WO2008139941A1 - Substituted imidazole compound and use thereof - Google Patents

Substituted imidazole compound and use thereof Download PDF

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Publication number
WO2008139941A1
WO2008139941A1 PCT/JP2008/058310 JP2008058310W WO2008139941A1 WO 2008139941 A1 WO2008139941 A1 WO 2008139941A1 JP 2008058310 W JP2008058310 W JP 2008058310W WO 2008139941 A1 WO2008139941 A1 WO 2008139941A1
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Prior art keywords
optionally
alkyl
substituent
carbonyl
phenyl
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PCT/JP2008/058310
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French (fr)
Inventor
Takanobu Kuroita
Tsuneo Oda
Yasutomi Asano
Naohiro Taya
Kouichi Iwanaga
Hidekazu Tokuhara
Yoshiyuki Fukase
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Takeda Pharmaceutical Company Limited
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Publication of WO2008139941A1 publication Critical patent/WO2008139941A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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.
  • 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 (All) , which is a major vasopressor factor, and takes an important role in the control of the blood pressure and the amount of body fluid. All exhibits a strong vasoconstrictive effect brought by the intervention of All 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 All 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 All action is broadly- classified into methods of inhibiting the biosynthesis of All and methods of inhibiting the binding of All to All receptors.
  • 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.
  • ACE angiotensin converting enzyme
  • ACE inhibitory drug inhibits the biosynthesis of All as well as the degradation of bradykinin.
  • 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.
  • All type 1 receptor blockers As the drugs inhibiting the binding of All to All receptors, All type 1 receptor blockers (ARB) have been developed. ARB has a merit in that it can inhibit, at the receptor level, the action of All 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.
  • PRA plasma renin activity
  • 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 All 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.
  • 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.).
  • 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.
  • the present invention relates to the following: [1] a compound represented by the formula:
  • R 1 is a substituent
  • R 2 is a cyclic group optionally having substituent (s) , C 1-10 alkyl optionally having substituent (s) , C 2-10 alkenyl optionally having substituent (s) or C 2-10 alkynyl optionally having substituent (s) ,
  • R 3 is a hydrogen atom, a halogen atom, C 1-S alkyl or C 1 _6 alkoxy,
  • X is bond or spacer having 1 to 6 atoms in the main chain
  • ring A is C 5 _ 7 cycloalkane optionally having substituent (s)
  • ring B is piperazine optionally further having substituent (s) besides R 1 , or a salt thereof [hereinafter to be sometimes abbreviated as compound (I) ] ;
  • R 1 is as defined above;
  • R 2 is optionally halogenated C 6-10 aryl
  • R 3 is a hydrogen atom, a halogen atom, C 1-3 alkyl or C 1-3 alkoxy
  • X is bond or C 1-6 alkylene optionally having substituent (s) ; and ring A is (a) C5-/7 cycloalkane substituted by hydroxy optionally having a substituent, and optionally further substituted by C 1-3 alkyl optionally having substituent (s) , or
  • 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;
  • 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.
  • halogen atom in the present specification include fluorine, chlorine, bromine and iodine.
  • C 1- . 4 alkylenedioxy in the present specification include methylenedioxy, ethylenedioxy, trimethylenedioxy and the like.
  • C 1-6 alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 2-ethylbutyl and the like.
  • Examples of the "C 1-6 alkoxy” in the present specification include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 1-6 alkoxy-carbonyl examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
  • C 1-6 alkyl-carbonyl examples include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like.
  • the "optionally halogenated” in the present specification means being optionally substituted by 1 to 5, preferably 1 to 3, halogen atoms .
  • Examples of the "hydrocarbon group" of the “hydrocarbon group optionally having substituent (s) " in the present specification include C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-3 alkylidene, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C4 -10 cycloalkadienyl, C 6-14 aryl, C 7-13 aralkyl, C 8-13 arylalkenyl, C 3-10 cycloalkyl-C 1-6 alkyl and the like.
  • the above-mentioned C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 4-10 cycloalkadienyl are each optionally condensed with a benzene ring.
  • C 1-10 alkyl examples 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.
  • C 1-6 alkyl is preferable.
  • C2 -1 0 alkenyl examples 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.
  • C 2-6 alkenyl is preferable.
  • C 2-10 alkynyl examples 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.
  • C 2-6 alkynyl is preferable.
  • C 1-3 alkylidene examples include methylene, ethylidene, propyTidene, isopropylidene and the like.
  • C 3-10 cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2. l]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. l]decyl, adamantyl and the like.
  • C 3 _ 6 cycloalkyl is preferable.
  • the above-mentioned C 3-1 0 cycloalkyl is optionally condensed with a benzene ring.
  • Examples of the condensed group include indanyl, tetrahydronaphthyl, fluorenyl and the like.
  • C 3-10 cycloalkenyl examples include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2- cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
  • the above- mentioned C 3-10 cycloalkenyl is optionally condensed with a ' benzene ring.
  • Examples of the condensed group include indenyl and the like.
  • C 4-10 cycloalkadienyl examples include 2, 4-cyclopentadien-1-yl, 2,4- cyclohexadien-1-yl, 2, 5-cyclohexadien-1-yl and the like.
  • the above-mentioned C 4-10 cycloalkadienyl is optionally condensed with a benzene ring.
  • C 6-14 aryl examples include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl and the like. Among these, C 6-10 aryl is preferable, and phenyl is more preferable.
  • the above-mentioned C 6-14 aryl is optionally condensed with C 3-10 cycloalkane (examples of the C 3-10 cycloalkane include rings corresponding to the above-mentioned C 3-10 cycloalkyl) .
  • the condensed group examples include tetrahydronaphthyl and the like.
  • Examples of the "C 7-13 aralkyl” in the present specification include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
  • C 8-13 arylalkenyl examples include styryl and the like.
  • C 3-10 cycloalkyl-C 1-6 alkyl examples include cyclopropylmethyl, cyclohexylmethyl and the like.
  • 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).
  • substituents e.g., 1 to 5, preferably 1 to 3 substituents
  • respective substituents may be the same or different.
  • C 6-14 aryl e.g., phenyl, naphthyl
  • substituents selected from
  • a non-aromatic heterocyclic group e.g., oxadiazolinyl
  • oxo optionally substituted by oxo
  • an aromatic heterocyclic group e.g., tetrazolyl
  • C 1-6 alkoxy-carbonyl optionally substituted by a non- aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from oxo and C 1-6 alkyl,
  • cyano, (x) sulfamoyl, (xi) halogen e.g., tetrazolyl
  • C 1-6 alkoxy-carbonyl optionally substituted by a non- aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from oxo and C 1-6 alkyl
  • cyano cyano
  • sulfamoyl e.g., sulfamoyl
  • halogen e.g., halogen,
  • non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl) optionally having 1 to 3 C 1-6 alkyl, (iii) C 3-6 cycloalkyl, (iv) C 6 -I 4 aryl, (v) hydroxy, (vi) C 1-6 alkoxy,
  • 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
  • a non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl) optionally having 1 to 3 C 1-6 alkyl, (i ⁇ ) C 3-6 cycloalkyl,
  • an aromatic heterocyclic group e.g., furyl, pyridyl, indolyl, imidazolyl, thienyl, pyrazolyl, pyrrolyl
  • an aromatic heterocyclic group e.g., furyl, pyridyl, indolyl, imidazolyl, thienyl, pyrazolyl, pyrrolyl
  • 1 to 3 substituents selected from 1) C 1-6 alkyl optionally substituted by hydroxy, 2) C 1-6 alkoxy-carbonyl,
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • C 3 _ 6 cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl)
  • C 7 _ 13 aralkyl e.g., benzyl
  • an aromatic heterocyclic group e.g., thienyl
  • C 6-14 aryl-carbonyl e.g., benzoyl
  • substituents selected from a halogen atom and C 1-6 alkoxy
  • aryl-carbamoyl e.g., phenylcarbamoyl, 1- naphthylcarbamoyl, 2-naphthylcarbamoyl
  • (xiii) C 1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) , (xiv) C 6-14 arylsulfonyl (e.g., benzenesulfonyl, toluenesulfonyl, 1-naphthalenesulfonyl, 2- naphthalenesulfonyl) , (xv) C 7-13 aralkylsulfonyl (e.g., benzylsulfonyl) , and (xvi) a heterocyclic group (the heterocyclic group is optionally oxidized; e.g., tetrahydrofuryl, tetrahydropyranyl, pyridyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzothieny
  • C 1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C 6-14 aryl (e.g., phenyl);
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom, hydroxy, carbamoyl and an aromatic heterocyclic group (e.g., furyl) , (ii) C 6-14 aryl (e.g., phenyl), (iii) C 7-13 aralkyl (e.g., benzyl), and (iv) aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl) ;
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1,1-dioxidotetrahydrothiopyranyl, 1,1- dioxidothiomorpholinyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo, and
  • C 3 -Io cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclohexyloxy, tetrahydronaphthyloxy, indanyloxy) optionally having oxo;
  • C 6-1 4 aryloxy e.g., phenyloxy, naphthyloxy; the C 6-14 aryl is optionally condensed with C 3 _ 10 cycloalkane
  • substituents selected from (i) a halogen atom, (ii) cyano
  • C 1-6 alkyl optionally having 1 or 2 substituents selected from a halogen atom, carboxy, hydroxy, C 1-6 alkoxy- carbonyl and mono- or di-C 1-6 alkylamino, (iv) C 1-6 alkoxy optionally having 1 to 3 substituents selected from a halogen atom and C 1-6 alkoxy,
  • xv a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl, C 1-4 alkylenedioxy and oxo, and
  • 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, benzis
  • Ce -14 arylsulfonyl e.g., phenylsulfonyl
  • C 3-10 cycloalkylsulfonyl e.g., cyclopropylsulfonyl
  • aromatic heterocyclylsulfonyl e.g., pyridylsulfonyl, pyrazolylsulfonyl, thienylsulfonyl, furylsulfonyl, imidazolylsulfonyl
  • aromatic heterocyclylsulfonyl e.g., pyridylsulfonyl, pyrazolylsulfonyl, thienylsulfonyl, furylsulfonyl, imidazolylsulfonyl
  • non-aromatic heterocyclylcarbonyl (the non-aromatic heterocycle is optionally oxidized; e.g., morpholinylcarbonyl, piperazinylcarbonyl) optionally substituted by C 1-6 alkyl optionally substituted by C 6-14 aryl (e.g., phenyl);
  • non-aromatic heterocyclylcarbonyloxy e.g., pyrrolidinylcarbonyloxy
  • C 1-6 alkyl optionally having 1 to 5 (preferably 1 to 3) substituents selected from (i) a halogen atom, (ii) carboxy, (iii) hydroxy, (iv) C 1-6 alkoxy, (v) C 1-6 alkoxy-carbonyl, (vi) C 1-S alkyl-carbonyloxy (e.g., acetyloxy, tert- . butylcarbonyloxy) ,
  • non-aromatic heterocyclic group (the non-aromatic heterocyclic group is optionally oxidized; e.g., piperidino, tetrahydrofuryl) optionally substituted by C 1-6 alkyl,
  • non-aromatic heterocyclylcarbonyl (the non-aromatic heterocycle is optionally oxidized; e.g., morpholinylcarbonyl) ,
  • C 2-6 alkenyl e.g., ethenyl, 1-propenyl
  • substituents selected from (i) a halogen atom
  • (48) optionally halogenated C 6-10 arylsulfonyl (e.g., phenylsulfonyl, fluorophenylsulfonyl) ; (49) heterocyclylthio (e.g., thiazolylthio, thiadiazolylthio, triazolylthio, benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio) optionally having C 1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6 alkyl- carbonyloxy; and the like.
  • arylsulfonyl e.g., phenylsulfonyl, fluorophenylsulfonyl
  • heterocyclylthio e.g., thiazolylthio, thiadiazolylthio, triazolylthio, benzothiazolylthio, benzimidazolyl
  • aromatic group examples include an aromatic hydrocarbon group and an aromatic heterocyclic group.
  • Examples of the "aromatic hydrocarbon group” include Ce-u aryl and the like.
  • Examples of the “aromatic heterocyclic group” include a 4- to 7-membered (preferably 5- or ⁇ -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.
  • fused aromatic heterocyclic group examples 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.
  • aromatic heterocyclic group examples 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-
  • non-aromatic cyclic group examples include a non- aromatic cyclic hydrocarbon group and a non-aromatic heterocyclic group.
  • non-aromatic cyclic hydrocarbon group examples include C 3-10 cycloalkyl, C 3-10 cycloalkenyl and C 4 -I 0 cycloalkadienyl, each of which is optionally condensed with a benzene ring, and the like.
  • ⁇ non-aromatic heterocyclic group examples include a 4- to 7-membered (preferably 5- or ⁇ -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.
  • fused non-aromatic heterocyclic group examples 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.
  • non-aromatic heterocyclic group examples 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.
  • the "cyclic group” optionally has substituent (s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position (s).
  • substituents e.g., 1 to 5, preferably 1 to 3 substituents
  • respective substituents may be the same or different.
  • substituents include groups exemplified as the substituents which the aforementioned "hydrocarbon group” optionally has, and the like.
  • aromatic heterocyclic group examples 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) ".
  • heterocyclic group optionally has substituent (s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position (s) .
  • substituents e.g., 1 to 5, preferably 1 to 3 substituents
  • respective substituents may be the same or different.
  • substituents include groups exemplified as the substituents which the aforementioned "hydrocarbon group” optionally has, and the like.
  • hydroxy optionally having a substituent examples 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.
  • hydroxy optionally having a substituent include (1) hydroxy, (2) hydroxy optionally having a substituent selected from C 1-I o alkyl optionally having substituent (s) , C 2 -1 0 alkenyl optionally having substituent (s) , C 3-10 cycloalkyl optionally having substituent (s) , C 3-10 cycloalkenyl optionally having substituent (s) , C 6-14 aryl optionally having substituent (s) , C 7-13 aralkyl optionally having substituent (s) , C 6-13 arylalkenyl optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , acyl and the like, and the like.
  • the aforementioned C 1-10 alkyl, C2 -10 alkenyl, C 3 -I 0 cycloalkyl, C 3-10 cycloalkenyl, C 6-14 aryl, C 7-13 aralkyl and C 8-13 arylalkenyl optionally have substituent (s) (preferably 1 to 3 substituents) at substitutable position (s) .
  • substituents preferably 1 to 3 substituents
  • Examples of the substifuent 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.
  • amino optionally having substituent (s) examples 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.
  • amino optionally having substituent (s) include (1) amino, (2) amino optionally having 1 or 2 substituents selected from C 1-10 alkyl optionally having substituent (s) , C 2-10 alkenyl optionally having substituent (s) , C 3-10 cycloalkyl optionally having substituent (s) , C 3-10 cycloalkenyl optionally having substituent (s) , C 6-14 aryl optionally having substituent (s) , C 7-13 aralkyl optionally having substituent (s) , C 8-13 arylalkenyl optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , acyl and the like, and the like.
  • the aforementioned C 1-10 alkyl, C2 -10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 6-14 aryl, C7-13 aralkyl and C 6-1 3 arylalkenyl optionally have substituent (s) (preferably 1 to 3 substituents) at substitutable position (s).
  • substituents 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.
  • mercapto optionally having a substituent examples include (1) mercapto, (2) mercapto optionally having a substituent selected from C 1-10 alkyl optionally having substituent (s) , C 2-10 alkenyl optionally having substituent (s) , C 3 _ 10 cycloalkyl optionally having substituent (s) , C 3 _ 10 cycloalkenyl optionally having substituent (s) , C 6-14 aryl optionally having substituent (s) , C 7-13 aralkyl optionally having substituent (s) , C 3-13 arylalkenyl optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , acyl and the like, and the like.
  • the aforementioned C 1-10 alkyl, C2 -10 alkenyl, C 3 -I 0 cycloalkyl, C 3-10 cycloalkenyl, C 6-14 aryl, C 7-13 aralkyl and C 8-13 arylalkenyl optionally have substituent (s) (preferably 1 to 3 substituents) at substitutable position (s).
  • substituents 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.
  • acyl in the present specification include a group represented by the formula: -C0R A , -C0-0R A , -SO 2 R A , -SOR A , -C0-NR A 'R B ' or -CS-NR A 'R B ' [wherein R A is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s) , and R A ' and R B ' are the same or different and each is a hydrogen atom, a hydrocarbon group optionally having substituent (s) or a heterocyclic group optionally having substituent (s) , or R A ' and R B ' optionally form, together with the adjacent nitrogen atom, a nitrogen-containing heterocycle optionally having substituent (s) ] and the like.
  • nitrogen-containing heterocycle of the "nitrogen-containing heterocycle optionally having substituent (s)" formed by R A ' and R B ' together with the adjacent nitrogen atom
  • 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.
  • 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).
  • substituents 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.
  • acyl include (1) formyl;
  • C 1-6 alkoxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C 1-6 alkoxy- carbonyl and C 1-6 alkyl-carbonyloxy (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxymethoxycarbonyl, carboxyethoxycarbonyl, carboxybutoxycarbonyl; carbamoylmethoxycarbonyl; thiocarbamoylmethoxycarbonyl; ethoxycarbonylmethoxycarbonyl, ethoxycarbonylethoxycarbonyl, methoxycarbonylbutoxycarbonyl, ethoxycarbonylbutoxycarbonyl; tert- butylcarbonyloxymethoxycarbonyl) ;
  • C 3-10 cycloalkyl-carbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl) .
  • C 6-14 aryl-carbonyl e.g., benzoyl, 1-naphthoyl, 2-naphthoyl
  • substituents selected from a halogen atom, cyano, C 1-6 alkyl optionally substituted by 1 to 3 halogen atoms, C 1-6 alkoxy, carboxy, C 1-6 alkoxy-carbonyl, an aromatic heterocyclic group (e.g., tetrazolyl, oxadiazolyl) , a non- aromatic heterocyclic group (e.g., oxooxadiazolyl) and carbamoyl;
  • C 6-14 aryloxy-carbonyl e.g., phenyloxycarbonyl, naphthyloxycarbonyl
  • substituents selected from carboxy, C 1-6 alkoxy-carbonyl and carbamoyl
  • C 7-13 aralkyloxy-carbonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl, thiocarbamoyl, C 1- 6 alkoxy-carbonyl, a halogen atom, cyano, nitro, C 1-6 alkoxy, C 1-6 alkylsulfonyl and C 1-6 alkyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl; carboxybenzyloxycarbonyl; methoxycarbonylbenzyloxycarbonyl; biphenylylmethoxycarbonyl) ;
  • substituents selected from carboxy, carbamoyl, thiocarbamoyl, C 1- 6 alkoxy-carbonyl, a halogen atom, cyano, nitro, C 1-6 alkoxy, C 1-6 alkylsulfonyl and C 1-6 alkyl (e.g., benzyloxycarbonyl, phen
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom and C 1-6 alkoxy (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, trifluoroethylcarbamoyl, N-methoxyethyl-N-methylcarbamoyl) ;
  • C 1-6 alkoxy e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, propylcarbamoyl, isopropy
  • C 1-6 alkylsulfonyl optionally having 1 to 3 substituents selected from carboxy, carbamoyl and C 1-6 alkoxy-carbonyl (e.g., methylsulfonyl, carboxymethylsulfonyl) ;
  • C 1-6 alkylsulfinyl e.g., methylsulfinyl
  • C 7 _i 3 aralkyl-carbonyl e.g., benzylcarbonyl, phenethylcarbonyl
  • 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
  • R 1 is a substituent.
  • substituents include a halogen atom, a hydrocarbon group optionally having substituent (s) , a heterocyclic group optionally having substituent (s) , hydroxy optionally having a substituent, amino optionally having substituent (s) , acyl and the like.
  • R 1 is preferably a halogen atom, a hydrocarbon group optionally having substituent (s) , hydroxy optionally having a substituent, amino optionally having substituent (s) or the like, more preferably a hydrocarbon group optionally having substituent (s) , further more preferably C 1-6 alkyl optionally having substituent (s) , C 7-13 aralkyl optionally having substituent (s) or the like, particularly preferably
  • substituent (c) C 7-13 aralkyl optionally having substituent (s) (e.g., a halogen atom, C 1-6 alkyl optionally having substituent (s) , cyano, hydroxy, C 1-6 alkoxy optionally having substituent (s) , a heterocyclic group optionally having substituent (s) ), or the like.
  • substituent (s) e.g., a halogen atom, C 1-6 alkyl optionally having substituent (s) , cyano, hydroxy, C 1-6 alkoxy optionally having substituent (s) , a heterocyclic group optionally having substituent (s) ), or the like.
  • R 1 is (a) C 1-6 alkyl substituted by hydroxy optionally having, a substituent (e.g., a fused aromatic heterocyclic, group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl) , benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl) , benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl) , benzisoxazolyl (e.g.,- 5-benzisoxazolyl, 6-benzisoxazolyl) , benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl) , benzimidazolyl (e.g., benzimidazol-5-yl) , benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl) , benzo
  • C 7 _i 3 aralkyl optionally having substituent (s) (e.g., a halogen atom, C 1-6 alkyl optionally having substituent (s) , C ⁇ -e alkoxy optionally having substituent (s) , a monocyclic aromatic heterocyclic group optionally having substituent (s) ), or the like.
  • substituent (s) e.g., a halogen atom, C 1-6 alkyl optionally having substituent (s) , C ⁇ -e alkoxy optionally having substituent (s) , a monocyclic aromatic heterocyclic group optionally having substituent (s) ), or the like.
  • R 1 Preferable embodiments of R 1 include
  • C 7-13 aralkyl e.g., benzyl, phenethyl, phenylpropyl
  • substituents selected from (i) a halogen atom
  • C 1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy, (iii) cyano, (iv) hydroxy, (v) optionally halogenated C 1-6 alkoxy (e.g., . trifluoromethoxy) , and
  • a 5- or 6-membered non-aromatic heterocyclic group e.g., morpholinyl
  • C 3-10 cycloalkyl-C 1-6 alkyl e.g., cyclopropylmethyl, cyclohexylmethyl
  • C 1-6 alkyl optionally having 1 to 5 substituents selected from
  • C 1-6 alkoxy e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy
  • E C 1-4 alkylenedioxy
  • C 1-6 alkylsulfonyl e.g., methylsulfonyl, trifluoromethylsulfonyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl
  • substituents selected from C 1-6 alkyl, C 1-6 alkyl- carbonyl and oxo
  • a 5- or ⁇ -membered aromatic heterocyclic group e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6 alkyl, C 1-6 alkoxy- carbonyl-C 1-6 alkyl, mono- or di-C 1-6 alkylamino-C 1-6 alkyl (e.g., dimethylaminomethyl) , C 6-10 aryl (e.g., phenyl), C 1-6 alkoxy-carbonyl and carboxy, (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, dihydrobenzoxazolyl, benzisoxazoly
  • a 9- or 10-membered fused heterocyclic group e.g., indolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl
  • a 9- or 10-membered fused heterocyclic group e.g., indolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl
  • substituents selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy-carbonyl and oxo
  • R 1 include (1) C 7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from (i) a halogen atom,
  • C 1-6 alkyl optionally having 1 to 5 substituents selected from a halogen atom and hydroxy, (iii) cyano, (iv) hydroxy, (v) optionally halogenated C 1-6 alkoxy (e.g., methoxy, trifluoromethoxy) , (vi) C 6-10 aryloxy (e.g., phenoxy) ,
  • a 5- or 6-membered non-aromatic heterocyclic group e.g., morpholinyl
  • a 5- or 6-membered aromatic heterocyclic grqup e.g., pyridyl, pyrazolyl, oxadiazolyl
  • substituents selected from C 1-6 alkyl ' and C 1-6 alkoxy
  • C) C 1-6 alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C 1-6 alkoxy-carbonyl and mono- or di-C 1-6 alkylamino,
  • C 1-6 alkoxy e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy
  • C 1-6 alkylsulfonyl e.g., methylsulfonyl, trifluoromethylsulfonyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl
  • 1 or 2 substituents selected from C 1-6 alkyl, C 1- 6 alkyl-carbonyl and oxo
  • Q a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo,
  • a 5- or 6-membered aromatic heterocyclic group e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or ⁇ -membered aromatic heterocyclic group is optionally oxidized
  • substituents selected from a halogen atom, cyano, optionally halogenated C 1-6 alkyl, C 1-6 alkoxy- carbonyl-C 1-6 alkyl, mono- or di-C 1-6 alkylamino-C 1-6 alkyl (e.g., dimethylaminomethyl) , C 6-10 aryl (e.g., phenyl), C 1-6 alkoxy-carbonyl and carboxy,
  • a 9- or 10-membered fused heterocyclic group e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-carbonyl, C 3-10 cycloalkyl,
  • C 6-10 aryl-carbamoyl e.g., phenylcarbamoyl
  • C 6-10 arylthio e.g., phenylthio
  • C 6-10 arylsulfinyl e.g., phenylsulfinyl
  • optionally halogenated C 6 _ 10 arylsulfonyl e.g., phenylsulfonyl, fluorophenylsulfonyl
  • Ci-e alkyl e.g., methyl, ethyl, isopropyl, trifluoromethyl
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • (k) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo,
  • a 5- or 6-membered heterocyclic group e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl
  • a 5- or 6-membered heterocyclic group e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl
  • a 9- or 10-membered fused heterocyclic group e.g., indolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy- carbonyl and oxo,
  • substituents selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy- carbonyl and oxo
  • xi a 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio) ; (4) C 3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl) ; and the like.
  • a 9- or 10-membered fused heterocyclylthio e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio
  • C 3-10 cycloalkyl optionally condensed with a benzene ring e.g., indanyl
  • R 1 include (1) C 7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from (i) a halogen atom,
  • C 1-6 alkoxy e.g., methoxy, trifluoromethoxy
  • C 6-10 aryloxy e.g., phenoxy
  • a 5- or 6-membered aromatic heterocyclic group e.g., pyridyl, pyrazolyl, oxadiazolyl
  • a 5- or 6-membered aromatic heterocyclic group e.g., pyridyl, pyrazolyl, oxadiazolyl
  • substituents selected from C 1-6 alkyl and C 1-6 alkoxy optionally having 1 to 3 substituents selected from C 1-6 alkyl and C 1-6 alkoxy
  • C) C 1-6 alkyl optionally having 1 to 3 substituents selected from a halogen atom, carboxy, hydroxy, C 1-6 alkoxy-carbonyl and mono- or di-C 1-6 alkylamino,
  • C 1-6 alkylsulfonyl e.g., methylsulfonyl, trifluoromethylsulfonyl
  • P a 5- or 6-membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1- .
  • cycloalkane e.g., tetrahydronaphthyl
  • a 5- or ⁇ -membered aromatic heterocyclic group e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized
  • substituents selected from a halogen atom, cyano, optionally halogenated C 1-6 alkyl, C 1-6 alkoxy- carbonyl-C 1-6 alkyl, mono- or di-C 1-6 alkylamino-C 1-6 alkyl (e.g., dimethylaminomethyl) , C 6-10 aryl (e.g., phenyl), C 1-6 alkoxy-carbonyl and carboxy,
  • a 9- or 10-membered fused heterocyclic group e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from C 1-6 alkoxy and C 1-6 alkoxy-carbonyl,
  • C 6-10 arylthio e.g., phenylthio
  • C 6-10 arylsulfinyl e.g., phenylsulfinyl
  • optionally halogenated C 6-10 arylsulfonyl e.g., phenylsulfonyl, fluorophenylsulfonyl
  • C 1-6 alkyl e.g., methyl, ethyl, isopropyl, trifluoromethyl
  • C) optionally halogenated C 1-6 alkoxy e.g., methoxy, trifluoromethoxy, difluoromethoxy
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • a 9- or 10-membered fused heterocyclic group e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzotriazolyl, indolyl, indazolyl, imidazopyridyl, pyrazolopyridyl, dihydrobenzoxazolyl, benzisoxazolyl, benzisothiazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromenyl, thienopyridyl, pyrrolopyrazinyl, imidazopyrazinyl, pyrazolothienyl, dihydrofuropyridyl, dihydrobenzoxazinyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo, (vii) a 5- or 6-membered heterocyclic
  • 5- or 6-membered heterocyclylthio e.g., thiazolylthio, thiadiazolylthio, triazolylthi
  • R 2 is a cyclic group optionally having substituent (s) , C 1-10 alkyl optionally having substituent (s) , C 2-10 alkenyl optionally having substituent (s) or C 2-10 alkynyl optionally having substituent (s) .
  • the aforementioned C 1-10 alkyl, C 2-10 alkenyl and C 2-10 alkynyl optionally have substituent (s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position (s).
  • substituents e.g., 1 to 5, preferably 1 to 3 substituents
  • substituents include groups exemplified as the substituents which the aforementioned "hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
  • R 2 is preferably C ⁇ -u aryl optionally having substituent (s) , . C 3-10 cycloalkyl optionally having substituent (s) or the like.
  • R 2 is more preferably optionally halogenated C 6-10 aryl (e.g., phenyl), C 3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) or the like.
  • R 2 is particularly preferably optionally halogenated C 6-10 aryl (e.g., phenyl) or the like.
  • R 3 is a hydrogen atom, a halogen atom, C 1-6 alkyl or C 1 _ 6 alkoxy.
  • R 3 is preferably a hydrogen atom, a halogen atom, C 1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl) , C 1-3 alkoxy (e.g., methoxy, ethpxy, propoxy, isopropoxy) or the like, more preferably a hydrogen atom or the like.
  • C 1-3 alkyl e.g., methyl, ethyl, propyl, isopropyl
  • C 1-3 alkoxy e.g., methoxy, ethpxy, propoxy, isopropoxy
  • 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., 0, S, N etc.), and may be saturated or unsaturated. In addition, S may be oxidized.
  • Examples of the "spacer having 1 to 6 atoms in the main chain” include straight chain C 1-6 alkylene, -X 3- -NH-X 2 -, -X 3- -O-X 2 - and -X 3- -S-X 2 - [wherein X 1 and X 2 are the same or different and each is bond or straight chain C 1-5 alkylene, when X 1 and X 2 are both straight chain C 1-5 alkylene, then the total carbon number of straight chain C 1-5 alkylene for X 3- and straight chain C 1-5 alkylene for X 2 is 5 or less, and S is optionally oxidized] and the like.
  • Examples of the "straight chain C 1-6 alkylene" include - CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - and - CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 - .
  • Examples of the "straight chain C 1-5 alkylene" for X 1 or X 2 include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - and - CH 2 CH 2 CH 2 CH 2 CH 2 - .
  • the "spacer having 1 to 6 atoms in the main chain” optionally has substituent (s) (preferably 1 to 3 substituents) at substitutable position (s) (optionally at the carbon atom and nitrogen atom constituting the main chain) .
  • substituents include groups exemplified as the substituents which the aforementioned "hydrocarbon group” optionally has, and the like. When the number of the substituents is not less than 2, respective substituents may be the same or different.
  • X is preferably bond, C 1-6 alkylene optionally having substituent (s) or the like.
  • X is more preferably ' (1) bond
  • C 1-6. alkylene optionally having substituent (s) selected from C 1-6 alkyl and C 6-10 aryl (e.g., phenyl) or the like.
  • Ring A is C 5 - 7 cycloalkane optionally having substituent (s) .
  • Examples of the "C 5 _ 7 cycloalkane” of the “C 5 _ 7 cycloalkane optionally having substituent (s) " include cyclopropane, cyclobutane, cyclopentane, cyclohexane, bicyclo [1.1. l]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 “C 5 _ 7 cycloalkane optionally having substituent (s) " optionally has substituent (s) (e.g., 1 to 5, preferably 1 to 3 substituents) at substitutable position (s).
  • substituents e.g., 1 to 5, preferably 1 to 3 substituents
  • respective substituents may be the same or different, and may be substituted at the same carbon of ring A.
  • two substituents may be bonded each other to form, with C 5 - 7 cycloalkane, an optionally substituted ring (a fused ring or spiro ring) .
  • fused ring or spiro ring examples include a fused ring or spiro ring consisting of C 5 _ 7 cycloalkane and C 3 -I 0 cycloalkane, C 3-10 cycloalkene, C 4-10 cycloalkadiene or a heterocycle.
  • Examples of the "C 3-10 cycloalkane”, “C 3 -I 0 cycloalkene”, “C 4-10 cycloalkadiene” and “heterocycle” include rings corresponding to the aforementioned C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 4-10 cycloalkadienyl and heterocyclic group.
  • Examples of the "substituent" of the “Cs_ 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 Cs_ 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) .
  • ring A is (a) C 5 - 7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent (s) (e.g., a halogen atom, a hydrocarbon group optionally having substituent (s) etc.), or (b) C5_ 7 cycloalkane substituted by amino optionally having substituent (s) (e.g., a hydrocarbon group optionally having substituent (s) , acyl etc.).
  • substituent (s) e.g., a halogen atom, a hydrocarbon group optionally having substituent (s) etc.
  • C5_ 7 cycloalkane substituted by amino optionally having substituent (s) e.g., a hydrocarbon group optionally having substituent (s) , acyl etc.
  • ring A is (a) C 5 _ 7 cycloalkane having hydroxy optionally having a substituent, and optionally further having substituent (s) (e.g., C 1-3 alkyl optionally having substituent (s) etc.), or (b) C 5 _ 7 cycloalkane substituted by amino optionally having substituent (s) (e.g., C 1-6 alkoxy-carbonyl etc.). Still more preferably, ring A is
  • ring A is
  • ring A is the following [A] and [B] and the like.
  • [A] C 5 - 7 cycloalkane optionally having 1 to 5 substituents selected from
  • a heterocyclic group e.g., a 5- or ⁇ -membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl and oxo,
  • a heterocyclic group e.g., a 5- or ⁇ -membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydr
  • C 3-6 cycloalkyloxy optionally condensed with a benzene ring e.g., cyclobutyloxy, indanyloxy
  • C 6-10 aryloxy e.g., phenoxy
  • 5- or 6-membered heterocyclyloxy e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyloxy
  • (xv) amino optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1 _ 6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl, 5- or 6-meinbered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl) and C 1-6 alkylsulfonyl-C 1-6 alkyl, and
  • carbamoyl optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl and 5- or 6- membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl);
  • C 1-3 alkylidene e.g., methylene
  • C 1-3 alkylidene optionally having a substituent selected from C 1-6 alkoxy-carbonyl and C 1-6 alkyl- carbamoyl
  • [B] C 5 - 7 cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., l-oxa-3- azaspiro[4.5]decyl) optionally having 1 or 2 oxo.
  • a spiro ring e.g., l-oxa-3- azaspiro[4.5]decyl
  • optionally having 1 or 2 oxo optionally having 1 or 2 oxo.
  • ring A 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) C 1-6 - alkyl optionally having 1 to 5 substituents selected from
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl and oxo, (vi) C 3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy) , (vii) C 6-10 aryloxy (e.g., phenoxy) , (viii) 5- or 6-membered heterocyclyloxy (e.g.,
  • (xv) amino optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl, 5- or 6-membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl) and C 1-6 alkylsulfonyl-C 1-6 alkyl, and
  • carbamoyl optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl and 5- or 6- membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl);
  • [B] C 5 - 7 cycloalkane forming, together with a 5- or 6-membered non-aromatic heterocycle, a spiro ring (e.g., l-oxa-3- azaspiro[4.5]decyl) optionally having 1 or 2 oxo.
  • a spiro ring e.g., l-oxa-3- azaspiro[4.5]decyl
  • optionally having 1 or 2 oxo optionally having 1 or 2 oxo.
  • Ring B is piperazine optionally further having substituent (s) besides R 1 .
  • ring B optionally further has examples include groups exemplified as the "substituent” for R 1 optionally has, and the like.
  • Specific examples of the ' “substituent” include optionally substituted C 1-6 alkyl, for example, C 1-6 alkyl optionally having a 5- or 6-membered non- aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo, and the like.
  • Ring B is preferably a ring represented by the formula:
  • the piperazine ring optionally has 1 to 3 C 1-6 alkyl at the ring-constituting carbon atom.
  • compound (I) include the following compounds .
  • Compound A Compound (I) wherein R 1 is a hydrocarbon group optionally having substituent (s) ;
  • R 2 is C 6-14 aryl optionally having substituent (s) or C 3 _ 10 cycloalkyl optionally having substituent (s) ;
  • R 3 is a hydrogen atom, a halogen atom, C ⁇ - 3 alkyl or C 1-3 alkoxy;
  • X is bond or C 1-6 alkylene optionally having substituent (s) ; and ring A is C 5 _ 7 cycloalkane optionally having substituent (s) selected from a halogen atom, a hydrocarbon group optionally having substituent (s) , hydroxy optionally having a substituent and amino optionally having substituent (s) .
  • R 1 is (a) C 1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl) , benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl) , benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl) , benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl) , benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl) , benzimidazolyl (e.g., benzimidazol-5-yl) , benzotriazolyl (e.g., 1H-1,2,3-benzotriazol-5-yl) , indolyl
  • R 2 is optionally halogenated C 6-10 aryl (e.g., phenyl), or C 3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) ;
  • R 3 is a hydrogen atom
  • (a) C 1-6 alkyl substituted by hydroxy optionally having a substituent e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl) , benzothienyl (e.g., 5-benzothienyl, 6-benzothienyl) , benzoxazolyl (e.g., 5-benzoxazolyl, 6-benzoxazolyl) , benzisoxazolyl (e.g., 5-benzisoxazolyl, 6-benzisoxazolyl) , benzothiazolyl (e.g., 5-benzothiazolyl, 6-benzothiazolyl) , benzimidazolyl (e.g., benzimidazol-5-yl) , benzotriazolyl (e.g., 1H-I, 2, 3-benzotriazol-5-yl) , indolyl (e.
  • R 2 is optionally halogenated C 6-10 aryl (e.g., phenyl);
  • R 3 is a hydrogen atom, a halogen atom, C 1-3 alkyl (e.g., methyl, ethyl, propyl, isopropyl) or C 1 _ 3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy) ;
  • X is
  • C 1-6 alkylene optionally having substituent (s) (e.g., C 1-6 alkyl, C 5-10 aryl (e.g., phenyl), etc.); and ring A is
  • R 1 is C 1-6 alkyl substituted by hydroxy optionally having a substituent (e.g., a fused aromatic heterocyclic group such as benzofuranyl (e.g., 5-benzofuranyl, 6-benzofuranyl) , benzothienyl (e.g., 5-benzothienyl, 6- benzothienyl) , benzoxazolyl (e.g., 5-benzoxazolyl, 6- benzoxazolyl) , benzisoxazolyl (e.g., 5-benzisoxazolyl, 6- benzisoxazolyl), benzothiazolyl (e.g., 5-benzothiazolyl, 6- benzothiazolyl) , benzimidazolyl (e.g., benzimidazol-5-yl) , benzotriazolyl (e.g., 1H-1,2, 3-benzotriazol-5-yl) , indolyl
  • R 1 is C 1-6 alkyl substituted by phenylamino optionally having substituent (s) (e.g., a halogen atom, C1 -6 alkyl optionally having substituent (s) , C 1-6 alkoxy optionally having substituent (s) ).
  • substituent (s) e.g., a halogen atom, C1 -6 alkyl optionally having substituent (s) , C 1-6 alkoxy optionally having substituent (s) ).
  • R 1 is C 7-13 aralkyl optionally having substituent (s) (e.g., a halogen atom, C 1-6 alkyl optionally having substituent (s) , C 1-6 alkoxy optionally having substituent (s) , a monocyclic aromatic heterocyclic group optionally having substituent (s) ).
  • substituent (s) e.g., a halogen atom, C 1-6 alkyl optionally having substituent (s) , C 1-6 alkoxy optionally having substituent (s) , a monocyclic aromatic heterocyclic group optionally having substituent (s) ).
  • C 7-13 aralkyl e.g., benzyl, phenethyl, phenylpropyl
  • substituents selected from (i) a halogen atom
  • halogenated C 1-6 alkoxy e.g., trifluoromethoxy
  • a 5- or 6-me ⁇ ibered non-aromatic heterocyclic group e.g., morpholinyl
  • C 3-10 cycloalkyl-C 1-6 alkyl e.g., cyclopropylmethyl, cyclohexylinethyl
  • C 1-6 alkyl optionally having 1 to 5 substituents selected from
  • C 1-6 alkoxy e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy
  • M mono- or di-C 1-6 alkylamino, 0) optionally halogenated C 1-6 alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl) , and
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl
  • a 9- or 10-membered fused heterocyclic group e.g., indolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl
  • a 9- or 10-membered fused heterocyclic group e.g., indolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl
  • substituents selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy-carbonyl and oxo
  • R 2 is optionally halogenated C 6-10 aryl (e.g., phenyl), or C 3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) ;
  • R 3 is a hydrogen atom, a halogen atom, C 1-3 alkyl or C 1- . 3 alkoxy;
  • X is (1) bond, or
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl and oxo, (vi) C 3-6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy) , (vii) C 5-10 aryloxy (e.g., phenoxy) , (viii) 5- or 6-membered heterocyclyloxy (e.g.,
  • (xv) amino optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl, 5- or ⁇ -membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl) and C 1-6 alkylsulfonyl-C 1-6 alkyl, and
  • carbamoyl optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl and 5- or 6- membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl);
  • C 1-3 alkylidene e.g., methylene
  • C 1-3 alkylidene optionally having a substituent selected from C 1-6 alkoxy-carbonyl and C 1-6 alkyl- carbamoyl
  • R 1 is (1) C 7-13 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from (i) a halogen atom,
  • C 1-6 alkoxy e.g., methoxy, trifluoromethoxy
  • C 6-10 aryloxy e.g., phenoxy
  • a 5- or 6-membered aromatic heterocyclic group e.g., pyridyl, pyrazolyl
  • a 5- or 6-membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from C 1-6 alkyl and C 1-6 alkoxy;
  • C) C 1-6 alkyl optionally having 1 or 2 substituents selected from carboxy, hydroxy, C x _ 6 alkoxy-carbonyl and mono- or di-C 1-6 alkylamino,
  • C 1-6 alkoxy e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy
  • Ci_ 4 alkylenedioxy
  • C 1-6 alkylsulfonyl e.g., methylsulfonyl, trifluoromethylsulfonyl
  • P a 5- or ⁇ -membered heterocyclic group (e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1- 6 alkyl-carbonyl and oxo
  • Q a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo
  • C 6-10 aryl condensed with C 3-10 cycloalkane e.g., tetrahydronaphthyl
  • a 9- or 10-membered fused heterocyclic group e.g., benzothiazolyl, benzimidazolyl, benzothienyl, dihydrobenzoxazolyl, benzisoxazolyl, benzofuranyl, dihydrobenzofuranyl, tetrahydroquinolyl, . tetrahydroisoquinolyl, chromenyl, thienopyridyl
  • Ce -10 aryl-carbamoyl e.g., phenylcarbamoyl
  • C 6-10 arylthio e.g., phenylthio
  • C 6-10 arylsulfinyl e.g., phenylsulfinyl
  • optionally halogenated C 6-10 arylsulfonyl e.g., phenylsulfonyl, fluorophenylsulfonyl
  • C 1-6 alkyl e.g., isopropyl, trifluoromethyl
  • a 5- or ⁇ -membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • a 5- or ⁇ -membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • C 3 - S cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl)
  • a benzene ring e.g., cyclopropyl, cyclohexyl, indanyl
  • a 9- or 10-membered fused heterocyclic group e.g., benzoxazolyl, benzothiazolyl, dihydrobenzofuranyl, indazolyl, dihydrofuropyridyl
  • a 5- or 6-membered heterocyclic group e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl
  • a 9- or 10-membered fused heterocyclic group e.g., i ⁇ dolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6 alkyl, C 3 _ 6 cycloalkyl, C 1-6 alkoxy- carbonyl and oxo, (ix) carbamoyl optionally having 1 or 2 substituents selected from C 1-6 alkyl and C 6-10 aryl,
  • xi a 9- or 10-membered fused heterocyclylthio (e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio) ; or (4) C 3-10 cycloalkyl optionally condensed with a benzene ring (e.g., indanyl) ;
  • R 2 is optionally halogenated C 6-10 aryl (e.g., phenyl), or C 3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) ;
  • R 3 is a hydrogen atom, a halogen atom, C 1-3 alkyl or C 1- . 3 alkoxy;
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from C 1-6 alkyl and oxo,
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl
  • C 3-6 cycloalkyloxy optionally condensed with a benzene ring e.g., cyclobutyloxy, indanyloxy
  • Ce -10 aryloxy e.g., phenoxy
  • 5- or 6-membered heterocyclyloxy e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyloxy
  • (xv) amino optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl, 5- or ⁇ -meinbered aromatic heterocyclyl-C 1-6 alkyl (e.g.., furfuryl) and C 1-6 alkylsulfonyl-C 1-6 alkyl, and
  • carbamoyl optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl and 5- or 6- membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl);
  • C 1-3 alkylidene e.g., methylene
  • C 1-3 alkylidene optionally having a substituent selected from C 1-6 alkoxy-carbonyl and C 1-6 alkyl- carbamoyl
  • ring B is piperazine optionally further having, besides R 1 , C 1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo.
  • C 1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo.
  • R 1 is (1) C 7 -I 3 aralkyl (e.g., benzyl, phenethyl, phenylpropyl, naphthylmethyl, biphenylylmethyl) optionally having 1 to 3 substituents selected from
  • a 5- or ⁇ -membered aromatic heterocyclic group e.g., pyridyl, pyrazolyl
  • a 5- or ⁇ -membered aromatic heterocyclic group optionally having 1 to 3 substituents selected from C 1-6 alkyl and C 1-6 alkoxy;
  • G C 1-6 alkyl-carbonyl
  • H C 1-6 alkoxy-carbonyl
  • I 5- or 6-me ⁇ ibered non-aromatic heterocyclylcarbonyl (e.g., azetidinylcarbonyl)
  • C 1-6 alkylsulfonyl e.g., methylsulfonyl, trifluoromethylsulfonyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl
  • a 5- or 6-membered heterocyclic group e.g., imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, morpholinyl
  • 1 or 2 substituents selected from C 1-6 alkyl, C 1- 6 alkyl-carbonyl and oxo
  • Q a 9- or 10-membered fused heterocyclic group (e.g., dihydroimidazoimidazolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo,
  • a 5- or 6-membered aromatic heterocyclic group e.g., pyrazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl; the 5- or 6-membered aromatic heterocyclic group is optionally oxidized) optionally having 1 to 3 substituents selected from a halogen atom, cyano, optionally halogenated C 1-6 alkyl, C 1-6 alkoxy- carbonyl-C 1-6 alkyl, mono- or di-C 1-6 alkylamino-C 1-6 alkyl (e.g., dimethylaminomethyl) , C 6-10 aryl (e.g., phenyl), C 1-6 alkoxy-carbonyl and carboxy, (d) a 9- or 10-membered fused heterocyclic group (e.g., benzothiazolyl, benzimidazolyl, benzothienyl, benzoxazo
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from C 1-6 alkoxy and C 1-6 alkoxy-carbonyl, B) C 1-6 alkoxy,
  • C 6-10 arylthio e.g., phenylthio
  • C 6-10 arylsulfinyl e.g., phenylsulfinyl
  • optionally halogenated C 6-10 arylsulfonyl e.g., phenylsulfonyl, fluorophenylsulfonyl
  • C 1-6 alkyl e.g., methyl, isopropyl, trifluoromethyl
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • a 5- or 6-membered heterocyclic group e.g., pyrazolyl, piperidinyl, dihydropyridyl
  • C 3-6 cycloalkyl optionally condensed with -a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl)
  • a 9- or 10-membered fused heterocyclic group e.g., benzoxazolyl, benzothiazolyl, dihydrobenzofuranyl, indazolyl, dihydrofuropyridyl
  • substituents selected from C ⁇ - ⁇ alkyl and oxo e.g., 1,3-bis(trifluorobutyl)
  • a 5- or ⁇ -membered heterocyclic group e.g., piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxadiazolyl, pyridyl, tetrazolyl
  • a 9- or 10-membered fused heterocyclic group e.g., indolyl, dihydroisoindolyl, indazolyl, dihydroindazolyl, tetrahydroindazolyl, benzotriazolyl, benzimidazolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoxaz.inyl, tetrahydroquinolyl, tetfahydroisoquinolyl) optionally having 1 to 3 substituents selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy- carbonyl and oxo,
  • substituents selected from cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy- carbonyl and oxo
  • heterocyclylthio e.g., thiazolylthio, thiadiazolylthio, ' triazolylthio
  • C 1-6 alkyl optionally having 1 to 3 substituents selected from hydroxy and C 1-6 alkyl-carbonyloxy
  • 9- or 10-membered fused heterocyclylthio e.g., benzothiazolylthio, benzimidazolylthio, thiazolopyridylthio
  • R 2 is optionally halogenated Ce -10 aryl (e.g., phenyl), or C 3-6 cycloalkyl (e.g., cyclopropyl, cyclohexyl) ;
  • R 3 is a hydrogen atom, a halogen atom, C 1-3 alkyl or C 1-3 alkoxy;
  • X is (1) bond, or
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyranyl and the like; benzimidazolyl; the heterocyclic group is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyl) optionally having 1 or 2 substituents selected from ' C ⁇ alkyl and oxo,
  • a heterocyclic group e.g., a 5- or 6-membered heterocyclic group such as thiazolyl, imidazolyl, pyrrolidinyl, oxazolidinyl, pyridyl, oxetanyl, tetrahydrothiopyranyl, tetrahydropyrany
  • C 3 _ 6 cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclobutyloxy, indanyloxy) , (vii) C 6-10 aryloxy (e.g., phenoxy) , (viii) 5- or ⁇ -membered heterocyclyloxy (e.g., tetrahydropyranyloxy, piperidinyloxy, tetrahydrothiopyranyloxy; the heterocycle is optionally oxidized, e.g., 1, 1-dioxidotetrahydrothiopyranyloxy) optionally having 1 or 2 substituents selected from C 1-6 alkyl and oxo,
  • a benzene ring e.g., cyclobutyloxy, indanyloxy
  • C 6-10 aryloxy e.g., phenoxy
  • 5- or ⁇ -membered heterocyclyloxy e.g., tetrahydr
  • carbamoyl optionally having 1 or 2 substituents selected from C 1-6 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl and 5- or 6- membered aromatic heterocyclyl-C 1-6 alkyl (e.g., furfuryl);
  • 5- or ⁇ -membered cyclic amino e.g., morpholino, oxazolidinyl
  • C 1-3 alkylidene e.g., methylene
  • ring B is piperazine optionally further having, besides R 1 , .
  • C 1-6 alkyl optionally having a 5- or 6-membered non-aromatic heterocyclic group (e.g., dioxolyl) optionally having 1 to 3 substituents selected from C 1-6 alkyl and oxo.
  • compound (I) examples include methyl [ (IS, 2S) -2- (4- ⁇ [ (2R) -2- (3, 5-difluorobenzyDpiperazin-1- yl] carbonyl ⁇ -5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, (lS,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,
  • compound (I) include (lS,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 [ (IS, 2S) -2- (4- ⁇ [ (2R) -2- (3, 5-difluorobenzyl)piperazin-1- yl] carbonyl ⁇ -5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, (IS, 2R) -1- (methoxymethyl) -2- [5-phenyl-4- ( ⁇ (2R) -2- [ (5-phenyl- 1, 3, 4-oxadiazol-2-yl)methyl]piperazin-1-yl ⁇ carbonyl)
  • 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.
  • 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.
  • the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like.
  • 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, methanes ⁇ lfonic 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.
  • a pharmaceutically acceptable salt is preferable.
  • 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like
  • 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.
  • 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.
  • 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.
  • a known method such as phase transfer, concentration, solvent extraction, fractional distillation, pH conversion, crystallization, recrystallization, chromatography and the like.
  • R is C 1-4 alkyl
  • Y is a hydrogen atom or an alkali metal atom
  • PG is an N-protecting group (e.g., benzyl, tert- butoxycarbonyl, benzyloxycarbonyl etc.), and the other symbols are as defined above.
  • This method is used for the production of compound (IV) wherein R 3 is a hydrogen atom.
  • Compound (II) may be commercially available, or can be produced according to a method known per se, for example, the method described in Tetrahedron: Asymmetry, 1997, vol. 8, pages 3153-3159, or the like, or a method analogous thereto.
  • the production of compound (III) , and the production of compound (IV) by the reaction of compound (II) with compound (III) are performed, for example, according to the method described in Journal of Organic Chemistry, 1994, vol.59, pages 7635-7642, or the like, or a method analogous thereto.
  • Compound (IV) wherein R 3 is a halogen atom, C 1-6 alkyl or C 1-6 alkoxy can be produced according to a method known per se, for example, the method described in Journal of Organic Chemistry, 2004, vol. 69, pages 8829-8835, or the like, or a method analogous thereto .
  • Compound (IV) can be modified by further carrying out one or more of known acylation reaction, alkylation reaction, amination reaction, oxidation-reduction reaction, cyclization reaction, carbon chain extension reaction, substituent exchange reaction and the like, as desired. (Reaction 2) hydrolysis
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. . (Reaction 3)
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • the condensation reaction is preferably carried out in a solvent.
  • 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.
  • 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) .
  • a protecting group generally used in peptide chemistry and the like may be introduced into these groups .
  • the objective compound can be obtained.
  • Introduction or removal of these protective groups may be carried out according to a method known per se, for example, the method disclosed in Theodora W. Greene and Peter G. M. Wuts, "Protective Groups in Organic Synthesis, 3 rd Ed.”, Wiley-Interscience (1999), or the like.
  • amino-protecting group for example, formyl group; C 1-6 alkyl-carbonyl group, phenylcarbonyl group, C 1-6 alkoxy- carbonyl group, allyloxycarbonyl (Alloc) group, phenyloxycarbonyl group, fluorenylmethyloxycarbonyl (Fmoc) group, C 7-10 aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), C 7-10 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl (Cbz) and the like), C 7-10 aralkyl group (e.g., benzyl and the like), trityl group, phthaloyl group, dithiasuccinoyl group, N, N- dimethylaminomethylene group, each optionally having substituent (s) , and the like can be mentioned.
  • substituent (s) for example, phenyl group, a halogen atom, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy group optionally substituted by halogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like) , nitro group and the like can be used.
  • the number of the substituent (s) is 1 to 3.
  • carboxyl-protecting group for example, C 1-6 alkyl group, allyl group, benzyl group, phenyl group, trityl group, trialkylsilyl group, each optionally having substituent (s) , and the like can be mentioned.
  • substituent (s) for example, a halogen atom, formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy group optionally substituted by halogen atom(s) (e.g., methoxy, ethoxy, trifluoromethoxy and the like) , nitro group and the like can be used.
  • the number of the substituent (s) is 1 to 3.
  • hydroxy-protecting group for example, C 1-6 alkyl group, C 7 - 2 o aralkyl group (e.g., benzyl, trityl and the like), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group, C 7 _ 10 aralkyl-carbonyl group (e.g., benzylcarbonyl and the like), 2- tetrahydropyranyl group, tetrahydrofuranyl group, trialkylsilyl group (e.g., trimethylsilyl, tert-butyldimethylsilyl, diisopropylethylsilyl and the like) , each optionally having substituent (s) , and the like can be mentioned.
  • C 1-6 alkyl group, C 7 - 2 o aralkyl group e.g., benzyl, trityl and the like
  • formyl group C 1-6 alkyl-carbony
  • substituent (s) for example, a halogen atom, C 1-6 alkyl. group, phenyl group, C 7-10 aralkyl group (e.g., benzyl and the like), C 1-6 alkoxy group, nitro group and the like can be used.
  • the number of the substituent (s) is 1 to 4.
  • 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, fumaryl
  • 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 KA1HATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990) .
  • any isomers and a mixture thereof are encompassed in compound (I) .
  • compound (I) has an isomer
  • an optical isomer resolved from a racemate is also encompassed in compound (I) .
  • Such isomer can be obtained as a single product by a synthesis method, a separation method (e.g., concentration, solvent extraction, column chromatography, recrystallization etc.), optical resolution method (e.g., fractional recrystallization, chiral column method, diastereomer method etc.) and the like known per se.
  • Compound (I) may be a crystal, and both a single crystal and crystal mixtures are encompassed in compound (I) . Crystals can be produced by crystallization according to crystallization methods known per se.
  • Compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate (e.g., non-hydrate etc.), both of which are encompassed in compound (I) .
  • a compound labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I and the like) and the like is also encompassed in compound (I) .
  • Compound (I) or its prodrug, or salts thereof 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 All, and is useful as an agent for the prophylaxis or treatment of various diseases caused by the RA system.
  • mammals e.g., mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human, etc.
  • disorders 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
  • 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,
  • 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 hydrochlor
  • 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.
  • an antithrombotic drug such as heparin sodium, heparin calcium, warfarin calcium (Warfarin) , a blood coagulation factor Xa
  • the compound can be used in combination with a lipid lowering drug or a cholesterol lowering drug.
  • a lipid lowering drug or a cholesterol lowering drug examples 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
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • NB-598 and its analogs, etc. oxidosqualene-lanosterol cyclase
  • oxidosqualene-lanosterol cyclase for example, a decalin derivative, an azadecalin derivative, an indane derivative and the like.
  • HMG-CoA reductase (3-hydroxy-3- methylglutaryl coenzyme A reductase) inhibitor
  • atorvastatin calcium . hydrate pravastatin sodium, simvastatin, itavastatin, lovastatin, fluvastatin, etc.
  • 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.
  • 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 ⁇ - 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, G
  • 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 als.o used in combination with, for example, gene therapy involving VEGF, TNF ⁇ 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.).
  • 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,
  • 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.
  • 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.
  • excipient examples include lactose, white sugar, D- mannitol, starch, corn starch, crystalline cellulose, light silicic anhydride and the like.
  • gliding agent examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binding agent examples include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.
  • disintegrant examples include starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.
  • dissolution aid examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples 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.
  • preservative examples include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfites, ascorbic acid, ⁇ -tocopherol and the like.
  • the colorant examples 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., ⁇ -carotene, chlorophyll, red iron oxide) and the like.
  • the sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • Reverse-phase HPLC analysis was carried out on an YMC CombiPrep ODS-A (20 mmID x 50 mmL, S-5 ⁇ m) 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.
  • 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. l]nonane,
  • BINAP 2, 2' -bis (diphenylphosphino) -1,1' -binaphthyl
  • DAST (diethylamino) sulfur trifluoride
  • DBU 1, 8-diazabicyclo [5.4.0] -7-undecene
  • DMAP 4- (dimethylamino) pyridine, dppf: 1, V -bis (diphenylphosphino) ferrocene, DTBAD: di-tert-butyl azodicarboxylate,
  • HATU 0-(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(O) ,
  • 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.
  • 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.
  • 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.
  • Reference Example 25 Ethyl 1- [ (IR, 2R) -2-aminocyclohexyl] -5-phenyl-1H-imidazole-4- carboxylate
  • 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.
  • 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 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.

Abstract

The present invention relates to a compound represented by the formula: wherein each symbol is as defined in the description, or a salt thereof or a prodrug thereof. The compound of the present invention has a 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.

Description

DESCRIPTION
SUBSTITUTED IMIDAZOLE COMPOUND AND USE THEREOF 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 the 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 (All) , which is a major vasopressor factor, and takes an important role in the control of the blood pressure and the amount of body fluid. All exhibits a strong vasoconstrictive effect brought by the intervention of All 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 All 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 All action is broadly- classified into methods of inhibiting the biosynthesis of All and methods of inhibiting the binding of All to All receptors. For the drugs inhibiting the biosynthesis of All, 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 All 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 All to All receptors, All type 1 receptor blockers (ARB) have been developed. ARB has a merit in that it can inhibit, at the receptor level, the action of All 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 All 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:
(I)
Figure imgf000004_0001
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-S 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-I4 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:
Figure imgf000005_0001
wherein R1 is as defined above;
[8] a compound represented by the formula:
Figure imgf000006_0001
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] (lS,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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5- difluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate or a salt thereof;
[11] (IS, 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] (IS, 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 [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyl)piρerazin- 1-yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) cyclohexyl] carbamate or a salt thereof;
[14] (lS,2R)-2-{4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol or a salt thereof; [15] (IS, 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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (2-anilinoethyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate or a salt thereof;
[17] (IS, 2R)-I- (Methoxymethyl) -2- (4-{ [ (2R) -2- (2- morpholinobenzyl)piperazin-1-yl] carbonyl}-5-phenyi-1H-imidazol-- 1-yl) cyclohexanol or a salt thereof;
[18] (lS,2R)-2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) -1-methylcyclohexanol or a salt thereof; [19] (IS, 2R)-I- (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] (IS, 2R)-I- (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] (IS, 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] (lS,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] l-[ (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 [I]; [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, propyTidene, isopropylidene and the like.
Examples of the "C3-10 cycloalkyl" in the present specification include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2. l]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. l]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 (xiϋ) 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-i4 aryl (e . g . , phenyl) ,
(d) C1-6 alkoxy,
( e) Cχ-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-I4 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-I4 aryl (e . g. , phenyl) , (d) Ci_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, (iϋ) 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,
(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 Ce-n 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-g 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_i3 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-S 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, (ϋi) 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-s 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-Io cycloalkyloxy optionally condensed with a benzene ring (e.g., cyclohexyloxy, tetrahydronaphthyloxy, indanyloxy) optionally having oxo;
(18) C7-I3 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) Ci_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, (xϋ) 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-Ci_6 alkyl,
(v) mono- or di-C1-6 alkylamino-Ci_6 alkyl (e.g., dimethylaminomethyl) , ' (vi) C5-10 aryl (e.g., phenyl),
(vii) C3-10 cycloalkyl,
(viii) Ci_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) C7-2o 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) Ce-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-S alkyl-carbonyloxy (e.g., acetyloxy, tert- . butylcarbonyloxy) ,
(vii) amino,
(viii) carbamoyl optionally mono- or di-substituted by C1-S ■ 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) Cβ-u 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, (ϋi) 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 Ce-u aryl and the like. Examples of the "aromatic heterocyclic group" include a 4- to 7-membered (preferably 5- or β-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-I0 cycloalkadienyl, each of which is optionally condensed with a benzene ring, and the like. Examples of the λΛnon-aromatic heterocyclic group" include a 4- to 7-membered (preferably 5- or β-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., l,l-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-Io 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) , C6-13 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-I0 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 substifuent 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 C6-13 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) , C3-13 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-I0 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 "acyl" in the present specification include a group represented by the formula: -C0RA, -C0-0RA, -SO2RA, -SORA, -C0-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_i3 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_i3 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_i3 aralkyl optionally having substituent (s) (e.g., a halogen atom, C1-6 alkyl optionally having substituent (s) , Cχ-e 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,
0) 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 β-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_io aryl (e . g . , phenyl) ,
(c) C3_6 cycloalkyl-carbonyl,
(d) C6-Io aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and Ci_6 alkoxy,
(e) C1-6 alkoxy-carbonyl-Ci_6 alkyl-carbonyl, and (f) carbamoyl-C1-6 alkyl-carbonyl, (v) a 5- or β-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 (vi±i) a 5- or 6-membered aromatic heterocyclic grqup (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,
0) 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 β-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 Ci-e 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) Cδ-io aryl-carbonyl optionally having 1 to 3 substituents selected from a halogen atom and C1-6 alkoxy, (h) Ci_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,
0) 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 β-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 β-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-I0 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, dihydrόbenzoxazinyl, 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 Cβ-u 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, ethpxy, 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., 0, 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, -X3--NH-X2-, -X3--O-X2- and -X3--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 X3- 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. l]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-I0 cycloalkane, C3-10 cycloalkene, C4-10 cycloalkadiene or a heterocycle. Examples of the "C3-10 cycloalkane", "C3-I0 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 "Cs_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 Cs_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 β-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-meinbered aromatic heterocyclyl-C1-6 alkyl (e.g., furfuryl) and C1-6 alkylsulfonyl-C1-6 alkyl, and
(xvi) a 5- or 6-meinbered 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., l-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, (iϋ) 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., l-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:
Figure imgf000054_0001
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, Cχ-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:
Figure imgf000055_0001
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-β- 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:
Figure imgf000056_0001
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-I, 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_i3 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, C5-10 aryl (e.g., phenyl), etc.); and ring A is
(a) Cs-η 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'-l]
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-β-yl) , indazolyl (e.g., 1H-indazol-5-yl, 1H- indazol-β-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:
Figure imgf000059_0001
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-meπibered non-aromatic heterocyclic group (e.g., morpholinyl) ;
(2) C3-10 cycloalkyl-C1-6 alkyl (e.g., cyclopropylmethyl, cyclohexylinethyl) 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, 0) 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 β-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 C1-5 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) , (iϋ) C6-Io 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) Cε-io 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., l-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) C5-10 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 β-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 β-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-s 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, Cx_6 alkoxy-carbonyl and mono- or di-C1-6 alkylamino,
D) optionally halogenated C1-6 alkoxy (e.g., methoxy, trifluoromethoxy, ethoxy, isopropoxy, difluoromethoxy) , E) Ci_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,
0) optionally halogenated C1-6 alkylsulfonyl (e.g., methylsulfonyl, trifluoromethylsulfonyl) , P) a 5- or β-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) Ce-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 β-membered heterocyclic group (e.g., pyrazolyl, piperidinyl, dihydropyridyl) optionally having 1 or 2 oxo, (c) C3-S cycloalkyl optionally condensed with a benzene ring (e.g., cyclopropyl, cyclohexyl, indanyl) ,
(d) C7-13 aralkyl (e.g., benzyl),
(e) C1S 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., iηdolyl, 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., l-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-s 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) Ce-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 β-meinbered 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-I3 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 β-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-meπibered 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,
0) 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_!o 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-S 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) Ci_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_i3 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 C±-β alkyl and oxo, (vii) a 5- or β-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, dihydrobenzoxaz.inyl, tetrahydroquinolyl, tetfahydroisoquinolyl) 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 Ce-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., l-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' Cχ~β 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 β-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 β-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 β-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_i3 aralkyl (e.g., benzyl),
(ii) C1-6 alkyl optionally having 1 to 3 substituents selected from C1-6 alkoxy and Cχ-ς 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-g 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 β-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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5-difluorobenzyDpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, (lS,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,
(lS,2R)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1-methylcyclohexanol dihydrochloride, (IS, 2R)-I- (methoxymethyl) -2-{ 4- [ ( (2R)-2-{2-[ (4-methoxy-2- methylphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol.-1-yl} cyclohexanol,
(IS, 2R)-I- (methoxymethyl) -2-{ 4- [ ( (2R)-2-{2-[ (5-methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol, (lS,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,
(IS, 2R) -2- [4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5- (3- fluorophenyl) -1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol, (IS, 2R)-I- (methoxymethyl) -2-{ 4- [( (2R)-2-{2-[ (2- methylphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol, (IS, 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, (lS,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,
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (2-fluorophenyl) amino] ethyl}piperazin- 1-yl) carbonyl] -5-phenyl-1H-imidazol-1-yl}-1- (methoxymethyl) cyclohexanol,
(IS, 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, (IS, 2R)-I- (methoxymethyl) -2-{ 4- [ ( (2R)-2-{2-[ (4- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol,
(IS, 2R)-I- (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, (lS,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, (lS,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, (IS, 2R)-I- (methoxymethyl) -2- (4-{ [ (2R) -2- (2- morpholinobenzyl) piperazin-1-yl] carbonyl} -5-phenyl-1H-imidazol- 1-yl) cyclohexanol, (lS,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, (IS, 2R) -1- (methoxymethyl) -2-{4- [ ( (2R) -2-{2- [ (2- methoxyphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol,
(IS, 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, (IS, 2R)-I- (methoxymethyl) -2-{ 4- [ ( (2R) -2-{2- [ (3- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol,
(lS,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 [ (IS, 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 (lS,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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5-difluorobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, (IS, 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, (IS, 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 [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyDpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, ethyl [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyl)piperazin-1- yl.] carbonyl } -5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate malonate,
(lS,2R)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl }-5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol dihydrochloride, (lS,2R)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl }-5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol fumarate, (IS, 2R) -2- [4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5- (3- fluorophenyl) -1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol, methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (2-anilinoethyl) piperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, (IS, 2R) -1- (methoxymethyl) -2- (4-{ [ (2R) -2- (2- morpholinobenzyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol- 1-yl) cyclohexanol,
(IS, 2R) -2- (4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1-methylcyclohexanol dihydrochloride,
(IS, 2R)-I- (methoxymethyl) -2- { 4- [ ( (2R) -2-{2- [ (3- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol,
(IS, 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,
(IS, 2R)-I- (methoxymethyl) -2-{ 4- [ ( (2R)-2-{2-[ (5-methoxy-2- methylphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl }cyclohexanol, (lS,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, l-[ (4-{ [ (2R) -2- (2-anilinoethyl) piperazin-1-yl] carbonyl} -5- phenyl-1H-imidazol-1-yl) methyl] cyclohexanol, (IS, 2R)-I- (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,
(IS, 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,
(lS,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 ( (lR,2R)-2-{4-[ ( (2R) -2-{2- [ (2-fluoro-3- methoxyphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexyl) carbamate,
(lS,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 [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyDpiperazin-1- yl] carbonyll-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, 4-{ [ (2R) -1- ( { 1- [ (IR, 2R) -2- (cyclopropylmethyl) -2- hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl]methyl }benzonitrile, isopropyl' [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5-difluorobenzyl)piperazin- 1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate, isopropyl [ (IS, 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
(IS, 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, methanesμlfonic 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. (Reaction 1)
Figure imgf000085_0001
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. (Reaction 2) hydrolysis
Figure imgf000086_0002
Figure imgf000086_0001
(IV) (V)
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. . (Reaction 3)
Figure imgf000087_0001
(VII)
deprotection
Figure imgf000087_0002
(I) 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, C7-2o 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 KA1HATSU (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 All, 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 a, 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, Deame.lin 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 als.o 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 x 35 mmL, 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 x 50 mmL, 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. l]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, V -bis (diphenylphosphino) ferrocene, DTBAD: di-tert-butyl azodicarboxylate,
HATU: 0-(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(O) ,
TBAF: tetra-n-butylammonium fluoride,
TFA: trifluoroacetic acid,
WSC-HCl: l-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride . Reference Example 1
Ethyl 2- (formylamino) -3-phenylacrylate
Figure imgf000103_0001
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
Figure imgf000103_0002
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
Figure imgf000104_0001
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 l-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylate
Figure imgf000105_0001
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+l) Reference Example 5
Methyl 1- [ (IS, 2S) -2- (benzyloxy) cyclohexyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000105_0002
(IS, 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- [ (IR, 2R) -2- (benzyloxy) cyclohexyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000106_0001
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
Figure imgf000106_0002
1H-NMR (CDCl3) 5 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 l-cyclopentyl-5-phenyl-1H-imidazole-4-carboxylate
Figure imgf000107_0001
1H-NMR (CDCl3) δ 1.53-1.70 (2H, m) , 1.75-1.91 (4H, in), 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 l-cycloheptyl-5-phenyl-1H-imidazole-4-carboxylate
Figure imgf000107_0002
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
Figure imgf000107_0003
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- [ (IR, 2R) -2- (benzyloxy) cyclopentyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000108_0001
1H-NMR (CDCl3) δ 1.67-1.87 (4H, m) , 1.95-2.09 (2H, m) , 2.13-2.21 (1H, in), 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+l) Reference Example 12
Methyl 1- [ (2R) -bicyclo [2.2.1] hept-2-yl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000108_0002
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+l) Reference Example 13
Methyl 1- [bicyclo [2.2.1] hept-2-yl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000109_0001
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+l) Reference Example 14
Methyl 1- [cis-2- (hydroxymethyl) cyclohexyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000109_0002
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, in), 7.32-7.41 (2H, m) , 7.41-7.54 (3H, m) , 7.71 (1H, s)
Reference Example 15
Ethyl 1- [ (IS, 2R) -2-hydroxycyclohexyl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000109_0003
(IR, 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 i5, the following compounds (Reference Examples 16 - 20) were obtained.
Reference Example 16 ' Ethyl l-[ (lS,2S)-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000110_0001
MS (ESI+, m/e) 315 (M+l) Reference Example 17
Ethyl 1- (cis-2-hydroxycyclohexyl) -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000111_0001
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- [ (IS) -1- (1-hydroxycyclohexyl) ethyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000111_0002
' 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
Figure imgf000111_0003
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
Figure imgf000112_0001
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- carboxylase
Figure imgf000112_0002
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+l) Reference Example 22
Ethyl 1- [ (1-hydroxycyclohexyl) methyl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000113_0001
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+l) Reference Example 23 Ethyl l-{ (IS, 2S) -2- [ (tert-butoxycarbonyl) amino] cyclohexyl}-5- phenyl-1H-imidazole-4-carboxylate
Figure imgf000114_0001
tert-Butyl [ (IS, 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)f 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- [ (IS, 2S) -2-aminocyclohexyl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000114_0002
(lS,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- [ (IR, 2R) -2-aminocyclohexyl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000115_0001
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
Figure imgf000116_0001
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, in) , 7.84 (1H, s) Reference Example 27
4- (4-Oxocyclohexyl)morpholin-3-one
Figure imgf000116_0002
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
Figure imgf000116_0003
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
Figure imgf000117_0001
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 l-{ [cis-1-hydroxy-4- (3-oxomorpholino) cyclohexyl]methyl} -5- phenyl-1H-imidazole-4-carboxylate
Figure imgf000118_0001
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 elμted 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 (HH, 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- [ (IS, 2S) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylate
Figure imgf000119_0001
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 (IS, 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+l)
In the same manner as in Reference Example 31, the following compounds (Reference Examples 32 - 38) were obtained. Reference Example 32
Methyl l-[ (IS, 2S) -2-aminocyclohexyl] -5- (3-fluorophenyl) -1H- imidazole-4-carboxylate
Figure imgf000121_0001
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, in) , 7.44-7.50 (1H, m) , 7.69 (1H, s) Reference Example 33 Methyl 1, 5-dicyclohexyl-1H-imidazole-4-carboxylate
Figure imgf000121_0002
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 l-cyclohexyl-5-cyclopropyl-1H-imidazole-4-carboxylate
Figure imgf000121_0003
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- [ (IS, 2R) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylate
Figure imgf000122_0001
MS (ESI+, m/e) 333 (M+l) Reference Example 36 Ethyl 5-(3,5-difluorophenyl)-1-[ (IS, 2R) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylate
Figure imgf000122_0002
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- [ (IS, 2S) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylate
Figure imgf000122_0003
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- [ (IS, 2S) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylate
Figure imgf000123_0001
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 l-{ (IS, 2S) -2- [ (ethoxycarbonyl) amino] cyclohexyl}-5-phenyl- 1H-imidazole-4-carboxylate
Figure imgf000123_0002
Ethyl l-[ (IS, 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 l-{ (IS, 2S) -2- [ (methoxycarbonyl) amino] cyclohexyl}-5-phenyl- 1H-imidazole-4-carboxylate
Figure imgf000124_0001
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 l-{ (IR, 2R) -2- [ (ethoxycarbonyl) amino] cyclohexyl }-5-phenyl- 1H-imidazole-4-carboxylate
Figure imgf000124_0002
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 l- { cis-2- [ (ethoxycarbonyl) amino] cyclohexyl } -5-phenyl-1H- iitιidazole-4-carboxylate
Figure imgf000125_0001
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-{ (IS, 2S) -2- [ (methoxycarbonyl) amino] cyclohexyl}-1H-imidazole-4-carboxylate
Figure imgf000125_0002
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 l-{ (IS, 2S) -2- [ (ethoxycarbonyl) amino] cyclohexyl}-5- (3- fluorophenyl) -1H-imidazole-4-carboxylate
Figure imgf000125_0003
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 l-{ (IS, 2S) -2- [ (methylsulfonyl) oxy] cyclohexyl}-5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000126_0001
Ethyl l-[ (lS,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- [ (IS, 2R) -2-azidocyclohexyl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000127_0001
A solution of ethyl l-{ (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 l-[ (lS,2R)-2-fluorocyclohexyl]-5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000127_0002
A solution of ethyl l-{ (IS, 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- [ (IS, 2R) -2-aminocyclohexyl] -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000128_0001
Ethyl 1- [ (IS, 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) δθ.98 (2H, br s) , 1.20-1.88 (1OH, 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 l-( (IS, 2R) -2-{ [ (benzyloxy) carbonyl] amino}cyclohexyl) -5- phenyl-1H-imidazole-4-carboxylate
Figure imgf000129_0001
Ethyl 1- [ (IS, 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) δl.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 (1OH, m) , 7.58 (1H, s)
Reference Example 50
Ethyl 1- (2-oxocyclohexyl) -5-phenyl-1H-imidazole-4-carboxylate
Figure imgf000129_0002
Ethyl 1- [ (IS, 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) δl.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
Figure imgf000130_0001
MS (ESI+, m/e) 331 (M+l) 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
Figure imgf000130_0002
(retention time: long) (retention time: short)
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) δl.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 IDx500 mmL 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
Figure imgf000132_0001
MS (ESI+, m/e) 344 (M+l) MS (EΞI+, m/e) 344 (M+l) Reference Example 54 Ethyl l-{2-[ (benzylamino) methyl] -2-hydroxycyclohexyl}-5-phenyl- 1H-imidazole-4-carboxylate
Figure imgf000132_0002
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) δl.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
Figure imgf000133_0001
Ethyl l-{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) δl.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 l-( (lS,2R)-2-hydroxy-2-{ [3- (methylthio)propoxy]methyl }cyclohexyl) -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000134_0001
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 IN 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+l) Reference Example 57
Ethyl 1- (2-methylenecyclohexyl) -5-phenyl-1H-imidazole-4- carboxylate
Figure imgf000134_0002
Ethyl 1- (2-oxocyclohexyl) -5-pher.yl-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) 51.24 (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
Figure imgf000135_0001
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 l-cyclohexyl-2-oxo-5-phenyl-2, 3-dihydro-1H-imidazole-4- carboxylate
Figure imgf000136_0001
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, itι) , 4.10 (2H, q) , 7.26-7.37 (2H, m) , 7.47 (2Hf d) , 7.42-7.51 (1H, m) , 8.87 (1H, br s) MS (ESI+, m/e) 315 (M+l) Reference Example 60 ' Ethyl l-cyclohexyl-2-ethoxy-5-phenyl-1H-imidazole-4-carboxylate
Figure imgf000137_0001
Ethyl l-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 (IM 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+l)
Reference Example 61 Ethyl 2-chloro-l-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylate
Figure imgf000138_0001
A mixture of ethyl l-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+l) Reference Example 62 Ethyl 3- [ (trans-2-hydroxycyclohexyl) amino] -2-nitro-3- phenylacrylate
Figure imgf000138_0002
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+l) Reference Example 63 Ethyl 1- (trans-2-hydroxycyclohexyl) -2-methyl-5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000139_0001
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+l)
Reference Example 64
1- [ (IS, 2S) -2- (Benzyloxy) cyclohexyl] -5-phenyl-1H-imidazole-4- carboxylic acid
Figure imgf000140_0001
Methyl 1- [ (IS, 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) 6 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) , 1.39-1.41 (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- [ (IR, 2R) -2- (Benzyloxy) cyclohexyl] -5-phenyl-1H-imidazole-4- carboxylic acid
Figure imgf000140_0002
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- [ (IR, 2R) -2- (Benzylόxy) cyclopentyl] -5-phenyl-1H-imidazole-4- carboxylic acid
Figure imgf000141_0001
A mixture of methyl 1- [ (IR, 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 IN 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+l) 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
Figure imgf000141_0002
MS (ESI+, m/e) 283. (M+l) Reference Example 68
1- [Bicyclo [2.2.1] hept-2-yl] -5-phenyl-1H-imidazole-4-carboxylic acid
Figure imgf000142_0001
MS (ESI+, m/e) 283 (M+l) Reference Example 69 l-Cyclohexyl-2-ethoxy-5-phenyl-1H-imidazole-4-carboxylic acid
Figure imgf000142_0002
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+l) Reference Example 70 2-Chloro-1-cyclohexyl-5-phenyl-1H-imidazole-4-carboxylic acid
Figure imgf000142_0003
1H-NMR (DMSO-de) 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+l) Reference Example 71
1- [ (IS, 2R) -2-Azidocyclohexyl] -5-phenyl-1H-imidazole-4-carboxylic acid
Figure imgf000143_0001
A solution of ethyl 1- [ (IS, 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 IN hydrochloric acid. The precipitated crystals were collected by filtration, and dried to give the object compound (1.86 g) .
1H-NMR (DMSO-de) 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 l-{ (IS, 2S) -2- [ (Methoxycafbonyl) amino] cyclohexyl} -5-phenyl-1H- imidazole-4-carboxylic acid.
Figure imgf000143_0002
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 l-{ (IS, 2S) -2- [ (Ethoxycarbonyl) amino] cyclohexyl}-5-phenyl-1H- imidazole-4-carboxylic acid
Figure imgf000144_0001
1H-NMR (DMS0-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 l-{ (IS, 2R) -2- [ (Ethoxycarbonyl) amino] cyclohexyl}-5-phenyl-1H- imidazole-4-carboxylic acid
Figure imgf000144_0002
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 l-[ (lS,2R)-2-Fluorocyclohexyl] -5-phenyl-1H-imidazole-4- carboxylic acid
Figure imgf000144_0003
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- [ (IS, 2R) -2-Hydroxycyclohexyl] -5-phenyl-1H-imidazole-4- carboxylic acid
Figure imgf000145_0001
Ethyl 1- [ (IS, 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 IN 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+l) Reference Example 77 5- (3-Fluorophenyl) -1- [ (IS, 2S) -2-hydroxycyclohexyl] -1H-imidazole- 4-carboxylic acid
Figure imgf000145_0002
Methyl 5- (3-fluorophenyl) -1- [ (IS, 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 IN 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
Figure imgf000146_0001
1H-NMR (DMSO-d6) δ 1.11-2.14 (2OH, m) , 3.10-3.33 (1H, m) , 4.04- 4.23 (1H, m) , 8.08 (1H, s) Reference Example 79 l-Cyclohexyl-3-cyclopropyl-1H-imidazole-4-carboxylic acid
Figure imgf000146_0002
(DMSO-d6) δ 0.61 (2H, br s) , 0.87 (2H, d) , 1.07-2.02 (HH, m) , 4.08 (1H, br s) , 4.90 (1 H, br s) , 7.33 (1 H, br s) Reference Example 80
5- (3-Fluorophenyl) -1-[ (IS, 2R) -2-hydroxycyclohexyl] -1H-imidazole- 4-carboxylic acid
Figure imgf000147_0001
MS (ESI+, m/e) 305 (M+l) Reference Example 81
5- (3, 5-Difluorophenyl) -1- [ (IS, 2R) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylic acid
Figure imgf000147_0002
MS (ESI+, m/e) 323 (M+l) Reference Example 82 5- (2, 3-Difluorophenyl) -1- [ (IS, 2S) -2-hydroxycyclohexyl] -1H- imidazole-4-carboxylic acid
Figure imgf000147_0003
MS (ESI+, m/e) 323 (M+l) Reference Example 83
5-(4-Fluorophenyl) -1- [ (IS, 2S) -2-hydroxycyclohexyl] -1H-imidazole- 4-carboxylic acid
Figure imgf000148_0001
MS (ESI+, m/e) 305 (M+l) Reference Example 84
1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazole-4-carboxylic acid
Figure imgf000148_0002
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-de) 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- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -1H-imidazole-4-carboxylic acid
Figure imgf000149_0001
MS (ESI+, m/e) 349 (M+l)
Reference Example 86
Ethyl N- (tert-butoxycarbonyl) -2-fluoro-D-phenylalanyl-N- benzylglycinate
Figure imgf000149_0002
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+l-"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
Figure imgf000150_0001
MS (ESI+, m/e) 359 (M+l-"Boc") Reference Example 88
Ethyl N- (tert-butoxycarbonyl) -4-fluoro-D-phenylalanyl-N- benzylglycinate
Figure imgf000150_0002
MS (ESI+, m/e) 359 (M+l-"Boc")
Reference Example 89
Ethyl N- (tert-butoxycarbonyl) -3, 4-difluoro-D-phenylalanyl-N- benzylglycinate
Figure imgf000150_0003
MS (ESI+, m/e) 377 (M+l-"Boc") Reference Example 90
Ethyl N- (tert-butoxycarbonyl) -3, 5-difluoro-D-phenylalanyl-N- benzylglycinate
Figure imgf000151_0001
MS (ESI+, m/e) 377 (M+l-λΛBoc") Reference Example 91
Ethyl N- (tert-butoxycarbonyl) -2, 4, 5-trifluoro-D-phenylalanyl-N- benzylglycinate
Figure imgf000151_0002
MS (ESI+, m/e) 395 (M+l-"Boc") Reference Example 92 ' Ethyl N- (tert-butoxycarbonyl) -2- (trifluoromethyl) -D- phenylal.anyl-N-benzylglycinate
Figure imgf000151_0003
MS (ESI+, m/e) 409 (M+l-"Boc") Reference Example 93
Ethyl N- (tert-butoxycarbonyl) -3- (trifluoromethyl) -D- phenylalanyl-N-benzylglycinate
Figure imgf000152_0001
MS (ESI+, m/e) 409 (M+l-"Boc") Reference Example 94
Ethyl N- (tert-butoxycarbonyl) -4- (trifluoromethyl) -D- phenylalanyl-N-benzylglycinate
Figure imgf000152_0002
MS (ESI+, m/e) 409 (M+l-"Boc") Reference Example 95 Ethyl N- (tert-butoxycarbonyl) -O-methyl-D-tyrosyl-N- benzylglycinate
Figure imgf000152_0003
MS (ESI+, m/e) 371 (M+l-"Boc") Reference Example 96
Ethyl 4-bromo-N- (tert-butoxycarbonyl) -D-phenylalanyl-N- benzylglycinate
Figure imgf000153_0001
MS (ESI+, m/e) 519 (M+l) Reference Example 97
Ethyl N-benzyl-N- [ (2R) -2- [ (tert-butoxycarbonyl) amino] -2- (2,3- dihydro-1H-inden-2-yl) acetyl] glycinate
Figure imgf000153_0002
-"Boc") Reference Example 98 Ethyl N- (tert-butoxycarbonyl) -4-methyl-D-leucyl-N- benzylglycinate
Figure imgf000153_0003
MS (ESI+, m/e) 421 (M+l) Reference Example 99
Ethyl N- (tert-butoxycarbonyl) -D-leucyl-N-benzylglycinate
Figure imgf000154_0001
MS (ESI+, m/e) 307 (M+l-λΛBoc") Reference Example 100
Ethyl N- (tert-butoxycarbonyl) -3-cyclohexyl-D-alanyl-N- benzylglycinate
Figure imgf000154_0002
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, in), 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
Figure imgf000154_0003
1H-NMR (CDCl3) δ 1.11-1.52 (12H, in) , 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 (1OH, m)
Reference Example 102
Ethyl N- (tert-butoxycarbonyl) -3- (pyridin-3-yl) -D-alanyl-N- benzylglycinate
Figure imgf000155_0001
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+l)
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
Figure imgf000155_0002
MS (ESI+, m/e) 442 (M+l) Reference Example 104
Ethyl N- (tert-butoxycarbonyl) -3- (pyridin-4-yl) -D-alanyl-N- benzylglycinate
Figure imgf000156_0001
MS (ESI+, m/e) 442 (M+l)
Reference Example 105
Ethyl N- (tert-butoxycarbonyl) -D-tryptophyl-N-benzylglycinate
Figure imgf000156_0002
MS (ESI+, m/e) 480 (M+l)
Reference Example 106
Ethyl N- (tert-butoxycarbonyl) -D-histidyl-N-benzylglycinate
Figure imgf000156_0003
MS (ESI+, m/e) 431 (M+l) Reference Example 107
Ethyl N- (tert-butoxycarbonyl) -2, 4-dichloro-D- phenylalanylglycinate
Figure imgf000157_0001
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+l-"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
Figure imgf000157_0002
MS (ESI+, m/e) 358.(M+l) Reference Example 109 .
(3R) -1-Benzyl-3- (2-fluorobenzyl) piperazine-2, 5-dione
Figure imgf000158_0001
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+l)
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
Figure imgf000159_0001
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+l) Reference Example 111 (3R) -1-Benzyl-3- (4-fluorobenzyl) piperazine-2, 5-dione
Figure imgf000159_0002
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+l) Reference Example 112 (3R) -1-Benzyl-3- (3, 4-difluorobenzyl) piperazine-2, 5-dione
Figure imgf000159_0003
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+l) Reference Example 113 (3R) -1-Benzyl-3- (3, 5-difluorobenzyl) piperazine-2, 5-dione
Figure imgf000160_0001
1H-NMR (CDCl3) δ 3.11-3.23 (2H, m) , 3.38 (1H, d) , 3.68 (1H, d) , 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+l) Reference Example 114 (3R) -1-Benzyl-3- (2,4, 5-trifluorobenzyl) piperazine-2, 5-dione
Figure imgf000160_0002
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+l)
Reference Example 115 (3R) -1-Benzyl-3- [2- (trifluoromethyl) benzyl] piperazine-2, 5-dione
Figure imgf000160_0003
MS (ESI+, m/e) 363 (M+l) Reference Example 116 (3R) -1-Benzyl-3- [3- (trifluoromethyl) benzyl]piperazine-2, 5-dione
Figure imgf000161_0001
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+l) Reference Example 117 (3R) -1-Benzyl-3- [4- (trifluoromethyl) benzyl] piperazine-2, 5-dione
Figure imgf000161_0002
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+l)
Reference Example 118
(3R) -1-Benzyl-3- (4-methoxybenzyl) piperazine-2, 5-dione
Figure imgf000161_0003
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, rα) , 7.29-7.34 (3H, m) MS (ESI+, m/e) 325 (M+l) Reference Example 119 (3R) -1-Benzyl-3- (4-bromobenzyl)piperazine-2, 5-dione
Figure imgf000162_0001
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, iti) , 7.27-7.36 (5H7 m)
MS (ESI+, m/e) 373 (M+l)
Reference Example 120
(3R) -l-Benzyl-3- (2, 3-dihydro-1H-inden-2-yl)piperazine-2, 5-dione
Figure imgf000162_0002
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+l) Reference Example 121
(3R) -l-Benzyl-3- (2, 2-dimethylpropyl)piperazine-2, 5-dione
Figure imgf000163_0001
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+l)
Reference Example 122 (3R) -l-Benzyl-3-isobutylpiperazine-2, 5-dione
Figure imgf000163_0002
MS (ESI+, m/e) 261 (M+l) Reference Example 123 (3R) -1-Benzyl-3- (cyclohexylmethyl)piperazine-2, 5-dione
Figure imgf000163_0003
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
Figure imgf000164_0001
1H-NMR (DMSO-de) 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
Figure imgf000164_0002
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+l)
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
Figure imgf000165_0001
MS (ESI+, m/e) 296 (M+l) Reference Example 127
(3R) -1-Benzyl-3- (pyridin-4-ylmethyl)piperazine-2, 5-dione
Figure imgf000165_0002
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+l)
Reference Example 128 (3R) -1-Benzyl-3- (1H-indol-3-ylmethyl) piperazine-2, 5-dione
Figure imgf000165_0003
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, in), 7.13-7.27 (5H, m) , 7.37 (1H, d) , 7.64 (1H, d), 8.21 (1H, s) MS (ESI+, m/e) 334 (M+l)
Reference Example 129 (3R)-l-Benzyl-3- (1H-imidazol-4-ylmethyl)piperazine-2, 5-dione
Figure imgf000166_0001
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+l) Reference Example 130
(3R) -3- (2, 4-Dichlorobenzyl) piperazine-2, 5-dione
Figure imgf000166_0002
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+l) Reference Example 131 (3R) -3- (1, 3-Thiazol-4-ylmethyl) piperazine-2, 5-dione
Figure imgf000167_0001
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+l) Reference Example 132 Benzyl 3- [ (2R) -4-benzyl-3, 6-dioxopiperazin-2-yl] propionate
Figure imgf000168_0001
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+l) Reference Example 133 (3R) -1-Benzyl-3- (2-fluorobenzyl) piperazine
Figure imgf000169_0001
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 IN 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+l)
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
Figure imgf000170_0001
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+l) Reference Example 135 (3R) -1-Benzyl-3- (4-fluorobenzyl) piperazine
Figure imgf000170_0002
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+l)
Reference Example 136 (3R) -1-Benzyl-3- (3, 4-difluorobenzyl) piperazine
Figure imgf000170_0003
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+l)
Reference Example 137
(3R) -l-Benzyl-3- (2, 4, 5-trifluorobenzyl) piperazine
Figure imgf000171_0001
MS (ESI+, m/e) 321 (M+l) Reference Example 138 (3R) -1-Benzyl-3- [2- (trifluoromethyl) benzyl] piperazine
Figure imgf000171_0002
MS (ESI+, m/e) 335 (M+l)
Reference Example 139
(3R) -1-Benzyl-3- [3- (trifluoromethyl) benzyl] piperazine
Figure imgf000171_0003
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+l) Reference Example 140 (3R) -1-Benzyl-3- [4- (trifluoroitiethyl) benzyl] piperazine
Figure imgf000172_0001
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+l) Reference Example 141 (3R) -1-Benzyl-3- (4-methoxybenzyl) piperazine
Figure imgf000172_0002
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+l) Reference Example 142 ( 3R) -l-Benzyl-3- ( 2 , 3-dihydro-1H-inden-2-yl ) piperazine
Figure imgf000172_0003
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+l) • Reference Example 143
(3R) -1-Benzyl-3- (2, 2-dimethylpropyl)piperazine
Figure imgf000173_0001
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+l) Reference Example 144 (3R) -1-Benzyl-3-isobutylpiperazine
Figure imgf000173_0002
MS. (ESI+, m/e) 233 (M+l)
Reference Example 145
(3R) -1-Benzyl-3- (cyclohexylmethyl) piperazine
Figure imgf000173_0003
MS (ESI+, m/e) 273 (M+l) Reference Example 146 4-{ [ (2R) -4-Benzylpiperazin-2-yl]methyl }phenol
Figure imgf000174_0001
1H-NMR (DMSO-de) 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+l) Reference Example 147 (3R) -1-Benzyl-3- (3, 5-difluorobenzyl) piperazine
Figure imgf000174_0002
(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+l)
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
Figure imgf000175_0001
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+l) Reference Example 149 (3R) -1-Benzyl-3- (pyridin-4-ylmethyl) piperazine
Figure imgf000175_0002
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+l) Reference Example 150
3-{ [ (2R) -4-Benzylpiperazin-2-yl]methyl}-1H-indole
Figure imgf000176_0001
MS (ESI+, m/e) 306 (M+l) Reference Example 151 (3R) -1-Benzyl-3- (1H-imidazol-4-ylmethyl) piperazine
Figure imgf000176_0002
1H-NMR (CDCl3) δ 1.83 (1H, t) , 2.06 (1H, dt) , 2.56 (1H, dd) , 2.64-3.07 (7H, in), 3.48 (2H, s) , 6.76 (1H, s) , 7.21-7.33 (6H, m) , 7.44 (1H, s)
' MS (ESI+, .m/e) 257 (M+l) Reference Example 152 (3R) -1-Benzyl-3- (4-bromobenzyl) piperazine
Figure imgf000176_0003
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+l) Reference Example 153
(3R) -1-Benzyl-3- (pyridin-3-ylmethyl) piperazine
Figure imgf000177_0001
(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+l) Reference Example 154
(2R) -2- (2, 4-Dichlorobenzyl) piperazine
Figure imgf000178_0001
(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-h, m/e) 245 (M+l)
Reference Example 155 tert-Butyl (3R) -3- (2, 4-dichlorobenzyl) piperazine-1-carboxylate
Figure imgf000178_0002
A mixture of (2R) -2- (2, 4-dichlorobenzyl) piperazine (1.08 g) , tert-butanol (20 ml) , water (15 ml) and IN 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+l) Reference Example 156 tert-Butyl (3R) -3- (1, 3-thiazol-4-ylmethyl) piperazine-1- carboxylate
Figure imgf000179_0001
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 IN 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+l) Reference Example 157 tert-Butyl (2R) -4-benzyl-2- (4-bromobenzyl) piperazine-1- carboxylate
Figure imgf000180_0001
(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) .
1H7NMR (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+l)
Reference Example 158 tert-Butyl (2R) -4-benzyl-2- (4-morpholinobenzyl) piperazine-1- carboxylate
Figure imgf000181_0001
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+l) Reference Example 159
4-.(4-{ [ (2R) -4-Benzylpiperazin-2-yl]methylIphenyl) morpholine
Figure imgf000181_0002
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+l) Reference Example 160
Di-tert-butyl (2R) -2- (4-hydroxybenzyl)piperazine-l, 4- dicarboxylate
Figure imgf000182_0001
4-{ [ (2R) -4-Benzylpiperazin-2-yl]methyllphenol (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+l) Reference Example 161 Di-tert-butyl (2R) -2- (4-
{ [ (trifluoromethyl) sulfonyl] oxy}benzyl)piperazine-l, 4- dicarboxylate
Figure imgf000183_0001
Di-tert-butyl (2R) -2- (4-hydroxybenzyl)piperazine-l, 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+l) Reference Example 162 tert-Butyl (3R) -3- (4-cyanobenzyl)piperazine-1-carboxylate
Figure imgf000184_0001
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-l, 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+l) Reference Example 163 tert-Butyl (3S) -4-benzyl-3- (hydroxymethyl)piperazine-1- carboxylate
Figure imgf000185_0001
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+l) Reference Example 164 tert-Butyl (2S) -4-benzyl-2- (hydroxymethyl)piperazine-1- carboxylate
Figure imgf000185_0002
[ (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+l) 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
N- Boc'
Figure imgf000186_0001
OH
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+l) Reference Example 166 tert-Butyl (2R) -4-benzyl-2- (3-hydroxypropyl) piperazine-1- carboxylate
Figure imgf000186_0002
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 IN 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+l) Reference Example 167 tert-But.yl (2S) -4-benzyl-2-formylpiperazine-1-carboxylate
Figure imgf000187_0001
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+l)
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
Figure imgf000188_0001
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+l)
Reference Example 169 tert-Butyl (3S) -4-benzyl-3- (bromomethyl) piperazine-1-carboxylate
Figure imgf000188_0002
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-l-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+l) Reference Example 170 tert-Butyl (3S) -3- [ (phenylthio)methyl] piperazine-1-carboxylate
Figure imgf000189_0001
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+l) Reference Example 171 tert-Butyl (2S) -4-benzyl-2-{2, 2, 2-trifluoro-1-
[ (trimethylsilyl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000190_0001
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+l)
Reference Example 172 tert-Butyl (2S) -4-benzyl-2-
[cyclopropyl (hydroxy) methyl] piperazine-1-carboxylate
Figure imgf000190_0002
tert-Butyl (2S) -4-benzyl-2-formylpiperazine-l-carboxylate (2.5 g) was dissolved in THF (25 ml), and the mixture was cooled to -30°C. Cyclopropylmagnesiuiti 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+l)
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
Figure imgf000191_0001
MS (ESI+, m/e) 339 (M+l)
Reference Example 174
1- [ (2S) -4~Benzylpiperazin-2-yl] -2 , 2, 2-trifluoroethanol
Figure imgf000191_0002
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+l)
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
Figure imgf000192_0001
MS (ESI+, m/e) 247 (M+l) Reference Example 176 tert-Butyl 3- (2-hydroxy-2-methylpropyl) piperazine-1-carboxylate
Figure imgf000192_0002
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+l) Reference Example 177 tert-Butyl (2R) -4-benzyl-2- [ (isopropylamino)methyl] piperazine-1- carboxylate
Figure imgf000193_0001
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+l)
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
Figure imgf000194_0001
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+l) Reference Example 179 tert-Butyl (2R) -4-benzyl-2-{ [ (2, 4- dimethoxybenzyl) amino]methyl }piperazine-1-carboxylate
Figure imgf000195_0001
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+l) Reference Example 180 tert-Butyl (2S) -4-benzyl-2-{ [ (4-ethoxy-4- oxobutanoyl) (phenyl) amino]methyl}piperazine-1-carboxylate
Figure imgf000195_0002
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+l) Reference Example 181 tert-Butyl (2S) -4-benzyl-2-{ [ (2, 4-dimethoxybenzyl) (2- methoxybenzoyl) amino]methyl}piperazine-1-carboxylate
Figure imgf000196_0001
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+l)
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
Figure imgf000197_0001
MS (ESI+, m/e) 560 (M+l) Reference Example 183 tert-Butyl (2S) -4-benzyl-2-{ [ (3, 5-difluorobenzoyl) (2,4- dimethoxybenzyl) amino] methyl}piperazine-1-carboxylate
Figure imgf000197_0002
MS (ESI+, m/e) 596 (M+l) Reference Example 184 tert-Butyl (2S) -4-benzyl-2-{ [ (cyclohexylcarbonyl) (2, 4- dimethoxybenzyl) amino]methyl}piperazine-1-carboxylate
Figure imgf000197_0003
MS (ESI+, m/e) 566 (M+l) Reference Example 185 tert-Butyl (2S) -4-benzyl-2-{ [ (isopropyl) (5-methoxy-4, 4-dimethyl- 5-oxopentanoyl) amino]methyl}piperazine-1-carboxylate
Figure imgf000198_0001
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+l)
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
Figure imgf000199_0001
MS (ESI+, m/e) 538 (M+l) Reference Example 187
4-[{ [ (2S) -4-Benzyl-1- (tert-butoxycarbonyl) piperazin-2- yl] methyl} (phenyl) amino] -4-oxobutyric acid
Figure imgf000199_0002
tert-Butyl (2S) -4-benzyl-2-{ [ (4-ethoxy-4- oxobutanoyl) (phenyl) amino]methyl }piperazine-1-carboxylate (3.55 g) was dissolved in ethariol (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+l) Reference Example 188 tert-Butyl (2S) -2-{ [ (4-amino-4- oxobuta'noyl) (phenyl) amino]methyl }-4-benzylpiperazine-1- carboxylate
Figure imgf000200_0001
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+l) Reference Example 189
Methyl 5- [ { [ (2S) -4-benzylpiperazin-2- yl]methyl} (isopropyl) amino] -2, 2-dimethyl-5-oxovalerate
Figure imgf000200_0002
tert-Butyl (2S) -4-benzyl-2-{ [ (isopropyl) (5-methoxy-4, 4- dimethyl-5-oxopentanoyl) amino]methyl}piperazine-l-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+l)
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
Figure imgf000201_0001
MS. (ESI+, m/e) 438 (M+l) Reference Example 191
N- { [ (2S) -4-Benzylpiperazin-2-yl]methyl }-N-phenylsuccinamide
Figure imgf000201_0002
MS (ESI+, m/e) 381 (M+l) Reference Example 192
N-{ [ (2R) -4-Benzylpiperazin-2-yl]methyl}-2-methoxybenzamide
Figure imgf000202_0001
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+l)
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 Jbenzamide
Figure imgf000203_0001
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+l) Reference Example 194 N-{ [ (2R) -4-Benzylpiperazin-2-yl]methyl}-3, 5-difluorobenzamide
Figure imgf000203_0002
1H-NMR (CDCl3) 52.17 (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+l) Reference Example 195 N-{ [ (2R) -4-Benzylpiperazin-2-yl]methyl } cyclohexanecarboxamide
Figure imgf000203_0003
fert-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+l) Reference Example 196 tert-Butyl (2R) -4-benzyl-2- [ (2E) -3-phenyl-2-propen-1- yl] piperazine-1-carboxylate
Figure imgf000204_0001
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 (1OH, m) MS (ESI+, We) 393 (M+l) Reference Example 197 tert-Butyl (2R) -4-benzyl-2- [ (E) -2-cyclopropylvinyl] piperazine-1- carboxylate
Figure imgf000205_0001
(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+l) Reference Example 198
Diethyl [2- (trifluoromethoxy) benzylJphosphonate
Figure imgf000206_0001
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) benzylJphosphonate
Figure imgf000206_0002
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
Figure imgf000207_0001
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
Figure imgf000207_0002
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+l) In the same manner as in Reference Example 201, the following compounds (Reference Examples 202 - 209) shown in Table 1 were obtained.
Table 1
Figure imgf000209_0001
Ref.Ex. R Compound MS(ESI+)
No. tert-Butyl (2R) -4-benzyl-2- [ (E) -2-
202 3-F (3-fluorophenyl)vinyl]piperazine-l- 397 carboxylate
tert-Butyl (2R) -4-benzyl-2- [ (E) -2-
203 4-F (4-fluorophenyl)vinyl]piperazine-1- 397 carboxylate
tert-Butyl (2R) -4-benzyl-2-{ (E) -2-
204 2-OCF3 [2- (trifluoromethoxy)phenyl]vinyl} 463 piperazine-1-carboxylate
tert-Butyl (2R) -4-benzyl-2-{ (E) -2-
205 3-OCF3 [3-(trifluoromethoxy)phenyl]vinyl} 463 piperazine-1-carboxylate
tert-Butyl (2R) -4-benzyl-2-{ (E) -2-
206 4-OCF3 [4-(trifluoromethoxy)phenyl]vinyl} 463 piperazine-1-carboxylate
tert-Butyl (2R) -4-benzyl-2-{ (E) -2-
207 2-CF3 [2- (trifluoromethyl)phenyl]vinyl} 447 piperazine-1-carboxylate
tert-Butyl (2R)-4-benzyl-2-{ (E) -2-
208 3-CF3 [3- (trifluoromethyl)phenyl]vinyl} 447 piperazine-1-carboxylate
tert-Butyl (2R)-4-benzyl-2-{ (E) -2-
209 4-CF3 [4-(trifluoromethyl)phenyl]vinyl} 447 piperazine-1-carboxylate Reference Example 210 tert-Butyl (2R) -4-benzyl-2- [ (E) -2- (pyridin-2- yl) vinyl] piperazine-1-carboxylate
Figure imgf000210_0001
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+l) ' Reference Example 211 (3R) -1-Benzyl-3- [ (2E) -3-phenyl-2-propen-1-yl]piperazine
Figure imgf000210_0002
tert-Butyl (2R) -4-benzyl-2- [ (2E) -3-phenyl-2-propen-1- yl]piperazine-1-carboχylate (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 (1OH, m) MS (ESI+, m/e) 293 (M+l)
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
Figure imgf000211_0001
MS (ESI+, m/e) 243 (M+l) . In the same manner as in Reference Example 211, the following compounds (Reference Examples 213 - 221) shown in Table 2 were obtained. Table 2
Figure imgf000212_0001
Reference Example 222
(3R) -1-Benzyl-3-[ (E) -2- (pyridin-2-yl) vinyl] piperazine dihydrochloride
Figure imgf000213_0001
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+l) Reference Example 223 [ (2R) -4-Benzyl-1- (tert-butoxycarbonyl) piperazin-2-yl] acetic acid
Figure imgf000213_0002
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+l)
Reference Example 224 tert-Butyl (2R) -4-benzyl-2- [ (5-phenyl-1,3, 4-oxadiazol-2- yl) methyl] piperazine-1-carboxylate
Figure imgf000214_0001
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+l) Reference Example 225
(3R) -1-Benzyl-3- [ (5-phenyl-1, 3, 4-oxadiazol-2- yl)methyl] piperazine
Figure imgf000215_0001
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+l) Reference Example 226 2-{ [ (2R) -4-Benzylpiperazin-2-yl]methyl}-1H-benzimidazole
Figure imgf000215_0002
A solution of [ (2R) -4-benzyl-l- (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+l)
Reference Example 227
Di-tert-butyl (2R) -2- [4- (ethoxycarbonyl) benzyl] piperazine-1, 4- dicarboxylate
Figure imgf000217_0001
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 (ESH:, m/e) 449 (M+l) Reference Example 228 tert-Butyl (3R) -3- [4- (2, 2, 2-trifluoro-1- hydroxyethyl) benzyl] piperazine-1-carboxylate
Figure imgf000217_0002
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, A- 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+l) Reference Example 229 tert-Butyl (3S) -4-benzyl-3- ({ [5- (methoxycarbonyl)pyridin-2- yl] oxyjmethyl) piperazine-1-carboxylate
Figure imgf000219_0001
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+l)
Reference Example 230 tert-Butyl (3S) -3- ( { [5- (methoxycarbonyl)pyridin-2- yl] oxy}methyl)piperazine-1-carboxylate
Figure imgf000220_0001
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+l) Reference Example 231 tert-Butyl (3S) -3- [ (2-cyanophenoxy) methyl] piperazine-1- carboxylate
Figure imgf000221_0001
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+l-"Boc") Reference Example 232 tert-Butyl (3S) -3- [ (3, 5-difluorophenoxy)methyl]piperazine-1- carboxylate
Figure imgf000222_0001
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+l-ΛΛBoc")
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
Figure imgf000223_0001
MS (ESI+, .m/e) 293 (M+l) Reference Example 234 tert-Butyl (3S) -3- [ (2, 6-difluorophenoxy) methyl] piperazine-1- carboxylate
Figure imgf000223_0002
MS (ESI+, m/e) 329 (M+l)
Reference Example 235 tert-Butyl (3S) -3- [ (4-methyl-1H-pyrazol-1-yl)methyl]piperazine-
1-carboxylate
Figure imgf000224_0001
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+l)
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-I, 2, 4-triazol-1-ylmethyl)piperazine-1- carboxylate
Figure imgf000225_0001
MS (ESI+, m/e) 268 (M+l) Reference Example 237 tert-Butyl (3S) -3- (1H-pyrazol-1-ylmethyl)piperazine-1- carboxylate
Figure imgf000225_0002
MS (ESI+, m/e) 267 (M+l) Reference Example 238 tert-Butyl (3S) -3- (1H-indazol-1-ylmethyl) piperazine-1- carboxylate
Figure imgf000225_0003
MS (ESI+, m/e) 317 (M+l) Reference Example 239 tert-Butyl (3S) -3- (1H-1,2, 3-benzotriazol-1-ylmethyl)piperazine- 1-carboxylate
Figure imgf000226_0001
MS (ESI+, m/e) 318 (M+l) Reference Example 240 tert-Butyl (3S) -3- (1H-imidazol-1-ylmethyl) piperazine-1- carboxylate
Figure imgf000226_0002
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+l)
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
Figure imgf000227_0001
MS (ESI+, m/e) 295 (M+l) Reference Example 242 tert-Butyl (3S) -3-{ [3- (trifluoromethyl) -1H-pyrazol-1- yl]methyl }piperazine-1-carboxylate
Figure imgf000227_0002
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+l) Reference Example 243 tert-Butyl (3S) -3- (1H-benzimidazol-1-ylmethyl)piperazine-1- carboxylate
Figure imgf000228_0001
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+l) Reference Example 244 tert-Butyl (3S)-3-[ (pyridin-2-yloxy)methyl] piperazine-1- carboxylate
Figure imgf000229_0001
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 reduqed 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 (ES];.+, m/e) 294 (M+l) Reference Example 245 tert-Butyl (3R) -3- (3-methoxybenzyl) piperazine-1-carboxylate
Figure imgf000229_0002
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 (IM 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 mi-xture 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 (67_0 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 ing) as an oil. MS (ESI+, m/e) 307 (M+l) Reference Example 246 (3R) -1-Benzyl-3- [2- (cyclopropylmethoxy) ethyl] piperazine dihydrochloride
Figure imgf000232_0001
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+l) Reference Example 247 tert-Butyl (3S)-3-({ [6- (trifluoromethyl) pyridin-2- yl] oxyjmethyl) piperazine-1-carboxylate
Figure imgf000233_0001
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] oxyjmethyl) 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+l)
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
Figure imgf000234_0001
MS (ESI+, m/e) 362 (M+l) Reference Example 249 tert-Butyl (3R) -3-{2- [4- (trifluoromethyl) phenyl] ethyl}piperazine-1-carboxylate
Figure imgf000234_0002
(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 IN 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 Jpiperazine as an amorphous solid. The total amount thereof was dissolved in tert-butanol (10 ml) and water (8 ml) , IN 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+l) Reference Example 250 tert-Butyl (2R) -2- (2-hydroxyethyl) piperazine-1-carboxylate
Figure imgf000235_0001
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+l)
Reference Example 251
1-tert-Butyl 4-benzyl (2R) -2- (2-hydroxyethyl) piperazine-1, 4- dicarboxylate
Figure imgf000236_0001
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+l-"Boc") Reference Example 252
1-tert-Butyl 4-benzyl (2R) -2- (2-bromoethyl)piperazine-l, A- dicarboxylate
Figure imgf000237_0001
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-l, A- 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+l) Reference Example 253 1-tert-Butyl 4-benzyl (2R) -2- [2- (4-methyl-1H-pyrazol-1- yl) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000238_0001
A mixture of 1-tert-butyl 4-benzyl (2R) -2- (2- bromoethyl)piperazine-1,4-dicarboxylate (320 ing) , 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+l) Reference . Example 254 1-tert-Butyl 4-benzyl (2R)-2-{2-
[ (methylsulfonyl) oxy] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000238_0002
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+l-XλBoc") Reference Example 255
1-tert-Butyl 4-benzyl (2R) -2- (2-phenoxyethyl)piperazine-1,4- dicarboxylate
Figure imgf000239_0001
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+l)
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+l- "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 3-1
Figure imgf000241_0001
Table 3-2
Figure imgf000242_0001
Table 3-3
Figure imgf000243_0001
Table 3-4
Figure imgf000244_0001
Table 3-5
Figure imgf000245_0001
Table 3-6
Figure imgf000246_0001
Figure imgf000247_0001
Reference Example 321
1-tert-Butyl 4-benzyl (2R) -2- [2- (2- fluorophenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000248_0001
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+l) Reference Example 322
1-tert-Butyl 4-benzyl (2R) -2-{2- [4-
(methoxycarbonyl) phenoxy] ethyl}piperazine-1, 4-dicarboxylate
Figure imgf000248_0002
1-tert-Butyl . 4-benzyl (2R) -2- { 2- [ (methylsulfonyl) oxy] ethyl }piperazine-1,4-dicarboxylat.e (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+l) Reference Example 323 1-tert-Butyl 4-benzyl (2R) -2- (2-{ [2- (methoxycarbonyl)pyridin-3- yl] oxy}ethyl)piperazine-1,4-dicarboxylate
Figure imgf000249_0001
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 (ESr+, m/e) 500 (M+l)
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+l- "Boc"" was obtained (a mass value of M+l was obtained for other compounds) .
Table 4-1
Figure imgf000251_0001
Table 4-2
Figure imgf000252_0002
Reference Example 336
2-Fluoro-4- (5-methyl-1, 3, 4-oxadiazol-2-yl) phenol
Figure imgf000252_0001
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 (2H7 m) , 7.7.3 (1H, t) ,
10.54 (1H, br s)
MS (ESI+, m/e) 195 (M+l)
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
Figure imgf000253_0001
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+l) Reference Example 338 4-Fluoro-3- (5-methyl-l, 3, 4-oxadiazol-2-yl) phenol
Figure imgf000253_0002
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+l) Reference Example 339
3-Methoxy-4- (5-methyl-l, 3, 4-oxadiazol-2-yl) phenol
Figure imgf000253_0003
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+l )
Reference Example 340
2-Methoxy-5- (5-methyl-l, 3, 4-oxadiazol-2-yl) phenol
Figure imgf000254_0001
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+l) Reference Example 341 1-tert-Butyl 4-benzyl (2R) -2- { 2- [2-methoxy-5-
(methoxycarbonyl) phenoxy] ethyl }piperazine-l, 4-dicarboxylate
Figure imgf000254_0002
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 scetate-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+l-"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-l, 3, 4- oxadiazol-2-yl) phenoxy] ethyl}piperazine-l, 4-dicarboxylate
Figure imgf000255_0001
MS (ESI+, m/e) 541 (M+l)
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
Figure imgf000255_0002
MS (ESI+, m/e) 541 (M+l) 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
Figure imgf000256_0001
MS (ESI+, m/e) 541 (M+l) 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
Figure imgf000256_0002
MS (ESI+, m/e) 553 (M+l) 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-lΛ 4-dicarboxylate
Figure imgf000256_0003
MS (ESI+, m/e) 553 (M+l) Reference Example 347
1-tert-Butyl 4-benzyl (2R) -2- [2- (1H-benzimidazol-1- yl) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000257_0001
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+l) 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
Figure imgf000257_0002
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+l) 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+l-"Boc"" was obtained, and "**" means that a mass value of "M+l-ΛxtBu"" was obtained (a mass value of M+l was obtained for other compounds) .
Table 5-1
Figure imgf000259_0001
Table 5-2
Figure imgf000260_0001
Reference Example 364 1-tert-Butyl 4-benzyl (2R) -2- [2- (3-oxo-2, 3-dihydro-1H-indazol-l- yl) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000261_0001
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-
[ (methylsulfonyl) oxy] ethyl }piperazine-l, 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+, itι/e) 481 (M+l)
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
Figure imgf000261_0002
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+l) Reference Example 366
1-tert-Butyl 4-benzyl (2R) -2- [2- (2-oxo-1,3-benzoxazol-3 (2H) - yl) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000262_0001
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+l) Reference Example 367
1-tert-Butyl 4-benzyl (2R) -2- [2- (3-oxo-2, 3-dihydro-4H-l, 4- benzoxazin-4-yl) ethyl]piperazine-1, 4-dicarboxylate
Figure imgf000262_0002
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+l) 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
Figure imgf000263_0001
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+l) 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-l, 4- dicarboxylate
Figure imgf000263_0002
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+l) 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
Figure imgf000264_0001
MS (ESI+, m/e) 488 (M+l)
Reference Example 371
1-tert-Butyl 4-benzyl (2R) -2-{2- [5- (ethoxycarbonyl) -1H-I, 2, 3- triazol-1-yl] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000264_0002
MS (ESI+, m/e) 488 (M+l) ' 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
Figure imgf000264_0003
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+l)
Reference Example 373
1-tert-Butyl 4-benzyl (2R) -2- (2-azidoethyl) piperazine-1, 4- dicarboxylate'
Figure imgf000265_0001
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+l) Reference Example 374
1-tert-Butyl 4-benzyl (2R) -2-{2- [4- (hydroxymethyl) -1H-I, 2, 3- triazol-1-yl] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000266_0001
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+l) 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-I, 2, 3- triazol-1-yl] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000267_0001
1H-NMR (CDCl3) δ 1.45 (9H, br s) , 1.79-1.95 (1H, m) , 2.03-2.19 (2H, in),. 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+l) 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
Figure imgf000267_0002
1H-NMR (CDCl3) δ 0.67 (1H, br s) , 0.84 (2H,. dd) , 0.89-1.04 (1H, in), 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+l)
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
Figure imgf000268_0001
MS (ESI+, m/e) 488 (M+l) 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
Figure imgf000268_0002
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+l)
Reference Example 379
1-tert-Butyl 4-benzyl (2R) -2- (2-{4- [ (acetyloxy)methyl] -1H-I, 2, 3- triazol-1-yl}ethyl) piperazine-1, 4-dicarboxylate
Figure imgf000268_0003
A mixture of .1-tert-butyl 4-benzyl (2R) -2-{2- [4- (hydroxymethyl) -1H-I, 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) 5 1.44 (9H, s) , 2.03-2.16 (4H, m) , 2.23 (3H1. 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+l) 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
Figure imgf000269_0001
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+l) MS (ESI+, m/e) 465 (M+l) 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
Figure imgf000270_0001
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-l, A- 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+l) MS (ESI+, m/e) 501 (M+l)
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 A- benzyl (2R) -2-{ 2- [3- (methoxycarbonyl) -2H-indazol-2- yl] ethyl}piperazine-1,4-dicarboxylate
Figure imgf000271_0001
MS (ESI+, m/e) 523 (M+l) MS (ESI+, m/e) 523 (M+l) Reference Example 383 Benzyl (3R) -3- (2-phenoxyethyl)piperazine-l-carboxylate
Figure imgf000271_0002
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+l)
In the same manner as in Reference Example 383, the following compounds (Reference Examples 384 - 422) shown in Table 6-1 - Table 6-5 were obtained.
Table 6-1
Figure imgf000273_0001
Table 6-2
Figure imgf000274_0001
Table 6-3
Figure imgf000275_0001
Table 6-4
Figure imgf000276_0001
Table 6-5
Figure imgf000277_0001
Reference Example 423
Benzyl (3R) -3- [2- (1H-indazol-1-yl) ethyl]piperazine-1-carboxylate
Figure imgf000277_0002
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+l)
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
Figure imgf000278_0001
MS (ESI+, m/e) 365 (M+l) Reference Example 425
Benzyl (3R) -3- [2- (3-oxo-2, 3-dihydro-1H-indazol-1- yl) ethyl] piperazine-1-carboxylate hydrochloride
Figure imgf000278_0002
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+l)
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
Figure imgf000279_0001
Table 7-2
Figure imgf000280_0001
Ref.Ex. R Compound MS(ESI+) No.
Benzyl (3R) -3- [2- (2-
435 acetylphenoxy) ethyl]piperazine-1- 383 carboxylate hydrochloride
Benzyl (3R) -3- [2- (3-
436 fluorophenoxy) ethyl]piperazine-2- 359 carboxylate hydrochloride
Benzyl (3R) -3- [2- (4-
437 fluorophenoxy) ethyl]piperazine-3- 359 carboxylate hydrochloride
Benzyl (3R) -3- [2- (2-
438 methoxyphenoxy) ethyl]piperazine-1- 371 carboxylate hydrochloride
Benzyl (3R) -3- [2- (3-
439 methoxyphenoxy) ethyl]piperazine-2- 371 carboxylate hydrochloride
Benzyl (3R)-3- (2-{4-
440 [ (trifluoromethyl) sulfonyl]phenoxy}e thyl)piperazine-1-carboxylate 473 hydrochloride
Benzyl (3R) -3-{2- [4- (methyl
441 sulfonyl)phenoxy] ethyl}piperazine-1- 419
Figure imgf000280_0002
carboxylate hydrochloride
442 °<3 Benzyl (3R) -3- [2- (2- chlorophenoxy) ethyl]piperazine-1- 375 carboxylate hydrochloride
Benzyl (3R)-3- [2- (3-
443 chlorophenoxy) ethyl]piperazine-2- 375 carboxylate hydrochloride
Benzyl (3R) -3- [2- (4-
444 chlorophenoxy) ethyl]piperazine-3- 375
Figure imgf000280_0003
carboxylate hydrochloride Table 7-3
Figure imgf000281_0001
Table 7-4
)
Figure imgf000282_0001
T?Q-F -P1V
No R Compound MS(ESI+)
Benzyl (3R) -3-{2- [3-fluoro-4-
455 (methoxycarbonyl)phenoxy] ethylJpipera 417 zine-1-carboxylate hydrochloride
Benzyl (3R) -3- [2- (4-acetyl-2-
456 fluorophenoxy) ethyl]piperazine-1- 401 carboxylate hydrochloride
Benzyl (3R) -3- [2- (4-fluoro-2-
457 rαethoxyphenoxy) ethyl]piperazine-1- 389 carboxylate hydrochloride
Benzyl (3R) -3-[2- (2-methoxy-4-
458 methylphenoxy) ethyl]piperazine-1- 385 carboxylate hydrochloride
Benzyl (3R) -3- [2- (4-acetyl-2-
459 methoxyphenoxy) ethyl]piperazine-1- 413 carboxylate hydrochloride
Benzyl (3R) -3-{2-[4- (ethoxycarbonyl) -
460 2-methoxyphenoxy] ethyl}piperazine-1- 443
Figure imgf000282_0002
carboxylate hydrochloride
Figure imgf000282_0003
Table 7-5
Figure imgf000283_0001
-
Figure imgf000284_0001
Table 7-7
Figure imgf000285_0001
Table 7-8
Figure imgf000286_0001
Reference Example 503
1-tert-Butyl 4-benzyl (2R) -2- (3-hydroxypropyl)piperazine-1,4- dicarboxylate
Figure imgf000287_0001
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+l) Reference Example 504
1-tert-Butyl 4-benzyl (2R) -2-{3-
[ (methylsulfonyl) oxy] propyl }piperazine-l, 4-dicarboxylate
Figure imgf000288_0001
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+l) Reference Example 505 Benzyl (3R) -3- (3-hydroxypropyl) piperazine-1-carboxylate
Figure imgf000288_0002
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+l)
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
Figure imgf000289_0001
MS (ESI+, m/e) 455 (M+l)
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
Figure imgf000289_0002
MS (ESI+, m/e) 479 (M+l) MS (ESI+, m/e) 479 (M+l)
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
Figure imgf000290_0001
MS (ESI+, m/e) 355 (M+l) Reference Example 509
Benzyl (3R) -3- [3- (1H-indazol-1-yl) propyl]piperazine-1- carboxylate
Figure imgf000290_0002
MS (ESI+, m/e) 379 (M+l)
Reference Example 510
Benzyl (3R) -3- [3- (2H-indazol-2-yl) propyl] piperazine-1- carboxylate
Figure imgf000290_0003
MS (ESI+, m/e) 379 (M+l) Reference Example 511
Benzyl (3R) -3- {3- [5- (ethoxycarbonyl) -3-methyl-1H-pyrazol-1- yl] propyl}piperazine-1-carboxylate
Figure imgf000291_0001
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+l) Reference Example 512 tert-Butyl (3R) -3-benzyl-3-methylpiperazine-l-carboxylate
Figure imgf000292_0001
(2R) -2-Benzyl-2-methylpiperazine (1.10 g) and triethylaitiine (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+l) Reference Example 513 tert-Butyl (3R) -3-benzyl-4- ({l-[ (IS, 2S) -2- (benzyloxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboxylate
Figure imgf000292_0002
l-[ (IS, 2S) -2- (Benzyloxy) cyclohexyl] -5-phenyl-1H-imidazole- 4-carboxylic acid (376 mg) was suspended in DMF (10 ml), tert- butyl (3R)-3-benzylpiperazine-l-carboxylate (332 mg), WSC-HCl (288 mg) and HOBt (184 rag) 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+l)
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- [ (IR, 2R) -2-
(benzyloxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboxylate
Figure imgf000293_0001
MS. (ESI+, m/e) 635 (M+l) Reference Example 515 tert-Butyl (3R) -4- ( { 1- [ (IS, 2R) -2-azidocyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl) -3-benzylpiperazine-1-carboxylate
Figure imgf000294_0001
MS (ESI+, m/e) 570 (M+l) Reference Example 516 tert-Butyl (3R) -3-benzyl-4- ( {5- (3-fluorophenyl) -1- [ (IS, 2S) -2- hydroxycyclohexyl] -1H-imidazol-4-yl}carbonyl)piperazine-1- carboxylate
Figure imgf000294_0002
To a solution of 5- (3-fluorophenyl) -1-[ (IS, 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+l) Reference Example 517 tert-Bύtyl (3R) -3-benzyl-4- ({1- [ (IR, 2S) -2-hydroxy-2- . (methoxymethyl) cyclohexyl] -5-phenyl-1H-iπιidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000295_0001
A solution of 1- [ (IR, 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+l) Reference Example 518
(IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-hydroxyethyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000296_0001
1- [ (IR, 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+l) Reference Example 519
Benzyl (3R) -3- [2- (2-fluorophenoxy) ethyl] -4- ( { 1- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl)'cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazine-1-carboxylate
Figure imgf000296_0002
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 concentrateci 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- [ (IR, 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+l) Reference Example 520 ' Benzyl (3R) -4- ( {1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3-{2- [4- (methoxycarbonyl)phenoxy] ethyl }piperazine-1-carboxylate
Figure imgf000297_0001
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- [ (IR, 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+l)
In the same manner as in Reference Example 520, the following compounds (Reference Examples 521 - 525) were obtained. Reference Example 521
Benzyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3-{2- [3- (methoxycarbonyl) phenoxy] ethyl }piperazine-1-carboxylate
Figure imgf000298_0001
MS (ESI+, m/e) 711 (M+l) Reference Example 522
Benzyl (3R) -4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3-{2-[2- (methoxycarbonyl)phenoxy] ethyl}piperazine-1-carboxylate
Figure imgf000299_0001
MS (ESI+, m/e) 711 (M+l) Reference Example 523
Benzyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) 3-{2- [ (1-oxidopyridin-3-yl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000299_0002
MS (ESI+, m/e) 669 (M+l) Reference Example 524
Benzyl (3R) -3-{2- [4- (4-acetylpiperazin-1-yl)phenoxy] ethyl}-4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000299_0003
MS (ESI+, m/e) 779 (M+l) Reference Example 525
Benzyl (3R) -3- [2- (4-cyano-2-methoxyphenoxy) ethyl] -4- ({1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000300_0001
MS (ESI+, m/e) 708 (M+l) Reference Example 526 Benzyl (3R) -4- ( {1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) 3- [2- (1H-indazol-1-yl) ethyl] piperazine-1-carboxylate
Figure imgf000300_0002
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+l)
In the same manner as in Reference Example 526, the following compound (Reference Example 527) was obtained. Reference Example 527
Benzyl (3R) -4- ( { 1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) 3- [2- (2H-indazol-2-yl) ethyl] piperazine-1-carboxylate
Figure imgf000301_0001
MS (ESI+, m/e) 677 (M+l) Reference Example 528 (IR, 2S) -2- [4- ( { (2R) -4-Benzyl-2- [ (E) -2- cyclopropylvinyl]piperazin-1-yl}carbonyl) -5-phenyl-1H-imidazol- 1-yl] cyclohexanol
Figure imgf000301_0002
A solution of 1- [ (IS, 2R) -2-hydroxycyclohexyl] -5-phenyl-1H- imidazole-4-carboxylic acid (144 mg) , (3R) -1-benzyl-3- [ (E) -2- cyclopropylvinyl] piperazine (125 mg) , WSC*HC1_ (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+l) Reference Example 529 tert-Butyl (3R) -3-benzyl-4- [ (1-cyclohexyl-5-phenyl-1H-imidazol- 4-yl) carbonyl]piperazine-1-carboxylate
Figure imgf000302_0001
Methyl l-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+l)
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
Figure imgf000303_0001
MS (ESI+, m/e) 531 (M+l)
Reference Example 531 tert-Butyl (3R) -3-benzyl-4-{ [1- (cis-2-hydroxycyclohexyl) -5- phenyl-1H-imidazol-4-yl]carbonyl}piperazine-1-carboxylate
Figure imgf000303_0002
MS (ESI+, m/e) 545 (M+l) ' Reference Example 532
{ (2S)-4-Benzyl-1-[ (1-cyclopentyl-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazin-2-yl} (cyclopropyl)methanol
Figure imgf000303_0003
MS (ESI+, m/e) 485. (M+l) Reference Example 533 trans-2- (4-{ [ (2R) -4-Benzyl-2-isobutylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) cyclopentanol
Figure imgf000304_0001
MS (ESI+, m/e) 487 (M+l) Reference Example 534
N- { [ (2R) -4-Benzyl-1-({l-[2-(ethoxymethyl)-2-hydroxycyclohexyl] 5-phenyl-1H-±midazol-4-yl}carbonyl)piperazin-2- yl]methylJbenzamide
Figure imgf000304_0002
MS (ESI+, m/e) 636 (M+l) Reference Example 535 2-[4-({ (2S) -4-Benzyl-2-[ (benzyloxy) methyl] piperazin-1- yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000305_0001
MS (ESI+, m/e) 609 (M+l) 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
Figure imgf000305_0002
MS (ESI+, m/e) 559 (M+l) Reference Example 537 tert-Butyl (3R) -3-benzyl-4-{ [1- (trans-2-hydroxycycloheptyl) -5- phenyl-1H-imidazol-4-yl] carbonyl }piperazine-1-carboxylate
Figure imgf000305_0003
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+, "πi/e) 559 (M+l) Reference Example 538
(IS, 2S) -2- (4-{ [ (2R) -2, 4-Dibenzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) cyclohexanamine
Figure imgf000306_0001
Ethyl l-{ (IS, 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+l) Reference Example 539
Ethyl [ (lS,2S)-2-(4-{ [ (2R) -4-benzyl-2- (3,5- difluorobenzyl) piperazin-1-yl] carbonyl } -5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000307_0001
Ethyl l-{ (lS,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+l) 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
Figure imgf000308_0001
Ethyl l-(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+l) Reference Example 541 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2S) -2- [ (ethoxycarbonyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000309_0001
Ethyl l-{ (IS, 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+l) Reference Example 542 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 2R) -2- (chloromethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-iiαidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000310_0001
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 5O0C for 15 hr. The mixture was neutralized with IN 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+l) Reference Example 543 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 2S) -2-hydroxycyclohexyl] -5- phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000311_0001
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 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+l)
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- [ (IR, 2R) -2-hydroxycyclohexyl] -5- phenyl-1H-imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000312_0001
MS (ESI+, m/e) 545 (M+l) Reference Example 545 tert-Butyl (3R) -4- ( { 1- [ (IS, 2S) -2- (acetyloxy) cyclohexyl] -5- phenyl-1H-imidazol-4-yl}carbonyl) -3-benzylpiperazine-1- carboxylate
Figure imgf000312_0002
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 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+l) Reference Example 546 tert-Butyl (3R)-3-benzyl-4-[ (1-{ (IS, 2R) -2- [ (4- nitrobenzoyl) oxy] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine-1-carboxylate
Figure imgf000313_0001
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 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+l)
Reference Example 547 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 2R) -2-hydroxycyclohexyl] -5- phenyl-1H-imidazol-4-yl} carbonyl) piperazine-1-carboxylate
Figure imgf000314_0001
tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 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+l) Reference Example 548 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 2S) -2- (3- methoxypropoxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000314_0002
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 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, l-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+l)
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- [ (IS, 2S) -2- (allyloxy) cyclohexyl] -5-phenyl- 1H-imidazol-4-yl}carbonyl) -3-benzylpiperazine-1-carboxylate
Figure imgf000315_0001
MS (ESI+, m/e) 585 (M+l) Reference Example 550 tert-Butyl (3R) -3-benzyl-4- ( { 5-phenyl-1- [ (IS, 2S) -2- propoxycyclohexyl] -1H-imidazol-4-yl}carbonyl)piperazine-1- carboxylate
Figure imgf000316_0001
MS (ESI+, m/e) 587 (M+l) Reference Example 551 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 2S) -2- (2- methoxyethoxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazine-1-carboxylate
Figure imgf000316_0002
MS (ESI+, m/e) 603 (M+l) Reference Example 552 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 2S) -2- (4- methoxybutoxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl }carbonyl) piperazine-1-carboxylate
Figure imgf000316_0003
MS (ESI+, m/e) 631 (M+l) Reference Example 553 tert-Butyl (3R)-4-[(1-{ (IS, 2S) -2- [3-
(acetylamino)propoxy] cyclohexyl} -5-phenyl-1H-imidazol-4- yl) carbonyl] -3-benzylpiperazine-1-carboxylate
Figure imgf000317_0001
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 2S) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piρerazine-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 rain. 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- [ (IS, 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+l) 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
Figure imgf000318_0001
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+l) Reference Example 555 tert-Butyl (3R) -3-benzyl-4- ( { 1- [cis-2-hydroxycycloheptyl] -5- phenyl-1H-imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000319_0001
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) , IN 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+l) 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
Figure imgf000319_0002
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 l-bromo-3-methoxypropane (45 mg) under ice-c.ooling, 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+l)
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
Figure imgf000320_0001
MS (ESI+, m/e) 617 (M+l) Reference Example 558 tert-Butyl (3R) -3-benzyl-4-{ [l-( (IS, 2S) -2-
{ [ (ethylamino) carbonyl] oxy}cyclohexyl) -5-phenyl-1H-imidazol-4- yl] carbonyl}piperazine-1-carboxylate
Figure imgf000321_0001
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 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 (IM 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+l) '
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- [ (IS, 2S) -2-
( { [ (ethyl) (methyl) amino] carbonyl}oxy) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000322_0001
MS (ESI+, m/e) 630 (M+l) Reference Example 560 tert-Butyl (3R) -3-benzyl-4-[ (1-{ (IS, 2S) -2- [ ({ (methyl) [2- (methylsulfonyl) ethyl] amino}carbonyl) oxy] cyclohexyl}-5-phenyl- 1H-imidazol-4-yl) carbonyl] piperazine-1-carboxylate
Figure imgf000322_0002
MS (ESI+, m/e) 708 (M+l) 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
Figure imgf000322_0003
A mixture of tert-butyl (3R) -3-benzyl-4- ( {1- [trans-2- hydroxycycloheptyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate (137 ing), 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+l) Reference Example 562 tert-Butyl (3R) -4- ( { 1- [ (IS, 2R) -2-aminocyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)-3-benzylpiperazine-1-carboxylate
Figure imgf000323_0001
tert-Butyl (3R) -4- ( { 1- [ (IS, 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+l) Reference Example 563 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2R) -2-
[ (cyclopropylmethyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000324_0001
tert-Butyl (3R) -4- ( { 1- [ (IS, 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+l)
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-{ (IS, 2R) -2-
[bis (cyclopropylmethyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000324_0002
MS (ESI+, m/e) 652. (M+l) Reference Example 565 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2R) -2-
[ (cyclopropylcarbonyl) amino] cyclohexylJ-5-phenyl-1H-imidazole yl) carbonyl] piperazine-1-carboxylate
Figure imgf000325_0001
tert-Butyl (3R) -4- ( {1- [ (IS, 2R) -2-aminocyclohexyl] -5- phenyl-1H-±midazol-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+l)
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-{ (IS, 2R) -2-
[ (cyclopropylsulfonyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine-1-carboxylate
Figure imgf000326_0001
MS (ESI+, m/e) 648 (M+l) Reference Example 567 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS, 2R) -2- (butyrylamino) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboxylate
Figure imgf000326_0002
MS (ESI+, m/e) 614 (M+l) Reference Example 568 tert-Butyl (3R) -3-benzyl-4-{ [l-( (IS, 2R) -2-
{ [ (ethylamino) carbonyl] amino}cyclohexyl) -5-phenyl-1H-imidazol-4- yl] carbonyl }piperazine-1-carboxylate
Figure imgf000326_0003
To a solution of tert-butyl (3R) -4- ({1- [ (IS, 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+l) Reference Example 569
Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2, 4-dibenzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000327_0001
(lS,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+l) Reference Example 570
Ethyl [ (IS, 2S) -2- (4-{ [ (2R) -2, 4-dibenzylpiperazin-1-yl] carbonyl}- 5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000328_0001
(IS, 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+l)
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
Figure imgf000328_0002
MS (ESI+, m/e) 620 (M+l) Reference Example 572 Isobutyl [ (lS,2S)-2-(4-{ [ (2R) -2, 4-dibenzylpiperazin-l- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000329_0001
MS (ESI+, m/e) 634 (M+l) Reference Example 573
2-Methoxyethyl [ (IS, 2S) -2- (4-{ [ (2R) -2, 4-dibenzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000329_0002
MS (ESI+, m/e) 636 (M+l) Reference Example 574
2-Chloroethyl [ (IS, 2S) -2- (4-{ [ (2R) -2, 4-dibenzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000329_0003
MS (ESI+, m/e) 641 (M+l)
Reference Example 575
3-[ (IS, 2S) -2- (4-{ [ (2R)-2,4-Dibenzylpiperazin-1-yl]carbonyl}-5- phenyl-1H-imidazol-1-yl) cyclohexyl] -1, 3-oxazolidin-2-one
Figure imgf000330_0001
2-Chloroethyl [ (IS, 2S) -2- (4-{ [ (2R) -2, 4-dibenzylpiperazin- 1-yl] carbonylJ-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+l) Reference Example 576 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2S) -2-
[ (ethoxycarbonyl) (methyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-
4-yl) carbonyl]piperazine-1-carboxylate
Figure imgf000330_0002
tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 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+l)
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-{ (IS, 2S) -2- [ (ethoxycarbonyl) (3- methoxypropyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine-1-carboxylate
Figure imgf000331_0001
MS. (ESI+, m/e) 688 (M+l) Reference Example 578 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS) -2-oxocyclohexyl] -5-phenyl- 1H-imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000331_0002
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ ( IS, 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+l)
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- [ (IR) -2-oxocyclohexyl] -5-phenyl- 1H-imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000332_0001
MS (ESI+, m/e) 543 (M+l) Reference Example 580 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-oxocyclohexyl) -5-phenyl-1H- imidazόl-4-yl] carbonyllpiperazine-1-carboxylate
Figure imgf000333_0001
MS (ESI+, m/e) 543 (M+l) Reference Example 581 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-butyl-2-hydroxycyclohexyl) -5- phenyl-1H-imidazol-4-yl] carbonyl}piperazine-1-carboxylate
Figure imgf000333_0002
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+l) Reference Example 582 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-hydroxy-2-methylcyclohexyl) -5- phenyl-1H-imidazol-4-yl] carbonyl }piperazine-1-carboxylate
Figure imgf000334_0001
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+l) 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
Figure imgf000334_0002
tert-Butyl (3R) -3-benzyl-4-{ [1- (2-oxocyclohexyl) -5-phenyl- 1H-imidazol-4-yl]carbonyl}pipera2ine-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+l) Reference Example 584 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -2- (2-ethoxy-2-oxoethyl) -2- hydroxycyclohexyl]-5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboxylate
Figure imgf000335_0001
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS) -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+l) Reference Example 585 [ (2S)-Z-(4-{ [ (2R)-2-Benzyl^4-(tert-butoxycarbonyl)piρerazin-l- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- hydroxycyclohexyl] acetic acid
Figure imgf000336_0001
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -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 IN 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+l) Reference Example 586 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS) -2-hydroxy-2- [2-
(methylamino) -2-oxoethyl] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000336_0002
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+l)
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-{ (IS) -2- [2- (dimethylamino) -2- oxoethyl] -2-hydroxycyclohexyl} -5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000337_0001
MS (ESI+, m/e) 630 (M+l) Reference Example 588 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS) -2-{2- [ (2- furylmethyl) amino] -2-oxoethyl}-2-hydroxycyclohexyl] -5-phenyl-1H- imidazol-4-yl } carbonyl) piperazine-1-carboxylate
Figure imgf000338_0001
MS (ESI+, m/e) 682 (M+l) Reference Example 589 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS) -2-hydroxy-2- (2- hydroxyethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazine-1-carboxylate
Figure imgf000338_0002
Sodium borohydride (862 ing) 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- [ (IS) -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+l) Reference Example 590 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS) -2-hydroxy-2- (2- oxoethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboxylate
Figure imgf000339_0001
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -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+l) Reference Example 591 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS) -2- [2- (benzylamino) ethyl] -2- hydroxycyclohexyl} -5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine-1-carboxylate
Figure imgf000339_0002
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -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+l)
Reference Example 592 ' tert-Butyl (3R) -4- ( {1- [ (IS) -2- (2-aminoethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) -3- benzylpiperazine-1-carboxylate
Figure imgf000340_0001
tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS) -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+l) Reference Example 593 tert-Butyl (3R) -4- ( {1- [ (IS) -2- (2-acetamidoethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) -3- benzylpiperazine-1-carboxylate
Figure imgf000341_0001
' tert-Butyl (3R) -4- ( { 1- [ (IS) -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+l) Reference Example 594 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -2-methoxy-2- (2- . methoxyethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000342_0001
A mixture of tert-butyl (3R) -3-benzyl-4- ({1- [ (IS) -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+l) Reference Example 595 tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -2-hydroxy-2- (2- methoxyethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000342_0002
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS) -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+l) Reference Example 596 tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 2E) -2- (2-ethoxy-2- oxoethylidene) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazine-1-carboxylate
Figure imgf000343_0001
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -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+l) Reference Example 597
(2E) - [ (2S) -2- (4-{ [ (2R) -2-Benzyl-4- (tert- butoxycarbonyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexylidene] acetic acid
Figure imgf000344_0001
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IS, 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+l) Reference Example 598 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2E) -2- [2-oxo-2- (propylamino) ethylidene] cyclohexyl } -5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000345_0001
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+l) 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
Figure imgf000345_0002
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-l-carboxylate (400 ing) 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+l) 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
Figure imgf000346_0001
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+l)
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
Figure imgf000348_0001
Table 8-2
Figure imgf000349_0001
Table 8-3
Figure imgf000350_0002
Reference Example 620 tert-Butyl ( 3R) -3-benzyl-4- [ ( l- { 2- [ (ethylamino) methyl] -2- hydroxycyclohexyl } -5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine-1-carboxylate
Figure imgf000350_0001
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+l)
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
Figure imgf000351_0001
MS (ESI+, m/e) 616 (M+l) Reference Example 622 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-{ [ (2- furylmethyl) amino]methyl} -2-hydroxycyclohexyl) -5-phenyl-1H- imidazol-4-yl] carbonyljpiperazine-1-carboxylate
Figure imgf000351_0002
MS (ESI+, m/e) 654 (M+l) 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
Figure imgf000352_0001
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+l) Reference Example 624 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-ethyl-2-hydroxycyclohexyl) -5- phenyl-1H-imidazol-4-yl] carbonyl}piperazine-1-carboxylate
Figure imgf000352_0002
Copper iodide (160 mg) was suspended in THF (5 ml) , and the suspension was ice-cooled. Methylmagnesium bromide (IM THF solution, 1.6 ml) was added, and the mixture was stirr.ed 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+l)
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
Figure imgf000353_0001
MS (ESI+, m/e) 587 (M+l)
Reference Example 626 tert-Butyl (3R) -3-benzyl-4- ({1- [ (IR, 2R) -2- (cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4- yl }carbonyl) piperazine-1-carboxylate and tert-butyl (3R) -3- benzyl-4- ( {1- [ (IS, 2S) -2- (cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000354_0001
Copper iodide (144 mg) was suspended in THF (5 ml) , and the suspension was ice-cooled. CyclopropyMagnesium 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- [ (IR, 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- [ (IS, 2S) -2-
(cyclopropylmethyl) -2-hydroxycyclohexyl] -5-phenyl-1H-imidazol-4- yljcarbonyl) piperazine-1-carboxylate (214 mg) as an amorphous solid.
MS (ESI+, m/e) 599 (M+l) MS (ESI+, m/e) 599 (M+l)
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- [ (IR, 2S) -2-butyl-2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboxylate and tert-butyl (3R) -3- benzyl-4- ( { 1- [ (IS, 2R) -2-butyl-2-hydroxycyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000355_0001
MS (ESI+, m/e) 601 (M+l)
MS (ESI+, m/e) 601 (M+l)
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 }piperaz±ne-1-carboxylate
Figure imgf000355_0002
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+l)
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
Figure imgf000356_0001
MS (ESI+, m/e) 695 (M+l) Reference Example 630 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-{ [ (1, l-dioxidotetrahydro-2H- thiopyran-4-yl) oxy]methyl} -2-hydroxycyclohexyl) -5-phenyl-1H- imidazol-4-yl] carbonyl }pipera2ine-l-carboxylate
Figure imgf000357_0001
MS (ESI+, m/e) 707 (M+l) Reference Example 631 tert-Butyl (3R) -3-benzyl-4-{ [1- (2-{ [ (1, l-dioxidotetrahydro-2H- thiopyran-4-yl)methoxy]methyl}-2-hydroxycyclohexyl) -5-phenyl-1H- imidazol-4-yl] carbonyl}piperazine-1-carboxylate
Figure imgf000357_0002
MS (ESI+, m/e) 721 (M+l) Reference Example 632 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2R) -2-hydroxy-2- [ (1, 3- thiazol-2-ylmethoxy) methyl] cyclohexyl}-5-phenyl-1H-imidazol- yl) carbonyl] piperazine-1-carboxylate
Figure imgf000357_0003
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- [ (IS, 2R) -2- (chloromethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboχylate (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+l)
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-{ [l-( (IS, 2R) -2-hydroxy-2-{ [2-(2- hydroxyethoxy) ethoxy]methyl}cyclohexyl) -5-phenyl-1H-imidazol-4- yl] carbonyl }piperazine-1-carboxylate
Figure imgf000358_0001
MS (ESI+, m/e) 663 (M+l)
Reference Example 634 tert-Butyl (3R) -3-benzyl-4-{ [l-( (lS,2R)-2-{ [3-
(dimethylamino)propoxy]methyl }-2-hydroxycyclohexyl) -5-phenyl-1H- imidazol-4-yl] carbonyl }piperazine-1-carboxylate
Figure imgf000359_0001
MS (ESI+, m/e) 660 (M+l) Reference Example 635 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2R) -2-hydroxy-2- [ (pyridin-2- ylmethoxy)methyl] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine-1-carboxylate
Figure imgf000359_0002
MS (ESI+, m/e) 666 (M+l) Reference Example 636 tert-Butyl (3R) -4- [ (1-{ (IS, 2R) -2- [ (1H-benzimidazol-2- ylmethoxy) methyl] -2-hydroxycyclohexyl } -S-phenyl-1H-imidazol-4- yl) carbonyl] -3-benzylpiperazine-1-carboxylate
Figure imgf000359_0003
MS (ESI+, m/e) 705 (M+l) Reference Example 637 tert-Butyl (3R) -3-benzyl-4- [ (1-{ (IS, 2R) -2- [ (2, 3-dihydro-1H- inden-2-yloxy) methyl] -2-hydroxycyclohexyl }-5-phenyl-1H-imidazol- 4-yl) carbonyl] piperazine-1-carboxylate
Figure imgf000360_0001
MS (ESI+, m/e) 691 (M+l) 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
Figure imgf000360_0002
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+l) 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
Figure imgf000361_0001
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+l) 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
Figure imgf000361_0002
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+l) 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] carbonyljpiperazine-1-carboxylate
Figure imgf000362_0001
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 (EΞI+, m/e) 659 (M+l) 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
Figure imgf000363_0001
tert-Butyl (3R) -3-benzyl-4- ( { 5- (3-fluorophenyl) -1- [ (lS,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+l) 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
Figure imgf000364_0001
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+l) Reference Example 644 tert-Butyl (3R) -3- (2-hydroxyethyl) -4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000365_0001
(IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-hydroxyethyl) piperazin- 1-yl] carbonyl}-5-phenyl-1H-imidazol-l-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+l) Reference Example 645 tert-Butyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl} carbonyl) - 3-{2- [ (pyrrolidin-1-ylcarbonyl) oxy] ethyl }piperazine-1- carboxylate
Figure imgf000366_0001
tert-Butyl (3R) -3- (2-hydroxyethyl) -4- ( {1- [ (IR, 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+l) Reference Example 646 tert-Butyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5~phenyl-1H-imidazol-4-yl } carbonyl) - 3- (2-oxoethyl) piperazine-1-carboxylate
Figure imgf000367_0001
tert-Butyl (3R) -3- (2-hydroxyethyl) -4- ( { 1- [ (IR, 2S) -2- hydroxy-2- (inethoxymethyl) 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+l-"Boc") . Reference Example 647 tert-Butyl (3R)-4-({l-[ (IR, 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-l-carboxylate and tert-butyl (3R) -4- ({1- [ (IR, 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
Figure imgf000368_0001
2-Bromo-β- (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- [ (IR, 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- [ (IR, 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- [ (IR, 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+l) MS (ESI+, m/e) 688 (M+l) Reference Example 648 tert-Butyl (3R) -4- ( { 1- [ (IR, 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- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3- [ (2S) -2-hydroxy-2-phenylethyl] piperazine-1-carboxylate
Figure imgf000369_0001
tert-Butyl (3R)-4-({l-[ (IR, 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- [ (IR, 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- [ (IR, 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+l) MS (ESI+, m/e) 619 (M+l) Reference Example 649 (IS, 2R) -2- (4-{ [ (2R)-4-Benzyl-2-(2-phenoxyethyl)piperazin-l- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000370_0001
(IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-hydroxyethyl)piperazin- 1-yl] carbonyll-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+l) Reference Example 650 tert-Butyl (3R) -4- ( {1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3- [2- (pyridin-2-yloxy) ethyl] piperazine-1-carboxylate
Figure imgf000370_0002
tert-Butyl (3R) -3- (2-hydroxyethyl) -4- ( {1- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imida.zol-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+l)
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-({l-[ (IR, 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
Figure imgf000371_0001
MS (ESI+, m/e) 688 (M+l) Reference Example 652 tert-Butyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) 3- [2- (pyrimidin-2-yloxy) ethyl] piperazine-1-carboxylate
Figure imgf000372_0001
MS (ESI+, m/e) 621 (M+l) Reference Example 653 tert-Butyl (3R)-4-({l-[ (IR, 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
Figure imgf000372_0002
MS (ESI+, m/e) 688 (M+l)
Reference Example 654 tert-Butyl (3R)-4-({l-[ (IR, 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
Figure imgf000372_0003
MS (ESI+, m/e) 688 (M+l) Reference Example 655 tert-Butyl (3R) -3-{2- [ (5-cyanopyridin-2-yl) oxy] ethyl}-4- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000373_0001
MS (ESI+, m/e) 645 (M+l) Reference Example 656 tert-Butyl (3R)-4-({l-[ (IR, 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
Figure imgf000373_0002
' MS (ESI+, m/e) 688 (M+l) Reference Example 657
4-{2-[ (2R) -4- [ (Benzyloxy)carbonyl]-1-({l-[ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl] ethoxy}benzoic acid
Figure imgf000373_0003
Benzyl (3R) -4- ( {1- [ (IR, 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) , IN 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 IN 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+l) Reference Example 658
Benzyl (3R) -3- (2-{4- [ (cyclopropylamino) carbonyl]phenoxy}ethyl) - 4- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl- 1H-imidazol-4-yl}carbonyl)piperazine-l-carboxylate
Figure imgf000374_0001
4-{2-[ (2R) -4- [ (Benzyloxy)carbonyl]-1-({1-[ (IR, 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+l)
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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000375_0001
MS (ESIH-, m/e) 724 (M+l) Reference Example 660
Benzyl (3R) -3-{2- [4- (azetidin-1-ylcarbonyl)phenoxy] ethyl} -4- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000375_0002
MS (ESI+, m/e) 736 (M+l) Reference Example 661 Benzyl (3R) -4- ( {1- [ (IR, 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
Figure imgf000375_0003
MS (ESI+, m/e ) 778 (M+l ) Reference Example 662
1-tert-Butyl 4-benzyl (2R) -2- (2-oxoethyl)piperazine-1,4- dicarboxylate
Figure imgf000376_0002
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
Figure imgf000376_0001
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+l) Reference Example 664 1-tert-Butyl 4-benzyl (2R)-2-{2-
[methyl (phenyl) amino] ethyl }piperazine-l, 4-dicarboxylate
Figure imgf000377_0001
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 (37.0 mg) as an oil.
MS (ESI+, m/e) 454 (M+l) Reference Example 665 Benzyl (3R) -3- (2-anilinoethyl)piperazine-1-carboxylate
Figure imgf000378_0001
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+l) Reference Example 666 Benzyl (3R) -3-{2- [methyl (phenyl) amino] ethyl }piperazine-1- carboxylate
Figure imgf000378_0002
1-tert-Butyl 4-benzyl (2R)-2-{2- [methyl (phenyl) amino] ethyl}piperazine-l, 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+l) Reference Example 667
Ethyl l-[ (IR, 2S) -2-ethyl-2-hydroxycyclohexyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000379_0001
Copper iodide (4.57 g) was suspended in THF (100 ml), and the suspension was ice-cooled. Methylmagnesium bromide (IM 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+l) In the same manner as in Reference Example 667, the following compound (Reference Example 668) was obtained. Reference Example 668
Ethyl 1- [ (IR, 2R) -2- (cyclopropylmethyl) -2-hydroxycyclohexyl] -5- phenyl-1H-imidazole-4-carboxylate
Figure imgf000380_0001
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+l)
Reference Example 669
Ethyl 1- [ (IR, 2S) -2-hydroxy-2-methylcyclohexyl] -5-phenyl-1H- imidazole-4-carboxylate
Figure imgf000380_0002
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+l) Reference Example 670 l-[ (lR,2S)-2-Ethyl-2-hydroxycyclohexyl]-5-phenyl-1H-imidazole-4- carboxylic acid
Figure imgf000381_0001
Ethyl 1- [ (IR, 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 (DMSCHd6) 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+l)
In the same manner as in Reference Example 670, the following compounds (Reference Examples 671 - 672) were obtained. Reference Example 671 1- [ (IR, 2R) -2- (Cyclopropylmethyl) -2-hydroxycyclohexyl] -5-phenyl- 1H-imidazole-4-carboxylic acid
Figure imgf000381_0002
1H-NMR (CDCl3) δ -0.16 (2H, br s) , 0.08-0.39 (3H, m)f 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+l) Reference Example 672
1- [ (IR, 2S) -2-Hydroxy-2-methylcyclohexyl] -5-phenyl-1H-imidazole- 4-carboxylic acid
Figure imgf000382_0001
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+l) Reference Example 673
1- [ (IR, 2S) -2- (Ethoxymethyl) -2-hydroxycyclohexyl] -5-phenyl-1H- imidazole-4-carboxylic acid
Figure imgf000382_0002
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. IN 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+l)
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
Figure imgf000383_0001
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
Figure imgf000383_0002
MS (ESI+, m/e) 417 (M+l-"Boc") Reference Example 676
Ethyl 2-bromo-N- (tert-butoxycarbonyl) -D-phenylalanyl-N- benzylglycinate
Figure imgf000384_0001
MS (ESI+, m/e) 519 (M+l) In the same manner as in Reference Example 109, the following compounds (Reference Examples 677 - 679) were obtained.
Reference Example 677 l-Benzyl-3- (2-methoxybenzyl)piperazine-2, 5-dione
Figure imgf000384_0002
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) -l-Benzyl-3- (biphenyl-4-ylmethyl) piperazine-2, 5-dione
Figure imgf000384_0003
1H-NMR (CDCl3) δ 3.06 (1H, d) , 3.21 (2H, d) , 3.54 (1H, d) , 4.35- 4.40 (1H, in), 4.43 (1H, d) , 4.55 (1H, d) , 6.49 (1H, s) , 7.16- 7.53 (14H, m)
MS (ESI+, m/e) 371 (M+l) Reference Example 679 (3R) -1-Benzyl-3- (2-bromobenzyl) piperazine-2 , 5-dione
Figure imgf000385_0001
MS (ESI+, m/e) 373 (M+l)
In the same manner as in Reference Example 133, the following compounds (Reference Examples 680 - 681) were obtained. Reference Example 680 l-Benzyl-3- (2-methoxybenzyl)piperazine
Figure imgf000385_0002
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+l) Reference Example 681 (3R) -1-Benzyl-3- (biphenyl-4-ylmethyl)piperazine
Figure imgf000385_0003
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+l)
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
Figure imgf000386_0001
MS (ESI+, rα/e) 345 (M+l)
Reference Example 683 tert-Butyl [ (IR) -1-benzyl-2- (benzylamino) propyl] carbamate
Figure imgf000386_0002
tert-Butyl [ (IR) -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+l) Reference Example 684
Ethyl N-benzyl-N-{ (2R) -2- [ (tert-butoxycarbonyl) amino] -1-methyl- 3-phenylpropyl }glycinate
Figure imgf000386_0003
A mixture of tert-butyl [ (IR) -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+l) Reference Example 685 ( 6R) -4, 6-Dibenzyl-5-methylpiperazin-2-one
Figure imgf000387_0001
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+l) Reference Example 686 (3R) -1, 3-Dibenzyl-2-methylpiperazine
Figure imgf000388_0001
A mixture of (6R) -4, β-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 IN 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+l)
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
Figure imgf000388_0002
MS (ESI+, m/e) 445 (M+l)
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
Figure imgf000389_0001
MS (ESI+, m/e) 452 (M+l) Reference Example 689 tert-Butyl (2R) -4-benzyl-2- [2- (2-methoxypyridin-3- yl) benzyl] piperazine-1-carboxylate
Figure imgf000389_0002
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+l) Reference Example 690 tert-Butyl (2R) -4-benzyl-2- [ (6-chloropyridin-2- yl) benzyl] piperazine-1-carboxylate
Figure imgf000390_0001
A mixture of tert-butyl (2R) -4-benzyl-2- (2- bromobenzyl) piperazine-1-carboxylate (445 mg) , 2-chloro-β- (tributylstannyl) pyridine (426 mg) , tetrakis (triphenylphosphine) palladium(O) (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+l) 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
Figure imgf000390_0002
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) 493 (M+l) Reference Example 692 tert-Butyl (2R) -4-benzyl-2- (2-hydroxybenzyl) piperazine-1- carboxylate
Figure imgf000391_0001
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 agueous 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+l) Reference Example 693 tert-Butyl (2R) -4-benzyl-2- (2-phenoxybenzyl) piperazine-1- carboxylate
Figure imgf000392_0001
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 4A (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+l) Reference Example 694 tert-Butyl (2R) -4-benzyl-2- [2- (1-methyl-1H-pyrazol-5- yl) benzyl] piperazine-1-carboxylate
Figure imgf000392_0002
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 ing) as an oil. MS (ESI+, m/e) 447 (M+l)
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
Figure imgf000393_0001
' MS (ESI+, m/e) 343 (M+l) Reference Example 696 tert-Butyl (3S) -3- [ (5-phenyl-1H-imidazol-1-yl) methyl]piperazine- 1-carboxylate
Figure imgf000393_0002
MS (ESI+, m/e) 343 (M+l)
Reference Example 697 l-Benzyl-3- (biphenyl-2-ylmethyl)piperazine-2, 5-dione
Figure imgf000394_0001
A mixture of (3R) -1-benzyl-3- (2-bromobenzyl) piperazine-
2,5-dione (500 nag), 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+l)
In the same manner as in Reference Example 133, the following compound (Reference Example 698) was obtained. Reference Example 698 l-Benzyl-3- (biphenyl-2-ylmethyl)piperazine
Figure imgf000394_0002
MS (ESI+, m/e) 343 (M+l) Reference Example 699 Benzyl (3S) -3- (hydroxymethyl) -4-tritylpiperazine-1-carboxylate
Figure imgf000395_0001
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+l)
Reference Example 700
Benzyl (3S) -3-{ [ (3-fluorophenyl) thio]methyl}-4-tritylpiperazine-
1-carboxylate
Figure imgf000395_0002
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+l-"Tr") Reference Example 701 Benzyl (3S)-3-{ [ (3-fluorophenyl) sulfonyl]methyl }piperazine-1- carboxylate
Figure imgf000396_0001
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+l) Reference Example 702 Benzyl (3S) -3-formyl-4-tritylpiperazine-1-carboxylate
Figure imgf000397_0001
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
Figure imgf000398_0001
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+l)
Reference Example 704
4- [4- (Benzyloxy) -3-methoxyphenyl]morpholine
Figure imgf000398_0002
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+l)
In the same manner as in Reference Example 704, the following compound (Reference Example 705) was obtained. Reference Example 705 l-Acetyl-4- [4- (benzyloxy) -3-methoxyphenyl]piperazine
Figure imgf000399_0001
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+l) Reference Example 706 2 -Methoxy- 4 -morpholinophenol
Figure imgf000399_0002
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+l)
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
Figure imgf000400_0001
1H-NMR (CDCl3) 52.14 (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+l)
Reference Example 708 4-Bromo-2-fluoro-1- [ (2-methyl-2-propen-1-yl) oxy] benzene
Figure imgf000400_0002
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) 5 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
Figure imgf000401_0001
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 IN 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
Figure imgf000402_0001
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 IN 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
Figure imgf000402_0002
(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+l-"Boc"" was obtained (a mass value of M+l was obtained for other compounds) .
Table 9
Figure imgf000404_0001
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
Figure imgf000406_0001
Table 10-2
Figure imgf000407_0002
Reference Example 735 1-tert-Butyl 4-benzyl (2R) -2- [2-
(phenylsulfinyl) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000407_0001
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+l) Reference Example 736 1-tert-Butyl 4-benzyl (2R) -2- [2- (phenylsulfonyl) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000408_0001
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+l) 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
Figure imgf000410_0001
Table 11-2
Figure imgf000411_0001
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
Figure imgf000413_0001
Table 12-2
Figure imgf000414_0001
Table 12-3
Figure imgf000415_0001
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
Figure imgf000417_0001
Table 13-2
Figure imgf000418_0001
Reference Example 804
Benzyl (3R)-3-{2-[ (4-acetylphenyl) amino] ethyl}piperazine-1- carboxylate
Figure imgf000419_0001
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-l, 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
Figure imgf000420_0001
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+l) Reference Example 806 2- [ (2R) -4-Benzyl-3, 6-dioxopiperazin-2-yl] -N-phenylacetamide
Figure imgf000420_0002
[ (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 IN 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+l) 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
Figure imgf000422_0001
Table 14-2
Figure imgf000423_0001
Reference Example 827
N-{ 2- [ (2R) -4-Benzylpiperazin-2-yl] ethyl}aniline
Figure imgf000424_0001
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 IN 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+l)
In the same manner as in Reference Example 827, the following compounds (Reference Examples 828 - 847) shown in Table 15-1 - Table 15-2 were obtained. Table 15-1
Figure imgf000425_0001
Table 15-2
Figure imgf000426_0001
Reference Example 848
N-{2-[ (2R)-4-Benzylpiperazin-2-yl]ethyl}-4- (difluoromethoxy) aniline
Figure imgf000427_0001
[ (2R) -4-Benzyl-3, 6-dioxopiperazin-2-yl] acetic acid (262 mg) and 4- (difluoroinethoxy) 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, IN 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+l)
In the same manner as in Reference Example 848, the following compounds (Reference Examples 849 - 854) shown in Table 16 were obtained.
Figure imgf000429_0001
Reference Example 855 . •
2- [ (2R) -4-Benzylpiperazin-2-yl] -N-phenylacetamide
Figure imgf000430_0001
[ (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+l)
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
Figure imgf000431_0001
MS (ESI+, m/e) 324 (M+l)
Reference Example 857
N- (3-Methoxyphenyl) -2-nitrobenzenesulfonamide
Figure imgf000431_0002
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
Figure imgf000431_0003
1H-NMR (CDCl3) 5 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
Figure imgf000432_0001
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
Figure imgf000432_0002
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-l, 3-benzothiazol-5-yl) -2-nitrobenzenesulfonamide
Figure imgf000432_0003
1H-NMR (DMSO-de) 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
Figure imgf000432_0004
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
Figure imgf000433_0001
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] aminojethyl) piperazine-1, 4- dicarboxylate
Figure imgf000433_0002
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+l)
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
Figure imgf000434_0001
MS (ESI+, m/e) 691 (M+l) Reference Example 866 1-tert-Butyl 4-benzyl (2R) -2- (2- { (2-methyl-l, 3-benzothiazol-5- yl ) [ (2-nitrophenyl) sulfonyl] aminoj ethyl) piperazine-1, 4- dicarboxylate
Figure imgf000434_0002
MS (ESI+, m/e) 696 (M+l) 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
Figure imgf000435_0001
MS (ESI+, m/e) 696 (M+l)
Reference Example 868
Benzyl (3R)-3-{2-[ (3-acetylphenyl) amino] ethyl }piperazine-l- carboxylate
Figure imgf000435_0002
1-tert-Butyl 4-benzyl (2R) -2- (2- { (3-acetylphenyl) [ (2- nitrophenyl) sulfonyl] aminojethyl) 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+l)
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
Figure imgf000436_0001
MS (ESI+, m/e) 424 (M+l) Reference Example 870 Benzyl (3R) -3- (2-{ [4- (1H-pyrazol-1- yl)phenyl] amino}ethyl) piperazine-1-carboxylate
Figure imgf000436_0002
MS (ESI+, m/e) 406 (M+l)
Reference Example 871
Benzyl (3R)-3-(2-{ (2-methoxyphenyl) [ (2- nitrophenyl) sulfonyl] amino}ethyl) piperazine-1-carboxylate
Figure imgf000437_0001
A mixture of 1-tert-butyl 4-benzyl (2R)-2-{2-
[ (methylsulfonyl) oxy] ethyl }piperazine-l, 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+l) 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
Figure imgf000438_0001
MS (ESI+, m/e) 555 (M+l) Reference Example 873
Benzyl (3R) -3- (2-{ (2-methyl-l, 3-benzothiazol-5-yl) [ (2- nitrophenyl) sulfonyl] amino}ethyl) piperazine-1-carboxylate
Figure imgf000438_0002
1-tert-Butyl 4-benzyl (2R) -2- (2-{ (2-methyl-l, 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+l)
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
Figure imgf000439_0001
MS (ESI+, m/e) 596 (M+l)
In the same manner as in Reference Example 529, the following compounds (Reference Examples 875 - 877) were obtained. Reference Example 875 l-{ [4-({ (2R)-4-Benzyl-2-[ (5-phenyl-l, 3, 4-oxadiazol-2- yl)methyl] piperazin-1-yl } carbonyl) -5-phenyl-1H-imidazol-1- yl]methyl }cyclohexanol
Figure imgf000439_0002
MS (ESI+, m/e) 617 (M+l) Reference Example 876 l-({4-[ ( (2R)-4-Benzyl-2-{2-[ (2-fluoro-4- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl }methyl) cyclohexanol
Figure imgf000439_0003
MS (ESI+, m/e) 626 (M+l) Reference Example 877 l-({4-[ ( (2R)-4-Benzyl-2-{2-[ (2-fluoro-3- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}methyl) cyclohexanol
Figure imgf000440_0001
MS (ESI+, m/e) 626 (M+l) Reference Example 878
Methyl [ (IS, 2S) -2- (4-{ [ (2R) -4-benzyl-2- (2-bromobenzyl)piperazin- 1-yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000440_0002
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). l-{ (IS, 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+l) Reference Example 879
(IS, 2R) -2- (4-{ [ (2S) -4-Benzyl-2- (hydroxymethyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol
Figure imgf000441_0001
( OIR, 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+l)
In the same manner as in Reference Example 879, the following compounds (Reference Examples 880 - 881) were obtained. Reference Example 880
(IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-bromobenzyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000442_0001
MS (ESI+, m/e) 657 (M+l) Reference Example 881 tert-Butyl (3S)-4-({l-[ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) 3- [ (phenylthio)methyl]piperazine-1-carboxylate
Figure imgf000442_0002
MS (ESI+, m/e) 621 (M+l) Reference Example 882 tert-Butyl (3S)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3- [ (phenylsulfinyl) methyl] piperazine-1-carboxylate
Figure imgf000442_0003
tert-Butyl (3S)-4-({l-[ (IR, 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+l) Reference Example 883 tert-Butyl (3S) -4- ( {1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3- [ (phenylsulfonyl)methyl]piperazine-1-carboxylate
Figure imgf000443_0001
tert-Butyl (3S) -4- ( {1- [ (IR, 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+l) Reference Example 884
(IS, 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
Figure imgf000444_0001
Α solution of 1- [ (1R,2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazole-4-carboxylic acid (200 mg) , l-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 (IS, 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 (IS, 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+l) MS (ESI+, m/e) 655 (M+l)
In the same manner as in Reference Example 884, the following compound . (Reference Example 885) was obtained. Reference Example 885 (IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-methoxybenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol and (IS, 2R) -2- (4-{ [ (2S) -4-benzyl-2- (2-methoxybenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-
1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000445_0001
MS (ESI+, m/e) 609 (M+l) MS (ESI+, m/e) 609 (M+l)
In the same manner as in Reference Example 519, the following compounds (Reference Examples 886 - 890) were obtained. Reference Example 886
(IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-morpholinobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000445_0002
MS (ESI+, m/e) 664 (M+l) Reference Example 887
(IS, 2R) -2- [4- ( { (2R) -4-Benzyl-2- [2- (2-methoxypyridin-3- yl) benzyl]piperazin-l-yl}carbonyl) ~5-phenyl-1H-imidazol-l-yl]-l~
(methoxymethyl) cyclohexanol
Figure imgf000446_0001
MS (ESI+, m/e) 686 (M+l) Reference Example 888
(IS, 2R) -2- (4-{ [ (2R) -4-Benzyl-2- (2-phenoxybenzyl)piperazin-l- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) -1-
(methoxymethyl) cyclohexanol
Figure imgf000446_0002
' MS (ESI+, m/e) 671 (M+l) Reference Example 889
(IS, 2R) -2- [4- ( { (2R) -4-Benzyl-2- [2- (l-methyl-1H-pyrazol-5- yl) benzyl]piperazin~l-yl}carbonyl) -5-phenyl-1H-imidazol-l-yl] -1- (methoxymethyl) cyclohexanol,
Figure imgf000446_0003
MS (ESI+, m/e) 659 (M+l) Reference Example 890
Benzyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3- (2-{ [3- (methoxycarbonyl) phenyl] amino}ethyl)piperazine-1- carboxylate
Figure imgf000447_0001
MS (ESI+, m/e) 710 (M+l) Reference Example 891
Benzyl (3R)-4-({l-[ (IR, 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
Figure imgf000447_0002
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+l)
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- [ (IR, 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
Figure imgf000448_0001
MS (ESI+, m/e) 867 (M+l) Reference Example 893
Benzyl (3R) -4- ( {1- [ (IR, 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
Figure imgf000448_0002
MS (ESI+, m/e) 908 (M+l)
Reference Example 894
Benzyl (3R)-4-({l-[ (IR, 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-l-carboxylate
Figure imgf000449_0001
MS (ESI+, m/e) 908 (M+l) Reference Example 895 Benzyl (3R) -4- ( {1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) - 3-{2- [ (2-methoxyphenyl) amino] ethyl}piperazine-1-carboxylate
Figure imgf000449_0002
Benzyl (3R) -4- ( {1- [ (IR, 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+l) 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- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) 3-{2- [ (3-methoxyphenyl) amino] ethyl }piperazine-1-carboxylate
Figure imgf000450_0001
MS (ESI+, m/e) 682 (M+l) Reference Example 897
Benzyl (3R)-4-({l-[ (IR, 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
Figure imgf000450_0002
MS (ESI+, m/e) 723 (M+l)
Reference Example 898
Benzyl (3R) -4- ( {1- [ (IR, 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-l- carboxylate
Figure imgf000451_0001
MS (ESI+, m/e) 723 (M+l)
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-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) -
3-{2- [ (piperidin-1-ylcarbonyl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000451_0002
MS (ESI+, m/e) 654 (M+l)
Reference Example 900 tert-Butyl (3R) -3-{2- [ (anilinocarbonyl) oxy] ethyl} -4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-l-carboxylate
Figure imgf000451_0003
MS (ESI+, m/e) 662 (M+l) Reference Example 901 [(2S)-4-benzyl-1-({l-[ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl]methyl phenylcarbamate
Figure imgf000452_0001
MS (ESI+, m/e) 638 (M+l) Reference Example 902
Benzyl (3R) -3-{2- [acetyl (phenyl) amino] ethyl} -4- ( {1- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazine-1-carboxylate
Figure imgf000452_0002
Benzyl (3R) -3- (2-anilinoethyl) -4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-iπύdazol-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+l)
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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000453_0001
MS (ESI+, m/e) 720 (M+l) Reference Example 904 tert-Butyl (3R) -3- [2- (4-bromo-2-fluorophenoxy) ethyl] -4- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000453_0002
(IS, 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+l) Reference Example 905 tert-Butyl (3R) -3-{2- [2-fluoro-4- (1H-pyrazol-1- yl) phenoxy] ethyl}-4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazine-1-carboxylate
Figure imgf000454_0001
tert-Butyl (3R) -3- [2- (4-bromo-2-fluorophenoxy) ethyl] -A- ( { 1- [ (IR, 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+l) Reference Example 906 tert-Butyl (3R) -3- [2- (1, 3-dihydro-2H-isoindol-2-yl) ethyl] -4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl) piperazine-1-carboxylate
Figure imgf000455_0001
tert-Butyl (3R)-4-({l-[ (IR, 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+l)
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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000456_0001
MS (ESI+, m/e) 658 (M+l) Reference Example 908 tert-Butyl (3R) -3- [2- (3, 4-dihydroquinolin-l (2H) -yl) ethyl] -4- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazine-1-carboxylate
Figure imgf000456_0002
MS (ESI+, m/e) 658 (M+l) Reference Example 909 tert-Butyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-im±dazol-4-yl}carbonyl) - 3- [2- (pyridin-2-ylamino) ethyl] piperazine-1-carboxylate
Figure imgf000456_0003
MS (ESI+, m/e) 619 (M+l)
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
Figure imgf000457_0001
MS (ESI+, m/e) 483 (M+l) Reference Example 911
1-tert-Butyl 4-benzyl (2R) -2-{2- [ (2-methyl-l, 3-benzoxazol-5- yl) oxy] ethyl}piperazine-1, 4-dicarboxylate
Figure imgf000457_0002
MS (ESI+, m/e) 496 (M+l) 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
Figure imgf000457_0003
MS (ESI+, m/e) 492 (M+l)
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-β- yloxy) ethyl] piperazine-1-carboxylate
Figure imgf000458_0001
MS (ESI+, m/e) 383 (M+l) Reference Example 914
Benzyl (3R)-3-{2-[ (2-methyl-1, 3-benzoxazol-5- yl) oxy] ethyl }piperazine-1-carboxylate
Figure imgf000458_0002
MS (ESI+, m/e) 396 (M+l) Reference Example 915 Benzyl (3R) -3- [2- ({4- [ (acetyloxy)methyl] -1, 3-thiazol-2- yl}thio) ethyl] piperazine-1-carboxylate
Figure imgf000458_0003
MS (ESI+, m/e) 392 (M+l) 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- [ (IR, 2R) -2- (cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) -3- [ (phenylthio)methyl] piperazine-1-carboxylate
Figure imgf000459_0001
MS (ESI+, m/e) 631 (M+l)
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- [ (IR, 2R) -2- (cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) -3- [ (phenylsulfonyl) methyl] piperazine-1-carboxylate
Figure imgf000459_0002
MS (ESI+, m/e) 663 (M+l)
Reference Example 918
2-Ethyl-l, 3-benzothiazol-5-ol and 2-isopropyl-1,3-benzothiazol-
5-ol
Figure imgf000459_0003
and
Figure imgf000459_0004
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 IN 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
Figure imgf000461_0001
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. l-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+, iti/e) 582 (M+l) 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
Figure imgf000462_0001
MS (ESI+, m/e) 568 (M+l) 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
Figure imgf000462_0002
MS (ESI+, m/e) 401 (M+l-"Boc") Reference Example 922
1-tert-Butyl 4-benzyl (2R) -2- [2- (3-methoxy-2- • methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000462_0003
MS (ESI+, m/e) 385 (M+l-vBoc")
Reference Example 923 1-tert-Butyl 4-benzyl (2R) -2- [2- (2-fluoro-4- methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000463_0001
MS (ESI+, m/e) 473 (M+l) Reference Example 924
1-tert-Butyl 4-benzyl (2R) -2- [2- (2-chloro-4- methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000463_0002
MS (ESI+, m/e) 489 (M+l) Reference Example 925
' 1-tert-Butyl 4-benzyl (2R) -2- [2- (4-chloro-2- fluorophenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000463_0003
MS (ESI+, m/e) 393 (M+l-^Boc") Reference Example 926 1-tert-Butyl 4-benzyl (2R) -2- [2- (2,3- dichlorophenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000464_0001
MS (ESI+, m/e) 409 (M+l-"Boc") Reference Example 927
1-tert-Butyl 4-benzyl (2R) -2- [2- (2-fluoro-3- methoxyphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000464_0002
MS (ESI+, m/e) 489 (M+l) Reference Example 928 1-tert-Butyl 4-benzyl (2R) -2-{2- [3- (3- methoxypropoxy) phenoxy] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000464_0003
MS (ESI+, m/e) 529 (M+l) Reference Example 929
1-tert-Butyl 4-benzyl (2R) -2-{2- [3- (2- methoxyethoxy) phenoxy] ethyl}piperazine-1,4-dicarboxylate
Figure imgf000464_0004
MS (ESI+, m/e) 515 (M+l) Reference Example 930
1-tert-Butyl 4-benzyl (2R) -2- [2- (2, 3-dihydro-1-benzofuran-6- yloxy) ethyl]piperazine-1, 4-dicarboxylate
Figure imgf000465_0001
MS (ESI+, m/e) 483 (M+l)
Reference Example 931
1-tert-Butyl 4-benzyl (2R) -2- [2- (5-methoxy-2- methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000465_0002
MS (ESI+, m/e) 485 (M+l) Reference Example 932
1-tert-Butyl 4-benzyl (2R) -2- [2- (5-chloro-2- methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000465_0003
MS (ESI+, m/e) 490 (M+l) Reference Example 933 1-tert-Butyl 4-benzyl (2R) -2- [2- (2-chloro-5- methoxyphenoxy) ethyl]piperazine-1, 4-dicarboxylate
Figure imgf000466_0001
MS (ESI+, m/e) 506 (M+l) Reference Example 934 1-tert-Butyl 4-benzyl (2R) -2- [2- (2-chloro-4- methoxyphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000466_0002
MS (ESI+, m/e) 506 (M+l) Reference Example 935
1-tert-Butyl 4-benzyl (2R) -2-{2- [ (2-cyclopropyl-1,3-benzoxazol- 5-yl) oxy] ethyl }piperazine-1, 4-dicarboxylate
Figure imgf000466_0003
MS (ESI+, m/e) 522 (M+l) 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
Figure imgf000467_0001
MS (ESI+, rα/e) 510 (M+l) Reference Example 937
1-tert-Butyl 4-benzyl (2R) -2-{2- [ (2-methyl-1,3-benzoxazol-β- yl) oxy] ethyl}piperazine-1,4-dicarboxylate
Figure imgf000467_0002
MS (ESI+, m/e) 496 (M+l) Reference Example 938 1-tert-Butyl 4-benzyl (2R) -2-{2- [ (2-ethyl-1,3-benzoxazol-5- yl) oxy] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000467_0003
MS (ESI+, m/e) 510 (M+l) 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
Figure imgf000467_0004
MS (ESI+, m/e) 524 (M+l)
Reference Example 940
1-tert-Butyl 4-benzyl (2R) -2-{2-[ (2-ethyl-1,3-benzoxazol-6- yl) oxy] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000468_0001
MS (ESI+, m/e) 510 (M+l) Reference Example 941
1-tert-Butyl 4-benzyl (2R) -2-{2- [ (2-methyl-1,3-benzoxazol-5- yl) oxy] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000468_0002
MS (ESI+, m/e) 496 (M+l) Reference Example 942 1-tert-Butyl 4-benzyl (2R) -2-{2- [3, 5- bis (trifluoromethyl) phenoxy] ethyl}piperazine-1,4-dicarboxylate
Figure imgf000468_0003
MS (ESI+, m/e) 577 (M+l) Reference Example 943 1-tert-Butyl 4-benzyl (2R) -2-{2- [3-fluoro-5- (trifluoromethyl)phenoxy] ethyl}piperazine-1,4-dicarboxylate
Figure imgf000469_0001
MS (ESI+, m/e) 527 (M+l) Reference Example 944 1-tert-Butyl 4-benzyl (2R) -2- [2- (3,5- difluorophenoxy) ethyl]piperazine-1, 4-dicarboxylate
Figure imgf000469_0002
MS (ESI+, m/e) 427 (M+l)
Reference Example 945
1-tert-Butyl 4-benzyl (2R) -2- (2-{ [3- (2-methoxy-2-oxoethyl) -2, 3- dihydro-1-benzofuran-5-yl] oxyjethyl) piperazine-1, 4-dicarboxylate
Figure imgf000469_0003
MS (ESI+, m/e) 555 (M+l) Reference Example 946
1-tert-Butyl 4-benzyl (2R) -2- [2- (4-tert- butylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000470_0001
MS (ESI+, m/e) 497 (M+l) Reference Example 947 1-tert-Butyl 4-benzyl (2R) -2- [2- (3,4- dimethylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000470_0002
MS (ESI+, m/e) 469 (M+l) Reference Example 948
1-tert-Butyl 4-benzyl (2R) -2-{2- [4- isopropylphenoxy] ethyl }piperazine-1, 4-dicarboxylate
Figure imgf000470_0003
MS (ESI+, m/e) 483 (M+l)
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
Figure imgf000471_0001
MS (ESI+, m/e) 488 (M+l) Reference Example 950
1-tert-Butyl 4-benzyl (2R) -2-{2- [ (2-fluoro-3- methoxyphenyl) amino] ethyl }piperazine-1,4-dicarboxylate
Figure imgf000471_0002
MS (ESI+, m/e) 488 (M+l) 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
Figure imgf000471_0003
MS (ESI+, m/e) 483 (M+l) 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
Figure imgf000472_0001
MS (ESI+, m/e) 482 (M+l) Reference Example 953
Benzyl (3R)-3-(2-{ [1- (2-methoxyethyl) -2-oxo-1,2, 3, 4- tetrahydroquinolin-β-yl] oxy}ethyl) piperazine-1-carboxylate
Figure imgf000472_0002
MS (ESI+, m/e) 468 (M+l) Reference Example 954 Benzyl (3R) -3- [2- (3, 4-dimethoxyphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000472_0003
MS (ESI+, m/e) 401 (M+l) Reference Example 955
Benzyl (3R) -3- [2- (3-methoxy-2-methylphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000472_0004
MS (ESI+, m/e) 385 (M+l)
Reference Example 956
Benzyl (3R) -3- [2- (2-fluoro-4-methylphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000473_0001
MS (ESI+, m/e) 373 (M+l) Reference Example 957
Benzyl (3R) -3- [2- (2-chloro-4-methylphenoxy) ethyl]piperazine-l- carboxylate
Figure imgf000473_0002
MS (ESI+, m/e) 389 (M+l) Reference Example 958 Benzyl (3R) -3- [2- (4-chloro-2-fluorophenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000473_0003
MS (ESI+, m/e) 393 (M+l) Reference Example 959
Benzyl (3R) -3- [2- [2, 3-dichlorophenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000474_0001
MS (ESI+, m/e) 409 (M+l) Reference Example 960
Benzyl (3R) -3- [2- (2-fluoro-3-methoxyphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000474_0002
MS (ESI+, m/e) 389 (M+l) Reference Example 961 Benzyl (3R) -3- {2- [3- (3-methoxypropoxy)phenoxy] ethyl}piperazine-- 1-carboxylate
Figure imgf000474_0003
MS (ESI+, m/e) 429 (M+l) Reference Example 962
Benzyl (3R) -3-{2- [3- (2-methoxyethoxy)phenoxy] ethyl}piperazine-l- carboxylate
Figure imgf000474_0004
MS (ESI+, m/e) 415 (M+l) Reference Example 963 Benzyl '(3R) -3- [2- (2, 3-dihydro-1-benzofuran-6- yloxy) ethyl] piperazine-1-carboxylate
Figure imgf000475_0001
MS (ESI+, m/e) 383 (M+l) Reference Example 964
Benzyl (3R) -3- [2- (5-methoxy-2-methylphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000475_0002
' MS (ESI+, m/e) 385 (M+l) Reference Example 965
Benzyl (3R) -3- [2- (5-chloro-2-methylphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000475_0003
MS (ESI+, m/e) 390 (M+l)
Reference Example 966
Benzyl (3R) -3- [2- (2-chloro-5-methoxyphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000476_0001
MS (ESI+, m/e) 406 (M+l) Reference Example 967
Benzyl (3R) -3- [2- (2-chloro-4-methoxyphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000476_0002
MS (ESI+, m/e) 406 (M+l) Reference Example 968 Benzyl (3R) -3-{2- [ (2-cyclopropyl-1,3-benzoxazol-5- yl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000476_0003
MS (ESI+, m/e) 422 (M+l) Reference Example 969
Benzyl (3R)-3-{2-[ (2, 7-dimethyl-1,3-benzoxazol-6- yl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000476_0004
MS (ESI+, m/e) 410 (M+l)
Reference Example 970
Benzyl (3R)-3-{2-[ (2-methyl-1, 3-benzoxazol-6- yl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000477_0001
MS (ESI+, m/e) 396 (M+l) Reference Example 971
Benzyl (3R) -3-{2- [ (2-ethyl-1,3-benzoxazol-5- yl) oxy] ethyl }piperazine-1-carboxylate
Figure imgf000477_0002
MS (ESI+, m/e) 410 (M+l) Reference Example 972 Benzyl (3R) -3-{2- [ (2-ethyl-7-methyl-l, 3-benzoxazol-6- yl) oxy] ethyl }piperazine-1-carboxylate
Figure imgf000477_0003
MS (ESI+, m/e) 424 (M+l) Reference Example 973
Benzyl (3R)-3-{2-[ (2-ethyl-1,3-benzoxazol-6- yl) oxy] ethyl}piperazine-1-carboxylate
Figure imgf000478_0001
MS (ESI+, m/e) 410 (M+l) Reference Example 974
Benzyl (3R)-3-{2-[ (2-methyl-1,3-benzoxazol-5- yl) oxy] ethyl}p±perazine-1-carboxylate
Figure imgf000478_0002
MS (ESI+, m/e) 396 (M+l) Reference Example 975 Benzyl (3R)-3-{2- [3,5- bis (trifluoromethyl) phenoxy] ethyl }piperazine-1-carboxylate
Figure imgf000478_0003
MS (ESI+, m/e) 477 (M+l) Reference Example 976
Benzyl (3R) -3-{2- [3-fluoro-5-
(trifluoromethyl) phenoxy] ethyl}piperazine-1-carboxylate
Figure imgf000479_0001
MS (ESI+, m/e) 427 (M+l) Reference Example 977
Benzyl (3R) -3- [2- (3, 5-difluorophenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000479_0002
MS (ESI+, m/e) 327 (M+l) Reference Example 978 Benzyl (3R) -3- (2-{ [3- (2-methoxy-2-oxoethyl) -2, 3-dihydro-1- ' benzofuran-5-yl] oxy}ethyl) piperazine-1-carboxylate
Figure imgf000479_0003
MS (ESI+, m/e) 455 (M+l) Reference Example 979
Benzyl (3R) -3- [2- (4-tert-butylphenoxy) ethyl]piperazine-1- carboxylate
Figure imgf000480_0001
MS (ESI+, m/e) 397 (M+l) Reference Example 980
Benzyl (3R) -3- [2- (3, 4-dimethylphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000480_0002
MS (ESI+, m/e) 369 (M+l) Reference Example 981 Benzyl (3R) -3-{2- [4-isopropylphenoxy] ethyl}piperaz±ne-l- carboxylate
Figure imgf000480_0003
MS (ESI+, m/e) 383 (M+l) Reference Example 982
Benzyl (3R) -3-{2- [ (5-chloro-2- methylphenyl) amino] ethyl }piperazine-1-carboxylate
Figure imgf000480_0004
MS (ESr+, m/e) 388 (M+l)
Reference Example 983
Benzyl (3R) -3- { 2- [ (2-fluoro~3- methoxyphenyl) amino] ethyl }piperazine-1-carboxylate
Figure imgf000481_0001
MS (ESI+, m/e) 388 (M+l) Reference Example 984
Benzyl (3R) -3- [2- (2, 3-dihydrofuro [3, 2-b]pyridin-5- ylamino) ethyl] piperazine-1-carboxylate
Figure imgf000481_0002
MS (ESI+, m/e) 383 (M+l)
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
Figure imgf000481_0003
MS (ESI+, m/e) 345 (M+l)
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) acet.amide
Figure imgf000482_0001
MS (ESI+, m/e) 366 (M+l) Reference Example 987 2- [ (2R) -4-Benzyl-3, 6-dioxopiperazin-2-yl] -N- (5-fluoro-2- methylphenyl) acetamide
Figure imgf000482_0002
MS (ESI+, m/e) 370 (M+l) Reference Example 988
2- [ (2R) -4-Benzyl-3, 6-dioxopiperazin-2-yl] -N- (2-fluoro-3- ' methoxyphenyl) acetamide
Figure imgf000482_0003
MS (ESI+, m/e) 386 (M+l)
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
Figure imgf000483_0001
MS (ESI+, m/e) 324 (M+l) Reference Example 990
N-{2-[ (2R) -4-Benzylpiperazin-2-yl] ethyl }-5-fluoro-2- methylaniline
Figure imgf000483_0002
MS (ESI+, m/e) 328 (M+l) Reference Example 991 N-{2-[ (2R)-4-Benzylpiperazin-2-yl]ethyl}-2-fluoro-3- methoxyaniline
Figure imgf000483_0003
MS (ESI+, m/e) 344 (M+l) 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
Figure imgf000484_0001
MS (ESI+, rα/e) 377 (M+l-Boc) Reference Example 993
1-tert-Butyl 4-benzyl (2R) -2- [2- (naphthalen-2- yloxy) ethyl]piperazine-1, 4-dicarboxylate
Figure imgf000484_0002
MS (ESI+, m/e) 391 (M+l-Boc) Reference Example 994 1-tert-Butyl 4-benzyl (2R) -2- [2- (4- methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000484_0003
MS (ESI+, m/e) 355 (M+l-Boc) Reference Example 995
1-tert-Butyl 4-benzyl (2R) -2- [2- (3-methoxy-4- methylphenoxy) ethyl] piperazine-1, 4-dicarboxylate
Figure imgf000484_0004
MS (ESI+, m/e) 385 (M+l-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
Figure imgf000485_0001
MS (ESI+, m/e) 377 (M+l)
Reference Example 997
Benzyl (3R) -3- [2- (naphthalen-2-yloxy) ethyl] piperazine-1- carboxylate
Figure imgf000485_0002
MS (ESI+, m/e) 391 (M+l)
Reference Example 998
Benzyl (3R) -3- [2- (4-methylphenoxy) ethyl] piperazine-1-carboxylate
Figure imgf000485_0003
MS (ESI+, m/e) 385 (M+l) Reference Example 999
Benzyl (3R) -3- [2- (3-methoxy-4-methylphenoxy) ethyl] piperazine-1- carboxylate
Figure imgf000486_0001
MS (ESI+, m/e) 385 (M+l) Reference Example 1000
Benzyl (3R) -3- [2- (2, 3-dihydro-1H-inden-2-yloxy) ethyl]piperazine- 1-carboxylate
Figure imgf000486_0002
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+l) 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
Figure imgf000487_0001
MS (ESI+, m/e) 670 (M+l) Reference Example 1002
(lS,2S)-2-(4-{ [ (2R) -4-Benzyl-2- (3, 5-difluorobenzyl) piperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexanamine
Figure imgf000487_0002
tert-Butyl [ (IS, 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+l) Reference Example 1003 l-[ (lS,2S)-2-{ [ (Cyclobutyloxy) carbonyl] amino}cyclohexyl] -5- phenyl-1H-imidazole-4-carboxylic acid
Figure imgf000488_0001
Ethyl 1- [ (IS, 2S) -2-aminocyclohexyl] -5-phenyl-1H-imidazole- • 4-carboxylate (1.57 g) and DMAP (916 rag) 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 IN 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- [ (IS, 2S) -2- { [ (cyclobutyloxy) carbonyl] aminoJcyclohexyl] -5-phenyl-1H- imidazole-4-carboxylate (1.22 g) as an amorphous solid. The obtained ethyl 1- [ (IS, 2S) -2- { [ (cyclobutyloxy) carbonyl] aminoJcyclohexyl] -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 wa_s 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-de) 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 l- [ (lS, 2S) -2- { [ (2-Methoxyethoxy) carbonyl] amino J cyclohexyl] -5- phenyl-1H-imidazole-4-carboxylic acid
Figure imgf000489_0001
Ethyl 1- [ (IS, 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- [ (IS, 2S) -2-{ [ (2- methoxyethoxy) carbonyl] amino}cyclohexyl] -5-phenyl-1H-imidazole- 4-carboxylate (1.20 g) . The obtained ethyl 1- [ (IS, 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 l-{ (IS, 2S) -2- [ (Methylsulfonyl) amino] cyclohexyl} -5-phenyl-1H- imidazole-4-carboxylic acid
Figure imgf000490_0001
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 l-{ (IS, 2S) -2- [ (isopropoxycarbonyl) amino] cyclohexyl}-5- phenyl-1H-imidazole-4-carboxylate
Figure imgf000490_0002
1H-NMR (CDCl3) δ: ppm 1.12-1.23 (HH, 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 l-{ (IS, 2S) -2- [ (Isopropoxycarbonyl) amino] cyclohexyl}-5-phenyl-1H- imidazole-4-carboxylic acid
Figure imgf000491_0001
1H-NMR (DMSOd6) δ: 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)
(IR, 2S) -2- (4-{ [ (2R) -2- (3, 5-Difluorobenzyl) piperazin-1- yl]carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexanol hydrochloride
Figure imgf000491_0002
A solution of l-[ (IS, 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 (IR, 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+l) Example 2 (Method B) (2R) -2-Benzyl-1- ( { 1- [ (IR, 2R) -2- (benzyloxy) cyclopentyl] -5-phenyl- 1H-imidazol-4-yl}carbonyl)piperazine
Figure imgf000492_0001
A solution of 1- [ (IR, 2R) -2- (benzyloxy) cyclopentyl] -5- phenyl-1H-imidazole-4-carboxylic acid (460 mg) , tert-butyl (3R)- 3-benzylpiperazine-1-carboxylate (368 mg) , WSOHCl (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- [ (IR, 2R) -2- (benzyloxy) cyclopentyl] -5-phenyl-1H- imidazol-4--yi}carbonyl)ρiperazine-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 (ESIH-, m/e) 521 (M+l) Example 3 (Method C)
(IS, 2R) -2- (4-{ [ (2R) -2- (2, 4-Dichlorobenzyl) piperazin-1- yl]carbonyl}-5-phenyl-lB-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol hydrochloride
Figure imgf000493_0001
A solution of 1- [ (IR, 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- [ (IR, 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+l) Example 4 (Method D) l-[ (4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H- imidazol-1-yl)methyl] cyclohexanol
Figure imgf000494_0001
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-({l-[ (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+l) Example 5 (Method E) l-[ (lS)-1-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) ethyl] cyclohexanol hydrochloride
Figure imgf000495_0001
Ethyl 1- [ (IS) -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- [ (IS) -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+l) Example 6 (Method F)
Methyl [ (1S,2S) -2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000496_0001
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+l) Example 7 (Method G) trans-2- (4-{ [ (2R) -2-Benzylpiperazin-l-yl] carbonyll-S-phenyl-1H- imidazol-1-yl) cycloheptanol
Figure imgf000497_0001
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+l)
Example 8 (Method H) cis-2- (4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cycloheptanol hydrochloride
Figure imgf000497_0002
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+l) Example 9 (Method I) (lS,2R)-2-{4-[( (2R)-2-{2-[(2,6-Dimethylpyridin-3- yl) oxy] ethyl}piperazin-l-yl) carbonyl] -5-phenyl-1H-imidazol-1- yl}-1- (methoxymethyl) cyclohexanol dihydrochloride
Figure imgf000498_0001
A solution of 1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazole-4-carboxylic acid (165 mg) , benzyl (3R) -3-{2- [ (2, β-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-({l-[(lR,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+l) Example 10 (Method J)"
(IS, 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
Figure imgf000499_0001
A solution of 1- [ (IR, 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- [ (IR, 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+l) Example 11 (Method K) (IS, 2R) -2- [4- ( { (2R) -2- [2- (2-Chlorophenoxy) ethyl] piperazin-1- yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000500_0001
A mixture of 1- [ (IR, 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- [ (IR, 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+l) ' Example 12 (Method L) l-{2- [ (2R) -1- ( {1- [ (IR, 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
Figure imgf000501_0001
A solution of 1- [ (IR, 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- [ (IR, 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-l-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+l) Example .13 (Method M) l-{2-[ (2R)-1-({l-[ (lR,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
Figure imgf000502_0001
A solution of l-[ (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 IUg), 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-inethanol (1:0 - 17:3) was concentrated under reduced pressure to give benzyl (3R) -4- ({1- [ (IR, 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 7O0C 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+l) Example 14 (Method N) l-{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
Figure imgf000503_0001
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] piρerazine-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+l) Example 15 (Method O)
Methyl 4-{2-[ (2R) -1- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl]ethoxy}benzoate
Figure imgf000505_0001
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-l-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+l)
In the same manner as in the above-mentioned Example 1 (Method A) - Example 15 (Method 0) , 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.
Figure imgf000506_0001
Figure imgf000507_0001
Table 17-3
Figure imgf000508_0001
Table 18-1
Figure imgf000509_0001
Table 18-2
Figure imgf000510_0001
Table 18-3
Figure imgf000511_0001
Table 18-4
Figure imgf000512_0001
Table 18-5
Figure imgf000513_0001
Table 18-6
Figure imgf000514_0001
Ex. No. R1 R2 Method Salt MS(ESI+)
Figure imgf000514_0002
Figure imgf000515_0001
Table 18-8
Figure imgf000516_0001
Table 18-9
Figure imgf000517_0001
Figure imgf000518_0001
Table 19-1
Figure imgf000519_0001
Table 19-2
Figure imgf000520_0001
Table 20-1
Figure imgf000521_0001
Ex. No. R1 R2 R3 Method Salt MS(ESI+)
Figure imgf000521_0002
Table 20-2
Figure imgf000522_0001
Table 21-1
Figure imgf000523_0001
Table 21-2
Figure imgf000524_0001
Table 21-3
Figure imgf000525_0001
Table 21-4
Figure imgf000526_0001
Table 22-1
Figure imgf000527_0001
Ex. No. R Method Salt MS(ESI+)
218 OH — 443
Figure imgf000527_0002
223 V H 3HCI 520
Figure imgf000527_0003
228 >—OMe L — 549
Figure imgf000527_0004
Table 22-2
Figure imgf000528_0001
Table 22-3
Figure imgf000529_0001
Table 22-4
Figure imgf000530_0001
Table 22-5
Figure imgf000531_0001
Table 22-6
Figure imgf000532_0001
Table 22-7
Figure imgf000533_0001
Table 22-8
Figure imgf000534_0001
Table 22-9
Figure imgf000535_0001
Table 22-10
Figure imgf000536_0001
Table 22-11
Figure imgf000537_0001
Table 22-12
Figure imgf000538_0001
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]- 5-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- [ (IR, 2R) -2- (benzyloxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl }carbonyl) piperazine Example 24: (2R) -2-Benzyl-1- ( {1- [ (IS, 2S) -2- (benzyloxy) cyclohexyl] -5-phenyl-1H-±midazol-4- yl } carbonyl) piperazine
Example 25: 1-{1- [ (l-Cyclohexyl-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazin-2-yl}-2-methylpropan-2-ol Example 26: (IS, 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: (IS, 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] -A- hydroxycyclohexyllmorpholin-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: l-[(S)-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) (phenyl) methyl] cyclohexanol hydrochloride
Example 38: l-[(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: l-{ [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: (IS, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexanol Example 44: (IR, 2R) -2- (4-{ [.(2R) -2-Benzylpiperazin-1- ylj 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: (IS, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl acetate hydrochloride
Example 48: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) cyclohexyl 4- nitrobenzoate hydrochloride Example 49: Ethyl [ (IR, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate Example 50: (2R) -2-Benzyl-1- ( { 1- [ (IS, 2R) -2-fluorocyclohexyl] -5- phenyl-1H-imidazol-4-yl}carbonyl)piperazine Example 51: (2R) -1- ( {1- [ (IS, 2R) -2-Azidocyclohexyl] -5-phenyl-1H- imidazol-4-yl} carbonyl) -2-benzylpiperazine Example 52: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexanamine dihydrochloride Example 53: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -N- (cyclopropylmethyl) cyclohexanamine dihydrochloride Example 54: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -N,N- bis (cyclopropylmethyl) cyclohexanamine dihydrochloride Example 55: N- [ (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl } -5-phenyl-1H-imidazol-1- yl) cyclohexyl] cyclopropanecarboxamide Example 56: N- [ (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- ' yl] carbonyl }-5-phenyl-1H-imidazol-1- yl) cyclohexyl] cyclopropanesulfonamide
Example 57: N- [ (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] butanamide Example 58: N- [ (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexyl] -N' -ethylurea Example 59: (IS, 2S) -2- [4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5- (2, 3-difluorophenyl) -1H-imidazol-1- yl] cyclohexanol Example 60: (IS, 2S) -2- [4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5- (3-fluorophenyl) -1H-imidazol-1-yl] cyclohexanol Example 61: (IS, 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- [ (IS, 2S) -2- (3- methoxypropoxy) cycloheptyl] -5-phenyl-1H-imidazol-4- yl }carbonyl) piperazine hydrochloride Example 64: (IS, 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- [ (IS, 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- [ (IS, 2S) -2- (3- methoxypropoxy) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazine hydrochloride
Example 68: (2R) -1- ( { 1- [ (IS, 2S) -2- (Allyloxy) cyclohexyl] -5- phenyl-1H-imidazol-4-yl}carbonyl) -2-benzylpiperazine hydrochloride
Example 69: (IS, 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: (IS, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexyl (ethyl) (methyl) carbamate hydrochloride Example 74: (IS, 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-l-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: (IS, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexanamine Example 80: N- (3-{ [ (IS, 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: (IS, 2R) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1-butylcyclohexanol hydrochloride
Example 84: (IR, 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- [ (IS, 2S) -2- propoxycyclohexyl] -1H-imidazol-4-yl}carbonyl) piperazine hydrochloride Example 90: (2R) -2-Benzyl-1- ( {1- [ (IS, 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- [ (IS, 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: l-(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- [ (IS) -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- [ (IS, 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 llβ: 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, l-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: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl]carbonyl}-5-phenyl-1H-imidazol-1-yl)-1-[ (1, 3-thiazo.l-2- ylmethoxy) methyl] cyclohexanol hydrochloride
Example 124: Ethyl [ (IR, 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: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylp±perazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1-{ [3- (dimethylamino)propoxy]methyl} cyclohexanol hydrochloride Example 127: (IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- [ (pyridin-2- ylmethoxy) methyl] cyclohexanol dihydrochloride Example 128: (IR, 2S) -1- [ (1H-Benzimidazol-2-ylmethoxy) methyl] -2- (4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol- 1-yl) cyclohexanol
Example 129: (IR, 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 [ (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbqnyl } -5-phenyl-1H-imidazol-1- yl) cyclohexyl] (methyl) carbamate
Example 131: Ethyl [ (IS, 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: (IR, 2S) -2- (4-{ [ (2R) -2- (4-Fluorobenzyl)piperazin-1- yl] carbonylJ-5-phenyl-1H-imidazol-1-yl) cyclohexanol hydrochloride
Example 134: (IR, 2S) -2- (5-Phenyl-4-{ [ (2S) -2- (2, 2, 2-trifluoro-1- hydroxyethyl)piperazin-1-yl] carbonyl}-1H-imidazol-1- yl) cyclohexanol Example 135: (IR, 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: (IR, 2S) -2- (4-{ [ (2R) -2- (2-Fluorobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexanol hydrochloride
Example 138: (IR, 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: (IR, 2S) -2- [5-Phenyl-4- ( { (2R) -2- [3- (trifluoromethyl) benzyl]piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol hydrochloride
Example 141: (IR, 2S) -2- [5-Phenyl-4- ( { (2R) -2- [4-
(trifluoromethyl) benzyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol hydrochloride ' Example 142: (IR, 2S) -2- (4-{ [ (2R) -2- (2, 3-Dihydro-1H-inden-2- yl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexanol hydrochloride
Example 143: 2-{ [ (2S) -1- ( {1- [ (IS, 2R) -2-Hydroxycyclohexyl] -5- phenyl-1H-imidazol-4-yl}carbonyl) piperazin-2- yl]methoxy}benzonitrile
Example 144: (IR, 2S) -2- (4-{ [ (2S) -2- (Phenoxymethyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexanol
Example 145: (IR, 2S) -2- (4-{ [ (2S) -2- (Phenoxymethyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexanol hydrochloride
Example 146: (IR, 2S) -2- (5-Phenyl-4-{ [ (2R) -2- (2, 4, 5- trifluorobenzyl) piperazin-1-yl] carbonyl} -1H-imidazol-1- yl) cyclohexanol hydrochloride
Example 147: (IR, 2S) -2- [5-Phenyl-4- ( { (2R) -2- [2- (trifluoromethyl) benzyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl]cyclohexanol hydrochloride Example 148: (IR, 2S) -2- [4- ({ (2S) -2- [ (3, 5-
Difluorophenoxy)methyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexanol hydrochloride Example 149: (IR, 2S) -2- [4- ({ (2S) -2- [ (2, 6-
Difluorophenoxy) methyl] piperazin-l-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexanol hydrochloride Example 150: (IR, 2S) -2- [5-Phenyl-4- ( { (2S) -2- [ (pyridin-2- yloxy)methyl]piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol dihydrochloride
Example 151: (IR, 2S) -2- (4-{ [ (2R) -2- (2-Phenoxyethyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexanol Example 152: Isopropyl [ (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate Example 153: Isobutyl [ (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate Example 154: 2-Methoxyethyl [ (IS, 2S) -2- (4-{ [ (2R) -2- benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate ' Example 155: Ethyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (2- fluorobenzyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Example 156: Ethyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (3- fluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Example 157: Ethyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (4- fluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- 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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5- difluorobenzyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate Example 160: Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (4- cyanobehzyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Example 161: Methyl { (IS, 2S) -2- [4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5- (3-fluorophenyl) -1H-imidazol-1- yl] cyclohexyl} carbamate
Example 162: Ethyl { (IS, 2S) -2- [4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5- (3-fluorophenyl) -1H-imidazol-1- yl] cyclohexyl }carbamate
Example 163: Methyl [ (IS, 2S) -2- (5-phenyl-4-{ [ (2R) -2- (2- phenylethyl) piperazin-1-yl] carbonyl }-1H-imidazol-1- yl) cyclohexyl] carbamate
Example 164: Methyl { (IS, 2S) -2- [5-phenyl-4- ( { (2S) -2-
[ (phenylthio) methyl] piperazin-1-yl }carbonyl) -1H-imidazol-1- yl] cyclohexyl }carbamate Example 165: Methyl [ (IS, 2S) -2- (4-{ [ (2S) -2-
(phenoxymethyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Example 166: Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (2- phenoxyethyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Example 167: Methyl { (IS, 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 [ (IS, 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- [ (IR, 2S) -2-Hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl)piperazin-2-yl]methylJbenzonitrile hydrochloride Example 170: (IS, 2R) -2- (4-{ [ (2R) -2- (Cyclohexylmethyl) piperazin- 1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol hydrochloride
Example 171: (IS, 2R) -2- (4-{ [ (2R) -2-Isobutylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol hydrochloride Example' 172: (IS, 2R) -2- (4-{ [ (2R) -2-Isopropylpiperazin-1- yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol hydrochloride
Example 173: (IS, 2R) -2- [4-( { (2S) -2- [ (Cyclopropyl) (hydroxy) methyl] piperazin-1-yl}carbonyl) -5-phenyl- 1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol hydrochloride
Example 174: (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2R) -2-
(pyridin-2-ylmethyl) piperazin-1-yl] carbonyl}-1H-imidazol-1- yl) cyclohexanol Example 175: (IS, 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: (IS, 2R) -2- [4-{ [ (2R) -2- (4-Fluorobenzyl) piperazin-1- yl] carbonyl} -5- (3-fluorophenyl) -1H-imidazol-1-yl] -1-
(methoxymethyl) cyclohexanol
Example 178: (IS, 2R) -2- [4-{ [ (2R) -2- (3-Fluorobenzyl)piperazin-1- yl] carbonyl} -5- (3-fluorophenyl) -1H-imidazol-1-yl] -1-
(methoxymethyl) cyclohexanol
Example 179: (IS, 2R) -2- (4-{ [ (2R) -2- (4-Methoxybenzyl) piperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol hydrochloride Example 180: (IS, 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: (IS, 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- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -1H-imidazol-4- yl }carbonyl) piperazin-2-yl]methyl }benzonitrile
Example 183: (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2R) -2- (1, 3-thiazol-4-ylmethyl) piperazin-1-yl] carbonyl }-1H-imidazol-1- yl) cycl'ohexanol dihydrochloride
Example 184: (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2R) -2-
(2-phenylethyl)piperazin-1-yl] carbonyl}-1H-imidazol-1- yl) cyclohexanol hydrochloride Example 185: (IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2R) -2- (4- morpholinobenzyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-
1-yl) cyclohexanol dihydrochloride
Example 186: (IS, 2R) -2- (4-{ [ (2R) -2- (2,2-
Dimethylpropyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-1- yl) -1- (methoxymethyl) cyclohexanol hydrochloride
Example 187: (IS, 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: (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2S) -2- (1H-I, 2, 4-triazol-l-ylmethyl) piperazin-1-yl] carbonyl}-1H- imidazol-1-yl) cyclohexanol
Example 189: (IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2S) -2-
(phenoxymethyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-1- yl) cyclohexanol hydrochloride ' Example 190: (IS, 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-l-yl) -1- (methoxymethyl) cyclohexanol hydrochloride
Example 192: 3, 5-Difluoro-N-{ [ (2S) -1- ( {1- [ (IR, 2S) -2-hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl]methyl }benzamide hydrochloride
Example 193: (IS, 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: (IS, 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: (IS, 2R) -2- (4-{ [ (2S) -2- (1H-I, 2, 3-Benzotriazol-1- ylmethyl)piperazin-l-yl] carbonyl }-5-phenyl-1H-imidazol-l-yl)-1- (methoxymethyl) cyclohexanol
Example 196: (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2S) -2- ( { [6- (trifluoromethyl)pyridin-2-yl]oxy}methyl)piperazin-l- yl] carbonyl}-1H-imidazol-1-yl) cyclohexanol
Example 197: (IS, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl]methoxy}nicotinate trihydrochloride Example 199: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2- (4-{ [ (2S) -2- (1H-Benzimidazol-1- ylmethyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Example 205: (IS, 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: (IS, 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 : (IS, 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: (IS, 2R) -2- (4-{ [ (2R) -2- (1H-Benzimidazol-2- ylmethyl) piperazin-1-yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol
Example 209: (IS, 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: (IS, 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: (IS, 2R) -2- (4-{ [ (2R) -2- (3-Hydroxypropyl) piperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol
Example 212: (IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2R) -2- (3- phenoxypropyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-1- yl) cyclohexanol
Example 213: (IS, 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: (IS, 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 l-{3- [ (2R) -1- ( {1- [ (IR, 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: (IS, 2R) -2- (4-{ [ (2S) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol
Example 217: (IS, 2R) -2- [5- (3-Fluorophenyl) -4- ( { (2R) -2- [2- (2- methoxyphenoxy) ethyl] piperazin-1-yl} carbonyl) -1H-imidazol-1-yl] - 1- (meth'oxymethyl) cyclohexanol
Example 218: (IS, 2R) -2- (4-{ [ (2R) -2- (2-Hydroxyethyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol Example 219: (IS, 2R) -2- [4- ({ (2R) -2- [2-
(Cyclopropylmethoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Example 220: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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 : (IS, 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: (IS, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethoxy}phenyl) ethanone Example 234: (IS, 2R) -2-{4- [ ( (2R) -2-{2- [4- (1H-Imidazol-1- yl) phenoxy] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol- l-yl}-1- (methoxymethyl) cyclohexanol
Example 235: (IS, 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: (IS, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethoxy} isoxazole-5-carboxylate bistrifluoroacetate
Example 238: (IS, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethoxy} -N, N-dimethylbenzamide Example 243: (IS, 2R) -2-{ 4- [ ( (2R) -2-{2- [4- (Azetidin-1- ylcarbonyl) phenoxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}-l- (methoxymethyl) cyclohexanol Example 244: (IS, 2R) -2- [4- ({ (2R) -2- [2- (3- Fluorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] -1- (methoxymethyl) cyclohexanol Example 245: (IS, 2R) -2- [4- ({ (2R) -2- [2- (4- Fluorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] -1- (methoxymethyl) cyclohexanol Example 246: (IS, 2R) -1- (Methoxymethyl) -2- [4- ({ (2R) -2- [2- (2- methoxyphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexanol Example 247: (IS, 2R) -1- (Methoxymethyl) -2- [4- ({ (2R) -2- [2- (3- methoxyphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexanol
Example 248: (IS, 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: (IS, 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: (IS, 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- [ (IR, 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: (IS, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxyjnicotinate dihydrochloride Example 254: 6-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxy}-3, 4-dihydronaphthalen-l (2H) - one hydrochloride
Example 255: (IS, 2R) -2- [4- ({ (2R) -2- [2- (3- Chlorophenoxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] -1- (methoxymethyl) cyclohexanol Example 256: (IS, 2R) -2- [4- ({ (2R) -2- [2- (4- ' Chlorophenoxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] -1- (methoxymethyl) cyclohexanol Example 257: (IS, 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: (IS, 2R) -1- (Methoxymethyl) -2-{5-phenyl-4- [( (2R) -2- {2- [4- (1H-I, 2, 3-triazol-1-yl)phenoxy] ethyl}piperazin-1- yl) carbonyl] -1H-imidazol-1-yl}cyclohexanol dihydrochloride Example 259: (IS, 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: (IS, 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-l-yl) carbonyl] -5-phenyl- 1H-imidazol-l-yl}-1- (methoxymethyl) cyclohexanol dihydrochloride Example 263: 4-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl)p±perazin-2-yl] ethoxy}-N- (2,2,2- trifluoroethyl) benzamide Example 264: 6-{2- [ (2R) -1- ( {1- [ (IR, 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: (IS, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yljcarbonyl) piperazin-2-yl] ethoxy}pyridine-2-carboxylate dihydrochloride ' Example 267: (IS, 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: (IS, 2R) -2-{4- [ ( (2R) -2-{2- [4- (4-Acetylpiperazin-1- yl) phenoxy] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol- l-yl}-1- (methoxymethyl) cyclohexanol dihydrochloride Example 269: Ethyl 4-{2- [ (2R) -1- ( { 1- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yljcarbonyl) piperazin-2-yl] ethoxy} -1H-pyrazol-4-yl) acetate hydrochloride Example 277: (IS, 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- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethoxy}phenyl) ethanone Example 281: (IS, 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: (IS, 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- [ (IR, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxy}-3-methoxybenzoate dihydrochloride
Example 285: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2- [4- ( { (2R) -2- [2- (2, 6-Dimethoxy-4- methylphenoxy) ethyl] piρerazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] -1- (methoxymethyl) cyclohexanol hydrochloride Example 293: 7-{2- [ (2R) -1- ({1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl]ethoxy}-6-methoxy-2H-chrorαen-2-one Example 294: 1- (4-{2- [ (2R) -1- ( { 1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethoxy}phenyl) pyrrolidin-2-one Example 295: (IS, 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: (IS, 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: (IS, 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- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethoxy} -3, 4-dihydroisoquinolin-l (2H) one
Example 301: (IS, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethoxy}-3-methoxyphenyl) acetate dihydrochloride Example 303: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2- [4- ( { (2R) -2- [2- (1H-I, 2, 3-Benzotriazol-1- yl) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1-
(methoxymethyl) cyclohexanol
Example 315: (IS, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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 l-{2- [ (2R) -1- ( {1- [ (IR, 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: (IS, 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: l-{2- [ (2R) -1- ( {1- [ (IR, 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 l-{2- [ (2R) -1- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethyl } -1H-indazole-4-carboxylate
Example 323: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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 l-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethyl} -1H-I, 2, 3-triazole-4- carboxylate
Example 331: Methyl l-{2- [ (2R) -1- ( {1- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethyl }-1H-I, 2, 3-triazol-4-yl) ethanone Example 334: Ethyl l-{2- [ (2R) -1- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethyl }-1H-pyrazole-4-carboxylate Example 335: Methyl l-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl] ethyl }-1H-pyrrole-3-carboxylate Example 336: Ethyl l-{2- [ (2R) -1- ( {1- [ (IR, 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- [ (IR, 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 l-{2- [ (2R) -1- ( { 1- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl }carbonyl) piperazin-2-yl] ethyl } -1H-pyrazole-5-carboxylate ' Example 341: l-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl }carbonyl) piperazin-2-yl] ethyl} -1H-indole-3-carbonitrile Example 342: Ethyl l-{2- [ (2R) -1- ( { 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethyl} -1H-I, 2, 3-triazole-5- carboxylate
Example 343: Ethyl 2-{2- [ (2R) -1- ( {1- [ (IR, 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
Figure imgf000567_0001
MS (ESI+, m/e) 435 (M+l) Example 345 (2R) -2-Benzyl-1- [ (1-cyclohexyl-5-cyclopropyl-1H-imidazol-4- yl) carbonyl]piperazine
Figure imgf000567_0002
MS (ESI+, m/e) 393 (M+l) Example 346
(2R) -2-Benzyl-1- [ (1-cyclohexyl-2-ethoxy-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazine
Figure imgf000567_0003
MS (ESI+, m/e) 473 (M+l) Example 347
(2R) -2-Benzyl-1- [ (2-chloro-1-cyclohexyl-5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine
Figure imgf000568_0001
MS (ESI+, m/e) 465 (M+l)
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)-I- ( {1- [2- (Ethoxymethyl) -2-hydroxycyclohexyl] -5-phenyl- 1H-imidazol-4-yl }carbonyl) piperazin-2-yl]methyl }benzamide hydrochloride
Figure imgf000568_0002
MS (ESI+, m/e) 546 (M+l) Example 349 (2R) -2-Benzyl-1- [ (1-cyclohexyl-5-phenyl-1H-imidazol-4- yl) carbonyl] piperazine
Figure imgf000568_0003
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+l) Example 350
(IR, 2R) -2- (4-{ [ (2R)-2-Benzylpiperazin-l-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl)cyclopentanol and (IS, 2S) -2- (4-{ [ (2R) -2- benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclopentanol
Figure imgf000569_0001
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 (IR, 2R) -2- (4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol- 1-yl) cyclopentanol (96 mg) and (IS, 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+l) MS (ESI+, m/e) 431 (M+l) Example 351 (IR, 2R) -2- (4-{ [ (2R) -2-Isobutylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl)cyclopentanol and (IS, 2S) -2- (4-{ [ (2R) -2- isobutylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclopentanol
Figure imgf000570_0001
trans-2- (4-{ [ (2R) -4-Benzyl-2-isobutylpiperazin-l- 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 (IS, 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 (IR, 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+l) MS (ESI+, m/e) 397 (M+l) Example 352
(lR,2S)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) cyclohexanol
Figure imgf000571_0001
To tert-butyl (3R) -3-benzyl-4- ( {1- [ (IS, 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+l)
Example 353
(lS,2R)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) cyclohexanol
Figure imgf000571_0002
To tert-butyl (3R) -3-benzyl-4-{ [1- (cis-2- hydroxycyclohexyl) -5-phenyl-1H-imidazol-4- yl]carbonyl}piperazine-l-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+l) (The other diastereomer obtained by this method is the same as the compound of the above-mentioned Example 352. ) Example 354
[ (lR,2S)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl)cyclohexyl]methanol, [ (IS, 2R) -2- (4-{ [(2R) -2- benzylpiperazin-1-yl] carbonyl } -5-phenyl-1H-imidazol-1- yl) cyclohexyl] methanol, [ (IR, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin- 1-yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) cyclohexyl]methyl acetate and [ (IS, 2R) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl]methyl acetate
Figure imgf000573_0001
(retention time: 1.23 min) (retention time: 1.31 min)
Figure imgf000573_0002
(retention time: 1.41 min) (retention time: 1.50 min)
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.
[ (lR,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+l) , retention time 1.23 min [ (lS,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+l), retention time 1.31 min
[ (lR,2S)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-l-yl)cyclohexyl]methyl acetate (55 mg) : MS (ESI+, m/e) 501 (M+l), retention time 1.41 min [ (lS,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+l), 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
Figure imgf000574_0001
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+l) Example 356 Ethyl (2S)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-l^yl) cyclohexylidene] acetate hydrochloride
Figure imgf000575_0001
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IS) -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+l)
Example 357
Ethyl [ (lS,2S)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000576_0001
Ethyl [ (lS,2S)-2-(4-{ [ (2R) -2, 4-dibenzylpiperazin-1- yl] carbonylJ-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+l) Example 358
Ethyl [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyDpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) cyclohexyl] carbamate '
Figure imgf000576_0002
Ethyl [(lS,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+l)
Example 359
Ethyl [(lS,2R)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000577_0001
Ethyl l-{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+l) Example 360 2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) -1-butylcyclohexanol hydrochloride
Figure imgf000578_0001
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+l)
Example 361
2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) -1- (ethoxymethyl) cyclohexanol
Figure imgf000579_0001
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-hydroxycyclohexyi] -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+l) 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
Figure imgf000580_0001
MS (ESI+, m/e) 489 (M+l) Example 363
(lR,2R)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1- (cyclopropylmethyl) cyclohexanol hydrochloride
Figure imgf000580_0002
tert-Butyl (3R) -3-benzyl-4- ( {1- [ (IR, 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+l)
In the same manner as in Example 363, the following compound (Example 364) was obtained. Example 364
(IS, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1- (cyclopropylmethyl) cyclohexanol hydrochloride
Figure imgf000581_0001
MS (ESI+, m/e) 499 (M+l)
Example 365
(lR,2R)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1- ( { [2-
(methylsulfonyl) ethyl] amino}methyl) cyclohexanol and (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-
1-yl) -1- ( { [2- (methylsulfonyl) ethyl] amino }methyl) cyclohexanol
Figure imgf000581_0002
tert-Butyl (3R) -3-benzyl-4-{ [1- (1-oxaspiro [2.5] oct-4-yl) - 5-phenyl-1H-imidazol-4-yl] carbonyljpiperazine-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] aminojmethyl) 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 (IR, 2R) -2- (4-{ [ (2R) -2- benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- ({ [2- (methylsulfonyl) ethyl] aminoJmethyl) cyclohexanol (26 mg) as an amorphous solid, and (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-l- 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+l) MS (ESI+, m/e) 580 (M+l) Example 366 Example 366a
(IS, 2R) -2- (4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl }-5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol hydrochloride Example 366b ' (IR, 2S)-2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol hydrochloride
Figure imgf000582_0001
(retention time: short) (retention time: long)
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 (IR, 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+l) MS (ESI+, m/e) 489 (M+l) Example 367 (the alternative synthetic method of the above- mentioned Example 366a; The object compound was isolated as a dihydrochloride . )
(lS,2R)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol dihydrochloride '
Figure imgf000583_0001
tert-Butyl (3R) -3-benzyl-4- ( { 1- [ (IR, 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 (IS, 2R) -2-.(4-{ [ (2R) - 2-benzylpiperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-1-yl)-l-
(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+l) Example 368
(IS, 2R) -2- (4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol fumarate
fumarate
Figure imgf000584_0001
(lS,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+l)
Example 369
(IR, 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 (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) -1- [2- (1H-tetrazol-5- yl) ethyl] cyclohexanol trifluoroacetate
Figure imgf000585_0001
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 (IR, 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 (IS, 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+l) MS' (ESI+, m/e) 541 (M+l) Example 370
N-{3-[ (lR,2R)-2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) -1-hydroxycyclohexyl] propyl Jacetamide trifluoroacetate and 'N-{3-[ (IS, 2S) -2- (4-{ [ (2R) -2- benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- hydroxycyclohexyl] propyl }acetamide trifluoroacetate
Figure imgf000586_0001
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 IM 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-[(lR,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-
[ (IS, 2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1-hydroxycyclohexyl] propyl Jacetamide trifluoroacetate (10 mg) as an amorphous solid.
MS (ESI+, m/e) 544 (M+l)
MS (ESI+, m/e) 544 (M+l)
Example 371
N-(2-{ [ (lS,2R)-2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) -1- hydroxycyclohexyl]methoxy} ethyl) acetamide trifluoroacetate and
N-(2-{ [ (lR,2S)-2-(4-{ [ (2R) -2-benzylpiperazin-1-yl] carbonyl} -5- phenyl-1H-imidazol-1-yl) -1- hydroxycyclohexyl ] methoxy } ethyl ) acetamide trifluoroacetate
Figure imgf000587_0001
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]carbόnyl}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-{ [ (IR, 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-{ [ (IS, 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+l) MS (ESI+, m/e) 560 (M+l)
In the same manner as in Example 371, the following compound (Example 372) was obtained. Example 372 (lS,2R)-2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1-{ [ (1-methylpiperidin-4- yl)oxy]methyl Jcyclohexanol trifluoroacetate and (IR, 2S) -2- (4- { [ (2R) -2-benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl)-1-{ [ (1-methylpiperidin-4-yl) oxy]methyl } cyclohexanol trifluoroacetate
Figure imgf000589_0001
MS (ESI+, m/e) 572 (M+l) MS (ESI+, m/e) 572 (M+l) Example 373
(lS,2R)-2-(4-{ [ (2R)-2-Benzylpiperazin-l-yl]carbonyl}-5-phenyl- 1H-imidazol-1-yl)-1-{ [ (1, l-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, l-dioxidotetrahydro-2H-thiopyran-4- yl) oxy]methyl}cyclohexanol
Figure imgf000589_0002
tert-Butyl (3R) -3-benzyl-4-{ [l-(2-{ [ (1,1- diox±dotetrahydro-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 (IS, 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 (IR, 2S) -2- (4-{ [ (2R) -2- benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- { [ (1, l-dioxidotetrahydro-2H-thiopyran-4- yl) oxy]methyl}cyclohexanol (30 mg) as an amorphous solid. MS (ESI+, m/e) 607 (M+l) MS (ESI+, m/e) 607 (M+l) Example 374 (IR, 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 (IS, 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
Figure imgf000590_0001
(retention time: 1.39 min) (retention time: 1.49 min) l-(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.
(lR,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+l) , retention time 1.39 min (IS, 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+l), 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 (lR,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 (IS, 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
Figure imgf000592_0001
(retention time: 1.39 rhin) (retention time: 1.49 min)
MS (ESI+, m/e) 600 (M+l) MS (ESI+, m/e) 600 (M+l) Example 376 2-(4-{ [ (2R)-2-Benzylpiperazin-1-yl]carbonyl}-5-phenyl-1H- imidazol-1-yl) -1- (hydroxymethyl) cyclohexanol hydrochloride
Figure imgf000592_0002
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+l) Example 377 2- (4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) -1- [ (3-^hydroxypropoxy)methyl] cyclohexanol dihydrochloride
Figure imgf000593_0001
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-l-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+l) Example 378
(IR, 2S) -2- (4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) -1-{ [3- (methylthio)propoxy]methyl}cyclohexanol
Figure imgf000594_0001
Ethyl l-( (lS,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- ( (IS, 2R) -2-hydroxy-2-{ [3- (methylthio) propoxy]methyl Jcyclohexyl) -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+l) Example 379
(IS, 2R) -2- (4-{ [ (2R) -2- (3, 5-Difluorobenzyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) -1- (methoxymethyl) cyclohexanol hydrochloride
Figure imgf000595_0001
A solution of 1- [ (IR, 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 (IS, 2R) -2- (4-{ [ (2R) -4-benzyl-2- (3, 5- difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1- yl) -1- (methoxymethyl) cyclohexanol (546 ing) 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+l) Example 380
(IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2R) -2- (pyridin-3- ylmethyl) piperazin-1-yl] carbonyl}-1H-imidazol-1-yl) cyclohexanol dihydrochloride
Figure imgf000596_0001
A solution of 1- [ (IR, 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 (lS,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+l) Example 381
(IS, 2R) -2- (4-{ [ (2R) -2- (1H-Imidazol-4-ylmethyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol hydrochloride
Figure imgf000597_0001
A solution of l- [ (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 (IS, 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+l) Example 382 (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2R) -2- (3- phenylpropyl) piperazin-1-yl] carbonyl } -1H-imidazol-1- yl)cycloheχanol hydrochloride
Figure imgf000599_0001
A solution of 1- [ (IR, 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- yljpiperazine (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 (IS, 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+l) Example 383
(IS, 2R) -2- [4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- (3- fluorophenyl) -1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000600_0001
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+l) Example 384 (IR, 2S) -2- [4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl}-5- (3- fluorophenyl) -1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000601_0001
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+l) 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
Figure imgf000601_0002
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+l) MS (ESI+, m/e) 429 (M+l) Example 386
(IS, 2R)-I- (Methoxymethyl) -2- (4- { [ (2R) -2- (2- phenoxyethyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexanol
Figure imgf000602_0001
(IS, 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+l)
Example 387 (the alternative synthetic method of the above- mentioned Example 386; The object compound was isolated as a dihydrochloride . ) (IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2R) -2- (2- phenoxyethyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexanol dihydrochloride
Figure imgf000603_0001
1- [ (IR, 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- C (IR, 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+l) Example 388
(IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ( { (2R) -2- [2- (pyridin-3- yloxy) ethyl]piperazin-1-yl }carbonyl) -1H-imidazol-1- yl] cyclohexanol
Figure imgf000604_0001
Benzyl (3R)-4-({l-[ (IR, 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+l) Example 389
(IS, 2R) -2- [4- ( { (2R) -2- [2- (2-Fluorophenoxy) ethyl] piperazin-1- yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000604_0002
Benzyl (3R) -3- [2- (2-fluorophenoxy) ethyl] -4- ( {1- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazine-1-carboχylate (205 nag) 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+l) Example 390
N-Cyclopropyl-4-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxy}benzamide
Figure imgf000605_0001
Benzyl (3R) -3- (2-{4-
[ (cyclopropylamino) carbonyl]phenoxy}ethyl) -4- ( {1- [ (IR, 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 (IS, 2R) -2- [4- ( { (2R) -2- [2- (1H-Indazol-1-yl) ethyl]piperazin-1- yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000606_0001
Benzyl (3R)-4-({l-[ (IR, 2S) -2-hydroxy-2-
(inethoxymethyl) 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+l)
In the same manner as in Example 391, the following compound (Example 392) was obtained. Example 392 (IS, 2R) -2- [4- ( { (2R) -2- [2- (2H-Indazol-2-yl) ethyl] piperazin-1- yl } carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000606_0002
MS (ESI+, m/e) 543 (M+l) Example 393 l-Cyclopentyl-3-{2-[ (2R)-1-({1- [ (IR, 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
Figure imgf000607_0001
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-benziπιidazol-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-
[ (IR, 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+l) Example 394 l-Cyclohexyl-3-{2-[ (2R) -1- ( {1- [ (IR, 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
Figure imgf000608_0001
A solution of l-[ (IR, 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- [ (IR, 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+l) Example 395 (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ( { (2R) -2- [2- (1H-I, 2, 3- triazol-1-yl) ethyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol
Figure imgf000609_0001
A solution of 1- [ (IR, 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- [ (IR, 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+l) Example 396
(IR, 2S) -2- [4- ( {2- [2- (2-Fluorophenyl) ethyl] piperazin-1- yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] cyclohexanol
Figure imgf000610_0001
A solution of l-[ (IS, 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 (IR, 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+l)
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.)
Figure imgf000612_0001
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
Figure imgf000614_0001
Ex. No. R salt Compound MS(ESI+)
(IS, 2R) -1- (Methoxymethyl) -2-{5-phenyl-
405 henyl] ethyl} 587 onyl] -1H-imidazol-
Figure imgf000614_0002
(IS, 2R) -1- (Methoxymethyl) -2-{5-phenyl-
406 ] ethyl} 587 -1H-imidazol-
Figure imgf000614_0003
(IS,2R) -1- (Methoxymethyl)-2-{5-phenyl-
407 nyl]ethyl} 571 nyl] -1H-imidazol-
Figure imgf000614_0004
(IS, 2R) -1- (Methoxymethyl) -2-{5-phenyl-
408 phenyl] ethyl} 571 rbonyl] -1H-imidazol-
Figure imgf000614_0005
(IS, 2R) -1- (Methoxymethyl) -2-{5-phenyl-
409 ] ethyl} 587 -1H-1midazol-
Figure imgf000614_0006
hloride
(IS, 2R)-1- (Methoxymethyl)-2-{5-phenyl-
410 ]ethyl} 587 -1H-imidazol-
Figure imgf000614_0007
hloride
(IS, 2R) -1- (Methoxymethyl) -2-{5-phenyl-
411 enyl] ethyl} 571
Figure imgf000614_0008
onyl] -1H-imidazol- 1-yl}cyclohexanol hydrochloride
(IS,2R) -1- (Methoxymethyl) -2-{5-phenyl-
412 ] ethyl} 571 ] -1H-imidazol-
Figure imgf000614_0009
chloride Example' 413
(IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [2- (2- (piperidin-2- yl) ethyl) piperazin-1-yl] carbonyl}-1H-imidazol-1-yl) cyclohexanol
Figure imgf000615_0001
A mixture of 1- [ (IR, 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 (IS, 2R) -2- [4- ( {4- benzyl-2- [ (E) -2- (pyridin-2-yl) vinyl] piperazin-1-yl Jcarbonyl) -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+l) Example 414
(IR, 2S) -2- {4- [ (2-Pentylpiperazin-l-yl)carbonyl]-5-phenyl-1H- imidazol-1-yl}cyclohexanol
Figure imgf000616_0001
(IR, 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+l) Example 415
(lS,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
Figure imgf000617_0001
(lS,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+l) Example 416 4-{2-[ (2R)-1-({l-[ (lR,2S)-2-Hydroxy-2- (methoxymethyl) cyclohexyl]-5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxy}benzoic acid trifluoroacetate
Figure imgf000617_0002
Benzyl (3R) -4- ( { 1- [ (IR, 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+l)
In the same manner as in Example 416, the following compounds (Examples 417 - 418) were obtained. Example 417
3-{2-[ (2R)-1-({l-[ (lR,2S)-2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl]ethoxy}benzoic acid trifluoroacetate
Figure imgf000618_0001
MS (ESI+, m/e) 563 (M+l) Example 418
2-{2-[ (2R)-1-({l-[ (IR, 2S)-2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethoxy}benzoic acid bistrifluoroacetate
Figure imgf000618_0002
MS (ESI+, m/e) 563 (M+l) Ih 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
(IS, 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
Figure imgf000619_0001
MS (ESI+, m/e) 536 (M+l) Example 420
6-{ [ (2S)-1-({l-[ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] - 5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin-2- yl]methoxy}nicotinic acid
Figure imgf000619_0002
A mixture of methyl 6-{ [ (2S) -1- ( {1- [ (IR, 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 IN 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 1/3 volume, and the resulting crystals were collected by filtration to give the object compound (147 mg) . MS (ESI+, m/e) 550 (M+l) Example 421
(4-{2- [ (2R) -1- ( {1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxy}phenyl) acetic acid
Figure imgf000620_0001
Methyl (4-{2-[ (2R)-I-(U-. (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yljcarbonyl) 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 IN 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+l) Example 422
(IS, 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
Figure imgf000621_0001
Benzyl (3R) -3-{ 2- [4- (4-acetylpiperazin-1- yl)phenoxy]ethyl}-4-({l-[ (IR, 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 650C 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+l) Example 423 4- { 2- [ (2R) -1- ( { 1- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethoxy} -3-methoxybenzamide dihydrochloride
Figure imgf000621_0002
Benzyl (3R) -3- [2- (4-cyano-2-methoxyphenoxy) ethyl] -4- ( { 1- [ (IR, 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+l) Example 424
(lS,2R)-2-{4-[ ( (2R)-2-{2-[2-(1- Hydroxyethyl)phenoxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl} -1- (methoxymethyl) cyclohexanol
Figure imgf000622_0001
1- (2-{2- [ (2R) -1- ( { 1- [ (IR, 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+l) Example 425
(lS,2R)-2-{4-[( (2R) -2- {2- [3- (1-
Hydroxyethyl)phenoxy] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-l-yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000623_0001
l-(3-{2-[ (2R)-1-({l-[ (lR,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+l) Example 426 ( lS , 2R) -2- { 4- [ ( ( 2R) -2- { 2- [ 4- ( l-
Hydroxyethyl) phenoxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000624_0001
1- (4-{2- [ (2R) -1- ( { 1- [ (IR, 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+l)
In the same manner as in Example 3 (Method C) , the following compound (Example 427) was obtained. Example 427 (lS,2R)-2-(4-{ [ (2R) -2-Benzyl-2-methylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol dihydrochloride
Figure imgf000625_0001
MS (ESI+, m/e) 503 (M+l) Example 428
(lS,2R)-2-(4-{ [ (2R)-2-(2-Anilinoethyl)piperazin-1-yl]carbonyl}- 5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000625_0002
A solution of 1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazole-4-carboxylic acid (650 mg) , benzyl (3R) -3- (2-anilinoethyl)piperazine-l- 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- [ (IR, 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)
5 was concentrated under reduced pressure to give the object compound (50 mg) as an amorphous solid. MS (ESI+, m/e) 518 (M+l) Example 429 (lS,2R)-1-(Methoxymethyl)-2-{4-[ ( (2R) -2-{2-o [methyl (phenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol trihydrochloride
Figure imgf000626_0001
A solution of 1- [ (IR, 2S) -2-hydroxy-2-5 (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 aqueous0 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, and5 the fraction eluted with ethyl acetate-methanol (1:0 - 9:1) was concentrated under reduced pressure to give benzyl (3R) -4- ({1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl } carbonyl) -3-{2- [methyl (phenyl) amino] ethyl }piperazine-1-carboxylate (180 mg) aso 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+l)
In the same manner as in the above-mentioned Example 1 (Method A) - Example 15 (Method O) , the following compounds (Examples 430 - 567) shown in Table 25-1 - Table 25-2, Table 26, Table 27-1 - Table 27-2 and Table 28-1 - Table 28-8 were obtained. Where necessary, each compound was isolated and purified by a known means such as phase transfer, liquid conversion, solvent extraction, silica gel column chromatography, reversed-phase preparative HPLC and the like. The final products were isolated as a hydrochloride by a treatment with 4N hydrogen chloride-ethyl acetate solution, as in Method A and the like, or isolated as crystals or an amorphous solid in a free from, as in Method B and the like. In the column of "Salt" in the Tables, the compounds described as "-" were isolated as a free form.
Table 25-1
Figure imgf000628_0001
Table 25-2
Figure imgf000629_0001
Table 26
Figure imgf000630_0001
Table 27-1
Figure imgf000631_0001
Table 27-2
Figure imgf000632_0001
Table 28-1
Figure imgf000633_0001
Table 28-2
Figure imgf000634_0001
Table 28-3
Figure imgf000635_0001
Table 28-4
Figure imgf000636_0001
Ex. No. R1 R2 Method Salt MS(ESI+)
Figure imgf000636_0002
Table 28-5
Figure imgf000637_0001
Table 28-6
Figure imgf000638_0001
Ex. No. R1 R2 Method Salt MS(ESI+)
Figure imgf000638_0002
Table 28-7
Figure imgf000639_0001
Table 28-8
Figure imgf000640_0001
The chemical names of the compounds (Examples 43.0 - 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 { (IS, 2S) -2- [5-phenyl-4- ( { (2R) -2- [2- (trifluoromethyl) benzyl]piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexyl} carbamate
Example 431: Methyl { (IS, 2S) -2- [5-phenyl-4- ( { (2R) -2- [3- (trifluoromethyl) benzyl] piperazin-l-yl}carbonyl) -1H-imidazol-1- yl] cyclohexyl}carbamate Example 432: Methyl { (IS, 2S) -2- [5-phenyl-4- ( { (2R) -2- [4-
(trifluoromethyl) benzyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexyl}carbamate
Example 433: Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 4- difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate
Example 434: Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (biphenyl-4- ylmethyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate Example 435: Methyl [ (IS, 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-{ (IS, 2S) -2- [ (ethoxycarbonyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazin-2-yl}ethoxy) benzoate Example 437: Methyl { (IS, 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 { (IS, 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 { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2- fluorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate Example 440: Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2- fluorophenoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yi] cyclohexyl}carbamate Example 441: Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3- fluorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl} carbamate Example 442: Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3- fluorophenoxy) ethyl] piperazin-l-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl }carbamate
Example 443: Methyl { (IS, 2S) -2- [5-phenyl-4- ( { (2R) -2- [2- (phenylthio) ethyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexyl } carbamate
Example 444: Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (2- anilinoethyl)piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate Example 445: Methyl ( (IS, 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 ( (IS, 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 ( (IS, 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 ( (IS, 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 ( (IR, 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 ( (IS, 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: (IS, 2R) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1- (ethoxymethyl) cyclohexanol dihydrochloride Example 452: (IS, 2R) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbbnyl}-5-phenyl-1H-imidazol-l-yl) -1-methylcyclohexanol dihydrochloride
Example 453: (IS, 2R) -2- (4-{ [ (2R) -2-Benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1-ethylcyclohexanol dihydrochloride
Example 454: (IR, 2R) -1- (Cyclopropylmethyl) -2- (5-phenyl-4-{ [ (2R) -
2- (pyridin-3-ylmethyl)piperazin-l-yl] carbonyl}-1H-imidazol-1- yl) cyclohexanol
Example 455: (IR, 2R) -1- (Cyclopropylmethyl) -2- (5-phenyl-4-{ [(2R)- 2- (pyridin-4-ylmethyl) piperazin-1-yl] carbonyl }-1H-imidazol-1- yl) cyclohexanol
Example 456: (IS, 2R) -1-Ethyl-2- [5-phenyl-4- ( { (2R) -2- [ (5-phenyl-
1,3, 4-oxadiazol-2-yl) methyl] piperazin-1-yl } carbonyl) -1H- imidazol-i-yl] cyclohexanol dihydrochloride Example 457: (IR, 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: (IS, 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: (IR, 2R) -1- (Cyclopropylmethyl) -2-{ 4- [( (2S) -2-{ [ (3- fluorophenyl) sulfonyl]methyl}piperazin-1-yl) carbonyl] -5-phenyl- 1H-imidazol-1-yl} cyclohexanol
Example 460: (IS, 2R) -2- [4- ({ (2R) -2- [2- (2- Flμorophenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] -1-methylcyclohexanol
Example 461: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2R) -2- (2-
Naphthylmethyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexanol hydrochloride
Example 465: (IS, 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- [ (IR, 2S) -2-Hydroxy-2-
(methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl]methyl phenylcarbamate Example 467: (IS, 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 : (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ( { (2S) -2-
[ (5-phenyi-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-l- yl] carbonyl }-5-phenyl-1H-imidazol-l-yl) -I-
(methoxymethyl) cyclohexanol
Example 471: (IS, 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: (IS, 2R) -2- (4-{ [ (2R) -2- (Biphenyl-2- ylmethyl) piperazin-1-yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) -1-
(methoxymethyl) cyclohexanol
Example 473: (IS, 2R) -2- (4-{ [ (2S) -2- (Biphenyl-2- ylmethyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Example 474: (IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2R) -2- (2- morpholinobenzyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-
1-yl) cyclohexanol
Example 475: (IS, 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: (IS, 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: (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ({ (2S) -2- [ (phenylthio) methyl] p'iperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol dihydrochloride
Example 478: (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ({ (2S) -2- [ (phenylsulfinyl) methyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol
Example 479: (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ({ (2S) -2- [ (phenylsulfonyl)methyl] piperazin-1-yl} carbonyl) -1H-imidazol-1- yl] cyclohexanol dihydrochloride Example 480: (IS, 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- [ (IR, 2S) -2-Hydroxy-2- (inethoxymethyl) 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2-{4- [ ( (2R) -2-{2- [3- (Difluόromethoxy) phenoxy] ethyl }piperazin-1-yl) carbonyl] -5- phenyl-1H-imidazol-1-yl}-1- (methoxymethyl) cyclohexanol hydrochloride
Example 488: 2- (4-{2- [ (2R)-I- ( {1- [ (IR, 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- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethoxy}-1-benzofuran-2-carboxylate Example 490: (IS, 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: (IS, 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: l-(4-{2-[ (2R) -1- ( {5- (3-Fluorophenyl) -1- [ (IR, 2S) -2- hydroxy-2- (methoxymethyl) cyclohexyl] -1H-imidazol-4- yl }carbonyl) piperazin-2-yl] ethoxy}phenyl) ethanone dihydrochloride
Example .493: (IS, 2R) -1- (Methoxymethyl) -2- [4- ({ (2R) -2- [2- (2- methylphenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexanol Example 494: (IS, 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: (IS, 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: (IS, 2R) -2-{4- [ ( (2R) -2-{2- [ (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 497: (IS, 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: (IS, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl) piperazin-2-yl] ethyl phenylcarbamate dihydrochloride
Example 501: (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ({ (2R) -2-
[2- (phenylthio) ethyl] piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexanol dihydrochloride Example 502: (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ({ (2R) -2-
[2- (phenylsulfinyl) ethyl] piperazin-1-yl} carbonyl) -1H-imidazol-1- yl] cyclohexanol
Example 503: (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ({ (2R) -2-
[2- (phenylsulfonyl) ethyl] piperazin-1-yl} carbonyl) -1H-imidazol-1- yl] cyclohexanol dihydrochloride
Example 504: (IS, 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 : (IS, 2R) -1- (Methoxymethyl) -2- [5-phenyl-4- ( { (2R) -2- [2- ( [1, 3] thiazolo [5, 4-b]pyridin-2-ylthio) ethyl] piperazin-1- yljcarbonyl) -1H-imidazol-1-yl] cyclohexanol
Example 506: (IS, 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: (IS, 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: (IS, 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: (IS, 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-l-yl}cyclohexanol Example 510: (IS, 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: (IS, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperazin-2-yl] ethyl } -N- phenylcyclopropanecarboxamide
Example 514: (IS, 2R) -2- [4- ( { (2R) -2- [2- (1, 3-Dihydro-2H-isoindol- 2-yl) ethyl] piperazin-l-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] - 1- (methoxymethyl) cyclohexanol trihydrochloride Example 515: (IS, 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: (IS, 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 : (IS, 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: (IS, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethyl}amino)benzonitrile Example 520: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2-{4- [ ( (2R) -2-{2- [ (2-
Chlorophenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-i-yl}-1- (methoxymethyl) cyclohexanol Example 525: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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- [ (IR, 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- [ (IR, 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- [ (IR, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl} carbonyl) piperazin-2-yl] ethyl}amino) phenyl] ethanone Example 535: (IS, 2R) -1- (Methoxymethyl) -2- (5-phenyl-4-{ [ (2R) -2- (2-{ [4- (trifluoromethoxy) phenyl] aminojethyl) piperazin-1- yl] carbonyl}-1H-imidazol-1-yl) cyclohexanol Example 536: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2- [4- ( { (2R) -2- [2- (1, 3-Be_nzodioxol-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- [ (IR, 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-l (3H) -one Example 544: (IS, 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: (IS, 2R) -1- (Methoxymethyl) -2-{4- [( (2R) -2-{2- [ (4- methoxy-2-methylphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5- phehyl-1H-imidazol-1-yl}cyclohexanol
Example 546: (IS, 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: (IS, 2R) -1- (Methoxymethyl) -2-{4- [( (2R) -2-{2- [ (2- methoxy-β-methylphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5- phenyl-1H-imidazol-1-yl } cyclohexanol Example 548: (IS, 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: (IS, 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: (IS, 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: (IS, 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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl] ethyl}amino) -2-ben_zofuran-l (3H) -one Example 553: 1- [4- ( {2- [ (2R) -1- ( {1- [ (IR, 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- [ (IR, 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: (IS, 2R) -1- (Methoxymethyl) -2-{4- [( (2R) -2-{2- [ (2- methyl-1, 3-benzoxazol-5-yl) amino] ethyl}piperaz±n-1-yl) carbonyl] - 5-phenyl-1H-imidazol-1-yl}cyclohexanol
Example 556: (IS, 2R) -2-{4- [ ( (2R) -2-{2- [ (2-ethyl-1,3-benzoxazol- 5-yl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol- l-yl}-1- (methoxymethyl) cyclohexanol
Example 557: (IS, 2R) -1- (Methoxymethyl) -2-{4- [( (2R) -2-{2- [ (2- methyl-1, 3-benzoxazol-6-yl) amino] ethyl}piperazin-l-yl) carbonyl] - 5-phenyl-1H-imidazol-1-yl} cyclohexanol Example 558: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 2R) -2-{ 4- [ ( (2R) -2-{2- [ (3-Fluoro-2- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-l-yl}-1- (methoxymethyl) cyclohexanol Example 563: (IS, 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: (IS, 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: (IS, 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: (IS, 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: (IS, 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
(lS,2R)-2-(4-{ [ (2R) -2-Benzyl-3-methylpiperazin-1-yl] carbonyl}-5- phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000653_0001
MS (ESI+, m/e) 503 (M+l)
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 l-{ [5-Phenyl-4-({ (2R) -2- [ (5-phenyl-1,3, 4-oxadiazol-2- yl) methyl]piperazin-1-yl}carbonyl) -1H-imidazol-1- yl]methyl}cyclohexanol
Figure imgf000653_0002
MS (ESI+, m/e) 527 (M+l) Example 570 l-({4-[((2R)-2-{2-[(2-Fluoro-4- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl }methyl) cyclohexanol
Figure imgf000654_0001
MS (ESI+, m/e) 536 (M+l) Example 571 l-({4-[((2R)-2-{2-[(2-Fluoro-3- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-i-yl}methyl) cyclohexanol
Figure imgf000654_0002
MS (ESI+, m/e) 536 (M+l) Example 572 (lS,2R)-1-(Methoxymethyl)-2-(4-{ [(2R)-2-(2- phenoxybenzyl) piperazin-1-yl] carbonyl }-5-phenyl-1H-imidazol-l- yl) cyclohexanol bistrifluoroacetate
Figure imgf000654_0003
MS (ESI+, m/e) 581 (M+l) Example 573 l-[ (4-{ [ (2R) -2- (2-Anilinoethyl) piperazin-1-yl] carbonyl} -5- phenyl-1H-imidazol-1-yl)methyl] cyclohexanol
Figure imgf000655_0001
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+l) Example 574 Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (2-bromobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000656_0001
Methyl [ (IS, 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+l)
In the same manner as in Example 574, the following compound (Example 575) was obtained. Example 575 (lS,2R)-2-(4-{ [ (2R)-2-(2-Bromobenzyl)piperazin-1-yl]carbonyl}-5- phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000657_0001
MS (ESI+, m/e) 567 (M+l)
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 [ (IS, 2S) -2- (5-phenyl-4-{ [(2R) -2- (3- phenylpropyl)piperazin-1-yl] carbonyl }-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000657_0002
MS (ESI+, m/e) 530 (M+l) Example 577 (lS,2R)-2-{4-[( (2R)-2-{2-
[Cyclohexyl (methyl) amino] ethyl }piperazin-1-yl) carbonyl] -5- phenyl-1H-imidazol-1-yl}-!- (methoxymethyl) cyclohexanol
Figure imgf000657_0003
Benzyl (3R) -4- ( { 1- [ (IR, 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+l)
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- [ (IR, 2S) -2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl}carbonyl)piperazin-2-yl] ethyl}amino) benzoic acid tri- trifluoroacetate
Figure imgf000658_0001
MS (ESI+, m/e) 562 (M+l) Example 579
(lS,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
Figure imgf000659_0001
MS (ΕSI+, m/e) 589 (M+l) Example 580
(lS,2R)-l-(Methoxymethyl)-2-{4-[((2R)-2-{2-[ (2-methyl-1, 3- benzothiazol-β-yl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl- 1H-imidazol-1-yl } cyclohexanol
Figure imgf000659_0002
MS (ESI+, m/e) 589 (M+l) Example 581
(lS,2R)-l-(Methoxymethyl)-2-(5-phenyl-4-{ [ (2R) -2- (2- (pyridin-2- yl) benzyl) piperazin-1-yl] carbonyl }-1H-imidazol-1-yl) cyclohexanol
Figure imgf000659_0003
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 (IS, 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+l) Example 582
(lS,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
Figure imgf000660_0001
Benzyl (3R) -3-{2- [ (2-methyl-1,3-benzothiazol-5- . yl) oxy] ethyl}piperazine-1-carboχylate (200 mg) was dissolved in DMF (30 ml), l-{ (IS, 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- { (IS, 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+l) Example 583
4-{ [ (3R) -3-Benzyl-4- ( {1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-imidazol-4- yl } carbonyl) piperaz.in-1-yl]methyl} -5-methyl-1, 3-dioxol-2-one
Figure imgf000662_0001
(lS,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+l) Example 584 l-[4-(2-{ (2R)-1-({l-[ (lR,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
Figure imgf000662_0002
l-(4-{2-[ (2R)-1-({l-[ (lR,2S)-2-Hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H-iπιidazol-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+l)
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
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (4-Methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl} -1-methylcyclohexanol
Figure imgf000663_0001
MS (ESI+, m/e) 532 (M+l) Example 586
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (5-Methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}-1-methylcyclohexanol
Figure imgf000664_0001
MS (1ESI+, m/e) 532 (M+l) Example 587 Methyl ( (IS, 2S) -2-{4- [ ( (2R) -2-{2- [ (4-methoxy-2- methylphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } cyclohexyl) carbamate
Figure imgf000664_0002
MS (ESI+, m/e) 575 (M+l)
Example 588
' Methyl ( (IS, 2S) -2-{ 4- [ ( (2R) -2-{2- [ (5-methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexyl) carbamate
Figure imgf000664_0003
MS (ESI+, m/e) 575 (M+l)
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 ( IS, 2R) -2- [4- ( { (2R) -2- [2- (2 , 3-Dihydro-l-benzofuran-6- . yloxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] ■
1- (methoxymethyl) cyclohexanol
Figure imgf000665_0001
MS (ESI+, m/e) 561 (M+l) Example 590
(IS, 2R) -2-{4- [ ( (2R) -2-{2- [ (3-Fluoro-2- methoxyphenyl) amino] ethyl }piperazin-l-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } -1-methylcyclohexanol
Figure imgf000665_0002
MS (ESI+, m/e) 536 (M+l) Example 591 Methyl ( (IS, 2S) -2-{4- [ ( (2R) -2-{2- [ (3-fluoro-2- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl }cyclohexyl) carbamate
Figure imgf000665_0003
MS (ESI+, m/e) 579 (M+l) Example 592
(IS, 2R)-I- (Methoxymethyl) -2-{ 4- [ ( (2R) -2-{2- [ (2-methyl-1,3- . benzoxazol-5-yl) oxy] ethyl}piperazin-l-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}cyclohexanol
Figure imgf000666_0001
MS (ESI+, m/e) 574 (M+l) Example 593
(IR, 2R)-1-(Cyclopropylmethyl)-2-{4-[ ( (2R)-2-{2-[ (2-methyl-1, 3- benzoxazol-5-yl) oxy] ethyl}piperazin-l-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } cyclohexanol
Figure imgf000666_0002
' MS (ESI+, m/e) 584 (M+l) Example .594 l-({4-[( (2R)-2-{2-[ (3-Fluoro-2- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}methyl) cyclohexanol
Figure imgf000666_0003
MS (ESI+, m/e) 536 (M+l) In the same manner as in Example 8 (Method H) , the following compound (Example 595) was obtained. Example 595
(IR, 2R) -1- (Cyclopropylmethyl) -2- [5-phenyl-4- ( { (2S) -2- [ (phenylsulfonyl)methyl]piperazin-1-yl}carbonyl) -1H-imidazol-1- yl]cyclohexanol dihydrochloride
Figure imgf000667_0001
MS (ESI+, m/e) 563 (M+l)
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-({l-[ (lR,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 (IS, 2R) -2- (4-{ [ (2R) -2- (2-{ [4- (hydroxymethyl) -1, 3- thiazol-2-yl] thiojethyl) piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000667_0002
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)-I- ({1- [ (IR, 2S) -2-hydroxy-2- (methoxymethyl) cyclohexyl] -5-phenyl-1H- imidazol-4-yl}carbonyl)piperazin-2-yl] ethyljthio) -1, 3-thiazol-< yl]methyl acetate (113 mg, MS (ESI+, m/e) 614 (M+l) ) as a component having a short retention time, and (IS, 2R) -2- (4- { [ (2R) -2- (2-{ [4- (hydroxymethyl) -I73-thiazol-2- yl]thio}ethyl)piperazin-l-yl] carbonyl }-5-phenyl-1H-imidazol-l- yl)-1- (methoxymethyl) cyclohexanol (20 mg, MS (ESI+, m/e) 570 (M+l)) 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 (lS,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
Figure imgf000668_0001
Example 598 (lS,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
Figure imgf000668_0002
Example 599
(IS, 2R) -2-{4- [ ( (2R) -2- {2- [ (7-Fluoro-2-methyl-l, 3-benzoxazol-6- yl) oxy] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol-1- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000669_0001
Example 600 (lS,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
Figure imgf000669_0002
Example 601
(lS,2R)-.2-{4-[ ( (2R)-2-{2-[ (2, 6-Dimethyl-l, 3-benzoxazol-5- yl) oxy] ethyl}piperazin-l-yl) carbonyl] -5-phenyl-1H-imidazol-l- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000669_0003
Example 602
(IS, 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
Figure imgf000670_0001
Example 603
(IS, 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
Figure imgf000670_0002
Example 604
(lS,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
Figure imgf000670_0003
Example 605 (lS,2R)-2-{4-[ ( (2R)-2-{2-[ (2-Cyclopropyl-1,3-benzoxazol-5- yl) oxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol-l- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000671_0001
Example 606
(IS, 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
Figure imgf000671_0002
Example 607
(lS,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
Figure imgf000671_0003
Example 608 (lS,2R)-2-{4-[((2R)-2-{2-[ (2-Cyclopropyl-4-fluoro-l, 3- benzoxazol-5-yl) oxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000672_0001
Example 609
(IS, 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
Figure imgf000672_0002
Example 610
(IS, 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
Figure imgf000672_0003
Example 611 (IS, 2R)-I- (Methoxymethyl) -2-{ 4- [ ( (2R)-2-{2-[ (2- methylimidazo[1,2-a]pyridin-6-yl) oxy] ethyl }piperazin-l- yl) carbonyl] -5-phenyl-1H-imidazol-1-yl}cyclohexanol
Figure imgf000673_0001
Example 612
(lS,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
Figure imgf000673_0002
Example 613
(IS, 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
Figure imgf000673_0003
Example 614 (IS, 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
Figure imgf000674_0001
Example 615
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (1, 2-Dimethyl-1H-indol-5- ■ yl) oxy] ethyl}piperazin-l-yl) carbonyl] -5-phenyl-1H-±midazol-l- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000674_0002
Example 616
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (1, 2-Dimethyl-1H-indol-6- yl) oxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol-l- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000674_0003
Example 617 (IS, 2R)-I- (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
Figure imgf000675_0001
Example 618
(lS,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
Figure imgf000675_0002
Example 619
(IS, 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
Figure imgf000675_0003
Example 620 (lS,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
Figure imgf000676_0001
Example 621
(lS,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
Figure imgf000676_0002
Example 622
(lR,2R)-2-{4-[ ( (2R)-2-{2-[ (2-Cyclopropyl-1,3-benzoxazol-5- yl) oxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol-l- yl}-1- (cyclopropylmethyl) cyclohexanol
Figure imgf000676_0003
Example 623 (lS,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
Figure imgf000677_0001
Example 624
(lS,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
Figure imgf000677_0002
Example 625
(lR,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
Figure imgf000677_0003
Example 626 (lR,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
Figure imgf000678_0001
Example 627
Ethyl { (lS,2S)-2-[4-({ (2R) -2- [2- (3, 5- difluorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl } carbamate
Figure imgf000678_0002
Example 628
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3, 5- dichlorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl }carbamate
Figure imgf000678_0003
Example 629 Methyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (3-chloro-5- fluorophenoxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000679_0001
Example 630
Methyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (3-fluoro-4- methylphenoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl} carbamate
Figure imgf000679_0002
Example 631
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3-chloro-4- methylphenoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl} carbamate
Figure imgf000679_0003
Example 632 Methyl ( (IS, 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
Figure imgf000680_0001
Example 633
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2-naphthyloxy) ethyl] piperazin- l-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000680_0002
Example 634
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3,4- difluorophenoxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000680_0003
Example 635
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3,4- dichlorophenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000681_0001
Example 636
(IS, 2R) -2-{4- [ ( (2R) -2-{2- [ (2-
Methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}-1-methylcyclohexanol
Figure imgf000681_0002
Example 637
(lS,2R)-2-{4-I ( (2R)-2-{2-[ (2-Methoxy-5- methylphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } -1-methylcyclohexanol
Figure imgf000681_0003
Example 638 (lS, 2R) -l-Methyl-2- { 4- [ ( (2R) -2- { 2- [ (2- methylphenyl ) amino] ethyl }piperazin-l-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } cyclohexanol
Figure imgf000682_0001
Example 639
(IS, 2R) -2-{4- [ ( (2R) -2-{2- [ (2-Fluorophenyl) amino] ethyl}piperazin- 1-yl) carbonyl] -5-phenyl-1H-iinidazol-1-yl}-1-methylcyclohexanol
Figure imgf000682_0002
Example 640
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (2-Methoxy-4- methylphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } -1-methylcyclohexanol
Figure imgf000682_0003
Example 641
(lS,2R)-2-{4-[ ( (2R) -2-{2- [(4- Methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl} -1-methylcyclohexanol
Figure imgf000683_0001
Example 642
(lS,2R)-2-{4-[( (2R)-2-{2-[ (3-Fluoro-4- methoxyphenyl) amino] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl} -1-methylcyclohexanol
Figure imgf000683_0002
Example 643
(lS,2R)-2-{4-[( (2R)-2-{2-[(3- Methoxyp.henyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl } -1-methylcyclohexanol
Figure imgf000683_0003
Example 644 (lS,2R)-2-{4-[( (2R)-2-{2-[(4-Fluoro-2- methoxyphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H- imidazol-1-yl}-1-methylcyclohexanol
Figure imgf000684_0001
Example 645
( lS, 2R) -2- (4- { t (2R) -2-Benzylpiperazin-l~yl] carbonyl } -5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl ) cyclohexanol 0 . 5 fumarate
Figure imgf000684_0002
(IS, 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
(IS, 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
Figure imgf000684_0003
(IS, 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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5-difluorobenzyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) cyclohexyl] carbamate succinate
Figure imgf000685_0001
Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5- difluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- 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 [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) cyclohexyl] carbamate malonate
Figure imgf000686_0001
Ethyl [(lS,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
Figure imgf000686_0002
(IS, 2S) -2- (4-{ [ (2R) -4-Benzyl-2- (3,5- difluorobenzyl)ρiperazin-l-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 [ (IS, 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] c'arbonyl}-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+, Ve) 566 (M+l) In the same manner as in Example 649, the following compounds (Examples 650 - 654) were obtained. Example 650
3-[ (lS,2S)-2-(4-{ [ (2R)-2-(3,5-Difluorobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] -1,1- dimethylurea
Figure imgf000687_0001
MS (ESI+, m/e) 551 (M+l) Example 651 N- [ (lS,2S)-2-(4-{ [ (2R)-2-(3,5-Difluorobenzyl)piperazin-1- yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) cyclohexyl] propanamide
Figure imgf000688_0001
MS (ESI+, m/e) 536 (M+l) Example 652
2-Methoxyethyl [ (1S,2S) -2- (4-{ [ (2R) -2- (3,5- difluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate
Figure imgf000688_0002
MS (ESI+, m/e) 582 (M+l) Example 653
Isobutyl [ (lS,2S)-2-(4-{ [ (2R) -2- (3, 5-difluorobenzyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000688_0003
MS (ESI+, m/e) 580 (M+l) Example 654
Isopropyl [ (1S,2S) -2- (4-{ [ (2R) -2- (3, 5-difluorobenzyl)p±perazin- 1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000689_0001
MS (ESI+, m/e) 566 (M+l) Example 655
2-Fluoroethyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (3,5- difluoroben2yl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000689_0002
(IS, 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
[ (IS, 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 [ (IS, 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+l)
In the same manner as in Example 655, the following compounds (Examples 656 - 659) were obtained. Example 656
N- [ (lS,2S)-2-(4-{ [ (2R)-2-(3,5-Difluorobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl]methanesulfonamide
Figure imgf000690_0001
MS (ESI+, m/e) 558 (M+l) Example 657
N'-[ (lS,2S)-2-(4-{ [ (2R)-2-(3,5-Difluorobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-yl) cyclohexyl] -N,N- dimethylsulfamide
Figure imgf000690_0002
MS (ESI+, m/e) 587 (M+l)
Example 658
N- [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5-DifluorobenzyDpiperazin-1- yl] carbonyl } -5-phenyl-1H-imidazol-1-yl) cyclohexyl] propane-1- sulfonamide
Figure imgf000691_0001
MS (ESI+, m/e) 586 (M+l) Example 659 N- [ (lS, 2S) -2- (4- { [ (2R) -2- (3 , 5-Difluorobenzyl) piperazin-l~ yl] carbonyl } -5-phenyl-1H-imidazol-l- yl) cyclohexyl] ethanesulfonarαide
Figure imgf000691_0002
MS (ESI+, m/e) 572 (M+l) Example 660
Cycloprqpylmethyl [ (1S,2S) -2- (4-{ [ (2R) -2- (3, 5- Difluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate
Figure imgf000691_0003
(lS,2S)-2-(4-{ [ (2R)-4-Benzyl-2-(3Λ5- 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 IN 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 [ (lS,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
[ (lS,2S)-2-(4-{ [ (2R)-4-benzyl-2-(3,5-difluorobenzyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-l-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+l)
In the same manner as in Example 660, the following compounds (Examples 661 - 663) were obtained. Example 661 l-tert-Butyl-3- [ (1S,2S) -2- (4-{ [ (2R) -2- (3, 5- difluorobenzyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] urea
Figure imgf000692_0001
MS (ESI+, m/e) 579. (M+l) Example 662
2,2-Difluoroethyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5- • difluorobenzyl)piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000693_0001
MS (ESI+, m/e) 588 (M+l) Example 663
Cyclobutyl [ (IS, 2S) -2- (4-{ [ (2R) -2- (3, 5-difluorobenzyl) piperazin- 1-yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000693_0002
MS (ESI+, m/e) 578 (M+l) '
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 (IS, 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
Figure imgf000694_0001
MS (ESI+, m/e) 576 (M+l) Example 665
(lS,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
Figure imgf000694_0002
MS (ESI+, m/e) 576 (M+l) Example 666
Cyclobutyl [ (IS, 2S) -2- (4-{ [ (2R) -2-{2- [ (4-methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000694_0003
MS (ESI+, m/e) 615 (M+l) Example 667
Cyclobutyl [ (IS, 2S) -2- (4-{ [ (2R) -2-{2- [ (3-methoxy-2- methylphenyl) amino] ethyl }piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000695_0001
MS CESI+, m/e) 615 (M+l) 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
Figure imgf000695_0002
MS (ESI+, m/e) 603 (M+l) Example 669
Isopropyl [ (IS, 2S) -2- (4-{ [ (2R)-2-{2-[ (3-methoxy-2- methylphenyl) amino] ethyl }piperazin-l-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000695_0003
MS (ESI+, m/e) 603 (M+l) Example 670
Ethyl [(lS,2S)-2-(4-{ [ (2R) -2-{2- [ (5-methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000696_0001
MS (ESI+, iti/e) 589 (M+l) Example 671 Ethyl [(lS,2S)-2-(4-{ [ (2R) -2-{2- [ (3-methoxy-2- methylphenyl) amino] ethyl }piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000696_0002
MS (ESI+, m/e) 589 (M+l) Example 672
Methyl [ (lS,2S)-2-(4-{ [ (2R) -2-{2- [ (3-methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl] carbonyl} -5-phenyl-1H- imidazol-1-yl) cyclohexyl]'carbamate
Figure imgf000696_0003
MS (ESI+, m/e) 575 (M+l) Example 673
(lS,2R)-2-(4-{ [(2R)-2-{2-[ (3-Methoxy-2- methylphenyl) amino] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) -1-methylcyclohexanol
Figure imgf000697_0001
MS (ESI+, m/e) 532 (M+l) Example 674 (IR, 2R) -1- (Cyclopropylmethyl) -2- (4-{ [ (2R) -2- (4- methoxybenzyl) piperazin-1-yl] carbonyl } -5-phenyl-1H-imidazol-1- yl) cyclohexanol
Figure imgf000697_0002
MS (ESI+, .m/e) 529 (M+l) Example .675
Isopropyl [ (IS, 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+l) Example 676 Cyclobutyl [ (IS, 2S) -2- (4-{ [ (2R) -2-{2- [ (2-fluoro-3- methoxyphenyl) amino] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000698_0001
MS (ESI+, m/e) 619 (M+l)
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-({l-[ (lR,2R)-2-(Cyclopropylmethyl)-2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl]methyl}benzonitrile
Figure imgf000698_0002
MS (ESI+, m/e) 524 (M+l ) Example 678 ( IR, 2R) -1- (Cyclopropylmethyl) -2- [5-phenyl-4- ( { (2S) -2- [ (5-phenyl- 2H-tetrazol-2-yl ) methyl ] piperazin-l-yl } carbonyl) -1H-imidazol-1- yl] cyclohexanol
Figure imgf000699_0001
MS (ESI+, m/e) 567 (M+l) Example 679
(IR, 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
Figure imgf000699_0002
MS (ESI+, m/e) 565 (M+l) Example 680
(IR, 2R) -1- (Cyclopropylmethyl) -2- (4-{ [ (2S) -2- (1H-indazol-1- ylmethyl)piperazin-1-yl] carbonyl}-5-phenyl-1H-±midazol-1- yl) cyclohexanol
Figure imgf000699_0003
MS (ESI+, m/e) 539 (M+l) Example 681
( IR, 2R) -2- ( 4- { [ (2S) -2- ( 1H-Benzimidazol-l-ylmethyl) piperazin-1- yl] carbonyl } -5-phenyl-1H-imidazol-l-yl) -1- (cyclopropylmethyl). cyclohexanol
Figure imgf000700_0001
MS (ESI+, m/e) 539 (M+l) Example 682 (lR,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
Figure imgf000700_0002
MS (ESI+, m/e) 503 (M+l)
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
Figure imgf000700_0003
MS (ESI+, m/e) 580 (M+l)
In the same manner as in Example 11 (Method K) , the following compounds. (Examples 684 - 692) were obtained. Example 684
Ethyl [(lS,2S)-2-(4-{ [ (2R) -2-{2- [ (5-chloro-2- methylphenyl) amino] ethyl}piperazin-1-yl] carbonyl } -5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000701_0001
MS (ESI+, m/e) 593 (M+l) Example 685
(lS,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
Figure imgf000701_0002
MS (ESI+, m/e) 566 (M+l) Example 686
Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2-chloro-4- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000701_0003
MS (ESI+, m/e) 594 (M+l) Example 687
Ethyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (4-chloro-2- fluorophenoxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000702_0001
MS (ESI+, m/e) 598 (M+l) Example 688 Ethyl { (lS,2S)-2-[4-({ (2R)-2-[2-(2,3- dichlorophenoxy) ethyl ] piperazin-1-yl } carbonyl ) -5-phenyl-1H- imidazol-1-yl] cyclohexyl } carbamate
Figure imgf000702_0002
MS. (ESI+, m/e) 614 (M+l) Example 689
Ethyl { (lS/2S)-2-[4-({ (2R) -2- [2- (4- chlorophenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl} carbamate
Figure imgf000703_0001
MS (ESI+, m/e) 580 (M+l) Example 690
Methyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (1-benzothiophen-4- yloxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H-imidazol-l- yl] cyclohexyl }carbamate
Figure imgf000703_0002
MS (ESI+, m/e) 588 (M+l) Example 691
(lS,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
Figure imgf000703_0003
MS (ESI+, m/e) 618 (M+l) Example 692
(lS,2R)-2-(4-{ [ (2R)-2-{2-[ (2-Ethyl-1,3-benzothiazol-5- yl) oxy] ethyl }piperazin-1-yl] carbonyl } -5-phenyl-1H-irαidazol-1- yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000704_0001
MS (ESI+, m/e) 604 (M+l)
In the same manner as in Example 9 (Method I) , the following compounds (Examples 693 - 762) were obtained. Example 693
(IS, 2R) -1- (Methoxymethyl) -2- (4-{ [ (2R) -2-{2- [3- (3- methoxypropoxy)phenoxy] ethyl}piperazin-1-yl] carbonyl}-5-phenyl- 1H-imidazol-1-yl) cyclohexanol
Figure imgf000704_0002
MS (ESI+, m/e ) 607 (M+l ) Example 694
( IS , 2R) -2- ( 4- { [ ( 2R) -2- { 2- [ 3- ( 2- Methoxyethoxy) phenoxy] ethyl }piperazin-1-yl] carbonyl } -5-phenyl- 1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000704_0003
MS (ESI+, m/e) 593 (M+l) Example 695 Ethyl { (IS, 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
Figure imgf000705_0001
MS (ESI+, m/e) 588 (M+l) Example 696
Ethyl { ( IS, 2S) -2- [4- ( { (2R) -2- [2- (2 , 3-dihydro-l-benzofuran-5- yloxy) ethyl] piperazin-l-yl } carbonyl) -5-phenyl-1H-imidazol-l- yl] cyclohexyl } carbamate
Figure imgf000705_0002
MS (ESI+, m/e) 588 (M+l) ' Example 697 Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (5-methoxy-2- methylphenoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl } carbamate
Figure imgf000705_0003
MS (ESI+, m/e) 590. (M+l) Example 698
Methyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (5-methoxy-2- • methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl} carbamate
Figure imgf000706_0001
MS (ESI+, m/e) 576 (M+l) Example 699
Ethyl { (lS,2S)-2-[4-({ (2R) -2- [2- (5-chloro-2- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl} carbamate
Figure imgf000706_0002
MS (ESI+, m/e) 595 (M+l) Example 700
Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2-chloro-5- • methoxyphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl } carbamate
Figure imgf000706_0003
MS (ESI+, m/e) 611 (M+l) Example 701
Ethyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (2-chloro-4- methoxyphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000707_0001
MS (ESI+, m/e) 611 (M+l) Example 702 (lS,2R)-2-(4-{ [ (2R)-2-{2-[ (2-Cyclopropyl-1,3-benzoxazol-5- yl) oxy] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000707_0002
MS (ESI+, m/e) 600 (M+l) Example 703
Ethyl [ (lS,2S)-2-(4-{ [ (2R)-2-{2-[ (2-cyclopropyl-1,3-benzoxazol- 5-yl) oxy] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate
Figure imgf000707_0003
MS (ESI+, m/e) 627. (M+l) Example' 704
Ethyl [ (IS, 2S) -2- (4-{ [ (2R) -2-{2- [ (2, 7-dimethyl-1,3-benzoxazol-β- yl) oxy] ethyl }piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000708_0001
MS (ESI+, m/e) 615 (M+l) Example 705
Ethyl [ (lS,2S)-2-(4-{ [ (2R)-2-{2-[ (2-methyl-1,3-benzoxazol-6- yl) oxy] ethyl }piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate
Figure imgf000708_0002
MS (ESI+, m/e) 601 (M+l) Example 706
Ethyl [ (IS, 2S) -2- (4-{ [ (2R) -2-{2- [ (2-ethyl-l, 3-benzoxazol-5- yl) oxy] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000708_0003
MS (ESI+, m/e) 615 (M+l) Example 707 Methyl ' [ ( IS , 2S) -2- ( 4- { [ (2R) -2- { 2- [ (2-ethyl-l , 3-benzoxazol-5- yl ) oxy] ethyl }piperazin-l-yl] carbonyl } -5-phenyl-1H-imidazol-l- yl) cyclohexyl] carbamate
Figure imgf000709_0001
MS (ESI+, m/e) 601 (M+l) Example 708
Methyl [ (1S,2S) -2- (4-{ [ (2R)-2-{2-[ (2-methyl-1,3-benzoxazol-β- yl) oxy] ethyl}piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol-1- yl) cyclohexyl] carbamate
Figure imgf000709_0002
MS (ESI+, m/e) 587 (M+l) Example 709 (lS,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
Figure imgf000709_0003
MS (ESI+, m/e) 588 (M+l) Example 710 (lS,2R)-2-(4-{ [(2R)-2-{2-[(2,7-Dimethyl-1,3-benzoxazol-6- yl)oxy] ethyl}piperazin-1-yl]carbonyl}-5-phenyl-1H-imidazol-l- yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000710_0001
MS (ESI+, m/e) 588 (M+l) Example 711
(IS, 2R)-I- (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
Figure imgf000710_0002
MS (ESI+, m/e) 574 (M+l) 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
Figure imgf000710_0003
MS (ESI+, m/e) 688 (M+l) Example 713 Methyl [ (IS, 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+l) Example 714
Methyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (3,5- difluorophenoxy) ethyl] piperazin-l-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl } carbamate
Figure imgf000711_0002
MS (ESI+, m/e) 568 (M+l) Example 715 Methyl [6- (2-{ (2R) -1- [ (1-{ (IS, 2S) -2- f (methoxycarbonyl) amino] cyclohexyl}-5-phenyl-1H-imidazol-4- yl) carbonyl]piperazin-2-yl}ethoxy) -2, 3-dihydro-1-benzofuran-3- yl] acetate
Figure imgf000711_0003
MS (ESI+, m/e) 646 (M+l) 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
Figure imgf000712_0001
MS (ESI+,. m/e) 588 (M+l) Example 717
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3,4- dimethylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000712_0002
MS (ESI+, m/e) 560 (M+l) Example 718 Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (4- isopropylphenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000712_0003
MS (ESI+, m/e) 574 (M+l) Example 719 (IS, 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
Figure imgf000713_0001
MS (ESI+, m/e) 602 (M+l) Example 720
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (2-Ethyl-1,3-benzoxazol-6- yl) oxy] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol-l- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000713_0002
MS (ESI+., m/e) 588 (M+l) Example 721 (lS,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
Figure imgf000713_0003
MS (ESI+, m/e) 544 (M+l) Example 722 Ethyl C(lS,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
Figure imgf000714_0001
MS (ESI+, m/e) 601 (M+l) Example 723
N-{ (lS,2S)-2-[4-({ (2R)-2-[2-(3,4-
Dimethylphenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}methanesulfonamide
Figure imgf000714_0002
MS (ESI+, m/e) 580 (M+l) Example 724 N-{ (IS, 2S) -2- [4- ({ (2R) -2- [2- (Naphthalen-2-yloxy) ethyl] piperazin- 1-yl} carbonyl) -5-phenyl-1H-imidazol-1- yl] cyclohexyl }methanesulfonamide
Figure imgf000714_0003
MS (ESI+, m/e) 602 (M+l) 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
Figure imgf000715_0001
MS (ESI+, m/e) 566 (M+l) Example 726
2-Methoxyethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (naphthalen-2- yloxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H-imidazol-l- yl] cyclohexyl}carbamate
Figure imgf000715_0002
MS (ESI+, m/e) 626 (M+l) Example 727 2-Methoxyethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (4- methylphenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl } carbamate
Figure imgf000715_0003
MS (ESI+, m/e) 590 (M+l) Example 728 Cyclobutyl { (IS, 2S) -2- [5-phenyl-4- ( { (2R) -2- [2- (phenylamino) ethyl]piperazin-1-yl}carbonyl) -1H-imidazol-1- yl] cyclohexyl}carbamate
Figure imgf000716_0001
MS (ESI+, m/e) 571 (M+l)
Example 729
Cyclobutyl [ (1S,2S) -2- (4-{ [ (2R) -2-benzylpiperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000716_0002
MS (ESI+, m/e) 542 (M+l) Example 730
(IS, 2R) -1- (Methoxymethyl) -2- [4- ( { (2R) -2- [2- (3-methoxy-4- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexanol
Figure imgf000716_0003
MS (ESI+, m/e) 563 (M+l) Example 731 Methyl { (IS, 2S) -2- [4- ( { (2R) -2- [2- (3-methoxy-4- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000717_0001
MS (ESI+, m/e) 576 (M+l) Example 732
Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (3-methoxy-4- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000717_0002
MS (ESI+, m/e) 590 (M+l) Example 733 Ethyl { (lS,2S)-2-[4-({ (2R) -2- [2- (4- methylphenoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000717_0003
MS (ESI+, m/e) 560 (M+l) Example' 734
Ethyl { (lS,2S)-2-[4-({ (2R) -2- [2- (naphthalen-2- . yloxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H-imidazol-1- yl] cyclohexyl}carbamate
Figure imgf000718_0001
MS (ESI+, m/e) 596 (M+l) Example 735
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (4- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- im±dazol-1-yl] cyclohexyl } carbamate
Figure imgf000718_0002
MS (ESI+, m/e) 546 (M+l) Example 736
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (naphthalen-2- yloxy) ethyl ] piperazin-l-yl } carbonyl) -5-phenyl-1H-imidazol-1- yl ] cyclohexyl } carbamate
Figure imgf000718_0003
111 MS (ESIH-, m/e) 582 (M+l) Example 737
Methyl { (IS, 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
Figure imgf000719_0001
MS (ESI+, m/e) 572 (M+l) Example 738 (IS, 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
Figure imgf000719_0002
MS (ESI+, m/e) 559 (M+l) Example 739
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2, 6- difluorophenoxy) ethyl] piperazin-1-yl} carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl }carbamate
Figure imgf000720_0001
MS (ESI+, m/e) 568 (M+l) Example 740
(IS, 2R) -2- [4- ( { (2R) -2- [2- (2, 6-Difluorophenoxy) ethyl] piperazin-1- yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1-
(methoxymethyl) cyclohexanol
Figure imgf000720_0002
MS (ESI+, m/e) 555 (M+l) Example 741
6-{2-[ (2R)-1-({l-[ (lR,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
Figure imgf000720_0003
MS (ESI+, m/e) 660 (M+l) Example 742 6-{2-[ (2R)-1-({l-[ (lR,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
Figure imgf000721_0001
MS (ESI+, m/e) 655 (M+l) Example 743
6-{2- [ (2R) -1- ( { 1- [ (IR, 2R) -2- (Cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl] ethoxy}-!- (3-methoxypropyl) -3, 4-dihydroquinolin-2 (1H) -one
Figure imgf000721_0002
MS (ESI+, m/e) 670 (M+l) Example 744 6-{2-[ (2R)-1-({l-[ (IR, 2R) -2- (Cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl] ethoxy} -2H-1, 4-benzoxazin-3 (4H) -one
Figure imgf000721_0003
MS (ESI+, m/e) 600.(M+l) Example 745
(IR, 2R) -2- (4-{ [ (2S) -2- (1H-Benzotriazol-1-ylmethyl) piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) -1- (cyclopropylmethyl) cyclohexanol
Figure imgf000722_0001
MS (ESI+, m/e) 540 (M+l) Example 746
(IR, 2R) -2- [4- ( { (2R) -2- [2- (1H-Benzotriazol-1-yl) ethyl] piperazin- l-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1-
(cyclopropylmethyl) cyclohexanol
Figure imgf000722_0002
MS (ESI+, m/e) 554 (M+l) Example 747
(IR, 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
Figure imgf000722_0003
MS (ESI+, πi/e) 597 (M+l) Example 748
(IR, 2R) -2- [4- ( { (2R) -2- [2- (1H-Benzimidazol-1-yl) ethyl] piperazin- l-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (cyclopropylmethyl) cyclohexanol
Figure imgf000723_0001
MS (ESI+, m/e) 553 (M+l) Example 749 (IS, 2R) -2- [4- ({ (2R)-2-[2-(3,4-Dimethoxyphenoxy)ethyl]piperazin- l-yl}carbonyl) -5-phenyl-1H-imidazol-1-yl] -1- (methoxymethyl) cyclohexanol
Figure imgf000723_0002
MS (ESI+, m/e) 579 (M+l) Example 750
6- { 2- [ (2R) -1- ( { 1- [ (IR, 2R) -2- (Cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl] ethoxy}-1,3-benzoxazol-2 (3H) -one
Figure imgf000724_0001
MS (ESIH-, m/e) 586 (MH-I) Example 751
7-{2- [ (2R) -1- ( {1- [ (IR, 2R) -2- (Cyclopropylmethyl) -2- hydroxycyclohexyl]-5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl]ethoxy}-3,4-dihydroquinolin-2 (1H) -one
Figure imgf000724_0002
MS (ESI+, m/e) 598 (MH-I) Example 752
5- { 2- [ (2.R) -1- ( { 1- [ (IR, 2R) -2- (Cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl) piperazin- 2-yl]ethoxy}-3,4-dihydroisoquinolin-l (2H) -one
Figure imgf000724_0003
MS (ESIH-, m/e) 598 (MH-I) Example 753
(lS,2R)-2-(4-{ [(2R)-2-{2-[(2,5-
Dimethylphenyl) amino] ethyl}ρiperazin-1-yl] carbonyl}-5-phenyl-1H- imidazol-1-yl) -1- (methoxymethyl) cyclohexanol
Figure imgf000725_0001
MS (ESI+, m/e) 546 (M+l) Example 754 (lS,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
Figure imgf000725_0002
MS (ESI+, m/e) 550 (M+l) Example .755
6- {2- [ (2R) -1- ( { 1- [ (IR, 2R) -2- (Cyclopropylmethyl) -2- hydroxycyclohexyl] -5-phenyl-1H-imidazol-4-yl}carbonyl)piperazin- 2-yl] ethoxy}-3, 4-dihydroquinolin-2 (1H) -one
Figure imgf000725_0003
MS (ESI+, m/e) 598 (M+l) Example 756 Ethyl {(lS,2S)-2-[4-({ (2R)-2-[2-(3-methoxy-2- methylphenoxy) ethyl] piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000726_0001
MS (ESI+, m/e) 590 (M+l) Example 757
Ethyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2-£luoro-4- methylphenoxy) ethyl]piperazin-1-yl}carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl }carbamate
Figure imgf000726_0002
MS (ESI+, m/e) 578 (M+l) Example 758 (lS,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
Figure imgf000726_0003
MS (ESI+, m/e) 586.(M+l) Example 759
(IR, 2R) -1- (Cyclopropylitiethyl) -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
Figure imgf000727_0001
MS (ESI+, m/e) 571 (M+l) Example 760
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2-fluoro-3- methoxyphenoxy) ethyl] piperazin-1-yl } carbonyl) -5-phenyl-1H- imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000727_0002
MS (ESI+, m/e) 580 (M+l) Example 761
Methyl [ (IS, 2S) -2- (4-{ [ (2R) -2-{2- [ (2-fluoro-3- methoxyphenyl) amino] ethyl}piperazin-1-yl] carbonyl }-5-phenyl-1H- imidazol-1-yl) cyclohexyl] carbamate
Figure imgf000727_0003
MS (ESI'+, m/e) 579 (M+l) Example 762
(IR, 2R) -1- (Cyclopropylmethyl) -2- (4-{ [ (2R) -2-{2- [ (2-ethyl-1,3- benzoxazol-5-yl) amino] ethyl}piperazin-l-yl] carbonyl }-5-phenyl- 1H-imidazol-1-yl) cyclohexanol
Figure imgf000728_0001
MS (ESI+, m/e) 597 (M+l)
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 ' (lS,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
Figure imgf000728_0002
MS (ESI+, m/e) 588 (M+l) Example 764
(lS,2R)-2-{4-[ ( (2R)-2-{2-[ (2-Cyclopropyl-1,3-benzoxazol-5- yl) oxy] ethyl}piperazin-1-yl) carbonyl] -5-phenyl-1H-imidazol-l- yl}-1- (methoxymethyl) cyclohexanol
Figure imgf000729_0001
MS (ESI+, m/e) 600 (M+l) Example 765
(lS,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
Figure imgf000729_0002
MS (ESI+, m/e) 588 (M+l) Example 766
Methyl { (IS, 2S) -2- [4- ({ (2R) -2- [2- (2-naphthyloxy) ethyl] piperazin- 1-yl} carbonyl) -5-phenyl-1H-imidazol-1-yl] cyclohexyl}carbamate
Figure imgf000729_0003
MS (ESI+, m/e) 588 (M+l)
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.l, and 5'-GGATCCTCAGCGGGCCAAGGC-S'; 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-S' ; 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-S'; SEQ ID No.5, and 5'- TTGGATCCTCATGCTGTGCTCAGCGGGTTGGCCACGCGG-S'; 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 PMlO 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/m'in, 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. x 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 (2x5 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) X 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 Biotecnology 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 Biotecnology 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:
Figure imgf000739_0001
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.
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:
Figure imgf000740_0001
wherein R1 is as defined in claim 1.
8. A compound represented by the formula:
Figure imgf000740_0002
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 Cχ-3 alkyl optionally having substituent (s) , or (b) G5_7 cycloalkane substituted by amino optionally haying substituent (s) .
9. (lS,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 [ (lS,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. (IS, 2R)-I- (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. (IS, 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 [ (IS, 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. (lS,2R)-2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl} -5- phenyl-1H-imidazol-1-yl) -1- (methoxymethyl) cyclohexanol or a salt thereof. .
15. (IS, 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 [ (IS, 2S) -2- (4-{ [ (2R) -2- (2-anilinoethyl)piperazin-1- yl] carbonyl}-5-phenyl-1H-imidazol-1-yl) cyclohexyl] carbamate or a salt thereof.
17 . (lS, 2R) -l- (Methoxymethyl) -2- (4- { [ (2R) -2- (2- morpholinobenzyl) piperazin-1-yl] carbonyl}-5-phenyl-1H-imidazol- 1-yl) cyclohexanol or a salt thereof.
■5 18. (lS/2R)-2-(4-{ [ (2R) -2-Benzylpiperazin-1-yl] carbonyl} -5- phenyl-1H-imidazol-1-yl) -1-methylcyclohexanol or a salt thereof.
19. (lS,2R)-1-(Methoxymethyl)-2-{4-[ ( (2R) -2-{2- [ (3- methoxyphenyl) amino] ethyl }piperazin-1-yl) carbonyl] -5-phenyl-1H-
10 imidazol-1-yl}cyclohexanol or a salt thereof.
20. (lS,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.
15
21. (lS,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.
20' 22. (lS,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. l-[ (4-{ [ (2R) -2- (2-Anilinoethyl) piperazin-1-yl] carbonyl} -5- 25 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 30 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.
PCT/JP2008/058310 2007-04-27 2008-04-23 Substituted imidazole compound and use thereof WO2008139941A1 (en)

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