WO2011068171A1 - Bicyclic nitrogen-containing saturated heterocyclic derivatives - Google Patents

Bicyclic nitrogen-containing saturated heterocyclic derivatives Download PDF

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WO2011068171A1
WO2011068171A1 PCT/JP2010/071608 JP2010071608W WO2011068171A1 WO 2011068171 A1 WO2011068171 A1 WO 2011068171A1 JP 2010071608 W JP2010071608 W JP 2010071608W WO 2011068171 A1 WO2011068171 A1 WO 2011068171A1
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group
cis
chloro
alkyl
methyl
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Japanese (ja)
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市郎 早川
潤 渡部
孝幸 百瀬
亘 富里
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第一三共株式会社
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Definitions

  • the present invention prevents rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, autoimmune diseases such as psoriasis, transplant organ rejection, allergic diseases, etc.
  • the present invention relates to a method for preventing or treating an autoimmune disease, which comprises administering to a mammal a compound having a therapeutic effect, a pharmaceutical composition containing the compound, or an effective amount of the pharmaceutical composition.
  • Non-Patent Documents 1 and 2 Conventionally, in the treatment of autoimmune diseases and the like, anti-inflammatory drugs such as steroids have been used as symptomatic treatment, and the development of fundamental treatment methods is desired. In addition, it has been reported that abnormalities of the immune system are involved in the onset of diabetes and nephritis (see, for example, Non-Patent Documents 1 and 2), but no drug has been developed to improve the abnormalities.
  • an object of the present invention is to provide a novel compound having a low toxicity and an excellent immunosuppressive action, a pharmacologically acceptable salt thereof or a pharmacologically acceptable prodrug thereof.
  • the present invention (1) A compound having the general formula (I) or a pharmacologically acceptable salt thereof.
  • X 1 , X 2 , X 3 , and X 4 each independently represents —C ⁇ or —N ⁇ ;
  • X 7 represents —CH (—R 6 ) — or —C ( ⁇ O) —
  • R 1 is a hydrogen atom, hydroxyl group, halogen
  • R 7 moieties may be the same or different, and each is a hydroxyl group, amino group, carboxy group, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group.
  • Y is a single bond, —CH 2 —, — (CR 8 R 8 ) r —, —CHR 8 C ( ⁇ O) —, — (CHR 8 ) r O—, — (CHR
  • the R 9 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a 6-14 membered aryl group, an aralkyl group.
  • C3-C10 cycloalkyl group —CN, — (CH 2 ) q OH, — (CH 2 ) q O—C1-C20 alkyl, — (CH 2 ) q O-6 to 14-membered aryl-C1- C20 alkyl, — (CH 2 ) q O-6 to 14-membered aryl, — (CH 2 ) q O aralkyl, — (CH 2 ) q O—C 3 -C 10 cycloalkyl, — (CH 2 ) q NH 2 , -(CH 2 ) q NH-C1-C20 alkyl,-(CH 2 ) q N (C1-C20 alkyl) 2 ,-(CH 2 ) q NH-6-14-membered aryl-C1-C20 alkyl,-( CH 2 ) q N H-6-14 membered aryl, — (CH 2 )
  • the R 10 moieties may be the same or different and each is a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a 6-14 membered aryl group, an aralkyl group, a C3 —C10 cycloalkyl group, — (CH 2 ) q OH, — (CH 2 ) q O—C1-C20 alkyl, — (CH 2 ) q O—C1-C20 alkyl—6- to 14-membered aryl, — (CH 2) q O-6 ⁇ 14 membered aryl, - (CH 2) q O aralkyl, - (CH 2) q O -C3-C10 cycloalkyl, - (CH 2) q NH2 , - (CH 2) q NH —C1-C20 alkyl, — (CH 2 ) q N (C1-C20 alkyl)
  • the R 11 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C2-C15 alkenyl group, a C1-C20 alkyl-6-14 membered aryl group, a C2-C15 Alkynyl group, C1-C20 alkoxy group, C1-C20 alkylamino group, C1-C20 alkylthiocarboxy group, C1-C20 alkyl-5-14 membered heteroaryl group, C1-C20 alkylthio group, C1-C20 alkylsulfinyl group, C1-C20 alkylsulfonyl group, C1-C20 alkoxycarbonyl group, C1-C20 aminoalkyl group, amidinyl group, aralkyl group, aralkenyl group, aralkoxy group, aralkoxycarbonyl group, aralkylthio group, 6-14 membered
  • the R 12 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C2-C15 alkenyl group, a C1-C20 alkyl-6-14 membered aryl group, a C2-C15 Alkynyl group, C1-C20 alkoxy group, C1-C20 alkylamino group, C1-C20 alkylthiocarboxy group, C1-C20 alkyl-5-14 membered heteroaryl group, C1-C20 alkylthio group, C1-C20 alkylsulfinyl group, C1-C20 alkylsulfonyl group, C1-C20 alkoxycarbonyl group, C1-C20 aminoalkyl group, amidinyl group, aralkyl group, aralkenyl group, aralkoxy group, aralkoxycarbonyl group, aralkylthio group, 6-14 membered
  • X 1 , X 2 , X 3 , X 4 , X 8 , and X 9 each independently represent —C ⁇ or —N ⁇
  • X 7 represents —CH (—R 6 ) — or —C ( ⁇ O) —
  • R 15 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a carbamoyl group, a C1-C6 alkylcarbamoyl group, a carboxy group optionally protected by a protecting group for carboxy group, a C1-C6 alkoxycarbonyl group, C1- A C6 hydroxyalkoxycarbonyl group or a 5-membered heteroaryl group optionally substituted with a group selected from the substituent group ⁇ , Y is a single bond, —CH 2 —, —C ( ⁇ O) —, —C ( ⁇ S) —, —C (—C1-C6 alkyl) —, or —C (-5-membered heteroaryl)- Wherein the 5-membered heteroaryl group may be substituted with a group selected from the substituent group ⁇ , A is a carbamoyl group, C1-C6 alkylcarbamoyl group, C
  • Substituent group ⁇ hydroxyl group, amino group, carboxy group, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 alkylamino group, C3 —C6 cycloalkylamino group, C1-C6 halogenoalkyl group, or C1-C6 halogenoalkoxy group]
  • a pharmaceutical composition comprising a compound having the general formula (I) or the general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient.
  • Autoimmune diseases are systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative Colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosa, psoriasis vulgaris, vascular inflammation group, Wegener granulomas , Uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension Disease, minimal
  • a in the general formula (I) or the general formula (II) is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group.
  • R 1 in the general formula (I) or the general formula (II) is a hydrogen atom, a hydroxyl group, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group
  • R 13 and R 14 in the general formula (II) are each independently a hydrogen atom or a halogen atom.
  • R 15 in the general formula (II) is a carbamoyl group or a carboxy group optionally protected by a protecting group for a carboxy group .
  • An effective amount of a pharmaceutical composition containing a compound having the general formula (I) or the general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient is administered to a mammal, A method for preventing or treating an immune disease.
  • Autoimmune diseases are systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative Colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosa, psoriasis vulgaris, vascular inflammation group, Wegener granulomas , Uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension Disease, minimal
  • a in the general formula (I) or the general formula (II) is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group.
  • a in the general formula (I) or the general formula (II) is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group.
  • X 5 in the general formula (I) or the general formula (II) is —CH 2 —, —CH 2 CH 2 — or —O—.
  • the compound of the present invention or a pharmacologically acceptable salt thereof has an excellent immunosuppressive action with low toxicity, and is used as a prophylactic or therapeutic agent for autoimmune diseases or other immune-related diseases against warm-blooded animals (particularly humans). Useful.
  • the halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a fluorine atom or a chlorine atom Preferable is a fluorine atom or a chlorine atom.
  • the C1-C20 alkyl group means an aliphatic hydrocarbon group which may be linear or branched and contains 1 to 20 carbon atoms in the chain.
  • the alkyl group contains 1 to 6 carbon atoms in the chain. More preferably it contains 1 to 3 carbon atoms in the chain.
  • Branching means that one or more lower alkyl groups (for example, a methyl group, an ethyl group, or a propyl group) are bonded to a linear alkyl chain.
  • the C1-C6 alkyl group is a C1-C20 alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • a methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert-butyl group is preferable, a methyl group or an ethyl group is more preferable, and an ethyl group is particularly preferable.
  • the C1-C20 alkoxy group means an alkyl-O group in which an oxygen atom is bonded to the alkyl group, and contains 1 to 20 carbon atoms in the chain. Preferably, it has 1 to 6 carbon atoms. More preferably, it has 1 to 3 carbon atoms. Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy.
  • the C1-C6 alkoxy group is a group containing 1 to 6 carbon atoms in the chain among the C1-C20 alkoxy groups, and preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Alternatively, it is a t-butoxy group, and more preferably a methoxy group.
  • a C3-C10 cycloalkyl group means a non-aromatic monocyclic or polycyclic ring system containing 3 to 10 carbon atoms.
  • the cycloalkyl ring contains 3 to 6 ring atoms.
  • monocyclic cycloalkyl include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
  • Specific examples of polycyclic cycloalkyl include 1-decalin group, norbornyl group, adamantyl group and the like.
  • the C3-C6 cycloalkyl group is a cyclic alkyl group containing 3 to 6 carbon atoms in the C3-C10 cycloalkyl group, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Group, more preferably a cyclopropyl group.
  • the C3-C10 cycloalkoxy group means a group having 3 to 10 carbon atoms, in which an oxygen atom is bonded to the C3-C10 cycloalkyl group.
  • the cycloalkoxy group contains 3 to 6 ring atoms.
  • Specific examples of the monocyclic cycloalkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, a cycloheptoxy group, and the like.
  • Specific examples of polycyclic cycloalkyl include 1-decalin group, norbornyl group, adamantyl group and the like.
  • C3-C6 cycloalkoxy group is a cyclic alkoxy group containing 3 to 6 carbon atoms among the above cycloalkoxy groups, for example, a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, or a cyclohexoxy group It is. Preferred is a cyclopropoxy group or a cyclobutoxy group, and more preferred is a cyclopropoxy group.
  • the C1-C20 halogenoalkyl group is a group in which a halogen atom is substituted on an alkyl group having 1 to 20 carbon atoms, preferably a group having 1 to 6 carbon atoms in which a fluorine atom or a bromine atom is substituted. More preferably, it is a group having 1 to 6 carbon atoms substituted with a fluorine atom. Particularly preferred is a group having 1 to 3 carbon atoms substituted with a fluorine atom.
  • the C1-C6 halogenoalkyl group is a group having 1 to 6 carbon atoms among the above halogenoalkyl groups.
  • it is a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, etc., preferably a fluoromethyl group, a difluoromethyl group, or trifluoro A methyl group, and more preferably a trifluoromethyl group.
  • the C1-C20 halogenoalkoxy group is a group in which an oxygen atom is bonded to the C1-C20 halogenoalkyl group, preferably a fluorine atom or a group having 1 to 6 carbon atoms substituted by a bromine atom, Preferred is a group having 1 to 6 carbon atoms substituted with a fluorine atom. Particularly preferred is a group having 1 to 3 carbon atoms substituted with a fluorine atom.
  • the C1-C6 halogenoalkoxy group is a group having 1 to 6 carbon atoms in the C1-C20 halogenoalkoxy group.
  • Specific examples include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a fluoroethoxy group, a difluoroethoxy group, and a trifluoroethoxy group, and a trifluoromethoxy group is preferable.
  • the C1-C6 alkylamino group is a group in which an amino group is bonded to the C1-C6 alkyl group. Specific examples include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a tert-butylamino group, a pentylamino group, and a hexylamino group.
  • a C1-C3 alkylamino group having 1 to 3 carbon atoms is preferable, a methyl group or an ethyl group is more preferable, and an ethyl group is particularly preferable.
  • the C3-C6 cycloalkylamino group is a group in which an amino group is bonded to the C3-C6 cycloalkyl group. Specific examples include a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, and a cyclohexylamino group. Preferred is a cycloalkylamino group having 3 to 4 carbon atoms, and more preferred is a cyclopropylamino group.
  • the C1-C6 alkylaminooxadiazolyl group is a group in which an oxadiazolyl group is bonded to the C1-C6 alkylamino group.
  • methylaminooxadiazolyl group ethylaminooxadiazolyl group, propylaminooxadiazolyl group, isopropylaminooxadiazolyl group, tert-butylaminooxadiazolyl group, pentylaminooxadiazolyl group, hexyl
  • An aminooxadiazolyl group and the like Preferred is a C1-C3 alkylaminooxadiazolyl group having 1 to 3 carbon atoms, more preferred is a methylaminooxadiazolyl group or ethylaminooxadiazolyl group, and particularly preferred.
  • the C1-C6 alkylcarbamoyl group is a group in which a carbamoyl group is bonded to the C1-C6 alkyl group. Specifically, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, or a tert- And a butylcarbamoyl group.
  • a group having 1 to 3 carbon atoms is preferable, and an ethylcarbamoyl group or an isopropylcarbamoyl group is more preferable.
  • the C1-C6 hydroxyalkylcarbamoyl group is a group in which a hydroxy group is substituted on the C1-C6 alkylcarbamoyl group, and specifically includes a hydroxymethylcarbamoyl group, a 1-hydroxyethylcarbamoyl group, a 2-hydroxyethylcarbamoyl group. 1-hydroxypropylcarbamoyl group, 2-hydroxypropylcarbamoyl group, 3-hydroxypropylcarbamoyl group, and the like.
  • Preferred is a group having 1 to 3 carbon atoms, more preferred is a hydroxymethylcarbamoyl group, 2-hydroxyethylcarbamoyl group or 3-hydroxypropylcarbamoyl group, and particularly preferred is 2-hydroxy An ethylcarbamoyl group.
  • the C3-C6 cycloalkyl carbamoyl group is a group in which a carbamoyl group is bonded to the above C3-C6 cycloalkyl group. And preferred is a cyclopropylcarbamoyl group.
  • the C3-C6 cycloalkyl-C1-C6 alkylcarbamoyl group is a group in which the C1-C6 alkylcarbamoyl group is bonded to the C3-C6 cycloalkyl group.
  • a cyclopropylmethylcarbamoyl group for example, a cyclopropylmethylcarbamoyl group, a cyclopropylethylcarbamoyl group Or a cyclopropylpropylcarbamoyl group and the like, and preferably a cyclopropylmethylcarbamoyl group.
  • the C1-C6 alkylsulfonyl group is a group in which a sulfonyl group is bonded to the C1-C6 alkyl group, and is preferably an alkylsulfonyl group having 1 to 3 carbon atoms.
  • C1-C6 alkylsulfonyl group examples include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, or a tert-butylsulfonyl group, a pentylsulfonyl group, a hexylsulfonyl group, and the like.
  • the C1-C6 alkylsulfonamido group is a group in which a sulfonamido group is bonded to the C1-C6 alkyl group, and preferably an alkylsulfonamido group having 1 to 3 carbon atoms.
  • C1-C6 alkylsulfonamide group examples include a methylsulfonamide group, an ethylsulfonamide group, a propylsulfonamide group, an isopropylsulfonamide group, a butylsulfonamide group, a tert-butylsulfonamide group, a pentylsulfonamide group, or Hexylsulfonamido group, etc., preferably methylsulfonamido group, ethylsulfonamido group, or propylsulfonamido group.
  • the C3-C6 cycloalkyl-C1-C6 alkylsulfonyl group is a group in which the C1-C6 alkylsulfonyl group is bonded to the C3-C6 cycloalkyl group, such as a cyclopropylmethylsulfonyl group, a cyclopropylethylsulfonyl group. , A cyclobutylmethylsulfonyl group, a cyclopentylmethylsulfonyl group, a cyclohexylmethylsulfonyl group, and the like, and preferably a cyclopropylmethylsulfonyl group.
  • the C1-C6 acylamino group is a hydrogen atom or a C1-C6 acyl group in which a saturated or unsaturated C1-C6 linear, branched, or cyclic hydrocarbon group is bonded to a carbonyl group. It is a bonded group.
  • An acylamino group having 4 to 6 carbon atoms is preferable, and an acylamino group having 4 carbon atoms is more preferable.
  • C1-C6 acylamino group examples include formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, cyclopropionylamino group, cyclobutyrylamino group Or a cyclopentanoylamino group, preferably an acetylamino group, a cyclopropionylamino group, a cyclobutyrylamino group, or a cyclopentanoylamino group, and more preferably an acetylamino group An amino group or a cyclopropionylamino group.
  • a 5- to 14-membered heteroaryl group includes 5 to 14 ring atoms, preferably 5 to 6 ring atoms, and one or more of these ring atoms may be used alone or in combination. And means an aromatic monocyclic or polycyclic ring system that is an element other than carbon (eg, nitrogen, oxygen or sulfur). Further preferred heteroaryl groups contain 5 ring atoms.
  • the prefix aza, oxa or thia before the heteroaryl group root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heteroaryl group can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
  • heteroaryl examples include pyridyl group, pyrazinyl group, furanyl group, thienyl group, pyrimidinyl group, isoxazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, pyrazolyl group, furazanyl group, pyrrolyl group, pyrazolyl group, triazolyl group, 1,2,4-thiadiazolyl group, pyridazinyl group, quinoxalinyl group, phthalazinyl group, imidazo [1,2-a] pyridinyl group, imidazo [2,1-b] thiazolyl group, benzofurazanyl group, indolyl group, azaindolyl group, benzoimidazolyl Group, benzothienyl group, quinolinyl group, imidazolyl group, thienopyridyl group, quinazolinyl group, thio
  • the 5-membered heteroaryl group is a group having 5 ring atoms among the 5- to 14-membered heteroaryl groups described above, for example, an imidazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, a furyl group. , Thiazolyl group, pyrazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, or oxadiazolyl group.
  • Preferred are imidazolyl group, pyrrolyl group, triazolyl group, tetrazolyl group and oxadiazolyl group, and more preferred is oxadiazolyl group.
  • Examples of the protecting group for carboxy group include Protective Groups in Organic Synthesis, 4th Edition, 533-646, 2006 by Greene, Wuts et al. Protecting groups described in John Wiley & Sons, Inc. can be mentioned, and specific examples include C1-C6 alkyl group, allyl group, benzyl group, diphenylmethyl group. , A trityl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, and the like. A C1-C6 alkyl group is preferable, and a methyl group or an ethyl group is more preferable.
  • the carboxy group which may be protected with a protecting group for carboxy group includes, in addition to an unsubstituted carboxy group, a C1-C6 alkyl group, an allyl group, a benzyl group, a diphenylmethyl group, a trityl group, a trimethylsilyl group, and Examples thereof include a carboxy group substituted with a group selected from tert-butyldimethylsilyl group, preferably a carboxy group or a carboxy group substituted with a C1-C6 alkyl group, and more preferably Is a carboxy group, a methoxycarbonyl group, or an ethoxycarbonyl group.
  • the C1-C20 alkoxycarbonyl group is a group in which a carbonyl group is bonded to the C1-20 alkoxy group, preferably an alkoxycarbonyl group having 1 to 6 carbon atoms, and more preferably 1 carbon atom.
  • the C1-C6 alkoxycarbonyl group is a group having 1 to 6 carbon atoms among the above C1-C20 alkoxycarbonyl groups, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, or , T-butoxycarbonyl group, etc., preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group, and more preferably a methoxycarbonyl group or an ethoxycarbonyl group.
  • the C1-C6 hydroxyalkoxycarbonyl group is a group in which a hydroxy group is bonded to the C1-C6 alkoxycarbonyl group, and preferably a group having 1 to 3 carbon atoms.
  • Specific examples of the C1-C6 hydroxyalkoxycarbonyl group include a hydroxymethoxycarbonyl group, a 2-hydroxyethoxycarbonyl group, a 3-hydroxypropoxycarbonyl group, a hydroxyisopropoxycarbonyl group, a 4-hydroxybutoxycarbonyl group, or a hydroxy-t- A butoxycarbonyl group and the like can be mentioned, and a hydroxymethoxycarbonyl group, a 2-hydroxyethoxycarbonyl group, or a 3-hydroxypropoxycarbonyl group is preferable.
  • a C1-C6 hydroxamate group means a C1-C6 alkyl-C ( ⁇ O) NH—O— group.
  • the bond to the parent moiety is through the oxygen group.
  • the alkyl moiety has 1 to 3 carbon atoms.
  • Specific examples of the C1-C6 hydroxamate group include acetyl-NH—O— group, propionyl-NH—O— group, butyryl-NH—O— group, isobutyryl-NH—O— group, valeryl-NH—O— group. Group, or isovaleryl-NH-O- group.
  • An acetyl-NH—O— group or a propionyl-NH—O— group is preferable.
  • An amidinyl group means a —C ( ⁇ NR) NHR group.
  • R groups are defined as H, alkyl, alkylaryl, heteroaryl, hydroxyl, alkoxy, amino, ester, CN, —NHSO 2 alkyl, —NHSO 2 aryl, —NHC ( ⁇ O) NHalkyl, and —NHalkyl. The The bond to the parent moiety is through the carbon.
  • a 3- to 10-membered heterocyclenyl group includes 3 to 10 ring atoms, preferably 5 to 10 ring atoms, one or more of these ring atoms, alone or in combination, Non-aromatic rings that are monocyclic or polycyclic and contain at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms present in the ring system.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclenyl may be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
  • monocyclic azaheterocyclenyl group examples include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyrimidine, dihydro Examples include -2-pyrrolinyl, dihydro-3-pyrrolinyl, dihydro-2-imidazolinyl, dihydro-2-pyrazolinyl, dihydro-4,5-trizolyl and the like.
  • oxaheterocyclenyl group examples include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl and the like.
  • a specific example of a polycyclic oxaheterocyclenyl group is a 7-oxabicyclo [2.2.1] heptenyl group.
  • Specific examples of the monocyclic thiaheterocyclenyl ring include dihydrothiophenyl and dihydrothiopyranyl.
  • a 3- to 10-membered heterocyclyl group contains 3 to 10 ring atoms, preferably 5 to 10 ring atoms, and one or more of the ring system atoms, alone or in combination, are carbon atoms.
  • Suitable heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, oxazolidinyl, imidazolidinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4 -Dioxanyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, tetrahydrothiopyranyl group and the like.
  • the compound having the general formula (I) is preferably a compound having the general formula (II), and more preferably a compound having a combination of the following substituents.
  • X 5 is preferably —CH 2 CH 2 —, —CH 2 —, or —O—, and more preferably —CH 2 CH 2 —.
  • X 6 is preferably X 6 and X 7 are both —CH 2 — or both —C ( ⁇ O) —, and more preferably both are —CH 2 —.
  • X 8 and X 9 are each independently —CH ⁇ or —N ⁇ , but preferably both are —CH ⁇ , or X 8 is —C ⁇ and X 9 is —N ⁇ . More preferably, both are —CH ⁇ .
  • R 1 is preferably a hydrogen atom, hydroxyl group, halogen atom, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 halogenoalkyl.
  • Group, or a C1-C6 halogenoalkoxy group more preferably a hydrogen atom, a halogen atom, or a C1-C6 alkyl group, and particularly preferably a hydrogen atom, a chlorine atom, or a methyl group. is there.
  • R 2 is preferably a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group, more preferably a hydrogen atom.
  • R 3 and R 4 are each independently preferably a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group, and more preferably a halogen atom or a C1-C6 alkyl group. And particularly preferably a fluorine atom or a methyl group.
  • R 5 and R 6 are preferably each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group, and more preferably a hydrogen atom.
  • R 13 and R 14 are preferably each independently a hydrogen atom, a halogen atom, a cyano group, or a carboxy group that may be protected with a protecting group for a carboxy group, and more preferably a hydrogen atom. Or a chlorine atom.
  • R 15 is preferably a hydrogen atom, a halogen atom, an amino group, a carbamoyl group, a carboxy group that may be protected with a protecting group for carboxy group, or a C1-C6 alkoxycarbonyl group, and more preferably , A fluorine atom, an amino group, a carbamoyl group, a carboxy group, or an ethoxycarbonyl group, and particularly preferably a carboxy group or an ethoxycarbonyl group.
  • A is preferably a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group, and more preferably an ethylcarbamoyl group, a propylcarbamoyl group, a tert -A butylcarbamoyl group, a cyclopropylcarbamoyl group, or a C1-C3 alkyloxadiazolyl group, and particularly preferably an ethylcarbamoyl group, a cyclocarbamoyl group, or an ethylaminooxadiazolyl group.
  • Y is preferably a single bond, —CH 2 —, —C ( ⁇ O) —, —C ( ⁇ S) —, —C (—C1-C6 alkyl) —, or —C (-5-membered ring).
  • More preferable examples of the compound having the general formula (I) or (II) include the compounds described in Examples.
  • “Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.
  • the “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
  • the pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt.
  • Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamate salts, aspartates, and alkali metal salts are preferred.
  • the pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably a hydrohalide
  • the compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization.
  • the present invention also includes such various hydrates, solvates and polymorphic compounds.
  • the light compounds of the present invention, salts thereof or solvates thereof may be isomers such as cis isomers and trans isomers, tautomers or optical isomers such as d isomers and l isomers, depending on the type and combination of substituents.
  • the compounds of the present invention include all isomers, stereoisomers and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. Is. A mixture of these isomers can be separated by a known resolution means.
  • the compound represented by the general formula (I) or (II) of the present invention may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms.
  • the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), carbon-14 ( 14 C), and the like. These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the compound represented by general formula (1) are included within the scope of the present invention, whether radioactive or not.
  • the present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention.
  • a pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions.
  • Drug-forming groups are described in Prog. Med., Volume 5, pages 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of.
  • the prodrug more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated).
  • hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated.
  • a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation or methylamidated compounds, etc.).
  • the compound of the present invention can be produced by applying various known synthesis methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
  • the prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can.
  • the reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
  • Step A-1 In this step, compound (1) is reacted with compound (2) to produce compound (3).
  • the reaction temperature is 70-200 ° C, preferably 70-100 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is 2-propanol or acetonitrile.
  • Step A-2 In this step, compound (3) and compound (4) are produced by reductive amination reaction. Any common reducing agent can be used in this reaction, and sodium triacetoxyborohydride is preferred.
  • the reaction temperature is 0-100 ° C, preferably 50-70 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is 1,2-dichloroethane.
  • Step A-3 In this step, compound (6) is produced by deprotecting the amino-protecting group of compound (5).
  • the protecting group is a t-butoxycarbonyl group
  • a general acid can be used.
  • the reaction temperature is 0-100 ° C, preferably 0-25 ° C.
  • the reaction time is 0.5h-24h, preferably 1-2h.
  • a suitable solvent for the reaction is dichloromethane or methanol.
  • the protecting group is a benzyloxycarbonyl group
  • a general hydrogenation reaction in the presence of a palladium catalyst can be used.
  • the reaction temperature is 0-100 ° C, preferably 0-25 ° C.
  • the reaction time is 0.5h-24h, preferably 1-4h.
  • a suitable solvent for the reaction is ethanol.
  • Step A-4 In this step, compound (I) is produced by reacting compound (6) with compound (7).
  • the reaction temperature is 0-80 ° C, preferably 0-25 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is 2-propanol or acetonitrile.
  • Process B-1 In this step, compound (Ia ′) is produced by deprotecting the protecting group for the carboxy group of compound (Ia).
  • a general base for example, an aqueous sodium hydroxide solution
  • a general base for example, an aqueous sodium hydroxide solution
  • the reaction temperature is 0-80 ° C, preferably 0-25 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • Suitable solvents for the reaction are ethanol, 1,4-dioxane or tetrahydrofuran.
  • R C represents an amino group such as —N (R a ) 2 , or —O (CH 2 ) 2 OH, 5-methyl-2-oxo- [1,3] dioxo-4-ylmethoxy
  • R a represents a C1-C6 alkyl group.
  • Step C-1 In this step, the carboxy group of compound (Ia ′) is converted into a prodrug by amidation or condensation reaction to produce compound (Ia ′′).
  • amidation 7N ammonia / methanol or primary or secondary alkylamine can be used.
  • the reaction temperature is 25-150 ° C, preferably 50-100 ° C.
  • the reaction time is 1h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is methanol, and in some cases, the reaction can be performed without using a solvent.
  • a general condensing agent can be used.
  • the reaction temperature is 0-100 ° C, preferably 0-25 ° C.
  • the reaction time is 1h-48h, preferably 18-20h.
  • a suitable solvent for the reaction is dichloromethane.
  • the reaction temperature is 0-150 ° C., preferably 0-25 ° C.
  • the reaction time is 1h-24h, preferably 1-5h.
  • a suitable solvent for the reaction is N, N-dimethylformamide.
  • Step D-1 In this step, compound (Ia) is reacted with an alkyl metal reagent such as Grignard reagent (RaMgBr) to produce compound (Ia ′ ′′).
  • RaMgBr Grignard reagent
  • Step E-1 In this step, compound (Ib) is reacted with an azide compound to produce compound (Ib ′).
  • the azide compound is not particularly limited as long as it is usually used for producing tetrazole, and is preferably sodium azide.
  • the reaction temperature is 0-80 ° C, preferably 0-25 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is N, N-dimethylformamide.
  • Step F-1 In this step, the compound (5 ′) is halogenated to produce the compound (5 ′′).
  • the halogenating reagent N-chlorosuccinimide, N-bromosuccinimide and the like can be used.
  • the reaction temperature is 10-100 ° C, preferably 25-40 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is N, N-dimethylformamide.
  • Step F-2-1 In this step, the halogen group of compound (5 ′′) is substituted with an alkyl group to produce compound (5 ′ ′′).
  • the reaction can be performed in the presence of C1-C6 alkylboronic acid, potassium carbonate as a base, and palladium (PdCl 2 (dppf) CH 2 Cl 2 ) as a catalyst.
  • the reaction temperature is 0-100 ° C, preferably 50-100 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is 1,2-dimethoxyethane.
  • Step F-2-2 In this step, the halogen group of compound (5 ′′) is substituted with an alkoxy group to produce compound (5 ′′ ′′).
  • the reaction can be carried out in the presence of C1-C6 alcohol, copper iodide, 1,10-phenanthroline and cesium carbonate.
  • the reaction temperature is 60-200 ° C, preferably 100-150 ° C.
  • the reaction time is 0.1h-24h, preferably 0.1-1h.
  • a suitable solvent for the reaction is methanol or ethanol.
  • G-1 process In this step, compound (5-a ′) is produced by amidating compound (5-a).
  • a C1-C6 alkylamine can be used as a reagent for amidation.
  • the reaction temperature is 40-200 ° C, preferably 100-150 ° C.
  • the reaction time is 1h-24h, preferably 1-2h.
  • a solvent may not be used.
  • the compound (5-a) can be deesterified and amidated with a general condensing agent such as 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and an amine.
  • a general condensing agent such as 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and an amine.
  • Step H-1 In this step, compound (5-b ′) is produced by reducing the nitro group of compound (5-b).
  • a common reducing agent may be used, preferably zinc powder.
  • the reaction temperature is 0-100 ° C, preferably 50-100 ° C.
  • the reaction time is 0.5h-24h, preferably 18-20h.
  • a suitable solvent for the reaction is methanol.
  • Step H-2 In this step, compound (5-b ′′) is produced by converting the amino group of compound (5-b ′) to an amide group.
  • the reagent to be used include C1-C6 alkylcarbonyl chloride and C1-C6 alkylsulfonyl chloride.
  • the base used is triethylamine.
  • the reaction temperature is 0-100 ° C, preferably 0-25 ° C.
  • the reaction time is 0.5h-24h, preferably 1-2h.
  • a suitable solvent for the reaction is dichloromethane or N, N-dimethylacetamide. (J method)
  • Process J-1 In this step, compound (5-a) is reacted with hydrazine to give acyl hydrazine and then further reacted with C1-C6 alkyl isothiocyanate to produce compound (5-c).
  • Reaction with hydrazine Hydrazine monohydrate can be used as a reagent.
  • the reaction temperature is 50-100 ° C, preferably 60-80 ° C.
  • the reaction time is 0.5h-24h, preferably 1-2h.
  • a suitable solvent for the reaction is methanol or ethanol.
  • (2) Reaction with alkyl isothiocyanate C1-C6 alkyl isothiocyanate is used as a reagent, and the reaction temperature is 0-80 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 20-24h.
  • a suitable solvent for the reaction is dichloromethane or ethanol.
  • Process J-2 In this step, compound (5-c ′) is produced by cyclizing compound (5-c).
  • the reagent to be used is a general condensing agent such as N, N-dicyclohexylcarbodiimide, diisopropylethylamide, etc., and a general base can be used if necessary.
  • the reaction temperature is 25-100 ° C, preferably 60-80 ° C.
  • the reaction time is 0.5h-24h, preferably 5-10h.
  • Suitable solvents for the reaction are acetone and methanol
  • the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
  • the pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
  • the preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives.
  • parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like.
  • the preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives.
  • Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
  • the dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, body weight, type of drug to be administered in combination, dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), or once or several times a day, orally or parenterally, in the equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.
  • the present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof. Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.
  • Formulation Example 1 Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender. (Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
  • test compound was orally administered once a day from the 21st to 41st day of CIA induction once a day. Only 0.5% methylcellulose solution was similarly administered to the control group.
  • the volume of the right hind limb was measured with a foot volume measuring device, and the average value of the swelling volume of each group was calculated.
  • the toe volume increase inhibition rate (%) was calculated by the following formula.
  • the compounds of the examples of the present application showed a therapeutic effect on mouse collagen-induced arthritis.
  • test compound was orally administered 5 mL / kg once a day for 18 days from the day of adjuvant injection. Only 0.5% methylcellulose solution was similarly administered to the control group.
  • Toe volume increase inhibition rate (%) (1-([footpad volume of test compound administration group] ⁇ [footpad volume of normal control group]) / [footpad volume of control group] ⁇ [normal control group] Footpad volume])) ⁇ 100
  • the compounds of Examples of the present application showed a therapeutic effect on rat adjuvant-induced arthritis.
  • EAE experimental autoimmune encephalomyelitis
  • the compound of the present example is an experimental autoimmune encephalomyelitis model On the other hand, it showed a therapeutic effect.
  • DSS Dextran sulfate sodium
  • Induction of DSS colitis DSS (MP Biomedicals) was dissolved in water to 2% and used as drinking water for 8 weeks old male C57BL. / 6 mice (CLEA Japan) were administered by ingestion freely for 6 days, or DSS was dissolved in water to 250 mg / mL, and once a day from day 0 to day 5, 10 mL / Colitis was induced by oral administration of kg. Only the water was administered to the normal control group.
  • (2) Preparation of test compound The test compound is used after being suspended or dissolved in a 0.5% methylcellulose solution.
  • test compound The prepared test compound was orally administered 10 mL / kg once a day from the 0th to the 5th day of colitis induction. Only 0.5% methylcellulose solution was similarly administered to the control group.
  • (4) Calculation of colon shortening suppression rate of test compound The length of the large intestine was measured on the 6th day after the start of administration, and the colon shortening suppression rate (%) was calculated by the following formula.
  • the compounds of Examples of the present application showed a therapeutic effect on DSS-induced colitis.
  • Inhibition rate of thickening of colon (%) (1-([testine weight / colon length of test compound administration group] ⁇ [colon weight / colon length of normal control group]) / [colon weight / colon length of control group] ⁇ [ Normal control group colon weight / colon length])) x 100
  • the compounds of Examples of the present application showed a therapeutic effect on the IL-10-deficient mouse spontaneous colitis model.
  • the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was washed with a mixed solvent such as hexane-ethyl acetate to obtain the title object compound (34.0 g, yield 92%).
  • the reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (524 mg, 2.47 mmol) was added, and the mixture was stirred at 70 ° C. for 2 days.
  • the reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was stirred for 10 min.
  • the reaction solution was extracted three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate.
  • Reference Example 5 5-chloro-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide 5,6-dichloro-N-cyclopropylnicotinamide (Reference Example 4) 6.35 g, 27.5 mmol), cis-decahydroquinoxaline (5.01 g, 35.8 mmol) in 2-propanol (30.0 mL), diisopropylethylamine (9.58 mL, 55.0 mmol) at room temperature. Added at. The reaction tube was sealed and stirred at 180 ° C. for 2 hours in a microwave reactor.
  • Cis-decahydroquinoxaline (675 mg, 9.63 mmol) was added, and the mixture was further stirred at 180 ° C. for 3 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using NH silica gel column chromatography (Biotage 40M NH, methanol / ethyl acetate, 100: 0-95: 5) to give the title object compound (6.45 g, Yield 70%).
  • Reference Example 6 4- [cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl 5-chloro-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide (Reference Example 5) (6.45 g, 19.3 mmol) of 1,2-dichloroethane (60 mL) To the solution was added 1-tert-butoxycarbonyl-4-piperidone (5.18 g, 26.0 mmol) at room temperature.
  • Reference Example 9 4- [cis-4- [3-Bromo-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference
  • the title target compound was obtained in the same manner as in Reference Example 3 using 5-bromo-N-ethyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 8. .
  • Reference Example 13 4- [cis-4- [3-Chloro-5- (methylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-N-methyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 12, the same reaction as in Reference Example 3 was carried out to obtain the title target compound. .
  • Reference Example 15 2-[( ⁇ 5-Chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] pyridin-3-yl ⁇ carbonyl) amino] ethyl acetate 2 prepared in Reference Example 14 The same reaction as in Reference Example 5 was carried out using — ⁇ [(5,6-dichloropyridin-3-yl) carbonyl] amino ⁇ ethyl acetate to obtain the title object compound.
  • Reference Example 16 4- [cis-4- ⁇ 5-[(2-acetoxyethyl) carbamoyl] -3-chloropyridin-2-yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone Tert-butyl acid Using 2-[( ⁇ 5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] pyridin-3-yl ⁇ carbonyl) amino] ethyl acetate prepared in Reference Example 15 In the same manner as in Reference Example 3, the title target compound was obtained.
  • the reaction tube was sealed and stirred at 180 ° C. for 15 minutes in a microwave reactor.
  • a 20% chloroform / methanol mixture (3 mL) and water (2 mL) were added to the reaction solution, and the mixture was separated.
  • the aqueous layer was extracted with a 20% chloroform / methanol mixture (2 ⁇ 3 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • the resulting residue was purified using silica gel column chromatography (Biotage 25M, methanol / chloroform, 100: 0-93: 7) to obtain the racemic form (102 mg) of the title object compound.
  • Reference Example 22 trans-2- ⁇ [(benzyloxy) carbonyl] amino ⁇ cyclopentyl methanesulfonate trans-2- ⁇ [(benzyloxy) carbonyl] amino ⁇ cyclopentyl methanesulfonate (Reference Example 21) (43.0 g , 184 mmol) and triethylamine (28.2 mL, 202 mmol) in dichloromethane (300 mL) were added dropwise methanesulfonyl chloride (18.4 mL, 193 mmol) at 0 ° C. for 10 minutes.
  • the organic layer was diluted with 1N hydrochloric acid (2 ⁇ 30 mL). Extracted. The aqueous layers were combined and washed with ethyl acetate (4 ⁇ 100 mL), 4N aqueous sodium hydroxide solution (40 mL) was added to the aqueous layer and stirred to make the aqueous solution basic (pH 11). Chloroform (150 mL) was added at room temperature for liquid separation, and the aqueous layer was extracted with chloroform (3 ⁇ 150 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title object compound (20.5 g, yield 76%).
  • Reference Example 27 cis-octahydro-1H-cyclopenta [b] pyrazine cis-hexahydro-1H-cyclopenta [b] pyrazine-2,3-dione (Reference Example 26) (9.60 g, 62.4 mmol) in tetrahydrofuran (Reference Example 27) (150 mL), 1N lithium aluminum hydride tetrahydrofuran solution (200 mL, 200 mmol) was added dropwise at 0 ° C. for 1 hour. The mixture was stirred at room temperature for 30 minutes and then stirred at 65 ° C. for 15 hours.
  • Reference Example 28 5-Chloro-N-ethyl-6- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] nicotinamide cis-octahydro-1H-cyclopenta [b] prepared in Reference Example 27 The same reaction as in Reference Example 5 was carried out using pyrazine to obtain the title object compound.
  • Reference Example 29 4- ⁇ cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylic acid tert -Butyl 5-chloro-N-ethyl-6- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] nicotinamide prepared in Reference Example 28 was used to carry out the same reaction as in Reference Example 3, The title object compound was obtained.
  • Reference Example 32 Methyl 2- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate Prepared in Reference Example 31 Using the methyl 2- [cis-octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate, the same reaction as in Reference Example 3 was carried out to obtain the title target compound.
  • Reference Example 33 4- [cis-4- [5- (ethylcarbamoyl) pyrimidin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl 2- [cis- 4- [1- (tert-Butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate (Reference Example 32) (197 mg, 0.429 mmol) in methanol ( To the 1 mL solution, tetrahydrofuran (2 mL) and 1N aqueous sodium hydroxide solution (1 mL, 1.00 mmol) were added at room temperature.
  • the obtained carboxylic acid was dissolved in N, N-dimethylformamide (2 mL), and hydroxybenzotriazole (74.8 mg, 0.554 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature. (106 mg, 0.554 mmol) and 2M ethylamine tetrahydrofuran solution (0.240 mL, 0.480 mmol) were added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, chloroform (5 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred, and the aqueous layer was extracted with chloroform (3 ⁇ 3 mL).
  • Reference Example 36 cis-4- [3-Bromo-5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -tert-butyl carboxylate cis-4-prepared in Reference Example 35 Dissolve tert-butyl [5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate (7.20 g, 19.1 mmol) in N, N-dimethylformamide (100 mL); N-bromosuccinimide (5.11 g, 28.7 mmol) was added and stirred at room temperature for 18 hours.
  • reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to give the title object compound (2.50 g, yield 29%).
  • reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (4.41 g, 20.8 mmol) was added, and the mixture was stirred at 70 ° C. for 18 hr.
  • 1-Boc-4-piperidone (4.14 g, 20.8 mmol) and sodium triacetoxyborohydride (4.41 g, 20.8 mmol) were again added to the reaction solution, and the mixture was stirred at 70 ° C. for 4 hours.
  • the reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution (about 100 mL) was added, and the mixture was stirred for 15 min.
  • reaction solution was extracted three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to give the title object compound (4.23 g, yield 76%).
  • Reference Example 41 4- [trans-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-N-ethyl-6- [trans-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 40, the reaction was carried out in the same manner as in Reference Example 3 to obtain the title target compound. It was.
  • Reference Example 44 5-Chloro-N-ethyl-6- [cis-hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] nicotinamide cis-octahydrofuro prepared in Reference Example 43 The same reaction as in Reference Example 5 was carried out using [3,4-b] pyrazine to obtain the title object compound.
  • Reference Example 45 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] piperidine- Tert-butyl 1-carboxylate Using 5-chloro-N-ethyl-6- [cis-hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] nicotinamide prepared in Reference Example 44 The same reaction as in Reference Example 3 was performed to obtain the title object compound.
  • Reference Example 48 4- [cis-4- [3-Bromo-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Using 5-bromo-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Reference Example 47, the reaction was carried out in the same manner as in Reference Example 3 to obtain the title target compound. Got.
  • Reference Example 49 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-Bromo-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- prepared in Reference Example 48 The reaction was conducted in the same manner as in Reference Example 10 using butyl to obtain the title object compound.
  • Reference Example 50 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2-carboxylate prepared in Reference Example 38 (970 mg, 2.05 mmol) was dissolved in cyclopropylamine (4 mL) and stirred at 160 ° C. for 1 hour in a microwave reactor.
  • Reference Example 51 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl A compound of Reference Example 50 having a retention time of 5.2 minutes.
  • Reference Example 52 5,6-Dichloro-N-isopropylnicotinamide The same reaction as in Reference Example 4 was performed using isopropylamine to obtain the title target compound.
  • Reference Example 54 4- [cis-4- [3-chloro-5- (isopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-N-isopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 53, the same reaction as in Reference Example 3 was carried out to obtain the title target compound. .
  • Reference Example 60 4- [cis-4- [5- (tert-butylcarbamoyl) -3-chloropyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- Butyl Using N-tert-butyl-5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Reference Example 59, the same reaction as in Reference Example 3 was carried out. A compound was obtained.
  • Reference Example 64 Ethyl 3-chloro-2-methylbenzoate The same reaction as in Reference Example 17 was performed using 3-chloro-2-methylbenzoic acid and ethanol to obtain the title target compound.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate.
  • the resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol, 100: 0-80: 20) to obtain the title object compound (2.05 g, yield 57%).
  • a compound having a retention time of 11.8 minutes is defined as Reference Example 70.
  • Reference Example 77 4- [cis-4- [3-Chloro-5- (hydrazinocarbonyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Ethyl 6- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -5-chloronicotinate (Reference Example 76) (576 mg, 1. 14 mmol) in ethanol (3 mL) was added hydrazine monohydrate (0.562 mL, 11.4 mmol) at room temperature. After stirring at 80 ° C.
  • Reference Example 78 4- [cis-4- [5- (5-amino-1,3,4-oxadiazol-2-yl) -3-chloropyridin-2-yl] octahydroquinoxaline-1 ( 2H) -yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-chloro-5- (hydrazinocarbonyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] Bromine cyanide (51.7 mg, 0.488 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (Reference Example 77) (226 mg, 0.458 mmol) in ethanol (3 mL) at room temperature.
  • reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain the title object compound (5.64 g, yield 92%).
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in dichloroethane (100 mL), 1-Boc-4-piperidone (5.26 g, 26.4 mmol) was added, and the mixture was stirred at 70 ° C. for 1.5 hr. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (5.60 g, 26.4 mmol) was added, and the mixture was stirred at 70 ° C.
  • Reference Example 81 4- [cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-chloropyrazine-2-carboxylate prepared in Reference Example 80 (2.29 g, 4.64 mmol) was dissolved in cyclopropylamine (6 mL) and stirred at 150 ° C.
  • Reference Example 84 cis-4- [5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyrazine-1-carboxylate 5- [cis-octahydro-1H-cyclopenta [ b] Methyl pyrazin-1-yl] pyrazine-2-carboxylate (Reference Example 83) (1.27 g, 4.84 mmol) in 1,4-dioxane (5 mL) at room temperature with water (5 mL), carbonic acid Sodium (1.08 g, 10.2 mmol) and di-tert-butyl dicarbonate (1.11 g, 5.08 mmol) were added.
  • Reference Example 86 cis-4- [5- (methoxycarbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate tert-butyl cis-4- [3- Chloro-5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyridine-carboxylate (Reference Example 85) (1.83 g, 4.61 mmol) 1,2- To a solution of dimethoxyethane (25 mL), potassium carbonate (1.91 g, 13.8 mmol), methylboranoic acid (245 mg, 5.07 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride Dichloromethane complex (282 mg, 0.346 mmol) was added at room temperature.
  • the obtained carboxylic acid was dissolved in N, N-dimethylformamide (3 mL), and hydroxybenzotriazole (164 mg, 1.22 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (233 mg) at room temperature. 1.22 mmol) and 2M ethylamine tetrahydrofuran solution (0.608 mL, 0.1.22 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, chloroform (5 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred, and the aqueous layer was extracted with chloroform (3 ⁇ 3 mL).
  • Reference Example 88 4- ⁇ cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylic acid tert -Butyl cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate tert-butyl (Reference Example 87) (439 mg, 1.
  • Reference Example 93 4- ⁇ cis-4- [5- (ethylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylic acid tert -Butyl cis-4- [3-Ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] benzyl carboxylate (Reference Example 92) (317 mg, 0.724 mmol) To an ethanol (10 mL) solution, 7.5% palladium carbon catalyst (50 mg) was added at room temperature.
  • Reference Example 100 4- [cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference The cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate benzyl (535 mg, 1.17 mmol) prepared in Example 99 was added to ethanol (10 mL). Then, 7.5% palladium carbon (214 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours.
  • reaction solution was extracted with dichloromethane, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to give the title object compound (323 mg, yield 58%).
  • Reference Example 105 cis-4- ⁇ 3-chloro-5-[(cyclopropylmethyl) sulfonyl] pyrazin-2-yl ⁇ octahydroquinoxaline-1 (2H) -benzyl carboxylate cis-4- of Reference Example 104
  • the reaction was carried out in the same manner as in Reference Example 79 using ⁇ 5-[(cyclopropylmethyl) sulfonyl] pyrazin-2-yl ⁇ octahydroquinoxaline-1 (2H) -carboxylate to obtain the title object compound.
  • Reference Example 107 4- [cis-4- ⁇ 5-[(Cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-Butyl Reference Example 106 using cis-4- ⁇ 5-[(cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl ⁇ octahydroquinoxaline-1 (2H) -carboxylate of Reference Example 106 The title compound was obtained in the same manner as above.
  • Reference Example 108 4- [cis-4- [3-cyclopropyl-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- Butyl 6-bromo-5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylic acid prepared in Reference Example 37 The reaction was conducted in the same manner as in Reference Example 62 using methyl and cyclopropylboronic acid, and then the reaction was carried out in the same manner as in Reference Example 50 to obtain the title object compound.
  • Reference Example 109 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Using Reference Example 37 and cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate prepared in Reference Example 124 The reaction was carried out in the same manner to obtain the title target compound.
  • Reference Example 110 4- [cis-4- [3-Chloro-5-( ⁇ 2-[(ethylamino) carbonothioyl] hydrazino ⁇ carbonyl) pyridin-2-yl] octahydroquinoxaline-1 (2H) -Yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-chloro-5- (hydrazinocarbonyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- To a solution of tert-butyl 1-carboxylate (Reference Example 77) (907 mg, 1.84 mmol) in ethanol (10 mL) was added a solution of ethyl isothiocyanate (0.169 mL, 1.93 mmol) in ethanol (5 mL) at room temperature.
  • Reference Example 113 4- [cis-4- [3-Ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference The reaction was conducted in the same manner as in Reference Example 100 using benzyl-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate of Example 112. The target compound was obtained.
  • reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to give the title object compound (2.05 g, yield 94%).
  • Reference Example 118 cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate tert-butyl cis-4- [5 -(Methoxycarbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyrazine-1-carboxylate (Reference Example 86) (707 mg, 1.88 mmol) in 2-propanol (0 .5 mL) solution was added cyclopropylamine (1.00 mL, 14.4 mmol) at room temperature.
  • the reaction tube was sealed and stirred at 140 ° C. for 1 hour in a microwave reactor.
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (Biotage 40S, ethyl acetate / chloroform, 0: 100-15: 85) to give the title object compound (569 mg, 76%). Obtained.
  • Reference Example 120 4- [cis-4- [3-Chloro-5-( ⁇ 2-[(ethylamino) carbonothioyl] hydrazino ⁇ carbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -Yl] piperidin-1-carboxylate tert-butyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl prepared in Reference Example 80 ] Methyl-6-chloropyrazine-2-carboxylate (728 mg, 1.47 mmol) was dissolved in methanol (20 mL), hydrazine monohydrate (4 mL) was added, and the mixture was heated to reflux for 1 hr.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in toluene and concentrated again under reduced pressure. After performing this three times, a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (10 mL), diisopropylethylamine (0.752 mL, 4.42 mmol) was added, and then ethyl isothiocyanate (0.374 mL, 4.42 mmol) was added. And stirred at room temperature for 18 hours.
  • Reference Example 122 4- [cis-4- ⁇ 3-Chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl ⁇ octahydroquinoxaline -1 (2H) -yl] piperidine-1-carboxylate tert-butyl Compound having a retention time in the HPLC of Reference Example 121 of 7.0 minutes.
  • reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to give the title object compound (661 mg, 7%).
  • Reference Example 129 4- [cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone Tert-Butyl acid Benzyl-cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylic acid prepared in Reference Example 128 And the reaction was conducted in the same manner as in Reference Example 93 to give the title object compound.
  • Reference Example 132 4- ⁇ cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylic acid tert-Butyl 5- ⁇ cis-4- [1- (tert-Butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ -6-ethylpyrazine prepared in Reference Example 131 The reaction was carried out in the same manner as in Reference Example 116 using methyl -2-carboxylate and cyclopropylamine to obtain the title compound.
  • Reference Example 134 4- ⁇ cis-4- [3-Methyl-5-( ⁇ 2-[(methylamino) carbonothioyl] hydrazino ⁇ carbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-butyl 5- ⁇ cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ -6-Methylpyrazine-2-carboxylate (Reference Example 133) and methyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
  • Reference Example 135 4- [cis-4- ⁇ 3-Methyl-5- [5- (methylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl ⁇ octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- ⁇ cis-4- [3-methyl-5-( ⁇ 2-[(methylamino) carbonothioyl] hydrazino ⁇ carbonyl ) Pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-Butyl (Reference Example 134) was used to carry out a reaction similar to Reference Example 121, and the title compound Got.
  • Reference Example 136 4- ⁇ cis-4- [5-( ⁇ 2-[(cyclopropylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b ] Pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-butyl 5- ⁇ cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1- Ile ⁇ -6-methylpyrazine-2-carboxylate (Reference Example 133) and cyclopropyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
  • Reference Example 137 4- [cis-4- ⁇ 5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl ⁇ octahydro- 1H-cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- ⁇ cis-4- [5-( ⁇ 2-[(cyclopropylamino) carbonothioyl] hydrazino ⁇ carbonyl)- 3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-Butyl (Reference Example 136) was used to carry out a reaction similar to Reference Example 121. The title compound was obtained.
  • Reference Example 138 4- ⁇ cis-4- [5-( ⁇ 2-[(Isopropylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-butyl 5- ⁇ cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ -6-Methylpyrazine-2-carboxylate (Reference Example 133) and isopropyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
  • Reference Example 139 4- [cis-4- ⁇ 5- [5- (Isopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl ⁇ octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- ⁇ cis-4- [5-( ⁇ 2-[(isopropylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3- Methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-Butyl (Reference Example 138) was used for the same reaction as Reference Example 121 to give the title compound Got.
  • Reference Example 140 4- ⁇ cis-4- [5-( ⁇ 2-[(Butylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-butyl 5- ⁇ cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ -6-Methylpyrazine-2-carboxylate (Reference Example 133) and butyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
  • Reference Example 141 4- [cis-4- ⁇ 5- [5- (Butylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl ⁇ octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- ⁇ cis-4- [5-( ⁇ 2-[(butylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3- Methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-Butyl (Reference Example 140) was used for the same reaction as Reference Example 121 to give the title compound Got.
  • Reference Example 142 4- [cis-4- [5-( ⁇ 2-[(cyclopropylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H ) -Yl] piperidine-1-carboxylic acid tert-butyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methyl
  • the title compound was obtained in the same manner as in Reference Example 120 using methyl pyrazine-2-carboxylate (Reference Example 38) and cyclopropyl isothiocyanate.
  • Reference Example 143 4- [cis-4- ⁇ 5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl ⁇ octahydro Quinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-butyl 4- [cis-4- [5-( ⁇ 2-[(cyclopropylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3-methyl Pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-Butyl (Reference Example 142) was used to carry out a reaction similar to Reference Example 121 to obtain the title compound.
  • Reference Example 144 4- ⁇ cis-4- [3-Methyl-5-( ⁇ 2-[(propylamino) carbonothioyl] hydrazino ⁇ carbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-butyl 5- ⁇ cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ -6-Methylpyrazine-2-carboxylate (Reference Example 133) and propyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
  • Reference Example 145 4- [cis-4- ⁇ 3-Methyl-5- [5- (propylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl ⁇ octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- ⁇ cis-4- [3-methyl-5-( ⁇ 2-[(propylamino) carbonothioyl] hydrazino ⁇ carbonyl ) Pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ piperidine-1-carboxylate tert-Butyl (Reference Example 144) was used for the same reaction as Reference Example 121 to give the title compound Got.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated brine.
  • the organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue is purified by silica gel column chromatography (hexane: ethyl acetate, 2-1-1: 5) to give the title object compound (47.8 g). Yield 97%).
  • Reference Example 148 5- ⁇ [(1R, 2S) -2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] (chloroacetyl) amino ⁇ cyclohexyl] amino ⁇ -6-chloropyrazine-2 -Methyl carboxylate 5- ⁇ [(1R, 2S) -2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] amino ⁇ cyclohexyl] amino ⁇ -6-chloropyrazine- prepared in Reference Example 147 Dissolve methyl 2-carboxylate (53 g, 0.113 mol) in dichloromethane (500 mL), add triethylamine (23.7 mL, 0.17 mol) and chloroacetyl chloride (10.8 mL, 0.136 mol) at 0 ° C.
  • Reference Example 156 4-[(4aR, 8aS) -4- [5- (Ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-Butyl 5-[(4aS, 8aR) -4- [1- (tert-Butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2-carboxylic acid The same reaction as in Reference Example 39 was carried out using methyl (Reference Example 155) to obtain the title compound.
  • Reference Example 157 4-[(4aR, 8aS) -4- [5-( ⁇ 2-[(Cyclopropylamino) carbonothioyl] hydrazino ⁇ carbonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline -1 (2H) -yl] piperidine-1-carboxylic acid tert-butyl 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxaline-1 (2H ) -Yl] -6-chloropyrazine-2-carboxylate (Reference Example 150) and cyclopropyl isothiocyanate were subjected to the same reaction as Reference Example 120 to obtain the title compound.
  • Reference Example 158 4-[(4aR, 8aS) -4- ⁇ 5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazine-2- Yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-butyl 4-[(4aR, 8aS) -4- [5-( ⁇ 2-[(cyclopropylamino) carbonothioyl] Hydrazino ⁇ carbonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (Reference Example 157) was used for the same reaction as Reference Example 121. The title compound was obtained.
  • Example 1-A 5-Chloro-2-( ⁇ 4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine prepared in Example 1 1-yl ⁇ methyl) methyl benzoate (Example 1-A) (36 mg, 61 ⁇ mol) was dissolved in ethanol (2 mL), 1N aqueous sodium hydroxide solution (0.2 mL) was added, and the mixture was heated at 60 ° C. for 18 hours. Stir. A 1N aqueous hydrochloric acid solution (0.2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Example 1-B (39 mg, 66 ⁇ mol) prepared in Example 1 was reacted in the same manner to obtain the title compound (37 mg, 98%, Example 2-B).
  • Example 1-B 45 mg, 77 ⁇ mol prepared in Example 1 was reacted in the same manner to obtain the title target compound (22 mg, 61%, Example 3-B).
  • the aqueous layer was extracted with a 20% methanol / chloroform mixture (3 ⁇ 50 mL).
  • the combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure.
  • Acetonitrile (20 mL), diisopropylethylamine (2.09 mL, 12.0 mmol), and methyl 2- (bromomethyl) -5-chlorobenzoate (1.58 g, 5.99 mmol) were added to the obtained residue, and Stir for hours.
  • the reaction solution was concentrated under reduced pressure, and water (15 mL) and chloroform (15 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted with chloroform (3 ⁇ 10 mL).
  • Title target compound (1) The title compound (1.09 g, 30%, Example 4-B) was obtained with 0.02 g, 28%, Example 4-A) and a retention time of 3.2 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate.
  • the resulting residue was dissolved in 2-propanol (4 mL) and diisopropylethylamine (0.147 mL, 0.844 mmol) and methyl 2- (bromomethyl) -5-chlorobenzoate (133 mg, 0.506 mmol) were added, Stir at room temperature for 18 hours.
  • reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain a racemic form (204 mg) of the title object compound.
  • Example 6-A 4- [cis-4- [3-Chloro-5- (methylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 13
  • the title target compound (Example 6-A) having a retention time of 4.6 minutes and a retention time of 3.3 minutes (Example 6-B) was obtained.
  • Example 7-A The reaction was conducted in the same manner as in Example 2 using Example 5-A prepared in Example 5 to obtain the title object compound (Example 7-A).
  • Example 5-B Example 5 to obtain the title object compound (Example 7-B).
  • Example 4-B produced in Example 4 was reacted in the same manner to give the title object compound (Example 8-B).
  • Example 9-A The reaction was conducted in the same manner as in Example 8 using Example 6-A prepared in Example 6 to obtain the title object compound (Example 9-A).
  • Example 6-B Example 6 to obtain the title object compound (Example 9-B).
  • Example 11-A The reaction was conducted in the same manner as in Example 8 using Example 10-A prepared in Example 10 to obtain the title compound (Example 11-A).
  • Example 10-B produced in Example 10, the reaction was conducted in the same manner as in Example 8 to obtain the title object compound (Example 11-B).
  • Example 12-A The reaction was conducted in the same manner as in Example 8 using Reference Example 20-A produced in Reference Example 20 to give the title object compound (Example 12-A).
  • the reaction was conducted in the same manner as in Example 8 using Reference Example 20-B produced in Reference Example 20 to give the title object compound (Example 12-B).
  • Example 13-A The reaction was conducted in the same manner as in Example 8 using Example 20-A prepared in Example 20 to obtain the title object compound (Example 13-A).
  • Example 20-B prepared in Example 20 to obtain the title object compound (Example 13-B).
  • reaction solution was concentrated under reduced pressure, and water (5 mL) and chloroform (5 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted with chloroform (3 ⁇ 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 25S, methanol / chloroform, 0 / 100-7 / 93) to obtain a racemic form (121 mg) of the title object compound.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate.
  • the obtained residue was dissolved in 2-propanol (20 mL), diisopropylethylamine (0.687 mL, 3.95 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate (657 mg, 2 .37 mmol) was added and stirred at room temperature for 18 hours.
  • reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol, 98: 2-80: 20) to obtain a racemic form (980 mg) of the title object compound.
  • Example 17-A 5-Chloro-2-( ⁇ 4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine prepared in Example 17 1-yl ⁇ methyl) methyl benzoate (Example 17-A) (93 mg, 163 ⁇ mol) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at 25 ° C. for 4 hours. Stir. A 1N aqueous hydrochloric acid solution (0.5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Example 18-B produced in Example 17 was reacted in the same manner to obtain the title compound (Example 18-B).
  • Example 19-A The reaction was conducted in the same manner as in Example 8 using Example 16-A prepared in Example 16 to obtain the title object compound (Example 19-A).
  • Example 16-B produced in Example 16 to obtain the title object compound (Example 19-B).
  • Example 23-A The reaction was conducted in the same manner as in Example 2 using Example 21-A produced in Example 21 to obtain the title object compound (Example 23-A).
  • Example 21-B prepared in Example 21 to give the title object compound (Example 23-B).
  • Example 24-A The reaction was conducted in the same manner as in Example 8 using Example 22-A produced in Example 22 to obtain the title object compound (Example 24-A).
  • Example 22-B prepared in Example 22 to give the title object compound (Example 24-B).
  • 1,3-diisopropylcarbodiimide (0.248 mL, 1.59 mmol) and 4-dimethylaminopyridine (65 mg, 0.529 mmol) were added, and the mixture was stirred at room temperature for 4 days.
  • the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (chloroform: methanol, 97: 3-80: 20) to give the title object compound (300 mg, 92%, Example 26-A).
  • Example 28-A The reaction was carried out in the same manner as in Example 30 using Example 27-A prepared in Example 27 to obtain the title object compound (Example 28-A).
  • the title compound (Example 29-A) having a retention time of 14.4 minutes and the title compound (Example 29-B) having a retention time of 14.4 minutes was obtained at (/ 70, 2.0 mL / min, 254 nm).
  • Example 29-A 5-Chloro-2-( ⁇ 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] prepared in Example 29 Piperidin-1-yl ⁇ methyl) ethyl benzoate (Example 29-A) (390 mg, 655 ⁇ mol) was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 25 ° C. for 18 hours. did. A 1N aqueous hydrochloric acid solution (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Example 32-A The reaction was conducted in the same manner as in Example 2 using Example 31-A prepared in Example 31 to give the title object compound (Example 32-A).
  • Example 32-B The reaction was conducted in the same manner as in Example 2 using Example 31-B prepared in Example 31 to obtain the title object compound (Example 32-B).
  • Example 34-A The reaction was conducted in the same manner as in Example 2 using Example 33-A prepared in Example 33 to obtain the title object compound (Example 34-A).
  • Example 34-B The reaction was conducted in the same manner as in Example 2 using Example 33-B prepared in Example 33 to obtain the title object compound (Example 34-B).
  • HPLC Chiralcel AD-H, 0.46 cm ⁇ ⁇ 25 cm, Daicel Chemical Industries, Ltd.
  • Example 38-A having a retention time of 5.4 minutes and the title compound (Example 38-B) having a retention time of 3.7 minutes at 30/70, 2.0 mL / min, 254 nm). Obtained.
  • Example 39-A The reaction was conducted in the same manner as in Example 2 using Example 36-A prepared in Example 36 to obtain the title object compound (Example 39-A).
  • Example 36-B prepared in Example 36 to give the title object compound (Example 39-B).
  • Example 40-A The reaction was conducted in the same manner as in Example 8 using Example 37-A produced in Example 37 to obtain the title object compound (Example 40-A).
  • Example 37-B produced in Example 37 to give the title object compound (Example 40-B).
  • Example using tert-butyl 4- [cis-4- [5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 66 And a retention time in HPLC (Chiralcel AD-H, 0.46 cm ⁇ ⁇ 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane 30/70, 2.0 mL / min, 254 nm).
  • the title target compound (Example 43-A) of 4 minutes and the title target compound (Example 43-B) having a retention time of 13.7 minutes were obtained.
  • Example 44-A The reaction was conducted in the same manner as in Example 30 using Example 41-A produced in Example 41 to obtain the title object compound (Example 44-A).
  • Example 41-B prepared in Example 41 to obtain the title object compound (Example 44-B).
  • Example 45-A The reaction was conducted in the same manner as in Example 30 using Example 43-A prepared in Example 43 to obtain the title object compound (Example 45-A).
  • Example 43-B prepared in Example 43 to obtain the title object compound (Example 45-B).
  • Example 46-A The reaction was conducted in the same manner as in Example 2 using Example 38-A prepared in Example 38 to give the title object compound (Example 46-A).
  • Example 38-B prepared in Example 38 to give the title object compound (Example 46-B).
  • Example 48-A The reaction was conducted in the same manner as in Example 8 using Example 42-A prepared in Example 42 to give the title object compound (Example 48-A).
  • Example 42-B prepared in Example 42 to give the title object compound (Example 48-B).
  • Example 49-A The reaction was conducted in the same manner as in Example 30 using Example 47-A prepared in Example 47 to obtain the title object compound (Example 49-A).
  • Example 47-B prepared in Example 47 to obtain the title object compound (Example 49-B).
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethanol (2 mL) and tetrahydrofuran (2 mL), 1N-aqueous sodium hydroxide solution (0.9 mL) was added, and the mixture was stirred at room temperature for 1 hr. A 1N hydrochloric acid aqueous solution (0.9 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethanol (1 mL) and tetrahydrofuran (1 mL), 1N-aqueous sodium hydroxide solution (0.25 mL) was added, and the mixture was stirred at room temperature for 1 hr. A 1N-hydrochloric acid aqueous solution (0.25 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure.
  • the title target compound (Example 52-A) having a retention time of 16.6 minutes and the title target compound (Example 52-B) of 4.9 minutes were obtained.
  • Example 54-A The reaction was conducted in the same manner as in Example 30 using Example 53-A prepared in Example 53, to give the title object compound (Example 54-A).
  • Example 56-A The reaction was conducted in the same manner as in Example 2 using Example 55-A prepared in Example 55, to give the title object compound (Example 56-A).
  • Example 55-B The reaction was conducted in the same manner as in Example 2 using Example 55-B prepared in Example 55, to give the title object compound (Example 56-B).
  • Example 57-A The reaction was conducted in the same manner as in Example 3 using Example 52-A prepared in Example 52 to obtain the title object compound (Example 57-A).
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate.
  • 70 mg was dissolved in N, N-dimethylacetamide (0.15 mL), and lithium 2-amino-5-chloronicotinate (WO 2006/091428) (41 mg, 0.228 mmol), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (67 mg, 0.351 mmol), 1-hydroxy-7-azabenzotriazole (54 mg, 0.351 mmol), and diisopropylethylamine (150 ⁇ L, 0.878 mmol) were added, The mixture was stirred at 70 ° C.
  • Example 61-A The reaction was conducted in the same manner as in Example 30 using Example 60-A prepared in Example 60 to obtain the title object compound (Example 61-A).
  • Example 63-B was obtained by reacting in the same manner as described above using Example 62-B produced in Example 62.
  • Example 68-A The reaction was conducted in the same manner as in Example 30 using Example 66-A prepared in Example 66 to obtain the title object compound (Example 68-A).
  • Example 66-B prepared in Example 66 to obtain the title object compound (Example 68-B).
  • Example 69-A The reaction was conducted in the same manner as in Example 30 using Example 67-A prepared in Example 67 to obtain the title object compound (Example 69-A).
  • Example 67-B The reaction was conducted in the same manner as in Example 30 using Example 67-B prepared in Example 67 to obtain the title object compound (Example 69-B).
  • Example 71-A The reaction was conducted in the same manner as in Example 30 using Example 70-A prepared in Example 70 to obtain the title object compound (Example 71-A).
  • Example 70-B The reaction was conducted in the same manner as in Example 30 using Example 70-B prepared in Example 70 to obtain the title object compound (Example 71-B).
  • Example 73-A The reaction was conducted in the same manner as in Example 30 using Example 72-A prepared in Example 72 to obtain the title object compound (Example 73-A).
  • Example 72-B The reaction was conducted in the same manner as in Example 30 using Example 72-B prepared in Example 72 to obtain the title object compound (Example 73-B).
  • Example 64-A 5-Chloro-2-[(4- ⁇ cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1- prepared in Example 64 Yl ⁇ piperidin-1-yl) methyl] ethyl benzoate (Example 64-A) (64 mg, 0.112 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (1 mL), and 1N aqueous sodium hydroxide solution ( 0.5 mL) was added, and the mixture was stirred at room temperature for 5 hours.
  • Example 75-B was obtained by reacting in the same manner as described above using Example 64-B produced in Example 64.
  • Example 76-A The reaction was conducted in the same manner as in Example 75 using Example 65-A prepared in Example 65 to obtain the title object compound (Example 76-A).
  • Example 65-B prepared in Example 65 to obtain the title object compound (Example 76-B).
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic phase was dried over anhydrous sodium sulfate.
  • the obtained residue was dissolved in acetonitrile, 2-propanol (1: 1, 30 mL), diisopropylethylamine (2.8 mL, 16.2 mmol), and 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 were used.
  • Ethyl acid (824 mg, 2.97 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours.
  • reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-40: 60) to obtain the racemic form (1.38 g) of the title object compound.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic phase was dried over anhydrous sodium sulfate.
  • the obtained residue was dissolved in acetonitrile, 2-propanol (1: 1, 30 mL), diisopropylethylamine (2.85 mL, 16.4 mmol), and 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 were obtained.
  • Ethyl acid (833 mg, 3.00 mmol) was added and stirred at room temperature for 2.5 hours.
  • reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-40: 60) to obtain the racemic form (1.38 g) of the title object compound.
  • Example 81-A The reaction was conducted in the same manner as in Example 30 using Example 78-A produced in Example 78 to obtain the title object compound (Example 81-A).
  • the reaction was conducted in the same manner as in Example 30 using Example 78-B prepared in Example 78 to give the title object compound (Example 81-B).
  • Example 83-A The reaction was conducted in the same manner as in Example 30 using Example 77-A prepared in Example 77 to obtain the title object compound (Example 83-A).
  • Example 77-B The reaction was conducted in the same manner as in Example 30 using Example 77-B prepared in Example 77 to obtain the title object compound (Example 83-B).
  • Example 84-B was obtained by reacting in the same manner as described above using Example 82-B produced in Example 82.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate.
  • a part (46 mg) of the obtained residue and ethyl 2- (bromomethyl) -5-chlorobenzoate (34 mg, 0.123 mmol) prepared in Reference Example 30 were dissolved in 2-propanol (1 mL), and diisopropylethylamine ( 35 ⁇ L, 0.206 mmol) was added and stirred at room temperature for 18 hours.
  • reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 98: 2-80: 20) to give the title object compound (55 mg, 78%, Example 86-A). .
  • Example 87-B was obtained by reacting in the same manner as above using Example 86-B prepared in Example 86.
  • Example 88-B was obtained by reacting in the same manner as described above using Example 79-B prepared in Example 79.
  • Example 80-A 5-chloro-2-[(4- ⁇ cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1 prepared in Example 80 -Yl ⁇ piperidin-1-yl) methyl] ethyl benzoate (Example 80-A) (690 mg, 1.15 mmol) was dissolved in 1,4-dioxane (6 mL) and 1N aqueous sodium hydroxide solution (3 mL) was dissolved. And stirred at room temperature for 18 hours.
  • Example 89-B was obtained by reacting in the same manner as described above using Example 80-B produced in Example 80.
  • the obtained residue was dissolved in acetonitrile, 2-propanol (1: 1, 5 mL), diisopropylamine (0.72 mL, 4.14 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate (191 mg, 0 689 mmol), and the mixture was stirred at room temperature for 2.5 hours.
  • the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the resulting organic phase was dried over anhydrous sodium sulfate.
  • Example 91-A The reaction was conducted in the same manner as in Example 91-A using Example 90-B prepared in Example 90 to give the title object compound (Example 91-B).
  • Example 93-B The reaction was conducted in the same manner as in Example 91 using Example 92-B prepared in Example 92, to give the title object compound (Example 93-B).
  • the reaction was conducted in the same manner as in Example 91 using Example 92-A prepared in Example 92 to give the title object compound (Example 93-A).
  • Example 86 Chloro-2-( ⁇ 4- [cis-4- ⁇ 3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazine- prepared in Example 86 2-yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl ⁇ methyl) ethyl benzoate (Example 86-B) was used in the same manner to give the title target compound (Example 94- B) was obtained.
  • Example 86 Chloro-2-( ⁇ 4- [cis-4- ⁇ 3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazine- prepared in Example 86 2-yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl ⁇ methyl) ethyl benzoate (Example 86-A) (107 mg, 172 ⁇ mol) in methyl magnesium bromide (1.0 M tetrahydrofuran solution) 3 mL, 3 mmol) and stirred at 50 ° C. for 6 hours.
  • 2-yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl ⁇ methyl) ethyl benzoate (Example 86-A) (107 mg, 172 ⁇ mol) in methyl magnesium bromide (1.0 M tetrahydrofuran solution) 3
  • Example 97-A The reaction was conducted in the same manner as in Example 3 using Example 96-A prepared in Example 96 to give the title object compound (Example 97-A).
  • Example 98-B The reaction was conducted in the same manner as in Example 3 using Example 96-B prepared in Example 96 to give the title object compound (Example 98-B).
  • Example 96-A prepared in Example 96 to obtain the title object compound (Example 98-A).
  • Example 101-B The reaction was conducted in the same manner as in Example 3 using Example 99-B prepared in Example 99 to obtain the title object compound (Example 101-B).
  • Example 99-A prepared in Example 99 to obtain the title object compound (Example 101-A).
  • Example 102-B The reaction was conducted in the same manner as in Example 3 using Example 100-B prepared in Example 100 to obtain the title object compound (Example 102-B).
  • Example 100-A prepared in Example 100 to obtain the title object compound (Example 102-A).
  • Example 104-B The reaction was conducted in the same manner as in Example 3 using Example 103-B prepared in Example 103 to obtain the title object compound (Example 104-B).
  • Example 103-A prepared in Example 103 to obtain the title object compound (Example 104-A).
  • the obtained organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain an amine (4.29 g) as a crude product.
  • the obtained amine (1.07 g, 2.78 mmol) was dissolved in acetonitrile, 2-propanol (1: 1, 20 mL), diisopropylamine (0.73 mL, 4.16 mmol), and bromo (4-chlorophenyl) acetic acid. Methyl (0.88 g, 3.33 mmol) was added and stirred at room temperature for 1.5 hours.
  • the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-85: 15) to obtain a highly polar compound (410 mg, Example 106-A) and its diastereomer. A low polarity compound (505 mg, Example 106-B) was obtained.
  • Example 106-A prepared in Example 106 (109 mg, 0.192 mmol) was dissolved in 1,2-dichloroethane (4 mL), trimethyltin hydroxide (346 mg, 1.92 mmol) was added, and the mixture was heated at 90 degrees for 18 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol, 99: 1-92: 8) to obtain the title object compound (48 mg, 45%).
  • Example 106-B prepared in Example 106 (98 mg, 0.172 mmol) was dissolved in 1,2-dichloroethane (4 mL), trimethyltin hydroxide (311 mg, 1.72 mmol) was added, and 90 ° C. for 18 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol, 99: 1-92: 8) to obtain the title object compound (52 mg, 54
  • Example 109-B The reaction was conducted in the same manner as in Example 3 using Example 105-B prepared in Example 105, to give the title object compound (Example 109-B).
  • Example 105-A prepared in Example 105, to give the title object compound (Example 109-A).
  • Example 110 5- ⁇ cis-4- [1- (4-Chloro-2-cyanobenzyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl ⁇ -N-ethyl- 6-Methylpyrazine-2-carboxamide
  • Example 110-B prepared in Example 110 66.2 mg (0.127 mmol), ammonium chloride 10.2 mg (0.190 mmol), sodium azide 17.5 mg (0.264 mmol) N, N-dimethylformamide (2 ml) ) The solution was stirred at 80 ° C. for 15 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, chloroform (5 ml) and water (5 ml) were added to the resulting residue, and the mixture was separated and extracted with chloroform (3 ⁇ 3.0 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 111-B The obtained residue was subjected to silica gel column chromatography (Biotage 25S, methanol / chloroform, 0-25%) to obtain the title compound (32 mg, 46%, Example 111-B).
  • the same reaction as in Example 110 was carried out using Example 110-A prepared in Example 110 to obtain the title compound (Example 111-A).
  • Example 112 (4-Chlorophenyl) ⁇ 4-[(4aR, 8aS) -4- ⁇ 5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3 -Methylpyrazin-2-yl ⁇ octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl ⁇ acetic acid
  • Example 1112-B The reaction was conducted in the same manner as in Example 107 using Example 108-B prepared in Example 108 to obtain the title object compound (Example 1112-B).
  • Example 108-A The reaction was conducted in the same manner as in Example 107 using Example 108-A prepared in Example 108 to obtain the title object compound (Example 1112-A).
  • Example 106-B prepared in Example 106 (86 mg, 0.151 mmol, low polarity compound) was dissolved in tetrahydrofuran (2 mL), lithium borohydride (13.2 mg, 0.604 mmol) was added, and 24 hours at room temperature. Stir for hours. The reaction solution was cooled to 0 ° C. and 1N hydrochloric acid was added dropwise. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Example 118-A high polarity compound

Abstract

Provided are compounds having prophylactic and/or therapeutic effect on chronic rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn diseases and ulcerative colitis, autoimmune diseases typified by psoriasis, rejection of a transplanted organ, allergic diseases and so on; medicinal compositions comprising these compounds; and a method for preventing or treating an autoimmune disease characterized by comprising administering an effective amount of a medicinal composition to a mammal. A compound represented by general formula (I) or a pharmacologically acceptable salt of the same.

Description

二環性含窒素飽和へテロ環誘導体Bicyclic nitrogen-containing saturated heterocyclic derivatives
　本発明は、慢性関節リウマチ、多発性硬化症、クローン病や潰瘍性大腸炎などの炎症性腸疾患、乾癬などを代表とする自己免疫性疾患や、移植臓器の拒絶反応、アレルギー疾患などの予防又は治療効果を有する化合物、それら化合物を含有する医薬組成物、又は医薬組成物の有効量を哺乳動物に投与することを特徴とする、自己免疫疾患の予防方法又は治療方法に関する。 The present invention prevents rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, autoimmune diseases such as psoriasis, transplant organ rejection, allergic diseases, etc. Alternatively, the present invention relates to a method for preventing or treating an autoimmune disease, which comprises administering to a mammal a compound having a therapeutic effect, a pharmaceutical composition containing the compound, or an effective amount of the pharmaceutical composition.
　従来、自己免疫疾患等の治療においては、対症療法としてステロイドなどの抗炎症薬が使用されており、根本的治療法の開発が望まれている。また、糖尿病、腎炎の発症においても免疫系の異常が関与することは報告されているが（例えば、非特許文献１及び２参照）、その異常を改善するような薬剤の開発には至っていない。 Conventionally, in the treatment of autoimmune diseases and the like, anti-inflammatory drugs such as steroids have been used as symptomatic treatment, and the development of fundamental treatment methods is desired. In addition, it has been reported that abnormalities of the immune system are involved in the onset of diabetes and nephritis (see, for example, Non-Patent Documents 1 and 2), but no drug has been developed to improve the abnormalities.
　 一方、免疫応答を抑制する方法の開発は、臓器及び細胞移植における拒絶反応の防止並びに種々の自己免疫疾患を治療及び予防する上でも極めて重要である。しかしながら、シクロスポリンＡ（ＣｓＡ）やタクロリムス（ＴＲＬ）等の従来知られている免疫抑制剤は、腎臓及び肝臓に対して毒性を示すことが知られており、そのような副作用を軽減するために、ステロイド類を併用するなどの治療が広く用いられてきたが、必ずしも副作用を示すことなく十分な免疫抑制効果を発揮するには至っていないのが現状である。 On the other hand, the development of a method for suppressing the immune response is extremely important for preventing rejection in organs and cell transplants and for treating and preventing various autoimmune diseases. However, conventionally known immunosuppressive agents such as cyclosporin A (CsA) and tacrolimus (TRL) are known to be toxic to the kidney and liver, and in order to reduce such side effects, Although treatments such as using steroids have been widely used, the current situation is that they do not necessarily exhibit sufficient immunosuppressive effects without showing side effects.
　 このような背景から、毒性が低く、優れた免疫抑制作用を有する化合物を見出すことが試みられている。これまでに、本発明の背景技術として、以下に示す文献が知られている。 From such a background, an attempt has been made to find a compound having a low toxicity and an excellent immunosuppressive action. So far, the following documents are known as background art of the present invention.
ＷＯ２００６／０８８８３６WO2006 / 088836 ＷＯ２００６／０８８８４０WO2006 / 088840 ＷＯ２００６／０８８９１９WO2006 / 088919 ＷＯ２００６／０８８９２１WO2006 / 088921 ＷＯ２００６／０９１４２８WO2006 / 091428 ＷＯ２００７／１０９２３８WO2007 / 109238 ＷＯ２００８／００８４５３WO2008 / 008453 ＷＯ２００８／０７９２７９WO2008 / 079279 ＷＯ２００９／０７９４９０WO2009 / 079490
　本発明者らは、毒性が低く優れた免疫抑制作用を有する新規化合物に関して、長年に亘り鋭意検討を重ねた結果、全身性エリトマトーデス、慢性関節リウマチ、多発性筋炎、結合組織炎、骨格筋炎、骨関節炎、変形性関節症、皮膚筋炎、強皮症、ベーチェット病、Chron病、潰瘍性大腸炎、自己免疫性肝炎、再生不良性貧血、特発性血小板減少性紫斑病、自己免疫性溶血性貧血、多発性硬化症、自己免疫性水疱症、尋常性乾癬、血管炎症群、Wegener肉芽腫、ぶどう膜炎、シェーグレン症候群、特発性間質性肺炎、Goodpasture症候群、サルコイドーシス、アレルギー性肉芽腫性血管炎、気管支喘息、心筋炎、心筋症、大動脈炎症候群、心筋梗塞後症候群、原発性肺高血圧症、微小変化型ネフローゼ、膜性腎症、膜性増殖性腎炎、巣状糸球体硬化症、半月体形成性腎炎、重症筋無力症、炎症性ニューロパチー、アトピー性皮膚炎、慢性光線性皮膚炎、日光過敏症、蓐瘡、Sydenham舞踏病、硬化症、成人発症糖尿病、インスリン依存性糖尿病、若年性糖尿病、アテローム性動脈硬化症、糸球体腎炎、IgA腎症、尿細管間質性腎炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、劇症肝炎、ウイルス性肝炎、GVHD、接触皮膚炎、敗血症等の自己免疫疾患又はその他免疫関連疾患（特に、全身性エリトマトーデス、慢性関節リウマチ、多発性硬化症、アトピー性皮膚炎等の自己免疫疾患）に有用である新規化合物を見出して、本発明を完成した。 As a result of intensive studies over many years on novel compounds having excellent immunosuppressive action with low toxicity, the present inventors have resulted in systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, bone Arthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, Multiple sclerosis, autoimmune bullous disease, psoriasis vulgaris, vascular inflammation group, Wegener granulomas, uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, Bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, minimal change nephrosis, membranous nephropathy, membranoproliferative nephritis, focal glomerulosclerosis, Luteinizing nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic actinic dermatitis, photosensitivity, pressure ulcer, Sydenham chorea, sclerosis, adult-onset diabetes, insulin-dependent diabetes, young Diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis, primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis And novel compounds useful for autoimmune diseases such as sepsis or other immune-related diseases (particularly autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and atopic dermatitis). Was completed.
　従って、本発明の課題は、毒性が低く優れた免疫抑制作用を有する新規化合物、その薬理上許容される塩又はその薬理上許容されるプロドラッグを提供することである。 Therefore, an object of the present invention is to provide a novel compound having a low toxicity and an excellent immunosuppressive action, a pharmacologically acceptable salt thereof or a pharmacologically acceptable prodrug thereof.
　すなわち本発明は、
（１）一般式を（Ｉ）を有する化合物又はその薬理上許容される塩。 That is, the present invention
(1) A compound having the general formula (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000003
［式中、Ｘ１、Ｘ２、Ｘ３、及びＸ４は、それぞれ独立に、－C＝、又は、－N＝を表わし、
Ｘ５は、－ＣＨ２－、－ＣＨ２ＣＨ２－、－Ｏ－、－ＣＨ２Ｏ－、－ＯＣＨ２－、－ＣＨ２Ｓ－、－ＳＣＨ２－、－ＣＨ２ＳＯ－、－ＳＯＣＨ２－、－、－ＣＨ２ＳＯ２－、－ＳＯ２ＣＨ２－、－Ｃ（－Ｒ３）（－Ｒ４）－、又は－Ｃ（－Ｒ３）（－Ｒ４）－Ｃ（－Ｒ３）（－Ｒ４）－を表わし、
Ｘ６は、－ＣＨ（－Ｒ５）－、又は－Ｃ（＝Ｏ）－を表わし、
Ｘ７は、－ＣＨ（－Ｒ６）－、又は－Ｃ（＝Ｏ）－を表わし、
Ｒ１は、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又はＣ１－Ｃ６ハロゲノアルコキシ基を表わし、
Ｒ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、又はカルボキシ基の保護基で保護されていてもよいカルボキシ基を表わし、
Ｒ３、Ｒ４、Ｒ５及びＲ６は、それぞれ独立に、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、又はＣ１－Ｃ６ハロゲノアルキル基を表わし、
Ａは、カルバモイル基、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６ヒドロキシアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アルキルスルホンアミド基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アシルアミノ基、又は、５員環へテロアリール基を表わし、ここで、５員環へテロアリール基は、非置換であるか、又は独立して選択される１～５個のＲ７部分で置換されていてもよく、
Figure JPOXMLDOC01-appb-C000003
[Wherein, X 1 , X 2 , X 3 , and X 4 each independently represents —C═ or —N═;
X 5 is, -CH 2 -, - CH 2 CH 2 -, - O -, - CH 2 O -, - OCH 2 -, - CH 2 S -, - SCH 2 -, - CH 2 SO -, - SOCH 2 —, —, —CH 2 SO 2 —, —SO 2 CH 2 —, —C (—R 3 ) (— R 4 ) —, or —C (—R 3 ) (— R 4 ) —C (— R 3 ) (— R 4 ) —
X 6 represents —CH (—R 5 ) — or —C (═O) —,
X 7 represents —CH (—R 6 ) — or —C (═O) —,
R 1 is a hydrogen atom, hydroxyl group, halogen atom, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 halogenoalkyl group, or C1 Represents a -C6 halogenoalkoxy group,
R 2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a carboxy group that may be protected with a protecting group for a carboxy group,
R 3 , R 4 , R 5 and R 6 each independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group;
A is a carbamoyl group, C1-C6 alkylcarbamoyl group, C1-C6 hydroxyalkylcarbamoyl group, C3-C6 cycloalkylcarbamoyl group, C3-C6 cycloalkyl-C1-C6 alkylcarbamoyl group, C1-C6 alkylsulfonyl group, C1 -C6 alkylsulfonamido group, C3-C6 cycloalkyl-C1-C6 alkylsulfonyl group, C1-C6 acylamino group, or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is unsubstituted Or optionally substituted with 1 to 5 independently selected R 7 moieties,
ここで、Ｒ７部分は、同じであっても異なっていてもよく、各々が、水酸基、アミノ基、カルボキシ基、ハロゲン基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、及びＣ１－Ｃ６ハロゲノアルコキシ基からなる群より独立して選択され、
Ｙは、単結合、－ＣＨ２－、－（ＣＲ８Ｒ８）ｒ－、－ＣＨＲ８Ｃ（＝Ｏ）－、－（ＣＨＲ８）ｒＯ－、－（ＣＨＲ８）ｒＮ（Ｒ９）－、－Ｃ（＝Ｏ）－、－Ｃ（＝Ｓ）－、－Ｃ（＝ＮＲ９）－、－Ｃ（＝Ｎ－ＯＲ９）－、－ＣＨ（Ｃ（＝Ｏ）ＮＨＲ９）－、－ＣＨ（－５～１４員環ヘテロアリール）－、－Ｃ（Ｒ８Ｒ８）ｒＣ（Ｒ８）＝Ｃ（Ｒ８）－、－（ＣＨＲ８）ｒＣ（＝Ｏ）－、及び－（ＣＨＲ８）ｒＮＨＣ（＝Ｏ）－からなる群より選択される基を表わし、あるいは、Ｃ３－Ｃ１０シクロアルキル基、3～１０員環ヘテロシクレニル基、又は3～１０員環ヘテロシクリル基であり、このＣ３－Ｃ１０シクロアルキル基、3～１０員環ヘテロシクレニル基、又は、3～１０員環ヘテロシクリル基は、環Ｄと縮合し、
Ｒ８部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、Ｃ３－Ｃ１０シクロアルキル基、Ｃ１－Ｃ２０アルコキシ基、６～１４員環アリール基、５～１４員環ヘテロアリール基、3～１０員環ヘテロシクレニル基、3～１０員環ヘテロシクリル基、Ｃ３－Ｃ１１スピロアルキル基、－ＣＮ、－ＣＯＯＨ、－Ｃ（＝Ｏ）Ｒ９、－Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－（ＣＨＲ９）ｑＯＨ、－（ＣＨＲ９）ｑＯＲ１０、－（ＣＨＲ９）ｑＮＨ２、－（ＣＨＲ９）ｑＮＨＲ１０、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨＲ１０、－（ＣＨ２）ｑＳＯ２Ｒ１０、－（ＣＨ２）ｑＮＳＯ２Ｒ１０、－（ＣＨ２）ｑＳＯ２ＮＨＲ１０、－ＮＨ２、－Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－ＯＨ、ＯＲ９、－ＳＯ２Ｎ（Ｒ９）２、および－ＳＯ２（Ｒ１０）からなる群より独立して選択され、 Here, the R 7 moieties may be the same or different, and each is a hydroxyl group, amino group, carboxy group, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group. Independently selected from the group consisting of a group, a C3-C6 cycloalkoxy group, a C1-C6 halogenoalkyl group, and a C1-C6 halogenoalkoxy group;
Y is a single bond, —CH 2 —, — (CR 8 R 8 ) r —, —CHR 8 C (═O) —, — (CHR 8 ) r O—, — (CHR 8 ) r N (R 9 )-, -C (= O)-, -C (= S)-, -C (= NR 9 )-, -C (= N-OR 9 )-, -CH (C (= O) NHR 9 ) -, -CH (-5 to 14-membered heteroaryl)-, -C (R 8 R 8 ) r C (R 8 ) = C (R 8 )-,-(CHR 8 ) r C (= O)- And a group selected from the group consisting of — (CHR 8 ) r NHC (═O) —, or a C3-C10 cycloalkyl group, a 3- to 10-membered heterocyclenyl group, or a 3- to 10-membered heterocyclyl group And this C3-C10 cycloalkyl group, 3- to 10-membered heterocyclenyl group, or 3- to 10-membered heterocyclyl group is Combined,
The R 8 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a C3-C10 cycloalkyl group, a C1- C20 alkoxy group, 6-14 membered aryl group, 5-14 membered heteroaryl group, 3-10 membered heterocyclenyl group, 3-10 membered heterocyclyl group, C3-C11 spiroalkyl group, —CN, —COOH, -C (= O) R 9 , -C (= O) N (R 9 ) 2 ,-(CHR 9 ) q OH,-(CHR 9 ) q OR 10 ,-(CHR 9 ) q NH 2 ,-( CHR 9 ) q NHR 10 , — (CH 2 ) q C (═O) NHR 10 , — (CH 2 ) q SO 2 R 10 , — (CH 2 ) q NSO 2 R 10 , — (CH 2 ) q SO 2 NHR 10 , —N H 2 , —N (R 9 ) 2 , —N (R 9 ) C (═O) N (R 9 ) 2 , —N (R 9 ) SO 2 (R 10 ), —OH, OR 9 , —SO Independently selected from the group consisting of 2 N (R 9 ) 2 and —SO 2 (R 10 );
Ｒ９部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、６～１４員環アリール基、アラルキル基、Ｃ３－Ｃ１０シクロアルキル基、－ＣＮ、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＯ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＯ－６～１４員環アリール、－（ＣＨ２）ｑＯアラルキル、－（ＣＨ２）ｑＯ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＮＨアラルキル、－（ＣＨ２）ｑＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨアルキル、－（ＣＨ２）ｑＣ（＝Ｏ）Ｎ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨアラルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２アラルキル、－（ＣＨ２）ｑＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＮＳＯ２アラルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２ＮＨアラルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ３－Ｃ１０シクロアルキル、3～１０員環ヘテロシクレニル基、3～１０員環ヘテロシクリル基、および５～１４員環ヘテロアリールからなる群より独立して選択され、 The R 9 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a 6-14 membered aryl group, an aralkyl group. Group, C3-C10 cycloalkyl group, —CN, — (CH 2 ) q OH, — (CH 2 ) q O—C1-C20 alkyl, — (CH 2 ) q O-6 to 14-membered aryl-C1- C20 alkyl, — (CH 2 ) q O-6 to 14-membered aryl, — (CH 2 ) q O aralkyl, — (CH 2 ) q O—C 3 -C 10 cycloalkyl, — (CH 2 ) q NH 2 , -(CH 2 ) q NH-C1-C20 alkyl,-(CH 2 ) q N (C1-C20 alkyl) 2 ,-(CH 2 ) q NH-6-14-membered aryl-C1-C20 alkyl,-( CH 2 ) q N H-6-14 membered aryl, — (CH 2 ) q NH aralkyl, — (CH 2 ) q NH—C 3 -C 10 cycloalkyl, — (CH 2 ) q C (═O) NH alkyl, — (CH 2 ) Q C (═O) N (C1-C20 alkyl) 2 , — (CH 2 ) q C (═O) NH-6-14 membered aryl-C1-C20 alkyl, — (CH 2 ) q C (= O) NH-6-14 membered aryl, — (CH 2 ) q C (═O) NH aralkyl, — (CH 2 ) q C (═O) NH—C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 -C1-C20 alkyl,-(CH 2 ) q SO 2 -6 to 14-membered ring aryl-C1-C20 alkyl,-(CH 2 ) q SO 2 -6 to 14-membered ring aryl,-(CH 2 ) q SO 2 aralkyl, - (CH 2) q SO -C3-C10 cycloalkyl, - (CH 2) q NSO 2 -C1-C20 alkyl, - (CH 2) q NSO 2 -6 ~ 14 membered aryl-C1-C20 alkyl, - (CH 2) q NSO 2 —6 to 14-membered aryl, — (CH 2 ) q NSO 2 aralkyl, — (CH 2 ) q NSO 2 —C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 NH—C 1 -C 20 alkyl, — ( CH 2 ) q SO 2 NH-6-14 membered aryl-C1-C20 alkyl, — (CH 2 ) q SO 2 NH-6-14 membered aryl, — (CH 2 ) q SO 2 NH aralkyl, — ( CH 2) q SO 2 NH- C3-C10 cycloalkyl, 3-10 membered ring heterocyclenyl group, 3-10-membered heterocyclyl group, and either 5-14 membered heteroaryl It is independently selected from the group consisting,
　Ｒ１０部分は、同じであっても異なっていてもよく、各々が、Ｃ１－Ｃ２０アルキル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、６～１４員環アリール基、アラルキル基、Ｃ３－Ｃ１０シクロアルキル基、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＯ－Ｃ１－Ｃ２０アルキル－６～１４員環アリール、－（ＣＨ２）ｑＯ－６～１４員環アリール、－（ＣＨ２）ｑＯアラルキル、－（ＣＨ２）ｑＯ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＮＨアラルキル、－（ＣＨ２）ｑＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＣ（＝Ｏ）Ｎ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨアラルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２アラルキル、－（ＣＨ２）ｑＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＮＳＯ２アラルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２ＮＨアラルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ３－Ｃ１０シクロアルキル、3～１０員環ヘテロシクレニル基、3～１０員環ヘテロシクリル基、および５～１４員環ヘテロアリール基からなる群より独立して選択され、
環Ｄは、５～９員の、シクロアルキル環、シクロアルケニル環、アリール環、ヘテロアリール環、ヘテロシクレニル環、又は、ヘテロシクリル環であり、ここで、該アリール環は、フェニルを除外し、該へテロアリール環、ヘテロシクレニル環、及びヘテロシクリル環は、Ｏ、Ｓ、又は、Ｎから環原子として独立して選択される、０～４個のヘテロ原子を有し、さらにここで、該環Ｄは、非置換であるか、又は、独立して選択される１～５個のＲ１１部分で置換されていてもよく、 The R 10 moieties may be the same or different and each is a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a 6-14 membered aryl group, an aralkyl group, a C3 —C10 cycloalkyl group, — (CH 2 ) q OH, — (CH 2 ) q O—C1-C20 alkyl, — (CH 2 ) q O—C1-C20 alkyl—6- to 14-membered aryl, — (CH 2) q O-6 ~ 14 membered aryl, - (CH 2) q O aralkyl, - (CH 2) q O -C3-C10 cycloalkyl, - (CH 2) q NH2 , - (CH 2) q NH —C1-C20 alkyl, — (CH 2 ) q N (C1-C20 alkyl) 2 , — (CH 2 ) q NH-6 to 14-membered aryl-C1-C20 alkyl, — (CH 2 ) q NH-6 14-member ring Reel, - (CH 2) q NH aralkyl, - (CH 2) q NH -C3-C10 cycloalkyl, - (CH 2) q C (= O) NH-C1-C20 alkyl, - (CH 2) q C (═O) N (C1-C20 alkyl) 2 , — (CH 2 ) q C (═O) NH-6-14-membered aryl-C1-C20 alkyl, — (CH 2 ) q C (═O) NH —6 to 14-membered aryl, — (CH 2 ) q C (═O) NH aralkyl, — (CH 2 ) q C (═O) NH—C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 — C1-C20 alkyl, - (CH 2) q SO 2 -6 ~ 14 membered aryl-C1-C20 alkyl, - (CH 2) q SO 2 -6 ~ 14 membered aryl, - (CH 2) q SO 2 Aralkyl, — (CH 2 ) q SO 2 — C3-C10 cycloalkyl, — (CH 2 ) q NSO 2 —C1-C20 alkyl, — (CH 2 ) q NSO 2 -6 to 14-membered aryl-C1-C20 alkyl, — (CH 2 ) q NSO 2 — 6-14 membered aryl, — (CH 2 ) q NSO 2 aralkyl, — (CH 2 ) q NSO 2 —C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 NH—C 1 -C 20 alkyl, — (CH 2 ) q SO 2 NH-6-14 membered aryl-C1-C20 alkyl, — (CH 2 ) q SO 2 NH-6-14 membered aryl, — (CH 2 ) q SO 2 NH aralkyl, — (CH 2 ) from qSO 2 NH—C3-C10 cycloalkyl, 3-10 membered heterocyclenyl group, 3-10 membered heterocyclyl group, and 5-14 membered heteroaryl group Selected independently from the group
Ring D is a 5- to 9-membered cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, heterocyclenyl ring, or heterocyclyl ring, wherein the aryl ring excludes phenyl and A teloaryl ring, heterocyclenyl ring, and heterocyclyl ring have 0 to 4 heteroatoms independently selected as ring atoms from O, S, or N, further wherein the ring D is non- May be substituted or optionally substituted with 1 to 5 independently selected R 11 moieties;
Ｒ１１部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ２―Ｃ１５アルケニル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、Ｃ２―Ｃ１５アルキニル基、Ｃ１－Ｃ２０アルコキシ基、Ｃ１－Ｃ２０アルキルアミノ基、Ｃ１－Ｃ２０アルキルチオカルボキシ基、Ｃ１－Ｃ２０アルキル－５～１４員環ヘテロアリール基、Ｃ１－Ｃ２０アルキルチオ基、Ｃ１－Ｃ２０アルキルスルフィニル基、Ｃ１－Ｃ２０アルキルスルホニル基、Ｃ１－Ｃ２０アルコキシカルボニル基、Ｃ１－Ｃ２０アミノアルキル基、アミジニル基、アラルキル基、アラルケニル基、アラルコキシ基、アラルコキシカルボニル基、アラルキルチオ基、６～１４員環アリール基、アロイル基、６～１４員環アリールオキシ基、シアノ基、Ｃ３－Ｃ１０シクロアルキル基、Ｃ３－Ｃ１０シクロアルケニル基、ホルミル基、グアニジニル基、ハロゲン原子、Ｃ１－Ｃ２０ハロゲノアルキル基、Ｃ１－Ｃ２０ハロゲノアルコキシ基、ヘテロアルキル基、ヘテロアリール基、ヘテロシクリル基、ヘテロシクレニル基、Ｃ１－Ｃ２０ヒドロキシアルキル基、Ｃ１－Ｃ６ヒドロキサメート基、ニトロ基、トリフルオロメチル基、トリフルオロメトキシ基、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯＲ１０、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨＲ１０、－（ＣＨ２）ｑＮ（Ｒ１０）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨＲ１０、－（ＣＨ２）ｑＳＯ２Ｒ１０、－（ＣＨ２）ｑＮＨＳＯ２Ｒ１０、－（ＣＨ２）ｑＳＯ２ＮＨＲ１０、－アルキニルＣ（Ｒ１０）２ＯＲ１０、－Ｃ（＝Ｏ）Ｒ９、－Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＲ９）ＮＨＲ９、－Ｃ（＝ＮＯＨ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＯＲ１０）Ｎ（Ｒ９）２、－Ｃ（＝Ｏ）ＯＲ９、－Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｒ１０、－ＮＨＣ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）ＯＲ１０、－Ｎ（Ｒ９）Ｃ（＝ＮＣＮ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｓ（Ｏ）２Ｎ（Ｒ９）２、－ＯＲ９、－ＯＣ（＝Ｏ）Ｎ（Ｒ９）２、－ＳＲ９、－ＳＯ２Ｎ（Ｒ９）２、－ＳＯ２（Ｒ１０）、－ＯＳＯ２（Ｒ１０）、および－ＯＳｉ（Ｒ９）３からなる群より独立して選択されるか；あるいは２つのＲ１１部分が、一緒に連結して、５員または６員の、アリール環、シクロアルキル環、ヘテロシクリル環、ヘテロシクレニル環、またはヘテロアリール環を形成し、ここで、これらの５員または６員の、アリール環、シクロアルキル環、ヘテロシクリル環、ヘテロシクレニル環、またはヘテロアリール環は、環Ｄに縮合し、そしてこの縮合環は、１～４個のＲ１２部分で置換されていてもよく、 The R 11 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C2-C15 alkenyl group, a C1-C20 alkyl-6-14 membered aryl group, a C2-C15 Alkynyl group, C1-C20 alkoxy group, C1-C20 alkylamino group, C1-C20 alkylthiocarboxy group, C1-C20 alkyl-5-14 membered heteroaryl group, C1-C20 alkylthio group, C1-C20 alkylsulfinyl group, C1-C20 alkylsulfonyl group, C1-C20 alkoxycarbonyl group, C1-C20 aminoalkyl group, amidinyl group, aralkyl group, aralkenyl group, aralkoxy group, aralkoxycarbonyl group, aralkylthio group, 6-14 membered aryl group , Aroyl group, 6-14 membered aryloxy group Cyano group, C3-C10 cycloalkyl group, C3-C10 cycloalkenyl group, formyl group, guanidinyl group, halogen atom, C1-C20 halogenoalkyl group, C1-C20 halogenoalkoxy group, heteroalkyl group, heteroaryl group, heterocyclyl Group, heterocyclenyl group, C1-C20 hydroxyalkyl group, C1-C6 hydroxamate group, nitro group, trifluoromethyl group, trifluoromethoxy group, — (CH 2 ) q OH, — (CH 2 ) q OR 10 , — (CH 2 ) q NH 2 , — (CH 2 ) q NHR 10 , — (CH 2 ) q N (R 10 ) 2 , — (CH 2 ) q C (═O) NHR 10 , — (CH 2 ) q SO 2 R 10, - ( CH 2) q NHSO 2 R 10, - (CH 2) q SO 2 NHR 10, Alkynyl C (R 10) 2OR 10, -C (= O) R 9, -C (= O) N (R 9) 2, -C (= NR 9) NHR 9, -C (= NOH) N (R 9 ) 2 , —C (═NOR 10 ) N (R 9 ) 2 , —C (═O) OR 9 , —N (R 9 ) 2 , —N (R 9 ) C (═O) R 10 , — NHC (═O) N (R 9 ) 2 , —N (R 9 ) C (═O) OR 10 , —N (R 9 ) C (═NCN) N (R 9 ) 2 , —N (R 9 ) C (═O) N (R 9 ) SO 2 (R 10 ), —N (R 9 ) C (═O) N (R 9 ) 2 , —N (R 9 ) SO 2 (R 10 ), —N (R 9 ) S (O) 2 N (R 9 ) 2 , —OR 9 , —OC (═O) N (R 9 ) 2 , —SR 9 , —SO 2 N (R 9 ) 2 , —SO 2 (R 10 ), —OSO 2 (R 10 ), And —OSi (R 9 ) 3 independently selected; or two R 11 moieties linked together to form a 5- or 6-membered aryl, cycloalkyl, heterocyclyl ring , A heterocyclenyl ring, or a heteroaryl ring, wherein these 5- or 6-membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl rings are fused to ring D; and This fused ring may be substituted with 1 to 4 R 12 moieties,
Ｒ１２部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ２－Ｃ１５アルケニル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、Ｃ２－Ｃ１５アルキニル基、Ｃ１－Ｃ２０アルコキシ基、Ｃ１－Ｃ２０アルキルアミノ基、Ｃ１－Ｃ２０アルキルチオカルボキシ基、Ｃ１－Ｃ２０アルキル－５～１４員環ヘテロアリール基、Ｃ１－Ｃ２０アルキルチオ基、Ｃ１－Ｃ２０アルキルスルフィニル基、Ｃ１－Ｃ２０アルキルスルホニル基、Ｃ１－Ｃ２０アルコキシカルボニル基、Ｃ１－Ｃ２０アミノアルキル基、アミジニル基、アラルキル基、アラルケニル基、アラルコキシ基、アラルコキシカルボニル基、アラルキルチオ基、６～１４員環アリール基、アロイル基、６～１４員環アリールオキシ基、カルボキサミド基、シアノ基、Ｃ３－Ｃ１０シクロアルキル基、Ｃ３－Ｃ１０シクロアルケニル基、ホルミル基、グアニジニル基、ハロゲン原子、Ｃ１－Ｃ２０ハロゲノアルキル基、ヘテロアルキル基、５～１４員環ヘテロアリール基、Ｃ３－Ｃ１０ヘテロシクリル基、Ｃ３－Ｃ１０ヘテロシクレニル基、Ｃ１－Ｃ２０ヒドロキシアルキル基、ヒドロキサメート基、ニトロ基、トリフルオロメトキシ基、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯＲ１０、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨＲ１０、－（ＣＨ２）ｑＮ（Ｒ１０）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨＲ１０、－（ＣＨ２）ｑＳＯ２Ｒ１０、－（ＣＨ２）ｑＮＳＯ２Ｒ１０、－（ＣＨ２）ｑＳＯ２ＮＨＲ１０、－アルキニルＣ（Ｒ１０）２ＯＲ１０、－Ｃ（＝Ｏ）Ｒ９、－Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＲ９）ＮＨＲ９、－Ｃ（＝ＮＯＨ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＯＲ１０）Ｎ（Ｒ９）２、－Ｃ（＝Ｏ）ＯＲ９、－Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｒ１０、－ＮＨＣ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）ＯＲ１０、－Ｎ（Ｒ９）Ｃ（＝ＮＣＮ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｓ（Ｏ）２Ｎ（Ｒ９）２、－ＯＲ９、－ＯＣ（＝Ｏ）Ｎ（Ｒ９）２、－ＳＲ９、－ＳＯ２Ｎ（Ｒ９）２、－ＳＯ２（Ｒ１０）、－ＯＳＯ２（Ｒ１０）、および－ＯＳｉ（Ｒ９）３からなる群より独立して選択され、
各ｑは、同じであっても異なっていてもよく、各々が独立して、１～５から選択され、
　ｒは、１～４であり、
ただし、いずれの環においても、２つの隣接する二重結合が存在せず、そして窒素が２つのアルキル基により置換される場合、これらの２つのアルキル基は、必要に応じて、互いに連結して、環を形成し得る。］ The R 12 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C2-C15 alkenyl group, a C1-C20 alkyl-6-14 membered aryl group, a C2-C15 Alkynyl group, C1-C20 alkoxy group, C1-C20 alkylamino group, C1-C20 alkylthiocarboxy group, C1-C20 alkyl-5-14 membered heteroaryl group, C1-C20 alkylthio group, C1-C20 alkylsulfinyl group, C1-C20 alkylsulfonyl group, C1-C20 alkoxycarbonyl group, C1-C20 aminoalkyl group, amidinyl group, aralkyl group, aralkenyl group, aralkoxy group, aralkoxycarbonyl group, aralkylthio group, 6-14 membered aryl group , Aroyl group, 6-14 membered aryloxy group Carboxamide group, cyano group, C3-C10 cycloalkyl group, C3-C10 cycloalkenyl group, formyl group, guanidinyl group, halogen atom, C1-C20 halogenoalkyl group, heteroalkyl group, 5- to 14-membered ring heteroaryl group, C3-C10 heterocyclyl group, C3-C10 heterocyclenyl group, C1-C20 hydroxyalkyl group, hydroxamate group, nitro group, trifluoromethoxy group, — (CH 2 ) q OH, — (CH 2 ) q OR 10 , — (CH 2 ) q NH 2 , — (CH 2 ) q NHR 10 , — (CH 2 ) q N (R 10 ) 2 , — (CH 2 ) q C (═O) NHR 10 , — (CH 2 ) q SO 2 R 10, - (CH 2) q NSO 2 R 10, - (CH 2) q SO 2 NHR 10, - alkynyl C R 10) 2 OR 10, -C (= O) R 9, -C (= O) N (R 9) 2, -C (= NR 9) NHR 9, -C (= NOH) N (R 9) 2 , —C (═NOR 10 ) N (R 9 ) 2 , —C (═O) OR 9 , —N (R 9 ) 2 , —N (R 9 ) C (═O) R 10 , —NHC ( = O) N (R 9 ) 2 , -N (R 9 ) C (= O) OR 10 , -N (R 9 ) C (= NCN) N (R 9 ) 2 , -N (R 9 ) C ( ═O) N (R 9 ) SO 2 (R 10 ), —N (R 9 ) C (═O) N (R 9 ) 2 , —N (R 9 ) SO 2 (R 10 ), —N (R 9 ) S (O) 2 N (R 9 ) 2 , —OR 9 , —OC (═O) N (R 9 ) 2 , —SR 9 , —SO 2 N (R 9 ) 2 , —SO 2 (R 10), - OSO 2 (R 10), and -OS (R 9) 3 are independently selected from the group consisting of,
Each q may be the same or different and each is independently selected from 1 to 5;
r is 1 to 4,
However, if there are no two adjacent double bonds in any ring and the nitrogen is substituted by two alkyl groups, then these two alkyl groups are optionally linked together. Can form a ring. ]
（２）一般式（ＩＩ）を有する化合物又はその薬理上許容される塩。 (2) A compound having the general formula (II) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000004
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ８、及びＸ９は、それぞれ独立に、－Ｃ＝、又は、－Ｎ＝を表わし、
Ｘ５は、－ＣＨ２－、－ＣＨ２ＣＨ２－、－Ｏ－、－ＣＨ２Ｏ－、－ＯＣＨ２－、－ＣＨ２Ｓ－、－ＳＣＨ２－、－ＣＨ２ＳＯ－、－ＳＯＣＨ２－、－、－ＣＨ２ＳＯ２－、－ＳＯ２ＣＨ２－、－Ｃ（－Ｒ３）（－Ｒ４）－、又は－Ｃ（－Ｒ３）（－Ｒ４）－Ｃ（－Ｒ３）（－Ｒ４）－、を表わし、
Ｘ６は、－ＣＨ（－Ｒ５）－、又は－Ｃ（＝Ｏ）－を表わし、
Ｘ７は、－ＣＨ（－Ｒ６）－、又は－Ｃ（＝Ｏ）－を表わし、
Ｒ１、Ｒ１３、及びＲ１４は、それぞれ独立に、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、Ｃ１－Ｃ６ハロゲノアルコキシ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基を表わし、
Ｒ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基を表わし、
Ｒ３、Ｒ４、Ｒ５及びＲ６は、それぞれ独立に、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、又はＣ１－Ｃ６ハロゲノアルキル基を表わし、
Figure JPOXMLDOC01-appb-C000004
[Wherein, X 1 , X 2 , X 3 , X 4 , X 8 , and X 9 each independently represent —C═ or —N═,
X 5 is, -CH 2 -, - CH 2 CH 2 -, - O -, - CH 2 O -, - OCH 2 -, - CH 2 S -, - SCH 2 -, - CH 2 SO -, - SOCH 2 —, —, —CH 2 SO 2 —, —SO 2 CH 2 —, —C (—R 3 ) (— R 4 ) —, or —C (—R 3 ) (— R 4 ) —C (— R 3 ) (— R 4 ) —
X 6 represents —CH (—R 5 ) — or —C (═O) —,
X 7 represents —CH (—R 6 ) — or —C (═O) —,
R 1 , R 13 , and R 14 are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy Group, a C1-C6 halogenoalkyl group, a C1-C6 halogenoalkoxy group, or a carboxy group optionally protected by a protecting group for a carboxy group,
R 2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group,
R 3 , R 4 , R 5 and R 6 each independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group;
Ｒ１５は、水素原子、ハロゲン原子、アミノ基、シアノ基、カルバモイル基、Ｃ１－Ｃ６アルキルカルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、Ｃ１－Ｃ６アルコキシカルボニル基、Ｃ１－Ｃ６ヒドロキシアルコキシカルボニル基、又は、置換基群αから選択される基で置換されていてもよい５員環へテロアリール基を表わし、
Ｙは、単結合、－ＣＨ２－、－Ｃ（＝Ｏ）－、－Ｃ（＝Ｓ）－、－Ｃ（－Ｃ１－Ｃ６アルキル）－、又は－C（－５員環へテロアリール）－を表わし、ここで、５員環へテロアリール基は、置換基群αから選択される基で置換されていてもよく、
Ａは、カルバモイル基、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６ヒドロキシアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アルキルスルホンアミド基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アシルアミノ基、又は、置換基群αから選択される基で置換されていてもよい５員環へテロアリール基を表わす。
置換基群α：水酸基、アミノ基、カルボキシ基、ハロゲン基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６アルキルアミノ基、Ｃ３－Ｃ６シクロアルキルアミノ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基］ R 15 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a carbamoyl group, a C1-C6 alkylcarbamoyl group, a carboxy group optionally protected by a protecting group for carboxy group, a C1-C6 alkoxycarbonyl group, C1- A C6 hydroxyalkoxycarbonyl group or a 5-membered heteroaryl group optionally substituted with a group selected from the substituent group α,
Y is a single bond, —CH 2 —, —C (═O) —, —C (═S) —, —C (—C1-C6 alkyl) —, or —C (-5-membered heteroaryl)- Wherein the 5-membered heteroaryl group may be substituted with a group selected from the substituent group α,
A is a carbamoyl group, C1-C6 alkylcarbamoyl group, C1-C6 hydroxyalkylcarbamoyl group, C3-C6 cycloalkylcarbamoyl group, C3-C6 cycloalkyl-C1-C6 alkylcarbamoyl group, C1-C6 alkylsulfonyl group, C1 -C6 alkylsulfonamido group, C3-C6 cycloalkyl-C1-C6 alkylsulfonyl group, C1-C6 acylamino group, or 5-membered heteroaryl group optionally substituted with a group selected from substituent group α Represents.
Substituent group α: hydroxyl group, amino group, carboxy group, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 alkylamino group, C3 —C6 cycloalkylamino group, C1-C6 halogenoalkyl group, or C1-C6 halogenoalkoxy group]
（３）Ｙが、－ＣＨ２－又はカルボニル基である、上記（１）乃至（２）に記載の化合物、又は、その薬理上許容される塩。
（４）Ａが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基である、上記（１）乃至（３）に記載の化合物、又は、その薬理上許容される塩。
（５）Ｘ５が、－ＣＨ２－、－ＣＨ２ＣＨ２－又は－Ｏ－である、上記（１）乃至（４）に記載の化合物、又は、その薬理上許容される塩。
（６）Ｘ２が、－Ｎ＝であり、Ｘ１、Ｘ３、及びＸ４が－Ｃ＝である、上記（１）乃至（５）に記載の化合物、又は、その薬理上許容される塩。
（７）Ｘ２及びＸ３が－Ｎ＝であり、Ｘ１及びＸ４が－Ｃ＝である、上記（１）乃至（５）に記載の化合物、又は、その薬理上許容される塩。
（８）Ｘ６及びＸ７がともに、－ＣＨ２－である、上記（１）乃至（７）に記載の化合物、又は、その薬理上許容される塩。
（９）Ｒ１が、水素原子、水酸基、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基、又はＣ１－Ｃ６アルコキシ基である、上記（１）乃至（８）に記載の化合物、又は、その薬理上許容される塩。
（１０）Ｘ８及びＸ９がともに、－Ｃ＝である、上記（２）乃至（９）に記載の化合物、又は、その薬理上許容される塩。
（１１）Ｒ１３及びＲ１４が、それぞれ独立に、水素原子又はハロゲン原子である、上記（２）乃至（１０）に記載の化合物、又は、その薬理上許容される塩。
（１２）Ｒ１５が、カルバモイル基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基である、上記（２）乃至（１１）に記載の化合物、又は、その薬理上許容される塩。 (3) The compound according to the above (1) or (2) or a pharmacologically acceptable salt thereof, wherein Y is —CH 2 — or a carbonyl group.
(4) The compound according to (1) to (3) above, wherein A is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group, or Its pharmacologically acceptable salt.
(5) X 5 is, -CH 2 -, - CH 2 CH 2 - or -O-, and compounds described in (1) to (4), or, a pharmacologically acceptable salt thereof.
(6) The compound according to the above (1) to (5), or a pharmacologically acceptable salt thereof, wherein X 2 is —N═ and X 1 , X 3 , and X 4 are —C═ salt.
(7) The compound according to (1) to (5) or a pharmacologically acceptable salt thereof, wherein X 2 and X 3 are —N═ and X 1 and X 4 are —C═.
(8) The compound according to (1) to (7) or a pharmacologically acceptable salt thereof, wherein X 6 and X 7 are both —CH 2 —.
(9) The compound according to any one of (1) to (8) above, wherein R 1 is a hydrogen atom, a hydroxyl group, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group, Or a pharmacologically acceptable salt thereof.
(10) The compound according to (2) to (9) or a pharmacologically acceptable salt thereof, wherein X 8 and X 9 are both —C═.
(11) The compound or pharmacologically acceptable salt thereof according to (2) to (10), wherein R 13 and R 14 are each independently a hydrogen atom or a halogen atom.
(12) The compound according to the above (2) to (11), or a pharmacologically acceptable salt thereof, wherein R 15 is a carbamoyl group or a carboxy group optionally protected by a protecting group for a carboxy group. salt.
（１３）一般式（ＩＩ）において、
Ｘ２が－Ｎ＝であり、Ｘ３が－Ｃ＝又は－Ｎ＝であって、Ｘ１及びＸ４がともに－Ｃ＝であり、
Ｘ５が、－ＣＨ２ＣＨ２－、－ＣＨ２－、又は、－Ｏ－であり、
Ｘ６及びＸ７が、ともに－ＣＨ２－、又は、ともに－Ｃ（＝Ｏ）－であり、
Ｘ８及びＸ９が、共に－ＣＨ＝であるか、又は、Ｘ８が－Ｃ＝であってＸ９が－Ｎ＝の組み合わせであり、
Ｒ１が、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基であり、
Ｒ２が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
Ｒ１３及びＲ１４が、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
Ｒ１５が、水素原子、ハロゲン原子、アミノ基、カルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、又は、Ｃ１－Ｃ６アルコキシカルボニル基であり、
Ａが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基であり、
Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、請求項２に記載の化合物、又は、その薬理上許容される塩。 (13) In the general formula (II),
X 2 is -N =, X 3 is -C = or -N =, and both X 1 and X 4 are -C =,
X 5 is —CH 2 CH 2 —, —CH 2 —, or —O—,
X 6 and X 7 are both —CH 2 — or both —C (═O) —;
X 8 and X 9 are both -CH =, or X 8 is -C = and X 9 is -N =
R 1 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a C1-C6 halogenoalkyl group, or A C1-C6 halogenoalkoxy group,
R 2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group,
R 13 and R 14 are each independently a hydrogen atom, a halogen atom, a cyano group, or a carboxy group which may be protected with a protecting group for a carboxy group,
R 15 is a hydrogen atom, a halogen atom, an amino group, a carbamoyl group, a carboxy group optionally protected by a protecting group for a carboxy group, or a C1-C6 alkoxycarbonyl group,
A is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group,
The compound according to claim 2, or a pharmacologically acceptable salt thereof, wherein Y is —CH 2 — or —C (═O) —.
（１４）一般式（ＩＩ）において、
Ｘ２が－Ｎ＝であって、Ｘ１、Ｘ３及びＸ４が－Ｃ＝であり、
Ｘ５が、－ＣＨ２ＣＨ２－であり、
Ｘ６が、ともに－ＣＨ２－であり、
Ｘ８及びＸ９が、ともに－ＣＨ＝であり、
Ｒ１が、水素原子、ハロゲン原子、又は、Ｃ１－Ｃ６アルキル基であり、
Ｒ２が、水素原子、Ｃ１－Ｃ６アルキル基、ハロゲン原子、カルボキシ基、又は、カルボニル基であり、
Ｒ１３及びＲ１４が、水素原子、又は、塩素原子であり、
Ｒ１５は、フッ素原子、アミノ基、カルバモイル基、カルボキシ基、又は、エトキシカルボニル基であり、
Ａが、エチルカルバモイル基、プロピルカルバモイル基、ｔｅｒｔ－ブチルカルバモイル基、シクロプロピルカルバモイル基、又は、エチルアミノオキサジアゾリル基であり、
Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、請求項２又は請求項１３のいずれか一項に記載の化合物、又は、その薬理上許容される塩。 (14) In the general formula (II),
X 2 is -N = and X 1 , X 3 and X 4 are -C =,
X 5 is —CH 2 CH 2 —;
X 6 are both —CH 2 —,
X 8 and X 9 are both —CH═,
R 1 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group,
R 2 is a hydrogen atom, a C1-C6 alkyl group, a halogen atom, a carboxy group, or a carbonyl group,
R 13 and R 14 are a hydrogen atom or a chlorine atom,
R 15 is a fluorine atom, an amino group, a carbamoyl group, a carboxy group, or an ethoxycarbonyl group,
A is an ethylcarbamoyl group, a propylcarbamoyl group, a tert-butylcarbamoyl group, a cyclopropylcarbamoyl group, or an ethylaminooxadiazolyl group,
14. The compound according to any one of claims 2 and 13, or a pharmacologically acceptable salt thereof, wherein Y is —CH 2 — or —C (═O) —.
（１５）一般式（Ｉ）又は一般式（ＩＩ）を有する化合物が以下の化合物群から選択される化合物である、請求項１乃至請求項２に記載の化合物又はその薬理上許容される塩。
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
６－［ｃｉｓ－４－［１－（２－カルバモイル－４－クロロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－５－クロロ－Ｎ－エチルニコチンアミド、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［cis－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－［ｃｉｓ－４－［１－（２－カルバモイル－４－クロロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド、
５－［ｃｉｓ－４－［１－（４－クロロ－２－フルオロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド、
５－［ｃｉｓ－４－｛１－［（２－アミノ－６－クロロピリジン－３－イル）カルボニル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
５－クロロ－２－［（４－｛ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル、
５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
５－｛６－クロロ－５－［ｃｉｓ－４－［１－（４－クロロベンゾイル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－イル｝－Ｎ－エチル－１，３，４－オキサジアゾール－２－アミン、
５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、及び、
５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 (15) The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) or the general formula (II) is a compound selected from the following compound group.
5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
6- [cis-4- [1- (2-carbamoyl-4-chlorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -5-chloro-N-ethylnicotinamide,
5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
5-chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid,
5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) ethyl benzoate,
5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) ethyl benzoate,
5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) methyl benzoate,
5-chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
5-chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
5- [cis-4- [1- (2-carbamoyl-4-chlorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl-6-methylpyrazine-2- Carboxamide,
5- [cis-4- [1- (4-Chloro-2-fluorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl-6-methylpyrazine-2- Carboxamide,
5- [cis-4- {1-[(2-amino-6-chloropyridin-3-yl) carbonyl] piperidin-4-yl} octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl- 6-methylpyrazine-2-carboxamide,
5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) ethyl benzoate,
5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
5-chloro-2-[(4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid,
5-chloro-2-[(4- {cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid,
5-Chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
5-chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1 -Yl) methyl] ethyl benzoate,
5-chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyridin-2-yl} Octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) benzoic acid,
5-chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1 -Yl) methyl] benzoic acid,
5- {6-Chloro-5- [cis-4- [1- (4-chlorobenzoyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazin-2-yl} -N-ethyl -1,3,4-oxadiazol-2-amine,
5-chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid, and
5-chloro-2-[(4- {cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1 -Il) methyl] benzoic acid
（１６）一般式（Ｉ）又は一般式（ＩＩ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。
（１７）自己免疫疾患を予防又は治療するために用いるための、上記（１４）に記載された医薬組成物。
（１８）自己免疫疾患が、全身性エリトマトーデス、慢性関節リウマチ、多発性筋炎、結合組織炎、骨格筋炎、骨関節炎、変形性関節症、皮膚筋炎、強皮症、ベーチェット病、Chron病、潰瘍性大腸炎、自己免疫性肝炎、再生不良性貧血、特発性血小板減少性紫斑病、自己免疫性溶血性貧血、多発性硬化症、自己免疫性水疱症、尋常性乾癬、血管炎症群、Wegener肉芽腫、ぶどう膜炎、シェーグレン症候群、特発性間質性肺炎、Goodpasture症候群、サルコイドーシス、アレルギー性肉芽腫性血管炎、気管支喘息、心筋炎、心筋症、大動脈炎症候群、心筋梗塞後症候群、原発性肺高血圧症、微小変化型ネフローゼ、膜性腎症、膜性増殖性腎炎、巣状糸球体硬化症、半月体形成性腎炎、重症筋無力症、炎症性ニューロパチー、アトピー性皮膚炎、慢性光線性皮膚炎、日光過敏症、蓐瘡、Sydenham舞踏病、硬化症、成人発症糖尿病、インスリン依存性糖尿病、若年性糖尿病、アテローム性動脈硬化症、糸球体腎炎、IgA腎症、尿細管間質性腎炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、劇症肝炎、ウイルス性肝炎、GVHD、接触皮膚炎、又は敗血症である、上記（１４）乃至（１５）に記載された医薬組成物。 (16) A pharmaceutical composition comprising a compound having the general formula (I) or the general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient.
(17) The pharmaceutical composition according to the above (14), which is used for preventing or treating an autoimmune disease.
(18) Autoimmune diseases are systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative Colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosa, psoriasis vulgaris, vascular inflammation group, Wegener granulomas , Uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension Disease, minimal change nephrosis, membranous nephropathy, membranoproliferative nephritis, focal glomerulosclerosis, crescent nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic light Dermatitis, photosensitivity, pressure ulcer, Sydenham chorea, sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis The pharmaceutical composition according to any of (14) to (15) above, which is primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, or sepsis.
（１９）自己免疫疾患が、慢性関節リウマチ、潰瘍性大腸炎、自己免疫性肝炎、多発性硬化症、又は尋常性乾癬である、上記（１６）乃至（１８）に記載された医薬組成物。
（２０）一般式（Ｉ）又は一般式（ＩＩ）におけるＹが、－ＣＨ２－又はカルボニル基である、上記（１６）乃至（１９）に記載された医薬組成物。
（２１）一般式（Ｉ）又は一般式（ＩＩ）におけるＡが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基である、上記（１６）乃至（１９）に記載された医薬組成物。
（２２）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ５が、－ＣＨ２－、－ＣＨ２ＣＨ２－又は－Ｏ－である、上記（１６）乃至（１９）に記載された医薬組成物。
（２３）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ２が、－Ｎ＝であり、Ｘ１、Ｘ３、及びＸ４が－Ｃ＝である、上記（１６）乃至（１９）に記載された医薬組成物。
（２４）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ２及びＸ３が－Ｎ＝であり、Ｘ１及びＸ４が－Ｃ＝である、上記（１６）乃至（１９）に記載された医薬組成物。
（２５）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ６及びＸ７がともに、－ＣＨ２－である、上記（１６）乃至（１９）に記載された医薬組成物。
（２６）一般式（Ｉ）又は一般式（ＩＩ）におけるＲ１が、水素原子、水酸基、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基、又はＣ１－Ｃ６アルコキシ基である、上記（１６）乃至（１９）に記載された医薬組成物。
（２７）一般式（ＩＩ）におけるＸ８及びＸ９がともに－Ｃ＝である、上記（１６）乃至（１９）に記載された医薬組成物。
（２８）一般式（ＩＩ）におけるＲ１３及びＲ１４が、それぞれ独立に、水素原子又はハロゲン原子である、上記（１６）乃至（１９）に記載された医薬組成物。
（２９）一般式（ＩＩ）におけるＲ１５が、カルバモイル基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基である、上記（１６）乃至（１９）に記載された医薬組成物。 (19) The pharmaceutical composition according to the above (16) to (18), wherein the autoimmune disease is rheumatoid arthritis, ulcerative colitis, autoimmune hepatitis, multiple sclerosis, or psoriasis vulgaris.
(20) The pharmaceutical composition according to the above (16) to (19), wherein Y in the general formula (I) or the general formula (II) is —CH 2 — or a carbonyl group.
(21) The above (16), wherein A in the general formula (I) or the general formula (II) is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group. The pharmaceutical composition described in (19) to (19).
(22) The medicament according to the above (16) to (19), wherein X 5 in the general formula (I) or the general formula (II) is —CH 2 —, —CH 2 CH 2 — or —O—. Composition.
(23) In the above formulas (16) to (19), X 2 in the general formula (I) or the general formula (II) is —N═, and X 1 , X 3 , and X 4 are —C═. The described pharmaceutical composition.
(24) In the above formulas (16) to (19), X 2 and X 3 in the general formula (I) or the general formula (II) are —N═, and X 1 and X 4 are —C═. Pharmaceutical composition.
(25) The pharmaceutical composition according to the above (16) to (19), wherein X 6 and X 7 in the general formula (I) or the general formula (II) are both —CH 2 —.
(26) The above, wherein R 1 in the general formula (I) or the general formula (II) is a hydrogen atom, a hydroxyl group, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group (16) The pharmaceutical composition as described in (19).
(27) The pharmaceutical composition according to the above (16) to (19), wherein X 8 and X 9 in the general formula (II) are both —C═.
(28) The pharmaceutical composition according to the above (16) to (19), wherein R 13 and R 14 in the general formula (II) are each independently a hydrogen atom or a halogen atom.
(29) The pharmaceutical composition according to the above (16) to (19), wherein R 15 in the general formula (II) is a carbamoyl group or a carboxy group optionally protected by a protecting group for a carboxy group .
（３０）一般式（Ｉ）又は一般式（ＩＩ）を有する化合物が、上記（１３）に挙げられた化合物から選択される化合物である、上記（１６）乃至（１９）に記載された医薬組成物。
（３１）一般式（ＩＩ）において、
Ｘ２が－Ｎ＝、Ｘ３が－Ｃ＝又は－Ｎ＝、Ｘ１及びＸ４がともに－Ｃ＝の組み合わせであり、
Ｘ５が、－ＣＨ２ＣＨ２－、－ＣＨ２－、又は、－Ｏ－であり、
Ｘ６及びＸ７が、ともに－ＣＨ２－、又は、ともに－Ｃ（＝Ｏ）－であり、
Ｘ８及びＸ９が、共に－ＣＨ＝であるか、又は、Ｘ８が－Ｃ＝であってＸ９が－Ｎ＝の組み合わせであり、
Ｒ１が、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基であり、
Ｒ２が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
Ｒ１３及びＲ１４が、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
Ｒ１５が、水素原子、ハロゲン原子、アミノ基、カルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、又は、Ｃ１－Ｃ６アルコキシカルボニル基であり、
Ａが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基であり、
Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、上記（１６）乃至（１９）に記載された医薬組成物。 (30) The pharmaceutical composition described in the above (16) to (19), wherein the compound having the general formula (I) or the general formula (II) is a compound selected from the compounds listed in the above (13) object.
(31) In the general formula (II),
X 2 is -N =, X 3 is -C = or -N =, X 1 and X 4 are both -C =
X 5 is —CH 2 CH 2 —, —CH 2 —, or —O—,
X 6 and X 7 are both —CH 2 — or both —C (═O) —;
X 8 and X 9 are both -CH =, or X 8 is -C = and X 9 is -N =
R 1 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a C1-C6 halogenoalkyl group, or A C1-C6 halogenoalkoxy group,
R 2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group,
R 13 and R 14 are each independently a hydrogen atom, a halogen atom, a cyano group, or a carboxy group which may be protected with a protecting group for a carboxy group,
R 15 is a hydrogen atom, a halogen atom, an amino group, a carbamoyl group, a carboxy group optionally protected by a protecting group for a carboxy group, or a C1-C6 alkoxycarbonyl group,
A is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group,
The pharmaceutical composition according to (16) to (19) above, wherein Y is —CH 2 — or —C (═O) —.
（３２）一般式（ＩＩ）において、
Ｘ２が－Ｎ＝、Ｘ１、Ｘ３及びＸ４が－Ｃ＝の組み合わせであり、
Ｘ５が、－ＣＨ２ＣＨ２－であり、
Ｘ６が、ともに－ＣＨ２－であり、
Ｘ８及びＸ９が、ともに－ＣＨ＝であり、
Ｒ１が、水素原子、ハロゲン原子、又は、Ｃ１－Ｃ６アルキル基であり、
Ｒ２が、水素原子、Ｃ１－Ｃ６アルキル基、ハロゲン原子、カルボキシ基、又は、カルボニル基であり、
Ｒ１３及びＲ１４が、水素原子、又は、塩素原子であり、
Ｒ１５は、フッ素原子、アミノ基、カルバモイル基、カルボキシ基、又は、エトキシカルボニル基であり、
Ａが、エチルカルバモイル基、プロピルカルバモイル基、ｔｅｒｔ－ブチルカルバモイル基、シクロプロピルカルバモイル基、又は、エチルアミノオキサジアゾリル基であり、
Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、上記（１６）乃至（１９）に記載された医薬組成物。 (32) In the general formula (II),
X 2 is -N =, X 1 , X 3 and X 4 are a combination of -C =,
X 5 is —CH 2 CH 2 —;
X 6 are both —CH 2 —,
X 8 and X 9 are both —CH═,
R 1 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group,
R 2 is a hydrogen atom, a C1-C6 alkyl group, a halogen atom, a carboxy group, or a carbonyl group,
R 13 and R 14 are a hydrogen atom or a chlorine atom,
R 15 is a fluorine atom, an amino group, a carbamoyl group, a carboxy group, or an ethoxycarbonyl group,
A is an ethylcarbamoyl group, a propylcarbamoyl group, a tert-butylcarbamoyl group, a cyclopropylcarbamoyl group, or an ethylaminooxadiazolyl group,
The pharmaceutical composition according to (16) to (19) above, wherein Y is —CH 2 — or —C (═O) —.
（３３）一般式（Ｉ）又は一般式（ＩＩ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物の有効量を哺乳動物に投与することを特徴とする、自己免疫疾患の予防方法又は治療方法。
（３４）自己免疫疾患が、全身性エリトマトーデス、慢性関節リウマチ、多発性筋炎、結合組織炎、骨格筋炎、骨関節炎、変形性関節症、皮膚筋炎、強皮症、ベーチェット病、Chron病、潰瘍性大腸炎、自己免疫性肝炎、再生不良性貧血、特発性血小板減少性紫斑病、自己免疫性溶血性貧血、多発性硬化症、自己免疫性水疱症、尋常性乾癬、血管炎症群、Wegener肉芽腫、ぶどう膜炎、シェーグレン症候群、特発性間質性肺炎、Goodpasture症候群、サルコイドーシス、アレルギー性肉芽腫性血管炎、気管支喘息、心筋炎、心筋症、大動脈炎症候群、心筋梗塞後症候群、原発性肺高血圧症、微小変化型ネフローゼ、膜性腎症、膜性増殖性腎炎、巣状糸球体硬化症、半月体形成性腎炎、重症筋無力症、炎症性ニューロパチー、アトピー性皮膚炎、慢性光線性皮膚炎、日光過敏症、蓐瘡、Sydenham舞踏病、硬化症、成人発症糖尿病、インスリン依存性糖尿病、若年性糖尿病、アテローム性動脈硬化症、糸球体腎炎、IgA腎症、尿細管間質性腎炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、劇症肝炎、ウイルス性肝炎、GVHD、接触皮膚炎、又は敗血症である、上記（３３）に記載された予防方法又は治療方法。 (33) An effective amount of a pharmaceutical composition containing a compound having the general formula (I) or the general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient is administered to a mammal, A method for preventing or treating an immune disease.
(34) Autoimmune diseases are systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative Colitis, autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune bullosa, psoriasis vulgaris, vascular inflammation group, Wegener granulomas , Uveitis, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension Disease, minimal change nephrosis, membranous nephropathy, membranoproliferative nephritis, focal glomerulosclerosis, crescent nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic light Dermatitis, photosensitivity, pressure ulcer, Sydenham chorea, sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis The prophylactic method or therapeutic method according to (33) above, which is primary biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, or sepsis.
（３５）自己免疫疾患が、慢性関節リウマチ、潰瘍性大腸炎、自己免疫性肝炎、多発性硬化症、又は尋常性乾癬である、上記（３３）乃至（３４）に記載された予防方法又は治療方法。
（３６）一般式（Ｉ）又は一般式（ＩＩ）におけるＹが、－ＣＨ２－又はカルボニル基である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（３７）一般式（Ｉ）又は一般式（ＩＩ）におけるＡが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（３８）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ５が、－ＣＨ２－、－ＣＨ２ＣＨ２－又は－Ｏ－である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（３９）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ２が、－Ｎ＝であり、Ｘ１、Ｘ３、及びＸ４が－Ｃ＝である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（４０）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ２及びＸ３が－Ｎ＝であり、Ｘ１及びＸ４が－Ｃ＝である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。 (35) The preventive method or treatment according to (33) to (34) above, wherein the autoimmune disease is rheumatoid arthritis, ulcerative colitis, autoimmune hepatitis, multiple sclerosis, or psoriasis vulgaris Method.
(36) The prevention method or treatment method according to the above (33) to (35), wherein Y in the general formula (I) or the general formula (II) is —CH 2 — or a carbonyl group.
(37) The above (33), wherein A in the general formula (I) or the general formula (II) is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group. ) To (35).
(38) The prevention according to the above (33) to (35), wherein X 5 in the general formula (I) or the general formula (II) is —CH 2 —, —CH 2 CH 2 — or —O—. Method or treatment method.
(39) In the above formulas (33) to (35), X 2 in the general formula (I) or the general formula (II) is —N═, and X 1 , X 3 , and X 4 are —C═. The described preventive or therapeutic method.
(40) In the above formulas (33) to (35), X 2 and X 3 in the general formula (I) or the general formula (II) are —N═, and X 1 and X 4 are —C═. Prophylactic or therapeutic methods.
（４１）一般式（Ｉ）又は一般式（ＩＩ）におけるＸ６及びＸ７がともに、－ＣＨ２－である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（４２）一般式（Ｉ）又は一般式（ＩＩ）におけるＲ１が、水素原子、水酸基、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基、又はＣ１－Ｃ６アルコキシ基である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（４３）一般式（ＩＩ）におけるＸ８及びＸ９がともに－Ｃ＝である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（４４）一般式（ＩＩ）におけるＲ１３及びＲ１４が、それぞれ独立に、水素原子又はハロゲン原子である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（４５）一般式（ＩＩ）におけるＲ１５が、カルバモイル基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。
（４６）一般式（Ｉ）又は一般式（ＩＩ）を有する化合物が、上記（１３）に挙げられた化合物から選択される化合物である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。 (41) The prevention method or the treatment method described in the above (33) to (35), wherein X 6 and X 7 in the general formula (I) or the general formula (II) are both —CH 2 —.
(42) The above, wherein R 1 in the general formula (I) or the general formula (II) is a hydrogen atom, a hydroxyl group, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group (33) The prevention method or the treatment method described in (35).
(43) The prevention method or the treatment method described in the above (33) to (35), wherein X 8 and X 9 in the general formula (II) are both —C═.
(44) The prevention method or the treatment method described in the above (33) to (35), wherein R 13 and R 14 in the general formula (II) are each independently a hydrogen atom or a halogen atom.
(45) The preventive method according to the above (33) to (35), wherein R 15 in the general formula (II) is a carbamoyl group or a carboxy group optionally protected by a protecting group for a carboxy group Method of treatment.
(46) The preventive method according to any one of (33) to (35) above, wherein the compound having the general formula (I) or the general formula (II) is a compound selected from the compounds listed in the above (13) Or a treatment method.
（４７）一般式（ＩＩ）において、
Ｘ２が－Ｎ＝、Ｘ３が－Ｃ＝又は－Ｎ＝、Ｘ１及びＸ４がともに－Ｃ＝の組み合わせであり、
Ｘ５が、－ＣＨ２ＣＨ２－、－ＣＨ２－、又は、－Ｏ－であり、
Ｘ６及びＸ７が、ともに－ＣＨ２－、又は、ともに－Ｃ（＝Ｏ）－であり、
Ｘ８及びＸ９が、共に－ＣＨ＝であるか、又は、Ｘ８が－Ｃ＝であってＸ９が－Ｎ＝の組み合わせであり、
Ｒ１が、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基であり、
Ｒ２が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
Ｒ１３及びＲ１４が、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
Ｒ１５が、水素原子、ハロゲン原子、アミノ基、カルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、又は、Ｃ１－Ｃ６アルコキシカルボニル基であり、
Ａが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基であり、
Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。 (47) In the general formula (II),
X 2 is -N =, X 3 is -C = or -N =, X 1 and X 4 are both -C =
X 5 is —CH 2 CH 2 —, —CH 2 —, or —O—,
X 6 and X 7 are both —CH 2 — or both —C (═O) —;
X 8 and X 9 are both -CH =, or X 8 is -C = and X 9 is -N =
R 1 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a C1-C6 halogenoalkyl group, or A C1-C6 halogenoalkoxy group,
R 2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group,
R 13 and R 14 are each independently a hydrogen atom, a halogen atom, a cyano group, or a carboxy group which may be protected with a protecting group for a carboxy group,
R 15 is a hydrogen atom, a halogen atom, an amino group, a carbamoyl group, a carboxy group optionally protected by a protecting group for a carboxy group, or a C1-C6 alkoxycarbonyl group,
A is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group,
The prevention method or treatment method according to any of (33) to (35) above, wherein Y is —CH 2 — or —C (═O) —.
（４８）一般式（ＩＩ）において、
Ｘ２が－Ｎ＝、Ｘ１、Ｘ３及びＸ４が－Ｃ＝の組み合わせであり、
Ｘ５が、－ＣＨ２ＣＨ２－であり、
Ｘ６が、ともに－ＣＨ２－であり、
Ｘ８及びＸ９が、ともに－ＣＨ＝であり、
Ｒ１が、水素原子、ハロゲン原子、又は、Ｃ１－Ｃ６アルキル基であり、
Ｒ２が、水素原子、Ｃ１－Ｃ６アルキル基、ハロゲン原子、カルボキシ基、又は、カルボニル基であり、
Ｒ１３及びＲ１４が、水素原子、又は、塩素原子であり、
Ｒ１５は、フッ素原子、アミノ基、カルバモイル基、カルボキシ基、又は、エトキシカルボニル基であり、
Ａが、エチルカルバモイル基、プロピルカルバモイル基、ｔｅｒｔ－ブチルカルバモイル基、シクロプロピルカルバモイル基、又は、エチルアミノオキサジアゾリル基であり、
Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、上記（３３）乃至（３５）に記載された予防方法又は治療方法。 (48) In the general formula (II),
X 2 is -N =, X 1 , X 3 and X 4 are a combination of -C =,
X 5 is —CH 2 CH 2 —;
X 6 are both —CH 2 —,
X 8 and X 9 are both —CH═,
R 1 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group,
R 2 is a hydrogen atom, a C1-C6 alkyl group, a halogen atom, a carboxy group, or a carbonyl group,
R 13 and R 14 are a hydrogen atom or a chlorine atom,
R 15 is a fluorine atom, an amino group, a carbamoyl group, a carboxy group, or an ethoxycarbonyl group,
A is an ethylcarbamoyl group, a propylcarbamoyl group, a tert-butylcarbamoyl group, a cyclopropylcarbamoyl group, or an ethylaminooxadiazolyl group,
The prevention method or treatment method according to any of (33) to (35) above, wherein Y is —CH 2 — or —C (═O) —.
　本発明の化合物又はその薬理上許容される塩は、毒性が低く優れた免疫抑制作用を有し、温血動物（特に、ヒト）に対する自己免疫疾患又はその他免疫関連疾患の予防剤若しくは治療剤として有用である。 The compound of the present invention or a pharmacologically acceptable salt thereof has an excellent immunosuppressive action with low toxicity, and is used as a prophylactic or therapeutic agent for autoimmune diseases or other immune-related diseases against warm-blooded animals (particularly humans). Useful.
　以下に本明細書中の置換基について説明する。 The substituents in this specification will be described below.
　ハロゲン原子とは、例えば、フッ素原子、塩素原子、臭素原子、又は、ヨウ素原子である。好適には、フッ素原子、又は、塩素原子である。
　Ｃ１－Ｃ２０アルキル基とは、直鎖であっても分枝鎖であってもよく、鎖中に１乃至２０個の炭素原子を含む、脂肪族炭化水素基を意味する。好適にはアルキル基は鎖中に１乃至６個の炭素原子を含む。より好適には鎖中に１乃至３個の炭素原子を含む。分枝とは、１個以上の低級アルキル基（例えば、メチル基、エチル基又はプロピル基）が、直鎖アルキル鎖に結合していることを意味する。
　Ｃ１－Ｃ６アルキル基とは、上記Ｃ１－Ｃ２０アルキル基のうち、炭素数１乃至６個のである。具体的には、メチル基、エチル基、プロピル基、イソプロピル基、ｔｅｒｔ－ブチル基、ペンチル基、ヘキシル基等である。好適には、メチル基、エチル基、プロピル基、イソプロピル基、又は、ｔｅｒｔ－ブチル基であり、さらに好適には、メチル基、又は、エチル基であり、特に好適には、エチル基である。 The halogen atom is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferable is a fluorine atom or a chlorine atom.
The C1-C20 alkyl group means an aliphatic hydrocarbon group which may be linear or branched and contains 1 to 20 carbon atoms in the chain. Preferably the alkyl group contains 1 to 6 carbon atoms in the chain. More preferably it contains 1 to 3 carbon atoms in the chain. Branching means that one or more lower alkyl groups (for example, a methyl group, an ethyl group, or a propyl group) are bonded to a linear alkyl chain.
The C1-C6 alkyl group is a C1-C20 alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a tert-butyl group, a pentyl group, and a hexyl group. A methyl group, an ethyl group, a propyl group, an isopropyl group, or a tert-butyl group is preferable, a methyl group or an ethyl group is more preferable, and an ethyl group is particularly preferable.
　Ｃ１－Ｃ２０アルコキシ基とは、上記アルキル基に酸素原子が結合した、アルキル－Ｏ基を意味し、鎖中に１乃至２０個の炭素原子を含む。好適には、炭素数１乃至６個である。より好適には、炭素数１乃至３個である。アルコキシ基の具体例としては、メトキシ、エトキシ、ｎ－プロポキシ、イソプロポキシ、ｎ－ブトキシ、ヘプトキシおよびメチルヒドロキシ等が挙げられる。
　Ｃ１－Ｃ６アルコキシ基とは、上記Ｃ１－Ｃ２０アルコキシ基のうち、鎖中に１乃至６個の炭素原子を含む基であり、好適には、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、又は、ｔ－ブトキシ基であり、さらに好適には、メトキシ基である。 The C1-C20 alkoxy group means an alkyl-O group in which an oxygen atom is bonded to the alkyl group, and contains 1 to 20 carbon atoms in the chain. Preferably, it has 1 to 6 carbon atoms. More preferably, it has 1 to 3 carbon atoms. Specific examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy.
The C1-C6 alkoxy group is a group containing 1 to 6 carbon atoms in the chain among the C1-C20 alkoxy groups, and preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Alternatively, it is a t-butoxy group, and more preferably a methoxy group.
　Ｃ３－Ｃ１０シクロアルキル基とは、３乃至１０個の炭素原子を含む、非芳香族の単環式環系または多環式環系を意味する。好適には、シクロアルキル環は、３乃至６個の環原子を含む。単環式シクロアルキルの具体例としては、シクロプロピル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基等が挙げられる。多環式シクロアルキルの具体例としては、１－デカリン基、ノルボルニル基、アダマンチル基等が挙げられる。
　Ｃ３－Ｃ６シクロアルキル基とは、上記Ｃ３－Ｃ１０シクロアルキル基のうち、３乃至6個炭素原子を含む環状アルキル基であり、好適には、シクロプロピル基、シクロブチル基、シクロペンチル基、又は、シクロヘキシル基であり、さらに好適には、シクロプロピル基である。 A C3-C10 cycloalkyl group means a non-aromatic monocyclic or polycyclic ring system containing 3 to 10 carbon atoms. Suitably, the cycloalkyl ring contains 3 to 6 ring atoms. Specific examples of monocyclic cycloalkyl include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Specific examples of polycyclic cycloalkyl include 1-decalin group, norbornyl group, adamantyl group and the like.
The C3-C6 cycloalkyl group is a cyclic alkyl group containing 3 to 6 carbon atoms in the C3-C10 cycloalkyl group, and is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. Group, more preferably a cyclopropyl group.
　Ｃ３－Ｃ１０シクロアルコキシ基とは、３乃至１０個の炭素原子を含む、上記Ｃ３－Ｃ１０シクロアルキル基に酸素原子が結合した基を意味する。好適には、シクロアルコキシ基は、３乃至６個の環原子を含む。単環式シクロアルコキシ基の具体例としては、シクロプロポキシ基、シクロブトキシ基、シクロペントキシ基、シクロヘキソキシ基、シクロヘプトキシ基等が挙げられる。多環式シクロアルキルの具体例としては、１－デカリン基、ノルボルニル基、アダマンチル基等が挙げられる。
　Ｃ３－Ｃ６シクロアルコキシ基とは、上記シクロアルコキシ基のうち、３乃至6個炭素原子を含む環状アルコキシ基であり、例えば、シクロプロポキシ基、シクロブトキシ基、シクロペントキシ基、又は、シクロヘキソキシ基である。好適には、シクロプロポキシ基、又は、シクロブトキシ基であり、より好適には、シクロプロポキシ基である。 The C3-C10 cycloalkoxy group means a group having 3 to 10 carbon atoms, in which an oxygen atom is bonded to the C3-C10 cycloalkyl group. Suitably, the cycloalkoxy group contains 3 to 6 ring atoms. Specific examples of the monocyclic cycloalkoxy group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a cyclohexoxy group, a cycloheptoxy group, and the like. Specific examples of polycyclic cycloalkyl include 1-decalin group, norbornyl group, adamantyl group and the like.
C3-C6 cycloalkoxy group is a cyclic alkoxy group containing 3 to 6 carbon atoms among the above cycloalkoxy groups, for example, a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, or a cyclohexoxy group It is. Preferred is a cyclopropoxy group or a cyclobutoxy group, and more preferred is a cyclopropoxy group.
　Ｃ１－Ｃ２０ハロゲノアルキル基とは、炭素数１乃至20個のアルキル基にハロゲン原子が置換した基であり、好適には、フッ素原子、又は臭素原子が置換した炭素数1乃至６の基であり、さらに好適には、フッ素原子が置換した炭素数1乃至６個の基である。特に好適には、フッ素原子が置換した炭素数１乃至３個の基である。
　Ｃ１－Ｃ６ハロゲノアルキル基とは、上記ハロゲノアルキル基のうち、炭素数１乃至６個の基である。具体的には、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、フルオロエチル基、ジフルオロエチル基、トリフルオロエチル基等であり、好適には、フルオロメチル基、ジフルオロメチル基、又は、トリフルオロメチル基であり、さらに好適には、トリフルオロメチル基である。 The C1-C20 halogenoalkyl group is a group in which a halogen atom is substituted on an alkyl group having 1 to 20 carbon atoms, preferably a group having 1 to 6 carbon atoms in which a fluorine atom or a bromine atom is substituted. More preferably, it is a group having 1 to 6 carbon atoms substituted with a fluorine atom. Particularly preferred is a group having 1 to 3 carbon atoms substituted with a fluorine atom.
The C1-C6 halogenoalkyl group is a group having 1 to 6 carbon atoms among the above halogenoalkyl groups. Specifically, it is a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, etc., preferably a fluoromethyl group, a difluoromethyl group, or trifluoro A methyl group, and more preferably a trifluoromethyl group.
　Ｃ１－Ｃ２０ハロゲノアルコキシ基とは、上記Ｃ１－Ｃ２０ハロゲノアルキル基に酸素原子が結合した基であり、好適には、フッ素原子、又は臭素原子が置換した炭素数1乃至６の基であり、さらに好適には、フッ素原子が置換した炭素数1乃至６個の基である。特に好適には、フッ素原子が置換した炭素数１乃至３個の基である。
　Ｃ１－Ｃ６ハロゲノアルコキシ基とは、上記Ｃ１－Ｃ２０ハロゲノアルコキシ基のうち、炭素数１乃至６個の基である。具体的には、フルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基、フルオロエトキシ基、ジフルオロエトキシ基、トリフルオロエトキシ基等であり、好適には、トリフルオロメトキシ基である。 The C1-C20 halogenoalkoxy group is a group in which an oxygen atom is bonded to the C1-C20 halogenoalkyl group, preferably a fluorine atom or a group having 1 to 6 carbon atoms substituted by a bromine atom, Preferred is a group having 1 to 6 carbon atoms substituted with a fluorine atom. Particularly preferred is a group having 1 to 3 carbon atoms substituted with a fluorine atom.
The C1-C6 halogenoalkoxy group is a group having 1 to 6 carbon atoms in the C1-C20 halogenoalkoxy group. Specific examples include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a fluoroethoxy group, a difluoroethoxy group, and a trifluoroethoxy group, and a trifluoromethoxy group is preferable.
　Ｃ１－Ｃ６アルキルアミノ基とは、上記Ｃ１－Ｃ６アルキル基にアミノ基が結合した基である。具体的には、メチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基、ｔｅｒｔ－ブチルアミノ基、ペンチルアミノ基、ヘキシルアミノ基等である。好適には、炭素数が１乃至３個のＣ１－Ｃ３アルキルアミノ基であり、さらに好適には、メチル基、又は、エチル基であり、特に好適には、エチル基である。
　Ｃ３－Ｃ６シクロアルキルアミノ基とは、上記Ｃ３－Ｃ６シクロアルキル基にアミノ基が結合した基である。具体的には、シクロプロピルアミノ基、シクロブチルアミノ基、シクロペンチルアミノ基、シクロヘキシルアミノ基等である。好適には、炭素数３乃至４個のシクロアルキルアミノ基であり、さらに好適には、シクロプロピルアミノ基である。
　Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基とは、上記Ｃ１－Ｃ６アルキルアミノ基にオキサジアゾリル基が結合した基である。具体的には、メチルアミノオキサジアゾリル基、エチルアミノオキサジアゾリル基、プロピルアミノオキサジアゾリル基、イソプロピルアミノオキサジアゾリル基、ｔｅｒｔ－ブチルアミノオキサジアゾリル基、ペンチルアミノオキサジアゾリル基、ヘキシルアミノオキサジアゾリル基等である。好適には、炭素数1乃至３個のＣ１－Ｃ３アルキルアミノオキサジアゾリル基であり、さらに好適には、メチルアミノオキサジアゾリル基、又は、エチルアミノオキサジアゾリル基であり、特に好適には、エチルアミノオキサジアゾリル基である。
　Ｃ１－Ｃ６アルキルカルバモイル基とは、上記Ｃ１－Ｃ６アルキル基にカルバモイル基が結合した基であり、具体的には、メチルカルバモイル基、エチルカルバモイル基、プロピルカルバモイル基、イソプロピルカルバモイル基、又は、ｔｅｒｔ－ブチルカルバモイル基等である。好適には、炭素数１乃至３個の基であり、さらに好適には、エチルカルバモイル基、又は、イソプロピルカルバモイル基である。
　Ｃ１－Ｃ６ヒドロキシアルキルカルバモイル基とは、上記Ｃ１－Ｃ６アルキルカルバモイル基にヒドロキシ基が置換した基であり、具体的には、ヒドロキシメチルカルバモイル基、１－ヒドロキシエチルカルバモイル基、２－ヒドロキシエチルカルバモイル基、１－ヒドロキシプロピルカルバモイル基、２－ヒドロキシプロピルカルバモイル基、又は、３－ヒドロキシプロピルカルバモイル基等である。好適には炭素数１乃至３個の基であり、さらに好適には、ヒドロキシメチルカルバモイル基、２－ヒドロキシエチルカルバモイル基、又は、３－ヒドロキシプロピルカルバモイル基であり、特に好適には、２－ヒドロキシエチルカルバモイル基である。 The C1-C6 alkylamino group is a group in which an amino group is bonded to the C1-C6 alkyl group. Specific examples include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a tert-butylamino group, a pentylamino group, and a hexylamino group. A C1-C3 alkylamino group having 1 to 3 carbon atoms is preferable, a methyl group or an ethyl group is more preferable, and an ethyl group is particularly preferable.
The C3-C6 cycloalkylamino group is a group in which an amino group is bonded to the C3-C6 cycloalkyl group. Specific examples include a cyclopropylamino group, a cyclobutylamino group, a cyclopentylamino group, and a cyclohexylamino group. Preferred is a cycloalkylamino group having 3 to 4 carbon atoms, and more preferred is a cyclopropylamino group.
The C1-C6 alkylaminooxadiazolyl group is a group in which an oxadiazolyl group is bonded to the C1-C6 alkylamino group. Specifically, methylaminooxadiazolyl group, ethylaminooxadiazolyl group, propylaminooxadiazolyl group, isopropylaminooxadiazolyl group, tert-butylaminooxadiazolyl group, pentylaminooxadiazolyl group, hexyl An aminooxadiazolyl group and the like; Preferred is a C1-C3 alkylaminooxadiazolyl group having 1 to 3 carbon atoms, more preferred is a methylaminooxadiazolyl group or ethylaminooxadiazolyl group, and particularly preferred. , An ethylaminooxadiazolyl group.
The C1-C6 alkylcarbamoyl group is a group in which a carbamoyl group is bonded to the C1-C6 alkyl group. Specifically, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, or a tert- And a butylcarbamoyl group. A group having 1 to 3 carbon atoms is preferable, and an ethylcarbamoyl group or an isopropylcarbamoyl group is more preferable.
The C1-C6 hydroxyalkylcarbamoyl group is a group in which a hydroxy group is substituted on the C1-C6 alkylcarbamoyl group, and specifically includes a hydroxymethylcarbamoyl group, a 1-hydroxyethylcarbamoyl group, a 2-hydroxyethylcarbamoyl group. 1-hydroxypropylcarbamoyl group, 2-hydroxypropylcarbamoyl group, 3-hydroxypropylcarbamoyl group, and the like. Preferred is a group having 1 to 3 carbon atoms, more preferred is a hydroxymethylcarbamoyl group, 2-hydroxyethylcarbamoyl group or 3-hydroxypropylcarbamoyl group, and particularly preferred is 2-hydroxy An ethylcarbamoyl group.
　Ｃ３－Ｃ６シクロアルキルカルバモイル基とは、上記Ｃ３－Ｃ６シクロアルキル基にカルバモイル基が結合した基であり、例えば、シクロプロピルカルバモイル基、シクロブチルカルバモイル基、シクロペンチルカルバモイル基、又は、シクロヘキシルカルバモイル基等であり、好適には、シクロプロピルカルバモイル基である。
　Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルカルバモイル基とは、上記Ｃ３－Ｃ６シクロアルキル基に上記Ｃ１－Ｃ６アルキルカルバモイル基が結合した基であり、例えば、シクロプロピルメチルカルバモイル基、シクロプロピルエチルカルバモイル基、又は、シクロプロピルプロピルカルバモイル基等であり、好適には、シクロプロピルメチルカルバモイル基である。 The C3-C6 cycloalkyl carbamoyl group is a group in which a carbamoyl group is bonded to the above C3-C6 cycloalkyl group. And preferred is a cyclopropylcarbamoyl group.
The C3-C6 cycloalkyl-C1-C6 alkylcarbamoyl group is a group in which the C1-C6 alkylcarbamoyl group is bonded to the C3-C6 cycloalkyl group. For example, a cyclopropylmethylcarbamoyl group, a cyclopropylethylcarbamoyl group Or a cyclopropylpropylcarbamoyl group and the like, and preferably a cyclopropylmethylcarbamoyl group.
　Ｃ１－Ｃ６アルキルスルホニル基とは、上記Ｃ１－Ｃ６アルキル基にスルホニル基が結合した基であり、好適には、炭素数１乃至３のアルキルスルホニル基である。Ｃ１－Ｃ６アルキルスルホニル基の具体例は、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、イソプロピルスルホニル基、又は、ｔｅｒｔ－ブチルスルホニル基、ペンチルスルホニル基、ヘキシルスルホニル基等であり、好適には、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、イソプロピルスルホニル基、又は、ｔｅｒｔ－ブチルスルホニル基である。さらに好適には、エチルスルホニル基である。 The C1-C6 alkylsulfonyl group is a group in which a sulfonyl group is bonded to the C1-C6 alkyl group, and is preferably an alkylsulfonyl group having 1 to 3 carbon atoms. Specific examples of the C1-C6 alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, or a tert-butylsulfonyl group, a pentylsulfonyl group, a hexylsulfonyl group, and the like. A methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, or a tert-butylsulfonyl group; More preferably, it is an ethylsulfonyl group.
　Ｃ１－Ｃ６アルキルスルホンアミド基とは、上記Ｃ１－Ｃ６アルキル基にスルホンアミド基が結合した基であり、好適には、炭素数１乃至３個のアルキルスルホンアミド基である。Ｃ１－Ｃ６アルキルスルホンアミド基の具体例は、メチルスルホンアミド基、エチルスルホンアミド基、プロピルスルホンアミド基、イソプロピルスルホンアミド基、ブチルスルホンアミド基、ｔｅｒｔ－ブチルスルホンアミド基、ペンチルスルホンアミド基、又は、ヘキシルスルホンアミド基等であり、好適には、メチルスルホンアミド基、エチルスルホンアミド基、又は、プロピルスルホンアミド基である。
　Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルスルホニル基とは、上記Ｃ３－Ｃ６シクロアルキル基に上記Ｃ１－Ｃ６アルキルスルホニル基が結合した基であり、例えば、シクロプロピルメチルスルホニル基、シクロプロピルエチルスルホニル基、シクロブチルメチルスルホニル基、シクロペンチルメチルスルホニル基、又は、シクロヘキシルメチルスルホニル基等であり、好適には、シクロプロピルメチルスルホニル基である。 The C1-C6 alkylsulfonamido group is a group in which a sulfonamido group is bonded to the C1-C6 alkyl group, and preferably an alkylsulfonamido group having 1 to 3 carbon atoms. Specific examples of the C1-C6 alkylsulfonamide group include a methylsulfonamide group, an ethylsulfonamide group, a propylsulfonamide group, an isopropylsulfonamide group, a butylsulfonamide group, a tert-butylsulfonamide group, a pentylsulfonamide group, or Hexylsulfonamido group, etc., preferably methylsulfonamido group, ethylsulfonamido group, or propylsulfonamido group.
The C3-C6 cycloalkyl-C1-C6 alkylsulfonyl group is a group in which the C1-C6 alkylsulfonyl group is bonded to the C3-C6 cycloalkyl group, such as a cyclopropylmethylsulfonyl group, a cyclopropylethylsulfonyl group. , A cyclobutylmethylsulfonyl group, a cyclopentylmethylsulfonyl group, a cyclohexylmethylsulfonyl group, and the like, and preferably a cyclopropylmethylsulfonyl group.
　Ｃ１－Ｃ６アシルアミノ基とは、水素原子、又は、飽和若しくは不飽和の炭素数1乃至６の鎖状、分岐、若しくは環状炭化水素基がカルボニル基に結合したＣ１－Ｃ６アシル基に、アミノ基が結合した基である。好適には、炭素数４乃至６個のアシルアミノ基であり、更に好適には、炭素数４個のアシルアミノ基である。Ｃ１－Ｃ６アシルアミノ基の具体例は、ホルミルアミノ基、アセチルアミノ基、プロピオニルアミノ基、ブチリルアミノ基、イソブチリルアミノ基、バレリルアミノ基、イソバレリルアミノ基、シクロプロピオニルアミノ基、シクロブチリルアミノ基、又は、シクロペンタノイルアミノ基等を挙げることができ、好適には、アセチルアミノ基、シクロプロピオニルアミノ基、シクロブチリルアミノ基、又は、シクロペンタノイルアミノ基であり、さらに好適には、アセチルアミノ基、又はシクロプロピオニルアミノ基である。 The C1-C6 acylamino group is a hydrogen atom or a C1-C6 acyl group in which a saturated or unsaturated C1-C6 linear, branched, or cyclic hydrocarbon group is bonded to a carbonyl group. It is a bonded group. An acylamino group having 4 to 6 carbon atoms is preferable, and an acylamino group having 4 carbon atoms is more preferable. Specific examples of the C1-C6 acylamino group include formylamino group, acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, cyclopropionylamino group, cyclobutyrylamino group Or a cyclopentanoylamino group, preferably an acetylamino group, a cyclopropionylamino group, a cyclobutyrylamino group, or a cyclopentanoylamino group, and more preferably an acetylamino group An amino group or a cyclopropionylamino group.
　５～１４員環ヘテロアリール基とは、５個乃至１４個の環原子、好適には、５個乃至６個の環原子を含み、これらの環原子のうちの１つ以上が、単独または組み合わせで、炭素以外の元素（例えば、窒素、酸素または硫黄）である、芳香族の単環式環系または多環式環系を意味する。さらに好適なヘテロアリール基は、５個の環原子を含む。ヘテロアリール基の語幹名の前の接頭語アザ、オキサまたはチアは、それぞれ、少なくとも１つの窒素原子、酸素原子または硫黄原子が、環原子として存在することを意味する。ヘテロアリール基の窒素原子または硫黄原子は、対応するＮ－オキシド、Ｓ－オキシドまたはＳ，Ｓ－ジオキシドに、必要に応じて酸化され得る。ヘテロアリールの具体例としては、ピリジル基、ピラジニル基、フラニル基、チエニル基、ピリミジニル基、イソオキサゾリル基、イソチアゾリル基、オキサゾリル基、チアゾリル基、ピラゾリル基、フラザニル基、ピロリル基、ピラゾリル基、トリアゾリル基、１，２，４－チアジアゾリル基、ピリダジニル基、キノキサリニル基、フタラジニル基、イミダゾ［１，２－ａ］ピリジニル基、イミダゾ［２，１－ｂ］チアゾリル基、ベンゾフラザニル基、インドリル基、アザインドリル基、ベンゾイミダゾリル基、ベンゾチエニル基、キノリニル基、イミダゾリル基、チエノピリジル基、キナゾリニル基、チエノピリミジル基、ピロロピリジル基、イミダゾピリジル基、イソキノリニル基、ベンゾアザインドリル基、１，２，４－トリアジニル基、ベンゾチアゾリル基等が挙げられる。 A 5- to 14-membered heteroaryl group includes 5 to 14 ring atoms, preferably 5 to 6 ring atoms, and one or more of these ring atoms may be used alone or in combination. And means an aromatic monocyclic or polycyclic ring system that is an element other than carbon (eg, nitrogen, oxygen or sulfur). Further preferred heteroaryl groups contain 5 ring atoms. The prefix aza, oxa or thia before the heteroaryl group root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heteroaryl group can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Specific examples of heteroaryl include pyridyl group, pyrazinyl group, furanyl group, thienyl group, pyrimidinyl group, isoxazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, pyrazolyl group, furazanyl group, pyrrolyl group, pyrazolyl group, triazolyl group, 1,2,4-thiadiazolyl group, pyridazinyl group, quinoxalinyl group, phthalazinyl group, imidazo [1,2-a] pyridinyl group, imidazo [2,1-b] thiazolyl group, benzofurazanyl group, indolyl group, azaindolyl group, benzoimidazolyl Group, benzothienyl group, quinolinyl group, imidazolyl group, thienopyridyl group, quinazolinyl group, thienopyrimidyl group, pyrrolopyridyl group, imidazolopyridyl group, isoquinolinyl group, benzoazaindolyl group, 1,2,4-triazini Group, benzothiazolyl group and the like.
　５員環へテロアリール基とは、上記５～１４員環ヘテロアリール基のうち、環構成原子５個の基であり、例えば、イミダゾリル基、ピロリル基、トリアゾリル基、テトラゾリル基、チエニル基、フリル基、チアゾリル基、ピラゾリル基、イソチアゾリル基、オキサゾリル基、イソオキサゾリル基、チアジアゾリル基、又は、オキサジアゾリル基等を挙げることができる。好適には、イミダゾリル基、ピロリル基、トリアゾリル基、テトラゾリル基、オキサジアゾリル基であり、さらに好適には、オキサジアゾリル基である。 The 5-membered heteroaryl group is a group having 5 ring atoms among the 5- to 14-membered heteroaryl groups described above, for example, an imidazolyl group, a pyrrolyl group, a triazolyl group, a tetrazolyl group, a thienyl group, a furyl group. , Thiazolyl group, pyrazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, or oxadiazolyl group. Preferred are imidazolyl group, pyrrolyl group, triazolyl group, tetrazolyl group and oxadiazolyl group, and more preferred is oxadiazolyl group.
　カルボキシ基の保護基とは、例えば、グリーン（Ｇｒｅｅｎｅ）、ウッツ（Ｗｕｔｓ）らによるプロテクティブ・グループ・イン・オーガニック・シンセシス（Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ）第４版、第５３３－６４６頁、２００６年、ジョン・ワイリー・アンド・サンズ社（Ｊｏｈｎ　Ｗｉｌｅｙ　＆　Ｓｏｎｓ，　Ｉｎｃ．）に記載されている保護基を挙げることができ、具体的には、Ｃ１－Ｃ６アルキル基、アリル基、ベンジル基、ジフェニルメチル基、トリチル基、トリメチルシリル基、ｔｅｒｔ－ブチルジメチルシリル基等を挙げることができ、好適には、Ｃ１－Ｃ６アルキル基であり、より好適には、メチル基、又は、エチル基である。
　カルボキシ基の保護基で保護されていてもよいカルボキシ基とは、置換されていないカルボキシ基に加えて、Ｃ１－Ｃ６アルキル基、アリル基、ベンジル基、ジフェニルメチル基、トリチル基、トリメチルシリル基、及びｔｅｒｔ－ブチルジメチルシリル基から選択される基で置換されているカルボキシ基を挙げることができ、好適には、カルボキシ基、又は、Ｃ１－Ｃ６アルキル基で置換されたカルボキシ基であり、さらに好適には、カルボキシ基、メトキシカルボニル基、又は、エトキシカルボニル基である。
　Ｃ１－Ｃ２０アルコキシカルボニル基とは、上記Ｃ１－２０アルコキシ基にカルボニル基が結合した基であり、好適には、炭素数１乃至６個のアルコキシカルボニル基であり、さらに好適には、炭素数１乃至３個のアルコキシカルボニル基である。具体的には、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、又は、ｔ－ブトキシカルボニル基等である。
　Ｃ１－Ｃ６アルコキシカルボニル基とは、上記Ｃ１－Ｃ２０アルコキシカルボニル基のうち、炭素数１乃至６個の基であり、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、又は、ｔ－ブトキシカルボニル基等であり、好適には、メトキシカルボニル基、エトキシカルボニル基、又は、プロポキシアルボニル基であり、さらに好適には、メトキシカルボニル基、又は、エトキシカルボニル基である。 Examples of the protecting group for carboxy group include Protective Groups in Organic Synthesis, 4th Edition, 533-646, 2006 by Greene, Wuts et al. Protecting groups described in John Wiley & Sons, Inc. can be mentioned, and specific examples include C1-C6 alkyl group, allyl group, benzyl group, diphenylmethyl group. , A trityl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, and the like. A C1-C6 alkyl group is preferable, and a methyl group or an ethyl group is more preferable.
The carboxy group which may be protected with a protecting group for carboxy group includes, in addition to an unsubstituted carboxy group, a C1-C6 alkyl group, an allyl group, a benzyl group, a diphenylmethyl group, a trityl group, a trimethylsilyl group, and Examples thereof include a carboxy group substituted with a group selected from tert-butyldimethylsilyl group, preferably a carboxy group or a carboxy group substituted with a C1-C6 alkyl group, and more preferably Is a carboxy group, a methoxycarbonyl group, or an ethoxycarbonyl group.
The C1-C20 alkoxycarbonyl group is a group in which a carbonyl group is bonded to the C1-20 alkoxy group, preferably an alkoxycarbonyl group having 1 to 6 carbon atoms, and more preferably 1 carbon atom. To 3 alkoxycarbonyl groups. Specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group, or the like.
The C1-C6 alkoxycarbonyl group is a group having 1 to 6 carbon atoms among the above C1-C20 alkoxycarbonyl groups, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, or , T-butoxycarbonyl group, etc., preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group, and more preferably a methoxycarbonyl group or an ethoxycarbonyl group.
　Ｃ１－Ｃ６ヒドロキシアルコキシカルボニル基とは、上記Ｃ１－Ｃ６アルコキシカルボニル基にヒドロキシ基が結合した基であり、好適には、炭素数１乃至３個の基である。Ｃ１－Ｃ６ヒドロキシアルコキシカルボニル基の具体例は、ヒドロキシメトキシカルボニル基、２－ヒドロキシエトキシカルボニル基、３－ヒドロキシプロポキシカルボニル基、ヒドロキシイソプロポキシカルボニル基、４－ヒドロキシブトキシカルボニル基、又は、ヒドロキシ－ｔ－ブトキシカルボニル基等を挙げることができ、好適にはヒドロキシメトキシカルボニル基、２－ヒドロキシエトキシカルボニル基、又は、３－ヒドロキシプロポキシカルボニル基である。 The C1-C6 hydroxyalkoxycarbonyl group is a group in which a hydroxy group is bonded to the C1-C6 alkoxycarbonyl group, and preferably a group having 1 to 3 carbon atoms. Specific examples of the C1-C6 hydroxyalkoxycarbonyl group include a hydroxymethoxycarbonyl group, a 2-hydroxyethoxycarbonyl group, a 3-hydroxypropoxycarbonyl group, a hydroxyisopropoxycarbonyl group, a 4-hydroxybutoxycarbonyl group, or a hydroxy-t- A butoxycarbonyl group and the like can be mentioned, and a hydroxymethoxycarbonyl group, a 2-hydroxyethoxycarbonyl group, or a 3-hydroxypropoxycarbonyl group is preferable.
　Ｃ１－Ｃ６ヒドロキサメート基とは、Ｃ１－Ｃ６アルキル－Ｃ（＝Ｏ）ＮＨ－Ｏ－基を意味する。親部分への結合は、酸素基を介する。好適には、アルキル部分の炭素数は１乃至３である。Ｃ１－Ｃ６ヒドロキサメート基の具体例は、アセチル－ＮＨ－Ｏ－基、プロピオニル－ＮＨ－Ｏ－基、ブチリル－ＮＨ－Ｏ－基、イソブチリル－ＮＨ－Ｏ－基、バレリル－ＮＨ－Ｏ－基、又は、イソバレリル－ＮＨ－Ｏ－基等である。好適には、アセチル－ＮＨ－Ｏ－基、又は、プロピオニル－ＮＨ－Ｏ－基である。
　アミジニル基とは、－Ｃ（＝ＮＲ）ＮＨＲ基を意味する。Ｒ基は、Ｈ、アルキル、アルキルアリール、ヘテロアリール、ヒドロキシル、アルコキシ、アミノ、エステル、ＣＮ、－ＮＨＳＯ２アルキル、－ＮＨＳＯ２アリール、－ＮＨＣ（＝Ｏ）ＮＨアルキル、および－ＮＨアルキルとして定義される。親部分への結合は、炭素を介する。 A C1-C6 hydroxamate group means a C1-C6 alkyl-C (═O) NH—O— group. The bond to the parent moiety is through the oxygen group. Preferably, the alkyl moiety has 1 to 3 carbon atoms. Specific examples of the C1-C6 hydroxamate group include acetyl-NH—O— group, propionyl-NH—O— group, butyryl-NH—O— group, isobutyryl-NH—O— group, valeryl-NH—O— group. Group, or isovaleryl-NH-O- group. An acetyl-NH—O— group or a propionyl-NH—O— group is preferable.
An amidinyl group means a —C (═NR) NHR group. R groups are defined as H, alkyl, alkylaryl, heteroaryl, hydroxyl, alkoxy, amino, ester, CN, —NHSO 2 alkyl, —NHSO 2 aryl, —NHC (═O) NHalkyl, and —NHalkyl. The The bond to the parent moiety is through the carbon.
　３～１０員環ヘテロシクレニル基とは、３乃至１０個の環原子、好適には、５乃至１０個の環原子を含み、これらの環原子のうちの１つ以上は、単独または組み合わせで、炭素以外の元素（例えば、窒素、酸素または硫黄原子）であり、少なくとも１つの炭素－炭素二重結合または炭素－窒素二重結合を含む、単環式又は多環式の非芳香族環である。隣接する酸素原子および／または硫黄原子は、この環系に存在しない。ヘテロシクレニルの語幹名の前の接頭語アザ、オキサまたはチアは、それぞれ、少なくとも窒素原子、酸素原子または硫黄原子が、環原子として存在することを意味する。ヘテロシクレニルの窒素原子または硫黄原子は、対応するＮ－オキシド、Ｓ－オキシドまたはＳ，Ｓ－ジオキシドに、酸化されていてもよい。単環式アザへテロシクレニル基の具体例としては、１，２，３，４－テトラヒドロピリジン、１，２－ジヒドロピリジル、１，４－ジヒドロピリジル、１，２，３，６－テトラヒドロピリミジン、ジヒドロ－２－ピロリニル、ジヒドロ－３－ピロリニル、ジヒドロ－２－イミダゾリニル、ジヒドロ－２－ピラゾリニル、ジヒドロ－４，５－トリゾリル等が挙げられる。オキサへテロシクレニル基の具体例としては、３，４－ジヒドロ－２Ｈ－ピラン、ジヒドロフラニル、フルオロジヒドロフラニル等が挙げられる。多環式オキサへテロシクレニル基の具体例は、７－オキサビシクロ［２．２．１］ヘプテニル基である。単環式チアへテロシクレニル環の具体例としては、ジヒドロチオフェニル、ジヒドロチオピラニル等が挙げられる。 A 3- to 10-membered heterocyclenyl group includes 3 to 10 ring atoms, preferably 5 to 10 ring atoms, one or more of these ring atoms, alone or in combination, Non-aromatic rings that are monocyclic or polycyclic and contain at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms present in the ring system. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heterocyclenyl may be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Specific examples of the monocyclic azaheterocyclenyl group include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyrimidine, dihydro Examples include -2-pyrrolinyl, dihydro-3-pyrrolinyl, dihydro-2-imidazolinyl, dihydro-2-pyrazolinyl, dihydro-4,5-trizolyl and the like. Specific examples of the oxaheterocyclenyl group include 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl and the like. A specific example of a polycyclic oxaheterocyclenyl group is a 7-oxabicyclo [2.2.1] heptenyl group. Specific examples of the monocyclic thiaheterocyclenyl ring include dihydrothiophenyl and dihydrothiopyranyl.
　３－１０員環ヘテロシクリル基とは、３乃至１０個の環原子、好ましくは、５乃至１０個の環原子を含み、この環系の原子のうちの１つ以上が、単独または組み合わせで、炭素以外の元素（例えば、窒素、酸素または硫黄）である、非芳香族の飽和単環式環系または飽和多環式環系を意味する。隣接する酸素原子および／または硫黄原子は、この環系に存在しない。好適なヘテロシクリルは、約５個～約６個の環原子を含む。ヘテロシクリルの語幹名の前の接頭語アザ、オキサまたはチアは、それぞれ、少なくとも窒素原子、酸素原子または硫黄原子が、環原子として存在することを意味する。ヘテロシクリルの窒素原子または硫黄原子は、対応するＮ－オキシド、Ｓ－オキシドまたはＳ，Ｓ－ジオキシドに、必要に応じて酸化され得る。適切な単環式ヘテロシクリル環の非限定的な例としては、ピペリジニル基、ピロリジニル基、ピペラジニル基、モルホリニル基、オキサゾリジニル基、イミダゾリジニル基、チオモルホリニル基、チアゾリジニル基、１，３－ジオキソラニル基、１，４－ジオキサニル基、テトラヒドロフラニル基、テトラヒドロチオフェニル基、テトラヒドロチオピラニル基等が挙げられる。　 A 3- to 10-membered heterocyclyl group contains 3 to 10 ring atoms, preferably 5 to 10 ring atoms, and one or more of the ring system atoms, alone or in combination, are carbon atoms. Means a non-aromatic saturated monocyclic or saturated polycyclic ring system that is an element other than (eg, nitrogen, oxygen or sulfur). There are no adjacent oxygen and / or sulfur atoms present in the ring system. Suitable heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, oxazolidinyl, imidazolidinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4 -Dioxanyl group, tetrahydrofuranyl group, tetrahydrothiophenyl group, tetrahydrothiopyranyl group and the like. *
　以下に、一般式（Ｉ）の各置換基について説明する。
一般式（Ｉ）を有する化合物として、好適には、一般式（ＩＩ）を有する化合物であり、さらに好適には、以下の置換基の組合せを有する化合物である。 Below, each substituent of general formula (I) is demonstrated.
The compound having the general formula (I) is preferably a compound having the general formula (II), and more preferably a compound having a combination of the following substituents.
　Ｘ１、Ｘ２、Ｘ３、及びＸ４の好適な組み合わせは、Ｘ２が－Ｎ＝であり、Ｘ３が－Ｃ＝又は－Ｎ＝であって、Ｘ１及びＸ４がともに－Ｃ＝の組み合わせであるが、さらに好適には、Ｘ２が－Ｎ＝であって、Ｘ１、Ｘ３及びＸ４が－Ｃ＝の組み合わせである。
　Ｘ５は、好適には、－ＣＨ２ＣＨ２－、－ＣＨ２－、又は、－Ｏ－であり、さらに好適には、－ＣＨ２ＣＨ２－である。
　Ｘ６は、好適には、Ｘ６及びＸ７は、ともに－ＣＨ２－、又は、ともに－Ｃ（＝Ｏ）－であり、さらに好適には、ともに－ＣＨ２－である。
　Ｘ８及びＸ９は、それぞれ独立に－ＣＨ＝又は－Ｎ＝であるが、好適には、共に－ＣＨ＝であるか、又は、Ｘ８が－Ｃ＝であってＸ９が－Ｎ＝の組み合わせであり、さらに好適には、ともに－ＣＨ＝である。 A preferred combination of X 1 , X 2 , X 3 , and X 4 is that X 2 is —N═, X 3 is —C═ or —N =, and both X 1 and X 4 are —C More preferably, X 2 is —N═, and X 1 , X 3 and X 4 are —C═.
X 5 is preferably —CH 2 CH 2 —, —CH 2 —, or —O—, and more preferably —CH 2 CH 2 —.
X 6 is preferably X 6 and X 7 are both —CH 2 — or both —C (═O) —, and more preferably both are —CH 2 —.
X 8 and X 9 are each independently —CH═ or —N═, but preferably both are —CH═, or X 8 is —C═ and X 9 is —N═. More preferably, both are —CH═.
　Ｒ１は、好適には、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基であり、さらに好適には、水素原子、ハロゲン原子、又は、Ｃ１－Ｃ６アルキル基であり、特に好適には、水素原子、塩素原子、又は、メチル基である。
　Ｒ２は、好適には、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基であり、さらに好適には、水素原子、Ｃ１－Ｃ６アルキル基、ハロゲン原子、カルボキシ基、又は、カルボニル基であり、特に好適には、水素原子、メチル基、又は、塩素原子である。
　Ｒ３及びＲ４は、それぞれ独立に、好適には、ハロゲン原子、Ｃ１－Ｃ６アルキル基、又はＣ１－Ｃ６ハロゲノアルキル基であり、さらに好適には、ハロゲン原子、又は、Ｃ１－Ｃ６アルキル基であり、特に好適には、フッ素原子、又は、メチル基である。
　Ｒ５及びＲ６は、好適には、それぞれ独立に、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、又はＣ１－Ｃ６ハロゲノアルキル基であり、さらに好適には、ともに水素原子である。 R 1 is preferably a hydrogen atom, hydroxyl group, halogen atom, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 halogenoalkyl. Group, or a C1-C6 halogenoalkoxy group, more preferably a hydrogen atom, a halogen atom, or a C1-C6 alkyl group, and particularly preferably a hydrogen atom, a chlorine atom, or a methyl group. is there.
R 2 is preferably a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group, more preferably a hydrogen atom. An atom, a C1-C6 alkyl group, a halogen atom, a carboxy group, or a carbonyl group, and particularly preferably a hydrogen atom, a methyl group, or a chlorine atom.
R 3 and R 4 are each independently preferably a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group, and more preferably a halogen atom or a C1-C6 alkyl group. And particularly preferably a fluorine atom or a methyl group.
R 5 and R 6 are preferably each independently a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group, and more preferably a hydrogen atom.
　Ｒ１３及びＲ１４は、好適には、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基であり、さらに好適には、水素原子、又は、塩素原子である。
　Ｒ１５は、好適には、水素原子、ハロゲン原子、アミノ基、カルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、又は、Ｃ１－Ｃ６アルコキシカルボニル基であり、さらに好適には、フッ素原子、アミノ基、カルバモイル基、カルボキシ基、又は、エトキシカルボニル基であり、特に好適には、カルボキシ基、又は、エトキシカルボニル基である。
　Ａは、好適には、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基であり、さらに好適には、エチルカルバモイル基、プロピルカルバモイル基、ｔｅｒｔ－ブチルカルバモイル基、シクロプロピルカルバモイル基、又は、Ｃ１－Ｃ３アルキルオキサジアゾリル基であり、特に好適には、エチルカルバモイル基、シクロカルバモイル基、又は、エチルアミノオキサジアゾリル基である。 R 13 and R 14 are preferably each independently a hydrogen atom, a halogen atom, a cyano group, or a carboxy group that may be protected with a protecting group for a carboxy group, and more preferably a hydrogen atom. Or a chlorine atom.
R 15 is preferably a hydrogen atom, a halogen atom, an amino group, a carbamoyl group, a carboxy group that may be protected with a protecting group for carboxy group, or a C1-C6 alkoxycarbonyl group, and more preferably , A fluorine atom, an amino group, a carbamoyl group, a carboxy group, or an ethoxycarbonyl group, and particularly preferably a carboxy group or an ethoxycarbonyl group.
A is preferably a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group, and more preferably an ethylcarbamoyl group, a propylcarbamoyl group, a tert -A butylcarbamoyl group, a cyclopropylcarbamoyl group, or a C1-C3 alkyloxadiazolyl group, and particularly preferably an ethylcarbamoyl group, a cyclocarbamoyl group, or an ethylaminooxadiazolyl group.
　Ｙは、好適には、単結合、－ＣＨ２－、－Ｃ（＝Ｏ）－、－Ｃ（＝Ｓ）－、－Ｃ（－Ｃ１－Ｃ６アルキル）－、又は－Ｃ（－５員環へテロアリール）－であり、ここで、５員環へテロアリール基は、置換基群αから選択される基で置換されていてもよく、さらに好適には、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－であり、特に好適には、－ＣＨ２－である。
　一般式（Ｉ）又は（ＩＩ）を有する化合物として、さらに好適には、実施例に記載の化合物である。 Y is preferably a single bond, —CH 2 —, —C (═O) —, —C (═S) —, —C (—C1-C6 alkyl) —, or —C (-5-membered ring). Heteroaryl)-, wherein the 5-membered heteroaryl group may be substituted with a group selected from the substituent group α, and more preferably —CH 2 — or —C ( ═O) —, and particularly preferably —CH 2 —.
More preferable examples of the compound having the general formula (I) or (II) include the compounds described in Examples.
　「治療」とは、病気又は症状を治癒させること又は改善させること或いは症状を抑制させることを意味する。
　「その薬理上許容される塩」とは、医薬として使用することができる塩を示す。本発明の化合物では、酸性基または塩基性基を有する場合に、塩基又は酸と反応させることにより、塩基性塩又は酸性塩にすることができるので、その塩を示す。
　本発明の化合物の薬理上許容される「塩基性塩」としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩；マグネシウム塩、カルシウム塩のようなアルカリ土類金属塩；Ｎ－メチルモルホリン塩、トリエチルアミン塩、トリブチルアミン塩、ジイソプロピルエチルアミン塩、ジシクロヘキシルアミン塩、Ｎ－メチルピペリジン塩、ピリジン塩、４－ピロリジノピリジン塩、ピコリン塩のような有機塩基塩類又はグリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、好適には、アルカリ金属塩である。
　本発明の化合物の薬理上許容される「酸性塩」としては、好適には、フッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、リン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩のようなアリ－ルスルホン酸塩、酢酸塩、リンゴ酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩であり、最も好適には、ハロゲン化水素酸塩である。 “Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.
The “pharmacologically acceptable salt” refers to a salt that can be used as a medicine. In the compound of this invention, when it has an acidic group or a basic group, since it can be made into a basic salt or an acidic salt by making it react with a base or an acid, the salt is shown.
The pharmacologically acceptable “basic salt” of the compound of the present invention is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt. Organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt; Amino acid salts such as lysine salts, arginine salts, ornithine salts, glutamate salts, aspartates, and alkali metal salts are preferred.
The pharmacologically acceptable “acid salt” of the compound of the present invention is preferably a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, Inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p- Organics such as aryl sulfonates such as toluene sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc. Acid salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, aspartate, and most preferably a hydrohalide salt.
　本発明の化合物又はその薬理上許容される塩は、大気中に放置したり又は再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となったりする場合があり、本発明には、そのような各種の水和物、溶媒和物及び結晶多形の化合物も包含する。 The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization. The present invention also includes such various hydrates, solvates and polymorphic compounds.
  本発の明化合物、その塩又はそれらの溶媒和物は、置換基の種類や組み合わせによって、シス体、トランス体等の幾何異性体、互変異性体又はｄ体、ｌ体等の光学異性体等の各種異性体が存在し得るが、本発明の化合物は、特に限定していない場合はそれら全ての異性体、立体異性体及びいずれの比率のこれら異性体及び立体異性体混合物をも包含するものである。これらの異性体の混合物は、公知の分割手段により分離することができる。 The light compounds of the present invention, salts thereof or solvates thereof may be isomers such as cis isomers and trans isomers, tautomers or optical isomers such as d isomers and l isomers, depending on the type and combination of substituents. The compounds of the present invention include all isomers, stereoisomers and any ratios of these isomers and stereoisomer mixtures, unless otherwise specified. Is. A mixture of these isomers can be separated by a known resolution means.
　本発明の一般式（Ｉ）又は（ＩＩ）で表される化合物は、構成する原子の一つまたは複数で非天然の比率の原子同位体を含むこともある。原子同位体としては、例えば、重水素（２Ｈ)、トリチウム（３Ｈ)、ヨウ素－１２５、（１２５Ｉ）または炭素－１４（１４Ｃ）などが挙げられる。これらの化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。一般式（１）で表される化合物のすべての同位体変種は、放射性であるかどうかにかかわらず、本発明の範囲内に含まれる。 The compound represented by the general formula (I) or (II) of the present invention may contain an unnatural proportion of atomic isotopes at one or more of the constituent atoms. Examples of the atomic isotope include deuterium ( 2 H), tritium ( 3 H), iodine-125, ( 125 I), carbon-14 ( 14 C), and the like. These compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotopic variants of the compound represented by general formula (1) are included within the scope of the present invention, whether radioactive or not.
　また、本発明には、本発明の化合物の薬理上許容されるプロドラッグも包含される。薬理上許容されるプロドラッグとは、加水分解により、若しくは、生理学的条件下で、本発明の化合物のアミノ基、水酸基、カルボキシル基等に変換し得る基を有する化合物であり、このようなプロドラッグを形成する基としては、Prog. Med.、第5巻、2157-2161ページ、1985年や、「医薬品の開発」（廣川書店、1990年）第7巻、分子設計163－198ページに記載の基である。当該プロドラッグとして、より具体的には、本発明の化合物に、アミノ基が存在する場合には、そのアミノ基がアシル化、アルキル化、りん酸化された化合物（例えば、そのアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔｅｒｔ－ブチル化された化合物等である）等を挙げることができ、本発明の化合物に、水酸基が存在する場合には、その水酸基がアシル化、アルキル化、りん酸化、ほう酸化された化合物（例えば、その水酸基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等である。）等を挙げることができる。また、本発明の化合物に、カルボキシ基が存在する場合には、そのカルボキシ基がエステル化、アミド化された化合物（例えば、そのカルボキシ基がエチル  エステル化、フェニル  エステル化、カルボキシメチル  エステル化、ジメチルアミノメチル  エステル化、ピバロイルオキシメチル  エステル化、エトキシカルボニルオキシエチル  エステル化、アミド化又はメチルアミド化された化合物等である。）等が挙げられる。 The present invention also includes pharmacologically acceptable prodrugs of the compounds of the present invention. A pharmacologically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of the compound of the present invention by hydrolysis or under physiological conditions. Drug-forming groups are described in Prog. Med., Volume 5, pages 2157-2161, 1985, “Development of Drugs” (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-198 It is the basis of. As the prodrug, more specifically, when an amino group is present in the compound of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosanoylated). Alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert- In the case where a hydroxyl group is present in the compound of the present invention, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or borated (for example, The hydroxyl group is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylated. Le aminomethyl carbonylated compounds and the like.), And the like. In addition, when a carboxy group is present in the compound of the present invention, a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethyl Aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, amidation or methylamidated compounds, etc.).
（製造法）
　本発明の化合物は、その基本骨格あるいは置換基の種類に基づく特徴を利用し、各種の公知の合成法を適用して製造することができる。公知の方法としては、例えば、「ORGANIC FUNCTIONAL GROUP PREPARATIONS」、第2版、ACADEMIC PRESS,INC.、1989年、「Comprehensive Organic Transformations」、VCH Publishers Inc.、1989年等に記載された方法がある。 (Production method)
The compound of the present invention can be produced by applying various known synthesis methods utilizing characteristics based on the basic skeleton or the type of substituent. Known methods include, for example, the methods described in “ORGANIC FUNCTIONAL GROUP PREPARATIONS”, 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989, and the like.
　その際、官能基の種類によっては、当該官能基を原料ないし中間体の段階で適当な保護基で保護、又は当該官能基に容易に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。
このような官能基としては、例えば、アミノ基、水酸基、カルボキシル基等があり、それらの保護基としては、例えばT.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第3版、1999年）」に記載の保護基があり、これらの反応条件に応じて適宜選択して用いればよい。このような方法によれば、当該置換基を導入して反応を行った後、必要に応じて保護基を除去、あるいは所望の基に転化することにより、所望の化合物を得ることができる。 In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with a suitable protecting group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There are cases.
Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like, and examples of such a protective group include Protective Groups in Organic Synthesis (3rd edition, 1999) by TW Greene and PG Wuts. May be appropriately selected depending on these reaction conditions. According to such a method, after carrying out the reaction by introducing the substituent, the desired compound can be obtained by removing the protective group as necessary or converting it to a desired group.
　また、本発明の化合物のプロドラッグは、上記保護基と同様に、原料ないし中間体の段階で特定の基を導入し、あるいは得られた本発明の化合物を用いて、反応を行うことで製造できる。反応は、通常のエステル化、アミド化、脱水、水素添加等、当業者により公知の方法を適用することにより行うことができる。 In addition, the prodrug of the compound of the present invention is produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention, in the same manner as the above protecting group. it can. The reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
　以下に本発明の化合物の製造方法について述べる。ただし、製造方法は、下記の方法に何ら限定されるものではない。
（Ａ法） The production method of the compound of the present invention is described below. However, the production method is not limited to the following method.
(Method A)
Figure JPOXMLDOC01-appb-C000005
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｒ１、Ｒ２、Ａ、Ｙ及びＤは上述と同様の基を表し、
ＬＧは、置換反応における脱離基を表し、Ｐｒａは、アミノ基の保護基を示す。］
Figure JPOXMLDOC01-appb-C000005
[Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 , A, Y and D represent the same groups as described above,
LG represents a leaving group in the substitution reaction, and Pra represents an amino-protecting group. ]
Ａ－１工程：
　化合物（１）と化合物（２）を反応させて化合物（３）を製造する工程である。
反応温度は、70-200℃であり、好適には、70-100℃である。反応時間は、0.5h-24hであり、好適には、 18-20hである。反応に好適な溶媒は、2-プロパノール又はアセトニトリルである。
Ａ－２工程：
　化合物（３）と化合物（４）を還元的アミノ化反応により、化合物（５）を製造する工程である。
一般的な還元剤であれば、本反応に用いることができるが、好適には、トリアセトキシ水素化ホウ素ナトリウムである。
　反応温度は、0-100℃であり、好適には、50-70℃である。反応時間は、0.5h-24hであり、好適には、 18-20hである。反応に好適な溶媒は、１，２－ジクロロエタンである。
Ａ－３工程：
　化合物（５）のアミノ基の保護基を脱保護することにより化合物（６）を製造する工程である。
保護基が、ｔ－ブトキシカルボニル基の場合には、一般的な酸を用いることができる。
反応温度は、0-100℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、 1-2hである。反応に好適な溶媒は、ジクロロメタン又はメタノールである。
　保護基が、ベンジルオキシカルボニル基の場合には、一般的なパラジウム触媒存在下での水素添加反応を用いることができる。
　反応温度は、0-100℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、 1-４hである。反応に好適な溶媒は、エタノールである。
Ａ－４工程：
　化合物（６）と化合物（７）を反応させて化合物（Ｉ）を製造する工程である。
反応温度は、0-80℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、 18-20hである。反応に好適な溶媒は、2-プロパノール又はアセトニトリルである。
（Ｂ法） Step A-1:
In this step, compound (1) is reacted with compound (2) to produce compound (3).
The reaction temperature is 70-200 ° C, preferably 70-100 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is 2-propanol or acetonitrile.
Step A-2:
In this step, compound (3) and compound (4) are produced by reductive amination reaction.
Any common reducing agent can be used in this reaction, and sodium triacetoxyborohydride is preferred.
The reaction temperature is 0-100 ° C, preferably 50-70 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is 1,2-dichloroethane.
Step A-3:
In this step, compound (6) is produced by deprotecting the amino-protecting group of compound (5).
When the protecting group is a t-butoxycarbonyl group, a general acid can be used.
The reaction temperature is 0-100 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 1-2h. A suitable solvent for the reaction is dichloromethane or methanol.
When the protecting group is a benzyloxycarbonyl group, a general hydrogenation reaction in the presence of a palladium catalyst can be used.
The reaction temperature is 0-100 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 1-4h. A suitable solvent for the reaction is ethanol.
Step A-4:
In this step, compound (I) is produced by reacting compound (6) with compound (7).
The reaction temperature is 0-80 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is 2-propanol or acetonitrile.
(Method B)
Figure JPOXMLDOC01-appb-C000006
 ［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｘ８、Ｘ９、Ｒ１、Ｒ２、Ｒ１３、Ｒ１４、Ａ及びＹは上述と同様の基を表し、
Ｐｒｃは、カルボキシ基の保護基を表す。］
Ｂ－１工程：
　化合物（Ｉ－ａ）のカルボキシ基の保護基を脱保護することによって、化合物（Ｉ－ａ’）を製造する工程である。
　カルボキシ基の保護基が、Ｃ１－Ｃ６アルキル基である場合には、一般的な塩基（例えば、水酸化ナトリウム水溶液）を用いることができる。
　反応温度は、0-80℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、 18-20hである。反応に好適な溶媒は、エタノール、１，４－ジオキサン又はテトラヒドロフランである。
（Ｃ法）
Figure JPOXMLDOC01-appb-C000006
 [Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 13 , R 14 , A and Y are the same as described above] Represents the group of
Prc represents a protecting group for a carboxy group. ]
Process B-1:
In this step, compound (Ia ′) is produced by deprotecting the protecting group for the carboxy group of compound (Ia).
When the protecting group for the carboxy group is a C1-C6 alkyl group, a general base (for example, an aqueous sodium hydroxide solution) can be used.
The reaction temperature is 0-80 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 18-20h. Suitable solvents for the reaction are ethanol, 1,4-dioxane or tetrahydrofuran.
(Method C)
Figure JPOXMLDOC01-appb-C000007
 ［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｘ８、Ｘ９、Ｒ１、Ｒ２、Ｒ１３、Ｒ１４、Ａ及びＹは上述と同様の基を表し、ＲＣは、－Ｎ（Ｒａ）２等のアミノ基、又は、－Ｏ（ＣＨ２）２ＯＨ、５－メチル－２－オキソ－［１，３］ジオキソ－４－イルメトキシ基等のカルボキシ基のプロドラックとなる基を表し、Ｒａは、Ｃ１－Ｃ６アルキル基を表す。］
Ｃ－１工程：
　化合物（Ｉ－ａ’）のカルボキシ基をアミド化又は縮合反応等によってプロドラッグ化して化合物（Ｉ－ａ’’）を製造する工程である。
アミド化の場合、７Ｎアンモニア / メタノール又は一級、二級アルキルアミンなどを用いることができる。
　反応温度は、25-150℃であり、好適には、50-100℃である。反応時間は、1h-24hであり、好適には、 18-20hである。反応に好適な溶媒は、メタノールであり、溶媒を用いなくても反応を行うことができる場合もある。
　エチレングリコールと縮合反応を行う場合には、一般的な縮合剤を用いることができる。
反応温度は、0-100℃であり、好適には、0-25℃である。反応時間は、1h-48hであり、好適には、18-20hである。反応に好適な溶媒は、ジクロロメタンである。
　５－メチル－２－オキソ－［１，３］ジオキソ－４－イルメチルブロミドと反応を行う場合には、反応温度は、0-150℃であり、好適には、0-25℃である。反応時間は、1h-24hであり、好適には、1-5hである。反応に好適な溶媒は、Ｎ，Ｎ－ジメチルホルムアミドである。
（Ｄ法）
Figure JPOXMLDOC01-appb-C000007
 [Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 13 , R 14 , A and Y are the same as described above] R C represents an amino group such as —N (R a ) 2 , or —O (CH 2 ) 2 OH, 5-methyl-2-oxo- [1,3] dioxo-4-ylmethoxy Represents a group that becomes a prodrug of a carboxy group such as a group, and R a represents a C1-C6 alkyl group. ]
Step C-1:
In this step, the carboxy group of compound (Ia ′) is converted into a prodrug by amidation or condensation reaction to produce compound (Ia ″).
In the case of amidation, 7N ammonia / methanol or primary or secondary alkylamine can be used.
The reaction temperature is 25-150 ° C, preferably 50-100 ° C. The reaction time is 1h-24h, preferably 18-20h. A suitable solvent for the reaction is methanol, and in some cases, the reaction can be performed without using a solvent.
In the case of performing a condensation reaction with ethylene glycol, a general condensing agent can be used.
The reaction temperature is 0-100 ° C, preferably 0-25 ° C. The reaction time is 1h-48h, preferably 18-20h. A suitable solvent for the reaction is dichloromethane.
When the reaction is carried out with 5-methyl-2-oxo- [1,3] dioxo-4-ylmethyl bromide, the reaction temperature is 0-150 ° C., preferably 0-25 ° C. The reaction time is 1h-24h, preferably 1-5h. A suitable solvent for the reaction is N, N-dimethylformamide.
(Method D)
Figure JPOXMLDOC01-appb-C000008
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｘ８、Ｘ９、Ｒ１、Ｒ２、Ｒ１３、Ｒ１４、Ｒａ、Ａ、Ｙ及びＰｒｃは上述と同様の基を表す。］
Ｄ－１工程：
　化合物（Ｉ－ａ）をグリニャール試薬（ＲａＭｇＢｒ）等のアルキル金属試薬と反応させて、化合物（Ｉ－ａ’’’）を製造する工程である。
（Ｅ法）
Figure JPOXMLDOC01-appb-C000008
[Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 13 , R 14 , R a , A, Y and Prc represents the same group as described above. ]
Step D-1:
In this step, compound (Ia) is reacted with an alkyl metal reagent such as Grignard reagent (RaMgBr) to produce compound (Ia ′ ″).
(E method)
Figure JPOXMLDOC01-appb-C000009
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｘ８、Ｘ９、Ｒ１、Ｒ２、Ｒ１３、Ｒ１４、Ａ及びＹは上述と同様の基を表す。］
Ｅ－１工程：
　化合物（Ｉ－ｂ）とアジ化化合物を反応させて、化合物（Ｉ－ｂ’）を製造する工程である。
アジ化化合物は、テトラゾールを製造するために通常用いられるものであればよく、好適には、アジ化ナトリウムである。
　反応温度は、0-80℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、18-20hである。反応に好適な溶媒は、Ｎ，Ｎ-ジメチルホルムアミドである。
（Ｆ法）
Figure JPOXMLDOC01-appb-C000009
[Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 13 , R 14 , A and Y are the same as described above] Represents a group of ]
Step E-1:
In this step, compound (Ib) is reacted with an azide compound to produce compound (Ib ′).
The azide compound is not particularly limited as long as it is usually used for producing tetrazole, and is preferably sodium azide.
The reaction temperature is 0-80 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is N, N-dimethylformamide.
(F method)
Figure JPOXMLDOC01-appb-C000010
［式中、Ｘ５、Ｘ６、Ｘ７、Ｒ１、Ｒ２、Ｒａ、Ａ及びＰｒａは上述と同様の基を表し、Ｈａｌはハロゲン基を表す。］
Ｆ－１工程：
　化合物（５’）をハロゲン化して化合物（５’’）を製造する工程である。
ハロゲン化試薬としては、Ｎ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド等を用いることができる。
　反応温度は、10-100℃であり、好適には、25-40℃である。反応時間は、0.5h-24hであり、好適には、18-20hである。反応に好適な溶媒は、Ｎ，Ｎ－ジメチルホルムアミドである。
Ｆ－２－１工程：
　化合物（５’’）のハロゲン基をアルキル基に置換することによって化合物（５’’’）を製造する工程である。例えば、Ｃ１－Ｃ６アルキルボロン酸、塩基として炭酸カリウム、触媒としてパラジウム（PdCl2(dppf)CH2Cl2）の存在下、反応を行うことができる。
　反応温度は、0-100℃であり、好適には、50-100℃である。反応時間は、0.5h-24hであり、好適には、18-20hである。反応に好適な溶媒は、１，２－ジメトキシエタンである。
Ｆ－２－２工程：
　化合物（５’’）のハロゲン基をアルコキシ基に置換することによって化合物（５’’’’）を製造する工程である。
　Ｃ１－Ｃ６アルコール、ヨウ化銅、１，１０－フェナントロリン、炭酸セシウムの存在下、反応を行うことができる。
　反応温度は、60-200℃であり、好適には、100-150℃である。反応時間は、0.1h-24hであり、好適には、0.1-1hである。反応に好適な溶媒は、メタノール又はエタノールである。
（Ｇ法）
Figure JPOXMLDOC01-appb-C000010
[Wherein, X 5 , X 6 , X 7 , R 1 , R 2 , R a , A and Pra represent the same groups as described above, and Hal represents a halogen group. ]
Step F-1:
In this step, the compound (5 ′) is halogenated to produce the compound (5 ″).
As the halogenating reagent, N-chlorosuccinimide, N-bromosuccinimide and the like can be used.
The reaction temperature is 10-100 ° C, preferably 25-40 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is N, N-dimethylformamide.
Step F-2-1:
In this step, the halogen group of compound (5 ″) is substituted with an alkyl group to produce compound (5 ′ ″). For example, the reaction can be performed in the presence of C1-C6 alkylboronic acid, potassium carbonate as a base, and palladium (PdCl 2 (dppf) CH 2 Cl 2 ) as a catalyst.
The reaction temperature is 0-100 ° C, preferably 50-100 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is 1,2-dimethoxyethane.
Step F-2-2:
In this step, the halogen group of compound (5 ″) is substituted with an alkoxy group to produce compound (5 ″ ″).
The reaction can be carried out in the presence of C1-C6 alcohol, copper iodide, 1,10-phenanthroline and cesium carbonate.
The reaction temperature is 60-200 ° C, preferably 100-150 ° C. The reaction time is 0.1h-24h, preferably 0.1-1h. A suitable solvent for the reaction is methanol or ethanol.
(G method)
Figure JPOXMLDOC01-appb-C000011
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｒ１、Ｒ２、Ｒａ及びＰｒａは上述と同様の基を表す。］
Ｇ－１工程：
　化合物（５－ａ）をアミド化することによって化合物（５－ａ’）を製造する工程である。
　アミド化の試薬としては、Ｃ１－Ｃ６アルキルアミンを使用することができる。
　反応温度は、40-200℃であり、好適には、100-150℃である。反応時間は、1h-24hであり、好適には、1-2hである。溶媒は使用しなくてもよい。
　また、化合物（５－ａ）を脱エステル化し、１－エチル－３(３－ジメチルアミノプロピル)カルボジイミド塩酸塩（ＥＤＣ）等の一般的な縮合剤及びアミンによりアミド化することもできる。
（Ｈ法）
Figure JPOXMLDOC01-appb-C000011
[Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 , Ra and Pra represent the same groups as described above. ]
G-1 process:
In this step, compound (5-a ′) is produced by amidating compound (5-a).
A C1-C6 alkylamine can be used as a reagent for amidation.
The reaction temperature is 40-200 ° C, preferably 100-150 ° C. The reaction time is 1h-24h, preferably 1-2h. A solvent may not be used.
Further, the compound (5-a) can be deesterified and amidated with a general condensing agent such as 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and an amine.
(Method H)
Figure JPOXMLDOC01-appb-C000012
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｒ１、Ｒ２、Ｒａ及びＰｒａは上述と同様の基を表す。］
Ｈ－１工程：
　化合物（５－ｂ）のニトロ基を還元することによって化合物（５－ｂ’）を製造する工程である。
　ニトロ基の還元には、一般的な還元剤を用いればよい、好適には、亜鉛粉末である。
　反応温度は、0-100℃であり、好適には、50-100℃である。反応時間は、0.5h-24hであり、好適には、18-20hである。反応に好適な溶媒は、メタノールである。
Ｈ－２工程：
　化合物（５－ｂ’）のアミノ基をアミド基に変換することによって化合物（５－ｂ’’）を製造する工程である。
　使用する試薬としては、Ｃ１－Ｃ６アルキルカルボニルクロリド又はＣ１－Ｃ６アルキルスルホニルクロリド等である。
　使用する塩基としては、トリエチルアミンである。
　反応温度は、0-100℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、1-2hである。反応に好適な溶媒は、ジクロロメタン又はＮ、Ｎ－ジメチルアセトアミドである。
（Ｊ法）
Figure JPOXMLDOC01-appb-C000012
[Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 , Ra and Pra represent the same groups as described above. ]
Step H-1:
In this step, compound (5-b ′) is produced by reducing the nitro group of compound (5-b).
For the reduction of the nitro group, a common reducing agent may be used, preferably zinc powder.
The reaction temperature is 0-100 ° C, preferably 50-100 ° C. The reaction time is 0.5h-24h, preferably 18-20h. A suitable solvent for the reaction is methanol.
Step H-2:
In this step, compound (5-b ″) is produced by converting the amino group of compound (5-b ′) to an amide group.
Examples of the reagent to be used include C1-C6 alkylcarbonyl chloride and C1-C6 alkylsulfonyl chloride.
The base used is triethylamine.
The reaction temperature is 0-100 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 1-2h. A suitable solvent for the reaction is dichloromethane or N, N-dimethylacetamide.
(J method)
Figure JPOXMLDOC01-appb-C000013
［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ５、Ｘ６、Ｘ７、Ｒ１、Ｒ２、Ｒａ及びＰｒａは上述と同様の基を表す。］
Ｊ－１工程：
　化合物（５－ａ）をヒドラジンと反応させて、アシルヒドラジンとした後に、さらに、Ｃ１－Ｃ６アルキルイソチオシアネートと反応させることによって化合物（５－ｃ）を製造する工程である。
（１）ヒドラジンとの反応
　ヒドラジン・１水和物を試薬として用いることができる。
　反応温度は、50-100℃であり、好適には、60-80℃である。反応時間は、0.5h-24hであり、好適には、1-2hである。反応に好適な溶媒は、メタノール又はエタノールである。
（２）アルキルイソチオシアネートとの反応
　Ｃ１－Ｃ６アルキルイソチオシアネートを試薬として用い、反応温度は、0-80℃であり、好適には、0-25℃である。反応時間は、0.5h-24hであり、好適には、20-24hである。反応に好適な溶媒は、ジクロロメタンまたはエタノールである。
Ｊ－２工程：
　化合物（５－ｃ）を環化させることによって化合物（５－ｃ’）を製造する工程である。
　使用する試薬は、Ｎ，Ｎ－ジシクロヘキシルカルボジイミド、ジイソプロピルエチルアミド等の一般的な縮合剤であり、必要に応じて一般的な塩基も使用することができる。
　反応温度は、25-100℃であり、好適には、60-80℃である。反応時間は、0.5h-24hであり、好適には、5-10hである。反応に好適な溶媒は、アセトン及びメタノールである。
Figure JPOXMLDOC01-appb-C000013
[Wherein, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , R 1 , R 2 , Ra and Pra represent the same groups as described above. ]
Process J-1:
In this step, compound (5-a) is reacted with hydrazine to give acyl hydrazine and then further reacted with C1-C6 alkyl isothiocyanate to produce compound (5-c).
(1) Reaction with hydrazine Hydrazine monohydrate can be used as a reagent.
The reaction temperature is 50-100 ° C, preferably 60-80 ° C. The reaction time is 0.5h-24h, preferably 1-2h. A suitable solvent for the reaction is methanol or ethanol.
(2) Reaction with alkyl isothiocyanate C1-C6 alkyl isothiocyanate is used as a reagent, and the reaction temperature is 0-80 ° C, preferably 0-25 ° C. The reaction time is 0.5h-24h, preferably 20-24h. A suitable solvent for the reaction is dichloromethane or ethanol.
Process J-2:
In this step, compound (5-c ′) is produced by cyclizing compound (5-c).
The reagent to be used is a general condensing agent such as N, N-dicyclohexylcarbodiimide, diisopropylethylamide, etc., and a general base can be used if necessary.
The reaction temperature is 25-100 ° C, preferably 60-80 ° C. The reaction time is 0.5h-24h, preferably 5-10h. Suitable solvents for the reaction are acetone and methanol.
　上記、Ｆ法、Ｇ法、Ｈ法、及びＪ法で合成した中間体は、Ａ法～Ｅ法を用いて一般式（Ｉ）で示される化合物を合成することができる。 The intermediates synthesized by Method F, Method G, Method H and Method J can synthesize compounds represented by general formula (I) using methods A to E.
　本発明の化合物又はその薬理上許容される塩を哺乳動物（特にヒト）に投与する場合には、全身的又は局所的に、経口又は非経口で投与することができる。 When the compound of the present invention or a pharmacologically acceptable salt thereof is administered to a mammal (particularly human), it can be administered systemically or locally, orally or parenterally.
　本発明の医薬組成物は、投与方法に応じて適当な形態を選択し、通常用いられている各種製剤の調製法によって製造できる。
経口用の医薬組成物の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている賦形剤、結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、希釈剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 The pharmaceutical composition of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
Examples of the form of the oral pharmaceutical composition include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of pharmaceuticals includes excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Perform in accordance with a conventional method using an oxidant, a colorant, a solubilizer, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc., as appropriate. Can do.
　非経口用の医薬組成物の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤、吸入剤等が挙げられる。これら形態の医薬の調製は、添加剤として通常用いられている安定化剤、防腐剤、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、溶解補助剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 The forms of parenteral pharmaceutical compositions include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and inhalations. Agents and the like. The preparation of these forms of pharmaceuticals involves the use of stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives. Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
　一般式（Ｉ）を有する化合物又はその薬理上許容される塩の投与量は、症状、年齢、体重、組み合わせて投与する薬剤の種類や投与量等によって異なるが、通常、一般式（Ｉ）を有する化合物の換算量で、成人一人（体重約６０ｋｇとして）一回につき０．００１ｍｇ～１０００ｍｇの範囲で、全身的又は局所的に、一日一回から数回、経口又は非経口投与されるか、或いは一日１時間～２４時間の範囲で静脈内に持続投与されるのが好ましい。 The dose of the compound having the general formula (I) or a pharmacologically acceptable salt thereof varies depending on the symptoms, age, body weight, type of drug to be administered in combination, dose, etc. Is it administered in the range of 0.001 mg to 1000 mg per adult (as a body weight of about 60 kg), or once or several times a day, orally or parenterally, in the equivalent amount of the compound it has? Alternatively, it is preferably administered intravenously in the range of 1 to 24 hours per day.
　さらに、本発明の医薬組成物には、本発明の効果を損なわない範囲において、必要に応じ、その他の有効成分を併用して用いることができる。
本発明には、本発明化合物又はその薬理上許容される塩を投与することを特徴とする前記疾患の防止方法及び／又は治療方法も含まれる。
さらに、本発明には、前記医薬組成物を製造するための本発明化合物、その薬理上許容される塩の使用も含まれる。 Furthermore, in the pharmaceutical composition of the present invention, other active ingredients can be used in combination as necessary, as long as the effects of the present invention are not impaired.
The present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a pharmacologically acceptable salt thereof.
Furthermore, the present invention includes the use of the compound of the present invention and a pharmacologically acceptable salt thereof for producing the pharmaceutical composition.
［製剤例］
　（製剤例１）散剤
本発明の化合物 ５ｇ、乳糖 ８９５ｇおよびトウモロコシデンプン １００ｇをブレンダーで混合することにより、散剤を得る。
　（製剤例２）顆粒剤
　本発明の化合物５ｇ、乳糖 ８６５ｇおよび低置換度ヒドロキシプロピルセルロース１００ｇを混合した後、１０％ヒドロキシプロピルセルロース水溶液 ３００ｇを加えて練合する。これを押し出し造粒機を用いて造粒し、乾燥して顆粒剤を得る。
（製剤例３）錠剤
　本発明の化合物５ｇ、乳糖 ９０ｇ、トウモロコシデンプン３４ｇ、結晶セルロース ２０ｇおよびステアリン酸マグネシウム １ｇをブレンダーで混合した後、錠剤機で打錠することにより、錠剤を得る。 [Formulation example]
(Formulation Example 1) Powder A powder is obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a blender.
(Formulation Example 2) Granules After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of 10% hydroxypropylcellulose aqueous solution is added and kneaded. This is granulated using an extrusion granulator and dried to obtain granules.
(Formulation Example 3) Tablet After mixing 5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and 1 g of magnesium stearate with a blender, the tablet is obtained by tableting with a tablet machine.
［試験例１］マウスコラーゲン誘導性関節炎（ＣＩＡ）モデルに対する評価
（１）CIAの誘導
ウシタイプIIコラーゲン(3 mg/mL、コラーゲン技術研修会)を50 mM酢酸と1 : 1の体積比で混合し、さらに、この混合液と完全フロイントアジュバント（Becton Dickinson）を1 : 1.3の体積比で混合し、エマルジョン化した。このエマルジョン(100 μL/mouse)を7週齢雌性DBA/1Jマウス（日本チャールズリバー）の尾根部に0日目と21日目の2回皮内投与した。
（２）被験化合物の調製
被験化合物を0.5%メチルセルロース液に懸濁また溶解して用いた。
（３）被験化合物の投与
調製した被験化合物を、CIA 誘導開始21日目から41日目まで1日1回、10 mL/kg経口投与した。対照群には0.5%メチルセルロース液のみを同様に投与した。
（４）関節炎スコアの判定
21日目から、各肢の腫脹を5段階でスコア化し、4肢の合計をその個体のスコアとした。
関節炎誘導後、31日目と41日目に右後肢の体積を足体積測定装置で測定し、各群の腫脹体積の平均値を算出した。次式により足蹠体積増加抑制率（%）を算出した。
　本願実施例の化合物は、マウスコラーゲン誘導性関節炎に対し治療効果を示した。 [Test Example 1] Evaluation of mouse collagen-induced arthritis (CIA) model (1) CIA-derived bovine type II collagen (3 mg / mL, collagen technology workshop) was mixed with 50 mM acetic acid in a volume ratio of 1: 1. Further, this mixed solution and complete Freund's adjuvant (Becton Dickinson) were mixed at a volume ratio of 1: 1.3 to be emulsified. This emulsion (100 μL / mouse) was intradermally administered twice on day 0 and day 21 to the ridge of 7-week-old female DBA / 1J mice (Nippon Charles River).
(2) Preparation of test compound The test compound was suspended or dissolved in a 0.5% methylcellulose solution.
(3) Administration of test compound The prepared test compound was orally administered once a day from the 21st to 41st day of CIA induction once a day. Only 0.5% methylcellulose solution was similarly administered to the control group.
(4) Determination of arthritis score
From day 21, the swelling of each limb was scored in 5 stages, and the total of the 4 limbs was taken as the score for that individual.
On the 31st and 41st days after the induction of arthritis, the volume of the right hind limb was measured with a foot volume measuring device, and the average value of the swelling volume of each group was calculated. The toe volume increase inhibition rate (%) was calculated by the following formula.
The compounds of the examples of the present application showed a therapeutic effect on mouse collagen-induced arthritis.
［試験例２］ラットアジュバント誘導性関節炎モデルに対する評価
（１）アジュバントの調製
Mycobacterium butyricam加熱死菌体をメノウ乳鉢で微細化後、乾熱滅菌した流動パラフィンに2 mg/mLになるように懸濁し、超音波処理をした。
（２）被験化合物の調製
被験化合物を0.5%メチルセルロース液に懸濁また溶解して用いた。
（３）アジュバント誘導性関節炎の惹起
調製したアジュバント0.05 mLを対照群および被験化合物投与群の6週齢雌性LEWラット（日本チャールズリバー）の右後肢足蹠皮内にそれぞれ注射した。正常対照群には、アジュバントを注射しなかった。
（４）被験化合物の投与
調製した被験化合物を、アジュバント注射日から18日間、1日1回、5 mL/kg経口投与した。対照群には0.5%メチルセルロース液のみを同様に投与した。
（５）被験化合物の足蹠体積増加抑制率の算出
投与開始後、11日目と18日目に右後肢の体積を足体積測定装置で測定し、各群の腫脹体積の平均値を算出し、次式により足蹠体積増加抑制率（%）を算出した。
足蹠体積増加抑制率（％）=（1-（［被験化合物投与群の足蹠体積］-［正常対照群の足蹠体積］）/［対照群の足蹠体積］-［正常対照群の足蹠体積］））×100
　本願実施例の化合物は、ラットアジュバント誘導性関節炎に対し治療効果を示した。 [Test Example 2] Evaluation for rat adjuvant-induced arthritis model (1) Preparation of adjuvant
Mycobacterium butyricam heated dead cells were refined with an agate mortar, suspended in dry paraffin sterilized liquid paraffin to 2 mg / mL, and sonicated.
(2) Preparation of test compound The test compound was suspended or dissolved in a 0.5% methylcellulose solution.
(3) Induction of adjuvant-induced arthritis 0.05 mL of the prepared adjuvant was injected into the right hind paw skin of 6-week-old female LEW rats (Charles River Japan) in the control group and the test compound administration group, respectively. The normal control group was not injected with adjuvant.
(4) Administration of test compound The prepared test compound was orally administered 5 mL / kg once a day for 18 days from the day of adjuvant injection. Only 0.5% methylcellulose solution was similarly administered to the control group.
(5) Calculation of inhibition rate of footpad volume increase of test compound After the start of administration, the volume of the right hind limb was measured with a foot volume measuring device on the 11th and 18th days, and the average value of the swelling volume of each group was calculated. The toe volume increase inhibition rate (%) was calculated by the following formula.
Toe volume increase inhibition rate (%) = (1-([footpad volume of test compound administration group] − [footpad volume of normal control group]) / [footpad volume of control group] − [normal control group] Footpad volume])) × 100
The compounds of Examples of the present application showed a therapeutic effect on rat adjuvant-induced arthritis.
［試験例３］実験的自己免疫性脳脊髄炎（ＥＡＥ）に対する評価
（１）EAEの誘導
　Myelin oligodendrocyte glycoprotein35-55 (MOG35-55, 株式会社ペプチド研究所)を4 mg/mLとなるように生理食塩水に溶解した。不完全フロイントアジュバント（Becton Dickinson）にM. Tuberculosis H37 RA（Becton Dickinson）を8 mg/mLとなるように加え、さらに当容量のMOG35-55溶液を加えた後、エマルジョン化した。このエマルジョンを0日目に6週齢雌性C57BL/6マウス（日本チャールズリバー）の両腋に50 μLずつ皮下注射した。百日咳毒素（Calbiochem）を1 μg/mLとなるように生理食塩水に溶解し、0日目と2日目にマウスの尾静脈内に注射した。
（２）被験化合物の調製
　被験化合物を0.5%メチルセルロース液に懸濁また溶解して用いた。
（３）被験化合物の投与
　調製した被験化合物を、EAE誘導開始0日目から20日目まで1日1回、10 mL/kg経口投与した。対照群には0.5%メチルセルロース液のみを同様に投与した。
（４）EAEスコアの判定
　7日目から21日目まで、EAE症状を以下のように6段階でスコア化した。
0, 異常なし; 1, 尾の弛緩; 2, 後肢の軽度麻痺; 3, 後肢の重度麻痺; 4, 四肢の麻痺; 5, 死亡
　本願実施例の化合物は、実験的自己免疫性脳脊髄炎モデルに対し、治療効果を示した。 [Test Example 3] Evaluation for experimental autoimmune encephalomyelitis (EAE) (1) Induction of EAE Physiology of Myelin oligodendrocyte glycoprotein35-55 (MOG35-55, Peptide Institute, Inc.) to 4 mg / mL Dissolved in saline. M. Tuberculosis H37 RA (Becton Dickinson) was added to incomplete Freund's adjuvant (Becton Dickinson) to 8 mg / mL, and an equal volume of MOG35-55 solution was added, followed by emulsification. On day 0, 50 μL of this emulsion was subcutaneously injected into both cages of 6-week-old female C57BL / 6 mice (Nippon Charles River). Pertussis toxin (Calbiochem) was dissolved in physiological saline at 1 μg / mL and injected into the tail vein of mice on day 0 and day 2.
(2) Preparation of test compound The test compound was suspended or dissolved in a 0.5% methylcellulose solution.
(3) Administration of test compound The prepared test compound was orally administered once a day from day 0 to day 20 of EAE induction once a day. Only 0.5% methylcellulose solution was similarly administered to the control group.
(4) Judgment of EAE score From day 7 to day 21, EAE symptoms were scored in 6 stages as follows.
0, no abnormalities; 1, tail relaxation; 2, mild paralysis of the hind limbs; 3, severe paralysis of the hind limbs; 4, paralysis of the limbs; 5, death The compound of the present example is an experimental autoimmune encephalomyelitis model On the other hand, it showed a therapeutic effect.
［試験例４］Dextran sulfate sodium (DSS)誘導性大腸炎に対する評価
（１）DSS大腸炎の誘導
　DSS（MP Biomedicals）を2%となるように水に溶解し、飲用水として8週齢雄性C57BL/6マウス（日本クレア）に6日間自由摂取させることによって投与し、もしくはDSSを250 mg/mLとなるように水に溶解し、0日目から5日目まで1日1回、10 mL/kgを経口投与することにより大腸炎を誘導した。正常対照群には水のみを投与した。
（２）被験化合物の調製
　被験化合物を0.5%メチルセルロース液に懸濁また溶解して用いる。
（３）被験化合物の投与
　調製した被験化合物を、大腸炎誘導開始0日目から5日目まで1日1回、10 mL/kg経口投与した。対照群には0.5%メチルセルロース液のみを同様に投与した。
（４）被験化合物の大腸短縮抑制率の算出
　投与開始後、6日目に大腸の長さを測定し、次式により大腸短縮抑制率（%）を算出した。
大腸短縮抑制率（％）=（1-（［正常対照群の大腸長］-［被験化合物投与群の大腸長］）/［正常対照群の大腸長］-［対照群の大腸長］））×100
　本願実施例の化合物は、DSS誘導性大腸炎に対し、治療効果を示した。 [Test Example 4] Evaluation for Dextran sulfate sodium (DSS) -induced colitis (1) Induction of DSS colitis DSS (MP Biomedicals) was dissolved in water to 2% and used as drinking water for 8 weeks old male C57BL. / 6 mice (CLEA Japan) were administered by ingestion freely for 6 days, or DSS was dissolved in water to 250 mg / mL, and once a day from day 0 to day 5, 10 mL / Colitis was induced by oral administration of kg. Only the water was administered to the normal control group.
(2) Preparation of test compound The test compound is used after being suspended or dissolved in a 0.5% methylcellulose solution.
(3) Administration of test compound The prepared test compound was orally administered 10 mL / kg once a day from the 0th to the 5th day of colitis induction. Only 0.5% methylcellulose solution was similarly administered to the control group.
(4) Calculation of colon shortening suppression rate of test compound The length of the large intestine was measured on the 6th day after the start of administration, and the colon shortening suppression rate (%) was calculated by the following formula.
Suppression rate of large intestine (%) = (1-([Large colon in normal control group] − [Large colon in test compound administration group]) / [Large colon in normal control group] − [Large colon in control group])) × 100
The compounds of Examples of the present application showed a therapeutic effect on DSS-induced colitis.
［試験例５］IL-10欠損マウス自然発症大腸炎モデルに対する評価
　ヒトの炎症性腸疾患に類似した大腸炎を発症するIL-10欠損マウス自然発症大腸炎モデルを用い、大腸肥厚抑制率を指標にして、大腸炎に対する本発明の化合物の効果を評価した。
　試験には6週齢雄性IL-10欠損マウス（Jackson Laboratories）を用い、正常対照群には野生型のC57BL6マウスを用いた。
（１）被験化合物の調製
　被験化合物を0.5%メチルセルロース液に懸濁また溶解して用いた。
（２）被験化合物の投与
　調製した被験化合物を、試験開始0週目から4 - 12週目まで1日1回、10 mL/kg経口投与した。対照群には0.5%メチルセルロース液のみを同様に投与した。
（３）被験化合物の大腸肥厚抑制率の算出
　投与終了後、大腸の長さおよび重量を測定し、次式により大腸肥厚抑制率（%）を算出した。
大腸肥厚抑制率（％）=（1-（［被験化合物投与群の大腸重量/大腸長］-［正常対照群の大腸重量/大腸長］）/［対照群の大腸重量/大腸長］-［正常対照群の大腸重量/大腸長］））×100
　本願実施例の化合物は、IL-10欠損マウス自然発症大腸炎モデルに対し、治療効果を示した。 [Test Example 5] Evaluation of IL-10-deficient mouse spontaneous colitis model Using the IL-10-deficient mouse spontaneous colitis model that develops colitis similar to human inflammatory bowel disease, the inhibition rate of colon thickening was used as an index Thus, the effect of the compound of the present invention on colitis was evaluated.
Six-week-old male IL-10-deficient mice (Jackson Laboratories) were used for the test, and wild-type C57BL6 mice were used for the normal control group.
(1) Preparation of test compound The test compound was used by suspending or dissolving it in a 0.5% methylcellulose solution.
(2) Administration of test compound The prepared test compound was orally administered once a day from the 0th week to the 4th to 12th week from the start of the test. Only 0.5% methylcellulose solution was similarly administered to the control group.
(3) Calculation of inhibition rate of colonic thickening of test compound After completion of administration, the length and weight of the large intestine were measured, and the inhibition rate of colonic thickening (%) was calculated by the following formula.
Inhibition rate of thickening of colon (%) = (1-([testine weight / colon length of test compound administration group] − [colon weight / colon length of normal control group]) / [colon weight / colon length of control group] − [ Normal control group colon weight / colon length])) x 100
The compounds of Examples of the present application showed a therapeutic effect on the IL-10-deficient mouse spontaneous colitis model.
　構造式中の＊は相対立体配置を示す。例えば、 * In the structural formula indicates relative configuration. For example,
Figure JPOXMLDOC01-appb-C000014
は、
Figure JPOXMLDOC01-appb-C000014
Is
Figure JPOXMLDOC01-appb-C000015
と
Figure JPOXMLDOC01-appb-C000015
When
Figure JPOXMLDOC01-appb-C000016
との立体異性体の混合物を示し、
Figure JPOXMLDOC01-appb-C000016
And a mixture of stereoisomers with
Figure JPOXMLDOC01-appb-C000017
は、
Figure JPOXMLDOC01-appb-C000017
Is
Figure JPOXMLDOC01-appb-C000018
と
Figure JPOXMLDOC01-appb-C000018
When
Figure JPOXMLDOC01-appb-C000019
との立体異性体の混合物を示す。
Figure JPOXMLDOC01-appb-C000019
And a mixture of stereoisomers.
（参考例１）５，６－ジクロロ－Ｎ－エチルニコチンアミド
　５，６－ジクロロニコチン酸（３２．４ｇ、１６９ｍｍｏｌ）を、Ｎ，Ｎ－ジメチルホルムアミド（２００ｍＬ）に溶解し、エチルアミン（２．０Ｍテトラヒドロフラン溶液）（１０１ｍＬ、２０２ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（３２．４ｇ、１６９ｍｍｏｌ）、及び１－ヒドロキシ－７－アザベンゾトリアゾール（２５．９ｇ、１６９ｍｍｏｌ）を加え、窒素雰囲気下、室温で３０分間攪拌した。反応液を減圧濃縮した後、酢酸エチルで希釈し、水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をヘキサン‐酢酸エチルなどの混合溶媒で洗浄し、標記目的化合物（３４．０ｇ、収率９２％）を得た。 Reference Example 1 5,6-Dichloro-N-ethylnicotinamide 5,6-Dichloronicotinic acid (32.4 g, 169 mmol) was dissolved in N, N-dimethylformamide (200 mL) and ethylamine (2.0 M Tetrahydrofuran solution) (101 mL, 202 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (32.4 g, 169 mmol), and 1-hydroxy-7-azabenzotriazole (25.9 g, 169 mmol) And stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was washed with a mixed solvent such as hexane-ethyl acetate to obtain the title object compound (34.0 g, yield 92%).
（参考例２）５－クロロ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例１で製造した５，６－ジクロロ－Ｎ－エチルニコチンアミド（１６．３ｇ、７４．６ｍｍｏｌ）とｃｉｓ－デカヒドロキノキサリン（１０．５ｇ、７４．６ｍｍｏｌ）を２－プロパノール（３０ｍＬ）に溶解し、７０℃で１８時間攪拌した。氷冷下、反応液に１Ｎ－水酸化ナトリウム水溶液を加えた後（ＰＨ＝１０）、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製し、標記目的化合物（７．４７ｇ、収率３１％）を得た。 Reference Example 2 5-Chloro-N-ethyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide 5,6-Dichloro-N-ethylnicotinamide prepared in Reference Example 1 (16 .3 g, 74.6 mmol) and cis-decahydroquinoxaline (10.5 g, 74.6 mmol) were dissolved in 2-propanol (30 mL) and stirred at 70 ° C. for 18 hours. Under ice-cooling, 1N-aqueous sodium hydroxide solution was added to the reaction solution (PH = 10), followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1). Dry with sodium. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) to obtain the title object compound (7.47 g, yield 31%). .
（参考例３）４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例２で製造した５－クロロ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド（３９８ｍｇ、１．２３ｍｍｏｌ）と１－Ｂｏｃ－４－ピペリドン（４９２ｍｇ、２．４７ｍｍｏｌ）をジクロロエタン（１０ｍＬ）に溶解し、７０℃で１時間攪拌した。反応液を室温まで冷却後、トリアセトキシ水素化ホウ素ナトリウム（５２４ｍｇ、２．４７ｍｍｏｌ）を加え、７０℃で二日間攪拌した。反応液を室温まで冷却後、飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加え、１０分間攪拌した。反応液をクロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製後、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－７０：３０）で精製し、標記目的化合物（４９１ｍｇ、収率７９％）を得た。 Reference Example 3 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference 5-Chloro-N-ethyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide (398 mg, 1.23 mmol) prepared in Example 2 and 1-Boc-4-piperidone (492 mg, 2 .47 mmol) was dissolved in dichloroethane (10 mL) and stirred at 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (524 mg, 2.47 mmol) was added, and the mixture was stirred at 70 ° C. for 2 days. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was stirred for 10 min. The reaction solution was extracted three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using NH silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) and then silica gel column chromatography (chloroform: methanol, 98: 2-70: 30). To give the title compound (491 mg, yield 79%).
　（参考例４）５，６－ジクロロ－Ｎ－シクロプロピルニコチンアミド
　５，６－ジクロロニコチン酸（５．７６ｇ、３０．０ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（１００ｍＬ）溶液に、室温にてヒドロキシベンゾトリアゾール（４．１８ｇ、３０．９ｍｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（５．９３ｇ、３０．９ｍｍｏｌ）およびシクロプロピルアミン（２．２９ｇ、３３．０ｍｍｏｌ）を加えた。１６時間撹拌後、反応液を減圧下濃縮し、クロロホルム（８０ｍＬ）及び飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え撹拌し、水槽をクロロホルム（３ｘ３０ｍＬ）で抽出した。有機層を合わせて減圧下溶媒を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　６５ｉ、酢酸エチル／クロロホルム、１００：０－８０：２０）を用いて精製し、標記目的化合物（６．３３ｇ、収率９１％）を得た。 Reference Example 4 5,6-Dichloro-N-cyclopropylnicotinamide To a solution of 5,6-dichloronicotinic acid (5.76 g, 30.0 mmol) in N, N-dimethylformamide (100 mL) at room temperature Benzotriazole (4.18 g, 30.9 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.93 g, 30.9 mmol) and cyclopropylamine (2.29 g, 33.0 mmol) Was added. After stirring for 16 hours, the reaction solution was concentrated under reduced pressure, chloroform (80 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL) were added and stirred, and the water bath was extracted with chloroform (3 × 30 mL). The organic layers were combined and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 65i, ethyl acetate / chloroform, 100: 0-80: 20) to obtain the title object compound (6.33 g, yield 91%).
　（参考例５）５－クロロ－Ｎ－シクロプロピル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　５，６－ジクロロ－Ｎ－シクロプロピルニコチンアミド（参考例４）（６．３５ｇ、２７．５ｍｍｏｌ）、ｃｉｓ－デカヒドロキノキサリン（５．０１ｇ、３５．８ｍｍｏｌ）の２－プロパノール（３０．０ｍＬ）懸濁液に、ジイソプロピルエチルアミン（９．５８ｍＬ、５５．０ｍｍｏｌ）を室温にて加えた。反応管を密閉し、マイクロウェーブ反応装置にて１８０℃で２時間撹拌した。ｃｉｓ－デカヒドロキノキサリン（６７５ｍｇ、９．６３ｍｍｏｌ）を加えてさらに１８０℃にて３時間、マイクロウェーブ反応装置で撹拌した。反応液を減圧下濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｍ　ＮＨ、メタノール／酢酸エチル、１００：０－９５：５）を用いて精製し、標記目的化合物（６．４５ｇ、収率７０％）を得た。 Reference Example 5 5-chloro-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide 5,6-dichloro-N-cyclopropylnicotinamide (Reference Example 4) 6.35 g, 27.5 mmol), cis-decahydroquinoxaline (5.01 g, 35.8 mmol) in 2-propanol (30.0 mL), diisopropylethylamine (9.58 mL, 55.0 mmol) at room temperature. Added at. The reaction tube was sealed and stirred at 180 ° C. for 2 hours in a microwave reactor. Cis-decahydroquinoxaline (675 mg, 9.63 mmol) was added, and the mixture was further stirred at 180 ° C. for 3 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using NH silica gel column chromatography (Biotage 40M NH, methanol / ethyl acetate, 100: 0-95: 5) to give the title object compound (6.45 g, Yield 70%).
　（参考例６）４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－クロロ－Ｎ－シクロプロピル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド（参考例５）（６．４５ｇ、１９．３ｍｍｏｌ）の１，２－ジクロロエタン（６０ｍＬ）溶液に、室温にて１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン（５．１８ｇ、２６．０ｍｍｏｌ）を室温にて加えた。７０℃にて３時間撹拌した後、室温にて反応液にトリアセトキシホウ水素化ナトリウム（６．４５ｇ、２８．９ｍｍｏｌ）を加えた。７０℃にて１４時間撹拌した後、反応液を室温まで冷却し、クロロホルム（５０ｍＬ）および飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加えた。室温にて１時間撹拌した後分液し、水層をクロロホルム（３ｘ３０ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　６５ｉ、メタノール／クロロホルム、１００：０－９２：８）を用いて精製し、標記目的化合物（３．５８ｇ、収率３６％）を得た。 Reference Example 6 4- [cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl 5-chloro-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide (Reference Example 5) (6.45 g, 19.3 mmol) of 1,2-dichloroethane (60 mL) To the solution was added 1-tert-butoxycarbonyl-4-piperidone (5.18 g, 26.0 mmol) at room temperature. After stirring at 70 ° C. for 3 hours, sodium triacetoxyborohydride (6.45 g, 28.9 mmol) was added to the reaction solution at room temperature. After stirring at 70 ° C. for 14 hours, the reaction solution was cooled to room temperature, and chloroform (50 mL) and a saturated aqueous sodium hydrogen carbonate solution (50 mL) were added. After stirring at room temperature for 1 hour, liquid separation was performed, and the aqueous layer was extracted with chloroform (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Biotage 65i, methanol / chloroform, 100: 0 to 92: 8) to obtain the title object compound (3.58 g, yield 36%).
　（参考例７）５，６－ジブロモ－Ｎ－エチルニコチンアミド
　５，６－ジブロモニコチン酸を用いて参考例１と同様に反応を行い、標記目的化合物を得た。 Reference Example 7 5,6-Dibromo-N-ethylnicotinamide A reaction was carried out in the same manner as in Reference Example 1 using 5,6-dibromonicotinic acid to obtain the title target compound.
　（参考例８）５－ブロモ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例７で製造した５，６－ジブロモ－Ｎ－エチルニコチンアミドを用いて参考例２と同様に反応を行い、標記目的化合物を得た。 Reference Example 8 5-Bromo-N-ethyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide Using 5,6-dibromo-N-ethylnicotinamide prepared in Reference Example 7 In the same manner as in Reference Example 2, the title target compound was obtained.
　（参考例９）４－［ｃｉｓ－４－［３－ブロモ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例８で製造した５－ブロモ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミドを用いて参考例３と同様に反応を行い、標記目的化合物を得た。 Reference Example 9 4- [cis-4- [3-Bromo-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference The title target compound was obtained in the same manner as in Reference Example 3 using 5-bromo-N-ethyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 8. .
　（参考例１０）４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例９で製造した４－［ｃｉｓ－４－［３－ブロモ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（２８７ｍｇ、０．５２１ｍｍｏｌ）をジメトキシエタン（６ｍＬ）に溶解し、メチルボロン酸（９４ｍｇ、１．５６ｍｍｏｌ）、炭酸カリウム（４３２ｍｇ、３．１３ｍｍｏｌ）、及び１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）二塩化物ジクロロメタン錯体（４３ｍｇ、５２μｍｏｌ）を加え、８５℃で１．５時間攪拌した。反応液に酢酸エチルを加えた後、水、飽和炭酸水素ナトリウム、及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９９：１－０：１００）を用いて精製し、標記目的化合物（２０９ｍｇ、収率８３％）を得た。 Reference Example 10 4- [cis-4- [5- (Ethylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Tert-Butyl 4- [cis-4- [3-bromo-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate prepared in Example 9 ( 287 mg, 0.521 mmol) was dissolved in dimethoxyethane (6 mL), methyl boronic acid (94 mg, 1.56 mmol), potassium carbonate (432 mg, 3.13 mmol), and 1,1′-bis (diphenylphosphino) ferrocene- Palladium (II) dichloride dichloromethane complex (43 mg, 52 μmol) was added and 1. Stir for 5 hours. Ethyl acetate was added to the reaction solution, followed by washing with water, saturated sodium hydrogen carbonate, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 99: 1-0: 100) to give the title object compound (209 mg, yield 83%).
　（参考例１１）５，６－ジクロロ－Ｎ－メチルニコチンアミド
　５，６－ジクロロニコチン酸およびメチルアミンを用いて参考例４と同様の反応を行い、標記目的化合物を得た。 Reference Example 11 5,6-Dichloro-N-methylnicotinamide The same reaction as in Reference Example 4 was carried out using 5,6-dichloronicotinic acid and methylamine to obtain the title target compound.
　（参考例１２）５－クロロ－Ｎ－メチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例１１で製造した５，６－ジクロロ－Ｎ－メチルニコチンアミドを用いて参考例５と同様の反応を行い、標記目的化合物を得た。 Reference Example 12 5-Chloro-N-methyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide Using 5,6-dichloro-N-methylnicotinamide prepared in Reference Example 11 In the same manner as in Reference Example 5, the title target compound was obtained.
　（参考例１３）４－［ｃｉｓ－４－［３－クロロ－５－（メチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１２で製造した５－クロロ－Ｎ－メチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミドを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 13 4- [cis-4- [3-Chloro-5- (methylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-N-methyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 12, the same reaction as in Reference Example 3 was carried out to obtain the title target compound. .
　（参考例１４）２－｛［（５，６－ジクロロピリジン－３－イル）カルボニル］アミノ｝エチルアセタート
　５，６－ジクロロニコチン酸（２．３０ｇ、１２．０ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（３０ｍＬ）溶液に、室温にてヒドロキシベンゾトリアゾール（１．７０ｇ、１２．６ｍｍｏｌ）、塩酸１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（２．４２ｇ、１２．６ｍｍｏｌ）および２－アミノエタノール（８８０ｍｇ、１４．４ｍｍｏｌ）を加えた。１６時間撹拌後、反応液を減圧下濃縮し、クロロホルム（１５ｍＬ）及び飽和炭酸水素ナトリウム水溶液（１５ｍＬ）を加え撹拌し、水層をクロロホルム（３ｘ１０ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄したのち、無水硫酸ナトリウムにて乾燥し、減圧下溶媒を濃縮した。得られた残渣に酢酸エチルを少量加え、生じた固体をろ過にて採取してアミド体（１．９７ｇ）を白色個体として得た。減圧下乾燥した白色個体の一部（９４０ｍｇ、４．００ｍｍｏｌ）のジクロロメタン（５ｍＬ）懸濁液に、ピリジン（３８８μｌ、４．８０ｍｍｏｌ）及び無水酢酸（４１５μｌ、４．４０ｍｍｏｌ）を室温にて加えた。１８時間室温にて撹拌した後、反応液に水（５ｍＬ）およびクロロホルム（１０ｍＬ）を加えて分液し、水層をクロロホルム（３ｘ５ｍＬ）で抽出した。合わせた有機層を３％硫酸銅水溶液（２ｘ２０ｍＬ）、飽和食塩水で洗浄したのち無水硫酸ナトリウムにて乾燥し、溶媒を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｓ、酢酸エチル／クロロホルム、１００：０－７５：２５）を用いて精製し、標記目的化合物（９９７ｍｇ、収率９０％）を得た。 Reference Example 14 2-{[(5,6-Dichloropyridin-3-yl) carbonyl] amino} ethyl acetate 5,6-dichloronicotinic acid (2.30 g, 12.0 mmol) in N, N-dimethyl To a solution of formamide (30 mL) at room temperature, hydroxybenzotriazole (1.70 g, 12.6 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.42 g, 12.6 mmol) and 2- Aminoethanol (880 mg, 14.4 mmol) was added. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure, chloroform (15 mL) and saturated aqueous sodium hydrogen carbonate solution (15 mL) were added and stirred, and the aqueous layer was extracted with chloroform (3 × 10 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. A small amount of ethyl acetate was added to the resulting residue, and the resulting solid was collected by filtration to obtain an amide compound (1.97 g) as a white solid. To a suspension of a part of white solid dried under reduced pressure (940 mg, 4.00 mmol) in dichloromethane (5 mL), pyridine (388 μl, 4.80 mmol) and acetic anhydride (415 μl, 4.40 mmol) were added at room temperature. . After stirring for 18 hours at room temperature, water (5 mL) and chloroform (10 mL) were added to the reaction solution, and the mixture was separated, and the aqueous layer was extracted with chloroform (3 × 5 mL). The combined organic layers were washed with 3% aqueous copper sulfate solution (2 × 20 mL) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 40S, ethyl acetate / chloroform, 100: 0-75: 25) to obtain the title object compound (997 mg, yield 90%).
　（参考例１５）２－［（｛５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピリジン－３－イル｝カルボニル）アミノ］エチルアセタート
　参考例１４で製造した２－｛［（５，６－ジクロロピリジン－３－イル）カルボニル］アミノ｝エチルアセタートを用いて参考例５と同様の反応を行い、標記目的化合物を得た。 Reference Example 15 2-[({5-Chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] pyridin-3-yl} carbonyl) amino] ethyl acetate 2 prepared in Reference Example 14 The same reaction as in Reference Example 5 was carried out using — {[(5,6-dichloropyridin-3-yl) carbonyl] amino} ethyl acetate to obtain the title object compound.
　（参考例１６）４－［ｃｉｓ－４－｛５－［（２－アセトキシエチル）カルバモイル］－３－クロロピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１５で製造した２－［（｛５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピリジン－３－イル｝カルボニル）アミノ］エチルアセタートを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 16 4- [cis-4- {5-[(2-acetoxyethyl) carbamoyl] -3-chloropyridin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone Tert-butyl acid Using 2-[({5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] pyridin-3-yl} carbonyl) amino] ethyl acetate prepared in Reference Example 15 In the same manner as in Reference Example 3, the title target compound was obtained.
　（参考例１７）５－ヨード－２－メチル安息香酸メチル
　５－ヨード－２－メチル安息香酸（７．８６ｇ、３０．０ｍｍｏｌ）のメタノール（１００ｍＬ）溶液に、塩化チオニル（４．３８ｍＬ、６０．０ｍｍｏｌ）を０℃にて加えた。１時間半加熱還流したのち、反応液を減圧下濃縮し、得られた残渣に酢酸エチル（５０ｍＬ）および飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え撹拌し、水層を酢酸エチル（３ｘ２０ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄したのち、無水硫酸ナトリウムにて乾燥し、減圧下溶媒を濃縮して標記目的化合物（８．１４ｇ、収率９８％）を得た。 Reference Example 17 Methyl 5-iodo-2-methylbenzoate To a solution of 5-iodo-2-methylbenzoic acid (7.86 g, 30.0 mmol) in methanol (100 mL) was added thionyl chloride (4.38 mL, 60. 0 mmol) was added at 0 ° C. After refluxing for 1 hour and a half, the reaction mixture was concentrated under reduced pressure. Ethyl acetate (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL) were added to the resulting residue and stirred, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). did. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title object compound (8.14 g, yield 98%).
　（参考例１８）２－（ブロモメチル）－５－ヨード安息香酸メチル
　５－ヨード－２－メチル安息香酸メチル（参考例１７）（８．１４ｇ、２８．４ｍｍｏｌ）の四塩化炭素（８５ｍＬ）溶液に、室温にてＮ－ブロモスクシンイミド（５．５７ｇ、３１．３ｍｍｏｌ）および２，２’－アゾビス（２－メチルプロピオニトリル）（２３．３ｍｇ、０．１４２ｍｍｏｌ）を加えた。ランプ（日立赤外電球、３７５Ｗ）を照射して２時間加熱還流後、反応液を室温まで冷却した。溶媒を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　６５ｉ、アセトン／ヘキサン、１００：０－９５：５）を用いて精製し、標記目的化合物（６．４５ｇ、収率６４％）を得た。 (Reference Example 18) Methyl 2- (bromomethyl) -5-iodobenzoate Methyl 5-iodo-2-methylbenzoate (Reference Example 17) (8.14 g, 28.4 mmol) in a carbon tetrachloride (85 mL) solution At room temperature, N-bromosuccinimide (5.57 g, 31.3 mmol) and 2,2′-azobis (2-methylpropionitrile) (23.3 mg, 0.142 mmol) were added. After irradiation with a lamp (Hitachi infrared bulb, 375 W) for 2 hours under reflux, the reaction solution was cooled to room temperature. The solvent was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (Biotage 65i, acetone / hexane, 100: 0-95: 5) to give the title object compound (6.45 g, yield 64%). )
　（参考例１９）２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－ヨード安息香酸メチル
　４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例３）（９５４ｍｇ、１．８８ｍｍｏｌ）をメタノール（４ｍＬ）に溶解し、４規程塩酸ジオキサン溶液（４ｍＬ）を加え、室温で１時間攪拌後、減圧濃縮した。得られた残渣に２０％メタノール／クロロホルム混合液（５ｍＬ）、飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加えて撹拌し、分液した後水層を２０％メタノール／クロロホルム混合液（３ｘ３ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣にアセトニトリル（１０ｍＬ）、２－（ブロモメチル）－５－ヨード安息香酸メチル（参考例１８）（６０９ｍｇ、１．７１ｍｍｏｌ）およびジイソプロピルエチルアミン（５９７μｌ、３．４３ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を減圧下濃縮し、反応液に水（５ｍＬ）、１０％メタノール／クロロホルム混合液（５ｍＬ）を加えて分液し、水層を１０％メタノール／クロロホルム混合液（３ｘ５ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムで乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｍ、メタノール／クロロホルム、１００：０－９５：５）を用いて精製し、標記目的化合物（９０２ｍｇ、収率８５％）を得た。 Reference Example 19 2-({4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) -5-iodobenzoate methyl 4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid Tert-butyl (Reference Example 3) (954 mg, 1.88 mmol) was dissolved in methanol (4 mL), 4N hydrochloric acid dioxane solution (4 mL) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A 20% methanol / chloroform mixed solution (5 mL) and a saturated aqueous sodium hydrogen carbonate solution (5 mL) were added to the obtained residue, and the mixture was stirred. After separation, the aqueous layer was extracted with a 20% methanol / chloroform mixed solution (3 × 3 mL). . The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Acetonitrile (10 mL), methyl 2- (bromomethyl) -5-iodobenzoate (Reference Example 18) (609 mg, 1.71 mmol) and diisopropylethylamine (597 μl, 3.43 mmol) were added to the resulting residue, and 18 mL was added at room temperature. Stir for hours. The reaction solution was concentrated under reduced pressure, water (5 mL) and a 10% methanol / chloroform mixture (5 mL) were added to the reaction solution, and the mixture was separated. The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Biotage 40M, methanol / chloroform, 100: 0-95: 5) to obtain the title object compound (902 mg, yield 85%).
　（参考例２０）２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－シアノ安息香酸メチル
　２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－ヨード安息香酸メチル（参考例１９）（１７０ｍｇ、０．２５０ｍｍｏｌ）のＮ－メチルピロリドン（０．５ｍＬ）溶液に、シアン化銅（２７．４ｍｇ、０．３００ｍｍｏｌ）を室温にて加えた。反応管を密閉し、マイクロウェーブ反応装置にて１８０℃で１５分間撹拌した。反応液に２０％クロロホルム／メタノール混合液（３ｍＬ）、水（２ｍＬ）を加えて分液し、水層を２０％クロロホルム／メタノール混合液（２ｘ３ｍＬ）で抽出した。あわせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、１００：０－９３：７）を用いて精製し、標記目的化合物のラセミ体（１０２ｍｇ）を得た。得られたラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール：ヘキサン＝３０：７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール：ヘキサン＝３０：７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が３．７分の標記目的化合物（３４ｍｇ、収率２４％）と保持時間が６．８分の化合物（３２ｍｇ、収率２２％）を得た。 Reference Example 20 2-({4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) -5-cyanobenzoate 2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- To a solution of methyl 1-yl} methyl) -5-iodobenzoate (Reference Example 19) (170 mg, 0.250 mmol) in N-methylpyrrolidone (0.5 mL), copper cyanide (27.4 mg, 0.300 mmol) Was added at room temperature. The reaction tube was sealed and stirred at 180 ° C. for 15 minutes in a microwave reactor. A 20% chloroform / methanol mixture (3 mL) and water (2 mL) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with a 20% chloroform / methanol mixture (2 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 25M, methanol / chloroform, 100: 0-93: 7) to obtain the racemic form (102 mg) of the title object compound. The obtained racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol: hexane = 30: 70, 10 mL / min, 254 nm). Title target compound with a retention time of 3.7 minutes on HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol: hexane = 30: 70, 2.0 mL / min, 254 nm) (34 mg, 24% yield) and a retention time of 6.8 minutes compound (32 mg, 22% yield) were obtained.
　（参考例２１）［ｔｒａｎｓ－２－ヒドロキシシクロペンチル］カルバミン酸ベンジル
　トランス－２－アミノシクロペンタノール塩酸塩（２６．１ｇ、１８４ｍｍｏｌ）、炭酸ナトリウム（４０．９ｇ、３８６ｍｍｏｌ）のジオキサン／水２０％混合液（３００ｍＬ）溶液に、クロロギ酸ベンジル（２８．４ｍＬ、１９３ｍｍｏｌ）を０℃にて１０分間滴下した。室温にて１６時間撹拌後、反応液に水（５０ｍＬ）およびクロロホルム（２００ｍＬ）を加えて分液し、有機層をクロロホルム（２ｘ１５０ｍＬ）で抽出した。合わせた有機層を飽和食塩水で洗浄、無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム、９５：５）を用いて精製し、標記目的化合物（４３．０ｇ、収率１００％）を得た。 Reference Example 21 [trans-2-hydroxycyclopentyl] carbamate benzyl trans-2-aminocyclopentanol hydrochloride (26.1 g, 184 mmol), sodium carbonate (40.9 g, 386 mmol) in dioxane / water 20% mixed To the liquid (300 mL) solution, benzyl chloroformate (28.4 mL, 193 mmol) was added dropwise at 0 ° C. for 10 minutes. After stirring at room temperature for 16 hours, water (50 mL) and chloroform (200 mL) were added to the reaction solution for liquid separation, and the organic layer was extracted with chloroform (2 × 150 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (methanol / chloroform, 95: 5) to obtain the title object compound (43.0 g, yield 100%).
　（参考例２２）メタンスルホン酸ｔｒａｎｓ－２－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロペンチル
　メタンスルホン酸ｔｒａｎｓ－２－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロペンチル（参考例２１）（４３．０ｇ、１８４ｍｍｏｌ）、トリエチルアミン（２８．２ｍＬ、２０２ｍｍｏｌ）のジクロロメタン（３００ｍＬ）溶液に、塩化メタンスルホニル（１８．４ｍＬ、１９３ｍｍｏｌ）を０℃にて１０分間滴下した。０℃にて１時間半撹拌後、反応液に水（１００ｍＬ）およびクロロホルム（５０ｍＬ）を加えて分液し、有機層をクロロホルム（３ｘ１５０ｍＬ）で抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液（３ｘ３０ｍＬ）、飽和食塩水で洗浄、無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／クロロホルム、１００：０－９５：５）を用いて精製し、標記目的化合物（３７．０ｇ、収率６４％）を得た。 Reference Example 22 trans-2-{[(benzyloxy) carbonyl] amino} cyclopentyl methanesulfonate trans-2-{[(benzyloxy) carbonyl] amino} cyclopentyl methanesulfonate (Reference Example 21) (43.0 g , 184 mmol) and triethylamine (28.2 mL, 202 mmol) in dichloromethane (300 mL) were added dropwise methanesulfonyl chloride (18.4 mL, 193 mmol) at 0 ° C. for 10 minutes. After stirring for 1 hour and a half at 0 ° C., water (100 mL) and chloroform (50 mL) were added to the reaction solution, and the mixture was separated, and the organic layer was extracted with chloroform (3 × 150 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (3 × 30 mL) and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / chloroform, 100: 0-95: 5) to obtain the title object compound (37.0 g, yield 64%).
　（参考例２３）［ｃｉｓ－２－アジドシクロペンチル］カルバミン酸ベンジル
　メタンスルホン酸ｔｒａｎｓ－２－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロペンチル（参考例２２）（３７．０ｇ、１１８ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（３００ｍＬ）溶液に、アジ化ナトリウム（１５．６ｇ、２３６ｍｍｏｌ）を室温にて加えた。窒素雰囲気下８５℃にて１８時間攪拌後、反応液を室温まで冷却した。反応液中の不溶物をろ過にて除去し、濾液を減圧下濃縮した。得られた残渣に酢酸エチル（２００ｍＬ）及び水（１５０ｍＬ）を加え分液し、水層を酢酸エチル（３ｘ１５０ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄、無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮して、標記目的化合物（３０．１ｇ、収率９８％）を得た。 Reference Example 23 benzyl [cis-2-azidocyclopentyl] carbamate trans-2-{[(benzyloxy) carbonyl] amino} cyclopentyl methanesulfonate (Reference Example 22) (37.0 g, 118 mmol) N, N -To a solution of dimethylformamide (300 mL), sodium azide (15.6 g, 236 mmol) was added at room temperature. After stirring at 85 ° C. for 18 hours under a nitrogen atmosphere, the reaction solution was cooled to room temperature. Insoluble matters in the reaction solution were removed by filtration, and the filtrate was concentrated under reduced pressure. To the obtained residue were added ethyl acetate (200 mL) and water (150 mL), and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (3 × 150 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title object compound (30.1 g, yield 98%).
　（参考例２４）［ｃｉｓ－２－アミノシクロペンチル］カルバミン酸ベンジル
　［ｃｉｓ－２－アジドシクロペンチル］カルバミン酸ベンジル（参考例２３）（３０．１ｇ、１１６ｍｍｏｌ）の１０％水／テトラヒドロフラン（３００ｍＬ）溶液に、トリフェニルホスフィン（３３．４ｇ、１２７ｍｍｏｌ）を室温にて加えた。７０℃にて３時間攪拌したのち反応液を減圧下濃縮し、得られた残渣に酢酸エチル（２００ｍＬ）及び１規程塩酸（２５０ｍＬ）を加え分液し、有機層を１規程塩酸（２ｘ３０ｍＬ）で抽出した。水層を合わせて酢酸エチル（４ｘ１００ｍＬ）で洗浄し、水層に４規程水酸化ナトリウム水溶液（４０ｍＬ）を加えて撹拌し、水溶液を塩基性（ｐＨ１１）とした。室温にてクロロホルム（１５０ｍＬ）を加えて分液し、水層をクロロホルム（３ｘ１５０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮して、標記目的化合物（２０．５ｇ、収率７６％）を得た。 (Reference Example 24) [cis-2-aminocyclopentyl] benzyl carbamate [cis-2-azidocyclopentyl] benzyl carbamate (Reference Example 23) (30.1 g, 116 mmol) in a 10% water / tetrahydrofuran (300 mL) solution , Triphenylphosphine (33.4 g, 127 mmol) was added at room temperature. After stirring at 70 ° C. for 3 hours, the reaction mixture was concentrated under reduced pressure, ethyl acetate (200 mL) and 1N hydrochloric acid (250 mL) were added to the residue, and the mixture was separated. The organic layer was diluted with 1N hydrochloric acid (2 × 30 mL). Extracted. The aqueous layers were combined and washed with ethyl acetate (4 × 100 mL), 4N aqueous sodium hydroxide solution (40 mL) was added to the aqueous layer and stirred to make the aqueous solution basic (pH 11). Chloroform (150 mL) was added at room temperature for liquid separation, and the aqueous layer was extracted with chloroform (3 × 150 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title object compound (20.5 g, yield 76%).
　（参考例２５）｛［ｃｉｓ－２－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロペンチル］アミノ｝（オキソ）酢酸メチル
　［ｃｉｓ－２－アミノシクロペンチル］カルバミン酸ベンジル（参考例２４）（２０．５ｇ、８７．５ｍｍｏｌ）、トリエチルアミン（１８．３ｍＬ、１３１ｍｍｏｌ）のジクロロメタン（２５０ｍＬ）溶液に、０℃にて塩化オキサリルメチル（８．０５ｍＬ，８７．５ｍｍｏｌ）を１０分間加えた。室温にて１時間攪拌後、反応液にクロロホルム（５０ｍＬ）及び水（１００ｍＬ）を加え分液し、水層をクロロホルム（３ｘ３０ｍＬ）で抽出した。有機層を合わせて飽和炭酸水素ナトリウム水溶液（３ｘ１５０ｍＬ）、飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥し、減圧下溶媒を濃縮した。得られた残渣に少量の酢酸エチルを加えて、生じた小片をろ過にて採取した。濾液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　６５ｉ、酢酸エチル／クロロホルム、１００：０－７０：３０）を用いて精製し、目的の分画とろ過にて採取した小片を合わせて、標記目的化合物（２０．０ｇ、収率７１％）を得た。 (Reference Example 25) {[cis-2-{[(Benzyloxy) carbonyl] amino} cyclopentyl] amino} (oxo) methyl acetate [cis-2-aminocyclopentyl] carbamate (Reference Example 24) (20.5 g 87.5 mmol) and triethylamine (18.3 mL, 131 mmol) in dichloromethane (250 mL) at 0 ° C. were added oxalylmethyl chloride (8.05 mL, 87.5 mmol) for 10 minutes. After stirring at room temperature for 1 hour, chloroform (50 mL) and water (100 mL) were added to the reaction solution and the phases were separated, and the aqueous layer was extracted with chloroform (3 × 30 mL). The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution (3 × 150 mL) and saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. A small amount of ethyl acetate was added to the resulting residue, and the resulting piece was collected by filtration. The filtrate was concentrated, and the resulting residue was purified using silica gel column chromatography (Biotage 65i, ethyl acetate / chloroform, 100: 0-70: 30). The target fraction and the small piece collected by filtration were combined. To give the title object compound (20.0 g, yield 71%).
　（参考例２６）ｃｉｓ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－２，３－ジオン
　｛［ｃｉｓ－２－｛［（ベンジルオキシ）カルボニル］アミノ｝シクロペンチル］アミノ｝（オキソ）酢酸メチル（参考例２５）（２０．０ｇ、６２．４ｍｍｏｌ）のメタノール（３００ｍＬ）溶液に、７．５％パラジウム炭素触媒（２．００ｇ）を室温にて加えた。水素気流下常圧で４時間攪拌したのち反応液中の触媒をろ過にて除去した。濾液を減圧下濃縮し、標記目的化合物（９．６０ｇ、収率１００％）を得た。 Reference Example 26 cis-hexahydro-1H-cyclopenta [b] pyrazine-2,3-dione {[cis-2-{[(benzyloxy) carbonyl] amino} cyclopentyl] amino} (oxo) acetic acid methyl (reference example 25) To a solution of (20.0 g, 62.4 mmol) in methanol (300 mL) was added 7.5% palladium carbon catalyst (2.00 g) at room temperature. After stirring for 4 hours at normal pressure under a hydrogen stream, the catalyst in the reaction solution was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title object compound (9.60 g, yield 100%).
　（参考例２７）ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン
　ｃｉｓ－ヘキサヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－２，３－ジオン（参考例２６）（９．６０ｇ、６２．４ｍｍｏｌ）のテトラヒドロフラン（１５０ｍＬ）懸濁液に、１規程リチウムアルミニウムヒドリドテトラヒドロフラン溶液（２００ｍＬ、２００ｍｍｏｌ）を０℃にて１時間滴下した。室温にて３０分間攪拌後、６５℃にて１５時間攪拌した。反応液を０℃に冷却したのち、１規程水酸化ナトリウム水溶液（３０．４ｍＬ、３０．４ｍｍｏｌ）を２時間滴下しながら、テトラヒドロフラン（３００ｍＬ）を数回に分けて加えた。反応液を室温にて３０分間撹拌した後、生じた不溶物をろ過にて取り除き、濾液を減圧下濃縮して標記目的化合物（７．５９ｇ、収率９６％）を得た。 Reference Example 27 cis-octahydro-1H-cyclopenta [b] pyrazine cis-hexahydro-1H-cyclopenta [b] pyrazine-2,3-dione (Reference Example 26) (9.60 g, 62.4 mmol) in tetrahydrofuran (Reference Example 27) (150 mL), 1N lithium aluminum hydride tetrahydrofuran solution (200 mL, 200 mmol) was added dropwise at 0 ° C. for 1 hour. The mixture was stirred at room temperature for 30 minutes and then stirred at 65 ° C. for 15 hours. After the reaction solution was cooled to 0 ° C., tetrahydrofuran (300 mL) was added in several portions while 1 N aqueous sodium hydroxide solution (30.4 mL, 30.4 mmol) was added dropwise for 2 hours. The reaction solution was stirred at room temperature for 30 minutes, and the resulting insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title object compound (7.59 g, yield 96%).
　（参考例２８）５－クロロ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ニコチンアミド
　参考例２７で製造したｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジンを用いて参考例５と同様の反応を行い、標記目的化合物を得た。 Reference Example 28 5-Chloro-N-ethyl-6- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] nicotinamide cis-octahydro-1H-cyclopenta [b] prepared in Reference Example 27 The same reaction as in Reference Example 5 was carried out using pyrazine to obtain the title object compound.
　（参考例２９）４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例２８で製造した５－クロロ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ニコチンアミドを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 29 4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert -Butyl 5-chloro-N-ethyl-6- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] nicotinamide prepared in Reference Example 28 was used to carry out the same reaction as in Reference Example 3, The title object compound was obtained.
　（参考例３０）２－（ブロモメチル）－５－クロロ安息香酸エチル
　５－クロロ－２－メチル安息香酸エチルを用いて参考例１８と同様の反応を行い、標記目的化合物を得た。 Reference Example 30 Ethyl 2- (bromomethyl) -5-chlorobenzoate The same reaction as in Reference Example 18 was carried out using ethyl 5-chloro-2-methylbenzoate to obtain the title target compound.
　（参考例３１）２－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピリミジン－５－カルボン酸メチル
　２－クロロピリミジン－５－カルボン酸メチル（５００ｍｇ、２．９０ｍｍｏｌ）のアセトニトリル（３０ｍＬ）溶液に、ｃｉｓ－デカヒドロキノキサリン（８１３ｍｇ、５．７９ｍｍｏｌ）、ジイソプロピルエチルアミン（１．２６ｍＬ、７．２４ｍｍｏｌ）を室温にて加えた。７０℃にて２時間攪拌したのち反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｓ、メタノール／クロロホルム、１００：０－９５：５）を用いて精製し、標記目的化合物（６６５ｍｇ、収率８３％）を得た。 Reference Example 31 2- [cis-Octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate methyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.90 mmol) in acetonitrile (30 mL) To the solution, cis-decahydroquinoxaline (813 mg, 5.79 mmol), diisopropylethylamine (1.26 mL, 7.24 mmol) were added at room temperature. After stirring at 70 ° C. for 2 hours, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (Biotage 40S, methanol / chloroform, 100: 0-95: 5) to give the title purpose. The compound (665 mg, yield 83%) was obtained.
　（参考例３２）２－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピリミジン－５－カルボン酸メチル
　参考例３１で製造した２－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピリミジン－５－カルボン酸メチルを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 32 Methyl 2- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate Prepared in Reference Example 31 Using the methyl 2- [cis-octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate, the same reaction as in Reference Example 3 was carried out to obtain the title target compound.
　（参考例３３）４－［ｃｉｓ－４－［５－（エチルカルバモイル）ピリミジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　２－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピリミジン－５－カルボン酸メチル（参考例３２）（１９７ｍｇ、０．４２９ｍｍｏｌ）のメタノール（１ｍＬ）溶液に、テトラヒドロフラン（２ｍＬ）、１規定水酸化ナトリウム水溶液（１ｍＬ、１．００ｍｍｏｌ）を室温にて加えた。室温にて１８時間攪拌後、反応液を減圧下濃縮し、得られた残渣に２０％メタノール／クロロホルム混合液（５ｍＬ）、水（２ｍＬ）を加えたのち、１規定塩酸にて中和して分液し、２０％メタノール／クロロホルム混合液（３ｘ３．０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮してカルボン酸（１６５ｍｇ）を得た。得られたカルボン酸をＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）に溶解し、室温にてヒドロキシベンゾトリアゾール（７４．８ｍｇ、０．５５４ｍｍｏｌ）、塩酸１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（１０６ｍｇ、０．５５４ｍｍｏｌ）および２Ｍエチルアミンテトラヒドロフラン溶液（０．２４０ｍＬ，０．４８０ｍｍｏｌ）を加えた。室温にて３時間撹拌後、反応液を減圧下濃縮し、クロロホルム（５ｍＬ）及び飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加え撹拌し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄したのち、無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、１００：０－９２：２）を用いて精製し、標記目的化合物（８４．７ｍｇ、収率４２％）を得た。 Reference Example 33 4- [cis-4- [5- (ethylcarbamoyl) pyrimidin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl 2- [cis- 4- [1- (tert-Butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrimidine-5-carboxylate (Reference Example 32) (197 mg, 0.429 mmol) in methanol ( To the 1 mL solution, tetrahydrofuran (2 mL) and 1N aqueous sodium hydroxide solution (1 mL, 1.00 mmol) were added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure, and 20% methanol / chloroform mixture (5 mL) and water (2 mL) were added to the resulting residue, followed by neutralization with 1N hydrochloric acid. Separated and extracted with 20% methanol / chloroform mixture (3 × 3.0 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain carboxylic acid (165 mg). The obtained carboxylic acid was dissolved in N, N-dimethylformamide (2 mL), and hydroxybenzotriazole (74.8 mg, 0.554 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at room temperature. (106 mg, 0.554 mmol) and 2M ethylamine tetrahydrofuran solution (0.240 mL, 0.480 mmol) were added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, chloroform (5 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred, and the aqueous layer was extracted with chloroform (3 × 3 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 25M, methanol / chloroform, 100: 0-92: 2) to obtain the title object compound (84.7 mg, yield 42%).
　（参考例３４）５－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチル
　５－クロロピラジン－２－カルボン酸メチル（７．０３ｇ、４０．４ｍｍｏｌ）とｃｉｓ－デカヒドロキノキサリン（５．７１ｇ、４０．７ｍｍｏｌ）を２－プロパノール（５０ｍＬ）に溶解し、７０℃で１８時間攪拌した。室温下、ジイソプロピルエチルアミン（約１０ｍＬ）とエタノール（約１０ｍＬ）を加えた後、反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－８０：２０）を用いて精製し、標記目的化合物（１０．９ｇ、収率９７％）を得た。 Reference Example 34 Methyl 5- [cis-octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylate Methyl 5-chloropyrazine-2-carboxylate (7.03 g, 40.4 mmol) and cis- Decahydroquinoxaline (5.71 g, 40.7 mmol) was dissolved in 2-propanol (50 mL) and stirred at 70 ° C. for 18 hours. After adding diisopropylethylamine (about 10 mL) and ethanol (about 10 mL) at room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform: methanol, 98: 2-80: 20). To give the title object compound (10.9 g, yield 97%).
　（参考例３５）ｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル
　参考例３４で製造した５－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチル（１０．９ｇ、３９．３ｍｍｏｌ）をジクロロメタン（２００ｍＬ）に溶解し、ジ－ｔｅｒｔ－ブチル　ジカーボネート（１０．３ｇ、４７．２ｍｍｏｌ）と４－ジメチルアミノピリジン（触媒量）を加え、室温で２４時間攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９８：２－０：１００）を用いて精製し、標記目的化合物（７．２１ｇ、収率４９％）を得た。 Reference Example 35 cis-4- [5- (Methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -tert-butyl carboxylate 5- [cis-octahydroquinoxaline prepared in Reference Example 34 -1 (2H) -yl] pyrazine-2-carboxylate (10.9 g, 39.3 mmol) in dichloromethane (200 mL) and di-tert-butyl dicarbonate (10.3 g, 47.2 mmol) and 4-Dimethylaminopyridine (catalytic amount) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 98: 2-0: 100) to give the title object compound (7.21 g, yield 49%). Obtained.
　（参考例３６）ｃｉｓ－４－［３－ブロモ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル
　参考例３５で製造したｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル（７．２０ｇ、１９．１ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（１００ｍＬ）に溶解し、Ｎ－ブロモスクシンイミド（５．１１ｇ、２８．７ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物（２．５０ｇ、収率２９％）を得た。 Reference Example 36 cis-4- [3-Bromo-5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -tert-butyl carboxylate cis-4-prepared in Reference Example 35 Dissolve tert-butyl [5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate (7.20 g, 19.1 mmol) in N, N-dimethylformamide (100 mL); N-bromosuccinimide (5.11 g, 28.7 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to give the title object compound (2.50 g, yield 29%).
　（参考例３７）６－ブロモ－５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチル
　参考例３６で製造したｃｉｓ－４－［３－ブロモ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル（４．７５ｇ、１０．４ｍｍｏｌ）をジクロロメタン（８０ｍＬ）に溶解し、トリフルオロ酢酸（２０ｍＬ）を加え、室温で１．５時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をジクロロエタン（１００ｍＬ）に溶解し、１－Ｂｏｃ－４－ピペリドン（４．１４ｇ、２０．８ｍｍｏｌ）を加え、７０℃で２時間攪拌した。反応液を室温まで冷却後、トリアセトキシ水素化ホウ素ナトリウム（４．４１ｇ、２０．８ｍｍｏｌ）を加え、７０℃で１８時間攪拌した。反応液に再び１－Ｂｏｃ－４－ピペリドン（４．１４ｇ、２０．８ｍｍｏｌ）と、トリアセトキシ水素化ホウ素ナトリウム（４．４１ｇ、２０．８ｍｍｏｌ）を加え、７０℃で４時間攪拌した。反応液を氷冷後、飽和炭酸水素ナトリウム水溶液（約１００ｍＬ）を加え、１５分間攪拌した。反応液をクロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物（４．２３ｇ、収率７６％）を得た。 Reference Example 37 Methyl 6-bromo-5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylate Reference The cis-4- [3-bromo-5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate tert-butyl (4.75 g, 10.4 mmol) prepared in Example 36 was used. It melt | dissolved in the dichloromethane (80 mL), trifluoroacetic acid (20 mL) was added, and it stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in dichloroethane (100 mL), 1-Boc-4-piperidone (4.14 g, 20.8 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hr. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (4.41 g, 20.8 mmol) was added, and the mixture was stirred at 70 ° C. for 18 hr. 1-Boc-4-piperidone (4.14 g, 20.8 mmol) and sodium triacetoxyborohydride (4.41 g, 20.8 mmol) were again added to the reaction solution, and the mixture was stirred at 70 ° C. for 4 hours. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution (about 100 mL) was added, and the mixture was stirred for 15 min. The reaction solution was extracted three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to give the title object compound (4.23 g, yield 76%).
　（参考例３８）５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－メチルピラジン－２－カルボン酸メチル
　参考例３７で製造した６－ブロモ－５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチル（３．１３ｇ、５．８１ｍｍｏｌ）をジメトキシエタン（６０ｍＬ）に溶解し、メチルボロン酸（１．０４ｇ、１７．４ｍｍｏｌ）、炭酸カリウム（４．８２ｇ、３４．９ｍｍｏｌ）、及び１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）二塩化物ジクロロメタン錯体（４７５ｍｇ、０．５８０ｍｍｏｌ）を加え、７０℃で２時間攪拌した。反応液に酢酸エチルを加えた後、水、飽和炭酸水素ナトリウム、及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物（１．６４ｇ、収率６０％）を得た。 Reference Example 38 Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2-carboxylate Reference Methyl 6-bromo-5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylate prepared in Example 37 ( 3.13 g, 5.81 mmol) are dissolved in dimethoxyethane (60 mL), methylboronic acid (1.04 g, 17.4 mmol), potassium carbonate (4.82 g, 34.9 mmol), and 1,1′-bis ( Add diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (475 mg, 0.580 mmol) It was stirred for 2 hours at 70 ° C.. Ethyl acetate was added to the reaction solution, followed by washing with water, saturated sodium hydrogen carbonate, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain the title object compound (1.64 g, yield 60%). .
　（参考例３９）４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例３８で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－メチルピラジン－２－カルボン酸メチル（１．４４ｇ、３．０４ｍｍｏｌ）をエタノール（４０ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（９ｍＬ）を加え、室温で３時間攪拌した後、１Ｎ－塩酸水溶液（９ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をジクロロメタン（５０ｍＬ）に溶解し、エチルアミン（２．０Ｍテトラヒドロフラン溶液）（６．０８ｍＬ、１２．２ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（１．１７ｇ、６．０８ｍｍｏｌ）、及び１－ヒドロキシ－７－アザベンゾトリアゾール（６９８ｍｇ、４．５６ｍｍｏｌ）を加え、窒素雰囲気下、室温で三日間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで３回抽出した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８０：２０－０：１００）を用いて精製し、標記目的化合物（１．４０ｇ、収率９５％）を得た。 (Reference Example 39) tert-butyl 4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate Reference Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2-carboxylate prepared in Example 38 1.44 g, 3.04 mmol) was dissolved in ethanol (40 mL), 1N-aqueous sodium hydroxide solution (9 mL) was added, and the mixture was stirred at room temperature for 3 hours. Then, 1N-hydrochloric acid aqueous solution (9 mL) was added, and the mixture was concentrated under reduced pressure. . Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (50 mL). Ethylamine (2.0 M tetrahydrofuran solution) (6.08 mL, 12.2 mmol), 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (1.17 g, 6.08 mmol) and 1-hydroxy-7-azabenzotriazole (698 mg, 4.56 mmol) were added, and the mixture was stirred at room temperature for 3 days under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 80: 20-0: 100) to obtain the title object compound (1.40 g, yield 95%).
　（参考例４０）５－クロロ－Ｎ－エチル－６－［ｔｒａｎｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例１で製造した５，６－ジクロロ－Ｎ－エチルニコチンアミドとｔｒａｎｓ－デカヒドロキノキサリンを用いて、参考例２と同様に反応を行い、標記目的化合物を得た。 Reference Example 40 5-Chloro-N-ethyl-6- [trans-octahydroquinoxalin-1 (2H) -yl] nicotinamide 5,6-Dichloro-N-ethylnicotinamide prepared in Reference Example 1 and trans -Decahydroquinoxaline was used in the same manner as in Reference Example 2 to obtain the title compound.
　（参考例４１）４－［ｔｒａｎｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例４０で製造した５－クロロ－Ｎ－エチル－６－［ｔｒａｎｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミドを用いて、参考例３と同様に反応を行い、標記目的化合物を得た。 Reference Example 41 4- [trans-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-N-ethyl-6- [trans-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 40, the reaction was carried out in the same manner as in Reference Example 3 to obtain the title target compound. It was.
　（参考例４２）ｃｉｓ－テトラヒドロフロ［３，４－ｂ］ピラジン－２，３（１Ｈ，４Ｈ）－ジオン
　塩酸ｃｉｓ－３，４－ジアミノテトラヒドロフラン（６６７ｍｇ、３．８１ｍｍｏｌ）のメタノール（９０ｍＬ）溶液に、ジクロロメタン（１０ｍＬ）及びアルゴゲルトリスアミン樹脂（５．６２ｇ、１５．２ｍｍｏｌ）を室温にて加えた。室温にて１４時間攪拌したのち、樹脂をろ過して濾液を減圧下濃縮した。得られた残渣にメタノール（８０ｍＬ）、シュウ酸ジメチル（４５０ｍｇ、３．８１ｍｍｏｌ）を室温にて加えた。２４時間加熱還流したのち反応液を室温まで冷却し、減圧下濃縮した。得られた残渣に少量のメタノールとクロロホルム（１５ｍＬ）を加えて析出した固体を濾過し、標記目的化合物（２８７ｍｇ、収率４８％）を得た。 Reference Example 42 cis-tetrahydrofuro [3,4-b] pyrazine-2,3 (1H, 4H) -dione A solution of cis-3,4-diaminotetrahydrofuran (667 mg, 3.81 mmol) in methanol (90 mL) To this was added dichloromethane (10 mL) and Argogeltrisamine resin (5.62 g, 15.2 mmol) at room temperature. After stirring at room temperature for 14 hours, the resin was filtered and the filtrate was concentrated under reduced pressure. Methanol (80 mL) and dimethyl oxalate (450 mg, 3.81 mmol) were added to the obtained residue at room temperature. After heating under reflux for 24 hours, the reaction solution was cooled to room temperature and concentrated under reduced pressure. A small amount of methanol and chloroform (15 mL) were added to the resulting residue, and the precipitated solid was filtered to obtain the title object compound (287 mg, yield 48%).
　（参考例４３）ｃｉｓ－オクタヒドロフロ［３，４－ｂ］ピラジン
　参考例４２で製造したｃｉｓ－テトラヒドロフロ［３，４－ｂ］ピラジン－２，３（１Ｈ，４Ｈ）－ジオンを用いて参考例２７と同様の反応を行い、標記目的化合物を得た。 (Reference Example 43) cis-octahydrofuro [3,4-b] pyrazine Using cis-tetrahydrofuro [3,4-b] pyrazine-2,3 (1H, 4H) -dione prepared in Reference Example 42 The same reaction as in Reference Example 27 was performed to obtain the title object compound.
　（参考例４４）５－クロロ－Ｎ－エチル－６－［ｃｉｓ－ヘキサヒドロフロ［３，４－ｂ］ピラジン－１（２Ｈ）－イル］ニコチンアミド
　参考例４３で製造したｃｉｓ－オクタヒドロフロ［３，４－ｂ］ピラジンを用いて参考例５と同様の反応を行い、標記目的化合物を得た。 Reference Example 44 5-Chloro-N-ethyl-6- [cis-hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] nicotinamide cis-octahydrofuro prepared in Reference Example 43 The same reaction as in Reference Example 5 was carried out using [3,4-b] pyrazine to obtain the title object compound.
　（参考例４５）４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］ヘキサヒドロフロ［３，４－ｂ］ピラジン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例４４で製造した５－クロロ－Ｎ－エチル－６－［ｃｉｓ－ヘキサヒドロフロ［３，４－ｂ］ピラジン－１（２Ｈ）－イル］ニコチンアミドを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 45 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] piperidine- Tert-butyl 1-carboxylate Using 5-chloro-N-ethyl-6- [cis-hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] nicotinamide prepared in Reference Example 44 The same reaction as in Reference Example 3 was performed to obtain the title object compound.
　（参考例４６）５，６－ジブロモ－Ｎ－シクロプロピルニコチンアミド
　５，６－ジブロモニコチン酸とシクロプロピルアミンを用いて、参考例１と同様に反応を行い、標記目的化合物を得た。 Reference Example 46 5,6-Dibromo-N-cyclopropylnicotinamide Using 5,6-dibromonicotinic acid and cyclopropylamine, a reaction was carried out in the same manner as in Reference Example 1 to obtain the title compound.
　（参考例４７）５－ブロモ－Ｎ－シクロプロピル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例４６で製造した５，６－ジブロモ－Ｎ－シクロプロピルニコチンアミドとｃｉｓ－デカヒドロキノキサリンを用いて、参考例２と同様に反応を行い、標記目的化合物を得た。 Reference Example 47 5-Bromo-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide 5,6-Dibromo-N-cyclopropylnicotinamide prepared in Reference Example 46 And cis-decahydroquinoxaline were reacted in the same manner as in Reference Example 2 to obtain the title compound.
　（参考例４８）４－［ｃｉｓ－４－［３－ブロモ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例４７で製造した５－ブロモ－Ｎ－シクロプロピル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミドを用いて、参考例３と同様に反応を行い、標記目的化合物を得た。 Reference Example 48 4- [cis-4- [3-Bromo-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Using 5-bromo-N-cyclopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Reference Example 47, the reaction was carried out in the same manner as in Reference Example 3 to obtain the title target compound. Got.
　（参考例４９）４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例４８で製造した４－［ｃｉｓ－４－［３－ブロモ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて、参考例１０と同様に反応を行い、標記目的化合物を得た。 Reference Example 49 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-Bromo-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- prepared in Reference Example 48 The reaction was conducted in the same manner as in Reference Example 10 using butyl to obtain the title object compound.
　（参考例５０）４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例３８で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－メチルピラジン－２－カルボン酸メチル（９７０ｍｇ、２．０５ｍｍｏｌ）をシクロプロピルアミン（４ｍＬ）に溶解し、マイクロウェーブ反応装置にて１６０℃で１時間攪拌した。反応液を減圧濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９５：５－６０：４０）を用いて精製し、標記目的化合物のラセミ体（８６７ｍｇ、収率８４％）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール：ヘキサン＝３０：７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール：ヘキサン＝３０：７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が３．４分の化合物（３３７ｍｇ、２３％）と保持時間が５．２分の化合物（５１４ｍｇ、３５％）を得た。保持時間が３．４分の化合物を参考例５０とする。 Reference Example 50 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2-carboxylate prepared in Reference Example 38 (970 mg, 2.05 mmol) was dissolved in cyclopropylamine (4 mL) and stirred at 160 ° C. for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using NH silica gel column chromatography (hexane: ethyl acetate, 95: 5-60: 40) to give the racemic title compound (867 mg, 84% yield). ) This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol: hexane = 30: 70, 10 mL / min, 254 nm), and HPLC (Chiralcel AD -H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol: hexane = 30: 70, 2.0 mL / min, 254 nm) and retention time of 3.4 min with compound (337 mg, 23%) The compound (514 mg, 35%) was obtained with a time of 5.2 minutes. A compound having a retention time of 3.4 minutes is defined as Reference Example 50.
　（参考例５１）４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例５０の保持時間５．２分の化合物。 Reference Example 51 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl A compound of Reference Example 50 having a retention time of 5.2 minutes.
　（参考例５２）５，６－ジクロロ－Ｎ－イソプロピルニコチンアミド
　イソプロピルアミンを用いて参考例４と同様の反応を行い、標記目的化合物を得た。 Reference Example 52 5,6-Dichloro-N-isopropylnicotinamide The same reaction as in Reference Example 4 was performed using isopropylamine to obtain the title target compound.
　（参考例５３）５－クロロ－Ｎ－イソプロピル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例５２で製造した５，６－ジクロロ－Ｎ－イソプロピルニコチンアミドを用いて参考例２と同様の反応を行い、標記目的化合物を得た。 Reference Example 53 5-Chloro-N-isopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide Using 5,6-dichloro-N-isopropylnicotinamide prepared in Reference Example 52 In the same manner as in Reference Example 2, the title target compound was obtained.
　（参考例５４）４－［ｃｉｓ－４－［３－クロロ－５－（イソプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例５３で製造した５－クロロ－Ｎ－イソプロピル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミドを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 54 4- [cis-4- [3-chloro-5- (isopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-N-isopropyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Example 53, the same reaction as in Reference Example 3 was carried out to obtain the title target compound. .
　（参考例５５）５，６－ジクロロ－Ｎ－プロピルニコチンアミド
　ｎ－プロピルアミンを用いて参考例４と同様の反応を行い、標記目的化合物を得た。 Reference Example 55 5,6-Dichloro-N-propylnicotinamide Using n-propylamine, the same reaction as in Reference Example 4 was carried out to obtain the title object compound.
　（参考例５６）５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－プロピルニコチンアミド
　参考例５５で製造した５，６－ジクロロ－Ｎ－プロピルニコチンアミドを用いて参考例２と同様の反応を行い、標記目的化合物を得た。 Reference Example 56 5-Chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] -N-propylnicotinamide Using 5,6-dichloro-N-propylnicotinamide prepared in Reference Example 55 In the same manner as in Reference Example 2, the title target compound was obtained.
　（参考例５７）４－［ｃｉｓ－４－［３－クロロ－５－（プロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例５６で製造した５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－プロピルニコチンアミドを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 57 4- [cis-4- [3-Chloro-5- (propylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference Using 5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] -N-propylnicotinamide prepared in Example 56, the same reaction as in Reference Example 3 was carried out to obtain the title target compound. .
　（参考例５８）Ｎ－ｔｅｒｔ－ブチル－５，６－ジクロロニコチンアミド
　ｔｅｒｔ－ブチルアミンを用いて参考例４と同様の反応を行い、標記目的化合物を得た。 Reference Example 58 N-tert-butyl-5,6-dichloronicotinamide A reaction similar to that of Reference Example 4 was carried out using tert-butylamine to obtain the title compound.
　（参考例５９）Ｎ－ｔｅｒｔ－ブチル－５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド
　参考例５８で製造したＮ－ｔｅｒｔ－ブチル－５，６－ジクロロニコチンアミドを用いて参考例２と同様の反応を行い、標記目的化合物を得た。 Reference Example 59 N-tert-butyl-5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide N-tert-butyl-5,6-dichloro prepared in Reference Example 58 The same reaction as in Reference Example 2 was performed using nicotinamide to obtain the title object compound.
　（参考例６０）４－［ｃｉｓ－４－［５－（ｔｅｒｔ－ブチルカルバモイル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例５９で製造したＮ－ｔｅｒｔ－ブチル－５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミドを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 60 4- [cis-4- [5- (tert-butylcarbamoyl) -3-chloropyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- Butyl Using N-tert-butyl-5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide prepared in Reference Example 59, the same reaction as in Reference Example 3 was carried out. A compound was obtained.
　（参考例６１）５－（ブロモメチル）－２－クロロ安息香酸エチル
　６－クロロ－３－メチル安息香酸エチルを用いて参考例１８と同様の反応を行い、標記目的化合物を得た。 Reference Example 61 Ethyl 5- (bromomethyl) -2-chlorobenzoate Using ethyl 6-chloro-3-methylbenzoate, the reaction was carried out in the same manner as in Reference Example 18 to obtain the title target compound.
　（参考例６２）５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－エチルピラジン－２－カルボン酸メチル
　参考例３７で製造した６－ブロモ－５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチル（５４０ｍｇ、１．００ｍｍｏｌ）をジメトキシエタン（１０ｍＬ）に溶解し、エチルボロン酸（２２２ｍｇ、３．００ｍｍｏｌ）、炭酸カリウム（８３２ｍｇ、６．００ｍｍｏｌ）、及び１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）二塩化物ジクロロメタン錯体（８２ｍｇ、０．１００ｍｍｏｌ）を加え、７０℃で１．５時間攪拌した。反応液に酢酸エチルを加えた後、水、飽和炭酸水素ナトリウム、及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８０：２０－０：１００）を用いて精製し、標記目的化合物（４４５ｍｇ、収率９１％）を得た。 Reference Example 62 Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-ethylpyrazine-2-carboxylate Reference Methyl 6-bromo-5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylate prepared in Example 37 ( 540 mg, 1.00 mmol) is dissolved in dimethoxyethane (10 mL), ethylboronic acid (222 mg, 3.00 mmol), potassium carbonate (832 mg, 6.00 mmol), and 1,1′-bis (diphenylphosphino) ferrocene— Palladium (II) dichloride dichloromethane complex (82 mg, 0.100 mmol) was added, And the mixture was stirred for 1.5 hours at 0 ℃. Ethyl acetate was added to the reaction solution, followed by washing with water, saturated sodium hydrogen carbonate, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 80: 20-0: 100) to give the title object compound (445 mg, yield 91%).
　（参考例６３）４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例６２で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－エチルピラジン－２－カルボン酸メチルを用いて、参考例５０と同様に反応を行い、標記目的化合物を得た。 Reference Example 63 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-ethylpyrazine-2-carboxylate prepared in Reference Example 62 Was used in the same manner as in Reference Example 50 to give the title object compound.
　（参考例６４）３－クロロ－２－メチル安息香酸エチル
　３－クロロ－２－メチル安息香酸とエタノールを用いて参考例１７と同様の反応を行い、標記目的化合物を得た。 Reference Example 64 Ethyl 3-chloro-2-methylbenzoate The same reaction as in Reference Example 17 was performed using 3-chloro-2-methylbenzoic acid and ethanol to obtain the title target compound.
　（参考例６５）２－（ブロモメチル）－３－クロロ安息香酸エチル
　参考例６４で製造した３－クロロ－２－メチル安息香酸エチルを用いて参考例１８と同様の反応を行い、標記目的化合物を得た。 Reference Example 65 Ethyl 2- (bromomethyl) -3-chlorobenzoate The same reaction as in Reference Example 18 was carried out using ethyl 3-chloro-2-methylbenzoate prepared in Reference Example 64, and the title compound was obtained. Obtained.
　（参考例６６）４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例３４で製造した５－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチルを用いて、参考例３と同様に反応を行い５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチルを製造した後、参考例５０と同様に反応を行い、標記目的化合物を得た。 (Reference Example 66) tert-butyl 4- [cis-4- [5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate In Reference Example 34 Using the produced methyl 5- [cis-octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylate, the reaction was carried out in the same manner as in Reference Example 3 to obtain 5- [cis-4- [1- (tert -Butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylate methyl was prepared and reacted in the same manner as in Reference Example 50 to obtain the title compound.
　（参考例６７）ｃｉｓ－１－（３－クロロ－５－ニトロピリジン－２－イル）デカヒドロキノキサリン
　２，３－ジクロロ－５－ニトロピリジンを用いて参考例２と同様に反応を行い、標記目的化合物を得た。 (Reference Example 67) cis-1- (3-Chloro-5-nitropyridin-2-yl) decahydroquinoxaline The reaction was conducted in the same manner as in Reference Example 2 using 2,3-dichloro-5-nitropyridine. The target compound was obtained.
　（参考例６８）４－［ｃｉｓ－４－（３－クロロ－５－ニトロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例６７で製造したｃｉｓ－１－（３－クロロ－５－ニトロピリジン－２－イル）デカヒドロキノキサリンを用いて、参考例３と同様に反応を行い、標記目的化合物を得た。 (Reference Example 68) tert-Butyl 4- [cis-4- (3-chloro-5-nitropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate In Reference Example 67 Using the produced cis-1- (3-chloro-5-nitropyridin-2-yl) decahydroquinoxaline, the reaction was carried out in the same manner as in Reference Example 3 to obtain the title object compound.
　（参考例６９）ｃｉｓ－１－（３－クロロ－５－ニトロピリジン－２－イル）－４－ピペリジン－４－イルデカヒドロキノキサリン
　参考例６８で製造した４－［ｃｉｓ－４－（３－クロロ－５－ニトロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（４．５７ｇ、９．５４ｍｍｏｌ）をジクロロメタン（１００ｍＬ）に溶解し、トリフルオロ酢酸（２５ｍＬ）を加え、室温で１時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール、１００：０－８０：２０）を用いて精製し、標記目的化合物（２．０５ｇ、収率５７％）を得た。 Reference Example 69 cis-1- (3-Chloro-5-nitropyridin-2-yl) -4-piperidin-4-yldecahydroquinoxaline 4- [cis-4- (3- Chloro-5-nitropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate (4.57 g, 9.54 mmol) was dissolved in dichloromethane (100 mL) Fluoroacetic acid (25 mL) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. The resulting residue was purified using NH silica gel column chromatography (ethyl acetate: methanol, 100: 0-80: 20) to obtain the title object compound (2.05 g, yield 57%).
　（参考例７０）５－クロロ－２－（｛４－［ｃｉｓ－４－（３－クロロ－５－ニトロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル
　参考例６９で製造したｃｉｓ－１－（３－クロロ－５－ニトロピリジン－２－イル）－４－ピペリジン－４－イルデカヒドロキノキサリン（２．０５ｇ、５．４１ｍｍｏｌ）と２－（ブロモメチル）－５－クロロ安息香酸メチル（１．５７ｇ、５．９５ｍｍｏｌ）を２－プロパノール（２０ｍＬ）とアセトニトリル（１０ｍＬ）の混合溶媒に溶解し、ジイソプロピルエチルアミン（１．８８ｍＬ、１０．８ｍｍｏｌ）を加え室温で１８時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物のラセミ体（２．７７ｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が１１．８分の化合物（１．２４ｇ、収率４１％）と保持時間が６．７分の化合物（１．２８ｇ、収率４２％）を得た。保持時間が１１．８分の化合物を参考例７０とする。 Reference Example 70 5-Chloro-2-({4- [cis-4- (3-chloro-5-nitropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl } Methyl) methyl benzoate cis-1- (3-chloro-5-nitropyridin-2-yl) -4-piperidin-4-yldecahydroquinoxaline (2.05 g, 5.41 mmol) prepared in Reference Example 69 And methyl 2- (bromomethyl) -5-chlorobenzoate (1.57 g, 5.95 mmol) are dissolved in a mixed solvent of 2-propanol (20 mL) and acetonitrile (10 mL), and diisopropylethylamine (1.88 mL, 10.5 mL) is dissolved. 8 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain the racemic form (2.77 g) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = 30/70, 10 mL / min, 254 nm), and HPLC (Chiralcel AD —H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) compound having a retention time of 11.8 min (1.24 g, yield 41) %) And a retention time of 6.7 minutes (1.28 g, 42% yield). A compound having a retention time of 11.8 minutes is defined as Reference Example 70.
　（参考例７１）５－クロロ－２－（｛４－［ｃｉｓ－４－（３－クロロ－５－ニトロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル
　参考例７０における保持時間が６．７分の化合物。 Reference Example 71 5-Chloro-2-({4- [cis-4- (3-chloro-5-nitropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl } Methyl) Methyl benzoate The compound in Reference Example 70 having a retention time of 6.7 minutes.
　（参考例７２）２－（｛４－［ｃｉｓ－４－（５－アミノ－３－クロロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸メチル
　参考例７０の５－クロロ－２－（｛４－［ｃｉｓ－４－（３－クロロ－５－ニトロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル（１．２４ｇ、２．２１ｍｍｏｌ）をメタノール（３０ｍＬ）とテトラヒドロフラン（１０ｍＬ）の混合溶媒に溶解し、亜鉛末（２．１７ｇ、３３．１ｍｍｏｌ）を加えた後、酢酸（１．２ｍＬ）を滴下した。反応液３時間加熱還流した後、反応液を室温まで冷却し、セライト濾過した。母液を減圧濃縮し、得られた残渣に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水、及び飽和食塩水で洗浄し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール、１００：０－８０：２０）を用いて精製し、標記目的化合物（８９０ｍｇ、収率７３％）を得た。 Reference Example 72 2-({4- [cis-4- (5-amino-3-chloropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl)- Methyl 5-chlorobenzoate 5-chloro-2-({4- [cis-4- (3-chloro-5-nitropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] of Reference Example 70 Piperidin-1-yl} methyl) methyl benzoate (1.24 g, 2.21 mmol) is dissolved in a mixed solvent of methanol (30 mL) and tetrahydrofuran (10 mL), and zinc dust (2.17 g, 33.1 mmol) is added. After that, acetic acid (1.2 mL) was added dropwise. After the reaction solution was heated to reflux for 3 hours, the reaction solution was cooled to room temperature and filtered through celite. The mother liquor was concentrated under reduced pressure, ethyl acetate was added to the resulting residue, washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol, 100: 0-80: 20) to obtain the title object compound (890 mg, yield 73%).
　（参考例７３）２－（｛４－［ｃｉｓ－４－（５－アミノ－３－クロロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸メチル
　参考例７１の５－クロロ－２－（｛４－［ｃｉｓ－４－（３－クロロ－５－ニトロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチルを用いて、参考例７２と同様に反応を行い、標記目的化合物を得た。 Reference Example 73 2-({4- [cis-4- (5-amino-3-chloropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl)- Methyl 5-chlorobenzoate 5-chloro-2-({4- [cis-4- (3-chloro-5-nitropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] of Reference Example 71 Using piperidin-1-yl} methyl) methyl benzoate, the reaction was carried out in the same manner as in Reference Example 72 to obtain the title compound.
　（参考例７４）４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例６２で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－エチルピラジン－２－カルボン酸メチルを用いて、参考例３９と同様に反応を行い、標記目的化合物を得た。 (Reference Example 74) tert-butyl 4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate Reference The methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-ethylpyrazine-2-carboxylate prepared in Example 62 was And the title compound was obtained in the same manner as in Reference Example 39.
　（参考例７５）５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチン酸エチル
　５，６－ジクロロニコチン酸エチルを用いて参考例２と同様の反応を行い、標記目的化合物を得た。 (Reference Example 75) Ethyl 5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinate Using ethyl 5,6-dichloronicotinate, the same reaction as in Reference Example 2 was carried out. The target compound was obtained.
　（参考例７６）６－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－５－クロロニコチン酸エチル
　参考例７５で製造した５－クロロ－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチン酸エチルを用いて参考例３と同様の反応を行い、標記目的化合物を得た。 Reference Example 76 Ethyl 6- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -5-chloronicotinate Prepared in Reference Example 75 The same reaction as in Reference Example 3 was performed using ethyl 5-chloro-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinate to obtain the title compound.
　（参考例７７）４－［ｃｉｓ－４－［３－クロロ－５－（ヒドラジノカルボニル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　６－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－５－クロロニコチン酸エチル（参考例７６）（５７６ｍｇ、１．１４ｍｍｏｌ）のエタノール（３ｍＬ）溶液に、室温にてヒドラジン一水和物（０．５６２ｍＬ、１１．４ｍｍｏｌ）を加えた。８０℃にて２４時間攪拌後、反応液を減圧下濃縮し、得られた残渣に酢酸エチル（５．０ｍＬ）及び水（３．０ｍＬ）を加え分液した。有機層を水（２ｘ３．０ｍＬ）で洗浄し、無水硫酸ナトリウムにて乾燥したのち、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｍ、メタノール／クロロホルム、１００：０－９２：２）を用いて精製し、標記目的化合物（２２６ｍｇ、収率４０％）を得た。 Reference Example 77 4- [cis-4- [3-Chloro-5- (hydrazinocarbonyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Ethyl 6- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -5-chloronicotinate (Reference Example 76) (576 mg, 1. 14 mmol) in ethanol (3 mL) was added hydrazine monohydrate (0.562 mL, 11.4 mmol) at room temperature. After stirring at 80 ° C. for 24 hours, the reaction mixture was concentrated under reduced pressure, and ethyl acetate (5.0 mL) and water (3.0 mL) were added to the resulting residue for liquid separation. The organic layer was washed with water (2 × 3.0 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 40M, methanol / chloroform, 100: 0-92: 2) to obtain the title object compound (226 mg, yield 40%).
　（参考例７８）４－［ｃｉｓ－４－［５－（５－アミノ－１，３，４－オキサジアゾール－２－イル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－［ｃｉｓ－４－［３－クロロ－５－（ヒドラジノカルボニル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例７７）（２２６ｍｇ、０．４５８ｍｍｏｌ）のエタノール（３ｍＬ）溶液に、シアン化臭素（５１．７ｍｇ、０．４８８ｍｍｏｌ）を室温にて加えた。室温にて１時間攪拌したのち反応液を減圧下濃縮し、得られた残渣に１０％メタノール／クロロホルム混合液（５ｍＬ）、水（２ｍＬ）および飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加えて分液した。水層を１０％メタノール／クロロホルム混合液（２ｘ３．０ｍＬ）で抽出し、合わせた有機層を無水硫酸ナトリウムにて乾燥したのち、濾液を減圧下濃縮して標記目的化合物（２３１ｍｇ、収率９７％）を得た。 Reference Example 78 4- [cis-4- [5- (5-amino-1,3,4-oxadiazol-2-yl) -3-chloropyridin-2-yl] octahydroquinoxaline-1 ( 2H) -yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-chloro-5- (hydrazinocarbonyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] Bromine cyanide (51.7 mg, 0.488 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (Reference Example 77) (226 mg, 0.458 mmol) in ethanol (3 mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and 10% methanol / chloroform mixture (5 mL), water (2 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL) were added to the resulting residue to separate the layers. did. The aqueous layer was extracted with a 10% methanol / chloroform mixture (2 × 3.0 mL), the combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give the title object compound (231 mg, yield 97%). )
　（参考例７９）ｃｉｓ－４－［３－クロロ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル
　参考例３５で製造したｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル（５．６１ｇ、１４．９ｍｍｏｌ）をＮ、Ｎ－ジメチルホルムアミド（６０ｍＬ）に溶解し、Ｎ－クロロスクシンイミド（２．９９ｇ、２２．４ｍｍｏｌ）を加え、室温で３日間攪拌した。反応液を減圧濃縮し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物（５．６４ｇ、収率９２％）を得た。 Reference Example 79 cis-4- [3-Chloro-5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -tert-butyl carboxylate cis-4-prepared in Reference Example 35 Dissolve tert-butyl [5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate (5.61 g, 14.9 mmol) in N, N-dimethylformamide (60 mL); N-chlorosuccinimide (2.99 g, 22.4 mmol) was added and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain the title object compound (5.64 g, yield 92%).
　（参考例８０）５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル
　参考例７９で製造したｃｉｓ－４－［３－クロロ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル（５．４２ｇ、１３．２ｍｍｏｌ）をジクロロメタン（１００ｍＬ）に溶解し、トリフルオロ酢酸（３０ｍＬ）を加え、室温で２時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をジクロロエタン（１００ｍＬ）に溶解し、１－Ｂｏｃ－４－ピペリドン（５．２６ｇ、２６．４ｍｍｏｌ）を加え、７０℃で１．５時間攪拌した。反応液を室温まで冷却後、トリアセトキシ水素化ホウ素ナトリウム（５．６０ｇ、２６．４ｍｍｏｌ）を加え、７０℃で１８時間攪拌した。反応液に再び１－Ｂｏｃ－４－ピペリドン（５．２６ｇ、２６．４ｍｍｏｌ）と、トリアセトキシ水素化ホウ素ナトリウム（５．６０ｇ、２６．４ｍｍｏｌ）を加え、７０℃で１８時間攪拌した。反応液を氷冷後、飽和炭酸水素ナトリウム水溶液（約１００ｍＬ）を加え、１５分間攪拌した。反応液をクロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物（４．１４ｇ、収率６３％）を得た。 Reference Example 80 Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-chloropyrazine-2-carboxylate Reference The cis-4- [3-chloro-5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate tert-butyl (5.42 g, 13.2 mmol) prepared in Example 79 was It melt | dissolved in the dichloromethane (100 mL), trifluoroacetic acid (30 mL) was added, and it stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in dichloroethane (100 mL), 1-Boc-4-piperidone (5.26 g, 26.4 mmol) was added, and the mixture was stirred at 70 ° C. for 1.5 hr. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (5.60 g, 26.4 mmol) was added, and the mixture was stirred at 70 ° C. for 18 hr. 1-Boc-4-piperidone (5.26 g, 26.4 mmol) and sodium triacetoxyborohydride (5.60 g, 26.4 mmol) were added to the reaction solution again, and the mixture was stirred at 70 ° C. for 18 hours. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution (about 100 mL) was added, and the mixture was stirred for 15 min. The reaction solution was extracted three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain the title object compound (4.14 g, yield 63%).
　（参考例８１）４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例８０で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル（２．２９ｇ、４．６４ｍｍｏｌ）をシクロプロピルアミン（６ｍＬ）に溶解し、マイクロウェーブ反応装置にて１５０℃で１時間攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製し、標記目的化合物（１．５５ｇ、収率６５％）を得た。 Reference Example 81 4- [cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-chloropyrazine-2-carboxylate prepared in Reference Example 80 (2.29 g, 4.64 mmol) was dissolved in cyclopropylamine (6 mL) and stirred at 150 ° C. for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) to give the title object compound (1.55 g, yield 65%). Obtained.
　（参考例８２）４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例８０で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル（１．８１ｇ、３．６６ｍｍｏｌ）をエタノール（６０ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（１０．９ｍＬ）を加え、室温で４時間攪拌した後、１Ｎ－塩酸水溶液（１０．９ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をＮ，Ｎ－ジメチルアセトアミド（４０ｍＬ）に溶解し、エチルアミン（２．０Ｍテトラヒドロフラン溶液）（３．６６ｍＬ、７．３２ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（１．４０ｇ、７．３２ｍｍｏｌ）、１－ヒドロキシ－７－アザベンゾトリアゾール（１．１２ｇ、７．３２ｍｍｏｌ）、及びジイソプロピルエチルアミン（１．２４ｍＬ、７．３２ｍｍｏｌ）を加え、窒素雰囲気下、室温で１８時間攪拌した。反応液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８０：２０－０：１００）を用いて精製し、標記目的化合物（１．５１ｇ、収率８１％）を得た。 Reference Example 82 tert-Butyl 4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate Reference Methyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-chloropyrazine-2-carboxylate prepared in Example 80 ( 1.81 g, 3.66 mmol) was dissolved in ethanol (60 mL), 1N aqueous sodium hydroxide solution (10.9 mL) was added, and the mixture was stirred at room temperature for 4 hours, and then 1N aqueous hydrochloric acid solution (10.9 mL) was added. And concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylacetamide (40 mL), and ethylamine (2.0 M tetrahydrofuran solution) (3.66 mL, 7.32 mmol), 1- (3-dimethylamino) was obtained. Propyl) -3-ethylcarbodiimide hydrochloride (1.40 g, 7.32 mmol), 1-hydroxy-7-azabenzotriazole (1.12 g, 7.32 mmol), and diisopropylethylamine (1.24 mL, 7.32 mmol) And stirred at room temperature for 18 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 80: 20-0: 100) to obtain the title object compound (1.51 g, yield 81%).
　（参考例８３）５－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピラジン－２－カルボン酸メチル
　５－クロロピラジン－２－カルボン酸メチル（５．１９ｇ、３０．１ｍｍｏｌ）の２－プロパノール（２５ｍＬ）溶液に、テトラヒドロフラン（２５ｍＬ）、ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン（参考例２７）（７．５９ｇ、６０．１ｍｍｏｌ）およびジイソプロピルエチルアミン（７．８６ｍＬ、４５．１ｍｍｏｌ）を加えた。室温にて７時間攪拌したのち、反応液に５－クロロピラジン－２－カルボン酸メチル（２．０８ｇ、１２．０ｍｍｏｌ）を加えて、さらに室温にて４時間半撹拌した。反応液を減圧下濃縮し、得られた残渣に２０％メタノール／クロロホルム混合液（５０ｍＬ）及び飽和炭酸水素ナトリウム水溶液（７０ｍＬ）を加え分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ２０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＢｉｏｔａｇｅＮＨ　４０Ｓ、酢酸エチル）を用いて精製し、標記目的化合物（１０．６ｇ、収率９６％）を得た。 Reference Example 83 Methyl 5- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] pyrazine-2-carboxylate Methyl 5-chloropyrazine-2-carboxylate (5.19 g, 30.1 mmol) In 2-propanol (25 mL), tetrahydrofuran (25 mL), cis-octahydro-1H-cyclopenta [b] pyrazine (Reference Example 27) (7.59 g, 60.1 mmol) and diisopropylethylamine (7.86 mL, 45.45). 1 mmol) was added. After stirring at room temperature for 7 hours, methyl 5-chloropyrazine-2-carboxylate (2.08 g, 12.0 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hours and a half. The reaction mixture was concentrated under reduced pressure, 20% methanol / chloroform mixture (50 mL) and saturated aqueous sodium hydrogen carbonate solution (70 mL) were added to the residue, and the mixture was separated. The aqueous layer was 20% methanol / chloroform mixture (3 × 20 mL). ). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (BiotageNH 40S, ethyl acetate) to obtain the title object compound (10.6 g, yield 96%).
　（参考例８４）ｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピラジン－２－カルボン酸メチル（参考例８３）（１．２７ｇ、４．８４ｍｍｏｌ）の１，４－ジオキサン（５ｍＬ）溶液に、室温にて水（５ｍＬ）、炭酸ナトリウム（１．０８ｇ、１０．２ｍｍｏｌ）およびジ－ｔｅｒｔ－ブチルジカルボナート（１．１１ｇ、５．０８ｍｍｏｌ）を加えた。室温にて５時間攪拌後、反応液を減圧下濃縮し、得られた残渣にクロロホルム（１５ｍＬ）及び水（１０ｍＬ）を加え分液し、水層をクロロホルム（３ｘ２０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｍ、酢酸エチル／クロロホルム、１００：０－６５：３５）を用いて精製し、標記目的化合物（１．１９ｇ、収率６８％）を得た。 Reference Example 84 cis-4- [5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyrazine-1-carboxylate 5- [cis-octahydro-1H-cyclopenta [ b] Methyl pyrazin-1-yl] pyrazine-2-carboxylate (Reference Example 83) (1.27 g, 4.84 mmol) in 1,4-dioxane (5 mL) at room temperature with water (5 mL), carbonic acid Sodium (1.08 g, 10.2 mmol) and di-tert-butyl dicarbonate (1.11 g, 5.08 mmol) were added. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure, chloroform (15 mL) and water (10 mL) were added to the resulting residue, and the mixture was separated, and the aqueous layer was extracted with chloroform (3 × 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 40M, ethyl acetate / chloroform, 100: 0-65: 35) to obtain the title object compound (1.19 g, yield 68%).
　（参考例８５）ｃｉｓ－４－［３－クロロ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例８４）（２．０３ｇ、５．６０ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（７５ｍＬ）溶液に、Ｎ－クロロスクシンイミド（１．１２ｇ、８．４０ｍｍｏｌ）を加えた。室温にて１７時間攪拌したのち、反応液に酢酸エチル（５０ｍＬ）及び水（３０ｍＬ）を加え分液し、水層を酢酸エチル（３ｘ２０ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄後、無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｍ、酢酸エチル／クロロホルム、１００：０－９２：２）を用いて精製し、標記目的化合物（１．８３ｇ、収率８２％）を得た。 Reference Example 85 cis-4- [3-Chloro-5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate tert-butyl cis-4- [5- (Methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyrazine-1-carboxylate (Reference Example 84) (2.03 g, 5.60 mmol) in N, N-dimethylformamide (75 mL) ) To the solution was added N-chlorosuccinimide (1.12 g, 8.40 mmol). After stirring at room temperature for 17 hours, ethyl acetate (50 mL) and water (30 mL) were added to the reaction solution and the phases were separated, and the aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 40M, ethyl acetate / chloroform, 100: 0-92: 2) to obtain the title object compound (1.83 g, yield 82%).
　（参考例８６）ｃｉｓ－４－［５－（メトキシカルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［３－クロロ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例８５）（１．８３ｇ、４．６１ｍｍｏｌ）の１，２－ジメトキシエタン（２５ｍＬ）溶液に、炭酸カリウム（１．９１ｇ、１３．８ｍｍｏｌ）、メチルボラン酸（２４５ｍｇ、５．０７ｍｍｏｌ）および１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）二塩化物ジクロロメタン錯体（２８２ｍｇ、０．３４６ｍｍｏｌ）を室温にて加えた。窒素雰囲気下８０℃にて１５時間攪拌したのち、反応液を室温まで冷却してクロロホルム（１５ｍＬ）及び水（１０ｍＬ）を加え分液し、クロロホルム（３ｘ２０ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥して濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｓ、ヘキサン／酢酸エチル、８５：１５－５０：５０）を用いて精製し、標記目的化合物（７０７ｍｇ、収率４１％）を得た。 Reference Example 86 cis-4- [5- (methoxycarbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate tert-butyl cis-4- [3- Chloro-5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyridine-carboxylate (Reference Example 85) (1.83 g, 4.61 mmol) 1,2- To a solution of dimethoxyethane (25 mL), potassium carbonate (1.91 g, 13.8 mmol), methylboranoic acid (245 mg, 5.07 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride Dichloromethane complex (282 mg, 0.346 mmol) was added at room temperature. After stirring at 80 ° C. for 15 hours under a nitrogen atmosphere, the reaction solution was cooled to room temperature, chloroform (15 mL) and water (10 mL) were added, and the mixture was separated, and extracted with chloroform (3 × 20 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 40S, hexane / ethyl acetate, 85: 15-50: 50) to obtain the title object compound (707 mg, yield 41%).
　（参考例８７）ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［５－（メトキシカルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例８６）（５６６ｍｇ、１．５０ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、テトラヒドロフラン（４ｍＬ）、１規定水酸化ナトリウム水溶液（２．００ｍＬ、２．００ｍｍｏｌ）を室温にて加えた。室温にて１８時間攪拌後、反応液を減圧下濃縮し、得られた残渣に２０％メタノール／クロロホルム混合液（５ｍＬ）、水（２ｍＬ）を加えたのち、１規定塩酸にて中和して分液し、２０％メタノール／クロロホルム混合液（３ｘ３．０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮してカルボン酸（４４０ｍｇ）を得た。得られたカルボン酸をＮ，Ｎ－ジメチルホルムアミド（３ｍＬ）に溶解し、室温にてヒドロキシベンゾトリアゾール（１６４ｍｇ、１．２２ｍｍｏｌ）、塩酸１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（２３３ｍｇ、１．２２ｍｍｏｌ）および２Ｍエチルアミンテトラヒドロフラン溶液（０．６０８ｍＬ，０．１．２２ｍｍｏｌ）を加えた。室温にて３時間撹拌後、反応液を減圧下濃縮し、クロロホルム（５ｍＬ）及び飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加え撹拌し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄したのち、無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、酢酸エチル／クロロホルム、１００：０－８５：１５）を用いて精製し、標記目的化合物（４３９ｍｇ、収率７５％）を得た。 Reference Example 87 cis-4- [5- (Ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate tert-butyl cis-4- [5- To a solution of (methoxycarbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyrazine-1-carboxylate (Reference Example 86) (566 mg, 1.50 mmol) in methanol (2 mL) , Tetrahydrofuran (4 mL), 1N aqueous sodium hydroxide solution (2.00 mL, 2.00 mmol) were added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was concentrated under reduced pressure, and 20% methanol / chloroform mixture (5 mL) and water (2 mL) were added to the resulting residue, followed by neutralization with 1N hydrochloric acid. Separated and extracted with 20% methanol / chloroform mixture (3 × 3.0 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain carboxylic acid (440 mg). The obtained carboxylic acid was dissolved in N, N-dimethylformamide (3 mL), and hydroxybenzotriazole (164 mg, 1.22 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (233 mg) at room temperature. 1.22 mmol) and 2M ethylamine tetrahydrofuran solution (0.608 mL, 0.1.22 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, chloroform (5 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred, and the aqueous layer was extracted with chloroform (3 × 3 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 25M, ethyl acetate / chloroform, 100: 0-85: 15) to obtain the title object compound (439 mg, yield 75%).
　（参考例８８）４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例８７）（４３９ｍｇ、１．１３ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、４規定塩酸ジオキサン溶液（２．００ｍＬ、２．００ｍｍｏｌ）を室温にて加えた。１５時間攪拌したのち反応液を減圧下濃縮した。得られた残渣に２０％メタノール／クロロホルム混合液（５ｍＬ）及び飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加え分液し、２０％メタノール／クロロホルム混合液（３ｘ５．０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣を１，２－ジクロロエタン（３ｍＬ）に溶解し、室温にて１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン（２４４ｍｇ、１．２３ｍｍｏｌ）を室温にて加えた。７０℃にて２時間半撹拌した後、室温にて反応液にトリアセトキシホウ水素化ナトリウム（３４４ｍｇ、１．５８ｍｍｏｌ）を加えた。７０℃にて４時間撹拌した後、反応液を室温まで冷却し、クロロホルム（５ｍＬ）および飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加えた。室温にて１時間撹拌した後分液し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、１００：０－９５：５）を用いて精製し、標記目的化合物（４０４ｍｇ、収率９８％）を得た。 Reference Example 88 4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert -Butyl cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate tert-butyl (Reference Example 87) (439 mg, 1. To a solution of 13 mmol) in methanol (2 mL), 4N hydrochloric acid dioxane solution (2.00 mL, 2.00 mmol) was added at room temperature. After stirring for 15 hours, the reaction solution was concentrated under reduced pressure. To the obtained residue, a 20% methanol / chloroform mixture (5 mL) and a saturated aqueous sodium hydrogen carbonate solution (5 mL) were added for liquid separation, and the mixture was extracted with a 20% methanol / chloroform mixture (3 × 5.0 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 1,2-dichloroethane (3 mL), and 1-tert-butoxycarbonyl-4-piperidone (244 mg, 1.23 mmol) was added at room temperature. After stirring at 70 ° C. for 2.5 hours, sodium triacetoxyborohydride (344 mg, 1.58 mmol) was added to the reaction solution at room temperature. After stirring at 70 ° C. for 4 hours, the reaction mixture was cooled to room temperature, and chloroform (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL) were added. After stirring at room temperature for 1 hour, liquid separation was performed, and the aqueous layer was extracted with chloroform (3 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 25M, methanol / chloroform, 100: 0-95: 5) to obtain the title object compound (404 mg, yield 98%).
　（参考例８９）ｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル
　５－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピラジン－２－カルボン酸メチル（参考例８３）（１０．６ｇ、４０．５ｍｍｏｌ）の水（９６ｍＬ）、１，４－ジオキサン（５４ｍＬ）混合溶液に、炭酸ナトリウム（９．０２ｇ、８５．１ｍｍｏｌ）、クロロギ酸ベンジル（６．０８ｍＬ、４２．５ｍｍｏｌ）を０℃にて１０分間滴下した。室温にて１７時間攪拌したのち、反応液にクロロホルム（８０ｍＬ）及び水（３０ｍＬ）を加え分液し、水層をクロロホルム（３ｘ８０ｍＬ）で抽出した。有機層を合わせて飽和炭酸水素ナトリウム水溶液（２ｘ４０ｍＬ）、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥したのち、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル、８０：２０－３５：６５）を用いて精製し、標記目的化合物（１１．２ｇ、収率７０％）を得た。 Reference Example 89 cis-4- [5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] benzyl carboxylic acid 5-benzyl [cis-octahydro-1H-cyclopenta [b] Pyrazin-1-yl] methyl pyrazine-2-carboxylate (Reference Example 83) (10.6 g, 40.5 mmol) in water (96 mL) and 1,4-dioxane (54 mL) were mixed with sodium carbonate (9. 02 g, 85.1 mmol) and benzyl chloroformate (6.08 mL, 42.5 mmol) were added dropwise at 0 ° C. for 10 minutes. After stirring at room temperature for 17 hours, chloroform (80 mL) and water (30 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted with chloroform (3 × 80 mL). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (2 × 40 mL) and saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate, 80: 20-35: 65) to obtain the title object compound (11.2 g, yield 70%).
　（参考例９０）ｃｉｓ－４－［３－ブロモ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル
　参考例８９で製造したｃｉｓ－４－［５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジルを用いて参考例３６と同様の反応を行い、標記目的化合物を得た。 Reference Example 90 cis-4- [3-Bromo-5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate benzyl cis-4 prepared in Reference Example 89 The title target compound was obtained in the same manner as in Reference Example 36 using benzyl-[5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate.
　（参考例９１）ｃｉｓ－４－［３－エチル－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル
　ｃｉｓ－４－［３－ブロモ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル（参考例９０）（６１５ｍｇ、１．２９ｍｍｏｌ）の１，２－ジメトキシエタン（６．５ｍＬ）溶液に、炭酸カリウム（５３６ｍｇ、３．８８ｍｍｏｌ）、エチルボラン酸（１０５ｍｇ、１．４２ｍｍｏｌ）および１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）二塩化物ジクロロメタン錯体（１０６ｍｇ、０．１２９ｍｍｏｌ）を室温にて加えた。窒素雰囲気下８０℃にて１５時間攪拌したのち、反応液を室温まで冷却してクロロホルム（１０．０ｍＬ）及び水（７．５ｍＬ）を加え分液し、クロロホルム（３ｘ５．０ｍＬ）で抽出した。有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥して濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｓ、ヘキサン／酢酸エチル、９５：５－６５：３５）を用いて精製し、標記目的化合物（４３６ｍｇ、収率８０％）を得た。 Reference Example 91 cis-4- [3-Ethyl-5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] benzyl carboxylic acid cis-4- [3-bromo- Benzyl 5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] benzylazine-1-carboxylate (Reference Example 90) (615 mg, 1.29 mmol) in 1,2-dimethoxyethane (6.5 mL) ) Solution of potassium carbonate (536 mg, 3.88 mmol), ethylboranoic acid (105 mg, 1.42 mmol) and 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (106 mg, 0 .129 mmol) was added at room temperature. After stirring at 80 ° C. for 15 hours under a nitrogen atmosphere, the reaction solution was cooled to room temperature, chloroform (10.0 mL) and water (7.5 mL) were added, and the mixture was separated, and extracted with chloroform (3 × 5.0 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Biotage 40S, hexane / ethyl acetate, 95: 5-65: 35) to obtain the title object compound (436 mg, yield 80%).
　（参考例９２）ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル
　参考例９１で製造したｃｉｓ－４－［３－エチル－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジルを用いて参考例３３と同様の反応を行い、標記目的化合物を得た。 Reference Example 92 cis-4- [3-Ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate benzyl cis-4 prepared in Reference Example 91 Using [benzyl]-[3-ethyl-5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate, the same reaction as in Reference Example 33 was carried out to obtain the title target compound. Obtained.
　（参考例９３）４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル（参考例９２）（３１７ｍｇ、０．７２４ｍｍｏｌ）のエタノール（１０ｍＬ）溶液に、７．５％パラジウム炭素触媒（５０ｍｇ）を室温にて加えた。水素気流下常圧で４時間攪拌したのち反応液中の触媒をろ過にて除去し、濾液を減圧下濃縮した。得られた残渣を１，２－ジクロロエタン（３ｍＬ）に溶解し、室温にて１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン（２０２ｍｇ、１．０１ｍｍｏｌ）を室温にて加えた。７０℃にて２時間半撹拌した後、室温にて反応液にトリアセトキシホウ水素化ナトリウム（２８５ｍｇ、１．３０ｍｍｏｌ）を加えた。７０℃にて４時間撹拌した後、反応液を室温まで冷却し、クロロホルム（５ｍＬ）および飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加えた。室温にて１時間撹拌した後分液し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、１００：０－９４：６）を用いて精製し、標記目的化合物（２９５ｍｇ、収率８４％）を得た。 Reference Example 93 4- {cis-4- [5- (ethylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert -Butyl cis-4- [3-Ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] benzyl carboxylate (Reference Example 92) (317 mg, 0.724 mmol) To an ethanol (10 mL) solution, 7.5% palladium carbon catalyst (50 mg) was added at room temperature. After stirring at normal pressure for 4 hours under a hydrogen stream, the catalyst in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 1,2-dichloroethane (3 mL), and 1-tert-butoxycarbonyl-4-piperidone (202 mg, 1.01 mmol) was added at room temperature. After stirring at 70 ° C. for 2.5 hours, sodium triacetoxyborohydride (285 mg, 1.30 mmol) was added to the reaction solution at room temperature. After stirring at 70 ° C. for 4 hours, the reaction mixture was cooled to room temperature, and chloroform (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL) were added. After stirring at room temperature for 1 hour, liquid separation was performed, and the aqueous layer was extracted with chloroform (3 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 25M, methanol / chloroform, 100: 0-94: 6) to obtain the title object compound (295 mg, yield 84%).
　（参考例９４）２－ブロモ－５－（エチルチオ）ピラジン
　２，５－ジブロモピラジン（５３３ｍｇ、２．２４ｍｍｏｌ）をアセトニトリル（７ｍＬ）に溶解し、０℃にてエタンチオール（０．１８ｍＬ、２．４６ｍｍｏｌ）、水素化ナトリウム（５９ｍｇ、２．４６ｍｍｏｌ）を加え、２５℃で１時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えてクエンチした後、酢酸エチルで希釈し、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９８：２－９０：１０）を用いて精製し、標記目的化合物（４８５ｍｇ、収率９９％）を得た。 Reference Example 94 2-Bromo-5- (ethylthio) pyrazine 2,5-dibromopyrazine (533 mg, 2.24 mmol) was dissolved in acetonitrile (7 mL), and ethanethiol (0.18 mL, 2. 46 mmol) and sodium hydride (59 mg, 2.46 mmol) were added, and the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 98: 2-90: 10) to give the title object compound (485 mg, yield 99%).
　（参考例９５）２－ブロモ－５－（エチルスルホニル）ピラジン
　参考例９４で製造した２－ブロモ－５－（エチルチオ）ピラジン（４８５ｍｇ、２．２１ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解し、０℃にてｍ－クロロ過安息香酸（１．１８ｇ、４．４３ｍｍｏｌ）を加え、２５℃で１時間攪拌した。反応液を濾過し、濾液を飽和重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－６７：３３）を用いて精製し、標記目的化合物（４９９ｍｇ、収率９０％）を得た。 (Reference Example 95) 2-Bromo-5- (ethylsulfonyl) pyrazine 2-Bromo-5- (ethylthio) pyrazine (485 mg, 2.21 mmol) prepared in Reference Example 94 was dissolved in dichloromethane (10 mL) and dissolved at 0 ° C. M-Chloroperbenzoic acid (1.18 g, 4.43 mmol) was added and stirred at 25 ° C. for 1 hour. The reaction mixture was filtered, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 85: 15-67: 33) to give the title object compound (499 mg, yield 90%).
　（参考例９６）ｃｉｓ－１－［５－（エチルスルホニル）ピラジン－２－イル］デカヒドロキノキサリン
　参考例９５の２－ブロモ－５－（エチルスルホニル）ピラジンを用いて参考例３４と同様に反応を行い、標記目的化合物を得た。 (Reference Example 96) cis-1- [5- (Ethylsulfonyl) pyrazin-2-yl] decahydroquinoxaline Reaction was carried out in the same manner as Reference Example 34 using 2-bromo-5- (ethylsulfonyl) pyrazine of Reference Example 95. To obtain the title compound.
　（参考例９７）ｃｉｓ－４－［５－（エチルスルホニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例９６のｃｉｓ－１－［５－（エチルスルホニル）ピラジン－２－イル］デカヒドロキノキサリンを用いて参考例８９と同様に反応を行い、標記目的化合物を得た。 Reference Example 97 cis-4- [5- (Ethylsulfonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate cis-1- [5- (ethylsulfonyl) pyrazine of Reference Example 96 The reaction was conducted in the same manner as in Reference Example 89 using -2-yl] decahydroquinoxaline to obtain the title object compound.
　（参考例９８）ｃｉｓ－４－［３－クロロ－５－（エチルスルホニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例９７のｃｉｓ－４－［５－（エチルスルホニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジルを用いて参考例７９と同様に反応を行い、標記目的化合物を得た。 (Reference Example 98) cis-4- [3-Chloro-5- (ethylsulfonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate cis-4- [5- (5- (Ethylsulfonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate was reacted in the same manner as in Reference Example 79 to obtain the title compound.
　（参考例９９）ｃｉｓ－４－［５－（エチルスルホニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例９８のｃｉｓ－４－［３－クロロ－５－（エチルスルホニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジルを用いて参考例１０と同様に反応を行い、標記目的化合物を得た。 (Reference Example 99) cis-4- [5- (Ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate cis-4- [3-Chloro of Reference Example 98 The reaction was carried out in the same manner as in Reference Example 10 using benzyl-5- (ethylsulfonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate to obtain the title compound.
　（参考例１００）４－［ｃｉｓ－４－［５－（エチルスルホニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例９９で製造したｃｉｓ－４－［５－（エチルスルホニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル（５３５ｍｇ、１．１７ｍｍｏｌ）をエタノール（１０ｍＬ）に溶解し、７．５％パラジウム炭素（２１４ｍｇ）を加え、水素雰囲気下で１．５時間攪拌した。セライト濾過にてパラジウム炭素を除去した後、ろ液を減圧濃縮した。得られた残渣（３５５ｍｇ、１．０９ｍｍｏｌ）をジクロロエタン（７ｍＬ）に溶解し、１－Ｂｏｃ－４－ピペリドン（４３６ｍｇ、２．１９ｍｍｏｌ）を加え、７０℃で２時間攪拌した。反応液を室温まで冷却後、トリアセトキシ水素化ホウ素ナトリウム（４６３ｍｇ、２．１９ｍｍｏｌ）を加え、７０℃で１８時間攪拌した。反応液を氷冷後、飽和炭酸水素ナトリウム水溶液（約１０ｍＬ）を加え、１５分間攪拌した。反応液をジクロロメタン抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－５０：５０）を用いて精製し、標記目的化合物（３２３ｍｇ、収率５８％）を得た。 Reference Example 100 4- [cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference The cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate benzyl (535 mg, 1.17 mmol) prepared in Example 99 was added to ethanol (10 mL). Then, 7.5% palladium carbon (214 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours. After removing palladium on carbon by Celite filtration, the filtrate was concentrated under reduced pressure. The obtained residue (355 mg, 1.09 mmol) was dissolved in dichloroethane (7 mL), 1-Boc-4-piperidone (436 mg, 2.19 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hr. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (463 mg, 2.19 mmol) was added, and the mixture was stirred at 70 ° C. for 18 hr. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution (about 10 mL) was added, and the mixture was stirred for 15 min. The reaction solution was extracted with dichloromethane, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to give the title object compound (323 mg, yield 58%).
（参考例１０１）２－ブロモ－５－［（シクロプロピルメチル）チオ］ピラジン
　２，５－ジブロモピラジン（１．２０ｇ、５．０４ｍｍｏｌ）をメタノール（１０ｍＬ）に溶解し、室温にて水硫化カリウム溶液（１０ｍＬ）を加え、５０℃で１時間攪拌した。反応液に１２Ｎ塩酸を加えてｐＨ５～６とした後、ジクロロメタンで希釈し、水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた固体を酢酸エチル：ヘキサン（１：３）を用いて洗浄し、５－ブロモピラジン－２－チオール（９０２ｍｇ、収率９４％）を得た。得られた５－ブロモピラジン－２－チオール（４５０ｍｇ、２．３６ｍｍｏｌ）をメタノール（９ｍＬ）に溶解し、室温にて炭酸カリウム（６５１ｍｇ、４．７１ｍｍｏｌ）、ブロモメチルシクロプロパン（０．４６ｍＬ、４．７１ｍｍｏｌ）を加え、１．５時間攪拌した。酢酸エチルで希釈し、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９８：２－８５：１５）を用いて精製し、標記目的化合物（５４３ｍｇ、収率９４％）を得た。 Reference Example 101 2-Bromo-5-[(cyclopropylmethyl) thio] pyrazine 2,5-dibromopyrazine (1.20 g, 5.04 mmol) was dissolved in methanol (10 mL), and potassium hydrosulfide at room temperature. The solution (10 mL) was added and stirred at 50 ° C. for 1 hour. The reaction solution was adjusted to pH 5-6 by adding 12N hydrochloric acid, diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with ethyl acetate: hexane (1: 3) to obtain 5-bromopyrazine-2-thiol (902 mg, yield 94%). The obtained 5-bromopyrazine-2-thiol (450 mg, 2.36 mmol) was dissolved in methanol (9 mL), and potassium carbonate (651 mg, 4.71 mmol), bromomethylcyclopropane (0.46 mL, 4 mL) were dissolved at room temperature. .71 mmol) was added and stirred for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 98: 2-85: 15) to give the title object compound (543 mg, yield 94%).
　（参考例１０２）２－ブロモ－５－［（シクロプロピルメチル）スルホニル］ピラジン
　参考例１０１の２－ブロモ－５－［（シクロプロピルメチル）チオ］ピラジンを用いて参考例９５と同様に反応を行い、標記目的化合物を得た。 (Reference Example 102) 2-Bromo-5-[(cyclopropylmethyl) sulfonyl] pyrazine Using 2-bromo-5-[(cyclopropylmethyl) thio] pyrazine of Reference Example 101, the reaction was carried out in the same manner as in Reference Example 95. The title compound was obtained.
　（参考例１０３）ｃｉｓ－１－｛５－［（シクロプロピルメチル）スルホニル］ピラジン－２－イル｝デカヒドロキノキサリン
　参考例１０２の２－ブロモ－５－［（シクロプロピルメチル）スルホニル］ピラジンを用いて参考例３４と同様に反応を行い、標記目的化合物を得た。 (Reference Example 103) cis-1- {5-[(Cyclopropylmethyl) sulfonyl] pyrazin-2-yl} decahydroquinoxaline Using 2-bromo-5-[(cyclopropylmethyl) sulfonyl] pyrazine of Reference Example 102 In the same manner as in Reference Example 34, the title target compound was obtained.
　（参考例１０４）ｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例１０３のｃｉｓ－１－｛５－［（シクロプロピルメチル）スルホニル］ピラジン－２－イル｝デカヒドロキノキサリンを用いて参考例８９と同様に反応を行い、標記目的化合物を得た。 Reference Example 104 cis-4- {5-[(Cyclopropylmethyl) sulfonyl] pyrazin-2-yl} octahydroquinoxaline-1 (2H) -carboxylate cis-1- {5- [ (Cyclopropylmethyl) sulfonyl] pyrazin-2-yl} decahydroquinoxaline was used in the same manner as in Reference Example 89 to give the title object compound.
　（参考例１０５）ｃｉｓ－４－｛３－クロロ－５－［（シクロプロピルメチル）スルホニル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例１０４のｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジルを用いて参考例７９と同様に反応を行い、標記目的化合物を得た。 Reference Example 105 cis-4- {3-chloro-5-[(cyclopropylmethyl) sulfonyl] pyrazin-2-yl} octahydroquinoxaline-1 (2H) -benzyl carboxylate cis-4- of Reference Example 104 The reaction was carried out in the same manner as in Reference Example 79 using {5-[(cyclopropylmethyl) sulfonyl] pyrazin-2-yl} octahydroquinoxaline-1 (2H) -carboxylate to obtain the title object compound.
　（参考例１０６）ｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例１０５のｃｉｓ－４－｛３－クロロ－５－［（シクロプロピルメチル）スルホニル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジルを用いて参考例１０と同様に反応を行い、標記目的化合物を得た。 Reference Example 106 cis-4- {5-[(Cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl} octahydroquinoxaline-1 (2H) -carboxylate cis-4- of Reference Example 105 {3-Chloro-5-[(cyclopropylmethyl) sulfonyl] pyrazin-2-yl} octahydroquinoxaline-1 (2H) -carboxylate is reacted in the same manner as in Reference Example 10 to obtain the title compound. Obtained.
　（参考例１０７）４－［ｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１０６のｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジルを用いて参考例１００と同様に反応を行い、標記目的化合物を得た。 Reference Example 107 4- [cis-4- {5-[(Cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-Butyl Reference Example 106 using cis-4- {5-[(cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl} octahydroquinoxaline-1 (2H) -carboxylate of Reference Example 106 The title compound was obtained in the same manner as above.
　（参考例１０８）４－［ｃｉｓ－４－［３－シクロプロピル－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例３７で製造した６－ブロモ－５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－カルボン酸メチルとシクロプロピルボロン酸を用いて参考例６２と同様に反応を行った後、参考例５０と同様に反応を行い、標記目的化合物を得た。 Reference Example 108 4- [cis-4- [3-cyclopropyl-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- Butyl 6-bromo-5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazine-2-carboxylic acid prepared in Reference Example 37 The reaction was conducted in the same manner as in Reference Example 62 using methyl and cyclopropylboronic acid, and then the reaction was carried out in the same manner as in Reference Example 50 to obtain the title object compound.
　（参考例１０９）４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１２４で製造したｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチルを用いて、参考例３７と同様に反応を行い、標記目的化合物を得た。 Reference Example 109 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Using Reference Example 37 and cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate prepared in Reference Example 124 The reaction was carried out in the same manner to obtain the title target compound.
　（参考例１１０）４－［ｃｉｓ－４－［３－クロロ－５－（｛２－［（エチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－［ｃｉｓ－４－［３－クロロ－５－（ヒドラジノカルボニル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例７７）（９０７ｍｇ、１．８４ｍｍｏｌ）のエタノール（１０ｍＬ）溶液に、イソチオシアン酸エチル（０．１６９ｍＬ、１．９３ｍｍｏｌ）のエタノール（５ｍＬ）溶液を室温にて加えた。８０℃にて３時間攪拌したのち反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ４０Ｍ、メタノール／クロロホルム、１００：０－９２：８）を用いて精製し、標記目的化合物（８０５ｍｇ、収率７６％）を得た。 Reference Example 110 4- [cis-4- [3-Chloro-5-({2-[(ethylamino) carbonothioyl] hydrazino} carbonyl) pyridin-2-yl] octahydroquinoxaline-1 (2H) -Yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-chloro-5- (hydrazinocarbonyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- To a solution of tert-butyl 1-carboxylate (Reference Example 77) (907 mg, 1.84 mmol) in ethanol (10 mL) was added a solution of ethyl isothiocyanate (0.169 mL, 1.93 mmol) in ethanol (5 mL) at room temperature. It was. After stirring at 80 ° C. for 3 hours, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified using silica gel column chromatography (Biotage 40M, methanol / chloroform, 100: 0-92: 8) to give the title target compound (805 mg, 76% yield) was obtained.
　（参考例１１１）４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－［ｃｉｓ－４－［３－クロロ－５－（｛２－［（エチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例１１０）（８３８ｍｇ、１．４４ｍｍｏｌ）のメタノール（５ｍＬ）溶液に、アセトン（５ｍＬ）、Ｎ，Ｎ－ジシクロヘキシルカルボジイミド（４４７ｍｇ、２．１７ｍｍｏｌ）を室温にて加えた。６５℃にて１０時間攪拌したのち、反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ４０Ｍ、メタノール／クロロホルム、１００：０－９５：５）を用いて精製し、標記目的化合物（４１７ｍｇ、収率５３％）を得た。 Reference Example 111 4- [cis-4- {3-Chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyridin-2-yl} octahydroquinoxaline -1 (2H) -yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-chloro-5-({2-[(ethylamino) carbonothioyl] hydrazino} carbonyl) pyridine- To a solution of 2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (Reference Example 110) (838 mg, 1.44 mmol) in methanol (5 mL), acetone (5 mL), N , N-dicyclohexylcarbodiimide (447 mg, 2.17 mmol) was added at room temperature. After stirring at 65 ° C. for 10 hours, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified using silica gel column chromatography (Biotage 40M, methanol / chloroform, 100: 0 to 95: 5) to give the title purpose. The compound (417 mg, 53% yield) was obtained.
　（参考例１１２）ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジル
　参考例８で製造した５－ブロモ－Ｎ－エチル－６－［ｃｉｓ－オクタヒドロキノキサリン－１（２Ｈ）－イル］ニコチンアミド（１．０３ｇ、２．８０ｍｍｏｌ）を酢酸エチル（１０ｍＬ）に溶解し、０℃にて１Ｎ－水酸化ナトリウム（１０ｍＬ）、ベンジルクロロホルメート（０．４４ｍＬ、３．０８ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を水、飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をジメトキシエタン（２０ｍＬ）に溶解し、エチルボロン酸（４４２ｍｇ、５．９８ｍｍｏｌ）、炭酸カリウム（１．６５ｇ、１２．０ｍｍｏｌ）、及び１，１’－ビス（ジフェニルホスフィノ）フェロセン－パラジウム（ＩＩ）二塩化物ジクロロメタン錯体（１９５ｍｇ、０．２３９ｍｍｏｌ）を加え、７０℃で３．５時間攪拌した。反応液に酢酸エチルを加えた後、水、飽和炭酸水素ナトリウム、及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、６７：３３－５０：５０）を用いて精製し、標記目的化合物（９０２ｍｇ、収率７１％）を得た。 Reference Example 112 cis-4- [3-Ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate 5-bromo-N— prepared in Reference Example 8 Ethyl-6- [cis-octahydroquinoxalin-1 (2H) -yl] nicotinamide (1.03 g, 2.80 mmol) was dissolved in ethyl acetate (10 mL) and 1N sodium hydroxide (10 mL) was added at 0 ° C. ), Benzyl chloroformate (0.44 mL, 3.08 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in dimethoxyethane (20 mL). Ethylboronic acid (442 mg, 5.98 mmol), potassium carbonate (1.65 g, 12.0 mmol), and 1,1′-bis (Diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (195 mg, 0.239 mmol) was added, and the mixture was stirred at 70 ° C. for 3.5 hours. Ethyl acetate was added to the reaction solution, followed by washing with water, saturated sodium hydrogen carbonate, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 67: 33-50: 50) to obtain the title object compound (902 mg, yield 71%).
　（参考例１１３）４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル
　参考例１１２のｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ベンジルを用いて参考例１００と同様に反応を行い、標記目的化合物を得た。 Reference Example 113 4- [cis-4- [3-Ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl Reference The reaction was conducted in the same manner as in Reference Example 100 using benzyl-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate of Example 112. The target compound was obtained.
　（参考例１１４）６－クロロ－５－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピラジン－２－カルボン酸メチル
　参考例８５で製造したｃｉｓ－４－［３－クロロ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（２．９１ｇ、７．３３ｍｍｏｌ）をジクロロメタン（３０ｍＬ）に溶解し、トリフルオロ酢酸（１０ｍＬ）を加え、室温で１時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物（２．０５ｇ、収率９４％）を得た。 (Reference Example 114) Methyl 6-chloro-5- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] pyrazine-2-carboxylate cis-4- [3-Chloro-- prepared in Reference Example 85 Tert-butyl 5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate (2.91 g, 7.33 mmol) was dissolved in dichloromethane (30 mL) to obtain trifluoroacetic acid. (10 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to give the title object compound (2.05 g, yield 94%).
　（参考例１１５）５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－クロロピラジン－２－カルボン酸メチル
　参考例１１４で製造した６－クロロ－５－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピラジン－２－カルボン酸メチル（２．０５ｇ、６．９１ｍｍｏｌ）をジクロロエタン（４０ｍＬ）に溶解し、１－Ｂｏｃ－４－ピペリドン（２．７５ｇ、１３．８ｍｍｏｌ）を加え、７０℃で２時間攪拌した。反応液を室温まで冷却後、トリアセトキシ水素化ホウ素ナトリウム（２．９３ｇ、１３．８ｍｍｏｌ）を加え、７０℃で１８時間攪拌した。反応液を氷冷後、飽和炭酸水素ナトリウム水溶液（約４０ｍＬ）を加え、１５分間攪拌した。反応液をジクロロメタン抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－５０：５０）を用いて精製し、標記目的化合物（２．８９ｇ、収率８７％）を得た。 Reference Example 115 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-chloropyrazine-2-carboxylic acid Methyl acid Methyl 6-chloro-5- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] pyrazine-2-carboxylate (2.05 g, 6.91 mmol) prepared in Reference Example 114 was added to dichloroethane ( 1-Boc-4-piperidone (2.75 g, 13.8 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (2.93 g, 13.8 mmol) was added, and the mixture was stirred at 70 ° C. for 18 hr. The reaction mixture was ice-cooled, saturated aqueous sodium hydrogen carbonate solution (about 40 mL) was added, and the mixture was stirred for 15 min. The reaction solution was extracted with dichloromethane, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to give the title object compound (2.89 g, yield 87%).
　（参考例１１６）４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１１５で製造した５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－クロロピラジン－２－カルボン酸メチル（３．６４ｇ、７．５８ｍｍｏｌ）をエタノール（３０ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（１５ｍＬ）を加え、室温で１．５時間攪拌した後、１Ｎ－塩酸水溶液（１５ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加え、ジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣（１．７７ｇ、３．８０ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（２５ｍＬ）に溶解し、エチルアミン（２．０Ｍテトラヒドロフラン溶液）（２．２８ｍＬ、４．５６ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（８７４ｍｇ、４．５６ｍｍｏｌ）、及び１－ヒドロキシベンゾトリアゾール（１７５ｍｇ、１．１４ｍｍｏｌ）を加え、窒素雰囲気下、室温で１時間攪拌した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－５０：５０）を用いて精製し、標記目的化合物（１．３３ｇ、収率７１％）を得た。 Reference Example 116 4- {cis-4- [3-Chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert -Butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-chloropyrazine- prepared in Reference Example 115 Methyl 2-carboxylate (3.64 g, 7.58 mmol) was dissolved in ethanol (30 mL), 1N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 1.5 hours, and then 1N aqueous hydrochloric acid solution ( 15 mL) and concentrated under reduced pressure. Water was added to the resulting residue, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue (1.77 g, 3.80 mmol) was dissolved in N, N-dimethylformamide (25 mL), and ethylamine (2.0 M tetrahydrofuran solution) (2.28 mL, 4.56 mmol) was dissolved. ), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (874 mg, 4.56 mmol), and 1-hydroxybenzotriazole (175 mg, 1.14 mmol) were added for 1 hour at room temperature under a nitrogen atmosphere. Stir. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to obtain the title object compound (1.33 g, yield 71%).
　（参考例１１７）４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１１５で製造した５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－クロロピラジン－２－カルボン酸メチル（３．６４ｇ、７．５８ｍｍｏｌ）をエタノール（３０ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（１５ｍＬ）を加え、室温で１．５時間攪拌した後、１Ｎ－塩酸水溶液（１５ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加え、ジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣（１．７７ｇ、３．８０ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（２５ｍＬ）に溶解し、シクロプロピルアミン（０．３２ｍＬ、４．５６ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（８７４ｍｇ、４．５６ｍｍｏｌ）、及び１－ヒドロキシベンゾトリアゾール（１７５ｍｇ、１．１４ｍｍｏｌ）を加え、窒素雰囲気下、室温で１時間攪拌した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－５０：５０）を用いて精製し、標記目的化合物（１．３８ｇ、収率７２％）を得た。 Reference Example 117 4- {cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert-Butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-chloropyrazine prepared in Reference Example 115 Methyl-2-carboxylate (3.64 g, 7.58 mmol) was dissolved in ethanol (30 mL), 1N aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at room temperature for 1.5 hours, and then 1N aqueous hydrochloric acid solution (15 mL) was added and concentrated under reduced pressure. Water was added to the resulting residue, extracted with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue (1.77 g, 3.80 mmol) was dissolved in N, N-dimethylformamide (25 mL), and cyclopropylamine (0.32 mL, 4.56 mmol), 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (874 mg, 4.56 mmol) and 1-hydroxybenzotriazole (175 mg, 1.14 mmol) were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to give the title object compound (1.38 g, yield 72%).
　（参考例１１８）ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［５－（メトキシカルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例８６）（７０７ｍｇ、１．８８ｍｍｏｌ）の２－プロパノール（０．５ｍＬ）溶液に、シクロプロピルアミン（１．００ｍＬ、１４．４ｍｍｏｌ）を室温にて加えた。反応管を密閉し、マイクロウェーブ反応装置にて１４０℃で１時間撹拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｓ、酢酸エチル／クロロホルム、０：１００－１５：８５）を用いて精製し、標記目的化合物（５６９ｍｇ、７６％）を得た。 Reference Example 118 cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate tert-butyl cis-4- [5 -(Methoxycarbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] tert-butyl pyrazine-1-carboxylate (Reference Example 86) (707 mg, 1.88 mmol) in 2-propanol (0 .5 mL) solution was added cyclopropylamine (1.00 mL, 14.4 mmol) at room temperature. The reaction tube was sealed and stirred at 140 ° C. for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (Biotage 40S, ethyl acetate / chloroform, 0: 100-15: 85) to give the title object compound (569 mg, 76%). Obtained.
　（参考例１１９）４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ｔｅｒｔ－ブチル（参考例１１８）（５６９ｍｇ、１．４２ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、４規定塩酸ジオキサン溶液（２．００ｍＬ、２．００ｍｍｏｌ）を室温にて加えた。１５時間攪拌したのち反応液を減圧下濃縮した。得られた残渣に２０％メタノール／クロロホルム混合液（５ｍＬ）及び飽和炭酸水素ナトリウム水溶液（５ｍＬ）を加え分液し、２０％メタノール／クロロホルム混合液（３ｘ１０ｍＬ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣を１，２－ジクロロエタン（４．５ｍＬ）に溶解し、室温にて１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン（２９４ｍｇ、１．４７ｍｍｏｌ）を室温にて加えた。７０℃にて５時間撹拌した後、室温にて反応液にトリアセトキシホウ水素化ナトリウム（３２２ｍｇ、１．４７ｍｍｏｌ）を加えた。７０℃にて１７時間撹拌した後、反応液を室温まで冷却し、クロロホルム（１０ｍＬ）および飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加えた。室温にて１時間撹拌した後分液し、水層をクロロホルム（３ｘ５ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、１００：０－９５：５）を用いて精製し、標記目的化合物（２３２ｍｇ、収率３４％）を得た。 Reference Example 119 4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert-butyl cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-carboxylate tert-butyl (Reference Example 118) (569 mg, To a solution of 1.42 mmol) in methanol (2 mL), 4N hydrochloric acid dioxane solution (2.00 mL, 2.00 mmol) was added at room temperature. After stirring for 15 hours, the reaction solution was concentrated under reduced pressure. To the obtained residue, a 20% methanol / chloroform mixture (5 mL) and a saturated aqueous sodium hydrogen carbonate solution (5 mL) were added for liquid separation, and the mixture was extracted with a 20% methanol / chloroform mixture (3 × 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 1,2-dichloroethane (4.5 mL), and 1-tert-butoxycarbonyl-4-piperidone (294 mg, 1.47 mmol) was added at room temperature. After stirring at 70 ° C. for 5 hours, sodium triacetoxyborohydride (322 mg, 1.47 mmol) was added to the reaction solution at room temperature. After stirring at 70 ° C. for 17 hours, the reaction mixture was cooled to room temperature, and chloroform (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added. After stirring at room temperature for 1 hour, the layers were separated, and the aqueous layer was extracted with chloroform (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage 25M, methanol / chloroform, 100: 0-95: 5) to obtain the title object compound (232 mg, yield 34%).
　（参考例１２０）４－［ｃｉｓ－４－［３－クロロ－５－（｛２－［（エチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例８０で製造した５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル（７２８ｍｇ、１．４７ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、ヒドラジン一水和物（４ｍＬ）を加え、１時間加熱還流した。反応液を減圧濃縮し、得られた残渣をトルエンに溶解し、再び減圧濃縮した。これを３回行った後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をジクロロメタン（１０ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．７５２ｍＬ、４．４２ｍｍｏｌ）を加えた後、イソチオシアン酸エチル（０．３７４ｍＬ、４．４２ｍｍｏｌ）を加え、室温で１８時間攪拌した。再びイソチオシアン酸エチル（０．３７４ｍＬ、４．４２ｍｍｏｌ）を加え、室温で３時間攪拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物（４３６ｍｇ、収率５１％）を得た。 Reference Example 120 4- [cis-4- [3-Chloro-5-({2-[(ethylamino) carbonothioyl] hydrazino} carbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -Yl] piperidin-1-carboxylate tert-butyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl prepared in Reference Example 80 ] Methyl-6-chloropyrazine-2-carboxylate (728 mg, 1.47 mmol) was dissolved in methanol (20 mL), hydrazine monohydrate (4 mL) was added, and the mixture was heated to reflux for 1 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in toluene and concentrated again under reduced pressure. After performing this three times, a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (10 mL), diisopropylethylamine (0.752 mL, 4.42 mmol) was added, and then ethyl isothiocyanate (0.374 mL, 4.42 mmol) was added. And stirred at room temperature for 18 hours. Ethyl isothiocyanate (0.374 mL, 4.42 mmol) was added again and stirred at room temperature for 3 hours, and then the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain the title object compound (436 mg, yield 51%).
　（参考例１２１）４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１２０で製造した４－［ｃｉｓ－４－［３－クロロ－５－（｛２－［（エチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（４３６ｍｇ、０．７５０ｍｍｏｌ）をアセトン（１０ｍＬ）とメタノール（１０ｍＬ）の混合溶媒に溶解し、Ｎ，Ｎ－ジシクロヘキシルカルボジイミド（２３２ｍｇ、１．１２ｍｍｏｌ）を加え、６５℃で１８時間攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９９：１－８０：２０）を用いて精製し、標記目的化合物のラセミ体（２１２ｍｇ、収率５２％）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール：ヘキサン＝１０：９０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール：ヘキサン＝１０：９０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が９．０分の化合物（６８ｍｇ、１７％）と保持時間が７．０分の化合物（６１ｍｇ、１５％）を得た。保持時間が９．０分の化合物を参考例１２１とする。 Reference Example 121 4- [cis-4- {3-Chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydroquinoxaline -1 (2H) -yl] piperidine-1-carboxylate tert-butyl 4- [cis-4- [3-chloro-5-({2-[(ethylamino) carbonothioyl]] prepared in Reference Example 120 Hydrazino} carbonyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (436 mg, 0.750 mmol) in a mixed solvent of acetone (10 mL) and methanol (10 mL) Into the solution, N, N-dicyclohexylcarbodiimide (232 mg, 1.12 mmol) was added and stirred at 65 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (chloroform: methanol, 99: 1-80: 20) to give the racemic title compound (212 mg, yield 52%). Obtained. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol: hexane = 10: 90, 10 mL / min, 254 nm), and HPLC ( Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2-propanol: hexane = 10: 90, 2.0 mL / min, 254 nm) retention time 9.0 min compound (68 mg, 17 %) And a retention time of 7.0 minutes (61 mg, 15%). A compound having a retention time of 9.0 minutes is referred to as Reference Example 121.
　（参考例１２２）４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１２１のHPLCにおける保持時間が７．０分の化合物。 Reference Example 122 4- [cis-4- {3-Chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydroquinoxaline -1 (2H) -yl] piperidine-1-carboxylate tert-butyl Compound having a retention time in the HPLC of Reference Example 121 of 7.0 minutes.
　（参考例１２３）ｃｉｓ－４－［３－ブロモ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸　ｔｅｒｔ－ブチル
　参考例３６で製造したｃｉｓ－４－［３－ブロモ－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル、及びシクロプロピルアミンを用いて、参考例３９と同様に反応を行い、標記目的化合物を得た。 Reference Example 123 cis-4- [3-Bromo-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate tert-butyl cis-4 prepared in Reference Example 36 Reaction was carried out in the same manner as in Reference Example 39 using tert-butyl- [3-bromo-5- (methoxycarbonyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate and cyclopropylamine. The title compound was obtained.
　（参考例１２４）ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸ｔｅｒｔ－ブチル
　参考例１２３で製造したｃｉｓ－４－［３－ブロモ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸　ｔｅｒｔ－ブチル（１．１１ｇ、２．３２ｍｍｏｌ）、ヨウ化銅（Ｉ）（４４ｍｇ、０．２３２ｍｍｏｌ）、１，１０－フェナントロリン（８３ｍｇ、０．４６３ｍｍｏｌ）、炭酸セシウム（１．５１ｇ、４．６４ｍｍｏｌ）をメタノール（１５ｍＬ）に溶解し、マイクロウェーブ反応装置にて１４０℃で１０分間攪拌した。反応液に水を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９５：５－０：１００）を用いて精製し、標記目的化合物（９７０ｍｇ、収率９７％）を得た。 Reference Example 124 cis-4- [5- (Cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxaline-1 (2H) -tert-butyl carboxylate cis-4 prepared in Reference Example 123 -[3-Bromo-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylate tert-butyl (1.11 g, 2.32 mmol), copper (I) iodide ( 44 mg, 0.232 mmol), 1,10-phenanthroline (83 mg, 0.463 mmol), cesium carbonate (1.51 g, 4.64 mmol) were dissolved in methanol (15 mL), and the mixture was dissolved in methanol at 140 ° C. at 140 ° C. Stir for minutes. Water was added to the reaction solution, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 95: 5-0: 100) to give the title object compound (970 mg, yield 97%).
（参考例１２５）ベンジル－ｃｉｓ－４－（３－クロロピラジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸
　２，３－ジクロロピラジン（６．７６ｇ、４５．４ｍｍｏｌ）とｃｉｓ－デカヒドロキノキサリン（７．０ｇ、４９．９ｍｍｏｌ）をＮ，Ｎ－ジメチルアセトアミド（１００mL）に溶解し、炭酸カリウム（９．４１ｇ、６８．１ｍｍｏｌ）を加え、１１０℃で１８時間攪拌した。反応液を室温まで冷却し、濾過した後、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣を酢酸エチル（１５０mL）に溶解し、０度にて０．５N水酸化ナトリウム（１５０mL）とベンジルクロロホルメート（７．１３mL、４９．９ｍｍｏｌ）を加えた。室温にて１時間攪拌した後、有機層を酢酸エチルで抽出し、飽和食塩水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－６７：３３）を用いて精製し、標記目的化合物（１０．１ｇ、５７％）を得た。 Reference Example 125 Benzyl-cis-4- (3-chloropyrazin-2-yl) octahydroquinoxaline-1 (2H) -carboxylic acid 2,3-dichloropyrazine (6.76 g, 45.4 mmol) and cis- Decahydroquinoxaline (7.0 g, 49.9 mmol) was dissolved in N, N-dimethylacetamide (100 mL), potassium carbonate (9.41 g, 68.1 mmol) was added, and the mixture was stirred at 110 ° C. for 18 hours. The reaction mixture was cooled to room temperature, filtered, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (150 mL), and 0.5N sodium hydroxide (150 mL) and benzyl chloroformate (7.13 mL, 49.9 mmol) were added at 0 degree. It was. After stirring at room temperature for 1 hour, the organic layer was extracted with ethyl acetate and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-67: 33) to obtain the title object compound (10.1 g, 57%).
（参考例１２６）ベンジル－ｃｉｓ－４－（３－メチルピラジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸
　参考例１２５で製造したベンジル－ｃｉｓ－４－（３－クロロピラジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸を用いて参考例３８と同様に反応を行い、標記目的化合物を得た。 Reference Example 126 Benzyl-cis-4- (3-methylpyrazin-2-yl) octahydroquinoxaline-1 (2H) -carboxylic acid Benzyl-cis-4- (3-chloropyrazine-) prepared in Reference Example 125 2-yl) octahydroquinoxaline-1 (2H) -carboxylic acid was used for the reaction as in Reference Example 38 to obtain the title compound.
（参考例１２７）ベンジル－ｃｉｓ－４－（５－ブロモ－３－メチルピラジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸
　参考例１２６で製造したベンジル－ｃｉｓ－４－（３－メチルピラジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸（７．４ｇ、２０．２ｍｍｏｌ）をジクロロメタン（１５０mＬ）に溶解し、Ｎ－ブロモスクシンイミド（３．９５g、２２．２ｍｍｏｌ）を加え、０℃で２時間攪拌した。反応液を飽和重曹水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－５０：５０）を用いて精製し、標記目的化合物（６６１mｇ、７％）を得た。 Reference Example 127 Benzyl-cis-4- (5-bromo-3-methylpyrazin-2-yl) octahydroquinoxaline-1 (2H) -carboxylic acid benzyl-cis-4- (3 prepared in Reference Example 126 -Methylpyrazin-2-yl) octahydroquinoxaline-1 (2H) -carboxylic acid (7.4 g, 20.2 mmol) was dissolved in dichloromethane (150 mL) and N-bromosuccinimide (3.95 g, 22.2 mmol) And stirred at 0 ° C. for 2 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 85: 15-50: 50) to give the title object compound (661 mg, 7%).
（参考例１２８）ベンジル－ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸
　参考例１２７で製造したベンジル－ｃｉｓ－４－（５－ブロモ－３－メチルピラジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸（４３１mｇ、０．９６８mmol）をN－メチルピロリジノン（６mＬ）に溶解し、イミダゾール（１９８mg、２．９０ｍｍｏｌ）および炭酸セシウム（６３１mg、１．９４ｍｍｏｌ）を加え、１００℃で６時間攪拌した。反応液を室温まで冷却し、水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、７５：２５－２５：７５）を用いて精製し、標記目的化合物（５２６mｇ、ｑｕａｎｔ．）を得た。 Reference Example 128 Benzyl-cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylic acid Prepared in Reference Example 127 Benzyl-cis-4- (5-bromo-3-methylpyrazin-2-yl) octahydroquinoxaline-1 (2H) -carboxylic acid (431 mg, 0.968 mmol) was dissolved in N-methylpyrrolidinone (6 mL) Imidazole (198 mg, 2.90 mmol) and cesium carbonate (631 mg, 1.94 mmol) were added, and the mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate, 75: 25-25: 75) to give the title object compound (526 mg, quant.).
（参考例１２９）４－［ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１２８で製造したベンジル－ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－カルボン酸を用いて参考例９３と同様に反応を行い、標記目的化合物を得た。 Reference Example 129 4- [cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone Tert-Butyl acid Benzyl-cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -carboxylic acid prepared in Reference Example 128 And the reaction was conducted in the same manner as in Reference Example 93 to give the title object compound.
（参考例１３０）６－エチル－５－［ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピラジン－２－カルボン酸メチル
　参考例９１で製造したｃｉｓ－４－［３－エチル－５－（メトキシカルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－カルボン酸ベンジル（３．０１ｇ、７．０９ｍｍｏｌ）をエタノール（６０mL）に溶解し、パラジウムカーボン（１．２ｇ）を加え、水素雰囲気下１．５時間攪拌した。反応液をセライト濾過し、減圧濃縮後、シリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物（２．０２ｇ、９８％）を得た。 (Reference Example 130) Methyl 6-ethyl-5- [cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl] pyrazine-2-carboxylate cis-4- [3-Ethyl- prepared in Reference Example 91 Benzyl 5- (methoxycarbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1-carboxylate (3.01 g, 7.09 mmol) was dissolved in ethanol (60 mL) and palladium carbon (1. 2 g) was added and stirred for 1.5 hours under hydrogen atmosphere. The reaction mixture was filtered through Celite, concentrated under reduced pressure, and purified by silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to give the title object compound (2.02 g, 98%).
（参考例１３１）５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－エチルピラジン－２－カルボン酸メチル
　参考例１３０で製造した６－エチル－５－（ｃｉｓ－オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル）ピラジン－２－カルボン酸メチルを用いて参考例１１５と同様に反応を行い、標記目的化合物を得た。 Reference Example 131 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-ethylpyrazine-2-carboxylic acid Methyl acid The reaction was carried out in the same manner as in Reference Example 115 using methyl 6-ethyl-5- (cis-octahydro-1H-cyclopenta [b] pyrazin-1-yl) pyrazine-2-carboxylate prepared in Reference Example 130. To give the title compound.
（参考例１３２）４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　参考例１３１で製造した５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－エチルピラジン－２－カルボン酸メチルとシクロプロピルアミンを用いて参考例１１６と同様に反応を行い、標記目的化合物を得た。 Reference Example 132 4- {cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert-Butyl 5- {cis-4- [1- (tert-Butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-ethylpyrazine prepared in Reference Example 131 The reaction was carried out in the same manner as in Reference Example 116 using methyl -2-carboxylate and cyclopropylamine to obtain the title compound.
（参考例１３３）５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－メチルピラジン－２－カルボン酸メチル
　５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－クロロピラジン－２－カルボン酸メチル（参考例１１５）を用いて参考例３８と同様の反応を行い、標記化合物を得た。 Reference Example 133 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-methylpyrazine-2-carboxylic acid Methyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -6-chloropyrazine-2-carboxylate ( The title compound was obtained in the same manner as in Reference Example 38 using Reference Example 115).
（参考例１３４）４－｛ｃｉｓ－４－［３－メチル－５－（｛２－［（メチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－メチルピラジン－２－カルボン酸メチル（参考例１３３）とイソチオシアン酸メチルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 134 4- {cis-4- [3-Methyl-5-({2-[(methylamino) carbonothioyl] hydrazino} carbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl} piperidine-1-carboxylate tert-butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } -6-Methylpyrazine-2-carboxylate (Reference Example 133) and methyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
（参考例１３５）４－［ｃｉｓ－４－｛３－メチル－５－［５－（メチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－｛ｃｉｓ－４－［３－メチル－５－（｛２－［（メチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１３４）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 135 4- [cis-4- {3-Methyl-5- [5- (methylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- {cis-4- [3-methyl-5-({2-[(methylamino) carbonothioyl] hydrazino} carbonyl ) Pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylate tert-Butyl (Reference Example 134) was used to carry out a reaction similar to Reference Example 121, and the title compound Got.
（参考例１３６）４－｛ｃｉｓ－４－［５－（｛２－［（シクロプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－メチルピラジン－２－カルボン酸　メチル（参考例１３３）とイソチオシアン酸シクロプロピルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 136 4- {cis-4- [5-({2-[(cyclopropylamino) carbonothioyl] hydrazino} carbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b ] Pyrazin-1-yl} piperidine-1-carboxylate tert-butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1- Ile} -6-methylpyrazine-2-carboxylate (Reference Example 133) and cyclopropyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
（参考例１３７）４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－｛ｃｉｓ－４－［５－（｛２－［（シクロプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１３６）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 137 4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro- 1H-cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- {cis-4- [5-({2-[(cyclopropylamino) carbonothioyl] hydrazino} carbonyl)- 3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylate tert-Butyl (Reference Example 136) was used to carry out a reaction similar to Reference Example 121. The title compound was obtained.
（参考例１３８）４－｛ｃｉｓ－４－［５－（｛２－［（イソプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－メチルピラジン－２－カルボン酸　メチル（参考例１３３）とイソチオシアン酸イソプロピルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 138 4- {cis-4- [5-({2-[(Isopropylamino) carbonothioyl] hydrazino} carbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl} piperidine-1-carboxylate tert-butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } -6-Methylpyrazine-2-carboxylate (Reference Example 133) and isopropyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
（参考例１３９）４－［ｃｉｓ－４－｛５－［５－（イソプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－｛ｃｉｓ－４－［５－（｛２－［（イソプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１３８）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 139 4- [cis-4- {5- [5- (Isopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- {cis-4- [5-({2-[(isopropylamino) carbonothioyl] hydrazino} carbonyl) -3- Methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylate tert-Butyl (Reference Example 138) was used for the same reaction as Reference Example 121 to give the title compound Got.
（参考例１４０）４－｛ｃｉｓ－４－［５－（｛２－［（ブチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－メチルピラジン－２－カルボン酸　メチル（参考例１３３）とイソチオシアン酸ブチルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 140 4- {cis-4- [5-({2-[(Butylamino) carbonothioyl] hydrazino} carbonyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl} piperidine-1-carboxylate tert-butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } -6-Methylpyrazine-2-carboxylate (Reference Example 133) and butyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
（参考例１４１）４－［ｃｉｓ－４－｛５－［５－（ブチルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－｛ｃｉｓ－４－［５－（｛２－［（ブチルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１４０）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 141 4- [cis-4- {5- [5- (Butylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- {cis-4- [5-({2-[(butylamino) carbonothioyl] hydrazino} carbonyl) -3- Methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylate tert-Butyl (Reference Example 140) was used for the same reaction as Reference Example 121 to give the title compound Got.
（参考例１４２）４－［ｃｉｓ－４－［５－（｛２－［（シクロプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル
　５－［ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－メチルピラジン－２－カルボン酸メチル（参考例３８）とイソチオシアン酸シクロプロピルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 142 4- [cis-4- [5-({2-[(cyclopropylamino) carbonothioyl] hydrazino} carbonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H ) -Yl] piperidine-1-carboxylic acid tert-butyl 5- [cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methyl The title compound was obtained in the same manner as in Reference Example 120 using methyl pyrazine-2-carboxylate (Reference Example 38) and cyclopropyl isothiocyanate.
（参考例１４３）４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル
　４－［ｃｉｓ－４－［５－（｛２－［（シクロプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１４２）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 143 4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro Quinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-butyl 4- [cis-4- [5-({2-[(cyclopropylamino) carbonothioyl] hydrazino} carbonyl) -3-methyl Pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-Butyl (Reference Example 142) was used to carry out a reaction similar to Reference Example 121 to obtain the title compound.
（参考例１４４）４－｛ｃｉｓ－４－［３－メチル－５－（｛２－［（プロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　５－｛ｃｉｓ－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－６－メチルピラジン－２－カルボン酸　メチル（参考例１３３）とイソチオシアン酸プロピルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 144 4- {cis-4- [3-Methyl-5-({2-[(propylamino) carbonothioyl] hydrazino} carbonyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] Pyrazin-1-yl} piperidine-1-carboxylate tert-butyl 5- {cis-4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } -6-Methylpyrazine-2-carboxylate (Reference Example 133) and propyl isothiocyanate were used for the same reaction as Reference Example 120 to obtain the title compound.
（参考例１４５）４－［ｃｉｓ－４－｛３－メチル－５－［５－（プロピルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル
　４－｛ｃｉｓ－４－［３－メチル－５－（｛２－［（プロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１４４）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 145 4- [cis-4- {3-Methyl-5- [5- (propylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro-1H -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate tert-butyl 4- {cis-4- [3-methyl-5-({2-[(propylamino) carbonothioyl] hydrazino} carbonyl ) Pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylate tert-Butyl (Reference Example 144) was used for the same reaction as Reference Example 121 to give the title compound Got.
（参考例１４６）５－（｛（１Ｒ，２Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝アミノ）ピラジン－２－カルボン酸メチル
　５－クロロピラジン－２－カルボン酸メチル（２９．０ｇ、０．１６８ｍｏｌ）とｃｉｓ－（１Ｓ，２Ｒ）－１Ｎ－Ｂｏｃ－シクロヘキサン－１，２－ジアミン（３０．０ｇ、０．１４０ｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（４００ｍＬ）に溶解し、ジイソプロピルエチルアミン（３６．６ｍL、０．２１ｍｏｌ）を加え、９０℃で５時間攪拌した。反応液を室温まで冷却し、酢酸エチルで希釈、水、飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、２：１－１：５）を用いて精製し、標記目的化合物（４７．８ｇ、収率９７％）を得た。 (Reference Example 146) 5-({(1R, 2S) -2-[(tert-butoxycarbonyl) amino] cyclohexyl} amino) pyrazine-2-carboxylate methyl 5-chloropyrazine-2-carboxylate (29. 0 g, 0.168 mol) and cis- (1S, 2R) -1N-Boc-cyclohexane-1,2-diamine (30.0 g, 0.140 mol) were dissolved in N, N-dimethylformamide (400 mL) and diisopropyl Ethylamine (36.6 mL, 0.21 mol) was added and stirred at 90 ° C. for 5 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated brine. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane: ethyl acetate, 2-1-1: 5) to give the title object compound (47.8 g). Yield 97%).
（参考例１４７）５－｛［（１Ｒ，２Ｓ）－２－｛［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］アミノ｝シクロヘキシル］アミノ｝－６－クロロピラジン－２－カルボン酸メチル
　参考例１４６で製造した５－（｛（１Ｒ，２Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキシル｝アミノ）ピラジン－２－カルボン酸メチル（４７．８ｇ、０．１３６ｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（５００mL）に溶解し、Ｎ－クロロスクシンイミド（１９．１g、０．１４３ｍｏｌ）を加え、５０℃で１時間攪拌した。反応液を室温まで冷却し、ジイソプロピルエーテルで希釈、水、飽和食塩水にて洗浄した。有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。得られた残渣をジクロロメタン（４００ｍＬ）に溶解し、トリフルオロ酢酸（２００ｍＬ）を加え、室温で１時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで２回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をテトラヒドロフラン（５００ｍＬ）に溶解し、１－Ｂｏｃ－４－ピペリドン（２７．６ｇ、０．１３９ｍｏｌ）およびトリアセトキシ水素化ホウ素ナトリウム（２９．４ｇ、０．１３９ｍｏｌ）を加え、室温で２．５時間攪拌した。反応液を減圧濃縮し、酢酸エチルで希釈後、水、飽和食塩水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、２：１－１：５）を用いて精製し、標記目的化合物（５３．０ｇ、収率８３％）を得た。 Reference Example 147 Methyl 5-{[(1R, 2S) -2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} cyclohexyl] amino} -6-chloropyrazine-2-carboxylate Methyl 5-({(1R, 2S) -2-[(tert-butoxycarbonyl) amino] cyclohexyl} amino) pyrazine-2-carboxylate (47.8 g, 0.136 mol) prepared in Reference Example 146 was replaced with N, The product was dissolved in N-dimethylformamide (500 mL), N-chlorosuccinimide (19.1 g, 0.143 mol) was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with diisopropyl ether, and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (400 mL), trifluoroacetic acid (200 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction twice with dichloromethane, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (500 mL), and 1-Boc-4-piperidone (27.6 g, 0.139 mol) and sodium triacetoxyborohydride (29.4 g, 0.139 mol) were added. The mixture was further stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate, 2: 1 to 1: 5) to give the title compound ( 53.0 g, 83% yield).
（参考例１４８）５－｛［（１Ｒ，２Ｓ）－２－｛［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］（クロロアセチル）アミノ｝シクロヘキシル］アミノ｝－６－クロロピラジン－２－カルボン酸メチル
　参考例１４７で製造した５－｛［（１Ｒ，２Ｓ）－２－｛［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］アミノ｝シクロヘキシル］アミノ｝－６－クロロピラジン－２－カルボン酸メチル（５３ｇ、０．１１３ｍｏｌ）をジクロロメタン（５００ｍＬ）に溶解し、トリエチルアミン（２３．７ｍL、０．１７ｍｏｌ）およびクロロアセチルクロリド（１０．８ｍL、０．１３６ｍｏｌ）を加え、０℃で１時間攪拌した。反応液に飽和重曹水（１００mＬ）を加えた後、水にて洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、２：１－１：１）を用いて精製し、標記目的化合物（５４．９ｇ、収率８９％）を得た。 Reference Example 148 5-{[(1R, 2S) -2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] (chloroacetyl) amino} cyclohexyl] amino} -6-chloropyrazine-2 -Methyl carboxylate 5-{[(1R, 2S) -2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} cyclohexyl] amino} -6-chloropyrazine- prepared in Reference Example 147 Dissolve methyl 2-carboxylate (53 g, 0.113 mol) in dichloromethane (500 mL), add triethylamine (23.7 mL, 0.17 mol) and chloroacetyl chloride (10.8 mL, 0.136 mol) at 0 ° C. Stir for 1 hour. Saturated aqueous sodium hydrogen carbonate (100 mL) was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2-1-1: 1) to obtain the title object compound (54.9 g, yield 89%).
（参考例１４９）５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］－３－オキソオクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル
　参考例１４８で製造した５－｛［（１Ｒ，２Ｓ）－２－｛［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］（クロロアセチル）アミノ｝シクロヘキシル］アミノ｝－６－クロロピラジン－２－カルボン酸メチル（５４．９ｇ、０．１０１ｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（５５０ｍＬ）に溶解し、酸化銀（Ｉ）（７０．０ｇ、０．３０２ｍｏｌ）を加え、１００℃で２．５時間攪拌した。反応液を室温まで冷却し、セライト濾過した。濾液に水（２L）を加えた後、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、２：１－１：２）を用いて精製し、標記目的化合物（４６．３ｇ、収率９０％）を得た。 Reference Example 149 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -3-oxooctahydroquinoxalin-1 (2H) -yl] -6-chloro Methyl pyrazine-2-carboxylate 5-{[(1R, 2S) -2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] (chloroacetyl) amino} cyclohexyl] amino prepared in Reference Example 148 } -6-chloropyrazine-2-carboxylate methyl (54.9 g, 0.101 mol) was dissolved in N, N-dimethylformamide (550 mL), and silver (I) oxide (70.0 g, 0.302 mol) was dissolved. In addition, the mixture was stirred at 100 ° C. for 2.5 hours. The reaction was cooled to room temperature and filtered through celite. Water (2 L) was added to the filtrate, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 2: 1-1: 2) to obtain the title object compound (46.3 g, yield 90%).
（参考例１５０）５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル
　参考例１４９で製造した５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］－３－オキソオクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル（４６．３ｇ、９１．０mｍｏｌ）をテトラヒドロフラン（５００ｍＬ）に溶解し、０℃にてボラン硫化ジメチル錯体（１７．３ｍＬ、０．１８２ｍｏｌ）を加え、４５℃で１．５時間攪拌した。反応液を０℃まで冷却し、１N塩酸（１５ｍL）を加えた。反応液に飽和重曹水（３０ｍＬ）を加え、減圧濃縮した。残渣を酢酸エチルで希釈後、水、飽和食塩水で洗浄した。得られた有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、６：１－２：１）を用いて精製し、標記目的化合物（３４．３ｇ、収率７６％）を得た。 Reference Example 150 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-chloropyrazine-2- Methyl carboxylate 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] -3-oxooctahydroquinoxalin-1 (2H) -yl] prepared in Reference Example 149 Methyl-6-chloropyrazine-2-carboxylate (46.3 g, 91.0 mmol) was dissolved in tetrahydrofuran (500 mL), borane sulfide dimethyl complex (17.3 mL, 0.182 mol) was added at 0 ° C., and 45 Stir at 1.5 ° C. for 1.5 hours. The reaction was cooled to 0 ° C. and 1N hydrochloric acid (15 mL) was added. Saturated aqueous sodium hydrogen carbonate (30 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate, 6: 1-2: 1) to give the title target compound ( 34.3 g, yield 76%).
（参考例１５１）２－（ブロモメチル）－５－クロロベンゾニトリル
　５－クロロ－２－メチルベンゾニトリルを用いて参考例３０と同様に反応を行い、標記目的化合物を得た。 Reference Example 151 2- (Bromomethyl) -5-chlorobenzonitrile The reaction was performed in the same manner as in Reference Example 30 using 5-chloro-2-methylbenzonitrile to obtain the title target compound.
（参考例１５２）５－クロロ－２－ビニル安息香酸メチル
　２－ブロモ－５－クロロ安息香酸メチル（２．２９ｇ、９．１８ｍｍｏｌ）をトルエン（５０mL）に溶解し、室温にてトリブチルビニルスズ（３．２２ｍＬ、１１．０ｍｍｏｌ）およびテトラキストリフェニルホスフィンパラジウム（０）（０．８５ｇ、０．７３４ｍｍｏｌ）を加え、１８時間加熱還流した。反応液を室温まで冷却し、セライト濾過した。濾液に飽和フッ化カリウム水溶液（１００ｍＬ）を加えた後、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９９：１－９５：５）を用いて精製し、標記目的化合物（１．２７ｇ、収率７０％）を得た。 (Reference Example 152) Methyl 5-chloro-2-vinylbenzoate Methyl 2-bromo-5-chlorobenzoate (2.29 g, 9.18 mmol) was dissolved in toluene (50 mL), and tributylvinyltin ( 3.22 mL, 11.0 mmol) and tetrakistriphenylphosphine palladium (0) (0.85 g, 0.734 mmol) were added and heated to reflux for 18 hours. The reaction was cooled to room temperature and filtered through celite. A saturated aqueous potassium fluoride solution (100 mL) was added to the filtrate, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 99: 1-95: 5) to give the title object compound (1.27 g, yield 70%).
（参考例１５３）５－クロロ－２－エチル安息香酸メチル
　参考例１５２で製造した５－クロロ－２－ビニル安息香酸メチル（１．２７ｇ、６．３９ｍｍｏｌ）を酢酸エチル／エタノール（４：１、２５ｍＬ）に溶解し、パラジウムカーボン（０．５ｇ）を加え、水素雰囲気下４時間攪拌した。反応液をセライト濾過し、減圧濃縮後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９９：１－９５：５）を用いて精製し、標記目的化合物（１．１２ｇ、８７％）を得た。 (Reference Example 153) Methyl 5-chloro-2-ethylbenzoate Methyl 5-chloro-2-vinylbenzoate (1.27 g, 6.39 mmol) prepared in Reference Example 152 was mixed with ethyl acetate / ethanol (4: 1, 25 mL), palladium carbon (0.5 g) was added, and the mixture was stirred for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate, 99: 1-95: 5) to give the title object compound (1.12 g, 87%).
（参考例１５４）２－（１－ブロモエチル）－５－クロロ安息香酸メチル
　参考例１５３で製造した５－クロロ－２－エチル安息香酸メチルを用いて参考例３０と同様に反応を行い、標記目的化合物を得た。 Reference Example 154 Methyl 2- (1-bromoethyl) -5-chlorobenzoate Using the methyl 5-chloro-2-ethylbenzoate prepared in Reference Example 153, the reaction was carried out in the same manner as in Reference Example 30, and the title A compound was obtained.
（参考例１５５）５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－メチルピラジン－２－カルボン酸メチル
　５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル(参考例１５０）を用いて参考例３８と同様の反応を行い、標記化合物を得た。 Reference Example 155 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2- Methyl carboxylate 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-chloropyrazine-2-carboxylic acid The same reaction as in Reference Example 38 was performed using methyl (Reference Example 150) to obtain the title compound.
（参考例１５６）４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル
　５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－メチルピラジン－２－カルボン酸メチル（参考例１５５）を用いて参考例３９と同様の反応を行い、標記化合物を得た。 Reference Example 156 4-[(4aR, 8aS) -4- [5- (Ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-Butyl 5-[(4aS, 8aR) -4- [1- (tert-Butoxycarbonyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -6-methylpyrazine-2-carboxylic acid The same reaction as in Reference Example 39 was carried out using methyl (Reference Example 155) to obtain the title compound.
（参考例１５７）４－［（４ａＲ，８ａＳ）－４－［５－（｛２－［（シクロプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル
　５－［（４ａＳ，８ａＲ）－４－［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－６－クロロピラジン－２－カルボン酸メチル（参考例１５０）とイソチオシアン酸シクロプロピルを用いて参考例１２０と同様の反応を行い、標記化合物を得た。 Reference Example 157 4-[(4aR, 8aS) -4- [5-({2-[(Cyclopropylamino) carbonothioyl] hydrazino} carbonyl) -3-methylpyrazin-2-yl] octahydroquinoxaline -1 (2H) -yl] piperidine-1-carboxylic acid tert-butyl 5-[(4aS, 8aR) -4- [1- (tert-butoxycarbonyl) piperidin-4-yl] octahydroquinoxaline-1 (2H ) -Yl] -6-chloropyrazine-2-carboxylate (Reference Example 150) and cyclopropyl isothiocyanate were subjected to the same reaction as Reference Example 120 to obtain the title compound.
（参考例１５８）４－［（４ａＲ，８ａＳ）－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル
　４－［（４ａＲ，８ａＳ）－４－［５－（｛２－［（シクロプロピルアミノ）カルボノチオイル］ヒドラジノ｝カルボニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（参考例１５７）を用いて参考例１２１と同様の反応を行い、標記化合物を得た。 Reference Example 158 4-[(4aR, 8aS) -4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazine-2- Yl} octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert-butyl 4-[(4aR, 8aS) -4- [5-({2-[(cyclopropylamino) carbonothioyl] Hydrazino} carbonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (Reference Example 157) was used for the same reaction as Reference Example 121. The title compound was obtained.
　参考例に記載の化合物の化学構造式および物理化学データを以下の表に示す。 The chemical structural formulas and physicochemical data of the compounds described in Reference Examples are shown in the following table.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
　（実施例１）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 1 5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000042
 及び
Figure JPOXMLDOC01-appb-C000042
 as well as
Figure JPOXMLDOC01-appb-C000043
 　参考例３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（４９１ｍｇ、０．９７２ｍｍｏｌ）をメタノール（５ｍＬ）に溶解し、４Ｎ－塩酸／ジオキサン（５ｍＬ）を加え、室温で１時間攪拌後、減圧濃縮した。得られた残渣にアセトニトリル（１０ｍＬ）、ジイソプロピルアミン（１．６９ｍＬ、９．７２ｍｍｏｌ）、及び２－（ブロモメチル）－５－クロロ安息香酸メチル（３０５ｍｇ、１．１７ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製し、目的化合物のラセミ体（２００ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール：ヘキサン＝３０：７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール：ヘキサン＝３０：７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．５分の標記目的化合物（９３ｍｇ、１６％、実施例１－Ａ）と保持時間が２．８分の標記目的化合物（８８ｍｇ、１５％、実施例１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000043
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 3 (491 mg, 0.972 mmol) was dissolved in methanol (5 mL), 4N-hydrochloric acid / dioxane (5 mL) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. Acetonitrile (10 mL), diisopropylamine (1.69 mL, 9.72 mmol), and methyl 2- (bromomethyl) -5-chlorobenzoate (305 mg, 1.17 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 18 hours. did. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using NH silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) to obtain the racemic product (200 mg) of the target compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol: hexane = 30: 70, 10 mL / min, 254 nm), and HPLC ( Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol: hexane = 30: 70, 2.0 mL / min, 254 nm) 16%, Example 1-A) and a retention time of 2.8 minutes were obtained for the title compound (88 mg, 15%, Example 1-B).
　（実施例２）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 2 5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000044
 　及び
Figure JPOXMLDOC01-appb-C000044
 as well as
Figure JPOXMLDOC01-appb-C000045
 　実施例１で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル（実施例１－Ａ）（３６ｍｇ、６１μｍｏｌ）をエタノール（２ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（０．２ｍＬ）を加え、６０℃で１８時間攪拌した。反応液に１Ｎ－塩酸水溶液（０．２ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９９：１－７０：３０）を用いて精製し、標記目的化合物（３５ｍｇ、９９％、実施例２－Ａ）を得た。
　実施例１で製造した実施例１－Ｂ（３９ｍｇ、６６μｍｏｌ）も同様に反応を行い、標記目的化合物（（３７ｍｇ、９８％、実施例２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000045
 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine prepared in Example 1 1-yl} methyl) methyl benzoate (Example 1-A) (36 mg, 61 μmol) was dissolved in ethanol (2 mL), 1N aqueous sodium hydroxide solution (0.2 mL) was added, and the mixture was heated at 60 ° C. for 18 hours. Stir. A 1N aqueous hydrochloric acid solution (0.2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 99: 1-70: 30) to obtain the title object compound (35 mg, 99%, Example 2-A). .
Example 1-B (39 mg, 66 μmol) prepared in Example 1 was reacted in the same manner to obtain the title compound (37 mg, 98%, Example 2-B).
　（実施例３）　６－［ｃｉｓ－４－［１－（２－カルバモイル－４－クロロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－５－クロロ－Ｎ－エチルニコチンアミド Example 3 6- [cis-4- [1- (2-carbamoyl-4-chlorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -5-chloro-N-ethyl Nicotinamide
Figure JPOXMLDOC01-appb-C000046
 　及び
Figure JPOXMLDOC01-appb-C000046
 as well as
Figure JPOXMLDOC01-appb-C000047
 　実施例１で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル（実施例１－Ａ）（４１ｍｇ、７０μｍｏｌ）を７Ｎアンモニア／メタノール（４ｍＬ）に溶解し、７０℃で４２時間攪拌した。反応液を減圧濃縮し、得られた残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製し、標記目的化合物（２２ｍｇ、５５％、実施例３－Ａ）を得た。
実施例１で製造した実施例１－Ｂ（４５ｍｇ、７７μｍｏｌ）も同様に反応を行い、標記目的化合物（２２ｍｇ、６１％、実施例３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000047
 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine prepared in Example 1 -1-yl} methyl) methyl benzoate (Example 1-A) (41 mg, 70 μmol) was dissolved in 7N ammonia / methanol (4 mL) and stirred at 70 ° C. for 42 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using NH silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) to give the title object compound (22 mg, 55%, Example 3- A) was obtained.
Example 1-B (45 mg, 77 μmol) prepared in Example 1 was reacted in the same manner to obtain the title target compound (22 mg, 61%, Example 3-B).
　（実施例４）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 4 5-Chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000048
 　及び
Figure JPOXMLDOC01-appb-C000048
 as well as
Figure JPOXMLDOC01-appb-C000049
 　参考例６で製造した４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（３．５８ｇ、６．９１ｍｍｏｌ）をメタノール（５ｍＬ）に溶解し、４Ｎ－塩酸／ジオキサン（５ｍＬ）を加え、室温で１６時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液（１５ｍＬ）、２０％メタノール／クロロホルム混合液（１０ｍＬ）を加えて分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ５０ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣にアセトニトリル（２０ｍＬ）、ジイソプロピルエチルアミン（２．０９ｍＬ、１２．０ｍｍｏｌ）、及び２－（ブロモメチル）－５－クロロ安息香酸メチル（１．５８ｇ、５．９９ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応液を減圧濃縮し、反応液に水（１５ｍＬ）、クロロホルム（１５ｍＬ）を加えて分液し、水層をクロロホルム（３ｘ１０ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　４０Ｍ、メタノール／クロロホルム、０／１００－７／９３）を用いて精製し、標記目的化合物のラセミ体（２．３３ｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が５．７分の標記目的化合物（１．０２ｇ、２８％、実施例４－Ａ）と保持時間が３．２分の標記目的化合物（１．０９ｇ、３０％、実施例４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000049
 4- [cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- prepared in Reference Example 6 Butyl (3.58 g, 6.91 mmol) was dissolved in methanol (5 mL), 4N-hydrochloric acid / dioxane (5 mL) was added, and the mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (15 mL) and a 20% methanol / chloroform mixture (10 mL) were added to the obtained residue, and the mixture was separated. The aqueous layer was extracted with a 20% methanol / chloroform mixture (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Acetonitrile (20 mL), diisopropylethylamine (2.09 mL, 12.0 mmol), and methyl 2- (bromomethyl) -5-chlorobenzoate (1.58 g, 5.99 mmol) were added to the obtained residue, and Stir for hours. The reaction solution was concentrated under reduced pressure, and water (15 mL) and chloroform (15 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted with chloroform (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 40M, methanol / chloroform, 0 / 100-7 / 93) to obtain a racemic form (2.33 g) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 10 mL / min, 254 nm). Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) Title target compound (1) The title compound (1.09 g, 30%, Example 4-B) was obtained with 0.02 g, 28%, Example 4-A) and a retention time of 3.2 minutes.
　（実施例５）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－メチル－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 5 5-Chloro-2-({4- [cis-4- [3-methyl-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000050
 　及び
Figure JPOXMLDOC01-appb-C000050
 as well as
Figure JPOXMLDOC01-appb-C000051
 　参考例１０で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［３－メチル－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル（２０５ｍｇ、０．４２２ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解し、トリフルオロ酢酸（３ｍＬ）を加え、室温で３時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。得られた残渣を２－プロパノール（４ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．１４７ｍＬ、０．８４４ｍｍｏｌ）、及び２－（ブロモメチル）－５－クロロ安息香酸メチル（１３３ｍｇ、０．５０６ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９０：１０－０：１００）を用いて精製し、標記目的化合物のラセミ体（２０４ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が７．１分の標記目的化合物（７６ｍｇ、３２％、実施例５－Ａ）と保持時間が３．６分の標記目的化合物（８０ｍｇ、３４％、実施例５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000051
 5-Chloro-2-({4- [cis-4- [3-methyl-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] prepared in Reference Example 10 Piperidin-1-yl} methyl) methyl benzoate (205 mg, 0.422 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. The resulting residue was dissolved in 2-propanol (4 mL) and diisopropylethylamine (0.147 mL, 0.844 mmol) and methyl 2- (bromomethyl) -5-chlorobenzoate (133 mg, 0.506 mmol) were added, Stir at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 90: 10-0: 100) to obtain a racemic form (204 mg) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 10 mL / min, 254 nm). Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) Title target compound (76 mg) having a retention time of 7.1 min , 32%, Example 5-A) and the retention time of 3.6 minutes were obtained for the title object compound (80 mg, 34%, Example 5-B).
　（実施例６）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（メチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 6 5-chloro-2-({4- [cis-4- [3-chloro-5- (methylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000052
 及び
Figure JPOXMLDOC01-appb-C000052
 as well as
Figure JPOXMLDOC01-appb-C000053
 　参考例１３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（メチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．６分の標記目的化合物（実施例６－Ａ）と保持時間３．３分（実施例６－Ｂ）の標記目的化合物を得た。
Figure JPOXMLDOC01-appb-C000053
 4- [cis-4- [3-Chloro-5- (methylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 13 The reaction was performed in the same manner as in Example 4 using HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm). The title target compound (Example 6-A) having a retention time of 4.6 minutes and a retention time of 3.3 minutes (Example 6-B) was obtained.
　（実施例７）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 7 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000054
 及び
Figure JPOXMLDOC01-appb-C000054
 as well as
Figure JPOXMLDOC01-appb-C000055
 　実施例５で製造した実施例５－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例７－Ａ）を得た。
　実施例５で製造した実施例５－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000055
 The reaction was conducted in the same manner as in Example 2 using Example 5-A prepared in Example 5 to obtain the title object compound (Example 7-A).
The reaction was conducted in the same manner as in Example 2 using Example 5-B prepared in Example 5 to obtain the title object compound (Example 7-B).
　（実施例８）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 8 5-Chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000056
 及び
Figure JPOXMLDOC01-appb-C000056
 as well as
Figure JPOXMLDOC01-appb-C000057
 　実施例４で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル（実施例４－Ａ）（７２ｍｇ、０．１１９ｍｍｏｌ）をメタノール（０．５ｍＬ）およびテトラヒドロフラン（１ｍＬ）に溶解し、１規定水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温にて５時間攪拌した。反応液に水（２ｍＬ）、１規定塩酸水溶液（０．５ｍＬ）およびクロロホルム（５ｍＬ）を加えて分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ５ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧濃縮した。得られた残渣にジメチルスルホキシド（２ｍＬ）を加え、不溶物を除去した後高速液体クロマトグラフィー（ＮＯＭＵＲＡ　Ｄｅｖｅｌｏｓｉｌ　Ｃｏｍｂｉ－ＲＰ５、ギ酸／アセトニトリル／水＝０．１／９／９１－０．１／４８／５２）にて精製し、標記目的化合物（４３．６ｍｇ、６２％、実施例８－Ａ）を得た。
実施例４で製造した実施例４－Ｂも同様に反応を行い、標記目的化合物（実施例８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000057
 5-Chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] prepared in Example 4 Piperidin-1-yl} methyl) methyl benzoate (Example 4-A) (72 mg, 0.119 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (1 mL), and 1N aqueous sodium hydroxide solution (0. 5 mL) was added and stirred at room temperature for 5 hours. Water (2 mL), 1N hydrochloric acid aqueous solution (0.5 mL) and chloroform (5 mL) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with a 20% methanol / chloroform mixture (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Dimethyl sulfoxide (2 mL) was added to the resulting residue to remove insoluble matters, and then high performance liquid chromatography (NOMURA Develosil Combi-RP5, formic acid / acetonitrile / water = 0.1 / 9 / 91-0.1 / 48 / 52) to give the title object compound (43.6 mg, 62%, Example 8-A).
Example 4-B produced in Example 4 was reacted in the same manner to give the title object compound (Example 8-B).
　（実施例９）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（メチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 9 5-Chloro-2-({4- [cis-4- [3-chloro-5- (methylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000058
 及び
Figure JPOXMLDOC01-appb-C000058
 as well as
Figure JPOXMLDOC01-appb-C000059
 　実施例６で製造した実施例６－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例９－Ａ）を得た。
　実施例６で製造した実施例６－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000059
 The reaction was conducted in the same manner as in Example 8 using Example 6-A prepared in Example 6 to obtain the title object compound (Example 9-A).
The reaction was conducted in the same manner as in Example 8 using Example 6-B prepared in Example 6 to obtain the title object compound (Example 9-B).
　（実施例１０）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［（２－ヒドロキシエチル）カルバモイル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 10 5-Chloro-2-({4- [cis-4- {3-chloro-5-[(2-hydroxyethyl) carbamoyl] pyridin-2-yl} octahydroquinoxaline-1 (2H) -Yl] piperidin-1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000060
 及び
Figure JPOXMLDOC01-appb-C000060
 as well as
Figure JPOXMLDOC01-appb-C000061
 　参考例１６で製造した４－［ｃｉｓ－４－｛５－［（２－アセトキシエチル）カルバモイル］－３－クロロピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が６．３分の標記目的化合物(実施例１０－Ａ)と保持時間２．９分(実施例１０－Ｂ)の標記目的化合物を得た。
Figure JPOXMLDOC01-appb-C000061
 4- [cis-4- {5-[(2-acetoxyethyl) carbamoyl] -3-chloropyridin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidine-1-prepared in Reference Example 16 Reaction was carried out in the same manner as in Example 4 using tert-butyl carboxylate, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30 / 70,2. The title target compound (Example 10-A) having a retention time of 6.3 minutes and a retention time of 2.9 minutes (Example 10-B) were obtained at 0 mL / min and 254 nm).
　（実施例１１）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［（２－ヒドロキシエチル）カルバモイル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 11 5-Chloro-2-({4- [cis-4- {3-chloro-5-[(2-hydroxyethyl) carbamoyl] pyridin-2-yl} octahydroquinoxaline-1 (2H) -Yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000062
 及び
Figure JPOXMLDOC01-appb-C000062
 as well as
Figure JPOXMLDOC01-appb-C000063
 　実施例１０で製造した実施例１０－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１１－Ａ）を得た。
　実施例１０で製造した実施例１０－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000063
 The reaction was conducted in the same manner as in Example 8 using Example 10-A prepared in Example 10 to obtain the title compound (Example 11-A).
Using Example 10-B produced in Example 10, the reaction was conducted in the same manner as in Example 8 to obtain the title object compound (Example 11-B).
　（実施例１２）２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－シアノ安息香酸 Example 12 2-({4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) -5-cyanobenzoic acid
Figure JPOXMLDOC01-appb-C000064
 及び
Figure JPOXMLDOC01-appb-C000064
 as well as
Figure JPOXMLDOC01-appb-C000065
 　参考例２０で製造した参考例２０－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１２－Ａ）を得た。
　参考例２０で製造した参考例２０－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000065
 The reaction was conducted in the same manner as in Example 8 using Reference Example 20-A produced in Reference Example 20 to give the title object compound (Example 12-A).
The reaction was conducted in the same manner as in Example 8 using Reference Example 20-B produced in Reference Example 20 to give the title object compound (Example 12-B).
　（実施例１３）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 13 5-Chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000066
 及び
Figure JPOXMLDOC01-appb-C000066
 as well as
Figure JPOXMLDOC01-appb-C000067
 　実施例２０で製造した実施例２０－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１３－Ａ）を得た。
　実施例２０で製造した実施例２０－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000067
 The reaction was conducted in the same manner as in Example 8 using Example 20-A prepared in Example 20 to obtain the title object compound (Example 13-A).
The reaction was conducted in the same manner as in Example 8 using Example 20-B prepared in Example 20 to obtain the title object compound (Example 13-B).
　（実施例１４）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 14 5-Chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000068
 及び
Figure JPOXMLDOC01-appb-C000068
 as well as
Figure JPOXMLDOC01-appb-C000069
 　参考例６で製造した４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（３．５８ｇ、６．９１ｍｍｏｌ）をメタノール（５ｍＬ）に溶解し、４Ｎ－塩酸／ジオキサン（５ｍＬ）を加え、室温で１６時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液（１５ｍＬ）、２０％メタノール／クロロホルム混合液（１０ｍＬ）を加えて分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ５０ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣の一部（１２０ｍｇ）にアセトニトリル（１．５ｍＬ）、ジイソプロピルエチルアミン（０．１００ｍＬ、０．５７５ｍｍｏｌ）、及び参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（７９．９ｍｇ、０．２８８ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応液を減圧濃縮し、反応液に水（５ｍＬ）、クロロホルム（５ｍＬ）を加えて分液し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｓ、メタノール／クロロホルム、０／１００－７／９３）を用いて精製し、標記目的化合物のラセミ体（１２１ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．８分の標記目的化合物（４９ｍｇ、２８％、実施例１４－Ａ）と保持時間が２．９分の標記目的化合物（５２ｍｇ、２９％、実施例１４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000069
 4- [cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert- prepared in Reference Example 6 Butyl (3.58 g, 6.91 mmol) was dissolved in methanol (5 mL), 4N-hydrochloric acid / dioxane (5 mL) was added, and the mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (15 mL) and a 20% methanol / chloroform mixture (10 mL) were added to the obtained residue, and the mixture was separated. The aqueous layer was extracted with a 20% methanol / chloroform mixture (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. A part of the obtained residue (120 mg) was mixed with acetonitrile (1.5 mL), diisopropylethylamine (0.100 mL, 0.575 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 ( (79.9 mg, 0.288 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and water (5 mL) and chloroform (5 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted with chloroform (3 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 25S, methanol / chloroform, 0 / 100-7 / 93) to obtain a racemic form (121 mg) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 10 mL / min, 254 nm). Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) Title target compound (49 mg) having a retention time of 4.8 minutes 28%, Example 14-A) and the retention time 2.9 minutes were obtained for the title compound (52 mg, 29%, Example 14-B).
　(実施例１５) ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 15 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000070
 及び
Figure JPOXMLDOC01-appb-C000070
 as well as
Figure JPOXMLDOC01-appb-C000071
 　参考例３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（９９５ｍｇ、１．９７ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解し、トリフルオロ酢酸（３ｍＬ）を加え、室温で３時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。得られた残渣を２－プロパノール（２０ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．６８７ｍＬ、３．９５ｍｍｏｌ）、及び参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（６５７ｍｇ、２．３７ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－８０：２０）を用いて精製し、標記目的化合物のラセミ体（９８０ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．１分の標記目的化合物（３９３ｍｇ、３３％、実施例１５－Ａ）と保持時間が２．５分の標記目的化合物（２４８ｍｇ、２１％、実施例１５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000071
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 3 (995 mg, 1.97 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. The obtained residue was dissolved in 2-propanol (20 mL), diisopropylethylamine (0.687 mL, 3.95 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate (657 mg, 2 .37 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol, 98: 2-80: 20) to obtain a racemic form (980 mg) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 10 mL / min, 254 nm). Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) The title compound of interest for which the retention time was 4.1 minutes (393 mg 33%, Example 15-A) and a retention time of 2.5 minutes were obtained for the title compound (248 mg, 21%, Example 15-B).
　（実施例１６）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）ピリミジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 16 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) pyrimidin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000072
 及び
Figure JPOXMLDOC01-appb-C000072
 as well as
Figure JPOXMLDOC01-appb-C000073
 　参考例３３で製造した４－［ｃｉｓ－４－［５－（エチルカルバモイル）ピリミジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が６．５分（実施例１６－Ａ）の標記目的化合物と保持時間４．２分の標記目的化合物（実施例１６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000073
 Performed using tert-butyl 4- [cis-4- [5- (ethylcarbamoyl) pyrimidin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate prepared in Reference Example 33 Reaction was carried out in the same manner as in Example 4, and retention time in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) Of 6.5 minutes (Example 16-A) and the title target compound (Example 16-B) having a retention time of 4.2 minutes were obtained.
　（実施例１７）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 17 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000074
 及び
Figure JPOXMLDOC01-appb-C000074
 as well as
Figure JPOXMLDOC01-appb-C000075
 　参考例３９の４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が６．０分（実施例１７－Ａ）の標記目的化合物と保持時間４．２分の標記目的化合物（実施例１７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000075
 Using Reference Example 39 tert-butyl 4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate Then, the reaction was carried out in the same manner as in Example 4, and in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) The title object compound having a retention time of 6.0 minutes (Example 17-A) and the title object compound (Example 17-B) having a retention time of 4.2 minutes were obtained.
　（実施例１８）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 18 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000076
 及び
Figure JPOXMLDOC01-appb-C000076
 as well as
Figure JPOXMLDOC01-appb-C000077
 　実施例１７で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル（実施例１７－Ａ）（９３ｍｇ、１６３μｍｏｌ）をエタノール（３ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（０．５ｍＬ）を加え、２５℃で４時間攪拌した。反応液に１Ｎ－塩酸水溶液（０．５ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－８０：２０）を用いて精製し、標記目的化合物（９０ｍｇ、１００％、実施例１８－Ａ）を得た。
　実施例１７で製造した実施例１７－Ｂも同様に反応を行い、標記目的化合物（実施例１８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000077
 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine prepared in Example 17 1-yl} methyl) methyl benzoate (Example 17-A) (93 mg, 163 μmol) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at 25 ° C. for 4 hours. Stir. A 1N aqueous hydrochloric acid solution (0.5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 98: 2-80: 20) to give the title object compound (90 mg, 100%, Example 18-A). .
Example 17-B produced in Example 17 was reacted in the same manner to obtain the title compound (Example 18-B).
　（実施例１９）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）ピリミジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 19 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) pyrimidin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000078
 及び
Figure JPOXMLDOC01-appb-C000078
 as well as
Figure JPOXMLDOC01-appb-C000079
 　実施例１６で製造した実施例１６－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１９－Ａ）を得た。
　実施例１６で製造した実施例１６－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例１９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000079
 The reaction was conducted in the same manner as in Example 8 using Example 16-A prepared in Example 16 to obtain the title object compound (Example 19-A).
The reaction was conducted in the same manner as in Example 8 using Example 16-B produced in Example 16 to obtain the title object compound (Example 19-B).
　（実施例２０）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 20 5-chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000080
 及び
Figure JPOXMLDOC01-appb-C000080
 as well as
Figure JPOXMLDOC01-appb-C000081
 　参考例２９製造した４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．４分（実施例２０－Ａ）の標記目的化合物と保持時間５．７分（実施例２０－Ｂ）の標記目的化合物を得た。
Figure JPOXMLDOC01-appb-C000081
 Reference Example 29 4- {cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid tert -Butyl was used in the same manner as in Example 14, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min) The title compound with a retention time of 4.4 minutes (Example 20-A) and a retention time of 5.7 minutes (Example 20-B) at 254 nm was obtained.
　（実施例２１）５－クロロ－２－（｛４－［ｔｒａｎｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 21 5-Chloro-2-({4- [trans-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000082
 及び
Figure JPOXMLDOC01-appb-C000082
 as well as
Figure JPOXMLDOC01-appb-C000083
 　参考例４１の４－［ｔｒａｎｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１０／９０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が７．５分の標記目的化合物（実施例２１－Ａ）と保持時間５．５分の標記目的化合物（実施例２１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000083
 Using Reference Example 41, tert-butyl 4- [trans-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate Then, the reaction was carried out in the same manner as in Example 1, and in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 10/90, 2.0 mL / min, 254 nm) The title object compound (Example 21-A) having a retention time of 7.5 minutes and the title object compound (Example 21-B) having a retention time of 5.5 minutes were obtained.
　（実施例２２）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］ヘキサヒドロフロ［３，４－ｂ］ピラジン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 22 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] hexahydrofuro [3,4-b] pyrazine-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000084
 及び
Figure JPOXMLDOC01-appb-C000084
 as well as
Figure JPOXMLDOC01-appb-C000085
 　参考例４５で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］ヘキサヒドロフロ［３，４－ｂ］ピラジン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．２分の標記目的化合物（実施例２２－Ａ）と保持時間６．１分の標記目的化合物（実施例２２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000085
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] hexahydrofuro [3,4-b] pyrazin-1 (2H) -yl] piperidine prepared in Reference Example 45 Reaction was carried out in the same manner as in Example 14 using tert-butyl-1-carboxylate, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2-propanol / hexane = 30/70) The title compound (Example 22-A) having a retention time of 4.2 minutes and the title compound (Example 22-B) having a retention time of 6.1 minutes was obtained at 2.0 mL / min, 254 nm).
　（実施例２３）５－クロロ－２－（｛４－［ｔｒａｎｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 23 5-Chloro-2-({4- [trans-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000086
 及び
Figure JPOXMLDOC01-appb-C000086
 as well as
Figure JPOXMLDOC01-appb-C000087
 　実施例２１で製造した実施例２１－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例２３－Ａ）を得た。
　実施例２１で製造した実施例２１－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例２３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000087
 The reaction was conducted in the same manner as in Example 2 using Example 21-A produced in Example 21 to obtain the title object compound (Example 23-A).
The reaction was conducted in the same manner as in Example 2 using Example 21-B prepared in Example 21 to give the title object compound (Example 23-B).
　（実施例２４）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］ヘキサヒドロフロ［３，４－ｂ］ピラジン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 24 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] hexahydrofuro [3,4-b] pyrazine-1 (2H) -yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000088
 及び
Figure JPOXMLDOC01-appb-C000088
 as well as
Figure JPOXMLDOC01-appb-C000089
 　実施例２２で製造した実施例２２－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例２４－Ａ）を得た。
　実施例２２で製造した実施例２２－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例２４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000089
 The reaction was conducted in the same manner as in Example 8 using Example 22-A produced in Example 22 to obtain the title object compound (Example 24-A).
The reaction was conducted in the same manner as in Example 8 using Example 22-B prepared in Example 22 to give the title object compound (Example 24-B).
　（実施例２５）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸　（５－メチル－２－オキソ－１，３－ジオキソール－４－イル）メチル Example 25 5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl
Figure JPOXMLDOC01-appb-C000090
 または
Figure JPOXMLDOC01-appb-C000090
 Or
Figure JPOXMLDOC01-appb-C000091
 　実施例２の５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸（実施例２－Ａ）（３９８ｍｇ、０．６９４ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（６ｍＬ）に溶解後、炭酸カリウム（１９２ｍｇ、１．３９ｍｍｏｌ）を加え室温で攪拌下、４－クロロメチル－５－メチル－１，３－ジオキソール－２－オン（１２４ｍｇ、０．８３３ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）溶液を加え、室温で３時間攪拌した。反応液をセライト濾過し、母液を減圧濃縮した。得られた残渣を酢酸エチルに溶解し、水、飽和炭酸水素ナトリウム、及び飽和食塩水で洗浄し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８０：２０－０：１００）を用いて精製し、標記目的化合物（３９８ｍｇ、８４％、実施例２５－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000091
 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1 of Example 2 -Il} methyl) benzoic acid (Example 2-A) (398 mg, 0.694 mmol) was dissolved in N, N-dimethylformamide (6 mL), potassium carbonate (192 mg, 1.39 mmol) was added, and the mixture was stirred at room temperature. 4-chloromethyl-5-methyl-1,3-dioxol-2-one (124 mg, 0.833 mmol) in N, N-dimethylformamide (2 mL) was added and stirred at room temperature for 3 hours. The reaction solution was filtered through Celite, and the mother liquor was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate, and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 80: 20-0: 100) to give the title object compound (398 mg, 84%, Example 25-A). It was.
　（実施例２６）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸　２－ヒドロキシエチル Example 26 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid 2-hydroxyethyl
Figure JPOXMLDOC01-appb-C000092
 または
Figure JPOXMLDOC01-appb-C000092
 Or
Figure JPOXMLDOC01-appb-C000093
 　実施例２の５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸（実施例２－Ａ）（３０３ｍｇ、０．５２９ｍｍｏｌ）とエチレングリコール（０．２９ｍＬ、５．２９ｍｍｏｌ）をジクロロメタン（７ｍＬ）に溶解後、１，３－ジイソプロピルカルボジイミド（０．２４８ｍＬ、１．５９ｍｍｏｌ）と４－ジメチルアミノピリジン（６５ｍｇ、０．５２９ｍｍｏｌ）を加え室温で１８時間攪拌した。さらに１，３－ジイソプロピルカルボジイミド（０．２４８ｍＬ、１．５９ｍｍｏｌ）と４－ジメチルアミノピリジン（６５ｍｇ、０．５２９ｍｍｏｌ）を加え、室温で４日間攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９７：３－８０：２０）を用いて精製し、標記目的化合物（３００ｍｇ、９２％、実施例２６－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000093
 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1 of Example 2 -Il} methyl) benzoic acid (Example 2-A) (303 mg, 0.529 mmol) and ethylene glycol (0.29 mL, 5.29 mmol) were dissolved in dichloromethane (7 mL), and 1,3-diisopropylcarbodiimide (0 248 mL, 1.59 mmol) and 4-dimethylaminopyridine (65 mg, 0.529 mmol) were added and stirred at room temperature for 18 hours. Further, 1,3-diisopropylcarbodiimide (0.248 mL, 1.59 mmol) and 4-dimethylaminopyridine (65 mg, 0.529 mmol) were added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (chloroform: methanol, 97: 3-80: 20) to give the title object compound (300 mg, 92%, Example 26-A). Got.
　（実施例２７）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 27 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000094
 及び
Figure JPOXMLDOC01-appb-C000094
 as well as
Figure JPOXMLDOC01-appb-C000095
 　参考例４９の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が８．３分の標記目的化合物（実施例２７－Ａ）と３．９分の標記目的化合物（実施例２７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000095
 The tert-butyl 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 49 was used. And the reaction was carried out in the same manner as in Example 14 and retained in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm). The title target compound (Example 27-A) with a time of 8.3 minutes and the title target compound (Example 27-B) of 3.9 minutes were obtained.
　（実施例２８）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 28 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000096
 または
Figure JPOXMLDOC01-appb-C000096
 Or
Figure JPOXMLDOC01-appb-C000097
 　実施例２７で製造した実施例２７－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例２８－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000097
 The reaction was carried out in the same manner as in Example 30 using Example 27-A prepared in Example 27 to obtain the title object compound (Example 28-A).
　（実施例２９）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 29 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000098
 及び
Figure JPOXMLDOC01-appb-C000098
 as well as
Figure JPOXMLDOC01-appb-C000099
 　参考例５０と参考例５１の１：１混合物であるラセミ体の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が１４．４分の標記目的化合物（実施例２９－Ａ）と４．８分の標記目的化合物（実施例２９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000099
 Racemic 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H), which is a 1: 1 mixture of Reference Example 50 and Reference Example 51 The reaction was carried out in the same manner as in Example 15 using tert-butyl-yl] piperidine-1-carboxylate, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = 30) The title compound (Example 29-A) having a retention time of 14.4 minutes and the title compound (Example 29-B) having a retention time of 14.4 minutes was obtained at (/ 70, 2.0 mL / min, 254 nm).
　（実施例３０）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 30 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000100
 または
Figure JPOXMLDOC01-appb-C000100
 Or
Figure JPOXMLDOC01-appb-C000101
 　実施例２９で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル（実施例２９－Ａ）（３９０ｍｇ、６５５μｍｏｌ）をエタノール（２０ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（２ｍＬ）を加え、２５℃で１８時間攪拌した。反応液に１Ｎ－塩酸水溶液（２ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９５：５－７０：３０）を用いて精製し、標記目的化合物（３６５ｍｇ、９８％、実施例３０－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000101
 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] prepared in Example 29 Piperidin-1-yl} methyl) ethyl benzoate (Example 29-A) (390 mg, 655 μmol) was dissolved in ethanol (20 mL), 1N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 25 ° C. for 18 hours. did. A 1N aqueous hydrochloric acid solution (2 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 95: 5-70: 30) to obtain the title object compound (365 mg, 98%, Example 30-A). .
　（実施例３１）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（イソプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 31 5-Chloro-2-({4- [cis-4- [3-chloro-5- (isopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000102
 及び
Figure JPOXMLDOC01-appb-C000102
 as well as
Figure JPOXMLDOC01-appb-C000103
 　参考例５４で製造した４－［ｃｉｓ－４－［３－クロロ－５－（イソプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．２分の標記目的化合物（実施例３１－Ａ）と保持時間２．６分の標記目的化合物（実施例３１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000103
 Tert-Butyl 4- [cis-4- [3-chloro-5- (isopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate prepared in Reference Example 54 In HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) The title object compound (Example 31-A) having a retention time of 4.2 minutes and the title object compound (Example 31-B) having a retention time of 2.6 minutes were obtained.
　（実施例３２）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（イソプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 32 5-Chloro-2-({4- [cis-4- [3-chloro-5- (isopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000104
 及び
Figure JPOXMLDOC01-appb-C000104
 as well as
Figure JPOXMLDOC01-appb-C000105
 　実施例３１で製造した実施例３１－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例３２－Ａ）を得た。
　実施例３１で製造した実施例３１－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例３２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000105
 The reaction was conducted in the same manner as in Example 2 using Example 31-A prepared in Example 31 to give the title object compound (Example 32-A).
The reaction was conducted in the same manner as in Example 2 using Example 31-B prepared in Example 31 to obtain the title object compound (Example 32-B).
　（実施例３３）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（プロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 33 5-Chloro-2-({4- [cis-4- [3-chloro-5- (propylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000106
 及び
Figure JPOXMLDOC01-appb-C000106
 as well as
Figure JPOXMLDOC01-appb-C000107
 　参考例５７で製造した４－［ｃｉｓ－４－［３－クロロ－５－（プロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．５分の標記目的化合物（実施例３３－Ａ）と保持時間２．８分の標記目的化合物（実施例３３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000107
 4- [cis-4- [3-Chloro-5- (propylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 57 In HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) The title object compound (Example 33-A) having a retention time of 4.5 minutes and the title object compound (Example 33-B) having a retention time of 2.8 minutes were obtained.
　（実施例３４）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（プロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 34 5-Chloro-2-({4- [cis-4- [3-chloro-5- (propylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000108
 及び
Figure JPOXMLDOC01-appb-C000108
 as well as
Figure JPOXMLDOC01-appb-C000109
 　実施例３３で製造した実施例３３－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例３４－Ａ）を得た。
　実施例３３で製造した実施例３３－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例３４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000109
 The reaction was conducted in the same manner as in Example 2 using Example 33-A prepared in Example 33 to obtain the title object compound (Example 34-A).
The reaction was conducted in the same manner as in Example 2 using Example 33-B prepared in Example 33 to obtain the title object compound (Example 34-B).
　（実施例３５）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 35 5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000110
 及び
Figure JPOXMLDOC01-appb-C000110
 as well as
Figure JPOXMLDOC01-appb-C000111
 　参考例３９の４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が８．９分の標記目的化合物（実施例３５－Ａ）と保持時間３．６分の標記目的化合物（実施例３５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000111
 Using Reference Example 39 tert-butyl 4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate Then, the reaction was carried out in the same manner as in Example 15, and the retention time in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) Gave 8.9 minutes of the title object compound (Example 35-A) and retention time 3.6 minutes of the title object compound (Example 35-B).
　（実施例３６）２－（｛４－［ｃｉｓ－４－［５－（ｔｅｒｔ－ブチルカルバモイル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸エチル Example 36 2-({4- [cis-4- [5- (tert-Butylcarbamoyl) -3-chloropyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1- Yl} methyl) -5-chlorobenzoate ethyl
Figure JPOXMLDOC01-appb-C000112
 及び
Figure JPOXMLDOC01-appb-C000112
 as well as
Figure JPOXMLDOC01-appb-C000113
 　参考例６０で製造した４－［ｃｉｓ－４－［５－（ｔｅｒｔ－ブチルカルバモイル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．２分の標記目的化合物（実施例３６－Ａ）と保持時間３．４分の標記目的化合物（実施例３６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000113
 4- [cis-4- [5- (tert-Butylcarbamoyl) -3-chloropyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert prepared in Reference Example 60 -Butyl was used in the same manner as in Example 14 and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 20/80, 2.0 mL / min) The title target compound (Example 36-A) having a retention time of 4.2 minutes at 254 nm) and the title target compound (Example 36-B) having a retention time of 3.4 minutes were obtained.
　（実施例３７）２－クロロ－５－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 37 2-Chloro-5-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000114
 及び
Figure JPOXMLDOC01-appb-C000114
 as well as
Figure JPOXMLDOC01-appb-C000115
 　参考例３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと参考例６１で製造した５－（ブロモメチル）－２－クロロ安息香酸エチルを用いて実施例１と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．６分の標記目的化合物（実施例３７－Ａ）と保持時間３．１分の標記目的化合物（実施例３７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000115
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 3 And ethyl 5- (bromomethyl) -2-chlorobenzoate prepared in Reference Example 61 was reacted in the same manner as in Example 1, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) Product, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) title object compound (Example 37-A) having a retention time of 4.6 minutes and title object compound having a retention time of 3.1 minutes (implementation) Example 37-B) was obtained.
　（実施例３８）４－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 38 4-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000116
 及び
Figure JPOXMLDOC01-appb-C000116
 as well as
Figure JPOXMLDOC01-appb-C000117
 　　参考例３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと２－（ブロモメチル）－４－クロロ安息香酸エチルを用いて実施例１と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が５．４分の標記目的化合物（実施例３８－Ａ）と保持時間３．７分の標記目的化合物（実施例３８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000117
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 3 And ethyl 2- (bromomethyl) -4-chlorobenzoate in the same manner as in Example 1. HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = The title compound (Example 38-A) having a retention time of 5.4 minutes and the title compound (Example 38-B) having a retention time of 3.7 minutes at 30/70, 2.0 mL / min, 254 nm). Obtained.
　（実施例３９）２－（｛４－［ｃｉｓ－４－［５－（ｔｅｒｔ－ブチルカルバモイル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸 Example 39 2-({4- [cis-4- [5- (tert-butylcarbamoyl) -3-chloropyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1- Yl} methyl) -5-chlorobenzoic acid
Figure JPOXMLDOC01-appb-C000118
 及び
Figure JPOXMLDOC01-appb-C000118
 as well as
Figure JPOXMLDOC01-appb-C000119
 　実施例３６で製造した実施例３６－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例３９－Ａ）を得た。
　実施例３６で製造した実施例３６－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例３９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000119
 The reaction was conducted in the same manner as in Example 2 using Example 36-A prepared in Example 36 to obtain the title object compound (Example 39-A).
The reaction was conducted in the same manner as in Example 2 using Example 36-B prepared in Example 36 to give the title object compound (Example 39-B).
　（実施例４０）２－クロロ－５－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 40 2-Chloro-5-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000120
 及び
Figure JPOXMLDOC01-appb-C000120
 as well as
Figure JPOXMLDOC01-appb-C000121
 　実施例３７で製造した実施例３７－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例４０－Ａ）を得た。
　実施例３７で製造した実施例３７－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例４０－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000121
 The reaction was conducted in the same manner as in Example 8 using Example 37-A produced in Example 37 to obtain the title object compound (Example 40-A).
The reaction was conducted in the same manner as in Example 8 using Example 37-B produced in Example 37 to give the title object compound (Example 40-B).
　（実施例４１）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 41 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000122
 及び
Figure JPOXMLDOC01-appb-C000122
 as well as
Figure JPOXMLDOC01-appb-C000123
 　参考例６３の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が１４．７分の標記目的化合物（実施例４１－Ａ）と保持時間３．５分の標記目的化合物（実施例４１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000123
 Reference Example 63 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl The reaction was performed in the same manner as in Example 15, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) The title compound (Example 41-A) having a retention time of 14.7 minutes and the title object compound (Example 41-B) having a retention time of 3.5 minutes were obtained.
　（実施例４２）３－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 42 3-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000124
 及び
Figure JPOXMLDOC01-appb-C000124
 as well as
Figure JPOXMLDOC01-appb-C000125
 　参考例３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと参考例６５で製造した２－（ブロモメチル）－３－クロロ安息香酸エチルを用いて実施例１と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が５．４分の標記目的化合物（実施例４２－Ａ）と保持時間３．７分の標記目的化合物（実施例４２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000125
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 3 And ethyl 2- (bromomethyl) -3-chlorobenzoate prepared in Reference Example 65 was reacted in the same manner as in Example 1, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) The title target compound (Example 42-A) having a retention time of 5.4 minutes and the title target compound having a retention time of 3.7 minutes in 2-propanol / hexane = 20/80, 2.0 mL / min, 254 nm) (Example 42-B) was obtained.
　（実施例４３）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 43 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl } Methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000126
 及び
Figure JPOXMLDOC01-appb-C000126
 as well as
Figure JPOXMLDOC01-appb-C000127
 　参考例６６の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が２２．４分の標記目的化合物（実施例４３－Ａ）と保持時間１３．７分の標記目的化合物（実施例４３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000127
 Example using tert-butyl 4- [cis-4- [5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 66 And a retention time in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm). The title target compound (Example 43-A) of 4 minutes and the title target compound (Example 43-B) having a retention time of 13.7 minutes were obtained.
　（実施例４４）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 44 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000128
 及び
Figure JPOXMLDOC01-appb-C000128
 as well as
Figure JPOXMLDOC01-appb-C000129
 　実施例４１で製造した実施例４１－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例４４－Ａ）を得た。
　実施例４１で製造した実施例４１－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例４４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000129
 The reaction was conducted in the same manner as in Example 30 using Example 41-A produced in Example 41 to obtain the title object compound (Example 44-A).
The reaction was conducted in the same manner as in Example 30 using Example 41-B prepared in Example 41 to obtain the title object compound (Example 44-B).
　（実施例４５）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 45 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl } Methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000130
 及び
Figure JPOXMLDOC01-appb-C000130
 as well as
Figure JPOXMLDOC01-appb-C000131
 　実施例４３で製造した実施例４３－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例４５－Ａ）を得た。
　実施例４３で製造した実施例４３－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例４５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000131
 The reaction was conducted in the same manner as in Example 30 using Example 43-A prepared in Example 43 to obtain the title object compound (Example 45-A).
The reaction was conducted in the same manner as in Example 30 using Example 43-B prepared in Example 43 to obtain the title object compound (Example 45-B).
　（実施例４６）４－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 46 4-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000132
 及び
Figure JPOXMLDOC01-appb-C000132
 as well as
Figure JPOXMLDOC01-appb-C000133
 　実施例３８で製造した実施例３８－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例４６－Ａ）を得た。
　実施例３８で製造した実施例３８－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例４６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000133
 The reaction was conducted in the same manner as in Example 2 using Example 38-A prepared in Example 38 to give the title object compound (Example 46-A).
The reaction was conducted in the same manner as in Example 2 using Example 38-B prepared in Example 38 to give the title object compound (Example 46-B).
（実施例４７）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［（シクロプロピルカルボニル）アミノ］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 47 5-Chloro-2-({4- [cis-4- {3-chloro-5-[(cyclopropylcarbonyl) amino] pyridin-2-yl} octahydroquinoxaline-1 (2H)- Yl] piperidin-1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000134
 及び
Figure JPOXMLDOC01-appb-C000134
 as well as
Figure JPOXMLDOC01-appb-C000135
　参考例７２で製造した２－（｛４－［ｃｉｓ－４－（５－アミノ－３－クロロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸メチル（１２１ｍｇ、０．２２５ｍｍｏｌ）とトリエチルアミン（０．１４ｍＬ、１．０２ｍｍｏｌ）をジクロロメタン（３ｍＬ）に溶解した後氷冷し、塩化シクロプロパンカルボニル（８１μＬ、０．９０ｍｍｏｌ）を滴下し、室温で１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、９８：２－０：１００）を用いて精製し、標記目的化合物（６６ｍｇ、収率４９％、実施例４７－Ａ）を得た。
　参考例７３で製造した化合物を用いて上記と同様に反応を行い、標記目的化合物実施例４７－Ｂを得た。
Figure JPOXMLDOC01-appb-C000135
2-({4- [cis-4- (5-amino-3-chloropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) prepared in Reference Example 72 Methyl -5-chlorobenzoate (121 mg, 0.225 mmol) and triethylamine (0.14 mL, 1.02 mmol) were dissolved in dichloromethane (3 mL) and then ice-cooled, and cyclopropanecarbonyl chloride (81 μL, 0.90 mmol) was added. The solution was added dropwise and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction three times with dichloromethane, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 98: 2-0: 100) to give the title object compound (66 mg, yield 49%, Example 47-A). )
The reaction was carried out in the same manner as described above using the compound produced in Reference Example 73 to obtain the title intended compound Example 47-B.
　（実施例４８）３－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 48 3-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000136
 及び
Figure JPOXMLDOC01-appb-C000136
 as well as
Figure JPOXMLDOC01-appb-C000137
 　実施例４２で製造した実施例４２－Ａを用いて実施例８と同様に反応を行い、標記目的化合物（実施例４８－Ａ）を得た。
　実施例４２で製造した実施例４２－Ｂを用いて実施例８と同様に反応を行い、標記目的化合物（実施例４８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000137
 The reaction was conducted in the same manner as in Example 8 using Example 42-A prepared in Example 42 to give the title object compound (Example 48-A).
The reaction was conducted in the same manner as in Example 8 using Example 42-B prepared in Example 42 to give the title object compound (Example 48-B).
　（実施例４９）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［（シクロプロピルカルボニル）アミノ］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 49 5-Chloro-2-({4- [cis-4- {3-chloro-5-[(cyclopropylcarbonyl) amino] pyridin-2-yl} octahydroquinoxaline-1 (2H)- Yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000138
 及び
Figure JPOXMLDOC01-appb-C000138
 as well as
Figure JPOXMLDOC01-appb-C000139
 　実施例４７で製造した実施例４７－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例４９－Ａ）を得た。
　実施例４７で製造した実施例４７－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例４９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000139
 The reaction was conducted in the same manner as in Example 30 using Example 47-A prepared in Example 47 to obtain the title object compound (Example 49-A).
The reaction was conducted in the same manner as in Example 30 using Example 47-B prepared in Example 47 to obtain the title object compound (Example 49-B).
　（実施例５０）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［（メチルスルホニル）アミノ］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 50 5-Chloro-2-({4- [cis-4- {3-chloro-5-[(methylsulfonyl) amino] pyridin-2-yl} octahydroquinoxalin-1 (2H) -yl ] Piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000140
または
Figure JPOXMLDOC01-appb-C000140
Or
Figure JPOXMLDOC01-appb-C000141
 　参考例７２で製造した２－（｛４－［ｃｉｓ－４－（５－アミノ－３－クロロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸メチル（８６ｍｇ、０．１６１ｍｍｏｌ）とトリエチルアミン（０．１０ｍＬ、０．８０７ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した後、メタンスルホニルクロライド（６２μＬ、０．８０７ｍｍｏｌ）を滴下し、室温で１８時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をエタノール（２ｍＬ）とテトラヒドロフラン（２ｍＬ）の混合溶媒に溶解し、１Ｎ－水酸化ナトリウム水溶液（０．９ｍＬ）を加え、室温で１時間攪拌した。反応液に１Ｎ－塩酸水溶液（０．９ｍＬ）を加え、反応液を減圧濃縮した。残渣に水を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－７０：３０）を用いて精製し、標記目的化合物（５８ｍｇ、収率６０％、実施例５０－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000141
 2-({4- [cis-4- (5-amino-3-chloropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) prepared in Reference Example 72 After dissolving methyl 5-chlorobenzoate (86 mg, 0.161 mmol) and triethylamine (0.10 mL, 0.807 mmol) in dichloromethane (2 mL), methanesulfonyl chloride (62 μL, 0.807 mmol) was added dropwise at room temperature. For 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethanol (2 mL) and tetrahydrofuran (2 mL), 1N-aqueous sodium hydroxide solution (0.9 mL) was added, and the mixture was stirred at room temperature for 1 hr. A 1N hydrochloric acid aqueous solution (0.9 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. Water was added to the residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 98: 2-70: 30) to give the title object compound (58 mg, yield 60%, Example 50-A). Obtained.
　（実施例５１）２－（｛４－［ｃｉｓ－４－（５－アセトアミド－３－クロロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸 Example 51 2-({4- [cis-4- (5-acetamido-3-chloropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl)- 5-chlorobenzoic acid
Figure JPOXMLDOC01-appb-C000142
 または
Figure JPOXMLDOC01-appb-C000142
 Or
Figure JPOXMLDOC01-appb-C000143
 　参考例７２で製造した２－（｛４－［ｃｉｓ－４－（５－アミノ－３－クロロピリジン－２－イル）オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸メチル（４５ｍｇ、８４μｍｏｌ）とトリエチルアミン（４６μＬ、０．３３８ｍｍｏｌ）をジクロロメタン（２ｍＬ）に溶解した後、無水酢酸（３２μＬ、０．３２８ｍｍｏｌ）を滴下し、室温で１．５時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をエタノール（１ｍＬ）とテトラヒドロフラン（１ｍＬ）の混合溶媒に溶解し、１Ｎ－水酸化ナトリウム水溶液（０．２５ｍＬ）を加え、室温で１時間攪拌した。反応液に１Ｎ－塩酸水溶液（０．２５ｍＬ）を加え、反応液を減圧濃縮した。残渣に水を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－７０：３０）を用いて精製し、標記目的化合物（２１ｍｇ、収率４５％、実施例５１－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000143
 2-({4- [cis-4- (5-amino-3-chloropyridin-2-yl) octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) prepared in Reference Example 72 After dissolving methyl 5-chlorobenzoate (45 mg, 84 μmol) and triethylamine (46 μL, 0.338 mmol) in dichloromethane (2 mL), acetic anhydride (32 μL, 0.328 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Stir. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethanol (1 mL) and tetrahydrofuran (1 mL), 1N-aqueous sodium hydroxide solution (0.25 mL) was added, and the mixture was stirred at room temperature for 1 hr. A 1N-hydrochloric acid aqueous solution (0.25 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. Water was added to the residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol, 98: 2-70: 30) to give the title object compound (21 mg, yield 45%, Example 51-A). Obtained.
　（実施例５２）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル Example 52 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) methyl benzoate
Figure JPOXMLDOC01-appb-C000144
 及び
Figure JPOXMLDOC01-appb-C000144
 as well as
Figure JPOXMLDOC01-appb-C000145
 　参考例５０と参考例５１の１：１混合物であるラセミ体の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が１６．６分の標記目的化合物（実施例５２－Ａ）と４．９分の標記目的化合物（実施例５２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000145
 Racemic 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H), which is a 1: 1 mixture of Reference Example 50 and Reference Example 51 The reaction was carried out in the same manner as in Example 5 using tert-butyl-yl] piperidine-1-carboxylate, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = 30) / 70, 2.0 mL / min, 254 nm) The title target compound (Example 52-A) having a retention time of 16.6 minutes and the title target compound (Example 52-B) of 4.9 minutes were obtained.
　（実施例５３）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 53 5-Chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000146
 及び
Figure JPOXMLDOC01-appb-C000146
 as well as
Figure JPOXMLDOC01-appb-C000147
 　参考例７４の４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が９．９分の標記目的化合物（実施例５３－Ａ）と保持時間２．７分の標記目的化合物(実施例５３－Ｂ)を得た。
Figure JPOXMLDOC01-appb-C000147
 4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 74 The reaction was carried out in the same manner as in No. 15, and the retention time in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) was 9. The title object compound (Example 53-A) having a retention time of 2.7 minutes and the title object compound (Example 53-B) having a retention time of 9 minutes was obtained.
　（実施例５４）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 54 5-Chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000148
 または
Figure JPOXMLDOC01-appb-C000148
 Or
Figure JPOXMLDOC01-appb-C000149
 　実施例５３で製造した実施例５３－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例５４－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000149
 The reaction was conducted in the same manner as in Example 30 using Example 53-A prepared in Example 53, to give the title object compound (Example 54-A).
　（実施例５５）２－（｛４－［ｃｉｓ－４－［５－（５－アミノ－１，３，４－オキサジアゾール－２－イル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸エチル Example 55 2-({4- [cis-4- [5- (5-amino-1,3,4-oxadiazol-2-yl) -3-chloropyridin-2-yl] octahydro Quinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) -5-chlorobenzoate ethyl
Figure JPOXMLDOC01-appb-C000150
 及び
Figure JPOXMLDOC01-appb-C000150
 as well as
Figure JPOXMLDOC01-appb-C000151
 　参考例７８で製造した４－［ｃｉｓ－４－［５－（５－アミノ－１，３，４－オキサジアゾール－２－イル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎｍ）における保持時間が３．４分の標記目的化合物（実施例５５－Ａ）と保持時間２．４分の標記目的化合物（実施例５５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000151
 4- [cis-4- [5- (5-Amino-1,3,4-oxadiazol-2-yl) -3-chloropyridin-2-yl] octahydroquinoxaline-1 prepared in Reference Example 78 (2H) -yl] piperidine-1-carboxylate was used in the same manner as in Example 14, followed by HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2- Title target compound (Example 55-A) having a retention time of 3.4 minutes in propanol / hexane = 25/75, 2.0 mL / min, 254 nm) and the title target compound (Example 55) having a retention time of 2.4 minutes -B) was obtained.
　（実施例５６）２－（｛４－［ｃｉｓ－４－［５－（５－アミノ－１，３，４－オキサジアゾール－２－イル）－３－クロロピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸 Example 56 2-({4- [cis-4- [5- (5-amino-1,3,4-oxadiazol-2-yl) -3-chloropyridin-2-yl] octahydro Quinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) -5-chlorobenzoic acid
Figure JPOXMLDOC01-appb-C000152
 及び
Figure JPOXMLDOC01-appb-C000152
 as well as
Figure JPOXMLDOC01-appb-C000153
 　実施例５５で製造した実施例５５－Ａを用いて実施例２と同様に反応を行い、標記目的化合物（実施例５６－Ａ）を得た。
　実施例５５で製造した実施例５５－Ｂを用いて実施例２と同様に反応を行い、標記目的化合物（実施例５６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000153
 The reaction was conducted in the same manner as in Example 2 using Example 55-A prepared in Example 55, to give the title object compound (Example 56-A).
The reaction was conducted in the same manner as in Example 2 using Example 55-B prepared in Example 55, to give the title object compound (Example 56-B).
　（実施例５７）５－［ｃｉｓ－４－［１－（２－カルバモイル－４－クロロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド Example 57 5- [cis-4- [1- (2-carbamoyl-4-chlorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl-6- Methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000154
 または
Figure JPOXMLDOC01-appb-C000154
 Or
Figure JPOXMLDOC01-appb-C000155
 　実施例５２で製造した実施例５２－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例５７－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000155
 The reaction was conducted in the same manner as in Example 3 using Example 52-A prepared in Example 52 to obtain the title object compound (Example 57-A).
　（実施例５８）５－［ｃｉｓ－４－［１－（４－クロロ－２－フルオロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド Example 58 5- [cis-4- [1- (4-Chloro-2-fluorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl-6- Methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000156
 及び
Figure JPOXMLDOC01-appb-C000156
 as well as
Figure JPOXMLDOC01-appb-C000157
 　参考例５１の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと４－クロロ－２－フルオロベンジルブロミドを用いて実施例５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が６．２分の標記目的化合物（実施例５８－Ａ）を得た。
　参考例５０を用いて上記と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．６分の標記目的化合物（実施例５８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000157
 4-t-butyl 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 51 4-Chloro-2-fluorobenzyl bromide was used in the same manner as in Example 5. HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = 30/70, The title compound (Example 58-A) having a retention time of 6.2 minutes at 2.0 mL / min (254 nm) was obtained.
Reaction was carried out in the same manner as described above using Reference Example 50, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) To give the title object compound (Example 58-B) having a retention time of 4.6 minutes.
　（実施例５９）５－［ｃｉｓ－４－｛１－［（２－アミノ－６－クロロピリジン－３－イル）カルボニル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド Example 59 5- [cis-4- {1-[(2-Amino-6-chloropyridin-3-yl) carbonyl] piperidin-4-yl} octahydroquinoxalin-1 (2H) -yl]- N-cyclopropyl-6-methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000158
 及び
Figure JPOXMLDOC01-appb-C000158
 as well as
Figure JPOXMLDOC01-appb-C000159
 　参考例５１の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（５００ｍｇ、１．００ｍｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、トリフルオロ酢酸（２ｍＬ）を加え、室温で２時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。得られた残渣のうち７０ｍｇをＮ、Ｎージメチルアセトアミド（０．１５ｍＬ）に溶解し、２－アミノ－５－クロロニコチン酸リチウム（ＷＯ２００６／０９１４２８）（４１ｍｇ、０．２２８ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミド塩酸塩（６７ｍｇ、０．３５１ｍｍｏｌ）、１－ヒドロキシ－７－アザベンゾトリアゾール（５４ｍｇ、０．３５１ｍｍｏｌ）、及びジイソプロピルエチルアミン（１５０μＬ、０．８７８ｍｍｏｌ）を加え、窒素雰囲気下、７０℃で２時間攪拌した。反応液を減圧濃縮した後、飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製し、標記目的化合物（８６ｍｇ、収率８８％、実施例５９－Ａ）を得た。
　参考例５０を用いて上記と同様に反応を行い、標記目的化合物（７９ｍｇ、収率８１％、実施例５９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000159
 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (Reference Example 51) 500 mg, 1.00 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. Of the obtained residue, 70 mg was dissolved in N, N-dimethylacetamide (0.15 mL), and lithium 2-amino-5-chloronicotinate (WO 2006/091428) (41 mg, 0.228 mmol), 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (67 mg, 0.351 mmol), 1-hydroxy-7-azabenzotriazole (54 mg, 0.351 mmol), and diisopropylethylamine (150 μL, 0.878 mmol) were added, The mixture was stirred at 70 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) to give the title object compound (86 mg, yield 88%, Example 59-A). )
The reaction was conducted in the same manner as described above using Reference Example 50 to obtain the title object compound (79 mg, 81% yield, Example 59-B).
　（実施例６０）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 60 5-Chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000160
 及び
Figure JPOXMLDOC01-appb-C000160
 as well as
Figure JPOXMLDOC01-appb-C000161
 　参考例８１の４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が１５．３分の標記目的化合物（実施例６０－Ａ）と保持時間４．５分の標記目的化合物（実施例６０－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000161
 The tert-butyl 4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 81 was used. And the reaction was carried out in the same manner as in Example 15 and maintained in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., ethanol / hexane = 30/70, 2.0 mL / min, 254 nm). The title object compound (Example 60-A) having a time of 15.3 minutes and the title object compound (Example 60-B) having a retention time of 4.5 minutes were obtained.
　（実施例６１）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 61 5-Chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000162
 または
Figure JPOXMLDOC01-appb-C000162
 Or
Figure JPOXMLDOC01-appb-C000163
 　実施例６０で製造した実施例６０－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例６１－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000163
 The reaction was conducted in the same manner as in Example 30 using Example 60-A prepared in Example 60 to obtain the title object compound (Example 61-A).
　（実施例６２）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 62 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000164
 及び
Figure JPOXMLDOC01-appb-C000164
 as well as
Figure JPOXMLDOC01-appb-C000165
 　参考例８２の４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が９．３分の標記目的化合物（実施例６２－Ａ）と保持時間３．４分の標記目的化合物（実施例６２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000165
 Using tert-butyl 4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate in Reference Example 82 Then, the reaction was carried out in the same manner as in Example 15, and the retention time in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm) Gave the title target compound (Example 62-A) of 9.3 minutes and the title target compound (Example 62-B) of retention time 3.4 minutes.
　（実施例６３）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 63 5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000166
 及び
Figure JPOXMLDOC01-appb-C000166
 as well as
Figure JPOXMLDOC01-appb-C000167
 　実施例６２で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル（実施例６２－Ａ）（６７０ｍｇ、１．１１ｍｍｏｌ）をエタノール（４０ｍＬ）とテトラヒドロフラン（２０ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（３．３ｍＬ）を加え、室温で１８時間攪拌した。反応液に１Ｎ－塩酸水溶液（３．３ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９９：１－７０：３０）を用いて精製して標記目的化合物（５８５ｍｇ、９２％、実施例６３－Ａ）を得た。
　実施例６２で製造した実施例６２－Ｂを用いて上記と同様に反応を行い、標記目的化合物（実施例６３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000167
 5-Chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine prepared in Example 62 -1-yl} methyl) ethyl benzoate (Example 62-A) (670 mg, 1.11 mmol) was dissolved in ethanol (40 mL) and tetrahydrofuran (20 mL), and 1N aqueous sodium hydroxide solution (3.3 mL) was added. The mixture was further stirred at room temperature for 18 hours. A 1N aqueous hydrochloric acid solution (3.3 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol, 99: 1-70: 30) to obtain the title object compound (585 mg, 92%, Example 63-A). .
The title compound (Example 63-B) was obtained by reacting in the same manner as described above using Example 62-B produced in Example 62.
　（実施例６４）５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 64 5-Chloro-2-[(4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000168
 及び
Figure JPOXMLDOC01-appb-C000168
 as well as
Figure JPOXMLDOC01-appb-C000169
 　参考例８８で製造した４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（４０４ｍｇ、０．８５５ｍｍｏｌ）をメタノール（０．７５ｍＬ）に溶解し、４Ｎ－塩酸／ジオキサン（０．７５ｍＬ）を加え、室温で４時間攪拌後、減圧濃縮した。得られた残渣（１２０ｍｇ）にアセトニトリル（２．５ｍＬ）、ジイソプロピルエチルアミン（０．５９６ｍＬ、３．４２ｍｍｏｌ）、及び参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（２３７ｍｇ、０．８５５ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応液を減圧濃縮し、反応液に水（５ｍＬ）、クロロホルム（５ｍＬ）を加えて分液し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、０／１００－８／９２）を用いて精製し、標記目的化合物のラセミ体（１８０ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．０分の標記目的化合物（７５．５ｍｇ、１６％、実施例６４－Ａ）と保持時間が３．２分の標記目的化合物（７７．８ｍｇ、１６％、実施例６４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000169
 4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid prepared in Reference Example 88 Tert-butyl (404 mg, 0.855 mmol) was dissolved in methanol (0.75 mL), 4N-hydrochloric acid / dioxane (0.75 mL) was added, and the mixture was stirred at room temperature for 4 hr and concentrated under reduced pressure. To the obtained residue (120 mg), acetonitrile (2.5 mL), diisopropylethylamine (0.596 mL, 3.42 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 (237 mg, 0 .855 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and water (5 mL) and chloroform (5 mL) were added to the reaction solution for liquid separation, and the aqueous layer was extracted with chloroform (3 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 25M, methanol / chloroform, 0 / 100-8 / 92) to obtain the racemic product (180 mg) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 25/75, 10 mL / min, 254 nm), and HPLC ( Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 25/75, 2.0 mL / min, 254 nm) The title compound (77.8 mg, 16%, Example 64-B) was obtained with a retention time of 3.2 minutes and 0.5 mg, 16%, Example 64-A).
　（実施例６５）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 65 5-Chloro-2-[(4- {cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000170
 及び
Figure JPOXMLDOC01-appb-C000170
 as well as
Figure JPOXMLDOC01-appb-C000171
 　参考例９３で製造した４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１４と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．２分の標記目的化合物（実施例６５－Ａ）と保持時間３．２分の標記目的化合物（実施例６５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000171
 4- {cis-4- [5- (ethylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid prepared in Reference Example 93 Reaction was performed in the same manner as in Example 14 using tert-butyl, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 20/80, 2.0 mL / Min, 254 nm) and the title object compound (Example 65-A) having a retention time of 4.2 minutes and the title object compound (Example 65-B) having a retention time of 3.2 minutes were obtained.
　（実施例６６）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルスルホニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 66 5-Chloro-2-({4- [cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000172
 及び
Figure JPOXMLDOC01-appb-C000172
 as well as
Figure JPOXMLDOC01-appb-C000173
 　参考例１００の４－［ｃｉｓ－４－［５－（エチルスルホニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと参考例３０の２－（ブロモメチル）－５－クロロ安息香酸エチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、２．０ｍＬ／分、２５４ｎｍ）における保持時間が８．１分の標記目的化合物（実施例６６－Ａ）と保持時間６．０分の標記目的化合物（実施例６６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000173
 Reference Example 100 tert-butyl 4- [cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate The reaction was performed in the same manner as in Example 15 using ethyl 2- (bromomethyl) -5-chlorobenzoate of Example 30, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2- Title target compound (Example 66-A) having a retention time of 8.1 minutes in propanol / hexane = 15/85, 2.0 mL / min, 254 nm) and title target compound (Example 66-A) having a retention time of 6.0 minutes -B) was obtained.
　（実施例６７）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 67 5-Chloro-2-({4- [cis-4- {5-[(cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl} octahydroquinoxaline-1 (2H)- Yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000174
 及び
Figure JPOXMLDOC01-appb-C000174
 as well as
Figure JPOXMLDOC01-appb-C000175
 　参考例１０７の４－［ｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと参考例３０の２－（ブロモメチル）－５－クロロ安息香酸エチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、２．０ｍＬ／分、２５４ｎｍ）における保持時間が８．８分の標記目的化合物（実施例６７－Ａ）と保持時間６．８分の標記目的化合物（実施例６７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000175
 4- [cis-4- {5-[(cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylic acid tert of Reference Example 107 -Butyl and ethyl 2- (bromomethyl) -5-chlorobenzoate of Reference Example 30 were reacted in the same manner as in Example 15, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) The title compound (Example 67-A) having a retention time of 8.8 minutes and the title compound having a retention time of 6.8 minutes in 2-propanol / hexane = 15/85, 2.0 mL / min, 254 nm) (Example 67-B) was obtained.
　（実施例６８）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルスルホニル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 68 5-Chloro-2-({4- [cis-4- [5- (ethylsulfonyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000176
 及び
Figure JPOXMLDOC01-appb-C000176
 as well as
Figure JPOXMLDOC01-appb-C000177
 　実施例６６で製造した実施例６６－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例６８－Ａ）を得た。
　実施例６６で製造した実施例６６－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例６８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000177
 The reaction was conducted in the same manner as in Example 30 using Example 66-A prepared in Example 66 to obtain the title object compound (Example 68-A).
The reaction was conducted in the same manner as in Example 30 using Example 66-B prepared in Example 66 to obtain the title object compound (Example 68-B).
　（実施例６９）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［（シクロプロピルメチル）スルホニル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 69 5-Chloro-2-({4- [cis-4- {5-[(cyclopropylmethyl) sulfonyl] -3-methylpyrazin-2-yl} octahydroquinoxaline-1 (2H)- Yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000178
 及び
Figure JPOXMLDOC01-appb-C000178
 as well as
Figure JPOXMLDOC01-appb-C000179
 　実施例６７で製造した実施例６７－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例６９－Ａ）を得た。
　実施例６７で製造した実施例６７－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例６９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000179
 The reaction was conducted in the same manner as in Example 30 using Example 67-A prepared in Example 67 to obtain the title object compound (Example 69-A).
The reaction was conducted in the same manner as in Example 30 using Example 67-B prepared in Example 67 to obtain the title object compound (Example 69-B).
　（実施例７０）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－シクロプロピル－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 70 5-Chloro-2-({4- [cis-4- [3-cyclopropyl-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] Piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000180
 及び
Figure JPOXMLDOC01-appb-C000180
 as well as
Figure JPOXMLDOC01-appb-C000181
 　参考例１０８の４－［ｃｉｓ－４－［３－シクロプロピル－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．８分の標記目的化合物（実施例７０－Ａ）と保持時間２．３分の標記目的化合物（実施例７０－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000181
 4- [cis-4- [3-cyclopropyl-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 108 Was used in the same manner as in Example 15, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 30/70, 2.0 mL / min, 254 nm) The title target compound (Example 70-A) having a retention time of 4.8 minutes and the title target compound (Example 70-B) having a retention time of 2.3 minutes were obtained.
　（実施例７１）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－シクロプロピル－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 71 5-Chloro-2-({4- [cis-4- [3-cyclopropyl-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] Piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000182
 及び
Figure JPOXMLDOC01-appb-C000182
 as well as
Figure JPOXMLDOC01-appb-C000183
 　実施例７０で製造した実施例７０－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例７１－Ａ）を得た。
　実施例７０で製造した実施例７０－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例７１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000183
 The reaction was conducted in the same manner as in Example 30 using Example 70-A prepared in Example 70 to obtain the title object compound (Example 71-A).
The reaction was conducted in the same manner as in Example 30 using Example 70-B prepared in Example 70 to obtain the title object compound (Example 71-B).
　（実施例７２）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 72 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000184
 及び
Figure JPOXMLDOC01-appb-C000184
 as well as
Figure JPOXMLDOC01-appb-C000185
 　参考例１０９の４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が９．３分の標記目的化合物（実施例７２－Ａ）と保持時間３．３分の標記目的化合物（実施例７２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000185
 The tert-butyl 4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate of Reference Example 109 was used. And the reaction was carried out in the same manner as in Example 15 and maintained in HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, ethanol / hexane = 30/70, 2.0 mL / min, 254 nm). The title object compound (Example 72-A) having a time of 9.3 minutes and the title object compound (Example 72-B) having a retention time of 3.3 minutes were obtained.
　（実施例７３）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 73 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000186
 及び
Figure JPOXMLDOC01-appb-C000186
 as well as
Figure JPOXMLDOC01-appb-C000187
 　実施例７２で製造した実施例７２－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例７３－Ａ）を得た。
　実施例７２で製造した実施例７２－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例７３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000187
 The reaction was conducted in the same manner as in Example 30 using Example 72-A prepared in Example 72 to obtain the title object compound (Example 73-A).
The reaction was conducted in the same manner as in Example 30 using Example 72-B prepared in Example 72 to obtain the title object compound (Example 73-B).
　（実施例７４）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－ヒドロキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 74 5-Chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-hydroxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine -1-yl} methyl) benzoic acid
または Or
Figure JPOXMLDOC01-appb-C000189
 　実施例７３で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メトキシピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸（実施例７３－Ａ）（２６ｍｇ、４５μｍｍｏｌ）をジクロロメタン１ｍＬに溶解し、窒素雰囲気下氷冷した。三臭化ホウ素（１．０Ｍジクロロメタン溶液）（６７０μＬ）を滴下後、氷冷のまま２時間攪拌した。反応液にメタノール（約３ｍＬ）を加えた後反応液を減圧濃縮し、得られた残渣にジイソプロピルエチルアミン（約２ｍＬ）とメタノール（約３ｍＬ）を加え、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９９：１－７０：３０）を用いて精製し、標記目的化合物（１７ｍｇ、収率６６％、実施例７４－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000189
 5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methoxypyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] prepared in Example 73 Piperidin-1-yl} methyl) benzoic acid (Example 73-A) (26 mg, 45 μmmol) was dissolved in 1 mL of dichloromethane and ice-cooled in a nitrogen atmosphere. Boron tribromide (1.0 M dichloromethane solution) (670 μL) was added dropwise, and the mixture was stirred for 2 hours while cooling with ice. Methanol (about 3 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure. Diisopropylethylamine (about 2 mL) and methanol (about 3 mL) were added to the resulting residue, and the residue obtained after concentration under reduced pressure was added to a silica gel column. Purification using chromatography (chloroform: methanol, 99: 1-70: 30) gave the title object compound (17 mg, 66% yield, Example 74-A).
　（実施例７５）５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 75 5-Chloro-2-[(4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000190
 及び
Figure JPOXMLDOC01-appb-C000190
 as well as
Figure JPOXMLDOC01-appb-C000191
 　実施例６４で製造した５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル（実施例６４－Ａ）（６４ｍｇ、０．１１２ｍｍｏｌ）をメタノール（０．５ｍＬ）およびテトラヒドロフラン（１ｍＬ）に溶解し、１規定水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温にて５時間攪拌した。反応液に水（２ｍＬ）、１規定塩酸水溶液（０．５ｍＬ）およびクロロホルム（５ｍＬ）を加えて分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ５ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ　ＮＨ、メタノール／酢酸エチル、５／９５－６０／４０）を用いて精製し、標記目的化合物（２１．７ｍｇ、３６％、実施例７５－Ａ）を得た。
実施例６４で製造した実施例６４－Ｂを用いて上記と同様に反応を行い、標記目的化合物（実施例７５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000191
 5-Chloro-2-[(4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1- prepared in Example 64 Yl} piperidin-1-yl) methyl] ethyl benzoate (Example 64-A) (64 mg, 0.112 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (1 mL), and 1N aqueous sodium hydroxide solution ( 0.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. Water (2 mL), 1N hydrochloric acid aqueous solution (0.5 mL) and chloroform (5 mL) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with a 20% methanol / chloroform mixture (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Biotage 25M NH, methanol / ethyl acetate, 5 / 95-60 / 40) to give the title object compound (21.7 mg, 36%, Example 75-A). Got.
The title compound (Example 75-B) was obtained by reacting in the same manner as described above using Example 64-B produced in Example 64.
　（実施例７６）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 76 5-Chloro-2-[(4- {cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000192
 及び
Figure JPOXMLDOC01-appb-C000192
 as well as
Figure JPOXMLDOC01-appb-C000193
 　実施例６５で製造した実施例６５－Ａを用いて実施例７５と同様に反応を行い、標記目的化合物（実施例７６－Ａ）を得た。
　実施例６５で製造した実施例６５－Ｂを用いて実施例７５と同様に反応を行い、標記目的化合物（実施例７６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000193
 The reaction was conducted in the same manner as in Example 75 using Example 65-A prepared in Example 65 to obtain the title object compound (Example 76-A).
The reaction was conducted in the same manner as in Example 75 using Example 65-B prepared in Example 65 to obtain the title object compound (Example 76-B).
　（実施例７７）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 77 5-Chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyridine -2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000194
 及び
Figure JPOXMLDOC01-appb-C000194
 as well as
Figure JPOXMLDOC01-appb-C000195
 　参考例１１１で製造した４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が４．０分の標記目的化合物（実施例７７－Ａ）と保持時間２．６分の標記目的化合物（実施例７７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000195
 4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyridin-2-yl} octahydro prepared in Reference Example 111 Quinoxalin-1 (2H) -yl] piperidine-1-carboxylate was reacted in the same manner as in Example 15, HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd.) , 2-propanol / hexane = 20/80, 2.0 mL / min, 254 nm) the title compound (Example 77-A) having a retention time of 4.0 minutes and the title compound having a retention time of 2.6 minutes (Example 77-A) Example 77-B) was obtained.
　（実施例７８）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 78 5-Chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000196
 及び
Figure JPOXMLDOC01-appb-C000196
 as well as
Figure JPOXMLDOC01-appb-C000197
 　参考例１１３の４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと参考例３０の２－（ブロモメチル）－５－クロロ安息香酸エチルを用いて実施例１５と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が７．５分の標記目的化合物（実施例７８－Ａ）と保持時間４．０分の標記目的化合物（実施例７８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000197
 Reference Example 113 4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate and reference Reaction was carried out in the same manner as in Example 15 using ethyl 2- (bromomethyl) -5-chlorobenzoate of Example 30, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2- Title target compound (Example 78-A) having a retention time of 7.5 minutes in propanol / hexane = 20/80, 2.0 mL / min, 254 nm) and title target compound (Example 78-A) having a retention time of 4.0 minutes -B) was obtained.
　（実施例７９）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 79 5-Chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000198
 及び
Figure JPOXMLDOC01-appb-C000198
 as well as
Figure JPOXMLDOC01-appb-C000199
 　参考例１１６で製造した４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（１．３３ｇ、２．７０ｍｍｏｌ）をジクロロメタン（１５ｍＬ）に溶解し、トリフルオロ酢酸（５ｍＬ）を加え、室温で１時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。得られた残渣をアセトニトリル、２－プロパノール（１：１、３０ｍＬ）に溶解し、ジイソプロピルエチルアミン（２．８ｍＬ、１６．２ｍｍｏｌ）、及び参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（８２４ｍｇ、２．９７ｍｍｏｌ）を加え、室温で２．５時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－４０：６０）を用いて精製し、標記目的化合物のラセミ体（１．３８ｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、１５ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、２．０ｍＬ／分、２５４ｎｍ）における保持時間が５．２分の標記目的化合物（６８２ｍｇ、４３％、実施例７９－Ａ）と保持時間が４．０分の標記目的化合物（６７２ｍｇ、４２％、実施例７９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000199
 4- {cis-4- [3-Chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid prepared in Reference Example 116 Tert-butyl (1.33 g, 2.70 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic phase was dried over anhydrous sodium sulfate. The obtained residue was dissolved in acetonitrile, 2-propanol (1: 1, 30 mL), diisopropylethylamine (2.8 mL, 16.2 mmol), and 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 were used. Ethyl acid (824 mg, 2.97 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-40: 60) to obtain the racemic form (1.38 g) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 15 mL / min, 254 nm). Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 2.0 mL / min, 254 nm) Title target compound (682 mg) having a retention time of 5.2 minutes 43%, Example 79-A) and a retention time of 4.0 minutes were obtained for the title compound (672 mg, 42%, Example 79-B).
　（実施例８０）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 80 5-chloro-2-[(4- {cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1- Yl} piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000200
 及び
Figure JPOXMLDOC01-appb-C000200
 as well as
Figure JPOXMLDOC01-appb-C000201
 　参考例１１７で製造した４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（１．３８ｇ、２．７３ｍｍｏｌ）をジクロロメタン（１５ｍＬ）に溶解し、トリフルオロ酢酸（５ｍＬ）を加え、室温で１時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。得られた残渣をアセトニトリル、２－プロパノール（１：１、３０ｍＬ）に溶解し、ジイソプロピルエチルアミン（２．８５ｍＬ、１６．４ｍｍｏｌ）、及び参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（８３３ｍｇ、３．００ｍｍｏｌ）を加え、室温で２．５時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、８５：１５－４０：６０）を用いて精製し、標記目的化合物のラセミ体（１．３８ｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、１５ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、２．０ｍＬ／分、２５４ｎｍ）における保持時間が６．６分の標記目的化合物（７０２ｍｇ、４３％、実施例８０－Ａ）と保持時間が４．９分の標記目的化合物（６９０ｍｇ、４２％、実施例８０－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000201
 4- {cis-4- [3-Chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylate prepared in Reference Example 117 Tert-butyl acid (1.38 g, 2.73 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the resulting organic phase was dried over anhydrous sodium sulfate. The obtained residue was dissolved in acetonitrile, 2-propanol (1: 1, 30 mL), diisopropylethylamine (2.85 mL, 16.4 mmol), and 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 were obtained. Ethyl acid (833 mg, 3.00 mmol) was added and stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate, 85: 15-40: 60) to obtain the racemic form (1.38 g) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 15 mL / min, 254 nm). Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 2.0 mL / min, 254 nm) Title target compound (702 mg) with a retention time of 6.6 min 43%, Example 80-A) and a retention time of 4.9 minutes were obtained for the title compound (690 mg, 42%, Example 80-B).
　（実施例８１）５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 81 5-Chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine- 1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000202
 及び
Figure JPOXMLDOC01-appb-C000202
 as well as
Figure JPOXMLDOC01-appb-C000203
 　実施例７８で製造した実施例７８－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例８１－Ａ）を得た。
　実施例７８で製造した実施例７８－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例８１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000203
 The reaction was conducted in the same manner as in Example 30 using Example 78-A produced in Example 78 to obtain the title object compound (Example 81-A).
The reaction was conducted in the same manner as in Example 30 using Example 78-B prepared in Example 78 to give the title object compound (Example 81-B).
　（実施例８２）５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 82 5-Chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1- Yl} piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000204
 及び
Figure JPOXMLDOC01-appb-C000204
 as well as
Figure JPOXMLDOC01-appb-C000205
 　参考例１１９で製造した４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（２３２ｍｇ、０．４７９ｍｍｏｌ）をメタノール（１ｍＬ）に溶解し、４Ｎ－塩酸／ジオキサン（１ｍＬ）を加え、室温で１６時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液（１０ｍＬ）、２０％メタノール／クロロホルム混合液（１０ｍＬ）を加えて分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ５ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣に２－プロパノール（５ｍＬ）、ジイソプロピルエチルアミン（０．１５９ｍＬ、０．９１３ｍｍｏｌ）、及び参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（１０１ｍｇ、０．３６５ｍｍｏｌ）を加え、室温で６時間攪拌した。反応液に水（５ｍＬ）、クロロホルム（５ｍＬ）を加えて分液し、水層をクロロホルム（３ｘ３ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ、メタノール／クロロホルム、０／１００－７／９３）を用いて精製し、標記目的化合物のラセミ体（１４８ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、１０ｍＬ／分、２５４ｎｍ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２０／８０、２．０ｍＬ／分、２５４ｎｍ）における保持時間が５．５分の標記目的化合物（５２．８ｍｇ、２０％、実施例８２－Ａ）と保持時間が４．１分の標記目的化合物（５５．８ｍｇ、２１％、実施例８２－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000205
 4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carboxylic acid prepared in Reference Example 119 Tert-butyl acid (232 mg, 0.479 mmol) was dissolved in methanol (1 mL), 4N-hydrochloric acid / dioxane (1 mL) was added, and the mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (10 mL) and a 20% methanol / chloroform mixed solution (10 mL) were added to the residue, and the mixture was separated. The aqueous layer was extracted with a 20% methanol / chloroform mixed solution (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. To the obtained residue, 2-propanol (5 mL), diisopropylethylamine (0.159 mL, 0.913 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate prepared in Reference Example 30 (101 mg, 0.365 mmol) And stirred at room temperature for 6 hours. Water (5 mL) and chloroform (5 mL) were added to the reaction solution and the phases were separated, and the aqueous layer was extracted with chloroform (3 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography (Biotage 25M, methanol / chloroform, 0 / 100-7 / 93) to obtain the racemic product (148 mg) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 20/80, 10 mL / min, 254 nm), and HPLC ( Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 20/80, 2.0 mL / min, 254 nm) Title target compound (52 8 mg, 20%, Example 82-A) and the retention time of 4.1 minutes were obtained for the title object compound (55.8 mg, 21%, Example 82-B).
　（実施例８３）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 83 5-Chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyridine -2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000206
 及び
Figure JPOXMLDOC01-appb-C000206
 as well as
Figure JPOXMLDOC01-appb-C000207
 　実施例７７で製造した実施例７７－Ａを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例８３－Ａ）を得た。
　実施例７７で製造した実施例７７－Ｂを用いて実施例３０と同様に反応を行い、標記目的化合物（実施例８３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000207
 The reaction was conducted in the same manner as in Example 30 using Example 77-A prepared in Example 77 to obtain the title object compound (Example 83-A).
The reaction was conducted in the same manner as in Example 30 using Example 77-B prepared in Example 77 to obtain the title object compound (Example 83-B).
　（実施例８４）５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 84 5-chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1- Yl} piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000208
 及び
Figure JPOXMLDOC01-appb-C000208
 as well as
Figure JPOXMLDOC01-appb-C000209
 　実施例８２で製造した５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル（実施例８２－Ａ）（４８．０ｍｇ、０．０８２６ｍｍｏｌ）をメタノール（０．５ｍＬ）およびテトラヒドロフラン（１ｍＬ）に溶解し、１規定水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温にて５時間攪拌した。反応液に水（２ｍＬ）、１規定塩酸水溶液（０．５ｍＬ）およびクロロホルム（５ｍＬ）を加えて分液し、水層を２０％メタノール／クロロホルム混合液（３ｘ５ｍＬ）で抽出した。合わせた有機層を無水硫酸ナトリウムにて乾燥し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｍ　ＮＨ、メタノール／クロロホルム、０／１００－１５／８５）を用いて精製し、標記目的化合物（４３．１ｍｇ、９４％、実施例８４－Ａ）を得た。
実施例８２で製造した実施例８２－Ｂを用いて上記と同様に反応を行い、標記目的化合物（実施例８４－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000209
 5-Chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1 prepared in Example 82 -Il} piperidin-1-yl) methyl] ethyl benzoate (Example 82-A) (48.0 mg, 0.0826 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (1 mL), and 1N hydroxide was added. Sodium aqueous solution (0.5 mL) was added, and the mixture was stirred at room temperature for 5 hours. Water (2 mL), 1N hydrochloric acid aqueous solution (0.5 mL) and chloroform (5 mL) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with a 20% methanol / chloroform mixture (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (Biotage 25M NH, methanol / chloroform, 0 / 100-15 / 85) to give the title object compound (43.1 mg, 94%, Example 84-A). Obtained.
The title target compound (Example 84-B) was obtained by reacting in the same manner as described above using Example 82-B produced in Example 82.
　（実施例８５）５－｛６－クロロ－５－［ｃｉｓ－４－［１－（４－クロロベンゾイル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－イル｝－Ｎ－エチル－１，３，４－オキサジアゾール－２－アミン Example 85 5- {6-Chloro-5- [cis-4- [1- (4-chlorobenzoyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazin-2-yl } -N-ethyl-1,3,4-oxadiazol-2-amine
Figure JPOXMLDOC01-appb-C000210
 及び
Figure JPOXMLDOC01-appb-C000210
 as well as
Figure JPOXMLDOC01-appb-C000211
 　参考例１２１で製造した４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（３８ｍｇ、８５μｍｏｌ）をジクロロメタン（１ｍＬ）に溶解し、ジイソプロピルエチルアミン（２９μＬ、０．１７０ｍｍｏｌ）を加えた後、４－クロロベンソイルクロライド（１６μＬ、０．１２７ｍｍｏｌ）を滴下し、室温で１時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、１００：０－０：１００）を用いて精製し、標記目的化合物（１３ｍｇ、収率２６％、実施例８５－Ａ）を得た。
参考例１２２で製造した４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて上記と同様に反応を行い、標記目的化合物（実施例８５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000211
 4- [cis-4- {3-Chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro prepared in Reference Example 121 Quinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (38 mg, 85 μmol) was dissolved in dichloromethane (1 mL), diisopropylethylamine (29 μL, 0.170 mmol) was added, and 4-chloroben Soil chloride (16 μL, 0.127 mmol) was added dropwise and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 100: 0-0: 100) to give the title object compound (13 mg, yield 26%, Example 85-A). Got.
4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro prepared in Reference Example 122 The reaction was carried out in the same manner as described above using tert-butyl quinoxaline-1 (2H) -yl] piperidine-1-carboxylate to obtain the title object compound (Example 85-B).
　（実施例８６）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 86 5-Chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazine -2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000212
 及び
Figure JPOXMLDOC01-appb-C000212
 as well as
Figure JPOXMLDOC01-appb-C000213
 　参考例１２１で製造した４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（１０４ｍｇ、１０９μｍｏｌ）をジクロロメタン（５ｍＬ）に溶解し、トリフルオロ酢酸（１．５ｍＬ）を加え、室温で１時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。得られた残渣の一部（４６ｍｇ）と参考例３０で製造した２－（ブロモメチル）－５－クロロ安息香酸エチル（３４ｍｇ、０．１２３ｍｍｏｌ）を２－プロパノール（１ｍＬ）に溶解し、ジイソプロピルエチルアミン（３５μＬ、０．２０６ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－８０：２０）を用いて精製し、標記目的化合物（５５ｍｇ、７８％、実施例８６－Ａ）を得た。
参考例１２２で製造した４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて上記と同様に反応を行い、標記目的化合物（実施例８６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000213
 4- [cis-4- {3-Chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro prepared in Reference Example 121 Quinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl (104 mg, 109 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. Concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. A part (46 mg) of the obtained residue and ethyl 2- (bromomethyl) -5-chlorobenzoate (34 mg, 0.123 mmol) prepared in Reference Example 30 were dissolved in 2-propanol (1 mL), and diisopropylethylamine ( 35 μL, 0.206 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with a mixed solvent of chloroform and 2-propanol (3: 1). The resulting organic layer was dried over anhydrous sodium sulfate. did. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 98: 2-80: 20) to give the title object compound (55 mg, 78%, Example 86-A). .
4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro prepared in Reference Example 122 Reaction was carried out in the same manner as above using tert-butyl quinoxalin-1 (2H) -yl] piperidine-1-carboxylate to obtain the title compound (Example 86-B).
　（実施例８７）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－エトキシ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 87 5-Chloro-2-({4- [cis-4- {3-ethoxy-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazine -2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000214
 及び
Figure JPOXMLDOC01-appb-C000214
 as well as
Figure JPOXMLDOC01-appb-C000215
 　実施例８６で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル（実施例８６－Ａ）（４５ｍｇ、７０μｍｏｌ）をエタノール（１ｍＬ）と１，４－ジオキサン（１ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（０．３ｍＬ）を加え、室温で１８時間攪拌した。反応液に１Ｎ－塩酸水溶液（０．３ｍＬ）を加えた後、反応液を減圧濃縮した。得られた残渣に水を加えた後、クロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－７０：３０）を用いて精製し、標記目的化合物（３０ｍｇ、６９％、実施例８７－Ａ）を得た。
実施例８６で製造した実施例８６－Ｂを用いて上記と同様に反応を行い、標記目的化合物（実施例８７－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000215
 5-Chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] prepared in Example 86] Pyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate (Example 86-A) (45 mg, 70 μmol) with ethanol (1 mL) and 1,4- The mixture was dissolved in dioxane (1 mL), 1N aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 18 hr. A 1N aqueous hydrochloric acid solution (0.3 mL) was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (chloroform: methanol, 98: 2-70: 30) to obtain the title object compound (30 mg, 69%, Example 87-A). .
The title compound (Example 87-B) was obtained by reacting in the same manner as above using Example 86-B prepared in Example 86.
　（実施例８８）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 88 5-Chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl } Piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000216
 及び
Figure JPOXMLDOC01-appb-C000216
 as well as
Figure JPOXMLDOC01-appb-C000217
 　実施例７９で製造した５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル（実施例７９－Ａ）（６７２ｍｇ、１．１４ｍｍｏｌ）を１，４－ジオキサン（６ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（３ｍＬ）を加え、室温で１８時間攪拌した。反応液に１Ｎ－塩酸水溶液（３ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加えた後、ジクロロメタンで３回抽出し、有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物（６３６ｍｇ、９９％、実施例８８－Ａ）を得た。
実施例７９で製造した実施例７９－Ｂ用いて上記と同様に反応を行い、標記目的化合物（実施例８８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000217
 5-Chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1- prepared in Example 79 Yl} piperidin-1-yl) methyl] ethyl benzoate (Example 79-A) (672 mg, 1.14 mmol) was dissolved in 1,4-dioxane (6 mL), and 1N aqueous sodium hydroxide solution (3 mL) was added. The mixture was further stirred at room temperature for 18 hours. To the reaction mixture was added 1N aqueous hydrochloric acid (3 mL), and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to obtain the title object compound (636 mg, 99%, Example 88-A). .
The title compound (Example 88-B) was obtained by reacting in the same manner as described above using Example 79-B prepared in Example 79.
　（実施例８９）５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 89 5-chloro-2-[(4- {cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1- Yl} piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000218
 及び
Figure JPOXMLDOC01-appb-C000218
 as well as
Figure JPOXMLDOC01-appb-C000219
 　実施例８０で製造した５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル（実施例８０－Ａ）（６９０ｍｇ、１．１５ｍｍｏｌ）を１，４－ジオキサン（６ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（３ｍＬ）を加え、室温で１８時間攪拌した。反応液に１Ｎ－塩酸水溶液（３ｍＬ）を加え、減圧濃縮した。得られた残渣に水を加えた後、ジクロロメタンで３回抽出し、有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物（５７３ｍｇ、８９％、実施例８９－Ａ）を得た。
　実施例８０で製造した実施例８０－Ｂ用いて上記と同様に反応を行い、標記目的化合物（実施例８９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000219
 5-chloro-2-[(4- {cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1 prepared in Example 80 -Yl} piperidin-1-yl) methyl] ethyl benzoate (Example 80-A) (690 mg, 1.15 mmol) was dissolved in 1,4-dioxane (6 mL) and 1N aqueous sodium hydroxide solution (3 mL) was dissolved. And stirred at room temperature for 18 hours. To the reaction mixture was added 1N aqueous hydrochloric acid (3 mL), and the mixture was concentrated under reduced pressure. Water was added to the resulting residue, followed by extraction three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to obtain the title object compound (573 mg, 89%, Example 89-A). .
The title compound (Example 89-B) was obtained by reacting in the same manner as described above using Example 80-B produced in Example 80.
（実施例９０）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 90 5-chloro-2-({4- [cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H) -Yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000220
 及び
Figure JPOXMLDOC01-appb-C000220
 as well as
Figure JPOXMLDOC01-appb-C000221
 　参考例１２９で製造した４－［ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル（３３２mｇ、０．６８９ｍｍｏｌ）をジクロロメタン（４．５ｍＬ）に溶解し、トリフルオロ酢酸（１．５ｍＬ）を加え、室温で１．５時間攪拌後、減圧濃縮した。得られた残渣をアセトニトリル、２－プロパノール（１：１、５ｍＬ）に溶解し、ジイソプロピルアミン（０．７２ｍＬ、４．１４ｍｍｏｌ）、及び２－（ブロモメチル）－５－クロロ安息香酸エチル（１９１ｍｇ、０．６８９ｍｍｏｌ）を加え、室温で２．５時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、ジクロロメタンで抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物のラセミ体（３２７ｍｇ）を得た。このラセミ体を、キラルカラムを用いたＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、２ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、１５ｍＬ／分、２５４ｎＭ）で光学分割し、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が保持時間が９．２分の標記目的化合物（１３９ｍｇ、３５％、実施例９０－Ａ）と保持時間が５．７分の標記目的化合物（１２９ｍｇ、３２％、実施例９０－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000221
 4- [cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-prepared in Reference Example 129 Tert-butyl carboxylate (332 mg, 0.689 mmol) was dissolved in dichloromethane (4.5 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 1.5 hr and concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile, 2-propanol (1: 1, 5 mL), diisopropylamine (0.72 mL, 4.14 mmol), and ethyl 2- (bromomethyl) -5-chlorobenzoate (191 mg, 0 689 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with dichloromethane, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to obtain a racemic form (327 mg) of the title object compound. This racemate was optically resolved by HPLC using a chiral column (Chiralcel AD-H, 2 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 15 mL / min, 254 nM). Chiralcel AD-H, 0.46 cmφ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 2.0 mL / min, 254 nM) The title target compound (129 mg, 32%, Example 90-B) was obtained with the compound (139 mg, 35%, Example 90-A) and a retention time of 5.7 minutes.
（実施９１）５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 91 5-Chloro-2-({4- [cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H)- Yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000222
 及び
Figure JPOXMLDOC01-appb-C000222
 as well as
Figure JPOXMLDOC01-appb-C000223
 　実施例９０で製造した５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（１Ｈ－イミダゾール－１－イル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル（実施例９０－Ａ）（１３４mｇ、０．２３２ｍｍｏｌ）を１，４－ジオキサン（２ｍＬ）に溶解し、１Ｎ－水酸化ナトリウム水溶液（１ｍＬ）を加え、室温で１６時間攪拌した後、１Ｎ－塩酸水溶液（１ｍＬ）を加え、減圧濃縮した。得られた残渣に飽和食塩水を加え、ジクロロメタンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物（１０５mｇ、収率８２％、実施例９１－Ａ）を得た。実施例９０で製造した実施例９０－Ｂを用いて実施例９１－Ａと同様に反応を行い、標記目的化合物（実施例９１－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000223
 5-chloro-2-({4- [cis-4- [5- (1H-imidazol-1-yl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H ) -Yl] piperidin-1-yl} methyl) ethyl benzoate (Example 90-A) (134 mg, 0.232 mmol) was dissolved in 1,4-dioxane (2 mL) and 1N aqueous sodium hydroxide solution (1 mL After stirring at room temperature for 16 hours, 1N aqueous hydrochloric acid solution (1 mL) was added, and the mixture was concentrated under reduced pressure. To the obtained residue was added saturated brine, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to give the title object compound (105 mg, yield 82%, Example 91- A) was obtained. The reaction was conducted in the same manner as in Example 91-A using Example 90-B prepared in Example 90 to give the title object compound (Example 91-B).
（実施例９２）５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル Example 92 5-Chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1- Yl} piperidin-1-yl) methyl] ethyl benzoate
Figure JPOXMLDOC01-appb-C000224
 及び
Figure JPOXMLDOC01-appb-C000224
 as well as
Figure JPOXMLDOC01-appb-C000225
 　参考例１３２で製造した４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルを用いて実施例９０と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝１５／８５、２．０ｍＬ／分、２５４ｎＭ）における保持時間６．８分の標記目的化合物（実施例９２－Ａ）と保持時間が４．６分の標記目的化合物（実施例９２－Ｂ）とを得た。
Figure JPOXMLDOC01-appb-C000225
 4- {cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1-carvone prepared in Reference Example 132 Reaction was performed in the same manner as in Example 90 using tert-butyl acid, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, 2-propanol / hexane = 15/85, 2.0 mL) The title compound (Example 92-A) having a retention time of 6.8 minutes and the title compound (Example 92-B) having a retention time of 4.6 minutes were obtained.
（実施例９３）５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸 Example 93 5-Chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazine-1- Yl} piperidin-1-yl) methyl] benzoic acid
Figure JPOXMLDOC01-appb-C000226
 及び
Figure JPOXMLDOC01-appb-C000226
 as well as
Figure JPOXMLDOC01-appb-C000227
 　実施例９２で製造した実施例９２－Ｂを用いて実施例９１と同様に反応を行い、標記目的化合物（実施例９３－Ｂ）を得た。実施例９２で製造した実施例９２－Ａを用いて実施例９１と同様に反応を行い、標記目的化合物（実施例９３－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000227
 The reaction was conducted in the same manner as in Example 91 using Example 92-B prepared in Example 92, to give the title object compound (Example 93-B). The reaction was conducted in the same manner as in Example 91 using Example 92-A prepared in Example 92 to give the title object compound (Example 93-A).
（実施例９４）２－［５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）フェニル］プロパン－２－オール Example 94 2- [5-Chloro-2-({4- [cis-4- {5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] -3 -Methylpyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) phenyl] propan-2-ol
Figure JPOXMLDOC01-appb-C000228
 及び
Figure JPOXMLDOC01-appb-C000228
 as well as
Figure JPOXMLDOC01-appb-C000229
 　実施例８６で製造したクロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル（実施例８６－Ｂ）を用いて同様に反応を行い、標記目的化合物（実施例９４－Ｂ）を得た。
　実施例８６で製造したクロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル（実施例８６－Ａ）（１０７ｍｇ、１７２μｍｏｌ）をメチルマグネシウムブロミド（１．０Ｍテトラヒドロフラン溶液）（３ｍＬ、３ｍｍｏｌ）に加え、５０℃で６時間攪拌した。反応液を室温まで冷却後、飽和炭酸水素ナトリウム水溶液を加え、１０分間攪拌した。反応液をクロロホルム、２－プロパノール（３：１）の混合溶媒で３回抽出し、得られた有機層を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール、９８：２－７０：３０）で精製し、標記目的化合物（１３ｍｇ、収率１２％、実施例９４－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000229
 Chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazine- prepared in Example 86 2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate (Example 86-B) was used in the same manner to give the title target compound (Example 94- B) was obtained.
Chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyrazine- prepared in Example 86 2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate (Example 86-A) (107 mg, 172 μmol) in methyl magnesium bromide (1.0 M tetrahydrofuran solution) 3 mL, 3 mmol) and stirred at 50 ° C. for 6 hours. After cooling the reaction solution to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and stirred for 10 minutes. The reaction solution was extracted three times with a mixed solvent of chloroform and 2-propanol (3: 1), and the obtained organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol, 98: 2-70: 30) to give the title object compound (13 mg, yield 12%, Example 94-A). .
（実施例９５）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－メチル－５－［５－（メチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 95 5-Chloro-2-({4- [cis-4- {3-methyl-5- [5- (methylamino) -1,3,4-oxadiazol-2-yl] pyrazine -2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000230
 及び
Figure JPOXMLDOC01-appb-C000230
 as well as
Figure JPOXMLDOC01-appb-C000231
 　参考例１３５の４－［ｃｉｓ－４－｛３－メチル－５－［５－（メチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が保持時間７．７分の標記目的化合物(実施例９５－Ａ）と４．４分の標記目的化合物(実施例９５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000231
 4- [cis-4- {3-methyl-5- [5- (methylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro-1H- of Reference Example 135 Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Example 9 and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) And the title compound (Example 95-A) having a retention time of 7.7 minutes and a title compound (Example 95-A) having a retention time of 7.7 minutes in ethanol / hexane = 25/75, 2.0 mL / min, 254 nM). Example 95-B) was obtained.
（実施例９６）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 96 5-Chloro-2-({4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methyl Pyrazin-2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000232
 及び
Figure JPOXMLDOC01-appb-C000232
 as well as
Figure JPOXMLDOC01-appb-C000233
 　参考例１３７の4-[cis-4-{5-[5-(シクロプロピルアミノ)-1,3,4-オキサジアゾール-2-イル]-3-メチルピラジン-2-イル}オクタヒドロ-1H-シクロペンタ[b]ピラジン-1-イル]ピペリジン-1-カルボン酸 tert-ブチルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、エタノール／ヘキサン＝３０／７０、２．０ｍＬ／分、２５４ｎＭ）における保持時間が８．１分の標記目的化合物（９６－Ａ）と保持時間が４．５分の標記目的化合物(実施例９６－Ｂ）とを得た。
Figure JPOXMLDOC01-appb-C000233
 4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro-1H of Reference Example 137 -Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Example 9 and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries Ltd.) Title target compound (96-A) having a retention time of 8.1 minutes and title target compound having a retention time of 4.5 minutes (made by company, ethanol / hexane = 30/70, 2.0 mL / min, 254 nM) Example 96-B) was obtained.
（実施例９７）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－メチル－５－［５－（メチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル)安息香酸 Example 97 5-Chloro-2-({4- [cis-4- {3-methyl-5- [5- (methylamino) -1,3,4-oxadiazol-2-yl] pyrazine -2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000234
 又は
Figure JPOXMLDOC01-appb-C000234
 Or
Figure JPOXMLDOC01-appb-C000235
 　実施例９６で製造した実施例９６－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例９７－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000235
 The reaction was conducted in the same manner as in Example 3 using Example 96-A prepared in Example 96 to give the title object compound (Example 97-A).
（実施例９８）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル)安息香酸 Example 98 5-Chloro-2-({4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methyl Pyrazin-2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000236
 及び
Figure JPOXMLDOC01-appb-C000236
 as well as
Figure JPOXMLDOC01-appb-C000237
 　実施例９６で製造した実施例９６－Ｂを用いて実施例３と同様に反応を行い、標記目的化合物（実施例９８－Ｂ）を得た。
　実施例９６で製造した実施例９６－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例９８－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000237
 The reaction was conducted in the same manner as in Example 3 using Example 96-B prepared in Example 96 to give the title object compound (Example 98-B).
The reaction was conducted in the same manner as in Example 3 using Example 96-A prepared in Example 96 to obtain the title object compound (Example 98-A).
（実施例９９）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（イソプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 99 5-Chloro-2-({4- [cis-4- {5- [5- (isopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazine -2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000238
 及び
Figure JPOXMLDOC01-appb-C000238
 as well as
Figure JPOXMLDOC01-appb-C000239
 　参考例１３９の４－［ｃｉｓ－４－｛５－［５－（イソプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が５．８分の標記目的化合物（実施例９９－Ａ）と保持時間が３．７分の標記目的化合物（実施例９９－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000239
 4- [cis-4- {5- [5- (isopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro-1H- of Reference Example 139 Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Example 9 and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) Title compound (Example 99-A) with a retention time of 5.8 minutes and a retention time of 3.7 minutes with 2-propanol / hexane = 25/75, 2.0 mL / min, 254 nM) The compound (Example 99-B) was obtained.
（実施例１００）２－（｛４－［ｃｉｓ－４－｛５－［５－（ブチルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸エチル Example 100 2-({4- [cis-4- {5- [5- (Butylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl } Octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) -5-chlorobenzoate ethyl
Figure JPOXMLDOC01-appb-C000240
 及び
Figure JPOXMLDOC01-appb-C000240
 as well as
Figure JPOXMLDOC01-appb-C000241
 　参考例１４１の４－［ｃｉｓ－４－｛５－［５－（ブチルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が５．８分の標記目的化合物（実施例１００－Ａ）と保持時間が３．７分の標記目的化合物（実施例１００－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000241
 4- [cis-4- {5- [5- (butylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro-1H- of Reference Example 141 Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Example 9 and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) Title compound (Example 100-A) with a retention time of 5.8 minutes and a retention time of 3.7 minutes with 2-propanol / hexane = 25/75, 2.0 mL / min, 254 nM) The compound (Example 100-B) was obtained.
（実施例１０１）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（イソプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル)安息香酸 Example 101 5-Chloro-2-({4- [cis-4- {5- [5- (isopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazine -2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000242
 及び
Figure JPOXMLDOC01-appb-C000242
 as well as
Figure JPOXMLDOC01-appb-C000243
 　実施例９９で製造した実施例９９－Ｂを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０１－Ｂ）を得た。
　実施例９９で製造した実施例９９－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０１－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000243
 The reaction was conducted in the same manner as in Example 3 using Example 99-B prepared in Example 99 to obtain the title object compound (Example 101-B).
The reaction was conducted in the same manner as in Example 3 using Example 99-A prepared in Example 99 to obtain the title object compound (Example 101-A).
（実施例１０２）２－（｛４－［ｃｉｓ－４－｛５－［５－（ブチルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）－５－クロロ安息香酸 Example 102 2-({4- [cis-4- {5- [5- (butylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl } Octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) -5-chlorobenzoic acid
Figure JPOXMLDOC01-appb-C000244
 及び
Figure JPOXMLDOC01-appb-C000244
 as well as
Figure JPOXMLDOC01-appb-C000245
 　実施例１００で製造した実施例１００－Ｂを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０２－Ｂ）を得た。
　実施例１００で製造した実施例１００－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０２－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000245
 The reaction was conducted in the same manner as in Example 3 using Example 100-B prepared in Example 100 to obtain the title object compound (Example 102-B).
The reaction was conducted in the same manner as in Example 3 using Example 100-A prepared in Example 100 to obtain the title object compound (Example 102-A).
（実施例１０３）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル)安息香酸エチル Example 103 5-Chloro-2-({4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methyl Pyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000246
 及び
Figure JPOXMLDOC01-appb-C000246
 as well as
Figure JPOXMLDOC01-appb-C000247
 　参考例１４３の４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が５．６分の標記目的化合物（実施例１０３－Ａ）と保持時間が３．３分の標記目的化合物（実施例１０３－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000247
 4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydroquinoxaline of Reference Example 143 -(2H) -yl] piperidine-1-carboxylate tert-butyl was reacted in the same manner as in Example 9, and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd.) The title target compound (Example 103-A) having a retention time of 5.6 minutes and the title target compound having a retention time of 3.3 minutes (2-propanol / hexane = 25/75, 2.0 mL / min, 254 nM) Example 103-B) was obtained.
（実施例１０４）５－クロロ－２－（｛４－［ｃｉｓ－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル)安息香酸 Example 104 5-Chloro-2-({4- [cis-4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methyl Pyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000248
 及び
Figure JPOXMLDOC01-appb-C000248
 as well as
Figure JPOXMLDOC01-appb-C000249
 　実施例１０３で製造した実施例１０３－Ｂを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０４－Ｂ）を得た。
　実施例１０３で製造した実施例１０３－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０４－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000249
 The reaction was conducted in the same manner as in Example 3 using Example 103-B prepared in Example 103 to obtain the title object compound (Example 104-B).
The reaction was conducted in the same manner as in Example 3 using Example 103-A prepared in Example 103 to obtain the title object compound (Example 104-A).
（実施例１０５）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－メチル－５－［５－（プロピルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）安息香酸エチル Example 105 5-chloro-2-({4- [cis-4- {3-methyl-5- [5- (propylamino) -1,3,4-oxadiazol-2-yl] pyrazine -2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) ethyl benzoate
Figure JPOXMLDOC01-appb-C000250
 及び
Figure JPOXMLDOC01-appb-C000250
 as well as
Figure JPOXMLDOC01-appb-C000251
 　参考例１４５の４－［ｃｉｓ－４－｛３－メチル－５－［５－（プロピルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が５．６分の標記目的化合物（実施例１０５－Ａ）と保持時間が３．３分の標記目的化合物（実施例１０５－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000251
 4- [cis-4- {3-methyl-5- [5- (propylamino) -1,3,4-oxadiazol-2-yl] pyrazin-2-yl} octahydro-1H- of Reference Example 145 Cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate The reaction was carried out in the same manner as in Example 9 and HPLC (Chiralcel AD-H, 0.46 cmΦ × 25 cm, Daicel Chemical Industries, Ltd.) The title objective compound (Example 105-A) having a retention time of 5.6 minutes and a retention time of 3.3 minutes in 2-propanol / hexane = 25/75, 2.0 mL / min, 254 nM) The compound (Example 105-B) was obtained.
（実施例１０６）（４－クロロフェニル）｛４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝酢酸メチル Example 106 (4-Chlorophenyl) {4-[(4aR, 8aS) -4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] Piperidin-1-yl} methyl acetate
Figure JPOXMLDOC01-appb-C000252
 及び
Figure JPOXMLDOC01-appb-C000252
 as well as
Figure JPOXMLDOC01-appb-C000253
 　参考例１５６で製造した４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル（４．５６ｇ、９．３７ｍｍｏｌ）をジクロロメタン（４０ｍＬ）に溶解し、トリフルオロ酢酸（２０ｍＬ）を加え、室温で１．５時間攪拌後、減圧濃縮した。得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで３回抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、粗生成物としてアミン（４．２９ｇ）を得た。得られたアミン（１．０７ｇ、２．７８ｍｍｏｌ）をアセトニトリル、２－プロパノール（１：１、２０ｍＬ）に溶解し、ジイソプロピルアミン（０．７３ｍＬ、４．１６ｍｍｏｌ）、及びブロモ（４－クロロフェニル）酢酸メチル（０．８８ｇ、３．３３ｍｍｏｌ）を加え、室温で１．５時間攪拌した。反応液を減圧濃縮し、反応液に飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルで抽出し、得られた有機相を無水硫酸ナトリウムで乾燥した。濾過後、減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル、５０：５０－８５：１５）を用いて精製し、高極性化合物（４１０ｍｇ、実施例１０６－Ａ）とそのジアステレオマーである低極性化合物（５０５ｍｇ、実施例１０６－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000253
 4-[(4aR, 8aS) -4- [5- (Ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone prepared in Reference Example 156 Acid tert-butyl (4.56 g, 9.37 mmol) was dissolved in dichloromethane (40 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted three times with dichloromethane. The obtained organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain an amine (4.29 g) as a crude product. The obtained amine (1.07 g, 2.78 mmol) was dissolved in acetonitrile, 2-propanol (1: 1, 20 mL), diisopropylamine (0.73 mL, 4.16 mmol), and bromo (4-chlorophenyl) acetic acid. Methyl (0.88 g, 3.33 mmol) was added and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the resulting organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate, 50: 50-85: 15) to obtain a highly polar compound (410 mg, Example 106-A) and its diastereomer. A low polarity compound (505 mg, Example 106-B) was obtained.
（実施例１０７）（４－クロロフェニル）｛４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝酢酸 Example 107 (4-Chlorophenyl) {4-[(4aR, 8aS) -4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] Piperidin-1-yl} acetic acid
Figure JPOXMLDOC01-appb-C000254
 及び
Figure JPOXMLDOC01-appb-C000254
 as well as
Figure JPOXMLDOC01-appb-C000255
 　実施例１０６で製造した実施例１０６－Ａ（１０９mｇ、０．１９２ｍｍｏｌ）を１，２－ジクロロエタン（４mL）に溶解し、水酸化トリメチルスズ（３４６mｇ、１．９２ｍｍｏｌ）を加え、９０度で１８時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９９：１－９２：８）を用いて精製し、標記目的化合物（４８ｍｇ、４５％）を得た。
　実施例１０６で製造した実施例１０６－Ｂ（９８mｇ、０．１７２ｍｍｏｌ）を１，２－ジクロロエタン（４mL）に溶解し、水酸化トリメチルスズ（３１１mｇ、１．７２ｍｍｏｌ）を加え、９０度で１８時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９９：１－９２：８）を用いて精製し、標記目的化合物（５２ｍｇ、５４％）を得た。
Figure JPOXMLDOC01-appb-C000255
 Example 106-A prepared in Example 106 (109 mg, 0.192 mmol) was dissolved in 1,2-dichloroethane (4 mL), trimethyltin hydroxide (346 mg, 1.92 mmol) was added, and the mixture was heated at 90 degrees for 18 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol, 99: 1-92: 8) to obtain the title object compound (48 mg, 45%).
Example 106-B prepared in Example 106 (98 mg, 0.172 mmol) was dissolved in 1,2-dichloroethane (4 mL), trimethyltin hydroxide (311 mg, 1.72 mmol) was added, and 90 ° C. for 18 hours. Stir. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol, 99: 1-92: 8) to obtain the title object compound (52 mg, 54%).
（実施例１０８）（４－クロロフェニル）｛４－［（４ａＲ，８ａＳ）－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝酢酸メチル Example 108 (4-Chlorophenyl) {4-[(4aR, 8aS) -4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3 -Methylpyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl acetate
Figure JPOXMLDOC01-appb-C000256
 及び
Figure JPOXMLDOC01-appb-C000256
 as well as
Figure JPOXMLDOC01-appb-C000257
 　参考例１５８で製造した４－［（４ａＲ，８ａＳ）－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルを用いて、実施例１０６と同様に反応を行い、低極性化合物（実施例１０８－Ａ）とそのジアステレオマーである高極性化合物（実施例１０８－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000257
 4-[(4aR, 8aS) -4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazine-2 prepared in Reference Example 158 -Il} octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-Butyl was reacted in the same manner as in Example 106 to produce a low polarity compound (Example 108-A) and its dia A highly polar compound (Example 108-B) which is a stereomer was obtained.
（実施例１０９）５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－メチル－５－［５－（プロピルアミノ）－１，３，４－オキサジアゾール－２－イル］ピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－イル｝メチル）安息香酸 Example 109 5-Chloro-2-({4- [cis-4- {3-methyl-5- [5- (propylamino) -1,3,4-oxadiazol-2-yl] pyrazine -2-yl} octahydro-1H-cyclopenta [b] pyrazin-1-yl] piperidin-1-yl} methyl) benzoic acid
Figure JPOXMLDOC01-appb-C000258
 及び
Figure JPOXMLDOC01-appb-C000258
 as well as
Figure JPOXMLDOC01-appb-C000259
 　実施例１０５で製造した実施例１０５－Ｂを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０９－Ｂ）を得た。
　実施例１０５で製造した実施例１０５－Ａを用いて実施例３と同様に反応を行い、標記目的化合物（実施例１０９－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000259
 The reaction was conducted in the same manner as in Example 3 using Example 105-B prepared in Example 105, to give the title object compound (Example 109-B).
The reaction was conducted in the same manner as in Example 3 using Example 105-A prepared in Example 105, to give the title object compound (Example 109-A).
（実施例１１０）５－｛ｃｉｓ－４－［１－（４－クロロ－２－シアノベンジル）ピペリジン－４－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝－Ｎ－エチル－６－メチルピラジン－２－カルボキサミド Example 110 5- {cis-4- [1- (4-Chloro-2-cyanobenzyl) piperidin-4-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} -N-ethyl- 6-Methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000260
 及び
Figure JPOXMLDOC01-appb-C000260
 as well as
Figure JPOXMLDOC01-appb-C000261
 　参考例８８の４－［ｃｉｓ－４－｛５－［５－（ブチルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルと参考例１５１の2-(ブロモメチル)-5-クロロベンゾニトリルを用いて実施例９と同様に反応を行い、ＨＰＬＣ（Ｃｈｉｒａｌｃｅｌ　ＡＤ－Ｈ、０．４６ｃｍΦ×２５ｃｍ、ダイセル化学工業株式会社製、２－プロパノール／ヘキサン＝２５／７５、２．０ｍＬ／分、２５４ｎＭ）における保持時間が５．８分の標記目的化合物（実施例１１０－Ａ）と保持時間が３．７分の標記目的化合物（実施例１１０－Ｂ）を得た。
Figure JPOXMLDOC01-appb-C000261
 4- [cis-4- {5- [5- (butylamino) -1,3,4-oxadiazol-2-yl] -3-methylpyrazin-2-yl} octahydro-1H- of Reference Example 88 The reaction was carried out in the same manner as in Example 9 using tert-butyl cyclopenta [b] pyrazin-1-yl] piperidine-1-carboxylate and 2- (bromomethyl) -5-chlorobenzonitrile of Reference Example 151, and HPLC ( Title target compound having a retention time of 5.8 minutes in Chiralcel AD-H, 0.46 cmΦ × 25 cm, manufactured by Daicel Chemical Industries, Ltd., 2-propanol / hexane = 25/75, 2.0 mL / min, 254 nM) The title object compound (Example 110-B) was obtained with Example 110-A) and a retention time of 3.7 minutes.
（実施例１１１）５－［ｃｉｓ－４－｛１－［４－クロロ－２－（２Ｈ－テトラゾール－５－イル）ベンジル］ピペリジン－４－イル｝オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル］－Ｎ－エチル－６－メチルピラジン－２－カルボキサミド Example 111 5- [cis-4- {1- [4-Chloro-2- (2H-tetrazol-5-yl) benzyl] piperidin-4-yl} octahydro-1H-cyclopenta [b] pyrazine-1 -Yl] -N-ethyl-6-methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000262
 及び
Figure JPOXMLDOC01-appb-C000262
 as well as
Figure JPOXMLDOC01-appb-C000263
 　実施例１１０で製造した実施例１１０－Ｂ６６．２ｍｇ（０．１２７ｍｍｏｌ）、塩化アンモニウム１０．２ｍｇ（０．１９０ｍｍｏｌ）、アジ化ナトリウム１７．５ｍｇ（０．２６４ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド（２ｍｌ）溶液を、窒素雰囲気下で８０℃にて１５時間撹拌した。室温まで冷却した後、反応液を減圧下濃縮し、得られた残渣にクロロホルム（５ｍｌ）、水（５ｍｌ）を加えて分液し、クロロホルム（３ｘ３．０ｍｌ）で抽出した。有機層を合わせて無水硫酸ナトリウムにて乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ　２５Ｓ、メタノール／クロロホルム、０－２５％）に付し、標記化合物（３２ｍｇ、４６％、実施例１１１－Ｂ）を得た。実施例１１０で製造した実施例１１０－Ａを用いて同様に反応を行い、標記目的化合物（実施例１１１－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000263
 Example 110-B prepared in Example 110 66.2 mg (0.127 mmol), ammonium chloride 10.2 mg (0.190 mmol), sodium azide 17.5 mg (0.264 mmol) N, N-dimethylformamide (2 ml) ) The solution was stirred at 80 ° C. for 15 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, chloroform (5 ml) and water (5 ml) were added to the resulting residue, and the mixture was separated and extracted with chloroform (3 × 3.0 ml). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Biotage 25S, methanol / chloroform, 0-25%) to obtain the title compound (32 mg, 46%, Example 111-B). The same reaction as in Example 110 was carried out using Example 110-A prepared in Example 110 to obtain the title compound (Example 111-A).
（実施例１１２）（４－クロロフェニル）｛４－［（４ａＲ，８ａＳ）－４－｛５－［５－（シクロプロピルアミノ）－１，３，４－オキサジアゾール－２－イル］－３－メチルピラジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝酢酸 Example 112 (4-Chlorophenyl) {4-[(4aR, 8aS) -4- {5- [5- (cyclopropylamino) -1,3,4-oxadiazol-2-yl] -3 -Methylpyrazin-2-yl} octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} acetic acid
Figure JPOXMLDOC01-appb-C000264
 及び
Figure JPOXMLDOC01-appb-C000264
 as well as
Figure JPOXMLDOC01-appb-C000265
 　実施例１０８で製造した実施例１０８－Ｂを用いて実施例１０７と同様に反応を行い、標記目的化合物（実施例１１１２－Ｂ）を得た。
　実施例１０８で製造した実施例１０８－Ａを用いて実施例１０７と同様に反応を行い、標記目的化合物（実施例１１１２－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000265
 The reaction was conducted in the same manner as in Example 107 using Example 108-B prepared in Example 108 to obtain the title object compound (Example 1112-B).
The reaction was conducted in the same manner as in Example 107 using Example 108-A prepared in Example 108 to obtain the title object compound (Example 1112-A).
（実施例１１３）５－クロロ－６－［ｃｉｓ－４－［１－（４－クロロ－２－シアノベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチルニコチンアミド Example 113 5-Chloro-6- [cis-4- [1- (4-chloro-2-cyanobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-ethyl Nicotinamide
Figure JPOXMLDOC01-appb-C000266
 または
Figure JPOXMLDOC01-appb-C000266
 Or
Figure JPOXMLDOC01-appb-C000267
 　参考例３で製造した４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチルと参考例１５１で製造した２－（ブロモメチル）－５－クロロベンゾニトリルを用いて実施例１と同様に反応を行い、保持時間が長い化合物を標記目的化合物とした。
Figure JPOXMLDOC01-appb-C000267
 4- [cis-4- [3-Chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carboxylate tert-butyl prepared in Reference Example 3 Using 2- (bromomethyl) -5-chlorobenzonitrile prepared in Reference Example 151, the reaction was carried out in the same manner as in Example 1, and the compound having a long retention time was determined as the title target compound.
（実施例１１４）５－クロロ－６－［（４ａＳ，８ａＲ）－４－｛１－［４－クロロ－２－（１Ｈ－テトラゾール－５－イル）ベンジル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチルニコチンアミド Example 114 5-Chloro-6-[(4aS, 8aR) -4- {1- [4-chloro-2- (1H-tetrazol-5-yl) benzyl] piperidin-4-yl} octahydroquinoxaline -1 (2H) -yl] -N-ethylnicotinamide
Figure JPOXMLDOC01-appb-C000268
 または
Figure JPOXMLDOC01-appb-C000268
 Or
Figure JPOXMLDOC01-appb-C000269
 　実施例１１３で製造した５－クロロ－６－［（４ａＳ，８ａＲ）－４－｛１－［４－クロロ－２－（１Ｈ－テトラゾール－５－イル）ベンジル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチルニコチンアミドを用いて実施例１０６と同様に反応を行い、標記目的化合物を得た。
Figure JPOXMLDOC01-appb-C000269
 5-chloro-6-[(4aS, 8aR) -4- {1- [4-chloro-2- (1H-tetrazol-5-yl) benzyl] piperidin-4-yl} octahydro prepared in Example 113 Reaction was carried out in the same manner as in Example 106 using quinoxalin-1 (2H) -yl] -N-ethylnicotinamide to obtain the title object compound.
（実施例１１５）５－［（４ａＳ，８ａＲ）－４－［１－（４－クロロ－２－シアノベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチル－６－メチルピラジン－２－カルボキサミド Example 115 5-[(4aS, 8aR) -4- [1- (4-Chloro-2-cyanobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-ethyl -6-methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000270
 　参考例１５６で製造した４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルと参考例１５１で製造した２－（ブロモメチル）－５－クロロベンゾニトリルを用いて実施例１０６と同様に反応を行い、標記目的化合物を得た。
Figure JPOXMLDOC01-appb-C000270
 4-[(4aR, 8aS) -4- [5- (Ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone prepared in Reference Example 156 The reaction was conducted in the same manner as in Example 106 using tert-butyl acid and 2- (bromomethyl) -5-chlorobenzonitrile prepared in Reference Example 151, to give the title object compound.
（実施例１１６）５－［（４ａＳ，８ａＲ）－４－｛１－［４－クロロ－２－（１Ｈ－テトラゾール－５－イル）ベンジル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチル－６－メチルピラジン－２－カルボキサミド Example 116 5-[(4aS, 8aR) -4- {1- [4-Chloro-2- (1H-tetrazol-5-yl) benzyl] piperidin-4-yl} octahydroquinoxaline-1 (2H ) -Yl] -N-ethyl-6-methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000271
 　実施例１１５で製造した５－［（４ａＳ，８ａＲ）－４－［１－（４－クロロ－２－シアノベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチル－６－メチルピラジン－２－カルボキサミド（２１３ｍｇ、０．３９７ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（５ｍＬ）に溶解し、アジ化ナトリウム（２５８ｍｇ、３．９７ｍｍｏｌ）、及び塩化アンモニウム（２１３ｍｇ、３．９７ｍｍｏｌ）を加え、１００度で１６時間攪拌した。反応液を室温まで冷却後、ジクロロメタンを加え、水、飽和食塩水で洗浄した。得られた有機相を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９８：２－９２：８）を用いて精製し、標記目的化合物（１０６ｍｇ、４６％）を得た。
Figure JPOXMLDOC01-appb-C000271
 5-[(4aS, 8aR) -4- [1- (4-Chloro-2-cyanobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N—prepared in Example 115 Ethyl-6-methylpyrazine-2-carboxamide (213 mg, 0.397 mmol) is dissolved in N, N-dimethylformamide (5 mL), sodium azide (258 mg, 3.97 mmol), and ammonium chloride (213 mg, 3.97 mmol). 97 mmol) was added and stirred at 100 degrees for 16 hours. The reaction mixture was cooled to room temperature, dichloromethane was added, and the mixture was washed with water and saturated brine. The obtained organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol, 98: 2-92: 8) to obtain the title object compound (106 mg, 46%).
（実施例１１７）５－クロロ－２－［１－｛４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝エチル］安息香酸 Example 117 5-Chloro-2- [1- {4-[(4aR, 8aS) -4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxaline-1 (2H ) -Yl] piperidin-1-yl} ethyl] benzoic acid
Figure JPOXMLDOC01-appb-C000272
 及び
Figure JPOXMLDOC01-appb-C000272
 as well as
Figure JPOXMLDOC01-appb-C000273
 　参考例１５６で製造した４－［（４ａＲ，８ａＳ）－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルと参考例１５４で製造した２－（１－ブロモエチル）－５－クロロ安息香酸メチルを用いて実施例１０６と同様に反応を行い、低極性のエステル体と高極性のエステル体を得た。得られた二つのエステル体の低極性の化合物を用いて実施例２と同様に反応を行い、標記目的化合物（実施例１１７－Ｂ）を得た。
　高極性化合物も実施例２と同様に反応を行い、標記目的化合物(実施例１１７－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000273
 4-[(4aR, 8aS) -4- [5- (Ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidine-1-carvone prepared in Reference Example 156 The reaction was carried out in the same manner as in Example 106 using tert-butyl acid and methyl 2- (1-bromoethyl) -5-chlorobenzoate prepared in Reference Example 154 to obtain a low polarity ester and a high polarity ester. Obtained. The obtained two ester low-polarity compounds were used in the same manner as in Example 2 to obtain the title object compound (Example 117-B).
The highly polar compound was also reacted in the same manner as in Example 2 to obtain the title compound (Example 117-A).
（実施例１１８）５－［（４ａＳ，８ａＲ）－４－｛１－［１－（４－クロロフェニル）－２－ヒドロキシエチル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－エチル－６－メチルピラジン－２－カルボキサミド Example 118 5-[(4aS, 8aR) -4- {1- [1- (4-chlorophenyl) -2-hydroxyethyl] piperidin-4-yl} octahydroquinoxalin-1 (2H) -yl] -N-ethyl-6-methylpyrazine-2-carboxamide
Figure JPOXMLDOC01-appb-C000274
 及び
Figure JPOXMLDOC01-appb-C000274
 as well as
Figure JPOXMLDOC01-appb-C000275
 　実施例１０６で製造した実施例１０６－Ｂ（８６mｇ、０．１５１ｍｍｏｌ、低極性化合物）をテトラヒドロフラン（２mL）に溶解し、水酸化ホウ素リチウム（１３．２mｇ、０．６０４ｍｍｏｌ）を加え、室温で２４時間攪拌した。反応液を０度に冷却し、１N塩酸を滴下した。反応液に１N水酸化ナトリウムを加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥し、濾過後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン：メタノール、９９：１－９２：８）を用いて精製し、標記目的化合物（６２ｍｇ、７６％、実施例１１８－Ｂ）を得た。
　実施例１０６で製造した１０６－Ａ（高極性化合物）も同様に反応を行い、標記目的化合物（実施例１１８－Ａ）を得た。
Figure JPOXMLDOC01-appb-C000275
 Example 106-B prepared in Example 106 (86 mg, 0.151 mmol, low polarity compound) was dissolved in tetrahydrofuran (2 mL), lithium borohydride (13.2 mg, 0.604 mmol) was added, and 24 hours at room temperature. Stir for hours. The reaction solution was cooled to 0 ° C. and 1N hydrochloric acid was added dropwise. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol, 99: 1-92: 8) to obtain the title object compound (62 mg, 76%, Example 118-B).
106-A (high polarity compound) produced in Example 106 was reacted in the same manner to obtain the title target compound (Example 118-A).
　実施例に記載の化合物の物理化学データを以下に示す。 Physicochemical data of the compounds described in the examples are shown below.
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000293
  
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000293
  

Claims (20)

  1. 一般式（Ｉ）を有する化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000001
    ［式中、Ｘ１、Ｘ２、Ｘ３、及びＸ４は、それぞれ独立に、－C＝、又は、－N＝を表わし、
    Ｘ５は、－ＣＨ２－、－ＣＨ２ＣＨ２－、－Ｏ－、－ＣＨ２Ｏ－、－ＯＣＨ２－、－ＣＨ２Ｓ－、－ＳＣＨ２－、－ＣＨ２ＳＯ－、－ＳＯＣＨ２－、－、－ＣＨ２ＳＯ２－、－ＳＯ２ＣＨ２－、－Ｃ（－Ｒ３）（－Ｒ４）－、又は－Ｃ（－Ｒ３）（－Ｒ４）－Ｃ（－Ｒ３）（－Ｒ４）－を表わし、
    Ｘ６は、－ＣＨ（－Ｒ５）－、又は－Ｃ（＝Ｏ）－を表わし、
    Ｘ７は、－ＣＨ（－Ｒ６）－、又は－Ｃ（＝Ｏ）－を表わし、
    Ｒ１は、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又はＣ１－Ｃ６ハロゲノアルコキシ基を表わし、
    Ｒ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、又はカルボキシ基の保護基で保護されていてもよいカルボキシ基を表わし、
    Ｒ３、Ｒ４、Ｒ５及びＲ６は、それぞれ独立に、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、又はＣ１－Ｃ６ハロゲノアルキル基を表わし、
    Ａは、カルバモイル基、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６ヒドロキシアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アルキルスルホンアミド基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アシルアミノ基、又は、５員環へテロアリール基を表わし、ここで、５員環へテロアリール基は、非置換であるか、又は独立して選択される１～５個のＲ７部分で置換されていてもよく、
    ここで、Ｒ７部分は、同じであっても異なっていてもよく、各々が、水酸基、アミノ基、カルボキシ基、ハロゲン基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、及びＣ１－Ｃ６ハロゲノアルコキシ基からなる群より独立して選択され、
    Ｙは、単結合、－ＣＨ２－、－（ＣＲ８Ｒ８）ｒ－、－ＣＨＲ８Ｃ（＝Ｏ）－、－（ＣＨＲ８）ｒＯ－、－（ＣＨＲ８）ｒＮ（Ｒ９）－、－Ｃ（＝Ｏ）－、－Ｃ（＝Ｓ）－、－Ｃ（＝ＮＲ９）－、－Ｃ（＝Ｎ－ＯＲ９）－、－ＣＨ（Ｃ（＝Ｏ）ＮＨＲ９）－、－ＣＨ（－５～１４員環ヘテロアリール）－、－Ｃ（Ｒ８Ｒ８）ｒＣ（Ｒ８）＝Ｃ（Ｒ８）－、－（ＣＨＲ８）ｒＣ（＝Ｏ）－、及び－（ＣＨＲ８）ｒＮＨＣ（＝Ｏ）－からなる群より選択される基を表わし、あるいは、Ｃ３－Ｃ１０シクロアルキル基、3～１０員環ヘテロシクレニル基、又は3～１０員環ヘテロシクリル基であり、このＣ３－Ｃ１０シクロアルキル基、3～１０員環ヘテロシクレニル基、又は、3～１０員環ヘテロシクリル基は、環Ｄと縮合し、
    Ｒ８部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、Ｃ３－Ｃ１０シクロアルキル基、Ｃ１－Ｃ２０アルコキシ基、６～１４員環アリール基、５～１４員環ヘテロアリール基、3～１０員環ヘテロシクレニル基、3～１０員環ヘテロシクリル基、Ｃ３－Ｃ１１スピロアルキル基、－ＣＮ、－ＣＯＯＨ、－Ｃ（＝Ｏ）Ｒ９、－Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－（ＣＨＲ９）ｑＯＨ、－（ＣＨＲ９）ｑＯＲ１０、－（ＣＨＲ９）ｑＮＨ２、－（ＣＨＲ９）ｑＮＨＲ１０、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨＲ１０、－（ＣＨ２）ｑＳＯ２Ｒ１０、－（ＣＨ２）ｑＮＳＯ２Ｒ１０、－（ＣＨ２）ｑＳＯ２ＮＨＲ１０、－ＮＨ２、－Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－ＯＨ、ＯＲ９、－ＳＯ２Ｎ（Ｒ９）２、および－ＳＯ２（Ｒ１０）からなる群より独立して選択され、
    Ｒ９部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、６～１４員環アリール基、アラルキル基、Ｃ３－Ｃ１０シクロアルキル基、－ＣＮ、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＯ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＯ－６～１４員環アリール、－（ＣＨ２）ｑＯアラルキル、－（ＣＨ２）ｑＯ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＮＨアラルキル、－（ＣＨ２）ｑＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨアルキル、－（ＣＨ２）ｑＣ（＝Ｏ）Ｎ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨアラルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２アラルキル、－（ＣＨ２）ｑＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＮＳＯ２アラルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２ＮＨアラルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ３－Ｃ１０シクロアルキル、3～１０員環ヘテロシクレニル基、3～１０員環ヘテロシクリル基、および５～１４員環ヘテロアリールからなる群より独立して選択され、
    　Ｒ１０部分は、同じであっても異なっていてもよく、各々が、Ｃ１－Ｃ２０アルキル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、６～１４員環アリール基、アラルキル基、Ｃ３－Ｃ１０シクロアルキル基、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＯ－Ｃ１－Ｃ２０アルキル－６～１４員環アリール、－（ＣＨ２）ｑＯ－６～１４員環アリール、－（ＣＨ２）ｑＯアラルキル、－（ＣＨ２）ｑＯ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＮＨアラルキル、－（ＣＨ２）ｑＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＣ（＝Ｏ）Ｎ（Ｃ１－Ｃ２０アルキル）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨアラルキル、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨ－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２アラルキル、－（ＣＨ２）ｑＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＮＳＯ２－６～１４員環アリール、－（ＣＨ２）ｑＮＳＯ２アラルキル、－（ＣＨ２）ｑＮＳＯ２－Ｃ３－Ｃ１０シクロアルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール－Ｃ１－Ｃ２０アルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－６～１４員環アリール、－（ＣＨ２）ｑＳＯ２ＮＨアラルキル、－（ＣＨ２）ｑＳＯ２ＮＨ－Ｃ３－Ｃ１０シクロアルキル、3～１０員環ヘテロシクレニル基、3～１０員環ヘテロシクリル基、および５～１４員環ヘテロアリール基からなる群より独立して選択され、
    環Ｄは、５～９員の、シクロアルキル環、シクロアルケニル環、アリール環、ヘテロアリール環、ヘテロシクレニル環、又は、ヘテロシクリル環であり、ここで、該アリール環は、フェニルを除外し、該へテロアリール環、ヘテロシクレニル環、及びヘテロシクリル環は、Ｏ、Ｓ、又は、Ｎから環原子として独立して選択される、０～４個のヘテロ原子を有し、さらにここで、該環Ｄは、非置換であるか、又は、独立して選択される１～５個のＲ１１部分で置換されていてもよく、
    Ｒ１１部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ２―Ｃ１５アルケニル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、Ｃ２―Ｃ１５アルキニル基、Ｃ１－Ｃ２０アルコキシ基、Ｃ１－Ｃ２０アルキルアミノ基、Ｃ１－Ｃ２０アルキルチオカルボキシ基、Ｃ１－Ｃ２０アルキル－５～１４員環ヘテロアリール基、Ｃ１－Ｃ２０アルキルチオ基、Ｃ１－Ｃ２０アルキルスルフィニル基、Ｃ１－Ｃ２０アルキルスルホニル基、Ｃ１－Ｃ２０アルコキシカルボニル基、Ｃ１－Ｃ２０アミノアルキル基、アミジニル基、アラルキル基、アラルケニル基、アラルコキシ基、アラルコキシカルボニル基、アラルキルチオ基、６～１４員環アリール基、アロイル基、６～１４員環アリールオキシ基、シアノ基、Ｃ３－Ｃ１０シクロアルキル基、Ｃ３－Ｃ１０シクロアルケニル基、ホルミル基、グアニジニル基、ハロゲン原子、Ｃ１－Ｃ２０ハロゲノアルキル基、Ｃ１－Ｃ２０ハロゲノアルコキシ基、ヘテロアルキル基、ヘテロアリール基、ヘテロシクリル基、ヘテロシクレニル基、Ｃ１－Ｃ２０ヒドロキシアルキル基、Ｃ１－Ｃ６ヒドロキサメート基、ニトロ基、トリフルオロメチル基、トリフルオロメトキシ基、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯＲ１０、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨＲ１０、－（ＣＨ２）ｑＮ（Ｒ１０）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨＲ１０、－（ＣＨ２）ｑＳＯ２Ｒ１０、－（ＣＨ２）ｑＮＨＳＯ２Ｒ１０、－（ＣＨ２）ｑＳＯ２ＮＨＲ１０、－アルキニルＣ（Ｒ１０）２ＯＲ１０、－Ｃ（＝Ｏ）Ｒ９、－Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＲ９）ＮＨＲ９、－Ｃ（＝ＮＯＨ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＯＲ１０）Ｎ（Ｒ９）２、－Ｃ（＝Ｏ）ＯＲ９、－Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｒ１０、－ＮＨＣ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）ＯＲ１０、－Ｎ（Ｒ９）Ｃ（＝ＮＣＮ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｓ（Ｏ）２Ｎ（Ｒ９）２、－ＯＲ９、－ＯＣ（＝Ｏ）Ｎ（Ｒ９）２、－ＳＲ９、－ＳＯ２Ｎ（Ｒ９）２、－ＳＯ２（Ｒ１０）、－ＯＳＯ２（Ｒ１０）、および－ＯＳｉ（Ｒ９）３からなる群より独立して選択されるか；あるいは２つのＲ１１部分が、一緒に連結して、５員または６員の、アリール環、シクロアルキル環、ヘテロシクリル環、ヘテロシクレニル環、またはヘテロアリール環を形成し、ここで、これらの５員または６員の、アリール環、シクロアルキル環、ヘテロシクリル環、ヘテロシクレニル環、またはヘテロアリール環は、環Ｄに縮合し、そしてこの縮合環は、１～４個のＲ１２部分で置換されていてもよく、
    Ｒ１２部分は、同じであっても異なっていてもよく、各々が、水素原子、Ｃ１－Ｃ２０アルキル基、Ｃ２－Ｃ１５アルケニル基、Ｃ１－Ｃ２０アルキル－６～１４員環アリール基、Ｃ２－Ｃ１５アルキニル基、Ｃ１－Ｃ２０アルコキシ基、Ｃ１－Ｃ２０アルキルアミノ基、Ｃ１－Ｃ２０アルキルチオカルボキシ基、Ｃ１－Ｃ２０アルキル－５～１４員環ヘテロアリール基、Ｃ１－Ｃ２０アルキルチオ基、Ｃ１－Ｃ２０アルキルスルフィニル基、Ｃ１－Ｃ２０アルキルスルホニル基、Ｃ１－Ｃ２０アルコキシカルボニル基、Ｃ１－Ｃ２０アミノアルキル基、アミジニル基、アラルキル基、アラルケニル基、アラルコキシ基、アラルコキシカルボニル基、アラルキルチオ基、６～１４員環アリール基、アロイル基、６～１４員環アリールオキシ基、カルボキサミド基、シアノ基、Ｃ３－Ｃ１０シクロアルキル基、Ｃ３－Ｃ１０シクロアルケニル基、ホルミル基、グアニジニル基、ハロゲン原子、Ｃ１－Ｃ２０ハロゲノアルキル基、ヘテロアルキル基、５～１４員環ヘテロアリール基、Ｃ３－Ｃ１０ヘテロシクリル基、Ｃ３－Ｃ１０ヘテロシクレニル基、Ｃ１－Ｃ２０ヒドロキシアルキル基、ヒドロキサメート基、ニトロ基、トリフルオロメトキシ基、－（ＣＨ２）ｑＯＨ、－（ＣＨ２）ｑＯＲ１０、－（ＣＨ２）ｑＮＨ２、－（ＣＨ２）ｑＮＨＲ１０、－（ＣＨ２）ｑＮ（Ｒ１０）２、－（ＣＨ２）ｑＣ（＝Ｏ）ＮＨＲ１０、－（ＣＨ２）ｑＳＯ２Ｒ１０、－（ＣＨ２）ｑＮＳＯ２Ｒ１０、－（ＣＨ２）ｑＳＯ２ＮＨＲ１０、－アルキニルＣ（Ｒ１０）２ＯＲ１０、－Ｃ（＝Ｏ）Ｒ９、－Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＲ９）ＮＨＲ９、－Ｃ（＝ＮＯＨ）Ｎ（Ｒ９）２、－Ｃ（＝ＮＯＲ１０）Ｎ（Ｒ９）２、－Ｃ（＝Ｏ）ＯＲ９、－Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｒ１０、－ＮＨＣ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）ＯＲ１０、－Ｎ（Ｒ９）Ｃ（＝ＮＣＮ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｃ（＝Ｏ）Ｎ（Ｒ９）２、－Ｎ（Ｒ９）ＳＯ２（Ｒ１０）、－Ｎ（Ｒ９）Ｓ（Ｏ）２Ｎ（Ｒ９）２、－ＯＲ９、－ＯＣ（＝Ｏ）Ｎ（Ｒ９）２、－ＳＲ９、－ＳＯ２Ｎ（Ｒ９）２、－ＳＯ２（Ｒ１０）、－ＯＳＯ２（Ｒ１０）、および－ＯＳｉ（Ｒ９）３からなる群より独立して選択され、
    各ｑは、同じであっても異なっていてもよく、各々が独立して、１～５から選択され、
    　ｒは、１～４であり、
    ただし、いずれの環においても、２つの隣接する二重結合が存在せず、そして窒素が２つのアルキル基により置換される場合、これらの２つのアルキル基は、必要に応じて、互いに連結して、環を形成し得る。］     A compound having the general formula (I) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
    [Wherein, X 1 , X 2 , X 3 , and X 4 each independently represents —C═ or —N═;
    X 5 is, -CH 2 -, - CH 2 CH 2 -, - O -, - CH 2 O -, - OCH 2 -, - CH 2 S -, - SCH 2 -, - CH 2 SO -, - SOCH 2 —, —, —CH 2 SO 2 —, —SO 2 CH 2 —, —C (—R 3 ) (— R 4 ) —, or —C (—R 3 ) (— R 4 ) —C (— R 3 ) (— R 4 ) —
    X 6 represents —CH (—R 5 ) — or —C (═O) —,
    X 7 represents —CH (—R 6 ) — or —C (═O) —,
    R 1 is a hydrogen atom, hydroxyl group, halogen atom, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 halogenoalkyl group, or C1 Represents a -C6 halogenoalkoxy group,
    R 2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a carboxy group that may be protected with a protecting group for a carboxy group,
    R 3 , R 4 , R 5 and R 6 each independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group;
    A is a carbamoyl group, C1-C6 alkylcarbamoyl group, C1-C6 hydroxyalkylcarbamoyl group, C3-C6 cycloalkylcarbamoyl group, C3-C6 cycloalkyl-C1-C6 alkylcarbamoyl group, C1-C6 alkylsulfonyl group, C1 -C6 alkylsulfonamido group, C3-C6 cycloalkyl-C1-C6 alkylsulfonyl group, C1-C6 acylamino group, or a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is unsubstituted Or optionally substituted with 1 to 5 independently selected R 7 moieties,
    Here, the R 7 moieties may be the same or different, and each is a hydroxyl group, amino group, carboxy group, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group. Independently selected from the group consisting of a group, a C3-C6 cycloalkoxy group, a C1-C6 halogenoalkyl group, and a C1-C6 halogenoalkoxy group;
    Y is a single bond, —CH 2 —, — (CR 8 R 8 ) r —, —CHR 8 C (═O) —, — (CHR 8 ) r O—, — (CHR 8 ) r N (R 9 )-, -C (= O)-, -C (= S)-, -C (= NR 9 )-, -C (= N-OR 9 )-, -CH (C (= O) NHR 9 ) -, -CH (-5 to 14-membered heteroaryl)-, -C (R 8 R 8 ) r C (R 8 ) = C (R 8 )-,-(CHR 8 ) r C (= O)- And a group selected from the group consisting of — (CHR 8 ) r NHC (═O) —, or a C3-C10 cycloalkyl group, a 3- to 10-membered heterocyclenyl group, or a 3- to 10-membered heterocyclyl group And this C3-C10 cycloalkyl group, 3- to 10-membered heterocyclenyl group, or 3- to 10-membered heterocyclyl group is Combined,
    The R 8 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a C3-C10 cycloalkyl group, a C1- C20 alkoxy group, 6-14 membered aryl group, 5-14 membered heteroaryl group, 3-10 membered heterocyclenyl group, 3-10 membered heterocyclyl group, C3-C11 spiroalkyl group, —CN, —COOH, -C (= O) R 9 , -C (= O) N (R 9 ) 2 ,-(CHR 9 ) q OH,-(CHR 9 ) q OR 10 ,-(CHR 9 ) q NH 2 ,-( CHR 9 ) q NHR 10 , — (CH 2 ) q C (═O) NHR 10 , — (CH 2 ) q SO 2 R 10 , — (CH 2 ) q NSO 2 R 10 , — (CH 2 ) q SO 2 NHR 10 , —N H 2 , —N (R 9 ) 2 , —N (R 9 ) C (═O) N (R 9 ) 2 , —N (R 9 ) SO 2 (R 10 ), —OH, OR 9 , —SO Independently selected from the group consisting of 2 N (R 9 ) 2 and —SO 2 (R 10 );
    The R 9 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a 6-14 membered aryl group, an aralkyl group. Group, C3-C10 cycloalkyl group, —CN, — (CH 2 ) q OH, — (CH 2 ) q O—C1-C20 alkyl, — (CH 2 ) q O-6 to 14-membered aryl-C1- C20 alkyl, — (CH 2 ) q O-6 to 14-membered aryl, — (CH 2 ) q O aralkyl, — (CH 2 ) q O—C 3 -C 10 cycloalkyl, — (CH 2 ) q NH 2 , -(CH 2 ) q NH-C1-C20 alkyl,-(CH 2 ) q N (C1-C20 alkyl) 2 ,-(CH 2 ) q NH-6-14-membered aryl-C1-C20 alkyl,-( CH 2 ) q N H-6-14 membered aryl, — (CH 2 ) q NH aralkyl, — (CH 2 ) q NH—C 3 -C 10 cycloalkyl, — (CH 2 ) q C (═O) NH alkyl, — (CH 2 ) Q C (═O) N (C1-C20 alkyl) 2 , — (CH 2 ) q C (═O) NH-6-14 membered aryl-C1-C20 alkyl, — (CH 2 ) q C (= O) NH-6-14 membered aryl, — (CH 2 ) q C (═O) NH aralkyl, — (CH 2 ) q C (═O) NH—C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 -C1-C20 alkyl,-(CH 2 ) q SO 2 -6 to 14-membered ring aryl-C1-C20 alkyl,-(CH 2 ) q SO 2 -6 to 14-membered ring aryl,-(CH 2 ) q SO 2 aralkyl, - (CH 2) q SO -C3-C10 cycloalkyl, - (CH 2) q NSO 2 -C1-C20 alkyl, - (CH 2) q NSO 2 -6 ~ 14 membered aryl-C1-C20 alkyl, - (CH 2) q NSO 2 —6 to 14-membered aryl, — (CH 2 ) q NSO 2 aralkyl, — (CH 2 ) q NSO 2 —C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 NH—C 1 -C 20 alkyl, — ( CH 2 ) q SO 2 NH-6-14 membered aryl-C1-C20 alkyl, — (CH 2 ) q SO 2 NH-6-14 membered aryl, — (CH 2 ) q SO 2 NH aralkyl, — ( CH 2) q SO 2 NH- C3-C10 cycloalkyl, 3-10 membered ring heterocyclenyl group, 3-10-membered heterocyclyl group, and either 5-14 membered heteroaryl It is independently selected from the group consisting,
    The R 10 moieties may be the same or different and each is a C1-C20 alkyl group, a C1-C20 alkyl-6-14 membered aryl group, a 6-14 membered aryl group, an aralkyl group, a C3 —C10 cycloalkyl group, — (CH 2 ) q OH, — (CH 2 ) q O—C1-C20 alkyl, — (CH 2 ) q O—C1-C20 alkyl—6- to 14-membered aryl, — (CH 2) q O-6 ~ 14 membered aryl, - (CH 2) q O aralkyl, - (CH 2) q O -C3-C10 cycloalkyl, - (CH 2) q NH2 , - (CH 2) q NH —C1-C20 alkyl, — (CH 2 ) q N (C1-C20 alkyl) 2 , — (CH 2 ) q NH-6 to 14-membered aryl-C1-C20 alkyl, — (CH 2 ) q NH-6 14-member ring Reel, - (CH 2) q NH aralkyl, - (CH 2) q NH -C3-C10 cycloalkyl, - (CH 2) q C (= O) NH-C1-C20 alkyl, - (CH 2) q C (═O) N (C1-C20 alkyl) 2 , — (CH 2 ) q C (═O) NH-6-14-membered aryl-C1-C20 alkyl, — (CH 2 ) q C (═O) NH —6 to 14-membered aryl, — (CH 2 ) q C (═O) NH aralkyl, — (CH 2 ) q C (═O) NH—C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 — C1-C20 alkyl, - (CH 2) q SO 2 -6 ~ 14 membered aryl-C1-C20 alkyl, - (CH 2) q SO 2 -6 ~ 14 membered aryl, - (CH 2) q SO 2 Aralkyl, — (CH 2 ) q SO 2 — C3-C10 cycloalkyl, — (CH 2 ) q NSO 2 —C1-C20 alkyl, — (CH 2 ) q NSO 2 -6 to 14-membered aryl-C1-C20 alkyl, — (CH 2 ) q NSO 2 — 6-14 membered aryl, — (CH 2 ) q NSO 2 aralkyl, — (CH 2 ) q NSO 2 —C 3 -C 10 cycloalkyl, — (CH 2 ) q SO 2 NH—C 1 -C 20 alkyl, — (CH 2 ) q SO 2 NH-6-14 membered aryl-C1-C20 alkyl, — (CH 2 ) q SO 2 NH-6-14 membered aryl, — (CH 2 ) q SO 2 NH aralkyl, — (CH 2 ) from qSO 2 NH—C3-C10 cycloalkyl, 3-10 membered heterocyclenyl group, 3-10 membered heterocyclyl group, and 5-14 membered heteroaryl group Selected independently from the group
    Ring D is a 5- to 9-membered cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, heterocyclenyl ring, or heterocyclyl ring, wherein the aryl ring excludes phenyl and A teloaryl ring, heterocyclenyl ring, and heterocyclyl ring have 0 to 4 heteroatoms independently selected as ring atoms from O, S, or N, further wherein the ring D is non- May be substituted or optionally substituted with 1 to 5 independently selected R 11 moieties;
    The R 11 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C2-C15 alkenyl group, a C1-C20 alkyl-6-14 membered aryl group, a C2-C15 Alkynyl group, C1-C20 alkoxy group, C1-C20 alkylamino group, C1-C20 alkylthiocarboxy group, C1-C20 alkyl-5-14 membered heteroaryl group, C1-C20 alkylthio group, C1-C20 alkylsulfinyl group, C1-C20 alkylsulfonyl group, C1-C20 alkoxycarbonyl group, C1-C20 aminoalkyl group, amidinyl group, aralkyl group, aralkenyl group, aralkoxy group, aralkoxycarbonyl group, aralkylthio group, 6-14 membered aryl group , Aroyl group, 6-14 membered aryloxy group Cyano group, C3-C10 cycloalkyl group, C3-C10 cycloalkenyl group, formyl group, guanidinyl group, halogen atom, C1-C20 halogenoalkyl group, C1-C20 halogenoalkoxy group, heteroalkyl group, heteroaryl group, heterocyclyl Group, heterocyclenyl group, C1-C20 hydroxyalkyl group, C1-C6 hydroxamate group, nitro group, trifluoromethyl group, trifluoromethoxy group, — (CH 2 ) q OH, — (CH 2 ) q OR 10 , — (CH 2 ) q NH 2 , — (CH 2 ) q NHR 10 , — (CH 2 ) q N (R 10 ) 2 , — (CH 2 ) q C (═O) NHR 10 , — (CH 2 ) q SO 2 R 10, - ( CH 2) q NHSO 2 R 10, - (CH 2) q SO 2 NHR 10, Alkynyl C (R 10) 2OR 10, -C (= O) R 9, -C (= O) N (R 9) 2, -C (= NR 9) NHR 9, -C (= NOH) N (R 9 ) 2 , —C (═NOR 10 ) N (R 9 ) 2 , —C (═O) OR 9 , —N (R 9 ) 2 , —N (R 9 ) C (═O) R 10 , — NHC (═O) N (R 9 ) 2 , —N (R 9 ) C (═O) OR 10 , —N (R 9 ) C (═NCN) N (R 9 ) 2 , —N (R 9 ) C (═O) N (R 9 ) SO 2 (R 10 ), —N (R 9 ) C (═O) N (R 9 ) 2 , —N (R 9 ) SO 2 (R 10 ), —N (R 9 ) S (O) 2 N (R 9 ) 2 , —OR 9 , —OC (═O) N (R 9 ) 2 , —SR 9 , —SO 2 N (R 9 ) 2 , —SO 2 (R 10 ), —OSO 2 (R 10 ), And —OSi (R 9 ) 3 independently selected; or two R 11 moieties linked together to form a 5- or 6-membered aryl, cycloalkyl, heterocyclyl ring , A heterocyclenyl ring, or a heteroaryl ring, wherein these 5- or 6-membered aryl, cycloalkyl, heterocyclyl, heterocyclenyl, or heteroaryl rings are fused to ring D; and This fused ring may be substituted with 1 to 4 R 12 moieties,
    The R 12 moieties may be the same or different and each is a hydrogen atom, a C1-C20 alkyl group, a C2-C15 alkenyl group, a C1-C20 alkyl-6-14 membered aryl group, a C2-C15 Alkynyl group, C1-C20 alkoxy group, C1-C20 alkylamino group, C1-C20 alkylthiocarboxy group, C1-C20 alkyl-5-14 membered heteroaryl group, C1-C20 alkylthio group, C1-C20 alkylsulfinyl group, C1-C20 alkylsulfonyl group, C1-C20 alkoxycarbonyl group, C1-C20 aminoalkyl group, amidinyl group, aralkyl group, aralkenyl group, aralkoxy group, aralkoxycarbonyl group, aralkylthio group, 6-14 membered aryl group , Aroyl group, 6-14 membered aryloxy group Carboxamide group, cyano group, C3-C10 cycloalkyl group, C3-C10 cycloalkenyl group, formyl group, guanidinyl group, halogen atom, C1-C20 halogenoalkyl group, heteroalkyl group, 5- to 14-membered ring heteroaryl group, C3-C10 heterocyclyl group, C3-C10 heterocyclenyl group, C1-C20 hydroxyalkyl group, hydroxamate group, nitro group, trifluoromethoxy group, — (CH 2 ) q OH, — (CH 2 ) q OR 10 , — (CH 2 ) q NH 2 , — (CH 2 ) q NHR 10 , — (CH 2 ) q N (R 10 ) 2 , — (CH 2 ) q C (═O) NHR 10 , — (CH 2 ) q SO 2 R 10, - (CH 2) q NSO 2 R 10, - (CH 2) q SO 2 NHR 10, - alkynyl C R 10) 2 OR 10, -C (= O) R 9, -C (= O) N (R 9) 2, -C (= NR 9) NHR 9, -C (= NOH) N (R 9) 2 , —C (═NOR 10 ) N (R 9 ) 2 , —C (═O) OR 9 , —N (R 9 ) 2 , —N (R 9 ) C (═O) R 10 , —NHC ( = O) N (R 9 ) 2 , -N (R 9 ) C (= O) OR 10 , -N (R 9 ) C (= NCN) N (R 9 ) 2 , -N (R 9 ) C ( ═O) N (R 9 ) SO 2 (R 10 ), —N (R 9 ) C (═O) N (R 9 ) 2 , —N (R 9 ) SO 2 (R 10 ), —N (R 9 ) S (O) 2 N (R 9 ) 2 , —OR 9 , —OC (═O) N (R 9 ) 2 , —SR 9 , —SO 2 N (R 9 ) 2 , —SO 2 (R 10), - OSO 2 (R 10), and -OS (R 9) 3 are independently selected from the group consisting of,
    Each q may be the same or different and each is independently selected from 1 to 5;
    r is 1 to 4,
    However, if there are no two adjacent double bonds in any ring and the nitrogen is substituted by two alkyl groups, then these two alkyl groups are optionally linked together. Can form a ring. ]
  2. 一般式（ＩＩ）を有する化合物又はその薬理上許容される塩。
    Figure JPOXMLDOC01-appb-C000002
    ［式中、Ｘ１、Ｘ２、Ｘ３、Ｘ４、Ｘ８、及びＸ９は、それぞれ独立に、－Ｃ＝、又は、－Ｎ＝を表わし、
    Ｘ５は、－ＣＨ２－、－ＣＨ２ＣＨ２－、－Ｏ－、－ＣＨ２Ｏ－、－ＯＣＨ２－、－ＣＨ２Ｓ－、－ＳＣＨ２－、－ＣＨ２ＳＯ－、－ＳＯＣＨ２－、－、－ＣＨ２ＳＯ２－、－ＳＯ２ＣＨ２－、－Ｃ（－Ｒ３）（－Ｒ４）－、又は－Ｃ（－Ｒ３）（－Ｒ４）－Ｃ（－Ｒ３）（－Ｒ４）－、を表わし、
    Ｘ６は、－ＣＨ（－Ｒ５）－、又は－Ｃ（＝Ｏ）－を表わし、
    Ｘ７は、－ＣＨ（－Ｒ６）－、又は－Ｃ（＝Ｏ）－を表わし、
    Ｒ１、Ｒ１３、及びＲ１４は、それぞれ独立に、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、Ｃ１－Ｃ６ハロゲノアルコキシ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基を表わし、
    Ｒ２は、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基を表わし、
    Ｒ３、Ｒ４、Ｒ５及びＲ６は、それぞれ独立に、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、又はＣ１－Ｃ６ハロゲノアルキル基を表わし、
    Ｒ１５は、水素原子、ハロゲン原子、アミノ基、シアノ基、カルバモイル基、Ｃ１－Ｃ６アルキルカルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、Ｃ１－Ｃ６アルコキシカルボニル基、Ｃ１－Ｃ６ヒドロキシアルコキシカルボニル基、又は、置換基群αから選択される基で置換されていてもよい５員環へテロアリール基を表わし、
    Ｙは、単結合、－ＣＨ２－、－Ｃ（＝Ｏ）－、－Ｃ（＝Ｓ）－、－Ｃ（－Ｃ１－Ｃ６アルキル）－、又は－C（－５員環へテロアリール）－を表わし、ここで、５員環へテロアリール基は、置換基群αから選択される基で置換されていてもよく、
    Ａは、カルバモイル基、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６ヒドロキシアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アルキルスルホンアミド基、Ｃ３－Ｃ６シクロアルキル－Ｃ１－Ｃ６アルキルスルホニル基、Ｃ１－Ｃ６アシルアミノ基、又は、置換基群αから選択される基で置換されていてもよい５員環へテロアリール基を表わす。
    置換基群α：水酸基、アミノ基、カルボキシ基、ハロゲン基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６アルキルアミノ基、Ｃ３－Ｃ６シクロアルキルアミノ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基］     A compound having the general formula (II) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000002
    [Wherein, X 1 , X 2 , X 3 , X 4 , X 8 , and X 9 each independently represent —C═ or —N═,
    X 5 is, -CH 2 -, - CH 2 CH 2 -, - O -, - CH 2 O -, - OCH 2 -, - CH 2 S -, - SCH 2 -, - CH 2 SO -, - SOCH 2 —, —, —CH 2 SO 2 —, —SO 2 CH 2 —, —C (—R 3 ) (— R 4 ) —, or —C (—R 3 ) (— R 4 ) —C (— R 3 ) (— R 4 ) —
    X 6 represents —CH (—R 5 ) — or —C (═O) —,
    X 7 represents —CH (—R 6 ) — or —C (═O) —,
    R 1 , R 13 , and R 14 are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy Group, a C1-C6 halogenoalkyl group, a C1-C6 halogenoalkoxy group, or a carboxy group optionally protected by a protecting group for a carboxy group,
    R 2 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group,
    R 3 , R 4 , R 5 and R 6 each independently represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a C1-C6 halogenoalkyl group;
    R 15 represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a carbamoyl group, a C1-C6 alkylcarbamoyl group, a carboxy group optionally protected by a protecting group for carboxy group, a C1-C6 alkoxycarbonyl group, C1- A C6 hydroxyalkoxycarbonyl group or a 5-membered heteroaryl group optionally substituted with a group selected from the substituent group α,
    Y is a single bond, —CH 2 —, —C (═O) —, —C (═S) —, —C (—C1-C6 alkyl) —, or —C (-5-membered heteroaryl)- Wherein the 5-membered heteroaryl group may be substituted with a group selected from the substituent group α,
    A is a carbamoyl group, C1-C6 alkylcarbamoyl group, C1-C6 hydroxyalkylcarbamoyl group, C3-C6 cycloalkylcarbamoyl group, C3-C6 cycloalkyl-C1-C6 alkylcarbamoyl group, C1-C6 alkylsulfonyl group, C1 -C6 alkylsulfonamido group, C3-C6 cycloalkyl-C1-C6 alkylsulfonyl group, C1-C6 acylamino group, or 5-membered heteroaryl group optionally substituted with a group selected from substituent group α Represents.
    Substituent group α: hydroxyl group, amino group, carboxy group, halogen group, C1-C6 alkyl group, C1-C6 alkoxy group, C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, C1-C6 alkylamino group, C3 —C6 cycloalkylamino group, C1-C6 halogenoalkyl group, or C1-C6 halogenoalkoxy group]
  3. Ｙが、－ＣＨ２－又はカルボニル基である、請求項１乃至２に記載の化合物、又は、その薬理上許容される塩。 The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein Y is —CH 2 — or a carbonyl group.
  4. Ａが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基である、請求項１乃至請求項３に記載の化合物、又は、その薬理上許容される塩。 The compound according to claim 1, wherein A is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group, or a pharmacologically acceptable salt thereof. Salt.
  5. Ｘ５が、－ＣＨ２－、－ＣＨ２ＣＨ２－又は－Ｏ－である、請求項１乃至請求項４に記載の化合物、又は、その薬理上許容される塩。 Salt or -O-, and A compound according to claims 1 to 4, or, which is pharmacologically acceptable - X 5 are, -CH 2 -, - CH 2 CH 2.
  6. Ｘ２が、－Ｎ＝であり、Ｘ１、Ｘ３、及びＸ４が－Ｃ＝である、請求項１乃至請求項５に記載の化合物、又は、その薬理上許容される塩。 The compound according to claim 1 , wherein X 2 is —N═, and X 1 , X 3 , and X 4 are —C═, or a pharmaceutically acceptable salt thereof.
  7. Ｘ２及びＸ３が－Ｎ＝であり、Ｘ１及びＸ４が－Ｃ＝である、請求項１乃至請求項５に記載の化合物、又は、その薬理上許容される塩。 6. The compound according to claim 1 or 5, or a pharmacologically acceptable salt thereof, wherein X 2 and X 3 are —N═ and X 1 and X 4 are —C═.
  8. Ｘ６及びＸ７がともに、－ＣＨ２－である、請求項１乃至請求項７に記載の化合物、又は、その薬理上許容される塩。 The compound according to claim 1 or 7, or a pharmacologically acceptable salt thereof, wherein X 6 and X 7 are both —CH 2 —.
  9. Ｒ１が、水素原子、水酸基、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ３－Ｃ６シクロアルキル基、又はＣ１－Ｃ６アルコキシ基である、請求項１乃至請求項８に記載の化合物、又は、その薬理上許容される塩。 9. The compound according to claim 1 , wherein R 1 is a hydrogen atom, a hydroxyl group, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group, or a pharmacological thereof Top acceptable salt.
  10. Ｘ８及びＸ９がともに－Ｃ＝である、請求項２乃至請求項９に記載の化合物、又は、その薬理上許容される塩。 10. The compound according to claim 2 or 9, or a pharmacologically acceptable salt thereof, wherein X 8 and X 9 are both —C═.
  11. Ｒ１３及びＲ１４が、それぞれ独立に、水素原子又はハロゲン原子である、請求項２乃至請求項１０に記載の化合物、又は、その薬理上許容される塩。 The compound according to claim 2 or 10, or a pharmacologically acceptable salt thereof, wherein R 13 and R 14 are each independently a hydrogen atom or a halogen atom.
  12. Ｒ１５が、カルバモイル基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基である、請求項２乃至請求項１１に記載の化合物、又は、その薬理上許容される塩。 The compound according to claim 2 to 11, or a pharmacologically acceptable salt thereof, wherein R 15 is a carbamoyl group or a carboxy group optionally protected by a protecting group for a carboxy group.
  13. 一般式（ＩＩ）において、
    Ｘ２が－Ｎ＝であり、Ｘ３が－Ｃ＝又は－Ｎ＝であって、Ｘ１及びＸ４がともに－Ｃ＝であり、
    Ｘ５が、－ＣＨ２ＣＨ２－、－ＣＨ２－、又は、－Ｏ－であり、
    Ｘ６及びＸ７が、ともに－ＣＨ２－、又は、ともに－Ｃ（＝Ｏ）－であり、
    Ｘ８及びＸ９が、共に－ＣＨ＝であるか、又は、Ｘ８が－Ｃ＝であってＸ９が－Ｎ＝の組み合わせであり、
    Ｒ１が、水素原子、水酸基、ハロゲン原子、シアノ基、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、Ｃ３－Ｃ６シクロアルキル基、Ｃ３－Ｃ６シクロアルコキシ基、Ｃ１－Ｃ６ハロゲノアルキル基、又は、Ｃ１－Ｃ６ハロゲノアルコキシ基であり、
    Ｒ２が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、Ｃ１－Ｃ６アルコキシ基、及びカルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
    Ｒ１３及びＲ１４が、それぞれ独立に、水素原子、ハロゲン原子、シアノ基、又は、カルボキシ基の保護基で保護されていてもよいカルボキシ基であり、
    Ｒ１５が、水素原子、ハロゲン原子、アミノ基、カルバモイル基、カルボキシ基の保護基で保護されていてもよいカルボキシ基、又は、Ｃ１－Ｃ６アルコキシカルボニル基であり、
    Ａが、Ｃ１－Ｃ６アルキルカルバモイル基、Ｃ３－Ｃ６シクロアルキルカルバモイル基、又は、Ｃ１－Ｃ６アルキルアミノオキサジアゾリル基であり、
    Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、請求項２に記載の化合物、又は、その薬理上許容される塩。     In general formula (II):
    X 2 is -N =, X 3 is -C = or -N =, and both X 1 and X 4 are -C =,
    X 5 is —CH 2 CH 2 —, —CH 2 —, or —O—,
    X 6 and X 7 are both —CH 2 — or both —C (═O) —;
    X 8 and X 9 are both -CH =, or X 8 is -C = and X 9 is -N =
    R 1 is a hydrogen atom, a hydroxyl group, a halogen atom, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a C1-C6 halogenoalkyl group, or A C1-C6 halogenoalkoxy group,
    R 2 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a carboxy group that may be protected with a protecting group for a carboxy group,
    R 13 and R 14 are each independently a hydrogen atom, a halogen atom, a cyano group, or a carboxy group which may be protected with a protecting group for a carboxy group,
    R 15 is a hydrogen atom, a halogen atom, an amino group, a carbamoyl group, a carboxy group optionally protected by a protecting group for a carboxy group, or a C1-C6 alkoxycarbonyl group,
    A is a C1-C6 alkylcarbamoyl group, a C3-C6 cycloalkylcarbamoyl group, or a C1-C6 alkylaminooxadiazolyl group,
    The compound according to claim 2, or a pharmacologically acceptable salt thereof, wherein Y is —CH 2 — or —C (═O) —.
  14. 一般式（ＩＩ）において、
    Ｘ２が－Ｎ＝であって、Ｘ１、Ｘ３及びＸ４が－Ｃ＝であり、
    Ｘ５が、－ＣＨ２ＣＨ２－であり、
    Ｘ６が、ともに－ＣＨ２－であり、
    Ｘ８及びＸ９が、ともに－ＣＨ＝であり、
    Ｒ１が、水素原子、ハロゲン原子、又は、Ｃ１－Ｃ６アルキル基であり、
    Ｒ２が、水素原子、Ｃ１－Ｃ６アルキル基、ハロゲン原子、カルボキシ基、又は、カルボニル基であり、
    Ｒ１３及びＲ１４が、水素原子、又は、塩素原子であり、
    Ｒ１５は、フッ素原子、アミノ基、カルバモイル基、カルボキシ基、又は、エトキシカルボニル基であり、
    Ａが、エチルカルバモイル基、プロピルカルバモイル基、ｔｅｒｔ－ブチルカルバモイル基、シクロプロピルカルバモイル基、又は、エチルアミノオキサジアゾリル基であり、
    Ｙが、－ＣＨ２－、又は、－Ｃ（＝Ｏ）－である、請求項２又は請求項１３のいずれか一項に記載の化合物、又は、その薬理上許容される塩。     In general formula (II):
    X 2 is -N = and X 1 , X 3 and X 4 are -C =,
    X 5 is —CH 2 CH 2 —;
    X 6 are both —CH 2 —,
    X 8 and X 9 are both —CH═,
    R 1 is a hydrogen atom, a halogen atom, or a C1-C6 alkyl group,
    R 2 is a hydrogen atom, a C1-C6 alkyl group, a halogen atom, a carboxy group, or a carbonyl group,
    R 13 and R 14 are a hydrogen atom or a chlorine atom,
    R 15 is a fluorine atom, an amino group, a carbamoyl group, a carboxy group, or an ethoxycarbonyl group,
    A is an ethylcarbamoyl group, a propylcarbamoyl group, a tert-butylcarbamoyl group, a cyclopropylcarbamoyl group, or an ethylaminooxadiazolyl group,
    14. The compound according to any one of claims 2 and 13, or a pharmacologically acceptable salt thereof, wherein Y is —CH 2 — or —C (═O) —.
  15. 一般式（Ｉ）又は一般式（ＩＩ）を有する化合物が以下の化合物群から選択される化合物である、請求項１乃至請求項２に記載の化合物又はその薬理上許容される塩。
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ６－［ｃｉｓ－４－［１－（２－カルバモイル－４－クロロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－５－クロロ－Ｎ－エチルニコチンアミド、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［cis－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－エチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸メチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－［ｃｉｓ－４－［１－（２－カルバモイル－４－クロロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド、
    ５－［ｃｉｓ－４－［１－（４－クロロ－２－フルオロベンジル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド、
    ５－［ｃｉｓ－４－｛１－［（２－アミノ－６－クロロピリジン－３－イル）カルボニル］ピペリジン－４－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］－Ｎ－シクロプロピル－６－メチルピラジン－２－カルボキサミド、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（エチルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－［３－エチル－５－（エチルカルバモイル）ピリジン－２－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸エチル、
    ５－クロロ－２－（｛４－［ｃｉｓ－４－｛３－クロロ－５－［５－（エチルアミノ）－１，３，４－オキサジアゾール－２－イル］ピリジン－２－イル｝オクタヒドロキノキサリン－１（２Ｈ）－イル］ピペリジン－１－イル｝メチル）安息香酸、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［５－（シクロプロピルカルバモイル）－３－メチルピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、
    ５－｛６－クロロ－５－［ｃｉｓ－４－［１－（４－クロロベンゾイル）ピペリジン－４－イル］オクタヒドロキノキサリン－１（２Ｈ）－イル］ピラジン－２－イル｝－Ｎ－エチル－１，３，４－オキサジアゾール－２－アミン、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（エチルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸、及び、
    ５－クロロ－２－［（４－｛ｃｉｓ－４－［３－クロロ－５－（シクロプロピルカルバモイル）ピラジン－２－イル］オクタヒドロ－１Ｈ－シクロペンタ［ｂ］ピラジン－１－イル｝ピペリジン－１－イル）メチル］安息香酸     The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein the compound having the general formula (I) or the general formula (II) is a compound selected from the following compound group.
    5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
    6- [cis-4- [1- (2-carbamoyl-4-chlorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -5-chloro-N-ethylnicotinamide,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
    5-chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) ethyl benzoate,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
    5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
    5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) ethyl benzoate,
    5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
    5-Chloro-2-({4- [cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
    5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-ethylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
    5-chloro-2-({4- [cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) methyl benzoate,
    5-chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
    5-chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
    5- [cis-4- [1- (2-carbamoyl-4-chlorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl-6-methylpyrazine-2- Carboxamide,
    5- [cis-4- [1- (4-Chloro-2-fluorobenzyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl-6-methylpyrazine-2- Carboxamide,
    5- [cis-4- {1-[(2-amino-6-chloropyridin-3-yl) carbonyl] piperidin-4-yl} octahydroquinoxalin-1 (2H) -yl] -N-cyclopropyl- 6-methylpyrazine-2-carboxamide,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) ethyl benzoate,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} Methyl) benzoic acid,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl ) Ethyl benzoate,
    5-chloro-2-({4- [cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
    5-chloro-2-[(4- {cis-4- [5- (ethylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid,
    5-chloro-2-[(4- {cis-4- [3-ethyl-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid,
    5-Chloro-2-({4- [cis-4- [3-ethyl-5- (ethylcarbamoyl) pyridin-2-yl] octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl )benzoic acid,
    5-chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1 -Yl) methyl] ethyl benzoate,
    5-chloro-2-({4- [cis-4- {3-chloro-5- [5- (ethylamino) -1,3,4-oxadiazol-2-yl] pyridin-2-yl} Octahydroquinoxalin-1 (2H) -yl] piperidin-1-yl} methyl) benzoic acid,
    5-chloro-2-[(4- {cis-4- [5- (cyclopropylcarbamoyl) -3-methylpyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1 -Yl) methyl] benzoic acid,
    5- {6-Chloro-5- [cis-4- [1- (4-chlorobenzoyl) piperidin-4-yl] octahydroquinoxalin-1 (2H) -yl] pyrazin-2-yl} -N-ethyl -1,3,4-oxadiazol-2-amine,
    5-chloro-2-[(4- {cis-4- [3-chloro-5- (ethylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1- Yl) methyl] benzoic acid, and
    5-chloro-2-[(4- {cis-4- [3-chloro-5- (cyclopropylcarbamoyl) pyrazin-2-yl] octahydro-1H-cyclopenta [b] pyrazin-1-yl} piperidine-1 -Il) methyl] benzoic acid
  16. 一般式（Ｉ）又は一般式（ＩＩ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising a compound having the general formula (I) or the general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient.
  17. 自己免疫疾患を予防又は治療するために用いるための、請求項１６に記載された医薬組成物。 The pharmaceutical composition according to claim 16, for use for preventing or treating an autoimmune disease.
  18. 自己免疫疾患が、全身性エリトマトーデス、慢性関節リウマチ、多発性筋炎、結合組織炎、骨格筋炎、骨関節炎、変形性関節症、皮膚筋炎、強皮症、ベーチェット病、Chron病、潰瘍性大腸炎、自己免疫性肝炎、再生不良性貧血、特発性血小板減少性紫斑病、自己免疫性溶血性貧血、多発性硬化症、自己免疫性水疱症、尋常性乾癬、血管炎症群、Wegener肉芽腫、ぶどう膜炎、シェーグレン症候群、特発性間質性肺炎、Goodpasture症候群、サルコイドーシス、アレルギー性肉芽腫性血管炎、気管支喘息、心筋炎、心筋症、大動脈炎症候群、心筋梗塞後症候群、原発性肺高血圧症、微小変化型ネフローゼ、膜性腎症、膜性増殖性腎炎、巣状糸球体硬化症、半月体形成性腎炎、重症筋無力症、炎症性ニューロパチー、アトピー性皮膚炎、慢性光線性皮膚炎、日光過敏症、蓐瘡、Sydenham舞踏病、硬化症、成人発症糖尿病、インスリン依存性糖尿病、若年性糖尿病、アテローム性動脈硬化症、糸球体腎炎、IgA腎症、尿細管間質性腎炎、原発性胆汁性肝硬変、原発性硬化性胆管炎、劇症肝炎、ウイルス性肝炎、GVHD、接触皮膚炎、又は敗血症である、請求項１６乃至請求項１７に記載された医薬組成物。 Autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, polymyositis, connective tissue inflammation, skeletal myositis, osteoarthritis, osteoarthritis, dermatomyositis, scleroderma, Behcet's disease, Chron's disease, ulcerative colitis, Autoimmune hepatitis, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, multiple sclerosis, autoimmune blistering, psoriasis vulgaris, vascular inflammation group, Wegener granulomas, uvea Inflammation, Sjogren's syndrome, idiopathic interstitial pneumonia, Goodpasture syndrome, sarcoidosis, allergic granulomatous vasculitis, bronchial asthma, myocarditis, cardiomyopathy, aortitis syndrome, post-myocardial infarction syndrome, primary pulmonary hypertension, micro Variant nephrosis, membranous nephropathy, membranoproliferative nephritis, focal glomerulosclerosis, crescent nephritis, myasthenia gravis, inflammatory neuropathy, atopic dermatitis, chronic photodermatitis Photosensitivity, pressure ulcer, Sydenham chorea, sclerosis, adult-onset diabetes, insulin-dependent diabetes, juvenile diabetes, atherosclerosis, glomerulonephritis, IgA nephropathy, tubulointerstitial nephritis, primary The pharmaceutical composition according to any one of claims 16 to 17, which is biliary cirrhosis, primary sclerosing cholangitis, fulminant hepatitis, viral hepatitis, GVHD, contact dermatitis, or sepsis.
  19. 自己免疫疾患が、慢性関節リウマチ、潰瘍性大腸炎、自己免疫性肝炎、多発性硬化症、又は尋常性乾癬である、請求項１６乃至請求項１８に記載された医薬組成物。 The pharmaceutical composition according to any one of claims 16 to 18, wherein the autoimmune disease is rheumatoid arthritis, ulcerative colitis, autoimmune hepatitis, multiple sclerosis, or psoriasis vulgaris.
  20. 一般式（Ｉ）又は一般式（ＩＩ）を有する化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物の有効量を哺乳動物に投与することを特徴とする、自己免疫疾患の予防方法又は治療方法。 An autoimmune disease characterized by administering an effective amount of a pharmaceutical composition containing a compound having the general formula (I) or general formula (II) or a pharmacologically acceptable salt thereof as an active ingredient to a mammal. Prophylactic or therapeutic methods.
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JP2013537875A (en) * 2010-09-13 2013-10-07 大塚製薬株式会社 Heterocyclic compounds
WO2013137479A1 (en) * 2012-03-12 2013-09-19 Otsuka Pharmaceutical Co., Ltd. Decahydroquinoxaline derivatives and analogs thereof
WO2018052119A1 (en) 2016-09-16 2018-03-22 住友化学株式会社 Heterocyclic compound, and harmful-arthropod-controlling agent containing same
WO2018101424A1 (en) 2016-12-01 2018-06-07 住友化学株式会社 Heterocyclic compound, and arthropod pest control composition containing same
WO2018221720A1 (en) 2017-06-01 2018-12-06 住友化学株式会社 Heterocyclic compound and composition containing same
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
WO2019124548A1 (en) 2017-12-22 2019-06-27 住友化学株式会社 Heterocyclic compound and harmful arthropod controlling agent containing same
WO2019189731A1 (en) 2018-03-30 2019-10-03 住友化学株式会社 Heterocyclic compound and arthropod pest control composition containing same
CN109048854A (en) * 2018-09-30 2018-12-21 平顶山学院 Cargo based on alga cells robot controllably transmits method for releasing
CN109048854B (en) * 2018-09-30 2021-06-04 平顶山学院 Controllable cargo transmission and release method based on algae cell robot
CN111499514A (en) * 2019-01-31 2020-08-07 连云港润众制药有限公司 Preparation method of intermediate of roxasistat
WO2024062089A1 (en) 2022-09-23 2024-03-28 Astrazeneca Ab Pcsk9 inhibitors and methods of use thereof

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