calif., USA) were transfected to the cells to give aequorins and human α7 nAChR stably expressing cells. The aequorins and human α7 nAChR stably expressing cells were screened with Zeocin (cat#R25001, invitrogen, Carlsbad, Calif., USA) and Geneticin (cat#10131-027, invitrogen, Carlsbad, Calif., USA), respectively. 
         [0240]    The cells were cultured in F-10 Nutrient Mixture (Ham) medium (cat#11550-043, invitrogen, Carlsbad, Calif., USA) containing 2.5% fetal bovine serum (cat#2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat#26050-088, invitrogen, Carlsbad, Calif., USA), 1 μg/mL Geneticin, and 5 μg/mL Puromycin (cat#14861-84, invitrogen, Carlsbad, Calif., USA), in a Collagen Type 1-coated dish (cat#4030-010, iwaki, Tokyo, Japan). During the culture, the medium was replaced with fresh medium in every 2 to 3 days, and the cells were treated with TrypLE Express (cat#45604-021, invitrogen, Carlsbad, Calif., USA) to collect them in every 7 days. Thus, the cells were subcultured. 
         [0241]    Seven days after subculturing, the cells were treated with TrypLE Express to collect them when they were about 80% confluent. The cells were suspended in a reaction medium containing Hanks (cat#14065-056, invitrogen, Carlsbad, Calif., USA)/20 mmol/L Hepes (cat#15630-080, invitrogen, Carlsbad, Calif., USA), Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), and 0.1 mg/mL Geneticin, and the suspension was seeded in a 384-well plate (cat#781090, Greiner, Germany) at 20000 cells/25 μL per well. 
         [0242]    On the next day after seeding, Viviren (cat#E649X, Promega, Madison, Wis., USA) was added to the medium so that the final concentration could be 4 μM (15 μL/well). The plates were centrifuged and then placed in the dark for 4 hours at room temperature. 
       (2) Preparation of the Test Samples 
       [0243]    Each of the test compounds was dissolved in DMSO to prepare each test sample at a concentration of 1000-fold the final concentration. To the solution was added Hanks/20 mM HEPES/0.2% BSA (cat#A3803, Sigma, St. Louis, Mo., USA), and the concentration was adjusted to 6-fold the final concentration. 
       (3) Evaluation of PAM Activity 
       [0244]    FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal evoked by α7 nAChR stimulation. The cells and a luminescent substrate were put on a plate, and the test sample was added thereto. After 150 seconds, ACh whose concentration shows 20% (EC 20 ) of the maximal signal was added thereto. After the addition of ACh, the luminescence signal (the central wavelength: 465 nm) was measured for 138 seconds to calculate RLU (Max-Min). The ratio of the RLU (Max-Min) of the test-compound-containing wells to that of the control wells was defined as PAM activity. 
         [0245]    Tables 18 to 25 show α7 PAM activity data of the representative compounds in the present invention. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 18 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1 
                 836 
               
               
                   
                 2 
                 117 
               
               
                   
                 3 
                 493 
               
               
                   
                 4 
                 220 
               
               
                   
                 5 
                 1151  
               
               
                   
                 6 
                 292 
               
               
                   
                 7 
                 644 
               
               
                   
                 8 
                 476 
               
               
                   
                 9 
                 121 
               
               
                   
                 10 
                 597 
               
               
                   
                 11 
                  116* 
               
               
                   
                 12 
                 283 
               
               
                   
                 13 
                 161 
               
               
                   
                 14 
                 351 
               
               
                   
                 15 
                 596 
               
               
                   
                 16 
                 1391  
               
               
                   
                 17 
                 1103  
               
               
                   
                 18 
                 1864  
               
               
                   
                 19 
                 3672  
               
               
                   
                 20 
                 656 
               
               
                   
                 21 
                 291 
               
               
                   
                 22 
                 1950  
               
               
                   
                 23 
                 209 
               
               
                   
                 24 
                 228 
               
               
                   
                 25 
                 2162  
               
               
                   
                 26 
                 563 
               
               
                   
                 27 
                 139 
               
               
                   
                 28 
                 798 
               
               
                   
                 29 
                 378 
               
               
                   
                 30 
                 319 
               
               
                   
                 31 
                 300 
               
               
                   
                 32 
                 993 
               
               
                   
                 33 
                  126* 
               
               
                   
                 34 
                 596 
               
               
                   
                 35 
                 878 
               
               
                   
                 36 
                 193 
               
               
                   
                 37 
                 366 
               
               
                   
                 38 
                 311 
               
               
                   
                 39 
                 823 
               
               
                   
                 40 
                 129 
               
               
                   
                 41 
                 832 
               
               
                   
                 42 
                 122 
               
               
                   
                 43 
                 250 
               
               
                   
                 44 
                 880 
               
               
                   
                 45 
                 260 
               
               
                   
                 46 
                  104* 
               
               
                   
                 47 
                 143 
               
               
                   
                 48 
                 305 
               
               
                   
                 49 
                 445 
               
               
                   
                 50 
                 489 
               
               
                   
                 51 
                 520 
               
               
                   
                 52 
                 205 
               
               
                   
                 53 
                 256 
               
               
                   
                 54 
                 371 
               
               
                   
                 55 
                 403 
               
               
                   
                 56 
                 169 
               
               
                   
                 57 
                 302 
               
               
                   
                 58 
                 318 
               
               
                   
                 59 
                 707 
               
               
                   
                 60 
                 616 
               
               
                   
                 61 
                 915 
               
               
                   
                 62 
                 146 
               
               
                   
                 63 
                 160 
               
               
                   
                 64 
                 149 
               
               
                   
                 65 
                 241 
               
               
                   
                 66 
                 1037  
               
               
                   
                 67 
                 317 
               
               
                   
                 68 
                 143 
               
               
                   
                 69 
                 305 
               
               
                   
                 70 
                 158 
               
               
                   
                 71 
                 422 
               
               
                   
                 72 
                 1616  
               
               
                   
                 73 
                 2536  
               
               
                   
                 74 
                 779 
               
               
                   
                 75 
                 1034  
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 19 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 76 
                 1297  
               
               
                   
                 77 
                 1198  
               
               
                   
                 78 
                 1068  
               
               
                   
                 79 
                  112* 
               
               
                   
                 80 
                 1436  
               
               
                   
                 81 
                 1479  
               
               
                   
                 82 
                 1133  
               
               
                   
                 83 
                 671 
               
               
                   
                 84 
                 747 
               
               
                   
                 85 
                 1647  
               
               
                   
                 86 
                 1310  
               
               
                   
                 87 
                 1273  
               
               
                   
                 88 
                 701 
               
               
                   
                 89 
                 596 
               
               
                   
                 90 
                 297 
               
               
                   
                 91 
                 1498  
               
               
                   
                 92 
                 758 
               
               
                   
                 93 
                 1539  
               
               
                   
                 94 
                 981 
               
               
                   
                 95 
                 761 
               
               
                   
                 96 
                 474 
               
               
                   
                 97 
                 197 
               
               
                   
                 98 
                 1659  
               
               
                   
                 99 
                 1702  
               
               
                   
                 100 
                 708 
               
               
                   
                 101 
                 1350  
               
               
                   
                 102 
                 641 
               
               
                   
                 103 
                 452 
               
               
                   
                 104 
                 1349  
               
               
                   
                 105 
                 1385  
               
               
                   
                 106 
                 945 
               
               
                   
                 107 
                 144 
               
               
                   
                 108 
                 576 
               
               
                   
                 109 
                 457 
               
               
                   
                 110 
                 201 
               
               
                   
                 111 
                 153 
               
               
                   
                 112 
                 1254  
               
               
                   
                 113 
                 882 
               
               
                   
                 114 
                 133 
               
               
                   
                 115 
                 1092  
               
               
                   
                 116 
                 131 
               
               
                   
                 117 
                 853 
               
               
                   
                 118 
                 1923  
               
               
                   
                 119 
                 1302  
               
               
                   
                 120 
                 208 
               
               
                   
                 121 
                 201 
               
               
                   
                 122 
                 459 
               
               
                   
                 123 
                 345 
               
               
                   
                 124 
                 572 
               
               
                   
                 125 
                 466 
               
               
                   
                 126 
                 780 
               
               
                   
                 127 
                 170 
               
               
                   
                 128 
                 188 
               
               
                   
                 129 
                 330 
               
               
                   
                 130 
                 376 
               
               
                   
                 131 
                 738 
               
               
                   
                 132 
                 151 
               
               
                   
                 133 
                 101 
               
               
                   
                 134 
                 171 
               
               
                   
                 135 
                 154 
               
               
                   
                 136 
                 309 
               
               
                   
                 137 
                 328 
               
               
                   
                 138 
                 597 
               
               
                   
                 139 
                 274 
               
               
                   
                 140 
                 127 
               
               
                   
                 141 
                 253 
               
               
                   
                 142 
                 163 
               
               
                   
                 143 
                 1286  
               
               
                   
                 144 
                 346 
               
               
                   
                 145 
                 363 
               
               
                   
                 146 
                 572 
               
               
                   
                 147 
                 484 
               
               
                   
                 148 
                 700 
               
               
                   
                 149 
                 862 
               
               
                   
                 150 
                 137 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 20 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 151 
                 155 
               
               
                   
                 152 
                 945 
               
               
                   
                 153 
                 538 
               
               
                   
                 154 
                 644 
               
               
                   
                 155 
                 252 
               
               
                   
                 156 
                 522 
               
               
                   
                 157 
                 236 
               
               
                   
                 158 
                 132 
               
               
                   
                 159 
                 692 
               
               
                   
                 160 
                 367 
               
               
                   
                 161 
                  233* 
               
               
                   
                 162 
                  323* 
               
               
                   
                 163 
                 144 
               
               
                   
                 164 
                 176 
               
               
                   
                 165 
                 557 
               
               
                   
                 166 
                 389 
               
               
                   
                 167 
                 221 
               
               
                   
                 168 
                 829 
               
               
                   
                 169 
                 454 
               
               
                   
                 170 
                 530 
               
               
                   
                 171 
                 551 
               
               
                   
                 172 
                 480 
               
               
                   
                 173 
                 400 
               
               
                   
                 174 
                 224 
               
               
                   
                 175 
                 397 
               
               
                   
                 176 
                  258* 
               
               
                   
                 177 
                  389* 
               
               
                   
                 178 
                 775 
               
               
                   
                 179 
                 269 
               
               
                   
                 180 
                 375 
               
               
                   
                 181 
                 641 
               
               
                   
                 182 
                  682* 
               
               
                   
                 183 
                 791 
               
               
                   
                 184 
                  303* 
               
               
                   
                 185 
                 576 
               
               
                   
                 186 
                 254 
               
               
                   
                 187 
                 379 
               
               
                   
                 188 
                 581 
               
               
                   
                 189 
                 624 
               
               
                   
                 190 
                 131 
               
               
                   
                 191 
                  364* 
               
               
                   
                 192 
                  274* 
               
               
                   
                 193 
                 187 
               
               
                   
                 194 
                 1177  
               
               
                   
                 195 
                 142 
               
               
                   
                 196 
                 498 
               
               
                   
                 197 
                 637 
               
               
                   
                 198 
                 799 
               
               
                   
                 199 
                  230* 
               
               
                   
                 200 
                  180* 
               
               
                   
                 201 
                 224 
               
               
                   
                 202 
                 263 
               
               
                   
                 203 
                 641 
               
               
                   
                 204 
                 172 
               
               
                   
                 205 
                 110 
               
               
                   
                 206 
                 102 
               
               
                   
                 207 
                 115 
               
               
                   
                 208 
                 202 
               
               
                   
                 209 
                 139 
               
               
                   
                 210 
                 122 
               
               
                   
                 211 
                 390 
               
               
                   
                 212 
                 135 
               
               
                   
                 213 
                 271 
               
               
                   
                 214 
                 273 
               
               
                   
                 215 
                 369 
               
               
                   
                 216 
                 235 
               
               
                   
                 217 
                 1207  
               
               
                   
                 218 
                 1727  
               
               
                   
                 219 
                 371 
               
               
                   
                 220 
                 120 
               
               
                   
                 221 
                 538 
               
               
                   
                 222 
                 592 
               
               
                   
                 223 
                 694 
               
               
                   
                 224 
                 1345  
               
               
                   
                 225 
                 151 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 21 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
                 226 
                 688 
               
               
                   
                 227 
                 818 
               
               
                   
                 228 
                 286 
               
               
                   
                 229 
                 1065  
               
               
                   
                 230 
                 1579  
               
               
                   
                 231 
                 149 
               
               
                   
                 232 
                 113 
               
               
                   
                 233 
                  102* 
               
               
                   
                 234 
                  130* 
               
               
                   
                 235 
                 631 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 22 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 236 
                 158 
               
               
                   
                 237 
                 405 
               
               
                   
                 238 
                 139 
               
               
                   
                 239 
                 207 
               
               
                   
                 240 
                 280 
               
               
                   
                 241 
                 314 
               
               
                   
                 242 
                 297 
               
               
                   
                 243 
                 290 
               
               
                   
                 244 
                 175 
               
               
                   
                 245 
                 197 
               
               
                   
                 246 
                 1256  
               
               
                   
                 247 
                 448 
               
               
                   
                 248 
                 901 
               
               
                   
                 249 
                 384 
               
               
                   
                 250 
                 1002  
               
               
                   
                 251 
                 369 
               
               
                   
                 252 
                 648 
               
               
                   
                 253 
                 899 
               
               
                   
                 254 
                 192 
               
               
                   
                 255 
                 759 
               
               
                   
                 256 
                 1345  
               
               
                   
                 257 
                 439 
               
               
                   
                 258 
                 1174  
               
               
                   
                 259 
                 420 
               
               
                   
                 260 
                 146 
               
               
                   
                 261 
                 399 
               
               
                   
                 262 
                 603 
               
               
                   
                 263 
                 193 
               
               
                   
                 264 
                 781 
               
               
                   
                 265 
                 990 
               
               
                   
                 266 
                 149 
               
               
                   
                 267 
                 594 
               
               
                   
                 268 
                 725 
               
               
                   
                 269 
                 452 
               
               
                   
                 270 
                 569 
               
               
                   
                 271 
                 275 
               
               
                   
                 272 
                 138 
               
               
                   
                 273 
                 139 
               
               
                   
                 274 
                 351 
               
               
                   
                 275 
                 912 
               
               
                   
                 276 
                 244 
               
               
                   
                 277 
                 424 
               
               
                   
                 278 
                 834 
               
               
                   
                 279 
                 236 
               
               
                   
                 280 
                 787 
               
               
                   
                 281 
                 411 
               
               
                   
                 282 
                 229 
               
               
                   
                 283 
                 390 
               
               
                   
                 284 
                 398 
               
               
                   
                 285 
                 869 
               
               
                   
                 286 
                 469 
               
               
                   
                 287 
                 1082  
               
               
                   
                 288 
                 327 
               
               
                   
                 289 
                 125 
               
               
                   
                 290 
                 194 
               
               
                   
                 291 
                 420 
               
               
                   
                 292 
                 101 
               
               
                   
                 293 
                 211 
               
               
                   
                 294 
                 326 
               
               
                   
                 295 
                  444* 
               
               
                   
                 296 
                  589* 
               
               
                   
                 297 
                 866 
               
               
                   
                 298 
                 166 
               
               
                   
                 299 
                 893 
               
               
                   
                 300 
                 1379  
               
               
                   
                 301 
                 828 
               
               
                   
                 302 
                 325 
               
               
                   
                 303 
                 208 
               
               
                   
                 304 
                  600* 
               
               
                   
                 305 
                 1285  
               
               
                   
                 306 
                 1145  
               
               
                   
                 307 
                 634 
               
               
                   
                 308 
                 513 
               
               
                   
                 309 
                  181* 
               
               
                   
                 310 
                 227 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 23 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 311 
                 290 
               
               
                   
                 312 
                 662 
               
               
                   
                 313 
                  273* 
               
               
                   
                 314 
                 591 
               
               
                   
                 315 
                 501 
               
               
                   
                 316 
                  267* 
               
               
                   
                 317 
                  345* 
               
               
                   
                 318 
                  179* 
               
               
                   
                 319 
                 328 
               
               
                   
                 320 
                 1340  
               
               
                   
                 321 
                 800 
               
               
                   
                 322 
                 314 
               
               
                   
                 323 
                 421 
               
               
                   
                 324 
                 860 
               
               
                   
                 325 
                 210 
               
               
                   
                 326 
                 1196  
               
               
                   
                 327 
                 1479  
               
               
                   
                 328 
                  859* 
               
               
                   
                 329 
                 643 
               
               
                   
                 330 
                 154 
               
               
                   
                 331 
                  467* 
               
               
                   
                 332 
                 464 
               
               
                   
                 333 
                 233 
               
               
                   
                 334 
                  212* 
               
               
                   
                 335 
                 312 
               
               
                   
                 336 
                 557 
               
               
                   
                 337 
                 492 
               
               
                   
                 338 
                 192 
               
               
                   
                 339 
                 351 
               
               
                   
                 340 
                 377 
               
               
                   
                 341 
                 233 
               
               
                   
                 342 
                 369 
               
               
                   
                 343 
                  380* 
               
               
                   
                 344 
                 220 
               
               
                   
                 345 
                 153 
               
               
                   
                 346 
                 169 
               
               
                   
                 347 
                 130 
               
               
                   
                 348 
                 131 
               
               
                   
                 349 
                 290 
               
               
                   
                 350 
                  670* 
               
               
                   
                 351 
                 540 
               
               
                   
                 352 
                 164 
               
               
                   
                 353 
                 518 
               
               
                   
                 354 
                 230 
               
               
                   
                 355 
                  118* 
               
               
                   
                 356 
                  119* 
               
               
                   
                 357 
                  130* 
               
               
                   
                 358 
                  126* 
               
               
                   
                 359 
                 581 
               
               
                   
                 360 
                 598 
               
               
                   
                 361 
                 794 
               
               
                   
                 362 
                 1896  
               
               
                   
                 363 
                 3665  
               
               
                   
                 364 
                 537 
               
               
                   
                 365 
                 1064  
               
               
                   
                 366 
                 834 
               
               
                   
                 367 
                 1380  
               
               
                   
                 368 
                 941 
               
               
                   
                 369 
                 404 
               
               
                   
                 370 
                 1309  
               
               
                   
                 371 
                 962 
               
               
                   
                 372 
                 569 
               
               
                   
                 373 
                 966 
               
               
                   
                 374 
                 820 
               
               
                   
                 375 
                 457 
               
               
                   
                 376 
                 426 
               
               
                   
                 377 
                 988 
               
               
                   
                 378 
                 854 
               
               
                   
                 379 
                 685 
               
               
                   
                 380 
                 1574  
               
               
                   
                 381 
                 377 
               
               
                   
                 382 
                 222 
               
               
                   
                 383 
                 598 
               
               
                   
                 384 
                  652* 
               
               
                   
                 385 
                  218* 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 24 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 386 
                 880 
               
               
                   
                 387 
                  315* 
               
               
                   
                 388 
                  335* 
               
               
                   
                 389 
                  163* 
               
               
                   
                 390 
                 683 
               
               
                   
                 391 
                 1703  
               
               
                   
                 392 
                 771 
               
               
                   
                 393 
                 1002  
               
               
                   
                 394 
                 455 
               
               
                   
                 395 
                 869 
               
               
                   
                 396 
                 585 
               
               
                   
                 397 
                 522 
               
               
                   
                 398 
                 607 
               
               
                   
                 399 
                 891 
               
               
                   
                 400 
                 1151  
               
               
                   
                 401 
                 879 
               
               
                   
                 402 
                 498 
               
               
                   
                 403 
                  590* 
               
               
                   
                 404 
                 292 
               
               
                   
                 405 
                 402 
               
               
                   
                 406 
                 629 
               
               
                   
                 407 
                 904 
               
               
                   
                 408 
                 140 
               
               
                   
                 409 
                 576 
               
               
                   
                 410 
                 197 
               
               
                   
                 411 
                 229 
               
               
                   
                 412 
                 423 
               
               
                   
                 413 
                 1407  
               
               
                   
                 414 
                 1019  
               
               
                   
                 415 
                 997 
               
               
                   
                 416 
                 2077  
               
               
                   
                 417 
                 1080  
               
               
                   
                 418 
                 1193  
               
               
                   
                 419 
                 913 
               
               
                   
                 420 
                 1189  
               
               
                   
                 421 
                 426 
               
               
                   
                 422 
                 131 
               
               
                   
                 423 
                  390* 
               
               
                   
                 424 
                 210 
               
               
                   
                 425 
                 155 
               
               
                   
                 426 
                 308 
               
               
                   
                 427 
                 305 
               
               
                   
                 428 
                 144 
               
               
                   
                 429 
                  111* 
               
               
                   
                 430 
                  110* 
               
               
                   
                 431 
                 836 
               
               
                   
                 432 
                 1131  
               
               
                   
                 433 
                 345 
               
               
                   
                 434 
                 512 
               
               
                   
                 435 
                 1030  
               
               
                   
                 436 
                 300 
               
               
                   
                 437 
                 533 
               
               
                   
                 438 
                 235 
               
               
                   
                 439 
                 813 
               
               
                   
                 440 
                 508 
               
               
                   
                 441 
                 451 
               
               
                   
                 442 
                 1038  
               
               
                   
                 443 
                  368* 
               
               
                   
                 444 
                 208 
               
               
                   
                 445 
                 272 
               
               
                   
                 446 
                 143 
               
               
                   
                 447 
                 268 
               
               
                   
                 448 
                 276 
               
               
                   
                 449 
                 183 
               
               
                   
                 450 
                 128 
               
               
                   
                 451 
                  143* 
               
               
                   
                 452 
                 1150  
               
               
                   
                 453 
                 1286  
               
               
                   
                 454 
                 1120  
               
               
                   
                 455 
                 1052  
               
               
                   
                 456 
                 1339  
               
               
                   
                 457 
                 865 
               
               
                   
                 458 
                 434 
               
               
                   
                 459 
                 730 
               
               
                   
                 460 
                 390 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                 TABLE 25 
               
               
                   
                   
               
               
                   
                   
                 α7PAM 
               
               
                   
                   
                 (%) 
               
               
                   
                 Example 
                 @10 μM 
               
               
                   
                   
               
             
             
               
                   
                 461 
                 162 
               
               
                   
                 462 
                 384 
               
               
                   
                 463 
                  181* 
               
               
                   
                 464 
                  124* 
               
               
                   
                   
               
               
                   
                 *α7PAM (%) @1 μM 
               
             
          
         
       
     
         [0246]    Tables 18 to 25 demonstrate that the present compounds have PAM activity for α7 nAChR according to the evaluation test of PAM activity. In particular, Examples 18, 19, 22, 25, 72, 73, 85, 93, 98, 99, 118, 218, 230, 362, 363, 380, 391 and 416 show a stronger PAM activity than others. 
       Test Example 2 
     Evaluation of Cognitive Function with Mice in Novel Object Recognition Test (Hereinafter. Referred to as “mORT”) 
       [0247]    Slc:ddY mice (25 to 30 g, male, Japan SLC) can be used in the novel object recognition test wherein the interval between the 1st trial (training) and the 2nd trial (test) correlates with the memory loss for the objects used in the 1st trial, and a significant memory-loss is observed when the 2nd trial is performed 24 hours after the 1st trial. According to the test mechanism, the present compounds were administered prior to the 1st trial, and the enhancement effect on memory in the 2nd trial was evaluated. The results confirmed that Examples 1, 183, 280, 370 and 452 have a significant memory enhancing effect in 3 mg/kg (oral). 
       Test Example 3 
     Evaluation on Improvement Against Cognitive Impairment with Rats in Y-Shaped Maze Test (Hereinafter, Referred to as “Y-Maze Test”) 
       [0248]    In Y-maze test, 0.6 mg/kg scopolamine HBr (cat#S0929, Sigma Aldrich, Japan) can be subcutaneously administered to Slc:Wistar rats (280 to 300 g, male, Japan SLC) to cause cognitive impairment and decrease the percentage of spontaneous alternation behavior. According to the test mechanism, the present compounds were treated prior to the administration of scopolamine, and the improvement effect on cognitive impairment is evaluated. The results confirmed that compounds of Examples 1 and 183 have a significant improvement effect on memory disorder in 3 mg/kg (oral). 
       INDUSTRIAL APPLICABILITY 
       [0249]    As explained above, the derivative of Formula (I) or a pharmaceutically acceptable salt thereof has potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR), and is thus useful for treating, for example, diseases associated with cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders, diseases such as inflammation and pain, and diseases associated with withdrawal symptoms caused by addictive drug abuse.