WO2011068171A1 - Dérivés hétérocycliques saturés à teneur en azote, bicycliques - Google Patents

Dérivés hétérocycliques saturés à teneur en azote, bicycliques 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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cis
chloro
alkyl
methyl
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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

L'invention porte sur des composés qui présentent un effet prophylactique et/ou thérapeutique sur l'arthrite rhumatoïde chronique, la sclérose en plaques, les maladies intestinales inflammatoires telles que les maladies de Crohn et la colite ulcérative, les maladies auto-immunes exemplifiées par le psoriasis, le rejet d'un organe transplanté, les maladies allergiques, etc. L'invention porte également sur des compositions médicinales comportant ces composés et sur un procédé pour prévenir ou traiter une maladie auto-immune, qui est caractérisé par le fait qu'il comporte l'administration d'une quantité efficace d'une composition médicinale à un mammifère. L'invention porte également sur un composé représenté par la formule générale (I) ou sur un sel de qualité pharmacologique de celui-ci.
PCT/JP2010/071608 2009-12-03 2010-12-02 Dérivés hétérocycliques saturés à teneur en azote, bicycliques WO2011068171A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
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WO2013137479A1 (fr) * 2012-03-12 2013-09-19 Otsuka Pharmaceutical Co., Ltd. Dérivés de décahydroquinoxaline et leurs analogues
JP2013537875A (ja) * 2010-09-13 2013-10-07 大塚製薬株式会社 複素環化合物
WO2018052119A1 (fr) 2016-09-16 2018-03-22 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2018101424A1 (fr) 2016-12-01 2018-06-07 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2018221720A1 (fr) 2017-06-01 2018-12-06 住友化学株式会社 Composé hétérocyclique et composition le contenant
CN109048854A (zh) * 2018-09-30 2018-12-21 平顶山学院 基于藻类细胞机器人的货物可控传输释放方法
WO2019124548A1 (fr) 2017-12-22 2019-06-27 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2019189731A1 (fr) 2018-03-30 2019-10-03 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
CN111499514A (zh) * 2019-01-31 2020-08-07 连云港润众制药有限公司 一种罗沙司他中间体的制备方法
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
WO2024062089A1 (fr) 2022-09-23 2024-03-28 Astrazeneca Ab Inhibiteurs de pcsk9 et leurs procédés d'utilisation

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JP2008530218A (ja) * 2005-02-16 2008-08-07 シェーリング コーポレイション Ｃｘｃｒ３アンタゴニスト活性を有する、ピリジルおよびフェニルで置換されたピペラジン−ピペリジン
JP2008530212A (ja) * 2005-02-16 2008-08-07 シェーリング コーポレイション Ｃｘｃｒ３アンタゴニスト活性を有するピペラジン−ピペリジン

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JP2008530218A (ja) * 2005-02-16 2008-08-07 シェーリング コーポレイション Ｃｘｃｒ３アンタゴニスト活性を有する、ピリジルおよびフェニルで置換されたピペラジン−ピペリジン
JP2008530212A (ja) * 2005-02-16 2008-08-07 シェーリング コーポレイション Ｃｘｃｒ３アンタゴニスト活性を有するピペラジン−ピペリジン

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013537875A (ja) * 2010-09-13 2013-10-07 大塚製薬株式会社 複素環化合物
WO2013137479A1 (fr) * 2012-03-12 2013-09-19 Otsuka Pharmaceutical Co., Ltd. Dérivés de décahydroquinoxaline et leurs analogues
WO2018052119A1 (fr) 2016-09-16 2018-03-22 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2018101424A1 (fr) 2016-12-01 2018-06-07 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2018221720A1 (fr) 2017-06-01 2018-12-06 住友化学株式会社 Composé hétérocyclique et composition le contenant
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
WO2019124548A1 (fr) 2017-12-22 2019-06-27 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
WO2019189731A1 (fr) 2018-03-30 2019-10-03 住友化学株式会社 Composé hétérocyclique et agent de lutte contre les arthropodes nuisibles le contenant
CN109048854A (zh) * 2018-09-30 2018-12-21 平顶山学院 基于藻类细胞机器人的货物可控传输释放方法
CN109048854B (zh) * 2018-09-30 2021-06-04 平顶山学院 基于藻类细胞机器人的货物可控传输释放方法
CN111499514A (zh) * 2019-01-31 2020-08-07 连云港润众制药有限公司 一种罗沙司他中间体的制备方法
WO2024062089A1 (fr) 2022-09-23 2024-03-28 Astrazeneca Ab Inhibiteurs de pcsk9 et leurs procédés d'utilisation

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