Patent Publication Number: US-2009227560-A1

Title: Substituted imidazole compound and use thereof

Description:
TECHNICAL FIELD 
     The present invention relates to a substituted imidazole compound and the like, which has a superior renin inhibitory activity and is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like. 
     BACKGROUND OF INVENTION 
     Hypertension is one of representative lifestyle-related diseases. Hypertension which is left untreated for long time lays a heavy burden on the cardiovascular system and results in arteriosclerosis to progress, thus causing various disorders in important organs, such as cerebral hemorrhage, cerebral infarction, cardiac failure, angina pectoris, myocardial infarction, renal failure and the like. Accordingly, the purpose of treating hypertension lies not only in lowering the blood pressure, but also in improving and/or preventing disorders in important organs including brain, heart and kidney, by controlling the blood pressure. As a method of treating hypertension, there are available fundamental treatments based on improvement in the lifestyle, such as dietetic therapy, exercise therapy and the like, as well as an attempt to control the blood pressure by positive pharmaceutical intervention. 
     The renin-angiotensin (RA) system is a system of biosynthesis of angiotensin II (AII), which is a major vasopressor factor, and takes an important role in the control of the blood pressure and the amount of body fluid. AII exhibits a strong vasoconstrictive effect brought by the intervention of AII receptors on the cellular membrane, thus raising the blood pressure, and also promotes cellular propagation or production of extracellular matrix by directly acting on the AII receptors in the cardiac cells or renal cells. Therefore, drugs inhibiting increase in the activity of the RA system can be expected to have a blood pressure lowering action as well as a powerful organ protecting action, and thus active researches on such drugs have been conducted so far. 
     The method of inhibiting the AII action is broadly classified into methods of inhibiting the biosynthesis of AII and methods of inhibiting the binding of AII to AII receptors. For the drugs inhibiting the biosynthesis of AII, angiotensin converting enzyme (ACE) inhibitory drugs have been already put to practical use and are being confirmed to have a blood pressure lowering action as well as an effect for protecting various organs. However, since ACE is an enzyme identical to kininase II, which is a bradykinin degrading enzyme, ACE inhibitory drug inhibits the biosynthesis of AII as well as the degradation of bradykinin. As a result, ACE inhibitory drugs are believed to induce side effects such as dry cough, angioedema and the like, which are considered to be caused by accumulation of bradykinin. 
     As the drugs inhibiting the binding of AII to AII receptors, AII type 1 receptor blockers (ARB) have been developed. ARB has a merit in that it can inhibit, at the receptor level, the action of AII that is biosynthesized by not only ACE but also an enzyme other than ACE, such as chymase and the like. It is known that administration of ACE inhibitors and ARB increases the plasma renin activity (PRA) as a compensatory feedback effect, since these drugs act on a more peripheral region of the RA system. 
     Renin is an enzyme occupying a position at the uppermost stream of the RA system, and converts angiotensinogen to angiotensin I. A renin inhibitory drug inhibits the RA system by inhibiting the biosynthesis of AII in the same manner as the ACE inhibitory drugs do, and thus can be expected to have a blood pressure lowering action or an effect of protecting various organs. Since the renin inhibitory drug does not have influence on the metabolism of bradykinin, it is believed to have no risk of side effects such as dry cough and the like, that are observed with the ACE inhibitory drugs. Furthermore, while the ACE inhibitory drugs or ARB increase the PRA level, the renin inhibitory drugs are the only drugs that can reduce PRA. 
     As renin inhibitors, orally administrable Aliskiren has been reported (Chem. Biol., 2000, vol. 7, pages 493-504; Hypertension, 2003, vol. 42, pages 1137-1143; J. Hypertens., 2005, vol. 23, pages 417-426 etc.). In addition, low molecular weight renin inhibitory drugs are disclosed in WO 2004/002957, WO 2004/089915 and the like. 
     Imidazole compounds have been reported as orexin receptor antagonists (e.g., WO 2003/002559, WO 2003/002561, WO 2003/032991, WO 2003/041711, WO 2003/051368, WO 2003/051871, WO 2003/051873, WO 2004/026866, WO 2004/041791 etc.). 
     DISCLOSURE OF THE INVENTION 
     There is a demand on the development of a novel compound having a superior renin inhibitory activity, which is useful as a pharmaceutical agent (e.g., hypertension, agent for the prophylaxis or treatment of various organ damages attributable to hypertension and the like, and the like). 
     The present inventors have conducted various studies, and as a result, first succeeded in the creation of a novel compound represented by the following formula (I) and a salt thereof, and found that the compound and a salt thereof unexpectedly have a superior renin inhibitory activity, and are useful as pharmaceutical agents, which resulted in the completion of the present invention. 
     Accordingly, the present invention relates to the following: 
     [1] a compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 
R 1  is a substituent,
 
R 2  is a cyclic group optionally having substituent(s), C 1-10  alkyl optionally having substituent(s), C 2-10  alkenyl optionally having substituent(s) or C 2-10  alkynyl optionally having substituent(s),
 
R 3  is a hydrogen atom, a halogen atom, C 1-6  alkyl or C 1-6  alkoxy,
 
X is bond or spacer having 1 to 6 atoms in the main chain,
 
ring A is C 5-7  cycloalkane optionally having substituent(s), and
 
ring B is piperazine optionally further having substituent(s) besides R 1 ,
 
or a salt thereof [hereinafter to be sometimes abbreviated as compound (I)];
 
[2] the compound of the aforementioned [1], wherein R 1  is a hydrocarbon group optionally having substituent(s);
 
[3] the compound of the aforementioned [1], wherein R 2  is C 6-14  aryl optionally having substituent(s) or C 3-10  cycloalkyl optionally having substituent(s);
 
[4] the compound of the aforementioned [1], wherein R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl or C 1-3  alkoxy;
 
[5] the compound of the aforementioned [1], wherein X is bond or C 1-6  alkylene optionally having substituent(s);
 
[6] the compound of the aforementioned [1], wherein ring A is C 5-7  cycloalkane optionally having substituent(s) selected from a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and amino optionally having substituent(s);
 
[7] the compound of the aforementioned [1], wherein ring B is a ring represented by the formula:
 
     
       
         
         
             
             
         
       
     
     wherein R 1  is as defined above;
 
[8] a compound represented by the formula:
 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1  is 
     (a) C 1-6  alkyl substituted by hydroxy optionally having a substituent,
 
(b) C 1-6  alkyl substituted by phenylamino optionally having substituent(s), or
 
(c) C 7-13  aralkyl optionally having substituent(s);
 
     R 2  is optionally halogenated C 6-10  aryl; 
     R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl or C 1-3  alkoxy; 
     X is bond or C 1-6  alkylene optionally having substituent(s); and 
     ring A is 
     (a) C 5-7  cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C 1-3  alkyl optionally having substituent(s), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s);
 
[9] (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol or a salt thereof;
 
[10] Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate or a salt thereof;
 
[11] (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol or a salt thereof;
 
[12] (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol or a salt thereof;
 
[13] Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate or a salt thereof;
 
[14] (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol or a salt thereof;
 
[15] (1S,2R)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol or a salt thereof;
 
[16] Methyl [(1S,2S)-2-(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate or a salt thereof;
 
[17] (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol or a salt thereof;
 
[18] (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol or a salt thereof;
 
[19] (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol or a salt thereof;
 
[20] (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol or a salt thereof;
 
[21] (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol or a salt thereof;
 
[22] (1S,2R)-2-{4-[((2R)-2-{2-[(2-Ethyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol or a salt thereof;
 
[23] 1-[(4-{[(2R)-2-(2-Anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol or a salt thereof;
 
[24] a prodrug of the compound of the aforementioned [1];
 
[25] a pharmaceutical agent comprising the compound of the aforementioned [1] or a prodrug thereof;
 
[26] the pharmaceutical agent of the aforementioned [25], which is a renin inhibitor;
 
[27] the pharmaceutical agent of the aforementioned [25], which is an agent for the prophylaxis or treatment of hypertension;
 
[28] the pharmaceutical agent of the aforementioned [25], which is an agent for the prophylaxis or treatment of various organ damages attributable to hypertension;
 
[29] a method for the prophylaxis or treatment of hypertension in a mammal, which comprises administering an effective amount of the compound of the aforementioned [1] or a prodrug thereof to the mammal;
 
[30] use of the compound of the aforementioned [1] or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hypertension; and the like.
 
     EFFECT OF THE INVENTION 
     Compound (I) has a superior renin inhibitory activity, and thus it is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Examples of the “halogen atom” in the present specification include fluorine, chlorine, bromine and iodine. 
     Examples of the “C 1-4  alkylenedioxy” in the present specification include methylenedioxy, ethylenedioxy, trimethylenedioxy and the like. 
     Examples of the “C 1-6  alkyl” in the present specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. 
     Examples of the “C 1-6  alkoxy” in the present specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. 
     Examples of the “C 1-6  alkoxy-carbonyl” in the present specification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like. 
     Examples of the “C 1-6  alkyl-carbonyl” in the present specification include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like. 
     The “optionally halogenated” in the present specification means being optionally substituted by 1 to 5, preferably 1 to 3, halogen atoms. 
     Examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” in the present specification include C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 1-3  alkylidene, C 3-10  cycloalkyl, C 3-10  cycloalkenyl, C 4-10  cycloalkadienyl, C 6-14  aryl, C 7-13  aralkyl, C 8-13  arylalkenyl, C 3-10  cycloalkyl-C 1-6  alkyl and the like. The above-mentioned C 3-10  cycloalkyl, C 3-10  cycloalkenyl and C 4-10  cycloalkadienyl are each optionally condensed with a benzene ring. 
     Examples of the “C 1-10  alkyl” in the present specification include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Among these, C 1-6  alkyl is preferable. 
     Examples of the “C 2-10  alkenyl” in the present specification include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like. Among these, C 2-6  alkenyl is preferable. 
     Examples of the “C 2-10  alkynyl” in the present specification include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like. Among these, C 2-6  alkynyl is preferable. 
     Examples of the “C 1-3  alkylidene” in the present specification include methylene, ethylidene, propylidene, isopropylidene and the like. 
     Examples of the “C 3-10  cycloalkyl” in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl and the like. Among these, C 3-6  cycloalkyl is preferable. The above-mentioned C 3-10  cycloalkyl is optionally condensed with a benzene ring. Examples of the condensed group include indanyl, tetrahydronaphthyl, fluorenyl and the like. 
     Examples of the “C 3-10  cycloalkenyl” in the present specification include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like. The above-mentioned C 3-10  cycloalkenyl is optionally condensed with a benzene ring. Examples of the condensed group include indenyl and the like. 
     Examples of the “C 4-10  cycloalkadienyl” in the present specification include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. The above-mentioned C 4-10  cycloalkadienyl is optionally condensed with a benzene ring. 
     Examples of the “C 6-14  aryl” in the present specification include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like. Among these, C 6-10  aryl is preferable, and phenyl is more preferable. The above-mentioned C 6-14  aryl is optionally condensed with C 3-10  cycloalkane (examples of the C 3-10  cycloalkane include rings corresponding to the above-mentioned C 3-10  cycloalkyl). Examples of the condensed group include tetrahydronaphthyl and the like. 
     Examples of the “C 7-13  aralkyl” in the present specification include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like. 
     Examples of the “C 8-13  arylalkenyl” in the present specification include styryl and the like. 
     Examples of the “C 3-10  cycloalkyl-C 1-6  alkyl” in the present specification include cyclopropylmethyl, cyclohexylmethyl and the like. 
     The “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” optionally have substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     Examples of the “substituent” of the “hydrocarbon group optionally having substituent(s)” include the following substituents. 
     (1) a halogen atom;
 
(2) C 3-10  cycloalkyl (e.g., cyclopropyl, cyclohexyl);
 
(3) C 6-14  aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
         (i) carboxy,   (ii) hydroxy,   (iii) C 1-6  alkyl optionally having 1 to 3 substituents selected from
           (a) hydroxy, and   (b) a halogen atom,   
           (iv) C 1-6  alkoxy optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkoxy,   (b) carbamoyl optionally mono- or di-substituted by substituent(s) selected from C 1-6  alkyl optionally substituted by carbamoyl, and C 1-6  alkylsulfonyl,   (c) carboxyl,   (d) C 1-6  alkoxy-carbonyl optionally substituted by a non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from oxo and C 1-6  alkyl,   (e) cyano, and   (f) a non-aromatic heterocyclic group (e.g., oxadiazolinyl) optionally substituted by oxo,   
           (v) carbamoyl optionally mono- or di-substituted by substituent(s) selected from
           (a) C 1-6  alkyl optionally substituted by hydroxy, and   (b) C 1-6  alkylsulfonyl,   
           (vi) a non-aromatic heterocyclic group (e.g., oxadiazolinyl) optionally substituted by oxo,   (vii) an aromatic heterocyclic group (e.g., tetrazolyl),   (viii) C 1-6  alkoxy-carbonyl optionally substituted by a non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from oxo and C 1-6  alkyl,   (ix) cyano,   (x) sulfamoyl,   (xi) halogen,   (xii) C 1-6  alkylsulfonyl (e.g., methylsulfonyl), and   (xiii) C 1-6  alkyl sulfonyloxy (e.g., methylsulfonyloxy);
 
(4) an aromatic heterocyclic group (e.g., thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyridyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl, imidazolyl, indazolyl, benzimidazolyl, benzotriazolyl) optionally having 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 6-14  aryl (e.g., phenyl),   (d) C 1-6  alkoxy,   (e) C 1-6  alkyl-carbonyloxy, and   (f) a non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl) optionally having 1 to 3 C 1-6  alkyl,   
           (iii) C 3-6  cycloalkyl,   (iv) C 6-14  aryl,   (v) hydroxy,   (vi) C 1-6  alkoxy,   (vii) C 1-6  alkyl-carbonyl optionally having amino optionally mono- or di-substituted by C 1-6  alkyl-carbonyl,   (viii) C 6-14  aryl-carbonyl (e.g., benzoyl),   (ix) C 1-6  alkoxy-carbonyl,   (x) carboxy,   (xi) carbamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and carbamoyl,   (xii) C 1-6  alkylsulfonyl,   (xiii) C 6-14  arylsulfonyl, and   (xiv) cyano;
 
(5) a non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1,3-dihydro-2-benzofuranyl, thiazolidinyl, oxadiazolidinyl, 1-oxidothiomorpholinyl, 1,1-dioxidothiomorpholinyl, tetrahydropyranyl, dihydroisoindolyl, dihydroindazolyl, tetrahydroindazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 6-14  aryl (e.g., phenyl),   (d) C 1-6  alkoxy,   (e) C 1-6  alkyl-carbonyloxy, and   (f) a non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl) optionally having 1 to 3 C 1-6  alkyl,   
           (iii) C 3-6  cycloalkyl,   (iv) C 6-14  aryl,   (v) hydroxy,   (vi) C 1-6  alkoxy,   (vii) C 1-6  alkyl-carbonyl optionally having amino optionally mono- or di-substituted by C 1-6  alkyl-carbonyl,   (viii) C 6 -C 14  aryl-carbonyl (e.g., benzoyl),   (ix) C 1-6  alkoxy-carbonyl,   (x) carboxy,   (xi) carbamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and carbamoyl,   (xii) C 1-6  alkylsulfonyl,   (xiii) C 6-14  arylsulfonyl,   (xiv) cyano, and   (xv) oxo;
 
(6) amino optionally mono- or di-substituted by substituent(s) selected from
   (i) C 1-10  alkyl optionally substituted by 1 to 3 substituents selected from
           (a) hydroxy,   (b) C 1-6  alkoxy optionally substituted by C 6-14  aryl (e.g., phenyl),   (c) carboxy,   (d) C 3-10  cycloalkyl (e.g., cyclopropyl) optionally substituted by C 1-6  alkoxy-carbonyl,   (e) a halogen atom,   (f) an aromatic heterocyclic group (e.g., furyl, pyridyl, indolyl, imidazolyl, thienyl, pyrazolyl, pyrrolyl) optionally having 1 to 3 substituents selected from
               1) C 1-6  alkyl optionally substituted by hydroxy,   2) C 1-6  alkoxy-carbonyl,   3) carboxy,   4) a halogen atom, and   5) C 1-6  alkylthio,   
               (g) C 6-14  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               1) amino optionally mono- or di-substituted by substituent(s) selected from C 1-6  alkyl and C 1-6  alkyl-carbonyl,   2) C 1-4  alkylenedioxy,   3) hydroxy, and   4) C 1-6  alkoxy optionally substituted by carboxy,   
               (h) C 1-6  alkylthio,   (i) C 1-6  alkylsulfonyl,   (j) amino optionally mono- or di-substituted by C 1-6  alkoxy-carbonyl optionally substituted by C 6-14  aryl (e.g., phenyl), and   (k) carbamoyl,   
           (ii) C 6-14  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
           (a) a halogen atom,   (b) optionally halogenated C 1-6  alkyl (e.g., isopropyl, trifluoromethyl),   (c) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),   (d) cyano,   (e) nitro,   (f) carboxy,   (g) C 1-6  alkyl-carbonyl,   (h) C 1-6  alkoxy-carbonyl,   (i) C 1-4  alkylenedioxy, and   (j) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,   
           (iii) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),   (iv) C 7-13  aralkyl (e.g., benzyl),   (v) C 1-6  alkyl-carbonyl optionally having 1 to 3 substituents selected from
           (a) carboxy,   (b) C 6-14  aryl (e.g., phenyl),   (c) amino optionally mono- or di-substituted by C 1-6  alkyl-carbonyl,   (d) C 1-6  alkoxy optionally substituted by C 1-6  alkoxy,   (e) an aromatic heterocyclic group (e.g., thienyl),   (f) C 1-6  alkoxy-carbonyl,   (g) carbamoyl optionally mono- or di-substituted by C 3-10  cycloalkyl, and   (h) non-aromatic heterocyclylcarbonyl (e.g., morpholinylcarbonyl),   
           (vi) C 3-10  cycloalkyl-carbonyl,   (vii) C 1-6  alkoxy-carbonyl optionally having 1 or 2 C 6-14  aryl (e.g., phenyl),   (viii) C 6-14  aryl-carbonyl (e.g., benzoyl) optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (ix) C 7-13  aralkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl),   (x) carbamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally having 1 to 3 substituents selected from
           (a) carboxy,   (b) C 1-6  alkoxy-carbonyl, and   (c) carbamoyl,   
           (xi) C 6-14  aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl),   (xii) C 7-13  aralkyl-carbamoyl (e.g., benzylcarbamoyl),   (xiii) C 1-6  alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl),   (xiv) C 6-14  arylsulfonyl (e.g., benzenesulfonyl, toluenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl),   (xv) C 7-13  aralkylsulfonyl (e.g., benzylsulfonyl), and   (xvi) a heterocyclic group (the heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl, tetrahydropyranyl, pyridyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzothienyl, benzofuranyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, indolyl, indazolyl, dihydrofuropyridyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, imidazopyridyl, pyrazolopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrobenzoxazinyl) optionally substituted by 1 to 3 substituents selected from hydroxy, C 1-6  alkyl and oxo;
 
(7) amidino;
 
(8) C 1-6  alkyl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and hydroxy;
 
(9) C 1-6  alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 6-14  aryl (e.g., phenyl);
 
(10) carbamoyl optionally mono- or di-substituted by substituent(s) selected from
   (i) C 1-6  alkyl optionally having 1 to 3 substituents selected from a halogen atom, hydroxy, carbamoyl and an aromatic heterocyclic group (e.g., furyl),   (ii) C 6-14  aryl (e.g., phenyl),   (iii) C 7-13  aralkyl (e.g., benzyl), and   (iv) aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl);
 
(11) thiocarbamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally substituted by 1 to 3 halogen atoms;
 
(12) sulfamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally substituted by 1 to 3 halogen atoms;
 
(13) carboxy;
 
(14) hydroxy;
 
(15) C 1-6  alkoxy optionally having 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) carboxy,   (iii) hydroxy,   (iv) C 1-6  alkoxy optionally having 1 or 2 hydroxy,   (v) C 6-14  aryl (e.g., phenyl) optionally substituted by C 1-6  alkylsulfonyl,   (vi) C 3-6  cycloalkyl,   (vii) C 1-6  alkoxy-carbonyl,   (viii) C 1-6  alkylsulfonyl (e.g., methylsulfonyl),   (ix) mono- or di-C 1-6  alkylamino,   (x) C 1-6  alkyl-carbonylamino,   (xi) C 1-6  alkylthio,   (xii) a heterocyclic group (e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl, 1,1-dioxidothiomorpholinyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo, and   (xiii) carbamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally having 1 to 3 substituents selected from carbamoyl and hydroxy;
 
(16) C 2-6  alkenyloxy (e.g., ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
 
(17) C 3-10  cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclohexyloxy, tetrahydronaphthyloxy, indanyloxy) optionally having oxo;
 
(18) C 7-13  aralkyloxy (e.g., benzyloxy);
 
(19) C 6-14  aryloxy (e.g., phenyloxy, naphthyloxy; the C 6-14  aryl is optionally condensed with C 3-10  cycloalkane) optionally having 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) cyano,   (iii) C 1-6  alkyl optionally having 1 or 2 substituents selected from a halogen atom, carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   (iv) C 1-6  alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (v) C 1-4  alkylenedioxy,   (vi) carboxy,   (vii) C 1-6  alkyl-carbonyl,   (viii) C 1-6  alkoxy-carbonyl,   (ix) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   (x) carbamoyl,   (xi) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   (xii) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   (xiii) mono- or di-C 1-6  alkylamino,   (xiv) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl),   (xv) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, C 1-4  alkylenedioxy and oxo, and   (xvi) a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo;
 
(20) C 3-10  cycloalkyl-C 1-6  alkyloxy (e.g., cyclopropylmethyloxy);
 
(21) heterocyclyloxy (e.g., 5- or 6-membered aromatic heterocyclyloxy such as pyrazolyloxy, triazolyloxy, thienyloxy, thiazolyloxy, isoxazolyloxy, oxadiazolyloxy, pyridyloxy, pyrimidinyloxy and the like; 5- or 6-membered non-aromatic heterocyclyloxy such as piperidinyloxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1-oxidotetrahydrothiopyranyloxy, 1,1-dioxidotetrahydrothiopyranyloxy and the like; 9- or 10-membered fused heterocyclyloxy such as benzothienyloxy, benzothiazolyloxy, benzofuranyloxy, benzimidazolyloxy, benzoxazolyloxy, dihydrobenzoxazolyloxy, benzisoxazolyloxy, benzisothiazolyloxy, dihydrobenzofuranyloxy, dihydroquinolyloxy, dihydroisoquinolyloxy, tetrahydroquinolyloxy, tetrahydroisoquinolyloxy, chromenyloxy, thienopyridyloxy, benzotriazolyloxy, indolyloxy, indazolyloxy, imidazopyridyloxy, pyrazolopyridyloxy, pyrrolopyrazinyloxy, imidazopyrazinyloxy, pyrazolothienyloxy, dihydrofuropyridyloxy, dihydrobenzoxazinyloxy and the like; the heterocycle is optionally oxidized) optionally having 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) cyano,   (iii) C 1-6  alkyl optionally having 1 to 3 substituents selected from a halogen atom, C 1-6  alkoxy and C 1-6  alkoxy-carbonyl,   (iv) C 1-6  alkoxy-carbonyl-C 1-6  alkyl,   (v) mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl),   (vi) C 6-10  aryl (e.g., phenyl),   (vii) C 3-10  cycloalkyl,   (viii) C 1-6  alkoxy,   (ix) C 1-6  alkoxy-carbonyl,   (x) carboxy, and   (xi) oxo;
 
(22) C 1-6  alkyl-carbonyloxy (e.g., acetyloxy, tert-butylcarbonyloxy);
 
(23) mercapto;
 
(24) C 1-6  alkylthio (e.g., methylthio, ethylthio) optionally substituted by 1 to 3 halogen atoms;
 
(25) C 7-20  aralkylthio (e.g., benzylthio, tritylthio);
 
(26) C 6-14  arylthio (e.g., phenylthio, naphthylthio);
 
(27) sulfo;
 
(28) C 1-6  alkylsulfinyl (e.g., methylsulfinyl);
 
(29) C 6-14  arylsulfinyl (e.g., phenylsulfinyl);
 
(30) C 1-6  alkylsulfonyl (e.g., methylsulfonyl) optionally substituted by 1 to 3 halogen atoms;
 
(31) C 6-14  arylsulfonyl (e.g., phenylsulfonyl) optionally substituted by C 1-6  alkoxy;
 
(32) C 3-10  cycloalkylsulfonyl (e.g., cyclopropylsulfonyl);
 
(33) aromatic heterocyclylsulfonyl (e.g., pyridylsulfonyl, pyrazolylsulfonyl, thienylsulfonyl, furylsulfonyl, imidazolylsulfonyl) optionally having 1 to 3 substituents selected from
   (i) C 1-6  alkyl,   (ii) C 1-6  alkoxy,   (iii) C 1-6  alkoxy-carbonyl, and   (iv) a halogen atom;
 
(34) cyano;
 
(35) azido;
 
(36) nitro;
 
(37) nitroso;
 
(38) oxo;
 
(39) non-aromatic heterocyclylcarbonyl (the non-aromatic heterocycle is optionally oxidized; e.g., morpholinylcarbonyl, piperazinylcarbonyl) optionally substituted by C 1-6  alkyl optionally substituted by C 6-14  aryl (e.g., phenyl);
 
(40) non-aromatic heterocyclylcarbonyloxy (e.g., pyrrolidinylcarbonyloxy);
 
(41) C 1-4  alkylenedioxy optionally substituted by 1 to 3 halogen atoms;
 
(42) hydroxyimino optionally substituted by C 1-6  alkyl;
 
(43) C 1-6  alkyl optionally having 1 to 5 (preferably 1 to 3) substituents selected from
   (i) a halogen atom,   (ii) carboxy,   (iii) hydroxy,   (iv) C 1-6  alkoxy,   (v) C 1-6  alkoxy-carbonyl,   (vi) C 1-6  alkyl-carbonyloxy (e.g., acetyloxy, tert-butylcarbonyloxy),   (vii) amino,   (viii) carbamoyl optionally mono- or di-substituted by C 1-6  alkyl optionally substituted by hydroxy,   (ix) a non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., piperidino, tetrahydrofuryl) optionally substituted by C 1-6  alkyl,   (x) non-aromatic heterocyclylcarbonyl (the non-aromatic heterocycle is optionally oxidized; e.g., morpholinylcarbonyl),   (xi) C 6-14  aryl (e.g., phenyl) optionally substituted by C 1-6  alkylsulfonyl,   (xii) C 3-10  cycloalkyl (e.g., cyclopropyl), and   (xiii) an aromatic heterocyclic group (e.g., furyl) optionally having 1 to 3 substituents selected from carboxy and C 1-6  alkoxy-carbonyl;
 
(44) C 2-6  alkenyl (e.g., ethenyl, 1-propenyl) optionally having 1 to 3 substituents selected from
   (i) a halogen atom,   (ii) carboxy,   (iii) C 1-6  alkoxy-carbonyl,   (iv) carbamoyl, and   (v) C 6-14  aryl (e.g., phenyl) optionally substituted by C 1-6  alkoxy-carbonyl;
 
(45) C 7-13  aralkyl (e.g., benzyl) optionally having 1 to 3 substituents selected from
   (i) C 1-6  alkyl optionally substituted by 1 to 3 halogen atoms,   (ii) hydroxy,   (iii) C 1-6  alkoxy, and   (iv) a halogen atom;
 
(46) C 6-10  aryl-carbamoyl (e.g., phenylcarbamoyl);
 
(47) C 6-10  arylsulfinyl (e.g., phenylsulfinyl);
 
(48) optionally halogenated C 6-10  arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl);
 
(49) heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio, benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio) optionally having C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6  alkyl-carbonyloxy; and the like.
       

     Examples of the “cyclic group” of the “cyclic group optionally having substituent(s)” in the present specification include an aromatic group, a non-aromatic cyclic group and the like. 
     Examples of the “aromatic group” include an aromatic hydrocarbon group and an aromatic heterocyclic group. 
     Examples of the “aromatic hydrocarbon group” include C 6-14  aryl and the like. 
     Examples of the “aromatic heterocyclic group” include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms, a 5-membered aromatic heterocycle containing one sulfur atom and a benzene ring are condensed, and the like. 
     Examples of the “aromatic heterocyclic group” include 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic groups such as furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g., 1,3,5-triazin-2-yl, 1,3,5-triazin-4-yl, 1,2,3-triazin-4-yl, 1,2,4-triazin-3-yl) and the like; 
     fused aromatic heterocyclic groups such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g., 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl), benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (e.g., 1H-indazol-3-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl, 2H-imidazo[1,2-a]pyridin-3-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-3-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl), pyrazolotriazinyl (e.g., pyrazolo[5,1-c][1,2,4]triazin-3-yl) and the like; and the like. 
     Examples of the “non-aromatic cyclic group” include a non-aromatic cyclic hydrocarbon group and a non-aromatic heterocyclic group. 
     Examples of the “non-aromatic cyclic hydrocarbon group” include C 3-10  cycloalkyl, C 3-10  cycloalkenyl and C 4-10  cycloalkadienyl, each of which is optionally condensed with a benzene ring, and the like. 
     Examples of the “non-aromatic heterocyclic group” include a 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused non-aromatic heterocyclic group. Examples of the fused non-aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to such 4- to 7-membered monocyclic non-aromatic heterocyclic group, and 1 or 2 rings selected from a 5- or 6-membered heterocycle containing 1 or 2 nitrogen atoms, a 5-membered heterocycle containing one sulfur atom and a benzene ring are condensed, and the like. 
     Examples of the “non-aromatic heterocyclic group” include 4- to 7-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (e.g., piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleniminyl (e.g., hexamethylenimin-1-yl), oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl (e.g., thiazolidin-2-yl), imidazolidinyl (e.g., imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl), thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl, imidazolin-3-yl), dioxolyl (e.g., 1,3-dioxol-4-yl), dioxolanyl (e.g., 1,3-dioxolan-4-yl), dihydrooxadiazolyl (e.g., 4,5-dihydro-1,2,4-oxadiazol-3-yl), 2-thioxo-1,3-oxazolidin-5-yl, pyranyl (e.g., 4-pyranyl), tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (e.g., 4-thiopyranyl), tetrahydrothiopyranyl (e.g., 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl), 1,1-dioxidotetrahydrothiopyranyl (e.g., 1,1-dioxidotetrahydrothiopyran-4-yl), tetrahydrofuryl (e.g., tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (e.g., pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (e.g., pyrazolin-1-yl), tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-1-yl), dihydrotriazolyl (e.g., 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (e.g., 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl) and the like; fused non-aromatic heterocyclic groups such as dihydroindolyl (e.g., 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g., 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-5-yl), dihydrobenzodioxinyl (e.g., 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (e.g., 3,4-dihydro-2H-1,5-benzodioxepinyl), tetrahydrobenzofuranyl (e.g., 4,5,6,7-tetrahydrobenzofuran-3-yl), chromenyl (e.g., 4H-chromen-2-yl, 2H-chromen-3-yl), dihydroquinolinyl (e.g., 1,2-dihydroquinolin-4-yl), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (e.g., 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (e.g., 1,4-dihydrophthalazin-4-yl) and the like; and the like. 
     The “cyclic group” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different. Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. 
     Examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent(s)” in the present specification include an aromatic heterocyclic group and a non-aromatic heterocyclic group. 
     Examples of the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” include those similar to the “aromatic heterocyclic group” and “non-aromatic heterocyclic group” which are exemplified as the “cyclic group” of the “cyclic group optionally having substituent(s)”. 
     The above-mentioned “heterocyclic group” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different. Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. 
     Examples of the “hydroxy optionally having a substituent” in the present specification include (1) hydroxy, (2) hydroxy having, instead of a hydrogen atom of hydroxy, for example, a substituent selected from the aforementioned “hydrocarbon group optionally having substituent(s)”, the aforementioned “heterocyclic group optionally having substituent(s)”, the groups exemplified as the substituents which the aforementioned “hydrocarbon group optionally having substituent(s)” optionally has, and the like, and the like. 
     Specific examples of the “hydroxy optionally having a substituent” include (1) hydroxy, (2) hydroxy optionally having a substituent selected from C 1-10  alkyl optionally having substituent(s), C 2-10  alkenyl optionally having substituent(s), C 3-10  cycloalkyl optionally having substituent(s), C 3-10  cycloalkenyl optionally having substituent(s), C 6-14  aryl optionally having substituent(s), C 7-13  aralkyl optionally having substituent(s), C 8-13  arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like. 
     The aforementioned C 1-10  alkyl, C 2-10  alkenyl, C 3-10  cycloalkyl, C 3-10  cycloalkenyl, C 6-14  aryl, C 7-13  aralkyl and C 8-13  arylalkenyl optionally have substituent(s) (preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     Examples of the “amino optionally having substituent(s)” in the present specification include (1) amino, (2) amino having, instead of hydrogen atom(s) of amino, for example, 1 or 2 substituents selected from the aforementioned “hydrocarbon group optionally having substituent(s)”, the aforementioned “heterocyclic group optionally having substituent(s)”, the groups exemplified as the substituents which the aforementioned “hydrocarbon group optionally having substituent(s)” optionally has, and the like, and the like. 
     Specific examples of the “amino optionally having substituent(s)” include (1) amino, (2) amino optionally having 1 or 2 substituents selected from C 1-10  alkyl optionally having substituent(s), C 2-10  alkenyl optionally having substituent(s), C 3-10  cycloalkyl optionally having substituent(s), C 3-10  cycloalkenyl optionally having substituent(s), C 6-14  aryl optionally having substituent(s), C 7-13  aralkyl optionally having substituent(s), C 8-13  arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like. 
     The aforementioned C 1-10  alkyl, C 2-10  alkenyl, C 3-10  cycloalkyl, C 3-10  cycloalkenyl, C 6-14  aryl, C 7-13  aralkyl and C 8-13  arylalkenyl optionally have substituent(s) (preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     Examples of the “mercapto optionally having a substituent” in the present specification include (1) mercapto, (2) mercapto having, instead of a hydrogen atom of mercapto, for example, a substituent selected from the aforementioned “hydrocarbon group optionally having substituent(s)”, the aforementioned “heterocyclic group optionally having substituent(s)”, the groups exemplified as the substituents which the aforementioned “hydrocarbon group optionally having substituent(s)” optionally has, and the like, and the like. 
     Specific examples of the “mercapto optionally having a substituent” include (1) mercapto, (2) mercapto optionally having a substituent selected from C 1-10  alkyl optionally having substituent(s), C 2-10  alkenyl optionally having substituent(s), C 3-10  cycloalkyl optionally having substituent(s), C 3-10  cycloalkenyl optionally having substituent(s), C 6-14  aryl optionally having substituent(s), C 7-13  aralkyl optionally having substituent(s), C 8-13  arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like. 
     The aforementioned C 1-10  alkyl, C 2-10  alkenyl, C 3-10  cycloalkyl, C 3-10  cycloalkenyl, C 6-14  aryl, C 7-13  aralkyl and CB-13 arylalkenyl optionally have substituent(s) (preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     Examples of the “acyl” in the present specification include a group represented by the formula: —COR A , —CO—OR A , —SO 2 R A , —SOR A , —CO—NR A ′R B ′ or —CS—NR A ′R B ′ [wherein R A  is a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), and R A ′ and R B ′ are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), or R A ′ and R B ′ optionally form, together with the adjacent nitrogen atom, a nitrogen-containing heterocycle optionally having substituent(s)] and the like. 
     Examples of the “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent(s)” formed by R A ′ and R B ′ together with the adjacent nitrogen atom include a 5- to 7-membered nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and optionally further containing one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Specific examples of the nitrogen-containing heterocycle include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like. 
     The nitrogen-containing heterocycle optionally has substituent(s) (preferably 1 to 3, more preferably 1 or 2 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     Preferable examples of the “acyl” include 
     (1) formyl;
 
(2) carboxy;
 
(3) carbamoyl;
 
(4) C 1-6  alkyl-carbonyl;
 
(5) C 1-6  alkoxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C 1-6  alkoxy-carbonyl and C 1-6  alkyl-carbonyloxy (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxymethoxycarbonyl, carboxyethoxycarbonyl, carboxybutoxycarbonyl; carbamoylmethoxycarbonyl; thiocarbamoylmethoxycarbonyl; ethoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl, methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl; tert-butylcarbonyloxymethoxycarbonyl);
 
(6) C 3-10  cycloalkyl-carbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl);
 
(7) C 6-14  aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) optionally having 1 to 3 substituents selected from a halogen atom, cyano, C 1-6  alkyl optionally substituted by 1 to 3 halogen atoms, C 1-6  alkoxy, carboxy, C 1-6  alkoxy-carbonyl, an aromatic heterocyclic group (e.g., tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (e.g., oxooxadiazolyl) and carbamoyl;
 
(8) C 6-14  aryloxy-carbonyl (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) optionally having 1 to 3 substituents selected from carboxy, C 1-6  alkoxy-carbonyl and carbamoyl;
 
(9) C 7-13  aralkyloxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C 1-6  alkoxy-carbonyl, a halogen atom, cyano, nitro, C 1-6  alkoxy, C 1-6  alkylsulfonyl and C 1-6  alkyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl; carboxybenzyloxycarbonyl; methoxycarbonylbenzyloxycarbonyl; biphenylylmethoxycarbonyl);
 
(10) carbamoyl mono- or di-substituted by C 1-6  alkyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl);
 
(11) C 1-6  alkylsulfonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl and C 1-6  alkoxy-carbonyl (e.g., methylsulfonyl, carboxymethylsulfonyl);
 
(12) C 1-6  alkylsulfinyl (e.g., methylsulfinyl);
 
(13) thiocarbamoyl;
 
(14) C 7-13  aralkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl);
 
(15) aromatic heterocyclyl (e.g., furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, benzofuryl, benzothienyl, quinoxalinyl)-carbonyl (e.g., furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl, pyrazolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, benzofurylcarbonyl, benzothienylcarbonyl, quinoxalinylcarbonyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl, C 6-14  aryl, C 7-13  aralkyl, C 1-6  alkoxy, carboxy, C 1-6  alkoxy-carbonyl and carbamoyl; and the like.
 
     Each symbol in the formula (I) is described in detail in the following. 
     R 1  is a substituent. 
     Examples of the “substituent” for R 1  include a halogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s), acyl and the like. 
     R 1  is preferably a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s) or the like, more preferably a hydrocarbon group optionally having substituent(s), further more preferably C 1-6  alkyl optionally having substituent(s), C 7-13  aralkyl optionally having substituent(s) or the like, particularly preferably 
     (a) C 1-6  alkyl substituted by hydroxy optionally having a substituent (e.g., a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), heterocyclylcarbonyl optionally having substituent(s)),
 
(b) C 1-6  alkyl substituted by a heterocyclic group optionally having substituent(s) or amino optionally having substituent(s),
 
(c) C 7-13  aralkyl optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), cyano, hydroxy, C 1-6  alkoxy optionally having substituent(s), a heterocyclic group optionally having substituent(s)), or the like.
 
     More preferably, R 1  is 
     (a) C 1-6  alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like),
 
(b) C 1-6  alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s)),
 
(c) C 7-13  aralkyl optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s)), or the like.
 
     Preferable embodiments of R 1  include 
     (1) C 7-13  aralkyl (e.g., benzyl, phenethyl, phenylpropyl) optionally having 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,   (iii) cyano,   (iv) hydroxy,   (v) optionally halogenated C 1-6  alkoxy (e.g., trifluoromethoxy), and   (vi) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl);
 
(2) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;
 
(3) C 1-6  alkyl optionally having 1 to 5 substituents selected from
   (i) a halogen atom,   (ii) hydroxy optionally having a substituent selected from
           (a) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) cyano,   C) C 1-6  alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   D) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy),   E) C 1-4  alkylenedioxy,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   J) carbamoyl,   K) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   L) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   M) mono- or di-C 1-6  alkylamino,   O) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl), and   P) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl and oxo,   
               (b) C 6-10  aryl condensed with C 3-10  cycloalkane (e.g., tetrahydronaphthyl) optionally having 1 or 2 oxo,   (c) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6  alkyl, C 1-6  alkoxy-carbonyl-C 1-6  alkyl, mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl), C 6-10  aryl (e.g., phenyl), C 1-6  alkoxy-carbonyl and carboxy,   (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, dihydrobenzoxazolyl, benzisoxazolyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl, C 1-6  alkoxy and oxo,   (e) C 7-13  aralkyl (e.g., benzyl),   (f) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl), and   (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),   
           (iii) C 6-10  arylthio (e.g., phenylthio),   (iv) amino optionally having 1 or 2 substituents selected from
           (a) C 1-6  alkyl,   (b) C 6-10  aryl (e.g., phenyl),   (c) C 3-6  cycloalkyl-carbonyl,   (d) C 6-10  aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (e) C 1-6  alkoxy-carbonyl-C 1-6  alkyl-carbonyl, and   (f) carbamoyl-C 1-6  alkyl-carbonyl,   
           (v) a 5- or 6-membered heterocyclic group (e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl) optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C 1-6  alkyl-carbonyloxy,   (b) C 3-6  cycloalkyl,   (c) C 6-10  aryl (e.g., phenyl),   (d) C 1-6  alkyl-carbonyl, and   (e) C 1-6  alkoxy-carbonyl, and   
           (vi) a 9- or 10-membered fused heterocyclic group (e.g., indolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from cyano, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy-carbonyl and oxo;
 
(4) C 3-10  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl); and the like.
       

     Other preferable embodiments of R 1  include 
     (1) C 7-13  aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,   (iii) cyano,   (iv) hydroxy,   (v) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy),   (vi) C 6-10  aryloxy (e.g., phenoxy),   (vii) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl), and   (viii) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl, pyrazolyl, oxadiazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and C 1-6  alkoxy;
 
(2) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;
 
(3) C 1-6  alkyl optionally having 1 to 5 substituents selected from
   (i) a halogen atom,   (ii) hydroxy optionally having a substituent selected from
           (a) C 6-10  aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) cyano,   C) C 1-6  alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   D) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy),   E) C 1-4  alkylenedioxy,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   J) carbamoyl,   K) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   L) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   M) mono- or di-C 1-6  alkylamino,   O) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl),   P) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl and oxo, and   Q) a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
               (b) C 6-10  aryl condensed with C 3-10  cycloalkane (e.g., tetrahydronaphthyl) optionally having 1 or 2 oxo,   (c) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6  alkyl, C 1-6  alkoxy-carbonyl-C 1-6  alkyl, mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl), C 6-10  aryl (e.g., phenyl), C 1-6  alkoxy-carbonyl and carboxy,   (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkoxy-carbonyl, C 3-10  cycloalkyl, a halogen atom and oxo,   (e) C 7-13  aralkyl (e.g., benzyl),   (f) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl),   (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl), and   (h) C 6-10  aryl-carbamoyl (e.g., phenylcarbamoyl),   
           (iii) C 6-10  arylthio (e.g., phenylthio),   (iv) C 6-10  arylsulfinyl (e.g., phenylsulfinyl),   (v) optionally halogenated C 6-10  arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),   (vi) amino optionally having 1 or 2 substituents selected from
           (a) C 1-6  alkyl,   (b) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) optionally halogenated C 1-6  alkyl (e.g., methyl, ethyl, isopropyl, trifluoromethyl),   C) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),   D) cyano,   E) nitro,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) C 1-4  alkylenedioxy, and   J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,   
               (c) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),   (d) C 7-13  aralkyl (e.g., benzyl),   (e) C 1-6  alkyl-carbonyl,   (f) C 3-6  cycloalkyl-carbonyl,   (g) C 6-10  aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (h) C 1-6  alkoxy-carbonyl-C 1-6  alkyl-carbonyl,   (i) carbamoyl-C 1-6  alkyl-carbonyl,   (j) a 5- or 6-membered heterocyclic group (e.g., pyridyl), and   (k) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
           (vii) a 5- or 6-membered heterocyclic group (e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl) optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C 1-6  alkyl-carbonyloxy,   (b) C 3-6  cycloalkyl,   (c) C 6-10  aryl (e.g., phenyl),   (d) C 1-6  alkyl-carbonyl, and   (e) C 1-6  alkoxy-carbonyl,   
           (viii) a 9- or 10-membered fused heterocyclic group (e.g., indolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy-carbonyl and oxo,   (ix) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and C 6-10  aryl,   (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6  alkyl-carbonyloxy, and   (xi) a 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio);
 
(4) C 3-10  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl); and the like.
       

     Still other preferable embodiments of R 1  include 
     (1) C 7-13  aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,   (iii) cyano,   (iv) hydroxy,   (v) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy),   (vi) C 6-10  aryloxy (e.g., phenoxy),   (vii) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl), and   (viii) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl, pyrazolyl, oxadiazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and C 1-6  alkoxy;
 
(2) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;
 
(3) C 1-6  alkyl optionally having 1 to 5 substituents selected from
   (i) a halogen atom,   (ii) hydroxy optionally having a substituent selected from
           (a) C 6-10  aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) cyano,   C) C 1-6  alkyl optionally having 1 to 3 substituents selected from a halogen atom, carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   D) C 1-6  alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   E) C 1-4  alkylenedioxy,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   J) carbamoyl,   K) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   L) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   M) mono- or di-C 1-6  alkylamino,   O) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl),   P) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl and oxo, and   Q) a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
               (b) C 6-10  aryl condensed with C 3-10  cycloalkane (e.g., tetrahydronaphthyl) optionally having 1 or 2 oxo,   (c) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6  alkyl, C 1-6  alkoxy-carbonyl-C 1-6  alkyl, mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl), C 6-10  aryl (e.g., phenyl), C 1-6  alkoxy-carbonyl and carboxy,   (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from
               A) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkoxy-carbonyl,   B) C 1-6  alkoxy,   C) C 1-6  alkoxy-carbonyl,   D) C 3-10  cycloalkyl,   E) a halogen atom, and   F) oxo,   
               (e) C 7-13  aralkyl (e.g., benzyl),   (f) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl),   (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),   (h) C 6-10  aryl-carbamoyl (e.g., phenylcarbamoyl), and   (i) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl),   
           (iii) C 6-10  arylthio (e.g., phenylthio),   (iv) C 6-10  arylsulfinyl (e.g., phenylsulfinyl),   (v) optionally halogenated C 6-10  arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),   (vi) amino optionally having 1 or 2 substituents selected from
           (a) C 1-6  alkyl,   (b) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) optionally halogenated C 1-6  alkyl (e.g., methyl, ethyl, isopropyl, trifluoromethyl),   C) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),   D) cyano,   E) nitro,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) C 1-4  alkylenedioxy, and   J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,   
               (c) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),   (d) C 7-13  aralkyl (e.g., benzyl),   (e) C 1-6  alkyl-carbonyl,   (f) C 3-6  cycloalkyl-carbonyl,   (g) C 6-10  aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (h) C 1-6  alkoxy-carbonyl-C 1-6  alkyl-carbonyl,   (i) carbamoyl-C 1-6  alkyl-carbonyl,   (j) a 5- or 6-membered heterocyclic group (e.g., pyridyl), and   (k) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
           (vii) a 5- or 6-membered heterocyclic group (e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl, tetrazolyl) optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C 1-6  alkyl-carbonyloxy,   (b) C 3-6  cycloalkyl,   (c) C 6-10  aryl (e.g., phenyl),   (d) C 1-6  alkyl-carbonyl, and   (e) C 1-6  alkoxy-carbonyl,   
           (viii) a 9- or 10-membered fused heterocyclic group (e.g., indolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy-carbonyl and oxo,   (ix) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and C 6-10  aryl,   (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6  alkyl-carbonyloxy, and   (xi) 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio);
 
(4) C 3-10  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl); and the like.
       

     R 2  is a cyclic group optionally having substituent(s), C 1-10  alkyl optionally having substituent(s), C 2-10  alkenyl optionally having substituent(s) or C 2-10  alkynyl optionally having substituent(s). 
     The aforementioned C 1-10  alkyl, C 2-10  alkenyl and C 2-10  alkynyl optionally have substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     R 2  is preferably C 6-14  aryl optionally having substituent(s), C 3-10  cycloalkyl optionally having substituent(s) or the like. 
     R 2  is more preferably optionally halogenated C 6-10  aryl (e.g., phenyl), C 3-6  cycloalkyl (e.g., cyclopropyl, cyclohexyl) or the like. 
     R 2  is particularly preferably optionally halogenated C 6-10  aryl (e.g., phenyl) or the like. 
     R 3  is a hydrogen atom, a halogen atom, C 1-6  alkyl or C 1-6  alkoxy. 
     R 3  is preferably a hydrogen atom, a halogen atom, C 1-3  alkyl (e.g., methyl, ethyl, propyl, isopropyl), C 1-3  alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy) or the like, more preferably a hydrogen atom or the like. 
     X is bond or spacer having 1 to 6 atoms in the main chain. 
     The “main chain” of the “spacer having 1 to 6 atoms in the main chain” for X is a straight chain connecting ring A and imidazole, and the atom number of the main chain is counted such that the number of atoms in the main chain will be minimum. The “main chain” consists of 1 to 6 atoms selected from a carbon atom and a hetero atom (e.g., O, S, N etc.), and may be saturated or unsaturated. In addition, S may be oxidized. 
     Examples of the “spacer having 1 to 6 atoms in the main chain” include straight chain C 1-6  alkylene, —X 1 —NH—X 2 —, —X 1 —O—X 2 — and —X 1 —S—X 2 — [wherein X 1  and X 2  are the same or different and each is bond or straight chain C 1-5  alkylene, when X 1  and X 2  are both straight chain C 1-5  alkylene, then the total carbon number of straight chain C 1-5  alkylene for X 1  and straight chain C 1-5  alkylene for X 2  is 5 or less, and S is optionally oxidized] and the like. 
     Examples of the “straight chain C 1-6  alkylene” include —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —. 
     Examples of the “straight chain C 1-5  alkylene” for X 1  or X 2  include —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 — and —CH 2 CH 2 CH 2 CH 2 CH 2 —. 
     The “spacer having 1 to 6 atoms in the main chain” optionally has substituent(s) (preferably 1 to 3 substituents) at substitutable position(s) (optionally at the carbon atom and nitrogen atom constituting the main chain). Examples of the substituent include groups exemplified as the substituents which the aforementioned “hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different. 
     X is preferably bond, C 1-6  alkylene optionally having substituent(s) or the like. 
     X is more preferably 
     (1) bond,
 
(2) C 1-6  alkylene optionally having substituent(s) selected from C 1-6  alkyl and C 6-10  aryl (e.g., phenyl) or the like.
 
     Ring A is C 5-7  cycloalkane optionally having substituent(s). 
     Examples of the “C 5-7  cycloalkane” of the “C 5-7  cycloalkane optionally having substituent(s)” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane and the like. 
     The “C 5-7  cycloalkane” of the “C 5-7  cycloalkane optionally having substituent(s)” optionally has substituent(s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position(s). When the number of the substituents is not less than 2, respective substituents may be the same or different, and may be substituted at the same carbon of ring A. In addition, two substituents may be bonded each other to form, with C 5-7  cycloalkane, an optionally substituted ring (a fused ring or spiro ring). 
     Examples of the fused ring or spiro ring include a fused ring or spiro ring consisting of C 5-7  cycloalkane and C 3-10  cycloalkane, C 3-10  cycloalkene, C 4-10  cycloalkadiene or a heterocycle. Examples of the “C 3-10  cycloalkane”, “C 3-10  cycloalkene”, “C 4-10  cycloalkadiene” and “heterocycle” include rings corresponding to the aforementioned C 3-10  cycloalkyl, C 3-10  cycloalkenyl, C 4-10  cycloalkadienyl and heterocyclic group. 
     Examples of the “substituent” of the “C 5-7  cycloalkane optionally having substituent(s)” include a halogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s), mercapto optionally having substituent(s), cyano, acyl and the like. Preferable example thereof include a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent, amino optionally having substituent(s) and the like. More preferable Example thereof include a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and the like. 
     Ring A is preferably C 5-7  cycloalkane optionally having substituent(s) selected from a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and amino optionally having substituent(s). 
     More preferably, ring A is 
     (a) C 5-7  cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., a halogen atom, a hydrocarbon group optionally having substituent(s) etc.), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., a hydrocarbon group optionally having substituent(s), acyl etc.).
 
     Further more preferably, ring A is 
     (a) C 5-7  cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., C 1-3  alkyl optionally having substituent(s) etc.), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., C 1-6  alkoxy-carbonyl etc.).
 
     Still more preferably, ring A is 
     (a) C 5-7  cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C 1-3  alkyl optionally having substituent(s), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., C 1-6  alkoxy-carbonyl etc.).
 
     Still more preferably, ring A is 
     (a) C 5-7  cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., cyclopropylmethyl, methyl, methoxymethyl, ethoxymethyl etc.), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., methoxycarbonyl, ethoxycarbonyl etc.).
 
     Preferable embodiments of ring A is the following [A] and [B] and the like. 
     [A]: C 5-7  cycloalkane optionally having 1 to 5 substituents selected from
 
(1) a halogen atom;
 
(2) C 1-6  alkyl optionally having 1 to 5 substituents selected from
         (i) a halogen atom,   (ii) cyano,   (iii) C 3-6  cycloalkyl,   (iv) hydroxy,   (v) C 1-6  alkoxy optionally having 1 or 2 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 1-6  alkoxy optionally having 1 or 2 hydroxy,   (d) C 3-6  cycloalkyl,   (e) mono- or di-C 1-6  alkylamino,   (f) C 1-6  alkyl-carbonylamino,   (g) C 1-6  alkylthio,   (h) C 1-6  alkylsulfonyl, and   (i) a heterocyclic group (e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   
           (vi) C 3-6  cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),   (vii) C 6-10  aryloxy (e.g., phenoxy),   (viii) 5- or 6-membered heterocyclyloxy (e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyloxy) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   (ix) C 1-6  alkyl-carbonyloxy,   (x) carboxy,   (xi) C 1-6  alkoxy-carbonyl,   (xii) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl),   (xiii) C 1-6  alkylthio,   (xiv) C 1-6  alkylsulfonyl,   (xv) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl) and C 1-6  alkylsulfonyl-C 1-6  alkyl, and   (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);
 
(3) hydroxy optionally having a substituent selected from
   (i) C 7-13  aralkyl (e.g., benzyl),   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkyl-carbonylamino,   (iii) C 2-6  alkenyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 6-10  aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and   (vi) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkylsulfonyl-C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl);
 
(4) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkoxy-C 2-6  alkyl, C 3-6  cycloalkyl-C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 3-6  cycloalkyl-carbonyl, C 1-6  alkoxy-carbonyl, C 1-6  alkoxy-C 1-6  alkoxy-carbonyl, mono- or di-C 1-6  alkyl-carbamoyl and C 3-6  cycloalkylsulfonyl;
 
(5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;
 
(6) C 1-3  alkylidene (e.g., methylene) optionally having a substituent selected from C 1-6  alkoxy-carbonyl and C 1-6  alkyl-carbamoyl;
 
(7) oxo; and
 
(8) azido;
 
[B]: C 5-7  cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo.
       

     More preferable embodiments of ring A is the following [A] and [B] and the like. 
     [A]: C 5-7  cycloalkane optionally having 1 to 5 substituents selected from
 
(1) a halogen atom;
 
(2) C 1-6  alkyl optionally having 1 to 5 substituents selected from
         (i) a halogen atom,   (ii) cyano,   (iii) C 3-6  cycloalkyl,   (iv) hydroxy,   (v) C 1-6  alkoxy optionally having 1 or 2 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 1-6  alkoxy optionally having 1 or 2 hydroxy,   (d) C 3-6  cycloalkyl,   (e) mono- or di-C 1-6  alkylamino,   (f) C 1-6  alkyl-carbonylamino,   (g) C 1-6  alkylthio,   (h) C 1-6  alkylsulfonyl, and   (i) a heterocyclic group (e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   
           (vi) C 3-6  cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),   (vii) C 6-10  aryloxy (e.g., phenoxy),   (viii) 5- or 6-membered heterocyclyloxy (e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyloxy) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   (ix) C 1-6  alkyl-carbonyloxy,   (x) carboxy,   (xi) C 1-6  alkoxy-carbonyl,   (xii) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl),   (xiii) C 1-6  alkylthio,   (xiv) C 1-6  alkylsulfonyl,   (xv) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl) and C 1-6  alkylsulfonyl-C 1-6  alkyl, and   (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);
 
(3) hydroxy optionally having a substituent selected from
   (i) C 7-13  aralkyl (e.g., benzyl),   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkyl-carbonylamino,   (iii) C 2-6  alkenyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 6-10  aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and   (vi) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkylsulfonyl-C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl);
 
(4) amino optionally having 1 or 2 substituents selected from
   (i) C 1-6  alkyl,   (ii) C 1-6  alkoxy-C 2-6  alkyl,   (iii) C 3-6  cycloalkyl-C 1-6  alkyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 3-6  cycloalkyl-carbonyl,   (vi) C 1-6  alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom, C 1-6  alkoxy and C 3-6  cycloalkyl,   (vii) C 3-6  cycloalkoxy-carbonyl,   (viii) C 1-6  alkoxy-C 1-6  alkoxy-carbonyl,   (ix) mono- or di-C 1-6  alkyl-carbamoyl,   (x) C 3-6  cycloalkylsulfonyl,   (xi) C 1-6  alkylsulfonyl, and   (xii) mono- or di-C 1-6  alkylsulfamoyl;
 
(5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;
 
(6) C 1-3  alkylidene (e.g., methylene) optionally having a substituent selected from C 1-6  alkoxy-carbonyl and C 1-6  alkyl-carbamoyl;
 
(7) oxo; and
 
(8) azido;
 
[B]: C 5-7  cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo.
       

     Ring B is piperazine optionally further having substituent(s) besides R 1 . 
     Examples of the “substituent” which ring B optionally further has include groups exemplified as the “substituent” for R 1  optionally has, and the like. Specific examples of the “substituent” include optionally substituted C 1-6  alkyl, for example, C 1-6  alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo, and the like. 
     Ring B is preferably a ring represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is as defined above. The piperazine ring optionally has 1 to 3 C 1-6  alkyl at the ring-constituting carbon atom. 
     Preferable examples of compound (I) include the following compounds. 
     [Compound A] 
     Compound (I) wherein 
     R 1  is a hydrocarbon group optionally having substituent(s); 
     R 2  is C 6-14  aryl optionally having substituent(s) or C 3-10  cycloalkyl optionally having substituent(s); 
     R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl or C 1-3  alkoxy; 
     X is bond or C 1-6  alkylene optionally having substituent(s); and 
     ring A is C 5-7  cycloalkane optionally having substituent(s) selected from a halogen atom, a hydrocarbon group optionally having substituent(s), hydroxy optionally having a substituent and amino optionally having substituent(s). 
     [Compound B] 
     A compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1  is 
     (a) C 1-6  alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like),
 
(b) C 1-6  alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s)), or
 
(c) C 7-13  aralkyl optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s));
 
     R 2  is optionally halogenated C 6-10  aryl (e.g., phenyl), or C 3-6  cycloalkyl (e.g., cyclopropyl, cyclohexyl); 
     R 3  is a hydrogen atom; 
     X is 
     (1) bond, or
 
(2) C 1-6  alkylene optionally having substituent(s) selected from C 1-6  alkyl and C 6-10  aryl (e.g., phenyl); and
 
     ring A is 
     (a) C 5-7  cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., C 1-3  alkyl optionally having substituent(s) etc.), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., C 1-6  alkoxy-carbonyl etc.).
 
     [Compound B′] 
     A compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1  is 
     (a) C 1-6  alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like),
 
(b) C 1-6  alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s)), or
 
(c) C 7-13  aralkyl optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s));
 
     R 2  is optionally halogenated C 6-10  aryl (e.g., phenyl); 
     R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl (e.g., methyl, ethyl, propyl, isopropyl) or C 1-3  alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy); 
     X is 
     (1) bond, or
 
(2) C 1-6  alkylene optionally having substituent(s) (e.g., C 1-6  alkyl, C 6-10  aryl (e.g., phenyl), etc.); and
 
     ring A is 
     (a) C 5-7  cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C 1-3  alkyl optionally having substituent(s), or
 
(b) C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., C 1-6  alkoxy-carbonyl etc.).
 
     [Compound B′-1] 
     Compound B′ wherein R 1  is C 1-6  alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl), benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl), benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl), benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-5-yl), benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g., indol-5-yl, indol-6-yl), indazolyl (e.g., 1H-indazol-5-yl, 1H-indazol-6-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridin-5-yl, 1H-imidazo[4,5-c]pyridin-5-yl, 2H-imidazo[1,2-a]pyridin-5-yl), imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazin-5-yl), pyrazolopyridyl (e.g., 1H-pyrazolo[4,3-c]pyridin-5-yl), pyrazolothienyl (e.g., 2H-pyrazolo[3,4-b]thiophen-2-yl) and the like). 
     [Compound B′-2] 
     Compound B′ wherein R 1  is C 1-6  alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s)). 
     [Compound B′-3] 
     Compound B′ wherein R 1  is C 7-13  aralkyl optionally having substituent(s) (e.g., a halogen atom, C 1-6  alkyl optionally having substituent(s), C 1-6  alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s)). 
     [Compound B′-4] 
     Compound B′ wherein ring A is C 5-7  cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C 1-3  alkyl optionally having substituent(s). 
     [Compound B′-4] 
     Compound B′ wherein ring A is C 5-7  cycloalkane substituted by amino optionally having substituent(s) (e.g., C 1-6  alkoxy-carbonyl etc.). 
     [Compound C] 
     A compound represented by the formula: 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1  is 
     (1) C 7-13  aralkyl (e.g., benzyl, phenethyl, phenylpropyl) optionally having 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,   (iii) cyano,   (iv) hydroxy,   (v) optionally halogenated C 1-6  alkoxy (e.g., trifluoromethoxy), and   (vi) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl);
 
(2) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;
 
(3) C 1-6  alkyl optionally having 1 to 5 substituents selected from
   (i) a halogen atom,   (ii) hydroxy optionally having a substituent selected from
           (a) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) cyano,   C) C 1-6  alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   D) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy),   E) C 1-4  alkylenedioxy,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   J) carbamoyl,   K) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   L) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   M) mono- or di-C 1-6  alkylamino,   O) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl), and   P) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl and oxo,   
               (b) C 6-10  aryl condensed with C 3-10  cycloalkane (e.g., tetrahydronaphthyl) optionally having 1 or 2 oxo,   (c) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6  alkyl, C 1-6  alkoxy-carbonyl-C 1-6  alkyl, mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl), C 6-10  aryl (e.g., phenyl), C 1-6  alkoxy-carbonyl and carboxy,   (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, dihydrobenzoxazolyl, benzisoxazolyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl, C 1-6  alkoxy and oxo,   (e) C 7-13  aralkyl (e.g., benzyl),   (f) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl), and   (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),   
           (iii) C 6-10  arylthio (e.g., phenylthio),   (iv) amino optionally having 1 or 2 substituents selected from
           (a) C 1-6  alkyl,   (b) C 6-10  aryl (e.g., phenyl),   (c) C 3-6  cycloalkyl-carbonyl,   (d) C 6-10  aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (e) C 1-6  alkoxy-carbonyl-C 1-6  alkyl-carbonyl, and   (f) carbamoyl-C 1-6  alkyl-carbonyl,   
           (v) a 5- or 6-membered heterocyclic group (e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl) optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C 1-6  alkyl-carbonyloxy,   (b) C 3-6  cycloalkyl,   (c) C 6-10  aryl (e.g., phenyl),   (d) C 1-6  alkyl-carbonyl, and   (e) C 1-6  alkoxy-carbonyl, and   
           (vi) a 9- or 10-membered fused heterocyclic group (e.g., indolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from cyano, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy-carbonyl and oxo; or
 
(4) C 3-10  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl);
       

     R 2  is optionally halogenated C 6-10  aryl (e.g., phenyl), or C 3-6  cycloalkyl (e.g., cyclopropyl, cyclohexyl); 
     R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl or C 1-3  alkoxy; 
     X is 
     (1) bond, or
 
(2) C 1-6  alkylene optionally having substituent(s) selected from C 1-6  alkyl and C 6-10  aryl (e.g., phenyl); and
 
     ring A is 
     [A] C 5-7  cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C 5-7  cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo:
 
(1) a halogen atom;
 
(2) C 1-6  alkyl optionally having 1 to 5 substituents selected from
         (i) a halogen atom,   (ii) cyano,   (iii) C 3-6  cycloalkyl,   (iv) hydroxy,   (v) C 1-6  alkoxy optionally having 1 or 2 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 1-6  alkoxy optionally having 1 or 2 hydroxy,   (d) C 3-6  cycloalkyl,   (e) mono- or di-C 1-6  alkylamino,   (f) C 1-6  alkyl-carbonylamino,   (g) C 1-6  alkylthio,   (h) C 1-6  alkylsulfonyl, and   (i) a heterocyclic group (e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   
           (vi) C 3-6  cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),   (vii) C 6-10  aryloxy (e.g., phenoxy),   (viii) 5- or 6-membered heterocyclyloxy (e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyloxy) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   (ix) C 1-6  alkyl-carbonyloxy,   (x) carboxy,   (xi) C 1-6  alkoxy-carbonyl,   (xii) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl),   (xiii) C 1-6  alkylthio,   (xiv) C 1-6  alkylsulfonyl,   (xv) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl) and C 1-6  alkylsulfonyl-C 1-6  alkyl, and   (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);
 
(3) hydroxy optionally having a substituent selected from
   (i) C 7-13  aralkyl (e.g., benzyl),   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkyl-carbonylamino,   (iii) C 2-6  alkenyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 6-10  aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and   (vi) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkylsulfonyl-C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl);
 
(4) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkoxy-C 2-6  alkyl, C 3-6  cycloalkyl-C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 3-6  cycloalkyl-carbonyl, C 1-6  alkoxy-carbonyl, C 1-6  alkoxy-C 1-6  alkoxy-carbonyl, mono- or di-C 1-6  alkyl-carbamoyl and C 3-6  cycloalkylsulfonyl;
 
(5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;
 
(6) C 1-3  alkylidene (e.g., methylene) optionally having a substituent selected from C 1-6  alkoxy-carbonyl and C 1-6  alkyl-carbamoyl;
 
(7) oxo; and
 
(8) azido.
       

     [Compound D] 
     Compound (I) wherein 
     R 1  is 
     (1) C 7-13  aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,   (iii) cyano,   (iv) hydroxy,   (v) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy),   (vi) C 6-10  aryloxy (e.g., phenoxy),   (vii) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl), and   (viii) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and C 1-6  alkoxy;
 
(2) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;
 
(3) C 1-6  alkyl optionally having 1 to 5 substituents selected from
   (i) a halogen atom,   (ii) hydroxy optionally having a substituent selected from
           (a) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) cyano,   C) C 1-6  alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   D) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy),   E) C 1-4  alkylenedioxy,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   J) carbamoyl,   K) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   L) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   M) mono- or di-C 1-6  alkylamino,   O) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl),   P) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl and oxo, and   Q) a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
               (b) C 6-10  aryl condensed with C 3-10  cycloalkane (e.g., tetrahydronaphthyl) optionally having 1 or 2 oxo,   (c) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6  alkyl, C 1-6  alkoxy-carbonyl-C 1-6  alkyl, mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl), C 6-10  aryl (e.g., phenyl), C 1-6  alkoxy-carbonyl and carboxy,   (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, dihydrobenzoxazolyl, benzisoxazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkoxy-carbonyl, a halogen atom and oxo,   (e) C 7-13  aralkyl (e.g., benzyl),   (f) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl),   (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl), and   (h) C 6-10  aryl-carbamoyl (e.g., phenylcarbamoyl),   
           (iii) C 6-10  arylthio (e.g., phenylthio),   (iv) C 6-10  arylsulfinyl (e.g., phenylsulfinyl),   (v) optionally halogenated C 6-10  arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),   (vi) amino optionally having 1 or 2 substituents selected from
           (a) C 1-6  alkyl,   (b) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) optionally halogenated C 1-6  alkyl (e.g., isopropyl, trifluoromethyl),   C) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),   D) cyano,   E) nitro,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) C 1-4  alkylenedioxy, and   J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,   
               (c) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),   (d) C 7-13  aralkyl (e.g., benzyl),   (e) C 1-6  alkyl-carbonyl,   (f) C 3-6  cycloalkyl-carbonyl,   (g) C 6-10  aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (h) C 1-6  alkoxy-carbonyl-C 1-6  alkyl-carbonyl,   (i) carbamoyl-C 1-6  alkyl-carbonyl,   (j) a 5- or 6-membered heterocyclic group (e.g., pyridyl), and   (k) a 9- or 10-membered fused heterocyclic group (e.g., benzoxazolyl, benzothiazolyl, dihydrobenzofuranyl, indazolyl, dihydrofuropyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
           (vii) a 5- or 6-membered heterocyclic group (e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl) optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C 1-6  alkyl-carbonyloxy,   (b) C 3-6  cycloalkyl,   (c) C 6-10  aryl (e.g., phenyl),   (d) C 1-6  alkyl-carbonyl, and   (e) C 1-6  alkoxy-carbonyl,   
           (viii) a 9- or 10-membered fused heterocyclic group (e.g., indolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy-carbonyl and oxo,   (ix) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and C 6-10  aryl,   (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6  alkyl-carbonyloxy, and   (xi) a 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio); or
 
(4) C 3-10  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl);
       

     R 2  is optionally halogenated C 6-10  aryl (e.g., phenyl), or C 3-6  cycloalkyl (e.g., cyclopropyl, cyclohexyl); 
     R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl or C 1-3  alkoxy; 
     X is 
     (1) bond, or
 
(2) C 1-6  alkylene optionally having substituent(s) selected from C 1-6  alkyl and C 6-10  aryl (e.g., phenyl);
 
     ring A is 
     [A] C 5-7  cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C 5-7  cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo:
 
(1) a halogen atom;
 
(2) C 1-6  alkyl optionally having 1 to 5 substituents selected from
         (i) a halogen atom,   (ii) cyano,   (iii) C 3-6  cycloalkyl,   (iv) hydroxy,   (v) C 1-6  alkoxy optionally having 1 or 2 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 1-6  alkoxy optionally having 1 or 2 hydroxy,   (d) C 3-6  cycloalkyl,   (e) mono- or di-C 1-6  alkylamino,   (f) C 1-6  alkyl-carbonylamino,   (g) C 1-6  alkylthio,   (h) C 1-6  alkylsulfonyl, and   (i) a heterocyclic group (e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   
           (vi) C 3-6  cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),   (vii) C 6-10  aryloxy (e.g., phenoxy),   (viii) 5- or 6-membered heterocyclyloxy (e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyloxy) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   (ix) C 1-6  alkyl-carbonyloxy,   (x) carboxy,   (xi) C 1-6  alkoxy-carbonyl,   (xii) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl),   (xiii) C 1-6  alkylthio,   (xiv) C 1-6  alkylsulfonyl,   (xv) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl) and C 1-6  alkylsulfonyl-C 1-6  alkyl, and   (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);
 
(3) hydroxy optionally having a substituent selected from
   (i) C 7-13  aralkyl (e.g., benzyl),   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkyl-carbonylamino,   (iii) C 2-6  alkenyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 6-10  aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and   (vi) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkylsulfonyl-C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl);
 
(4) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkoxy-C 2-6  alkyl, C 3-6  cycloalkyl-C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 3-6  cycloalkyl-carbonyl, C 1-6  alkoxy-carbonyl, C 1-6  alkoxy-C 1-6  alkoxy-carbonyl, mono- or di-C 1-6  alkyl-carbamoyl and C 3-6  cycloalkylsulfonyl;
 
(5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;
 
(6) C 1-3  alkylidene (e.g., methylene) optionally having a substituent selected from C 1-6  alkoxy-carbonyl and C 1-6  alkyl-carbamoyl;
 
(7) oxo; and
 
(8) azido; and
       

     ring B is piperazine optionally further having, besides R 1 , C 1-6  alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo. 
     [Compound E] 
     Compound (I) wherein 
     R 1  is 
     (1) C 7-13  aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
         (i) a halogen atom,   (ii) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,   (iii) cyano,   (iv) hydroxy,   (v) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy),   (vi) C 6-10  aryloxy (e.g., phenoxy),   (vii) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl), and   (viii) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl, pyrazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and C 1-6  alkoxy;
 
(2) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;
 
(3) C 1-6  alkyl optionally having 1 to 5 substituents selected from
   (i) a halogen atom,   (ii) hydroxy optionally having a substituent selected from
           (a) C 6-10  aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) cyano,   C) C 1-6  alkyl optionally having 1 to 3 substituents selected from a halogen atom, carboxy, hydroxy, C 1-6  alkoxy-carbonyl and mono- or di-C 1-6  alkylamino,   D) C 1-6  alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   E) C 1-4  alkylenedioxy,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),   J) carbamoyl,   K) optionally halogenated mono- or di-C 1-6  alkyl-carbamoyl,   L) C 3-6  cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),   M) mono- or di-C 1-6  alkylamino,   O) optionally halogenated C 1-6  alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl),   P) a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl and oxo, and   Q) a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
               (b) C 6-10  aryl condensed with C 3-10  cycloalkane (e.g., tetrahydronaphthyl) optionally having 1 or 2 oxo,   (c) a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6  alkyl, C 1-6  alkoxy-carbonyl-C 1-6  alkyl, mono- or di-C 1-6  alkylamino-C 1-6  alkyl (e.g., dimethylaminomethyl), C 6-10  aryl (e.g., phenyl), C 1-6  alkoxy-carbonyl and carboxy,   (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, indolyl, dihydrobenzoxazolyl, benzisoxazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from
               A) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkoxy-carbonyl,   B) C 1-6  alkoxy,   C) C 1-6  alkoxy-carbonyl,   D) C 3-10  cycloalkyl,   E) a halogen atom, and   F) oxo,   
               (e) C 7-13  aralkyl (e.g., benzyl),   (f) C 3-10  cycloalkyl-C 1-6  alkyl (e.g., cyclopropylmethyl),   (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),   (h) C 6-10  aryl-carbamoyl (e.g., phenylcarbamoyl), and   (i) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl),   
           (iii) C 6-10  arylthio (e.g., phenylthio),   (iv) C 6-10  arylsulfinyl (e.g., phenylsulfinyl),   (v) optionally halogenated C 6-10  arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),   (vi) amino optionally having 1 or 2 substituents selected from
           (a) C 1-6  alkyl,   (b) C 6-10  aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
               A) a halogen atom,   B) optionally halogenated C 1-6  alkyl (e.g., methyl, isopropyl, trifluoromethyl),   C) optionally halogenated C 1-6  alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),   D) cyano,   E) nitro,   F) carboxy,   G) C 1-6  alkyl-carbonyl,   H) C 1-6  alkoxy-carbonyl,   I) C 1-4  alkylenedioxy, and   J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,   
               (c) C 3-6  cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),   (d) C 7-13  aralkyl (e.g., benzyl),   (e) C 1-6  alkyl-carbonyl,   (f) C 3-6  cycloalkyl-carbonyl,   (g) C 6-10  aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6  alkoxy,   (h) C 1-6  alkoxy-carbonyl-C 1-6  alkyl-carbonyl,   (i) carbamoyl-C 1-6  alkyl-carbonyl,   (j) a 5- or 6-membered heterocyclic group (e.g., pyridyl), and   (k) a 9- or 10-membered fused heterocyclic group (e.g., benzoxazolyl, benzothiazolyl, dihydrobenzofuranyl, indazolyl, dihydrofuropyridyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo,   
           (vii) a 5- or 6-membered heterocyclic group (e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl, tetrazolyl) optionally having 1 to 3 substituents selected from
           (a) C 1-6  alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C 1-6  alkyl-carbonyloxy,   (b) C 3-6  cycloalkyl,   (c) C 6-10  aryl (e.g., phenyl),   (d) C 1-6  alkyl-carbonyl, and   (e) C 1-6  alkoxy-carbonyl,   
           (viii) a 9- or 10-membered fused heterocyclic group (e.g., indolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6  alkyl, C 3-6  cycloalkyl, C 1-6  alkoxy-carbonyl and oxo,   (ix) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and C 6-10  aryl,   (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C 1-6  alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6  alkyl-carbonyloxy, and   (xi) 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio); or
 
(4) C 3-10  cycloalkyl optionally condensed with a benzene ring (e.g., indanyl);
       

     R 2  is optionally halogenated C 6-10  aryl (e.g., phenyl), or C 3-6  cycloalkyl (e.g., cyclopropyl, cyclohexyl); 
     R 3  is a hydrogen atom, a halogen atom, C 1-3  alkyl or C 1-3  alkoxy; 
     X is 
     (1) bond, or
 
(2) C 1-6  alkylene optionally having substituent(s) selected from C 1-6  alkyl and C 6-10  aryl (e.g., phenyl);
 
     ring A is 
     [A] C 5-7  cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C 5-7  cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., 1-oxa-3-azaspiro[4.5]decyl) optionally having 1 or 2 oxo:
 
(1) a halogen atom;
 
(2) C 1-6  alkyl optionally having 1 to 5 substituents selected from
         (i) a halogen atom,   (ii) cyano,   (iii) C 3-6  cycloalkyl,   (iv) hydroxy,   (v) C 1-6  alkoxy optionally having 1 or 2 substituents selected from
           (a) a halogen atom,   (b) hydroxy,   (c) C 1-6  alkoxy optionally having 1 or 2 hydroxy,   (d) C 3-6  cycloalkyl,   (e) mono- or di-C 1-6  alkylamino,   (f) C 1-6  alkyl-carbonylamino,   (g) C 1-6  alkylthio,   (h) C 1-6  alkylsulfonyl, and   (i) a heterocyclic group (e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   
           (vi) C 3-6  cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),   (vii) C 6-10  aryloxy (e.g., phenoxy),   (viii) 5- or 6-membered heterocyclyloxy (e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyloxy) optionally having 1 or 2 substituents selected from C 1-6  alkyl and oxo,   (ix) C 1-6  alkyl-carbonyloxy,   (x) carboxy,   (xi) C 1-6  alkoxy-carbonyl,   (xii) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl),   (xiii) C 1-6  alkylthio,   (xiv) C 1-6  alkylsulfonyl,   (xv) amino optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkyl-carbonyl, C 1-6  alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C 1-16  alkyl (e.g., furfuryl) and C 1-6  alkylsulfonyl-C 1-6  alkyl, and   (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);
 
(3) hydroxy optionally having a substituent selected from
   (i) C 7-13  aralkyl (e.g., benzyl),   (ii) C 1-6  alkyl optionally having 1 to 3 substituents selected from C 1-6  alkoxy and C 1-6  alkyl-carbonylamino,   (iii) C 2-6  alkenyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 6-10  aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and   (vi) carbamoyl optionally having 1 or 2 substituents selected from C 1-6  alkyl, C 1-6  alkylsulfonyl-C 1-6  alkyl and 5- or 6-membered aromatic heterocyclyl-C 1-6  alkyl (e.g., furfuryl);
 
(4) amino optionally having 1 or 2 substituents selected from
   (i) C 1-6  alkyl,   (ii) C 1-6  alkoxy-C 2-6  alkyl,   (iii) C 3-6  cycloalkyl-C 1-6  alkyl,   (iv) C 1-6  alkyl-carbonyl,   (v) C 3-6  cycloalkyl-carbonyl,   (vi) C 1-6  alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom, C 1-6  alkoxy and C 3-6  cycloalkyl,   (vii) C 3-6  cycloalkoxy-carbonyl,   (viii) C 1-6  alkoxy-C 1-6  alkoxy-carbonyl,   (ix) mono- or di-C 1-6  alkyl-carbamoyl,   (X) C 3-6  cycloalkylsulfonyl,   (xi) C 1-6  alkylsulfonyl, and   (xii) mono- or di-C 1-6  alkylsulfamoyl;
 
(5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;
 
(6) C 1-3  alkylidene (e.g., methylene) optionally having a substituent selected from C 1-6  alkoxy-carbonyl and C 1-6  alkyl-carbamoyl;
 
(7) oxo; and
 
(8) azido; and
       

     ring B is piperazine optionally further having, besides R 1 , C 1-6  alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6  alkyl and oxo. 
     Specific examples of compound (I) include
     methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,   (1S,2R)-2-{4-[((2R)-2-{2-[(2-fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol dihydrochloride,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methoxy-5-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-2-[4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-2-{4-[((2R)-2-{2-[(3-fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   (1S,2R)-2-{4-[((2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   (1S,2R)-2-{4-[((2R)-2-{2-[(2-fluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol dihydrochloride,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol hydrochloride,   (1S,2R)-2-{4-[((2R)-2-{2-[(3-fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride,   (1S,2R)-2-{4-[((2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-(4-{[(2R)-2-(2-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol,   (1S,2R)-2-{4-[((2R)-2-{2-[(4-fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   1-[(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol hydrochloride,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-(5-phenyl-4-{([(2R)-2-(2-{[4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol, and   methyl [(1S,2S)-2-(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,
 
and a salt thereof, and the like.
   

     Another specific examples of compound (I) include
     (1S,2R)-1-(methoxymethyl)-2-{(4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol hydrochloride,   methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,   (1S,2R)-1-(methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol hydrochloride,   (1S,2R)-1-(methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol dihydrochloride,   ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,   ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate malonate,   (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol dihydrochloride,   (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol fumarate,   (1S,2R)-2-[4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol,   methyl [(1S,2S)-2-(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,   (1S,2R)-1-(methoxymethyl)-2-(4-{[(2R)-2-(2-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol,   (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol dihydrochloride,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-2-{4-[((2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   1-[(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-1-(methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol,   (1S,2R)-2-{4-[((2R)-2-{2-[(3-fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   ethyl ((1R,2R)-2-{4-[((2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate,   (1S,2R)-2-{4-[((2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol,   propyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,   4-{[(2R)-1-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzonitrile,   isopropyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate,   isopropyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate, and   (1S,2R)-1-(methoxymethyl)-2-(4-{[(2R)-2-{2-[(2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol,
 
and a salt thereof, and the like.
   

     Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. 
     Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. 
     Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine or the like. 
     Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like. 
     Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or the like. 
     Preferable examples of the salt with basic amino acid include a salt with arginine, lysine, ornithine or the like. 
     Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid or the like. 
     Of these, a pharmaceutically acceptable salt is preferable. When the compound has an acidic functional group, examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and the like, ammonium salts, and the like. When the compound has a basic functional group, examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like. 
     The production methods of compound (I) are shown in the following. 
     Compound (I) is obtained by, for example, a method shown in the following reaction scheme or a method analogous thereto, or the like. 
     Each of compounds (II)-(VIII) shown in the reaction scheme may form a salt. Examples of the salt include salts similar to the salts of compound (I). 
     The compound obtained in each step can also be used for the next reaction directly as the reaction mixture or as a crude product. In addition, it can also be isolated from the reaction mixture according to a conventional method, and can be isolated and purified by a known method such as phase transfer, concentration, solvent extraction, fractional distillation, pH conversion, crystallization, recrystallization, chromatography and the like. 
     The schematic drawings of the reaction scheme are shown in the following. 
     R is C 1-4  alkyl, Y is a hydrogen atom or an alkali metal atom, PG is an N-protecting group (e.g., benzyl, tert-butoxycarbonyl, benzyloxycarbonyl etc.), and the other symbols are as defined above. 
     
       
         
         
             
             
         
       
     
     This method is used for the production of compound (IV) wherein R 3  is a hydrogen atom. 
     Compound (II) may be commercially available, or can be produced according to a method known per se, for example, the method described in Tetrahedron: Asymmetry, 1997, vol. 8, pages 3153-3159, or the like, or a method analogous thereto. 
     The production of compound (III), and the production of compound (IV) by the reaction of compound (II) with compound (III) are performed, for example, according to the method described in Journal of Organic Chemistry, 1994, vol. 59, pages 7635-7642, or the like, or a method analogous thereto. 
     Compound (IV) wherein R 3  is a halogen atom, C 1-6  alkyl or C 1-6  alkoxy can be produced according to a method known per se, for example, the method described in Journal of Organic Chemistry, 2004, vol. 69, pages 8829-8835, or the like, or a method analogous thereto. 
     Compound (IV) can be modified by further carrying out one or more of known acylation reaction, alkylation reaction, amination reaction, oxidation-reduction reaction, cyclization reaction, carbon chain extension reaction, substituent exchange reaction and the like, as desired. 
     
       
         
         
             
             
         
       
     
     Compound (V) can be produced by subjecting compound (IV) to known hydrolysis, for example, alkali-hydrolysis or acid-hydrolysis. 
     The reaction is advantageously carried out under alkali conditions. Preferable examples of the alkali to be used for this step include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. The amount of the alkali to be used is about 1 mol to large excess, preferably 1 to 5 mol, per 1 mol of compound (IV). 
     The reaction is advantageously carried out in an inert solvent. While the solvent is not particularly limited as long as the reaction proceeds, preferable examples of the solvent include alcohols such as methanol, ethanol, propanol and the like; hydrocarbons such as benzene, toluene, cyclohexane, hexane and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, a mixed solvent thereof, and the like. 
     While the reaction time varies depending on the reagent or solvent to be used, it is generally 30 min to 24 hr, preferably 30 min to 8 hr. 
     The reaction temperature is generally 0 to 150° C., preferably 20 to 80° C. 
     After the reaction, compound (V) (wherein Y is a hydrogen atom) is obtained as a free form by neutralizing the reaction mixture with a mineral acid (e.g., hydrochloric acid, sulfuric acid etc.), an organic acid (e.g., acetic acid etc.) or an ion exchange resin. Alternatively, compound (V) (wherein Y is an alkali metal atom such as lithium, sodium, potassium and the like) is obtained as an alkali metal salt of the carboxylic acid by directly concentrating the reaction mixture. 
     
       
         
         
             
             
         
       
     
     Compound (VII) can be produced by a condensation reaction of compound (V) with compound (VI). 
     Compound (VI) may be commercially available, or can be produced according to a method known per se, for example, the method described in WO 2003/000181 or the like, or a method analogous thereto. 
     When Y is a hydrogen atom, the condensation reaction is carried out according to a conventional peptide synthesis technique, for example, an acid chloride method, an acid anhydride method, a mixed anhydride method, a method of using N,N′-dicyclohexylcarbodiimide (DCC), an active ester method, a method of using N,N′-carbonyldiimidazole (CDI), a method of using diethyl cyanophosphate (DEPC), a method of using N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl) and 1-hydroxybenzotriazole (HOBt), or the like. Compound (VI) is used in an amount of about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of compound (V). The reagent for the aforementioned methods is used in an amount of about 1 to 2 mol, preferably about 1.1 to 1.3 mol, per 1 mol of compound (V). The reaction temperature is generally −10 to 80° C., preferably 0 to 30° C. 
     When Y is an alkali metal atom, the condensation reaction is advantageously carried out according to a method using WSC HCl and HOBt. Compound (VI) is used in an amount of about 1 to 2 mol, preferably about 1.0 to 1.1 mol, per 1 mol of compound (V). WSC.HCl is used in an amount of about 1 to 4 mol, preferably about 1.5 to 2.5 mol, per 1 mol of compound (V). HOBt is used in an amount of about 1 to 8 mol, preferably about 2.5 to 5.0 mol, per 1 mol of compound (V). The reaction temperature is generally −10 to 100° C., preferably 40 to 70° C. 
     In any case, the condensation reaction is preferably carried out in a solvent. Examples of the solvent to be used include the above-mentioned halogenated hydrocarbons; the above-mentioned ethers; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; dimethyl sulfoxide, pyridine, acetonitrile and a mixed solvent thereof. 
     While the reaction time varies depending on the reagent or solvent to be used, it is generally 30 min to 3 days, preferably 30 min to 15 hr. 
     Compound (VII) can also be produced by further carrying out one or more of known hydrolysis reaction, acylation reaction, alkylation reaction, amination reaction, oxidation-reduction reaction, cyclization reaction, carbon chain extension reaction, substituent exchange reaction and the like, as desired. 
     Compound (I) can be produced by removing the N-protecting group PG of compound (VII). In addition, in each of the aforementioned reactions, when the starting compound has an amino group, a carboxyl group or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be obtained. Introduction or removal of these protective groups may be carried out according to a method known per se, for example, the method disclosed in Theodora W. Greene and Peter G. M. Wuts, “Protective Groups in Organic Synthesis, 3 rd  Ed.”, Wiley-Interscience (1999), or the like. 
     As the amino-protecting group, for example, formyl group; C 1-6  alkyl-carbonyl group, phenylcarbonyl group, C 1-6  alkoxy-carbonyl group, allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group, fluorenylmethyloxycarbonyl (Fmoc) group, C 7-10  aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), C 7-10  aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl (Cbz) and the like), C 7-10  aralkyl group (e.g., benzyl and the like), trityl group, phthaloyl group, dithiasuccinoyl group, N,N-dimethylaminomethylene group, each optionally having substituent(s), and the like can be mentioned. As the substituent(s), for example, phenyl group, a halogen atom, C 1-6  alkyl-carbonyl group, C 1-6  alkoxy group optionally substituted by halogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like), nitro group and the like can be used. The number of the substituent(s) is 1 to 3. 
     As the carboxyl-protecting group, for example, C 1-6  alkyl group, allyl group, benzyl group, phenyl group, trityl group, trialkylsilyl group, each optionally having substituent(s), and the like can be mentioned. As the substituent(s), for example, a halogen atom, formyl group, C 1-6  alkyl-carbonyl group, C 1-6  alkoxy group optionally substituted by halogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like), nitro group and the like can be used. The number of the substituent(s) is 1 to 3. 
     As the hydroxy-protecting group, for example, C 1-6  alkyl group, C 7-20  aralkyl group (e.g., benzyl, trityl and the like), formyl group, C 1-6  alkyl-carbonyl group, benzoyl group, C 7-10  aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), 2-tetrahydropyranyl group, tetrahydrofuranyl group, trialkylsilyl group (e.g., trimethylsilyl, tert-butyldimethylsilyl, diisopropylethylsilyl and the like), each optionally having substituent(s), and the like can be mentioned. As the substituent(s), for example, a halogen atom, C 1-6  alkyl group, phenyl group, C 7-10  aralkyl group (e.g., benzyl and the like), C 1-6  alkoxy group, nitro group and the like can be used. The number of the substituent(s) is 1 to 4. 
     When compound (I) is obtained as a free compound, it can be converted to the object salt according to a method known per se or a method analogous thereto, and when it is obtained as a salt, it can be converted to a free compound or the object salt according to a method known per se or a method analogous thereto. 
     Compound (I) may be used as a prodrug. A prodrug of compound (I) means a compound which is converted to compound (I) with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to compound (I) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to compound (I) by hydrolysis etc. due to gastric acid, etc. 
     Examples of a prodrug of compound (I) include a compound wherein an amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., compound wherein amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, and the like); a compound wherein a hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein a hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated, and the like); a compound wherein a carboxyl group of compound (I) is esterified or amidated (e.g., a compound wherein a carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated, and the like) and the like. These compounds can be produced from compound (I) by a method known per se. 
     A prodrug of compound (I) may also be one which is converted into compound (I) under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990). 
     When compound (I) has an isomer such as optical isomer, steric isomer, positional isomer, rotational isomer and the like, any isomers and a mixture thereof are encompassed in compound (I). For example, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I). Such isomer can be obtained as a single product by a synthesis method, a separation method (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), optical resolution method (e.g., fractional recrystallization, chiral column method, diastereomer method etc.) and the like known per se. 
     Compound (I) may be a crystal, and both a single crystal and crystal mixtures are encompassed in compound (I). Crystals can be produced by crystallization according to crystallization methods known per se. 
     Compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate (e.g., non-hydrate etc.), both of which are encompassed in compound (I). 
     A compound labeled with an isotope (e.g.,  3 H,  14 C,  35 S,  125 I and the like) and the like is also encompassed in compound (I). 
     Deuterium-converted compound wherein  1 H has been converted to  2 H(D) are also encompassed in the compound (I). 
     Compound (I) or its prodrug, or salts thereof (hereinafter, sometimes to be abbreviated to as a compound of the present invention) exhibit superior renin inhibitory activity. They have low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, drug interaction, carcinogenicity, etc.) and high water-solubility, and are excellent in the aspects of stability, pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.) and efficacy, thus being useful as medicine. 
     The compound of the present invention acts as a renin inhibitory drug in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human, etc.), and is useful as a drug inhibiting the RA system by inhibiting the biosynthesis of AII, and is useful as an agent for the prophylaxis or treatment of various diseases caused by the RA system. 
     Examples of such diseases include hypertension (e.g., essential hypertension, renal vascular hypertension, renoparenchymal hypertension, primary aldosteronism, Cushing&#39;s syndrome etc.), blood pressure circadian rhythm abnormality, heart diseases (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, failure of expansion, cardiac myopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, cardiac infraction etc.), cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorder, transient cerebral ischemia, apoplexy, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction etc.), cerebral edema, cerebral circulatory disorder, recurrence and sequela of cerebrovascular disorders (e.g., neurotic symptom, psychic symptom, subjective symptom, disorder in daily living activities etc.), ischemic peripheral circulation disorder, myocardial ischemia, venous insufficiency, progression of cardiac insufficiency after cardiac infarction, renal diseases (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, nephrotic syndrome, thrombotic vasculopathy, complication of dialysis, organ damage including nephropathy by radiation irradiation etc.), arteriosclerosis including atherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis etc.), vascular hypertrophy, vascular hypertrophy or obliteration and organ damages after intervention (e.g., percutaneous transluminal coronary angioplasty, stenting, coronary angioscopy, intravascular ultrasound, dounce thrombolytic therapy etc.), vascular re-obliteration and restenosis after bypass, polycythemia, hypertension, organ damage and vascular hypertrophy after transplantation, rejection after transplantation, ocular diseases (e.g., glaucoma, ocular hypertension etc.), thrombosis, multiple organ disorder, endothelial dysfunction, hypertensive tinnitus, other cardiovascular diseases (e.g., deep vein thrombosis, obstructive peripheral circulatory disorder, arteriosclerosis obliterans, obstructive thromboangiitis, ischemic cerebral circulatory disorder, Raynaud&#39;s disease, Berger disease etc.), metabolic and/or nutritional disorders (e.g., diabetes, impaired glucose tolerance, insulin resistance, hyperinsulinemia, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, obesity, hyperlipidemia, hypercholesterolemia, hyperuricacidemia, hyperkalemia, hypernatremia etc.), metabolic syndrome, nerve degeneration diseases (e.g., Alzheimer&#39;s disease, Parkinson&#39;s syndrome, Creutzfeldt-Jakob disease, multiple sclerosis, amyotrophic lateral sclerosis, AIDS encephalopathy etc.), central nervous system disorders (e.g., damages such as cerebral hemorrhage and cerebral infarction, and sequela and complication thereof, head injury, spinal injury, cerebral edema, sensory malfunction, sensory functional disorder, autonomic nervous system disorder, autonomic nervous system malfunction etc.), dementia, migraine, defects of memory, disorder of consciousness, amnesia, anxiety symptom, catatonic symptom, discomfort mental state, sleep disorder, agrypnia, sychopathies (e.g., depression, epilepsy, alcoholism etc.), inflammatory diseases (e.g., arthritis such as rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammation after operation or injury; remission of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory intestinal diseases such as Crohn&#39;s disease, ulcerative colitis etc.; meningitis; inflammatory ocular disease; inflammatory pulmonary disease such as pneumonia, pulmonary silicosis, pulmonary sarcoidosis, pulmonary tuberculosis etc.), allergic diseases (e.g., allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis etc.), chronic obstructive pulmonary disease, interstitial pneumonia, pneumocytis carinni pneumonia, collagen diseases (e.g., systemic lupus erythematodes, scleroderma, polyarteritis etc.), hepatic diseases (e.g., hepatitis including chronic hepatitis, hepatic cirrhosis etc.), portal hypertension, digestive system disorders (e.g., gastritis, gastric ulcer, gastric cancer, gastric disorder after operation, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, varices ruptures of esophagus and stomach etc.), blood and/or myelopoietic diseases (e.g., erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy etc.), bone diseases (e.g., fracture, refracture, osteoporosis, osteomalacia, bone Paget&#39;s disease, sclerosing myelitis, rheumatoid arthritis, joint tissue dysfunction and the like caused by osteoarthritis of the knee and diseases similar to these), solid tumor, tumors (e.g., malignant melanoma, malignant lymphoma, cancer of digestive organs (e.g., stomach, intestine etc.) etc.), cancer and cachexia following cancer, metastasis cancer, endocrinopathy (e.g., Addison&#39;s disease, pheochromocytoma etc.), urinary organ and/or male genital diseases (e.g., cystitis, prostatic hypertrophy, prostatic cancer, sex infectious disease etc.), female disorders (e.g., climacteric disorder, gestosis, endometriosis, hysteromyoma, ovarian disease, breast disease, sex infectious disease etc.), disease relating to environment and occupational factors (e.g., radiation hazard, hazard by ultraviolet, infrared or laser beam, altitude sickness etc.), respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombosis and pulmonary embolism etc.), infectious diseases (e.g., viral infectious diseases with cytomegalovirus, influenza virus, herpes virus etc., rickettsiosis, bacterial infectious disease etc.), toxemias (e.g., sepsis, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome etc.), otorhinolaryngological diseases (e.g., Meniere&#39;s syndrome, tinnitus, dysgeusia, vertigo, disequilibrium, dysphagia etc.), skin diseases (e.g., keloid, hemangioma, psoriasis etc.), intradialytic hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome and the like. 
     The compound of the present invention can be used in combination with an existing hypertension therapeutic drug such as an ACE inhibitor (captopril, enalapril maleate, alacepril, delapril hydrochloride, imidapril hydrochloride, quinapril hydrochloride, cilazapril, temocapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril, lisinopril, etc.), ARB (losartan potassium, candesartan cilexetil, valsartan, TAK-536, TAK-491, irbesartan, telmisartan, eprosartan, olmesartan medoxomil, etc.), an aldosterone receptor antagonist (spironolactone, eplerenone, etc.), a Ca-ion channel inhibitor (verapamil hydrochloride, diltiazem hydrochloride, nifedipine, amlodipine hydrochloride, azelnidipine, aranidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nisoldipine, nitrendipine, nilvadipine, barnidipine hydrochloride, felodipine, benidipine hydrochloride, manidipine hydrochloride, etc.), diuretic (trichlormethiazide, hydrochlorothiazide, benzylhydrochlorothiazide, indapamide, tripamide, meticrane, mefruside, furosemide, triamterene, chlorthalidon etc.), a β-blocker (propranolol hydrochloride, atenolol, metoprolol tartrate, bisoprolol fumarate, etc.), an α,β-blocker (carvedilol, etc.), and the like. 
     Moreover, the compound of the present invention can be also used in combination with an antithrombotic drug such as heparin sodium, heparin calcium, warfarin calcium (Warfarin), a blood coagulation factor Xa inhibitor, drug having a function of balance correction in the coagulation-fibrinolysis system, an oral thrombin inhibitor, a thrombolytic drug (tPA, urokinase, etc.), an antiplatelet drug [aspirin, sulfinpyrazone (Anturane), dipyridamol (Persantine), ticlopidine hydrochloride (Panaldine), clopidogrel, cilostazol (Pletal), GPIIb/IIIa antagonist (ReoPro, etc.)], and the like. Also, the compound can be used in combination with a lipid lowering drug or a cholesterol lowering drug. Examples thereof include a squalene synthase inhibitor (lapaquistat acetate etc.), fibrates (clofibrate, benzafibrate, gemfibrozil, etc.), nicotinic acid, its derivatives and analogs (acipimox, probucol, etc.), a bile acid binding resin (cholestyramine, colestipol, etc.), an omega-3 polyunsaturated fatty acid (EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid), or a mixture thereof etc.), a compound inhibiting cholesterol absorption (sitosterol, neomycin, etc.), and a squalene epoxidase inhibitor (NB-598 and its analogs, etc.). Furthermore, other possible combination components are an oxidosqualene-lanosterol cyclase, for example, a decalin derivative, an azadecalin derivative, an indane derivative and the like. Combination with a HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) inhibitor (atorvastatin calcium hydrate, pravastatin sodium, simvastatin, itavastatin, lovastatin, fluvastatin, etc.) is also possible. 
     The compound of the present invention can also be used in combination with a therapeutic drug for diabetes or a therapeutic drug for diabetic complications. For example, the compound of the present invention can be used in combination with an insulin preparation, an insulin sensitivity improving drug [pioglitazone hydrochloride, rosiglitazone, etc.], an α-glucosidase inhibitor [voglibose, acarbose, miglitol, emiglitate etc.], biguanide [phenformin, metformin, buformine etc.], insulin secretagogue [tolbutamide, glibenclamide, gliclazide, nateglinide, mitiglinide, glimepiride etc.], a dipeptidylpeptidase IV inhibitor [Alogliptin benzoate, Vidagliptin (LAF237), P32/98, Saxagliptin (BMS-477118) etc.], Kinedak, Penfill, Humulin, Euglucon, Glimicron, Daonil, Novolin, Monotard, Glucobay, Dimelin, Rastinon, Bacilcon, Deamelin S, Iszilin family, or the like. 
     In addition, the compound can be also used together with other pharmaceutical components, including a bone disease medicine, a myocardial protective drug, a coronary artery disease medicine, a chronic cardiac failure medicine, a hypothyroidism medicine, a nephrotic syndrome medicine, a chronic renal failure medicine, a gynecological disease medicine, an infection medicine, or the like. 
     The administration mode may be exemplified by (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) simultaneous administration through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the combination drug, (3) administration with a time interval through the same administration route of two preparations obtained by separately formulating the compound of the present invention and the combination drug, (4) simultaneous administration through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the combination drug, (5) administration with a time interval through different administration routes of two preparations obtained by separately formulating the compound of the present invention and the combination drug (for example, administration in order of the compound of the present invention and then the combination drug, or administration in the reverse order), or the like. The amount of the combination drug to be administered can be appropriately selected with reference to the clinically used dosage. The mixing ratio of the compound of the present invention and the combination drug can be appropriately selected in accordance with the subject of administration, administration route, disease to be treated, symptoms, combination, and the like. 
     The compound of the present invention can be also used in combination with, for example, gene therapy involving VEGF, TNFα or the like, or therapeutic methods involving various antibody medicines or the like. 
     The compound of the present invention can be safely administered individually, or according to ordinary methods (for example, methods described in the Japanese Pharmacopeia, etc.), as a pharmaceutical composition mixed with pharmaceutically acceptable carriers, for example, a tablet (including a sugar-coated tablet and a film-coated tablet), a film, a powder, a granule, a capsule, a liquid, an emulsion, a suspension, an injectable preparation, a suppository, a sustained release preparation, a patch and the like, either orally or parenterally (e.g., topical, rectal, intravenous administration, etc.). 
     The dosage form of the aforementioned pharmaceutical preparation may be exemplified by oral preparations such as a tablet (including a sublingual tablet and a buccal disintegration tablet), a film (including a buccal disintegration film), a capsule (including a soft capsule and a microcapsule), a granule, a powder, a troche, a syrup, an emulsion, a suspension and the like; and parenteral preparations such as an injectable preparation (e.g., a subcutaneous injectable preparation, an intravenous injectable preparation, intramuscular injectable preparation, intraperitoneal injectable preparation, a drip infusion), external preparation (e.g., a percutaneous preparation, an ointment), a suppository (e.g., a rectal suppository, a vaginal suppository), a pellet, a transnasal preparation, a transpulmonary preparation (inhalant), an eye drop and the like. 
     These preparations may be controlled release preparations such as a rapid release preparation, a sustained release preparation and the like (e.g., a sustained release microcapsule). 
     The content of the compound of the present invention in the pharmaceutical composition is about 0.01 to 100% by weight of the entire composition. 
     The amount of administration of the compound of the present invention may vary depending on the subject of administration, administration route, subject disease or the like; however, in the case of administering orally to an adult as a hypertension medicine, the amount of administration is about 0.0005 to 2 mg/kg of body weight, preferably about 0.001 to 1 mg/kg of body weight, and more preferably about 0.001 to 0.5 mg/kg of body weight, in terms of compound (I), the active ingredient, possibly once to several times a day. 
     The aforementioned pharmaceutically acceptable carrier may be exemplified by various organic or inorganic carrier materials that are conventionally used as preparation materials, for example, excipient, gliding agent, binding agent and disintegrant for solid preparations; or solvent, solution aid, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations. Further, if necessary, additives such as preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can be also used. 
     Examples of the excipient include lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride and the like. 
     Examples of the gliding agent include magnesium stearate, calcium stearate, talc, colloidal silica and the like. 
     Examples of the binding agent include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like. 
     Examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like. 
     Examples of the solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like. 
     Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. 
     Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like. 
     Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. 
     Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like. 
     Examples of the soothing agent include benzyl alcohol and the like. 
     Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. 
     Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like. 
     Examples of the colorant include water-soluble Food coal tar dyes (e.g., Food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, and the like), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble Food coal tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide) and the like. 
     Examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like. 
     EXAMPLES 
     The present invention is explained in detail in the following by referring to Reference Examples, Examples, Preparation Examples and Experimental Examples, which are not to be construed as limitative. Of the synthesis starting materials used in Reference Examples and Examples, synthetic methods of known compounds are omitted. 
     “Room temperature” in the following Reference Examples and Examples represents a temperature of about 10° C. to about 35° C., and “%” represents weight % unless otherwise stated. Provided that, yield represents mol/mol %. 
       1 H-NMR spectra were measured with a Varian MERCURY 300 (300 MHz) spectrometer or a BRUKER ADVANCE 300 spectrometer (300 MHz) using tetramethylsilane as an internal standard. All of the δ values are represented in ppm. 
     LC/MS spectra were measured under the following conditions. 
     Equipment: Agilent 1100 HPLC (Gilson 215 autosampler)/Waters ZQ, or Waters 2795/ZQ
 
Column: CapcellPak C18UG120 (1.5 mmID×35 mL, S-3 μm), manufactured by Shiseido Co., Ltd.
 
Solvent: Solution A (0.05% trifluoroacetic acid-containing water), Solution B (0.04% trifluoroacetic acid-containing water)
 
Gradient cycle: 0.00 min (A/B=90/10), 2.00 min (A/B=5/95), 2.75 min (A/B=5/95), 2.76 min (A/B=90/10), 3.45 min (A/B=90/10)
 
Flow rate: 0.5 ml/min
 
     Detection: UV (220 nm) 
     Mass spectrum: electrospray ionization (ESI) 
     Reverse-phase HPLC analysis was carried out on an YMC CombiPrep ODS-A (20 mmID×50 mL, S-5 μm) Column using a Gilson UniPoint system, and eluted with 0.1% trifluoroacetic acid-containing acetonitrile/water (10:90-100:0) at a flow rate of 25 ml/min. 
     The microwave reactor used was Discover of CEM. 
     Other symbols used in the present text indicate the following meanings. 
     s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, td: triple doublet, dq: double quartet, tq: triple quartet, ddd: double double doublet, m: multiplet, br: broad.
 
Me: methyl, Et: ethyl, nPr: n-propyl, iPr: isopropyl, nBu: n-butyl, iBu: isobutyl,  t Bu: tert-butyl, Boc: tert-butoxycarbonyl, Cbz: benzyloxycarbonyl, Tr: trityl.
 
DMA: N,N-dimethylacetamide, DME: 1,2-dimethoxyethane, DMF: N,N-dimethylformamide, DMSO: dimethyl sulfoxide, THF: tetrahydrofuran.
 
ADDP: 1,1′-(azodicarbonyl)dipiperidine,
 
9-BBN: 9-borabicyclo[3.3.1]nonane,
 
BEMP: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin,
 
BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,
 
DAST: (diethylamino)sulfur trifluoride,
 
DBU: 1,8-diazabicyclo[5.4.0]-7-undecene,
 
DCC: dicyclohexylcarbodiimide,
 
DEAD: diethyl azodicarboxylate,
 
DMAP: 4-(dimethylamino)pyridine,
 
dppf: 1,1′-bis(diphenylphosphino)ferrocene,
 
DTBAD: di-tert-butyl azodicarboxylate,
 
HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate,
 
HOBt: 1-hydroxybenzotriazole,
 
mCPBA: m-chloroperbenzoic acid,
 
     NBS: N-bromosuccinimide, 
     Pd 2  (dba) 3: tris(dibenzylideneacetone)dipalladium(0),
 
TBAF: tetra-n-butylammonium fluoride,
 
TFA: trifluoroacetic acid,
 
WSC.HCl: 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride.
 
     Reference Example 1 
     Ethyl 2-(formylamino)-3-phenylacrylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil) (11.62 g) was suspended in THF (270 ml), and, while stirring the suspension, a solution of benzaldehyde (28.27 g) and ethyl isocyanoacetate (27.39 g) in THF (55 ml) was added dropwise over 20 min at room temperature. The mixture was stirred at room temperature for 2.5 hr, and ice-cooled. Acetic acid (45 ml) was added dropwise, and the mixture was stirred for 10 min, poured into ice water, and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2-2:1) was concentrated under reduced pressure to give the object compound (40.27 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 0.98-1.40 (3H, m), 4.06-4.38 (2H, m), 7.06-7.68 (7H, m), 8.21-8.47 (1H, m) 
     Reference Example 2 
     Ethyl 3-bromo-2-(formylamino)-3-phenylacrylate 
     
       
         
         
             
             
         
       
     
     Ethyl 2-(formylamino)-3-phenylacrylate (40.27 g) was dissolved in carbon tetrachloride-chloroform (3:1, 440 ml), the solution was ice-cooled, and NBS (34.33 g) was added. The mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 3 hr, and ice-cooled again. Triethylamine (19.52 g) was added, and the mixture was stirred at 0° C. for 20 min, and then at room temperature for 40 min. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3-1:2) was concentrated under reduced pressure to give the object compound (44.88 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 0.89-1.45 (3H, m), 3.97-4.46 (2H, m), 6.91 (1H, br s), 7.28-7.46 (5H, m), 7.95-8.28 (1H, m) 
     Reference Example 3 
     Ethyl 3-bromo-2-isocyano-3-phenylacrylate 
     
       
         
         
             
             
         
       
     
     Ethyl 3-bromo-2-(formylamino)-3-phenylacrylate (16.33 g) and triethylamine (13.86 g) were dissolved in dichloromethane (150 ml), and the solution was ice-cooled. Phosphoryl chloride (9.24 g) was added, and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was vigorously stirred at room temperature for 1 hr, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:6) was concentrated under reduced pressure at 30° C. or below to give the object compound (14.82 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.03-1.42 (3H, m), 4.04-4.42 (2H, m), 7.25-7.56 (5H, m) 
     Reference Example 4 
     Methyl 1-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Cyclohexylamine (0.21 ml) and triethylamine (0.26 ml) were dissolved in DMF (5 ml), and the solution was ice-cooled. Methyl 3-bromo-2-isocyano-3-phenylacrylate (500 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (240 mg). 
     MS (ESI+, m/e) 285 (M+1) 
     Reference Example 5 
     Methyl 1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-2-(Benzyloxy)cyclohexylamine (848 mg) and triethylamine (1.06 ml) were dissolved in DMF (10 ml), and the solution was ice-cooled. Methyl 3-bromo-2-isocyano-3-phenylacrylate (1.0 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (1.26 g). 
       1 H-NMR (CDCl 3 ) δ 1.05-1.38 (3H, m), 1.56-1.84 (3H, m), 1.91-2.01 (1H, m), 2.17-2.30 (1H, m), 3.44-3.59 (1H, m), 3.68-3.78 (1H, m), 3.79 (3H, s), 4.25 (1H, d), 4.43 (1H, d), 6.99-7.09 (2H, m), 7.22-7.33 (3H, m), 7.33-7.48 (5H, m), 7.57 (1H, s) 
     In the same manner as in Reference Example 5, the following compounds (Reference Examples 6-14) were obtained. 
     Reference Example 6 
     Methyl 1-[(1R,2R)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.05-1.38 (3H, m), 1.56-1.84 (3H, m), 1.91-2.01 (1H, m), 2.17-2.30 (1H, m), 3.44-3.59 (1H, m), 3.68-3.78 (1H, m), 3.79 (3H, s), 4.25 (1H, d), 4.43 (1H, d), 6.99-7.09 (2H, m), 7.22-7.33 (3H, m), 7.33-7.48 (5H, m), 7.57 (1H, s) 
     Reference Example 7 
     Methyl 1-(trans-4-hydroxycyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.17-1.36 (2H, m), 1.68-1.87 (2H, m), 1.96-2.09 (4H, m), 3.65-3.79 (5H, m), 7.28-7.37 (2H, m), 7.45-7.55 (3H, m), 7.64 (1H, s) 
     Reference Example 8 
     Methyl 1-cyclopentyl-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.53-1.70 (2H, m), 1.75-1.91 (4H, m), 1.96-2.15 (2H, m), 3.77 (3H, s), 4.18-4.29 (1H, m), 7.29-7.39 (2H, m), 7.43-7.52 (2H, m), 7.65 (1H, s) 
     Reference Example 9 
     Methyl 1-cycloheptyl-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.26-1.40 (2H, m), 1.49-1.63 (4H, m), 1.64-1.82 (2H, m), 1.83-1.93 (2H, m), 1.95-2.05 (2H, m), 3.77 (3H, s), 3.81-3.93 (1H, m), 7.32 (2H, s), 7.43-7.53 (3H, m), 7.66 (1H, s) 
     Reference Example 10 
     Methyl 1-(trans-2-hydroxycyclopentyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.52-1.71 (2H, m), 1.73-1.86 (3H, m), 2.04-2.22 (2H, m), 2.62 (1H, br s), 3.75 (3H, s), 4.10 (1H, s), 7.34-7.42 (2H, m), 7.44-7.52 (3H, m), 7.61 (1H, s) 
     Reference Example 11 
     Methyl 1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.67-1.87 (4H, m), 1.95-2.09 (2H, m), 2.13-2.21 (1H, m), 3.78 (3H, s), 4.03-4.09 (1H, m), 4.22-4.37 (2H, m), 7.12-7.15 (2H, m), 7.26-7.47 (7H, m), 7.57 (1H, s) 
     MS (ESI+, m/e) 377 (M+1) 
     Reference Example 12 
     Methyl 1-[(2R)-bicyclo[2.2.1]hept-2-yl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.04-1.09 (2H, m), 1.36-1.74 (5H, m), 1.83-1.93 (1H, m), 2.41-2.49 (2H, m), 3.76 (3H, s), 3.76-3.82 (1H, m), 7.32-7.35 (2H, m), 7.46-7.49 (3H, m), 7.69 (1H, s) 
     MS (ESI+, m/e) 297 (M+1) 
     Reference Example 13 
     Methyl 1-[bicyclo[2.2.1]hept-2-yl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.31-1.45 (4H, m), 1.51-1.57 (1H, m), 1.63-1.72 (1H, m), 1.99-2.13 (2H, m), 2.33-2.36 (1H, m), 3.76 (3H, s), 4.24-4.31 (1H, m), 7.31-7.35 (2H, m), 7.45-7.48 (2H, m), 7.67 (1H, s) 
     MS (ESI+, m/e) 297 (M+1) 
     Reference Example 14 
     Methyl 1-[cis-2-(hydroxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.37-1.51 (2H, m), 1.51-1.65 (2H, m), 1.65-1.79 (3H, m), 1.86 (2H, dd), 3.44 (1H, d), 3.57 (1H, s), 3.75 (3H, s), 4.14-4.24 (2H, m), 7.32-7.41 (2H, m), 7.41-7.54 (3H, m), 7.71 (1H, s) 
     Reference Example 15 
     Ethyl 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     (1R,2S)-2-Aminocyclohexanol hydrochloride (5.3 g) and triethylamine (15.1 ml) were dissolved in DMF (100 ml), and the solution was ice-cooled. Ethyl 3-bromo-2-isocyano-3-phenylacrylate (9.8 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (6.13 g). 
       1 H-NMR (CDCl 3 ) δ 1.10 (3H, t), 1.21-1.37 (2H, m), 1.38-1.52 (1H, m), 1.60-1.79 (2H, m), 1.80-1.97 (2H, m), 2.22-2.37 (2H, m), 3.76 (1H, dt), 4.04 (1H, br s), 4.13 (2H, q), 7.20-7.31 (2H, m), 7.39-7.51 (3H, m), 7.86 (1H, s) 
     In the same manner as in Reference Example 15, the following compounds (Reference Examples 16-20) were obtained. 
     Reference Example 16 
     Ethyl 1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 315 (M+1) 
     Reference Example 17 
     Ethyl 1-(cis-2-hydroxycyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.10 (3H, t), 1.21-1.37 (2H, m), 1.38-1.52 (1H, m), 1.60-1.79 (2H, m), 1.80-1.97 (2H, m), 2.22-2.37 (2H, m), 3.76 (1H, dt), 4.04 (1H, br s), 4.13 (2H, q), 7.20-7.31 (2H, m), 7.39-7.51 (3H, m), 7.86 (1H, s) 
     Reference Example 18 
     Ethyl 1-[(1S)-1-(1-hydroxycyclohexyl)ethyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 0.99-1.14 (3H, m), 1.17-1.26 (3H, m), 1.29-1.37 (2H, m), 1.43-1.58 (5H, m), 1.61-1.68 (5H, m), 3.81 (1H, q), 4.22 (2H, dq), 7.47 (3H, td), 7.96 (1H, s) 
     Reference Example 19 
     Ethyl 1-[(S)-(1-hydroxycyclohexyl)(phenyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.19 (3H, t), 1.33-1.47 (3H, m), 1.49-1.65 (7H, m), 4.19 (2H, dd), 4.64 (1H, s), 7.10-7.24 (3H, m), 7.31-7.40 (4H, m), 7.46 (3H, s), 8.57 (1H, s) 
     Reference Example 20 
     Ethyl 1-[(R)-(1-hydroxycyclohexyl)(phenyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.20 (3H, t), 1.35-1.47 (3H, m), 1.49-1.60 (3H, m), 1.68 (4H, d), 4.19 (2H, dq), 4.64 (1H, s), 7.21 (3H, dd), 7.31-7.36 (4H, m), 7.40-7.49 (3H, m), 8.57 (1H, s) 
     Reference Example 21 
     Ethyl 1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 3-bromo-2-isocyano-3-phenylacrylate (1.50 g), trans-2-aminocycloheptanol (1.05 g), triethylamine (4.50 ml) and DMF (20 ml) was stirred at room temperature for 2 days, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (860 mg). 
       1 H-NMR (CDCl 3 ) δ 1.21 (3H, t), 1.27-1.41 (1H, m), 1.51-1.61 (3H, m), 1.63-1.72 (3H, m), 1.77-1.84 (2H, m), 1.88-2.01 (1H, m), 3.74-3.86 (1H, m), 3.93-4.04 (1H, m), 4.19 (2H, q), 7.36-7.49 (5H, m), 7.61 (1H, s) 
     MS (ESI+, m/e) 329 (M+1) 
     Reference Example 22 
     Ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 3-bromo-2-isocyano-3-phenylacrylate (500 mg), 1-(aminomethyl)cyclohexanol (440 mg), N,N-diisopropylethylamine (1.9 ml) and DMF (7 ml) was stirred at room temperature for 12 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (447 mg). 
       1 H-NMR (CDCl 3 ) δ 1.02-1.17 (3H, m), 1.23 (3H, t), 1.28-1.37 (4H, m), 1.44-1.47 (1H, m), 1.63 (3H, br s), 3.80 (2H, s), 4.19 (2H, q), 7.28-7.37 (2H, m), 7.39-7.50 (3H, m), 7.79 (1H, s) 
     MS (ESI+, m/e) 329 (M+1) 
     Reference Example 23 
     Ethyl 1-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl [(1S,2S)-2-aminocyclohexyl]carbamate (1.29 g) and ethyl 3-bromo-2-isocyano-3-phenylacrylate (1.4 g) were dissolved in DMF (15 ml). N,N-Diisopropylethylamine (1.29 g) was added, and the mixture was stirred at room temperature for 40 hr. DBU (761 mg) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. Saturated brine was added to the reaction mixture, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with 6% aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (1.24 g). 
       1 H-NMR (CDCl 3 ) δ 1.05-1.41 (6H, m), 1.34 (9H, s), 1.75-1.85 (3H, m), 2.06 (2H, t), 3.44-3.51 (1H, m), 3.73-3.79 (1H, m), 4.05 (1H, s), 4.22 (2H, q), 7.32-7.34 (2H, m), 7.48-7.52 (3H, m), 7.72 (1H, s) 
     Reference Example 24 
     Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-Cyclohexane-1,2-diamine (1.37 g) and ethyl 3-bromo-2-isocyano-3-phenylacrylate (1.12 g) were dissolved in DMF (5 ml), and the mixture was stirred at room temperature for 15 hr. Saturated brine was added to the reaction mixture, and the liberated oil was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (860 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.02-1.44 (6H, m), 1.21 (3H, t), 1.59-1.81 (3H, m), 1.95-2.00 (2H, m), 3.02 (1H, dt), 3.43 (1H, dt), 4.22 (2H, q), 7.36-7.38 (2H, m), 7.46-7.49 (3H, m), 7.69 (1H, s) 
     In the same manner as in Reference Example 24, the following compounds (Reference Examples 25-26) were obtained. 
     Reference Example 25 
     Ethyl 1-[(1R,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.03-1.39 (3H, m), 1.22 (3H, t), 1.45 (2H, br s), 1.59-1.82 (3H, t), 1.96-2.01 (2H, m), 3.02 (1H, dt), 3.44 (1H, dt), 4.22 (2H, q), 7.36-7.38 (2H, m), 7.44-7.50 (3H, m), 7.69 (1H, s) 
     Reference Example 26 
     Ethyl 1-(cis-2-aminocyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.19-1.85 (12H, m), 2.17-2.31 (1H, m), 3.03 (1H, br s), 3.84-3.90 (1H, m), 4.22 (2H, q), 7.30-7.33 (2H, m), 7.44-7.48 (3H, m), 7.84 (1H, s) 
     Reference Example 27 
     4-(4-Oxocyclohexyl)morpholin-3-one 
     
       
         
         
             
             
         
       
     
     4-(1,4-Dioxaspiro[4.5]dec-8-yl)morpholin-3-one (1.24 g) was dissolved in acetic acid-THF-water (4:2:1, 40 ml), and the solution was stirred at 65° C. for 17 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (700 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.67-2.09 (4H, m), 2.43-2.63 (4H, m), 3.30 (2H, t), 3.85-3.92 (2H, m), 4.22 (2H, s), 4.93-5.04 (1H, m) 
     Reference Example 28 
     4-(1-Oxaspiro[2.5]oct-6-yl)morpholin-3-one 
     
       
         
         
             
             
         
       
     
     Trimethylsulfoxonium iodide (5.4 g) was dissolved in DMSO (40 ml). Sodium hydride (60% in oil, 972 mg) was added, and the mixture was stirred at room temperature for 30 min. A solution of 4-(4-oxocyclohexyl)morpholin-3-one (4.0 g) in DMSO (80 ml) was added thereto, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and extracted with ethyl acetate-THF (1:1). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (2.0 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.30-1.38 (2H, m), 1.69-1.89 (4H, m), 2.05-2.16 (2H, m), 2.69 (2H, s), 3.32-3.35 (2H, m), 3.87-3.90 (2H, m), 4.20 (2H, s), 4.59-4.69 (1H, m) 
     Reference Example 29 
     4-[4-(Aminomethyl)-4-hydroxycyclohexyl]morpholin-3-one 
     
       
         
         
             
             
         
       
     
     4-(1-Oxaspiro[2.5]oct-6-yl)morpholin-3-one (2.0 g) and benzylamine (3.0 g) were dissolved in ethanol (20 ml), and the solution was stirred at 80° C. for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure. This was dissolved in methanol (20 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (1.5 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.30-1.46 (2H, m), 1.48-1.59 (2H, m), 1.64-1.73 (2H, m), 1.77-2.02 (4H, m), 2.53-2.63 (2H, m), 2.62 (1H, s), 3.29-3.39 (2H, m), 3.80-3.91 (2H, m), 4.18-4.19 (2H, m), 4.39-4.55 (1H, m) 
     Reference Example 30 
     Ethyl 1-{[cis-1-hydroxy-4-(3-oxomorpholino)cyclohexyl]methyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of methyl 3-bromo-2-isocyano-3-phenylacrylate (1.23 g), 4-[4-(aminomethyl)-4-hydroxycyclohexyl]morpholin-3-one (1.5 g) and triethylamine (1.85 ml) in DMF (15 ml) was stirred at room temperature for 12 hr in an argon stream, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (700 mg). 
       1 H-NMR (CDCl 3 ) δ 1.02-2.08 (11H, m), 2.35 (2H, s), 3.20-3.37 (3H, m), 3.75-3.91 (4H, m), 4.07-4.51 (4H, m), 7.09-7.56 (5H, m), 7.88 (1H, s) 
     Reference Example 31 
     Ethyl 5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil, 10.1 g) was suspended in THF (200 ml), and the suspension was ice-cooled. A solution of methyl isocyanoacetate (21.8 g) and 3-fluorobenzenecarbaldehyde (23.3 g) in THF (50 ml) was added dropwise thereto. After the completion of the dropwise addition, the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled, acetic acid (40 ml) was gradually added thereto, and the mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give ethyl 3-(3-fluorophenyl)-2-(formylamino)acrylate (34.5 g) as a solid. 
     The total amount thereof was dissolved in carbon tetrachloride-chloroform (1:1, 400 ml), and the solution was ice-cooled. NBS (27.1 g) was added thereto, and the mixture was stirred at 0° C. for 1.5 hr, and then at room temperature for 3 hr. The reaction mixture was ice-cooled again, triethylamine (21.2 ml) was added, and the mixture was stirred at 0° C. for 20 min, and then at room temperature for 40 min. The reaction mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give ethyl 3-bromo-3-(3-fluorophenyl)-2-(formylamino)acrylate (39.2 g) as an oil. 
     The total amount thereof and triethylamine (45.3 ml) were dissolved in diethyl ether (300 ml), and the solution was ice-cooled. A solution of phosphorus oxychloride (21.0 ml) in diethyl ether (100 ml) was added dropwise, and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was ice-cooled, poured into 10% potassium carbonate aqueous solution (400 ml), and the mixture was vigorously stirred at room temperature for 2 hr. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:17) was concentrated under reduced pressure to give ethyl 3-bromo-3-(3-fluorophenyl)-2-(isocyano)acrylate (19.76 g) as an oil. 
     The total amount thereof was dissolved in DMF (50 ml), the solution was added to a solution of (1S,2S)-2-aminocyclohexanol (9.6 g) and triethylamine (21.0 ml) in DMF (150 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (9.15 g) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.12 (3H, t), 1.20-1.44 (4H, m), 1.55-1.82 (3H, m), 1.84-1.96 (1H, m), 2.04-2.17 (1H, m), 3.49-3.63 (1H, m), 3.79-3.93 (1H, m), 4.06-4.17 (2H, m), 7.07-7.17 (2H, m), 7.35-7.49 (2H, m), 7.63 (1H, s) 
     MS (ESI+, m/e) 333 (M+1) 
     In the same manner as in Reference Example 31, the following compounds (Reference Examples 32-38) were obtained. 
     Reference Example 32 
     Methyl 1-[(1S,2S)-2-aminocyclohexyl]-5-(3-fluorophenyl)-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.07-1.45 (6H, m), 1.60-1.83 (3H, m), 1.93-2.03 (2H, m), 3.05 (1H, dt), 3.43 (1H, dt), 3.78 (3H, s), 7.23-7.27 (2H, m), 7.44-7.50 (1H, m), 7.69 (1H, s) 
     Reference Example 33 
     Methyl 1,5-dicyclohexyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.15-1.55 (6H, m), 1.56-2.15 (14H, m), 3.25 (1H, br s), 3.88 (3H, s), 3.93-4.05 (1H, m), 7.46 (1H, s) 
     Reference Example 34 
     Methyl 1-cyclohexyl-5-cyclopropyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 0.74-0.85 (2H, m), 1.06-1.18 (2H, m), 1.19-1.34 (2H, m), 1.37-1.52 (2H, m), 1.55-1.86 (5H, m), 1.95 (2H, s), 2.08 (2H, s), 3.88 (3H, s), 4.28 (1H, tt), 7.48 (1H, s) 
     Reference Example 35 
     Ethyl 5-(2-fluorophenyl)-1-[(1S,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 333 (M+1) 
     Reference Example 36 
     Ethyl 5-(3,5-difluorophenyl)-1-[(1S,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.10 (3H, t), 1.19-1.77 (6H, m), 1.83-2.02 (2H, m), 2.30 (1H, qd), 3.64-3.76 (1H, m), 4.08-4.20 (3H, m), 6.77-6.85 (2H, m), 6.92 (1H, tt), 7.84 (1H, s) 
     Reference Example 37 
     Ethyl 5-(2,3-difluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.13-1.43 (5H, m), 1.53-1.86 (4H, m), 1.98-2.22 (2H, m), 2.65-2.90 (1H, m), 3.51 (1H, dd), 3.75-3.86 (1H, m), 4.12-4.30 (2H, m), 7.15-7.22 (1H, m), 7.24-7.35 (2H, m), 7.72-7.75 (1H, m) 
     Reference Example 38 
     Ethyl 5-(4-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.14 (3H, t), 1.23-1.37 (2H, m), 1.62-1.69 (1H, m), 1.70-1.83 (2H, m), 1.89-2.03 (1H, m), 2.07-2.17 (1H, m), 3.52-3.66 (1H, m), 3.79-3.93 (1H, m), 4.15 (2H, q), 7.11-7.27 (3H, m), 7.33-7.46 (1H, m), 7.66 (1H, s) 
     Reference Example 39 
     Ethyl 1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (850 mg) and triethylamine (378 mg) were dissolved in dichloromethane (10 ml), and the solution was ice-cooled. Ethyl chloroformate (322 mg) was added, and the mixture was stirred at 0° C. for 2 hr. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (450 mg). 
       1 H-NMR (CDCl 3 ) δ 1.05-1.23 (8H, m), 1.32-1.45 (1H, m), 1.79 (3H, t), 2.05-2.08 (2H, m), 3.52 (1H, br t), 3.85 (1H, br s), 3.79-4.05 (2H, m), 4.15-4.25 (3H, m), 7.30-7.32 (2H, m), 7.48-7.51 (3H, m), 7.72 (1H, s) 
     In the same manner as in Reference Example 39, the following compounds (Reference Examples 40-44) were obtained. 
     Reference Example 40 
     Ethyl 1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.17-1.23 (5H, m), 1.32-1.45 (1H, m), 1.74-1.83 (3H, m), 2.05-2.07 (2H, m), 3.55 (4H, s), 3.85 (1H, br s), 4.15-4.24 (2H, m), 4.42 (1H, br s), 7.11-7.48 (5H, m), 7.72 (1H, s) 
     Reference Example 41 
     Ethyl 1-{(1R,2R)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.11-1.26 (8H, m), 1.31-1.46 (1H, m), 1.74-1.82 (3H, m), 2.05-2.08 (2H, m), 3.53 (1H, t), 3.86 (1H, br s), 3.97-4.05 (2H, m), 4.15-4.25 (3H, m), 7.30-7.32 (2H, m), 7.47-7.49 (3H, m), 7.72 (1H, s) 
     Reference Example 42 
     Ethyl 1-{cis-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.14-1.44 (9H, m), 1.57-1.60 (1H, m), 1.71-1.74 (1H, m), 1.87-1.91 (3H, m), 3.89-4.02 (4H, m), 4.14-4.22 (2H, m), 4.93 (1H, br d), 7.43-7.47 (5H, m), 7.57 (1H, s) 
     Reference Example 43 
     Methyl 5-(3-fluorophenyl)-1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.15-1.46 (4H, m), 1.77-1.85 (3H, m), 2.05-2.06 (2H, m), 3.55 (3H, br s), 3.75 (3H, s), 3.84 (1H, br s), 7.02-7.10 (2H, m), 7.19 (1H, dt), 7.43-7.51 (1H, m), 7.72 (1H, s) 
     Reference Example 44 
     Methyl 1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-(3-fluorophenyl)-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.15-1.27 (5H, m), 1.33-1.46 (1H, m), 1.71-1.85 (3H, m), 2.05-2.09 (2H, m), 3.56 (1H, dt), 3.74 (3H, s), 3.85 (1H, br s), 3.96-4.04 (2H, m), 4.47 (1H, br d), 7.03-7.11 (2H, m), 7.15-7.21 (1H, m), 7.43-7.50 (1H, m), 7.74 (1H, s) 
     Reference Example 45 
     Ethyl 1-{(1S,2S)-2-[(methylsulfonyl)oxy]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (3.14 g) was dissolved in pyridine (50 ml), and the solution was ice-cooled. Methanesulfonyl chloride (1.49 g) was added dropwise over 1 min, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (3.35 g) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.20 (3H, t), 1.35-1.56 (2H, m), 1.77-1.87 (3H, m), 2.09-2.14 (1H, m), 2.34-2.40 (1H, m), 2.61 (3H, s), 3.80-3.89 (1H, m), 4.17-4.26 (2H, m), 4.74-4.82 (1H, m), 7.33-7.35 (2H, m), 7.49-7.52 (3H, m), 7.77 (1H, s) 
     Reference Example 46 
     Ethyl 1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of ethyl 1-{(1S,2S)-2-[(methylsulfonyl)oxy]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (3.0 g) and sodium azide (3.9 g) in DMSO (30 ml) was stirred at 80° C. for 15 hr. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (2.1 g). 
       1 H-NMR (CDCl 3 ) δ 1.22 (3H, t), 1.28-1.44 (2H, m), 1.50-1.60 (2H, m), 1.78-2.03 (3H, m), 2.10-2.24 (1H, m), 3.69-3.70 (1H, m), 3.83-3.89 (1H, m), 4.22 (2H, q), 7.30-7.33 (2H, m), 7.46-7.51 (3H, m), 7.79 (1H, s) 
     Reference Example 47 
     Ethyl 1-[(1S,2R)-2-fluorocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of ethyl 1-{(1S,2S)-2-[(methylsulfonyl)oxy]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (785 mg) and TBAF (1.40 g) in acetonitrile (10 ml) was heated under reflux for 20 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (430 mg). 
       1 H-NMR (CDCl 3 ) δ 1.22 (3H, t), 1.25-1.34 (1H, m), 1.42-1.67 (3H, m), 1.81-1.91 (2H, m), 2.04-2.24 (2H, m), 3.71-3.86 (1H, m), 4.23 (2H, q), 4.70 (1H, d), 7.28-7.32 (2H, m), 7.47-7.49 (3H, m), 7.82 (1H, d) 
     Reference Example 48 
     Ethyl 1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (2.00 g) was dissolved in methanol (15 ml), 10% palladium-carbon (50% containing water, 500 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (1.84 g). 
       1 H-NMR (CDCl 3 ) δ 0.98 (2H, br s), 1.20-1.88 (10H, m), 2.18-2.31 (1H, m), 3.03 (1H, br s), 3.84-3.90 (1H, m), 4.22 (2H, q), 7.30-7.33 (2H, m), 7.44-7.51 (3H, m), 7.84 (1H, s) 
     Reference Example 49 
     Ethyl 1-((1S,2R)-2-{[(benzyloxy)carbonyl]amino}cyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.80 g) was dissolved in THF (10 ml), and the solution was ice-cooled. Triethylamine (865 mg) and benzyl chloroformate (1.18 g) were added. The mixture was stirred at 0° C. for 1 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with 6% aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (1.61 g). 
       1 H-NMR (CDCl 3 ) δ 1.18 (3H, t), 1.23-1.44 (3H, m), 1.56-1.60 (1H, m), 1.68-1.75 (1H, m), 1.87-1.90 (3H, m), 3.91-4.04 (1H, m), 4.20 (2H, q), 4.92-5.07 (3H, m), 7.34-7.47 (10H, m), 7.58 (1H, s) 
     Reference Example 50 
     Ethyl 1-(2-oxocyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (5.5 g) and triethylamine (5.3 g) were dissolved in DMSO (55 ml), and the solution was cooled to 15° C. 
     A solution of pyridine-sulfur trioxide complex (8.4 g) in DMSO (20 ml) was added dropwise over 5 min. The mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with 6% aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (5.4 g). 
       1 H-NMR (CDCl 3 ) δ 1.21 (3H, t), 1.70-1.76 (2H, m), 2.03-2.30 (4H, m), 2.39-2.45 (1H, m), 2.54-2.60 (1H, m), 4.22 (2H, q), 4.46 (1H, dd), 7.24-7.27 (2H, m), 7.42-7.46 (3H, m), 7.58 (1H, s) 
     In the same manner as in Reference Example 50, the following compound (Reference Example 51) was obtained. 
     Reference Example 51 
     Ethyl 5-(3-fluorophenyl)-1-(2-oxocyclohexyl)-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 331 (M+1) 
     Reference Example 52 
     Ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate and ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Trimethylsulfoxonium iodide (17.96 g) was dissolved in DMSO (300 ml), and sodium hydride (60% in oil, 3.26 g) was added at room temperature. After stirring for 30 min, the mixture was cooled to 15 to 20° C. A solution of ethyl 1-(2-oxocyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (21.24 g) in DMSO (75 ml) was added dropwise thereto over 20 min, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice water, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give a racemic mixture (18.54 g) of ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate and ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate. 
       1 H-NMR (CDCl 3 ) δ 1.23 (3H, t), 1.35-1.44 (2H, m), 1.65-2.17 (8H, m), 1.51 (1H, d), 4.11 (1H, dd), 4.22 (2H, q), 7.26-7.30 (2H, m), 7.46-7.50 (3H, m), 7.71 (1H, s) 
     The obtained racemate was optically resolved by normal phase chiral HPLC under the following conditions. 
     column: CHIRALPAK AD 50 mm ID×500 mL
 
mobile phase: hexane-ethanol (9:1)
 
flow rate: 80 ml/min
 
temperature: 30° C.
 
detection: UV (254 nm)
 
injection volume-concentration: 10 mg/ml, 47 ml (load: 470 mg)
 
     In the same manner as in Reference Example 52, the following compound (Reference Example 53) was obtained. 
     Reference Example 53 
     Ethyl 5-(3-fluorophenyl)-1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-1H-imidazole-4-carboxylate and ethyl 5-(3-fluorophenyl)-1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 344 (M+1) 
     MS (ESI+, m/e) 344 (M+1) 
     Reference Example 54 
     Ethyl 1-{2-[(benzylamino)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazole-4-carboxylate (680 mg) and benzylamine (430 mg) were dissolved in acetonitrile (10 ml). Lithium perchlorate (426 mg) was added, and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-7:3) was concentrated under reduced pressure to give the object compound (785 mg) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.01 (1H, dt), 1.15-1.25 (1H, m), 1.21 (3H, t), 1.48-1.52 (1H, m), 1.65-1.86 (5H, m), 2.11 (2H, s), 2.26 (2H, dq), 3.52 (1H, dd), 3.67 (2H, s), 4.21 (2H, dq), 7.10-7.18 (4H, m), 7.28-7.46 (6H, m), 7.06 (1H, s) 
     Reference Example 55 
     Ethyl 1-(2-{[(ethoxycarbonyl)amino]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-{2-[(benzylamino)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (770 mg) was dissolved in methanol (8 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 1-[2-(aminomethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (590 mg). 
       1 H-NMR (CDCl 3 ) δ 1.02 (1H, dt), 1.17 (3H, t), 1.22-1.28 (1H, m), 1.51-1.54 (1H, m), 1.66-1.88 (4H, m), 2.20-2.33 (3H, m), 2.56 (3H, br s), 3.58 (1H, dd), 4.13-4.24 (2H, m), 7.29 (2H, br s), 7.45-7.49 (3H, m), 8.08 (1H, s) 
     The above-mentioned ethyl 1-[2-(aminomethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (584 mg) and triethylamine (258 mg) were dissolved in dichloromethane (10 ml), and the solution was ice-cooled. Ethyl chloroformate (203 mg) was added, and the mixture was stirred at 0° C. for 2 hr, and concentrated under reduced pressure. To the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (615 mg) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.07-1.22 (8H, m), 1.51-1.83 (6H, m), 2.22 (1H, dq), 2.73-2.84 (2H, m), 3.63 (1H, dd), 3.91 (1H, br s), 4.05 (2H, dq), 4.20 (2H, q), 5.47 (1H, br t), 7.30 (2H, br s), 7.48-7.51 (3H, m), 8.05 (1H, s) 
     Reference Example 56 
     Ethyl 1-((1S,2R)-2-hydroxy-2-{[3-(methylthio)propoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil, 88 mg) was suspended in DMF (3 ml), 3-(methylthio)propan-1-ol (267 μl) was added thereto, and the mixture was stirred at room temperature for 30 min. To this was added ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (240 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (318 mg). 
     MS (ESI+, m/e) 433 (M+1) 
     Reference Example 57 
     Ethyl 1-(2-methylenecyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-(2-oxocyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (6.5 g) and methyltriphenylphosphonium bromide (11.15 g) were dissolved in THF (100 ml), and potassium tert-butoxide (3.5 g) was added at 15 to 17° C. After stirring at room temperature for 2 hr, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate. The mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-3:2) was concentrated under reduced pressure to give the object compound (6.0 g) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.24 (3H, t), 1.37-1.46 (2H, m), 1.81-2.01 (4H, m), 2.09-2.13 (1H, m), 2.46 (1H, d), 4.19-4.28 (4H, m), 4.85 (1H, s), 7.34-7.36 (2H, m), 7.43-7.45 (3H, m), 7.66 (1H, s) 
     Reference Example 58 
     Ethyl 1-(2-ethoxy-2-{[(ethoxycarbonyl)amino]methyl}cyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 1-(2-methylenecyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (4.66 g), ethyl {[(4-nitrophenyl)sulfonyl]oxy}carbamate (8.7 g), calcium oxide (1.68 g) and dichloromethane (100 ml) was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-3:2) was concentrated under reduced pressure to give a mixture (ratio 3:2, 2.16 g) as an amorphous solid of ethyl 4-[4-(ethoxycarbonyl)-5-phenyl-1H-imidazol-1-yl]-1-azaspiro[2.5]octane-1-carboxylate and the starting material. This was dissolved in ethanol (15 ml), and boron trifluoride diethyl etherate (425 mg) was added. The mixture was stirred at 70° C. for 26 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (276 mg) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 0.94 (3H, t), 1.24 (6H, t), 1.44-1.53 (2H, m), 1.53-1.67 (2H, m), 1.80-1.84 (2H, m), 2.00-2.11 (2H, m), 2.64-2.74 (1H, m), 3.00-3.17 (2H, m), 3.64-3.71 (1H, m), 4.05-4.16 (2H, m), 4.18-4.28 (3H, m), 4.55 (1H, br s), 7.34-7.48 (5H, m), 7.67 (1H, s) 
     Reference Example 59 
     Ethyl 1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of cyclohexylurea (755 mg), ethyl 2-diazo-3-oxo-3-phenylpropionate (1.00 g), rhodium (II) acetate dimmer (30 mg), toluene (10 ml) and 1,2-dichloroethane (10 ml) was stirred at 80° C. for 1 hr, and cooled to room temperature. TFA (1.0 ml) was added, and the reaction mixture was stirred at room temperature for 2 days, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-4:1) was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (1.01 g). 
       1 H-NMR (CDCl 3 ) δ 1.10 (6H, t), 1.71 (3H, t), 1.69 (2H, br s), 2.27 (2H, d), 3.44-3.57 (1H, m), 4.10 (2H, q), 7.26-7.37 (2H, m), 7.47 (2H, d), 7.42-7.51 (1H, m), 8.87 (1H, br s) 
     MS (ESI+, m/e) 315 (M+1) 
     Reference Example 60 
     Ethyl 1-cyclohexyl-2-ethoxy-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (500 mg) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. Triethyloxonium tetrafluoroborate (1M dichloromethane solution, 5.0 ml) was added dropwise, and the reaction mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-4:1) was concentrated under reduced pressure to give the object compound (319 mg). 
       1 H-NMR (CDCl 3 ) δ 1.11 (6H, q), 1.45 (3H, t), 1.58 (1H, d), 1.74 (2H, d), 1.65-1.80 (2H, m), 2.05 (1H, dd), 1.97-2.12 (1H, m), 3.51 (1H, t), 4.15 (2H, q), 4.56 (2H, q), 7.26-7.33 (1H, m), 7.29 (1H, dd), 7.40-7.46 (1H, m), 7.43 (2H, d) 
     MS (ESI+, m/e) 343 (M+1) 
     Reference Example 61 
     Ethyl 2-chloro-1-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (10.0 g) and phosphoryl chloride (70 ml) was stirred at 100° C. for 31 hr, and cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-7:3) was concentrated under reduced pressure to give the object compound (4.69 g). 
       1 H-NMR (CDCl 3 ) δ 1.08-1.21 (6H, m), 1.53-1.68 (2H, m), 1.71-1.85 (5H, m), 3.85 (1H, br s), 4.09-4.23 (2H, m), 7.25-7.34 (2H, m), 7.42-7.51 (3H, m) 
     MS (ESI+, m/e) 333 (M+1) 
     Reference Example 62 
     Ethyl 3-[(trans-2-hydroxycyclohexyl)amino]-2-nitro-3-phenylacrylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 3-iodo-2-nitro-3-phenylacrylate (7.00 g), trans-2-aminocyclohexanol hydrochloride (4.59 g), triethylamine (12.5 ml) and acetonitrile (60 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-4:1) was concentrated under reduced pressure to give the object compound (5.28 g). 
       1 H-NMR (CDCl 3 ) δ 0.88-1.01 (3H, m), 1.23-1.30 (2H, m), 1.38-1.48 (1H, m), 1.57-1.71 (4H, m), 1.78-1.89 (1H, m), 1.94-2.06 (1H, m), 2.18 (1H, br s), 2.94-3.07 (1H, m), 3.50-3.62 (1H, m), 3.90 (2H, br s), 7.24-7.35 (2H, m), 7.40-7.51 (3H, m) 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 63 
     Ethyl 1-(trans-2-hydroxycyclohexyl)-2-methyl-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 3-[(trans-2-hydroxycyclohexyl)amino]-2-nitro-3-phenylacrylate (4.49 g), 10% palladium-carbon (50% containing water, 500 mg) and trimethyl orthoacetate (150 ml) was subjected to catalytic reduction at 80° C. for 11 hr under hydrogen pressure (5 kgf/cm 2 ). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (360 mg). 
       1 H-NMR (CDCl 3 ) δ 0.83-0.97 (1H, m), 1.12-1.26 (4H, m), 1.63-1.73 (2H, m), 1.76-1.83 (1H, m), 1.97-2.08 (2H, m), 2.13-2.29 (3H, m), 2.45 (1H, br s), 3.06-3.21 (1H, m), 3.61-3.77 (1H, m), 4.05-4.21 (3H, m), 7.24-7.36 (4H, m), 7.44 (1H, br s) 
     MS (ESI+, m/e) 329 (M+1) 
     Reference Example 64 
     1-[(1S,2S)-2-(Benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Methyl 1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.25 g) was dissolved in methanol-THF (1:1, 20 ml). 8N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and partitioned between ethyl acetate and 10% aqueous citric acid solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (1.11 g) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.14-1.29 (3H, m), 1.59-1.87 (3H, m), 1.92-2.06 (1H, m), 2.20-2.36 (1H, m), 3.55 (1H, td), 3.75-3.87 (1H, m), 4.23 (1H, d), 4.48 (1H, d), 7.01 (2H, s), 7.19-7.32 (4H, m), 7.39-7.47 (5H, m), 7.91 (1H, br s) 
     In the same manner as in Reference Example 64, the following compound (Reference Example 65) was obtained. 
     Reference Example 65 
     1-[(1R,2R)-2-(Benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.14-1.29 (3H, m), 1.59-1.87 (3H, m), 1.92-2.06 (1H, m), 2.20-2.36 (1H, m), 3.55 (1H, td), 3.75-3.87 (1H, m), 4.23 (1H, d), 4.48 (1H, d), 7.01 (2H, s), 7.19-7.32 (4H, m), 7.39-7.47 (5H, m), 7.91 (1H, br s) 
     Reference Example 66 
     1-[(1R,2R)-2-(Benzyloxy)cyclopentyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     A mixture of methyl 1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazole-4-carboxylate (680 mg), lithium hydroxide monohydrate (400 mg), THF (4 ml), methanol (4 ml) and water (6 ml) was stirred at 70° C. for 12 hr, and concentrated under reduced pressure. The residual aqueous solution was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (468 mg). 
     MS (ESI+, m/e) 363 (M+1) 
     In the same manner as in Reference Example 66, the following compounds (Reference Examples 67-70) were obtained. 
     Reference Example 67 
     1-[(2R)-Bicyclo[2.2.1]hept-2-yl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 283 (M+1) 
     Reference Example 68 
     1-[Bicyclo[2.2.1]hept-2-yl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 283 (M+1) 
     Reference Example 69 
     1-Cyclohexyl-2-ethoxy-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.12 (3H, br s), 1.46 (3H, t), 1.61 (1H, br s), 1.67-1.83 (2H, m), 1.76 (2H, d), 2.05 (1H, s), 2.07 (1H, d), 3.58 (1H, dd), 4.50 (2H, q), 7.25-7.37 (2H, m), 7.38-7.49 (1H, m), 7.44 (2H, d) 
     MS (ESI+, m/e) 315 (M+1) 
     Reference Example 70 
     2-Chloro-1-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 0.96-1.11 (3H, m), 1.53 (1H, br s), 1.68-1.83 (4H, m), 1.87-2.03 (2H, m), 3.62-3.77 (1H, m), 7.34-7.42 (2H, m), 7.44-7.53 (3H, m) 
     MS (ESI+, m/e) 305 (M+1) 
     Reference Example 71 
     1-[(1S,2R)-2-Azidocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     A solution of ethyl 1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (2.30 g) and potassium hydroxide (1.15 g) in ethanol (20 ml) was heated under reflux for 1.5 hr. The solvent was evaporated under reduced pressure, and the residue was acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration, and dried to give the object compound (1.86 g). 
       1 H-NMR (DMSO-d 6 ) δ 1.22-1.40 (4H, m), 1.74-1.84 (3H, m), 2.06-2.19 (1H, m), 3.81-3.90 (2H, m), 7.37-7.52 (5H, m), 7.90 (1H, s), 11.90 (1H, br s) 
     In the same manner as in Reference Example 71, the following compounds (Reference Examples 72-75) were obtained. 
     Reference Example 72 
     1-{(1S,2S)-2-[(Methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 0.93-0.98 (1H, m), 1.28-1.34 (2H, m), 1.60-1.79 (5H, m), 3.44 (3H, s), 3.55-3.61 (1H, m), 3.90-3.93 (1H, m), 7.09-7.12 (1H, m), 7.31-7.49 (5H, m), 7.89 (1H, s), 11.74 (1H, br s) 
     Reference Example 73 
     1-{(1S,2S)-2-[(Ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 0.94-0.98 (1H, m), 1.08 (3H, t), 1.25-1.33 (2H, m), 1.60-1.79 (5H, m), 3.54-3.60 (1H, m), 3.85-3.91 (3H, m), 7.06-7.09 (1H, m), 7.32-7.49 (5H, m), 7.96 (1H, s), 11.80 (1H, br s) 
     Reference Example 74 
     1-{(1S,2R)-2-[(Ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 1.09 (3H, s), 1.20-1.34 (2H, m), 1.53-1.57 (2H, m), 1.73-1.84 (2H, m), 3.38 (2H, q), 3.69 (1H, br s), 3.88-4.00 (3H, m), 7.44-7.58 (5H, m), 8.81 (1H, s), 13.00 (1H, br s) 
     Reference Example 75 
     1-[(1S,2R)-2-Fluorocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 1.24-1.44 (4H, m), 1.74-1.82 (2H, m), 1.83-1.95 (1H, m), 2.08-2.20 (1H, m), 3.71-3.87 (1H, m), 4.73 (1H, d), 7.36-7.48 (5H, m), 7.91 (1H, d), 11.96 (1H, br s) 
     Reference Example 76 
     1-[(1S,2R)-2-Hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (6.1 g) was dissolved in ethanol-THF (1:1, 200 ml). 8N aqueous sodium hydroxide solution (10 ml) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give the object compound (4.52 g) as an amorphous solid. 
     MS (ESI+, m/e) 287 (M+1) 
     Reference Example 77 
     5-(3-Fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Methyl 5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylate (1.05 g) was dissolved in methanol-THF (1:1, 20 ml). 8N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give the object compound (981 mg) as an amorphous solid. 
       1 H-NMR (DMSO-d 6 ) δ 0.71-1.41 (5H, m), 1.41-1.99 (5H, m), 2.89-3.94 (2H, m), 6.88-7.67 (4H, m), 7.84 (1H, br s) 
     In the same manner as in Reference Example 77, the following compounds (Reference Examples 78-83) were obtained. 
     Reference Example 78 
     1,5-Dicyclohexyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 1.11-2.14 (20H, m), 3.10-3.33 (1H, m), 4.04-4.23 (1H, m), 8.08 (1H, s) 
     Reference Example 79 
     1-Cyclohexyl-3-cyclopropyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 0.61 (2H, br s), 0.87 (2H, d), 1.07-2.02 (11H, m), 4.08 (1H, br s), 4.90 (1H, br s), 7.33 (1H, br s) 
     Reference Example 80 
     5-(3-Fluorophenyl)-1-[(1S,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 305 (M+1) 
     Reference Example 81 
     5-(3,5-Difluorophenyl)-1-[(1S,2R)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 323 (M+1) 
     Reference Example 82 
     5-(2,3-Difluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 323 (M+1) 
     Reference Example 83 
     5-(4-Fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 305 (M+1) 
     Reference Example 84 
     1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (7.83 g) was dissolved in methanol (120 ml). Sodium methoxide (28% methanol solution, 23.1 ml) was added at room temperature, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added water (24 ml), and the mixture was further stirred at 60° C. for 6 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was dissolved in water, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water, and the fraction eluted with acetone was concentrated under reduced pressure to give the object compound (7.92 g) as an amorphous solid. 
       1 H-NMR (DMSO-d 6 ) δ 1.03 (1H, t), 1.26-1.44 (2H, m), 1.44-1.79 (4H, m), 1.96-2.14 (1H, m), 2.58-2.65 (1H, m), 2.68-2.77 (1H, m), 2.90-3.00 (3H, m), 3.62-3.73 (1H, m), 5.08 (1H, br s), 7.21-7.47 (5H, m), 7.95 (1H, s), 11.74 (1H, br s) 
     In the same manner as in Reference Example 84, the following compound (Reference Example 85) was obtained. 
     Reference Example 85 
     5-(3-Fluorophenyl)-1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 349 (M+1) 
     Reference Example 86 
     Ethyl N-(tert-butoxycarbonyl)-2-fluoro-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     A solution of N-(tert-butoxycarbonyl)-2-fluoro-D-phenylalanine (999 mg), ethyl N-benzylglycinate (716 mg), WSC HCl (811 mg) and HOBt (524 mg) in DMF (18 ml) was stirred at room temperature for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (1.62 g) as an amorphous solid. 
     MS (ESI+, m/e) 359 (M+1-“Boc”) 
     In the same manner as in Reference Example 86, the following compounds (Reference Examples 87-101) were obtained. 
     Reference Example 87 
     Ethyl N-(tert-butoxycarbonyl)-3-fluoro-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 359 (M+1-“Boc”) 
     Reference Example 88 
     Ethyl N-(tert-butoxycarbonyl)-4-fluoro-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 359 (M+1-“Boc”) 
     Reference Example 89 
     Ethyl N-(tert-butoxycarbonyl)-3,4-difluoro-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 377 (M+1-“Boc”) 
     Reference Example 90 
     Ethyl N-(tert-butoxycarbonyl)-3,5-difluoro-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 377 (M+1-“Boc”) 
     Reference Example 91 
     Ethyl N-(tert-butoxycarbonyl)-2,4,5-trifluoro-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 395 (M+1-“Boc”) 
     Reference Example 92 
     Ethyl N-(tert-butoxycarbonyl)-2-(trifluoromethyl)-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 409 (M+1-“Boc”) 
     Reference Example 93 
     Ethyl N-(tert-butoxycarbonyl)-3-(trifluoromethyl)-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 409 (M+1-“Boc”) 
     Reference Example 94 
     Ethyl N-(tert-butoxycarbonyl)-4-(trifluoromethyl)-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 409 (M+1-“Boc”) 
     Reference Example 95 
     Ethyl N-(tert-butoxycarbonyl)-O-methyl-D-tyrosyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 371 (M+1-“Boc”) 
     Reference Example 96 
     Ethyl 4-bromo-N-(tert-butoxycarbonyl)-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 519 (M+1) 
     Reference Example 97 
     Ethyl N-benzyl-N-[(2R)-2-[(tert-butoxycarbonyl)amino]-2-(2,3-dihydro-1H-inden-2-yl)acetyl]glycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 367 (M+1-“Boc”) 
     Reference Example 98 
     Ethyl N-(tert-butoxycarbonyl)-4-methyl-D-leucyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 421 (M+1) 
     Reference Example 99 
     Ethyl N-(tert-butoxycarbonyl)-D-leucyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 307 (M+1-“Boc”) 
     Reference Example 100 
     Ethyl N-(tert-butoxycarbonyl)-3-cyclohexyl-D-alanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 0.74-1.88 (25H, m), 3.70-3.89 (1H, m), 4.09-4.29 (2H, m), 4.42-4.61 (2H, m), 4.74-4.92 (2H, m), 5.10-5.18 (1H, m), 7.18-7.38 (5H, m) 
     Reference Example 101 
     Ethyl N-(tert-butoxycarbonyl)-D-tyrosyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.11-1.52 (12H, m), 3.66-4.26 (5H, m), 4.36-4.78 (3H, m), 4.83-5.13 (1H, m), 5.22-5.37 (1H, m), 5.65 (1H, br s), 6.61-7.49 (10H, m) 
     Reference Example 102 
     Ethyl N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-D-alanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     A solution of N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-D-alanine (5.00 g), ethyl N-benzylglycinate (3.81 g), WSC.HCl (4.32 g) and HOBt (2.79 g) in DMF (85 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (8.28 g) as an oil (it was allowed to crystallization at low temperature). 
     MS (ESI+, m/e) 442 (M+1) 
     In the same manner as in Reference Example 102, the following compounds (Reference Examples 103-106) were obtained. 
     Reference Example 103 
     Ethyl N-(tert-butoxycarbonyl)-3-(pyridin-2-yl)-D-alanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 442 (M+1) 
     Reference Example 104 
     Ethyl N-(tert-butoxycarbonyl)-3-(pyridin-4-yl)-D-alanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 442 (M+1) 
     Reference Example 105 
     Ethyl N-(tert-butoxycarbonyl)-D-tryptophyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 480 (M+1) 
     Reference Example 106 
     Ethyl N-(tert-butoxycarbonyl)-D-histidyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 431 (M+1) 
     Reference Example 107 
     Ethyl N-(tert-butoxycarbonyl)-2,4-dichloro-D-phenylalanylglycinate 
     
       
         
         
             
             
         
       
     
     A mixture of N-(tert-butoxycarbonyl)-2,4-dichloro-D-phenylalanine (5.00 g), glycine ethyl ester hydrochloride (2.19 g), WSC.HCl (3.44 g), HOBt (2.22 g), triethylamine (1.82 g) and DMF (70 ml) was stirred at room temperature for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (5.69 g). 
       1 H-NMR (CDCl 3 ) δ 1.28 (3H, t), 1.36 (9H, s), 3.00-3.07 (1H, m), 3.31 (1H, dd), 3.95 (1H, dd), 4.05 (1H, dd), 4.21 (2H, q), 4.48-4.50 (1H, m), 5.05-5.07 (1H, m), 6.52 (1H, br s), 7.15-7.21 (2H, m), 7.38 (1H, s) 
     MS (ESI+, m/e) 319 (M+1-“Boc”) 
     In the same manner as in Reference Example 107, the following compound (Reference Example 108) was obtained. 
     Reference Example 108 
     Ethyl N-(tert-butoxycarbonyl)-3-(1,3-thiazol-4-yl)-D-alanylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 358 (M+1) 
     Reference Example 109 
     (3R)-1-Benzyl-3-(2-fluorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     To a solution of ethyl N-(tert-butoxycarbonyl)-2-fluoro-D-phenylalanyl-N-benzylglycinate (1.58 g) in dichloromethane (0.9 ml) was added TFA (9 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in dichloromethane (15 ml), triethylamine (3 ml) was added, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF (4:1, 100 ml). The solution was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (950 mg). 
       1 H-NMR (CDCl 3 ) δ 3.14 (1H, dd), 3.22 (1H, d), 3.38 (1H, dd), 3.63 (1H, d), 4.33-4.37 (1H, m), 4.49 (1H, d), 4.56 (1H, d), 6.18 (1H, s), 6.93-7.06 (2H, m), 7.14 (1H, dt), 7.20-7.28 (3H, m), 7.31-7.36 (3H, m) 
     MS (ESI+, m/e) 313 (M+1) 
     In the same manner as in Reference Example 109, the following compounds (Reference Examples 110-124) were obtained. 
     Reference Example 110 
     (3R)-1-Benzyl-3-(3-fluorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.12-3.24 (3H, m), 3.61 (1H, d), 4.33-4.37 (1H, m), 4.49 (1H, d), 4.56 (1H, d), 6.51 (1H, s), 6.92-6.99 (3H, m), 7.19-7.24 (3H, m), 7.30-7.37 (3H, m) 
     MS (ESI+, m/e) 313 (M+1) 
     Reference Example 111 
     (3R)-1-Benzyl-3-(4-fluorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.02 (1H, d), 3.08 (1H, dd), 3.21 (1H, dd), 3.55 (1H, d), 4.32-4.36 (1H, m), 4.39 (1H, d), 4.55 (1H, d), 6.68 (1H, s), 6.84-6.91 (2H, m), 7.07-7.18 (4H, m), 7.30-7.33 (3H, m) 
     MS (ESI+, m/e) 313 (M+1) 
     Reference Example 112 
     (3R)-1-Benzyl-3-(3,4-difluorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.09 (1H, dd), 3.20 (1H, dd), 3.23 (1H, d), 3.63 (1H, d), 4.32-4.37 (1H, m), 4.41 (1H, d), 4.62 (1H, d), 6.85 (1H, s), 6.87-6.89 (1H, m), 6.94-7.06 (2H, m), 7.16-7.19 (2H, m), 7.31-7.36 (3H, m) 
     MS (ESI+, m/e) 331 (M+1) 
     Reference Example 113 
     (3R)-1-Benzyl-3-(3,5-difluorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.11-3.23 (2H, m), 3.38 (1H, d), 3.68 (1H, d), δ 4.33-4.37 (1H, m), 4.48 (1H, d), 4.61 (1H, d), 6.67-6.79 (4H, m), 7.17-7.20 (2H, m), 7.28-7.37 (3H, m) 
     MS (ESI+, m/e) 331 (M+1) 
     Reference Example 114 
     (3R)-1-Benzyl-3-(2,4,5-trifluorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.14 (1H, dd), 3.27 (1H, dd), 3.42 (1H, d), 3.70 (1H, d), 4.36-4.39 (1H, m), 4.44 (1H, d), 4.65 (1H, d), 6.55 (1H, s), 6.85-6.93 (1H, m), 7.01-7.10 (1H, m), 7.17-7.20 (2H, m), 7.30-7.35 (3H, m) 
     MS (ESI+, m/e) 349 (M+1) 
     Reference Example 115 
     (3R)-1-Benzyl-3-[2-(trifluoromethyl)benzyl]piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 363 (M+1) 
     Reference Example 116 
     (3R)-1-Benzyl-3-[3-(trifluoromethyl)benzyl]piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.13 (1H, d), 3.21-3.31 (2H, m), 3.60 (1H, d), 4.37 (1H, d), 4.37-4.41 (1H, m), 4.62 (1H, d), 6.66 (1H, s), 7.15-7.20 (2H, m), 7.28-7.39 (5H, m), 7.50-7.56 (2H, m) 
     MS (ESI+, m/e) 363 (M+1) 
     Reference Example 117 
     (3R)-1-Benzyl-3-[4-(trifluoromethyl)benzyl]piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.07 (1H, d), 3.18 (1H, dd), 3.28 (1H, dd), 3.58 (1H, d), 4.29 (1H, d), 4.37-4.41 (1H, m), 4.68 (1H, d), 6.50 (1H, s), 7.16-7.19 (2H, m), 7.24-7.27 (2H, m), 7.32-7.35 (3H, m), 7.43 (2H, d) 
     MS (ESI+, m/e) 363 (M+1) 
     Reference Example 118 
     (3R)-1-Benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.97 (1H, d), 3.06 (1H, dd), 3.15 (1H, dd), 3.51 (1H, d), 3.75 (3H, s), 4.28-4.32 (1H, m), 4.43 (1H, d), 4.51 (1H, d), 6.43 (1H, s), 6.72 (2H, d), 7.04 (2H, d), 7.16-7.20 (2H, m), 7.29-7.34 (3H, m) 
     MS (ESI+, m/e) 325 (M+1) 
     Reference Example 119 
     (3R)-1-Benzyl-3-(4-bromobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.06 (1H, dd), 3.07 (1H, d), 3.18 (1H, dd), 3.56 (1H, d), 4.32-4.36 (1H, m), 4.35 (1H, d), 4.60 (1H, d), 6.63 (1H, s), 7.00 (2H, d), 7.14-7.17 (2H, m), 7.27-7.36 (5H, m) 
     MS (ESI+, m/e) 373 (M+1) 
     Reference Example 120 
     (3R)-1-Benzyl-3-(2,3-dihydro-1H-inden-2-yl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.76 (1H, dd), 2.88-3.16 (4H, m), 3.78 (1H, d), 3.88 (1H, d), 4.15 (1H, dd), 4.48 (1H, d), 4.75 (1H, d), 6.87 (1H, s), 7.10-7.20 (4H, m), 7.25-7.40 (5H, m) 
     MS (ESI+, m/e) 321 (M+1) 
     Reference Example 121 
     (3R)-1-Benzyl-3-(2,2-dimethylpropyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.01 (9H, s), 1.55 (1H, dd), 2.11 (1H, dd), 3.79 (1H, d), 3.87 (1H, dd), 4.06 (1H, dt), 4.54 (1H, d), 4.63 (1H, d), 6.32 (1H, br s), 7.23-7.26 (2H, m), 7.30-7.38 (3H, m) 
     MS (ESI+, m/e) 275 (M+1) 
     Reference Example 122 
     (3R)-1-Benzyl-3-isobutylpiperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 261 (M+1) 
     Reference Example 123 
     (3R)-1-Benzyl-3-(cyclohexylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 0.93-1.05 (2H, m), 1.12-1.29 (3H, m), 1.40-1.46 (1H, m), 1.57-1.89 (8H, m), 3.76-3.89 (2H, m), 4.06-4.12 (1H, m), 4.59 (2H, dd), 6.98 (1H, s), 7.24-7.38 (5H, m) 
     Reference Example 124 
     (3R)-1-Benzyl-3-(4-hydroxybenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.70-2.82 (1H, m), 2.99-3.11 (1H, m), 3.32-3.43 (2H, m), 4.14-4.26 (2H, m), 4.55 (1H, d), 6.52 (2H, d), 6.83 (2H, d), 7.11 (2H, m), 7.23-7.39 (3H, m), 8.23-8.31 (1H, m), 9.26 (1H, s) 
     Reference Example 125 
     (3R)-1-Benzyl-3-(pyridin-3-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     To a solution of ethyl N-(tert-butoxycarbonyl)-3-(pyridin-3-yl)-D-alanyl-N-benzylglycinate (8.27 g) in dichloromethane (5 ml) was added TFA (50 ml), and the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in dichloromethane (75 ml), triethylamine (15 ml) was added thereto, the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure, and the residue was dissolved in chloroform (about 200 ml). The solution was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (4.14 g). 
       1 H-NMR (CDCl 3 ) δ 3.14 (1H, dd), 3.16 (1H, d), 3.26 (1H, dd), 3.60 (1H, d), 4.37-4.41 (1H, m), 4.50 (2H, s), 7.12-7.19 (3H, m), 7.24 (1H, s), 7.28-7.33 (3H, m), 7.50 (1H, dt), 8.48-8.50 (2H, m) 
     MS (ESI+, m/e) 296 (M+1) 
     In the same manner as in Reference Example 125, the following compounds (Reference Examples 126-129) were obtained. 
     Reference Example 126 
     (3R)-1-Benzyl-3-(pyridin-2-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 296 (M+1) 
     Reference Example 127 
     (3R)-1-Benzyl-3-(pyridin-4-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.14 (1H, dd), 3.22 (1H, dd), 3.26 (1H, d), 3.64 (1H, d), 4.38-4.43 (1H, m), 4.40 (1H, d), 4.61 (1H, d), 6.91 (1H, s), 7.10 (2H, d), 7.16-7.21 (2H, m), 7.31-7.39 (3H, m), 8.44 (2H, d) 
     MS (ESI+, m/e) 296 (M+1) 
     Reference Example 128 
     (3R)-1-Benzyl-3-(1H-indol-3-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.02 (1H, d), 3.36 (2H, d), 3.50 (1H, d), 4.12 (1H, d), 4.35-4.39 (1H, m), 4.59 (1H, d), 6.31 (1H, s), 6.98 (1H, d), 7.02-7.05 (2H, m), 7.13-7.27 (5H, m), 7.37 (1H, d), 7.64 (1H, d), 8.21 (1H, s) 
     MS (ESI+, m/e) 334 (M+1) 
     Reference Example 129 
     (3R)-1-Benzyl-3-(1H-imidazol-4-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.18 (1H, dd), 3.30 (1H, dd), 3.42 (1H, d), 3.70 (1H, d), 4.34-4.37 (1H, m), 4.50 (1H, d), 4.59 (1H, d), 6.83 (1H, s), 7.18-7.22 (2H, m), 7.28-7.36 (4H, m), 7.63 (1H, s), 8.11 (1H, s) 
     MS (ESI+, m/e) 285 (M+1) 
     Reference Example 130 
     (3R)-3-(2,4-Dichlorobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     Ethyl N-(tert-butoxycarbonyl)-2,4-dichloro-D-phenylalanylglycinate (5.68 g) was suspended in dichloromethane (4 ml). TFA (40 ml) was added, and the mixture was stirred at room temperature for 50 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in ethanol (60 ml), triethylamine (12 ml) was added, and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (3.40 g). 
       1 H-NMR (DMSO-d 6 ) δ 3.06 (1H, dd), 3.17 (1H, dd), 3.53 (1H, dd), 3.64 (1H, d), 3.94-3.98 (1H, m), 7.32 (1H, d), 7.39 (1H, dd), 7.58 (1H, d), 8.07 (2H, s) 
     MS (ESI+, m/e) 273 (M+1) 
     Reference Example 131 
     (3R)-3-(1,3-Thiazol-4-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     Ethyl N-(tert-butoxycarbonyl)-3-(1,3-thiazol-4-yl)-D-alanylglycinate (5.6 g) was dissolved in dichloromethane (5 ml). TFA (15 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure to remove TFA. The residue was dissolved in methanol (40 ml), triethylamine (8 ml) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF (4:1, 250 ml). The solution was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (2.4 g) as an amorphous solid. 
     MS (ESI+, m/e) 212 (M+1) 
     Reference Example 132 
     Benzyl 3-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]propionate 
     
       
         
         
             
             
         
       
     
     A solution of (2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (50 g), ethyl N-benzylglycinate (28.6 g), WSC.HCl (34 g) and HOBt (25 g) in DMF (300 ml) was stirred at room temperature for 12 hr, and poured into aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (150 ml), TFA (15 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with toluene. The mixture was again concentrated under reduced pressure. The residue was dissolved in chloroform (400 ml), triethylamine (70 ml) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was washed successively with water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate-hexane (1:1), and the precipitated crystals were collected by filtration to give the object compound (57 g). 
     MS (ESI+, m/e) 367 (M+1) 
     Reference Example 133 
     (3R)-1-Benzyl-3-(2-fluorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
     A mixture of (3R)-1-benzyl-3-(2-fluorobenzyl)piperazine-2,5-dione (942 mg) and THF (25 ml) was ice-cooled, and lithium aluminum hydride (458 mg) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 60° C. for 1.5 hr. The mixture was cooled to −78° C., and ethanol-ethyl acetate (1:1, 3 ml) and 1N aqueous sodium hydroxide solution (6 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-10:1) was concentrated under reduced pressure to give the object compound (595 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.57 (1H, br s), 1.90 (1H, t), 2.06 (1H, dt), 2.61 (1H, dd), 2.68-2.85 (4H, m), 2.92 (1H, dt), 3.00-3.06 (1H, m), 3.44 (1H, d), 3.55 (1H, d), 6.98-7.07 (2H, m), 7.15-7.32 (7H, m) 
     MS (ESI+, m/e) 285 (M+1) 
     In the same manner as in Reference Example 133, the following compounds (Reference Examples 134-146) were obtained. 
     Reference Example 134 
     (3R)-1-Benzyl-3-(3-fluorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.65 (1H, br s), 1.88 (1H, dd), 2.08 (1H, dt), 2.54 (1H, dd), 2.66-3.03 (6H, m), 3.46 (1H, d), 3.53 (1H, d), 6.87-6.97 (3H, m), 7.20-7.32 (6H, m) 
     MS (ESI+, m/e) 285 (M+1) 
     Reference Example 135 
     (3R)-1-Benzyl-3-(4-fluorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.62 (1H, br s), 1.86 (1H, t), 2.03-2.11 (1H, m), 2.51 (1H, dd), 2.64-2.99 (6H, m), 3.46 (1H, d), 3.53 (1H, d), 6.49-7.00 (2H, m), 7.12-7.18 (2H, m), 7.21-7.32 (5H, m) 
     MS (ESI+, m/e) 285 (M+1) 
     Reference Example 136 
     (3R)-1-Benzyl-3-(3,4-difluorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.61 (1H, br s), 1.85 (1H, t), 2.07 (1H, dt), 2.50 (1H, dd), 2.65 (1H, dd), 2.71-2.84 (3H, m), 2.89-2.99 (2H, m), 3.46 (1H, d), 3.53 (1H, d), 6.86-6.90 (1H, m), 6.95-7.10 (2H, m), 7.22-7.32 (5H, m) 
     MS (ESI+, m/e) 303 (M+1) 
     Reference Example 137 
     (3R)-1-Benzyl-3-(2,4,5-trifluorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 321 (M+1) 
     Reference Example 138 
     (3R)-1-Benzyl-3-[2-(trifluoromethyl)benzyl]piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 139 
     (3R)-1-Benzyl-3-[3-(trifluoromethyl)benzyl]piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.61 (1H, br s), 1.88 (1H, t), 2.08 (1H, dt), 2.61 (1H, dd), 2.73-2.85 (4H, m), 2.92 (1H, dt), 2.97-3.06 (1H, m), 3.47 (1H, d), 3.53 (1H, d), 7.21-7.48 (9H, m) 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 140 
     (3R)-1-Benzyl-3-[4-(trifluoromethyl)benzyl]piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.59 (1H, br s), 1.89 (1H, t), 2.08 (1H, dt), 2.61 (1H, dd), 2.71-2.84 (4H, m), 2.91 (1H, dt), 2.97-3.06 (1H, m), 3.47 (1H, d), 3.53 (1H, d), 7.21-7.31 (8H, m), 7.54 (1H, d) 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 141 
     (3R)-1-Benzyl-3-(4-methoxybenzyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.64 (1H, br s), 1.87 (1H, t), 2.07 (1H, dt), 2.47 (1H, dd), 2.65 (1H, dd), 2.71-2.95 (5H, m), 3.46 (1H, d), 3.54 (1H, d), 3.79 (3H, s), 6.83 (2H, d), 7.11 (2H, d), 7.23-7.32 (5H, m) 
     MS (ESI+, m/e) 297 (M+1) 
     Reference Example 142 
     (3R)-1-Benzyl-3-(2,3-dihydro-1H-inden-2-yl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.53 (1H, br s), 1.86 (1H, t), 2.05 (1H, dt), 2.33-2.45 (1H, m), 2.62-3.10 (9H, m), 3.46 (1H, d), 3.58 (1H, d), 7.08-7.32 (9H, m) 
     MS (ESI+, m/e) 293 (M+1) 
     Reference Example 143 
     (3R)-1-Benzyl-3-(2,2-dimethylpropyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 0.91 (9H, s), 1.18-1.20 (2H, m), 1.62 (1H, br s), 1.75 (1H, t), 1.94-2.02 (1H, m), 2.70-2.92 (5H, m), 3.44 (1H, d), 3.53 (1H, d), 7.22-7.31 (5H, m) 
     MS (ESI+, m/e) 247 (M+1) 
     Reference Example 144 
     (3R)-1-Benzyl-3-isobutylpiperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 233 (M+1) 
     Reference Example 145 
     (3R)-1-Benzyl-3-(cyclohexylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 273 (M+1) 
     Reference Example 146 
     4-{[(2R)-4-Benzylpiperazin-2-yl]methyl}phenol 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 1.52-2.88 (8H, m), 3.08-3.73 (4H, m), 6.64 (2H, d), 6.94 (2H, d), 7.16-7.35 (5H, m), 9.17 (1H, br s) 
     MS (ESI+, m/e) 283 (M+1) 
     Reference Example 147 
     (3R)-1-Benzyl-3-(3,5-difluorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
     (3R)-1-Benzyl-3-(3,5-difluorobenzyl)piperazine-2,5-dione (4.36 g) was dissolved in THF (55 ml), and borane-THF (1.0M THF solution, 105.6 ml) was added dropwise at room temperature over 15 min. The mixture was stirred at room temperature for 1 hr, and then at 60° C. for 15 hr. The reaction mixture was ice-cooled, and water (6 ml) was added dropwise over 5 min. The mixture was stirred at room temperature for 10 min, and the reaction mixture was concentrated under reduced pressure. To the residue was added 2N hydrochloric acid (60 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled again, basified with 8N aqueous sodium hydroxide solution to weak basic (pH 8-9), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give the object compound (1.81 g) as an oil (it was allowed to crystallization at low temperature). 
       1 H-NMR (CDCl 3 ) δ 1.64 (1H, br s), 1.86 (1H, t), 2.08 (1H, dt), 2.54 (1H, dd), 2.64-3.01 (6H, m), 3.47 (1H, d), 3.53 (1H, d), 6.61-6.74 (3H, m), 7.24-7.32 (5H, m) 
     MS (ESI+, m/e) 303 (M+1) 
     In the same manner as in Reference Example 147, the following compounds (Reference Examples 148-152) were obtained. 
     Reference Example 148 
     (3R)-1-Benzyl-3-(pyridin-2-ylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.14-2.28 (3H, m), 2.78-2.93 (5H, m), 3.19-3.32 (1H, m), 3.50 (1H, d), 3.67 (1H, d), 3.81 (1H, s), 7.04-7.19 (2H, m), 7.22-7.37 (5H, m), 7.58 (1H, td), 8.53 (1H, dd). 
     MS (ESI+, m/e) 268 (M+1) 
     Reference Example 149 
     (3R)-1-Benzyl-3-(pyridin-4-ylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.60 (1H, br s), 1.88 (1H, t), 2.09 (1H, dt), 2.56 (1H, dd), 2.66-3.07 (6H, m), 3.47 (1H, d), 3.53 (1H, d), 7.12 (2H, d), 7.24-7.35 (5H, m), 8.51 (2H, d) 
     MS (ESI+, m/e) 268 (M+1) 
     Reference Example 150 
     3-{[(2R)-4-Benzylpiperazin-2-yl]methyl}-1H-indole 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 306 (M+1) 
     Reference Example 151 
     (3R)-1-Benzyl-3-(1H-imidazol-4-ylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.83 (1H, t), 2.06 (1H, dt), 2.56 (1H, dd), 2.64-3.07 (7H, m), 3.48 (2H, s), 6.76 (1H, s), 7.21-7.33 (6H, m), 7.44 (1H, s) 
     MS (ESI+, m/e) 257 (M+1) 
     Reference Example 152 
     (3R)-1-Benzyl-3-(4-bromobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.62 (1H, br s), 1.87 (1H, t), 2.07 (1H, dt), 2.50 (1H, dd), 2.66 (1H, dd), 2.71-2.99 (5H, m), 3.46 (1H, d), 3.53 (1H, d), 7.07 (2H, d), 7.21-7.32 (5H, m), 7.41 (2H, d) 
     MS (ESI+, m/e) 345 (M+1) 
     Reference Example 153 
     (3R)-1-Benzyl-3-(pyridin-3-ylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
     (3R)-1-Benzyl-3-(pyridin-3-ylmethyl)piperazine-2,5-dione (4.13 g) was dissolved in THF (60 ml), and borane-THF (1.0M THF solution, 111.9 ml) was added dropwise at room temperature over 15 min. The mixture was stirred at room temperature for 1 hr, and then at 60° C. for 15 hr. The reaction mixture was ice-cooled, water (6.5 ml) was added dropwise over 5 min, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, to the residue was added 2N hydrochloric acid (65 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled again, basified with 8N aqueous sodium hydroxide solution to weak basic (pH 8-9), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol-triethylamine (1:0:0-100:5:2) was concentrated under reduced pressure to give the object compound (1.98 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.76 (1H, br s), 1.88 (1H, t), 2.08 (1H, dt), 2.57 (1H, dd), 2.67-3.04 (6H, m), 3.46 (1H, d), 3.53 (1H, d), 7.19-7.34 (6H, m), 7.50 (1H, dt), 8.45-8.47 (2H, m) 
     MS (ESI+, m/e) 268 (M+1) 
     Reference Example 154 
     (2R)-2-(2,4-Dichlorobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
     (3R)-3-(2,4-Dichlorobenzyl)piperazine-2,5-dione (3.39 g) was dissolved in THF (55 ml), and borane-THF (1.0M THF solution, 99.3 ml) was added dropwise at room temperature over 15 min. The mixture was stirred at room temperature for 1 hr, and then at 60° C. for 6 hr, and the reaction mixture was ice-cooled. Water (6 ml) was added dropwise over 5 min, and the mixture was stirred at room temperature for 10 min, and concentrated under reduced pressure. To the residue was added 2N hydrochloric acid (60 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was ice-cooled again, basified with 8N aqueous sodium hydroxide solution to weak basic (pH 8-9), and extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (1.09 g). 
     MS (ESI+, m/e) 245 (M+1) 
     Reference Example 155 
     tert-Butyl (3R)-3-(2,4-dichlorobenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of (2R)-2-(2,4-dichlorobenzyl)piperazine (1.08 g), tert-butanol (20 ml), water (15 ml) and 1N aqueous sodium hydroxide solution (4.63 ml) was ice-cooled, and di-tert-butyl bicarbonate (1.01 g) was added thereto. The mixture was stirred at room temperature for 6 hr, and concentrated under reduced pressure to about half-volume. The residue was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:8:0-20:0:1) was concentrated under reduced pressure to give the object compound (154 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.45 (9H, s), 2.62-2.71 (3H, m), 2.81-2.95 (5H, m), 3.87-3.91 (2H, m), 7.15-7.21 (2H, m), 7.38 (1H, s) 
     MS (ESI+, m/e) 345 (M+1) 
     Reference Example 156 
     tert-Butyl (3R)-3-(1,3-thiazol-4-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of (3R)-3-(1,3-thiazol-4-ylmethyl)piperazine-2,5-dione (1.0 g) and THF (30 ml) was ice-cooled, and lithium aluminum hydride (0.9 g) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 50° C. for 2 hr, and cooled to −78° C. Sodium sulfate hydrate and 1N aqueous sodium hydroxide solution (0.5 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure. The residue was dissolved in tert-butanol (5 ml), 2.5N aqueous sodium hydroxide solution (5 ml) and di-tert-butyl bicarbonate (2.18 g) were successively added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (100 mg) as an oil. 
     MS (ESI+, m/e) 284 (M+1) 
     Reference Example 157 
     tert-Butyl (2R)-4-benzyl-2-(4-bromobenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (3R)-1-Benzyl-3-(4-bromobenzyl)piperazine (2.64 g) was dissolved in THF (20 ml), and di-tert-butyl bicarbonate (1.75 g) was added. The mixture was stirred at room temperature for 3 hr, and the reaction mixture was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (2.87 g). 
       1 H-NMR (CDCl 3 ) δ 1.38 (9H, s), 1.95 (1H, dd), 2.08 (1H, dt), 2.58 (1H, d), 2.82-2.98 (3H, m), 3.17 (1H, dt), 3.31 (1H, d), 3.55 (1H, d), 3.91-4.08 (2H, m), 6.87 (2H, d), 7.24-7.34 (7H, m) 
     MS (ESI+, m/e) 445 (M+1) 
     Reference Example 158 
     tert-Butyl (2R)-4-benzyl-2-(4-morpholinobenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (2R)-4-benzyl-2-(4-bromobenzyl)piperazine-1-carboxylate (1.00 g), morpholine (215 mg), BINAP (140 mg), sodium tert-butoxide (324 mg), Pd 2 (dba) 3  (82 mg) and toluene (20 ml) was stirred at 90° C. for 15 hr in an argon stream, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:5-1:2) was concentrated under reduced pressure to give the object compound (986 mg) as an oil (it was allowed to crystallization at low temperature). 
       1 H-NMR (CDCl 3 ) δ 1.39 (9H, s), 1.95 (1H, dd), 2.04 (1H, dt), 2.63 (1H, d), 2.72-2.84 (2H, m), 2.96-3.04 (1H, m), 3.07 (4H, dd), 3.18 (1H, dt), 3.36 (1H, d), 3.51 (1H, d), 3.84 (4H, dd), 3.85-4.15 (2H, m), 6.72 (2H, d), 6.95 (2H, d), 7.27-7.34 (5H, m) 
     MS (ESI+, m/e) 452 (M+1) 
     Reference Example 159 
     4-(4-{[(2R)-4-Benzylpiperazin-2-yl]methyl}phenyl)morpholine 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(4-morpholinobenzyl)piperazine-1-carboxylate (937 mg) was dissolved in dichloromethane (2 ml). TFA (5 ml) was added, and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2-1:0) was concentrated under reduced pressure to give the object compound (728 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.63 (1H, br s), 1.87 (1H, t), 2.07 (1H, dt), 2.45 (1H, dd), 2.63 (1H, dd), 2.71-2.97 (5H, m), 3.13 (4H, dd), 3.46 (1H, d), 3.53 (1H, d), 3.84 (4H, dd), 6.84 (2H, d), 7.09 (2H, d), 7.21-7.31 (5H, m) 
     MS (ESI+, m/e) 352 (M+1) 
     Reference Example 160 
     Di-tert-butyl (2R)-2-(4-hydroxybenzyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     4-{[(2R)-4-Benzylpiperazin-2-yl]methyl}phenol (12 g) was dissolved in methanol (240 ml), 20% palladium hydroxide-carbon (50% containing water, 3.0 g) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in a mixed solvent of tert-butanol (100 ml) and water (100 ml), and 2.5N sodium hydroxide (40 ml) and di-tert-butyl bicarbonate (17.6 g) were added under ice-cooling. After stirring for 12 hr, the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (10.7 g) as an amorphous solid. 
     MS (ESI+, m/e) 393 (M+1) 
     Reference Example 161 
     Di-tert-butyl (2R)-2-(4-{[(trifluoromethyl)sulfonyl]oxy}benzyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     Di-tert-butyl (2R)-2-(4-hydroxybenzyl)piperazine-1,4-dicarboxylate (10.7 g), 4-nitrophenyl trifluoromethanesulfonate (8.1 g) and potassium carbonate (7.6 g) were suspended in DMF (170 ml), and the suspension was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (11.2 g) as an amorphous solid. 
     MS (ESI+, m/e) 525 (M+1) 
     Reference Example 162 
     tert-Butyl (3R)-3-(4-cyanobenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of di-tert-butyl (2R)-2-(4-{[(trifluoromethyl)sulfonyl]oxy}benzyl)piperazine-1,4-dicarboxylate (1.05 g), zinc cyanide (282 mg) and tetrakis(triphenylphosphine)palladium(0) (231 mg) in DMF (10 ml) was stirred at 80° C. for 15 hr. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give di-tert-butyl (2R)-2-(4-cyanobenzyl)piperazine-1,4-dicarboxylate (570 mg) as crystals. 
     The total amount thereof was dissolved in dichloromethane (1 ml), and TFA (3 ml) was added thereto. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. To the residue was 6% aqueous sodium bicarbonate was added by small portions to neutralize the residue, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 4-[(2R)-piperazin-2-ylmethyl]benzonitrile (600 mg) as an oil. 
     The total amount thereof and aqueous sodium hydroxide solution (100 mg/10 ml) were dissolved in tert-butanol (10 ml), and the solution was ice-cooled. Di-tert-butyl bicarbonate (546 mg) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-4:1) was concentrated under reduced pressure to give the object compound (145 mg) as an amorphous solid. 
     MS (ESI+, m/e) 302 (M+1) 
     Reference Example 163 
     tert-Butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (15.1 g), benzaldehyde (7.4 g) and acetic acid (4.2 g) were dissolved in 1,2-dichloroethane (200 ml), and the solution was ice-cooled. Sodium triacetoxyborohydride (19.3 g) was added, and the mixture was stirred at room temperature for 15 hr, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object compound (16.1 g) as crystals. 
     MS (ESI+, m/e) 307 (M+1) 
     Reference Example 164 
     tert-Butyl (2S)-4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     [(2S)-4-Benzylpiperazin-2-yl]methanol (25.84 g) was dissolved in THF (250 ml). Di-tert-butyl bicarbonate (27.34 g) was added by small portions, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1.5:1) was concentrated under reduced pressure to give the object compound (38.34 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.45 (9H, s), 2.09 (1H, dt), 2.31 (1H, dd), 2.83 (1H, d), 2.97 (1H, d), 3.36-3.53 (3H, m), 3.83-3.99 (5H, m), 7.25-7.33 (5H, m) 
     MS (ESI+, m/e) 307 (M+1) 
     In the same manner as in Reference Example 164, the following compound (Reference Example 165) was obtained. 
     Reference Example 165 
     tert-Butyl (2R)-4-benzyl-2-(2-hydroxyethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.46 (9H, s), 2.01 (1H, dt), 2.20-2.24 (1H, m), 2.25 (1H, dd), 2.68-2.72 (2H, m), 3.01 (1H, dt), 3.37-3.60 (4H, m), 3.85-3.98 (3H, m), 4.26-4.30 (1H, m), 7.25-7.34 (5H, m) 
     MS (ESI+, m/e) 321 (M+1) 
     Reference Example 166 
     tert-Butyl (2R)-4-benzyl-2-(3-hydroxypropyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl 3-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]propionate (25 g) was dissolved in THF (350 ml), and the solution was cooled to −20° C. Lithium aluminum hydride (13 g) was added over 30 min, and the mixture was stirred at room temperature for 30 min, and then at 50° C. for 12 hr. The mixture was cooled to −78° C., and sodium sulfate hydrate and 1N aqueous sodium hydroxide solution (5 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (150 ml), di-tert-butyl bicarbonate (13.4 g) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (8.2 g) as an oil. 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 167 
     tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-(hydroxymethyl)piperazine-1-carboxylate (12.26 g) was dissolved in dichloromethane (130 ml), and a solution of pyridine-sulfur trioxide complex (19.10 g) in DMSO (130 ml) and triethylamine (12.14 g) were added at 0° C. The reaction mixture was stirred at 0° C. for 2 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (6.28 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.43-1.48 (9H, m), 2.12 (1H, dt), 2.27 (1H, dd), 2.69-2.73 (1H, m), 3.06-3.15 (1H, m), 3.30 (1H, d), 3.44 (1H, d), 3.56 (1H, d), 3.78 (0.5H, d), 3.90 (0.5H, d), 4.38 (0.5H, s), 4.58 (0.5H, s), 7.22-7.34 (5H, m), 9.49 (1H, s) 
     MS (ESI+, m/e) 305 (M+1) 
     In the same manner as in Reference Example 167, the following compound (Reference Example 168) was obtained. 
     Reference Example 168 
     tert-Butyl (2R)-4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.44 (9H, s), 2.04 (1H, dt), 2.20 (1H, dd), 2.66-2.84 (4H, m), 3.01-3.09 (1H, m), 3.42 (1H, d), 3.51 (1H, d), 3.84-3.88 (1H, m), 4.60-4.64 (1H, m), 7.25-7.28 (5H, m), 9.73 (1H, s) 
     MS (ESI+, m/e) 319 (M+1) 
     Reference Example 169 
     tert-Butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Triphenylphosphine (9.4 g) and carbon tetrabromide (11.9 g) were suspended in diethyl ether (200 ml), tert-butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (9.2 g) was added over 5 min by small portions, and the mixture was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give the object compound (8.5 g) as an oil. 
     MS (ESI+, m/e) 370 (M+1) 
     Reference Example 170 
     tert-Butyl (3S)-3-[(phenylthio)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (3.69 g) was dissolved in DMF (35 ml). Sodium benzenethiolate (1.98 g) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added 6% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(phenylthio)methyl]piperazine-1-carboxylate (3.77 g) as an oil. 3.67 g therefrom was dissolved in 1,2-dichloroethane (30 ml), and 1-chloroethyl chloroformate (1.58 g) was added. The mixture was heated under reflux for 5 hr, and concentrated under reduced pressure. To the residue was added methanol (30 ml), and the mixture was further heated under reflux for 4 hr, and concentrated under reduced pressure. The residue was neutralized with 6% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (1.44 g) as an oil. 
     MS (ESI+, m/e) 309 (M+1) 
     Reference Example 171 
     tert-Butyl (2S)-4-benzyl-2-{2,2,2-trifluoro-1-[(trimethylsilyl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (912 mg) and trimethyl(trifluoromethyl)silane (853 mg) were dissolved in THF (20 ml). TBAF (several mg) was added, and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure to give the object compound (1.34 g) as an oil. 
     MS (ESI+, m/e) 447 (M+1) 
     Reference Example 172 
     tert-Butyl (2S)-4-benzyl-2-[cyclopropyl(hydroxy)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (2.5 g) was dissolved in THF (25 ml), and the mixture was cooled to −30° C. Cyclopropylmagnesium bromide (0.5M THF solution, 40 ml) was added thereto, and the mixture was stirred at −20° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (2.2 g) as an amorphous solid. 
     MS (ESI+, m/e) 347 (M+1) 
     In the same manner as in Reference Example 172 and by the reaction of known methyl (1,4-dibenzylpiperazin-2-yl)acetate with methylmagnesium bromide, the following compound (Reference Example 173) was obtained. 
     Reference Example 173 
     1-(1,4-Dibenzylpiperazin-2-yl)-2-methylpropan-2-ol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 339 (M+1) 
     Reference Example 174 
     1-[(2S)-4-Benzylpiperazin-2-yl]-2,2,2-trifluoroethanol 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-{2,2,2-trifluoro-1-[(trimethylsilyl)oxy]ethyl}piperazine-1-carboxylate (1.34 g) was dissolved in chloroform (2 ml). TFA (2 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions, and the mixture was basified with small amount of potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (772 mg) as an oil. 
     MS (ESI+, m/e) 275 (M+1) 
     In the same manner as in Reference Example 174, the following compound (Reference Example 175) was obtained. 
     Reference Example 175 
     [(2S)-4-Benzylpiperazin-2-yl](cyclopropyl)methanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 247 (M+1) 
     Reference Example 176 
     tert-Butyl 3-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-(1,4-Dibenzylpiperazin-2-yl)-2-methylpropan-2-ol (1.0 g) was dissolved in methanol (30 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 17 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue and potassium carbonate (300 mg) were dissolved in THF (15 ml) and water (30 ml), and the mixture was cooled to 0° C. (2Z)-{[(tert-Butoxycarbonyl)oxy]imino}(phenyl)acetonitrile (726 mg) was added thereto, and the mixture was stirred at the same temperature for 1 hr, and then at room temperature for 3 hr. To the reaction mixture was added 30% aqueous citric acid solution, and the mixture was washed with diethyl ether twice. The aqueous layer was saturated with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (500 mg) as an oil. 
     MS (ESI+, m/e) 259 (M+1) 
     Reference Example 177 
     tert-Butyl (2R)-4-benzyl-2-[(isopropylamino)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (6.27 g), isopropylamine (2.44 g), acetic acid (2.47 g) and dichloromethane (80 ml) in DMF (40 ml) was stirred at room temperature for 40 min, sodium triacetoxyborohydride (8.73 g) was added, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. After stirring, the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (6.37 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 0.98 (3H, d), 1.00 (3H, d), 1.46 (9H, s), 1.99-2.08 (2H, m), 2.73-2.96 (6H, m), 3.07 (1H, dt), 3.38 (1H, d), 3.54 (1H, d), 3.85-3.89 (1H, m), 4.07 (1H, br s), 7.30-7.32 (5H, m) 
     MS (ESI+, m/e) 348 (M+1) 
     In the same manner as in Reference Example 177, the following compounds (Reference Examples 178-179) were obtained. 
     Reference Example 178 
     tert-Butyl (2R)-2-(anilinomethyl)-4-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.45 (9H, s), 2.02-2.11 (2H, m), 2.80-2.84 (2H, m), 3.12 (1H, dt), 3.39-4.28 (7H, m), 6.54 (2H, d), 6.62-6.67 (1H, m), 7.10-7.15 (2H, m), 7.27-7.34 (5H, m) 
     MS (ESI+, m/e) 382 (M+1) 
     Reference Example 179 
     tert-Butyl (2R)-4-benzyl-2-{[(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.44 (9H, s), 1.59 (1H, br s), 1.97 (1H, dd), 2.00 (1H, dd), 2.09 (1H, dd), 2.71 (1H, d), 2.85-3.03 (4H, m), 3.46 (2H, s), 3.71 (2H, s), 3.77 (3H, s), 3.80 (3H, s), 3.80-3.86 (1H, m), 6.40-6.46 (2H, m), 7.12 (1H, d), 7.20-7.33 (5H, m) 
     MS (ESI+, m/e) 456 (M+1) 
     Reference Example 180 
     tert-Butyl (2S)-4-benzyl-2-{[(4-ethoxy-4-oxobutanoyl)(phenyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-2-(anilinomethyl)-4-benzylpiperazine-1-carboxylate (2.75 g) and triethylamine (1.46 g) were dissolved in THF (60 ml), ethylsuccinyl chloride (2.37 g) was added, and the mixture was stirred at room temperature for 3 hr. The mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-hexane (1:1:4) was concentrated under reduced pressure to give the object compound (3.56 g) as an oil. 
     MS (ESI+, m/e) 510 (M+1) 
     Reference Example 181 
     tert-Butyl (2S)-4-benzyl-2-{[(2,4-dimethoxybenzyl)(2-methoxybenzoyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-{[(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate (1.91 g) and triethylamine (850 mg) were dissolved in THF (35 ml), and 2-methoxybenzoyl chloride (1.43 g) was added. The mixture was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2-1:1) was concentrated under reduced pressure to give the object compound (1.90 g) as an amorphous solid. 
     MS (ESI+, m/e) 590 (M+1) 
     In the same manner as in Reference Example 181, the following compounds (Reference Examples 182-184) were obtained. 
     Reference Example 182 
     tert-Butyl (2S)-2-{[(benzoyl)(2,4-dimethoxybenzyl)amino]methyl}-4-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 560 (M+1) 
     Reference Example 183 
     tert-Butyl (2S)-4-benzyl-2-{[(3,5-difluorobenzoyl)(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 596 (M+1) 
     Reference Example 184 
     tert-Butyl (2S)-4-benzyl-2-{[(cyclohexylcarbonyl)(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 566 (M+1) 
     Reference Example 185 
     tert-Butyl (2S)-4-benzyl-2-{[(isopropyl)(5-methoxy-4,4-dimethyl-5-oxopentanoyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     5-Methoxy-4,4-dimethyl-5-oxovaleric acid (4.46 g) was dissolved in THF (100 ml), and oxalyl chloride (3.90 g) and DMF (50 μl) were added. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in THF (10 ml), and the solution was added to a solution of tert-butyl (2R)-4-benzyl-2-[(isopropylamino)methyl]piperazine-1-carboxylate (4.24 g) and triethylamine (2.59 g) in THF (90 ml). The mixture was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3-1:1) was concentrated under reduced pressure to give the object compound (5.91 g) as an oil. 
     MS (ESI+, m/e) 504 (M+1) 
     In the same manner as in Reference Example 185, the following compound (Reference Example 186) was obtained. 
     Reference Example 186 
     tert-Butyl (2S)-4-benzyl-2-{[(5-methoxy-4,4-dimethyl-5-oxopentanoyl)(phenyl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 538 (M+1) 
     Reference Example 187 
     4-[{[(2S)-4-Benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]methyl}(phenyl)amino]-4-oxobutyric acid 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-{[(4-ethoxy-4-oxobutanoyl)(phenyl)amino]methyl}piperazine-1-carboxylate (3.55 g) was dissolved in ethanol (115 ml), and 2N aqueous lithium hydroxide solution (75 ml) was added. The mixture was stirred at room temperature for 1 hr, and poured into ice water. While vigorously stirring the mixture, 6N hydrochloric acid was added by small portions to neutralize the mixture. The mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (3.21 g) as an amorphous solid. 
     MS (ESI+, m/e) 482 (M+1) 
     Reference Example 188 
     tert-Butyl (2S)-2-{[(4-amino-4-oxobutanoyl)(phenyl)amino]methyl}-4-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 4-[{[(2S)-4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]methyl}(phenyl)amino]-4-oxobutyric acid (3.20 g), HOBt ammonium salt (1.21 g), WSC.HCl (1.53 g) and DMF (45 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (3.00 g) as an amorphous solid. 
     MS (ESI+, m/e) 481 (M+1) 
     Reference Example 189 
     Methyl 5-[{[(2S)-4-benzylpiperazin-2-yl]methyl}(isopropyl)amino]-2,2-dimethyl-5-oxovalerate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-{[(isopropyl)(5-methoxy-4,4-dimethyl-5-oxopentanoyl)amino]methyl}piperazine-1-carboxylate (3.03 g) was dissolved in dichloromethane (7.5 ml), TFA (15 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions, and potassium carbonate was added by small portions to basify the mixture. The mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (2.41 g) as an oil. 
     MS (ESI+, m/e) 404 (M+1) 
     In the same manner as in Reference Example 189, the following compounds (Reference Examples 190-191) were obtained. 
     Reference Example 190 
     Methyl 5-[{[(2S)-4-benzylpiperazin-2-yl]methyl}(phenyl)amino]-2,2-dimethyl-5-oxovalerate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 438 (M+1) 
     Reference Example 191 
     N-{[(2S)-4-Benzylpiperazin-2-yl]methyl}-N-phenylsuccinamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 381 (M+1) 
     Reference Example 192 
     N-{[(2R)-4-Benzylpiperazin-2-yl]methyl}-2-methoxybenzamide 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-{[(2,4-dimethoxybenzyl)(2-methoxybenzoyl)amino]methyl}piperazine-1-carboxylate (1.89 g) was dissolved in dichloromethane (3 ml), TFA (12 ml) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was extracted with ethyl acetate (along with which the insoluble material was filtered off). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to about 50 ml. The insoluble material was filtered off again. The filtrate was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (1.09 g). 
       1 H-NMR (CDCl 3 ) δ 2.01 (1H, t), 2.22 (1H, dt), 2.78 (1H, d), 2.88 (1H, d), 2.96 (1H, dt), 3.12 (1H, dt), 3.19-3.27 (1H, m), 3.44-3.57 (4H, m), 3.85-3.96 (4H, m), 6.94 (1H, d), 7.05 (1H, dt), 7.22-7.32 (5H, m), 7.43 (1H, ddd), 8.13 (1H, dd), 8.18 (1H, t) 
     MS (ESI+, m/e) 340 (M+1) 
     In the same manner as in Reference Example 192, the following compounds (Reference Examples 193-194) were obtained. 
     Reference Example 193 
     N-{[(2R)-4-Benzylpiperazin-2-yl]methyl}benzamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.18 (1H, t), 2.30 (1H, t), 2.74 (1H, d), 2.88 (1H, d), 2.95 (1H, t), 3.14 (1H, d), 3.32-3.34 (1H, m), 3.47 (1H, d), 3.54 (1H, d), 3.60 (1H, d), 3.61 (1H, d), 5.47 (1H, br s), 7.26-7.49 (8H, m), 7.58 (1H, t), 7.80-7.82 (2H, m) 
     MS (ESI+, m/e) 310 (M+1) 
     Reference Example 194 
     N-{[(2R)-4-Benzylpiperazin-2-yl]methyl}-3,5-difluorobenzamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.17 (1H, dd), 2.30 (1H, dt), 2.76 (1H, d), 2.86 (1H, d), 2.98 (1H, dt), 3.16 (1H, dt), 3.27-3.31 (1H, m), 3.47-3.59 (4H, m), 4.96 (1H, br s), 6.88-6.95 (1H, m), 7.24-7.34 (7H, m), 7.45 (1H, br t) 
     MS (ESI+, m/e) 346 (M+1) 
     Reference Example 195 
     N-{[(2R)-4-Benzylpiperazin-2-yl]methyl}cyclohexanecarboxamide 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-{[(cyclohexylcarbonyl)(2,4-dimethoxybenzyl)amino]methyl}piperazine-1-carboxylate (2.26 g) was dissolved in dichloromethane (3.5 ml), TFA (15 ml) was added thereto, and the mixture was stirred at room temperature for 1.5 hr, and then at 70° C. for 10 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was extracted with ethyl acetate (along with which the insoluble material was filtered off). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to about 50 ml. The insoluble material was filtered off again. The filtrate was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (473 mg). 
       1 H-NMR (CDCl 3 ) δ 1.17-1.85 (12H, m), 2.01-2.09 (2H, m), 2.68-2.74 (2H, m), 2.82-3.01 (3H, m), 3.16 (1H, ddd), 3.28 (1H, dt), 3.48 (2H, s), 5.88 (1H, br s), 7.23-7.34 (5H, m) 
     MS (ESI+, m/e) 316 (M+1) 
     Reference Example 196 
     tert-Butyl (2R)-4-benzyl-2-[(2E)-3-phenyl-2-propen-1-yl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Diethyl benzylphosphonate (473 mg) was dissolved in THF (9 ml), the solution was ice-cooled, and sodium hydride (60% in oil) (113 mg) was added. The mixture was stirred at room temperature for 30 min, and ice-cooled again, and a solution of tert-butyl (2R)-4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate (600 mg) in THF (3 ml) was added. The mixture was further stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9) was concentrated under reduced pressure to give the object compound (428 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.40 (9H, s), 2.02-2.11 (2H, m), 2.61 (2H, t), 2.74 (1H, d), 2.80 (1H, d), 3.12 (1H, dt), 3.36 (1H, d), 3.57 (1H, d), 3.83-3.87 (1H, m), 4.09-4.13 (1H, m), 6.00-6.11 (1H, m), 6.32 (1H, d), 7.13-7.36 (10H, m) 
     MS (ESI+, m/e) 393 (M+1) 
     Reference Example 197 
     tert-Butyl (2R)-4-benzyl-2-[(E)-2-cyclopropylvinyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (Cyclopropylmethyl)(triphenyl)phosphonium bromide (385 mg) was dissolved in THF (10 ml), and the mixture was cooled to −78° C. N-Butyllithium (1.6M hexane solution, 1.25 ml) was added thereto, and the mixture was stirred at −20° C. for 20 min. A solution of tert-butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (608 mg) in THF (5 ml) was added thereto, and the mixture was further stirred at −20° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (700 mg) as an oil. 
     MS (ESI+, m/e) 343 (M+1) 
     Reference Example 198 
     Diethyl [2-(trifluoromethoxy)benzyl]phosphonate 
     
       
         
         
             
             
         
       
     
     1-(Bromomethyl)-2-(trifluoromethoxy)benzene (1.37 g) and triethyl phosphite (1.2 ml) were dissolved in toluene (2.4 ml), and the mixture was heated under reflux for 15 hr. The reaction mixture was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (1.77 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.25 (6H, t), 3.21 (1H, s), 3.28 (1H, s), 3.97-4.22 (4H, m), 7.19-7.34 (3H, m), 7.46-7.55 (1H, m) 
     In the same manner as in Reference Example 198, the following compounds (Reference Examples 199-200) were obtained. 
     Reference Example 199 
     Diethyl [3-(trifluoromethoxy)benzyl]phosphonate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.25 (6H, t), 3.12 (1H, s), 3.19 (1H, s), 3.97-4.18 (4H, m), 7.04-7.40 (4H, m) 
     Reference Example 200 
     Diethyl [4-(trifluoromethoxy)benzyl]phosphonate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.25 (6H, t), 3.11 (1H, s), 3.18 (1H, s), 3.95-4.19 (4H, m), 7.12-7.21 (2H, m), 7.29-7.37 (2H, m) 
     Reference Example 201 
     tert-Butyl (2R)-4-benzyl-2-[(E)-2-(2-fluorophenyl)vinyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Diethyl (2-fluorobenzyl)phosphonate (500 mg) was dissolved in THF (10 ml), and the solution was ice-cooled. Sodium hydride (60% in oil) (112 mg) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was ice-cooled again, a solution of tert-butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (562 mg) in THF (5 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (943 mg) as an oil. 
     MS (ESI+, m/e) 397 (M+1) 
     In the same manner as in Reference Example 201, the following compounds (Reference Examples 202-209) shown in Table 1 were obtained. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. 
                   
                   
                   
               
               
                 No. 
                 R 
                 Compound 
                 MS (ESI+) 
               
               
                   
               
               
                 202 
                 3-F 
                 tert-Butyl (2R)-4-benzyl-2-[(E)-2- 
                 397 
               
               
                   
                   
                 (3-fluorophenyl)vinyl]piperazine-1- 
               
               
                   
                   
                 carboxylate 
               
               
                 203 
                 4-F 
                 tert-Butyl (2R)-4-benzyl-2-[(E)-2- 
                 397 
               
               
                   
                   
                 (4-fluorophenyl)vinyl]piperazine-1- 
               
               
                   
                   
                 carboxylate 
               
               
                 204 
                 2-OCF 3   
                 tert-Butyl (2R)-4-benzyl-2-{(E)-2- 
                 463 
               
               
                   
                   
                 [2-(trifluoromethoxy)phenyl]vinyl} 
               
               
                   
                   
                 piperazine-1-carboxylate 
               
               
                 205 
                 3-OCF 3   
                 tert-Butyl (2R)-4-benzyl-2-{(E)-2- 
                 463 
               
               
                   
                   
                 [3-(trifluoromethoxy)phenyl]vinyl) 
               
               
                   
                   
                 piperazine-1-carboxylate 
               
               
                 206 
                 4-OCF 3   
                 tert-Butyl (2R)-4-benzyl-2-{(E)-2- 
                 463 
               
               
                   
                   
                 [4-(trifluoromethoxy)phenyl)vinyl} 
               
               
                   
                   
                 piperazine-1-carboxylate 
               
               
                 207 
                 2-CF 3   
                 tert-Butyl (2R)-4-benzyl-2-{(E)-2- 
                 447 
               
               
                   
                   
                 [2-(trifluoromethyl)phenyl]vinyl} 
               
               
                   
                   
                 piperazine-1-carboxylate 
               
               
                 208 
                 3-CF 3   
                 tert-Butyl (2R)-4-benzyl-2-{(E)-2- 
                 447 
               
               
                   
                   
                 [3-(trifluoromethyl)phenyl]vinyl} 
               
               
                   
                   
                 piperazine-1-carboxylate 
               
               
                 209 
                 4-CF 3   
                 tert-Butyl (2R)-4-benzyl-2-{(E)-2- 
                 447 
               
               
                   
                   
                 [4-(trifluoromethyl)phenyl]vinyl} 
               
               
                   
                   
                 piperazine-1-carboxylate 
               
               
                   
               
            
           
         
       
     
     Reference Example 210 
     tert-Butyl (2R)-4-benzyl-2-[(E)-2-(pyridin-2-yl)vinyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (500 mg) was dissolved in THF (5 ml), and the solution was cooled to 0° C. Triphenyl (pyridin-2-ylmethyl)phosphonium chloride-potassium hydride (1:1) (1059 mg) was added thereto, and the mixture was stirred at room temperature for 17 hr. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (590 mg) as an oil. 
     MS (ESI+, m/e) 380 (M+1) 
     Reference Example 211 
     (3R)-1-Benzyl-3-[(2E)-3-phenyl-2-propen-1-yl]piperazine 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-[(2E)-3-phenyl-2-propen-1-yl]piperazine-1-carboxylate (424 mg) was dissolved in dichloromethane (1.5 ml), TFA (3 ml) was added thereto, and the mixture was stirred at room temperature for 40 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (315 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 2.05 (1H, t), 2.21 (1H, dt), 2.40 (2H, t), 2.72 (1H, d), 2.85-3.09 (4H, m), 3.47 (1H, d), 3.56 (1H, d), 4.54 (1H, br s), 6.11 (1H, dt), 6.43 (1H, d), 7.16-7.33 (10H, m) 
     MS (ESI+, m/e) 293 (M+1) 
     In the same manner as in Reference Example 211, the following compound (Reference Example 212) was obtained. 
     Reference Example 212 
     (3R)-1-Benzyl-3-[(E)-2-cyclopropylvinyl]piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 243 (M+1) 
     In the same manner as in Reference Example 211, the following compounds (Reference Examples 213-221) shown in Table 2 were obtained. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. 
                   
                   
                   
               
               
                 No. 
                 R 
                 Compound 
                 MS (ESI+) 
               
               
                   
               
               
                 213 
                 2-F 
                 (3R)-1-Benzyl-3-[(E)-2-(2- 
                 297 
               
               
                   
                   
                 fluorophenyl)vinyl]piperazine 
               
               
                 214 
                 3-F 
                 (3R)-1-Benzyl-3-[(E)-2-(3- 
                 297 
               
               
                   
                   
                 fluorophenyl)vinyl]piperazine 
               
               
                 215 
                 4-F 
                 (3R)-1-Benzyl-3-[(E)-2-(4- 
                 297 
               
               
                   
                   
                 fluorophenyl)vinyl]piperazine 
               
               
                 216 
                 2-OCF 3   
                 (3R)-1-Benzyl-3-{(E)-2-[2- 
                 363 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]vinyl} 
               
               
                   
                   
                 piperazine 
               
               
                 217 
                 3-OCF 3   
                 (3R)-1-Benzyl-3-{(E)-2-[3- 
                 363 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]vinyl} 
               
               
                   
                   
                 piperazine 
               
               
                 218 
                 4-OCF 3   
                 (3R)-1-Benzyl-3-{(E)-2-[4- 
                 363 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]vinyl} 
               
               
                   
                   
                 piperazine 
               
               
                 219 
                 2-CF 3   
                 (3R)-1-Benzyl-3-{(E)-2-[2- 
                 347 
               
               
                   
                   
                 (trifluoromethyl)phenyl]vinyl} 
               
               
                   
                   
                 piperazine 
               
               
                 220 
                 3-CF 3   
                 (3R)-1-Benzyl-3-{(E)-2-[3- 
                 347 
               
               
                   
                   
                 (trifluoromethyl)phenyl]vinyl} 
               
               
                   
                   
                 piperazine 
               
               
                 221 
                 4-CF 3   
                 (3R)-1-Benzyl-3-{(E)-2-[4- 
                 347 
               
               
                   
                   
                 (trifluoromethyl)phenyl]vinyl} 
               
               
                   
                   
                 piperazine 
               
               
                   
               
            
           
         
       
     
     Reference Example 222 
     (3R)-1-Benzyl-3-[(E)-2-(pyridin-2-yl)vinyl]piperazine dihydrochloride 
     
       
         
         
             
             
         
       
     
     To tert-butyl (2R)-4-benzyl-2-[(E)-2-(pyridin-2-yl)vinyl]piperazine-1-carboxylate (280 mg) was added 4N hydrogen chloride-ethyl acetate solution (10 ml), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (260 mg). 
     MS (ESI+, m/e) 280 (M+1) 
     Reference Example 223 
     [(2R)-4-Benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-oxoethyl)piperazine-1-carboxylate (1.42 g) and 2-methyl-2-butene (4.6 ml) were dissolved in dioxane (17 ml), and a solution of sodium chlorite (2.22 g) and sodium dihydrogen phosphate (3.06 g) in water (11.5 ml) was added thereto. After stirring at room temperature for 1.5 hr, sodium chlorite (0.55 g) and sodium dihydrogen phosphate (0.55 g) were added thereto, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-2:1) was concentrated under reduced pressure to give the object compound (882 mg) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.44 (9H, s), 2.16 (1H, dt), 2.38 (1H, dd), 2.65 (1H, dd), 2.86-2.99 (3H, m), 3.17-3.21 (2H, m), 3.57 (1H, d), 3.65 (1H, d), 3.88-3.92 (1H, m), 4.44 (1H, br s), 7.26-7.36 (5H, m) 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 224 
     tert-Butyl (2R)-4-benzyl-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of [(2R)-4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (300 mg), 5-phenyl-1H-tetrazole (144 mg), DCC (204 mg) and toluene (6 ml) was stirred at 100° C. for 4 hr, and cooled to room temperature. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (332 mg). 
       1 H-NMR (CDCl 3 ) δ 1.27 (9H, s), 2.09 (1H, t), 2.25 (1H, dd), 2.78-2.82 (2H, m), 3.22-3.26 (2H, m), 3.47 (1H, d), 3.56 (1H, d), 3.53-3.58 (1H, m), 4.04-4.10 (1H, m), 4.55-4.59 (1H, m), 7.22-7.34 (5H, m), 7.43-7.50 (3H, m), 7.96-7.99 (2H, m) 
     MS (ESI+, m/e) 435 (M+1) 
     Reference Example 225 
     (3R)-1-Benzyl-3-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazine 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazine-1-carboxylate (332 mg) was dissolved in dichloromethane (1.5 ml), TFA (3 ml) was added thereto, and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (254 mg) as an oil. 
       1 H-NMR (CDCl 3 ) δ 2.02 (1H, t), 2.13-2.21 (3H, m), 2.74 (1H, d), 2.86 (1H, d), 2.90-3.07 (3H, m), 3.32-3.41 (1H, m), 3.53 (2H, s), 7.22-7.32 (5H, m), 7.45-7.55 (3H, m), 7.98-8.01 (2H, m) 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 226 
     2-{[(2R)-4-Benzylpiperazin-2-yl]methyl}-1H-benzimidazole 
     
       
         
         
             
             
         
       
     
     A solution of [(2R)-4-benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (576 mg), o-phenylenediamine (931 mg), WSC.HCl (660 mg) and HOBt (466 mg) in DMF (18 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-THF (4:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic acid (25 ml), and the solution was stirred at 65° C. for 3 hr, and concentrated under reduced pressure. TFA (5 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate-THF (4:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-10:0:1) was concentrated under reduced pressure to give the object compound (290 mg) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 1.89 (1H, t), 2.10 (1H, dt), 2.73-2.83 (2H, m), 2.87-3.11 (4H, m), 3.24-3.32 (1H, m), 3.47 (2H, s), 7.17-7.33 (9H, m), 7.53 (2H, br s) 
     MS (ESI+, m/e) 307 (M+1) 
     Reference Example 227 
     Di-tert-butyl (2R)-2-[4-(ethoxycarbonyl)benzyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     Di-tert-butyl (2R)-2-(4-{([(trifluoromethyl)sulfonyl]oxy}benzyl)piperazine-1,4-dicarboxylate (6.0 g), triethylamine (11 ml), palladium(II) acetate (510 mg) and dppf (1.26 g) were suspended in ethanol (65 ml), and the suspension was stirred at 80° C. for 12 hr under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water, and the insoluble material was filtered through celite. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (4.1 g). 
     MS (ESI+, m/e) 449 (M+1) 
     Reference Example 228 
     tert-Butyl (3R)-3-[4-(2,2,2-trifluoro-1-hydroxyethyl)benzyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Di-tert-butyl (2R)-2-[4-(ethoxycarbonyl)benzyl]piperazine-1,4-dicarboxylate (1.79 g) was dissolved in ethanol (15 ml), pulverized potassium hydroxide (673 mg) was added, and the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (5 ml). The mixture was weakly acidified (pH 3-4) with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-{[(2R)-1,4-bis(tert-butoxycarbonyl)piperazin-2-yl]methyl}benzoic acid (1.67 g) as crystals. 1.65 g therefrom was dissolved in THF (15 ml), the solution was ice-cooled, N-methylmorpholine (435 mg) and ethyl chloroformate (467 mg) were successively added. The mixture was stirred at 0-5° C. for 1 hr, and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (30 ml). The solution was washed successively with 6% aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give di-tert-butyl (2R)-2-(4-{([(ethoxycarbonyl)oxy]carbonyl}benzyl)piperazine-1,4-dicarboxylate (1.48 g) as an oil. 
     The total amount thereof was dissolved in THF (15 ml), and the solution was ice-cooled. Sodium borohydride (379 mg) was added, and then methanol (3 ml) was added dropwise over 5 min. The mixture was stirred at the same temperature for 30 min, and saturated aqueous ammonium chloride solution (5 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give di-tert-butyl (2R)-2-[4-(hydroxymethyl)benzyl]piperazine-1,4-dicarboxylate (1.11 g) as an amorphous solid. 1.10 g therefrom was dissolved in dichloromethane (20 ml), manganese dioxide (2.35 g) was added thereto, and the mixture was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give di-tert-butyl (2R)-2-(4-formylbenzyl)piperazine-1,4-dicarboxylate (1.01 g) as an oil. 1.00 g therefrom and trimethyl(trifluoromethyl)silane (702 mg) were dissolved in THF (10 ml), and TBAF (several mg) was added thereto. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure to give di-tert-butyl (2R)-2-[4-(2,2,2-trifluoro-1-hydroxyethyl)benzyl]piperazine-1,4-dicarboxylate (1.35 g) as an oil. 
     To the total amount thereof was added TFA (3 ml), and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was dissolved in THF (15 ml), and the solution was ice-cooled. N,N-Diisopropylethylamine (1.28 g) and di-tert-butyl bicarbonate (539 mg) were successively added, and the mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1-7:3) was concentrated under reduced pressure to give the object compound (0.9 g) as an amorphous solid. 
     MS (ESI+, m/e) 375 (M+1) 
     Reference Example 229 
     tert-Butyl (3S)-4-benzyl-3-({[5-(methoxycarbonyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (3.00 g), sodium hydride (60% in oil) (500 mg) and THF (50 ml) was stirred at room temperature for 1 hr, and ice-cooled, and methyl 6-chloronicotinate (1.68 g) was added. The reaction mixture was further stirred at room temperature for 2 hr, and poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-3:2) was concentrated under reduced pressure to give the object compound (2.83 g). 
       1 H-NMR (CDCl 3 ) δ 1.43 (9H, s), 2.31 (1H, br s), 2.75 (1H, dd), 2.91 (1H, br s), 3.45 (3H, br s), 3.58 (2H, br s), 3.91 (3H, s), 3.97-4.09 (1H, m), 4.50 (1H, d), 4.63 (1H, br s), 6.78 (1H, d), 7.21-7.36 (5H, m), 8.15 (1H, dd), 8.80 (1H, d) 
     MS (ESI+, m/e) 442 (M+1) 
     Reference Example 230 
     tert-Butyl (3S)-3-({[5-(methoxycarbonyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-4-benzyl-3-({[5-(methoxycarbonyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate (1.00 g) was dissolved in methanol (30 ml), 20% palladium hydroxide-carbon (50% containing water, 150 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (747 mg). 
       1 H-NMR (CDCl 3 ) δ 1.47 (9H, s), 1.91 (1H, br s), 2.81 (1H, dd), 3.08 (2H, td), 2.96-3.12 (1H, m), 3.73 (2H, s), 3.91 (4H, s), 4.30 (1H, d), 4.36 (1H, d), 6.78 (1H, d), 8.16 (1H, dd), 8.80 (1H, d) 
     MS (ESI+, m/e) 352 (M+1) 
     Reference Example 231 
     tert-Butyl (3S)-3-[(2-cyanophenoxy)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (1.85 g), 2-cyanophenol (471 mg), potassium carbonate (1.04 mg) and DMF (5 ml) was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(2-cyanophenoxy)methyl]piperazine-1-carboxylate (2.00 g) as an oil. 
     The total amount thereof was dissolved in 1,2-dichloromethane (50 ml), and the solution was ice-cooled. 1-Chloroethyl chloroformate (830 μl) was added thereto, and the mixture was stirred at 80° C. for 2 hr. After stirring, the solvent was evaporated under reduced pressure. Methanol (3 ml) was added to the residue, and the mixture was heated under reflux for 1 hr. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was suspended in THF (20 ml), N,N-diisopropylethylamine (3.4 ml) and di-tert-butyl bicarbonate (1.07 g) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (805 mg) as an amorphous solid. 
     MS (ESI+, m/e) 218 (M+1-“Boc”) 
     Reference Example 232 
     tert-Butyl (3S)-3-[(3,5-difluorophenoxy)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (1.2 g) and 3,5-difluorophenol (509 mg) were dissolved in acetonitrile (30 ml), potassium carbonate (663 mg) was added thereto, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(3,5-difluorophenoxy)methyl]piperazine-1-carboxylate (1.09 g) as an amorphous solid. The total amount thereof was dissolved in methanol (20 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (906 mg) as an amorphous solid. 
     MS (ESI+, m/e) 273 (M+1-“Boc”) 
     In the same manner as in Reference Example 232, the following compounds (Reference Examples 233-234) were obtained. 
     Reference Example 233 
     tert-Butyl (3S)-3-(phenoxymethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 293 (M+1) 
     Reference Example 234 
     tert-Butyl (3S)-3-[(2,6-difluorophenoxy)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 329 (M+1) 
     Reference Example 235 
     tert-Butyl (3S)-3-[(4-methyl-1H-pyrazol-1-yl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (370 mg) and 4-methylpyrazole (99 mg) in DMF (5 ml) was ice-cooled, and sodium hydride (60% in oil, 60 mg) was added thereto. The mixture was stirred at 0° C. for 15 min, and then at room temperature for 1 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 70 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (90 mg) as an oil. 
     MS (ESI+, m/e) 281 (M+1) 
     In the same manner as in Reference Example 235, the following compounds (Reference Examples 236-239) were obtained. 
     Reference Example 236 
     tert-Butyl (3S)-3-(1H-1,2,4-triazol-1-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 268 (M+1) 
     Reference Example 237 
     tert-Butyl (3S)-3-(1H-pyrazol-1-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 267 (M+1) 
     Reference Example 238 
     tert-Butyl (3S)-3-(1H-indazol-1-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 317 (M+1) 
     Reference Example 239 
     tert-Butyl (3S)-3-(1H-1,2,3-benzotriazol-1-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 318 (M+1) 
     Reference Example 240 
     tert-Butyl (3S)-3-(1H-imidazol-1-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (600 mg) and imidazole (150 mg) in DMF (10 ml) was ice-cooled, and sodium hydride (60% in oil, 84 mg) was added thereto. The mixture was stirred at 0° C. for 15 min, and then at 60° C. for 1 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (210 mg) as an oil. 
     MS (ESI+, m/e) 267 (M+1) 
     In the same manner as in Reference Example 240, the following compound (Reference Example 241) was obtained. 
     Reference Example 241 
     tert-Butyl (3S)-3-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 295 (M+1) 
     Reference Example 242 
     tert-Butyl (3S)-3-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (370 mg) and 3-trifluoromethylpyrazole (272 mg) in DMF (3 ml) was added BEMP (600 mg). The mixture was stirred at room temperature for 2 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (4:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (261 mg) as an oil. 
     MS (ESI+, m/e) 335 (M+1) 
     Reference Example 243 
     tert-Butyl (3S)-3-(1H-benzimidazol-1-ylmethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3S)-4-benzyl-3-(bromomethyl)piperazine-1-carboxylate (370 mg), 1H-benzimidazole (236 mg), potassium carbonate (690 mg) and DMF (5 ml) was stirred at 60° C. for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (160 mg) as an oil. 
     MS (ESI+, m/e) 317 (M+1) 
     Reference Example 244 
     tert-Butyl (3S)-3-[(pyridin-2-yloxy)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Potassium tert-butoxide (1.58 g) was dissolved in tert-butanol (60 ml), tert-butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (3.06 g) and 2-bromopyridine (1.74 g) were added, and the mixture was stirred at 80° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-[(pyridin-2-yloxy)methyl]piperazine-1-carboxylate (1.67 g) as an amorphous solid. The total amount thereof was dissolved in methanol (50 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (990 mg) as an amorphous solid. 
     MS (ESI+, m/e) 294 (M+1) 
     Reference Example 245 
     tert-Butyl (3R)-3-(3-methoxybenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2S)-4-benzyl-2-formylpiperazine-1-carboxylate (1.00 g) was dissolved in THF (10 ml), and the solution was ice-cooled. 3-Methoxyphenylmagnesium bromide (1M THF solution, 4.0 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give tert-butyl (2S)-4-benzyl-2-[(hydroxy) (3-methoxyphenyl)methyl]piperazine-1-carboxylate (1.26 g) as an amorphous solid. 
     The total amount thereof and lithium chloride (1.26 g) were suspended in 1,2-dichloroethane (15 ml), and the suspension was ice-cooled. Methanesulfonyl chloride (280 μl) and triethylamine (970 μl) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give (8aS)-7-benzyl-1-(3-methoxyphenyl)hexahydro[1,3]oxazolo[3,4-a]pyrazin-3-one (942 mg) as an amorphous solid. 900 mg therefrom was dissolved in ethanol-THF (1:1, 30 ml), 8N aqueous sodium hydroxide solution (5 ml) was added thereto, and the mixture was stirred at 50° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 ml) and THF (10 ml). Benzyl chloroformate (420 μl) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give benzyl (2S)-4-benzyl-2-[(hydroxy)(3-methoxyphenyl)methyl]piperazine-1-carboxylate (469 mg) as an amorphous solid. 
     460 mg therefrom was dissolved in dichloromethane (10 ml), DAST (240 μl) was added thereto at −78° C., and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:2) was concentrated under reduced pressure to give benzyl (2S)-4-benzyl-2-[(fluoro)(3-methoxyphenyl)methyl]piperazine-1-carboxylate (449 mg) as an amorphous solid. 
     300 mg therefrom was dissolved in ethanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give (2R)-2-(3-methoxybenzyl)piperazine as an amorphous solid. The total amount thereof was dissolved in tert-butanol (5 ml) and water (4 ml), 8N aqueous sodium hydroxide solution (670 μl) and di-tert-butyl bicarbonate (146 mg) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (17:3) was concentrated under reduced pressure to give the object compound (55 mg) as an oil. 
     MS (ESI+, m/e) 307 (M+1) 
     Reference Example 246 
     (3R)-1-Benzyl-3-[2-(cyclopropylmethoxy)ethyl]piperazine dihydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-hydroxyethyl)piperazine-1-carboxylate (320 mg) was dissolved in DMF (5 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 48 mg) was added thereto, and the mixture was stirred at 0° C. for 10 min. After stirring, (bromomethyl)cyclopropane (120 μl) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give tert-butyl (2R)-4-benzyl-2-[2-(cyclopropylmethoxy)ethyl]piperazine-1-carboxylate (150 mg) as an amorphous solid. To 140 mg therefrom was added 4N hydrogen chloride-ethyl acetate solution (5 ml), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure to give the object compound (141 mg) as an amorphous solid. 
     MS (ESI+, m/e) 275 (M+1) 
     Reference Example 247 
     tert-Butyl (3S)-3-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (1.00 g) was dissolved in DMF (15 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 156 mg) was added thereto, and the mixture was stirred at 0° C. for 10 min. After stirring, 2-bromo-6-(trifluoromethyl)pyridine (884 mg) was added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (2:3) was concentrated under reduced pressure to give tert-butyl (3S)-4-benzyl-3-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate (1.44 g) as an amorphous solid. 1.41 g therefrom was dissolved in ethanol (50 ml), 20% palladium hydroxide-carbon (50% containing water, 300 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (937 mg) as an oil. 
     MS (ESI+, m/e) 362 (M+1) 
     In the same manner as in Reference Example 247, the following compound (Reference Example 248) was obtained. 
     Reference Example 248 
     tert-Butyl (3S)-3-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 362 (M+1) 
     Reference Example 249 
     tert-Butyl (3R)-3-{2-[4-(trifluoromethyl)phenyl]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (2R)-1,4-Dibenzyl-2-vinylpiperazine (1.10 g) was dissolved in THF (10 ml), 9-BBN (0.5M THF solution, 30 ml) was added, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture were added triphenylphosphine (168 mg), 1-iodo-4-(trifluoromethyl)benzene (1.53 g), tetrakis(triphenylphosphine)palladium(0) (92 mg) and 3N aqueous sodium hydroxide solution (3.1 ml), and the mixture was stirred at 70° C. for 24 hr. The solvent was evaporated under reduced pressure, 2N aqueous sodium hydroxide solution (80 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with diethyl ether, and the organic layer was back-extracted with 1N hydrochloric acid. The acidic aqueous layer was separated, basified with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give (2R)-1,4-dibenzyl-2-{2-[4-(trifluoromethyl)phenyl]ethyl}piperazine (751 mg) as an amorphous solid. 
     The total amount thereof was dissolved in ethanol (20 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give (2R)-2-{2-[4-(trifluoromethyl)phenyl]ethyl}piperazine as an amorphous solid. The total amount thereof was dissolved in tert-butanol (10 ml) and water (8 ml), 1N aqueous sodium hydroxide solution (1.71 ml) and di-tert-butyl bicarbonate (373 mg) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (17:3) was concentrated under reduced pressure to give the object compound (455 mg) as an oil. 
     MS (ESI+, m/e) 359 (M+1) 
     Reference Example 250 
     tert-Butyl (2R)-2-(2-hydroxyethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-hydroxyethyl)piperazine-1-carboxylate (13.33 g) was dissolved in methanol (135 ml), 20% palladium hydroxide-carbon (50% containing water, 4.0 g) was added thereto, and the mixture was subjected to catalytic reduction at room temperature for 4 hr under moderate-pressure (5.0 kgf/cm 2 ). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (9.44 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.47 (9H, s), 1.68 (1H, br s), 2.07-2.11 (1H, m), 2.36-2.40 (3H, m), 2.64-2.75 (1H, m), 2.85-2.96 (3H, m), 3.38-3.42 (1H, m), 3.66 (1H, dt), 3.82-3.86 (1H, m), 4.24 (1H, br s) 
     MS (ESI+, m/e) 231 (M+1) 
     Reference Example 251 
     1-tert-Butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-2-(2-hydroxyethyl)piperazine-1-carboxylate (9.44 g) was dissolved in dioxane (90 ml), and the solution was ice-cooled. A solution of sodium carbonate (4.78 g) in water (45 ml) and benzyl chloroformate (7.34 g) were added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-2:1) was concentrated under reduced pressure to give the object compound (14.17 g) as an oil. 
     MS (ESI+, m/e) 265 (M+1-“Boc”) 
     Reference Example 252 
     1-tert-Butyl 4-benzyl (2R)-2-(2-bromoethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     Triphenylphosphine (1.29 g) and carbon tetrabromide (1.63 g) were suspended in diethyl ether (20 ml), a solution of 1-tert-butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (1.50 g) in diethyl ether (10 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added THF (30 ml), triphenylphosphine (1.29 g) and carbon tetrabromide (1.63 g) were added thereto, and the mixture was further stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (60 ml). Triphenylphosphine (1.29 g) and carbon tetrabromide (1.63 g) were further added thereto, and the mixture was stirred at room temperature for 3 days. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-3:7) was concentrated under reduced pressure to give the object compound (697 mg) as an oil. 
     MS (ESI+, m/e) 427 (M+1) 
     Reference Example 253 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(4-methyl-1H-pyrazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-(2-bromoethyl)piperazine-1,4-dicarboxylate (320 mg), 4-methyl-1H-pyrazole (123 mg), potassium carbonate (415 mg) and DMF (5 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:1) was concentrated under reduced pressure to give the object compound (330 mg) as an oil. 
     MS (ESI+, m/e) 429 (M+1) 
     Reference Example 254 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (14.17 g) and triethylamine (5.90 g) were dissolved in THF (80 ml), and the solution was ice-cooled. Methanesulfonyl chloride (5.57 g) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals were collected by filtration to give the object compound (15.54 g). 
       1 H-NMR (CDCl 3 ) δ 1.47 (9H, s), 1.88-2.04 (2H, m), 2.93-2.98 (5H, m), 3.95-4.33 (7H, m), 5.10 (1H, d), 5.17 (1H, d), 7.30-7.39 (5H, m) 
     MS (ESI+, m/e) 343 (M+1-“Boc”) 
     Reference Example 255 
     1-tert-Butyl 4-benzyl (2R)-2-(2-phenoxyethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (708 mg), phenol (188 mg), potassium carbonate (332 mg), potassium iodide (133 mg) and DMF (16 ml) was stirred at 65° C. for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (591 mg) as an oil. 
     MS (ESI+, m/e) 441 (M+1) 
     In the same manner as in Reference Example 255, the following compounds (Reference Examples 256-320) shown in Table 3-1-Table 3-7 were obtained. In the column of “MS (ESI+)” in the Tables, “*” means that a mass value of “M+1-“Boc”” was obtained, and “**” means that a mass value of “M+1-“ t Bu”” was obtained (a mass value of M+1 was obtained for other compounds). 
     
       
         
           
               
             
               
                 TABLE 3-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[1- methyl-5-(trifluoromethyl)-1H-pyrazol- 3-yl]oxy}ethyl)piperazine-1,4- dicarboxylate 
                 513 
               
               
                   
               
               
                 257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[2- (trifluoromethoxy)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                 525 
               
               
                   
               
               
                 258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl 4-benzyl (2R)-2-(2-{[1- methyl-3-(triofluoromethyl)-1H- pyrazol-5-yl]oxy}ethyl) piperzine-1,4-dicarboxylate 
                 513 
               
               
                   
               
               
                 259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- methoxyphenoxy)ethyl]piperzine-1,4- dicarboxylate 
                 471 
               
               
                   
               
               
                 260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[3- (methoxycarbonyl)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                 499 
               
               
                   
               
               
                 261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- acetyiphenoxy) ethyl]piperazine-1,4- dicarboxylate 
                 483 
               
               
                   
               
               
                 262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(3- acetylphenoxy)ethyl]piperzine-1,4- dicarboxylate 
                 483 
               
               
                   
               
               
                 363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [4-(1H-imidazol-1- yl)phenoxy]ethyl}piperzine-1,4- dicarboxylate 
                 507 
               
               
                   
               
               
                 264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(1,2- benzisoxazol-3-yloxy)ethyl]piperzine- 1,4-dicarboxylate 
                 482 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[3-(2- methyl-1H-midazol-1- yl)phenoxyl]ethyl}piperazine-1,4- dicarboxylate 
                 521 
               
               
                   
               
               
                 266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[5- (methoxycarbonyl)-isoxazol-3- yl]oxy}ethyl)piperazine-1,4- dicarboxylate 
                 490 
               
               
                   
               
               
                 267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (1H-pyrazol-1-yl)phenoxy]ethyl) piperazine-1,4-dicarboxylate 
                  407* 
               
               
                   
               
               
                 268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- acetylphenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 483 
               
               
                   
               
               
                 269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[2- (methoxycarbonyl)phenoxy]ethyl) piperazine-1,4-dicarboxylate 
                 499 
               
               
                   
               
               
                 270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(3- fluorophenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 459 
               
               
                   
               
               
                 271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- fluorophenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 459 
               
               
                   
               
               
                 272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- methoxyphenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 471 
               
               
                   
               
               
                 273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(3- methoxyphenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 471 
               
               
                   
               
               
                 274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{4- [(trifluoromethyl)sulfonyl]phenoxy} ethyl) piperazine-1,4-dicarboxylate 
                  473* 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (methylsulfonyl)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                  419* 
               
               
                   
               
               
                 276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(2,6-dimethylpyridin-3- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                 470 
               
               
                   
               
               
                 277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- methyl-1,3-benzothiazol-5- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                 512 
               
               
                   
               
               
                 278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(2,2-dimethyl-2,3-dihydro-1- benzofuran-7-yl)oxy]ethyl} piperazine-1,4-dicarboxylate 
                 511 
               
               
                   
               
               
                 279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- oxo-1,2,3,4-tetrahydroquinolin-6- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                 510 
               
               
                   
               
               
                 280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[5- (methoxycarbonyl)pyridin-3- yl]oxy}ethyl)piperazine-1,4- dicarboxylate 
                 500 
               
               
                   
               
               
                 281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(5- oxo-5,6,7,8-tetrahydronaphthalen-2- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                  453** 
               
               
                   
               
               
                 282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- chlorophenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 475 
               
               
                   
               
               
                 283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(3- chlorophenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 475 
               
               
                   
               
               
                 284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- chlorophenoxy)ethyl]piperazine-1,4- dicarboxylate 
                 475 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- bromo-2-fluorophenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 538 
               
               
                   
               
               
                 286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (1H-1,2,3-triazol-1-yl) phenoxy]ethyl}piperzine- 1,4-dicarboxylate 
                 508 
               
               
                   
               
               
                 287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (5-methyl-1,3,4-oxadiazol-2-yl) phenoxy]ethyl}piperzine- 1,4-dicarboxylate 
                 523 
               
               
                   
               
               
                 288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- methylphenoxy)-ethyl]piperazine- 1,4-dicarboxylate 
                 455 
               
               
                   
               
               
                 289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (2-methoxy-2-oxoethyl)phenoxy] ethyl}piperazine-1,4-dicarboxylate 
                 513 
               
               
                   
               
               
                 290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{-2-[(1- oxidopyridin-3-yl)oxy]ethyl} piperazine-1,4-dicarboxylate 
                 458 
               
               
                   
               
               
                 291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[3- (diethylamino)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                 512 
               
               
                   
               
               
                 292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- oxo-2,3-dihydro-1,3-benzoxazol-6- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                 498 
               
               
                   
               
               
                 293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(3,5,6-trifluoropyridin-2- yl)oxy]ethyl}piperzine-1,4- dicarboxylate 
                  396* 
               
               
                   
               
               
                 294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[6- (methoxycarbonyl)pyridin-3- yl]oxy}ethyl)piperzine-1,4- dicarboxylate 
                 500 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3-5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[3- (5-methyl-1,3,4-oxadiazol-2- yl)phenoxy]ethyl}piperazine-1,4- dicarboxylate 
                 523 
               
               
                   
               
               
                 296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-[4- (4-acetylpiperazin-1- yl)phenoxy]ethyl}piperazine-1,4- dicarboxylate 
                 567 
               
               
                   
               
               
                 297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2- {[5-(ethoxycarbonyl)-2-methyl-1,3- thiazol-4-yl]oxy}ethyl) piperazine-1,4-dicarboxylate 
                 534 
               
               
                   
               
               
                 298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (3-methoxy-3-oxopropyl)phenoxy] ethyl}piperazine-1,4-dicarboxylate 
                 527 
               
               
                   
               
               
                 299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- cyanophenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 466 
               
               
                   
               
               
                 300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[2- fluoro-4-(methoxycarbonyl) phenoxy]ethyl}piperazine-1,4- dicarboxylate 
                 517 
               
               
                   
               
               
                 301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[3- fluoro-4-(methoxycarbonyl) phenoxy]ethyl}piperazine-1,4- dicarboxylate 
                 517 
               
               
                   
               
               
                 302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2- {[4-(ethoxycarbonyl)-1-methyl-1H- pyrazol-5-yl]oxy}ethyl) piperazine-1,4-dicarboxylate 
                 517 
               
               
                   
               
               
                 303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2- {[1-ethyl-4-(2-methoxy-2-oxo ethyl)-1H-pyrazol-3-yl]oxy}ethyl) piperazine-1,4-dicarboxylate 
                 531 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3-6 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- oxo-1,2,3,4-tetrahydroquinolin-7- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                  410* 
               
               
                   
               
               
                 305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[2- (methoxycarbonyl)-3- thienyl]oxy}ethyl)piperazine-1,4- dicarboxylate 
                  405* 
               
               
                   
               
               
                 306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- acetyl-2-fluorophenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 501 
               
               
                   
               
               
                 307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- fluoro-2-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 489 
               
               
                   
               
               
                 308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- methoxy-4-methylphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 485 
               
               
                   
               
               
                 309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- acetyl-2-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 513 
               
               
                   
               
               
                 310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- cyano-2-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 496 
               
               
                   
               
               
                 311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (ethoxycarbonyl)-2-methoxyphenoxy] ethyl)piperazine-1,4-dicarboxylate 
                 543 
               
               
                   
               
               
                 312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{4- [(dimethylamino)methyl]phenoxy} ethyl)piperazine-1,4-dicarboxylate 
                 498 
               
               
                   
               
               
                 313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{4- [(dimethylamino)methyl]-2- fluorophenoxy}ethyl)piperazine-1,4- dicarboxylate 
                 516 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3-7 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- fluoro-6-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 489 
               
               
                   
               
               
                 315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (2-oxopyrrolidin-1-yl)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                 524 
               
               
                   
               
               
                 316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- fluoro-4-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 489 
               
               
                   
               
               
                 317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(5- fluoro-2-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 489 
               
               
                   
               
               
                 318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- fluoro-4-methylphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 473 
               
               
                   
               
               
                 319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [4-fluoro-3-(methoxycarbonyl) phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                 517 
               
               
                   
               
               
                 320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [4-(2-ethoxy-2-oxoethyl)-2-methoxy- phenoxy]ethyl}piperazine-1,4- dicarboxylate 
                 557 
               
               
                   
               
            
           
         
       
     
     Reference Example 321 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-fluorophenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (221 mg), 2-fluorophenol (84 mg), potassium carbonate (138 mg), potassium iodide (83 mg) and DMF (5 ml) was stirred at 65° C. for 15 hr. Saturated brine was added to the reaction mixture, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with 6% aqueous sodium bicarbonate, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-3:7) was concentrated under reduced pressure to give the object compound (210 mg) as an oil. 
     MS (ESI+, m/e) 459 (M+1) 
     Reference Example 322 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (1.11 g) was dissolved in DMF (10 ml), methyl 4-hydroxybenzoate (681 mg), potassium carbonate (1.38 g) and potassium iodide (415 mg) were added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (452 mg) as an oil. 
     MS (ESI+, m/e) 499 (M+1) 
     Reference Example 323 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{[2-(methoxycarbonyl)pyridin-3-yl]oxy}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (708 mg), methyl 3-hydroxypyridine-2-carboxylate (490 mg), potassium carbonate (332 mg), potassium iodide (266 mg) and DMF (16 ml) was stirred at 65° C. for 15 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was ice-cooled, and washed successively with 0.5N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (658 mg) as an oil. 
     MS (ESI+, m/e) 500 (M+1) 
     In the same manner as in Reference Example 323, the following compounds (Reference Examples 324-335) shown in Table 4-1-Table 4-2 were obtained. In the column of “MS (ESI+)” in the Tables, “*” means that a mass value of “M+1-“Boc”” was obtained (a mass value of M+1 was obtained for other compounds). 
     
       
         
           
               
             
               
                 TABLE 4-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-({2- [(dimethylamino)methyl]pyridin-3- yl}oxy)ethyl]piperazine-1,4- dicarboxylate 
                 499 
               
               
                   
               
               
                 325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- bromo-2-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                  449* 
               
               
                   
               
               
                 326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- chloro-2-methoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                  405* 
               
               
                   
               
               
                 327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- ethoxyphenoxy)ethyl]piperazine-1,4- dicarboxylate 
                  385* 
               
               
                   
               
               
                 328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2,3- dimethoxyphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                  401* 
               
               
                   
               
               
                 329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2,6- dimethoxy-4-methylphenoxy) ethyl]piperazine-1,4-dicarboxylate 
                  415* 
               
               
                   
               
               
                 330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(6- methoxy-2-oxo-2H-chromen-7- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                  439* 
               
               
                   
               
               
                 331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(1- oxo-1,2,3,4-tetrahydro isoquinolin-5-yl)oxy]ethyl} piperazine-1,4-dicarboxylate 
                 510 
               
               
                   
               
               
                 332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (thieno[3,2-b]pyridin-7- yloxy)ethyl]piperazine-1,4- dicarboxylate 
                 498 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- isopropoxyphenoxy)ethyl]piperazine- 1,4-dicarboxylate 
                  399* 
               
               
                   
               
               
                 334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (1,3-benzodioxol-5-yloxy)ethyl] piperazine-1,4-dicarboxylate 
                  385* 
               
               
                   
               
               
                 335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(1- phenyl-1H-1,2,4-triazol-3- yl)oxy]ethyl}piperazine-1,4- dicarboxylate 
                 508 
               
               
                   
               
            
           
         
       
     
     Reference Example 336 
     2-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol 
     
       
         
         
             
             
         
       
     
     Methyl 3-fluoro-4-hydroxybenzoate (1.0 g) was dissolved in ethanol (10 ml), hydrazine monohydrate (2.9 g) was added thereto, and the mixture was heated under reflux for 12 hr. The solvent was evaporated under reduced pressure, triethyl orthoformate (10 ml) was added thereto, and the mixture was heated under reflux for 12 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated crystals were collected by filtration to give the object compound (755 mg). 
       1 H-NMR (DMSO-d 6 ) δ 2.11 (3H, s), 6.61-6:75 (2H, m), 7.73 (1H, t), 10.54 (1H, br s) 
     MS (ESI+, m/e) 195 (M+1) 
     In the same manner as in Reference Example 336, the following compounds (Reference Examples 337-340) were obtained. 
     Reference Example 337 
     3-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.55 (3H, s), 7.13 (1H, t), 7.56-7.75 (2H, m), 10.79 (1H, br s) 
     MS (ESI+, m/e) 195 (M+1) 
     Reference Example 338 
     4-Fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenol 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.59 (3H, s), 6.95-7.07 (1H, m), 7.22-7.38 (2H, m), 9.92 (1H, br s) 
     MS (ESI+, m/e) 195 (M+1) 
     Reference Example 339 
     3-Methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.55 (3H, s), 3.86 (3H, s), 6.94 (1H, d), 7.37-7.44 (2H, m), 9.88 (1H, s) 
     MS (ESI+, m/e) 207 (M+1) 
     Reference Example 340 
     2-Methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenol 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.54 (3H, s), 3.84 (3H, s), 7.09 (1H, d), 7.35-7.51 (2H, m), 9.59 (1H, br s) 
     MS (ESI+, m/e) 207 (M+1) 
     Reference Example 341 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[2-methoxy-5-(methoxycarbonyl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (442 mg) was dissolved in DMA (10 ml), and methyl 3-hydroxy-4-methoxybenzoate (273 mg) and cesium carbonate (652 mg) were added thereto. The mixture was stirred at 60° C. for 15 hr, and the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give the object compound (482 mg) as a colorless amorphous solid. 
     MS (ESI+, m/e) 429 (M+1-“Boc”) 
     In the same manner as in Reference Example 341, the following compounds (Reference Examples 342-346) were obtained. 
     Reference Example 342 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[2-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 541 (M+1) 
     Reference Example 343 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 541 (M+1) 
     Reference Example 344 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 541 (M+1) 
     Reference Example 345 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[2-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 553 (M+1) 
     Reference Example 346 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[2-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 553 (M+1) 
     Reference Example 347 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (619 mg), 1H-benzimidazole (331 mg), potassium carbonate (1.20 g) and DMF (7 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object compound (510 mg) as an oil. 
     MS (ESI+, m/e) 465 (M+1) 
     Reference Example 348 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3,5-di-tert-butyl-1H-pyrazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     3,5-Di-tert-butyl-1H-pyrazole (204 mg) was dissolved in DMF (7 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 46 mg) was added thereto, and the mixture was stirred at 0° C. for 15 min. After stirring, 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (250 mg) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (220 mg) as an oil. 
     MS (ESI+, m/e) 527 (M+1) 
     In the same manner as in Reference Example 347 or Reference Example 348, the following compounds (Reference Examples 349-363) shown in Table 5-1-Table 5-2 were obtained. In the column of “Base” in the Tables, the compounds described as “K 2 CO 3 ” were synthesized according to the method of Reference Example 347 and the compounds described as “NaH” were synthesized according to the method of Reference Example 348. In addition, in the column of “MS (ESI+)” in the Tables, “*” means that a mass value of “M+1-“Boc”” was obtained, and “**” means that a mass value of “M+1-“ t Bu”” was obtained (a mass value of M+1 was obtained for other compounds). 
     
       
         
           
               
             
               
                 TABLE 5-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 Base 
                 MS(ESI+) 
               
               
                   
               
               
                 349 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[3- (trifluoromethyl)-1H-pyrazol-1- yl]ethyl}piperazine-1,4- dicarboxylate 
                 K 2 CO 3   
                 483 
               
               
                   
               
               
                 350 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (1H-1,2,3-benzotriazol-1-yl)ethyl] piperazine-1,4-dicarboxylate 
                 K 2 CO 3   
                 466 
               
               
                   
               
               
                 351 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(3- phenyl-1H-pyrazol-1-yl)ethyl] piperazine-1,4-dicarboxylate 
                 K 2 CO 3   
                 491 
               
               
                   
               
               
                 352 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (4,5,6,7-tetrahydro-1H-indazol-1- yl)ethyl]piperazine-1,4- dicarboxylate 
                 K 2 CO 3   
                 469 
               
               
                   
               
               
                 353 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (methoxycarbonyl)-1H-indazol-1-yl] ethyl}piperazine-1,4-dicarboxylate 
                 K 2 CO 3   
                 523 
               
               
                   
               
               
                 354 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (1H-indol-1-yl)ethyl]piperazine- 1,4-dicarboxylate 
                 NaH 
                  364* 
               
               
                   
               
               
                 355 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- phenyl-1H-imidazol-1-yl)ethyl] piperazine-1,4-dicarboxylate 
                 NaH 
                 491 
               
               
                   
               
               
                 356 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (3,5-dimethyl-1H-pyrazol-1-yl)ethyl] piperazine-1,4-dicarboxylate 
                 K 2 CO 3   
                 443 
               
               
                   
               
               
                 357 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (methoxycarbonyl)-3,5-dimethyl-1H- pyrazol-1-yl]ethyl}piperazine- 1,4-dicarboxylate 
                 NaH 
                 501 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 Base 
                 MS(ESI+) 
               
               
                   
               
               
                 358 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [3-tert-butyl-5-(ethoxycarbonyl)- 1H-pyrazol-1-yl]ethyl}piperazine- 1,4-dicarboxylate 
                 NaH 
                 543 
               
               
                   
               
               
                 359 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)- 2-{2-[4-(ethoxycarbonyl)-1H- pyrazol-1-yl]ethyl} piperazine-1,4-dicarboxylate 
                 K 2 CO 3   
                 487 
               
               
                   
               
               
                 360 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)- 2-{2-[3-(methoxycarbonyl)- 1H-pyrrol-1-yl]ethyl} piperazine-1,4-dicarboxylate 
                 NaH 
                 472 
               
               
                   
               
               
                 361 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)- 2-{2-[3-(ethoxycarbonyl)-2- methyl-1H-pyrrol-1-yl]ethyl} piperazine-1,4-dicarboxylate 
                 NaH 
                 500 
               
               
                   
               
               
                 362 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)- 2-{2-[3-cyclopropyl-5-(ethoxy- carbonyl)-1H-pyrazol-1-yl]ethyl} piperazine-1,4-dicarboxylate 
                 K 2 CO 3   
                 527 
               
               
                   
               
               
                 363 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)- 2-[2-(3-cyano-1H-1ndol-1-yl)ethyl] piperazine-1,4-dicarboxylate 
                 NaH 
                  433** 
               
               
                   
               
            
           
         
       
     
     Reference Example 364 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (700 mg), 1,2-dihydro-3H-indazol-3-one (212 mg), potassium carbonate (450 mg) and DMF (6 ml) was stirred at 80° C. for 3 hr, the insoluble material was filtered off using silica gel, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (423 mg). 
       1 H-NMR (CDCl 3 ) δ 1.36 (9H, s), 2.05 (1H, s), 2.19 (1H, br s), 2.89 (1H, br s), 3.08 (2H, br s), 4.05-4.16 (1H, m), 4.12 (1H, d), 4.41 (2H, br s), 5.14 (2H, s), 7.07 (1H, td), 7.25-7.39 (9H, m), 7.65 (1H, br s) 
     MS (ESI+, m/e) 481 (M+1) 
     In the same manner as in Reference Example 364, the following compounds (Reference Examples 365-371) were obtained. 
     Reference Example 365 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.35 (9H, br s), 1.98 (4H, br s), 2.90 (1H, br s), 3.04 (2H, br s), 3.84 (1H, br s), 3.96 (1H, br s), 4.14 (2H, br s), 5.14 (2H, br s), 7.03 (3H, br s), 7.29 (6H, br s), 9.17 (1H, br s) 
     MS (ESI+, m/e) 481 (M+1) 
     Reference Example 366 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-oxo-1,3-benzoxazol-3(2H)-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.38 (9H, s), 1.95 (2H, br s), 3.03 (2H, br s), 3.81 (2H, br s), 3.95 (1H, br s), 4.04-4.19 (1H, m), 4.12 (2H, d), 5.14 (2H, q), 7.05 (1H, s), 7.17 (3H, ddd), 7.11-7.22 (1H, m), 7.25-7.35 (5H, m) 
     MS (ESI+, m/e) 482 (M+1) 
     Reference Example 367 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.44 (9H, br s), 1.88 (2H, br s), 2.90 (1H, br s), 3.05 (2H, br s), 3.82 (2H, br s), 4.09 (4H, br s), 4.60 (2H, br s), 5.14 (2H, br s), 6.96 (4H, br s), 7.31 (5H, br s) 
     MS (ESI+, m/e) 496 (M+1) 
     Reference Example 368 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-(cyclopent-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.36 (9H, br s), 1.89 (1H, d), 2.08 (1H, qd), 1.98-2.13 (3H, m), 2.56 (2H, td), 2.81-2.97 (3H, m), 3.00 (1H, d), 3.09 (2H, br s), 3.83 (1H, d), 3.94 (1H, br s), 4.21 (2H, br s), 5.13 (2H, q), 5.92 (1H, t), 6.91 (1H, br s), 7.03-7.12 (2H, m), 7.13-7.20 (1H, m), 7.22-7.36 (4H, m), 7.28 (1H, d) 
     MS (ESI+, m/e) 547 (M+1) 
     Reference Example 369 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-(cyclopent-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.38 (9H, br s), 1.69-1.79 (2H, m), 1.80-1.93 (3H, m), 2.25-2.41 (4H, m), 2.28 (3H, d), 2.89 (1H, br s), 3.04 (2H, br s), 3.84 (1H, d), 3.94 (1H, br s), 4.11 (2H, br s), 5.13 (2H, q), 5.91 (1H, br s), 6.95-7.09 (4H, m), 7.22-7.37 (5H, m) 
     MS (ESI+, m/e) 561 (M+1) 
     Reference Example 370 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(ethoxycarbonyl)-2H-1,2,3-triazol-2-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 488 (M+1) 
     Reference Example 371 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[5-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 488 (M+1) 
     Reference Example 372 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (515 mg), methyl iodide (100 μl), cesium carbonate (1.00 g) and DMA (5 ml) was stirred at room temperature for 3 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (473 mg). 
       1 H-NMR (CDCl 3 ) δ 1.30 (9H, br s), 1.85-2.01 (2H, m), 2.93 (1H, d), 3.01 (2H, br s), 3.34-3.45 (3H, m), 3.81 (2H, br s), 3.94 (1H, br s), 4.04-4.20 (1H, m), 4.12 (2H, q), 5.05-5.20 (2H, m), 6.87-7.02 (2H, m), 7.03-7.14 (1H, m), 7.03-7.14 (1H, m), 7.22-7.36 (5H, m) 
     MS (ESI+, m/e) 495 (M+1) 
     Reference Example 373 
     1-tert-Butyl 4-benzyl (2R)-2-(2-azidoethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (3.00 g), sodium azide (2.50 g) and DMF (20 ml) was stirred at 80° C. for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-4:1) was concentrated under reduced pressure to give the object compound (2.19 g). 
       1 H-NMR (CDCl 3 ) δ 1.47 (9H, s), 1.69 (1H, br s), 1.84 (1H, t), 1.84 (1H, d), 2.93 (1H, d), 2.92 (1H, d), 3.01 (1H, br s), 3.25 (2H, br s), 4.00 (2H, br s), 4.27 (1H, br s), 5.14 (2H, d), 7.30-7.40 (5H, m) 
     MS (ESI+, m/e) 390 (M+1) 
     Reference Example 374 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-(2-azidoethyl)piperazine-1,4-dicarboxylate (500 mg), propargyl alcohol (360 mg) and toluene (7 ml) was stirred at 130° C. for 12 hr in a sealed stainless tube, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:19-4:1) was concentrated under reduced pressure to give the object compound (510 mg). 
       1 H-NMR (CDCl 3 ) δ 1.46 (9H, d), 1.77-1.94 (1H, m), 2.04 (1H, br s), 2.18 (1H, d), 2.95 (2H, br s), 3.26 (1H, br s), 3.86 (1H, br s), 4.02 (2H, br s), 4.13 (1H, br s), 4.27 (2H, br s), 4.64 (1H, br s), 4.78 (1H, s), 5.14 (2H, d), 7.09-7.21 (1H, m), 7.23-7.38 (5H, m) 
     MS (ESI+, m/e) 446 (M+1) 
     In the same manner as in Reference Example 374, the following compounds (Reference Examples 375-378) were obtained. 
     Reference Example 375 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(2-hydroxyethyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.45 (9H, br s), 1.79-1.95 (1H, m), 2.03-2.19 (2H, m), 2.34 (1H, br s), 2.50 (1H, br s), 2.90 (4H, br s), 3.27 (1H, br s), 3.74 (1H, br s), 3.85 (1H, br s), 3.95 (2H, br s), 4.06 (1H, br s), 4.28 (1H, br s), 5.14 (2H, br s), 7.16 (1H, br s), 7.26 (1H, br s), 7.35 (4H, br s) 
     MS (ESI+, m/e) 460 (M+1) 
     Reference Example 376 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 0.67 (1H, br s), 0.84 (2H, dd), 0.89-1.04 (1H, m), 0.94 (2H, td), 1.43 (9H, d), 1.94 (1H, dt), 2.14 (1H, br s), 2.35 (1H, s), 2.87 (1H, br s), 3.03 (1H, br s), 4.12 (2H, d), 4.08 (1H, br s), 4.25 (2H, br s), 5.13 (2H, d), 7.15-7.19 (1H, m), 7.22-7.37 (5H, m) 
     MS (ESI+, m/e) 456 (M+1) 
     Reference Example 377 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(ethoxycarbonyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 488 (M+1) 
     Reference Example 378 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(4-acetyl-1H-1,2,3-triazol-1-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.44 (9H, s), 1.98-2.08 (1H, m), 2.25 (1H, d), 2.69 (3H, s), 2.92 (2H, d), 3.03 (1H, br s), 3.94 (1H, br s), 3.98-4.21 (3H, m), 4.38 (2H, br s), 5.06-5.21 (1H, m), 5.14 (1H, d), 7.34 (5H, s), 8.15 (1H, s) 
     MS (ESI+, m/e) 458 (M+1) 
     Reference Example 379 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{4-[(acetyloxy)methyl]-1H-1,2,3-triazol-1-yl}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazine-1,4-dicarboxylate (360 mg), acetic anhydride (1.0 ml) and pyridine (1.0 ml) was stirred at room temperature for 12 hr, and concentrated under reduced pressure to give the object compound (390 mg). 
       1 H-NMR (CDCl 3 ) δ 1.44 (9H, s), 2.03-2.16 (4H, m), 2.23 (3H, s), 2.89 (1H, br s), 2.96 (1H, br s), 3.04 (1H, br s), 4.15 (1H, br s), 4.21-4.36 (3H, m), 5.07-5.22 (4H, m), 7.30-7.40 (5H, m), 7.55-7.72 (1H, m) 
     MS (ESI+, m/e) 488 (M+1) 
     Reference Example 380 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate and 1-tert-butyl 4-benzyl (2R)-2-[2-(2H-indazol-2-yl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (620 mg), 1H-indazole (331 mg), potassium carbonate (1.2 g) and DMF (7 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-hexane (1:1) were concentrated under reduced pressure, respectively. The residue of the less polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-[2-(1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (380 mg), and the residue of the more polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-[2-(2H-indazol-2-yl)ethyl]piperazine-1,4-dicarboxylate (170 mg), as an amorphous solid, respectively. 
     MS (ESI+, m/e) 465 (M+1) 
     MS (ESI+, m/e) 465 (M+1) 
     Reference Example 381 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl]ethyl}piperazine-1,4-dicarboxylate and 1-tert-butyl 4-benzyl (2R)-2-{2-[3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (800 mg), ethyl 5-methyl-1H-pyrazole-3-carboxylate (560 mg), potassium carbonate (1.1 g) and DMF (20 ml) was stirred at 50° C. for 10 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-hexane (1:1) were concentrated under reduced pressure, respectively. The residue of the less polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-{2-[3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-1-yl]ethyl}piperazine-1,4-dicarboxylate (470 mg), and the residue of the more polar fraction was vacuum-dried to give 1-tert-butyl 4-benzyl (2R)-2-{2-[5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl]ethyl}piperazine-1,4-dicarboxylate (390 mg), as an amorphous solid, respectively. 
     MS (ESI+, m/e) 501 (M+1) 
     MS (ESI+, m/e) 501 (M+1) 
     In the same manner as in Reference Example 381, the following compound (Reference Example 382) was obtained. 
     Reference Example 382 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[3-(methoxycarbonyl)-1H-indazol-1-yl]ethyl}piperazine-1,4-dicarboxylate and 1-tert-butyl 4-benzyl (2R)-2-{2-[3-(methoxycarbonyl)-2H-indazol-2-yl]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 523 (M+1) 
     MS (ESI+, m/e) 523 (M+1) 
     Reference Example 383 
     Benzyl (3R)-3-(2-phenoxyethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-phenoxyethyl)piperazine-1,4-dicarboxylate (585 mg) was dissolved in dichloromethane (2 ml), TFA (4 ml) was added thereto, and the mixture was stirred at room temperature for 50 min. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate-saturated brine (1:1) by small portions. To the mixture was added potassium carbonate by small portions to basify the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (435 mg) as an oil. 
     MS (ESI+, m/e) 341 (M+1) 
     In the same manner as in Reference Example 383, the following compounds (Reference Examples 384-422) shown in Table 6-1-Table 6-5 were obtained. 
     
       
         
           
               
             
               
                 TABLE 6-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 384 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1,2- benzisoxazol-3-yloxy)ethyl] piperazine-1-carboxylate 
                 382 
               
               
                   
               
               
                 385 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(2-methyl- 1H-imidazol-1-yl)phenoxy]ethyl} piperazine-1-carboxylate 
                 421 
               
               
                   
               
               
                 386 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[5-(methoxy carbonyl)-isoxazol-3-yl]oxy} ethyl)piperazine-1-carboxylate 
                 390 
               
               
                   
               
               
                 387 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2,6- dimethylpyridin-3-yl)oxy]ethyl} piperazine-1-carboxylate 
                 370 
               
               
                   
               
               
                 388 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-methyl-1,3- benzothiazol-5-yl)oxy]ethyl} piperazine-1-carboxylate 
                 412 
               
               
                   
               
               
                 389 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2,2-dimethyl- 2,3-dihydro-1-benzofuran-7-yl)-oxy] ethyl}piperazine-1-carboxylate 
                 411 
               
               
                   
               
               
                 390 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)oxy]ethyl} piperazine-1-carboxylate 
                 410 
               
               
                   
               
               
                 391 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[5-(methoxy carbonyl)pyridin-3-yl]oxy} ethyl)piperazine-1-carboxylate 
                 400 
               
               
                   
               
               
                 392 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(5-oxo-5,6,7,8- tetrahydronaphthalen-2-yl)oxy] ethyl}piperazine-1-carboxylate 
                 409 
               
               
                   
               
               
                 393 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-oxo-2,3- dihydro-1,3-benzoxazol-6-yl)oxy] ethyl}piperazine-1-carboxylate 
                 398 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 394 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(3,5,6- trifluoropyridin-2-yl)oxy] ethyl}piperazine-1-carboxylate 
                 396 
               
               
                   
               
               
                 395 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[6- (methoxycarbonyl)pyridin-3-yl] oxy}ethyl)piperazine-1-carboxylate 
                 400 
               
               
                   
               
               
                 396 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[5-(ethoxy- carbonyl)-2-methyl-1,3-thiazol-4-yl] oxy}ethyl)piperazine-1-carboxylate 
                 434 
               
               
                   
               
               
                 397 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[2-(methoxy carbonyl)pyridin-3-yl]oxy}ethyl) piperazine-1-carboxylate 
                 400 
               
               
                   
               
               
                 398 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[4-(ethoxy- carbonyl)-1-methyl-1H-pyrazol-5-yl] oxy}ethyl)piperazine-1-carboxylate 
                 417 
               
               
                   
               
               
                 399 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[1-ethyl-4-(2- methoxy-2-oxoethyl)-1H-pyrazol-3-yl] oxy}ethyl)piperazine-1-carboxylate 
                 431 
               
               
                   
               
               
                 400 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-({2-[(dimethyl- amino)methyl]pyridin-3-yl}oxy) ethyl]piperazine-1-carboxylate 
                 399 
               
               
                   
               
               
                 401 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-oxo-1,2,3,4- tetrahydroquinolin-7-yl)oxy] ethyl}piperazine-1-carboxylate 
                 410 
               
               
                   
               
               
                 402 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[2- (methoxycarbonyl)-3-thienyl]oxy} ethyl)piperazine-1-carboxylate 
                 405 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 403 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-bromo-2- methoxyphenoxy)ethyl]piperazine-1- carboxylate 
                 449 
               
               
                   
               
               
                 404 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-chloro-2- methoxyphenoxy)ethyl]piperazine-1- carboxylate 
                 405 
               
               
                   
               
               
                 405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-ethoxyphenoxy) ethyl]piperazine-1-carboxylate 
                 385 
               
               
                   
               
               
                 406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2,3-dimethoxy- phenoxy)ethyl]piperazine- 1-carboxylate 
                 401 
               
               
                   
               
               
                 407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2,6-dimethoxy-4- methylphenoxy)ethyl]piperazine-1- carboxylate 
                 415 
               
               
                   
               
               
                 408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(6-methoxy-2- oxo-2H-chromen-7-yl)oxy]ethyl} piperazine-1-carboxylate 
                 439 
               
               
                   
               
               
                 409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(1-oxo-1,2,3,4- tetrahydroisoquinolin-5-yl)oxy] ethyl}piperazine-1-carboxylate 
                 410 
               
               
                   
               
               
                 410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(thieno[3,2- b]pyridin-7-yloxy)ethyl]piperazine- 1-carboxylate 
                 398 
               
               
                   
               
               
                 411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-isopropoxy- phenoxy)ethyl]piperazine- 1-carboxylate 
                 399 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1-3-benzodioxol- 5-yloxy)ethyl]piperazine-1-carboxylate 
                 385 
               
               
                   
               
               
                 413 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(1-phenyl-1H- 1,2,4-triazol-3-yl)oxy]ethyl} piperazine-1-carboxylate 
                 408 
               
               
                   
               
               
                 414 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-methyl-1H- pyrazol-1-yl)ethyl]piperazine-1- carboxylate 
                 329 
               
               
                   
               
               
                 415 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1H-benzimidazol- 1-yl)ethyl]piperazine-1-carboxylate 
                 365 
               
               
                   
               
               
                 416 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3- (trifluoromethyl)-1H-pyrazol-1- yl]ethyl}piperazine-1-carboxylate 
                 383 
               
               
                   
               
               
                 417 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1H-benzotriazol- 1-yl) ethyl]piperazine-1-carboxylate 
                 366 
               
               
                   
               
               
                 418 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3-phenyl-1H- pyrazol-1-yl)ethyl]piperazine-1- carboxylate 
                 391 
               
               
                   
               
               
                 419 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[5- (ethoxycarbonyl)-3-methyl-1H- pyrazol-1-yl]ethyl}piperazine- 1-carboxylate 
                 401 
               
               
                   
               
               
                 420 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3- (ethoxycarbonyl)-5-methyl-1H- pyrazol-1-yl]ethyl}piperazine- 1-carboxylate 
                 401 
               
               
                   
               
               
                 421 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4,5,6,7- tetrahydro-1H-indazol-1- yl)ethyl]piperazine-1-carboxylate 
                 369 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6-5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. 
                   
                   
                   
               
               
                 Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 422 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4- (methoxycarbonyl)- 1H-indazol-1-yl]ethyl) piperazine-1- carboxylate 
                 423 
               
               
                   
               
            
           
         
       
     
     Reference Example 423 
     Benzyl (3R)-3-[2-(1H-indazol-1-yl)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-[2-(1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (380 mg) was dissolved in chloroform (5 ml), TFA (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with toluene (10 ml), and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (300 mg) as an oil. 
     MS (ESI+, m/e) 365 (M+1) 
     In the same manner as in Reference Example 423, the following compound (Reference Example 424) was obtained. 
     Reference Example 424 
     Benzyl (3R)-3-[2-(2H-indazol-2-yl)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 365 (M+1) 
     Reference Example 425 
     Benzyl (3R)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1,4-dicarboxylate (415 mg) and 2N hydrogen chloride-ethyl acetate solution was stirred at room temperature for 4 hr, and concentrated under reduced pressure to give the object compound (325 mg). 
     MS (ESI+, m/e) 381 (M+1) 
     In the same manner as in Reference Example 425, the following compounds (Reference Examples 426-502) shown in Table 7-1-Table 7-8 were obtained. 
     
       
         
           
               
             
               
                 TABLE 7-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 426 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-phenoxyethyl) piperazine-1-carboxylate hydrochloride 
                 341 
               
               
                   
               
               
                 427 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[1-methyl-5- (trifluoromethyl)-1H-pyrazol-3- yl]oxy}ethyl)piperazine-1- carboxylate hydrochloride 
                 413 
               
               
                   
               
               
                 428 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-(trifluoro methoxy)phenoxy]ethyl}piperazine- 1-carboxylate hydrochloride 
                 425 
               
               
                   
               
               
                 429 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[1-methyl-3- (trifluoromethyl)-1H-pyrazol-5- yl]oxy}ethyl)piperazine-1- carboxylate hydrochloride 
                 413 
               
               
                   
               
               
                 430 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4- methoxyphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 371 
               
               
                   
               
               
                 431 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4- acetylphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 383 
               
               
                   
               
               
                 432 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3- acetylphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 383 
               
               
                   
               
               
                 433 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(1H- imidazol-1-yl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 407 
               
               
                   
               
               
                 434 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4- (1H-pyrazol-1-yl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 407 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 435 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2- acetylphenoxy)ethyl]piperazine- 1-carboxylate hydrochloride 
                 383 
               
               
                   
               
               
                 436 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3- fluorophenoxy)ethyl]piperazine- 2-carboxylate hydrochloride 
                 359 
               
               
                   
               
               
                 437 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4- fluorophenoxy)ethyl]piperazine- 3-carboxylate hydrochloride 
                 359 
               
               
                   
               
               
                 438 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2- methoxyphenoxy)ethyl]piperazine- 1-carboxylate hydrochloride 
                 371 
               
               
                   
               
               
                 439 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3- methoxyphenoxy)ethyl]piperazine- 2-carboxylate hydrochloride 
                 371 
               
               
                   
               
               
                 440 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{4- [(trifluoromethyl)sulfonyl]phenoxy} ethyl)piperazine-1-carboxylate hydrochloride 
                 473 
               
               
                   
               
               
                 441 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(methyl sulfonyl)phenoxy]ethyl}piperazine- 1-carboxylate hydrochloride 
                 419 
               
               
                   
               
               
                 442 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2- chlorophenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 375 
               
               
                   
               
               
                 443 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3- chlorophenoxy)ethyl]piperazine- 2-carboxylate hydrochloride 
                 375 
               
               
                   
               
               
                 444 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4- chlorophenoxy)ethyl]piperazine-3- carboxylate hydrochloride 
                 375 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 445 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-bromo-2- fluorophenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 438 
               
               
                   
               
               
                 446 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(1H-1,2,3- triazol-1-yl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 408 
               
               
                   
               
               
                 447 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(5-methyl- 1,3,4-oxadiazol-2-yl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 423 
               
               
                   
               
               
                 448 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4- methylphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 355 
               
               
                   
               
               
                 449 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(2- methoxy-2-oxoethyl)phenoxy)ethyl} piperazine-1-carboxylate hydrochloride 
                 413 
               
               
                   
               
               
                 450 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3- (diethylamino) phenoxy]ethyl} piperazine-1-carboxylate dihydrochloride 
                 412 
               
               
                   
               
               
                 451 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(5-methyl- 1,3,4-oxadiazol-2-yl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 423 
               
               
                   
               
               
                 452 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(3- methoxy-3-oxopropyl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 427 
               
               
                   
               
               
                 453 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4- cyanophenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 366 
               
               
                   
               
               
                 454 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-fluoro-4- (methoxycarbonyl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 417 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 455 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-fluoro-4- (methoxycarbonyl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 417 
               
               
                   
               
               
                 456 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-acetyl-2- fluorophenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 401 
               
               
                   
               
               
                 457 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-fluoro-2- methoxyphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 389 
               
               
                   
               
               
                 458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-methoxy-4- methylphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 385 
               
               
                   
               
               
                 459 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-acetyl-2- methoxyphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 413 
               
               
                   
               
               
                 460 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(ethoxycarbonyl)- 2-methoxyphenoxy)ethyl}piperazine-1- carboxylate hydrochloride 
                 443 
               
               
                   
               
               
                 461 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{4-[(dimethylamino) methyl]phenoxy} ethyl)piperazine- 1-carboxylate dihydrochloride 
                 398 
               
               
                   
               
               
                 462 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{4-[(dimethylamino) methyl]-2-fluorophenoxy}ethyl) piperazine-1-carboxylate dihydrochloride 
                 416 
               
               
                   
               
               
                 463 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-fluoro-6-methoxy- phenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 389 
               
               
                   
               
               
                 464 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(2-oxopyrrolidin- 1-yl)phenoxy)ethyl}piperazine-1- carboxylate hydrochloride 
                 424 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 465 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-fluoro-4- methoxyphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 389 
               
               
                   
               
               
                 466 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(5-fluoro-2- methoxyphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 389 
               
               
                   
               
               
                 467 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-fluoro-4- methylphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 373 
               
               
                   
               
               
                 468 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-fluoro-3- (methoxycarbonyl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 417 
               
               
                   
               
               
                 469 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-methoxy-5- (methoxycarbonyl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 429 
               
               
                   
               
               
                 470 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(2-ethoxy-2- oxoethyl)-2-methoxyphenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 457 
               
               
                   
               
               
                 471 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-fluoro-4-(5- methyl-1,3,4-oxadiazol-2-yl)phenoxy] ethyl}piperazine-1- carboxylate hydrochloride 
                 441 
               
               
                   
               
               
                 472 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-fluoro-4-(5- methyl-1,3,4-oxadiazol-2-yl)phenoxy] ethyl}piperazine-1- carboxylate hydrochloride 
                 441 
               
               
                   
               
               
                 473 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-fluoro-3-(5- methyl-1,3,4-oxadiazol-2-yl)phenoxy] ethyl}piperazine-1- carboxylate hydrochloride 
                 441 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-6 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 474 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-methoxy-4-(5- methyl-1,3,4-oxadiazol-2-yl)phenoxy] ethyl}piperazine-1- carboxylate hydrochloride 
                 453 
               
               
                   
               
               
                 475 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-methoxy-5-(5- methyl-1,3,4-oxadiazol-2-yl)phenoxy] ethyl}piperazine-1- carboxylate hydrochloride 
                 453 
               
               
                   
               
               
                 476 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-oxo-2,3- dihydro-1H-benzimidazol-1-yl)ethyl] piperazine-1-carboxylate hydrochloride 
                 381 
               
               
                   
               
               
                 477 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-oxo-1,3- benzoxazol-3(2H)-yl)ethyl]piperazine- 1-carboxylate hydrochloride 
                 382 
               
               
                   
               
               
                 478 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3-oxo-2,3-dihydro- 4H-1,4-benzoxazin-4-yl)ethyl] piperazine-1-carboxylate hydrochloride 
                 396 
               
               
                   
               
               
                 479 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3-methyl-2-oxo-2,3- dihydro-1H-benzimidazol-1-yl)ethyl] piperazine-1-carboxylate hydrochloride 
                 395 
               
               
                   
               
               
                 480 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(cyclopent-1-en-1- yl)-2-oxo-2,3-dihydro-1H- benzimidazol-1-yl]ethyl}piperazine- 1-carboxylate hydrochloride 
                 447 
               
               
                   
               
               
                 481 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(cyclohex-1-en-1- yl)-2-oxo-2,3-dihydro-1H- benzimidazol-1-yl]ethyl}piperazine- 1-carboxylate hydrochloride 
                 461 
               
               
                   
               
               
                 482 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3,5-di-tert-butyl-1H- pyrazol-1-yl)ethyl]piperazine-1- carboxylate hydrochloride 
                 427 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-7 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 483 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1H-indol-1-yl)ethyl] piperazine-1-carboxylate hydrochloride 
                 364 
               
               
                   
               
               
                 484 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-phenyl-1H- imidazol-1-yl)ethyl]piperazine- 1-carboxylate hydrochloride 
                 391 
               
               
                   
               
               
                 485 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3,5-dimethyl-1H- pyrazol-1-yl)ethyl]piperazine-1- carboxylate hydrochloride 
                 343 
               
               
                   
               
               
                 486 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(hydroxymethyl)- 1H-1,2,3-triazol-1-yl]ethyl} piperazine-1-carboxylate hydrochloride 
                 346 
               
               
                   
               
               
                 487 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(2- hydroxyethyl)-1H-1,2,3-triazol-1-yl] ethyl}piperazine-1-carboxylate hydrochloride 
                 360 
               
               
                   
               
               
                 488 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-cyclopropyl-1H- 1,2,3-triazol-1-yl)ethyl]piperazine- 1-carboxylate hydrochloride 
                 356 
               
               
                   
               
               
                 489 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(ethoxycarbonyl)- 1H-1,2,3-triazol-1-yl]ethyl} piperazine-1-carboxylate hydrochloride 
                 388 
               
               
                   
               
               
                 490 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(methoxy- carbonyl)-3,5-dimethyl-1H-pyrazol-1- yl]ethyl}piperazine-1- carboxylate hydrochloride 
                 401 
               
               
                   
               
               
                 491 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-tert-butyl-5- (ethoxycarbonyl)-1H-pyrazol-1-yl] ethyl}piperazine-1-carboxylate hydrochloride 
                 443 
               
               
                   
               
               
                 492 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-acetyl-1H-1,2,3- triazol-1-yl)ethyl]piperazine-1- carboxylate hydrochloride 
                 358 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7-8 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 493 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(ethoxycarbonyl)- 1H-pyrazol-1-yl]ethyl}piperazine-1- carboxylate hydrochloride 
                 387 
               
               
                   
               
               
                 494 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(ethoxycarbonyl)- 2H-1,2,3-triazol-2-yl]ethyl}piperazine- 1-carboxylate hydrochloride 
                 388 
               
               
                   
               
               
                 495 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[5-(ethoxycarbonyl)- 1H-1,2,3-triazol-1-yl]ethyl}piperazine- 1-carboxylate hydrochloride 
                 388 
               
               
                   
               
               
                 496 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(methoxy- carbonyl)-1H-pyrrol-1-yl]ethyl} piperazine-1-carboxylate hydrochloride 
                 372 
               
               
                   
               
               
                 497 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(ethoxycarbonyl)- 2-methyl-1H-pyrrol-1-yl]ethyl} piperazine-1-carboxylate hydrochloride 
                 400 
               
               
                   
               
               
                 498 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{4-[(acetyloxy) methyl]-1H-1,2,3-triazol-1-yl}ethyl) piperazine-1-carboxylate hydrochloride 
                 388 
               
               
                   
               
               
                 499 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(methoxy- carbonyl)-1H-indazol-1-yl]ethyl} piperazine-1-carboxylate hydrochloride 
                 423 
               
               
                   
               
               
                 500 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-(methoxy- carbonyl)-2H-indazol-2-yl]ethyl} piperazine-1-carboxylate hydrochloride 
                 423 
               
               
                   
               
               
                 501 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3-cyclopropyl-5- (ethoxycarbonyl)-1H-pyrazol-1-yl] ethyl}piperazine-1-carboxylate hydrochloride 
                 427 
               
               
                   
               
               
                 502 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(3-cyano-1H-indol-1- yl)ethyl]piperazine-1-carboxylate hydrochloride 
                 389 
               
               
                   
               
            
           
         
       
     
     Reference Example 503 
     1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(3-hydroxypropyl)piperazine-1-carboxylate (8.0 g) was dissolved in methanol (100 ml), 20% palladium hydroxide-carbon (50% containing water, 4.0 g) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (70 ml), and the solution was ice-cooled. Benzyl chloroformate (4.1 g), sodium carbonate (2.8 g) and water (35 ml) were added, and the mixture was stirred at 0° C. for 15 min, and then at room temperature for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (8.1 g) as an oil. 
     MS (ESI+, m/e) 379 (M+1) 
     Reference Example 504 
     1-tert-Butyl 4-benzyl (2R)-2-{3-[(methylsulfonyl)oxy]propyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (2.0 g) was dissolved in THF (10 ml), and the solution was ice-cooled. Triethylamine (1.1 ml) and methanesulfonyl chloride (510 μl) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (2.1 g) as an amorphous solid. 
     MS (ESI+, m/e) 457 (M+1) 
     Reference Example 505 
     Benzyl (3R)-3-(3-hydroxypropyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (250 mg) was dissolved in chloroform (2 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (200 mg) as an oil. 
     MS (ESI+, m/e) 279 (M+1) 
     In the same manner as in Reference Example 255, the following compound (Reference Example 506) was obtained. 
     Reference Example 506 
     1-tert-Butyl 4-benzyl (2R)-2-(3-phenoxypropyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 455 (M+1) 
     In the same manner as in Reference Example 380, the following compound (Reference Example 507) was obtained. 
     Reference Example 507 
     1-tert-Butyl 4-benzyl (2R)-2-[3-(1H-indazol-1-yl)propyl]piperazine-1,4-dicarboxylate and 1-tert-butyl 4-benzyl (2R)-2-[3-(2H-indazol-2-yl)propyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 479 (M+1) 
     MS (ESI+, m/e) 479 (M+1) 
     In the same manner as in Reference Example 383, the following compounds (Reference Examples 508-510) were obtained. 
     Reference Example 508 
     Benzyl (3R)-3-(3-phenoxypropyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 355 (M+1) 
     Reference Example 509 
     Benzyl (3R)-3-[3-(1H-indazol-1-yl)propyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 379 (M+1) 
     Reference Example 510 
     Benzyl (3R)-3-[3-(2H-indazol-2-yl)propyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 379 (M+1) 
     Reference Example 511 
     Benzyl (3R)-3-{3-[5-(ethoxycarbonyl)-3-methyl-1H-pyrazol-1-yl]propyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (500 mg), ethyl 5-methyl-1H-pyrazole-3-carboxylate (550 mg) and tri-tert-butylphosphine (267 mg) were dissolved in toluene (20 ml), ADDP (420 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and the solvent was evaporated under reduced pressure to give the object compound (140 mg) as an oil. 
     MS (ESI+, m/e) 415 (M+1) 
     Reference Example 512 
     tert-Butyl (3R)-3-benzyl-3-methylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (2R)-2-Benzyl-2-methylpiperazine (1.10 g) and triethylamine (1.61 ml) was dissolved in THF (50 ml), and the solution was ice-cooled. A solution of di-tert-butyl bicarbonate (1.61 ml) in THF (10 ml) was added over 30 min, and the mixture was stirred at 0° C. for 3 hr. The solvent was evaporated under reduced pressure, to the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (4:1) was concentrated under reduced pressure to give the object compound (1.06 g). 
     MS (ESI+, m/e) 291 (M+1) 
     Reference Example 513 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-[(1S,2S)-2-(Benzyloxy)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (376 mg) was suspended in DMF (10 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (332 mg), WSC.HCl (288 mg) and HOBt (184 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (762 mg) as an amorphous solid. 
     MS (ESI+, m/e) 635 (M+1) 
     In the same manner as in Reference Example 513, the following compounds (Reference Examples 514-515) were obtained. 
     Reference Example 514 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 635 (M+1) 
     Reference Example 515 
     tert-Butyl (3R)-4-({1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 570 (M+1) 
     Reference Example 516 
     tert-Butyl (3R)-3-benzyl-4-({5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     To a solution of 5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazole-4-carboxylic acid (304 mg) in DMF (8 ml) were added tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (332 mg), WSC.HCl (288 mg) and HOBt (184 mg), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (380 mg) as an amorphous solid. 
     MS (ESI+, m/e) 563 (M+1) 
     Reference Example 517 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (3.30 g), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (3.32 g), WSC.HCl (2.88 g) and HOBt (2.30 g) in DMF (100 ml) was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (5.45 g) as an amorphous solid. 
     MS (ESI+, m/e) 589 (M+1) 
     Reference Example 518 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (330 mg) was suspended in DMF (5 ml), 2-[(2R)-4-benzylpiperazin-2-yl]ethanol (264 mg), WSC.HCl (230 mg) and HOBt (168 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (355 mg) as an amorphous solid. 
     MS (ESI+, m/e) 533 (M+1) 
     Reference Example 519 
     Benzyl (3R)-3-[2-(2-fluorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-fluorophenoxy)ethyl]piperazine-1,4-dicarboxylate (210 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in toluene (1 ml). The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (2 ml), 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (135 mg), WSC.HCl (118 mg), HOBt (94 mg) and triethylamine (83 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (205 mg) as an amorphous solid. 
     MS (ESI+, m/e) 671 (M+1) 
     Reference Example 520 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1,4-dicarboxylate (409 mg) was dissolved in methanol (2 ml), 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was suspended in DMF (5 ml), 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (271 mg), WSC.HCl (236 mg), HOBt (151 mg) and triethylamine (229 μl) were added, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (486 mg) as an amorphous solid. 
     MS (ESI+, m/e) 711 (M+1) 
     In the same manner as in Reference Example 520, the following compounds (Reference Examples 521-525) were obtained. 
     Reference Example 521 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[3-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 711 (M+1) 
     Reference Example 522 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[2-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 711 (M+1) 
     Reference Example 523 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(1-oxidopyridin-3-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 669 (M+1) 
     Reference Example 524 
     Benzyl (3R)-3-{2-[4-(4-acetylpiperazin-1-yl)phenoxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 779 (M+1) 
     Reference Example 525 
     Benzyl (3R)-3-[2-(4-cyano-2-methoxyphenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 708 (M+1) 
     Reference Example 526 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(1H-indazol-1-yl)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (110 mg) was suspended in DMF (5 ml), benzyl (3R)-3-[2-(1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (121 mg), WSC.HCl (126 mg) and HOBt (202 mg) were added, and the mixture was stirred at 60° C. for 10 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (140 mg) as an amorphous solid. 
     MS (ESI+, m/e) 677 (M+1) 
     In the same manner as in Reference Example 526, the following compound (Reference Example 527) was obtained. 
     Reference Example 527 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(2H-indazol-2-yl)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 677 (M+1) 
     Reference Example 528 
     (1R,2S)-2-[4-({(2R)-4-Benzyl-2-[(E)-2-cyclopropylvinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (144 mg), (3R)-1-benzyl-3-[(E)-2-cyclopropylvinyl]piperazine (125 mg), WSC.HCl (125 mg), HOBt (23 mg), N,N-diisopropylethylamine (181 μl) and DMAP (12 mg) in DMF (2 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-4:0:1) was concentrated under reduced pressure to give the object compound (110 mg) as an amorphous solid. 
     MS (ESI+, m/e) 511 (M+1) 
     Reference Example 529 
     tert-Butyl (3R)-3-benzyl-4-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Methyl 1-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylate (240 mg) was dissolved in ethanol-THF (1:1, 10 ml), lithium hydroxide monohydrate (30 mg) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethanol, and the suspension was again concentrated under reduced pressure. This was suspended in DMF (15 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (240 mg), WSC.HCl (178 mg) and HOBt (142 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (321 mg) as an amorphous solid. 
     MS (ESI+, m/e) 529 (M+1) 
     In the same manner as in Reference Example 529, the following compounds (Reference Examples 530-536) were obtained. 
     Reference Example 530 
     tert-Butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycyclopentyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 531 (M+1) 
     Reference Example 531 
     tert-Butyl (3R)-3-benzyl-4-{[1-(cis-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 545 (M+1) 
     Reference Example 532 
     {(2S)-4-Benzyl-1-[(1-cyclopentyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}(cyclopropyl)methanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 485 (M+1) 
     Reference Example 533 
     trans-2-(4-{[(2R)-4-Benzyl-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 487 (M+1) 
     Reference Example 534 
     N-{[(2R)-4-Benzyl-1-({1-[2-(ethoxymethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 636 (M+1) 
     Reference Example 535 
     2-[4-({(2S)-4-Benzyl-2-[(benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 609 (M+1) 
     Reference Example 536 
     tert-Butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycyclohexyl)-2-methyl-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 559 (M+1) 
     Reference Example 537 
     tert-Butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycycloheptyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 1-(trans-2-hydroxycycloheptyl)-5-phenyl-1H-imidazole-4-carboxylate (860 mg), lithium hydroxide monohydrate (165 mg), ethanol (10 ml) and water (6 ml) was stirred at 65° C. for 3 hr, and concentrated under reduced pressure. The residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (868 mg), WSC.HCl (1.00 g), HOBt (1.60 g) and DMF (15 ml), and the mixture was stirred at 50° C. for 12 hr, and poured into water. The obtained crystals were collected by filtration, and washed successively with water and ethyl acetate to give the object compound (421 mg). The filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (754 mg). The yield of the obtained object compound was 1.17 g in total. 
     MS (ESI+, m/e) 559 (M+1) 
     Reference Example 538 
     (1S,2S)-2-(4-{[(2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine 
     
       
         
         
             
             
         
       
     
     Ethyl 1-{(1S,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (400 mg) was dissolved in methanol-water (2:1, 6 ml), lithium hydroxide monohydrate (63 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (8 ml), (3R)-1,3-dibenzylpiperazine (320 mg), WSC.HCl (383 mg) and HOBt (613 g) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give tert-butyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (550 mg) as an amorphous solid. 539 mg therefrom was dissolved in dichloromethane (2 ml), TFA (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. The liberated oil was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (450 mg) as an amorphous solid. 
     MS (ESI+, m/e) 534 (M+1) 
     Reference Example 539 
     Ethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (424 mg) was dissolved in ethanol-water (2:1, 6 ml), lithium hydroxide monohydrate (69 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (5 ml), (3R)-1-benzyl-3-(3,5-difluorobenzyl)piperazine (333 mg), WSC.HCl (422 mg) and HOBt (674 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (530 mg) as an amorphous solid. 
     MS (ESI+, m/e) 642 (M+1) 
     Reference Example 540 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxo-1-oxa-3-azaspiro[4.5]deca-6-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-(2-{[(ethoxycarbonyl)amino]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (300 mg) was dissolved in ethanol-water (2:1, 6 ml), lithium hydroxide monohydrate (45 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (8 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (240 mg), WSC.HCl (277 mg) and HOBt (442 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (300 mg) as an amorphous solid. 
     MS (ESI+, m/e) 600 (M+1) 
     Reference Example 541 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (540 mg) was dissolved in ethanol-water (2:1, 9 ml), lithium hydroxide monohydrate (88 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was concentrated again, and the residue was vacuum-dried. This was suspended in DMF (10 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (464 mg), WSC.HCl (537 mg) and HOBt (858 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (385 mg) as an amorphous solid. 
     MS (ESI+, m/e) 616 (M+1) 
     Reference Example 542 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-(chloromethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(3R,4S)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (1.31 g) was dissolved in methanol-THF (1:4, 25 ml), lithium hydroxide monohydrate (505 mg) and water (10 ml) were added, and the mixture was stirred at 50° C. for 15 hr. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was suspended in DMF (10 ml), tert-butyl 3-benzylpiperazine-1-carboxylate (817 mg), WSC.HCl (1.13 g) and HOBt (1.36 g) were added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (914 mg) as an amorphous solid. 
     MS (ESI+, m/e) 593 (M+1) 
     Reference Example 543 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (500 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (264 mg) as an amorphous solid. 
     MS (ESI+, m/e) 545 (M+1) 
     In the same manner as in Reference Example 543, the following compound (Reference Example 544) was obtained. 
     Reference Example 544 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 545 (M+1) 
     Reference Example 545 
     tert-Butyl (3R)-4-({1-[(1S,2S)-2-(acetyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (272 mg) was dissolved in THF (10 ml), acetic acid (20 μl), WSC.HCl (144 mg) and DMAP (6 mg) were added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (268 mg) as an amorphous solid. 
     MS (ESI+, m/e) 587 (M+1) 
     Reference Example 546 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(4-nitrobenzoyl)oxy]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (250 mg) and 4-nitrobenzoic acid were dissolved in THF (20 ml), DTBAD (424 mg) and PS-triphenylphosphine resin (manufactured by Argonaut Technologies, 2.15 mmol/g, 856 mg) were added, and the mixture was stirred at room temperature for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (207 mg) as an amorphous solid. 
     MS (ESI+, m/e) 694 (M+1) 
     Reference Example 547 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(4-nitrobenzoyl)oxy]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (205 mg) was dissolved in methanol-THF (1:1, 10 ml), 8N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (117 mg) as an amorphous solid. 
     MS (ESI+, m/e) 545 (M+1) 
     Reference Example 548 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(3-methoxypropoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (163 mg) was dissolved in THF (2 ml), sodium hydride (60% in oil, 60 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. After stirring, 1-bromo-3-methoxypropane (115 mg) was added thereto. The reaction mixture was heated under reflux for 15 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (66 mg) as an amorphous solid. 
     MS (ESI+, m/e) 617 (M+1) 
     In the same manner as in Reference Example 548, the following compounds (Reference Examples 549-552) were obtained. 
     Reference Example 549 
     tert-Butyl (3R)-4-({1-[(1S,2S)-2-(allyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 585 (M+1) 
     Reference Example 550 
     tert-Butyl (3R)-3-benzyl-4-({5-phenyl-1-[(1S,2S)-2-propoxycyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 587 (M+1) 
     Reference Example 551 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(2-methoxyethoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 603 (M+1) 
     Reference Example 552 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(4-methoxybutoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 631 (M+1) 
     Reference Example 553 
     tert-Butyl (3R)-4-[(1-{(1S,2S)-2-[3-(acetylamino)propoxy]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (191 mg) was dissolved in DMF (2 ml), sodium hydride (60% in oil, 70 mg) was added, and the mixture was stirred at room temperature for 30 min. After stirring, 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (245 mg) was added thereto. The mixture was stirred at 80° C. for 15 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[(1S,2S)-2-(3-aminopropoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (160 mg) as an amorphous solid. This was mixed with triethylamine (40 mg) and dichloromethane (2 ml), and the mixture was ice-cooled. Acetyl chloride (25 mg) was added thereto, and the mixture was stirred at 0° C. for 30 min. After stirring, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (120 mg) as an amorphous solid. 
     MS (ESI+, m/e) 644 (M+1) 
     Reference Example 554 
     tert-Butyl (3R)-3-benzyl-4-[(1-{cis-2-[(4-nitrobenzoyl)oxy]cycloheptyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycycloheptyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (280 mg), 4-nitrobenzoic acid (335 mg), PS-triphenylphosphine resin (manufactured by Argonaut Technologies, 1.99 mmol/g) (930 mg), DTBAD (460 mg) and THF (20 ml) was stirred at room temperature for 3 days, and the insoluble material was filtered off. The filtrate was diluted with ethyl acetate, and washed successively with 0.5N aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure to give the object compound (224 mg). 
     MS (ESI+, m/e) 708 (M+1) 
     Reference Example 555 
     tert-Butyl (3R)-3-benzyl-4-({1-[cis-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3R)-3-benzyl-4-[(1-{cis-2-[(4-nitrobenzoyl)oxy]cycloheptyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (220 mg), 1N aqueous sodium hydroxide solution (1.5 ml) and ethanol (6 ml) was stirred at room temperature for 13 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (171 mg). 
     MS (ESI+, m/e) 559 (M+1) 
     Reference Example 556 
     tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-(3-methoxypropoxy)cycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (105 mg), sodium hydride (60% in oil, 15 mg) and THF (5 ml) was stirred at room temperature for 1 hr, and ice-cooled. To the reaction mixture was added 1-bromo-3-methoxypropane (45 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hr, and then at 65° C. for 12 hr. The mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure to give the object compound (40 mg). 
     MS (ESI+, m/e) 631 (M+1) 
     In the same manner as in Reference Example 556, the following compound (Reference Example 557) was obtained. 
     Reference Example 557 
     tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-(2-methoxyethoxy)cycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 617 (M+1) 
     Reference Example 558 
     tert-Butyl (3R)-3-benzyl-4-{[1-((1S,2S)-2-{[(ethylamino)carbonyl]oxy}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (163 mg) and DMAP (220 mg) were dissolved in THF (5 ml), and the solution was ice-cooled. 4-Nitrophenyl chloroformate (182 mg) was added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added ethylamine (1M THF solution, 2 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (190 mg) as an amorphous solid. 
     MS (ESI+, m/e) 616 (M+1) 
     In the same manner as in Reference Example 558, the following compounds (Reference Examples 559-560) were obtained. 
     Reference Example 559 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-({[(ethyl)(methyl)amino]carbonyl}oxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 630 (M+1) 
     Reference Example 560 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2S)-2-[({(methyl)[2-(methylsulfonyl)ethyl]amino}carbonyl)oxy]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 708 (M+1) 
     Reference Example 561 
     tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-({[(2-furylmethyl)amino]carbonyl}oxy)cycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (137 mg), 4-nitrophenyl chloroformate (75 mg), DMAP (100 mg) and THF (3 ml) was stirred at room temperature for 1 hr, and furfurylamine (110 mg) was added thereto. The reaction mixture was further stirred at room temperature for 3 days, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (2:3-1:0) was concentrated under reduced pressure to give the object compound (115 mg). 
     MS (ESI+, m/e) 682 (M+1) 
     Reference Example 562 
     tert-Butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-4-({1-[(1S,2R)-2-azidocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (2.5 g) was dissolved in methanol (25 ml), 10% palladium-carbon (50% containing water, 800 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (2.26 g) as an amorphous solid. 
     MS (ESI+, m/e) 544 (M+1) 
     Reference Example 563 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(cyclopropylmethyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (217 mg) and cyclopropanecarbaldehyde (28 mg) were dissolved in dichloroethane (2 ml), and acetic acid (24 mg) and sodium triacetoxyborohydride (110 mg) were added. The mixture was stirred at room temperature for 5 hr, and neutralized with 6% aqueous sodium bicarbonate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (150 mg) as an amorphous solid. 
     MS (ESI+, m/e) 598 (M+1) 
     In the same manner as in Reference Example 563, the following compound (Reference Example 564) was obtained. 
     Reference Example 564 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[bis(cyclopropylmethyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 652 (M+1) 
     Reference Example 565 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(cyclopropylcarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (217 mg) and triethylamine (60 mg) were dissolved in dichloromethane (3 ml), the solution was ice-cooled, and cyclopropanecarbonyl chloride (52 mg) was added. The mixture was stirred at 0° C. for 30 min, and neutralized with 6% aqueous sodium bicarbonate (2 ml). The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (203 mg) as an amorphous solid. 
     MS (ESI+, m/e) 612 (M+1) 
     In the same manner as in Reference Example 565, the following compounds (Reference Examples 566-567) were obtained. 
     Reference Example 566 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(cyclopropylsulfonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 648 (M+1) 
     Reference Example 567 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-(butyrylamino)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 614 (M+1) 
     Reference Example 568 
     tert-Butyl (3R)-3-benzyl-4-{[1-((1S,2R)-2-{[(ethylamino)carbonyl]amino}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     To a solution of tert-butyl (3R)-4-({1-[(1S,2R)-2-aminocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (217 mg) in dichloromethane (3 ml) were added ethyl isocyanate (36 mg) and triethylamine (1 drop) at room temperature. The mixture was stirred at room temperature for 2 hr, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (175 mg) as an amorphous solid. 
     MS (ESI+, m/e) 615 (M+1) 
     Reference Example 569 
     Methyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-2-(4-{[(2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (160 mg) and triethylamine (36 mg) were dissolved in dichloromethane (2 ml), and the solution was ice-cooled. Methyl chloroformate (28 mg) was added thereto, and the mixture was stirred at 0° C. for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (100 mg) as an amorphous solid. 
     MS (ESI+, m/e) 592 (M+1) 
     Reference Example 570 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-2-(4-{[(2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (300 mg) and triethylamine (85 mg) were dissolved in dichloromethane (5 ml), and the solution was ice-cooled. Ethyl chloroformate (73 mg) was added thereto, and the mixture was stirred at 0° C. for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (260 mg) as an amorphous solid. 
     MS (ESI+, m/e) 606 (M+1) 
     In the same manner as in Reference Example 570, the following compounds (Reference Examples 571-574) were obtained. 
     Reference Example 571 
     Isopropyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 620 (M+1) 
     Reference Example 572 
     Isobutyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 634 (M+1) 
     Reference Example 573 
     2-Methoxyethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 636 (M+1) 
     Reference Example 574 
     2-Chloroethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 641 (M+1) 
     Reference Example 575 
     3-[(1S,2S)-2-(4-{[(2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]-1,3-oxazolidin-2-one 
     
       
         
         
             
             
         
       
     
     2-Chloroethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (192 mg) was dissolved in THF (3 ml), sodium hydride (60% in oil, 14 mg) was added thereto, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (120 mg) as an amorphous solid. 
     MS (ESI+, m/e) 604 (M+1) 
     Reference Example 576 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2S)-2-[(ethoxycarbonyl)(methyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (185 mg) was dissolved in DMF (2 ml), sodium hydride (60% in oil, 24 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. After stirring, methyl iodide (85 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (145 mg) as an amorphous solid. 
     MS (ESI+, m/e) 630 (M+1) 
     In the same manner as in Reference Example 576, the following compound (Reference Example 577) was obtained. 
     Reference Example 577 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2S)-2-[(ethoxycarbonyl)(3-methoxypropyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 688 (M+1) 
     Reference Example 578 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-oxocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (4.2 g) was dissolved in dichloromethane (60 ml). A solution of Dess-Martin reagent (3.9 g) in dichloromethane (60 ml) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF. 10% Aqueous sodium thiosulfate solution was added thereto, and the mixture was stirred at room temperature for 30 min. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration to give the object compound (2.35 g). The second crystals (1.37 g) of the object compound were obtained from the mother liquor. The yield of the obtained object compound was 3.72 g in total. 
     MS (ESI+, m/e) 543 (M+1) 
     In the same manner as in Reference Example 578, the following compounds (Reference Examples 579-580) were obtained. 
     Reference Example 579 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R)-2-oxocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 543 (M+1) 
     Reference Example 580 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 543 (M+1) 
     Reference Example 581 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-butyl-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (150 mg) was dissolved in THF (5 ml), and the solution was cooled to −78° C. n-Butylmagnesium chloride (2M THF solution, 560 μl) was added thereto, and the mixture was stirred at −78° C. for 1.5 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (36 mg) as an amorphous solid. 
     MS (ESI+, m/e) 601 (M+1) 
     Reference Example 582 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-methylcyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (163 mg) was dissolved in THF (2 ml), and the solution was ice-cooled. Methylmagnesium bromide (3M diethyl ether solution, 300 μl) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (110 mg) as an amorphous solid. 
     MS (ESI+, m/e) 559 (M+1) 
     Reference Example 583 
     tert-Butyl (3R)-3-benzyl-4-({1-[2-hydroxy-2-(trifluoromethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (150 mg) and trimethyl(trifluoromethyl)silane (79 mg) were dissolved in THF (2 ml), TBAF (several mg) was added, and the mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give the object compound (38 mg) as an amorphous solid. 
     MS (ESI+, m/e) 613 (M+1) 
     Reference Example 584 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-oxocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (150 mg) was dissolved in THF (5 ml), bromo(2-ethoxy-2-oxoethyl)zinc (0.5M THF solution, 4 ml) was added thereto at room temperature, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (140 mg) as an amorphous solid. 
     MS (ESI+, m/e) 631 (M+1) 
     Reference Example 585 
     [(2S)-2-(4-{[(2R)-2-Benzyl-4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]acetic acid 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (300 mg) was dissolved in ethanol (2 ml), and 1N aqueous sodium hydroxide solution (4 ml) was added. The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residual aqueous solution was washed with ethyl acetate, and neutralized with 10% aqueous citric acid solution. This was extracted with ethyl acetate, the extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (280 mg). 
     MS (ESI+, m/e) 603 (M+1) 
     Reference Example 586 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S)-2-hydroxy-2-[2-(methylamino)-2-oxoethyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of [(2S)-2-(4-{[(2R)-2-benzyl-4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]acetic acid (100 mg), methylamine (2M THF solution, 91 μl), WSC.HCl (41 mg) and HOBt (30 mg) in DMF (2 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (70 mg) as an amorphous solid. 
     MS (ESI+, m/e) 616 (M+1) 
     In the same manner as in Reference Example 586, the following compounds (Reference Examples 587-588) were obtained. 
     Reference Example 587 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S)-2-[2-(dimethylamino)-2-oxoethyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 630 (M+1) 
     Reference Example 588 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-{2-[(2-furylmethyl)amino]-2-oxoethyl}-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 682 (M+1) 
     Reference Example 589 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium borohydride (862 mg) was suspended in ethanol (9 ml), and the suspension was ice-cooled. Calcium chloride (1.23 g) was added over 10 min, and the mixture was stirred at 0° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (900 mg) in THF (9 ml) was added thereto over 20 min, and the mixture was stirred at 0° C. for 2 hr, and then at room temperature for 2 hr. Water (20 ml) was slowly added. This was extracted with ethyl acetate, the extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (830 mg) as an amorphous solid. 
     MS (ESI+, m/e) 589 (M+1) 
     Reference Example 590 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-oxoethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (530 mg) was dissolved in dichloromethane (7 ml). A solution of Dess-Martin reagent (460 mg) in dichloromethane (5 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform (30 ml), 10% aqueous sodium thiosulfate solution was added, and the mixture was stirred for 30 min. The organic layer was separated, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (517 mg). 
     MS (ESI+, m/e) 586 (M+1) 
     Reference Example 591 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S)-2-[2-(benzylamino)ethyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-oxoethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (300 mg) was dissolved in DMF-dichloromethane (1:2, 3 ml), benzylamine (134 μl) and acetic acid (2 drops) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (163 mg) was added thereto, and the mixture was further stirred at room temperature for 12 hr. To the reaction mixture was added ethyl acetate (3 ml) over 15 min, and the mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (9:1) was concentrated under reduced pressure to give the object compound (85 mg) as an amorphous solid. 
     MS (ESI+, m/e) 678 (M+1) 
     Reference Example 592 
     tert-Butyl (3R)-4-({1-[(1S)-2-(2-aminoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S)-2-[2-(benzylamino)ethyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (100 mg) was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (25 mg) as an amorphous solid. 
     MS (ESI+, m/e) 588 (M+1) 
     Reference Example 593 
     tert-Butyl (3R)-4-({1-[(1S)-2-(2-acetamidoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-4-({1-[(1S)-2-(2-aminoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (150 mg) and triethylamine (13 mg) were dissolved in dichloromethane (3.5 ml), acetyl chloride (8 mg) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give the object compound (41 mg) as an amorphous solid. 
     MS (ESI+, m/e) 630 (M+1) 
     Reference Example 594 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-methoxy-2-(2-methoxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (100 mg), silver oxide (44 mg), methyl iodide (0.150 ml) and dichloromethane (2 ml) was heated under reflux for 12 hr. The reaction mixture was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (60 mg) as an amorphous solid. 
     MS (ESI+, m/e) 617 (M+1) 
     Reference Example 595 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-methoxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-hydroxy-2-(2-hydroxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (110 mg) was dissolved in DMF (2 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 18 mg) was added thereto, and the mixture was stirred at 0° C. for 30 min. Methyl iodide (14 μl) was added thereto, and the mixture was further stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (70 mg) as an amorphous solid. 
     MS (ESI+, m/e) 603 (M+1) 
     Reference Example 596 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2E)-2-(2-ethoxy-2-oxoethylidene)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-oxocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (500 mg) and ethyl (diethoxyphosphoryl)acetate (227 mg) were dissolved in THF (5 ml), and the solution was ice-cooled. Sodium hydride (60% in oil) (55 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (440 mg) as an amorphous solid. 
     MS (ESI+, m/e) 613 (M+1) 
     Reference Example 597 
     (2E)-[(2S)-2-(4-{[(2R)-2-Benzyl-4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexylidene]acetic acid 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2E)-2-(2-ethoxy-2-oxoethylidene)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (230 mg) was dissolved in ethanol (2 ml), 2N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature for 1 hr, and neutralized with 10% aqueous citric acid solution. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate-THF. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (220 mg). 
     MS (ESI+, m/e) 585 (M+1) 
     Reference Example 598 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2E)-2-[2-oxo-2-(propylamino)ethylidene]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of (2E)-[(2S)-2-(4-{[(2R)-2-benzyl-4-(tert-butoxycarbonyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexylidene]acetic acid (120 mg), propylamine (25 μl), WSC.HCl (59 mg) and HOBt (38 mg) in DMF (2 ml) was stirred at room temperature for 12 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (180 mg) as an oil. 
     MS (ESI+, m/e) 626 (M+1) 
     Reference Example 599 
     tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Trimethylsulfoxonium iodide (106 mg) was dissolved in DMSO (5 ml), sodium hydride (60% in oil, 19 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(2-oxocyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (400 mg) in DMSO (10 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (221 mg) as an amorphous solid. 
     MS (ESI+, m/e) 557 (M+1) 
     Reference Example 600 
     tert-Butyl (3R)-3-benzyl-4-({1-[2-hydroxy-2-(propoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil) (60 mg) was suspended in DMF (3 ml), 1-propanol (135 μl) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (167 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (160 mg) as an amorphous solid. 
     MS (ESI+, m/e) 617 (M+1) 
     In the same manner as in Reference Example 600, the following compounds (Reference Examples 601-619) shown in Table 8-1-Table 8-3 were obtained. 
     
       
         
           
               
             
               
                 TABLE 8-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 601 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(2-methoxyethoxy)methyl] cyclohexyl}-5-phenyl-1H-imidazol-4- yl)carbonyl]piperazine-1-carboxylate 
                 633 
               
               
                   
               
               
                 602 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(3-methoxypropoxy)methyl] cyclohexyl}-5-phenyl-1H-imidazol-4- yl)carbonyl]piperazine-1-carboxylate 
                 647 
               
               
                   
               
               
                 603 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(2,2- difluoroethoxy)methyl]-2-hydroxy- cyclohexyl}-5-phenyl-1H-imidazol-4- yl)carbonyl]piperazine-1-carboxylate 
                 639 
               
               
                   
               
               
                 604 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(2,2,2-trifluoroethoxy) methyl]cyclohexyl}-5-phenyl-1H- imidazol-4-yl)carbonyl]piperazine- 1-carboxylate 
                 657 
               
               
                   
               
               
                 605 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- [(cyclopropylmethoxylmethyl]-2- hydroxycyclohexyl}-5-phenyl-1H- imidazol-4-yl)carbonyl] piperazine-1-carboxylate 
                 629 
               
               
                   
               
               
                 606 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- [(cyclobutyloxy)methyl]-2- hydroxycyclohexyl-5-phenyl-1H- imidazol-4-yl)carbonyl] piperazine-1-carboxylate 
                 629 
               
               
                   
               
               
                 607 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-{[1-(2- hydroxy-2-{[2-(2-oxopyrrolidin-1- yl)ethoxy]methyl}cyclohexyl)-5- phenyl-1H-imidazol-4-yl]carbonyl} piperazine-1-carboxylate 
                 686 
               
               
                   
               
               
                 608 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-{[1-(2- hydroxy-2-{[2-(2-oxo-1,3-oxazolidin-3- yl)ethoxy]methyl}cyclohexyl)-5-phenyl- 1H-imidazol-4-yl]carbonyl}piperazine- 1-carboxylate 
                 688 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 609 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(3-hydroxy-3-methylbutoxy) methyl]cyclohexyl}-5-phenyl-1H-imidazol-4- yl)carbonyl]piperazine-1-carboxylate 
                 661 
               
               
                   
               
               
                 610 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-({1-[2- hydroxy-2-(isopropoxymethyl)cyclohexyl]- 5-phenyl-1H-imidazol-4-yl }carbonyl) piperazine-1-carboxylate 
                 617 
               
               
                   
               
               
                 611 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(tetrahydro-2H-pyran-4-yloxy) methyl]cyclohexyl}-5-phenyl-1H-imidazol- 4-yl)carbonyl]piperazine-1-carboxylate 
                 659 
               
               
                   
               
               
                 612 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(1,3-thiazol-2-ylmethoxy)methyl] cyclohexyl}-5-phenyl-1H-imidazol-4-yl) carbonyl]piperazine-1-carboxylate 
                 672 
               
               
                   
               
               
                 613 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-{[1-(2-hydroxy- 2-{[(1-methyl-1H-imidazol-2-yl)methoxy] methyl}cyclohexyl)-5-phenyl-1H-imidazol- 4-yl]carbonyl}piperazine-1-carboxylate 
                 669 
               
               
                   
               
               
                 614 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-{[1-(2- hydroxy-2-{[2-(methylthio)ethoxy]methyl} cyclohexyl)-5-phenyl-1H-imidazol-4-yl] carbonyl}piperazine-1-carboxylate 
                 649 
               
               
                   
               
               
                 615 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-{[1-(2- hydroxy-2-{[3-(methylthio)propoxy]methyl} cyclohexyl)-5-phenyl-1H-imidazol-4-yl] carbonyl}piperazine-1-carboxylate 
                 663 
               
               
                   
               
               
                 616 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(tetrahydro-2H-thiopyran-4-yloxy) methyl]cyclohexyl}-5-phenyl-1H-imidazol-4- yl)carbonyl]piperazine-1-carboxylate 
                 675 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. 
                   
                   
                   
               
               
                 Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 617 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4- [(1-{2-hydroxy-2-[(tetra- hydro-2H-thiopyran-4-yl- methoxy)methyl]cyclohexyl}- 5-phenyl-1H-imidazol-4-yl) carbonyl]piperazine-1- carboxylate 
                 689 
               
               
                   
               
               
                 618 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4- [(1-{2-hydroxy-2-[(tetra- hydro-2H-pyran-4-ylmethoxy) methyl]cyclohexyl}-5-phenyl- 1H-imidazol-4-yl)carbonyl] piperazine-1-carboxylate 
                 673 
               
               
                   
               
               
                 619 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 tert-Butyl (3R)-3-benzyl-4- ({1-[2-hydroxy-2-(phenoxy- methyl)cyclohexyl]-5-phenyl- 1H-imidazol-4-yl}carbonyl) piperazine-1-carboxylate 
                 651 
               
               
                   
               
            
           
         
       
     
     Reference Example 620 
     tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylamino)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (240 mg) and ethylamine (2M THF solution, 650 μl) were dissolved in acetonitrile (3 ml), lithium perchlorate (92 mg) was added, and the mixture was reacted at 100° C. for 5 min using microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (220 mg) as an amorphous solid. 
     MS (ESI+, m/e) 602 (M+1) 
     In the same manner as in Reference Example 620, the following compounds (Reference Examples 621-622) were obtained. 
     Reference Example 621 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-{[(ethyl)(methyl)amino]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 616 (M+1) 
     Reference Example 622 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-{[(2-furylmethyl)amino]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 654 (M+1) 
     Reference Example 623 
     tert-Butyl (3R)-4-{[1-(2-{[(acetyl)(ethyl)amino]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylamino)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (120 mg) was dissolved in pyridine (2 ml), and the solution was ice-cooled. Acetic anhydride (19 μl) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (105 mg) as an amorphous solid. 
     MS (ESI+, m/e) 644 (M+1) 
     Reference Example 624 
     tert-Butyl (3R)-3-benzyl-4-{([1-(2-ethyl-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Copper iodide (160 mg) was suspended in THF (5 ml), and the suspension was ice-cooled. Methylmagnesium bromide (1M THF solution, 1.6 ml) was added, and the mixture was stirred at 0° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (111 mg) in THF (5 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (73 mg) as an amorphous solid. 
     MS (ESI+, m/e) 573 (M+1) 
     In the same manner as in Reference Example 624, the following compound (Reference Example 625) was obtained. 
     Reference Example 625 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-propylcyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 587 (M+1) 
     Reference Example 626 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate and tert-butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Copper iodide (144 mg) was suspended in THF (5 ml), and the suspension was ice-cooled. Cyclopropylmagnesium bromide (0.5M THF solution, 2.9 ml) was added, and the mixture was stirred at 0° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (200 mg) in THF (5 ml) was added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (4:1) were concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (49 mg) as an amorphous solid, and tert-butyl (3R)-3-benzyl-4-({1-[(1S,2S)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (214 mg) as an amorphous solid. 
     MS (ESI+, m/e) 599 (M+1) 
     MS (ESI+, m/e) 599 (M+1) 
     In the same manner as in Reference Example 626, the following compound (Reference Example 627) was obtained. 
     Reference Example 627 
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2S)-2-butyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate and tert-butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-butyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 601 (M+1) 
     MS (ESI+, m/e) 601 (M+1) 
     Reference Example 628 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-{[2-(methylsulfonyl)ethoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil) (100 mg) was suspended in DMF (3 ml), 2-(methylthio)ethanol (280 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (280 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-{[2-(methylthio)ethoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (270 mg) as an amorphous solid. 145 mg therefrom was dissolved in dichloromethane (3 ml), and the solution was ice-cooled. mCPBA (119 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (119 mg) as an amorphous solid. 
     MS (ESI+, m/e) 681 (M+1) 
     In the same manner as in Reference Example 628, the following compounds (Reference Examples 629-631) were obtained. 
     Reference Example 629 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-{[3-(methylsulfonyl)propoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 695 (M+1) 
     Reference Example 630 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 707 (M+1) 
     Reference Example 631 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 721 (M+1) 
     Reference Example 632 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-hydroxy-2-[(1,3-thiazol-2-ylmethoxy)methyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil) (24 mg) was suspended in DMF (3 ml), 1,3-thiazol-2-ylmethanol (81 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-(chloromethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (119 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (96 mg) as an amorphous solid. 
     MS (ESI+, m/e) 672 (M+1) 
     In the same manner as in Reference Example 632, the following compounds (Reference Examples 633-637) were obtained. 
     Reference Example 633 
     tert-Butyl (3R)-3-benzyl-4-{[1-((1S,2R)-2-hydroxy-2-{[2-(2-hydroxyethoxy)ethoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 663 (M+1) 
     Reference Example 634 
     tert-Butyl (3R)-3-benzyl-4-{[1-((1S,2R)-2-{[3-(dimethylamino)propoxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 660 (M+1) 
     Reference Example 635 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-hydroxy-2-[(pyridin-2-ylmethoxy)methyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 666 (M+1) 
     Reference Example 636 
     tert-Butyl (3R)-4-[(1-{(1S,2R)-2-[(1H-benzimidazol-2-ylmethoxy)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]-3-benzylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 705 (M+1) 
     Reference Example 637 
     tert-Butyl (3R)-3-benzyl-4-[(1-{(1S,2R)-2-[(2,3-dihydro-1H-inden-2-yloxy)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 691 (M+1) 
     Reference Example 638 
     tert-Butyl (3R)-3-benzyl-4-({1-[2-(2-cyanoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Lithium bis(trimethylsilyl)amide (1.1M THF solution, 3.6 ml) was dissolved in THF (5 ml), and the solution was cooled to −10° C. A solution of acetonitrile (221 μl) in THF (3 ml) was added over 3 min, and the mixture was stirred at −10° C. for 30 min. A solution of tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (557 mg) in THF (5 ml) was added thereto, and the mixture was stirred at −10° C. for 1 hr, and then at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (370 mg) as an oil. 
     MS (ESI+, m/e) 598 (M+1) 
     Reference Example 639 
     tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylthio)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (334 mg) was dissolved in DMF (5 ml), sodium ethanethiolate (80%) (315 mg) was added, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (324 mg) as an amorphous solid. 
     MS (ESI+, m/e) 619 (M+1) 
     Reference Example 640 
     tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylsulfonyl)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-[(1-{2-[(ethylthio)methyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (105 mg) was dissolved in dichloromethane (5 ml), and the solution was ice-cooled, m-chloroperbenzoic acid (95 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (52 mg) as an amorphous solid. 
     MS (ESI+, m/e) 651 (M+1) 
     Reference Example 641 
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-hydroxy-2-{[(3-methyloxetan-3-yl)methoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil) (40 mg) was suspended in DMF (3 ml), (3-methyloxetan-3-yl)methanol (120 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (110 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (100 mg) as an amorphous solid. 
     MS (ESI+, m/e) 659 (M+1) 
     Reference Example 642 
     tert-Butyl (3R)-3-benzyl-4-{[5-(3-fluorophenyl)-1-(cis-1-oxaspiro[2.5]oct-4-yl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({5-(3-fluorophenyl)-1-[(1S,2S)-2-hydroxycyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (825 mg) was dissolved in 1,2-dichloroethane (30 ml), Dess-Martin reagent (929 mg) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF. 10% Aqueous sodium thiosulfate solution was added thereto, and the mixture was stirred for 30 min. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration to give tert-butyl (3R)-3-benzyl-4-{[5-(3-fluorophenyl)-1-(2-oxocyclohexyl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (650 mg). 
     Trimethylsulfoxonium iodide (376 mg) was dissolved in DMSO (10 ml), sodium hydride (60% in oil, 55 mg) was added thereto, and the mixture was stirred at room temperature for 30 min. A solution of the oxo form obtained in the above in DMSO (20 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (401 mg) as an amorphous solid. 
     MS (ESI+, m/e) 575 (M+1) 
     Reference Example 643 
     tert-Butyl (3R)-3-benzyl-4-({5-(3-fluorophenyl)-1-[cis-2-hydroxy-2-(methoxymethyl)cyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[5-(3-fluorophenyl)-1-(cis-1-oxaspiro[2.5]oct-4-yl)-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (390 mg) was dissolved in methanol (5 ml), sodium methoxide (28% methanol solution, 650 μl) was added, and the mixture was stirred at 50° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (337 mg) as an amorphous solid. 
     MS (ESI+, m/e) 607 (M+1) 
     Reference Example 644 
     tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (3.39 g) was dissolved in methanol (200 ml), 20% palladium hydroxide-carbon (50% containing water, 500 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (50 ml), and the solution was ice-cooled. Di-tert-butyl bicarbonate (1.66 g) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (3.52 g) as an amorphous solid. 
     MS (ESI+, m/e) 543 (M+1) 
     Reference Example 645 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(pyrrolidin-1-ylcarbonyl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (108 mg) and DMAP (73 mg) were dissolved in THF (5 ml), 4-nitrophenyl chloroformate (60 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added pyrrolidine (142 mg), and the mixture was further stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (90 mg) as an amorphous solid. 
     MS (ESI+, m/e) 640 (M+1) 
     Reference Example 646 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (560 mg) was dissolved in 1,2-dichloroethane (10 ml), Dess-Martin reagent (657 mg) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate-THF. 10% Aqueous sodium thiosulfate solution was added thereto, and the mixture was stirred at room temperature for 30 min. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (17:3) was concentrated under reduced pressure to give the object compound (411 mg) as an amorphous solid. 
     MS (ESI+, m/e) 541 (M+1-“Boc”). 
     Reference Example 647 
     tert-Butyl (3R)-4-({1-[((1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{(2R)-2-hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazine-1-carboxylate and tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{(2S)-2-hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     2-Bromo-6-(trifluoromethyl)pyridine (375 mg) was dissolved in diethyl ether (10 ml), and the solution was cooled to −78° C. Butyllithium (1.6M hexane solution, 0.95 ml) was added, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added a solution of tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate (250 mg) in diethyl ether (10 ml) at −78° C., and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (19:1) were concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{(2R)-2-hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazine-1-carboxylate (65 mg) as an amorphous solid, and tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{(2S)-2-hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazine-1-carboxylate (73 mg) as an amorphous solid. 
     MS (ESI+, m/e) 688 (M+1) 
     MS (ESI+, m/e) 688 (M+1) 
     Reference Example 648 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(2R)-2-hydroxy-2-phenylethyl]piperazine-1-carboxylate and tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(2S)-2-hydroxy-2-phenylethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate (150 mg) was dissolved in THF (10 ml), and the solution was ice-cooled. Phenylmagnesium bromide (1.08M THF solution, 0.85 ml) was added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (19:1) were concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(2R)-2-hydroxy-2-phenylethyl]piperazine-1-carboxylate (45 mg) as an amorphous solid, and tert-butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(2S)-2-hydroxy-2-phenylethyl]piperazine-1-carboxylate (73 mg) as an amorphous solid. 
     MS (ESI+, m/e) 619 (M+1) 
     MS (ESI+, m/e) 619 (M+1) 
     Reference Example 649 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-hydroxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (242 mg), phenol (64 mg) and triphenylphosphine (239 mg) were dissolved in THF (15 ml), DEAD (40% toluene solution, 396 μl) was added, and the mixture was stirred at room temperature for 5 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give the object compound (32 mg) as an amorphous solid. 
     MS (ESI+, m/e) 609 (M+1) 
     Reference Example 650 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(pyridin-2-yloxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-(2-hydroxyethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (109 mg) was dissolved in DMF (3 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 18 mg) was added thereto, and the mixture was stirred at 0° C. for 10 min. After stirring, 2-bromopyridine (29 μl) was added thereto at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (19:1) was concentrated under reduced pressure to give the object compound (16 mg) as an oil. 
     MS (ESI+, m/e) 620 (M+1) 
     In the same manner as in Reference Example 650, the following compounds (Reference Examples 651-656) were obtained. 
     Reference Example 651 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{[6-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 688 (M+1) 
     Reference Example 652 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(pyrimidin-2-yloxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 621 (M+1) 
     Reference Example 653 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{[4-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 688 (M+1) 
     Reference Example 654 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{[3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 688 (M+1) 
     Reference Example 655 
     tert-Butyl (3R)-3-{2-[(5-cyanopyridin-2-yl)oxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 645 (M+1) 
     Reference Example 656 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 688 (M+1) 
     Reference Example 657 
     4-{2-[(2R)-4-[(Benzyloxy)carbonyl]-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate (940 mg) was dissolved in methanol (50 ml), 1N aqueous sodium hydroxide solution (26.4 ml) was added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the solvent was concentrated under reduced pressure. The residue was diluted with ethyl acetate-THF (3:1), and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (896 mg). 
     MS (ESI+, m/e) 697 (M+1) 
     Reference Example 658 
     Benzyl (3R)-3-(2-{4-[(cyclopropylamino)carbonyl]phenoxy}ethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     4-{2-[(2R)-4-[(Benzyloxy)carbonyl]-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid (139 mg) was suspended in DMF (3 ml), cyclopropylamine (23 mg), WSC.HCl (58 mg) and HOBt (37 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (98 mg) as an amorphous solid. 
     MS (ESI+, m/e) 736 (M+1) 
     In the same manner as in Reference Example 658, the following compounds (Reference Examples 659-661) were obtained. 
     Reference Example 659 
     Benzyl (3R)-3-(2-{4-[(dimethylamino)carbonyl]phenoxy}ethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 724 (M+1) 
     Reference Example 660 
     Benzyl (3R)-3-{2-[4-(azetidin-1-ylcarbonyl)phenoxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 736 (M+1) 
     Reference Example 661 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 778 (M+1) 
     Reference Example 662 
     1-tert-Butyl 4-benzyl (2R)-2-(2-oxoethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (2.0 g) and triethylamine (2.3 ml) were dissolved in DMSO (20 ml), a solution of pyridine-sulfur trioxide complex (2.6 g) in DMSO (10 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object compound (1.9 g) as an oil. 
       1 H-NMR (CDCl 3 ) δ 1.45 (9H, s), 2.48-2.74 (2H, m), 2.82-3.18 (3H, m), 3.77-4.20 (3H, m), 4.54-4.84 (1H, m), 5.02-5.25 (2H, m), 7.21-7.51 (5H, m), 9.53-9.84 (1H, m) 
     Reference Example 663 
     1-tert-Butyl 4-benzyl (2R)-2-(2-anilinoethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-oxoethyl)piperazine-1,4-dicarboxylate (1.5 g) and aniline (1.1 g) were dissolved in dichloromethane-DMF (2:1, 30 ml), acetic acid (0.5 ml) was added, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (2.6 g) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (1.8 g) as an oil. 
     MS (ESI+, m/e) 440 (M+1) 
     Reference Example 664 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[methyl(phenyl)amino]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-oxoethyl)piperazine-1,4-dicarboxylate (400 mg) and N-methylaniline (237 mg) were dissolved in dichloromethane-DMF (2:1, 8 ml), acetic acid (0.29 ml) was added, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (466 mg) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give the object compound (370 mg) as an oil. 
     MS (ESI+, m/e) 454 (M+1) 
     Reference Example 665 
     Benzyl (3R)-3-(2-anilinoethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-anilinoethyl)piperazine-1,4-dicarboxylate (380 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (670 mg) as an oil. 
     MS (ESI+, m/e) 340 (M+1) 
     Reference Example 666 
     Benzyl (3R)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-{2-[methyl(phenyl)amino]ethyl}piperazine-1,4-dicarboxylate (380 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (260 mg) as an oil. 
     MS (ESI+, m/e) 354 (M+1) 
     Reference Example 667 
     Ethyl 1-[(1R,2S)-2-ethyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Copper iodide (4.57 g) was suspended in THF (100 ml), and the suspension was ice-cooled. Methylmagnesium bromide (1M THF solution, 45 ml) was added, and the mixture was stirred at 0° C. for 30 min. A solution of ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (4.90 g) in THF (50 ml) was added thereto, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (4.61 g) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 0.61 (3H, t), 0.90-1.32 (7H, m), 1.44-1.95 (7H, m), 2.12-2.33 (1H, m), 3.62 (1H, dd), 4.16-4.28 (1H, m), 7.19-7.37 (2H, m), 7.38-7.54 (3H, m), 8.04 (1H, s) 
     MS (ESI+, m/e) 389 (M+1) 
     In the same manner as in Reference Example 667, the following compound (Reference Example 668) was obtained. 
     Reference Example 668 
     Ethyl 1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ −0.18-0.06 (2H, m), 0.25-0.50 (2H, m), 0.63-0.80 (1H, m), 1.07-1.33 (5H, m), 1.45-2.00 (8H, m), 2.24 (1H, dd), 3.45-3.71 (1H, m), 4.08-4.31 (2H, m), 7.12-7.36 (3H, m), 7.36-7.55 (2H, m), 8.03 (1H, s) 
     MS (ESI+, m/e) 369 (M+1) 
     Reference Example 669 
     Ethyl 1-[(1R,2S)-2-hydroxy-2-methylcyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (1.0 g) was dissolved in ethanol (30 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (972 mg) as an amorphous solid. 
       1 H-NMR (CDCl 3 ) δ 0.84 (3H, s), 1.22 (5H, t), 1.42-1.93 (6H, m), 2.19 (1H, dd), 3.56 (1H, dd), 4.12-4.29 (2H, m), 7.17-7.40 (2H, m), 7.41-7.53 (3H, m), 8.04 (1H, s) 
     MS (ESI+, m/e) 329 (M+1) 
     Reference Example 670 
     1-[(1R,2S)-2-Ethyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1R,2S)-2-ethyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (3.85 g) was dissolved in ethanol (30 ml), 4N aqueous sodium hydroxide solution (14 ml) was added thereto, and the mixture was stirred at 60° C. for 15 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in THF (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (4.30 g) as a powder mixed with an inorganic salt thereof. 
       1 H-NMR (DMSO-d 6 ) δ 0.52 (3H, t), 0.60-1.22 (6H, m), 1.23-1.47 (1H, m), 1.50-1.90 (4H, m), 1.95-2.32 (1H, m), 7.35 (6H, m) 
     MS (ESI+, m/e) 315 (M+1) 
     In the same manner as in Reference Example 670, the following compounds (Reference Examples 671-672) were obtained. 
     Reference Example 671 
     1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ −0.16 (2H, br s), 0.08-0.39 (3H, m), 0.66-1.05 (2H, m), 1.05-1.34 (2H, m), 1.43 (1H, s), 1.53-1.97 (4H, m), 2.03-2.30 (1H, m), 3.48-3.67 (1H, m), 3.68-3.84 (1H, m), 7.10-7.44 (5H, m), 7.95 (1H, s) 
     MS (ESI+, m/e) 341 (M+1) 
     Reference Example 672 
     1-[(1R,2S)-2-Hydroxy-2-methylcyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 0.66 (3H, s), 0.97-1.23 (2H, m), 1.28-1.43 (1H, m), 1.49-1.88 (4H, m), 2.16 (1H, tq), 3.39-3.56 (1H, m), 3.55-3.68 (1H, m), 7.30-7.44 (2H, m), 7.46-7.58 (3H, m), 8.34-8.52 (1H, m) 
     MS (ESI+, m/e) 301 (M+1) 
     Reference Example 673 
     1-[(1R,2S)-2-(Ethoxymethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(3S,4R)-1-oxaspiro[2.5]oct-4-yl]-5-phenyl-1H-imidazole-4-carboxylate (1.96 g) was dissolved in ethanol (30 ml), sodium ethoxide (20% ethanol solution, 11.8 ml) was added thereto at room temperature, and the mixture was stirred at 60° C. for 3 hr. 1N Aqueous sodium hydroxide solution (6 ml) was added thereto, and the mixture was further stirred at 60° C. for 3 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (2.28 g) as a powder mixed with an inorganic salt thereof. 
       1 H-NMR (CDCl 3 ) δ 1.00 (3H, t), 1.12-1.29 (2H, m), 1.41-1.54 (1H, m), 1.59-1.71 (1H, m), 1.71-1.83 (3H, m), 2.11-2.27 (1H, m), 2.80 (2H, s), 3.26 (2H, q), 3.66-3.82 (1H, m), 4.29 (1H, br s), 7.23-7.36 (2H, m), 7.38-7.46 (3H, m), 8.12 (1H, s) 
     MS (ESI+, m/e) 345 (M+1) 
     In the same manner as in Reference Example 86, the following compounds (Reference Examples 674-676) were obtained. 
     Reference Example 674 
     Ethyl N-(tert-butoxycarbonyl)-DL-2-methoxyphenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.19-1.72 (12H, m), 2.50-3.31 (2H, m), 3.64-3.90 (3H, m), 4.00-4.27 (3H, m), 4.48-5.46 (3H, m), 6.75-6.92 (2H, m), 7.01-7.42 (7H, m) 
     Reference Example 675 
     Ethyl N-(tert-butoxycarbonyl)-D-(biphenyl-4-yl)alanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 417 (M+1-“Boc”) 
     Reference Example 676 
     Ethyl 2-bromo-N-(tert-butoxycarbonyl)-D-phenylalanyl-N-benzylglycinate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 519 (M+1) 
     In the same manner as in Reference Example 109, the following compounds (Reference Examples 677-679) were obtained. 
     Reference Example 677 
     1-Benzyl-3-(2-methoxybenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.90-3.00 (1H, m), 3.04-3.19 (2H, m), 3.47 (1H, d), 3.74 (3H, s), 4.08-4.15 (1H, m), 4.43 (2H, s), 6.64-6.76 (4H, m), 6.96 (2H, dd), 8.09 (1H, br s) 
     Reference Example 678 
     (3R)-1-Benzyl-3-(biphenyl-4-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 3.06 (1H, d), 3.21 (2H, d), 3.54 (1H, d), 4.35-4.40 (1H, m), 4.43 (1H, d), 4.55 (1H, d), 6.49 (1H, s), 7.16-7.53 (14H, m) 
     MS (ESI+, m/e) 371 (M+1) 
     Reference Example 679 
     (3R)-1-Benzyl-3-(2-bromobenzyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 373 (M+1) 
     In the same manner as in Reference Example 133, the following compounds (Reference Examples 680-681) were obtained. 
     Reference Example 680 
     1-Benzyl-3-(2-methoxybenzyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.51-3.10 (9H, m), 3.40-3.61 (2H, m), 3.66-3.74 (1H, m), 3.80 (3H, s), 6.80-6.93 (4H, m), 7.09-7.36 (5H, m) 
     MS (ESI+, m/e) 297 (M+1) 
     Reference Example 681 
     (3R)-1-Benzyl-3-(biphenyl-4-ylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 1.64 (1H, br s), 1.92 (1H, t), 2.10 (1H, dt), 2.57 (1H, dd), 2.72-2.94 (5H, m), 2.98-3.07 (1H, m), 3.48 (1H, d), 3.55 (1H, d), 7.21-7.58 (14H, m) 
     MS (ESI+, m/e) 343 (M+1) 
     In the same manner as in Reference Example 147, the following compound (Reference Example 682) was obtained. 
     Reference Example 682 
     (3R)-1-Benzyl-3-(2-bromobenzyl)piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 345 (M+1) 
     Reference Example 683 
     tert-Butyl [(1R)-1-benzyl-2-(benzylamino)propyl]carbamate 
     
       
         
         
             
             
         
       
     
     tert-Butyl [(1R)-1-benzyl-2-oxopropyl]carbamate (3.42 g) was dissolved in 1,2-dichloroethane (50 ml), benzylamine (1.39 g) and acetic acid (780 mg) were added, and the mixture was stirred at room temperature for 15 min. Sodium triacetoxyborohydride (3.6 g) was added thereto, and the mixture was further stirred at room temperature for 15 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (4.40 g) as an oil. 
     MS (ESI+, m/e) 355 (M+1) 
     Reference Example 684 
     Ethyl N-benzyl-N-{(2R)-2-[(tert-butoxycarbonyl)amino]-1-methyl-3-phenylpropyl}glycinate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl [(1R)-1-benzyl-2-(benzylamino)propyl]carbamate (1.06 g), potassium carbonate (498 mg), ethyl bromoacetate (501 mg) and ethanol (10 ml) was stirred at 50° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (430 mg) as an oil. 
     MS (ESI+, m/e) 441 (M+1) 
     Reference Example 685 
     (6R)-4,6-Dibenzyl-5-methylpiperazin-2-one 
     
       
         
         
             
             
         
       
     
     Ethyl N-benzyl-N-{(2R)-2-[(tert-butoxycarbonyl)amino]-1-methyl-3-phenylpropyl}glycinate (419 mg) was dissolved in dichloromethane (1 ml), TFA (2 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (5 ml). Triethylamine (1 ml) was added thereto at room temperature, and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (270 mg) as an oil. 
     MS (ESI+, m/e) 295 (M+1) 
     Reference Example 686 
     (3R)-1,3-Dibenzyl-2-methylpiperazine 
     
       
         
         
             
             
         
       
     
     A mixture of (6R)-4,6-dibenzyl-5-methylpiperazin-2-one (265 mg) and THF (6 ml) was ice-cooled, and lithium aluminum hydride (68 mg) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 60° C. for 3 hr. The mixture was cooled to −78° C., and ethanol-ethyl acetate (1:1, 2 ml) and 1N aqueous sodium hydroxide solution (2 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (240 mg) as an oil. 
     MS (ESI+, m/e) 281 (M+1) 
     In the same manner as in Reference Example 157, the following compound (Reference Example 687) was obtained. 
     Reference Example 687 
     tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 445 (M+1) 
     In the same manner as in Reference Example 158, the following compound (Reference Example 688) was obtained. 
     Reference Example 688 
     tert-Butyl (2R)-4-benzyl-2-(2-morpholinobenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 452 (M+1) 
     Reference Example 689 
     tert-Butyl (2R)-4-benzyl-2-[2-(2-methoxypyridin-3-yl)benzyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (445 mg), (2-methoxypyridin-3-yl)boronic acid (184 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg) and sodium carbonate (254 mg) were suspended in 1,2-dimethoxyethane-water (2:1, 9 ml), and the suspension was stirred at 100° C. for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (145 mg) as an oil. 
     MS (ESI+, m/e) 473 (M+1) 
     Reference Example 690 
     tert-Butyl (2R)-4-benzyl-2-[(6-chloropyridin-2-yl)benzyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (445 mg), 2-chloro-6-(tributylstannyl)pyridine (426 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg) and toluene (5 ml) was stirred at 100° C. for 15 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (140 mg) as an oil. 
     MS (ESI+, m/e) 478 (M+1) 
     Reference Example 691 
     tert-Butyl (2R)-4-benzyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (890 mg), bis(pinacolato)diboron (584 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (65 mg) and potassium acetate (590 mg) were dissolved in DMF (10 ml), and the solution was stirred at 120° C. for 20 hr. Ethyl acetate-water (2:1) was added to the reaction mixture, and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:2) was concentrated under reduced pressure to give the object compound (500 mg) as an oil. 
     MS (ESI+, m/e) 4.93 (M+1) 
     Reference Example 692 
     tert-Butyl (2R)-4-benzyl-2-(2-hydroxybenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine-1-carboxylate (420 mg) was dissolved in acetone (4 ml), and a solution of potassium peroxymonosulfate (524 mg) in water (4 ml) was added at room temperature. The mixture was stirred at room temperature for 10 min, saturated aqueous sodium thiosulfate solution (4 ml) was added, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (300 mg) as an oil. 
     MS (ESI+, m/e) 383 (M+1) 
     Reference Example 693 
     tert-Butyl (2R)-4-benzyl-2-(2-phenoxybenzyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-hydroxybenzyl)piperazine-1-carboxylate (300 mg), phenylboronic acid (95 mg), copper(II) acetate (283 mg), pyridine (308 mg), triethylamine (395 mg) and pulverized molecular sieves 4 A (600 mg) were suspended in dichloromethane, and the suspension was stirred at room temperature for 20 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (150 mg) as an oil. 
     MS (ESI+, m/e) 459 (M+1) 
     Reference Example 694 
     tert-Butyl (2R)-4-benzyl-2-[2-(1-methyl-1H-pyrazol-5-yl)benzyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of tert-butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (445 mg), 1-methyl-5-(tributylstannyl)-1H-pyrazole (426 mg), tetrakis(triphenylphosphine)palladium(0) (58 mg) and toluene (5 ml) was stirred at 100° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (240 mg) as an oil. 
     MS (ESI+, m/e) 447 (M+1) 
     In the same manner as in Reference Example 243, the following compounds (Reference Examples 695-696) were obtained. 
     Reference Example 695 
     tert-Butyl (3S)-3-[(2-phenyl-1H-imidazol-1-yl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 343 (M+1) 
     Reference Example 696 
     tert-Butyl (3S)-3-[(5-phenyl-1H-imidazol-1-yl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 343 (M+1) 
     Reference Example 697 
     1-Benzyl-3-(biphenyl-2-ylmethyl)piperazine-2,5-dione 
     
       
         
         
             
             
         
       
     
     A mixture of (3R)-1-benzyl-3-(2-bromobenzyl)piperazine-2,5-dione (500 mg), phenylboronic acid (250 mg), tetrakis(triphenylphosphine)palladium(0) (231 mg), sodium carbonate (355 mg), DME(7 ml) and water (3.5 ml) was heated under reflux for 12 hr, and concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with 10% aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (290 mg) (The racemization proceeded in the course of the reaction.) 
     MS (ESI+, m/e) 371 (M+1) 
     In the same manner as in Reference Example 133, the following compound (Reference Example 698) was obtained. 
     Reference Example 698 
     1-Benzyl-3-(biphenyl-2-ylmethyl)piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 343 (M+1) 
     Reference Example 699 
     Benzyl (3S)-3-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (8.36 g) and triethylamine (9.3 ml) were dissolved in DMF (50 ml), and the solution was ice-cooled. Trityl chloride (9.78 g) was added, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (8.54 g) as an amorphous solid. 
     MS (ESI+, m/e) 493 (M+1) 
     Reference Example 700 
     Benzyl (3S)-3-{[(3-fluorophenyl)thio]methyl}-4-tritylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3S)-3-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate (985 mg), 3-fluorothiophenol (308 mg) and tri-tert-butylphosphine (486 mg) were dissolved in toluene (40 ml), ADDP (757 mg) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (600 mg) as an amorphous solid. 
     MS (ESI+, m/e) 361 (M+1-“Tr”) 
     Reference Example 701 
     Benzyl (3S)-3-{[(3-fluorophenyl)sulfonyl]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3S)-3-{[(3-fluorophenyl)thio]methyl}-4-tritylpiperazine-1-carboxylate (600 mg) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. mCPBA (542 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give benzyl (3S)-3-{[(3-fluorophenyl)sulfonyl]methyl}-4-tritylpiperazine-1-carboxylate (624 mg) as an amorphous solid. The total amount thereof was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (250 mg) as an oil. 
     MS (ESI+, m/e) 393 (M+1) 
     Reference Example 702 
     Benzyl (3S)-3-formyl-4-tritylpiperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3S)-3-(hydroxymethyl)-4-tritylpiperazine-1-carboxylate (985 mg) and triethylamine (836 μl) were dissolved in DMSO (10 ml), a solution of sulfur trioxide pyridine complex (955 mg) in DMSO (5 ml) was added while cooling in water bath, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (591 mg). 
       1 H-NMR (CDCl 3 ) δ 2.94-3.38 (4H, m), 3.71-4.06 (2H, m), 4.24-4.38 (1H, m), 5.03 (2H, s), 7.12-7.37 (14H, m), 7.39-7.64 (6H, m), 8.51 (1H, br s) 
     Reference Example 703 
     Benzyl (3R)-3-{[(2-ethyl-1,3-benzoxazol-5-yl)amino]methyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3S)-3-formyl-4-tritylpiperazine-1-carboxylate (295 mg) and 2-ethyl-1,3-benzoxazole-5-amine (97 mg) were dissolved in 1,2-dichloroethane (5 ml), acetic acid (0.25 ml) and sodium triacetoxyborohydride (191 mg) were added, and the mixture was stirred at room temperature for 15 hr. 4N Hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (128 mg) as an oil. 
     MS (ESI+, m/e) 395 (M+1) 
     Reference Example 704 
     4-[4-(Benzyloxy)-3-methoxyphenyl]morpholine 
     
       
         
         
             
             
         
       
     
     A mixture of 1-(benzyloxy)-4-bromo-2-methoxybenzene (1.47 g), morpholine (479 mg), BINAP (311 mg), sodium tert-butoxide (721 mg), Pd 2 (dba) 3  (183 mg) and toluene (45 ml) was stirred at 90° C. for 15 hr in an argon stream, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-THF (3:1) (along with which the insoluble material was filtered off). The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:6-1:2) was concentrated under reduced pressure, and the crystals were collected by filtration to give the object compound (1.13 g). 
       1 H-NMR (CDCl 3 ) δ 3.05-3.08 (4H, m), 3.83-3.86 (4H, m), 3.87 (3H, s), 5.08 (2H, s), 6.37 (1H, dd), 6.55 (1H, d), 6.80 (1H, d), 7.28-7.44 (5H, m) 
     MS (ESI+, m/e) 300 (M+1) 
     In the same manner as in Reference Example 704, the following compound (Reference Example 705) was obtained. 
     Reference Example 705 
     1-Acetyl-4-[4-(benzyloxy)-3-methoxyphenyl]piperazine 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.13 (3H, s), 3.02-3.08 (4H, m), 3.61 (2H, t), 3.76 (2H, t), 3.88 (3H, s), 5.09 (2H, s), 6.38 (1H, dd), 6.57 (1H, d), 6.80 (1H, d), 7.28-7.44 (5H, m) 
     MS (ESI+, m/e) 341 (M+1) 
     Reference Example 706 
     2-Methoxy-4-morpholinophenol 
     
       
         
         
             
             
         
       
     
     4-[4-(Benzyloxy)-3-methoxyphenyl]morpholine (1.12 g) was dissolved in methanol-THF (3:1, 40 ml), 20% palladium hydroxide-carbon (50% containing water, 560 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the crystals were collected by filtration to give the object compound (684 mg). 
       1 H-NMR (CDCl 3 ) δ 3.04-3.07 (4H, m), 3.85-3.87 (4H, m), 3.87 (3H, s), 5.30 (1H, br s), 6.44 (1H, dd), 6.54 (1H, s), 6.83 (1H, d) 
     MS (ESI+, m/e) 210 (M+1) 
     In the same manner as in Reference Example 706, the following compound (Reference Example 707) was obtained. 
     Reference Example 707 
     4-(4-Acetylpiperazin-1-yl)-2-methoxyphenol 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.14 (3H, s), 3.00-3.06 (4H, m), 3.61 (2H, t), 3.77 (2H, t), 3.87 (3H, s), 5.41 (1H, br s), 6.44 (1H, dd), 6.54 (1H, d), 6.83 (1H, d) 
     MS (ESI+, m/e) 251 (M+1) 
     Reference Example 708 
     4-Bromo-2-fluoro-1-[(2-methyl-2-propen-1-yl)oxy]benzene 
     
       
         
         
             
             
         
       
     
     4-Bromo-2-fluorophenol (26.8 g) and 3-chloro-2-methyl-1-propene (13.7 ml) were dissolved in acetone (420 ml), potassium carbonate (29.0 g) was added thereto, and the mixture was heated under reflux for 15 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (29.9 g). 
       1 H-NMR (CDCl 3 ) δ 1.83 (3H, s), 4.48 (2H, s), 5.04 (2H, d), 6.84 (1H, t), 7.13 (2H, m) 
     Reference Example 709 
     5-Bromo-7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran 
     
       
         
         
             
             
         
       
     
     A mixture of 4-bromo-2-fluoro-1-[(2-methyl-2-propen-1-yl)oxy]benzene (29.9 g) and N,N-diethylaniline (30 ml) was stirred at 190° C. for 5 hr. The mixture was cooled to room temperature, and diisopropyl ether was added thereto. The mixture was washed successively with 1N hydrochloric acid, water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (240 ml), boron trifluoride diethyl ether complex (30 ml) was added thereto, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (18.9 g). 
       1 H-NMR (CDCl 3 ) δ 1.51 (6H, s), 3.04 (2H, s), 6.97-7.24 (2H, m) 
     Reference Example 710 
     (7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid 
     
       
         
         
             
             
         
       
     
     5-Bromo-7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran (18.9 g) was dissolved in THF (250 ml), and the solution was cooled to −78° C. n-Butyllithium (1.6M hexane solution, 53 ml) was added, and the mixture was stirred at −78° C. for 1 hr. Triisopropyl borate (21 ml) was added thereto at −78° C., and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added 1N hydrochloric acid (150 ml), and the mixture was stirred at room temperature for 3 hr, and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (6.54 g). 
       1 H-NMR (DMSO-d 6 ) δ 1.16-1.35 (2H, m), 1.45 (6H, s), 7.26-7.50 (2H, m), 7.90 (2H, br s) 
     Reference Example 711 
     7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-ol 
     
       
         
         
             
             
         
       
     
     (7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.2 g) was dissolved in acetone (20 ml), a solution of OXONE (3.7 g) in water (20 ml) was added dropwise at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added 10% aqueous sodium thiosulfate solution (100 ml), and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:3) was concentrated under reduced pressure to give the object compound (600 mg). 
       1 H-NMR (DMSO-d 6 ) δ 1.50 (2H, m), 3.00 (6H, s), 4.86 (1H, br s), 6.41-6.50 (2H, m) 
     In the same manner as in Reference Example 255, the following compounds (Reference Examples 712-719) shown in Table 9 were obtained. In the column of “MS (ESI+)” in the Table, “*” means that a mass value of “M+1-“Boc”” was obtained (a mass value of M+1 was obtained for other compounds). 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 712 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(1- benzothien-4-yloxy}ethyl] piperazine-1,4-dicarboxylate 
                 497 
               
               
                   
               
               
                 713 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- methoxy-4-morpholinophenoxy) ethyl]piperazine-1,4-dicarboxylate 
                 556 
               
               
                   
               
               
                 714 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (4-acetylpiperazin-1-yl)-2- methoxyphenoxy]ethyl}piperazine- 1,4-dicarboxylate 
                 597 
               
               
                   
               
               
                 715 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-(3- (difluoromethoxy)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                  407* 
               
               
                   
               
               
                 716 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (5-methyl-3-oxo-1H-imidazo[1,5-c] imidazol-2(3H)-yl)phenoxy]ethyl} piperazine-1,4-dicarboxylate 
                 576 
               
               
                   
               
               
                 717 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[2- (ethoxycarbonyl)-1-benzofuran-5-yl] oxy}ethyl)piperazine-1,4- dicarboxylate 
                 553 
               
               
                   
               
               
                 718 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(2,2-dimethyl-2,3-dihydro-1- benzofuran-5-yl)oxy]ethyl} piperazine-1,4-dicarboxylate 
                 511 
               
               
                   
               
               
                 719 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(7-fluoro-2,2-dimethyl-2,3-dihydro- 1-benzofuran-5-yl)oxy]ethyl} piperazine-1,4-dicarboxylate 
                 529 
               
               
                   
               
            
           
         
       
     
     In the same manner as in Reference Example 341, the following compounds (Reference Examples 720-734) shown in Table 10-1-Table 10-2 were obtained. 
     
       
         
           
               
             
               
                 TABLE 10-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 720 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-(2- methoxy-4-(1H-pyrazol-1-yl)phenoxy] ethyl}piperazine-1,4-dicarboxylate 
                 537 
               
               
                   
               
               
                 721 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2- methylphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 455 
               
               
                   
               
               
                 722 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(4- methoxy-2-methylphenoxy)ethyl] piperazine-1,4-dicarboxylate 
                 485 
               
               
                   
               
               
                 723 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (2,3-dihydro-1-benzofuran-5-yloxy) ethyl]piperazine-1,4-dicarboxylate 
                 483 
               
               
                   
               
               
                 724 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(1,2- dimethyl-1H-benzimidazol-5-yl)oxy] ethyl}piperazine-1,4-dicarboxylate 
                 509 
               
               
                   
               
               
                 725 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (phenylthio)ethyl]piperazine-1,4- dicarboxylate 
                 457 
               
               
                   
               
               
                 726 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (1,3-benzothiazol-2-ylthio)ethyl] piperazine-1,4-dicarboxylate 
                 514 
               
               
                   
               
               
                 727 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-([1,3] thiazolo[5,4-b]pyridin-2-ylthio) ethyl]piperazine-1,4-dicarboxylate 
                 515 
               
               
                   
               
               
                 728 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(4-methyl-1,3-thiazol-2-yl)thio] ethyl}piperazine-1,4-dicarboxylate 
                 478 
               
               
                   
               
               
                 729 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [4-tert-butyl-1,3-thiazol-2-yl)thio] ethyl}piperazine-1,4-dicarboxylate 
                 520 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 730 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(4,5- dimethyl-1,3-thiazol-2-yl)thio]ethyl} piperazine-1,4-dicarboxylate 
                 492 
               
               
                   
               
               
                 731 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(5- methyl-1,3,4-thiadiazol-2-yl)thio] ethyl}piperazine-1,4-dicarboxylate 
                 479 
               
               
                   
               
               
                 732 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(1H- benzimidazol-2-ylthio)ethyl] piperazine-1,4-dicarboxylate 
                 497 
               
               
                   
               
               
                 733 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(4- methyl-4H-1,2,4-triazol-3-yl)thio] ethyl}piperazine-1,4-dicarboxylate 
                 462 
               
               
                   
               
               
                 734 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(1,3- benzothiazol-2-ylamino)ethyl] piperazine-1,4-dicarboxylate 
                 497 
               
               
                   
               
            
           
         
       
     
     Reference Example 735 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(phenylsulfinyl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-[2-(phenylthio)ethyl]piperazine-1,4-dicarboxylate (0.8 g) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. mCPBA (0.3 g) was added thereto, and the mixture was stirred at 0° C. for 1 hr. mCPBA (0.2 g) was further added under ice-cooling, and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was poured into aqueous sodium hydrogensulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (0.78 g) as an amorphous solid. 
     MS (ESI+, m/e) 473 (M+1) 
     Reference Example 736 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(phenylsulfonyl)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-[2-(phenylthio)ethyl]piperazine-1,4-dicarboxylate (0.8 g) was dissolved in dichloromethane (10 ml), and the solution was ice-cooled. mCPBA (0.6 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into aqueous sodium hydrogensulfite solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure to give the object compound (0.85 g) as an amorphous solid. 
     MS (ESI+, m/e) 489 (M+1) 
     In the same manner as in Reference Example 663, the following compounds (Reference Examples 737-756) shown in Table 11-1-Table 11-2 were obtained. 
     
       
         
           
               
             
               
                 TABLE 11-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 737 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2{[2- (trifluoromethyl)phenyl]amino} ethyl)piperazine-1,4-dicarboxylate 
                 508 
               
               
                   
               
               
                 738 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- cyanophenyl)amino]ethyl} piperazine-1,4-dicarboxylate 
                 465 
               
               
                   
               
               
                 739 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [benzyl(cyclopropyl)amino]ethyl} piperazine-1,4-dicarboxylate 
                 494 
               
               
                   
               
               
                 740 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- fluorophenyl)amino]ethyl) piperazine-1,4-dicarboxylate 
                 458 
               
               
                   
               
               
                 741 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- chlorophenyl)amino}ethyl} piperazine-1,4-dicarboxylate 
                 474 
               
               
                   
               
               
                 742 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- nitrophenyl)amino]ethyl} piperazine-1,4-dicarboxylate 
                 485 
               
               
                   
               
               
                 743 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(4- methoxyphenyl)amino]ethyl} piperazine-1,4-dicarboxylate 
                 470 
               
               
                   
               
               
                 744 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[4- (methoxycarbonyl)phenyl]amino} ethyl)piperazine-1,4-dicarboxylate 
                 498 
               
               
                   
               
               
                 745 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[3- (methoxycarbonyl)phenyl]amino} ethyl)piperazine-1,4-dicarboxylate 
                 498 
               
               
                   
               
               
                 746 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[2- chloro-5-(methoxycarbonyl)phenyl] amino}ethyl)piperazine- 1,4-dicarboxylate 
                 532 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 747 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(1-oxo-1,3-dihydro-2-benzofuran-5- yl)amino]ethyl}piperazine-1,4- dicarboxylate 
                 496 
               
               
                   
               
               
                 748 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(3-oxo-1,3-dihydro-2-benzofuran-5- yl)amino]ethyl}piperazine-1,4- dicarboxylate 
                 496 
               
               
                   
               
               
                 749 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[4- (2-oxopiperidin-1-yl)phenyl]amino} ethyl)piperazine-1,4-dicarboxylate 
                 537 
               
               
                   
               
               
                 750 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-(2-{[4- (2-oxopyridin-1(2H)-yl)phenyl] amino}ethyl)piperazine- 1,4-dicarboxylate 
                 533 
               
               
                   
               
               
                 751 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- methyl-1,3-benzoxazol-5-yl)amino] ethyl}piperazine-1,4-dicarboxylate 
                 495 
               
               
                   
               
               
                 752 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- ethyl-1,3-benzoxazol-5-yl)amino] ethyl}piperazine-1,4-dicarboxylate 
                 509 
               
               
                   
               
               
                 753 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2-[(2- methyl-1,3-benzoxazol-6-yl)amino] ethyl}piperazine-1,4-dicarboxylate 
                 495 
               
               
                   
               
               
                 754 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2- (1H-indazol-5-ylamino)ethyl] piperazine-1,4-dicarboxylate 
                 480 
               
               
                   
               
               
                 755 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-[2-(2,3- dihydrofuro[3,2-b]pyridin-5- ylamino)ethyl]piperazine-1,4- dicarboxylate 
                 483 
               
               
                   
               
               
                 756 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1-tert-Butyl 4-benzyl (2R)-2-{2- [(2-fluorophenyl)(methyl)amino] ethyl}piperazine-1,4-dicarboxylate 
                 472 
               
               
                   
               
            
           
         
       
     
     In the same manner as in Reference Example 383 or Reference Example 665, the following compounds (Reference Examples 757-783) shown in Table 12-1-Table 12-3 were obtained. In the column of “Acid” in the Tables, the compounds described as “TFA” were synthesized according to the method of Reference Example 383 and the compounds described as “HCl” were synthesized according to the method of Reference Example 665. 
     
       
         
           
               
             
               
                 TABLE 12-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 Acid 
                 MS(ESI+) 
               
               
                   
               
               
                 757 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-methoxy-4- morpholinophenoxy)ethyl] piperazine-1-carboxylate 
                 TFA 
                 456 
               
               
                   
               
               
                 758 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(4-acetyl- piperazin-1-yl)-2-methoxyphenoxy] ethyl}piperazine-1-carboxylate 
                 TFA 
                 497 
               
               
                   
               
               
                 759 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3- (difluoromethoxy)phenoxy]ethyl} piperazine-1-carboxylate 
                 TFA 
                 407 
               
               
                   
               
               
                 760 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1-benzothien-4- yloxy)ethyl]piperazine-1-carboxylate 
                 HCl 
                 397 
               
               
                   
               
               
                 761 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2,2-dimethyl- 2,3-dihydro-1-benzofuran-5-yl) oxy]ethyl}piperazine-1-carboxylate 
                 HCl 
                 411 
               
               
                   
               
               
                 762 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(7-fluoro-2,2- dimethyl-2,3-dihydro-1-benzofuran- 5-yl)oxy]ethyl}piperazine-1- carboxylate 
                 HCl 
                 429 
               
               
                   
               
               
                 763 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-([1,3]thia- zolo[5,4-b]pyridin-2-ylthio)ethyl] piperazine-1-carboxylate 
                 HCl 
                 415 
               
               
                   
               
               
                 764 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(4-tert-butyl- 1,3-thiazol-2-yl)thio]ethyl} piperazine-1-carboxylate 
                 HCl 
                 420 
               
               
                   
               
               
                 765 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(4,5-dimethyl- 1,3-thiazol-2-yl)thio]ethyl} piperazine-1-carboxylate 
                 HCl 
                 392 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 Acid 
                 MS(ESI+) 
               
               
                   
               
               
                 766 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[2- (trifluoromethyl)phenyl]amino} ethyl)piperazine-1-carboxylate 
                 HCl 
                 408 
               
               
                   
               
               
                 767 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2- cyanophenyl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 365 
               
               
                   
               
               
                 768 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2- [benzyl(cyclopropyl)amino] ethyl}piperazine-1-carboxylate 
                 HCl 
                 394 
               
               
                   
               
               
                 769 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2- fluorophenyl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 358 
               
               
                   
               
               
                 770 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2- chlorophenyl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 374 
               
               
                   
               
               
                 771 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2- nitrophenyl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 385 
               
               
                   
               
               
                 772 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(4- methoxyphenyl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 370 
               
               
                   
               
               
                 773 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[4- (methoxycarbonyl)phenyl]amino} ethyl)piperazine-1-carboxylate 
                 HCl 
                 398 
               
               
                   
               
               
                 774 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[3- (methoxycarbonyl)phenyl]amino} ethyl)piperazine-1-carboxylate 
                 HCl 
                 398 
               
               
                   
               
               
                 775 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[2-chloro-5- (methoxycarbonyl)phenyl]amino} ethyl)piperazine-1-carboxylate 
                 HCl 
                 432 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 Acid 
                 MS(ESI+) 
               
               
                   
               
               
                 776 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(1-oxo-1,3- dihydro-2-benzofuran-5-yl)amino] ethyl}piperazine-1-carboxylate 
                 HCl 
                 396 
               
               
                   
               
               
                 777 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(3-oxo-1,3- dihydro-2-benzofuran-5-yl)amino] ethyl}piperazine-1-carboxylate 
                 HCl 
                 396 
               
               
                   
               
               
                 778 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[4-(2-oxo- piperidin-1-yl)phenyl]amino} ethyl)piperazine-1-carboxylate 
                 HCl 
                 437 
               
               
                   
               
               
                 779 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[4-(2-oxo- pyridin-1(2H)-yl)phenyl]amino} ethyl)piperazine-1-carboxylate 
                 HCl 
                 433 
               
               
                   
               
               
                 780 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-methyl-1,3- benzoxazol-5-yl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 395 
               
               
                   
               
               
                 781 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-ethyl-1,3- benzoxazol-5-yl)amino]ethyl} piperazine-1-carboxylate 
                 HCl 
                 409 
               
               
                   
               
               
                 782 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1H-indazol-5- ylamino)ethyl]piperazine-1- carboxylate 
                 HCl 
                 380 
               
               
                   
               
               
                 783 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2,3-dihydro- furo[3,2-b]pyridin-5-ylamino) ethyl]piperazine-1-carboxylate 
                 HCl 
                 383 
               
               
                   
               
            
           
         
       
     
     In the same manner as in Reference Example 425, the following compounds (Reference Examples 784-803) shown in Table 13-1-Table 13-2 were obtained. 
     
       
         
           
               
             
               
                 TABLE 13-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 784 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-fluoro- phenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 359 
               
               
                   
               
               
                 785 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2-methyl- phenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 355 
               
               
                   
               
               
                 786 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[3- (methoxycarbonyl)phenoxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 399 
               
               
                   
               
               
                 787 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[4-(5-methyl- 3-oxo-1H-imidazo[1,5-c]imidazol- 2(3H)-yl)phenoxy]ethyl}piperazine-1- carboxylate hydrochloride 
                 476 
               
               
                   
               
               
                 788 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-(2-{[2-(ethoxycarbonyl)- 1-benzofuran-5-yl]oxy}ethyl) piperazine-1-carboxylate hydrochloride 
                 453 
               
               
                   
               
               
                 789 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[2-methoxy-4-(1H- pyrazol-1-yl)phenoxy]ethyl}piperazine- 1-carboxylate hydrochloride 
                 437 
               
               
                   
               
               
                 790 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(4-methoxy-2- methylphenoxy)ethyl]piperazine-1- carboxylate hydrochloride 
                 385 
               
               
                   
               
               
                 791 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(2,3-dihydro-1- benzofuran-5-yloxy)ethyl}piperazine- 1-carboxylate hydrochloride 
                 383 
               
               
                   
               
               
                 792 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(1,2-dimethyl-1H- benzimidazol-5-yl)oxy]ethyl} piperazine-1-carboxylate hydrochloride 
                 409 
               
               
                   
               
               
                 793 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(phenylthio]ethyl] piperazinel-1-carboxylate hydrochloride 
                 357 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 794 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(phenylsulfinyl) ethyl]piperazine-1- carboxylate hydrochloride 
                 373 
               
               
                   
               
               
                 795 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(phenylsulfonyl) ethyl]piperazine-1- carboxylate hydrochloride 
                 389 
               
               
                   
               
               
                 796 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1,3-benzothiazol- 2-ylthio)ethyl]piperazine-1- carboxylate hydrochloride 
                 414 
               
               
                   
               
               
                 797 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(4-methyl-1,3- thiazol-2-yl)thio]ethyl}piperazine- 1-carboxylate hydrochloride 
                 378 
               
               
                   
               
               
                 798 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(5-methyl-1,3,4- thiadiazol-2-yl)thio]ethyl}piperazine- 1-carboxylate hydrochloride 
                 379 
               
               
                   
               
               
                 799 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1H-benzimidazol-2- ylthio)ethyl]piperazine-1- carboxylate hydrochloride 
                 397 
               
               
                   
               
               
                 800 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(4-methyl- 4H-1,2,4-triazol-3-yl)thio]ethyl} piperazine-1-carboxylate hydrochloride 
                 362 
               
               
                   
               
               
                 801 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-methyl-1,3- benzoxazol-6-yl)amino]ethyl} piperazine-1-carboxylate dihydrochloride 
                 395 
               
               
                   
               
               
                 802 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-[2-(1,3-benzothiazol- 2-ylamino)ethyl]piperazine-1- carboxylate dihydrochloride 
                 397 
               
               
                   
               
               
                 803 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 Benzyl (3R)-3-{2-[(2-fluorophenyl) (methyl)amino]ethyl}piperazine-1- carboxylate dihydrochloride 
                 372 
               
               
                   
               
            
           
         
       
     
     Reference Example 804 
     Benzyl (3R)-3-{2-[(4-acetylphenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     4-Acetylaniline (540 mg) was dissolved in DMF (20 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 160 mg) was added thereto, and the mixture was stirred at 0° C. for 15 min. After stirring, 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (885 mg) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-{2-[(4-acetylphenyl)amino]ethyl}piperazine-1,4-dicarboxylate (740 mg) as an oil. The total amount thereof was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (650 mg). 
     MS (ESI+, m/e) 382 (M+1) 
     Reference Example 805 
     [(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]acetic acid 
     
       
         
         
             
             
         
       
     
     Benzyl [(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]acetate (2.00 g) was dissolved in methanol (40 ml), 20% palladium hydroxide-carbon (50% containing water, 500 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 17 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (1.41 g). 
       1 H-NMR (DMSO-d 6 ) δ 2.68 (1H, dd), 2.85 (1H, dd), 3.78 (2H, q), 4.24 (1H, s), 4.36 (1H, d), 4.69 (1H, d), 7.27-7.36 (5H, m), 8.22 (1H, s), 12.50 (1H, br s) 
     MS (ESI+, m/e) 263 (M+1) 
     Reference Example 806 
     2-[(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]-N-phenylacetamide 
     
       
         
         
             
             
         
       
     
     [(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]acetic acid (262 mg), aniline (102 mg) and HATU (570 mg) were dissolved in pyridine (5 ml), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (40 ml), and the precipitated crystals were collected by filtration, washed with water, and vacuum-dried to give the object compound (320 mg). 
     MS (ESI+, m/e) 338 (M+1) 
     In the same manner as in Reference Example 806, the following compounds (Reference Examples 807-826) shown in Table 14-1-Table 14-2 were obtained. 
     
       
         
           
               
             
               
                 TABLE 14-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 807 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(3-fluorophenyl)acetamide 
                 356 
               
               
                   
               
               
                 808 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(4-fluorophenyl)acetamide 
                 356 
               
               
                   
               
               
                 809 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2-methylphenyl)acetamide 
                 352 
               
               
                   
               
               
                 810 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(4-methylphenyl)acetamide 
                 352 
               
               
                   
               
               
                 811 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-[2-(difluoromethoxy)phenyl] acetamide 
                 404 
               
               
                   
               
               
                 812 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-[3-(difluoromethoxy)phenyl] acetamide 
                 404 
               
               
                   
               
               
                 813 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-[2-methoxy-5-(trifluoromethyl) phenyl]acetamide 
                 436 
               
               
                   
               
               
                 814 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2,3-dihydro-1H-inden-4- yl)acetamide 
                 378 
               
               
                   
               
               
                 815 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-(1,3-Benzodioxol-5-yl)-2-[(2R)-4- benzyl-3,6-dioxopiperazin-2- yl]acetamide 
                 382 
               
               
                   
               
               
                 816 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(4-methoxy-2- methylphenyl)acetamide 
                 382 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 817 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(5-methoxy-2-methylphenyl)acetamide 
                 382 
               
               
                   
               
               
                 818 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2-methoxy-6-methylphenyl)acetamide 
                 382 
               
               
                   
               
               
                 819 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2-methoxy-4-methylphenyl)acetamide 
                 382 
               
               
                   
               
               
                 820 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2-methoxy-5-methylphenyl)acetamide 
                 382 
               
               
                   
               
               
                 821 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(3-methoxy-4-methylphenyl)acetamide 
                 382 
               
               
                   
               
               
                 822 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(3-methoxy-2-methylphenyl)acetamide 
                 382 
               
               
                   
               
               
                 823 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(4-fluoro-3-methoxyphenyl)acetamide 
                 386 
               
               
                   
               
               
                 824 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2-isopropylphenyl)acetamide 
                 380 
               
               
                   
               
               
                 825 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(2,4-difluorophenyl)acetamide 
                 374 
               
               
                   
               
               
                 826 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2-[(2R)-4-Benzyl-3,6-dioxopiperazin- 2-yl]-N-(3,5-difluorophenyl)acetamide 
                 374 
               
               
                   
               
            
           
         
       
     
     Reference Example 827 
     N-{2-[(2R)-4-Benzylpiperazin-2-yl]ethyl}aniline 
     
       
         
         
             
             
         
       
     
     A mixture of 2-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]-N-phenylacetamide (320 mg) and THF (10 ml) was ice-cooled, and lithium aluminum hydride (216 mg) was added by small portions. The mixture was stirred at room temperature for 30 min, and then at 60° C. for 15 hr, and cooled to −78° C. Ethanol-ethyl acetate (1:1, 1 ml) and 1N aqueous sodium hydroxide solution (2 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with ethyl acetate. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (145 mg) as an oil. 
     MS (ESI+, m/e) 296 (M+1) 
     In the same manner as in Reference Example 827, the following compounds (Reference Examples 828-847) shown in Table 15-1-Table 15-2 were obtained. 
     
       
         
           
               
             
               
                 TABLE 15-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 828 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-3-fluoroaniline 
                 314 
               
               
                   
               
               
                 829 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-4-fluoroaniline 
                 314 
               
               
                   
               
               
                 830 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-methylaniline 
                 310 
               
               
                   
               
               
                 831 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-4-methylaniline 
                 310 
               
               
                   
               
               
                 832 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-(difluoromethoxy)aniline 
                 362 
               
               
                   
               
               
                 833 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-3-(difluoromethoxy)aniline 
                 362 
               
               
                   
               
               
                 834 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-methoxy-5- (trifluoromethyl)aniline 
                 394 
               
               
                   
               
               
                 835 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}indan-4-amine 
                 336 
               
               
                   
               
               
                 836 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-1,3-benzodioxol-5-amine 
                 340 
               
               
                   
               
               
                 837 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-4-methoxy-2-methylaniline 
                 340 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 838 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-5-methoxy-2-methylaniline 
                 340 
               
               
                   
               
               
                 839 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-2-methoxy-6-methylaniline 
                 340 
               
               
                   
               
               
                 840 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-2-methoxy-4-methylaniline 
                 340 
               
               
                   
               
               
                 841 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-2-methoxy-5-methylaniline 
                 340 
               
               
                   
               
               
                 842 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-3-methoxy-4-methylaniline 
                 340 
               
               
                   
               
               
                 843 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-3-methoxy-2-methylaniline 
                 340 
               
               
                   
               
               
                 844 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-4-fluoro-3-methoxyaniline 
                 344 
               
               
                   
               
               
                 845 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-2-isopropylaniline 
                 338 
               
               
                   
               
               
                 846 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}2,4-difluoroaniline 
                 332 
               
               
                   
               
               
                 847 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2-yl] ethyl}-3,5-difluoroaniline 
                 332 
               
               
                   
               
            
           
         
       
     
     Reference Example 848 
     N-{2-[(2R)-4-Benzylpiperazin-2-yl]ethyl}-4-(difluoromethoxy)aniline 
     
       
         
         
             
             
         
       
     
     [(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]acetic acid (262 mg) and 4-(difluoromethoxy)aniline (159 mg) were dissolved in pyridine (5 ml), HATU (570 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with heptane, and the mixture was again concentrated under reduced pressure to remove pyridine. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crystals were collected by filtration to give 2-[(2R)-4-benzyl-3,6-dioxopiperazin-2-yl]-N-[4-(difluoromethoxy)phenyl]acetamide (370 mg). The total amount thereof was suspended in THF (10 ml), and the suspension was ice-cooled. Lithium aluminum hydride (200 mg) was added by small portions, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 3 hr, and was cooled to −78° C. Water (0.2 ml), 4N aqueous sodium hydroxide solution (0.2 ml) and water (0.6 ml) were successively added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 40 min. The insoluble material was filtered, and washed with THF. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-10:1) was concentrated under reduced pressure to give the object compound (330 mg) as an oil. 
     MS (ESI+, m/e) 362 (M+1) 
     In the same manner as in Reference Example 848, the following compounds (Reference Examples 849-854) shown in Table 16 were obtained. 
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ref. Ex. No. 
                 R 
                 Compound 
                 MS(ESI+) 
               
               
                   
               
               
                 849 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-fluoro-4-methoxyaniline 
                 344 
               
               
                   
               
               
                 850 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-4-fluoro-2-methoxyaniline 
                 344 
               
               
                   
               
               
                 851 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-3-fluoro-2-methoxyaniline 
                 344 
               
               
                   
               
               
                 852 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-fluoro-3-methoxyaniline 
                 344 
               
               
                   
               
               
                 853 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-fluoro-5-methoxyaniline 
                 344 
               
               
                   
               
               
                 854 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N-{2-[(2R)-4-Benzylpiperazin-2- yl]ethyl}-2-fluoro-3-methoxyaniline 
                 344 
               
               
                   
               
            
           
         
       
     
     Reference Example 855 
     2-[(2R)-4-Benzylpiperazin-2-yl]-N-phenylacetamide 
     
       
         
         
             
             
         
       
     
     [(2R)-4-Benzyl-1-(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (200 mg) and aniline (55 mg) were dissolved in pyridine (5 ml), HATU (340 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with heptane, and the mixture was again concentrated under reduced pressure to remove pyridine. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give tert-butyl (2R)-2-(2-anilino-2-oxoethyl)-4-benzylpiperazine-1-carboxylate (120 mg) as an amorphous solid. This was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (5 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (110 mg). 
     MS (ESI+, m/e) 310 (M+1) 
     In the same manner as in Reference Example 855, the following compound (Reference Example 856) was obtained. 
     Reference Example 856 
     2-[(2R)-4-Benzylpiperazin-2-yl]-N-methyl-N-phenylacetamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 324 (M+1) 
     Reference Example 857 
     N-(3-Methoxyphenyl)-2-nitrobenzenesulfonamide 
     
       
         
         
             
             
         
       
     
     3-Methoxyaniline (1.2 g) and triethylamine (2 ml) were dissolved in THF (20 ml), and the solution was ice-cooled. 2-Nitrobenzenesulfonyl chloride (2.65 g) was added thereto, and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (3.2 g). 
       1 H-NMR (CDCl 3 ) δ 3.77 (3H, s), 6.68-6.78 (2H, m), 6.82 (1H, t), 7.16 (1H, t), 7.55-7.76 (2H, m), 7.83-7.91 (2H, m) 
     In the same manner as in Reference Example 857, the following compounds (Reference Examples 858-862) were obtained. 
     Reference Example 858 
     N-(3-Acetylphenyl)-2-nitrobenzenesulfonamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.57 (3H, s), 7.36-7.54 (3H, m), 7.54-7.66 (1H, m), 7.68-7.79 (3H, m), 7.83-7.90 (2H, m) 
     Reference Example 859 
     2-Nitro-N-[4-(trifluoromethoxy)phenyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 7.05-7.39 (4H, m), 7.53-8.00 (4H, m) 
     Reference Example 860 
     2-Nitro-N-[4-(1H-pyrazol-1-yl)phenyl]benzenesulfonamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 6.47-6.58 (1H, m), 7.23 (2H, d), 7.67-8.09 (5H, m), 8.39 (1H, d), 10.81 (1H, s) 
     Reference Example 861 
     N-(2-Methyl-1,3-benzothiazol-5-yl)-2-nitrobenzenesulfonamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) δ 2.75 (3H, s), 3.58 (1H, br s), 7.18 (1H, dd), 7.60 (1H, d), 7.73-8.04 (5H, m), 10.88 (4H, s) 
     Reference Example 862 
     N-(2-Methyl-1,3-benzothiazol-6-yl)-2-nitrobenzenesulfonamide 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) δ 2.82 (3H, s), 7.20 (1H, dd), 7.46 (1H, br s), 7.50-7.58 (1H, m), 7.64-7.73 (1H, m), 7.75-7.83 (3H, m), 7.87 (1H, dd) 
     Reference Example 863 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{(3-acetylphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (885 mg) was dissolved in DMF (20 ml), N-(3-acetylphenyl)-2-nitrobenzenesulfonamide (1.3 g) and cesium carbonate (1.3 g) were added thereto. The mixture was stirred at 60° C. for 12 hr, and the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (700 mg) as an amorphous solid. 
     MS (ESI+, m/e) 555 (M+1) 
     Reference Example 864 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{[(2-nitrophenyl)sulfonyl][4-(trifluoromethoxy)phenyl]amino}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     2-Nitro-N-[4-(trifluoromethoxy)phenyl]benzenesulfonamide (652 mg), 1-tert-butyl 4-benzyl (2R)-2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate (550 mg) and triphenylphosphine (472 mg) were dissolved in toluene (20 ml), DEAD (40% toluene solution, 1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (740 mg) as an amorphous solid. 
     MS (ESI+, m/e) 709 (M+1) 
     In the same manner as in Reference Example 864, the following compounds (Reference Examples 865-867) were obtained. 
     Reference Example 865 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{[(2-nitrophenyl)sulfonyl][4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 691 (M+1) 
     Reference Example 866 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{(2-methyl-1,3-benzothiazol-5-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 696 (M+1) 
     Reference Example 867 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{(2-methyl-1,3-benzothiazol-6-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 696 (M+1) 
     Reference Example 868 
     Benzyl (3R)-3-{2-[(3-acetylphenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-{(3-acetylphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate (700 mg) and mercaptoacetic acid (0.22 ml) were dissolved in DMF (5 ml), lithium hydroxide monohydrate (264 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and poured into saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-{2-[(3-acetylphenyl)amino]ethyl}piperazine-1,4-dicarboxylate (190 mg) as an amorphous solid. The total amount thereof was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (120 mg). 
     MS (ESI+, m/e) 382 (M+1) 
     In the same manner as in Reference Example 868, the following compounds (Reference Examples 869-870) were obtained. 
     Reference Example 869 
     Benzyl (3R)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 424 (M+1) 
     Reference Example 870 
     Benzyl (3R)-3-(2-{[4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 406 (M+1) 
     Reference Example 871 
     Benzyl (3R)-3-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (530 mg), N-(2-methoxyphenyl)-2-nitrobenzenesulfonamide (490 mg), potassium carbonate (415 mg) and DMF (10 ml) was stirred at 50° C. for 12 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate (650 mg) as an oil. This was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (490 mg). 
     MS (ESI+, m/e) 555 (M+1) 
     In the same manner as in Reference Example 871, the following compound (Reference Example 872) was obtained. 
     Reference Example 872 
     Benzyl (3R)-3-(2-{(3-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 555 (M+1) 
     Reference Example 873 
     Benzyl (3R)-3-(2-{(2-methyl-1,3-benzothiazol-5-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     1-tert-Butyl 4-benzyl (2R)-2-(2-{(2-methyl-1,3-benzothiazol-5-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1,4-dicarboxylate (420 mg) was dissolved in ethyl acetate (5 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and the suspension was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (310 mg). 
     MS (ESI+, m/e) 596 (M+1) 
     In the same manner as in Reference Example 873, the following compound (Reference Example 874) was obtained. 
     Reference Example 874 
     Benzyl (3R)-3-(2-{(2-methyl-1,3-benzothiazol-6-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 596 (M+1) 
     In the same manner as in Reference Example 529, the following compounds (Reference Examples 875-877) were obtained. 
     Reference Example 875 
     1-{[4-({(2R)-4-Benzyl-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]methyl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 617 (M+1) 
     Reference Example 876 
     1-({4-[((2R)-4-Benzyl-2-{2-[(2-fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}methyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 626 (M+1) 
     Reference Example 877 
     1-({4-[((2R)-4-Benzyl-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}methyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 626 (M+1) 
     Reference Example 878 
     Methyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(2-bromobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-bromobenzyl)piperazine-1-carboxylate (1.78 g) was dissolved in methanol (5 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in DMF (30 ml). 1-{(1S,2S)-2-[(Methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid (1.37 g), WSC.HCl (1.15 g), HOBt (757 mg) and N,N-diisopropylethylamine (3.56 ml) were added, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (2.31 g) as an amorphous solid. 
     MS (ESI+, m/e) 670 (M+1) 
     Reference Example 879 
     (1S,2R)-2-(4-{[(2S)-4-Benzyl-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (330 mg) and [(2S)-4-benzylpiperazin-2-yl]methanol (206 mg) were suspended in DMF (10 ml), WSC.HCl (288 mg) and HOBt (189 mg) were added thereto, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (410 mg) as an amorphous solid. 
     MS (ESI+, m/e) 519 (M+1) 
     In the same manner as in Reference Example 879, the following compounds (Reference Examples 880-881) were obtained. 
     Reference Example 880 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-bromobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 657 (M+1) 
     Reference Example 881 
     tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylthio)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 621 (M+1) 
     Reference Example 882 
     tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylsulfinyl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylthio)methyl]piperazine-1-carboxylate (310 mg) was dissolved in dichloromethane (5 ml), and the solution was ice-cooled. mCPBA (123 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (312 mg) as an amorphous solid. 
     MS (ESI+, m/e) 637 (M+1) 
     Reference Example 883 
     tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylsulfonyl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3S)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylthio)methyl]piperazine-1-carboxylate (310 mg) was dissolved in dichloromethane (5 ml), and the solution was ice-cooled. mCPBA (247 mg) was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (317 mg) as an amorphous solid. 
     MS (ESI+, m/e) 653 (M+1) 
     Reference Example 884 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol and (1S,2R)-2-(4-{[(2S)-4-benzyl-2-(biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (200 mg), 1-benzyl-3-(biphenyl-2-ylmethyl)piperazine (240 mg), WSC.HCl (173 mg) and HOBt (110 mg) in DMF (7 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fractions eluted with ethyl acetate-methanol (4:1) were concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (180 mg) as an amorphous solid, and (1S,2R)-2-(4-{[(2S)-4-benzyl-2-(biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (130 mg) as an amorphous solid. 
     MS (ESI+, m/e) 655 (M+1) 
     MS (ESI+, m/e) 655 (M+1) 
     In the same manner as in Reference Example 884, the following compound (Reference Example 885) was obtained. 
     Reference Example 885 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol and (1S,2R)-2-(4-{[(2S)-4-benzyl-2-(2-methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 609 (M+1) 
     MS (ESI+, m/e) 609 (M+1) 
     In the same manner as in Reference Example 519, the following compounds (Reference Examples 886-890) were obtained. 
     Reference Example 886 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 664 (M+1) 
     Reference Example 887 
     (1S,2R)-2-[4-({(2R)-4-Benzyl-2-[2-(2-methoxypyridin-3-yl)benzyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 686 (M+1) 
     Reference Example 888 
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-phenoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 671 (M+1) 
     Reference Example 889 
     (1S,2R)-2-[4-({(2R)-4-Benzyl-2-[2-(1-methyl-1H-pyrazol-5-yl)benzyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 659 (M+1) 
     Reference Example 890 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{[3-(methoxycarbonyl)phenyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 710 (M+1) 
     Reference Example 891 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (490 mg), benzyl (3R)-3-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate (290 mg), WSC.HCl (253 mg) and HOBt (175 mg) in DMF (10 ml) was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object compound (600 mg) as an amorphous solid. 
     MS (ESI+, m/e) 867 (M+1) 
     In the same manner as in Reference Example 891, the following compounds (Reference Examples 892-894) were obtained. 
     Reference Example 892 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{(3-methoxyphenyl) [(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 867 (M+1) 
     Reference Example 893 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{(2-methyl-1,3-benzothiazol-5-yl) [(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 908 (M+1) 
     Reference Example 894 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{(2-methyl-1,3-benzothiazol-6-yl) [(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 908 (M+1) 
     Reference Example 895 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(2-methoxyphenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-{(2-methoxyphenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)piperazine-1-carboxylate (300 mg) and mercaptoacetic acid (92 mg) were dissolved in DMF (5 ml), lithium hydroxide monohydrate (84 mg) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and poured into saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (190 mg) as an amorphous solid. 
     MS (ESI+, m/e) 682 (M+1) 
     In the same manner as in Reference Example 895, the following compounds (Reference Examples 896-898) were obtained. 
     Reference Example 896 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(3-methoxyphenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 682 (M+1) 
     Reference Example 897 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 723 (M+1) 
     Reference Example 898 
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(2-methyl-1,3-benzothiazol-6-yl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 723 (M+1) 
     In the same manner as in Reference Example 645, the following compounds (Reference Examples 899-901) were obtained. 
     Reference Example 899 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(piperidin-1-ylcarbonyl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 654 (M+1) 
     Reference Example 900 
     tert-Butyl (3R)-3-{2-[(anilinocarbonyl)oxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 662 (M+1) 
     Reference Example 901 
     [(2S)-4-benzyl-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl phenylcarbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 638 (M+1) 
     Reference Example 902 
     Benzyl (3R)-3-{2-[acetyl(phenyl)amino]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-3-(2-anilinoethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate obtained in the course of the below-mentioned Example 428 (150 mg) and triethylamine (0.048 ml) were dissolved in dichloromethane (5 ml), and the solution was ice-cooled. Acetyl chloride (59 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure to give the object compound (90 mg) as an amorphous solid. 
     MS (ESI+, m/e) 694 (M+1) 
     In the same manner as in Reference Example 902, the following compound (Reference Example 903) was obtained. 
     Reference Example 903 
     Benzyl (3R)-3-{2-[(cyclopropylcarbonyl)(phenyl)amino]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 720 (M+1) 
     Reference Example 904 
     tert-Butyl (3R)-3-[2-(4-bromo-2-fluorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-[4-({(2R)-2-[2-(4-Bromo-2-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (the compound of the below-mentioned Example 257) (220 mg) was dissolved in THF (10 ml), di-tert-butyl bicarbonate (94 mg) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (270 mg) as an amorphous solid. 
     MS (ESI+, m/e) 715 (M+1) 
     Reference Example 905 
     tert-Butyl (3R)-3-{2-[2-fluoro-4-(1H-pyrazol-1-yl)phenoxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-[2-(4-bromo-2-fluorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (220 mg), potassium carbonate (85 mg), copper iodide (I) (19 mg) and pyrazole (42 mg) were suspended in DMF (5 ml), and the suspension was reacted at 160° C. for 5 min using microwave reactor. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (30 mg) as an amorphous solid. 
     MS (ESI+, m/e) 703 (M+1) 
     Reference Example 906 
     tert-Butyl (3R)-3-[2-(1,3-dihydro-2H-isoindol-2-yl)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-oxoethyl)piperazine-1-carboxylate (200 mg) and isoindoline (132 mg) were dissolved in dichloromethane-DMF (2:1, 3 ml), acetic acid (67 μl) was added, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (235 mg) was added thereto, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (110 mg) as an oil. 
     MS (ESI+, m/e) 644 (M+1) 
     In the same manner as in Reference Example 906, the following compounds (Reference Examples 907-909) were obtained. 
     Reference Example 907 
     tert-Butyl (3R)-3-[2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 658 (M+1) 
     Reference Example 908 
     tert-Butyl (3R)-3-[2-(3,4-dihydroquinolin-1(2H)-yl)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 658 (M+1) 
     Reference Example 909 
     tert-Butyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(pyridin-2-ylamino)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 619 (M+1) 
     In the same manner as in Reference Example 341, the following compounds (Reference Examples 910-912) were obtained. 
     Reference Example 910 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2,3-dihydro-1-benzofuran-6-yloxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 483 (M+1) 
     Reference Example 911 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 496 (M+1) 
     Reference Example 912 
     1-tert-Butyl 4-benzyl (2R)-2-[2-({4-[(acetyloxy)methyl]-1,3-thiazol-2-yl}thio)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 492 (M+1) 
     In the same manner as in Reference Example 425, the following compounds (Reference Examples 913-915) were obtained. 
     Reference Example 913 
     Benzyl (3R)-3-[2-(2,3-dihydro-1-benzofuran-6-yloxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 383 (M+1) 
     Reference Example 914 
     Benzyl (3R)-3-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 396 (M+1) 
     Reference Example 915 
     Benzyl (3R)-3-[2-({4-[(acetyloxy)methyl]-1,3-thiazol-2-yl}thio)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 392 (M+1) 
     In the same manner as in Reference Example 879, the following compound (Reference Example 916) was obtained. 
     Reference Example 916 
     tert-Butyl (3S)-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylthio)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 631 (M+1) 
     In the same manner as in Reference Example 883, the following compound (Reference Example 917) was obtained. 
     Reference Example 917 
     tert-Butyl (3S)-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[(phenylsulfonyl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 663 (M+1) 
     Reference Example 918 
     2-Ethyl-1,3-benzothiazol-5-ol and 2-isopropyl-1,3-benzothiazol-5-ol 
     
       
         
         
             
             
         
       
     
     To an ice-cooled solution of diisopropylamine (1.5 ml) in THF (6 ml) was added dropwise n-butyllithium (5 ml, 2.5M hexane solution), and the mixture was stirred for 30 min. The mixture was added dropwise to a solution of 5-bromo-2-methyl-1,3-benzothiazole (1.14 g) in THF (6 ml) which was cooled to −78° C., and the mixture was stirred at the same temperature for 30 min. Methyl iodide (1.6 ml) was added, and the mixture was further stirred for 1 hr. To the reaction mixture was added ethyl acetate (50 ml), and the mixture was allowed to warm to room temperature, and washed successively with 1N hydrochloric acid (10 ml) and brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure. The residue, bis(pinacolato)diboron (1.5 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (200 g) and potassium acetate (4 g) were dissolved in THF (40 ml), and the solution was stirred at refluxing temperature for 20 hr. To the reaction mixture was added ethyl acetate-water (2:1), and the insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure. The residue was dissolved in acetone (20 ml), and a solution of potassium peroxymonosulfate (3.0 g) in water (20 ml) was added at room temperature. The mixture was stirred at room temperature for 10 min, aqueous saturated thiosodium sulfate solution (20 ml) was added, and the liberated oil was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 2-ethyl-1,3-benzothiazol-5-ol (324 mg) and 2-isopropyl-1,3-benzothiazol-5-ol (245 mg) as an amorphous solid, respectively. 
     2-Ethyl-1,3-benzothiazol-5-ol 
       1 H-NMR (CDCl 3 ) δ 1.48 (3H, t), 3.21 (2H, q), 6.77 (1H, br s), 6.99 (1H, dd), 7.47-7.72 (2H, m) 
     2-Isopropyl-1,3-benzothiazol-5-ol 
       1 H-NMR (CDCl 3 ) δ 1.50 (6H, d), 3.54 (1H, dt), 5.46 (1H, br s), 6.98 (1H, dd), 7.53 (1H, d), 7.63 (1H, d). 
     Reference Example 919 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     A solution of 1-tert-butyl 4-benzyl (2R)-2-{2-[(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy]ethyl}piperazine-1,4-dicarboxylate (152 mg) in DMF (5 ml) was ice-cooled, sodium hydride (60% in oil) (12 mg) was added, and the mixture was stirred at room temperature for 30 min. 1-Bromo-3-methoxypropane (46 mg) was added, and the mixture was stirred for 2 hr, and poured into ice-cooled saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (220 mg) as an oil. 
     MS (ESI+, m/e) 582 (M+1) 
     In the same manner as in Reference Example 919, the following compound (Reference Example 920) was obtained. 
     Reference Example 920 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{[1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 568 (M+1) 
     In the same manner as in Reference Example 341, the following compounds (Reference Examples 921-948) were obtained. 
     Reference Example 921 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 401 (M+1-“Boc”) 
     Reference Example 922 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-methoxy-2-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 385 (M+1-“Boc”) 
     Reference Example 923 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-fluoro-4-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 473 (M+1) 
     Reference Example 924 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-chloro-4-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 489 (M+1) 
     Reference Example 925 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(4-chloro-2-fluorophenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 393 (M+1-“Boc”) 
     Reference Example 926 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2,3-dichlorophenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 409 (M+1-“Boc”) 
     Reference Example 927 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-fluoro-3-methoxyphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 489 (M+1) 
     Reference Example 928 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[3-(3-methoxypropoxy)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 529 (M+1) 
     Reference Example 929 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[3-(2-methoxyethoxy)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 515 (M+1) 
     Reference Example 930 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2,3-dihydro-1-benzofuran-6-yloxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 483 (M+1) 
     Reference Example 931 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(5-methoxy-2-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 485 (M+1) 
     Reference Example 932 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(5-chloro-2-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 490 (M+1) 
     Reference Example 933 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-chloro-5-methoxyphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 506 (M+1) 
     Reference Example 934 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2-chloro-4-methoxyphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 506 (M+1) 
     Reference Example 935 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 522 (M+1) 
     Reference Example 936 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2,7-dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 510 (M+1) 
     Reference Example 937 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 496 (M+1) 
     Reference Example 938 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 510 (M+1) 
     Reference Example 939 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-ethyl-7-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 524 (M+1) 
     Reference Example 940 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-ethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 510 (M+1) 
     Reference Example 941 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 496 (M+1) 
     Reference Example 942 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[3,5-bis(trifluoromethyl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 577 (M+1) 
     Reference Example 943 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[3-fluoro-5-(trifluoromethyl)phenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 527 (M+1) 
     Reference Example 944 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3,5-difluorophenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 427 (M+1) 
     Reference Example 945 
     1-tert-Butyl 4-benzyl (2R)-2-(2-{[3-(2-methoxy-2-oxoethyl)-2,3-dihydro-1-benzofuran-5-yl]oxy}ethyl)piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 555 (M+1) 
     Reference Example 946 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(4-tert-butylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 497 (M+1) 
     Reference Example 947 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3,4-dimethylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 469 (M+1) 
     Reference Example 948 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[4-isopropylphenoxy]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 483 (M+1) 
     In the same manner as in Reference Example 663, the following compounds (Reference Examples 949-951) were obtained. 
     Reference Example 949 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(5-chloro-2-methylphenyl)amino]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 488 (M+1) 
     Reference Example 950 
     1-tert-Butyl 4-benzyl (2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 488 (M+1) 
     Reference Example 951 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2,3-dihydrofuro[3,2-b]pyridin-5-ylamino)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 483 (M+1) 
     In the same manner as in Reference Example 383, the following compounds (Reference Examples 952-981) were obtained. 
     Reference Example 952 
     Benzyl (3R)-3-(2-{[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 482 (M+1) 
     Reference Example 953 
     Benzyl (3R)-3-(2-{[1-(2-methoxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 468 (M+1) 
     Reference Example 954 
     Benzyl (3R)-3-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 401 (M+1) 
     Reference Example 955 
     Benzyl (3R)-3-[2-(3-methoxy-2-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 385 (M+1) 
     Reference Example 956 
     Benzyl (3R)-3-[2-(2-fluoro-4-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 373 (M+1) 
     Reference Example 957 
     Benzyl (3R)-3-[2-(2-chloro-4-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 389 (M+1) 
     Reference Example 958 
     Benzyl (3R)-3-[2-(4-chloro-2-fluorophenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 393 (M+1) 
     Reference Example 959 
     Benzyl (3R)-3-[2-(2,3-dichlorophenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 409 (M+1) 
     Reference Example 960 
     Benzyl (3R)-3-[2-(2-fluoro-3-methoxyphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 389 (M+1) 
     Reference Example 961 
     Benzyl (3R)-3-{2-[3-(3-methoxypropoxy)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 429 (M+1) 
     Reference Example 962 
     Benzyl (3R)-3-{2-[3-(2-methoxyethoxy)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 415 (M+1) 
     Reference Example 963 
     Benzyl (3R)-3-[2-(2,3-dihydro-1-benzofuran-6-yloxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 383 (M+1) 
     Reference Example 964 
     Benzyl (3R)-3-[2-(5-methoxy-2-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 385 (M+1) 
     Reference Example 965 
     Benzyl (3R)-3-[2-(5-chloro-2-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 390 (M+1) 
     Reference Example 966 
     Benzyl (3R)-3-[2-(2-chloro-5-methoxyphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 406 (M+1) 
     Reference Example 967 
     Benzyl (3R)-3-[2-(2-chloro-4-methoxyphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 406 (M+1) 
     Reference Example 968 
     Benzyl (3R)-3-{2-[(2-cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 422 (M+1) 
     Reference Example 969 
     Benzyl (3R)-3-{2-[(2,7-dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 410 (M+1) 
     Reference Example 970 
     Benzyl (3R)-3-{2-[(2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 396 (M+1) 
     Reference Example 971 
     Benzyl (3R)-3-{2-[(2-ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 410 (M+1) 
     Reference Example 972 
     Benzyl (3R)-3-{2-[(2-ethyl-7-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 424 (M+1) 
     Reference Example 973 
     Benzyl (3R)-3-{2-[(2-ethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 410 (M+1) 
     Reference Example 974 
     Benzyl (3R)-3-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 396 (M+1) 
     Reference Example 975 
     Benzyl (3R)-3-{2-[3,5-bis(trifluoromethyl)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 477 (M+1) 
     Reference Example 976 
     Benzyl (3R)-3-{2-[3-fluoro-5-(trifluoromethyl)phenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 427 (M+1) 
     Reference Example 977 
     Benzyl (3R)-3-[2-(3,5-difluorophenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 327 (M+1) 
     Reference Example 978 
     Benzyl (3R)-3-(2-{[3-(2-methoxy-2-oxoethyl)-2,3-dihydro-1-benzofuran-5-yl]oxy}ethyl)piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 455 (M+1) 
     Reference Example 979 
     Benzyl (3R)-3-[2-(4-tert-butylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 397 (M+1) 
     Reference Example 980 
     Benzyl (3R)-3-[2-(3,4-dimethylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 369 (M+1) 
     Reference Example 981 
     Benzyl (3R)-3-{2-[4-isopropylphenoxy]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 383 (M+1) 
     Reference Example 982 
     Benzyl (3R)-3-{2-[(5-chloro-2-methylphenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 388 (M+1) 
     Reference Example 983 
     Benzyl (3R)-3-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 388 (M+1) 
     Reference Example 984 
     Benzyl (3R)-3-[2-(2,3-dihydrofuro[3,2-b]pyridin-5-ylamino)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 383 (M+1) 
     In the same manner as in Reference Example 243, the following compound (Reference Example 985) was obtained. 
     Reference Example 985 
     tert-Butyl (3S)-3-[(5-phenyl-2H-tetrazol-2-yl)methyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 345 (M+1) 
     In the same manner as in Reference Example 806, the following compounds (Reference Examples 986-988) were obtained. 
     Reference Example 986 
     2-[(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]-N-(2,5-dimethylphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 366 (M+1) 
     Reference Example 987 
     2-[(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]-N-(5-fluoro-2-methylphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 370 (M+1) 
     Reference Example 988 
     2-[(2R)-4-Benzyl-3,6-dioxopiperazin-2-yl]-N-(2-fluoro-3-methoxyphenyl)acetamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 386 (M+1) 
     In the same manner as in Reference Example 827, the following compounds (Reference Examples 989-991) were obtained. 
     Reference Example 989 
     N-{2-[(2R)-4-Benzylpiperazin-2-yl]ethyl}-2,5-dimethylaniline 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 324 (M+1) 
     Reference Example 990 
     N-{2-[(2R)-4-Benzylpiperazin-2-yl]ethyl}-5-fluoro-2-methylaniline 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 328 (M+1) 
     Reference Example 991 
     N-{2-[(2R)-4-Benzylpiperazin-2-yl]ethyl}-2-fluoro-3-methoxyaniline 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 344 (M+1) 
     In the same manner as in Reference Example 255, the following compounds (Reference Examples 992-995) were obtained. 
     Reference Example 992 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(2,6-difluorophenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 377 (M+1-Boc) 
     Reference Example 993 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(naphthalen-2-yloxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 391 (M+1-Boc) 
     Reference Example 994 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(4-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 355 (M+1-Boc) 
     Reference Example 995 
     1-tert-Butyl 4-benzyl (2R)-2-[2-(3-methoxy-4-methylphenoxy)ethyl]piperazine-1,4-dicarboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 385 (M+1-Boc) 
     In the same manner as in Reference Example 383, the following compounds (Reference Examples 996-999) were obtained. 
     Reference Example 996 
     Benzyl (3R)-3-[2-(2,6-difluorophenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 377 (M+1) 
     Reference Example 997 
     Benzyl (3R)-3-[2-(naphthalen-2-yloxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 391 (M+1) 
     Reference Example 998 
     Benzyl (3R)-3-[2-(4-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 385 (M+1) 
     Reference Example 999 
     Benzyl (3R)-3-[2-(3-methoxy-4-methylphenoxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 385 (M+1) 
     Reference Example 1000 
     Benzyl (3R)-3-[2-(2,3-dihydro-1H-inden-2-yloxy)ethyl]piperazine-1-carboxylate 
     
       
         
         
             
             
         
       
     
     2,3-Dihydro-1H-inden-2-ol (161 mg) was dissolved in DMF (5 ml), sodium hydride (60% in oil) (60 mg) was added, and the mixture was stirred at room temperature for 1 hr. 1-tert-Butyl 4-benzyl (2R)-2-{2-[(methylsulfonyl)oxy]ethyl}piperazine-1,4-dicarboxylate (443 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give 1-tert-butyl 4-benzyl (2R)-2-[2-(2,3-dihydro-1H-inden-2-yloxy)ethyl]piperazine-1,4-dicarboxylate (252 mg) as an oil. The obtained 1-tert-butyl 4-benzyl (2R)-2-[2-(2,3-dihydro-1H-inden-2-yloxy)ethyl]piperazine-1,4-dicarboxylate (252 mg) was dissolved in methanol (5 ml), 4N hydrogen chloride-ethyl acetate solution was added. The mixture was stirred at room temperature for 5 hr, and concentrated to give the object compound (157 mg). 
     MS (ESI+, m/e) 381 (M+1) 
     In the same manner as in Reference Example 529, the following compound (Reference Example 1001) was obtained. 
     Reference Example 1001 
     tert-Butyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 670 (M+1) 
     Reference Example 1002 
     (1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine 
     
       
         
         
             
             
         
       
     
     tert-Butyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (5.04 g) was dissolved in methanol (10 ml), 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 5 hr, and concentrated. Aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the object compound (4.02 g). 
     MS (ESI+, m/e) 570 (M+1) 
     Reference Example 1003 
     1-[(1S,2S)-2-{[(Cyclobutyloxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.57 g) and DMAP (916 mg) were dissolved in THF (50 ml), and the solution was ice-cooled. 4-Nitrophenyl chloroformate (1.21 g) was added, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 2 hr. To the reaction mixture was added cyclobutanol (0.77 ml), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give ethyl 1-[(1S,2S)-2-{[(cyclobutyloxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.22 g) as an amorphous solid. The obtained ethyl 1-[(1S,2S)-2-{[(cyclobutyloxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.22 g) was dissolved in ethanol (30 ml), 2N aqueous sodium hydroxide solution (14.8 ml) was added, and the mixture was stirred at 60° C. for 15 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (1.20 g) as a powder mixed with an inorganic salt thereof. 
     NMR (DMSO-d 6 ) δ: 0.84-1.13 (1H, m), 1.36 (3H, br. s.), 1.42-2.01 (8H, m), 2.04-2.26 (2H, m), 3.11-3.24 (1H, m), 3.70-3.97 (1H, m), 4.67 (1H, t, J=7.5), 7.12 (1H, d, J=9.0), 7.29-7.40 (2H, m), 7.39-7.59 (3H, m), 8.31 (1H, s), 12.23 (1H, br. s.). 
     Reference Example 1004 
     1-[(1S,2S)-2-{[(2-Methoxyethoxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S,2S)-2-aminocyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (940 mg) and triethylamine (0.836 ml) were dissolved in THF (50 ml), 2-methoxyethyl chlorocarbonate (499 mg) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give ethyl 1-[(1S,2S)-2-{[(2-methoxyethoxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.20 g). The obtained ethyl 1-[(1S,2S)-2-{[(2-methoxyethoxy)carbonyl]amino}cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (1.20 g) was dissolved in methoxyethanol (30 ml), 2N aqueous sodium hydroxide solution (14.5 ml) was added, and the mixture was stirred at 60° C. for 15 hr. After cooling to room temperature, the mixture was neutralized (pH 7) with diluted hydrochloric acid, and the solvent was evaporated under reduced pressure. The residue was suspended in ethanol (100 ml), and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (1.23 g) as a powder mixed with an inorganic salt thereof. 
     NMR (CDCl 3 ) δ: 0.93-1.48 (4H, m), 1.48-2.08 (4H, m), 2.08-2.56 (2H, m), 2.94-4.10 (8H, m), 6.76-7.89 (6H, m). 
     In the same manner as in Reference Example 1004, the following compound (Reference Example 1005) was obtained. 
     Reference Example 1005 
     1-{(1S,2S)-2-[(Methylsulfonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
     NMR (DMSO-d 6 ) δ: 0.86-1.07 (1H, m), 1.14-1.46 (1H, m), 1.62 (3H, d, J=9.8), 1.70-1.91 (2H, m), 2.56 (3H, s), 2.96-3.63 (2H, m), 3.63-3.86 (1H, m), 7.10 (1H, d, J=9.1), 7.27-7.39 (2H, m), 7.38-7.47 (3H, m), 7.98 (1H, s). 
     In the same manner as in Reference Example 39, the following compound (Reference Example 1006) was obtained. 
     Reference Example 1006 
     Ethyl 1-{(1S,2S)-2-[(isopropoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate 
     
       
         
         
             
             
         
       
     
       1 H-NMR (CDCl 3 ) 6: ppm 1.12-1.23 (11H, m), 1.34-1.46 (1H, m), 1.73-1.86 (3H, m), 2.02-2.10 (2H, m), 3.46-3.53 (1H, m), 3.85 (1H, brs), 4.09-4.13 (1H, m), 4.20 (2H, q), 4.72-4.80 (1H, m), 7.30-7.32 (2H, m), 7.48-7.51 (3H, m), 7.73 (1H, s). 
     In the same manner as in Reference Example 66, the following compound (Reference Example 1007) was obtained. 
     Reference Example 1007 
     1-{(1S,2S)-2-[(Isopropoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid 
     
       
         
         
             
             
         
       
     
       1 H-NMR (DMSO-d 6 ) 6: ppm 1.08 (6H, dd), 1.07-1.09 (1H, m), 1.24-1.35 (2H, m), 1.63-1.78 (3H, m), 1.94-2.07 (2H, m), 3.49-3.58 (1H, m), 3.86-3.88 (1H, m), 4.53-4.61 (1H, m), 7.15 (1H, d), 7.39-7.41 (2H, m), 7.54-7.57 (3H, m), 9.40 (1H, brs), 11.99 (1H, brs). 
     Example 1 
     Method A 
     (1R,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (129 mg), (3R)-1-benzyl-3-(3,5-difluorobenzyl)piperazine (142 mg), WSC.HCl (104 mg) and HOBt (73 mg) in DMF (3 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give (1R,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol (205 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (6 ml), 20% palladium hydroxide-carbon (50% containing water, 105 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (50:1-10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (2 ml), 4N hydrogen chloride-ethyl acetate solution (99 μl) was added, and the precipitated crystals were collected by filtration to give the object compound (89 mg). 
     MS (ESI+, m/e) 481 (M+1) 
     Example 2 
     Method B 
     (2R)-2-Benzyl-1-({1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazole-4-carboxylic acid (460 mg), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (368 mg), WSC.HCl (292 mg) and HOBt (206 mg) in DMF (8 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(benzyloxy)cyclopentyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (401 mg) as an amorphous solid. 200 mg therefrom was dissolved in dichloromethane (1 ml), TFA (1 ml) was added thereto, and the mixture was stirred at room temperature for 30 min. After stirring, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (152 mg). 
     MS (ESI+, m/e) 521 (M+1) 
     Example 3 
     Method C 
     (1S,2R)-2-(4-{[(2R)-2-(2,4-Dichlorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (132 mg), tert-butyl (3R)-3-(2,4-dichlorobenzyl)piperazine-1-carboxylate (145 mg), WSC.HCl (92 mg) and HOBt (65 mg) in DMF (3.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give tert-butyl (3R)-3-(2,4-dichlorobenzyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (194 mg) as an amorphous solid. The total amount thereof was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with diethyl ether (8 ml), and the precipitated crystals were collected by filtration to give the object compound (93 mg). 
     MS (ESI+, m/e) 557 (M+1) 
     Example 4 
     Method D 
     1-[(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate (440 mg), lithium hydroxide monohydrate (100 mg), ethanol (3 ml) and water (3 ml) was stirred at 60° C. for 10 hr, and concentrated under reduced pressure. The residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (440 mg), WSC.HCl (640 mg), HOBt (1.00 g) and DMF (7 ml). The mixture was stirred at 50° C. for 3 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4-1:0) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (510 mg) as an amorphous solid. 200 mg therefrom was dissolved in dichloromethane (2 ml), and TFA (2 ml) was added thereto. The mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object compound (116 mg). 
     MS (ESI+, m/e) 459 (M+1) 
     Example 5 
     Method E 
     1-[(1S)-1-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)ethyl]cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     Ethyl 1-[(1S)-1-(1-hydroxycyclohexyl)ethyl]-5-phenyl-1H-imidazole-4-carboxylate (900 mg) and lithium hydroxide monohydrate (220 mg) were dissolved in a mixed solvent of methanol (10 ml) and water (2 ml). The solution was heated under reflux for 15 hr, and concentrated under reduced pressure. The residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (730 mg), WSC.HCl (610 mg), HOBt (1.21 g) and DMF (10 ml). The mixture was stirred at 60° C. for 3 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[(1S)-1-(1-hydroxycyclohexyl)ethyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate. The total amount thereof was dissolved in ethyl acetate (2.5 ml), and 4N hydrogen chloride-ethyl acetate solution (2.5 ml) was added thereto. The mixture was stirred for 30 min, and concentrated under reduced pressure to give the object compound (696 mg). 
     MS (ESI+, m/e) 473 (M+1) 
     Example 6 
     Method F 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     Methyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (100 mg) was dissolved in methanol (2 ml), 20% palladium hydroxide-carbon (50% containing water, 30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (78 mg) as an amorphous solid. 
     MS (ESI+, m/e) 502 (M+1) 
     Example 7 
     Method G 
     trans-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cycloheptanol 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (250 mg) was dissolved in dichloromethane (2 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (199 mg). 
     MS (ESI+, m/e) 459 (M+1) 
     Example 8 
     Method H 
     cis-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cycloheptanol hydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[cis-2-hydroxycycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (165 mg) was dissolved in ethyl acetate (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hr. Diethyl ether (10 ml) was added, and the crystals were collected by filtration, and washed with diethyl ether to give the object compound (146 mg). 
     MS (ESI+, m/e) 459 (M+1). 
     Example 9 
     Method I 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,6-Dimethylpyridin-3-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-{2-[(2,6-dimethylpyridin-3-yl)oxy]ethyl}piperazine-1-carboxylate (194 mg), WSC.HCl (115 mg) and HOBt (81 mg) in DMF (3.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give benzyl (3R)-3-{2-[(2,6-dimethylpyridin-3-yl)oxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (268 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (7.5 ml), 20% palladium hydroxide-carbon (50% containing water, 135 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (25:1-10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (5 ml), 4N hydrogen chloride-ethyl acetate solution (216 μl) was added thereto, and the precipitated crystals were collected by filtration to give the object compound (184 mg). 
     MS (ESI+, m/e) 548 (M+1) 
     Example 10 
     Method J 
     1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (216 mg), WSC.HCl (115 mg) and HOBt (81 mg) in DMF (3.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (290 mg) as an amorphous solid. The total amount thereof was dissolved in 25% hydrogen bromide-acetic acid solution (2 ml), and the solution was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was washed with diethyl ether. Potassium carbonate was added by small portions to the aqueous layer to basify the layer, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (25:1-10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (3 ml), 4N hydrogen chloride-ethyl acetate solution (110 μl) was added thereto, and the precipitated crystals were collected by filtration to give the object compound (68 mg). 
     MS (ESI+, m/e) 590 (M+1) 
     Example 11 
     Method K 
     (1S,2R)-2-{4-([(2R)-2-[2-(2-Chlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     A mixture of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-[2-(2-chlorophenoxy)ethyl]piperazine-1-carboxylate hydrochloride (208 mg), WSC.HCl (144 mg), HOBt (115 mg), triethylamine (101 mg) and DMF (2 ml) was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give benzyl (3R)-3-[2-(2-chlorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (200 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (95 mg) as an amorphous solid. 
     MS (ESI+, m/e) 554 (M+1) 
     Example 12 
     Method L 
     1-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (100 mg), benzyl (3R)-3-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (125 mg), WSC.HCl (115 mg), HOBt (45 mg) and triethylamine (150 μl) in DMF (4 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-17:3) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)ethyl]piperazine-1-carboxylate (124 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 10 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (55 mg). 
     MS (ESI+, m/e) 559 (M+1) 
     Example 13 
     Method M 
     1-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1,2-dihydro-3H-indazol-3-one dihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (100 mg), benzyl (3R)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (125 mg), WSC HCl (115 mg), HOBt (45 mg) and triethylamine (150 μl) in DMF (4 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-17:3) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (49 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (3 ml), 4N aqueous sodium hydroxide solution (1 ml) was added thereto, and the mixture was stirred at 70° C. for 10 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (16 mg). 
     MS (ESI+, m/e) 559 (M+1) 
     Example 14 
     Method N 
     1-{2-[(2R)-1-({1-[(1-Hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1,2-dihydro-3H-indazol-3-one dihydrochloride 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate (100 mg), lithium hydroxide monohydrate (20 mg), ethanol (3 ml) and water (1 ml) was stirred at 80° C. for 3 hr, and concentrated under reduced pressure. The residue was mixed with benzyl (3R)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (134 mg), WSC.HCl (115 mg), HOBt (230 mg), triethylamine (150 μl) and DMF (4 ml). The mixture was stirred at 50° C. for 5 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:9:0-17:0:3) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(3-oxo-2,3-dihydro-1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (43 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (4 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (37 mg). 
     MS (ESI+, m/e) 529 (M+1) 
     Example 15 
     Method O 
     Methyl 4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoate 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate (216 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (115 mg) as an amorphous solid. 
     MS (ESI+, m/e) 577 (M+1) 
     In the same manner as in the above-mentioned Example 1 (Method A)-Example 15 (Method O), the following compounds (Examples 16-343) shown in Table 17-1-Table 17-3, Table 18-1-Table 18-10, Table 19-1-Table 19-2, Table 20-1-Table 20-2, Table 21-1-Table 21-4 and Table 22-1-Table 22-12 were obtained. Where necessary, each compound was isolated and purified by a known means such as phase transfer, liquid conversion, solvent extraction, silica gel column chromatography, reversed-phase preparative HPLC and the like. The final products were isolated as a hydrochloride by a treatment with 4N hydrogen chloride-ethyl acetate solution, as in Method A and the like, or isolated as crystals or an amorphous solid in a free from, as in Method B and the like. In the column of “Salt” in the Tables, the compounds described as “-” were isolated as a free form. 
     
       
         
           
               
             
               
                 TABLE 17-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 441 
               
               
                   
               
               
                 17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 441 
               
               
                   
               
               
                 18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 D 
                 — 
                 415 
               
               
                   
               
               
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 HCl 
                 395 
               
               
                   
               
               
                 20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 D 
                 — 
                 443 
               
               
                   
               
               
                 21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 527 
               
               
                   
               
               
                 22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 2HCl 
                 459 
               
               
                   
               
               
                 23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 535 
               
               
                   
               
               
                 24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 535 
               
               
                   
               
               
                 25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 411 
               
               
                   
               
               
                 26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 543 
               
               
                   
               
               
                 27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 475 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 566 
               
               
                   
               
               
                 29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 600 
               
               
                   
               
               
                 30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 543 
               
               
                   
               
               
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 502 
               
               
                   
               
               
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 472 
               
               
                   
               
               
                 33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 478 
               
               
                   
               
               
                 34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 435 
               
               
                   
               
               
                 35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 D 
                 TFA 
                 558 
               
               
                   
               
               
                 36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 G 
                 — 
                 500 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 E 
                 HCl 
                 535 
               
               
                   
               
               
                 38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 E 
                 — 
                 535 
               
               
                   
               
               
                 39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 459 
               
               
                   
               
               
                 40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 N 
                 2HCl 
                 489 
               
               
                   
               
               
                 41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 519 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                 MS 
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
               
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 E 
                 HCl 
                 445 
               
               
                   
               
               
                 43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 445 
               
               
                   
               
               
                 44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 445 
               
               
                   
               
               
                 45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 443 
               
               
                   
               
               
                 46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 443 
               
               
                   
               
               
                 47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 HCl 
                 487 
               
               
                   
               
               
                 48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 HCl 
                 594 
               
               
                   
               
               
                 49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 B 
                 — 
                 516 
               
               
                   
               
               
                 50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 B 
                 — 
                 447 
               
               
                   
               
               
                 51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 470 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 444 
               
               
                   
               
               
                 53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 571 
               
               
                   
               
               
                 54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 652 
               
               
                   
               
               
                 55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 512 
               
               
                   
               
               
                 56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 548 
               
               
                   
               
               
                 57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 514 
               
               
                   
               
               
                 58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 515 
               
               
                   
               
               
                 59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 2,3-F 2   
                 B 
                 — 
                 481 
               
               
                   
               
               
                 60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 3-F 
                 G 
                 — 
                 463 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 4-F 
                 B 
                 — 
                 463 
               
               
                   
               
               
                 62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 513 
               
               
                   
               
               
                 63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 531 
               
               
                   
               
               
                 64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 582 
               
               
                   
               
               
                 65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 517 
               
               
                   
               
               
                 66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 531 
               
               
                   
               
               
                 67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 517 
               
               
                   
               
               
                 68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 485 
               
               
                   
               
               
                 69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 — 
                 516 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 TFA 
                 503 
               
               
                   
               
               
                 71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 516 
               
               
                   
               
               
                 72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 530 
               
               
                   
               
               
                 73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 530 
               
               
                   
               
               
                 74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 608 
               
               
                   
               
               
                 75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 533 
               
               
                   
               
               
                 76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 TFA 
                 530 
               
               
                   
               
               
                 77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 502 
               
               
                   
               
               
                 78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 547 
               
               
                   
               
               
                 79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 F 
                 — 
                 444 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 544 
               
               
                   
               
               
                 81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 516 
               
               
                   
               
               
                 82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 — 
                 544 
               
               
                   
               
               
                 83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 501 
               
               
                   
               
               
                 84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 501 
               
               
                   
               
               
                 85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 582 
               
               
                   
               
               
                 86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 517 
               
               
                   
               
               
                 87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 539 
               
               
                   
               
               
                 88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 557 
               
               
                   
               
               
                 89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 487 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-6 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 503 
               
               
                   
               
               
                 91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 459 
               
               
                   
               
               
                 92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 531 
               
               
                   
               
               
                 93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 519 
               
               
                   
               
               
                 94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 529 
               
               
                   
               
               
                 95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 529 
               
               
                   
               
               
                 96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 586 
               
               
                   
               
               
                 97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 588 
               
               
                   
               
               
                 98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 HCl 
                 489 
               
               
                   
               
               
                 99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 HCl 
                 517 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-7 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 HCl 
                 503 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 551 
               
               
                   
               
               
                 102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 526 
               
               
                   
               
               
                 103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 561 
               
               
                   
               
               
                 104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 517 
               
               
                   
               
               
                 105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 559 
               
               
                   
               
               
                 106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 473 
               
               
                   
               
               
                 107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 487 
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 498 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 F 
                 — 
                 514 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-8 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 559 
               
               
                   
               
               
                 111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 572 
               
               
                   
               
               
                 112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 569 
               
               
                   
               
               
                 113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 549 
               
               
                   
               
               
                 114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 563 
               
               
                   
               
               
                 115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 575 
               
               
                   
               
               
                 116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 589 
               
               
                   
               
               
                 117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 573 
               
               
                   
               
               
                 118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 581 
               
               
                   
               
               
                 119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 595 
               
               
                   
               
               
                 120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 621 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-9 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 551 
               
               
                   
               
               
                 122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 554 
               
               
                   
               
               
                 123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 572 
               
               
                   
               
               
                 124 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 D 
                 — 
                 516 
               
               
                   
               
               
                 125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 — 
                 563 
               
               
                   
               
               
                 126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 560 
               
               
                   
               
               
                 127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 2HCl 
                 566 
               
               
                   
               
               
                 128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 — 
                 605 
               
               
                   
               
               
                 129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 HCl 
                 591 
               
               
                   
               
               
                 130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 530 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18-10 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                 MS 
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
               
                 131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 G 
                 — 
                 588 
               
               
                   
               
               
                 132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 D 
                 — 
                 574 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                   
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 133 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 463 
               
               
                   
               
               
                 134 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 453 
               
               
                   
               
               
                 135 
                 2-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 463 
               
               
                   
               
               
                 136 
                 3,5-F 2   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 481 
               
               
                   
               
               
                 137 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 463 
               
               
                   
               
               
                 138 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 463 
               
               
                   
               
               
                 139 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 481 
               
               
                   
               
               
                 140 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 513 
               
               
                   
               
               
                 141 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 513 
               
               
                   
               
               
                 142 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 471 
               
               
                   
               
               
                 143 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 486 
               
               
                   
               
               
                 144 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 D 
                 — 
                 461 
               
               
                   
               
               
                 145 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 E 
                 HCl 
                 461 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 146 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 499 
               
               
                   
               
               
                 147 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 513 
               
               
                   
               
               
                 148 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 E 
                 HCl 
                 497 
               
               
                   
               
               
                 149 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 E 
                 HCl 
                 497 
               
               
                   
               
               
                 150 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 E 
                 2HCl 
                 462 
               
               
                   
               
               
                 151 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 475 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 R3 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 530 
               
               
                   
               
               
                 153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 544 
               
               
                   
               
               
                 154 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 546 
               
               
                   
               
               
                 155 
                 Et 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 534 
               
               
                   
               
               
                 156 
                 Et 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 534 
               
               
                   
               
               
                 157 
                 Et 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 534 
               
               
                   
               
               
                 158 
                 Et 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 541 
               
               
                   
               
               
                 159 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 538 
               
               
                   
               
               
                 160 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 527 
               
               
                   
               
               
                 161 
                 Me 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 D 
                 — 
                 520 
               
               
                   
               
               
                 162 
                 Et 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 D 
                 — 
                 534 
               
               
                   
               
               
                 163 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 516 
               
               
                   
               
               
                 164 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 534 
               
               
                   
               
               
                 165 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 518 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 R3 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 166 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 532 
               
               
                   
               
               
                 167 
                 Me 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 556 
               
               
                   
               
               
                 168 
                 Et 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 546 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 169 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 HCl 
                 513 
               
               
                   
               
               
                 170 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 495 
               
               
                   
               
               
                 171 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 455 
               
               
                   
               
               
                 172 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 441 
               
               
                   
               
               
                 173 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 469 
               
               
                   
               
               
                 174 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 490 
               
               
                   
               
               
                 175 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 2HCl 
                 490 
               
               
                   
               
               
                 176 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 543 
               
               
                   
               
               
                 177 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 525 
               
               
                   
               
               
                 178 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 525 
               
               
                   
               
               
                 179 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 519 
               
               
                   
               
               
                 180 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 528 
               
               
                   
               
               
                 181 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 525 
               
               
                   
               
               
                 182 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 532 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 183 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 2HCl 
                 496 
               
               
                   
               
               
                 184 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 503 
               
               
                   
               
               
                 185 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 2HCl 
                 574 
               
               
                   
               
               
                 186 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 469 
               
               
                   
               
               
                 187 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 493 
               
               
                   
               
               
                 188 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 — 
                 480 
               
               
                   
               
               
                 189 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 HCl 
                 505 
               
               
                   
               
               
                 190 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 508 
               
               
                   
               
               
                 191 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 HCl 
                 519 
               
               
                   
               
               
                 192 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 568 
               
               
                   
               
               
                 193 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 HCl 
                 479 
               
               
                   
               
               
                 194 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 HCl 
                 529 
               
               
                   
               
               
                 195 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 — 
                 530 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 196 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 574 
               
               
                   
               
               
                 197 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 574 
               
               
                   
               
               
                 198 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 3HCl 
                 564 
               
               
                   
               
               
                 199 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 588 
               
               
                   
               
               
                 200 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 588 
               
               
                   
               
               
                 201 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 3HCl 
                 479 
               
               
                   
               
               
                 202 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 2HCl 
                 507 
               
               
                   
               
               
                 203 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 2HCl 
                 547 
               
               
                   
               
               
                 204 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 — 
                 529 
               
               
                   
               
               
                 205 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 519 
               
               
                   
               
               
                 206 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 519 
               
               
                   
               
               
                 207 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 557 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 21-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 208 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 529 
               
               
                   
               
               
                 209 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 B 
                 — 
                 571 
               
               
                   
               
               
                 210 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 615 
               
               
                   
               
               
                 211 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 457 
               
               
                   
               
               
                 212 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 533 
               
               
                   
               
               
                 213 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 557 
               
               
                   
               
               
                 214 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 557 
               
               
                   
               
               
                 215 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 593 
               
               
                   
               
               
                 216 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 489 
               
               
                   
               
               
                 217 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 567 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 218 
                 OH 
                 F 
                 — 
                 443 
               
               
                   
               
               
                 219 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 497 
               
               
                   
               
               
                 220 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 591 
               
               
                   
               
               
                 221 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 603 
               
               
                   
               
               
                 222 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 591 
               
               
                   
               
               
                 223 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 520 
               
               
                   
               
               
                 224 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 588 
               
               
                   
               
               
                 225 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 521 
               
               
                   
               
               
                 226 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 588 
               
               
                   
               
               
                 227 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 588 
               
               
                   
               
               
                 228 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 549 
               
               
                   
               
               
                 229 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 577 
               
               
                   
               
               
                 230 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 545 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 231 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 561 
               
               
                   
               
               
                 232 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 561 
               
               
                   
               
               
                 233 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 561 
               
               
                   
               
               
                 234 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 585 
               
               
                   
               
               
                 235 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 560 
               
               
                   
               
               
                 236 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 599 
               
               
                   
               
               
                 237 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 2TFA 
                 568 
               
               
                   
               
               
                 238 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 585 
               
               
                   
               
               
                 239 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 540 
               
               
                   
               
               
                 240 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 561 
               
               
                   
               
               
                 241 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 577 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 242 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 590 
               
               
                   
               
               
                 243 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 602 
               
               
                   
               
               
                 244 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 537 
               
               
                   
               
               
                 245 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 537 
               
               
                   
               
               
                 246 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 549 
               
               
                   
               
               
                 247 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 549 
               
               
                   
               
               
                 248 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 651 
               
               
                   
               
               
                 249 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 597 
               
               
                   
               
               
                 250 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 589 
               
               
                   
               
               
                 251 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 588 
               
               
                   
               
               
                 252 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 588 
               
               
                   
               
               
                 253 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 578 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                 MS 
               
               
                 No. 
                 R 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
               
                 254 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 587 
               
               
                   
               
               
                 255 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 554 
               
               
                   
               
               
                 256 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 554 
               
               
                   
               
               
                 257 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 616 
               
               
                   
               
               
                 258 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 586 
               
               
                   
               
               
                 259 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 601 
               
               
                   
               
               
                 260 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 533 
               
               
                   
               
               
                 261 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 591 
               
               
                   
               
               
                 262 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 590 
               
               
                   
               
               
                 263 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 644 
               
               
                   
               
               
                 264 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 576 
               
               
                   
               
               
                 265 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 574 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 266 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 578 
               
               
                   
               
               
                 267 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 601 
               
               
                   
               
               
                 268 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 2HCl 
                 645 
               
               
                   
               
               
                 269 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 HCl 
                 612 
               
               
                   
               
               
                 270 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 605 
               
               
                   
               
               
                 271 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 544 
               
               
                   
               
               
                 272 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 595 
               
               
                   
               
               
                 273 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 595 
               
               
                   
               
               
                 274 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 578 
               
               
                   
               
               
                 275 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 595 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-6 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 276 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 609 
               
               
                   
               
               
                 277 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 3HCl 
                 577 
               
               
                   
               
               
                 278 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 588 
               
               
                   
               
               
                 279 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 HCl 
                 583 
               
               
                   
               
               
                 280 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 579 
               
               
                   
               
               
                 281 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 567 
               
               
                   
               
               
                 282 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 563 
               
               
                   
               
               
                 283 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 2HCl 
                 591 
               
               
                   
               
               
                 284 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 621 
               
               
                   
               
               
                 285 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 576 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-7 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 286 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 594 
               
               
                   
               
               
                 287 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 567 
               
               
                   
               
               
                 288 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 HCl 
                 627 
               
               
                   
               
               
                 289 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 HCl 
                 583 
               
               
                   
               
               
                 290 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 563 
               
               
                   
               
               
                 291 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 579 
               
               
                   
               
               
                 292 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 593 
               
               
                   
               
               
                 293 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 617 
               
               
                   
               
               
                 294 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 602 
               
               
                   
               
               
                 295 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 567 
               
               
                   
               
               
                 296 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 567 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-8 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                 MS 
               
               
                 No. 
                 R 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
               
                 297 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 551 
               
               
                   
               
               
                 298 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 595 
               
               
                   
               
               
                 299 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 607 
               
               
                   
               
               
                 300 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 588 
               
               
                   
               
               
                 301 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 2HCl 
                 576 
               
               
                   
               
               
                 302 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 635 
               
               
                   
               
               
                 303 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 577 
               
               
                   
               
               
                 304 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 563 
               
               
                   
               
               
                 305 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 586 
               
               
                   
               
               
                 306 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 619 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-9 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                 MS 
               
               
                 No. 
                 R 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
               
                 307 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 619 
               
               
                   
               
               
                 308 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 619 
               
               
                   
               
               
                 309 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 631 
               
               
                   
               
               
                 310 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 631 
               
               
                   
               
               
                 311 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 507 
               
               
                   
               
               
                 312 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 543 
               
               
                   
               
               
                 313 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 561 
               
               
                   
               
               
                 314 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 544 
               
               
                   
               
               
                 315 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 569 
               
               
                   
               
               
                 316 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 2HCl 
                 574 
               
               
                   
               
               
                 317 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 2HCl 
                 560 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-10 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 318 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 579 
               
               
                   
               
               
                 319 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 579 
               
               
                   
               
               
                 320 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 681 
               
               
                   
               
               
                 321 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 573 
               
               
                   
               
               
                 322 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 601 
               
               
                   
               
               
                 323 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 605 
               
               
                   
               
               
                 324 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 542 
               
               
                   
               
               
                 325 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 569 
               
               
                   
               
               
                 326 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 521 
               
               
                   
               
               
                 327 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 524 
               
               
                   
               
               
                 328 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 538 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-11 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 329 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 534 
               
               
                   
               
               
                 330 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 566 
               
               
                   
               
               
                 331 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 579 
               
               
                   
               
               
                 332 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 621 
               
               
                   
               
               
                 333 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 536 
               
               
                   
               
               
                 334 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 565 
               
               
                   
               
               
                 335 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 550 
               
               
                   
               
               
                 336 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 578 
               
               
                   
               
               
                 337 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 2HCl 
                 566 
               
               
                   
               
               
                 338 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 601 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22-12 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 MS(ESI+) 
               
               
                   
               
               
                 339 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 601 
               
               
                   
               
               
                 340 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 605 
               
               
                   
               
               
                 341 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 567 
               
               
                   
               
               
                 342 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 566 
               
               
                   
               
               
                 343 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 566 
               
               
                   
               
            
           
         
       
     
     The chemical names of the compounds (Examples 16-343) shown in Table 17-1-Table 17-3, Table 18-1-Table 18-10, Table 19-1-Table 19-2, Table 20-1-Table 20-2, Table 21-1-Table 21-4 and Table 22-1-Table 22-12 are as follows.
     Example 16: (2R)-2-Benzyl-1-({1-[(2R)-bicyclo[2.2.1]hept-2-yl]-phenyl-1H-imidazol-4-yl}carbonyl)piperazine   Example 17: (2R)-2-Benzyl-1-{[1-(bicyclo[2.2.1]hept-2-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine   Example 18: (2R)-2-Benzyl-1-[(1-cyclopentyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine   Example 19: {(2S)-1-[(1-Cyclopentyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}(cyclopropyl)methanol hydrochloride   Example 20: (2R)-2-Benzyl-1-[(1-cycloheptyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine   Example 21: 1-[4-({(2R)-1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)phenyl]-2,2,2-trifluoroethanol   Example 22: (2S)-2-[(Benzyloxy)methyl]-1-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine dihydrochloride   Example 23: (2R)-2-Benzyl-1-({1-[(1R,2R)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine   Example 24: (2R)-2-Benzyl-1-({1-[(1S,2S)-2-(benzyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine   Example 25: 1-{1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}-2-methylpropan-2-ol   Example 26: (1S,2S)-2-[5-Phenyl-4-({(2R)-2-[4-(2,2,2-trifluoro-1-hydroxyethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 27: (1S,2S)-2-[4-({(2S)-2-[(Benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 28: Methyl 5-[({(2S)-1-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)(isopropyl)amino]-2,2-dimethyl-5-oxopentanoate hydrochloride   Example 29: Methyl 5-[({(2S)-1-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)(phenyl)amino]-2,2-dimethyl-5-oxopentanoate hydrochloride   Example 30: N-({(2S)-1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)-N-phenylsuccinamide hydrochloride   Example 31: N-({(2S)-1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)-2-methoxybenzamide hydrochloride   Example 32: N-({(2S)-1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)benzamide hydrochloride   Example 33: N-({(2S)-1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}methyl)cyclohexanecarboxamide hydrochloride   Example 34: (2R)-2-(Cyclohexylmethyl)-1-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine   Example 35: 4-{cis-4-[(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]-4-hydroxycyclohexyl}morpholin-3-one trifluoroacetate   Example 36: (6S)-6-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-oxa-3-azaspiro[4.5]decan-2-one   Example 37: 1-[(S)-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)(phenyl)methyl]cyclohexanol hydrochloride   Example 38: 1-[(R)-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)(phenyl)methyl]cyclohexanol   Example 39: (2R)-1-[(1-Cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]-2-(2-phenoxyethyl)piperazine dihydrochloride   Example 40: 1-[(4-{[(2R)-2-(2-Phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol dihydrochloride   Example 41: 1-{[4-({(2R)-2-[2-(2-Methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]methyl}cyclohexanol   Example 42: trans-4-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 43: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 44: (1R,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 45: (2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanone hydrochloride   Example 46: (2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanone hydrochloride   Example 47: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl acetate hydrochloride   Example 48: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl 4-nitrobenzoate hydrochloride   Example 49: Ethyl [(1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 50: (2R)-2-Benzyl-1-({1-[(1S,2R)-2-fluorocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine   Example 51: (2R)-1-({1-[(1S,2R)-2-Azidocyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-2-benzylpiperazine   Example 52: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine dihydrochloride   Example 53: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-N-(cyclopropylmethyl)cyclohexanamine dihydrochloride   Example 54: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-N,N-bis(cyclopropylmethyl)cyclohexanamine dihydrochloride   Example 55: N-[(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]cyclopropanecarboxamide   Example 56: N-[(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]cyclopropanesulfonamide   Example 57: N-[(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]butanamide   Example 58: N-[(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]-N′-ethylurea   Example 59: (1S,2S)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(2,3-difluorophenyl)-1H-imidazol-1-yl]cyclohexanol   Example 60: (1S,2S)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]cyclohexanol   Example 61: (1S,2S)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(4-fluorophenyl)-1H-imidazol-1-yl]cyclohexanol   Example 62: (2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(trifluoromethyl)cyclohexanol hydrochloride   Example 63: (2R)-2-Benzyl-1-({1-[(1S,2S)-2-(3-methoxypropoxy)cycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 64: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cycloheptyl(2-furylmethyl)carbamate hydrochloride   Example 65: (2R)-2-Benzyl-1-({1-[(1S,2S)-2-(2-methoxyethoxy)cycloheptyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 66: Ethyl [(2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]acetate   Example 67: (2R)-2-Benzyl-1-({1-[(1S,2S)-2-(3-methoxypropoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 68: (2R)-1-({1-[(1S,2S)-2-(Allyloxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-2-benzylpiperazine hydrochloride   Example 69: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl ethylcarbamate   Example 70: [(2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]acetic acid trifluoroacetate   Example 71: 2-[(2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]-N-methylacetamide   Example 72: 2-[(2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]-N,N-dimethylacetamide   Example 73: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl (ethyl)(methyl)carbamate hydrochloride   Example 74: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl methyl[2-(methylsulfonyl)ethyl]carbamate hydrochloride   Example 75: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(2-methoxyethoxy)methyl]cyclohexanol hydrochloride   Example 76: N-{2-[(2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]ethyl}acetamide trifluoroacetate   Example 77: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(ethylamino)methyl]cyclohexanol dihydrochloride   Example 78: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(3-methoxypropoxy)methyl]cyclohexanol hydrochloride   Example 79: (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine   Example 80: N-(3-{[(1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]oxy}propyl)acetamide   Example 81: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(ethyl)(methyl)amino]methyl}cyclohexanol dihydrochloride   Example 82: N-{[2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methyl}-N-ethylacetamide   Example 83: (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-butylcyclohexanol hydrochloride   Example 84: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-butylcyclohexanol hydrochloride   Example 85: 2-[(2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]-N-(2-furylmethyl)acetamide   Example 86: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(propoxymethyl)cyclohexanol hydrochloride   Example 87: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(2,2-difluoroethoxy)methyl]cyclohexanol hydrochloride   Example 88: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(2,2,2-trifluoroethoxy)methyl]cyclohexanol hydrochloride   Example 89: (2R)-2-Benzyl-1-({5-phenyl-1-[(1S,2S)-2-propoxycyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 90: (2R)-2-Benzyl-1-({1-[(1S,2S)-2-(2-methoxyethoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 91: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol hydrochloride   Example 92: (2R)-2-Benzyl-1-({1-[(1S,2S)-2-(4-methoxybutoxy)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 93: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(ethylthio)methyl]cyclohexanol hydrochloride   Example 94: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(cyclopropylmethoxy)methyl]cyclohexanol hydrochloride   Example 95: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(cyclobutyloxy)methyl]cyclohexanol hydrochloride   Example 96: 1-(2-{[2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)pyrrolidin-2-one hydrochloride   Example 97: 3-(2-{[2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)-1,3-oxazolidin-2-one hydrochloride   Example 98: (2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(2-hydroxyethyl)cyclohexanol hydrochloride   Example 99: (2R)-2-Benzyl-1-({1-[(1S)-2-methoxy-2-(2-methoxyethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine hydrochloride   Example 100: (2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(2-methoxyethyl)cyclohexanol hydrochloride   Example 101: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(ethylsulfonyl)methyl]cyclohexanol hydrochloride   Example 102: (2E)-2-[(2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexylidene]-N-propylacetamide hydrochloride   Example 103: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(3-hydroxy-3-methylbutoxy)methyl]cyclohexanol hydrochloride   Example 104: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(isopropoxymethyl)cyclohexanol hydrochloride   Example 105: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(tetrahydro-2H-pyran-4-yloxy)methyl]cyclohexanol hydrochloride   Example 106: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-ethylcyclohexanol hydrochloride   Example 107: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-propylcyclohexanol hydrochloride   Example 108: 3-[2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propanenitrile   Example 109: 3-[(1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]-1,3-oxazolidin-2-one   Example 110: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(3-methyloxetan-3-yl)methoxy]methyl}cyclohexanol   Example 111: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(1,3-thiazol-2-ylmethoxy)methyl]cyclohexanol hydrochloride   Example 112: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1-methyl-1H-imidazol-2-yl)methoxy]methyl}cyclohexanol dihydrochloride   Example 113: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[2-(methylthio)ethoxy]methyl}cyclohexanol hydrochloride   Example 114: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[3-(methylthio)propoxy]methyl}cyclohexanol hydrochloride   Example 115: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(tetrahydro-2H-thiopyran-4-yloxy)methyl]cyclohexanol hydrochloride   Example 116: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(tetrahydro-2H-thiopyran-4-ylmethoxy)methyl]cyclohexanol hydrochloride   Example 117: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(tetrahydro-2H-pyran-4-ylmethoxy)methyl]cyclohexanol hydrochloride   Example 118: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[2-(methylsulfonyl)ethoxy]methyl}cyclohexanol hydrochloride   Example 119: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[3-(methylsulfonyl)propoxy]methyl}cyclohexanol hydrochloride   Example 120: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]methyl}cyclohexanol hydrochloride   Example 121: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(phenoxymethyl)cyclohexanol hydrochloride   Example 122: 2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(2-furylmethyl)amino]methyl}cyclohexanol hydrochloride   Example 123: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(1,3-thiazol-2-ylmethoxy)methyl]cyclohexanol hydrochloride   Example 124: Ethyl [(1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 125: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[2-(2-hydroxyethoxy)ethoxy]methyl}cyclohexanol   Example 126: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[3-(dimethylamino)propoxy]methyl}cyclohexanol hydrochloride   Example 127: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(pyridin-2-ylmethoxy)methyl]cyclohexanol dihydrochloride   Example 128: (1R,2S)-1-[(1H-Benzimidazol-2-ylmethoxy)methyl]-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 129: (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(2,3-dihydro-1H-inden-2-yloxy)methyl]cyclohexanol hydrochloride   Example 130: Ethyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl](methyl)carbamate   Example 131: Ethyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl](3-methoxypropyl)carbamate   Example 132: Ethyl {[2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-ethoxycyclohexyl]methyl}carbamate   Example 133: (1R,2S)-2-(4-{[(2R)-2-(4-Fluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 134: (1R,2S)-2-(5-Phenyl-4-{[(2S)-2-(2,2,2-trifluoro-1-hydroxyethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 135: (1R,2S)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(2-fluorophenyl)-1H-imidazol-1-yl]cyclohexanol   Example 136: (1R,2S)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(3,5-difluorophenyl)-1H-imidazol-1-yl]cyclohexanol   Example 137: (1R,2S)-2-(4-{[(2R)-2-(2-Fluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 138: (1R,2S)-2-(4-{[(2R)-2-(3-Fluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 139: (1R,2S)-2-(4-{[(2R)-2-(3,4-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 140: (1R,2S)-2-[5-Phenyl-4-({(2R)-2-[3-(trifluoromethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol hydrochloride   Example 141: (1R,2S)-2-[5-Phenyl-4-({(2R)-2-[4-(trifluoromethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol hydrochloride   Example 142: (1R,2S)-2-(4-{[(2R)-2-(2,3-Dihydro-1H-inden-2-yl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 143: 2-{[(2S)-1-({1-[(1S,2R)-2-Hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methoxy}benzonitrile   Example 144: (1R,2S)-2-(4-{[(2S)-2-(Phenoxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 145: (1R,2S)-2-(4-{[(2S)-2-(Phenoxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 146: (1R,2S)-2-(5-Phenyl-4-{[(2R)-2-(2,4,5-trifluorobenzyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 147: (1R,2S)-2-[5-Phenyl-4-({(2R)-2-[2-(trifluoromethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol hydrochloride   Example 148: (1R,2S)-2-[4-({(2S)-2-[(3,5-Difluorophenoxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol hydrochloride   Example 149: (1R,2S)-2-[4-({(2S)-2-[(2,6-Difluorophenoxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol hydrochloride   Example 150: (1R,2S)-2-[5-Phenyl-4-({(2S)-2-[(pyridin-2-yloxy)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 151: (1R,2S)-2-(4-{[(2R)-2-(2-Phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 152: Isopropyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 153: Isobutyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 154: 2-Methoxyethyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 155: Ethyl [(1S,2S)-2-(4-{[(2R)-2-(2-fluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 156: Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3-fluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 157: Ethyl [(1S,2S)-2-(4-{[(2R)-2-(4-fluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 158: Ethyl [(1S,2S)-2-(4-{[(2R)-2-(4-cyanobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 159: Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 160: Methyl [(1S,2S)-2-(4-{[(2R)-2-(4-cyanobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 161: Methyl {(1S,2S)-2-[4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 162: Ethyl {(1S,2S)-2-[4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 163: Methyl [(1S,2S)-2-(5-phenyl-4-{[(2R)-2-(2-phenylethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 164: Methyl {(1S,2S)-2-[5-phenyl-4-({(2S)-2-[(phenylthio)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 165: Methyl [(1S,2S)-2-(4-{[(2S)-2-(phenoxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 166: Methyl [(1S,2S)-2-(4-{[(2R)-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 167: Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(1H-indazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 168: Ethyl [(1S,2S)-2-(4-{[(2R)-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 169: 4-{[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzonitrile hydrochloride   Example 170: (1S,2R)-2-(4-{[(2R)-2-(Cyclohexylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 171: (1S,2R)-2-(4-{[(2R)-2-Isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 172: (1S,2R)-2-(4-{[(2R)-2-Isopropylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 173: (1S,2R)-2-[4-({(2S)-2-[(Cyclopropyl)(hydroxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 174: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(pyridin-2-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 175: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(pyridin-4-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol dihydrochloride   Example 176: (1S,2R)-2-[4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 177: (1S,2R)-2-[4-{[(2R)-2-(4-Fluorobenzyl)piperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 178: (1S,2R)-2-[4-{[(2R)-2-(3-Fluorobenzyl)piperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 179: (1S,2R)-2-(4-{[(2R)-2-(4-Methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 180: (1S,2R)-2-(4-{[(2R)-2-(1H-Indol-3-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 181: (1S,2R)-2-[4-{[(2R)-2-(2-Fluorobenzyl)piperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 182: 4-{[(2R)-1-({5-(3-Fluorophenyl)-1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzonitrile   Example 183: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(1,3-thiazol-4-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol dihydrochloride   Example 184: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-phenylethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 185: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(4-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol dihydrochloride   Example 186: (1S,2R)-2-(4-{[(2R)-2-(2,2-Dimethylpropyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 187: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2S)-2-[(4-methyl-1H-pyrazol-1-yl)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 188: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2S)-2-(1H-1,2,4-triazol-1-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 189: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2S)-2-(phenoxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 190: (1S,2R)-2-(5-(3-Fluorophenyl)-4-{[(2R)-2-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 191: (1S,2R)-2-(4-{[(2R)-2-(3-Methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 192: 3,5-Difluoro-N-{[(2S)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzamide hydrochloride   Example 193: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2S)-2-(1H-pyrazol-1-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 194: (1S,2R)-2-(4-{[(2S)-2-(1H-Indazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 195: (1S,2R)-2-(4-{[(2S)-2-(1H-1,2,3-Benzotriazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 196: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2S)-2-({[6-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 197: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2S)-2-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 198: Methyl 6-{[(2S)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methoxy}nicotinate trihydrochloride   Example 199: (1S,2R)-2-{4-[((2R)-2-{(2R)-2-Hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 200: (1S,2R)-2-{4-[((2R)-2-{(2S)-2-Hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 201: (1S,2R)-2-(4-{[(2S)-2-(1H-Imidazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 202: (1S,2R)-2-[4-({(2S)-2-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 203: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2S)-2-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol dihydrochloride   Example 204: (1S,2R)-2-(4-{[(2S)-2-(1H-Benzimidazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 205: (1S,2R)-2-[4-({(2R)-2-[(2R)-2-Hydroxy-2-phenylethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 206: (1S,2R)-2-[4-({(2R)-2-[(2S)-2-Hydroxy-2-phenylethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 207: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol hydrochloride   Example 208: (1S,2R)-2-(4-{[(2R)-2-(1H-Benzimidazol-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 209: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[4-(trifluoromethyl)phenyl]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol   Example 210: (1S,2R)-2-{5-(3-Fluorophenyl)-4-[((2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 211: (1S,2R)-2-(4-{[(2R)-2-(3-Hydroxypropyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 212: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(3-phenoxypropyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 213: (1S,2R)-2-[4-({(2R)-2-[3-(1H-Indazol-1-yl)propyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 214: (1S,2R)-2-[4-({(2R)-2-[3-(2H-Indazol-2-yl)propyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 215: Ethyl 1-{3-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]propyl}-3-methyl-1H-pyrazole-5-carboxylate   Example 216: (1S,2R)-2-(4-{[(2S)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 217: (1S,2R)-2-[5-(3-Fluorophenyl)-4-({(2R)-2-[2-(2-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 218: (1S,2R)-2-(4-{[(2R)-2-(2-Hydroxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 219: (1S,2R)-2-[4-({(2R)-2-[2-(Cyclopropylmethoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 220: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol dihydrochloride   Example 221: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[2-(trifluoromethoxy)phenoxy]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol dihydrochloride   Example 222: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol dihydrochloride   Example 223: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(pyridin-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol trihydrochloride   Example 224: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[6-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol trihydrochloride   Example 225: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(pyrimidin-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 226: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[4-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol trihydrochloride   Example 227: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol trihydrochloride   Example 228: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(4-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 229: Methyl 3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoate   Example 230: 6-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}nicotinonitrile trihydrochloride   Example 231: 1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone   Example 232: 1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone dihydrochloride   Example 233: 1-(3-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone   Example 234: (1S,2R)-2-{4-[((2R)-2-{2-[4-(1H-Imidazol-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 235: (1S,2R)-2-[4-({(2R)-2-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 236: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[3-(2-methyl-1H-imidazol-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 237: Methyl 3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}isoxazole-5-carboxylate bistrifluoroacetate   Example 238: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[4-(1H-pyrazol-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol   Example 239: 2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl pyrrolidine-1-carboxylate dihydrochloride   Example 240: 1-(2-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone   Example 241: Methyl 2-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoate   Example 242: 4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-N,N-dimethylbenzamide   Example 243: (1S,2R)-2-{4-[((2R)-2-{2-[4-(Azetidin-1-ylcarbonyl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 244: (1S,2R)-2-[4-({(2R)-2-[2-(3-Fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 245: (1S,2R)-2-[4-({(2R)-2-[2-(4-Fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 246: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 247: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(3-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 248: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{4-[(trifluoromethyl)sulfonyl]phenoxy}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 249: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 250: (1S,2R)-2-{4-[((2R)-2-{2-[(2,2-Dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol hydrochloride   Example 251: 6-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydroquinolin-2(1H)-one   Example 252: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol trihydrochloride   Example 253: Methyl 5-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}nicotinate dihydrochloride   Example 254: 6-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydronaphthalen-1(2H)-one hydrochloride   Example 255: (1S,2R)-2-[4-({(2R)-2-[2-(3-Chlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 256: (1S,2R)-2-[4-({(2R)-2-[2-(4-Chlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 257: (1S,2R)-2-[4-({(2R)-2-[2-(4-Bromo-2-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 258: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol dihydrochloride   Example 259: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol dihydrochloride   Example 260: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 261: Methyl (4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)acetate   Example 262: (1S,2R)-2-{4-[((2R)-2-{2-[3-(Diethylamino)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 263: 4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-N-(2,2,2-trifluoroethyl)benzamide   Example 264: 6-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1,3-benzoxazol-2(3H)-one   Example 265: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[(3,5,6-trifluoropyridin-2-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol dihydrochloride   Example 266: Methyl 5-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}pyridine-2-carboxylate dihydrochloride   Example 267: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol dihydrochloride   Example 268: (1S,2R)-2-{4-[((2R)-2-{2-[4-(4-Acetylpiperazin-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 269: Ethyl 4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-2-methyl-1,3-thiazole-5-carboxylate hydrochloride   Example 270: Methyl 3-(4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)propionate   Example 271: 4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzonitrile   Example 272: Methyl 3-fluoro-4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoate   Example 273: Methyl 2-fluoro-4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoate   Example 274: Methyl 3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}pyridine-2-carboxylate dihydrochloride   Example 275: Ethyl 5-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1-methyl-1H-pyrazole-4-carboxylate hydrochloride   Example 276: Methyl (1-ethyl-3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1H-pyrazol-4-yl)acetate hydrochloride   Example 277: (1S,2R)-2-[4-({(2R)-2-[2-({2-[(Dimethylamino)methyl]pyridin-3-yl}oxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 278: 7-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydroquinolin-2(1H)-one   Example 279: Methyl 3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}thiophene-2-carboxylate hydrochloride   Example 280: 1-(3-Fluoro-4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone   Example 281: (1S,2R)-2-[4-({(2R)-2-[2-(4-Fluoro-2-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 282: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 283: 1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3-methoxyphenyl)ethanone dihydrochloride   Example 284: Ethyl 4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3-methoxybenzoate dihydrochloride   Example 285: (1S,2R)-2-(4-{[(2R)-2-(2-{4-[(Dimethylamino)methyl]phenoxy}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 286: (1S,2R)-2-(4-{[(2R)-2-(2-{4-[(Dimethylamino)methyl]-2-fluorophenoxy}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 287: (1S,2R)-2-[4-({(2R)-2-[2-(2-Fluoro-6-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 288: (1S,2R)-2-[4-({(2R)-2-[2-(4-Bromo-2-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 289: (1S,2R)-2-[4-({(2R)-2-[2-(4-Chloro-2-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 290: (1S,2R)-2-[4-({(2R)-2-[2-(2-Ethoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 291: (1S,2R)-2-[4-({(2R)-2-[2-(2,3-Dimethoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 292: (1S,2R)-2-[4-({(2R)-2-[2-(2,6-Dimethoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 293: 7-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-6-methoxy-2H-chromen-2-one   Example 294: 1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)pyrrolidin-2-one   Example 295: (1S,2R)-2-[4-({(2R)-2-[2-(2-Fluoro-4-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 296: (1S,2R)-2-[4-({(2R)-2-[2-(5-Fluoro-2-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 297: (1S,2R)-2-[4-({(2R)-2-[2-(2-Fluoro-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 298: Methyl 2-fluoro-5-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoate   Example 299: Methyl 3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-4-methoxybenzoate   Example 300: 5-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydroisoquinolin-1(2H)-one   Example 301: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(thieno[3,2-b]pyridine-7-yloxy)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 302: Ethyl (4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3-methoxyphenyl)acetate dihydrochloride   Example 303: (1S,2R)-2-[4-({(2R)-2-[2-(2-Isopropoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 304: (1S,2R)-2-[4-({(2R)-2-[2-(1,3-Benzodioxol-5-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol hydrochloride   Example 305: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[(1-phenyl-1H-1,2,4-triazol-3-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol hydrochloride   Example 306: (1S,2R)-2-{4-[((2R)-2-{2-[2-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 307: (1S,2R)-2-{4-[((2R)-2-{2-[3-Fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 308: (1S,2R)-2-{4-[((2R)-2-{2-[4-Fluoro-3-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 309: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[2-methoxy-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 310: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[2-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 311: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(4-methyl-1H-pyrazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 312: (1S,2R)-2-[4-({(2R)-2-[2-(1H-Benzimidazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 313: (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl-4-[((2R)-2-{2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]ethyl}piperazin-1-yl)carbonyl]-1H-imidazol-1-yl}cyclohexanol   Example 314: (1S,2R)-2-[4-({(2R)-2-[2-(1H-1,2,3-Benzotriazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 315: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(3-phenyl-1H-pyrazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 316: 4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-2H-1,4-benzoxazin-3(4H)-one dihydrochloride   Example 317: 3-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1,3-benzoxazol-2(3H)-one dihydrochloride   Example 318: Ethyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-3-methyl-1H-pyrazole-5-carboxylate   Example 319: Ethyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-5-methyl-1H-pyrazole-3-carboxylate   Example 320: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({2-[2-(4,5,6,7-tetrahydro-1H-indazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 321: 1-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-3-methyl-1,3-dihydro-2H-benzimidazol-2-one   Example 322: Methyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-indazole-4-carboxylate   Example 323: (1S,2R)-2-[4-({(2R)-2-[2-(3,5-Di-tert-butyl-1H-pyrazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 324: (1S,2R)-2-[4-({(2R)-2-[2-(1H-Indol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 325: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(2-phenyl-1H-imidazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 326: (1S,2R)-2-[4-({(2R)-2-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 327: (1S,2R)-2-{4-[((2R)-2-{2-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 328: (1S,2R)-2-{4-[((2R)-2-{2-[4-(2-Hydroxyethyl)-1H-1,2,3-triazol-1-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 329: (1S,2R)-2-[4-({(2R)-2-[2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 330: Ethyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-1,2,3-triazole-4-carboxylate   Example 331: Methyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-3,5-dimethyl-1H-pyrazole-4-carboxylate   Example 332: Ethyl 3-tert-butyl-1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-pyrazole-5-carboxylate   Example 333: 1-(1-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-1,2,3-triazol-4-yl)ethanone   Example 334: Ethyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-pyrazole-4-carboxylate   Example 335: Methyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-pyrrole-3-carboxylate   Example 336: Ethyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-2-methyl-1H-pyrrole-3-carboxylate   Example 337: (1-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-1,2,3-triazol-4-yl)methyl acetate dihydrochloride   Example 338: Methyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-indazole-3-carboxylate   Example 339: Methyl 2-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-2H-indazole-3-carboxylate   Example 340: Ethyl 3-cyclopropyl-1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-pyrazole-5-carboxylate   Example 341: 1-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-indole-3-carbonitrile   Example 342: Ethyl 1-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1H-1,2,3-triazole-5-carboxylate   Example 343: Ethyl 2-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-2H-1,2,3-triazole-4-carboxylate   

     In the same manner as in Example 2 (Method B), the following compounds (Examples 344-347) were obtained. 
     Example 344 
     (2R)-2-Benzyl-1-[(1,5-dicyclohexyl-1H-imidazol-4-yl)carbonyl]piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 435 (M+1) 
     Example 345 
     (2R)-2-Benzyl-1-[(1-cyclohexyl-5-cyclopropyl-1H-imidazol-4-yl)carbonyl]piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 393 (M+1) 
     Example 346 
     (2R)-2-Benzyl-1-[(1-cyclohexyl-2-ethoxy-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 473 (M+1) 
     Example 347 
     (2R)-2-Benzyl-1-[(2-chloro-1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 465 (M+1) 
     In the same manner as in Example 6 (Method F) except that the final product was isolated as a hydrochloride by treating with 4N hydrogen chloride-ethyl acetate solution, the following compound (Example 348) was obtained. 
     Example 348 
     N-{[(2S)-1-({1-[2-(Ethoxymethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzamide hydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 546 (M+1) 
     Example 349 
     (2R)-2-Benzyl-1-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine 
     
       
         
         
             
             
         
       
     
     To tert-butyl (3R)-3-benzyl-4-[(1-cyclohexyl-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (300 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (232 mg). 
     MS (ESI+, m/e) 429 (M+1) 
     Example 350 
     (1R,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol 
     
       
         
         
             
             
         
       
     
     To tert-butyl (3R)-3-benzyl-4-{[1-(trans-2-hydroxycyclopentyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (1.15 g) was added TFA (10 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (96 mg) and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (72 mg), as an amorphous solid, respectively. 
     MS (ESI+, m/e) 431 (M+1) 
     MS (ESI+, m/e) 431 (M+1) 
     Example 351 
     (1R,2R)-2-(4-{[(2R)-2-Isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol and (1S,2S)-2-(4-{[(2R)-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol 
     
       
         
         
             
             
         
       
     
     trans-2-(4-{[(2R)-4-Benzyl-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (270 mg) was dissolved in methanol (8 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were neutralized with saturated aqueous sodium hydrogen carbonate, and the mixtures were extracted with chloroform, respectively. The extracts were dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure, respectively. The residue of the less polar fraction was vacuum-dried to give (1S,2S)-2-(4-{[(2R)-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (60 mg), and the residue of the more polar fraction was vacuum-dried to give (1R,2R)-2-(4-{[(2R)-2-isobutylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclopentanol (50 mg), as an amorphous solid, respectively. 
     MS (ESI+, m/e) 397 (M+1) 
     MS (ESI+, m/e) 397 (M+1) 
     Example 352 
     (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     To tert-butyl (3R)-3-benzyl-4-({1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (110 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (92 mg). 
     MS (ESI+, m/e) 445 (M+1) 
     Example 353 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     To tert-butyl (3R)-3-benzyl-4-{[1-(cis-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (260 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (89 mg). 
     MS (ESI+, m/e) 445 (M+1) (The other diastereomer obtained by this method is the same as the compound of the above-mentioned Example 352.) 
     Example 354 
     [(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methanol, [(1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methanol, [(1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methyl acetate and [(1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methyl acetate 
     
       
         
         
             
             
         
       
     
     Methyl 1-[cis-2-(hydroxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylate (containing a trace of ethyl acetate) (600 mg) and lithium hydroxide (120 mg) were dissolved in a mixed solvent of methanol (10 ml) and water (2 ml), and the solution was heated under reflux for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (530 mg), WSC.HCl (440 mg), HOBt (2.90 g) and DMF (10 ml). The mixture was stirred at 60° C. for 3 hr, poured into aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in TFA (5 ml). The solution was stirred for 30 min, and poured into aqueous potassium carbonate solution, and the mixture was extracted with dichloroethane. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were diluted with aqueous potassium carbonate solution, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compounds as an amorphous solid, respectively.
     [(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methanol (46 mg): MS (ESI+, m/e) 459 (M+1), retention time 1.23 min   [(1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methanol (42 mg): MS (ESI+, m/e) 459 (M+1), retention time 1.31 min   [(1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methyl acetate (55 mg): MS (ESI+, m/e) 501 (M+1), retention time 1.41 min   [(1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methyl acetate (74 mg): MS (ESI+, m/e) 501 (M+1), retention time 1.51 min
 
(The above-mentioned “retention time” means retention time during LC/MS spectrum measurement under the aforementioned conditions.)
   

     Example 355 
     trans-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-2-methyl-5-phenyl-1H-imidazol-1-yl)cyclohexanol trifluoroacetate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[trans-2-hydroxycyclohexyl]-2-methyl-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (55 mg) was dissolved in 1,2-dichloroethane (2 ml), TFA (2 ml) was added, and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was washed with diethyl ether to give the object compound (46 mg) as a TFA salt. 
     MS (ESI+, m/e) 459 (M+1) 
     Example 356 
     Ethyl (2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexylidene]acetate hydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1S)-2-(2-ethoxy-2-oxoethylidene)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (100 mg) was dissolved in acetic acid-water (2:1, 1.5 ml), and the solution was stirred at 80° C. for 12 hr. The reaction mixture was poured into water, and the mixture was neutralized with aqueous sodium bicarbonate, and extracted with ethyl acetate-THF (1:1). The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and 4N hydrogen chloride-ethyl acetate solution was added thereto. The solvent was evaporated under reduced pressure to give the object compound (70 mg) as an amorphous solid. 
     MS (ESI+, m/e) 513 (M+1) 
     Example 357 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     Ethyl [(1S,2S)-2-(4-{[(2R)-2,4-dibenzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (500 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (420 mg) as an amorphous solid. 
     MS (ESI+, m/e) 516 (M+1) 
     Example 358 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     Ethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (530 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (415 mg) as an amorphous solid. 
     MS (ESI+, m/e) 552 (M+1) 
     Example 359 
     Ethyl [(1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     Ethyl 1-{cis-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylate (501 mg) was dissolved in ethanol-water (2:1, 6 ml), lithium hydroxide monohydrate (69 mg) was added, and the mixture was stirred at 65° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was again concentrated under reduced pressure, and the residue was vacuum-dried. This was suspended in DMF (5 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (360 mg), WSC.HCl (498 mg) and HOBt (796 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (3:7-7:3) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-[(1-{cis-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (560 mg) as an amorphous solid. 500 mg therefrom was dissolved in dichloromethane (1 ml), TFA (1 ml) was added at room temperature, and the mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 6% aqueous sodium bicarbonate. The liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object less polar fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (55 mg) as an amorphous solid. 
     MS (ESI+, m/e) 516 (M+1) 
     Example 360 
     2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-butylcyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-butyl-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (36 mg) was dissolved in ethyl acetate (0.5 ml), 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure to give the object compound (30 mg). 
     MS (ESI+, m/e) 501 (M+1) 
     Example 361 
     2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(ethoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (170 mg) was dissolved in DMF (3 ml), sodium ethoxide (61 mg) was added, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[2-(ethoxymethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (70 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object compound (30 mg) as an amorphous solid. 
     MS (ESI+, m/e) 503 (M+1) 
     In the same manner as in Example 361 except that the object compound was isolated as a hydrochloride, the following compound (Example 362) was obtained. 
     Example 362 
     2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 489 (M+1) 
     Example 363 
     (1R,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(cyclopropylmethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2R)-2-(cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (49 mg) was dissolved in methanol (2 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. To the residue was toluene (5 ml) was added, and the mixture was further concentrated under reduced pressure to give the object compound (15 mg) as an amorphous solid. 
     MS (ESI+, m/e) 499 (M+1) 
     In the same manner as in Example 363, the following compound (Example 364) was obtained. 
     Example 364 
     (1S,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(cyclopropylmethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 499 (M+1) 
     Example 365 
     (1R,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexanol and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (221 mg) and 2-(methylsulfonyl)ethanamine (99 mg) were dissolved in acetonitrile (5 ml), lithium perchlorate (85 mg) was added, and the mixture was reacted at 100° C. for 5 min using microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[2-hydroxy-2-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (235 mg) as an amorphous solid. To the total amount thereof was added 4N hydrogen chloride-ethyl acetate solution (2 ml), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were neutralized with saturated aqueous sodium hydrogen carbonate, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure to give (1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexanol (26 mg) as an amorphous solid, and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-({[2-(methylsulfonyl)ethyl]amino}methyl)cyclohexanol (15 mg) as an amorphous solid. 
     MS (ESI+, m/e) 580 (M+1) 
     MS (ESI+, m/e) 580 (M+1) 
     Example 366 
     Example 366a 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride 
     Example 366b 
     (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride (70 mg) was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fractions were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, respectively. The organic layers were dried over anhydrous sodium sulfate, and the solvents were evaporated under reduced pressure, respectively. 4N Hydrogen chloride-ethyl acetate solutions (1 ml) were added to the residues, and the mixtures were concentrated under reduced pressure, respectively. Toluene (5 ml) was added to the residues, and the mixtures were again concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride (HPLC retention time: short, Example 366a, 24 mg) as an amorphous solid, and (1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride (HPLC retention time: long, Example 366b, 17 mg) as an amorphous solid. 
     MS (ESI+, m/e) 489 (M+1) 
     MS (ESI+, m/e) 489 (M+1) 
     Example 367 
     (the alternative synthetic method of the above-mentioned Example 366a; The object compound was isolated as a dihydrochloride.) 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (5.45 g) was dissolved in methanol (10 ml), 4N hydrogen chloride-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (4.47 g). 2.73 g therefrom was dissolved in ethanol (10 ml), 4N hydrogen chloride-ethyl acetate solution (3.07 ml) was added, and the mixture was heated with stirring to 70° C. Ethanol (5 ml) was added at the same temperature, and the mixture was cooled to room temperature while stirring. The precipitated crystals were collected by filtration to give the object compound (2.57 g). 
     MS (ESI+, m/e) 489 (M+1) 
     Example 368 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol fumarate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol obtained in the course of the above-mentioned Example 367 (1.00 g) was dissolved in ethyl acetate (20 ml), a solution of fumaric acid (238 mg) in ethanol (5 ml) was added, and the mixture was heated at 70° C. to give a homogeneous solution. Ethyl acetate (10 ml) was added at the same temperature, the mixture was left to stand at room temperature for 15 hr, and the precipitated crystals were collected by filtration to give the object compound (1.13 g). 
     MS (ESI+, m/e) 489 (M+1) 
     Example 369 
     (1R,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[2-(1H-tetrazol-5-yl)ethyl]cyclohexanol trifluoroacetate and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[2-(1H-tetrazol-5-yl)ethyl]cyclohexanol trifluoroacetate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[2-(2-cyanoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (150 mg) was dissolved in toluene (5 ml), and trimethylsilylazide (33 μl) and dibutyl(oxo)tin (6 mg) were added. The mixture was heated under reflux for 12 hr, and the solvent was evaporated under reduced pressure. To the residue was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-[(1-{2-hydroxy-2-[2-(1H-tetrazol-5-yl)ethyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (27 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (1 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give (1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[2-(1H-tetrazol-5-yl)ethyl]cyclohexanol trifluoroacetate (6 mg) as an amorphous solid, and (1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[2-(1H-tetrazol-5-yl)ethyl]cyclohexanol trifluoroacetate (9 mg) as an amorphous solid. 
     MS (ESI+, m/e) 541 (M+1) 
     MS (ESI+, m/e) 541 (M+1) 
     Example 370 
     N-{3-[(1R,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propyl}acetamide trifluoroacetate and N-{3-[(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propyl}acetamide trifluoroacetate 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-({1-[2-(2-cyanoethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (150 mg) was dissolved in 1M ammonia-ethanol solution (15 ml), Raney cobalt (30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give tert-butyl (3R)-4-({1-[2-(3-aminopropyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate (200 mg) as an oil. The total amount thereof was dissolved in pyridine (2 ml), and the solution was ice-cooled. Acetic anhydride (24 μl) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-4-[(1-{2-[3-(acetylamino)propyl]-2-hydroxycyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]-3-benzylpiperazine-1-carboxylate (32 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (1 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give N-{3-[(1R,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propyl}acetamide trifluoroacetate (11 mg) as an amorphous solid, and N-{3-[(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]propyl}acetamide trifluoroacetate (10 mg) as an amorphous solid. 
     MS (ESI+, m/e) 544 (M+1) 
     MS (ESI+, m/e) 544 (M+1) 
     Example 371 
     N-(2-{[(1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)acetamide trifluoroacetate and N-(2-{[(1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)acetamide trifluoroacetate 
     
       
         
         
             
             
         
       
     
     60% Sodium hydride (40 mg) was suspended in DMF (3 ml), N-(2-hydroxyethyl)acetamide (124 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (111 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-4-{[1-(2-{[2-(acetylamino)ethoxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}-3-benzylpiperazine-1-carboxylate (79 mg) as an amorphous solid. To the total amount thereof was added 4N hydrogen chloride-ethyl acetate solution (2 ml), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give N-(2-{[(1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)acetamide trifluoroacetate (32 mg) as an amorphous solid, and N-(2-{[(1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-hydroxycyclohexyl]methoxy}ethyl)acetamide trifluoroacetate (37 mg) as an amorphous solid. 
     MS (ESI+, m/e) 560 (M+1) 
     MS (ESI+, m/e) 560 (M+1) 
     In the same manner as in Example 371, the following compound (Example 372) was obtained. 
     Example 372 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1-methylpiperidin-4-yl)oxy]methyl}cyclohexanol trifluoroacetate and (1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1-methylpiperidin-4-yl)oxy]methyl}cyclohexanol trifluoroacetate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 572 (M+1) 
     MS (ESI+, m/e) 572 (M+1) 
     Example 373 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}cyclohexanol and (1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(2-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (74 mg) was dissolved in methanol (1 ml), 4N hydrogen chloride-ethyl acetate solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were collected, saturated aqueous sodium hydrogen carbonates were added, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}cyclohexanol (31 mg) as an amorphous solid, and (1R,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]methyl}cyclohexanol (30 mg) as an amorphous solid. 
     MS (ESI+, m/e) 607 (M+1) 
     MS (ESI+, m/e) 607 (M+1) 
     Example 374 
     (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[1-(1,3-thiazol-2-yl)ethoxy]methyl}cyclohexanol hydrochloride and (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[1-(1,3-thiazol-2-yl)ethoxy]methyl}cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     1-(1,3-Thiazol-2-yl)ethanol (230 mg) was dissolved in DMF (10 ml), and the solution was ice-cooled. Sodium hydride (60% in oil, 70 mg) was added thereto, and then tert-butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (200 mg) was added, and the mixture was stirred at 50° C. for 15 hr. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (2.5 ml), 4N hydrogen chloride-ethyl acetate solution (2.5 ml) was added, and the mixture was stirred for 30 min, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were collected, and diluted with aqueous potassium carbonate solution, and the mixtures were extracted with ethyl acetate, respectively. The extracts were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, respectively. The residues were treated with 4N hydrogen chloride-ethyl acetate solution to give the object compound, respectively.
     (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[1-(1,3-thiazol-2-yl)ethoxy]methyl}cyclohexanol hydrochloride (32 mg): MS (ESI+, m/e) 586 (M+1), retention time 1.39 min   (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[1-(1,3-thiazol-2-yl)ethoxy]methyl}cyclohexanol hydrochloride (41 mg): MS (ESI+, m/e) 586 (M+1), retention time 1.49 min
 
(The above-mentioned “retention time” means retention time during LC/MS spectrum measurement under the aforementioned conditions.)
   

     In the same manner as in Example 374, the following compound (Example 375) was obtained. 
     Example 375 
     (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[1-methyl-1-(1,3-thiazol-2-yl)ethoxy]methyl}cyclohexanol dihydrochloride and (1S,2R)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[1-methyl-1-(1,3-thiazol-2-yl)ethoxy]methyl}cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 600 (M+1) 
     MS (ESI+, m/e) 600 (M+1) 
     Example 376 
     2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(hydroxymethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (111 mg) was dissolved in DMF (3 ml), lithium hydroxide monohydrate (84 mg) was added, and the mixture was stirred at 100° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-({1-[2-hydroxy-2-(hydroxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (70 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (1 ml), 5% hydrogen chloride-methanol solution (1 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added toluene, and the mixture was again concentrated under reduced pressure to give the object compound (60 mg) as an amorphous solid. 
     MS (ESI+, m/e) 475 (M+1) 
     Example 377 
     2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[(3-hydroxypropoxy)methyl]cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     Sodium hydride (60% in oil) (40 mg) was suspended in DMF (3 ml), propane-1,3-diol (91 mg) was added, and the mixture was stirred at room temperature for 30 min. tert-Butyl (3R)-3-benzyl-4-{[1-(1-oxaspiro[2.5]oct-4-yl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (110 mg) was added thereto, and the mixture was stirred at 60° C. for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-[(1-{2-hydroxy-2-[(3-hydroxypropoxy)methyl]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazine-1-carboxylate (91 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 5% hydrogen chloride-methanol solution (2 ml) was added, and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. To the residue was added toluene (5 ml), and the mixture was again concentrated under reduced pressure to give the object compound (100 mg) as an amorphous solid. 
     MS (ESI+, m/e) 533 (M+1) 
     Example 378 
     (1R,2S)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-{[3-(methylthio)propoxy]methyl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Ethyl 1-((1S,2R)-2-hydroxy-2-{[3-(methylthio)propoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazole-4-carboxylate (318 mg) was dissolved in ethanol-THF (1:1, 4 ml), lithium hydroxide monohydrate (23 mg) and water (1 ml) were added thereto, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethanol. The suspension was again concentrated under reduced pressure, and the residue was vacuum-dried. The half amount of the residue was suspended in DMF (5 ml), tert-butyl (3R)-3-benzylpiperazine-1-carboxylate (153 mg), WSC.HCl (142 mg) and HOBt (113 mg) were added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3R)-3-benzyl-4-{[1-((1S,2R)-2-hydroxy-2-{[3-(methylthio)propoxy]methyl}cyclohexyl)-5-phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate (94 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (2 ml), and 4N hydrogen chloride-ethyl acetate solution (2 ml) was added thereto. The mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (60 mg) as an amorphous solid. 
     MS (ESI+, m/e) 563 (M+1) 
     Example 379 
     (1S,2R)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (569 mg), (3R)-1-benzyl-3-(3,5-difluorobenzyl)piperazine (496 mg), WSC.HCl (377 mg) and HOBt (266 mg) in DMF (9 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1.5:1-2:1) was concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (546 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (15 ml), 20% palladium hydroxide-carbon (50% containing water, 275 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-chloroform-methanol (1:1:0-10:10:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (6 ml), and 4N hydrogen chloride-ethyl acetate solution (244 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (366 mg). 
     MS (ESI+, m/e) 525 (M+1) 
     Example 380 
     (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (132 mg), (3R)-1-benzyl-3-(pyridin-3-ylmethyl)piperazine (112 mg), WSC.HCl (92 mg) and HOBt (65 mg) in DMF (2.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-20:1) was concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (202 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (5.5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fractions were collected, and diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (6 ml), and 4N hydrogen chloride-ethyl acetate solution (192 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (103 mg). 
     MS (ESI+, m/e) 490 (M+1) 
     Example 381 
     (1S,2R)-2-(4-{[(2R)-2-(1H-Imidazol-4-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (132 mg), (3R)-1-benzyl-3-(1H-imidazol-4-ylmethyl)piperazine (108 mg), WSC.HCl (92 mg) and HOBt (65 mg) in DMF (2.5 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-10:1) was concentrated under reduced pressure to give (1S,2R)-2-(4-{[(2R)-4-benzyl-2-(1H-imidazol-4-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (140 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 140 mg) was added thereto, and the mixture was subjected to catalytic reduction at 60° C. for 10 hr under moderate-pressure (5 kgf/cm 2 ). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (2 ml), and 4N hydrogen chloride-ethyl acetate solution (68 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (37 mg). 
     MS (ESI+, m/e) 479 (M+1) 
     Example 382 
     (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(3-phenylpropyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol hydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (198 mg), (3R)-1-benzyl-3-[(2E)-3-phenyl-2-propen-1-yl]piperazine (184 mg), WSC.HCl (138 mg) and HOBt (97 mg) in DMF (4 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-20:0:1) was concentrated under reduced pressure to give (1S,2R)-2-[4-({(2R)-4-benzyl-2-[(2E)-3-phenyl-2-propen-1-yl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (301 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (8.5 ml), 20% palladium hydroxide-carbon (50% containing water, 150 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (25:1) was concentrated under reduced pressure. The residue was diluted with diethyl ether (3 ml), and 4N hydrogen chloride-ethyl acetate solution (137 μl) was added thereto. The precipitated crystals were collected by filtration to give the object compound (175 mg). 
     MS (ESI+, m/e) 517 (M+1) 
     Example 383 
     (1S,2R)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     To tert-butyl (3R)-3-benzyl-4-({5-(3-fluorophenyl)-1-[cis-2-hydroxy-2-(methoxymethyl)cyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (330 mg) was added TFA (3 ml), and the mixture was stirred at room temperature for 5 min, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fractions were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (103 mg). 
     MS (ESI+, m/e) 507 (M+1) 
     Example 384 
     (1R,2S)-2-[4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-(3-fluorophenyl)-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     The fractions containing the other diastereomer obtained by the reversed-phase preparative HPLC in the above-mentioned Example 383 were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (109 mg). 
     MS (ESI+, m/e) 507 (M+1) 
     Example 385 
     2-[4-({(2S)-2-[(Benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol and 2-(4-{[(2S)-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     2-[4-({(2S)-4-Benzyl-2-[(benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (530 mg) was dissolved in ethanol (15 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fractions were collected, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, respectively. The organic layers were dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure to give 2-[4-({(2S)-2-[(benzyloxy)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (244 mg) and 2-(4-{[(2S)-2-(hydroxymethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (9 mg). 
     MS (ESI+, m/e) 519 (M+1) 
     MS (ESI+, m/e) 429 (M+1) 
     Example 386 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-4-Benzyl-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (32 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 10 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (23 mg) as an amorphous solid. 
     MS (ESI+, m/e) 519 (M+1) 
     Example 387 
     (the alternative synthetic method of the above-mentioned Example 386; The object compound was isolated as a dihydrochloride.) 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (330 mg) was suspended in DMF (10 ml), benzyl (3R)-3-(2-phenoxyethyl)piperazine-1-carboxylate hydrochloride (377 mg), WSC.HCl (288 mg), HOBt (184 mg) and triethylamine (0.279 ml) were added thereto, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-(2-phenoxyethyl)piperazine-1-carboxylate (452 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (50 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol, the solution was acidified with 4N hydrogen chloride-ethyl acetate solution, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give the object compound (334 mg). 
     MS (ESI+, m/e) 519 (M+1) 
     Example 388 
     (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(pyridin-3-yloxy)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[(1-oxidopyridin-3-yl)oxy]ethyl}piperazine-1-carboxylate (80 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (43 mg) as an amorphous solid. 
     MS (ESI+, m/e) 520 (M+1) 
     Example 389 
     (1S,2R)-2-[4-({(2R)-2-[2-(2-Fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-3-[2-(2-fluorophenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (205 mg) was dissolved in methanol (2 ml), 20% palladium hydroxide-carbon (50% containing water, 200 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (145 mg) as an amorphous solid. 
     MS (ESI+, m/e) 537 (M+1) 
     Example 390 
     N-Cyclopropyl-4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzamide 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-3-(2-{4-[(cyclopropylamino)carbonyl]phenoxy}ethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (98 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, and the suspension was washed with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (60 mg) as an amorphous solid. 
     Example 391 
     (1S,2R)-2-[4-({(2R)-2-[2-(1H-Indazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-[2-(1H-indazol-1-yl)ethyl]piperazine-1-carboxylate (140 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 70 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (71 mg) as an amorphous solid. 
     MS (ESI+, m/e) 543 (M+1) 
     In the same manner as in Example 391, the following compound (Example 392) was obtained. 
     Example 392 
     (1S,2R)-2-[4-({(2R)-2-[2-(2H-Indazol-2-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 543 (M+1) 
     Example 393 
     1-Cyclopentyl-3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (150 mg), benzyl (3R)-3-{2-[3-(cyclopent-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}piperazine-1-carboxylate hydrochloride (230 mg), WSC.HCl (180 mg), HOBt (70 mg) and triethylamine (220 μl) in DMF (7 ml) was stirred at 50° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-9:0:1) was concentrated under reduced pressure to give benzyl (3R)-3-{2-[3-(cyclopent-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (122 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (4 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 16 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (44 mg). 
     MS (ESI+, m/e) 627 (M+1) 
     Example 394 
     1-Cyclohexyl-3-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (150 mg), benzyl (3R)-3-{2-[3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}piperazine-1-carboxylate hydrochloride (237 mg), WSC.HCl (180 mg), HOBt (70 mg) and triethylamine (220 μl) in DMF (7 ml) was stirred at 50° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-9:0:1) was concentrated under reduced pressure to give benzyl (3R)-3-{2-[3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (146 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (4 ml), 20% palladium hydroxide-carbon (50% containing water, 20 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 16 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate-saturated brine (1:1), and the mixture was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was treated with 2N hydrogen chloride-ethyl acetate solution to give the object compound (60 mg). 
     MS (ESI+, m/e) 641 (M+1) 
     Example 395 
     (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(1H-1,2,3-triazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (409 mg), benzyl (3R)-3-[2-(4-acetyl-1H-1,2,3-triazol-1-yl)ethyl]piperazine-1-carboxylate hydrochloride (512 mg), WSC HCl (475 mg), HOBt (190 mg) and triethylamine (520 μl) in DMF (8 ml) was stirred at room temperature for 14 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:9:0-17:0:3) was concentrated under reduced pressure to give benzyl (3R)-3-[2-(4-acetyl-1H-1,2,3-triazol-1-yl)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (616 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (6 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-4:1) was concentrated under reduced pressure to give the object compound (16 mg). 
     MS (ESI+, m/e) 494 (M+1) 
     Example 396 
     (1R,2S)-2-[4-({2-[2-(2-Fluorophenyl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1S,2R)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (144 mg), (3R)-1-benzyl-3-[(E)-2-(2-fluorophenyl)vinyl]piperazine (158 mg), WSC.HCl (125 mg), HOBt (20 mg), N,N-diisopropylethylamine (181 μl) and DMAP (12 mg) in DMF (2 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give (1R,2S)-2-[4-({(2R)-4-benzyl-2-[(E)-2-(2-fluorophenyl)vinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol (184 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 100 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The crystals were collected by filtration to give the object compound (67 mg). (During the catalytic reduction, the racemization of the piperazine side chain proceeded together with the removal of the benzyl protecting group and the reduction of the unsaturated bond.) 
     MS (ESI+, m/e) 477 (M+1) 
     In the same manner as in Example 396, the following compounds (Examples 397-404) shown in Table 23 were obtained. (Each compound was isolated as a diastereomer mixture.) 
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Ex. No. 
                 R 
                 Compound 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 397 
                 3-F 
                 (1R,2S)-2-[4-({2-[2-(3- 
                 477 
               
               
                   
                   
                 Fluorophenyl)ethyl]piperazin-1- 
               
               
                   
                   
                 yl}carbonyl)-5-phenyl-1H-imidazol-1- 
               
               
                   
                   
                 yl]cyclohexanol 
               
               
                 398 
                 4-F 
                 (1R,2S)-2-[4-({2-[2-(4- 
                 477 
               
               
                   
                   
                 Fluorophenyl)ethyl]piperazin-1- 
               
               
                   
                   
                 yl}carbonyl)-5-phenyl-1H-imidazol-1- 
               
               
                   
                   
                 yl]cyclohexanol 
               
               
                 399 
                 2-OCF 3   
                 (1R,2S)-2-{5-Phenyl-4-[(2-{2-[2- 
                 543 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]ethyl} 
               
               
                   
                   
                 piperazin-1-yl)carbonyl]-1H-imidazol-1- 
               
               
                   
                   
                 yl}cyclohexanol 
               
               
                 400 
                 3-OCF 3   
                 (1R,2S)-2-{5-Phenyl-4-[(2-{2-[3- 
                 543 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]ethyl} 
               
               
                   
                   
                 piperazin-1-yl)carbonyl]-1H-imidazol-1- 
               
               
                   
                   
                 yl}cyclohexanol 
               
               
                 401 
                 4-OCF 3   
                 (1R,2S)-2-{5-Phenyl-4-[(2-{2-[4- 
                 543 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]ethyl} 
               
               
                   
                   
                 piperazin-1-yl)carbonyl]-1H-imidazol-1- 
               
               
                   
                   
                 yl}cyclohexanol 
               
               
                 402 
                 2-CF 3   
                 (1R,2S)-2-{5-Phenyl-4-[(2-{2-[2- 
                 527 
               
               
                   
                   
                 (trifluoromethoxy)phenyl]ethyl} 
               
               
                   
                   
                 piperazin-1-yl)carbonyl]-1H-imidazol-1- 
               
               
                   
                   
                 yl}cyclohexanol 
               
               
                 403 
                 3-CF 3   
                 (1R,2S)-2-{5-Phenyl-4-[(2-{2-[3- 
                 527 
               
               
                   
                   
                 (trifluoromethyl)phenyl]ethyl} 
               
               
                   
                   
                 piperazin-1-yl)carbonyl]-1H-imidazol-1- 
               
               
                   
                   
                 yl}cyclohexanol 
               
               
                 404 
                 4-CF 3   
                 (1R,2S)-2-{5-Phenyl-4-[(2-{2-[4- 
                 527 
               
               
                   
                   
                 (trifluoromethyl)phenyl]ethyl} 
               
               
                   
                   
                 piperazin-1-yl)carbonyl]-1H-imidazol-1- 
               
               
                   
                   
                 yl}cyclohexanol 
               
               
                   
               
            
           
         
       
     
     In the same manner as in Example 396, the following compounds (Examples 405-412) shown in Table 24 were obtained. Each compound was isolated as a diastereomer by subjecting the diastereomer mixture to optical resolution by reversed-phase preparative HPLC (the purification conditions are described above). The final products were isolated as crystals or an amorphous solid in a free form or a hydrochloride by a known means such as phase transfer, liquid conversion, solvent extraction and the like. In the column of “Salt” in the Table, the compounds described as “-” were isolated as a free form. 
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
               
               
                 No. 
                 R 
                 salt 
                 Compound 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 405 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2R)-2-{2-[2- (trifluoromethoxy)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol 
                 587 
               
               
                   
               
               
                 406 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2S)-2-{2-[2- (trifluoromethoxy)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol 
                 587 
               
               
                   
               
               
                 407 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2R)-2-{2-[2- (trifluoromethyl)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol 
                 571 
               
               
                   
               
               
                 408 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 — 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2S)-2-{2-[2- (trifluoromethyl)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol 
                 571 
               
               
                   
               
               
                 409 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 HCl 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2R)-2-{2-[3- (trifluoromethoxy)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol hydrochloride 
                 587 
               
               
                   
               
               
                 410 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 HCl 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2S)-2-{2-[3- (trifluoromethoxy)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol hydrochloride 
                 587 
               
               
                   
               
               
                 411 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 HCl 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2R)-2-{2-[3- (trifluoromethyl)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol hydrochloride 
                 571 
               
               
                   
               
               
                 412 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 HCl 
                 (1S,2R)-1-(Methoxymethyl)-2-{5-phenyl- 4-[((2S)-2-{2-[3- (trifluoromethyl)phenyl]ethyl} piperazin-1-yl)carbonyl]-1H-imidazol- 1-yl}cyclohexanol hydrochloride 
                 571 
               
               
                   
               
            
           
         
       
     
     Example 413 
     (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[2-(2-(piperidin-2-yl)ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     A mixture of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), (3R)-1-benzyl-3-[(E)-2-(pyridin-2-yl)vinyl]piperazine dihydrochloride (261 mg), WSC.HCl (192 mg), HOBt (306 mg), triethylamine (670 μl) and DMF (10 ml) was stirred at 60° C. for 5 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-7:0:3) was concentrated under reduced pressure to give (1S,2R)-2-[4-({4-benzyl-2-[(E)-2-(pyridin-2-yl)vinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (208 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (6 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (120 mg). (During the catalytic reduction, the racemization of the piperazine side chain and the reduction of the pyridine ring proceeded together with the removal of the benzyl protecting group and the reduction of the unsaturated bond.) 
     MS (ESI+, m/e) 510 (M+1) 
     Example 414 
     (1R,2S)-2-{4-[(2-Pentylpiperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     (1R,2S)-2-[4-({(2R)-4-Benzyl-2-[(E)-2-cyclopropylvinyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol (100 mg) was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 30 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate, the suspension was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:1) was concentrated under reduced pressure. The residue was vacuum-dried to give the object compound (25 mg) as an amorphous solid. (During the catalytic reduction, the ring-opening of the cyclopropyl group and the racemization of the piperazine side chain proceeded together with the removal of the benzyl protecting group and the reduction of the unsaturated bond.) 
     MS (ESI+, m/e) 425 (M+1) 
     Example 415 
     (1S,2R)-2-{4-[((2R)-2-{2-Hydroxy-2-[6-(trifluoromethyl)piperidin-2-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-{4-[((2R)-2-{(2RS)-2-Hydroxy-2-[6-(trifluoromethyl)pyridin-2-yl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride (1:1 mixture of the compounds of Example 199 and 200, 104 mg) was dissolved in methanol (10 ml), 20% palladium hydroxide-carbon (50% containing water, 50 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride-ethyl acetate solution to give the object compound (103 mg). (The hydroxyl group was not removed, and the reduction of the pyridine ring alone proceeded.) 
     MS (ESI+, m/e) 593 (M+1) 
     Example 416 
     4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid trifluoroacetate 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[4-(methoxycarbonyl)phenoxy]ethyl}piperazine-1-carboxylate (486 mg) was dissolved in ethanol (8 ml), 4N aqueous sodium hydroxide solution (4 ml) was added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, the residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above), and the object fraction was concentrated under reduced pressure to give the object compound (237 mg). 
     MS (ESI+, m/e) 563 (M+1) 
     In the same manner as in Example 416, the following compounds (Examples 417-418) were obtained. 
     Example 417 
     3-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid trifluoroacetate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 563 (M+1) 
     Example 418 
     2-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid bistrifluoroacetate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 563 (M+1) 
     In the same manner as in Example 416 except that the final product was isolated as a dihydrochloride by a known operation such as phase transfer, liquid conversion, solvent extraction and the like, the following compound (Example 419) was obtained. 
     Example 419 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(1-oxidopyridin-3-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 536 (M+1) 
     Example 420 
     6-{[(2S)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methoxy}nicotinic acid 
     
       
         
         
             
             
         
       
     
     A mixture of methyl 6-{[(2S)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methoxy}nicotinate trihydrochloride (the compound of Example 198, 220 mg), lithium hydroxide monohydrate (140 mg), methanol (3 ml) and water (3 ml) was stirred at room temperature for 3 days, and methanol was evaporated under reduced pressure. The residual aqueous solution was adjusted with 1N hydrochloric acid to pH 6-8. The solution was subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to about ⅓ volume, and the resulting crystals were collected by filtration to give the object compound (147 mg). 
     MS (ESI+, m/e) 550 (M+1) 
     Example 421 
     (4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)acetic acid 
     
       
         
         
             
             
         
       
     
     Methyl (4-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)acetate (the compound of Example 261) (125 mg) was dissolved in methanol (3 ml), potassium hydroxide (36 mg) was added, and the mixture was stirred at 65° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid. The mixture was again concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (62 mg) as an amorphous solid. 
     MS (ESI+, m/e) 577 (M+1) 
     Example 422 
     (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(4-(piperazin-1-yl)phenoxy)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-3-{2-[4-(4-acetylpiperazin-1-yl)phenoxy]ethyl}-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (120 mg) was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:1:0-10:0:1) was concentrated under reduced pressure to give the object compound (80 mg) as an amorphous solid. 
     MS (ESI+, m/e) 603 (M+1) 
     Example 423 
     4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3-methoxybenzamide dihydrochloride 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-3-[2-(4-cyano-2-methoxyphenoxy)ethyl]-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (25 mg) was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added thereto, and the mixture was stirred at 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was treated with 4N hydrogen chloride-ethyl acetate solution to give the object compound (3 mg). 
     MS (ESI+, m/e) 592 (M+1) 
     Example 424 
     (1S,2R)-2-{4-[((2R)-2-{2-[2-(1-Hydroxyethyl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     1-(2-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone (the compound of Example 240, 105 mg) was dissolved in methanol (5 ml), and the solution was ice-cooled. Sodium borohydride (11 mg) was added, and the mixture was stirred at 0° C. for 5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC (the purification conditions are described above). The object fraction was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the object compound (63 mg). 
     MS (ESI+, m/e) 563 (M+1) 
     Example 425 
     (1S,2R)-2-{4-[((2R)-2-{2-[3-(1-Hydroxyethyl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     1-(3-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone (the compound of Example 233) (50 mg) was dissolved in methanol (10 ml), and the solution was ice-cooled. Sodium borohydride (4 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give the object compound (14 mg) as an amorphous solid. 
     MS (ESI+, m/e) 563 (M+1) 
     Example 426 
     (1S,2R)-2-{4-[((2R)-2-{2-[4-(1-Hydroxyethyl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone (the compound of Example 231) (50 mg) was dissolved in methanol (10 ml), and the solution was ice-cooled. Sodium borohydride (4 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the object fraction was concentrated under reduced pressure to give the object compound (13 mg) as an amorphous solid. 
     MS (ESI+, m/e) 563 (M+1) 
     In the same manner as in Example 3 (Method C), the following compound (Example 427) was obtained. 
     Example 427 
     (1S,2R)-2-(4-{[(2R)-2-Benzyl-2-methylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 503 (M+1) 
     Example 428 
     (1S,2R)-2-(4-{[(2R)-2-(2-Anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (650 mg), benzyl (3R)-3-(2-anilinoethyl)piperazine-1-carboxylate (800 mg), WSC.HCl (566 mg) and HOBt (360 mg) in DMF (10 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give benzyl (3R)-3-(2-anilinoethyl)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (850 mg) as an amorphous solid. 120 mg therefrom was dissolved in methanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added thereto, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water, and the suspension was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure to give the object compound (50 mg) as an amorphous solid. 
     MS (ESI+, m/e) 518 (M+1) 
     Example 429 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[methyl(phenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol trihydrochloride 
     
       
         
         
             
             
         
       
     
     A solution of 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (165 mg), benzyl (3R)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate (195 mg), WSC.HCl (144 mg) and HOBt (92 mg) in DMF (10 ml) was stirred at room temperature for 15 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate (180 mg) as an amorphous solid. 160 mg therefrom was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 80 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 1 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was acidified with 4N hydrogen chloride-ethyl acetate solution, and concentrated under reduced pressure to give the object compound (130 mg) as an amorphous solid. 
     MS (ESI+, m/e) 532 (M+1) 
     In the same manner as in the above-mentioned Example 1 (Method A)-Example 15 (Method O), the following compounds (Examples 430-567) shown in Table 25-1-Table 25-2, Table 26, Table 27-1-Table 27-2 and Table 28-1-Table 28-8 were obtained. Where necessary, each compound was isolated and purified by a known means such as phase transfer, liquid conversion, solvent extraction, silica gel column chromatography, reversed-phase preparative HPLC and the like. The final products were isolated as a hydrochloride by a treatment with 4N hydrogen chloride-ethyl acetate solution, as in Method A and the like, or isolated as crystals or an amorphous solid in a free from, as in Method B and the like. In the column of “Salt” in the Tables, the compounds described as “-” were isolated as a free form. 
     
       
         
           
               
             
               
                 TABLE 25-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 430 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 570  
               
               
                   
               
               
                 431 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 570 
               
               
                   
               
               
                 432 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 570 
               
               
                   
               
               
                 433 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 538 
               
               
                   
               
               
                 434 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 578 
               
               
                   
               
               
                 435 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 528 
               
               
                   
               
               
                 436 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 604 
               
               
                   
               
               
                 437 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 580 
               
               
                   
               
               
                 438 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 594 
               
               
                   
               
               
                 439 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 550 
               
               
                   
               
               
                 440 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 564 
               
               
                   
               
               
                 441 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 550 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 25-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 442 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 564 
               
               
                   
               
               
                 443 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 548 
               
               
                   
               
               
                 444 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 531 
               
               
                   
               
               
                 445 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 573 
               
               
                   
               
               
                 446 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 567 
               
               
                   
               
               
                 447 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 567 
               
               
                   
               
               
                 448 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 593 
               
               
                   
               
               
                 449 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 593 
               
               
                   
               
               
                 450 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 563 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 451 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 2HCl 
                 503 
               
               
                   
               
               
                 452 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 2HCl 
                 459 
               
               
                   
               
               
                 453 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 2HCl 
                 473 
               
               
                   
               
               
                 454 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 500 
               
               
                   
               
               
                 455 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 500 
               
               
                   
               
               
                 456 
                 Et 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 2HCl 
                 541 
               
               
                   
               
               
                 457 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 567 
               
               
                   
               
               
                 458 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 571 
               
               
                   
               
               
                 459 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 581 
               
               
                   
               
               
                 460 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 507 
               
               
                   
               
               
                 461 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 560 
               
               
                   
               
               
                 462 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 536 
               
               
                   
               
               
                 463 
                 Me 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 536 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 27-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 MS 
               
               
                 Ex. No. 
                 R 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 464 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 539 
               
               
                   
               
               
                 465 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 HCl 
                 565 
               
               
                   
               
               
                 466 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 548 
               
               
                   
               
               
                 467 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 3HCl 
                 555 
               
               
                   
               
               
                 468 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 C 
                 3HCl 
                 555 
               
               
                   
               
               
                 469 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 519 
               
               
                   
               
               
                 470 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 519 
               
               
                   
               
               
                 471 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 515 
               
               
                   
               
               
                 472 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 565 
               
               
                   
               
               
                 473 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 565 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 27-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                 MS 
               
               
                 No. 
                 R 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 474 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 574 
               
               
                   
               
               
                 475 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 596 
               
               
                   
               
               
                 476 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 F 
                 — 
                 569 
               
               
                   
               
               
                 477 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 521 
               
               
                   
               
               
                 478 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 G 
                 — 
                 537 
               
               
                   
               
               
                 479 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 553 
               
               
                   
               
               
                 480 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 571 
               
               
                   
               
               
                 481 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 532 
               
               
                   
               
               
                 482 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 546 
               
               
                   
               
               
                 483 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 560 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-1 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 484 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 575 
               
               
                   
               
               
                 485 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 634 
               
               
                   
               
               
                 486 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 675 
               
               
                   
               
               
                 487 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 HCl 
                 585 
               
               
                   
               
               
                 488 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 654 
               
               
                   
               
               
                 489 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 631 
               
               
                   
               
               
                 490 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 603 
               
               
                   
               
               
                 491 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 560 
               
               
                   
               
               
                 492 
                 3-F 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 2HCl 
                 579 
               
               
                   
               
               
                 493 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 533 
               
               
                   
               
               
                 494 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 563 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-2 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 MS 
               
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 495 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 561 
               
               
                   
               
               
                 496 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 589 
               
               
                   
               
               
                 497 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 607 
               
               
                   
               
               
                 498 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 587 
               
               
                   
               
               
                 499 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 554 
               
               
                   
               
               
                 500 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 2HCl 
                 562 
               
               
                   
               
               
                 501 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 2HCl 
                 535 
               
               
                   
               
               
                 502 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 551 
               
               
                   
               
               
                 503 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 2HCl 
                 567 
               
               
                   
               
               
                 504 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 592 
               
               
                   
               
               
                 505 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 593 
               
               
                   
               
               
                 506 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 556 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-3 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 MS 
               
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 507 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 598 
               
               
                   
               
               
                 508 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 570 
               
               
                   
               
               
                 509 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 557 
               
               
                   
               
               
                 510 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 575 
               
               
                   
               
               
                 511 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 M 
                 — 
                 540 
               
               
                   
               
               
                 512 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 560 
               
               
                   
               
               
                 513 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 586 
               
               
                   
               
               
                 514 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 544 
               
               
                   
               
               
                 515 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 558 
               
               
                   
               
               
                 516 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 3HCl 
                 558 
               
               
                   
               
               
                 517 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 — 
                 519 
               
               
                   
               
               
                 518 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 586 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-4 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                   
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 519 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 543 
               
               
                   
               
               
                 520 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 572 
               
               
                   
               
               
                 521 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 536 
               
               
                   
               
               
                 522 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 536 
               
               
                   
               
               
                 523 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 536 
               
               
                   
               
               
                 524 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 552 
               
               
                   
               
               
                 525 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 563 
               
               
                   
               
               
                 526 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 532 
               
               
                   
               
               
                 527 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 532 
               
               
                   
               
               
                 528 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 548 
               
               
                   
               
               
                 529 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 548 
               
               
                   
               
               
                 530 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 548 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-5 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                 MS 
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 531 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 576 
               
               
                   
               
               
                 532 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 560 
               
               
                   
               
               
                 533 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 O 
                 — 
                 576 
               
               
                   
               
               
                 534 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 K 
                 — 
                 560 
               
               
                   
               
               
                 535 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 602 
               
               
                   
               
               
                 536 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 584 
               
               
                   
               
               
                 537 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 584 
               
               
                   
               
               
                 538 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 584 
               
               
                   
               
               
                 539 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 616 
               
               
                   
               
               
                 540 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 558 
               
               
                   
               
               
                 541 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-6 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                 MS 
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 542 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 J 
                 — 
                 610 
               
               
                   
               
               
                 543 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 574 
               
               
                   
               
               
                 544 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 584 
               
               
                   
               
               
                 545 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 546 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 547 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 548 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 549 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 550 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 551 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 562 
               
               
                   
               
               
                 552 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 574 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-7 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 553 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 615 
               
               
                   
               
               
                 554 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 611 
               
               
                   
               
               
                 555 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 573 
               
               
                   
               
               
                 556 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 587 
               
               
                   
               
               
                 557 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 573 
               
               
                   
               
               
                 558 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 L 
                 — 
                 575 
               
               
                   
               
               
                 559 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 566 
               
               
                   
               
               
                 560 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 566 
               
               
                   
               
               
                 561 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 566 
               
               
                   
               
               
                 562 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 566 
               
               
                   
               
               
                 563 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 566 
               
               
                   
               
               
                 564 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 — 
                 566 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28-8 
               
             
            
               
                   
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Ex. 
                   
                   
                   
                   
                   
               
               
                 No. 
                 R1 
                 R2 
                 Method 
                 Salt 
                 MS (ESI+) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 565 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 A 
                 3HCl 
                 566 
               
               
                   
               
               
                 566 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 578 
               
               
                   
               
               
                 567 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 I 
                 — 
                 561 
               
               
                   
               
            
           
         
       
     
     The chemical names of the compounds (Examples 430-567) shown in Table 25-1-Table 25-2, Table 26, Table 27-1-Table 27-2 and Table 28-1-Table 28-8 are as follows.
     Example 430: Methyl {(1S,2S)-2-[5-phenyl-4-({(2R)-2-[2-(trifluoromethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 431: Methyl {(1S,2S)-2-[5-phenyl-4-({(2R)-2-[3-(trifluoromethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 432: Methyl {(1S,2S)-2-[5-phenyl-4-({(2R)-2-[4-(trifluoromethyl)benzyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 433: Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,4-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 434: Methyl [(1S,2S)-2-(4-{[(2R)-2-(biphenyl-4-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 435: Methyl [(1S,2S)-2-(4-{[(2R)-2-(2,3-dihydro-1H-inden-2-yl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 436: Methyl 3-(2-{(2R)-1-[(1-{(1S,2S)-2-[(ethoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl] piperazin-2-yl}ethoxy)benzoate   Example 437: Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-fluoro-4-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 438: Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-fluoro-4-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 439: Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 440: Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 441: Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 442: Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 443: Methyl {(1S,2S)-2-[5-phenyl-4-({(2R)-2-[2-(phenylthio)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexyl}carbamate   Example 444: Methyl [(1S,2S)-2-(4-{[(2R)-2-(2-anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate   Example 445: Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(2-isopropylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate   Example 446: Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(2,4-difluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate   Example 447: Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(3,5-difluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate   Example 448: Ethyl ((1S,2S)-2-{4-[((2R)-2-{2-[(2-fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate   Example 449: Ethyl ((1R,2R)-2-{4-[((2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate   Example 450: Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(2-fluorophenyl)(methyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate   Example 451: (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(ethoxymethyl)cyclohexanol dihydrochloride   Example 452: (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol dihydrochloride   Example 453: (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-ethylcyclohexanol dihydrochloride   Example 454: (1R,2R)-1-(Cyclopropylmethyl)-2-(5-phenyl-4-{[(2R)-2-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 455: (1R,2R)-1-(Cyclopropylmethyl)-2-(5-phenyl-4-{[(2R)-2-(pyridin-4-ylmethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 456: (1S,2R)-1-Ethyl-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 457: (1R,2R)-1-(Cyclopropylmethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 458: (1S,2R)-1-(Ethoxymethyl)-2-[5-phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 459: (1R,2R)-1-(Cyclopropylmethyl)-2-{4-[((2S)-2-{[(3-fluorophenyl)sulfonyl]methyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 460: (1S,2R)-2-[4-({(2R)-2-[2-(2-Fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-methylcyclohexanol   Example 461: (1S,2R)-1-Methyl-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 462: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol   Example 463: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol   Example 464: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-Naphthylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol hydrochloride   Example 465: (1S,2R)-2-(4-{[(2R)-2-(Biphenyl-4-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol hydrochloride   Example 466: [(2S)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl phenylcarbamate   Example 467: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2S)-2-[(2-phenyl-1H-imidazol-1-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol trihydrochloride   Example 468: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2S)-2-[(5-phenyl-1H-imidazol-1-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol trihydrochloride   Example 469: (1S,2R)-2-(4-{[(2R)-2-(2-Methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 470: (1S,2R)-2-(4-{[(2S)-2-(2-Methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 471: (1S,2R)-2-(4-{[(2R)-2-(2,3-Dihydro-1H-inden-2-yl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 472: (1S,2R)-2-(4-{[(2R)-2-(Biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 473: (1S,2R)-2-(4-{[(2S)-2-(Biphenyl-2-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 474: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-morpholinobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 475: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxypyridin-3-yl)benzyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 476: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(1-methyl-1H-pyrazol-5-yl)benzyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 477: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2S)-2-[(phenylthio)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 478: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2S)-2-[(phenylsulfinyl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 479: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2S)-2-[(phenylsulfonyl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 480: (1S,2R)-2-{4-[((2S)-2-{[(3-Fluorophenyl)sulfonyl]methyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 481: 2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]-N-phenylacetamide   Example 482: 2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]-N-methyl-N-phenylacetamide   Example 483: (1S,2R)-2-{4-[((2S)-2-{[(2-Ethyl-1,3-benzoxazol-5-yl)amino]methyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 484: (1S,2R)-2-[4-({(2R)-2-[2-(1-Benzothien-4-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 485: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methoxy-4-morpholinophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 486: (1S,2R)-2-{4-[((2R)-2-{2-[4-(4-Acetylpiperazin-1-yl)-2-methoxyphenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 487: (1S,2R)-2-{4-[((2R)-2-{2-[3-(Difluoromethoxy)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol hydrochloride   Example 488: 2-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one   Example 489: Ethyl 5-{2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1-benzofuran-2-carboxylate   Example 490: (1S,2R)-2-{4-[((2R)-2-{2-[2-Fluoro-4-(1H-pyrazol-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol dihydrochloride   Example 491: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[2-methoxy-4-(1H-pyrazol-1-yl)phenoxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 492: 1-(4-{2-[(2R)-1-({5-(3-Fluorophenyl)-1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)ethanone dihydrochloride   Example 493: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(2-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 494: (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(4-methoxy-2-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol   Example 495: (1S,2R)-2-[4-({(2R)-2-[2-(2,3-Dihydro-1-benzofuran-5-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 496: (1S,2R)-2-{4-[((2R)-2-{2-[(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)oxyl]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 497: (1S,2R)-2-{4-[((2R)-2-{2-[(7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 498: (1S,2R)-2-{4-[((2R)-2-{2-[(1,2-Dimethyl-1H-benzimidazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 499: 2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl piperidine-1-carboxylate dihydrochloride   Example 500: 2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl phenylcarbamate dihydrochloride   Example 501: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(phenylthio)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 502: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(phenylsulfinyl)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 503: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(phenylsulfonyl)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride   Example 504: (1S,2R)-2-[4-({(2R)-2-[2-(1,3-Benzothiazol-2-ylthio)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 505: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-([1,3]thiazolo[5,4-b]pyridin-2-ylthio)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 506: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methyl-1,3-thiazol-2-yl)thio]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 507: (1S,2R)-2-{4-[((2R)-2-{2-[(4-tert-Butyl-1,3-thiazol-2-yl)thio]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 508: (1S,2R)-2-{4-[((2R)-2-{2-[(4,5-Dimethyl-1,3-thiazol-2-yl)thio]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 509: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 510: (1S,2R)-2-[4-({(2R)-2-[2-(1H-Benzimidazol-2-ylthio)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 511: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 512: N-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-N-phenylacetamide   Example 513: N-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}-N-phenylcyclopropanecarboxamide   Example 514: (1S,2R)-2-[4-({(2R)-2-[2-(1,3-Dihydro-2H-isoindol-2-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 515: (1S,2R)-2-[4-({(2R)-2-[2-(3,4-Dihydroisoquinolin-2(1H)-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 516: (1S,2R)-2-[4-({(2R)-2-[2-(3,4-Dihydroquinolin-1(2H)-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 517: (1S,2R)-1-(Methoxymethyl)-2-[5-phenyl-4-({(2R)-2-[2-(pyridin-2-ylamino)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol   Example 518: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[2-(trifluoromethyl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 519: 2-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)benzonitrile   Example 520: (1S,2R)-2-{4-[((2R)-2-{2-[Benzyl(cyclopropyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 521: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 522: (1S,2R)-2-{4-[((2R)-2-{2-[(3-Fluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 523: (1S,2R)-2-{4-[((2R)-2-{2-[(4-Fluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 524: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Chlorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 525: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-nitrophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 526: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 527: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 528: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 529: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 530: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 531: Methyl 4-({2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)benzoate   Example 532: 1-[4-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)phenyl]ethanone   Example 533: Methyl 3-({2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)benzoate   Example 534: 1-[3-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)phenyl]ethanone   Example 535: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[4-(trifluoromethoxy)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 536: (1S,2R)-2-(4-{[(2R)-2-(2-{[2-(Difluoromethoxy)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl--1-(methoxymethyl)cyclohexanol   Example 537: (1S,2R)-2-(4-{[(2R)-2-(2-{[3-(Difluoromethoxy)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 538: (1S,2R)-2-(4-{[(2R)-2-(2-{[4-(Difluoromethoxy)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol   Example 539: (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-{[2-methoxy-5-(trifluoromethyl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol   Example 540: (1S,2R)-2-[4-({(2R)-2-[2-(2,3-Dihydro-1H-inden-4-ylamino)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 541: (1S,2R)-2-[4-({(2R)-2-[2-(1,3-Benzodioxol-5-ylamino)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 542: Methyl 4-chloro-3-({2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)benzoate   Example 543: 5-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)-2-benzofuran-1(3H)-one   Example 544: (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-{[4-(1H-pyrazol-1-yl)phenyl]amino}ethyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol   Example 545: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(4-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 546: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 547: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methoxy-6-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 548: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methoxy-4-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 549: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methoxy-5-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 550: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxy-4-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 551: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(3-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 552: 6-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)-2-benzofuran-1(3H)-one   Example 553: 1-[4-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)phenyl]piperidin-2-one   Example 554: 1-[4-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)phenyl]pyridin-2(1H)-one   Example 555: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 556: (1S,2R)-2-{4-[((2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 557: (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-6-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol   Example 558: (1S,2R)-2-[4-({(2R)-2-[2-(1,3-Benzothiazol-2-ylamino)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 559: (1S,2R)-2-{4-[((2R)-2-{2-[(4-Fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 560: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 561: (1S,2R)-2-{4-[((2R)-2-{2-[(4-Fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 562: (1S,2R)-2-{4-[((2R)-2-{2-[(3-Fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 563: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 564: (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluoro-5-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol   Example 565: (1S,2R)-2-{4-[((2R)-2-{2-[(3-Fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol trihydrochloride   Example 566: (1S,2R)-2-[4-({(2R)-2-[2-(1H-Indazol-5-ylamino)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   Example 567: (1S,2R)-2-[4-({(2R)-2-[2-(2,3-Dihydrofuro[3,2-b]pyridin-5-ylamino)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol   

     In the same manner as in Example 1 (Method A) except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compound (Example 568) was obtained as a free amorphous solid. 
     Example 568 
     (1S,2R)-2-(4-{[(2R)-2-Benzyl-3-methylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 503 (M+1) 
     In the same manner as in Example 6 (Method F), the following compounds (Examples 569-572) were obtained. The compound of Example 572 was isolated as a 2 TFA salt by subjecting the final product to reversed-phase preparative HPLC (the purification conditions are described above), and directly concentrating the object fraction under reduced pressure. 
     Example 569 
     1-{[5-Phenyl-4-({(2R)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]methyl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 527 (M+1) 
     Example 570 
     1-({4-[((2R)-2-{2-[(2-Fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}methyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 536 (M+1) 
     Example 571 
     1-({4-[((2R)-2-{2-[(2-Fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}methyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 536 (M+1) 
     Example 572 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-phenoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol bistrifluoroacetate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 581 (M+1) 
     Example 573 
     1-[(4-{[(2R)-2-(2-Anilinoethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)methyl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     A mixture of ethyl 1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazole-4-carboxylate (100 mg), lithium hydroxide monohydrate (20 mg), ethanol (3 ml) and water (1 ml) was stirred at 80° C. for 3 hr, and concentrated under reduced pressure. The residue was mixed with benzyl (3R)-3-(2-anilinoethyl)piperazine-1-carboxylate (109 mg), WSC.HCl (115 mg), HOBt (230 mg) and DMF (4 ml). The mixture was stirred at 50° C. for 5 hr, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane-methanol (1:9:0-17:0:3) was concentrated under reduced pressure to give benzyl (3R)-3-(2-anilinoethyl)-4-({1-[(1-hydroxycyclohexyl)methyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate (116 mg) as an amorphous solid. The total amount thereof was dissolved in ethanol (2 ml), 4N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at 65° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the liberated oil was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object compound (55 mg) as an amorphous solid. 
     MS (ESI+, m/e) 488 (M+1) 
     Example 574 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-(2-bromobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     Methyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(2-bromobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (671 mg) was dissolved in 1,2-dichloroethane (15 ml), 1-chloroethyl chloroformate (715 mg) was added, and the mixture was heated under reflux for 8 hr, and concentrated under reduced pressure. To the residue was added methanol (15 ml), and the mixture was further heated under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, to the residue saturated was added aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (204 mg) as an amorphous solid. 
     MS (ESI+, m/e) 580 (M+1) 
     In the same manner as in Example 574, the following compound (Example 575) was obtained. 
     Example 575 
     (1S,2R)-2-(4-{[(2R)-2-(2-Bromobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 567 (M+1) 
     In the same manner as in Example 382 except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compound (Example 576) was obtained as an amorphous solid. 
     Example 576 
     Methyl [(1S,2S)-2-(5-phenyl-4-{[(2R)-2-(3-phenylpropyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 530 (M+1) 
     Example 577 
     (1S,2R)-2-{4-[((2R)-2-{2-[Cyclohexyl(methyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-3-{2-[methyl(phenyl)amino]ethyl}piperazine-1-carboxylate obtained in the course of Example 429 (150 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water, 70 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:2) was concentrated under reduced pressure to give the object compound (75 mg) as an amorphous solid. 
     MS (ESI+, m/e) 538 (M+1) 
     In the same manner as in Example 416, the following compounds (Examples 578-580) were obtained. The compounds of Examples 579-580 were isolated as free amorphous solids by extracting the final product with ethyl acetate and subjecting the extract to basic silica gel column chromatography. 
     Example 578 
     3-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}amino)benzoic acid tri-trifluoroacetate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 562 (M+1) 
     Example 579 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-5-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 589 (M+1) 
     Example 580 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzothiazol-6-yl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 589 (M+1) 
     Example 581 
     (1S,2R)-1-(Methoxymethyl)-2-(5-phenyl-4-{[(2R)-2-(2-(pyridin-2-yl)benzyl)piperazin-1-yl]carbonyl}-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     tert-Butyl (2R)-4-benzyl-2-(2-(pyridin-2-yl)benzyl)piperazine-1-carboxylate (140 mg) was dissolved in ethyl acetate (1 ml), 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in toluene (1 ml), and the suspension was again concentrated under reduced pressure. The residue was suspended in DMF (2 ml), 1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazole-4-carboxylic acid (96 mg), WSC.HCl (83 mg), HOBt (67 mg), triethylamine (187 mg) were added, and the suspension was stirred at room temperature for 12 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give (1S,2R)-2-[4-({(2R)-4-benzyl-2-[2-(6-chloropyridin-2-yl)benzyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol (115 mg) as an amorphous solid. The total amount thereof was dissolved in methanol (3 ml), 20% palladium hydroxide-carbon (50% containing water, 60 mg) was added thereto, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 6 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (67 mg). (During the catalytic reduction, the removal of the chlorine atom proceeded together with the removal of the benzyl protecting group.) 
     MS (ESI+, m/e) 566 (M+1) 
     Example 582 
     (1S,2S)-2-{4-[((2R)-2-{2-[(2-Methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanamine 
     
       
         
         
             
             
         
       
     
     Benzyl (3R)-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (200 mg) was dissolved in DMF (30 ml), 1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazole-4-carboxylic acid (168 mg), WSC.HCl (142 mg), HOBt (93 mg) and N,N-diisopropylethylamine (253 μl) were added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give benzyl (3R)-4-[(1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]-3-{2-[(2-methyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazine-1-carboxylate (100 mg) as an amorphous solid. The total amount thereof was dissolved in 25% hydrogen bromide-acetic acid solution (2 ml), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was washed with ethyl acetate. To the aqueous layer was added potassium carbonate by small portions to basify the layer, and the mixture was saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (4:1) was concentrated under reduced pressure to give the object compound (11 mg) as an amorphous solid. 
     MS (ESI+, m/e) 545 (M+1) 
     Example 583 
     4-{[(3R)-3-Benzyl-4-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-1-yl]methyl}-5-methyl-1,3-dioxol-2-one 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol obtained in the course of Example 367 (489 mg) and 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (149 mg) were dissolved in DMF (5 ml), potassium hydrogen carbonate (150 mg) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (28 mg) as an amorphous solid. 
     MS (ESI+, m/e) 601 (M+1) 
     Example 584 
     1-[4-(2-{(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)-4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-2-yl}ethoxy)phenyl]pyrrolidin-2-one 
     
       
         
         
             
             
         
       
     
     1-(4-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}phenyl)pyrrolidin-2-one (the compound of Example 294) (105 mg) and potassium hydrogen carbonate were suspended in DMF (3 ml). A solution of 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (37 mg) in DMF (2 ml) which was cooled to 0° C. was added dropwise thereto, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (7:3) was concentrated under reduced pressure to give the object compound (71 mg) as an amorphous solid. 
     MS (ESI+, m/e) 714 (M+1) 
     In the same manner as in Example 1 (Method A) except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 585-588) were obtained as a free amorphous solid. 
     Example 585 
     (1S,2R)-2-{4-[((2R)-2-{2-[(4-Methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 532 (M+1) 
     Example 586 
     (1S,2R)-2-{4-[((2R)-2-{2-[(5-Methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 532 (M+1) 
     Example 587 
     Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(4-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 575 (M+1) 
     Example 588 
     Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 575 (M+1) 
     In the same manner as in Example 9 (Method I) except that the treatment of the final product (excluding Example 595) with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 589-594) were obtained as a free amorphous solid. 
     Example 589 
     (1S,2R)-2-[4-({(2R)-2-[2-(2,3-Dihydro-1-benzofuran-6-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 561 (M+1) 
     Example 590 
     (1S,2R)-2-{4-[((2R)-2-{2-[(3-Fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 536 (M+1) 
     Example 591 
     Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(3-fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 579 (M+1) 
     Example 592 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 574 (M+1) 
     Example 593 
     (1R,2R)-1-(Cyclopropylmethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 584 (M+1) 
     Example 594 
     1-({4-[((2R)-2-{2-[(3-Fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}methyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 536 (M+1) 
     In the same manner as in Example 8 (Method H), the following compound (Example 595) was obtained. 
     Example 595 
     (1R,2R)-1-(Cyclopropylmethyl)-2-[5-phenyl-4-({(2S)-2-[(phenylsulfonyl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol dihydrochloride 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 563 (M+1) 
     In the same manner as in Example 10 (Method J) except that the treatment of the final product with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compound (Examples 596) was obtained as a free amorphous solid. 
     Example 596 
     [2-({2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}thio)-1,3-thiazol-4-yl]methyl acetate and (1S,2R)-2-(4-{[(2R)-2-(2-{[4-(hydroxymethyl)-1,3-thiazol-2-yl]thio}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     After the reaction by Method J, the residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (100:0-80:20) was concentrated under reduced pressure to give [2-({2-[(2R)-1-({1-[(1R,2S)-2-hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethyl}thio)-1,3-thiazol-4-yl]methyl acetate (113 mg, MS (ESI+, m/e) 614 (M+1)) as a component having a short retention time, and (1S,2R)-2-(4-{[(2R)-2-(2-{[4-(hydroxymethyl)-1,3-thiazol-2-yl]thio}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol (20 mg, MS (ESI+, m/e) 570 (M+1)) as a component having a long retention time. 
     The following compounds of Examples 597-644 can be synthesized according to the above-mentioned methods. 
     Example 597 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,4-Dimethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 598 
     (1S,2R)-2-{4-[((2R)-2-{2-[(4-Fluoro-2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 599 
     (1S,2R)-2-{4-[((2R)-2-{2-[(7-Fluoro-2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 600 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,7-Dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 601 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,6-Dimethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 602 
     (1S,2R)-2-{4-[((2R)-2-{2-[(6-Fluoro-2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 603 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,7-Dimethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 604 
     (1S,2R)-2-{4-[((2R)-2-{2-[(7-Fluoro-2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 605 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 606 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 607 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Cyclopropyl-4-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 608 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Cyclopropyl-4-fluoro-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 609 
     (1S,2R)-2-[4-({(2R)-2-[2-(1,2-Benzisoxazol-5-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 610 
     (1S,2R)-2-[4-({(2R)-2-[2-(1,2-Benzisoxazol-6-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 611 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methylimidazo[1,2-a]pyridin-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 612 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methylimidazo[1,2-a]pyridine-7-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 613 
     (1S,2R)-2-[4-({(2R)-2-[2-(1,2-Benzisothiazol-5-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 614 
     (1S,2R)-2-[4-({(2R)-2-[2-(1,2-Benzisothiazol-6-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 615 
     (1S,2R)-2-{4-[((2R)-2-{2-[(1,2-Dimethyl-1H-indol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 616 
     (1S,2R)-2-{4-[((2R)-2-{2-[(1,2-Dimethyl-1H-indol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 617 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1-benzofuran-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 618 
     (1S,2R)-1-(Methoxymethyl)-2-{4-[((2R)-2-{2-[(2-methyl-1-benzofuran-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 619 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,4-Dimethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 620 
     (1S,2R)-2-{4-[((2R)-2-{2-[(4-Fluoro-2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 621 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 622 
     (1R,2R)-2-{4-[((2R)-2-{2-[(2-Cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(cyclopropylmethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 623 
     (1S,2R)-2-{4-[((2R)-2-{2-[(7-Fluoro-2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 624 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,7-Dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 625 
     (1R,2R)-1-(Cyclopropylmethyl)-2-{4-[((2R)-2-{2-[(2,4-dimethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 626 
     (1R,2R)-1-(Cyclopropylmethyl)-2-{4-[((2R)-2-{2-[(4-fluoro-2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 627 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(3,5-difluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 628 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3,5-dichlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 629 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-chloro-5-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 630 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-fluoro-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 631 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-chloro-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 632 
     Methyl ((1S,2S)-2-{4-[((2R)-2-{2-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate 
     
       
         
         
             
             
         
       
     
     Example 633 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-naphthyloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 634 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3,4-difluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 635 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3,4-dichlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     Example 636 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 637 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Methoxy-5-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 638 
     (1S,2R)-1-Methyl-2-{4-[((2R)-2-{2-[(2-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 639 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Fluorophenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 640 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Methoxy-4-methylphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 641 
     (1S,2R)-2-{4-[((2R)-2-{2-[(4-Methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 642 
     (1S,2R)-2-{4-[((2R)-2-{2-[(3-Fluoro-4-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 643 
     (1S,2R)-2-{4-[((2R)-2-{2-[(3-Methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 644 
     (1S,2R)-2-{4-[((2R)-2-{2-[(4-Fluoro-2-methoxyphenyl)amino]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     Example 645 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 0.5 fumarate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol fumarate (50 mg) was dissolved in methanol (1.5 ml) at 60° C., ethyl acetate (15 ml) was added, and the mixture was cooled to 0° C. The precipitated crystals were collected by filtration to give the object compound (41 mg). 
     Example 646 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol fumarate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol (3.75 g) and fumaric acid (736 mg) were dissolved in ethanol (100 ml) while heating (60° C.), and the solvent (about 50 ml) was evaporated under reduced pressure. To the residue was added acetonitrile (150 ml), and the solvent (about 100 ml) was evaporated under reduced pressure. The residue was left to stand at room temperature for 1 hr, and the crystals were collected by filtration, washed with a small amount of acetonitrile, and dried under reduced pressure to give the object compound (3.5 g) as crystals. 
     melting point: 157-158° C. 
     Example 647 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate succinate 
     
       
         
         
             
             
         
       
     
     Methyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (900 mg) and succinic acid (197 mg) were dissolved in ethanol (20 ml) while heating (60° C.), and the solvent was evaporated under reduced pressure. To the residue were added acetonitrile (20 ml) and ethyl acetate (30 ml), and the mixture was stirred at room temperature for 12 hr. The crystals were collected by filtration, washed with a small amount of acetonitrile, and dried under reduced pressure to give the object compound (800 mg) as crystals. 
     melting point: 157-176° C. 
     Example 648 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate malonate 
     
       
         
         
             
             
         
       
     
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (36 g) and malonic acid (6.45 g) were dissolved in ethanol (500 ml) while heating (80° C.), and the solvent was evaporated under reduced pressure. To the residue were added ethanol (300 ml) and water (30 ml), and the mixture was heated (80° C.). Ethyl acetate (300 ml) was added, and the mixture was stirred at room temperature for 12 hr. The crystals were collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to give the object compound as crystals (25.2 g). 
     melting point: 166-167° C. 
     Example 649 
     Propyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (171 mg) and DMAP (44 mg) were dissolved in THF (3 ml), propyl chlorocarbonate (39 mg) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give propyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (182 mg). The obtained propyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (182 mg) was dissolved in methanol (5 ml), 20% palladium hydroxide-carbon (50% containing water) (20 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (94 mg). 
     MS (ESI+, m/e) 566 (M+1) 
     In the same manner as in Example 649, the following compounds (Examples 650-654) were obtained. 
     Example 650 
     3-[(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]-1,1-dimethylurea 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 551 (M+1) 
     Example 651 
     N-[(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]propanamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 536 (M+1) 
     Example 652 
     2-Methoxyethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 582 (M+1) 
     Example 653 
     Isobutyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 580 (M+1) 
     Example 654 
     Isopropyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 566 (M+1) 
     Example 655 
     2-Fluoroethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (171 mg) and triethylamine (0.209 ml) were dissolved in THF (3 ml), 2-fluoroethyl chlorocarbonate (0.057 ml) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give 2-fluoroethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (113 mg). The obtained 2-fluoroethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (113 mg) was dissolved in THF (5 ml), 20% palladium hydroxide-carbon (50% containing water) (20 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (91 mg). 
     MS (ESI+, m/e) 570 (M+1) 
     In the same manner as in Example 655, the following compounds (Examples 656-659) were obtained. 
     Example 656 
     N-[(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]methanesulfonamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 558 (M+1) 
     Example 657 
     N′-[(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]-N,N-dimethylsulfamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 587 (M+1) 
     Example 658 
     N-[(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]propane-1-sulfonamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 586 (M+1) 
     Example 659 
     N-[(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]ethanesulfonamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 572 (M+1) 
     Example 660 
     Cyclopropylmethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-Difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     (1S,2S)-2-(4-{[(2R)-4-Benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanamine (171 mg) and DMAP (110 mg) were dissolved in THF (5 ml), and the solution was ice-cooled. 4-Nitrophenyl chloroformate (91 mg) was added, and the mixture was stirred at 0° C. for 1 hr, and then at room temperature for 2 hr. To the reaction mixture was added cyclopropylmethanol (0.791 ml), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give cyclopropylmethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (130 mg) as an amorphous solid. The obtained cyclopropylmethyl [(1S,2S)-2-(4-{[(2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (130 mg) was dissolved in THF (5 ml), 20% palladium hydroxide-carbon (50% containing water) (20 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature and normal pressure for 15 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (88 mg). 
     MS (ESI+, m/e) 578 (M+1) 
     In the same manner as in Example 660, the following compounds (Examples 661-663) were obtained. 
     Example 661 
     1-tert-Butyl-3-[(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]urea 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 579 (M+1) 
     Example 662 
     2,2-Difluoroethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 663 
     Cyclobutyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 578 (M+1) 
     In the same manner as in Example 1 (Method A) except that the treatment of the final compound with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 664-676) were obtained by isolating as a free amorphous solid. 
     Example 664 
     (1S,2R)-1-(Ethoxymethyl)-2-(4-{[(2R)-2-{2-[(4-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 576 (M+1) 
     Example 665 
     (1S,2R)-1-(Ethoxymethyl)-2-(4-{[(2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 576 (M+1) 
     Example 666 
     Cyclobutyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(4-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 615 (M+1) 
     Example 667 
     Cyclobutyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(3-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 615 (M+1) 
     Example 668 
     Isopropyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 603 (M+1) 
     Example 669 
     Isopropyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(3-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 603 (M+1) 
     Example 670 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(5-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 589 (M+1) 
     Example 671 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(3-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 589 (M+1) 
     Example 672 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(3-methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 575 (M+1) 
     Example 673 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(3-Methoxy-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 532 (M+1) 
     Example 674 
     (1R,2R)-1-(Cyclopropylmethyl)-2-(4-{[(2R)-2-(4-methoxybenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 529 (M+1) 
     Example 675 
     Isopropyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 607 (M+1) 
     Example 676 
     Cyclobutyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 619 (M+1) 
     In the same manner as in Example 3 (Method C) except that the treatment of the final compound with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 677-682) were obtained by isolating as a free amorphous solid. 
     Example 677 
     4-{[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]methyl}benzonitrile 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 524 (M+1) 
     Example 678 
     (1R,2R)-1-(Cyclopropylmethyl)-2-[5-phenyl-4-({(2S)-2-[(5-phenyl-2H-tetrazol-2-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 567 (M+1) 
     Example 679 
     (1R,2R)-1-(Cyclopropylmethyl)-2-[5-phenyl-4-({(2S)-2-[(2-phenyl-1H-imidazol-1-yl)methyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 565 (M+1) 
     Example 680 
     (1R,2R)-1-(Cyclopropylmethyl)-2-(4-{[(2S)-2-(1H-indazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 539 (M+1) 
     Example 681 
     (1R,2R)-2-(4-{[(2S)-2-(1H-Benzimidazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(cyclopropylmethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 539 (M+1) 
     Example 682 
     (1R,2R)-1-(Cyclopropylmethyl)-2-[4-({(2S)-2-[(4-methyl-1H-pyrazol-1-yl)methyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 503 (M+1) 
     In the same manner as in Example 6 (Method F), the following compound (Example 683) was obtained. 
     Example 683 
     tert-Butyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 580 (M+1) 
     In the same manner as in Example 11 (Method K), the following compounds (Examples 684-692) were obtained. 
     Example 684 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(5-chloro-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 593 (M+1) 
     Example 685 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(5-Chloro-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 566 (M+1) 
     Example 686 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-chloro-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 594 (M+1) 
     Example 687 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-chloro-2-fluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 598 (M+1) 
     Example 688 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2,3-dichlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 614 (M+1) 
     Example 689 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-chlorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 580 (M+1) 
     Example 690 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(1-benzothiophen-4-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 691 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-(2-{[2-isopropyl-1,3-benzothiazol-5-yl]oxy}ethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 618 (M+1) 
     Example 692 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(2-Ethyl-1,3-benzothiazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 604 (M+1) 
     In the same manner as in Example 9 (Method I), the following compounds (Examples 693-762) were obtained. 
     Example 693 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-{2-[3-(3-methoxypropoxy)phenoxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 607 (M+1) 
     Example 694 
     (1S,2R)-2-(4-{[(2R)-2-{2-[3-(2-Methoxyethoxy)phenoxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 593 (M+1) 
     Example 695 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2,3-dihydro-1-benzofuran-6-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 696 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2,3-dihydro-1-benzofuran-5-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 697 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(5-methoxy-2-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 590 (M+1) 
     Example 698 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(5-methoxy-2-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 576 (M+1) 
     Example 699 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(5-chloro-2-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 595 (M+1) 
     Example 700 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-chloro-5-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 611 (M+1) 
     Example 701 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-chloro-4-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 611 (M+1) 
     Example 702 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(2-Cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 600 (M+1) 
     Example 703 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 627 (M+1) 
     Example 704 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2,7-dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 615 (M+1) 
     Example 705 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 601 (M+1) 
     Example 706 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 615 (M+1) 
     Example 707 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 601 (M+1) 
     Example 708 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl] carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 587 (M+1) 
     Example 709 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(2-Ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 710 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(2,7-Dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 711 
     (1S,2R)-1-(Methoxymethyl)-2-(4-{[(2R)-2-{2-[(2-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 574 (M+1) 
     Example 712 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-{2-[3,5-bis(trifluoromethyl)phenoxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 688 (M+1) 
     Example 713 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-{2-[3-fluoro-5-(trifluoromethyl)phenoxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 618 (M+1) 
     Example 714 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3,5-difluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 568 (M+1) 
     Example 715 
     Methyl [6-(2-{(2R)-1-[(1-{(1S,2S)-2-[(methoxycarbonyl)amino]cyclohexyl}-5-phenyl-1H-imidazol-4-yl)carbonyl]piperazin-2-yl}ethoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 646 (M+1) 
     Example 716 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-tert-butylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 717 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3,4-dimethylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 560 (M+1) 
     Example 718 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-isopropylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 574 (M+1) 
     Example 719 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Ethyl-7-methyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 602 (M+1) 
     Example 720 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Ethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 721 
     (1S,2R)-1-Methyl-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 544 (M+1) 
     Example 722 
     Ethyl ((1S,2S)-2-{4-[((2R)-2-{2-[(2-methyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}cyclohexyl)carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 601 (M+1) 
     Example 723 
     N-{(1S,2S)-2-[4-({(2R)-2-[2-(3,4-Dimethylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}methanesulfonamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 580 (M+1) 
     Example 724 
     N-{(1S,2S)-2-[4-({(2R)-2-[2-(Naphthalen-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}methanesulfonamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 602 (M+1) 
     Example 725 
     N-{(1S,2S)-2-[4-({(2R)-2-[2-(4-Methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}methanesulfonamide 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 566 (M+1) 
     Example 726 
     2-Methoxyethyl {(1S,2S)-2-[4-({(2R)-2-[2-(naphthalen-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 626 (M+1) 
     Example 727 
     2-Methoxyethyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 590 (M+1) 
     Example 728 
     Cyclobutyl {(1S,2S)-2-[5-phenyl-4-({(2R)-2-[2-(phenylamino)ethyl]piperazin-1-yl}carbonyl)-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 571 (M+1) 
     Example 729 
     Cyclobutyl [(1S,2S)-2-(4-{[(2R)-2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 542 (M+1) 
     Example 730 
     (1S,2R)-1-(Methoxymethyl)-2-[4-({(2R)-2-[2-(3-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 563 (M+1) 
     Example 731 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 576 (M+1) 
     Example 732 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-methoxy-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 590 (M+1) 
     Example 733 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 560 (M+1) 
     Example 734 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(naphthalen-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 596 (M+1) 
     Example 735 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 546 (M+1) 
     Example 736 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(naphthalen-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 582 (M+1) 
     Example 737 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2,3-dihydro-1H-inden-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 572 (M+1) 
     Example 738 
     (1S,2R)-2-[4-({(2R)-2-[2-(2,3-Dihydro-1H-inden-2-yloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 559 (M+1) 
     Example 739 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2,6-difluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 568 (M+1) 
     Example 740 
     (1S,2R)-2-[4-({(2R)-2-[2-(2,6-Difluorophenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 555 (M+1) 
     Example 741 
     6-{2-[(2R)-1-({1-[(1R,2S)-2-Hydroxy-2-(methoxymethyl)cyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1-(3-methoxypropyl)-3,4-dihydroquinolin-2(1H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 660 (M+1) 
     Example 742 
     6-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 655 (M+1) 
     Example 743 
     6-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1-(3-methoxypropyl)-3,4-dihydroquinolin-2(1H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 670 (M+1) 
     Example 744 
     6-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-2H-1,4-benzoxazin-3(4H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 600 (M+1) 
     Example 745 
     (1R,2R)-2-(4-{[(2S)-2-(1H-Benzotriazol-1-ylmethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(cyclopropylmethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 540 (M+1) 
     Example 746 
     (1R,2R)-2-[4-({(2R)-2-[2-(1H-Benzotriazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(cyclopropylmethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 554 (M+1) 
     Example 747 
     (1R,2R)-1-(cyclopropylmethyl)-2-(4-{[(2R)-2-{2-[(1,2-dimethyl-1H-benzimidazol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 597 (M+1) 
     Example 748 
     (1R,2R)-2-[4-({(2R)-2-[2-(1H-Benzimidazol-1-yl)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(cyclopropylmethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 553 (M+1) 
     Example 749 
     (1S,2R)-2-[4-({(2R)-2-[2-(3,4-Dimethoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 579 (M+1) 
     Example 750 
     6-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-1,3-benzoxazol-2(3H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 586 (M+1) 
     Example 751 
     7-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydroquinolin-2(1H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 598 (M+1) 
     Example 752 
     5-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydroisoquinolin-1(2H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 598 (M+1) 
     Example 753 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(2,5-Dimethylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 546 (M+1) 
     Example 754 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(5-Fluoro-2-methylphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 550 (M+1) 
     Example 755 
     6-{2-[(2R)-1-({1-[(1R,2R)-2-(Cyclopropylmethyl)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2-yl]ethoxy}-3,4-dihydroquinolin-2(1H)-one 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 598 (M+1) 
     Example 756 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(3-methoxy-2-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 590 (M+1) 
     Example 757 
     Ethyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-fluoro-4-methylphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 578 (M+1) 
     Example 758 
     (1S,2R)-2-(4-{[(2R)-2-{2-[(1,2-Dimethyl-1H-indol-5-yl)oxy]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 586 (M+1) 
     Example 759 
     (1R,2R)-1-(Cyclopropylmethyl)-2-[4-({(2R)-2-[2-(2,3-dihydrofuro[3,2-b]pyridin-5-ylamino)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 571 (M+1) 
     Example 760 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-fluoro-3-methoxyphenoxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 580 (M+1) 
     Example 761 
     Methyl [(1S,2S)-2-(4-{[(2R)-2-{2-[(2-fluoro-3-methoxyphenyl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 579 (M+1) 
     Example 762 
     (1R,2R)-1-(Cyclopropylmethyl)-2-(4-{[(2R)-2-{2-[(2-ethyl-1,3-benzoxazol-5-yl)amino]ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 597 (M+1) 
     In the same manner as in Example 9 (Method I) except that the treatment of the final compound with 4N hydrogen chloride-ethyl acetate solution was omitted, the following compounds (Examples 763-766) were obtained by isolating as a free amorphous solid. 
     Example 763 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2,7-Dimethyl-1,3-benzoxazol-6-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 764 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Cyclopropyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 600 (M+1) 
     Example 765 
     (1S,2R)-2-{4-[((2R)-2-{2-[(2-Ethyl-1,3-benzoxazol-5-yl)oxy]ethyl}piperazin-1-yl)carbonyl]-5-phenyl-1H-imidazol-1-yl}-1-(methoxymethyl)cyclohexanol 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 766 
     Methyl {(1S,2S)-2-[4-({(2R)-2-[2-(2-naphthyloxy)ethyl]piperazin-1-yl}carbonyl)-5-phenyl-1H-imidazol-1-yl]cyclohexyl}carbamate 
     
       
         
         
             
             
         
       
     
     MS (ESI+, m/e) 588 (M+1) 
     Example 767 
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate succinate 
     
       
         
         
             
             
         
       
     
     Ethyl [(1S,2S)-2-(4-{[(2R)-2-(3,5-difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)cyclohexyl]carbamate (1.00 g) and succinic acid (0.21 g) were dissolved in ethanol (10 ml) while heating (80° C.), and the mixture was cooled to room temperature without stirring and stood still at room temperature for 2 days. The crystals were collected by filtration, washed with a small amount of ethanol, and dried under reduced pressure to give the object compound as crystals (1.01 g). 
     melting point: 204-205° C. 
     Example 768 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol 0.5 fumarate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol (0.11 g) and fumaric acid (0.027 g) were dissolved in ethanol (5 ml) while heating (80° C.), and the mixture was cooled to room temperature without stirring and stood still at room temperature for 15 hours. The crystals were collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to give the object compound as crystals (0.091 g). 
     melting point: 191° C. 
     Example 769 
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol 0.5 succinate 
     
       
         
         
             
             
         
       
     
     (1S,2R)-2-(4-{[(2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-methylcyclohexanol (0.11 g) and succinic acid (0.028 g) were dissolved in ethanol (5 ml) while heating (80° C.), and the mixture was cooled to room temperature without stirring and stood still at room temperature for 15 hours. The crystals were collected by filtration, washed with a small amount of ethyl acetate, and dried under reduced pressure to give the object compound as crystals (0.062 g). 
     melting point: 192° C. 
     Preparation Example 1 
       
     
       
         
           
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 (1) Compound of Example 1 
                 10.0 
                 g 
               
               
                   
                 (2) Lactose 
                 70.0 
                 g 
               
               
                   
                 (3) Cornstarch 
                 50.0 
                 g 
               
               
                   
                 (4) Soluble starch 
                 7.0 
                 g 
               
               
                   
                 (5) Magnesium stearate 
                 3.0 
                 g 
               
               
                   
                   
               
            
           
         
       
     
     10.0 g of the compound of Example 1 and 3.0 g of magnesium stearate are granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), then and the mixture is dried and mixed with 70.0 g of lactose and 50.0 g of corn starch (any of lactose, corn starch, soluble starch and magnesium stearate is products in conformity to the 14 th  revision of the Japanese Pharmacopoeia). The mixture is compressed to give tablets. 
     Experimental Example 1 
     Human renin was obtained by expressing preprorenin (1-406) in an animal cell, treating the prorenin (24-406) contained in the culture supernatant with trypsin, and taking the active type (67-406). 
     (1) Construction of Renin-Expressing Vector 
     A plasmid DNA to express human renin in HEK293 cells was prepared as follows. PCR was carried out using human renal cDNA (Clontech Laboratories, Inc., Marathon Ready cDNA) as the template and using two synthetic DNAs (5′-AAGCTTATGGATGGATGGAGA-3′; SEQ ID No.1, and 5′-GGATCCTCAGCGGGCCAAGGC-3′; SEQ ID No.2), and the obtained fragments were cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtained fragments were subcloned into pcDNA3.1(+) that had been cleaved by HindIII and BamHI, thus to obtain a plasmid DNA for human preprorenin expression (pcDNA3.1(+)/hREN). 
     (2) Construction of Angiotensinogen-Expressing Vector 
     A plasmid DNA to express human angiotensinogen in HEK293 cells was prepared as follows. PCR was carried out using human liver cDNA (Clontech Laboratories, Inc., Marathon Ready cDNA) as the template and using two synthetic DNAs (5′-AAGCTTATGCGGAAGCGAGCACCCCAGTCT-3′; SEQ ID No.3, and 5′-GGATCCTCACTTGTCATCGTCGTCCTTGTAGTCTGCTGTGCTCAGCGGGTTGGCCACGC-3′; SEQ ID No.4), and the obtained fragments were cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtained fragments were subcloned into pcDNA3.1(+) that had been cleaved by HindIII and BamHI, thereby to give a plasmid DNA for expression of human angiotensinogen having a FLAGtag on the C-terminal (pcDNA3.1(+)/hAngiotensinogen-FLAG). Then, PCR was carried out using the pcDNA3.1(+)/hAngiotensinogen-FLAG as the template and using two synthetic DNAs (5′-CCTTAAGCTTCCACCATGCGGAAGCGAGCACCCCAGTCT-3′; SEQ ID No.5, and 5′-TTGGATCCTCATGCTGTGCTCAGCGGGTTGGCCACGCGG-3′; SEQ ID No.6), and the obtained fragments were cloned using a TOPO TA Cloning Kit (Invitrogen Corp.). The obtained fragments were subcloned into pcDNA3.1(+) that had been cleaved by HindIII and BamHI, thus to obtain a plasmid DNA for human angiotensinogen expression (pcDNA3.1(+)/hAngiotensinogen). 
     (3) Expression of Preprorenin and Purification of Prorenin (24-406) 
     Expression of human preprorenin was conducted using FreeStyle 293 Expression System (Invitrogen Corp.). According to the manual accompanying the FreeStyle 293 Expression System, the plasmid DNA for human preprorenin expression (pcDNA3.1(+)/hREN) constructed in the above-mentioned (1) was used to conduct transient expression by FreeStyle 293-F cells. After transfection of the plasmid DNA, the cells were subjected to shaking culture under the conditions of 37° C., 8% CO 2  and 125 rpm for 3 days. A 600-ml aliquot of the culture solution was centrifuged at 2,000 rpm for 10 min to recover the culture supernatant containing prorenin (24-406). The culture supernatant was concentrated by ultrafiltration using a PM10 membrane (Millipore, Inc.) to a volume of about 50 ml, and then was dialyzed against 20 mM Tris-hydrochloric acid (pH 8.0). The dialyzate was fed to a 6-ml RESOURCE Q column (GE Healthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) at a flow rate of 3 ml/min to adsorb the prorenin (24-406). After washing the column with the buffer solution used in the equilibration, elution was carried out by means of a linear concentration gradient of sodium chloride from 0 M to 0.4 M. The fraction containing prorenin (24-406) was collected and concentrated using Vivaspin 20 (molecular weight cut off 10,000; Vivascience, Inc.) to a volume of about 2 ml. 
     The concentrated liquid was subjected to gel filtration chromatography using HiLoad 16/60 Superdex 200 pg (GE Healthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing 0.15 M sodium chloride, at a flow rate of 1.4 ml/min, thus to obtain 3.6 mg of purified prorenin (24-406). 
     (4) Purification of Active Type Renin (67-406) 
     To 3.6 mg of prorenin (24-406) dissolved in 5.2 ml of 0.1 M Tris-hydrochloric acid (pH 8.0), 12 μg of trypsin (Roche Diagnostics Corp.) was added, and the mixture was allowed to react at 28° C. for 55 min to carry out activation of renin. After the reaction, 0.4 ml of immobilized trypsin inhibitor (Pierce Biotechnology, Inc.) was added to remove the trypsin used in the activation by adsorption. The reaction liquid containing the active type renin was concentrated using Vivaspin 20 (molecular weight cut off 10,000, Vivascience, Inc.), and was diluted with 20 mM Tris-hydrochloric acid (pH 8.0). The diluted liquid was fed to a TSKgel DEAE-5PW column (7.5 mm I.D.×75 mm, Tosoh Corp.) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) at a flow rate of 1 ml/min to adsorb the active type renin (67-406). The column was washed with the buffer solution used for the equilibration, and then elution was carried out by means of a sodium chloride linear concentration gradient from 0 M to 0.3 M, thus to obtain 1.5 mg of a purified product of active type renin (67-406). 
     (5) Purification of Angiotensinogen 
     Expression of human angiotensinogen was conducted using FreeStyle 293 Expression System (Invitrogen Corp.). According to the manual accompanying the FreeStyle 293 Expression System, the plasmid DNA for human angiotensinogen expression (pcDNA3.1(+)/hAngiotensinogen) constructed in the above-mentioned (2) was used to conduct transient expression by FreeStyle 293-F cells. After transfection of the plasmid DNA, the cells were subjected to shaking culture under the conditions of 37° C., 8% CO 2  and 125 rpm for 3 days. A 600-ml aliquot of the culture solution was centrifuged at 2,000 rpm for 10 min to recover the culture supernatant containing angiotensinogen. To the culture supernatant was added ammonium sulfate (30% saturated concentration), and the mixture was thoroughly stirred and centrifuged at 8,000 rpm for 20 min. The obtained supernatant was added to TOYO Pearl butyl 650M (2×5 cm, Tosoh Corporation) equilibrated with 50 mM tris-hydrochloric acid (pH 8.0) containing 30% saturated ammonium sulfate, at a flow rate of 25 ml/min to allow adsorption. After washing with equilibration buffer, angiotensinogen was eluted by linear concentration gradient from the buffer used for equilibration to 20 mM tris-hydrochloric acid (pH 8.0). The eluate containing angiotensinogen was applied to repeated concentration and dilution using Vivaspin 20 (molecular weight cut off 10,000, Vivascience, Inc.), and the buffer was changed to 20 mM tris-hydrochloric acid (pH 8.0). The eluate was fed to a 6-ml RESOURCE Q column (Amersham Biosciences, Inc.) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing 50 mM sodium chloride at a flow rate of 6 ml/min to adsorb the angiotensinogen. After washing the column with the buffer solution used in the equilibration, elution was carried out by means of a linear concentration gradient of sodium chloride from 50 mM to 400 mM. The fractions containing angiotensinogen were collected and concentrated using Vivaspin 20 (molecular weight cut off 10,000, Vivascience, Inc.) to a volume of about 2 ml. The concentrated liquid was subjected to gel filtration chromatography using HiLoad 26/60 Superdex 200 pg (GE Healthcare) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing 0.15 M sodium chloride, at a flow rate of 2.0 ml/min, thus to obtain 7.0 mg of purified angiotensinogen. 
     (6) Measurement of Renin Inhibition Value—A 
     As a substrate for renin activity measurement, a substrate peptide (FITC-Acp-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Gln-Arg-NH 2 ; SEQ ID No.8) wherein the N-terminal of a peptide prepared in reference to a partial sequence (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Glu-NH 2 ; SEQ ID No.7) of human angiotensinogen was bound with epsilon aminocaproic acid (Acp) as a linker and labeled with a fluorescence reagent Fluorescein isothiocyanate (FITC). 2 μl each of the test compound (containing 100% DMSO) was added to each well of a 384-well black plate (Nalge Nunc International Co., Ltd.). Renin was diluted with a buffer solution for reaction (20 mM citric acid-sodium citrate (pH 6.0)) to a concentration of 4.7 nM, and 30 μl each of the dilution was added to each well. The dilution was left to stand at 37° C. for 10 min, and then 8 μl of each of a 25 μM solution of substrate peptide was added to each well to initiate the reaction. The reaction mixture was left to stand at 37° C. for 30 min, and then 40 μl each of a reaction terminating solution [200 mM Tris-hydrochloric acid (pH 8.0), 0.04% Triton-X 100, 0.4% Coating 3 reagent (Caliper Life Sciences Corp.) and 1 μM CGP-29287 (Bachem Holding AG)] was added to each well to terminate the reaction. 
     The substrate peptide and the product peptide were separated by a microchip type capillary electrophoresis system 250HTS (Caliper Life Sciences Co., Ltd.), and the rate of reaction [(peak height of product)/(peak height of product+peak height of substrate)×100(%)] was calculated from the ratio of the respective peak height of the peptides obtained by fluorimetric detection (excitation wavelength 457 nm, measurement wavelength 530 nm), and was used as an index of the renin activity. 
     While the reaction rate of the well where 100% DMSO only was added was taken as 0% inhibition rate, and the reaction rate of the well where 10 μM of CGP-29287 was added was taken as 100% inhibition rate, the renin inhibitory activity of the wells where the test compound (containing 100% DMSO) was added was calculated. 
     The results are presented in Table 29. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 29 
               
               
                   
                   
               
               
                   
                   
                 inhibitory activity 
               
               
                   
                 Ex. No. 
                 (%) at 1 μM 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 96 
               
               
                   
                 4 
                 99 
               
               
                   
                 6 
                 98 
               
               
                   
                 7 
                 100 
               
               
                   
                 15 
                 96 
               
               
                   
                 349 
                 101 
               
               
                   
                 352 
                 101 
               
               
                   
                 357 
                 100 
               
               
                   
                 358 
                 103 
               
               
                   
                 360 
                 99 
               
               
                   
                 361 
                 100 
               
               
                   
                 363 
                 98 
               
               
                   
                 367 
                 99 
               
               
                   
                 378 
                 99 
               
               
                   
                 379 
                 99 
               
               
                   
                 380 
                 100 
               
               
                   
                 383 
                 100 
               
               
                   
                 387 
                 109 
               
               
                   
                 389 
                 106 
               
               
                   
                 390 
                 105 
               
               
                   
                 391 
                 109 
               
               
                   
                   
               
            
           
         
       
     
     It can be seen from the results of Table 29 that compound (I) of the present invention has a superior renin inhibitory activity as evidenced by an IC 50  value of 1 μM or less. 
     (7) Measurement of Renin Inhibition Value—B 
     As a substrate for renin activity measurement, the angiotensinogen mentioned in (5) above was used. 1 μl each of the test compound (containing 100% DMSO) was added to each well of a 384-well plate (ABgene). Renin was diluted with a buffer solution for reaction (20 mM sodium phosphate (pH 7.4)) to a concentration of 57 pM, and 14 μl each of the dilution was added to each well. The dilution was left to stand at 37° C. for 10 min, and then 5 μl of each of a 6 μM solution of substrate angiotensinogen was added to each well to initiate the reaction. The reaction mixture was left to stand at 37° C. for 30 min, and then 20 μl each of a reaction terminating solution [20 mM Tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween 20 and 1 μM CGP-29287] was added to each well to terminate the reaction, thus an enzyme reaction solution was obtained. The amount of angiotensin I produced by an enzyme reaction was quantified by Enzyme Immuno Assay (EIA) described below. 
     Anti-angiotensin I antibody (Peninsula Laboratories Inc.) diluted 5,000-fold with PBS was added to each well of a 384 well black plate (Nalge Nunc International Co., Ltd.) by 25 μl, and left standing overnight at 4° C. to immobilize the antibody in the plate. The antibody solution was removed, PBS solution (100 μl) containing 1% BSA was added to each well, and the mixture was left standing at room temperature for 2 hr for blocking. The blocking solution was removed, and each well was washed 5 times with 100 μl of 0.05% Tween20-PBS. An angiotensin I standard solution (Wako Pure Chemical Industries, Ltd.) prepared to 0.156-10 nM with an enzyme reaction solution or buffer [20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween20] was dispensed to each well by 10 μl. Then, a biotinated angiotensin I solution (AnaSpec, 15 μl) prepared to 1.6 nM with a buffer [20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.01% BSA, 0.05% Tween20] was added to each well, mixed with a plate mixer and left standing at room temperature for 1 hr. The solutions were removed from each well, and each well was washed 5 times with 100 μl of 0.05% Tween20-PBS. Horseradish peroxydase Streptavidin (PIERCE Biotechnology inc., 25 μl) diluted to 100 ng/ml with a buffer [20 mM tris-hydrochloric acid (pH 7.4), 150 mM sodium chloride, 0.1% BSA, 0.05% Tween 20] was added to each well and the mixture was left standing at room temperature for 30 min. The solutions were removed from each well, and each well was washed 5 times with 100 μl of 0.05% Tween20-PBS. SuperSignal ELISA femto Maximum Sensitivity Substrate (PIERCE Biotechnology Inc.) was added by 25 μl and luminescence intensity was measured by EnVision (Perkin Elmer Inc.). An analytical curve was drawn from the luminescence intensity of a well containing an angiotensin I standard solution, and the amount of angiotensin I produced by an enzyme reaction was calculated and used as an index of renin activity. 
     While the reaction rate of the well where 100% DMSO only was added was taken as 0% inhibition rate, and the reaction rate of the well where angiotensin I was not contained was taken as 100% inhibition rate, the renin inhibitory activity of the wells where the test compound (containing 100% DMSO) was added was calculated. 
     (8) Results 
     Example compounds 1-367, 369-429 were measured by the method of the above-mentioned (6) or (7). As a result, all compounds showed a renin inhibitory activity of 30% or above at a concentration of 1 μM. 
     Example compounds 430-596, 645-766 were measured by the method of the above-mentioned (7). As a result, all compounds showed a renin inhibitory activity of 25% or above at a concentration of 0.1 μM. 
     It is clear therefrom that compound (I) of the present invention has a superior renin inhibitory activity. 
     Sequence Listing Free Text 
     [SEQ ID NO: 1] primer
 
[SEQ ID NO: 2] primer
 
[SEQ ID NO: 3] primer
 
[SEQ ID NO: 4] primer
 
[SEQ ID NO: 5] primer
 
[SEQ ID NO: 6] primer
 
[SEQ ID NO: 7] partial sequence of human angiotensinogen
 
[SEQ ID NO: 8] substrate peptide of renin
 
     INDUSTRIAL APPLICABILITY 
     Compound (I) has superior renin inhibitory activity and thus is useful as an agent for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension, and the like. 
     This application is based on patent application Nos. 120292/2007 and 207271/2007 filed in Japan, the contents of which are hereby incorporated by reference.