Substituted imidazole compound and use thereof

Abstract
The present invention relates to a compound represented by the formula:
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


R1 is a substituent,


R2 is a cyclic group optionally having substituent(s), C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s) or C2-10 alkynyl optionally having substituent(s),


R3 is a hydrogen atom, a halogen atom, C1-6 alkyl or C1-6 alkoxy,


X is bond or spacer having 1 to 6 atoms in the main chain,


ring A is C5-7 cycloalkane optionally having substituent(s), and


ring B is piperazine optionally further having substituent(s) besides R1,


or a salt thereof [hereinafter to be sometimes abbreviated as compound (I)];


[2] the compound of the aforementioned [1], wherein R1 is a hydrocarbon group optionally having substituent(s);


[3] the compound of the aforementioned [1], wherein R2 is C6-14 aryl optionally having substituent(s) or C3-10 cycloalkyl optionally having substituent(s);


[4] the compound of the aforementioned [1], wherein R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;


[5] the compound of the aforementioned [1], wherein X is bond or C1-6 alkylene optionally having substituent(s);


[6] the compound of the aforementioned [1], wherein ring A is C5-7 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 R1 is as defined above;


[8] a compound represented by the formula:







wherein


R1 is


(a) C1-6 alkyl substituted by hydroxy optionally having a substituent,


(b) C1-6 alkyl substituted by phenylamino optionally having substituent(s), or


(c) C7-13 aralkyl optionally having substituent(s);


R2 is optionally halogenated C6-10 aryl;


R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;


X is bond or C1-6 alkylene optionally having substituent(s); and


ring A is


(a) C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s), or


(b) C5-7 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 “C1-4 alkylenedioxy” in the present specification include methylenedioxy, ethylenedioxy, trimethylenedioxy and the like.


Examples of the “C1-6 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 “C1-6 alkoxy” in the present specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.


Examples of the “C1-6 alkoxy-carbonyl” in the present specification include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.


Examples of the “C1-6 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 C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-3 alkylidene, C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10 cycloalkadienyl, C6-14 aryl, C7-13 aralkyl, C8-13 arylalkenyl, C3-10 cycloalkyl-C1-6 alkyl and the like. The above-mentioned C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl are each optionally condensed with a benzene ring.


Examples of the “C1-10 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, C1-6 alkyl is preferable.


Examples of the “C2-10 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, C2-6 alkenyl is preferable.


Examples of the “C2-10 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, C2-6 alkynyl is preferable.


Examples of the “C1-3 alkylidene” in the present specification include methylene, ethylidene, propylidene, isopropylidene and the like.


Examples of the “C3-10 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, C3-6 cycloalkyl is preferable. The above-mentioned C3-10 cycloalkyl is optionally condensed with a benzene ring. Examples of the condensed group include indanyl, tetrahydronaphthyl, fluorenyl and the like.


Examples of the “C3-10 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 C3-10 cycloalkenyl is optionally condensed with a benzene ring. Examples of the condensed group include indenyl and the like.


Examples of the “C4-10 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 C4-10 cycloalkadienyl is optionally condensed with a benzene ring.


Examples of the “C6-14 aryl” in the present specification include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like. Among these, C6-10 aryl is preferable, and phenyl is more preferable. The above-mentioned C6-14 aryl is optionally condensed with C3-10 cycloalkane (examples of the C3-10 cycloalkane include rings corresponding to the above-mentioned C3-10 cycloalkyl). Examples of the condensed group include tetrahydronaphthyl and the like.


Examples of the “C7-13 aralkyl” in the present specification include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.


Examples of the “C8-13 arylalkenyl” in the present specification include styryl and the like.


Examples of the “C3-10 cycloalkyl-C1-6 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) C3-10 cycloalkyl (e.g., cyclopropyl, cyclohexyl);


(3) C6-14 aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from

    • (i) carboxy,
    • (ii) hydroxy,
    • (iii) C1-6 alkyl optionally having 1 to 3 substituents selected from
      • (a) hydroxy, and
      • (b) a halogen atom,
    • (iv) C1-6 alkoxy optionally having 1 to 3 substituents selected from
      • (a) C1-6 alkoxy,
      • (b) carbamoyl optionally mono- or di-substituted by substituent(s) selected from C1-6 alkyl optionally substituted by carbamoyl, and C1-6 alkylsulfonyl,
      • (c) carboxyl,
      • (d) C1-6 alkoxy-carbonyl optionally substituted by a non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from oxo and C1-6 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) C1-6 alkyl optionally substituted by hydroxy, and
      • (b) C1-6 alkylsulfonyl,
    • (vi) a non-aromatic heterocyclic group (e.g., oxadiazolinyl) optionally substituted by oxo,
    • (vii) an aromatic heterocyclic group (e.g., tetrazolyl),
    • (viii) C1-6 alkoxy-carbonyl optionally substituted by a non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from oxo and C1-6 alkyl,
    • (ix) cyano,
    • (x) sulfamoyl,
    • (xi) halogen,
    • (xii) C1-6 alkylsulfonyl (e.g., methylsulfonyl), and
    • (xiii) C1-6 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) C1-6 alkyl optionally having 1 to 3 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C6-14 aryl (e.g., phenyl),
      • (d) C1-6 alkoxy,
      • (e) C1-6 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 C1-6 alkyl,
    • (iii) C3-6 cycloalkyl,
    • (iv) C6-14 aryl,
    • (v) hydroxy,
    • (vi) C1-6 alkoxy,
    • (vii) C1-6 alkyl-carbonyl optionally having amino optionally mono- or di-substituted by C1-6 alkyl-carbonyl,
    • (viii) C6-14 aryl-carbonyl (e.g., benzoyl),
    • (ix) C1-6 alkoxy-carbonyl,
    • (x) carboxy,
    • (xi) carbamoyl optionally mono- or di-substituted by C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and carbamoyl,
    • (xii) C1-6 alkylsulfonyl,
    • (xiii) C6-14 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) C1-6 alkyl optionally having 1 to 3 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C6-14 aryl (e.g., phenyl),
      • (d) C1-6 alkoxy,
      • (e) C1-6 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 C1-6 alkyl,
    • (iii) C3-6 cycloalkyl,
    • (iv) C6-14 aryl,
    • (v) hydroxy,
    • (vi) C1-6 alkoxy,
    • (vii) C1-6 alkyl-carbonyl optionally having amino optionally mono- or di-substituted by C1-6 alkyl-carbonyl,
    • (viii) C6-C14 aryl-carbonyl (e.g., benzoyl),
    • (ix) C1-6 alkoxy-carbonyl,
    • (x) carboxy,
    • (xi) carbamoyl optionally mono- or di-substituted by C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and carbamoyl,
    • (xii) C1-6 alkylsulfonyl,
    • (xiii) C6-14 arylsulfonyl,
    • (xiv) cyano, and
    • (xv) oxo;


      (6) amino optionally mono- or di-substituted by substituent(s) selected from
    • (i) C1-10 alkyl optionally substituted by 1 to 3 substituents selected from
      • (a) hydroxy,
      • (b) C1-6 alkoxy optionally substituted by C6-14 aryl (e.g., phenyl),
      • (c) carboxy,
      • (d) C3-10 cycloalkyl (e.g., cyclopropyl) optionally substituted by C1-6 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) C1-6 alkyl optionally substituted by hydroxy,
        • 2) C1-6 alkoxy-carbonyl,
        • 3) carboxy,
        • 4) a halogen atom, and
        • 5) C1-6 alkylthio,
      • (g) C6-14 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • 1) amino optionally mono- or di-substituted by substituent(s) selected from C1-6 alkyl and C1-6 alkyl-carbonyl,
        • 2) C1-4 alkylenedioxy,
        • 3) hydroxy, and
        • 4) C1-6 alkoxy optionally substituted by carboxy,
      • (h) C1-6 alkylthio,
      • (i) C1-6 alkylsulfonyl,
      • (j) amino optionally mono- or di-substituted by C1-6 alkoxy-carbonyl optionally substituted by C6-14 aryl (e.g., phenyl), and
      • (k) carbamoyl,
    • (ii) C6-14 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
      • (a) a halogen atom,
      • (b) optionally halogenated C1-6 alkyl (e.g., isopropyl, trifluoromethyl),
      • (c) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),
      • (d) cyano,
      • (e) nitro,
      • (f) carboxy,
      • (g) C1-6 alkyl-carbonyl,
      • (h) C1-6 alkoxy-carbonyl,
      • (i) C1-4 alkylenedioxy, and
      • (j) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,
    • (iii) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),
    • (iv) C7-13 aralkyl (e.g., benzyl),
    • (v) C1-6 alkyl-carbonyl optionally having 1 to 3 substituents selected from
      • (a) carboxy,
      • (b) C6-14 aryl (e.g., phenyl),
      • (c) amino optionally mono- or di-substituted by C1-6 alkyl-carbonyl,
      • (d) C1-6 alkoxy optionally substituted by C1-6 alkoxy,
      • (e) an aromatic heterocyclic group (e.g., thienyl),
      • (f) C1-6 alkoxy-carbonyl,
      • (g) carbamoyl optionally mono- or di-substituted by C3-10 cycloalkyl, and
      • (h) non-aromatic heterocyclylcarbonyl (e.g., morpholinylcarbonyl),
    • (vi) C3-10 cycloalkyl-carbonyl,
    • (vii) C1-6 alkoxy-carbonyl optionally having 1 or 2 C6-14 aryl (e.g., phenyl),
    • (viii) C6-14 aryl-carbonyl (e.g., benzoyl) optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
    • (ix) C7-13 aralkyl-carbonyl (e.g., benzylcarbonyl, phenethylcarbonyl),
    • (x) carbamoyl optionally mono- or di-substituted by C1-6 alkyl optionally having 1 to 3 substituents selected from
      • (a) carboxy,
      • (b) C1-6 alkoxy-carbonyl, and
      • (c) carbamoyl,
    • (xi) C6-14 aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl),
    • (xii) C7-13 aralkyl-carbamoyl (e.g., benzylcarbamoyl),
    • (xiii) C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl),
    • (xiv) C6-14 arylsulfonyl (e.g., benzenesulfonyl, toluenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl),
    • (xv) C7-13 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, C1-6 alkyl and oxo;


      (7) amidino;


      (8) C1-6 alkyl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and hydroxy;


      (9) C1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C6-14 aryl (e.g., phenyl);


      (10) carbamoyl optionally mono- or di-substituted by substituent(s) selected from
    • (i) C1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom, hydroxy, carbamoyl and an aromatic heterocyclic group (e.g., furyl),
    • (ii) C6-14 aryl (e.g., phenyl),
    • (iii) C7-13 aralkyl (e.g., benzyl), and
    • (iv) aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl);


      (11) thiocarbamoyl optionally mono- or di-substituted by C1-6 alkyl optionally substituted by 1 to 3 halogen atoms;


      (12) sulfamoyl optionally mono- or di-substituted by C1-6 alkyl optionally substituted by 1 to 3 halogen atoms;


      (13) carboxy;


      (14) hydroxy;


      (15) C1-6 alkoxy optionally having 1 to 3 substituents selected from
    • (i) a halogen atom,
    • (ii) carboxy,
    • (iii) hydroxy,
    • (iv) C1-6 alkoxy optionally having 1 or 2 hydroxy,
    • (v) C6-14 aryl (e.g., phenyl) optionally substituted by C1-6 alkylsulfonyl,
    • (vi) C3-6 cycloalkyl,
    • (vii) C1-6 alkoxy-carbonyl,
    • (viii) C1-6 alkylsulfonyl (e.g., methylsulfonyl),
    • (ix) mono- or di-C1-6 alkylamino,
    • (x) C1-6 alkyl-carbonylamino,
    • (xi) C1-6 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 C1-6 alkyl and oxo, and
    • (xiii) carbamoyl optionally mono- or di-substituted by C1-6 alkyl optionally having 1 to 3 substituents selected from carbamoyl and hydroxy;


      (16) C2-6 alkenyloxy (e.g., ethenyloxy) optionally substituted by 1 to 3 halogen atoms;


      (17) C3-10 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclohexyloxy, tetrahydronaphthyloxy, indanyloxy) optionally having oxo;


      (18) C7-13 aralkyloxy (e.g., benzyloxy);


      (19) C6-14 aryloxy (e.g., phenyloxy, naphthyloxy; the C6-14 aryl is optionally condensed with C3-10 cycloalkane) optionally having 1 to 3 substituents selected from
    • (i) a halogen atom,
    • (ii) cyano,
    • (iii) C1-6 alkyl optionally having 1 or 2 substituents selected from a halogen atom, carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
    • (iv) C1-6 alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
    • (v) C1-4 alkylenedioxy,
    • (vi) carboxy,
    • (vii) C1-6 alkyl-carbonyl,
    • (viii) C1-6 alkoxy-carbonyl,
    • (ix) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
    • (x) carbamoyl,
    • (xi) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
    • (xii) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
    • (xiii) mono- or di-C1-6 alkylamino,
    • (xiv) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, C1-4 alkylenedioxy and oxo, and
    • (xvi) a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C1-6 alkyl and oxo;


      (20) C3-10 cycloalkyl-C1-6 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) C1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom, C1-6 alkoxy and C1-6 alkoxy-carbonyl,
    • (iv) C1-6 alkoxy-carbonyl-C1-6 alkyl,
    • (v) mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl),
    • (vi) C6-10 aryl (e.g., phenyl),
    • (vii) C3-10 cycloalkyl,
    • (viii) C1-6 alkoxy,
    • (ix) C1-6 alkoxy-carbonyl,
    • (x) carboxy, and
    • (xi) oxo;


      (22) C1-6 alkyl-carbonyloxy (e.g., acetyloxy, tert-butylcarbonyloxy);


      (23) mercapto;


      (24) C1-6 alkylthio (e.g., methylthio, ethylthio) optionally substituted by 1 to 3 halogen atoms;


      (25) C7-20 aralkylthio (e.g., benzylthio, tritylthio);


      (26) C6-14 arylthio (e.g., phenylthio, naphthylthio);


      (27) sulfo;


      (28) C1-6 alkylsulfinyl (e.g., methylsulfinyl);


      (29) C6-14 arylsulfinyl (e.g., phenylsulfinyl);


      (30) C1-6 alkylsulfonyl (e.g., methylsulfonyl) optionally substituted by 1 to 3 halogen atoms;


      (31) C6-14 arylsulfonyl (e.g., phenylsulfonyl) optionally substituted by C1-6 alkoxy;


      (32) C3-10 cycloalkylsulfonyl (e.g., cyclopropylsulfonyl);


      (33) aromatic heterocyclylsulfonyl (e.g., pyridylsulfonyl, pyrazolylsulfonyl, thienylsulfonyl, furylsulfonyl, imidazolylsulfonyl) optionally having 1 to 3 substituents selected from
    • (i) C1-6 alkyl,
    • (ii) C1-6 alkoxy,
    • (iii) C1-6 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 C1-6 alkyl optionally substituted by C6-14 aryl (e.g., phenyl);


      (40) non-aromatic heterocyclylcarbonyloxy (e.g., pyrrolidinylcarbonyloxy);


      (41) C1-4 alkylenedioxy optionally substituted by 1 to 3 halogen atoms;


      (42) hydroxyimino optionally substituted by C1-6 alkyl;


      (43) C1-6 alkyl optionally having 1 to 5 (preferably 1 to 3) substituents selected from
    • (i) a halogen atom,
    • (ii) carboxy,
    • (iii) hydroxy,
    • (iv) C1-6 alkoxy,
    • (v) C1-6 alkoxy-carbonyl,
    • (vi) C1-6 alkyl-carbonyloxy (e.g., acetyloxy, tert-butylcarbonyloxy),
    • (vii) amino,
    • (viii) carbamoyl optionally mono- or di-substituted by C1-6 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 C1-6 alkyl,
    • (x) non-aromatic heterocyclylcarbonyl (the non-aromatic heterocycle is optionally oxidized; e.g., morpholinylcarbonyl),
    • (xi) C6-14 aryl (e.g., phenyl) optionally substituted by C1-6 alkylsulfonyl,
    • (xii) C3-10 cycloalkyl (e.g., cyclopropyl), and
    • (xiii) an aromatic heterocyclic group (e.g., furyl) optionally having 1 to 3 substituents selected from carboxy and C1-6 alkoxy-carbonyl;


      (44) C2-6 alkenyl (e.g., ethenyl, 1-propenyl) optionally having 1 to 3 substituents selected from
    • (i) a halogen atom,
    • (ii) carboxy,
    • (iii) C1-6 alkoxy-carbonyl,
    • (iv) carbamoyl, and
    • (v) C6-14 aryl (e.g., phenyl) optionally substituted by C1-6 alkoxy-carbonyl;


      (45) C7-13 aralkyl (e.g., benzyl) optionally having 1 to 3 substituents selected from
    • (i) C1-6 alkyl optionally substituted by 1 to 3 halogen atoms,
    • (ii) hydroxy,
    • (iii) C1-6 alkoxy, and
    • (iv) a halogen atom;


      (46) C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl);


      (47) C6-10 arylsulfinyl (e.g., phenylsulfinyl);


      (48) optionally halogenated C6-10 arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl);


      (49) heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio, benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio) optionally having C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C1-6 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 C6-14 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 C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 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 C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s), C3-10 cycloalkenyl optionally having substituent(s), C6-14 aryl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s), C8-13 arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like.


The aforementioned C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-13 aralkyl and C8-13 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 C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s), C3-10 cycloalkenyl optionally having substituent(s), C6-14 aryl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s), C8-13 arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like.


The aforementioned C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-13 aralkyl and C8-13 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 C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s), C3-10 cycloalkenyl optionally having substituent(s), C6-14 aryl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s), C8-13 arylalkenyl optionally having substituent(s), a heterocyclic group optionally having substituent(s), acyl and the like, and the like.


The aforementioned C1-10 alkyl, C2-10 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, C6-14 aryl, C7-13 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: —CORA, —CO—ORA, —SO2RA, —SORA, —CO—NRA′RB′ or —CS—NRA′RB′ [wherein RA is a hydrogen atom, a hydrocarbon group optionally having substituent(s) or a heterocyclic group optionally having substituent(s), and RA′ and RB′ 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 RA′ and RB′ 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 RA′ and RB′ 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) C1-6 alkyl-carbonyl;


(5) C1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C1-6 alkoxy-carbonyl and C1-6 alkyl-carbonyloxy (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxymethoxycarbonyl, carboxyethoxycarbonyl, carboxybutoxycarbonyl; carbamoylmethoxycarbonyl; thiocarbamoylmethoxycarbonyl; ethoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl, methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl; tert-butylcarbonyloxymethoxycarbonyl);


(6) C3-10 cycloalkyl-carbonyl (e.g., cyclopentylcarbonyl, cyclohexylcarbonyl);


(7) C6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) optionally having 1 to 3 substituents selected from a halogen atom, cyano, C1-6 alkyl optionally substituted by 1 to 3 halogen atoms, C1-6 alkoxy, carboxy, C1-6 alkoxy-carbonyl, an aromatic heterocyclic group (e.g., tetrazolyl, oxadiazolyl), a non-aromatic heterocyclic group (e.g., oxooxadiazolyl) and carbamoyl;


(8) C6-14 aryloxy-carbonyl (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) optionally having 1 to 3 substituents selected from carboxy, C1-6 alkoxy-carbonyl and carbamoyl;


(9) C7-13 aralkyloxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C1-6 alkoxy-carbonyl, a halogen atom, cyano, nitro, C1-6 alkoxy, C1-6 alkylsulfonyl and C1-6 alkyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl; carboxybenzyloxycarbonyl; methoxycarbonylbenzyloxycarbonyl; biphenylylmethoxycarbonyl);


(10) carbamoyl mono- or di-substituted by C1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl);


(11) C1-6 alkylsulfonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl and C1-6 alkoxy-carbonyl (e.g., methylsulfonyl, carboxymethylsulfonyl);


(12) C1-6 alkylsulfinyl (e.g., methylsulfinyl);


(13) thiocarbamoyl;


(14) C7-13 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 C1-6 alkyl, C6-14 aryl, C7-13 aralkyl, C1-6 alkoxy, carboxy, C1-6 alkoxy-carbonyl and carbamoyl; and the like.


Each symbol in the formula (I) is described in detail in the following.


R1 is a substituent.


Examples of the “substituent” for R1 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.


R1 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 C1-6 alkyl optionally having substituent(s), C7-13 aralkyl optionally having substituent(s) or the like, particularly preferably


(a) C1-6 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) C1-6 alkyl substituted by a heterocyclic group optionally having substituent(s) or amino optionally having substituent(s),


(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), cyano, hydroxy, C1-6 alkoxy optionally having substituent(s), a heterocyclic group optionally having substituent(s)), or the like.


More preferably, R1 is


(a) C1-6 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) C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)),


(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s)), or the like.


Preferable embodiments of R1 include


(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl) optionally having 1 to 3 substituents selected from

    • (i) a halogen atom,
    • (ii) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,
    • (iii) cyano,
    • (iv) hydroxy,
    • (v) optionally halogenated C1-6 alkoxy (e.g., trifluoromethoxy), and
    • (vi) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl);


      (2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;


      (3) C1-6 alkyl optionally having 1 to 5 substituents selected from
    • (i) a halogen atom,
    • (ii) hydroxy optionally having a substituent selected from
      • (a) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) cyano,
        • C) C1-6 alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
        • D) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy),
        • E) C1-4 alkylenedioxy,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
        • J) carbamoyl,
        • K) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
        • L) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
        • M) mono- or di-C1-6 alkylamino,
        • O) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 alkyl-carbonyl and oxo,
      • (b) C6-10 aryl condensed with C3-10 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 C1-6 alkyl, C1-6 alkoxy-carbonyl-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl), C6-10 aryl (e.g., phenyl), C1-6 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 C1-6 alkyl, C1-6 alkoxy and oxo,
      • (e) C7-13 aralkyl (e.g., benzyl),
      • (f) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl), and
      • (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),
    • (iii) C6-10 arylthio (e.g., phenylthio),
    • (iv) amino optionally having 1 or 2 substituents selected from
      • (a) C1-6 alkyl,
      • (b) C6-10 aryl (e.g., phenyl),
      • (c) C3-6 cycloalkyl-carbonyl,
      • (d) C6-10 aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
      • (e) C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl, and
      • (f) carbamoyl-C1-6 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) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C1-6 alkyl-carbonyloxy,
      • (b) C3-6 cycloalkyl,
      • (c) C6-10 aryl (e.g., phenyl),
      • (d) C1-6 alkyl-carbonyl, and
      • (e) C1-6 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, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy-carbonyl and oxo;


      (4) C3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl); and the like.


Other preferable embodiments of R1 include


(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from

    • (i) a halogen atom,
    • (ii) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,
    • (iii) cyano,
    • (iv) hydroxy,
    • (v) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy),
    • (vi) C6-10 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 C1-6 alkyl and C1-6 alkoxy;


      (2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;


      (3) C1-6 alkyl optionally having 1 to 5 substituents selected from
    • (i) a halogen atom,
    • (ii) hydroxy optionally having a substituent selected from
      • (a) C6-10 aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) cyano,
        • C) C1-6 alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
        • D) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy),
        • E) C1-4 alkylenedioxy,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
        • J) carbamoyl,
        • K) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
        • L) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
        • M) mono- or di-C1-6 alkylamino,
        • O) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 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 C1-6 alkyl and oxo,
      • (b) C6-10 aryl condensed with C3-10 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 C1-6 alkyl, C1-6 alkoxy-carbonyl-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl), C6-10 aryl (e.g., phenyl), C1-6 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 C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, C3-10 cycloalkyl, a halogen atom and oxo,
      • (e) C7-13 aralkyl (e.g., benzyl),
      • (f) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl),
      • (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl), and
      • (h) C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl),
    • (iii) C6-10 arylthio (e.g., phenylthio),
    • (iv) C6-10 arylsulfinyl (e.g., phenylsulfinyl),
    • (v) optionally halogenated C6-10 arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),
    • (vi) amino optionally having 1 or 2 substituents selected from
      • (a) C1-6 alkyl,
      • (b) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) optionally halogenated C1-6 alkyl (e.g., methyl, ethyl, isopropyl, trifluoromethyl),
        • C) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),
        • D) cyano,
        • E) nitro,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) C1-4 alkylenedioxy, and
        • J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,
      • (c) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),
      • (d) C7-13 aralkyl (e.g., benzyl),
      • (e) C1-6 alkyl-carbonyl,
      • (f) C3-6 cycloalkyl-carbonyl,
      • (g) C6-10 aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
      • (h) C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl,
      • (i) carbamoyl-C1-6 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 C1-6 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) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C1-6 alkyl-carbonyloxy,
      • (b) C3-6 cycloalkyl,
      • (c) C6-10 aryl (e.g., phenyl),
      • (d) C1-6 alkyl-carbonyl, and
      • (e) C1-6 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, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy-carbonyl and oxo,
    • (ix) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and C6-10 aryl,
    • (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C1-6 alkyl-carbonyloxy, and
    • (xi) a 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio);


      (4) C3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl); and the like.


Still other preferable embodiments of R1 include


(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from

    • (i) a halogen atom,
    • (ii) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,
    • (iii) cyano,
    • (iv) hydroxy,
    • (v) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy),
    • (vi) C6-10 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 C1-6 alkyl and C1-6 alkoxy;


      (2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;


      (3) C1-6 alkyl optionally having 1 to 5 substituents selected from
    • (i) a halogen atom,
    • (ii) hydroxy optionally having a substituent selected from
      • (a) C6-10 aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) cyano,
        • C) C1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom, carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
        • D) C1-6 alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
        • E) C1-4 alkylenedioxy,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
        • J) carbamoyl,
        • K) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
        • L) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
        • M) mono- or di-C1-6 alkylamino,
        • O) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 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 C1-6 alkyl and oxo,
      • (b) C6-10 aryl condensed with C3-10 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 C1-6 alkyl, C1-6 alkoxy-carbonyl-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl), C6-10 aryl (e.g., phenyl), C1-6 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) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkoxy-carbonyl,
        • B) C1-6 alkoxy,
        • C) C1-6 alkoxy-carbonyl,
        • D) C3-10 cycloalkyl,
        • E) a halogen atom, and
        • F) oxo,
      • (e) C7-13 aralkyl (e.g., benzyl),
      • (f) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl),
      • (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),
      • (h) C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl), and
      • (i) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl),
    • (iii) C6-10 arylthio (e.g., phenylthio),
    • (iv) C6-10 arylsulfinyl (e.g., phenylsulfinyl),
    • (v) optionally halogenated C6-10 arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),
    • (vi) amino optionally having 1 or 2 substituents selected from
      • (a) C1-6 alkyl,
      • (b) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) optionally halogenated C1-6 alkyl (e.g., methyl, ethyl, isopropyl, trifluoromethyl),
        • C) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),
        • D) cyano,
        • E) nitro,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) C1-4 alkylenedioxy, and
        • J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,
      • (c) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),
      • (d) C7-13 aralkyl (e.g., benzyl),
      • (e) C1-6 alkyl-carbonyl,
      • (f) C3-6 cycloalkyl-carbonyl,
      • (g) C6-10 aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
      • (h) C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl,
      • (i) carbamoyl-C1-6 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 C1-6 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) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C1-6 alkyl-carbonyloxy,
      • (b) C3-6 cycloalkyl,
      • (c) C6-10 aryl (e.g., phenyl),
      • (d) C1-6 alkyl-carbonyl, and
      • (e) C1-6 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, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy-carbonyl and oxo,
    • (ix) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and C6-10 aryl,
    • (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C1-6 alkyl-carbonyloxy, and
    • (xi) 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio);


      (4) C3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl); and the like.


R2 is a cyclic group optionally having substituent(s), C1-10 alkyl optionally having substituent(s), C2-10 alkenyl optionally having substituent(s) or C2-10 alkynyl optionally having substituent(s).


The aforementioned C1-10 alkyl, C2-10 alkenyl and C2-10 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.


R2 is preferably C6-14 aryl optionally having substituent(s), C3-10 cycloalkyl optionally having substituent(s) or the like.


R2 is more preferably optionally halogenated C6-10 aryl (e.g., phenyl), C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) or the like.


R2 is particularly preferably optionally halogenated C6-10 aryl (e.g., phenyl) or the like.


R3 is a hydrogen atom, a halogen atom, C1-6 alkyl or C1-6 alkoxy.


R3 is preferably a hydrogen atom, a halogen atom, C1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl), C1-3 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 C1-6 alkylene, —X1—NH—X2—, —X1—O—X2— and —X1—S—X2— [wherein X1 and X2 are the same or different and each is bond or straight chain C1-5 alkylene, when X1 and X2 are both straight chain C1-5 alkylene, then the total carbon number of straight chain C1-5 alkylene for X1 and straight chain C1-5 alkylene for X2 is 5 or less, and S is optionally oxidized] and the like.


Examples of the “straight chain C1-6 alkylene” include —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2— and —CH2CH2CH2CH2CH2CH2—.


Examples of the “straight chain C1-5 alkylene” for X1 or X2 include —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2— and —CH2CH2CH2CH2CH2—.


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, C1-6 alkylene optionally having substituent(s) or the like.


X is more preferably


(1) bond,


(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl) or the like.


Ring A is C5-7 cycloalkane optionally having substituent(s).


Examples of the “C5-7 cycloalkane” of the “C5-7 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 “C5-7 cycloalkane” of the “C5-7 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 C5-7 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 C5-7 cycloalkane and C3-10 cycloalkane, C3-10 cycloalkene, C4-10 cycloalkadiene or a heterocycle. Examples of the “C3-10 cycloalkane”, “C3-10 cycloalkene”, “C4-10 cycloalkadiene” and “heterocycle” include rings corresponding to the aforementioned C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10 cycloalkadienyl and heterocyclic group.


Examples of the “substituent” of the “C5-7 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 C5-7 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) C5-7 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) C5-7 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) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., C1-3 alkyl optionally having substituent(s) etc.), or


(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).


Still more preferably, ring A is


(a) C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s), or


(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).


Still more preferably, ring A is


(a) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., cyclopropylmethyl, methyl, methoxymethyl, ethoxymethyl etc.), or


(b) C5-7 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]: C5-7 cycloalkane optionally having 1 to 5 substituents selected from


(1) a halogen atom;


(2) C1-6 alkyl optionally having 1 to 5 substituents selected from

    • (i) a halogen atom,
    • (ii) cyano,
    • (iii) C3-6 cycloalkyl,
    • (iv) hydroxy,
    • (v) C1-6 alkoxy optionally having 1 or 2 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C1-6 alkoxy optionally having 1 or 2 hydroxy,
      • (d) C3-6 cycloalkyl,
      • (e) mono- or di-C1-6 alkylamino,
      • (f) C1-6 alkyl-carbonylamino,
      • (g) C1-6 alkylthio,
      • (h) C1-6 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 C1-6 alkyl and oxo,
    • (vi) C3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),
    • (vii) C6-10 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 C1-6 alkyl and oxo,
    • (ix) C1-6 alkyl-carbonyloxy,
    • (x) carboxy,
    • (xi) C1-6 alkoxy-carbonyl,
    • (xii) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl),
    • (xiii) C1-6 alkylthio,
    • (xiv) C1-6 alkylsulfonyl,
    • (xv) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl) and C1-6 alkylsulfonyl-C1-6 alkyl, and
    • (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);


      (3) hydroxy optionally having a substituent selected from
    • (i) C7-13 aralkyl (e.g., benzyl),
    • (ii) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkyl-carbonylamino,
    • (iii) C2-6 alkenyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C6-10 aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and
    • (vi) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkylsulfonyl-C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl);


      (4) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkoxy-C2-6 alkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C1-6 alkoxy-C1-6 alkoxy-carbonyl, mono- or di-C1-6 alkyl-carbamoyl and C3-6 cycloalkylsulfonyl;


      (5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;


      (6) C1-3 alkylidene (e.g., methylene) optionally having a substituent selected from C1-6 alkoxy-carbonyl and C1-6 alkyl-carbamoyl;


      (7) oxo; and


      (8) azido;


      [B]: C5-7 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]: C5-7 cycloalkane optionally having 1 to 5 substituents selected from


(1) a halogen atom;


(2) C1-6 alkyl optionally having 1 to 5 substituents selected from

    • (i) a halogen atom,
    • (ii) cyano,
    • (iii) C3-6 cycloalkyl,
    • (iv) hydroxy,
    • (v) C1-6 alkoxy optionally having 1 or 2 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C1-6 alkoxy optionally having 1 or 2 hydroxy,
      • (d) C3-6 cycloalkyl,
      • (e) mono- or di-C1-6 alkylamino,
      • (f) C1-6 alkyl-carbonylamino,
      • (g) C1-6 alkylthio,
      • (h) C1-6 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 C1-6 alkyl and oxo,
    • (vi) C3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),
    • (vii) C6-10 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 C1-6 alkyl and oxo,
    • (ix) C1-6 alkyl-carbonyloxy,
    • (x) carboxy,
    • (xi) C1-6 alkoxy-carbonyl,
    • (xii) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl),
    • (xiii) C1-6 alkylthio,
    • (xiv) C1-6 alkylsulfonyl,
    • (xv) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl) and C1-6 alkylsulfonyl-C1-6 alkyl, and
    • (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);


      (3) hydroxy optionally having a substituent selected from
    • (i) C7-13 aralkyl (e.g., benzyl),
    • (ii) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkyl-carbonylamino,
    • (iii) C2-6 alkenyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C6-10 aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and
    • (vi) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkylsulfonyl-C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl);


      (4) amino optionally having 1 or 2 substituents selected from
    • (i) C1-6 alkyl,
    • (ii) C1-6 alkoxy-C2-6 alkyl,
    • (iii) C3-6 cycloalkyl-C1-6 alkyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C3-6 cycloalkyl-carbonyl,
    • (vi) C1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom, C1-6 alkoxy and C3-6 cycloalkyl,
    • (vii) C3-6 cycloalkoxy-carbonyl,
    • (viii) C1-6 alkoxy-C1-6 alkoxy-carbonyl,
    • (ix) mono- or di-C1-6 alkyl-carbamoyl,
    • (x) C3-6 cycloalkylsulfonyl,
    • (xi) C1-6 alkylsulfonyl, and
    • (xii) mono- or di-C1-6 alkylsulfamoyl;


      (5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;


      (6) C1-3 alkylidene (e.g., methylene) optionally having a substituent selected from C1-6 alkoxy-carbonyl and C1-6 alkyl-carbamoyl;


      (7) oxo; and


      (8) azido;


      [B]: C5-7 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 R1.


Examples of the “substituent” which ring B optionally further has include groups exemplified as the “substituent” for R1 optionally has, and the like. Specific examples of the “substituent” include optionally substituted C1-6 alkyl, for example, C1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C1-6 alkyl and oxo, and the like.


Ring B is preferably a ring represented by the formula:







wherein R1 is as defined above. The piperazine ring optionally has 1 to 3 C1-6 alkyl at the ring-constituting carbon atom.


Preferable examples of compound (I) include the following compounds.


[Compound A]

Compound (I) wherein


R1 is a hydrocarbon group optionally having substituent(s);


R2 is C6-14 aryl optionally having substituent(s) or C3-10 cycloalkyl optionally having substituent(s);


R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;


X is bond or C1-6 alkylene optionally having substituent(s); and


ring A is C5-7 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


R1 is


(a) C1-6 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) C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)), or


(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s));


R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);


R3 is a hydrogen atom;


X is


(1) bond, or


(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl); and


ring A is


(a) C5-7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent(s) (e.g., C1-3 alkyl optionally having substituent(s) etc.), or


(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).


[Compound B′]

A compound represented by the formula:







wherein


R1 is


(a) C1-6 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) C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)), or


(c) C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s));


R2 is optionally halogenated C6-10 aryl (e.g., phenyl);


R3 is a hydrogen atom, a halogen atom, C1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl) or C1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy);


X is


(1) bond, or


(2) C1-6 alkylene optionally having substituent(s) (e.g., C1-6 alkyl, C6-10 aryl (e.g., phenyl), etc.); and


ring A is


(a) C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s), or


(b) C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).


[Compound B′-1]

Compound B′ wherein R1 is C1-6 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 R1 is C1-6 alkyl substituted by phenylamino optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s)).


[Compound B′-3]

Compound B′ wherein R1 is C7-13 aralkyl optionally having substituent(s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent(s), C1-6 alkoxy optionally having substituent(s), a monocyclic aromatic heterocyclic group optionally having substituent(s)).


[Compound B′-4]

Compound B′ wherein ring A is C5-7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C1-3 alkyl optionally having substituent(s).


[Compound B′-4]

Compound B′ wherein ring A is C5-7 cycloalkane substituted by amino optionally having substituent(s) (e.g., C1-6 alkoxy-carbonyl etc.).


[Compound C]

A compound represented by the formula:







wherein


R1 is


(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl) optionally having 1 to 3 substituents selected from

    • (i) a halogen atom,
    • (ii) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,
    • (iii) cyano,
    • (iv) hydroxy,
    • (v) optionally halogenated C1-6 alkoxy (e.g., trifluoromethoxy), and
    • (vi) a 5- or 6-membered non-aromatic heterocyclic group (e.g., morpholinyl);


      (2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;


      (3) C1-6 alkyl optionally having 1 to 5 substituents selected from
    • (i) a halogen atom,
    • (ii) hydroxy optionally having a substituent selected from
      • (a) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) cyano,
        • C) C1-6 alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
        • D) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy),
        • E) C1-4 alkylenedioxy,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
        • J) carbamoyl,
        • K) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
        • L) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
        • M) mono- or di-C1-6 alkylamino,
        • O) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 alkyl-carbonyl and oxo,
      • (b) C6-10 aryl condensed with C3-10 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 C1-6 alkyl, C1-6 alkoxy-carbonyl-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl), C6-10 aryl (e.g., phenyl), C1-6 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 C1-6 alkyl, C1-6 alkoxy and oxo,
      • (e) C7-13 aralkyl (e.g., benzyl),
      • (f) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl), and
      • (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),
    • (iii) C6-10 arylthio (e.g., phenylthio),
    • (iv) amino optionally having 1 or 2 substituents selected from
      • (a) C1-6 alkyl,
      • (b) C6-10 aryl (e.g., phenyl),
      • (c) C3-6 cycloalkyl-carbonyl,
      • (d) C6-10 aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
      • (e) C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl, and
      • (f) carbamoyl-C1-6 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) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C1-6 alkyl-carbonyloxy,
      • (b) C3-6 cycloalkyl,
      • (c) C6-10 aryl (e.g., phenyl),
      • (d) C1-6 alkyl-carbonyl, and
      • (e) C1-6 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, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy-carbonyl and oxo; or


      (4) C3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl);


R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);


R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;


X is


(1) bond, or


(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl); and


ring A is


[A] C5-7 cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C5-7 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) C1-6 alkyl optionally having 1 to 5 substituents selected from

    • (i) a halogen atom,
    • (ii) cyano,
    • (iii) C3-6 cycloalkyl,
    • (iv) hydroxy,
    • (v) C1-6 alkoxy optionally having 1 or 2 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C1-6 alkoxy optionally having 1 or 2 hydroxy,
      • (d) C3-6 cycloalkyl,
      • (e) mono- or di-C1-6 alkylamino,
      • (f) C1-6 alkyl-carbonylamino,
      • (g) C1-6 alkylthio,
      • (h) C1-6 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 C1-6 alkyl and oxo,
    • (vi) C3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),
    • (vii) C6-10 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 C1-6 alkyl and oxo,
    • (ix) C1-6 alkyl-carbonyloxy,
    • (x) carboxy,
    • (xi) C1-6 alkoxy-carbonyl,
    • (xii) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl),
    • (xiii) C1-6 alkylthio,
    • (xiv) C1-6 alkylsulfonyl,
    • (xv) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl) and C1-6 alkylsulfonyl-C1-6 alkyl, and
    • (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);


      (3) hydroxy optionally having a substituent selected from
    • (i) C7-13 aralkyl (e.g., benzyl),
    • (ii) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkyl-carbonylamino,
    • (iii) C2-6 alkenyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C6-10 aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and
    • (vi) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkylsulfonyl-C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl);


      (4) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkoxy-C2-6 alkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C1-6 alkoxy-C1-6 alkoxy-carbonyl, mono- or di-C1-6 alkyl-carbamoyl and C3-6 cycloalkylsulfonyl;


      (5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;


      (6) C1-3 alkylidene (e.g., methylene) optionally having a substituent selected from C1-6 alkoxy-carbonyl and C1-6 alkyl-carbamoyl;


      (7) oxo; and


      (8) azido.


[Compound D]

Compound (I) wherein


R1 is


(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from

    • (i) a halogen atom,
    • (ii) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,
    • (iii) cyano,
    • (iv) hydroxy,
    • (v) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy),
    • (vi) C6-10 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 C1-6 alkyl and C1-6 alkoxy;


      (2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;


      (3) C1-6 alkyl optionally having 1 to 5 substituents selected from
    • (i) a halogen atom,
    • (ii) hydroxy optionally having a substituent selected from
      • (a) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) cyano,
        • C) C1-6 alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
        • D) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy),
        • E) C1-4 alkylenedioxy,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
        • J) carbamoyl,
        • K) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
        • L) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
        • M) mono- or di-C1-6 alkylamino,
        • O) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 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 C1-6 alkyl and oxo,
      • (b) C6-10 aryl condensed with C3-10 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 C1-6 alkyl, C1-6 alkoxy-carbonyl-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl), C6-10 aryl (e.g., phenyl), C1-6 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 C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, a halogen atom and oxo,
      • (e) C7-13 aralkyl (e.g., benzyl),
      • (f) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl),
      • (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl), and
      • (h) C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl),
    • (iii) C6-10 arylthio (e.g., phenylthio),
    • (iv) C6-10 arylsulfinyl (e.g., phenylsulfinyl),
    • (v) optionally halogenated C6-10 arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),
    • (vi) amino optionally having 1 or 2 substituents selected from
      • (a) C1-6 alkyl,
      • (b) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) optionally halogenated C1-6 alkyl (e.g., isopropyl, trifluoromethyl),
        • C) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),
        • D) cyano,
        • E) nitro,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) C1-4 alkylenedioxy, and
        • J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,
      • (c) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),
      • (d) C7-13 aralkyl (e.g., benzyl),
      • (e) C1-6 alkyl-carbonyl,
      • (f) C3-6 cycloalkyl-carbonyl,
      • (g) C6-10 aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
      • (h) C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl,
      • (i) carbamoyl-C1-6 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 C1-6 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) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C1-6 alkyl-carbonyloxy,
      • (b) C3-6 cycloalkyl,
      • (c) C6-10 aryl (e.g., phenyl),
      • (d) C1-6 alkyl-carbonyl, and
      • (e) C1-6 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, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy-carbonyl and oxo,
    • (ix) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and C6-10 aryl,
    • (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C1-6 alkyl-carbonyloxy, and
    • (xi) a 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio); or


      (4) C3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl);


R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);


R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;


X is


(1) bond, or


(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl);


ring A is


[A] C5-7 cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C5-7 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) C1-6 alkyl optionally having 1 to 5 substituents selected from

    • (i) a halogen atom,
    • (ii) cyano,
    • (iii) C3-6 cycloalkyl,
    • (iv) hydroxy,
    • (v) C1-6 alkoxy optionally having 1 or 2 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C1-6 alkoxy optionally having 1 or 2 hydroxy,
      • (d) C3-6 cycloalkyl,
      • (e) mono- or di-C1-6 alkylamino,
      • (f) C1-6 alkyl-carbonylamino,
      • (g) C1-6 alkylthio,
      • (h) C1-6 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 C1-6 alkyl and oxo,
    • (vi) C3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),
    • (vii) C6-10 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 C1-6 alkyl and oxo,
    • (ix) C1-6 alkyl-carbonyloxy,
    • (x) carboxy,
    • (xi) C1-6 alkoxy-carbonyl,
    • (xii) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl),
    • (xiii) C1-6 alkylthio,
    • (xiv) C1-6 alkylsulfonyl,
    • (xv) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl) and C1-6 alkylsulfonyl-C1-6 alkyl, and
    • (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);


      (3) hydroxy optionally having a substituent selected from
    • (i) C7-13 aralkyl (e.g., benzyl),
    • (ii) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkyl-carbonylamino,
    • (iii) C2-6 alkenyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C6-10 aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and
    • (vi) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkylsulfonyl-C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl);


      (4) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkoxy-C2-6 alkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C1-6 alkoxy-C1-6 alkoxy-carbonyl, mono- or di-C1-6 alkyl-carbamoyl and C3-6 cycloalkylsulfonyl;


      (5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;


      (6) C1-3 alkylidene (e.g., methylene) optionally having a substituent selected from C1-6 alkoxy-carbonyl and C1-6 alkyl-carbamoyl;


      (7) oxo; and


      (8) azido; and


ring B is piperazine optionally further having, besides R1, C1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C1-6 alkyl and oxo.


[Compound E]

Compound (I) wherein


R1 is


(1) C7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from

    • (i) a halogen atom,
    • (ii) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy,
    • (iii) cyano,
    • (iv) hydroxy,
    • (v) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy),
    • (vi) C6-10 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 C1-6 alkyl and C1-6 alkoxy;


      (2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylmethyl) optionally having one hydroxy;


      (3) C1-6 alkyl optionally having 1 to 5 substituents selected from
    • (i) a halogen atom,
    • (ii) hydroxy optionally having a substituent selected from
      • (a) C6-10 aryl (e.g., phenyl, naphthyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) cyano,
        • C) C1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom, carboxy, hydroxy, C1-6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
        • D) C1-6 alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
        • E) C1-4 alkylenedioxy,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl),
        • J) carbamoyl,
        • K) optionally halogenated mono- or di-C1-6 alkyl-carbamoyl,
        • L) C3-6 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl),
        • M) mono- or di-C1-6 alkylamino,
        • O) optionally halogenated C1-6 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 C1-6 alkyl, C1-6 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 C1-6 alkyl and oxo,
      • (b) C6-10 aryl condensed with C3-10 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 C1-6 alkyl, C1-6 alkoxy-carbonyl-C1-6 alkyl, mono- or di-C1-6 alkylamino-C1-6 alkyl (e.g., dimethylaminomethyl), C6-10 aryl (e.g., phenyl), C1-6 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) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkoxy-carbonyl,
        • B) C1-6 alkoxy,
        • C) C1-6 alkoxy-carbonyl,
        • D) C3-10 cycloalkyl,
        • E) a halogen atom, and
        • F) oxo,
      • (e) C7-13 aralkyl (e.g., benzyl),
      • (f) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl),
      • (g) 5- or 6-membered non-aromatic heterocyclylcarbonyl (e.g., pyrrolidinylcarbonyl),
      • (h) C6-10 aryl-carbamoyl (e.g., phenylcarbamoyl), and
      • (i) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl),
    • (iii) C6-10 arylthio (e.g., phenylthio),
    • (iv) C6-10 arylsulfinyl (e.g., phenylsulfinyl),
    • (v) optionally halogenated C6-10 arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl),
    • (vi) amino optionally having 1 or 2 substituents selected from
      • (a) C1-6 alkyl,
      • (b) C6-10 aryl (e.g., phenyl) optionally having 1 to 3 substituents selected from
        • A) a halogen atom,
        • B) optionally halogenated C1-6 alkyl (e.g., methyl, isopropyl, trifluoromethyl),
        • C) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, difluoromethoxy),
        • D) cyano,
        • E) nitro,
        • F) carboxy,
        • G) C1-6 alkyl-carbonyl,
        • H) C1-6 alkoxy-carbonyl,
        • I) C1-4 alkylenedioxy, and
        • J) a 5- or 6-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo,
      • (c) C3-6 cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl),
      • (d) C7-13 aralkyl (e.g., benzyl),
      • (e) C1-6 alkyl-carbonyl,
      • (f) C3-6 cycloalkyl-carbonyl,
      • (g) C6-10 aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy,
      • (h) C1-6 alkoxy-carbonyl-C1-6 alkyl-carbonyl,
      • (i) carbamoyl-C1-6 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 C1-6 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) C1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom, hydroxy and C1-6 alkyl-carbonyloxy,
      • (b) C3-6 cycloalkyl,
      • (c) C6-10 aryl (e.g., phenyl),
      • (d) C1-6 alkyl-carbonyl, and
      • (e) C1-6 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, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy-carbonyl and oxo,
    • (ix) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and C6-10 aryl,
    • (x) 5- or 6-membered heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio) optionally having C1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C1-6 alkyl-carbonyloxy, and
    • (xi) 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio); or


      (4) C3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl);


R2 is optionally halogenated C6-10 aryl (e.g., phenyl), or C3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl);


R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy;


X is


(1) bond, or


(2) C1-6 alkylene optionally having substituent(s) selected from C1-6 alkyl and C6-10 aryl (e.g., phenyl);


ring A is


[A] C5-7 cycloalkane optionally having 1 to 5 substituents selected from the following (1) to (8), or [B] C5-7 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) C1-6 alkyl optionally having 1 to 5 substituents selected from

    • (i) a halogen atom,
    • (ii) cyano,
    • (iii) C3-6 cycloalkyl,
    • (iv) hydroxy,
    • (v) C1-6 alkoxy optionally having 1 or 2 substituents selected from
      • (a) a halogen atom,
      • (b) hydroxy,
      • (c) C1-6 alkoxy optionally having 1 or 2 hydroxy,
      • (d) C3-6 cycloalkyl,
      • (e) mono- or di-C1-6 alkylamino,
      • (f) C1-6 alkyl-carbonylamino,
      • (g) C1-6 alkylthio,
      • (h) C1-6 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 C1-6 alkyl and oxo,
    • (vi) C3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy),
    • (vii) C6-10 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 C1-6 alkyl and oxo,
    • (ix) C1-6 alkyl-carbonyloxy,
    • (x) carboxy,
    • (xi) C1-6 alkoxy-carbonyl,
    • (xii) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl),
    • (xiii) C1-6 alkylthio,
    • (xiv) C1-6 alkylsulfonyl,
    • (xv) amino optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C1-16 alkyl (e.g., furfuryl) and C1-6 alkylsulfonyl-C1-6 alkyl, and
    • (xvi) a 5- or 6-membered aromatic heterocyclic group (e.g., tetrazolyl);


      (3) hydroxy optionally having a substituent selected from
    • (i) C7-13 aralkyl (e.g., benzyl),
    • (ii) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and C1-6 alkyl-carbonylamino,
    • (iii) C2-6 alkenyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C6-10 aryl-carbonyl (e.g., benzoyl) optionally having 1 or 2 nitro, and
    • (vi) carbamoyl optionally having 1 or 2 substituents selected from C1-6 alkyl, C1-6 alkylsulfonyl-C1-6 alkyl and 5- or 6-membered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl);


      (4) amino optionally having 1 or 2 substituents selected from
    • (i) C1-6 alkyl,
    • (ii) C1-6 alkoxy-C2-6 alkyl,
    • (iii) C3-6 cycloalkyl-C1-6 alkyl,
    • (iv) C1-6 alkyl-carbonyl,
    • (v) C3-6 cycloalkyl-carbonyl,
    • (vi) C1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom, C1-6 alkoxy and C3-6 cycloalkyl,
    • (vii) C3-6 cycloalkoxy-carbonyl,
    • (viii) C1-6 alkoxy-C1-6 alkoxy-carbonyl,
    • (ix) mono- or di-C1-6 alkyl-carbamoyl,
    • (X) C3-6 cycloalkylsulfonyl,
    • (xi) C1-6 alkylsulfonyl, and
    • (xii) mono- or di-C1-6 alkylsulfamoyl;


      (5) 5- or 6-membered cyclic amino (e.g., morpholino, oxazolidinyl) optionally having 1 or 2 oxo;


      (6) C1-3 alkylidene (e.g., methylene) optionally having a substituent selected from C1-6 alkoxy-carbonyl and C1-6 alkyl-carbamoyl;


      (7) oxo; and


      (8) azido; and


ring B is piperazine optionally further having, besides R1, C1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C1-6 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 C1-4 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 R3 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 R3 is a halogen atom, C1-6 alkyl or C1-6 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, 3rd Ed.”, Wiley-Interscience (1999), or the like.


As the amino-protecting group, for example, formyl group; C1-6 alkyl-carbonyl group, phenylcarbonyl group, C1-6 alkoxy-carbonyl group, allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group, fluorenylmethyloxycarbonyl (Fmoc) group, C7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), C7-10 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl (Cbz) and the like), C7-10 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, C1-6 alkyl-carbonyl group, C1-6 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, C1-6 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, C1-6 alkyl-carbonyl group, C1-6 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, C1-6 alkyl group, C7-20 aralkyl group (e.g., benzyl, trityl and the like), formyl group, C1-6 alkyl-carbonyl group, benzoyl group, C7-10 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, C1-6 alkyl group, phenyl group, C7-10 aralkyl group (e.g., benzyl and the like), C1-6 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., 3H, 14C, 35S, 125I and the like) and the like is also encompassed in compound (I).


Deuterium-converted compound wherein 1H has been converted to 2H(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'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'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's disease, Parkinson'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'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'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'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'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 %.



1H-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, tBu: 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,

Pd2 (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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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/cm2). 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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).



1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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.



1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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.



1H-NMR (DMSO-d6) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (DMSO-d6) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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), Pd2(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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.


MS


No.
R
Compound
(ESI+)





202
3-F
tert-Butyl (2R)-4-benzyl-2-[(E)-2-(3-
397




fluorophenyl)vinyl]piperazine-1-carboxylate


203
4-F
tert-Butyl (2R)-4-benzyl-2-[(E)-2-(4-
397




fluorophenyl)vinyl]piperazine-1-carboxylate


204
2-OCF3
tert-Butyl (2R)-4-benzyl-2-{(E)-2-[2-
463




(trifluoromethoxy)phenyl]vinyl}piperazine-




1-carboxylate


205
3-OCF3
tert-Butyl (2R)-4-benzyl-2-{(E)-2-[3-
463




(trifluoromethoxy)phenyl]vinyl}piperazine-




1-carboxylate


206
4-OCF3
tert-Butyl (2R)-4-benzyl-2-{(E)-2-[4-
463




(trifluoromethoxy)phenyl]vinyl}piperazine-




1-carboxylate


207
2-CF3
tert-Butyl (2R)-4-benzyl-2-{(E)-2-[2-
447




(trifluoromethyl)phenyl]vinyl}piperazine-1-




carboxylate


208
3-CF3
tert-Butyl (2R)-4-benzyl-2-{(E)-2-[3-
447




(trifluoromethyl)phenyl]vinyl}piperazine-1-




carboxylate


209
4-CF3
tert-Butyl (2R)-4-benzyl-2-{(E)-2-[4-
447




(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.



1H-NMR (CDCl3) 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.


MS


No.
R
Compound
(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-OCF3
(3R)-1-Benzyl-3-{(E)-2-[2-
363




(trifluoromethoxy)phenyl]vinyl}piperazine


217
3-OCF3
(3R)-1-Benzyl-3-{(E)-2-[3-
363




(trifluoromethoxy)phenyl]vinyl}piperazine


218
4-OCF3
(3R)-1-Benzyl-3-{(E)-2-[4-
363




(trifluoromethoxy)phenyl]vinyl}piperazine


219
2-CF3
(3R)-1-Benzyl-3-{(E)-2-[2-
347




(trifluoromethyl)phenyl]vinyl}piperazine


220
3-CF3
(3R)-1-Benzyl-3-{(E)-2-[3-
347




(trifluoromethyl)phenyl]vinyl}piperazine


221
4-CF3
(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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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/cm2). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (9.44 g) as an oil.



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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-“tBu”” was obtained (a mass value of M+1 was obtained for other compounds).









TABLE 3

























Ref. Ex.


MS


No.
R
Compound
(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





1-tert-Butyl 4-benzyl (2R)-2-(2-{[1-methyl-3- (trifluoromethyl)-1H-pyrazol-5- yl]oxy}ethyl)piperazine-1,4-dicarboxylate
513





259





1-tert-Butyl 4-benzyl (2R)-2-[2-(4- methoxyphenoxy)ethyl]piperazine-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- acetylphenoxy)ethyl]piperazine-1,4-dicarboxylate
483





262





1-tert-Butyl 4-benzyl (2R)-2-[2-(3- acetylphenoxy)ethyl]piperazine-1,4-dicarboxylate
483





263





1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(1H-imidazol-1- yl)phenoxy]ethyl}piperazine-1,4-dicarboxylate
507





264





1-tert-Butyl 4-benzyl (2R)-2-[2-(1,2-benzisoxazol-3- yloxy)ethyl]piperazine-1,4-dicarboxylate
482





265





1-tert-Butyl 4-benzyl (2R)-2-{2-[3-(2-methyl-1H- imidazol-1-yl)phenoxy]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*





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-[3-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





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}piperazine-1,4-dicarboxylate
508





287





1-tert-Butyl 4-benzyl (2R)-2-{2-[4-(5-methyl-1,3,4- oxadiazol-2-yl)phenoxy]ethyl}piperazine-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}piperazine-1,4- dicarboxylate
 396*





294





1-tert-Butyl 4-benzyl (2R)-2-(2-{[6- (methoxycarbonyl)pyridin-3-yl]oxy}ethyl)piperazine- 1,4-dicarboxylate
500





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





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





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-methoxyphenoxy]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

























Ref. Ex.


MS


No.
R
Compound
(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





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).



1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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 “K2CO3” 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-“tBu”” was obtained (a mass value of M+1 was obtained for other compounds).









TABLE 5


























Ref. Ex.



MS


No.
R
Compound
Base
(ESI+)














349





1-tert-Butyl 4-benzyl (2R)-2-{2-[3- (trifluoromethyl)-1H-pyrazol-1- yl]ethyl}piperazine-1,4- dicarboxylate
K2CO3
483





350





1-tert-Butyl 4-benzyl (2R)-2-[2- (1H-1,2,3-benzotriazol-1- yl)ethyl]piperazine-1,4- dicarboxylate
K2CO3
466





351





1-tert-Butyl 4-benzyl (2R)-2-[2-(3- phenyl-1H-pyrazol-1- yl)ethyl]piperazine-1,4- dicarboxylate
K2CO3
491





352





1-tert-Butyl 4-benzyl (2R)-2-[2- (4,5,6,7-tetrahydro-1H-indazol-1- yl]ethyl)piperazine-1,4- dicarboxylate
K2CO3
469





353





1-tert-Butyl 4-benzyl (2R)-2-{2-[4- (methoxycarbonyl)-1H-indazol-1- yl]ethyl)piperazine-1,4- dicarboxylate
K2CO3
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
K2CO3
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





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
K2CO3
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-(ethoxycarbonyl)- 1H-pyrazol-1-yl]ethyl}piperazine- 1,4-dicarboxylate
K2CO3
527





363





1-tert-Butyl 4-benzyl (2R)-2-[2-(3- cyano-1H-indol-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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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

























Ref. Ex.


MS


No.
R
Compound
(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- (methoxycarbonyl)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- (methoxycarbonyl)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





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- (ethoxycarbonyl)-2-methyl-1,3- thiazol-4-yl]oxy}ethyl)piperazine-1- carboxylate
434





397





Benzyl (3R)-3-(2-{[2- (methoxycarbonyl)pyridin-3- yl]oxy}ethyl)piperazine-1- carboxylate
400





398





Benzyl (3R)-3-(2-{[4- (ethoxycarbonyl)-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- [(dimethylamino)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





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- dimethoxyphenoxy)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- isopropoxyphenoxy)ethyl]piperazine- 1-carboxylate
399





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





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.


MS


No.
R
Compound
(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





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





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





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- methoxyphenoxy)ethyl]piperazine-1- carboxylate hydrochloride
389





464





Benzyl (3R)-3-{2-[4-(2-oxopyrrolidin- 1-yl)phenoxy]ethyl}piperazine-1- carboxylate hydrochloride
424





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





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)- 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





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- (methoxycarbonyl)-3,5-dimethyl-1H- pyrazol-1-yl]ethyl}piperazine-1- carboxylate hydrochloride
401





491





Benzyl (3R)-3-{2-[3-tertbutyl-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





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- (methoxycarbonyl)-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- (methoxycarbonyl)-1H-indazol-1- yl]ethyl}piperazine-1-carboxylate hydrochloride
423





500





Benzyl (3R)-3-{2-[3- (methoxycarbonyl)-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.


MS


No.
R
Compound
(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- hydroxycyclohexyl}-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- [(cyclopropylmethoxy)methyl]-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





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





617





tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(tetrahydro-2H-thiopyran-4- ylmethoxy)methyl]cyclohexyl}-5-phenyl- 1H-imidazol-4-yl)carbonyl]piperazine- 1-carboxylate
689





618





tert-Butyl (3R)-3-benzyl-4-[(1-{2- hydroxy-2-[(tetrahydro-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-(phenoxymethyl)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.



1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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.



1H-NMR (CDCl3) 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.



1H-NMR (DMSO-d6) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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.



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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), Pd2(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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (CDCl3) 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).



1H-NMR (DMSO-d6) 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).



1H-NMR (DMSO-d6) 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.


MS


No.
R
Compound
(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.


MS


No.
R
Compound
(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- 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





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- 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.


MS


No.
R
Compound
(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





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- 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.



MS


No.
R
Compound
Acid
(ESI+)





757





Benzyl (3R)-3-[2-(2-methoxy-4- morpholinophenoxy) ethyl] piperazine-1-carboxylate
TFA
456





758





Benzyl (3R)-3-{2-[4-(4- acetylpiperazin-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]thiazolo[5,4-b]pyridin-2- ylthio)ethyl]piperazine-1- carboxylate
HCl
415





764





Benzyl (3R)-3-{2-[(4-tertbutyl- 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





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





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- oxopiperidin-1-yl)phenyl] amino}ethyl)piperazine-1- carboxylate
HCl
437





779





Benzyl (3R)-3-(2-{[4-(2- oxopyridin-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- dihydrofuro[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.


MS


No.
R
Compound
(ESI+)





784





Benzyl (3R)-3-[2-(2- fluorophenoxy)ethyl]piperazine-1- carboxylate hydrochloride
359





785





Benzyl (3R)-3-[2-(2- methylphenoxy)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]piperazine-1- carboxylate hydrochloride
357





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).



1H-NMR (DMSO-d6) 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.


MS


No.
R
Compound
(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- (difluorornethoxy)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





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

























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- tl]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





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-gluoro-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).



1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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







1H-NMR (DMSO-d6) 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







1H-NMR (CDCl3) 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


1H-NMR (CDCl3) 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


1H-NMR (CDCl3) 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-d6) 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 (CDCl3) 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-d6) 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







1H-NMR (CDCl3) 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







1H-NMR (DMSO-d6) 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
























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





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





37










E
HCl
535





38










E

535





39










K
2HCl
459





40










N
2HCl
489





41










L

519
















TABLE 18



























Ex. No.
R1
R2
Method
Salt
MS (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





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-F2
B

481





60





3-F
G

463





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





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





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





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





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





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





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





131





H
G

588





132





H
D

574
















TABLE 19



























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-F2





B

481





137
H





A
HCl
463





138
H





A
HCl
463





139
H





A
HCl
481





140
H





A
HCl
513





141






A
HCl
513





142
H





A
HCl
471





143
H





B

486





144
H





D

461





145
H





E
HCl
461





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




























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





166
Me
H





I

532





167
Me
H





I

556





168
Et
H





I

546
















TABLE 21



























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





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





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





208
H





A

529





209
H





B

571





210
3-F





L

515





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


























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





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





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





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





I

644





264





I

576





265





I
2HCl
574





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





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





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





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





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





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





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





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/cm2). 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-OCF3
(1R,2S)-2-(5-Phenyl-4-[(2-{2-[2-
543




(trifluoromethoxy)phenyl]ethyl}




piperazin-1-yl)carbonyl]-1H-imidazol-1-




yl}cyclohexanol


400
3-OCF3
(1R,2S)-2-{5-Phenyl-4-[(2-{2-[3-
543




(trifluoromethoxy)phenyl]ethyl}




piperazin-1-yl)carbonyl]-1H-imidazol-1-




yl}cyclohexanol


401
4-OCF3
(1R,2S)-2-{5-Phenyl-4-[(2-{2-[4-
543




(trifluoromethoxy)phenyl]ethyl}




piperazin-1-yl)carbonyl]-1H-imidazol-1-




yl}cyclohexanol


402
2-CF3
(1R,2S)-2-{5-Phenyl-4-[(2-{2-[2-
527




(trifluoromethyl)phenyl]ethyl}




piperazin-1-yl)carbonyl]-1H-imidazol-1-




yl}cyclohexanol


403
3-CF3
(1R,2S)-2-{5-Phenyl-4-[(2-{2-[3-
527




(trifluoromethyl)phenyl]ethyl}




piperazin-1-yl)carbonyl]-1H-imidazol-1-




yl}cyclohexanol


404
4-CF3
(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



























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





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


























Ex. No.
R
Method
Salt
MS (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





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



























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





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





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





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





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





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





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

586





560
H





A

566





561
H





A

566





562
H





A

566





563
H





A

566





564
H





A

566





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)


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 14th 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% CO2 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% CO2 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-NH2; 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-NH2; 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 IC50 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.

Claims
  • 1. A compound represented by the formula:
  • 2. The compound of claim 1, wherein R1 is a hydrocarbon group optionally having substituent(s).
  • 3. The compound of claim 1, wherein R2 is C6-14 aryl optionally having substituent(s) or C3-10 cycloalkyl optionally having substituent(s).
  • 4. The compound of claim 1, wherein R3 is a hydrogen atom, a halogen atom, C1-3 alkyl or C1-3 alkoxy.
  • 5. The compound of claim 1, wherein X is bond or C1-6 alkylene optionally having substituent(s).
  • 6. The compound of claim 1, wherein ring A is C5-7 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 claim 1, wherein ring B is a ring represented by the formula:
  • 8. A compound represented by the formula:
  • 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 claim 1.
  • 25. A pharmaceutical agent comprising the compound of claim 1 or a prodrug thereof.
  • 26. The pharmaceutical agent of claim 25, which is a renin inhibitor.
  • 27. The pharmaceutical agent of claim 25, which is an agent for the prophylaxis or treatment of hypertension.
  • 28. The pharmaceutical agent of claim 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 claim 1 or a prodrug thereof to the mammal.
  • 30. Use of the compound of claim 1 or a prodrug thereof for the production of an agent for the prophylaxis or treatment of hypertension.
Priority Claims (2)
Number Date Country Kind
120292/2007 Apr 2007 JP national
207271/2007 Aug 2007 JP national