Nothing Special   »   [go: up one dir, main page]

WO2006022442A1 - Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity - Google Patents

Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity Download PDF

Info

Publication number
WO2006022442A1
WO2006022442A1 PCT/JP2005/016048 JP2005016048W WO2006022442A1 WO 2006022442 A1 WO2006022442 A1 WO 2006022442A1 JP 2005016048 W JP2005016048 W JP 2005016048W WO 2006022442 A1 WO2006022442 A1 WO 2006022442A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituent
pyrrolidine
compound
phenyl
Prior art date
Application number
PCT/JP2005/016048
Other languages
French (fr)
Japanese (ja)
Inventor
Mamoru Matsuda
Toshiyuki Mori
Noriko Mishina
Hiroyuki Mogi
Minoru Yamamoto
Koushi Fujisawa
Yumi Hagiwara
Junko Fujikawa
Original Assignee
Santen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2006022442A1 publication Critical patent/WO2006022442A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel heterocyclic amide derivative useful as a pharmaceutical or a salt thereof.
  • the derivative has dihydrorotate dehydrogenase (hereinafter referred to as “DHODH”) inhibitory activity, cell proliferation, osteoclast differentiation, excessive immune reaction (autoimmune reaction, allergic reaction, organ transplantation). It is useful as a prophylactic or therapeutic agent for diseases involving occasional rejection, graft versus host disease, etc.
  • DHODH dihydrorotate dehydrogenase
  • cancer bone 'joint diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Shi X-Glen syndrome, grapes) Meningitis, polymyositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), It is useful as a preventive or therapeutic agent for organ rejection and graft-versus-host disease.
  • autoimmune diseases psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Shi X-Glen syndrome, grapes
  • Meningitis polymyositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.
  • D H O D H is an enzyme involved in the redox step of dihydrorotate to orotate, which is the rate-limiting factor in pyrimidine biosynthesis, and is an essential enzyme for cell growth.
  • This DH ODH is known to be overexpressed in proliferating cells and lymphocytes during the immune response. By inhibiting this DH ODH, cell proliferation, osteoclast differentiation, excessive immune response (autoimmune reaction) It is also known that allergic reactions, rejection during organ transplantation, graft-versus-host disease, etc.) are suppressed (see Non-Patent Document 1, Non-Patent Document 2, and Non-Patent Document 3).
  • drugs that inhibit DHODH are diseases involving cell proliferation such as cancer (see Non-Patent Document 4), bone-related diseases involving osteoclast differentiation such as osteoporosis and osteoarthritis (Non-Patent Document) 1), psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Sjoegren's syndrome, uveitis, type I diabetes, ulcerative colitis, Crohn's disease, etc.
  • diseases involving cell proliferation such as cancer (see Non-Patent Document 4)
  • bone-related diseases involving osteoclast differentiation such as osteoporosis and osteoarthritis (Non-Patent Document) 1)
  • psoriasis rheumatoid arthritis
  • multiple sclerosis multiple sclerosis
  • systemic lupus erythematosus multiple sclerosis
  • Sjoegren's syndrome systemic lupus erythematosus
  • Non-patent document 2 Non-patent document 3, Non-patent document 5, Refer to non-patent document 6, Refer to non-patent document 7 or Refer to non-patent document 8
  • atopic dermatitis atopic dermatitis, allergic dermatitis, allergic rhinitis , Allergic conjunctivitis, bronchial asthma and other allergic diseases
  • Non-Patent Document 9 rejection at the time of organ transplantation, graft-versus-host disease (see Non-Patent Document 3)) ing.
  • Patent Document 1 or Patent Document 2 discloses leflunomide, which is an isoxazol derivative, and related compounds as DHODOH inhibitors.
  • a quinolinecarboxylic acid derivative is disclosed in Patent Document 3 or Patent Document 4, and a cyclopentene 1,2-dicarboxylic acid monoamide derivative is disclosed in Patent Document 5.
  • these derivatives all differ in basic chemical structure from the compounds of the present invention.
  • Patent Document 6 compounds having a proline amide or thiazolidine carboxylic acid amide structure are disclosed in Patent Document 6, Patent Document 7 or Patent Document 8.
  • the compounds disclosed in Patent Document 6 relate to antibiotics having a urea structure as the main skeleton, and all of the compounds disclosed in Patent Document 7 or Patent Document 8 treat hyperlipidemia having a benzamide structure as the main skeleton. It relates to drugs or analgesics.
  • Patent Document 2
  • the present inventors have conducted synthetic studies on hetero-amide derivatives having a new chemical structure and succeeded in creating many new compounds. Furthermore, as a result of studying the pharmacological action of the derivative, the derivative was found to have a DHODH inhibitory activity, an anti-arthritic effect, a delayed hypersensitivity (hereinafter referred to as “DTH”) inhibitory effect, and a mixed lymphocyte reaction (hereinafter referred to as ⁇ MLR).
  • DTH delayed hypersensitivity
  • ⁇ MLR mixed lymphocyte reaction
  • autoimmune reactions that have an activity-inhibiting effect and involve cell proliferation, osteoclast differentiation, excessive immune reactions (autoimmune reactions, allergic reactions, rejection during organ transplantation, graft-versus-host diseases, etc.) That is, cancer, bone 'joint disease (osteoporosis, osteoarthritis, etc.), autoimmune disease (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, shi: E-Glen syndrome, uveitis, multiple occurrences) Myositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), rejection during organ transplantationResponse, found to be useful as a prophylactic or therapeutic agent such as graft-versus-host disease, thereby completing the present invention.
  • the present invention relates to a compound represented by the following general formula (1) or a salt thereof (hereinafter referred to as “the compound of the present invention”) and a pharmaceutical composition containing them.
  • a preferred invention for its pharmaceutical use relates to a DH O DH inhibitor, and its target diseases include cell proliferation and destruction. Diseases involving bone cell differentiation, excessive immune response (autoimmune reaction, allergic reaction, rejection response at the time of organ transplantation, graft-versus-host disease, etc.) can be mentioned.
  • cancer bone Related diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Siegren's syndrome, uveitis, polymyositis, type I sugar Urine disease, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), rejection during organ transplantation, transplantation One-to-one host disease and the like can be mentioned.
  • a preferred invention is an invention relating to a prophylactic or therapeutic agent for these diseases.
  • R 1 represents a lower alkyl group which may have a substituent, an aryl group which may have a substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, and a substituent.
  • each R 1 may be the same or different;
  • R 2 may have a hydrogen atom, a lower alkyl group that may have a substituent, an aryl group that may have a substituent, an aralkyl group that may have a substituent, a formyl group, or a substituent.
  • R 3 represents a hydrogen atom or an optionally substituted lower alkyl group
  • R 4 is a halogen atom, an optionally substituted lower alkyl group, a halogeno lower alkyl group, A lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a hydroxy group, An ester of a hydroxy group, a lower alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aralkyloxy group which may have a substituent, an amino group, an amide of an amino group, Lower alkylamino group which may have a substituent, Amide of lower alkylamino group which may have a substituent, Arylamino group which may have a substituent, Arylamino group which may have a substituent A group selected from an amide, a carboxy group, an ester of a carboxy group, an amide
  • each R 4 may be the same or different;
  • R 5 is a halogen atom, a hydrogen atom, an optionally substituted lower alkyl group, a halogeno lower alkyl group, an optionally substituted lower cycloalkyl group, or an optionally substituted aryl.
  • a heterocyclic group which may have a substituent an aralkyl group which may have a substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group
  • An arylthio group, an optionally substituted heterocyclic thio group, an optionally substituted aralkylthio group, an amino group, an amide of an amino group, an optionally substituted lower alkylamino Group may have a lower alkylamino group which may have a substituent may have an aryl substituent, an amide, a formyl group or a substituent of an arylamino group which may have a substituent
  • R 6 represents a hydrogen atom or an optionally substituted lower alkyl group
  • R 7 and R 8 are the same or different and are a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, A heterocyclic group which may have a substituent, a carboxy group, an ester of a carboxy group or an amide of a carboxy group;
  • R 9 has a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent.
  • R 1 Q represents an aryl group which may have a substituent. same as below. ]
  • the present invention provides a novel heterocyclic amide derivative useful as a medicine.
  • the compound of the present invention has excellent DHODH inhibitory activity, anti-arthritic effect, delayed type hypersensitivity (hereinafter referred to as “DTH”) inhibitory effect, and lymphocyte mixed reaction (hereinafter referred to as “MLRJ”) inhibitory effect.
  • DTH delayed type hypersensitivity
  • MLRJ lymphocyte mixed reaction
  • autoimmune reaction involving cell proliferation, osteoclast differentiation, excessive immune response
  • cancer bone ⁇ joint diseases (osteoporosis, osteoarthritis, etc.)
  • autoimmune diseases psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, siegren syndrome, uveitis, polymyositis, Type I diabetes, ulcerative colitis, Crohn's disease, etc.
  • allergic diseases atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.
  • rejection during organ transplantation The graft It is useful as a preventive or therapeutic agent for host disease etc.
  • Halogen atom refers to a fluorine, chlorine, bromine or iodine atom.
  • the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isoptyl, sec-butyl, tert-butyl, isobutyl. An nyl group and the like.
  • halogeno lower alkyl group refers to a lower alkyl group having one or more halogen atoms as a substituent. Specific examples include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, tripromomethyl, triodomethyl group and the like.
  • lower alkenyl group refers to a straight or branched alkenyl group having 2 to 8 carbon atoms. Specific examples include vinyl, probenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, isopropenyl, 2-methyl-1-propenyl, 2-methyl-2-butenyl and the like.
  • lower alkynyl group refers to a straight chain or branched alkynyl group having 2 to 8 carbon atoms. Specific examples include ethynyl, propynyl, petynyl, pentynyl, hexynyl, heptynyl, octynyl, isoptynyl, isopentynyl group and the like.
  • the “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups.
  • Aryl group means a monocyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or a residue obtained by removing one hydrogen atom from a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon. Indicates a group. Specific examples include phenyl, naphthyl, anthryl, phenanthryl groups and the like.
  • Heterocyclic group means a saturated or unsaturated monocyclic heterocycle having one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring, or a bicyclic or tricyclic ring. A residue obtained by removing one hydrogen atom from a fused polycyclic heterocycle.
  • saturated monocyclic heterocycles include pyrrolidine, virazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine having nitrogen atoms in the ring, Homopiperazine rings, etc.
  • tetrahydrofuran tetrahydropyran rings, etc., which have oxygen atoms in the ring
  • tetrahydrothiophene tetrahydrothiopyran rings, etc.
  • sulfur atoms in the ring nitrogen and oxygen atoms in the ring
  • Thiazolidine having a nitrogen atom and a sulfur atom in the ring, such as having an oxazolidine, isoxazolidine, morpholine ring, etc. , Isothiazolidine, thiomorpholine ring and the like.
  • unsaturated monocyclic heterocycles include dihydropyrrole, pyrrole, dihydropyrazol, pyrazole, dihydroimidazole, imidazole, dihydrotriazole, triazol, tetrahydro having nitrogen atoms in the ring.
  • Pyran, pyran ring isotonic dihydrothiophene, thiophene, dihydrothiopyran, thiopyran ring, etc. having a sulfur atom in the ring are dihydrooxazol, oxazol, dihydroisoxoxax having a nitrogen atom and an oxygen atom in the ring.
  • a ring etc. are mentioned.
  • these unsaturated monocyclic heterocycles are condensed with a benzene ring or the like to form indol, indazole, benzimidazole, benzotriazol, dihydroquinoline, quinoline, dihydroisoquinoline, isoquinoline, phenol.
  • a cyclic heterocyclic ring may be formed.
  • the “aralkyl group” refers to a lower alkyl group having one or more aryl groups as a substituent. Specific examples include benzyl, phenethyl, naphthylmethyl, diphenylmethyl groups and the like.
  • the “lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, ⁇ -pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group, etc. Is mentioned. .
  • halogeno lower alkoxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a halogeno lower alkyl group.
  • Specific examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, monochloromethoxy, dichloromethoxy, trichloromethoxy, tripromomethoxy, triiodomethoxy group and the like.
  • lower alkenyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkenyl group.
  • Specific examples include vinyloxy, probenoxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, isopropenyloxy, 2-methyl-1-proenyloxy, 2-methyl-2-butenyloxy and the like.
  • lower alkynyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkynyl group.
  • Specific examples include ethynyloxy, propynyloxy, ptynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, isoptynyloxy, isopentynyloxy groups and the like.
  • the “lower cycloalkyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower cycloalkyl group. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy groups, and the like.
  • the “aryloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryl group. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy groups and the like.
  • Heterocyclicoxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a heterocyclic group.
  • aralkyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aralkyl group. Specific examples include benzyloxy, phenethyloxy, naphthylmethoxy, diphenylmethoxy groups and the like.
  • lower alkylthio group refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower alkyl group.
  • Specific examples include methylthio, ethylthio, n-propylthio, n-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio Groups and the like.
  • halogeno lower alkylthio group refers to a group in which a hydrogen atom of a mercapto group is substituted with a halogeno lower alkyl group.
  • Specific examples include monofluoromethi) retio, difluoromethylthio, trifluoromethylthio, trifluoroethylthio, monochloromethylthio, dichloromethylthio, trichloromethylthio, tripromomethylthio, triiodomethylthio groups and the like.
  • lower cycloalkylthio group refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower cycloalkyl group.
  • Specific examples include cyclopropylthio, cycloptylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio or cyclooctylthio groups.
  • arylthio group refers to a group in which a hydrogen atom of a mercapto group is substituted with an aryl group. Specific examples include phenylthio, naphthylthio, anthrylthio, phenanthrylthio groups and the like.
  • heterocyclic thio group refers to a group in which a hydrogen atom of a mercapto group is substituted with a heterocyclic group.
  • ⁇ aralkylthio group refers to a group in which a hydrogen atom of a mercapto group is substituted with an aralkyl group. Specific examples include benzylthio, phenethylthio, naphthylmethylthio, diphenylmethylthio groups and the like.
  • the “lower alkylamino group” refers to a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkyl group. Specific examples include methylamino, ethylamino, propylamido dimellami decylamino, ethylmethylamino groups and the like.
  • aryl amino group is a group in which one or both hydrogen atoms of an amino group are substituted with an aryl group, or one hydrogen atom of an amino group is substituted with an aryl group and the other hydrogen atom is substituted with a lower alkyl group.
  • the group is shown. Specific examples include phenylamino, naphthylamino, anthrylamino, phenanthrinoleamino, diphenylamino, methylphenylamino phenylamine groups and the like.
  • lower alkylcarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkyl group.
  • Specific examples include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, n-butyl carbonyl, n-pentyl carbonyl, n-hexyl carbonyl, n-heptyl carbonyl, n-octyl carbonyl, isopropyl carbonyl, isobutyl.
  • Arylcarbonyl group refers to a group in which a hydrogen atom of a formyl group is substituted with an aryl group. Specific examples include phenylcarbonyl, naphthylcarbonyl, anthryl strength sulfonyl, phenanthrylcarbonyl group, and the like.
  • the “lower alkoxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is replaced with a lower alkoxy group.
  • Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, n-pentoxycarbonyl, n-hexyloxyl sulfonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl, iso Examples thereof include propoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentoxycarbonyl group and the like.
  • aryloxycarbonyl group refers to a group in which a hydrogen atom of a formyl group is replaced with an aryloxy group. Specific examples thereof include phenoxy strength sulfonyl, naphthoxycarbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl group, and the like.
  • “Lower alkylsulfinyl group” means that the hydroxy of the sulfinic acid group is a lower alkyl group. Indicates a substituted group. Specific examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl, n-pentylsulfinyl, n-hexylsulfinyl, n-heptylsulfinyl, n-octylsulfinyl, isopropylsulfinyl, isoso Examples thereof include butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, isopentylsulfinyl group and the like.
  • arylsulfinyl group refers to a group in which a hydroxyl group of a sulfinic acid group is substituted with an aryl group.
  • Specific examples include phenylsulfinyl, naphthylsulfinyl, anthrylsulfinyl, phenylanthrylsulfinyl groups, and the like.
  • lower alkylsulfonyl group refers to a group in which a hydride of a sulfonic acid group is replaced with a lower alkyl group.
  • Specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl, ⁇ -hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl, isopropylsulfonyl, isobutylsulfonyl. Sec-butylsulfonyl, tert-butylsulfonyl, isopentylsulfonyl group and the like.
  • Arylsulfonyl group refers to a group in which hydroxy of a sulfonic acid group is substituted with an aryl group. Specific examples include phenylsulfonyl, naphthylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl groups, and the like.
  • lower alkoxycarbonyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkoxycarbonyl group.
  • Specific examples include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, n-butoxycarbonyloxy, n-pentoxycarbonyloxy, n-hexyloxycarbonyl, n-heptyloxycarbonyl.
  • aryloxycarbonyloxy group refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryloxycarbonyl group.
  • Specific examples include phenoxycarbonyloxy, naphthoxycarbonyloxy, anthryloxycarbonyloxy, phenanthryloxycarboxyl. Examples include a ruoxy group.
  • “Ester of hydroxy group” refers to an ester formed from a hydroxy group and carboxylic acids.
  • Ester of mercapto group refers to a thiester formed from a mercapto group and carboxylic acids.
  • Amino group amide refers to an amide formed from an amino group and a carboxylic acid.
  • lower alkylamino group amide refers to an amide formed from a lower alkylamino group and a carboxylic acid.
  • amide of an arylamino group refers to an amide formed from an arylamino group and a carboxylic acid.
  • Carboxylic acids refers to R a COOH (where R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an aryl group which may have a substituent.
  • R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an aryl group which may have a substituent.
  • saturated aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and vivalic acid; oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, etc.
  • Saturated aliphatic dicarboxylic acids Saturated aliphatic dicarboxylic acids; unsaturated aliphatic carboxylic acids such as acrylic acid, propiolic acid, crotonic acid, and gay cinnamate; carbocycles such as benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, and toluic acid Examples thereof include heterocyclic carboxylic acids; heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, nicotinic acid, and isonicotinic acid.
  • these carboxylic acid anhydrides [(R a CO) 2 0] and acid halides (R a C OX, X represents a halogen atom) are also included in the “carboxylic acids”.
  • Ester of carboxy group refers to an ester formed from a carboxy group and alcohols or phenols.
  • Ester of sulfinic acid group refers to an ester formed from a sulfinic acid group and alcohols or phenols.
  • Ester of ⁇ sulfonic acid group means from sulfonic acid group and alcohols or phenols.
  • Alcohols means a saturated aliphatic hydroxy compound represented by R b OH (R b represents a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, etc.), An unsaturated aliphatic hydroxy compound is shown. Specific examples include saturated aliphatic hydroxy compounds such as methanol, ethanol, propanol, butanol and isopropanol; unsaturated aliphatic hydroxy compounds such as vinyl alcohol; aralkyl alcohols such as benzyl alcohol and phenethyl alcohol. .
  • Phenols J refers to carbocyclic hydroxy compounds represented by R b OH (R b represents an aryl group that may have a substituent, etc.). Specific examples include phenol, naphthol, anthrolo. And ferrules.
  • the “amide of carboxy group” refers to an acid amide formed from a carboxy group and amines.
  • the “amide of sulfinic acid group” refers to an acid amide formed from a sulfinic acid group and amines.
  • Gamma sulfonic acid group amide J refers to an acid amide formed from a sulfonic acid group and an amine.
  • “Amin” means HNR. (R d )
  • R. And R d are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, or a heterocyclic group.
  • Etc., and also R. Ammonia and also with R d forms a together a connexion piperazines Well, represented by, saturated aliphatic Amin compounds, carbocyclic Amin compounds, heterocyclic Amin compound, a saturated cyclic amine compound or the like Show.
  • saturated aliphatic amine compounds such as methylamine, ethylamine, propylamine, pentylamine, dimethylamine, jetylamine, and ethylmethylamine
  • Carbocyclic amine compounds such as ethenylphenylamine and benzylamine
  • heterocyclic amine compounds such as furanylamine, thiophenylamine, pyrrolidylamine, pyridylamine, quinolylamine and methylpyridylamine
  • saturated cyclic amine compounds such as piperidine and 4-methylbiperidine.
  • Optionally substituted lower cycloalkyl group”, “optionally substituted aryl group”, “optionally substituted heterocyclic group”, “optionally substituted” Preferred lower cycloalkyloxy group J, “optionally substituted aryloxy group”, “optionally substituted heterocyclicoxy group”, “optionally substituted lower cycloalkylthio group , “Optionally substituted aryl group”, “optionally substituted heterocyclic group”, “optionally substituted aryl group”, “substituted”
  • the arylcarbonyl group which may have a substituent an arylcarbonyl group which may have a substituent, an arylsulfinyl group which may have a substituent, and an aryl group which may have a substituent.
  • Halogen atom lower alkyl group, halogeno lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, halogeno lower alkoxy group, lower alkenyloxy Group, lower cycloalkyloxy group, aryloxy group, aralkyloxy group, aryloxycarbonyloxy group, mercapto group, lower alkylthio group, arylthio group, amino group, amide of amino group, lower alkylamino Group, lower alkylamino group amide, arylamine group, arylamine group amide, formyl group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, carboxyl group ester, carboxy group Amide, sulfonic acid group, ester of sulfonic acid group, sulfonic acid The group consisting of amide, nitro group, and
  • the aralkyl group which may have a substituent may have one or more substituents selected from (preferably group 2 ) ⁇ and / or for its aryl moiety, one or more selected from group 1 (preferably group 2 ) A ⁇ aralkyl group, a ⁇ aralkyloxy group, or an aralkylthio group J which may have a substituent is shown.
  • the aryloxy group in the S 2 group may have one or more halogen atoms as substituents.
  • the lower alkyl group or the lower alkoxy group in the 5 1 or S 2 group may have one or more substituents selected from the r 1 group (preferably the r 2 group).
  • the “plural groups” in the present invention may be the same or different, and the number of these groups is preferably 2 to 3. Hydrogen atoms and halogen atoms are also included in the “group”.
  • the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, Acetic acid, fumaric acid, maleic acid, succinic acid, succinic acid, tartaric acid, adipic acid, gluconic acid, darcohebutyric acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid , Isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl
  • the compound of the present invention may take the form of a hydrate or a solvate.
  • Preferable examples of the compound of the present invention include a compound represented by the general formula (1) or a salt thereof, wherein each group is a group shown below.
  • R 1 is a lower alkyl group, Ariru group, hydroxy group And represents a group selected from an ester of a hydroxy group, an alkoxy group, and an aryloxy group;
  • each R 1 may be the same or different; and / or
  • R 2 is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, or a lower alkylsulfonyl group.
  • R 2 is an aralkyl group, an arylaryl group or an arylsulfonyl group, the aralkyl group, the arylcarbonyl group or the arylsulfonyl group is 1 or May have multiple halogen atoms as substituents and / or
  • R 3 represents a hydrogen atom or a lower alkyl group
  • R 4 is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, a hydroxy group, an ester of a hydroxy group, Lower alkoxy group, aryloxy group, aralkyloxy group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, allylamino group, amide of allylamino group, carboxy group, ester of carboxy group, amide of carboxy group
  • R 4 represents a group selected from R 4 and when R 4 is a lower alkenyl group, the lower alkenyl group may have one or more aryl groups as a substituent.
  • each R 4 may be the same or different; and / or
  • R 5 is a halogen atom, hydrogen atom, lower alkyl group, halogeno lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, Halogeno lower alkoxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, aralkyloxy group, mercapto group, ester of mercapto group, lower alkylthio group, halogeno lower alkylthio group, lower cycloalkylthio group, aryl Ruthio group, heterothio group, aralkylthio group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamino group, amide of arylalkylamino group, formyl group, lower alkylcarbonyl group , Arylcarbonyl, carb
  • One or more groups selected from amide, carboxy group, ester of carboxy group, amide of carboxy group, and cyano group may be substituted.
  • R 5 is an aryl group
  • Groups are halogen atoms, lower alkyl groups, halogeno lower alkyl groups, hydroxy groups, esters of hydroxy groups, lower alkoxy groups, halogeno lower alkoxy groups, nitro groups, and cyano groups
  • One or more groups selected from the above may be substituted.
  • R 5 is a heterocyclic group
  • the heterocyclic group is selected from a halogen atom, a lower alkyl group, and a lower halogenoalkyl group.
  • One or more groups may be substituted, and when R 5 is an aralkyl group, the aralkyl group is a hydroxy group, an ester of a hydroxy group, a lower alkoxy group.
  • an amino group, an amide of Amino group, a lower alkylamino group, and an amide force lower alkylamino group may have one or a plurality of groups are al selected as substituents, R 5 is a lower alkoxy group In this case, the lower alkoxy group may have one or more heterocyclic groups as a substituent, and when R 5 is an aryloxy group, the aryloxy group is a substituent of one or more lower alkyl groups.
  • the aralkyloxy group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, or a halogeno lower alkoxy group. 1 or a plurality of groups selected from may be substituted, and when R 5 is a lower alkylthio group, the lower alkylthio group is a lower cycloalkyl group. 1 or a plurality of groups selected from the group consisting of alkyl group, aryl group, and heterocyclic group may be substituted.
  • R 5 is arylthio group
  • the arylthio group is a halogen atom, lower alkyl group.
  • R 5 may have one or more groups selected from a group, a halogeno lower alkyl group, an amino group, an amide of an amino group, a lower alkylamino group, and an amide of a lower alkylamino group as a substituent.
  • the aralkylthio group is one or more selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, and a halogeno lower alkoxy group.
  • R 5 may have a group as a substituent, when R 5 is the ⁇ Li one Rusuruhoniru group, said ⁇ Li one Rusuruhoni Le groups Amino groups, amides of Amino groups, lower alk Arylamino group, and it may have a one or a plurality of group a substituent selected from ⁇ bromide lower alkylamino group; and or
  • R 6 represents a hydrogen atom or a lower alkyl group
  • R 7 and R 8 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a carboxy group, an ester of a carboxy group, or an amide of a carboxy group.
  • R 7 or R 8 is an aryl group
  • the aryl group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a hydroxy group Esters, lower alkoxy groups, halogeno lower alkoxy groups, lower cycloalkyloxy groups, aryloxy groups, heterocyclic oxy groups, aralkyloxy groups, mercapto groups, esters of mercapto groups, lower alkylthio groups, arylthio groups, amino groups, Amido amide, lower alkylamino group, lower alkylamino amide, aryl Lumino group, arylamine group of arylamino group, lower alkylcarbonyl group, aryl group, sulfonyl group, carboxy group, carboxy group ester, carboxy group
  • R 9 represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, or a heterocyclic group, and when R 9 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, 1 Or a lower alkyl group substituted with a plurality of hydroxy groups, a lower alkyl group substituted with one or more hydroxy group esters, a lower alkyl group substituted with one or more lower alkoxy groups, 1 Or a lower alkyl group substituted by a plurality of aryloxy groups, a lower alkyl group substituted by one or more carboxy groups, a lower alkyl group substituted by an ester of one or more carboxy groups, 1 or Lower alkyl group substituted with amides of a plurality of carboxyl groups, lower alkyl group substituted with one or more cyano groups, lower halogeno group An alkyl group, a lower alkyl group
  • R ′ represents a group selected from a lower alkyl group, an aryl group, a hydroxy group, and an ester of a hydroxy group
  • R 2 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a lower alkyl carbonyl group, an aryl carbonyl group, a lower alkoxy carbonyl group, a lower alkyl sulfo group; or an aryl sulfonyl group.
  • R 2 is an aralkyl group, an arylcarbonyl group, or an arylsulfonyl group
  • the aralkyl group, the arylcarbonyl group, or the arylsulfonyl group May have one or more halogen atoms as substituents and / or
  • R 3 represents a hydrogen atom
  • R 4 is selected from a halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkenyl group, aralkyl group, lower alkoxy group, aryloxy group, aralkyloxy group, lower alkylamino group, carboxy group amide, and cyano group
  • R 4 is a lower alkenyl group
  • the lower alkenyl group may have one or more aryl groups as a substituent, and / or
  • each R 4 may be the same or different; and or
  • R 5 is a halogen atom, a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a lower alkoxy group, a halogeno lower alkoxy group, an aryloxy group.
  • R 5 is an aryl group
  • the aryl group is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a nitro group, and a cyan group.
  • R 5 is a heterocyclic group
  • the heterocyclic group is substituted with one or more groups selected from a halogen atom, a lower alkyl group, and a halogeno lower alkyl group.
  • the aralkyl group may have one or a plurality of groups selected from a lower alkoxy group and an amino group as a substituent, and R 5 is a lower group.
  • a lower alkoxy group is one or more heterocyclic groups
  • the aryloxy group may have one or more lower alkyl groups as a substituent.
  • the aralkyloxy group May have one or more groups selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, and a lower alkoxy group as a substituent, and when R 5 is a lower alkylthio group, The group may have one or more groups selected from a lower cycloalkyl group and a heterocyclic group as a substituent.
  • R 5 is an arylthio group
  • the arylthio group is a halogen atom, halogeno-lower alkyl group, ⁇ Pi Amino group or al selected is 1 or good
  • R 5 may have a plurality of groups as substituents case of Ararukiruchio group, said Ararukiruchio group halogen atom ,
  • a lower alkyl group, a halogeno lower alkyl group, and a lower alkoxy group may have one or more groups as a substituent.
  • the arylylsulfonyl group is 1 Or may have multiple amino groups as substituents; and / or
  • R 6 represents a hydrogen atom
  • R 7 represents a hydrogen atom
  • R 8 represents a hydrogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, or an ester of a carboxy group
  • R 8 is an aryl group
  • the aryl group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a lower alkoxy group, or a halogeno lower alkoxy group.
  • Aryloxy group, aralkyloxy group, lower alkylthio group, amino group, amide of amino group, lower alkylamino group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, amide of sulfonic acid group, nitro group, and cyano And may have one or more groups selected from the group as a substituent; and or (b 1 3) R 9 represents a hydrogen atom, an aryl group, or a heterocyclic group,
  • R 9 is an aryl group
  • the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with one or more hydroxy groups, or a lower alkyl substituted with one or more lower alkoxy groups.
  • Preferred examples of each group or combination of groups in the compound of the present invention include compounds that satisfy the following conditions (c) or (d) or salts thereof.
  • R 5 includes a compound satisfying the following condition (e) or a salt thereof.
  • R 5 is a halogen atom, an optionally substituted lower alkyl group, A halogeno lower alkyl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group, a hydroxy group, an ester of a hydroxy group, an optionally substituted lower alkoxy group, a halogeno A lower alkoxy group, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, or a substituent.
  • a heterocyclic group which may have a substituent, a hydroxy group, a hydroxy group
  • Heterocyclic oxy group and substituent which may have An aralkyloxy group, a mercapto group, an ester of a mercapto group, a lower alkylthio group which may have a substituent, a halogeno lower alkylthio group, a lower cycloalkylthio group which may have a substituent, and a substituent.
  • An arylthio group that may have, a heterocyclic group that may have a substituent, an aralkylthio group that may have a substituent, CR 6 CR 7 (R 8 ), or C ⁇ CR 9
  • a compound or a salt thereof is more preferable.
  • R 5 include compounds satisfying the following conditions (f) to (j) or salts thereof.
  • a compound in which R 5 represents a heterocyclic group which may have a substituent is preferable, and in particular, the heterocyclic ring of the heterocyclic group is piperazine, morpholine, pyrrolidine, pyridine. , Thiophene, indole, benzoimidazole, quinoline, quinoxaline, benzofuran, benzothiophene, benzoxazoline, or benzothiazoline or a salt thereof is more preferable.
  • R 5 is a hydroxy group, an ester of a hydroxy group, an optionally substituted lower alkoxy group, a halogeno-lower alkoxy group, or an optionally substituted lower cycloalkyloxy.
  • a compound showing a group, an aryloxy group which may have a substituent, a heterocyclic group which may have a substituent, or an aralkyloxy group which may have a substituent, or a salt thereof is preferable.
  • a compound showing a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, an aryloxy group which may have a substituent or an aralkyloxy group which may have a substituent or a salt thereof is more preferable.
  • R 5 is a mercapto group, an ester of a mercapto group, an optionally substituted lower alkylthio group, a halogeno lower alkylthio group, or an optionally substituted lower cyclothio group.
  • a compound showing an alkylthio group, an arylthio group which may have a substituent, a heterocyclic thio group which may have a substituent, or an aralkylthio group which may have a substituent or a salt thereof is preferred.
  • R 5 is preferably a compound in which C ⁇ CR 9 or a salt thereof is preferred ⁇ is a hydrogen atom, an optionally substituted aryl group or a heterocyclic group A compound or a salt thereof is more preferred.
  • the compound of the present invention has an asymmetric carbon atom in the following A part of the general formula (1), and the cubic structure of the part is preferably as follows.
  • a compound having a steric structure at the A part is preferably an RS form or an R form.
  • An R form compound is particularly preferred.
  • X 1 —X 2 is S—CH 2
  • a compound in which the steric structure of the A part is RS or S is preferable, and a compound of S is particularly preferable.
  • the compound (I) of the present invention (a compound in which R 2 is a hydrogen atom in the general formula [1]) can be synthesized according to synthesis route 1. That is, the compound ( ⁇ ) is treated in an organic solvent such as ethyl acetate, 1,4-dioxane, methanol and methylene chloride in the presence of an acid such as hydrogen chloride and trifluoroacetic acid at 0 ° C. to room temperature for 30 minutes to 12 hours. As a result, the compound of the present invention can be obtained.
  • an organic solvent such as ethyl acetate, 1,4-dioxane, methanol and methylene chloride
  • an acid such as hydrogen chloride and trifluoroacetic acid
  • the compound ( ⁇ ) can be synthesized according to synthetic route 2. That is, the compound (m) and the compound (17) are mixed in an organic solvent such as N, N-dimethylformamide (hereinafter referred to as DMF) or methylene chloride, and N, N′-dicyclohexyl carpositimide (hereinafter referred to as DCC).
  • an organic solvent such as N, N-dimethylformamide (hereinafter referred to as DMF) or methylene chloride
  • DCC N, N′-dicyclohexyl carpositimide
  • HATU O- (7-azabenzotriazol 1-yl) 1 N, N, N, N-tetramethyluronium hexafluorophosphate
  • DIEA diisopropylethylamine
  • Synthesis route 2 Compound ( ⁇ )-(a) (compound ( ⁇ ) in which R 5 is O—R ′′) is added to synthesis route 3. It can be synthesized accordingly. That is, compound (II)-(b) is obtained from compound (II) and compound (W)-(a) (compound (IV) where R 5 is —O-benzyl) according to synthesis route 2. It is The resulting compound ( ⁇ ) _ (b) is treated in an organic solvent such as methanol or ethanol in the presence of a catalyst such as palladium on carbon in a hydrogen atmosphere at room temperature for 1 to 24 hours. c) can be obtained.
  • an organic solvent such as methanol or ethanol
  • a catalyst such as palladium on carbon
  • the compound (V)-(G) and the corresponding halogenated compound (V) are added in an organic solvent such as DMF or ethanol in the presence of a base such as potassium carbonate or DIEA at room temperature to 100 ° C for 1 to 24 hours.
  • a base such as potassium carbonate or DIEA
  • Compound ( ⁇ )-(a) can be obtained by reacting for a period of time.
  • Compound ( ⁇ )-(d) (compound ( ⁇ ) in which R 5 is S—R ′′) can also be synthesized according to synthesis route 4. That is, from compound (m) and compound (VI) The compound ( ⁇ H) is obtained according to the synthesis route 2. The obtained compound (VII) is mixed with an organic solvent such as acetone, 1,4-dioxane, and water in the presence of an alkylphosphine such as tri-n-butylphosphine.
  • an organic solvent such as acetone, 1,4-dioxane
  • an alkylphosphine such as tri-n-butylphosphine.
  • compound (n) — (e) can be obtained by treating at room temperature for 1 to 24 hours, and further, compound (H)-(e) and the corresponding halogenated compound (V) are converted to DMF, Compound (H)-(d) can be obtained by reacting in an organic solvent such as ethanol in the presence of a base such as potassium carbonate or DIEA at room temperature to 100 ° C for 1 to 24 hours.
  • a base such as potassium carbonate or DIEA
  • compound ( ⁇ )-(g) and the corresponding alkene compound (VI) are present in an organic solvent such as DMF, a base such as DIEA, a ligand such as tree 0-tolylphosphine and a catalyst such as palladium acetate ( ⁇ )
  • organic solvent such as DMF
  • a base such as DIEA
  • a ligand such as tree 0-tolylphosphine
  • a catalyst such as palladium acetate
  • the compound (H) — (f) can be obtained by reacting at 80 ° C. to 120 ° C. for 30 minutes to 24 hours.
  • compound (()-(f) can also be synthesized according to synthesis route 6. That is, compound ( ⁇ )-(h) is obtained from compound (H) and compound (17)-(G) (compound (IV) where R 5 is an alkenyl group) according to synthesis route 2. Furthermore, the halogenated compound (K) corresponding to the compound (H) _ (h) is mixed with an organic solvent such as DMF, a base such as DIEA, a ligand such as tree O-tolylphosphine, and palladium acetate (H). By reacting at 80 ° C. to 120 ° C. for 30 minutes to 24 hours in the presence of a catalyst, the compound ( ⁇ )-(f) can be obtained.
  • organic solvent such as DMF
  • a base such as DIEA
  • a ligand such as tree O-tolylphosphine
  • Synthesis route 6 Compound ()-(i) (compound ( ⁇ ) in which R 5 is C ⁇ CR 9 ) can also be synthesized according to synthesis route 7. That is, compound (()-(j) is obtained from compound (m) and compound (IV)-(d) (compound (a compound in which R 5 is ethynyl group in ⁇ )) according to synthesis route 2.
  • Synthetic Route 7 Compound (() — (i) can also be synthesized according to Synthetic Route 8. That is, the compound (n)-(g) and the corresponding alkyne compound (XI) are mixed with an organic solvent such as DMF, a base such as triethylamine, sodium hydroxide, copper iodide (1), tetrakis (triphenylphosphine). ) Compound ( ⁇ )-(i) can be obtained by reacting in the presence of a catalyst such as palladium (0) at room temperature for 2 to 12 hours.
  • a catalyst such as palladium (0)
  • Synthetic Route 8 The compound of the present invention produced by the above synthetic route can be converted into the above-mentioned salt, hydrate or solvate form using a widely used technique.
  • a human type recombinant DHODH protein was used, and Achieves' Ob Biochemistry 'and' Biophysics, 323, 79-86 (1995) [ Archives of Biochemistry and Biophysics, 323, 79-86 (1995)]
  • NB Ding nitro blue tetrazole
  • the compound of the present invention is deeply involved in cell proliferation, osteoclast differentiation, excessive immune reaction (autoimmune reaction, allergic reaction, rejection at the time of organ transplantation, graft-versus-host disease, etc.), etc.
  • autoimmune diseases that inhibit DH ODH activity and are involved in cell proliferation, osteoclast differentiation, excessive immune responses (autoimmune reactions, allergic reactions, rejection during organ transplantation, graft-versus-host diseases, etc.) More specifically, cancer, bone 'joint diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Shigren's syndrome, uvea) Inflammation, polymyositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), Refusal during organ transplantation Reaction, it has been demonstrated to be useful as a prophylactic or therapeutic agent such as graft-versus-host disease.
  • the compound of the present invention can be administered orally or parenterally.
  • the dosage form include tablets IJ, capsules, granules, powders, injections, eye drops, and the like, and they can be formulated using a widely used technique.
  • oral preparations such as tablets, capsules, granules, powders, etc.
  • excipients such as lactose, mannitol, denpene, crystalline cellulose, light anhydrous key acid, calcium carbonate, calcium hydrogen phosphate, stearic acid, stearic acid Lubricants such as magnesium and talc, binders such as starch, hydroxypropyl pill cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone
  • coating agents such as methylcellulose, macrogol and silicone resin, stabilizers such as ethyl oxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances as necessary.
  • parenterals such as injections and eye drops include isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, phosphate Buffering agents such as sodium hydrogen, sodium acetate, citrate, glacial acetic acid, trometh-amol, surfactants such as polyoxyethylene sorbitan monooleate, polyoxy stearate 40, polyoxyethylene hydrogenated castor oil, Stabilizers such as sodium citrate and sodium edetate, benzalkonium chloride, paraben, benzotonium chloride, paraoxy benzoate, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citrate, phosphoric acid, ice PH adjusters such as acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate
  • a necessary amount of a soothing agent such as benzyl alcohol can be used
  • the present invention comprises a method for inhibiting dihydrophosphate dehydrogenase comprising administering an effective amount of a compound of the present invention or a salt thereof to a patient, and administering an effective amount of the compound of the present invention or a salt thereof to a patient.
  • the present invention also relates to a method for preventing or treating a disease involving cell proliferation, osteoclast differentiation or excessive immune response.
  • the dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like.
  • an oral preparation is usually administered in an amount of 0.001 to 1 000 mg, preferably;! To 100 mg per day, in one or several divided doses.
  • eye drops are usually administered at a concentration of 0.0001% to 1 O o / o (w Zv), preferably 0.01% to 5% (wZv) in one or several divided doses.
  • w Zv 0.0001% to 1 O o / o
  • wZv 0.01% to 5%
  • Reference compound 20-2 and a commercially available compound were used below to obtain reference compound 5-2 according to the production method of reference compound 5-1.
  • Reference Example 6 Bis [4- (1 tert-butoxycarbonylpyrrolidine- 1 HNR (500 MHz, DMSO-d 6 ) 2-ylcarbonylamino) phenyl] disulfide (reference ⁇ 1.25, 1.39 (s, 18 ⁇ ), 1.77- 1.
  • the reference compound 6 was obtained according to the manufacturing method of the reference compound 6-1 using a commercially available compound.
  • Reference Compound Fu-2 was obtained using Reference Compound 6-2 in accordance with the production method of Reference Compound Fu-1.
  • Reference compounds 8-2 to 9-4 were obtained using Reference Compound 8 and commercially available compounds according to the production method of Reference Compound 9-1.
  • reference compounds 11-2 to 11-5 were obtained using a compound selected from reference compounds 9_2 to 9-4 and 10 according to the production method of reference compound 11-11.
  • reference compounds 1 2-2 to 1 2-28 were obtained using commercially available compounds according to the production method of Reference compound 1 2-1.
  • reference compounds 13-2 to 13-6 were used and reference compounds 14-1 According to the production method of Reference Compound 14 1-2 2-14 16 were obtained.
  • Reference compound 15-2 was used below, and reference compound 16-2 was obtained according to the production method of reference compound 16-1 .
  • Reference compounds 17-2 to 17-29 were obtained using reference compound 24 and commercially available compounds according to the production method of reference compound 17-1. .
  • Zen (reference compound 17-21) ⁇ 1.29-1.38 (m, 2H), 1.55-1.67 (m, 4
  • Reference Compound 18-12 was obtained according to the production method of Reference Compound 18-1.
  • the reference compound 20 1-2 was obtained according to the manufacturing method of the reference compound 20-1 using the commercially available compound.
  • Reference Compound 21-12 was obtained according to the production method of Reference Compound 21-1.
  • Reference Compound 26-2 was obtained according to the production method of Reference Compound 26-1.
  • compounds 4_2 to 4-19 were obtained according to the production method of compound 4-1, using compounds selected from compounds 1-13, 1-30, 1-81 to 1_84, and commercially available compounds. .
  • compounds 6-2 to 6-12 were obtained according to the production method of compound 6-1 using a compound selected from compound 5 and commercially available compounds.
  • compounds 9_2 to 9-3 were obtained according to the production method of compound 9-1 using compounds selected from Compound 1-154 and commercially available compounds.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pulmonology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Transplantation (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Novel heterocyclic amide derivatives having pharmacological effects, that is, compounds represented by the general formula (1) or salts thereof: (1) wherein X1-X2 is S-CH2 or the like; R1 is alkyl or the like; p is 0 to 7; R2 is hydrogen, alkyl, or the like; R3 is hydrogen, alkyl, or the like; Y1-Y2 is CH=CH or the like; R4 is halogeno, alkyl, or the like; q is 0 to 4; and R5 is halogeno, hydrogen, alkyl, or the like.

Description

明 細 書 ジヒドロォロテートデヒドロゲナーゼ阻害活性を有する新規複素環アミド誘導体 技術分野  A novel heterocyclic amide derivative having dihydrorotate dehydrogenase inhibitory activity Technical Field
本発明は医薬として有用な新規複素環アミド誘導体又はその塩に関する。その誘導 体はジヒドロォロテートデヒドロゲナ一ゼ（以下、「D H O D H」とする）阻害活性を有し、細 胞増殖、破骨細胞分化、過剰な免疫反応（自己免疫反応、アレルギー反応、臓器移植 時の拒絶反応、移植片対宿主疾患（graft versus host disease)等）等が関与する疾 患の予防又は治療剤として有用である。より具体的には、癌、骨'関節疾患（骨粗鬆症、 変形性関節症等）、自己免疫疾患（乾癬、関節リウマチ、多発性硬化症、全身性エリテ マト一デス、シ X—グレン症候群、ぶどう膜炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎 、クローン病等）、アレルギー性疾患（アトピー性皮膚炎、アレルギー性皮膚炎、アレルギ 一性鼻炎、アレルギ一性結膜炎、気管支喘息等）、臓器移植時の拒絶反応、移植片対 宿主疾患等の予防又は治療剤として有用である。 背景技術  The present invention relates to a novel heterocyclic amide derivative useful as a pharmaceutical or a salt thereof. The derivative has dihydrorotate dehydrogenase (hereinafter referred to as “DHODH”) inhibitory activity, cell proliferation, osteoclast differentiation, excessive immune reaction (autoimmune reaction, allergic reaction, organ transplantation). It is useful as a prophylactic or therapeutic agent for diseases involving occasional rejection, graft versus host disease, etc. More specifically, cancer, bone 'joint diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Shi X-Glen syndrome, grapes) Meningitis, polymyositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), It is useful as a preventive or therapeutic agent for organ rejection and graft-versus-host disease. Background art
D H O D Hはピリミジンの生合成の律速となるジヒドロォロト酸からォロト酸への酸化還 元段階に関与する酵素であり、細胞増殖のための必須酵素である。この DH O D Hは増 殖性細胞や免疫応答時のリンパ球で過剰発現することが知られており、この D H ODHを 阻害することで細胞増殖、破骨細胞分化、過剰な免疫反応（自己免疫反応、アレルギー 反応、臓器移植時の拒絶反応、移植片対宿主疾患等）等が抑制されることも知られて いる（非特許文献 1、非特許文献 2及び非特許文献 3参照）。  D H O D H is an enzyme involved in the redox step of dihydrorotate to orotate, which is the rate-limiting factor in pyrimidine biosynthesis, and is an essential enzyme for cell growth. This DH ODH is known to be overexpressed in proliferating cells and lymphocytes during the immune response. By inhibiting this DH ODH, cell proliferation, osteoclast differentiation, excessive immune response (autoimmune reaction) It is also known that allergic reactions, rejection during organ transplantation, graft-versus-host disease, etc.) are suppressed (see Non-Patent Document 1, Non-Patent Document 2, and Non-Patent Document 3).
これらのことから D H O D Hを阻害する薬物が癌等の細胞増殖が関与する疾患（非特 許文献 4参照）、骨粗鬆症、変形性関節症等の破骨細胞分化が関与する骨"関節疾患 (非特許文献 1参照）、乾癬、関節リウマチ、多発性硬化症、全身性エリテマトーデス、シ ェ一グレン症候群、ぶどう膜炎、 I型糖尿病、潰瘍性大腸炎、クローン病等の自己免疫 疾患（非特許文献 2、非特許文献 3、非特許文献 5、非特許文献 6参照、非特許文献 7 参照又は非特許文献 8参照、）、アトピー性皮膚炎、アレルギー性皮膚炎、アレルギー性 鼻炎、アレルギー性結膜炎、気管支喘息等のアレルギー性疾患（非特許文献 9参照）、 臓器移植時の拒絶反応、移植片対宿主疾患（非特許文献 3參照）の予防又は治療に 有用であると考えられている。 Based on these findings, drugs that inhibit DHODH are diseases involving cell proliferation such as cancer (see Non-Patent Document 4), bone-related diseases involving osteoclast differentiation such as osteoporosis and osteoarthritis (Non-Patent Document) 1), psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Sjoegren's syndrome, uveitis, type I diabetes, ulcerative colitis, Crohn's disease, etc. Disease (Non-patent document 2, Non-patent document 3, Non-patent document 5, Refer to non-patent document 6, Refer to non-patent document 7 or Refer to non-patent document 8), atopic dermatitis, allergic dermatitis, allergic rhinitis , Allergic conjunctivitis, bronchial asthma and other allergic diseases (see Non-Patent Document 9), rejection at the time of organ transplantation, graft-versus-host disease (see Non-Patent Document 3)) ing.
また、 D H O D H阻害剤としては、イソキサゾ一ル誘導体であるレフルノミド及びその関 連化合物が特許文献 1又は特許文献 2に開示されている。また、キノリンカルボン酸誘 導体が特許文献 3又は特許文献 4に、シクロペンテン一 1 , 2—ジカルボン酸モノアミド誘 導体が特許文献 5に開示されている。しかし、これらの誘導体はいずれも本発明化合物 とは基本化学構造を異にする。  Patent Document 1 or Patent Document 2 discloses leflunomide, which is an isoxazol derivative, and related compounds as DHODOH inhibitors. A quinolinecarboxylic acid derivative is disclosed in Patent Document 3 or Patent Document 4, and a cyclopentene 1,2-dicarboxylic acid monoamide derivative is disclosed in Patent Document 5. However, these derivatives all differ in basic chemical structure from the compounds of the present invention.
—方、プロリンアミド又はチアゾリジンカルボン酸アミド構造を有する化合物が特許文 献 6、特許文献 7又は特許文献 8に開示されている。特許文献 6に開示の化合物はウレ ァ構造を主骨格とする抗生物質に関するものであり、特許文献 7又は特許文献 8に開示 の化合物はいずれもべンズアミド構造を主骨格とする高脂血症治療剤又は鎮痛剤に関 するものである。  On the other hand, compounds having a proline amide or thiazolidine carboxylic acid amide structure are disclosed in Patent Document 6, Patent Document 7 or Patent Document 8. The compounds disclosed in Patent Document 6 relate to antibiotics having a urea structure as the main skeleton, and all of the compounds disclosed in Patent Document 7 or Patent Document 8 treat hyperlipidemia having a benzamide structure as the main skeleton. It relates to drugs or analgesics.
尚、それらの文献には D H O D H阻害剤としての用途は一切記載されておらず、また、 それらの文献に開示されている化合物は、いずれも本発明化合物とは基本化学構造を 異にする。  These documents do not describe any use as a D H O D H inhibitor, and all of the compounds disclosed in these documents differ in basic chemical structure from the compounds of the present invention.
非特許文献 1  Non-patent literature 1
アースライティス.アンド-リューマテイズム、 50卷（3号）、 794- 804頁（2004年） [Arthriti s & Rheumatism, 50(3), 794-804(2004)]  Earthlightis and Rheumatism, 50 卷 (3), 794-804 (2004) [Arthriti s & Rheumatism, 50 (3), 794-804 (2004)]
非特許文献 2  Non-Patent Document 2
エキスパート'オピニオン'オン'セラピューティック'パテント、 9卷（1号）、 41 -45頁（1 99 9年） [Expert Opinion on Therapeutic Patents, 9(1 ),41 -45(1 999)]  Expert 'Opinion' On 'Therapeutic' Patent, 9 卷 (1), 41-45 (1 99 9) [Expert Opinion on Therapeutic Patents, 9 (1), 41 -45 (1 999)]
非特許文献 3 .  Non-patent literature 3.
カレント'オピニオン■イン 'インべスティゲショナル 'ドラッグス、 2卷 (2号）、 222- 230頁（ 2001年） [Current Opin ion in Investigational Drugs, (2 ， 222— 230(2001 )] 非特許文献 4 Current 'Opinion ■ In' Investigational 'Drugs, 2 卷 (2), pp. 222-230 (2001) [Current Opin ion in Investigational Drugs, (2, 222-230 (2001)] Non Patent Literature 4
キャンサー'リサーチ、 46巻、 5014- 501 9頁（1 986年） [ Cancer Research, 46, 501 4 - 50 1 9(1 986)]  Cancer Research, 46, 5014-501 9 (1 986) [Cancer Research, 46, 501 4-50 1 9 (1 986)]
非特許文献 5  Non-Patent Document 5
ザ'アメリカン'ジャーナル'ォブ'ザ 'メディカル'サイエンス、 323巻 (4号）、 1 90-1 93頁（ The 'American' Journal 'Ob' The 'Medical' Science, Volume 323 (4), 1 90-1 93 (
2002年） [The American Journal of The Medical Sciences, 323(4), 1 90-1 93(2002)] 非特許文献 6 2002) [The American Journal of The Medical Sciences, 323 (4), 1 90-1 93 (2002)]
エージェンッ，アクション、 42卷、 1 67- 1 72頁（1 994年） [Agents Action,42,1 67-1 72(1 9 Agent, Action, 42 卷, 1 67- 1 72 (1 994) [Agents Action, 42, 1 67-1 72 (1 9
94)] 94)]
非特許文献 7  Non-Patent Document 7
卜ランスプランテーション-プロシ一ディンヮス [Transplantation Proceedings, 30,41 3 2-41 33(1 998)]  卜 Lance Plantation-Proceedings [Transplantation Proceedings, 30,41 3 2-41 33 (1 998)]
非特許文献 8  Non Patent Literature 8
エキスパート'オピニオン.オン'ィべスチゲイショナル■ドラッグス、 1 3巻、 373-391頁（20 04年） [Expert Opinion on Investigational Drugs, 1 3,373-391 (2004)]  Expert 'Opinion. On' vestigational ■ Drugs, Vol. 1, pp. 373-391 (2004) [Expert Opinion on Investigational Drugs, 1 3,373-391 (2004)]
非特許文献 9  Non-Patent Document 9
ザ.ジャーナル'ォブ 'ファーマコロジ一■アンド'ェクスペリメンタル.セラピューティック ス、 288卷（2号）、 849 - 857頁（1 999年） [The Journal of Pharmacology and Experiment al Therapeutics, 288(2),849-857(1 999)]  The Journal of Pharmacology and Experiment al Therapeutics, 288 (2), 849-857 (1 999) [The Journal of Pharmacology and Experiment al Therapeutics, 288 ( 2), 849-857 (1 999)]
特許文献 1  Patent Literature 1
独国出願公開第 2525023号明細書  German Application No. 2525023
特許文献 2  Patent Document 2
欧州特許第 484223号明細書  European Patent No. 484223
特許文献 3  Patent Document 3
米国特許第 4680299号明細書 .  U.S. Pat.
特許文献 4  Patent Document 4
米国特許第 491 8077号明細書 米国特許出願公開第 2002ノ 003951号明細書 U.S. Pat.No. 491 8077 US Patent Application Publication No. 2002-003951
特許文献 6  Patent Document 6
米国特許出願公開第 2002 1 1 9962号明細書  US Patent Application Publication No. 2002 1 1 9962
特許文献 7  Patent Document 7
特表 2001 - 51 6335号公報  Special table 2001-51 6335 gazette
特許文献 8  Patent Document 8
特開 2002— 241 273号公報  JP 2002-241 273
発明の開示 Disclosure of the invention
新規複素環アミド誘導体の合成研究及びその誘導体の薬理作用を見出すことは非 常に興味深い課題である。  Synthetic studies of new heterocyclic amide derivatives and finding the pharmacological actions of these derivatives are very interesting issues.
本発明者等は新たな化学構造を有する複素璟アミド誘導体の合成研究を行い、数多 くの新規化合物を創製することに成功した。さらに、その誘導体の薬理作用を研究した 結果、その誘導体は DHODH阻害活性、抗関節炎効果、遅延型過敏症（以下、「DTH」 とする）抑制効果、及びリンパ球混合反応（以下、 Γ M L R」とする）活性抑制効果を有し、 細胞増殖、破骨細胞分化、過剰な免疫反応（自己免疫反応、アレルギー反応、臓器移 植時の拒絶反応、移植片対宿主疾患等）等が関与する疾患、すなわち、癌、骨'関節疾 患（骨粗鬆症、変形性関節症等）、自己免疫疾患（乾癬、関節リウマチ、多発性硬化症 、全身性エリテマトーデス、シ: E—グレン症候群、ぶどう膜炎、多発性筋炎、 I型糖尿病、 潰瘍性大腸炎、クローン病等）、アレルギー性疾患（アトピー性皮膚炎、アレルギー性皮 膚炎、アレルギー性鼻炎、アレルギー性結膜炎、気管支喘息等）、臓器移植時の拒絶 反応、移植片対宿主疾患等の予防又は治療剤として有用であることを見出し、本発明 を完成させた。  The present inventors have conducted synthetic studies on hetero-amide derivatives having a new chemical structure and succeeded in creating many new compounds. Furthermore, as a result of studying the pharmacological action of the derivative, the derivative was found to have a DHODH inhibitory activity, an anti-arthritic effect, a delayed hypersensitivity (hereinafter referred to as “DTH”) inhibitory effect, and a mixed lymphocyte reaction (hereinafter referred to as Γ MLR). Diseases that have an activity-inhibiting effect and involve cell proliferation, osteoclast differentiation, excessive immune reactions (autoimmune reactions, allergic reactions, rejection during organ transplantation, graft-versus-host diseases, etc.) That is, cancer, bone 'joint disease (osteoporosis, osteoarthritis, etc.), autoimmune disease (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, shi: E-Glen syndrome, uveitis, multiple occurrences) Myositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), rejection during organ transplantationResponse, found to be useful as a prophylactic or therapeutic agent such as graft-versus-host disease, thereby completing the present invention.
すなわち、本発明は下記一般式（1 )で表される化合物又はその塩（以下、「本発明化 合物」とする）及びそれらを含む医薬組成物に関する。また、その医薬用途における好ま しい発明は DH O DH阻害剤に関するものであり、その対象疾患としては、細胞増殖、破 骨細胞分化、過剰な免疫反応（自己免疫反応、アレルギー反応、臓器移植時の拒絶反 応、移植片対宿主疾患等）等が関与する疾患が挙げられ、より具体的には、癌、骨'関 節疾患（骨粗鬆症、変形性関節症等）、自己免疫疾患（乾癬、関節リウマチ、多発性硬 化症、全身性エリ亍マト一デス、シエーグレン症候群、ぶどう膜炎、多発性筋炎、 I型糖 尿病、潰瘍性大腸炎、クローン病等）、アレルギー性疾患（アトピー性皮膚炎、アレルギ 一性皮膚炎、ァレルギ一性鼻炎、アレルギー性結膜炎、気管支喘息等）、臓器移植時の 拒絶反応、移植片対宿主疾患等が挙げられる。好ましい発明はこれらの疾患の予防又 は治療剤に関する発明である。 That is, the present invention relates to a compound represented by the following general formula (1) or a salt thereof (hereinafter referred to as “the compound of the present invention”) and a pharmaceutical composition containing them. In addition, a preferred invention for its pharmaceutical use relates to a DH O DH inhibitor, and its target diseases include cell proliferation and destruction. Diseases involving bone cell differentiation, excessive immune response (autoimmune reaction, allergic reaction, rejection response at the time of organ transplantation, graft-versus-host disease, etc.) can be mentioned. More specifically, cancer, bone Related diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Siegren's syndrome, uveitis, polymyositis, type I sugar Urine disease, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), rejection during organ transplantation, transplantation One-to-one host disease and the like can be mentioned. A preferred invention is an invention relating to a prophylactic or therapeutic agent for these diseases.
Figure imgf000007_0001
Figure imgf000007_0001
[式中、 X1— X2は S— CH2、 CH2— S、 CH2— CH2、又は CH = CHを示し； [Wherein X 1 — X 2 represents S—CH 2 , CH 2 — S, CH 2 — CH 2 , or CH = CH;
R1は置換基を有してもよい低級アルキル基、置換基を有してもよいァリール基、ヒドロキ シ基、ヒドロキシ基のエステル、置換基を有してもよい低級アルコキシ基、及び置換基を 有してもよいァリールォキシ基から選択される基を示し； R 1 represents a lower alkyl group which may have a substituent, an aryl group which may have a substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, and a substituent. A group selected from an aryloxy group which may have
pは 0~ 7を示し、 pが 2〜7である場合、各 R1は同一又は異なってもよく； p represents 0-7, and when p is 2-7, each R 1 may be the same or different;
R2は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいァリール 基、置換基を有してもよいァラルキル基、ホルミル基、置換基を有してもよい低級アルキ ルカルポニル基、置換基を有してもよいァリールカルボ二ル基、置換基を有してもよい低 級アルコキシカルボニル基、置換基を有してもよいァリールォキシカルポニル基、置換基 を有してもよい低級アルキルスルフィニル基、置換基を有してもよいァリールスルフィニル 基、置換基を有してもよい低級アルキルスルホニル基、又は置換基を有してもよいァリ一 ルスルホニル基を示し； R 2 may have a hydrogen atom, a lower alkyl group that may have a substituent, an aryl group that may have a substituent, an aralkyl group that may have a substituent, a formyl group, or a substituent. Good lower alkylcarbonyl group, optionally substituted arylcarbonyl group, optionally substituted lower alkoxycarbonyl group, optionally substituted aryloxycarbonyl group, substituent A lower alkylsulfinyl group which may have a substituent, an arylsulfinyl group which may have a substituent, a lower alkylsulfonyl group which may have a substituent, or an aryl which may have a substituent Represents a sulfonyl group;
R3は水素原子、又は置換基を有してもよい低級アルキル基を示し； R 3 represents a hydrogen atom or an optionally substituted lower alkyl group;
Y1— Y2は CH = CH、 N = CH、又は CH = Nを示し； Y 1 — Y 2 represents CH = CH, N = CH, or CH = N;
R4はハロゲン原子、置換基を有してもよい低級アルキル基、ハロゲノ低級アルキル基、 置換基を有してもよい低級アルケニル基、置換基を有してもよい低級アルキニル基、置 換基を有してもよいァリール基、置換基を有してもよいァラルキル基、ヒドロキシ基、ヒドロ キシ基のエステル、置換基を有してもよい低級アルコキシ基、置換基を有してもよいァリ ールォキシ基、置換基を有してもよいァラルキルォキシ基、アミノ基、ァミノ基のアミド、置 換基を有してもよい低級アルキルアミノ基、置換基を有してもよい低級アルキルアミノ基 のアミド、置換基を有してもよいァリールアミノ基、置換基を有してもよいァリールアミノ基 のアミド、カルポキシ基、カルボキシ基のエステル、カルボキシ基のアミド、及びシァノ基か ら選択される基を示し； R 4 is a halogen atom, an optionally substituted lower alkyl group, a halogeno lower alkyl group, A lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a hydroxy group, An ester of a hydroxy group, a lower alkoxy group which may have a substituent, an aryloxy group which may have a substituent, an aralkyloxy group which may have a substituent, an amino group, an amide of an amino group, Lower alkylamino group which may have a substituent, Amide of lower alkylamino group which may have a substituent, Arylamino group which may have a substituent, Arylamino group which may have a substituent A group selected from an amide, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, and a cyan group;
qは 0~ 4を示し、 qが 2〜4である場合、各 R4は同一又は異なってもよく； q represents 0-4, and when q is 2-4, each R 4 may be the same or different;
R5はハロゲン原子、水素原子、置換基を有してもよい低級アルキル基.、ハロゲノ低級ァ ルキル基、置換基を有してもよい低級シクロアルキル基、置換基を有してもよいァリール 基、置換基を有してもよい複素環基、置換基を有してもよいァラルキル基、ヒドロキシ基、 ヒドロキシ基のエステル、置換基を有してもよい低級アルコキシ基、ハロゲノ低級アルコキ シ基、置換基を有してもよい低級シクロアルキルォキシ基、置換基を有してもよいァリー ルォキシ基、置換基を有してもよい複素環ォキシ基、置換基を有してもよいァラルキルォ キシ基、メルカプト基、メルカプト基のエステル、置換基を有してもよい低級アルキルチオ 基、ハロゲノ低級アルキルチオ基、置換基を有してもよい低級シクロアルキルチオ基、置 換基を有してもよいァリ一ルチオ基、置換基を有してもよい複素環チォ基、置換基を有し てもよぃァラルキルチオ基、アミノ基、ァミノ基のアミド、置換基を有してもよい低級アルキ ルァミノ基、置換基を有してもよい低級アルキルアミノ基のアミ 置換基を有してもよい ァリールアミノ基、置換基を有してもよいァリ一ルァミノ基のアミド、ホルミル基、置換基を 有してもよい低級アルキルカルボ二ル基、置換基を有してもよいァリ一ルカルポ二ル基、 カルボキシ基、カルポキシ基のエステル、カルボキシ基のアミド、置換基を有してもよい低 級アルキルスルフィニル基、置換基を有してもよいァリールスルフィニル基、置換基を有し てもよい低級アルキルスルホニル基、置換基を有してもよいァリ一ルスルホニル基、スル フィン酸基、スルフィン酸基のエステル、スルフィン酸基のアミド、スルホン酸基、スルホン 酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ基、 CR6 = CR7 (R8)、 C≡CR9、 又は N = N R1 ()を示し； R 5 is a halogen atom, a hydrogen atom, an optionally substituted lower alkyl group, a halogeno lower alkyl group, an optionally substituted lower cycloalkyl group, or an optionally substituted aryl. Group, a heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group A lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, and an aralkylo which may have a substituent Xyl group, mercapto group, ester of mercapto group, optionally substituted lower alkylthio group, halogeno-lower alkylthio group, optionally substituted lower cycloalkylthio group, may have a substituent. An arylthio group, an optionally substituted heterocyclic thio group, an optionally substituted aralkylthio group, an amino group, an amide of an amino group, an optionally substituted lower alkylamino Group, may have a lower alkylamino group which may have a substituent may have an aryl substituent, an amide, a formyl group or a substituent of an arylamino group which may have a substituent A lower alkyl carbonyl group which may be substituted, an arylcarbonyl group which may have a substituent, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, a lower class which may have a substituent An alkylsulfinyl group, an arylsulfinyl group which may have a substituent, a lower alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfinic acid group, Sulfinic acid group Esters, amides of a sulfinic acid group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, Shiano group, CR 6 = CR 7 (R 8), C≡CR 9, Or N = NR 1 () ;
R6は水素原子、又は置換基を有してもよい低級アルキル基を示し； R 6 represents a hydrogen atom or an optionally substituted lower alkyl group;
R7と R8は同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基 を有してもよい低級シクロアルキル基、置換基を有してもよいァリール基、置換基を有し てもよい複素環基、カルボキシ基、カルポキシ基のエステル、又はカルボキシ基のアミドを 示し； R 7 and R 8 are the same or different and are a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, A heterocyclic group which may have a substituent, a carboxy group, an ester of a carboxy group or an amide of a carboxy group;
R9は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよい低級シク 口アルキル基、置換基を有してもよいァリール基、又は置換基を有してもよい複素環基を 示し、 R 9 has a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. A good heterocyclic group,
R1 Qが置換基を有してもよいァリール基を示す。以下、同じ。] R 1 Q represents an aryl group which may have a substituent. same as below. ]
本発明は医薬として有用な新規複素環アミド誘導体を提供する。本発明化合物は優 れた DH OD H阻害活性、抗関節炎効果、遅延型過敏症（以下、「DTH」とする）抑制効果 、及びリンパ球混合反応（以下、「MLRJとする）活性抑制効果を有し、細胞増殖、破骨細 胞分化、過剰な免疫反応（自己免疫反応、アレルギー反応、臓器移植時の拒絶反応、 移植片対宿主疾患等）等が関与する疾患の予防又は治療剤として有用であり、特に癌 、骨■関節疾患（骨粗鬆症、変形性関節症等）、自己免疫疾患（乾癬、関節リウマチ、多 発性硬化症、全身性エリテマトーデス、シエーグレン症候群、ぶどう膜炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎、クローン病等）、アレルギー性疾患（アトピー性皮膚炎、ァ レルギ一性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎、気管支喘息等）、臓器移 植時の拒絶反応、移植片対宿主疾患等の予防又は治療剤として有用である。 発明を実施するための最良の形態  The present invention provides a novel heterocyclic amide derivative useful as a medicine. The compound of the present invention has excellent DHODH inhibitory activity, anti-arthritic effect, delayed type hypersensitivity (hereinafter referred to as “DTH”) inhibitory effect, and lymphocyte mixed reaction (hereinafter referred to as “MLRJ”) inhibitory effect. It is useful as a preventive or therapeutic agent for diseases involving cell proliferation, osteoclast differentiation, excessive immune response (autoimmune reaction, allergic reaction, rejection during organ transplantation, graft-versus-host disease, etc.) In particular, cancer, bone ■ joint diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, siegren syndrome, uveitis, polymyositis, Type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), rejection during organ transplantation The graft It is useful as a preventive or therapeutic agent for host disease etc. BEST MODE FOR CARRYING OUT THE INVENTION
本明細書中で使用される原子又は基について以下に詳しく説明する。  The atoms or groups used in this specification will be described in detail below.
「ハロゲン原子」とは、フッ素、塩素、臭素又はヨウ素原子を示す。  “Halogen atom” refers to a fluorine, chlorine, bromine or iodine atom.
「低級アルキル基」とは、炭素原子数が 1 ~ 8個の直鎖又は分枝のアルキル基を示す 。具体例として、メチル、ェチル、 n—プロピル、 n—プチル、 n—ペンチル、 n—へキシル、 n 一へプチル、 n—ォクチル、イソプロピル、イソプチル、 sec—ブチル、 tert—プチル、イソべ ンチル基等が挙げられる。 The “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isoptyl, sec-butyl, tert-butyl, isobutyl. An nyl group and the like.
「ハロゲノ低級アルキル基」とは、 1又は複数個のハロゲン原子を置換基として有する 低級アルキル基を示す。具体例として、モノフルォロメチル、ジフルォロメチル、トリフルォ ロメチル、トリフルォロェチル、モノクロロメチル、ジクロロメチル、トリクロロメチル、トリプロ モメチル、トリョードメチル基等が挙げられる。  The “halogeno lower alkyl group” refers to a lower alkyl group having one or more halogen atoms as a substituent. Specific examples include monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, tripromomethyl, triodomethyl group and the like.
「低級アルケニル基」とは、炭素原子数が 2 ~ 8個の直鎖又は分枝のアルケニル基を 示す。具体例として、ビニル、プロべニル、ブテニル、ペンテニル、へキセニル、ヘプテニル 、ォクテニル、イソプロぺニル、 2—メチル一1—プロぺニル、 2—メチルー 2—ブテニル基 等が挙げられる。  The “lower alkenyl group” refers to a straight or branched alkenyl group having 2 to 8 carbon atoms. Specific examples include vinyl, probenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, isopropenyl, 2-methyl-1-propenyl, 2-methyl-2-butenyl and the like.
「低級アルキニル基」とは、炭素原子数が 2 ~ 8個の直鎖又は分枝のアルキニル基を 示す。具体例として、ェチニル、プロピニル、プチニル、ペンチニル、へキシニル、へプチ二 ル、ォクチニル、イソプチニル、イソペンチニル基等が挙げられる。  The “lower alkynyl group” refers to a straight chain or branched alkynyl group having 2 to 8 carbon atoms. Specific examples include ethynyl, propynyl, petynyl, pentynyl, hexynyl, heptynyl, octynyl, isoptynyl, isopentynyl group and the like.
「低級シクロアルキル基」とは、炭素原子数が 3 ~ 8個のシクロアルキル基を示す。具 体例として、シクロプロピル、シクロブチル、シクロペンチル、シクロへキシル、シクロへプチ ル又はシクロォクチル基が挙げられる。  The “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups.
「ァリール基」とは、炭素原子数が 6 ~ 1 4個の単環式芳香族炭化水素基又は 2環式 若しくは 3環式の縮合多環式芳香族炭化水素から水素 1原子を除いた残基を示す。具 体例として、フエニル、ナフチル、アントリル、フエナントリル基等が挙げられる。  “Aryl group” means a monocyclic aromatic hydrocarbon group having 6 to 14 carbon atoms or a residue obtained by removing one hydrogen atom from a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon. Indicates a group. Specific examples include phenyl, naphthyl, anthryl, phenanthryl groups and the like.
「複素環基」とは、窒素原子、酸素原子及び硫黄原子から選択される 1又は複数個の ヘテロ原子を環内に有する飽和或いは不飽和単環式複素環又は 2環式若しくは 3環式 の縮合多環式複素環から水素 1原子を除いた残基を示す。  “Heterocyclic group” means a saturated or unsaturated monocyclic heterocycle having one or more heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring, or a bicyclic or tricyclic ring. A residue obtained by removing one hydrogen atom from a fused polycyclic heterocycle.
飽和の単環式複素環の具体例として、窒素原子を環内に有するピロリジン、ビラゾリ ジン、イミダゾリジン、トリァゾリジン、ピぺリジン、へキサヒドロピリダジン、へキサヒドロピリ ミジン、ピぺラジン、ホモピぺリジン、ホモピぺラジン環等が、酸素原子を環内に有するテト ラヒドロフラン、テトラヒドロピラン環等が、硫黄原子を環内に有するテトラヒドロチォフェン 、テトラヒドロチォピラン環等が、窒素原子と酸素原子を環内に有するォキサゾリジン、ィ ソォキサゾリジン、モルホリン環等が、窒素原子と硫黄原子を環内に有するチアゾリジン 、イソチアゾリジン、チオモルホリン環等が挙げられる。 Specific examples of saturated monocyclic heterocycles include pyrrolidine, virazolidine, imidazolidine, triazolidine, piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine, homopiperidine having nitrogen atoms in the ring, Homopiperazine rings, etc. include tetrahydrofuran, tetrahydropyran rings, etc., which have oxygen atoms in the ring, tetrahydrothiophene, tetrahydrothiopyran rings, etc., which have sulfur atoms in the ring, nitrogen and oxygen atoms in the ring Thiazolidine having a nitrogen atom and a sulfur atom in the ring, such as having an oxazolidine, isoxazolidine, morpholine ring, etc. , Isothiazolidine, thiomorpholine ring and the like.
また、それらの飽和の単環式複素璟はベンゼン環等と縮合してジヒドロインドール、ジ ヒドロインダゾ一ル、ジヒドロべンゾイミダゾール、テトラヒドロキノリン、テトラヒドロイソキノ リン、テトラヒドロシンノリン、テトラヒドロフタラジン、テトラヒドロキナゾリン、テトラヒドロキノ キサリン、ジヒドロべンゾフラン、ジヒドロイソべンゾフラン、クロマン、イソクロマン、ジヒドロ ベンゾチォフェン、ジヒドロイソベンゾチォフェン、チォクロマン、イソチォクロマン、ジヒドロ ベンゾォキサゾ一ル、ジヒドロべンゾイソォキサゾ一ル、ジヒドロべンゾォキサジン、ジヒドロ ベンゾチアゾ一ル、ジヒドロべンゾイソチアゾ一ル、ジヒドロべンゾチアジン、キサンテン、 4a 一力ルバゾール、ペリミジン環等の 2環式又は 3環式の縮合多環式複素環を形成しても よい。  These saturated monocyclic heterocycles are condensed with a benzene ring or the like to form dihydroindole, dihydroindazol, dihydrobenzimidazole, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydrocinnoline, tetrahydrophthalazine, tetrahydro Quinazoline, tetrahydroquinoxaline, dihydrobenzazofuran, dihydroisobenzofuran, chroman, isochroman, dihydrobenzothiophene, dihydroisobenzothiophene, thiochroman, isothiochroman, dihydrobenzoxazol, dihydrobenzoisoxazol, dihydrobenzoxazine, dihydrobenzothazol , Dihydrobenzoisothiazol, dihydrobenzothiazine, xanthene, 4a rubazole, perimidine ring, etc. If polycyclic heterocycle may be formed.
不飽和の単環式複素璟の具体例として、窒素原子を環内に有するジヒドロピロール、 ピロ一ル、ジヒドロピラゾ一ル、ピラゾール、ジヒドロイミダゾ一ル、イミダゾ一ル、ジヒドロト リアゾール、トリァゾ一ル、テトラヒドロピリジン、ジヒドロピリジン、ピリジン、テトラヒドロピリ ダジン、ジヒドロピリダジン、ピリダジン、テトラヒドロピリミジン、ジヒドロピリミジン、ピリミジ ン、テトラヒドロビラジン、ジヒドロビラジン、ピラジン環等が、酸素原子を環内に有するジヒ ドロフラン、フラン、ジヒドロピラン、ピラン環等力 硫黄原子を環内に有するジヒドロチオフ ェン、チォフェン、ジヒドロチォピラン、チォピラン環等が、窒素原子と酸素原子を環内に 有するジヒドロォキサゾ一ル、ォキサゾ一ル、ジヒドロイソォキサゾ一ル、イソォキサゾ一ル 、ジヒドロォキサジン、ォキサジン環等が、窒素原子と硫黄原子を環内に有するジヒドロ チアゾ一ル、チアゾール、ジヒドロイソチアゾ一ル、イソチアゾ一ル、ジヒドロチアジン、チア ジン環等が挙げられる。  Specific examples of unsaturated monocyclic heterocycles include dihydropyrrole, pyrrole, dihydropyrazol, pyrazole, dihydroimidazole, imidazole, dihydrotriazole, triazol, tetrahydro having nitrogen atoms in the ring. Pyridine, dihydropyridine, pyridine, tetrahydropyridazine, dihydropyridazine, pyridazine, tetrahydropyrimidine, dihydropyrimidine, pyrimidin, tetrahydrovirazine, dihydrovirazine, pyrazine ring, etc. are dihydrofuran, furan, dihydro, which have an oxygen atom in the ring. Pyran, pyran ring isotonic dihydrothiophene, thiophene, dihydrothiopyran, thiopyran ring, etc. having a sulfur atom in the ring are dihydrooxazol, oxazol, dihydroisoxoxax having a nitrogen atom and an oxygen atom in the ring. Dihydrothiazol, thiazole, dihydroisothiazol, isothiazol, dihydrothiazine, thiazine having a nitrogen atom and a sulfur atom in the ring. A ring etc. are mentioned.
また、それらの不飽和の単環式複素環はベンゼン環等と縮合してインド一ル、インダゾ —ル、ベンゾイミダゾ一ル、ベンゾトリアゾ一ル、ジヒドロキノリン、キノリン、ジヒドロイソキノ リン、イソキノリン、フエナントリジン、ジヒドロシンノリン、シンノリン、ジヒドロフタラジン、フタ ラジン、ジヒドロキナゾリン、キナゾリン、ジヒドロキノキサリン、キノキサリン、ベンゾフラン、 イソべンゾフラン、クロメン、イソクロメン、ベンゾチォフェン、イソベンゾチォフェン、チォクロ メン、イソチォクロメン、ベンゾォキサゾ一ル、ベンゾイソォキサゾール、ベンゾォキサジン、 ― ベンゾチアゾール、ベンゾイソチアゾール、ベンゾチアジン、フエノキサンチン、カルバゾ一 ル、 j8—カルボリン、フエナントリジン、ァクリジン、フエナント口リン、フエナジン、フエノチア ジン、フヱノキサジン環等の 2環式又は 3環式の縮合多環式複素環を形成してもよい。 「ァラルキル基」とは、 1又は複数個のァリール基を置換基として有する低級アルキル 基を示す。具体例として、ベンジル、フエネチル、ナフチルメチル、ジフエニルメチル基等が 挙げられる。 In addition, these unsaturated monocyclic heterocycles are condensed with a benzene ring or the like to form indol, indazole, benzimidazole, benzotriazol, dihydroquinoline, quinoline, dihydroisoquinoline, isoquinoline, phenol. Nanthridine, dihydrocinnoline, cinnoline, dihydrophthalazine, phthalazine, dihydroquinazoline, quinazoline, dihydroquinoxaline, quinoxaline, benzofuran, isobenzofuran, chromene, isochromene, benzothiophene, isobenzothiophene, thiochromene, isothiochromene, benzoxazo , Benzoisoxazole, benzoxazine, ― Benzothiazole, benzoisothiazole, benzothiazine, phenoxanthine, carbazole, j8-carboline, phenanthridine, acridine, phenanthorin, phenazine, phenothiazine, phenoxazine ring, etc. A cyclic heterocyclic ring may be formed. The “aralkyl group” refers to a lower alkyl group having one or more aryl groups as a substituent. Specific examples include benzyl, phenethyl, naphthylmethyl, diphenylmethyl groups and the like.
「低級アルコキシ基」とは、ヒドロキシ基の水素原子が低級アルキル基で置換された基 を示す。具体例として、メトキシ、エトキシ、 n—プロポキシ、 n—ブトキシ、 π—ペントキシ、 n —へキシルォキシ、 n—へプチルォキシ、 n—ォクチルォキシ、イソプロポキシ、イソブトキシ 、 sec—ブトキシ、 tert—ブトキシ、イソペントキシ基等が挙げられる。 .  The “lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, π-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group, etc. Is mentioned. .
「ハロゲノ低級アルコキシ基」とは、ヒドロキシ基の水素原子がハロゲノ低級アルキル 基で置換された基を示す。具体例として、モノフルォロメトキシ、ジフルォロメトキシ、トリフ ルォロメトキシ、トリフルォロエトキシ、モノクロロメトキシ、ジクロロメトキシ、トリクロロメトキ シ、トリプロモメトキシ、トリヨ一ドメトキシ基等が挙げられる。  The “halogeno lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a halogeno lower alkyl group. Specific examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, monochloromethoxy, dichloromethoxy, trichloromethoxy, tripromomethoxy, triiodomethoxy group and the like.
「低級アルケニルォキシ基」とは、ヒドロキシ基の水素原子が低級アルケニル基で置換 された基を示す。具体例として、ビニルォキシ、プロべニルォキシ、ブテニルォキシ、ペンテ ニルォキシ、へキセニルォキシ、ヘプテニルォキシ、ォクテニルォキシ、イソプロぺニルォキ シ、 2—メチル一1—プロべニルォキシ、 2—メチルー 2—ブテニルォキシ基等が挙げられ る。  The “lower alkenyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkenyl group. Specific examples include vinyloxy, probenoxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, isopropenyloxy, 2-methyl-1-proenyloxy, 2-methyl-2-butenyloxy and the like.
「低級アルキニルォキシ基」とは、ヒドロキシ基の水素原子が低級アルキニル基で置換 された基を示す。具体例として、ェチニルォキシ、プロピニルォキシ、プチニルォキシ、ペン チニルォキシ、へキシニルォキシ、へプチニルォキシ、ォクチニルォキシ、イソプチニルォ キシ、イソペンチニルォキシ基等が挙げられる。  The “lower alkynyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkynyl group. Specific examples include ethynyloxy, propynyloxy, ptynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, isoptynyloxy, isopentynyloxy groups and the like.
「低級シクロアルキルォキシ基」とは、ヒドロキシ基の水素原子が低級シクロアルキル 基で置換された基を示す。具体例として、シクロプロピルォキシ、シクロブチルォキジ、シ クロペンチルォキシ、シクロへキシルォキシ、シクロへプチルォキシ、シクロォクチルォキシ 基等が挙げられる。 「ァリールォキシ基」とは、ヒドロキシ基の水素原子がァリール基で置換された基を示す 。具体例として、フエノキシ、ナフトキシ、アントリルォキシ、フエナントリルォキシ基等が挙 げられる。 The “lower cycloalkyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower cycloalkyl group. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy groups, and the like. The “aryloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryl group. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy groups and the like.
「複素環ォキシ基」とは、ヒドロキシ基の水素原子が複素環基で置換された基を示す。 「ァラルキルォキシ基」とは、ヒドロキシ基の水素原子がァラルキル基で置換された基 を示す。具体例として、ベンジルォキシ、フエネチルォキシ、ナフチルメトキシ、ジフエニルメ トキシ基等が挙げられる。  “Heterocyclicoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a heterocyclic group. The “aralkyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aralkyl group. Specific examples include benzyloxy, phenethyloxy, naphthylmethoxy, diphenylmethoxy groups and the like.
「低級アルキルチオ基」とは、メルカプト基の水素原子が低級アルキル基で置換された 基を示す。具体例として、メチルチオ、ェチルチオ、 n—プロピルチオ、 n—プチルチオ、 n— ペンチルチオ、 n—へキシルチオ、 n—へプチルチオ、 n—ォクチルチオ、イソプロピルチオ、 イソプチルチオ、 sec—ブチルチオ、 tert—プチルチオ、イソペンチルチオ基等が挙げられ る。  The “lower alkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower alkyl group. Specific examples include methylthio, ethylthio, n-propylthio, n-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio, isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio Groups and the like.
「ハロゲノ低級アルキルチオ基」とは、メルカプト基の水素原子がハロゲノ低級アルキル 基で置換された基を示す。具体例として、モノフルォロメチ)レチォ、ジフルォロメチルチオ、 トリフルォロメチルチオ、トリフルォロェチルチオ、モノクロロメチルチオ、ジクロロメチルチオ 、トリクロロメチルチオ、トリプロモメチルチオ、トリヨ一ドメチルチオ基等が挙げられる。 The “halogeno lower alkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a halogeno lower alkyl group. Specific examples include monofluoromethi) retio, difluoromethylthio, trifluoromethylthio, trifluoroethylthio, monochloromethylthio, dichloromethylthio, trichloromethylthio, tripromomethylthio, triiodomethylthio groups and the like.
「低級シクロアルキルチオ基」とは、メルカプト基の水素原子が低級シクロアルキル基 で置換された基を示す。具体例として、シクロプロピルチオ、シクロプチルチオ、シクロペン チルチオ、シクロへキシルチオ、シクロへプチルチオ又はシクロォクチルチオ基が挙げられ る。 The “lower cycloalkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a lower cycloalkyl group. Specific examples include cyclopropylthio, cycloptylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio or cyclooctylthio groups.
「ァリ一ルチオ基」とは、メルカプト基の水素原子がァリール基で置換された基を示す。 具体例として、フエ二ルチオ、ナフチルチオ、アントリルチオ、フエナントリルチオ基等が挙 げられる。  The “arylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with an aryl group. Specific examples include phenylthio, naphthylthio, anthrylthio, phenanthrylthio groups and the like.
「複素環チォ基」とは、メルカプト基の水素原子が複素環基で置換された基を示す。  The “heterocyclic thio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with a heterocyclic group.
Γァラルキルチオ基」とは、メルカプト基の水素原子がァラルキル基で置換された基を 示す。具体例として、ベンジルチオ、フエネチルチオ、ナフチルメチルチオ、ジフエ二ルメチ ルチオ基等が挙げられる。 「低級アルキルアミノ基」とは、ァミノ基の—方又は両方の水素原子が低級アルキル基 で置換された基を示す。具体例として、メチルァミノ、ェチルァミノ、プロピルアミ人ジメル アミ人ジェチルァミノ、ェチルメチルァミノ基等が挙げられる。 The “Γaralkylthio group” refers to a group in which a hydrogen atom of a mercapto group is substituted with an aralkyl group. Specific examples include benzylthio, phenethylthio, naphthylmethylthio, diphenylmethylthio groups and the like. The “lower alkylamino group” refers to a group in which one or both hydrogen atoms of an amino group are substituted with a lower alkyl group. Specific examples include methylamino, ethylamino, propylamido dimellami decylamino, ethylmethylamino groups and the like.
「ァリールアミノ基」として、ァミノ基の一方若しくは両方の水素原子がァリール ¾で置 換された基、又はアミノ基の一方の水素原子がァリール基で、他方の水素原子が低級ァ ルキル基で置換された基を示す。具体的として、フエニルァミノ、ナフチルァミノ、アントリ ルァミノ、フエナントリノレアミノ、ジフエニルァミノ、メチルフエニルアミ人ェチルフエニルァミノ 基等が挙げられる。  An “aryl amino group” is a group in which one or both hydrogen atoms of an amino group are substituted with an aryl group, or one hydrogen atom of an amino group is substituted with an aryl group and the other hydrogen atom is substituted with a lower alkyl group. The group is shown. Specific examples include phenylamino, naphthylamino, anthrylamino, phenanthrinoleamino, diphenylamino, methylphenylamino phenylamine groups and the like.
「低級アルキルカルポニル基」とは、ホルミル基の水素原子が低級アルキル基で置換 された基を示す。具体例としてメチルカルポニル、ェチルカルボニル、 n—プロピル力ルポ ニル、 n—ブチルカ'ルポニル、 n—ペンチルカルボニル、 n—へキシルカルポニル、 n—ヘプ チルカルポニル、 n—ォクチルカルポニル、イソプロピルカルボニル、イソブチルカルポ；ル 、 sec—プチルカルポニル、 tert—プチルカルポニル、イソペンチルカルポニル基等が挙げ られる。  The “lower alkylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with a lower alkyl group. Specific examples include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, n-butyl carbonyl, n-pentyl carbonyl, n-hexyl carbonyl, n-heptyl carbonyl, n-octyl carbonyl, isopropyl carbonyl, isobutyl. Carboxyl; sec-butyl carbonyl, tert-butyl carbonyl, isopentyl carbonyl, and the like.
「ァリールカルボニル基」とは、ホルミル基の水素原子がァリ一ル基で置換された基を 示す。具体例として、フエ二ルカルポニル、ナフチルカルポニル、アントリル力ルポニル、フ ェナントリルカルボニル基等が挙げられる。  “Arylcarbonyl group” refers to a group in which a hydrogen atom of a formyl group is substituted with an aryl group. Specific examples include phenylcarbonyl, naphthylcarbonyl, anthryl strength sulfonyl, phenanthrylcarbonyl group, and the like.
「低級アルコキシカルボ二ル基」とは、ホルミル基の水素原子が低級アルコキシ基で置 換された基を示す。具体例として、メトキシカルボニル、エトキシカルボニル、 n—プロポキ シカルポニル、 n—ブトキシカルポニル、 n—ペントキシカルポニル、 n—へキシルォキシ力 ルポニル、 n—へプチルォキシカルポニル、 n—ォクチルォキシカルボニル、イソプロポキシ カルボニル、イソブトキシカルポニル、 sec—ブトキシカルボニル、 tert—ブトキシカルボ二 ル、イソペントキシカルボニル基等が挙げられる。  The “lower alkoxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is replaced with a lower alkoxy group. Specific examples include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, n-pentoxycarbonyl, n-hexyloxyl sulfonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl, iso Examples thereof include propoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, isopentoxycarbonyl group and the like.
「ァリールォキシカルボニル基」とは、ホルミル基の水素原子がァリールォキシ基で置 換された基を示す。具体例として、フエノキシ力ルポニル、ナフトキシカル.ボニル、アントリ ルォキシカルポニル、フヱナントリルォキシカルボニル基等が挙げられる。  The “aryloxycarbonyl group” refers to a group in which a hydrogen atom of a formyl group is replaced with an aryloxy group. Specific examples thereof include phenoxy strength sulfonyl, naphthoxycarbonyl, anthryloxycarbonyl, phenanthryloxycarbonyl group, and the like.
「低級アルキルスルフィニル基」とは、スルフィン酸基のヒドロキシが低級アルキル基で 置換された基を示す。具体例として、メチルスルフィニル、ェチルスルフィニル、 n—プロピ ルスルフィニル、 n—ブチルスルフィニル、 n—ペンチルスルフィニル、 n—へキシルスルフィ ニル、 n—へプチルスルフィニル、 n—ォクチルスルフィニル、イソプロピルスルフィニル、ィ ソブチルスルフィニル、 sec—プチルスルフィニル、 tert—プチルスルフィニル、イソペンチ ルスルフィニル基等が挙げられる。 “Lower alkylsulfinyl group” means that the hydroxy of the sulfinic acid group is a lower alkyl group. Indicates a substituted group. Specific examples include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, n-butylsulfinyl, n-pentylsulfinyl, n-hexylsulfinyl, n-heptylsulfinyl, n-octylsulfinyl, isopropylsulfinyl, isoso Examples thereof include butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, isopentylsulfinyl group and the like.
Γァリ一ルスルフィニル基」とは、スルフィン酸基のヒドロキジがァリ一ル基で置換された 基を示す。具体例として、フエニルスルフィニル、ナフチルスルフィニル、アントリルスルフィ ニル、フ Iナントリルスルフィニル基等が挙げられる。  The term “Γ arylsulfinyl group” refers to a group in which a hydroxyl group of a sulfinic acid group is substituted with an aryl group. Specific examples include phenylsulfinyl, naphthylsulfinyl, anthrylsulfinyl, phenylanthrylsulfinyl groups, and the like.
「低級アルキルスルホニル基」とは、スルホン酸基のヒドロキジが低級アルキル基で置 換された基を示す。具体例として、メチルスルホニル、ェチルスルホニル、 n—プロピルス ルホニル、 n—ブチルスルホニル、 n—ペンチルスルホニル、 π—へキシルスルホニル、 n— へプチルスルホニル、 n—ォクチルスルホニル、イソプロピルスルホニル、イソブチルスルホ ニル、 sec—ブチルスルホニル、 tert—ブチルスルホニル、イソペンチルスルホニル基等が 挙げられる。  The “lower alkylsulfonyl group” refers to a group in which a hydride of a sulfonic acid group is replaced with a lower alkyl group. Specific examples include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl, π-hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl, isopropylsulfonyl, isobutylsulfonyl. Sec-butylsulfonyl, tert-butylsulfonyl, isopentylsulfonyl group and the like.
「ァリールスルホニル基」とは、スルホン酸基のヒドロキシがァリール基で置換された基 を示す。具体例として、フエニルスルホニル、ナフチルスルホニル、アントリルスルホニル、 フエナントリルスルホニル基等が挙げられる。  “Arylsulfonyl group” refers to a group in which hydroxy of a sulfonic acid group is substituted with an aryl group. Specific examples include phenylsulfonyl, naphthylsulfonyl, anthrylsulfonyl, phenanthrylsulfonyl groups, and the like.
「低級アルコキシカルボニルォキシ基」とは、ヒドロキシ基の水素原子が低級アルコキ シカルボニル基で置換された基を示す。具体例として、メトキシカルボニルォキシ、ェトキ シカルポニルォキシ、 n—プロポキシカルボニルォキシ、 n—ブトキシカルポニルォキシ、 n 一ペントキシカルボニルォキシ、 n—へキシルォキシ力ルポニルォキシ、 n—へプチルォキ シカルボニルォキシ、 n—ォクチルォキシカルポニルォキシ、イソプロポキシ力ルポニルォ キシ、イソブトキシカルポニルォキシ、 sec—ブトキシカルポニルォキシ、 tert—ブトキシカ ルポニルォキシ、イソペントキシカルポニルォキシ基等が挙げられる。  The “lower alkoxycarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkoxycarbonyl group. Specific examples include methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycarbonyloxy, n-butoxycarbonyloxy, n-pentoxycarbonyloxy, n-hexyloxycarbonyl, n-heptyloxycarbonyl. Oxy, n-octyloxycarbonyloxy, isopropoxy sulfonyloxy, isobutoxycarbonyloxy, sec-butoxycarbonyloxy, tert-butoxycarbonyloxy, isopentoxycarbonyloxy groups and the like.
「ァリールォキシカルポニルォキシ基」とは、ヒドロキシ基の水素原子がァリールォキシ カルポニル基で置換された基を示す。具体例として、フヱノキシカルボニルォキシ、ナフト キシカルボニルォキシ、アントリルォキシカルボニルォキシ、フヱナントリルォキシカルボ二 ルォキシ基等が挙げられる。 The “aryloxycarbonyloxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with an aryloxycarbonyl group. Specific examples include phenoxycarbonyloxy, naphthoxycarbonyloxy, anthryloxycarbonyloxy, phenanthryloxycarboxyl. Examples include a ruoxy group.
「ヒドロキシ基のエステル」とは、ヒドロキシ基とカルボン酸類とから形成されるエステル を示す。  “Ester of hydroxy group” refers to an ester formed from a hydroxy group and carboxylic acids.
「メルカプト基のエステル」とは、メルカプト基とカルボン酸類とから形成されるチォエス テルを示す。  “Ester of mercapto group” refers to a thiester formed from a mercapto group and carboxylic acids.
「アミノ基のアミド」とは、ァミノ基とカルボン酸類とから形成されるアミドを示す。  “Amino group amide” refers to an amide formed from an amino group and a carboxylic acid.
「低級アルキルアミノ基のアミド」とは低級アルキルアミノ基とカルボン酸類とから形成さ れるアミドを示す。  The “lower alkylamino group amide” refers to an amide formed from a lower alkylamino group and a carboxylic acid.
「ァリールァミノ基のアミド」とは、ァリ一ルァミノ基とカルボン酸類とから形成されるアミ ドを示す。  The “amide of an arylamino group” refers to an amide formed from an arylamino group and a carboxylic acid.
「カルボン酸類」とは、 RaCOOH ( Raは水素原子、置換基を有してもよい低級アルキル 基、置換基を有してもよいアルケニル基、置換基を有してもよいァリール基、置換基を有 してもよいァラルキル基、置換基を有してもよい複素環基等を示す）で示される飽和脂肪 族モノカルボン酸、飽和脂肪族ジカルボン酸、不飽和脂肪族カルボン酸、炭素環系カル ボン酸、複素環系カルボン酸等を示す。具体例として、ギ酸、酢酸、プロピオン酸、酪酸、 イソ酪酸、吉草酸、イソ吉草酸、ビバル酸等の飽和脂肪族モノカルボン酸；シユウ酸、マ ロン酸、コハク酸、グルタル酸、アジピン酸等の飽和脂肪族ジカルボン酸；アクリル酸、プ ピオル酸、クロトン酸、ゲイ皮酸等の不飽和脂肪族カルボン酸；安息香酸、フタル酸、 イソフタル酸、テレフタル酸、ナフトェ酸、トルィル酸等の炭素環系カルポン酸；フランカル ボン酸、チオフヱンカルボン酸、ニコチン酸、イソニコチン酸等の複素環系カルボン酸等が 挙げられる。また、これらのカルボン酸の酸無水物 [ ( RaCO ) 20 ]、酸ハロゲン化物（RaC OX、Xはハロゲン原子を示す）も「カルボン酸類」に含まれる。 “Carboxylic acids” refers to R a COOH (where R a is a hydrogen atom, a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, or an aryl group which may have a substituent. A saturated aliphatic monocarboxylic acid, a saturated aliphatic dicarboxylic acid, an unsaturated aliphatic carboxylic acid represented by the following formulas: an aralkyl group that may have a substituent, a heterocyclic group that may have a substituent, and the like; Examples thereof include carbocyclic carboxylic acids and heterocyclic carboxylic acids. Specific examples include saturated aliphatic monocarboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and vivalic acid; oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, etc. Saturated aliphatic dicarboxylic acids; unsaturated aliphatic carboxylic acids such as acrylic acid, propiolic acid, crotonic acid, and gay cinnamate; carbocycles such as benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, and toluic acid Examples thereof include heterocyclic carboxylic acids; heterocyclic carboxylic acids such as furan carboxylic acid, thiophene carboxylic acid, nicotinic acid, and isonicotinic acid. In addition, these carboxylic acid anhydrides [(R a CO) 2 0] and acid halides (R a C OX, X represents a halogen atom) are also included in the “carboxylic acids”.
「カルボキシ基のエステル」とは、カルボキシ基とアルコール類又はフヱノール類とから 形成されるエステルを示す。  “Ester of carboxy group” refers to an ester formed from a carboxy group and alcohols or phenols.
「スルフィン酸基のエステル」とは、スルフィン酸基とアルコール類又はフエノール類とか ら形成されるエステルを示す。  “Ester of sulfinic acid group” refers to an ester formed from a sulfinic acid group and alcohols or phenols.
Γスルホン酸基のエステル」とは、スルホン酸基とアルコール類又はフエノール類とから  "Ester of Γ sulfonic acid group" means from sulfonic acid group and alcohols or phenols.
4 形成されるエステルを示す。 Four The ester formed is indicated.
「アルコール類」とは、 RbOH (Rbは置換基を有してもよい低級アルキル基、置換基を有し てもよいアルケニル基等を示す）で示される飽和脂肪族系ヒドロキシ化合物、不飽和脂 肪族系ヒドロキシ化合物等を示す。具体例として、メタノール、エタノール、プロパノール、 ブタノール、イソプロパノール等の飽和脂肪族系ヒドロキシ化合物；ビニルアルコール等 の不飽和脂肪族系ヒドロキシ化合物；ベンジルアルコール、フヱネチルアルコール等のァラルキ ルアルコール等を示す。 “Alcohols” means a saturated aliphatic hydroxy compound represented by R b OH (R b represents a lower alkyl group which may have a substituent, an alkenyl group which may have a substituent, etc.), An unsaturated aliphatic hydroxy compound is shown. Specific examples include saturated aliphatic hydroxy compounds such as methanol, ethanol, propanol, butanol and isopropanol; unsaturated aliphatic hydroxy compounds such as vinyl alcohol; aralkyl alcohols such as benzyl alcohol and phenethyl alcohol. .
「フエノール類 Jとは、 RbOH (Rbは置換基を有してもよいァリール基等を示す）で示され る炭素環系ヒドロキシ化合物等を示す。具体例として、フエノール、ナフトール、アントロー ル、フヱナントロール等が挙げられる。 “Phenols J refers to carbocyclic hydroxy compounds represented by R b OH (R b represents an aryl group that may have a substituent, etc.). Specific examples include phenol, naphthol, anthrolo. And ferrules.
「カルボキシ基のアミド」とは、カルポキシ基とアミン類とから形成される酸アミドを示す。 「スルフィン酸基のアミド」とは、スルフィン酸基とアミン類とから形成される酸アミドを示 す。  The “amide of carboxy group” refers to an acid amide formed from a carboxy group and amines. The “amide of sulfinic acid group” refers to an acid amide formed from a sulfinic acid group and amines.
Γスルホン酸基のアミド Jとは、スルホン酸基とァミン類から形成される酸アミドを示す。 「ァミン類」とは、 H N R。（Rd) [R。と Rdは同一又は異なって、水素原子、置換基を有して もよい低級アルキル基、置換基を有してもよいァリール基、置換基を有してもよいァラル キル基、複素環基等を示し、また、 R。と Rdとが一緒になつて飽和環状アミンを形成しても よし、]で示されるアンモニア、飽和脂肪族系ァミン化合物、炭素環系ァミン化合物、複素 環系ァミン化合物、飽和環状アミン化合物等を示す。具体例として、アンモニア；メチルァ ミン、ェチルァミン、プロピルァミン、ペンチルァミン、ジメチルァミン、ジェチルァミン、ェチ ルメチルァミン等の飽和脂肪族系ァミン化合物；フエニルァミン、ナフチルァミン、アントリ ルァミン、フエナントリルアミン、ジフエニルァミン、メチルフエニルァミン、ェチルフエニルアミ ン、ベンジルァミン等の炭素環系ァミン化合物；フラニルァミン、チォフエニルァミン、ピロリ ジルァミン、ピリジルァミン、キノリルァミン、メチルピリジルァミン等の複素環系ァミン化合 物；アジリジン、ァゼチジン、ピロリジン、ピぺリジン、 4ーメチルビペリジン等の飽和環状ァ ミン化合物等を示す。 Gamma sulfonic acid group amide J refers to an acid amide formed from a sulfonic acid group and an amine. “Amin” means HNR. (R d ) [R. And R d are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, or a heterocyclic group. Etc., and also R. Ammonia and also with R d forms a together a connexion piperazines Well, represented by, saturated aliphatic Amin compounds, carbocyclic Amin compounds, heterocyclic Amin compound, a saturated cyclic amine compound or the like Show. Specific examples include ammonia; saturated aliphatic amine compounds such as methylamine, ethylamine, propylamine, pentylamine, dimethylamine, jetylamine, and ethylmethylamine; phenylamine, naphthylamine, anthrylamine, phenanthrylamine, diphenylamine, methylphenylamine , Carbocyclic amine compounds such as ethenylphenylamine and benzylamine; heterocyclic amine compounds such as furanylamine, thiophenylamine, pyrrolidylamine, pyridylamine, quinolylamine and methylpyridylamine; aziridine, azetidine, pyrrolidine And saturated cyclic amine compounds such as piperidine and 4-methylbiperidine.
「置換基を有してもよい低級アルキル基」、「置換基を有してもよい低級アルケニル基」  "Lower alkyl group optionally having substituent", "Lower alkenyl group optionally having substituent"
5 、「置換基を有してもよい低級アルキニル基 J、「置換基を有してもよい低級アルコキシ基 J、「置換基を有してもよい低級アルキルチオ基」、「置換基を有してもよい低級アルキル ァミノ基」、「置換基を有してもよい低級アルキルカルボニル基」、「置換基を有してもよい 低級アルコキシカルボニル基」、「置換基を有してもよい低級アルキルスルフィニル基」、 「置換基を有してもよい低級アルキルスルホニル基」又は「置換基を有してもよい低級ァ ルコキシカルボニルォキシ基」とは、下記、 α 1群（好ましくは α 2群）から選択される 1又は 複数個の置換基を有してもよい「低級アルキル基」、「低級アルケニル基」、「低級アルキ ニル基」、「低級アルコキシ基」、「低級アルキルチオ基」、「低級アルキルアミノ基 J、「低 級アルキルカルボニル基」、「低級アルコキシカルポニル基」、「低級アルキルスルフィニル 基」、「低級アルキルスルホニル基」又は「低級アルコキシカルポニルォキシ基」を示す。 Five , “Lower alkynyl group J which may have a substituent,” “lower alkoxy group J which may have a substituent,” “lower alkylthio group which may have a substituent”, “having a substituent May be a lower alkylamino group ”,“ lower alkylcarbonyl group optionally having substituent ”,“ lower alkoxycarbonyl group optionally having substituent ”,“ lower alkylsulfinyl optionally having substituent ” “Group”, “lower alkylsulfonyl group optionally having substituent (s)” or “lower alkoxycarbonyloxy group optionally having substituent (s)” are the following group α 1 (preferably group α 2 Or a lower alkyl group, lower alkenyl group, lower alkynyl group, lower alkoxy group, lower alkylthio group, which may have one or more substituents selected from Lower alkylamino group J, “lower grade “Alkylcarbonyl group”, “lower alkoxycarbonyl group”, “lower alkylsulfinyl group”, “lower alkylsulfonyl group” or “lower alkoxycarbonyloxy group”.
[ひ1群] _ [ One group] _
低級シクロアルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基、ヒドロキ シ基のエステル、低級アルコキシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ 基、低級アルキニルォキシ基、低級シクロアルキルォキシ基、ァリールォキシ基、複素環 ォキシ基、ァラルキルォキシ基、メルカプト基、メルカプト基のエステル、低級アルキルチ ォ基、ハロゲノ低級アルキルチオ基、低級シクロアルキルチオ基、ァリ一ルチオ基、複素 環チォ基、ァラルキルチオ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級ァ ルキルアミノ基のアミド、ァリ一ルァミノ基、ァリ一ルァミノ基のアミド、ホルミル基、低級ァ ルキルカルボニル基、ァリ一ルカルポ二ル基、低級アルコキシカルボニル基、ァリ一ルォ キシカルポニル基、カルポキシ基、カルポキシ基のエステル、カルポキシ基のアミド、スル フィン酸基、低級アルキルスルフィニル基、ァリ一ルスルフィニル基、低級アルキルスルホ ニル基、ァリ一ルスルホニル基、スルフィン酸基のエステル、スルフィン酸基のアミド、スル ホン酸基、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ基、低級ァ ルコキシカルボニルォキシ基、及びァリールォキシカルボニルォキシ基からなる群。  Lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, halogeno lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, lower cycloalkyloxy Group, aryloxy group, heterocyclic oxy group, aralkyloxy group, mercapto group, mercapto group ester, lower alkylthio group, halogeno lower alkylthio group, lower cycloalkylthio group, arylthio group, heterocyclic thio group, aralkylthio group, Amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamine group, amide of arylamino group, formyl group, lower alkylcarbonyl group, arylcarbonyl group , Lower alkoxycarbonyl group, aryloxy Nyl group, carboxy group, ester of carboxy group, amide of carboxy group, sulfinic acid group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, sulfinic acid group Esters, sulfinic acid amides, sulfonic acid groups, sulfonic acid group esters, sulfonic acid group amides, nitro groups, cyano groups, lower alkoxycarbonyloxy groups, and aryloxycarbonyloxy groups A group.
[ Of 2群] . [Of 2 groups].
低級シクロアルキル基、ァリール基、複素環基、アミノ基、ァミノ基のアミド、カルボキシ 基、カルボキシ基のエステル、カルボキシ基のアミド、及びシァノ基からなる群。 「置換基を有してもよい低級シクロアルキル基」、「置換基を有してもよいァリール基」、 「置換基を有してもよい複素環基」、「置換基を有してもよい低級シクロアルキルォキシ基 J、「置換基を有してもよいァリールォキシ基」、「置換基を有してもよい複素環ォキシ基」 、「置換基を有してもよい低級シクロアルキルチオ基」、「置換基を有してもよいァリールチ ォ基」、「置換基を有してもよい複素環チォ基」、「置換基を有してもよいァリールアミノ基」 、「置換基を有してもよいァリ一ルカルポニル基」、「置換基を有してもよいァリールォキシ カルポニル基」、「置換基を有してもよいァリールスルフィニル基」、「置換基を有してもよ ぃァリールスルホニル基」、「置換基を有してもよいァリールォキシカルボニルォキシ基」と は 1群〔好ましくは; s 2群〕から選択される 1又は複数個の置換基を有してもよい「低級シ クロアルキル基」、「ァリール基」、「複素環基」、「低級シクロアルキルォキシ基」、「ァリー ルォキシ基」、 r複素環ォキシ基」、「低級シクロアルキルチオ基」、 rァリ一ルチオ基」、「複 素璟チォ基」、「ァリ一ルァミノ基」、 rァリールカルボニル基」、 rァリールォキシカルボニル 基」、「ァリ一ルスルフィニル基」、「ァリ一ルスルホニル基」又は「ァリ一ルォキシカルポ二 ルォキシ基」を示す。 A group consisting of a lower cycloalkyl group, an aryl group, a heterocyclic group, an amino group, an amide of an amino group, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, and a cyano group. “Optionally substituted lower cycloalkyl group”, “optionally substituted aryl group”, “optionally substituted heterocyclic group”, “optionally substituted” Preferred lower cycloalkyloxy group J, “optionally substituted aryloxy group”, “optionally substituted heterocyclicoxy group”, “optionally substituted lower cycloalkylthio group , “Optionally substituted aryl group”, “optionally substituted heterocyclic group”, “optionally substituted aryl group”, “substituted” The arylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, an arylsulfinyl group which may have a substituent, and an aryl group which may have a substituent. A “reelsulfonyl group”, “an optionally substituted aryloxycarbonyloxy” 1 group and group "[preferably; s 2 group] 1 or more which may have a substituent" lower cyclo alkyl group selected from "," Ariru group "," heterocyclic group ", “Lower cycloalkyloxy group”, “aryloxy group”, r heterocyclic oxy group ”,“ lower cycloalkylthio group ”, r arylthio group”, “complex thio group”, “arylamino” “Group”, “rarylcarbonyl group”, “raryloxycarbonyl group”, “arylsulfinyl group”, “arylsulfonyl group” or “aryloxycarbonyloxy group”.
[ 1群] [ 1 group]
ハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、低級アルケニル基、低級 アルキニル基、低級シクロアルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ 基、ヒドロキシ基のエステル、低級アルコキシ基、ハロゲノ低級アルコキシ基、低級アルケ ニルォキシ基、低級アルキニルォキシ基、低級シクロアルキルォキシ基、ァリールォキシ 基、複素環ォキシ基、ァラルキルォキシ基、メルカプト基、メルカプト基のエステル、低級 アルキルチオ基、ハロゲノ低級アルキルチオ基、低級シクロアルキルチオ基、ァリールチ ォ基、複素環チォ基、ァラルキルチオ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ 基、低級アルキルアミノ基のアミド、ァリールアミノ基、ァリ一ルァミノ基のアミド、ホルミル 基、低級アルキルカルポニル基、ァリ一ルカルポ二ル基、低級アルコキシカルポニル基、 ァリールォキシカルポニル基、カルボキシ基、カルポキシ基のエステル、カルボキシ基のァ ミド、スルフィン酸基、低級アルキルスルフィニル基、ァリールスルフィニル基、低級アルキ ルスルホニル基、ァリールスルホニル基、スルフィン酸基のエステル、スルフィン酸基のァ ミド、スルホン酸基、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ基 、低級アルコキシカルボニルォキシ基、及びァリールォキシカルボニルォキシ基からなる 群。 Halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkenyl group, lower alkynyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, halogeno lower alkoxy Group, lower alkenyloxy group, lower alkynyloxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, aralkyloxy group, mercapto group, ester of mercapto group, lower alkylthio group, halogeno lower alkylthio group, lower cyclo Alkylthio group, arylthio group, heterocyclic thio group, aralkylthio group, amino group, amido group amide, lower alkylamino group, lower alkylamino group amide, allylamino group, arylamine group amide, formyl group, lower group Alkylcarbonyl group, arylcarbonyl group, lower alkoxycarbonyl group, aryloxycarbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, sulfinic acid group, lower alkylsulfinyl group, arylsulfinyl group Group, lower alkyl sulfonyl group, aryl sulfonyl group, sulfinic acid group ester, sulfinic acid group A group consisting of amide, sulfonic acid group, ester of sulfonic acid group, amide of sulfonic acid group, nitro group, cyano group, lower alkoxycarbonyloxy group, and aryloxycarbonyloxy group.
[ 2群] [Group 2 ]
ハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、低級シクロアルキル基、ァ リール基、複素環基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコ キシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ基、低級シクロアルキルォキ シ基、ァリールォキシ基、ァラルキルォキシ基、ァリールォキシカルボニルォキシ基、メル カプト基、低級アルキルチオ基、ァリ一ルチオ基、アミノ基、ァミノ基のアミド、低級アルキ ルァミノ基、低級アルキルアミノ基のアミド、ァリ一ルァミノ基、ァリ一ルァミノ基のアミド、 ホルミル基、低級アルキルカルボニル基、ァリ一ルカルポ二ル基、カルボキシ基、カルボキ シ基のエステル、カルポキシ基のアミド、スルホン酸基、スルホン酸基のエステル、スルホ ン酸基のアミド、ニトロ基、及びシァノ基からなる群。  Halogen atom, lower alkyl group, halogeno lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, halogeno lower alkoxy group, lower alkenyloxy Group, lower cycloalkyloxy group, aryloxy group, aralkyloxy group, aryloxycarbonyloxy group, mercapto group, lower alkylthio group, arylthio group, amino group, amide of amino group, lower alkylamino Group, lower alkylamino group amide, arylamine group, arylamine group amide, formyl group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, carboxyl group ester, carboxy group Amide, sulfonic acid group, ester of sulfonic acid group, sulfonic acid The group consisting of amide, nitro group, and Shiano group.
「置換基を有してもよいァラルキル基」、「置換基を有してもよいァラルキルォキシ基」 又は「置換基を有してもよいァラルキルチオ基」とは、その低級アルキル基部分について は、 群（好ましくは 2群）から選択される 1又は複数個の置換基を有してもよ《及び /又はそのァリール部分については、 1群（好ましくは 2群）から選択される 1又は複数 個の置換基を有してもよい Γァラルキル基」、 Γァラルキルォキシ基」又は「ァラルキルチオ 基 Jを示す。 “The aralkyl group which may have a substituent”, “the aralkyloxy group which may have a substituent” or “the aralkylthio group which may have a substituent” It may have one or more substituents selected from (preferably group 2 ) << and / or for its aryl moiety, one or more selected from group 1 (preferably group 2 ) A Γ aralkyl group, a Γ aralkyloxy group, or an aralkylthio group J which may have a substituent is shown.
/8 1又は S 2群中のァリールォキシ基は、 1又は複数個のハロゲン原子を置換基と して有してもよい。 / 8 1 or the aryloxy group in the S 2 group may have one or more halogen atoms as substituents.
;5 1又は S 2群中の低級アルキル基若し〈は低級アルコキシ基は、 r 1群（好ましくは r 2 群）から選択される 1又は複数個の置換基を有してもよい。 ; The lower alkyl group or the lower alkoxy group in the 5 1 or S 2 group may have one or more substituents selected from the r 1 group (preferably the r 2 group).
[ r 1群] [r 1 group]
低級シクロアルキル基、ァリ一ル基、複素璟基、ァラルキル基、ヒドロキシ基、ヒドロキ シ基のエステル、低級アルコキシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ 基、低級アルキニルォキシ基、低級シクロアルキルォキシ基、ァリールォキシ基、複素環 ォキシ基、ァラルキルォキシ基、メルカプト基、メルカプト基のエステル、低級アルキルチ ォ基、ハロゲノ低級アルキルチオ基、低級シクロアルキルチオ基、ァリールチオ基、複素 環チォ基、ァラルキルチオ基、アミノ基、ァミノ基のアミ 低級アルキルアミノ基、低級ァ ルキルアミノ基のアミド、ァリールアミノ基、ァリ一ルァミノ基のアミド、ホルミル基、低級ァ ルキルカルポニル基、ァリールカルボニル基、低級アルコキシカルボ二ル基、ァリールォ キシカルボ二ル基、カルボキシ基、カルボキシ基のエステル、カルボキシ基のアミド、スル フィン酸基、低級アルキルスルフィニル基、ァリールスルフィニル基、低級アルキルスルホ ニル基、ァリ一ルスルホニル基、スルフィン酸基のエステル、スルフィン酸基のアミド、スル ホン酸基、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ基、低級ァ ルコキシカルポニルォキシ基、及びァリールォキシカルボニルォキシ基からなる群。 Lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, halogeno lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, lower cyclo Alkyloxy group, aryloxy group, heterocyclic ring Oxy group, aralkyloxy group, mercapto group, ester of mercapto group, lower alkylthio group, halogeno lower alkylthio group, lower cycloalkylthio group, allylthio group, heterocyclic thio group, aralkylthio group, amino group, amino amino group lower alkylamino Group, lower alkylamino group amide, arylamino group, arylalkylamino group amide, formyl group, lower alkylcarbonyl group, arylcarbonyl group, lower alkoxycarbonyl group, aryloxycarbonyl group, carboxy group, Carboxy group ester, carboxy group amide, sulfinic acid group, lower alkyl sulfinyl group, aryl sulfinyl group, lower alkyl sulfonyl group, arylsulfonyl group, sulfinic acid group ester, sulfinic acid group amide, Sul Hong Group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, Shiano group, a lower § Turkey carboxymethyl Cal Poni Ruo alkoxy group, and the group consisting § reel O alkoxycarbonyl O alkoxy group.
[ 群] [Group]
低級シクロアルキル基、複素環基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコ キシ基、ァリールォキシ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、カルボキシ 基、カルポキシ基のエステル、カルボキシ基のアミド及びシァノ基からなる群。  Lower cycloalkyl group, heterocyclic group, hydroxy group, ester of hydroxy group, lower alkoxy group, aryloxy group, amino group, amide of amino group, lower alkylamino group, ester of carboxy group, carboxy group, amide of carboxy group And a group consisting of a cyano group.
本発明でいう「複数個の基」とは、夫々の基が同一であっても異なるものであってもよく 、それらの基の個数は、 2 ~ 3個が好ましい。また、水素原子やハロゲン原子も「基」のネ既 Ξく 曰まれる。  The “plural groups” in the present invention may be the same or different, and the number of these groups is preferably 2 to 3. Hydrogen atoms and halogen atoms are also included in the “group”.
本発明化合物における「塩」とは、医薬として許容される塩であれば、特に制限はな 塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、酢酸、フマル 酸、マレイン酸、コハク酸、クェン酸、酒石酸、アジピン酸、グルコン酸、ダルコへブト酸、 グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、 1 , 2—ェタンジスルホン 酸、イセチオン酸、ラクトビオン酸、ォレイン酸、パモ酸、ポリガラクッロン酸、ステアリン酸 、タンニン酸、トリフルォロメタンスルホン酸、ベンゼンスルホン酸、 p—トルエンスルホン酸 、硫酸ラウリルエステル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸等の有機 酸との塩、臭化メチル、ヨウ化メチル等との四級アンモニゥム塩、臭素イオン、塩素イオン 、ヨウ素イオン等のハロゲンイオンとの塩、リチウム、ナトリウム、カリウム等のアルカリ金 属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩鉄、亜鉛等との金属  The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, Acetic acid, fumaric acid, maleic acid, succinic acid, succinic acid, tartaric acid, adipic acid, gluconic acid, darcohebutyric acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid , Isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfone Salt with organic acid such as salicylic acid, quaternary ammonium salt with methyl bromide, methyl iodide, bromine ion, chloride ion, iodine Salts with halogen ions such as urine ions, salts with alkali metals such as lithium, sodium and potassium, metals with alkaline earth metals such as calcium and magnesium, metals with iron and zinc
9 塩、アンモニアとの塩、トリエチレンジァミン、 2—アミノエタノール、 2， 2—イミノビス（エタノ 一ル）、 1—デォキシ一 1— (メチルァミノ）一 2_D—ソルビトール、 2—アミノー 2—（ヒドロ キシメチル）ー1 , 3—プロパンジオール、プロ力イン、 N, N—ビス（フエニルメチル）一 1 , 2 一エタンジァミン等の有機ァミンとの塩等が挙げられる。 9 Salt, salt with ammonia, triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- 1- (methylamino) -1-2_D-sorbitol, 2-amino-2- (hydro And salts with organic amines such as N, N-bis (phenylmethyl) 1-1,2 ethanediamine, and the like.
本発明化合物に幾何異性体又は光学異性体が存在する場合は、それらの異性体も 本発明の範囲に含まれる。  When geometrical isomers or optical isomers are present in the compound of the present invention, these isomers are also included in the scope of the present invention.
また、本発明化合物は水和物又は溶媒和物の形態をとつていてもよい。  The compound of the present invention may take the form of a hydrate or a solvate.
さらに、本発明化合物にプロトン互変異性が存在する場合には、それらの互変異性体 も本発明に含まれる。  Furthermore, when proton tautomerism exists in this invention compound, those tautomers are also included in this invention.
(a)本発明化合物における好ましい例として、一般式（1 )で示される.化合物又はその 塩において、各基が下記に示す基である化合物又はその塩が挙げられる。  (a) Preferable examples of the compound of the present invention include a compound represented by the general formula (1) or a salt thereof, wherein each group is a group shown below.
一般式（1)において、  In general formula (1),
(a1 )Χ' - X2が S— CH2、 CH2— S、 CH2— CH2、又は CH = CHを示し; 及び/又は (a2)R1が低級アルキル基、ァリール基、ヒドロキシ基、ヒドロキシ基のエステル、アルコキ シ基、及びァリ一ルォキシ基から選択される基を示し；及び 又は (a1) Χ '- X 2 is S- CH 2, CH 2 - S , CH 2 - CH 2, or shows a CH = CH; and / or (a2) R 1 is a lower alkyl group, Ariru group, hydroxy group And represents a group selected from an ester of a hydroxy group, an alkoxy group, and an aryloxy group; and
(a3)Pが 0、 1又は 2を示し、 pが 2である場合、各 R1は同一又は異なってもよく；及び/ 又は (a3) when P represents 0, 1 or 2 and p is 2, each R 1 may be the same or different; and / or
(a4)R2が水素原子、低級アルキル基、ァリール基、ァラルキル基、ホルミル基、低級ァ ルキルカルポニル基、ァリ一ルカルポ二ル基、低級アルコキシカルポニル基、ァリールォ キシカルポニル基、低級アルキルスルホニル基、又はァリールスルホニル基を示し、 R2が ァラルキル基、ァリール力ルポニル基又はァリ一ルスルホニル基の場合、該ァラルキル基 、該ァリ一ルカルポニル基又は該ァリ一ルスルホニル基は 1又は複数個のハロゲン原子 を置換基として有してもよぐ及び 又は (a4) R 2 is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a formyl group, a lower alkylcarbonyl group, an arylcarbonyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, or a lower alkylsulfonyl group. , Or an arylsulfonyl group, and when R 2 is an aralkyl group, an arylaryl group or an arylsulfonyl group, the aralkyl group, the arylcarbonyl group or the arylsulfonyl group is 1 or May have multiple halogen atoms as substituents and / or
(a5)R3が水素原子、又は低級アルキル基を示し；及び 又は (a5) R 3 represents a hydrogen atom or a lower alkyl group; and or
(a6)Y1— Y2が CH = CH、 N = CH、又は CH = Nを示し；及び/又は (a6) Y 1 — Y 2 represents CH = CH, N = CH, or CH = N; and / or
(a7)R4がハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、低級アルケニル基 、低級アルキニル基、ァリール基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のエステル、 低級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基、アミノ基、ァミノ基のアミド、 低級アルキルアミノ基、低級アルキルアミノ基のアミド、ァリールアミノ基、ァリールァミノ 基のアミド、カルポキシ基、カルボキシ基のエステル、カルボキシ基のアミド、及びシァノ基 力、ら選択される基を示し、 R4が低級アルケニル基の場合、該低級アルケニル基は 1又は 複数個のァリール基を置換基として有してもよ 及び 又は (a7) R 4 is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, a hydroxy group, an ester of a hydroxy group, Lower alkoxy group, aryloxy group, aralkyloxy group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, allylamino group, amide of allylamino group, carboxy group, ester of carboxy group, amide of carboxy group And R 4 represents a group selected from R 4 and when R 4 is a lower alkenyl group, the lower alkenyl group may have one or more aryl groups as a substituent.
(38 ^カ 0、 1又は 2を示し、 qが 2である場合、各 R4は同一又は異なってもよく；及び/ 又は (38 ^ indicates 0, 1 or 2, and when q is 2, each R 4 may be the same or different; and / or
(a9 ) R5がハロゲン原子、水素原子、低級アルキル基、ハロゲノ低級アルキル基、低級シ クロアルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のェ ステル、低級アルコキシ基、ハロゲノ低級アルコキシ基、低級シクロアルキルォキシ基、ァ リールォキシ基、複素環ォキシ基、ァラルキルォキシ基、メルカプト基、メルカプト基のェ ステル、低級アルキルチオ基、ハロゲノ低級アルキルチオ基、低級シクロアルキルチオ基 、ァリ一ルチオ基、複素璟チォ基、ァラルキルチオ基、アミノ基、ァミノ基のアミド、低級ァ ルキルアミノ基、低級アルキルアミノ基のアミド、ァリールアミノ基、ァリ一ルァミノ基のアミ ド、ホルミル基、低級アルキルカルボニル基、ァリ一ルカルポニル基、カルポキシ基、カル ポキシ基のエステル、カルボキシ基のアミド、低級アルキルスルホニル基、ァリールスルホ ニル基、スルホン酸基、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ 基、 CR6 = CR7 ( R8)、 C≡CR9、又は N = N R1 Dを示し、 R5が低級アルキル基の場合、該 低級アルキル基は複素環基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級ァ ルキルアミノ基のアミド、カルボキシ基、カルボキシ基のエステル、カルボキシ基のアミド、 及びシァノ基から選択さ る 1又は複数個の基を置換基として有してもよ R5がァリ一 ル基の場合、該ァリール基はハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基 、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、ハロゲノ低級アルコキシ基、 ニトロ基、及びシァノ基から選択される 1又は複数個の基を置換基として有してもよぐ R5 が複素環基の場合、該複素環基はハロゲン原子、低級アルキル基、及び低級ハロゲノ アルキル基から選択される 1又は複数個の基を置換基として有してもよく、 R5がァラルキ ル基の場合、該ァラルキル基はヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ (a9) R 5 is a halogen atom, hydrogen atom, lower alkyl group, halogeno lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, Halogeno lower alkoxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, aralkyloxy group, mercapto group, ester of mercapto group, lower alkylthio group, halogeno lower alkylthio group, lower cycloalkylthio group, aryl Ruthio group, heterothio group, aralkylthio group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamino group, amide of arylalkylamino group, formyl group, lower alkylcarbonyl group , Arylcarbonyl, carboxy, carboxy Ester groups, amides of carboxy groups, lower alkylsulfonyl groups, Arirusuruho group, a sulfonic acid group, an ester of a sulfonic acid group, an amide of a sulfonic acid group, a nitro group, Shiano group, CR 6 = CR 7 (R 8), C≡CR 9 or N = NR 1 D, and when R 5 is a lower alkyl group, the lower alkyl group is a heterocyclic group, an amino group, an amide of an amino group, a lower alkylamino group, or a lower alkylamino group. One or more groups selected from amide, carboxy group, ester of carboxy group, amide of carboxy group, and cyano group may be substituted. When R 5 is an aryl group, Groups are halogen atoms, lower alkyl groups, halogeno lower alkyl groups, hydroxy groups, esters of hydroxy groups, lower alkoxy groups, halogeno lower alkoxy groups, nitro groups, and cyano groups One or more groups selected from the above may be substituted. When R 5 is a heterocyclic group, the heterocyclic group is selected from a halogen atom, a lower alkyl group, and a lower halogenoalkyl group. One or more groups may be substituted, and when R 5 is an aralkyl group, the aralkyl group is a hydroxy group, an ester of a hydroxy group, a lower alkoxy group.
2 基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、及び低級アルキルアミノ基のアミド 力、ら選択される 1又は複数個の基を置換基として有してもよく、 R5が低級アルコキシ基の 場合、該低級アルコキシ基は 1又は複数個の複素環基を置換基として有してもよく、 R5 がァリールォキシ基の場合、該ァリールォキシ基は 1又は複数個の低級アルキル基を置 換基として有してもよ《 R5がァラルキルォキシ基の場合、該ァラルキルォキシ基はハロ ゲン原子、低級アルキル基、ハロゲノ低級アルキル基、ヒドロキシ基、ヒドロキシ基のエス テル、低級アルコキシ基、及びハロゲノ低級アルコキシ基から選択される 1又は複数個の 基を置換基として有してもよく、 R5が低級アルキルチオ基の場合、該低級アルキルチオ 基は低級シクロアルキル基、ァリール基、及び複素環基から選択される 1又は複数個の 基を置換基として有してもよ R5がァリ一ルチオ基の場合、該ァリールチオ基はハロゲ ン原子、低級アルキル基、ハロゲノ低級アルキル基、アミノ基、ァミノ基のアミド、低級ァ ルキルアミノ基、及び低級アルキルアミノ基のアミドから選択される 1又は複数個の基を 置換基として有してもよく、 R5がァラルキルチオ基の場合、該ァラルキルチオ基はハロゲ ン原子、低級アルキル基、ハロゲノ低級アルキル基、ヒドロキシ基、ヒドロキシ基のエステ ル、、低級アルコキシ基、及びハロゲノ低級アルコキシ基から選択される 1又は複数個の 基を置換基として有してもよく、 R5がァリ一ルスルホニル基の場合、該ァリ一ルスルホニ ル基はァミノ基、ァミノ基のアミド、低級アルキルアミノ基、及び低級アルキルアミノ基のァ ミドから選択される 1又は複数個の基を置換基として有してもよく；及び 又は 2 Group, an amino group, an amide of Amino group, a lower alkylamino group, and an amide force lower alkylamino group may have one or a plurality of groups are al selected as substituents, R 5 is a lower alkoxy group In this case, the lower alkoxy group may have one or more heterocyclic groups as a substituent, and when R 5 is an aryloxy group, the aryloxy group is a substituent of one or more lower alkyl groups. << When R 5 is an aralkyloxy group, the aralkyloxy group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, or a halogeno lower alkoxy group. 1 or a plurality of groups selected from may be substituted, and when R 5 is a lower alkylthio group, the lower alkylthio group is a lower cycloalkyl group. 1 or a plurality of groups selected from the group consisting of alkyl group, aryl group, and heterocyclic group may be substituted. When R 5 is arylthio group, the arylthio group is a halogen atom, lower alkyl group. R 5 may have one or more groups selected from a group, a halogeno lower alkyl group, an amino group, an amide of an amino group, a lower alkylamino group, and an amide of a lower alkylamino group as a substituent. In the case of an aralkylthio group, the aralkylthio group is one or more selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, and a halogeno lower alkoxy group. may have a group as a substituent, when R 5 is the § Li one Rusuruhoniru group, said § Li one Rusuruhoni Le groups Amino groups, amides of Amino groups, lower alk Arylamino group, and it may have a one or a plurality of group a substituent selected from § bromide lower alkylamino group; and or
(a 1 0) R6が水素原子、又は低級アルキル基を示し；及びノ又は (a 1 0) R 6 represents a hydrogen atom or a lower alkyl group; and
(a 1 1 ) R7と R8が同一又は異なって、水素原子、低級アルキル基、低級シクロアルキル基 、ァリール基、複素環基、カルポキシ基、カルボキシ基のエステル、又はカルボキシ基の アミドを示し、 R7又は R8がァリール基の場合、該ァリール基はハロゲン原子、低級アルキ ル基、ハロゲノ低級アルキル基、低級シクロアルキル基、ァリール基、複素環基、ァラル キル基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、ハロゲノ低級アルコ キシ基、低級シクロアルキルォキシ基、ァリールォキシ基、複素環ォキシ基、ァラルキル ォキシ基、メルカプト基、メルカプト基のエステル、低級アルキルチオ基、ァリールチオ基、 アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキルアミノ基のアミド、ァリー ルァミノ基、ァリ一ルァミノ基のアミ ホルミル基、低級アルキルカルボニル基、ァリール 力ルポニル基、カルボキシ基、カルボキシ基のエステル、カルポキシ基のアミド、スルホン 酸基、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、及びシァノ基から選択 される 1又は複数個の基を置換基として有してもよぐ及び/又は (a 1 1) R 7 and R 8 are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a carboxy group, an ester of a carboxy group, or an amide of a carboxy group. When R 7 or R 8 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a hydroxy group Esters, lower alkoxy groups, halogeno lower alkoxy groups, lower cycloalkyloxy groups, aryloxy groups, heterocyclic oxy groups, aralkyloxy groups, mercapto groups, esters of mercapto groups, lower alkylthio groups, arylthio groups, amino groups, Amido amide, lower alkylamino group, lower alkylamino amide, aryl Lumino group, arylamine group of arylamino group, lower alkylcarbonyl group, aryl group, sulfonyl group, carboxy group, carboxy group ester, carboxy group amide, sulfonic acid group, sulfonic acid group ester, sulfonic acid group It may have one or more groups selected from amide, nitro group, and cyan group as substituents and / or
( a 1 2 ) R9が水素原子、低級アルキル基、低級シクロアルキル基、ァリール基、又は複素 環基を示し、 R9がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基、 1 若しくは複数個のヒドロキシ基で置換された低級アルキル基、 1若しくは複数個のヒドロ キシ基のエステルで置換された低級アルキル基、 1若しくは複数個の低級アルコキシ基で 置換.された低級アルキル基、 1若しくは複数個のァリールォキシ基で置換された低級ァ ルキル基、 1若しくは複数個のカルボキシ基で置換された低級アルキル基、 1若しくは複 数個のカルポキシ基のエステルで置換された低級アルキル基、 1若しくは複数個のカル ポキシ基のアミドで置換された低級アルキル基、 1若しくは複数個のシァノ基で置換され た低級アルキル基、ハロゲノ低級アルキル基、低級シクロアルキル基、ァリール基、複素 環基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、 1若しく は複数個の低級アルキル基で置換された低級アルコキシ基、 1若しくは複数個の低級シ クロアルキル基で置換された低級アルコキシ基、 1若しくは複数個のァリール基で置換さ れた低級アルコキシ基、 1若しくは複数個の複素環基で置換された低級アルコキシ基、 1 若しくは複数個のヒドロキシ基で置換された低級アルコキシ基、 1若しくは複数個のヒドロ キシ基のエステルで置換された低級アルコキシ基、 1若しくは複数個の低級アルコキシ基 で置換された低級アルコキシ基、 1若しくは複数個の低級シクロアルキルォキシ基で置換 された低級アルコキシ基、 1若しくは複数個のァリールォキシ基で置換された低級アルコ キシ基、 1若し ま複数個の複素環ォキシ基で置換された低級アルコキシ基、 1若しくは 複数個のァミノ基で置換された低級アルコキシ基、 1若しくは複数個のァミノ基のアミドで 置換された低級アルコキシ基、 1若しくは複数個の低級アルキルアミノ基で置換された低 級アルコキシ基、 1若しくは複数個の低級アルキルアミノ基のアミドで置換された低級ァ ルコキシ基、 1若しくは複数個のァリールァミノ基で置換された低級アルコキシ基、 1若し ま複数個のァリールァミノ基のアミドで置換された低級アルコキシ基、 1若しくは複数個 のカルボキシ基で置換された低級アルコキシ基、 1若しくは複数個のカルボキシ基のエス テルで置換された低級アルコキシ基、 1若しくは複数個のカルポキシ基のアミドで置換さ れた低級アルコキシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ基、低級アル キニルォキシ基、低級シクロアルキルォキシ基、ァリールォキシ基、 1若しくは複数個の ハロゲン原子で置換されたァリールォキシ基、複素環ォキシ基、ァラルキルォキシ基、低 級アルコキシカルボニルォキシ基、ァリールォキシカルボニルォキシ基、メルカプト基、メ ルカプト基のエステル、低級アルキルチオ基、ァリールチオ基、アミノ基、ァミノ基のアミド 、低級アルキルアミノ基、低級アルキルアミノ基のアミド、ァリールアミノ基、ァリールァミノ 基のアミド、ホルミル基、低級アルキルカルポニル基、ァリ一ルカルポ二ル基、カルポキシ 基、カルポキシ基のエステル、カルポキシ基のアミド、スルホン酸基、スルホン酸基のエス テル、スルホン酸基のアミド、ニトロ基、及びシァノ基から選択される 1又は複数個の基を 置換基として有してもよく；及び 又は (a 1 2) R 9 represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, or a heterocyclic group, and when R 9 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, 1 Or a lower alkyl group substituted with a plurality of hydroxy groups, a lower alkyl group substituted with one or more hydroxy group esters, a lower alkyl group substituted with one or more lower alkoxy groups, 1 Or a lower alkyl group substituted by a plurality of aryloxy groups, a lower alkyl group substituted by one or more carboxy groups, a lower alkyl group substituted by an ester of one or more carboxy groups, 1 or Lower alkyl group substituted with amides of a plurality of carboxyl groups, lower alkyl group substituted with one or more cyano groups, lower halogeno group An alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group substituted with one or more lower alkyl groups, 1 or A lower alkoxy group substituted with a plurality of lower cycloalkyl groups, a lower alkoxy group substituted with one or more aryl groups, a lower alkoxy group substituted with one or more heterocyclic groups, 1 or A lower alkoxy group substituted with a plurality of hydroxy groups, a lower alkoxy group substituted with one or more esters of a hydroxy group, a lower alkoxy group substituted with one or more lower alkoxy groups, one or more A lower alkoxy group substituted with one lower cycloalkyloxy group, one or more aryloxy groups A lower alkoxy group substituted with one or more heterocyclic oxy groups, a lower alkoxy group substituted with one or more amino groups, one or more lower alkoxy groups substituted with one or more heterocyclic oxy groups, A lower alkoxy group substituted with an amide of an amino group, a lower alkoxy group substituted with one or more lower alkylamino groups, a lower alkoxy group substituted with an amide of one or more lower alkylamino groups, A lower alkoxy group substituted with one or more arylamine groups, a lower alkoxy group substituted with an amide of one or more arylamine groups, one or more A lower alkoxy group substituted with one or more carboxy group esters, a lower alkoxy group substituted with one or more carboxy group amides, a halogeno lower alkoxy group. Group, lower alkenyloxy group, lower alkynoxy group, lower cycloalkyloxy group, aryloxy group, aryloxy group substituted by one or more halogen atoms, heterocyclic oxy group, aralkyloxy group, lower alkoxycarbonyl group Xyl group, aryloxycarbonyloxy group, mercapto group, ester of mercapto group, lower alkylthio group, aryloxy group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamino group Amides of allylamino groups Formyl group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, sulfonic acid group, ester of sulfonic acid group, amide of sulfonic acid group, nitro group, and May have one or more groups selected from a cyano group as substituents; and or
(a13) R1Dがァリール基を示す請求項 1記載の化合物又はその塩。 (a13) The compound or salt thereof according to claim 1, wherein R 1D represents an aryl group.
すなわち、一般式（1 )で示される化合物において、上記（a1)、（a2)、（a3)、（a4)、 ( a5)、（a6)、（a7)、（a8)、（a9)、（a10)、 (a")、 (a12)及び（a13)から選択される 1 又は 2以上の各組み合わせからなる化合物又はその塩。  That is, in the compound represented by the general formula (1), the above (a1), (a2), (a3), (a4), (a5), (a6), (a7), (a8), (a9), A compound or a salt thereof comprising one or more combinations selected from (a10), (a "), (a12) and (a13).
(b)本発明化合物におけるより好ましい例として、一般式（1 )で示される化合物又は その塩において、各基が下記に示す基である化合物又はその塩が挙げられる。  (b) As a more preferred example of the compound of the present invention, there can be mentioned a compound represented by the general formula (1) or a salt thereof, a compound wherein each group is a group shown below, or a salt thereof.
一般式（1)において、  In general formula (1),
(b1 )X1— X2が S— CH2、 CH2— CH2、又は CH = CHを示し；及びノ又は (b1) X 1 — X 2 represents S—CH 2 , CH 2 —CH 2 , or CH = CH; and
(b2)R'が低級アルキル基、ァリール基、ヒドロキシ基、及びヒドロキシ基のエステルから 選択される基を示し；及びノ又は  (b2) R ′ represents a group selected from a lower alkyl group, an aryl group, a hydroxy group, and an ester of a hydroxy group; and
(b3)pが 0、 1又は 2を示し、 pが？である場合、各 R1は同一であり；及び/又は (b3) p is 0, 1 or 2, p is? Each R 1 is the same; and / or
(b4)R2が水素原子、低級アルキル基、ァラルキル基、低級アルキルカルポニル基、ァリ —ルカルポニル基、低級アルコキシカルボ二ル基、低級アルキルスルホ；ル基、又はァリ —ルスルホニル基を示し、 R2がァラルキル基、ァリ一ルカルポニル基又はァリールスルホ ニル基の場合、該ァラルキル基、該ァリールカルボニル基又は該ァリールスルホニル基 は 1又は複数個のハロゲン原子を置換基として有してもよ 及び/又は (b4) R 2 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a lower alkyl carbonyl group, an aryl carbonyl group, a lower alkoxy carbonyl group, a lower alkyl sulfo group; or an aryl sulfonyl group. , When R 2 is an aralkyl group, an arylcarbonyl group, or an arylsulfonyl group, the aralkyl group, the arylcarbonyl group, or the arylsulfonyl group May have one or more halogen atoms as substituents and / or
(b5 ) R3が水素原子を示し；及び 又は (b5) R 3 represents a hydrogen atom; and or
(b6 ) Y1— Y2が CH = CH、 N = CH、又は CH = Nを示し；及び 又は (b6) Y 1 — Y 2 represents CH = CH, N = CH, or CH = N; and or
(b7 ) R4がハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、低級アルケニル基 、ァラルキル基、低級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基、低級アルキ ルァミノ基、カルボキシ基のアミド、及びシァノ基から選択される基を示し、 R4が低級アル ケニル基の場合、該低級アルケニル基は 1又は複数個のァリール基を置換基として有し てもよぐ及び 又は (b7) R 4 is selected from a halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkenyl group, aralkyl group, lower alkoxy group, aryloxy group, aralkyloxy group, lower alkylamino group, carboxy group amide, and cyano group And when R 4 is a lower alkenyl group, the lower alkenyl group may have one or more aryl groups as a substituent, and / or
(b8 ) qが 0、 1又は 2を示し、 9カ 2である場合、各 R4は同一又は異なってもよく；及び 又は (b8) when q represents 0, 1 or 2 and is 9 or 2, each R 4 may be the same or different; and or
(b9 ) R5がハロゲン原子、水素原子、低級アルキル基、ハロゲノ低級アルキル基、低級シ クロアルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基、低級アルコキシ基 、ハロゲノ低級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基、メルカプト基、低 級アルキルチオ基、ハロゲノ低級アルキルチオ基、ァリールチオ基、複素環チォ基、ァラ ルキルチオ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキルアミノ基 のアミド、ァリ一ルァミノ基、低級アルキルカルボニル基、ァリ一ルカルポニル基、カルポキ シ基、カルボキシ基のエステル、カルボキシ基のアミド、低級アルキルスルホニル基、ァリ 一ルスルホニル基、スルホン酸基のアミド、ニトロ基、シァノ基、 CR6 = CR7 (R8)、 C≡CR9 、又は N = N R1 Qを示し、 R5が低級アルキル基の場合、該低級アルキル基は複素環基、 アミノ基、カルボキシ基のエステル、及びシァノ基から選択される 1又は複数個の基を置 換基として有してもよく、 R5がァリール基の場合、該ァリール基はハロゲン原子、低級ァ ルキル基、ハロゲノ低級アルキル基、低級アルコキシ基、ニトロ基、及びシァノ基から選 択される 1又は複数個の基を置換基として有してもよく、 R5が複素環基の場合、該複素 璟基はハロゲン原子、低級アルキル基、及びハロゲノ低級アルキル基から選択される 1 又は複数個の基を置換基として有してもよく、 R5がァラルキル基の場合、該ァラルキル基 は低級アルコキシ基及びァミノ基から選択される 1又は複数個の基を置換基として有して もよく、 R5が低級アルコキシ基の場合、該低級アルコキシ基は 1又は複数個の複素環基 を置換基として有してもよぐ R5がァリールォキシ基の場合、該ァリールォキシ基は 1又は 複数個の低級アルキル基を置換基として有してもよ R5がァラルキルォキシ基の場合、 該ァラルキルォキシ基はハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、及 び低級アルコキシ基から選択される 1又は複数個の基を置換基として有してもよく、 R5が 低級アルキルチオ基の場合、該低級アルキルチオ基は低級シクロアルキル基、及び複 素環基から選択される 1又は複数個の基を置換基として有してもよく、 R5がァリ一ルチオ 基の場合、該ァリールチオ基はハロゲン原子、ハロゲノ低級アルキル基、及ぴァミノ基か ら選択される 1又は複数個の基を置換基として有してもよ R5がァラルキルチオ基の場 合、該ァラルキルチオ基はハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、及 び低級アルコキシ基から選択される 1又は複数個の基を置換基として有してもよぐ が ァリールスルホニル基の場合、該ァリールスルホニル基は 1又は複数個のアミノ基を置 換基として有してもよく；及び 又は (b9) R 5 is a halogen atom, a hydrogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a lower alkoxy group, a halogeno lower alkoxy group, an aryloxy group. Group, aralkyloxy group, mercapto group, lower alkylthio group, halogeno lower alkylthio group, arylothio group, heterocyclic thio group, aralkylthio group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group , Arylamino groups, lower alkylcarbonyl groups, arylcarbonyl groups, carboxy groups, esters of carboxy groups, amides of carboxy groups, lower alkylsulfonyl groups, arylsulfonyl groups, amides of sulfonic acid groups, Nitro group, cyano group, CR 6 = CR 7 (R 8 ), C≡CR 9 , or N = NR 1 Q, and when R 5 is a lower alkyl group, the lower alkyl group is substituted with one or more groups selected from a heterocyclic group, an amino group, an ester of a carboxy group, and a cyano group. When R 5 is an aryl group, the aryl group is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a nitro group, and a cyan group. And when R 5 is a heterocyclic group, the heterocyclic group is substituted with one or more groups selected from a halogen atom, a lower alkyl group, and a halogeno lower alkyl group. When R 5 is an aralkyl group, the aralkyl group may have one or a plurality of groups selected from a lower alkoxy group and an amino group as a substituent, and R 5 is a lower group. In the case of an alkoxy group, A lower alkoxy group is one or more heterocyclic groups In the case where R 5 is an aryloxy group, the aryloxy group may have one or more lower alkyl groups as a substituent. In the case where R 5 is an aralkyloxy group, the aralkyloxy group May have one or more groups selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, and a lower alkoxy group as a substituent, and when R 5 is a lower alkylthio group, The group may have one or more groups selected from a lower cycloalkyl group and a heterocyclic group as a substituent. When R 5 is an arylthio group, the arylthio group is a halogen atom, halogeno-lower alkyl group,及Pi Amino group or al selected is 1 or good R 5 may have a plurality of groups as substituents case of Ararukiruchio group, said Ararukiruchio group halogen atom , A lower alkyl group, a halogeno lower alkyl group, and a lower alkoxy group may have one or more groups as a substituent. In the case of an arylsulfonyl group, the arylylsulfonyl group is 1 Or may have multiple amino groups as substituents; and / or
(b 1 0) R6が水素原子を示し；及び 又は (b 1 0) R 6 represents a hydrogen atom; and or
( b 1 1 ) R7が水素原子を示し；及ぴ 又は (b 1 1) R 7 represents a hydrogen atom;
( b 1 2 ) R8が水素原子、低級シクロアルキル基、ァリール基、複素環基、又はカルボキシ 基のエステルを示し、 (b 1 2) R 8 represents a hydrogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, or an ester of a carboxy group,
R8がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基、ハロゲノ低級 アルキル基、低級シクロアルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基 、低級アルコキシ基、ハロゲノ低 アルコキシ基、ァリールォキシ基、ァラルキルォキシ基 、低級アルキルチオ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキル カルボニル基、ァリ一ルカルポニル基、カルポキシ基、スルホン酸基のアミド、ニトロ基、及 びシァノ基から選択される 1又は複数個の基を置換基として有してもよく；及び 又は (b 1 3 ) R9が水素原子、ァリール基、又は複素環基を示し、 When R 8 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a lower alkoxy group, or a halogeno lower alkoxy group. , Aryloxy group, aralkyloxy group, lower alkylthio group, amino group, amide of amino group, lower alkylamino group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, amide of sulfonic acid group, nitro group, and cyano And may have one or more groups selected from the group as a substituent; and or (b 1 3) R 9 represents a hydrogen atom, an aryl group, or a heterocyclic group,
R9がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基、 1若しくは複数 個のヒドロキシ基で置換された低級アルキル基、 1若し ま複数個の低級アルコキシ基で 置換された低級アルキル基、 1若しくは複数個のァリールォキシ基で置換された低級ァ ルキル基、 1若しくは複数個のカルボキシ基で置換された低級アルキル基、 1若しくは複 数個のカルポキシ基のエステルで置換された低級アルキル基、 1若しくは複数個のシァノ 基で置換された低級アルキル基、ハロゲノ低級アルキル基、低級シクロアルキル基、ァリ ール基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、 1若し くは複数個の低級シクロアルキル基で置換された低級アルコキシ基、 1若しくは複数個の 複素環基で置換された低級アルコキシ基、 1若しくは複数個のヒドロキシ基で置換された 低級アルコキシ基、 1若しくは複数個の低級アルコキシ基で置換された低級アルコキシ 基、 1若しくは複数個のァミノ基で置換された低級アルコキシ基、 1若しくは複数個のカル ポキシ基で置換された低級アルコキシ基、 1若しくは複数個のカルボキシ基のエステルで 置換された低級アルコキシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ基、低 級シクロアルキルォキシ基、 1若しくは複数個のハロゲン原子で置換されたァリールォキ シ基、ァラルキルォキシ基、ァリ一ルォキシカルポニルォキシ基、低級アルキルチオ基、 アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキルカルボニル基、ァリール カルボニル基、カルポキシ基、カルポキシ基のアミド、スルホン酸基のアミド、ニトロ基、及 びシァノ基から選択される 1又は複数個の基を置換基として有してもよぐ及び/又は (b 1 4) R1°がァリール基を示す請求項 1又は 2記載の化合物又はその塩。 When R 9 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with one or more hydroxy groups, or a lower alkyl substituted with one or more lower alkoxy groups. A lower alkyl group substituted with one or more aryloxy groups, a lower alkyl group substituted with one or more carboxy groups, one or more Lower alkyl group substituted with several carboxy ester, lower alkyl group substituted with one or more cyan groups, halogeno lower alkyl group, lower cycloalkyl group, aryl group, aralkyl group, hydroxy Group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted by one or more lower cycloalkyl groups, lower alkoxy group substituted by one or more heterocyclic groups, one or more A lower alkoxy group substituted with one hydroxy group, a lower alkoxy group substituted with one or more lower alkoxy groups, a lower alkoxy group substituted with one or more amino groups, one or more carboxyls A lower alkoxy group substituted with a group, or a lower alkoxy substituted with an ester of one or more carboxy groups Group, halogeno lower alkoxy group, lower alkenyloxy group, lower cycloalkyloxy group, aryloxy group substituted with one or more halogen atoms, aralkyloxy group, aryloxycarbonyloxy group, lower Selected from alkylthio group, amino group, amide of amino group, lower alkylamino group, lower alkylcarbonyl group, arylylcarbonyl group, carboxy group, amide of carboxy group, amide of sulfonic acid group, nitro group, and cyano group 3. The compound or a salt thereof according to claim 1 or 2, wherein one or more groups may be substituted and / or (b 14) R 1 ° represents an aryl group.
すなわち、一般式（1 )で示される化合物において、上記（b 1 )、（b2 )、（b3 )、（b4 )、 ( b5)、（b6 )、（b7 )、（b8 )、（b9 )、（b 1 0)、（b "；)、（b 1 2)、（b 1 3 )及び（b l 4)から選 択される 1又は 2以上の各組み合わせからなる化合物又はその塩。  That is, in the compound represented by the general formula (1), the above (b 1), (b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9) , (B 10), (b ″;), (b 12), (b 13) and (bl 4), or a compound comprising one or more combinations thereof, or a salt thereof.
本発明化合物における各基又は各基の組み合わせの好ましい例として、下記（c)又 は（d)の条件を充足する化合物又はその塩が挙げられる。  Preferred examples of each group or combination of groups in the compound of the present invention include compounds that satisfy the following conditions (c) or (d) or salts thereof.
(c)一般式（1 )において、 X1— X2が CH2— CH2を、 Y1— Y2が CH = CHを、 pが 0を、 R2t R3がともに水素原子を示す化合物又はその塩。 (c) In general formula (1), X 1 — X 2 represents CH 2 — CH 2 , Y 1 — Y 2 represents CH = CH, p represents 0, and R 2 t R 3 both represent hydrogen atoms. Compound or salt thereof.
(d)—般式（1 )において、 X1— X2が CH2— CH2を、 Y1— Y2は N = CH、又は CH = Nを、 卩カ 0を、 R2と R3がともに水素原子を示す化合物又はその塩。 (d) —In the general formula (1), X 1 — X 2 is CH 2 — CH 2 , Y 1 — Y 2 is N = CH or CH = N, 0 0, R 2 and R 3 Or a salt thereof, in which both represent a hydrogen atom.
一般式（1 )で表される本発明化合物において、 R5の好ましい例として、下記（e)の条 件を充足する化合物又はその塩が挙げられる。 In the compound of the present invention represented by the general formula (1), a preferred example of R 5 includes a compound satisfying the following condition (e) or a salt thereof.
(e)—般式（1 )において、 R5がハロゲン原子、置換基を有してもよい低級アルキル基、 ハロゲノ低級アルキル基、置換基を有してもよい複素環基、置換基を有してもよいァラル キル基、ヒドロキシ基、ヒドロキシ基のエステル、置換基を有してもよい低級アルコキシ基 、ハロゲノ低級アルコキシ基、置換基を有してもよい低級シクロアルキルォキシ基、置換 基を有してもよいァリールォキシ基、置換基を有してもよい複素環ォキシ基、置換基を有 してもよいァラルキルォキシ基、メルカプト基、メルカプト基のエステル、置換基を有しても よい低級アルキルチオ基、ハロゲノ低級アルキルチオ基、置換基を有してもよい低級シク ロアルキルチオ基、置換基を有してもよいァリールチオ基、置換基を有してもよい複素環 チォ基、置換基を有してもよいァラルキルチオ基、アミノ基、ァミノ基のアミド、置換基を有 してもよい低級アルキルアミノ基、置換基を有してもよい低級アルキルアミノ基のアミド、 置換基を有してもよいァリ一ルァミノ基、置換基を有してもよいァリ一ルァミノ基のアミド、 ホルミル基、置換基を有してもよい低級アルキルカルポニル基、置換基を有してもよいァ リールカルボ二ル基、置換基を有してもよい低級アルキルスルホニル基、置換基を有して もよぃァリールスルホニル基、 C R6 = CR7 ( R8 )、又は C≡CR9を示す化合物又はその塩 が好まし 置換基を有してもよい複素環基、ヒドロキシ基、ヒドロキシ基のエステル、置 換基を有してもよい低級アルコキシ基、ハロゲノ低級アルコキシ基、置換基を有してもよ い低級シクロアルキルォキシ基、置換基を有してもよいァリールォキシ基、置換基を有し てもよい複素環ォキシ基、置換基を有してもよいァラルキルォキシ基、メルカプト基、メル カプト基のエステル、置換基を有してもよい低級アルキルチオ基、ハロゲノ低級アルキル チォ基、置換基を有してもよい低級シクロアルキルチオ基、置換基を有してもよいァリー ルチオ基、置換基を有してもよい複素環チォ基、置換基を有してもよいァラルキルチオ基 、 CR6 = CR7 ( R8)、又は C≡CR9を示す化合物又はその塩がより好ましい。 (e) —in the general formula (1), R 5 is a halogen atom, an optionally substituted lower alkyl group, A halogeno lower alkyl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group, a hydroxy group, an ester of a hydroxy group, an optionally substituted lower alkoxy group, a halogeno A lower alkoxy group, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, or a substituent. Good aralkyloxy group, mercapto group, ester of mercapto group, optionally substituted lower alkylthio group, halogeno-lower alkylthio group, optionally substituted lower cycloalkylthio group, optionally substituted May have a good aryloxy group, a heterocyclic thio group which may have a substituent, an aralkylthio group which may have a substituent, an amino group, an amide of an amino group, or a substituent. A primary alkylamino group, an amide of a lower alkylamino group which may have a substituent, an arylamino group which may have a substituent, an amide of an arylamino group which may have a substituent, A formyl group, a lower alkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, a lower alkylsulfonyl group which may have a substituent, and a substituent. A compound having a aryl sulfonyl group, CR 6 = CR 7 (R 8 ), or C≡CR 9 or a salt thereof is preferred. A heterocyclic group which may have a substituent, a hydroxy group, a hydroxy group An ester, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, and a substituent Heterocyclic oxy group and substituent which may have An aralkyloxy group, a mercapto group, an ester of a mercapto group, a lower alkylthio group which may have a substituent, a halogeno lower alkylthio group, a lower cycloalkylthio group which may have a substituent, and a substituent. An arylthio group that may have, a heterocyclic group that may have a substituent, an aralkylthio group that may have a substituent, CR 6 = CR 7 (R 8 ), or C≡CR 9 A compound or a salt thereof is more preferable.
一般式（1 )で表される本発明化合物において、 R5のより好ましい例として、下記（f)〜 (j)の条件を充足する化合物又はその塩が挙げられる。 In the compound of the present invention represented by the general formula (1), more preferable examples of R 5 include compounds satisfying the following conditions (f) to (j) or salts thereof.
(f)一般式（1 )において、 R5が置換基を有してもよい複素環基を示す化合物が好ましく、 特に、該複素環基の複素環が、ピぺラジン、モルホリン、ピロリジン、ピリジン、チォフェン 、インドール、ベンゾイミダゾ一ル、キノリン、キノキサリン、ベンゾフラン、ベンゾチォフェン、 ベンゾォキサゾリン、又はべンゾチアゾリンを示す化合物又はその塩がより好ましい。 (g)—般式（1 )において、 R5がヒドロキシ基、ヒドロキシ基のエステル、置換基を有しても よい低級アルコキシ基、ハロゲノ低級アルコキシ基、置換基を有してもよい低級シクロア ルキルォキシ基、置換基を有してもよいァリールォキシ基、置換基を有してもよい複素環 ォキシ基、又は置換基を有してもよいァラルキルォキシ基を示す化合物又はその塩が好 ましく、ヒドロキシ基、置換基を有してもよい低級アルコキシ基、ハロゲノ低級アルコキシ 基、置換基を有してもよいァリールォキシ基、又は置換基を有してもよいァラルキルォキ シ基を示す化合物又はその塩がより好ましい。 (f) In the general formula (1), a compound in which R 5 represents a heterocyclic group which may have a substituent is preferable, and in particular, the heterocyclic ring of the heterocyclic group is piperazine, morpholine, pyrrolidine, pyridine. , Thiophene, indole, benzoimidazole, quinoline, quinoxaline, benzofuran, benzothiophene, benzoxazoline, or benzothiazoline or a salt thereof is more preferable. (g) —In the general formula (1), R 5 is a hydroxy group, an ester of a hydroxy group, an optionally substituted lower alkoxy group, a halogeno-lower alkoxy group, or an optionally substituted lower cycloalkyloxy. A compound showing a group, an aryloxy group which may have a substituent, a heterocyclic group which may have a substituent, or an aralkyloxy group which may have a substituent, or a salt thereof is preferable. Further, a compound showing a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, an aryloxy group which may have a substituent or an aralkyloxy group which may have a substituent or a salt thereof is more preferable. .
( h)—般式（1 )において、 R5がメルカプト基、メルカプト基のエステル、置換基を有しても よい低級アルキルチオ基、ハロゲノ低級アルキルチオ基、置換基を有してもよい低級シク ロアルキルチオ基、置換基を有してもよいァリールチオ基、置換基を有してもよい複素環 チォ基、又は置換基を有してもよいァラルキルチオ基を示す化合物又はその塩が好まし く、メルカプト基、置換基を有してもよい低級アルキルチオ基、ハロゲノ低級アルキルチオ 基、置換基を有してもよいァリ一ルチオ基、複素環チォ基、又は置換基を有してもよいァ ラルキルチオ基を示す化合物又はその塩がより好ましい。 (h) —In the general formula (1), R 5 is a mercapto group, an ester of a mercapto group, an optionally substituted lower alkylthio group, a halogeno lower alkylthio group, or an optionally substituted lower cyclothio group. A compound showing an alkylthio group, an arylthio group which may have a substituent, a heterocyclic thio group which may have a substituent, or an aralkylthio group which may have a substituent or a salt thereof is preferred. Group, lower alkylthio group optionally having substituent, halogeno lower alkylthio group, arylthio group optionally having substituent, heterocyclic thio group, or aralkylthio group optionally having substituent Or a salt thereof is more preferred.
( i )一般式（1 )において、 R5が CR6 = CR7 ( R8)を示す化合物又はその塩が好ましく、 R6 が水素原子を、 R7が水素原子を、 R8が水素原子、低級シクロアルキル基、置換基を有し てもよぃァリール基、複素環基、又はカルボキシ基のエステルを示す化合物又はその塩 力 り好ましい。 (i) In general formula (1), a compound or a salt thereof in which R 5 represents CR 6 = CR 7 (R 8 ) is preferred, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 8 is a hydrogen atom , A lower cycloalkyl group, a compound which may have a substituent, an aryl group, a heterocyclic group, or an ester of a carboxy group or a salt thereof is preferred.
(j)—般式（1 )において、 R5が C≡CR9を示す化合物又はその塩が好まし《 が水素原 子、置換基を有してもよいァリール基、又複素環基を示す化合物又はその塩がより好ま しい。 (j) —In the general formula (1), R 5 is preferably a compound in which C≡CR 9 or a salt thereof is preferred << is a hydrogen atom, an optionally substituted aryl group or a heterocyclic group A compound or a salt thereof is more preferred.
( k)本発明化合物は一般式（1 )の下記 A部に不斉炭素原子を有するが、その部分の立 体構造は以下のものが好ましい。  (k) The compound of the present invention has an asymmetric carbon atom in the following A part of the general formula (1), and the cubic structure of the part is preferably as follows.
1 ) X1— X2が CH2— CH2、 CH = CH又は CH2— Sの場合は、 A部の立体構造が RS体又は R体の化合物が好ましぐ R体の化合物が特に好ましい。 1) When X 1 — X 2 is CH 2 — CH 2 , CH = CH or CH 2 — S, a compound having a steric structure at the A part is preferably an RS form or an R form. An R form compound is particularly preferred. .
2) X1— X2が S— CH2の場合は、 A部の立体構造が RS体又は S体の化合物が好ましく、 S体の化合物が特に好ましい。
Figure imgf000032_0001
2) In the case where X 1 —X 2 is S—CH 2 , a compound in which the steric structure of the A part is RS or S is preferable, and a compound of S is particularly preferable.
Figure imgf000032_0001
(I)本発明化合物における特に好ましい具体例として下記の化合物又はその塩が挙げら れる。  (I) Particularly preferred specific examples of the compound of the present invention include the following compounds or salts thereof.
■(R) -Ν 一（4一トリフルォロメチルフエニル）ピロリジン一 2—カルポキサミド、  ■ (R) -Ν One (4 trifluoromethylphenyl) pyrrolidine 1 2-carboxamide,
'(R) — Ν _(4 η—ォクチルフエニル）ピロリジン一 2—カルポキサミド、  '(R) — Ν _ (4 η-octylphenyl) pyrrolidine 1-carboxamide,
■(R) -Ν _ (4一べンジルフエニル）ピロリジン _ 2—カルポキサミド、  ■ (R) -Ν _ (4 monophenylphenyl) pyrrolidine _ 2-carpoxamide,
■(R) -Ν 一（4—ョ一ドフエニル）ピロリジン一 2—力ルポキサミド、  ■ (R) -Ν (4-phenyl) pyrrolidine-1 2-power lupoxamide,
"(R) -Ν _ (4一ベンゾィルフエニル）ピロリジン一 2—カルボキサミド、  "(R) -Ν _ (4 benzoylphenyl) pyrrolidine 1 2-carboxamide,
•(R) -Ν —(6—クロロー 3—ピリジル）ピロリジン一 2—カルボキサミド、  • (R) -Ν— (6-chloro-3-pyridyl) pyrrolidine-1-carboxamide,
•(R) -Ν 一（4一トリフルォロメトキシフエ二ル）ピロリジン一 2—力ルポキサミド、 • (R) -Ν- (4-1trifluoromethoxyphenyl) pyrrolidine-1-2-lupoxamide,
■(R) — Ν 一（4一べンジルォキシフエニル）ピロリジン一 2—カルポキサミド、 ■ (R) — Ν One (4-Benzyloxyphenyl) pyrrolidine One 2-Carpoxamide,
'(R)一 Ν 一 [4一（3—メトキシベンジルォキシ）フエニル]ピロリジン一 2—カルボキサミド  '(R) Ν Ν [4 (3-Methoxybenzyloxy) phenyl] pyrrolidine-1 2-carboxamide
■ (R)-N' — [4— (3—メチルベンジルォキシ）フエニル]ピロリジン一2—カルポキサミド、■ (R) -N '— [4- (3-Methylbenzyloxy) phenyl] pyrrolidine 1-carboxamide,
■ (R)-N'一 [4— (3—クロ口ベンジルォキシ）フエニル]ピロリジン一 2—カルポキサミド、 ■( )-N' — [4— (4—クロ口ベンジルォキシ）フエニル]ピロリジン一 2—カルボキサミド、■ (R) -N '-[4 -— (3-Chronobenzyloxy) phenyl] pyrrolidine-one 2-carboxamide, ■ () -N' — [4-(4-Chronobenzyloxy) phenyl] pyrrolidine-one 2-carboxamide ,
■ (R)-N'一 [4— (2—トリフルォロメチルベンジルォキシ）フエニル]ピロリジン一 2—カル ポキサミド、 ■ (R) -N ′-[4- (2-trifluoromethylbenzyloxy) phenyl] pyrrolidine-1-2-carboxamide,
■ (R)-N'一 [4— (3—トリフルォロメチルベンジルォキシ）フエ二ノレ]ピロリジン一 2—カル ポキサミド、  ■ (R) -N ′-[4— (3-Trifluoromethylbenzyloxy) phenolin] pyrrolidine-1-2-carboxamide,
■ (R) -N'一 [4— (4一トリフルォロメチルベンジルォキシ）フエニル]ピロリジン一 2—カル ポキサミド、  ■ (R) -N ′-[4 -— (4-Trifluoromethylbenzyloxy) phenyl] pyrrolidine-1-2-carboxamide,
■(R)-N'一（4一ベンジルォキシ _3—クロ口）フエニルピロリジン一 2—力ルポキサミド、■ (R) -N '-(4-Benzyloxy_3-Cro-mouth) Phenylpyrrolidine- 1-Power Lupoxamide,
■ (R) -N'一 [3—メチルー 4— (4一メチルベンジルォキシ）フエニル]ピロリジン一 2—力 ルポキサミド、 ■ (R) -N '-[3-Methyl-4- (4-Methylbenzyloxy) phenyl] pyrrolidine-2 Lupoxamide,
■(R)-N' _ [4— (3—ピリジルメチルォキシ）フエニル]ピロリジン一 2—力ルポキサミド、 ■ (R) -N '_ [4— (3-Pyridylmethyloxy) phenyl] pyrrolidine 1-power lupoxamide,
"(R)-N' - (4—フエノキシフエニル）ピロリジン一 2_カルポキサミド、 "(R) -N '-(4-Phenoxyphenyl) pyrrolidine 1_carboxamide,
■(R)-N' - (4—トリフルォロメチルチオフエニル）ピロリジン一 2—カルボキサミド、 ■ (R) -N ′-(4-Trifluoromethylthiophenenyl) pyrrolidine-2-carboxamide,
, (R)-N'一（4一フエ二ルチオフエニル）ピロリジン一 2—カルボキサミド、 , (R) -N ′-(4-1-phenylthiophenyl) pyrrolidine-1 2-carboxamide,
■(R)— N'—(4—べンジルチオフエニル）ピロリジン一 2—カルボキサミド、  ■ (R) —N ′ — (4-Benzylthiophenyl) pyrrolidine-1-carboxamide,
'(R)-N'— [4— (2—クロ口べンジルチオ）フエニル]ピロリジン一 2—カルボキサミド、 '(R) -N'— [4— (2-Chronobenzoylthio) phenyl] pyrrolidine mono 2-carboxamide,
- (R)-N' - [4- (2—トリフルォロメチルベンジルチオ）フエニル]ピロリジン一 2—力ルポ キサミド、 -(R) -N '-[4- (2-trifluoromethylbenzylthio) phenyl] pyrrolidine mono-2-streptoxamide,
■(R)-N'— [4一（2—メトキシベンジルチオ）フエニル]ピロリジン一 2—カルボキサミド、 ■(R)-N'— [4一（3—メトキシベンジルチオ）フエニル]ピロリジン一 2—カルボキサミド、 ■(R)-N'—[4- (4—メトキシベンジルチオ）フエニル]ピロリジン一 2—力ルポキサミド、 '(R)—N'—[4— (4—ピリジルメチルチオ）フエニル]ピロリジン一2—カルボキサミド、 ■(R)-N' _[4— (1—メチル一 1 -フエ二ルェチルチオ）フエニル]ピロリジン一 2—力ルポ キサミド、  ■ (R) -N '— [4 (2-methoxybenzylthio) phenyl] pyrrolidine-1-carboxamide, ■ (R) -N' — [4 (3-methoxybenzylthio) phenyl] pyrrolidine-2- Carboxamide, ■ (R) -N '— [4- (4-Methoxybenzylthio) phenyl] pyrrolidine 2-Role Lupoxamide,' (R) —N '— [4- (4-Pyridylmethylthio) phenyl] pyrrolidine 1 2-Carboxamide, (R) -N ′ _ [4— (1-Methyl-1- (1-phenylethylthio) phenyl] pyrrolidine-1-2-Lupoxamide,
■(R)-N'— (4—フエネチルチオフエニル）ピロリジン一 2—カルボキサミド、  ■ (R) -N'— (4-Phenethylthiophenyl) pyrrolidine-2-carboxamide,
, (R)-N'一 [4— (3—フエニルプロピルチオ）フエニル]ピロリジン一 2—カルポキサミド、 , (R) -N'one [4-((3-phenylpropylthio) phenyl] pyrrolidine-one 2-carboxamide,
■ (R)-N'—(4一 n—プチルチオフエニル）ピロリジン一 2—カルポキサミド、 ■ (R) -N ′ — (4 n-Ptylthiophenenyl) pyrrolidine-2-caroxamide,
■(R)-N'—(4—シクロへキシルメチルチオフエニル）ピロリジン一 2—カルボキサミド、 ■(R)-N'—（6—ベンジルチオ一 3—ピリジル）ピロリジン一 2—カルボキサミド、 ■ (R) -N '-(4-cyclohexylmethylthiophenenyl) pyrrolidine-1-2-carboxamide, ■ (R) -N'-(6-benzylthio-1-3-pyridyl) pyrrolidine-1-2-carboxamide,
'(R)—N'—[4— (2—ナフチル）フエニル]ピロリジン一 2 _カルボキサミド、 '(R) —N' — [4— (2-naphthyl) phenyl] pyrrolidine 1 2 _carboxamide,
■ (R)-N'一 [4一（ベ ゾチォフェン一2—ィル）フエニル]ピロリジン一 2—力ルポキサミド  ■ (R) -N'1 [4 (bezothiophene-2-yl) phenyl] pyrrolidine-1 2-power lupoxamide
■ (R)-N'一 [4— (ベンゾチアゾ一ルー 2—ィノレ）フエニル]ピロリジン一 2—カルポキサミド ■ (R) -N '-[4— (Benzothiazo-Lu 2-ynole) phenyl] pyrrolidine-I 2-Carpoxamide
■(R)-N'— [4一 [(E)— 2—フエ二ルー 1—ェテニル]フエニル]ピロリジン一 2—カルボ キサミド、 ■ (R) -N'— [4 1 [(E) — 2 -phenyl-2-phenyl] pyrrolidine 1 2-carboxamide,
3 . (R)—N，一 [4一 [(E)— 2—（2—メチルフエニル）一 1—ェテニル]フエニル]ピロリジン 一 2—カルボキサミド、 Three (R) —N, 1 [4 1 [(E) — 2— (2-methylphenyl) 1 1-ethenyl] phenyl] pyrrolidine 1 2 —carboxamide,
■(R)-N'— [4— [(E)— 2— (3—メチルフエ二ル）一 1—ェテニル]フエニル]ピロリジン —2-カルボキサミド、  ■ (R) -N'— [4— [(E) — 2— (3-Methylphenyl)-1-ethenyl] phenyl] pyrrolidine —2-carboxamide,
- (R)-N'一 [4一 [(E)— 2—（4—メチルフエ二ル）一 1—ェテニル]フエニル]ピロリジン —2—カルボキサミド、 -(R) -N'one [41] [(E) — 2- (4-methylphenyl) -one 1-ethenyl] phenyl] pyrrolidine —2-carboxamide,
■(R)-N'一 [4— [(E)— 2—（2—クロロフヱニル）一 1ーェテニル]フエニル]ピロリジン一 2—力ルポキサミド、  ■ (R) -N ′-[4 -— ((E) —2- (2-Chlorophenyl) -1-1-ethenyl] phenyl] pyrrolidine-1-2-lupoxamide,
. (R)-N'—[4— [(E)—2—（3—クロ口フエニル）ー1—ェテニル]フエニル]ピロリジン一 2—カルボキサミド、  (R) -N '— [4 — [(E) -2— (3-clophenyl) -1-ethenyl] phenyl] pyrrolidine mono 2-carboxamide,
, (R)-N'一 [4一 [(E) _2—（4—クロ口フエニル）一 1—ェテニル]フエニル]ピロリジン一 2—カルポキサミド、  , (R) -N'1 [4 1 [(E) _2— (4-Clophenyl) 1-ethenyl] phenyl] pyrrolidine 1 2-carboxamide,
■(R)-N'—[3—メチル一4一 [(E) -2—フエニル一 1—ェテニソレ]フエニル]ピロリジン一 2—カルボキサミド、  ■ (R) -N '— [3-Methyl-4-one [(E) -2-phenyl-1- 1-ethenisol] phenyl] pyrrolidine-1-2-carboxamide,
-(R)-N' _[3—クロ口 _4一 [(E)— 2—フエ二ルー 1ーェテニル]フエニル]ピロリジン一 2—カルボキサミド、 ' -(R) -N '_ [3—Black mouth _4 1 [(E) -2 2-phenyl 1-phenyl] phenyl] pyrrolidine 1 2-carboxamide,'
- (R)-N'— [4— [(E)— 2—シクロへキシル一1—ェテニル]フエニル]ピロリジン一 2_ カルボキサミド、  -(R) -N'— [4— [(E) — 2-cyclohexyl-1-ethenyl] phenyl] pyrrolidine-2-carboxamide,
- (R)-N' - [4_ [(E)—2— (4—イソプロポキシフエ二ル）一 1—ェテニル]フエニル]ピ 口リジン一 2—力ルポキサミド、  -(R) -N '-[4_ [(E) —2— (4-Isopropoxyphenyl) -1- 1-ethenyl] phenyl] pi-lysine 1-strength lupoxamide,
. (R)-N'— [4— [(E)— 2—（4—ニトロフエニル）一 1—ェテニル]フエニル]ピロリジン一 2—力ルポキサミド、  (R) -N'— [4— [(E) — 2— (4-Nitrophenyl) 1-ethenyl] phenyl] pyrrolidine 1 2-streptoxamide,
■ (R)— N'— [4一 [(E)— 2— (4—べンジルフエニル）一 1ーェテニル]フエニル]ピロリジ ン一 2 _カルポキサミド、  ■ (R) — N′— [4 1 [(E) — 2— (4-Benzylphenyl) 1 1-ethenyl] phenyl] pyrrolidine 1 2 _carboxamide,
- (R)-N'— [4— [(E)— 2—（1—ナフチル）_ 1—ェテニル]フエ二ル].ピロリジン一 2— カルボキサミド、 -(R) -N'— [4— [(E) — 2- (1-naphthyl) _ 1-ethenyl] phenyl] .pyrrolidine mono 2-carboxamide,
■ (R)-N'一 [4_ [(E)— 2—（4—ピリジル）一 1ーェテニル]フエニル]ピロリジン一 2—力 ルポキサミド、 ■ (R) -N '1 [4_ [(E) — 2— (4-Pyridyl) 1 1-ethenyl] phenyl] pyrrolidine 1 2—Power Lupoxamide,
' (R)—N，一[4一 [(E)— 2— (2、チェ二ル）一 1—ェテニル]フエ二ノレ]ピロリジン一 2— カルポキサミド、  '(R) —N, 1 [4 1 [(E) — 2— (2, Cheryl) 1 1-ethenyl] phenenole] pyrrolidine 1 2 — carpoxamide,
' (R)— N'— [4_(2_フエ二ルー 1—ェチニル）フエニル]ピロリジン一 2—カルボキサミド 、  '(R) — N'— [4_ (2_phenyl 2-phenyl) phenyl] pyrrolidine 1-carboxamide,
' (R)-N' -[4-[2- (2—メチルフエニル）一 1ーェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、  '(R) -N'-[4- [2- (2-Methylphenyl) -1- 1-ethynyl] phenyl] pyrrolidine-1 2-force lupoxamide,
' (R)-N'一 [4， [2— (3—メチルフエ二ル）一 1ーェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、  '(R) -N' 1 [4, [2— (3-Methylphenyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2 — force lupoxamide,
- (R)-N'— [4— [2_(4—メチルフエ二ル）一 1—ェチニル]フエニル]ピロリジン一2—力 ルポキサミド、 -(R) -N'— [4— [2_ (4-Methylphenyl) -1- 1-ethynyl] phenyl] pyrrolidine 1-2-power lupoxamide,
' (R)-N' - [4— [2— (2—トリフルォロメチルフエ二ル）一 1ーェチニル]フエニル]ピロリ ジン一 2—カルボキサミド、  '(R) -N'-[4— [2— (2-Trifluoromethylphenyl) 1-1-ethynyl] phenyl] pyrrolidine-1-2-carboxamide,
■ (R)-N'— [4— [2—（3—トリフルォロメチルフエ二ル）一 1一ェチニノレ]フエニル]ピロリ ジン一 2—カルボキサミド、  ■ (R) -N'— [4— [2— (3-Trifluoromethylphenyl) 1 1 ethyninole] phenyl] pyrrolidine 1 2 carboxamide,
. (R)— N'—[4— [2— (4—トリフルォロメチルフエ二ル）一 1ーェチニル]フエニル]ピロり ジン一 2—力ルポキサミド、  (R) — N ′ — [4— [2— (4-Trifluoromethylphenyl) 1-1-ethynyl] phenyl] pyrrolidin-zine 2-power lupoxamide,
■ (R)-N'—[4— [2- (4—二トロフエニル）一 1ーェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、 ，  ■ (R) -N '— [4— [2- (4-Trotropenyl) 1-1-ethynyl] phenyl] pyrrolidine1-2-force lupoxamide,,
- (R)-N'— [4— [2— (4—ベンジルフエ二ル）一 1—ェチ.ニル]フエニル]ピロリジン一 2 一力ルポキサミド、 -(R) -N'— [4— [2— (4-Benzylphenyl) 1-1-ethynyl] phenyl] pyrrolidine-1 2 lrpoxamide,
, (R)— N'—[4— [2—（4ーシクロへキシルメトキシフエ二ル）一 1—ェチニル]フエニル]ピ 口リジン一 2—力ルポキサミド、  , (R) — N ′ — [4— [2- (4-cyclohexylmethoxyphenyl) -1-1-ethynyl] phenyl] pi- lysine 1-strength lupoxamide,
-(R)-N'—[4一 [2—（4—イソプロポキシフエ二ル）一 1ーェチニル]フエニル]ピロリジン 一 2—カルボキサミド、  -(R) -N '— [4 1 [2- (4-Isopropoxyphenyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2-carboxamide,
■ (R)— N'—[4— [2— (4—べンジルォキシフエ二ル）一 1ーェチニル]フエニル]ピロリジ ン一 2—カルボキサミド、 ' (R)-N'—[4— [2— (4—ピリジルメチルォキシフエニル）一 1—ェチニル]フエ二ノレ]ピロ リジン一 2—力ルポキサミド、 ■ (R) —N ′ — [4— [2— (4-Benzyloxyphenyl) 1-1-ethynyl] phenyl] pyrrolidin-1-2-carboxamide, '(R) -N' — [4 -— [2 -— (4-Pyridylmethyloxyphenyl) -1-1-ethynyl] phenyleno] pyrrolidine-2—power lupoxamide,
■ (R)-N' -[4-[2-(1一ナフチル）一 1ーェチニル]フヱニル]ピロリジン一 2—力ルポ キサミド、  ■ (R) -N '-[4- [2- (1-Naphtyl) -1-1-ethynyl] phenyl] pyrrolidine-1-2-Lupoxamide,
- (R)-N' _ [2—メチルー 4_ (2—フエニル一 1—ェチニノレ）フエニル]ピロリジン一2—力 ルポキサミド、 -(R) -N '_ [2-Methyl-4_ (2-phenyl-1- 1-ethininole) phenyl] pyrrolidine-2-power lupoxamide,
. (R)—N'— [2—クロロー 4— (2—フエニル一 1ーェチニル）フエニル]ピロリジン _2_力 ルポキサミド、 .  (R) —N'— [2-Chloro-4- (2-phenyl-1- 1-ethynyl) phenyl] pyrrolidine _2_force lupoxamide,.
■ (R)-N'—[3—メチルー 4一（2—フエ二ルー 1ーェチニル）フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) -N '— [3-Methyl-4-one (2-phenyl-2-ethynyl) phenyl] pyrrolidine-1-2 force Lupoxamide,
■(R)— N' _[3—クロロー 4一（2—フエニル一 1—ェチニル）フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) —N ′ _ [3-Chloro-4 (2-phenyl-1- 1-ethynyl) phenyl] pyrrolidine 1-2-power lupoxamide,
■ (R)_N'—[5— (2—フエニル一 1—ェチニル）一 2—ピリジル]ピロリジン一 2—カルボ キサミド、  ■ (R) _N '— [5— (2-phenyl-1- 1-ethynyl) -1-2-pyridyl] pyrrolidine 2-carboxamide,
- (R) -Ν'一 [6— (2—フエニル一 1—ェチ二ル）一 3—ピリジル]ピロリジン一 2_力ルポ キサミド、 -(R) -Ν'1 [6— (2-phenyl-1- 1-ethynyl) -1-3-pyridyl] pyrrolidine 1-2_lupoxamide,
■ (R)-N'— [5— [2—（4—トリフルォロメチルフエニル）一1 _ェチニル]— 2—ピリジル] ピロリジン一 2—力ルポキサミド、  ■ (R) -N '— [5— [2- (4-Trifluoromethylphenyl) 1-1_ethynyl] —2-pyridyl] pyrrolidine-1-2-lupoxamide,
, (S)-N'—[4— [(E)— 2—フエニル _1—ェテニル]フエニル]チアゾリジン一 4_カル ポキサミド、  , (S) -N '— [4 — [(E) —2-phenyl_1-ethenyl] phenyl] thiazolidine mono 4_carboxamide,
-Ν'一 [4— [(E)— 2— (4—メトキシフエ二ル）一 1—ェテニル]フエニル]一 2, 5—ジヒドロ ピロール一 2—カルボキサミド、  -Ν'1 [4— [(E) — 2— (4-methoxyphenyl) -1- 1-ethenyl] phenyl] -1,2,5-dihydropyrrole 2-2-carboxamide,
■ (R)-N' -[4-(1—メチルインド一ルー 5—ィル）フエニル]ピロリジン一 2—カルポキサ ミド、  ■ (R) -N '-[4- (1-Methylindo-roux 5-yl) phenyl] pyrrolidine-one 2-carboxamide,
■ (R)— N'—[4— (インドール一 5—ィル）フエニル]ピロリジン一 2—力ルポキサミド、■ (R) — N '— [4— (Indole 1-yl) phenyl] pyrrolidine 1-strength lupoxamide,
- (R)-N'—[4— [(E)— 2— (4— tert—ブトキシフエ二ル）一 1—ェテニル]フエニル]ピ 口リジン一 2—力ルポキサミド、 ' (R)-N'—(4—フエネチルフエニル）ピロリジン一 2—カルボキサミド、-(R) -N '— [4— [(E) — 2— (4-tert-butoxyphenyl) -1- 1-ethenyl] phenyl] bis-lysine 1-strength lupoxamide, '(R) -N' — (4-phenethylphenyl) pyrrolidine mono 2-carboxamide,
. (R)-N'—[4— [2— (2—フエニルフエ二ル）一 1ーェチニル]フエニル]ピロリジン一 2— カルポキサミド、 (R) -N '— [4— [2— (2-phenylphenyl) 1-1-ethynyl] phenyl] pyrrolidine-1-2-carboxamide,
'(R)— N' _[6_メチル一 5— [2—（1—ナフチル）一1—ェチニル]一 2—ピリジル]ピロ リジン一 2—カルボキサミド、  '(R) —N' _ [6_methyl-1-5- [2- (1-naphthyl) -1-1-ethynyl] -1-2-pyridyl] pyrolidine-1-2-carboxamide,
■(R)-N' _ [4— [2— (4—メトキシー 2—メチルフエニル）一 1—ェチニル]フエニル]ピロ リジン一 2—カルボキサミド、  ■ (R) -N '_ [4— [2— (4-Methoxy-2-methylphenyl) -1-1-ethynyl] phenyl] pyrrolidin-1-carboxamide,
■ (R)-N'一 [4— [2— (2—チェニル）一 1—ェチニル]フエニル]ピロリジン一 2—力ルポ キサミド、  ■ (R) -N '-[4 -— [2 -— (2-Chenyl) -1-1-ethynyl] phenyl] pyrrolidine-2—power lupoxamide,
- (R)-N'一 [4_[2_(5—トリフルォロメチル一 1一ナフチノレ）一 1—ェチニル]フエニル] ピロリジン一 2—力ルポキサミド、 -(R) -N '-[4_ [2_ (5-trifluoromethyl-1 1-naphthynole) -1 1-ethynyl] phenyl] pyrrolidine 1 2-streptoxamide,
■ (R)-N'— [5— [2— (1—ナフチル）一1 _ェチニル]— 2—ピリジル]ピロリジン一 2— カルボキサミド、  ■ (R) -N'— [5— [2— (1-Naphtyl) 1 _ethynyl] — 2-pyridyl] pyrrolidine 1 2 — carboxamide,
■(R)-N'一 [4— [2— (4—インドリル）一 1—ェチニル]フエニル]ピロリジン一 2—カルボ キサミド、  ■ (R) -N '-[4 -— [2 -— (4-Indolyl)-1-ethynyl] phenyl] pyrrolidine-1 2-carboxamide,
' (R) _Ν' _ [4— [2— (ベンゾチォフェン一 3—ィル） - 1ーェチニル]フエニル]ピロリジン 一 2—カルポキサミド、  '(R) _Ν' _ [4— [2— (benzothiophene 1-yl) -1-ethynyl] phenyl] pyrrolidine 1 2-carboxamide,
- (R)-N'— [4— [2— (4—ァミノ一 2—メチルフエ二ル）一 1ーェチニル]フエニル]ピロリ ジン一 2—カルポキサミド、  -(R) -N'— [4— [2— (4-amino-2-methylphenyl) 1-1-ethynyl] phenyl] pyrrolidine-1-2-carboxamide,
-(R)-N'—[4— [2— (4—トリフルォロメトキシフエ二ル）一 1—ェチニル]フエニル]ピロ リジン一 2—カルボキサミド、及び -(R) -N '— [4— [2— (4-trifluoromethoxyphenyl) 1-1-ethynyl] phenyl] pyrrolidine-1-2-carboxamide, and
' (R)—N'—[4— [2— (4—イソプロポキシ一 3—メチルフエ二ル）一 1—ェチニル]フエ二 ル]ピロリジン一 2—力ルポキサミド 本発明化合物は、以下の方法により製造することができる。尚、個々の具体的な製造 方法については、後述の実施例『製造例の項』で詳細に説明する。また、これらの例示は 本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。尚 、下記の合成経路中で示されている Halはハロゲン原子を、 Bocは tert—ブトキシカルボ ニル基を、 Bnはベンジル基を示す。 '(R) —N' — [4— [2— (4-Isopropoxy-3-methylphenyl) 1-1-ethynyl] phenyl] pyrrolidine-1-2-Lupoxamide The compound of the present invention is prepared by the following method. Can be manufactured. Each specific manufacturing method will be described in detail in the “Production Example” section described later. Moreover, these illustrations are for understanding the present invention better and are not intended to limit the scope of the present invention. still In the following synthesis route, Hal represents a halogen atom, Boc represents a tert-butoxycarbonyl group, and Bn represents a benzyl group.
本発明化合物（ I ) (一般式 [1]において R2が水素原子である化合物）は合成経路 1 に従い合成することができる。すなわち、化合物（Π)を酢酸ェチルエステル、 1 , 4ージォ キサン、メタノール、塩化メチレン等の有機溶媒中、塩化水素、トリフルォロ酢酸等の酸 存在下、 0°Cから室温で、 30分から 12時間処理することによリ本発明化合物を得ること ができる。 The compound (I) of the present invention (a compound in which R 2 is a hydrogen atom in the general formula [1]) can be synthesized according to synthesis route 1. That is, the compound (Π) is treated in an organic solvent such as ethyl acetate, 1,4-dioxane, methanol and methylene chloride in the presence of an acid such as hydrogen chloride and trifluoroacetic acid at 0 ° C. to room temperature for 30 minutes to 12 hours. As a result, the compound of the present invention can be obtained.
Figure imgf000038_0001
Figure imgf000038_0001
合成経路 1 前記の化合物（Π)は合成経路 2に従い合成することできる。すなわち、化合物（m)と 化合物（17)を N, N—ジメチルホルムアミド（以下、 DMFとする）、塩化メチレン等の有機 溶媒中、 N, N'ージシクロへキシルカルポジイミド（以下、 DCCとする）、 O— (7—ァザべ ンゾトリァゾ一ルー 1—ィル）一N, N, N, N—テトラメチルゥロニゥムへキサフルォロホス フェート（以下、 HATUとする）等の縮合剤及び N， N—ジイソプロピルェチルァミン（以下、 DIEAとする）等の塩基存在下、室温から 50°Cで、 1時間から 3日間反応させることによ リ、化合物（ Π )を得ること力できる。  Synthetic route 1 The compound (Π) can be synthesized according to synthetic route 2. That is, the compound (m) and the compound (17) are mixed in an organic solvent such as N, N-dimethylformamide (hereinafter referred to as DMF) or methylene chloride, and N, N′-dicyclohexyl carpositimide (hereinafter referred to as DCC). , O- (7-azabenzotriazol 1-yl) 1 N, N, N, N-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU) and N, N —Compound (Π) can be obtained by reacting at room temperature to 50 ° C for 1 hour to 3 days in the presence of a base such as diisopropylethylamine (hereinafter referred to as DIEA).
Figure imgf000038_0002
Figure imgf000038_0002
合成経路 2 化合物（Π)—（a) (化合物（Π)において、 R5が O— R"である化合物）は合成経路 3に 従い合成することもできる。すなわち、化合物（ΙΠ)と化合物（W)—（a) (化合物（IV)にお いて R5がー O—ベンジルである化合物）より、合成経路 2に従い化合物（II)— (b)が得ら れる。得られる化合物（ Π ) _ (b)をメタノール、エタノール等の有機溶媒中、パラジウム 炭素等の触媒存在下、水素雰囲気下、室温で、 1時間から 24時間処理することにより 化合物（ H )一（c)を得ることができる。さらに、化合物（ Π )— (G)と対応するハロゲン化 化合物（V)を DMF、エタノール等の有機溶媒中、炭酸カリウム、 DIEA等の塩基存在下 、室温から 100°Cで、 1時間から 24時間反応させることにより化合物（Π)— (a)を得るこ とができる。 Synthesis route 2 Compound (Π)-(a) (compound (Π) in which R 5 is O—R ″) is added to synthesis route 3. It can be synthesized accordingly. That is, compound (II)-(b) is obtained from compound (II) and compound (W)-(a) (compound (IV) where R 5 is —O-benzyl) according to synthesis route 2. It is The resulting compound (化合物) _ (b) is treated in an organic solvent such as methanol or ethanol in the presence of a catalyst such as palladium on carbon in a hydrogen atmosphere at room temperature for 1 to 24 hours. c) can be obtained. Further, the compound (V)-(G) and the corresponding halogenated compound (V) are added in an organic solvent such as DMF or ethanol in the presence of a base such as potassium carbonate or DIEA at room temperature to 100 ° C for 1 to 24 hours. Compound (Π)-(a) can be obtained by reacting for a period of time.
Figure imgf000039_0001
化合物（Π)—（d) (化合物（Π)において、 R5が S— R"である化合物）は合成経路 4に 従い合成することもできる。すなわち、化合物（m)と化合物（VI)より、合成経路 2に従い 化合物（¥H)が得られる。得られる化合物（VII)をアセトン、 1 , 4一ジォキサン等の有機溶 媒と水の混合溶媒中、トリ一 n—ブチルホスフィン等アルキルホスフィン存在下、室温で、 1時間から 24時間処理することで化合物（n)— (e)を得ることができる。さらに、化合物 (H)-(e)と対応するハロゲン化化合物（ V)を DMF、エタノール等の有機溶媒中、炭酸 カリウム、 DIEA等の塩基存在下、室温から 100¾で、 1時間から 24時間反応させること により化合物（ H )— (d)を得ることができる。
Figure imgf000040_0001
Figure imgf000039_0001
Compound (Π)-(d) (compound (Π) in which R 5 is S—R ″) can also be synthesized according to synthesis route 4. That is, from compound (m) and compound (VI) The compound (¥ H) is obtained according to the synthesis route 2. The obtained compound (VII) is mixed with an organic solvent such as acetone, 1,4-dioxane, and water in the presence of an alkylphosphine such as tri-n-butylphosphine. Then, compound (n) — (e) can be obtained by treating at room temperature for 1 to 24 hours, and further, compound (H)-(e) and the corresponding halogenated compound (V) are converted to DMF, Compound (H)-(d) can be obtained by reacting in an organic solvent such as ethanol in the presence of a base such as potassium carbonate or DIEA at room temperature to 100 ° C for 1 to 24 hours.
Figure imgf000040_0001
(Π)  (Π)
(V)  (V)
Figure imgf000040_0002
Figure imgf000040_0002
合成経路 4  Synthesis route 4
化合物（ Π )—（f) (化合物（ Π )において、 R5が CR6 = CR7(R8)である化合物）は合成 経路 5に従い合成することもできる。すなわち、化合物（ΙΠ)と化合物（IV)— (b) (化合物 (N)において R5がハロゲン原子である化合物）より、合成経路 2に従い化合物（ H )—（g )が得られる。さらに化合物（Π )— (g)と対応するアルケン化合物（VI)を DMF等の有機 溶媒中、 DIEA等の塩基、トリー 0—トリルホスフィン等の配位子及び酢酸パラジウム（Π )等の触媒存在下、 80°Cから 120°Cで、 30分から 24時間反応させることにより、化合 物（ H )— (f)を得ることができる。 Compound (Π) — (f) (compound (Π) in which R 5 is CR 6 = CR 7 (R 8 )) can also be synthesized according to synthesis route 5. That is, compound (H)-(g) is obtained from compound (IV) and compound (IV)-(b) (compound (N) wherein R 5 is a halogen atom) according to synthesis route 2. Furthermore, compound (Π)-(g) and the corresponding alkene compound (VI) are present in an organic solvent such as DMF, a base such as DIEA, a ligand such as tree 0-tolylphosphine and a catalyst such as palladium acetate (Π) The compound (H) — (f) can be obtained by reacting at 80 ° C. to 120 ° C. for 30 minutes to 24 hours.
Figure imgf000040_0003
合成経路 5 また、化合物（ Π )— (f)は合成経路 6に従い合成することもできる。すなわち、化合物（ H)と化合物（17)— (G) (化合物（IV)において R5がアルケニル基である化合物）より、合 成経路 2に従い化合物（Π)—（h)が得られる。さらに化合物（H)_(h)と対応するハロ ゲン化化合物（K)を DMF等の有機溶媒中、 DIEA等の塩基、トリー O—トリルホスフィン 等の配位子及び酢酸パラジウム（H)等の触媒存在下、 80°Cから 120°Cで、 30分から 24時間反応させることにより、化合物（Π)— (f)を得ることができる。
Figure imgf000040_0003
Synthesis route 5 In addition, compound (（)-(f) can also be synthesized according to synthesis route 6. That is, compound (Π)-(h) is obtained from compound (H) and compound (17)-(G) (compound (IV) where R 5 is an alkenyl group) according to synthesis route 2. Furthermore, the halogenated compound (K) corresponding to the compound (H) _ (h) is mixed with an organic solvent such as DMF, a base such as DIEA, a ligand such as tree O-tolylphosphine, and palladium acetate (H). By reacting at 80 ° C. to 120 ° C. for 30 minutes to 24 hours in the presence of a catalyst, the compound (Π)-(f) can be obtained.
Figure imgf000041_0001
Figure imgf000041_0001
(ΠΗί)  (ΠΗί)
合成経路 6 化合物（Π)—（i) (化合物（Π)において、 R5が C≡CR9である化合物）は合成経路 7に 従い合成することもできる。すなわち、化合物（m)と化合物（IV)— (d) (化合物（ππにお いて R5がェチニル基である化合物）より、合成経路 2に従い化合物（ Π ) - (j)が得られる 。さらに化合物（H)— (j)と対応するハロゲン化化合物（X)を DMF等の有機溶媒中、ト リエチルァミン、水酸化ナトリウム等の塩基、よう化銅（1)、テトラキス（トリフエニルホスフィ ン）パラジウム（0)等の触媒存在下、室温で、 2時間から 24時間反応させることによリ化 合物（π)_ωを得ることができる。
Figure imgf000042_0001
Synthesis route 6 Compound ()-(i) (compound (化合物) in which R 5 is C≡CR 9 ) can also be synthesized according to synthesis route 7. That is, compound (（)-(j) is obtained from compound (m) and compound (IV)-(d) (compound (a compound in which R 5 is ethynyl group in ππ)) according to synthesis route 2. Compound (H) — (j) and the corresponding halogenated compound (X) in an organic solvent such as DMF, bases such as triethylamine and sodium hydroxide, copper iodide (1), tetrakis (triphenylphosphine) The compound (π) _ω can be obtained by reacting at room temperature for 2 to 24 hours in the presence of a catalyst such as palladium (0).
Figure imgf000042_0001
(m) (3V)-(d) (H)-(j)  (m) (3V)-(d) (H)-(j)
Figure imgf000042_0002
Figure imgf000042_0002
(ΠΗΟ  (ΠΗΟ
合成経路 7 また、化合物（ Π )— (i)は合成経路 8に従って合成することもできる。すなわち、化合 物（n)— (g)と対応するアルキン化合物（XI)を DMF等の有機溶媒中で、トリェチルアミ ン、水酸化ナトリウム等の塩基、よう化銅（1)、テトラキス（トリフエニルホスフィン）パラジゥ ム（0)等の触媒存在下、室温で、 2時間から 12時間反応させることにより化合物（Π)— (i)を得ることができる。  Synthetic Route 7 Compound (（) — (i) can also be synthesized according to Synthetic Route 8. That is, the compound (n)-(g) and the corresponding alkyne compound (XI) are mixed with an organic solvent such as DMF, a base such as triethylamine, sodium hydroxide, copper iodide (1), tetrakis (triphenylphosphine). ) Compound (Π)-(i) can be obtained by reacting in the presence of a catalyst such as palladium (0) at room temperature for 2 to 12 hours.
Figure imgf000042_0003
合成経路 8 前記の合成経路により製造した本発明化合物は、汎用されている技術を使用して、前 述した塩、水和物又は溶媒和物の形態とすることもできる。 本発明化合物の医薬としての有用性を見出すために、ヒト型リコンビナント DHODHタ ンパクを使用し、アチーブス 'ォブ■バイオケミストリ一'アンド'バイオフィジックス、 323巻、 79-86頁（1995年） [Archives of Biochemistry and Biophysics, 323, 79- 86(1995)]に 報告されているニトロブル一テトラゾリゥ厶 （以下、「N B丁」とする） の酸化還元反応を使 用した DHODH阻害活性の評価方法に準じて、本発明化合物の DHODH阻害活性を評 価'検討し、本発明化合物が優れた DH ODH阻害活性を有することを見出した。 さらに本発明化合物のより具体的な疾患への適用を評価'検討するため、
Figure imgf000042_0003
Synthetic Route 8 The compound of the present invention produced by the above synthetic route can be converted into the above-mentioned salt, hydrate or solvate form using a widely used technique. In order to find out the usefulness of the compound of the present invention as a medicine, a human type recombinant DHODH protein was used, and Achieves' Ob Biochemistry 'and' Biophysics, 323, 79-86 (1995) [ Archives of Biochemistry and Biophysics, 323, 79-86 (1995)] In accordance with the reported method for evaluating DHODH inhibitory activity using the oxidation-reduction reaction of nitro blue tetrazole (hereinafter referred to as “NB Ding”), the DHODH inhibitory activity of the compound of the present invention was evaluated and examined. It has been found that the compounds of the present invention have excellent DH ODH inhibitory activity. In order to further evaluate the application of the compounds of the present invention to more specific diseases,
1 )マウスタイプ Πコラーゲン誘発関節炎モデルにおける本発明化合物の抗関節炎効果 試験、  1) Mouse type: Anti-arthritic effect test of the compound of the present invention in collagen-induced arthritis model,
2 )マウス遅延型過敏症モデルにおける本発明化合物の細胞性免疫に対する抑制効果 試験、すなわち、 DTH抑制効果試験、  2) Inhibitory effect test on cellular immunity of the compound of the present invention in a mouse delayed hypersensitivity model, that is, DTH inhibitory effect test,
3 )本発明化合物の in vitroにおけるマウス同種異系リンパ球混合反応 (MLR)活性抑制 効果試験を実施し、 3) In vitro mouse allogeneic lymphocyte mixing reaction (MLR) activity inhibitory effect test of the compound of the present invention was conducted,
いずれにおいても優れた効果を見出した。 In any case, an excellent effect was found.
尚、その詳細については、後述の実施例「薬理試験の項」で詳細に説明する。 上記試験の結果より、本発明化合物は、細胞増殖、破骨細胞分化、過剰な免疫反応 (自己免疫反応、アレルギー反応、臓器移植時の拒絶反応、移植片対宿主疾患等）等 に深く関与している DH O D Hの活性を阻害し、細胞増殖、破骨細胞分化、過剰な免疫反 応（自己免疫反応、アレルギー反応、臓器移植時の拒絶反応、移植片対宿主疾患等） 等に関与する疾患、より具体的には、癌、骨'関節疾患（骨粗鬆症、変形性関節症等）、 自己免疫疾患（乾癬、関節リウマチ、多発性硬化症、全身性エリテマトーデス、シ Iーグ レン症候群、ぶどう膜炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎、クローン病等）、ァ レルギ一性疾患（アトピー性皮膚炎、アレルギー性皮膚炎、アレルギー性鼻炎、アレルギ 一性結膜炎、気管支喘息等）、臓器移植時の拒絶反応、移植片対宿主疾患等の予防 又は治療剤として有用であることが実証された。  Details thereof will be described in detail in the “pharmacological test section” in the following Examples. From the above test results, the compound of the present invention is deeply involved in cell proliferation, osteoclast differentiation, excessive immune reaction (autoimmune reaction, allergic reaction, rejection at the time of organ transplantation, graft-versus-host disease, etc.), etc. Diseases that inhibit DH ODH activity and are involved in cell proliferation, osteoclast differentiation, excessive immune responses (autoimmune reactions, allergic reactions, rejection during organ transplantation, graft-versus-host diseases, etc.) More specifically, cancer, bone 'joint diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Shigren's syndrome, uvea) Inflammation, polymyositis, type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), Refusal during organ transplantation Reaction, it has been demonstrated to be useful as a prophylactic or therapeutic agent such as graft-versus-host disease.
本発明化合物は経口でも、非経口でも投与することができる。投与剤型として、錠斉 IJ、 カプセル剤、顆粒剤、散剤、注射剤、点眼剤等が挙げられ、それらは汎用される技術を 使用して製剤化することができる。 例えば、錠剤、カプセル剤、顆粒剤、散剤等の経口剤は、乳糖、マンニトール、デンプ ン、結晶セルロース、軽質無水ケィ酸、炭酸カルシウム、リン酸水素カルシウム等の賦形 剤、ステアリン酸、ステアリン酸マグネシウム、タルク等の滑沢剤、デンプン、ヒドロキシプ 口ピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン等の結合剤 、カルボキシメチルセルロース、低置換度ヒドロキシプロピルメチルセルロース、クェン酸力 ルシゥ厶等の崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹 脂等のコーティング剤、パラォキシ安息香酸ェチル、ベンジルアルコール等の安定化剤、 甘味料、酸味料、香料等の矯味矯臭剤等を必要に応じて、必要量を使用し、調製するこ とができる。 The compound of the present invention can be administered orally or parenterally. Examples of the dosage form include tablets IJ, capsules, granules, powders, injections, eye drops, and the like, and they can be formulated using a widely used technique. For example, oral preparations such as tablets, capsules, granules, powders, etc. are excipients such as lactose, mannitol, denpene, crystalline cellulose, light anhydrous key acid, calcium carbonate, calcium hydrogen phosphate, stearic acid, stearic acid Lubricants such as magnesium and talc, binders such as starch, hydroxypropyl pill cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone Use the required amounts of coating agents such as methylcellulose, macrogol and silicone resin, stabilizers such as ethyl oxybenzoate and benzyl alcohol, and flavoring agents such as sweeteners, acidulants and fragrances as necessary. Can be prepared
また、注射剤、点眼剤等の非経口剤は、塩化ナトリウム、濃グリセリン、プロピレングリ コール、ポリエチレングリコール、塩化カリウム、ソルビ! ^一ル、マンニトール等の等張化剤 、リン酸ナトリウム、リン酸水素ナトリウム、酢酸ナトリウム、クェン酸， 氷酢酸、トロメ.タモ —ル等の緩衝化斉 ij、ポリオキシエチレンソルビタンモノォレート、ステアリン酸ポリオキシ 4 0、ポリオキシエチレン硬化ヒマシ油等の界面活性剤、クェン酸ナトリウム、ェデト酸ナトリ ゥム等の安定化剤、塩化ベンザルコニゥム、パラベン、塩化べンゾトニゥム、パラォキシ 安息香酸エステル、安息香酸ナトリウム、クロロブタノ一ル等の防腐剤、塩酸、クェン酸、 リン酸、氷酢酸、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム等の pH調整剤 、ベンジルアルコール等の無痛化剤等を必要に応じて、必要量を使用し、調製することが できる。  In addition, parenterals such as injections and eye drops include isotonic agents such as sodium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, potassium chloride, sorbitol, mannitol, sodium phosphate, phosphate Buffering agents such as sodium hydrogen, sodium acetate, citrate, glacial acetic acid, trometh-amol, surfactants such as polyoxyethylene sorbitan monooleate, polyoxy stearate 40, polyoxyethylene hydrogenated castor oil, Stabilizers such as sodium citrate and sodium edetate, benzalkonium chloride, paraben, benzotonium chloride, paraoxy benzoate, sodium benzoate, preservatives such as chlorobutanol, hydrochloric acid, citrate, phosphoric acid, ice PH adjusters such as acetic acid, sodium hydroxide, sodium carbonate, sodium bicarbonate In addition, a necessary amount of a soothing agent such as benzyl alcohol can be used if necessary.
本発明は、本発明化合物又はその塩を患者に有効な量投与することからなるジヒドロ ォロテートデヒドロゲナーゼの阻害方法、および、本発明化合物又はその塩を患者に有 効な量投与することからなる細胞増殖、破骨細胞分化又は過剰な免疫反応が関与する 疾患の予防又は治療方法にも関する。  The present invention comprises a method for inhibiting dihydrophosphate dehydrogenase comprising administering an effective amount of a compound of the present invention or a salt thereof to a patient, and administering an effective amount of the compound of the present invention or a salt thereof to a patient. The present invention also relates to a method for preventing or treating a disease involving cell proliferation, osteoclast differentiation or excessive immune response.
本発明化合物の投与量は、症状、年齢、剤型等により適宜選択して使用することがで きる。例えば、経口剤は通常 1日当たり 0. 0 1〜1 000m g、好ましくは;!〜 1 00mgを 1 回又は数回に分けて投与することができる。また、点眼剤は通常 0. 0001 %〜 1 O o/o (w Zv)、好まし ま 0. 01 % ~ 5 % (wZv)の濃度のものを 1回又は数回に分けて投与する ことが'できる 以下に本発明化合物の製造例、製剤例及び薬理試験の結果を示す。尚、これらの例 示は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない The dose of the compound of the present invention can be appropriately selected and used depending on symptoms, age, dosage form and the like. For example, an oral preparation is usually administered in an amount of 0.001 to 1 000 mg, preferably;! To 100 mg per day, in one or several divided doses. In addition, eye drops are usually administered at a concentration of 0.0001% to 1 O o / o (w Zv), preferably 0.01% to 5% (wZv) in one or several divided doses. The production examples, formulation examples and pharmacological test results of the compounds of the present invention are shown below. These examples are for better understanding of the present invention and do not limit the scope of the present invention.
[製造例] [Production example]
参考例 1  Reference example 1
4一（3—メチルフエノキシ）一 1一二トロベンゼン（参考化合物 1)  4 (3-methylphenoxy) 1 1 1 2 trobenzene (reference compound 1)
4一フルオロー 1—ニトロベンゼン（500〃し 4. 71mmol)を N, N—ジメチルホルムァ ミド（20ml)に溶解し、 m—クレゾ一ル（492 し 4. 71 mmol)、炭酸カリウム（977mg , フ. 07mmol)を加え、 60度で 2時間攪拌した。放冷後、反応液に酢酸ェチル（70ml) とエーテル（70ml)を加え、水（100mし 3回）および飽和食塩水（50ml)で洗浄した。有 機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより標記参考化 合物（1. 10g)を黄色油状物として得た。（収率 100%)  4 Dissolve 1-fluoro-1-nitrobenzene (500 to 4.71 mmol) in N, N-dimethylformamide (20 ml), and add m-cresol (492 to 4.71 mmol), potassium carbonate (977 mg, chloroform). 07 mmol) was added and stirred at 60 degrees for 2 hours. After allowing to cool, ethyl acetate (70 ml) and ether (70 ml) were added to the reaction mixture, and the mixture was washed with water (100 ml, 3 times) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the titled reference compound (1.10 g) as a yellow oil. (Yield 100%)
Figure imgf000045_0001
参考例 2
Figure imgf000045_0001
Reference example 2
4一（3—メチルフエノキシ）ァニリン（参考化合物 2)  4- (3-Methylphenoxy) aniline (reference compound 2)
4— (3—メチルフエノキシ）一1一二トロベンゼン（参考化合物 1、 1. 07g、4. 67mmo I)をエタノール（1 Oml)に溶解し、 10%パラジウム一炭素（98mg)を加え、水素雰囲気 下、室温で 2時間攪拌した。反応液をセライト濾過し、減圧下溶媒を留去した。得られた 残留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することによ リ標記参考化合物（81 Omg)を淡褐色油状物として得た。（収率 870/0) -
Figure imgf000046_0001
参考例 3 4- (3-Methylphenoxy) 1 1 12 trobenzene (Reference compound 1, 1.07g, 4.67mmo I) dissolved in ethanol (1Oml), 10% palladium on carbon (98mg) was added, and hydrogen atmosphere The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to give the titled reference compound (81 Omg) as a pale brown oil. (Yield 870/0)-
Figure imgf000046_0001
Reference example 3
3—メチル一4一（4—メチルベンジルォキシ）_1—ニトロベンゼン（参考化合物 3)  3-methyl 4- (4-methylbenzyloxy) _1-nitrobenzene (reference compound 3)
2—メチルー 4—ニトロフエノール（500mg、 3. 26mmol)を N, N—ジメチルホルムアミ ド（20ml)に溶角¥し、 4ーメチノレべンジ レブロミド（603mg、 3, 26mmol)、炭酸カリウム (676mg, 4. 89mmol)を加え、 60度で 2時間攪拌した。放冷後、反応液に酢酸ェチ ル（70ml)とエーテル（70ml)を加え、水（1 OOmし 3回）および飽和食塩水（50ml)で 洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより 標記参考化合物（744mg)を淡黄色固体として得た。（収率 89%)  2-Methyl-4-nitrophenol (500 mg, 3.26 mmol) was dissolved in N, N-dimethylformamide (20 ml), and 4-methinolevendrebromide (603 mg, 3, 26 mmol), potassium carbonate (676 mg, 4. 89 mmol) was added and the mixture was stirred at 60 degrees for 2 hours. After allowing to cool, ethyl acetate (70 ml) and ether (70 ml) were added to the reaction mixture, and the mixture was washed with water (1 OOm, 3 times) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title reference compound (744 mg) as a pale yellow solid. (Yield 89%)
Figure imgf000046_0002
参考例 4
Figure imgf000046_0002
Reference example 4
3—メチル一4一（4—メチルベンジルォキシ）ァニリン（参考化合物 4)  3-methyl 4- (4-methylbenzyloxy) aniline (reference compound 4)
3—メチル一4一（4一メチルベンジルォキシ）一1一二トロベンゼン（参考化合物 3、 73 2mg、2. 85mmol)を N, N—ジメチルホルムアミド（20ml)に溶解し、塩化すず（ Π )'二 水和物（1. 29g、5. 72mmol)を加え、 70度で 3時間攪拌した。反応液を氷水（200m I)にあけ、 2規定水酸化ナトリウム水溶液（30ml)を加えてアルカリ性とした。エーテル（2 OOml)で抽出した後、有機層を水（100ml)および飽和食塩水（50ml)で洗浄し、無水 硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラ ムクロマトグラフィー（へキサン一酢酸ェチル）で精製することにより標記参考化合物（21 8mg)を淡茶色固体として得た。（収率 34%) 1H-NMR (500 Hz, CDCI3) 3-Methyl 4-1 (4 1-methylbenzyloxy) 1 1-12 benzene (Reference compound 3, 73 2 mg, 2.85 mmol) was dissolved in N, N-dimethylformamide (20 ml) and tin chloride (塩 化) ′ Dihydrate (1.29 g, 5.72 mmol) was added and stirred at 70 ° C. for 3 hours. The reaction solution was poured into ice water (200 ml), and 2N aqueous sodium hydroxide solution (30 ml) was added to make it alkaline. After extraction with ether (2 OOml), the organic layer was washed with water (100ml) and saturated brine (50ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the titled reference compound (218 mg) as a light brown solid. (Yield 34%) 1 H-NMR (500 Hz, CDCI 3 )
δ 2.20 (s, 3H), 2.35 (s, 3H), 3.36 (b r s, 2H), 4.94 (s, 2H)， 6.47 (dd, J = 8.5, 2.8 Hz, 1H), 6.55 (d, J = 2.8 Hz, δ 2.20 (s, 3H), 2.35 (s, 3H), 3.36 (brs, 2H), 4.94 (s, 2H), 6.47 (dd, J = 8.5, 2.8 Hz, 1H), 6.55 (d, J = 2.8 Hz,
1H), 6.71 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H)， 7.31 (d, J = 7.81H), 6.71 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8
Hz, 2H) 参考例 5 (Hz, 2H) Reference Example 5
ビス [4一 [(R)— 1— tert—ブトキシカルボニルピロリジン一 2—ィルカルポニルァミノ]フエ ニル]ジスルフイド (参考化合物 5— "!）  Bis [41] [(R) — 1- tert-Butoxycarbonylpyrrolidine-1-ylcarbonylamino] phenyl] disulfide (Reference compound 5— “!”)
(R)— 1—tert—ブトキシカルポニルピロリジン一 2—カルボン酸（2. 13g、 1 Ommol) と 4—ァミノフエニルジスルフイド（1. 02g、 4mmol)を N, N—ジメチルホルムアミド（28ml )に溶解し、氷冷下、 N, N—ジイソプロピルェチルァミン（3. 6mし 21mmol)と O—（7— ァザべンゾトリアゾ一ル一1一ィル） _N， N, N, N—テトラメチルゥロニゥムへキサフルォ 口ホスフエ一ト（4. 02g、 11mmol)を力□え、室温に戻した後、 3曰間攪拌した。反応液に 酢酸ェチル（150ml)を加え、水（70ml)および飽和食塩水（150ml)で洗浄した。有機 層を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲ ルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することによ y標記参考化合 物（2. 89g)を淡橙色固体として得た。（定量的）  (R) — 1-tert-Butoxycarbonylpyrrolidine-2-carboxylic acid (2.13 g, 1 Ommol) and 4-aminophenyldisulfide (1.02 g, 4 mmol) were combined with N, N-dimethylformamide (28 ml) And dissolved in ice, under ice-cooling, N, N-diisopropylethylamine (3.6m, 21mmol) and O- (7-azabenzotriazol 11-l) _N, N, N, N— Tetramethyluronium hexafluorate phosphate (4.02 g, 11 mmol) was added, and after returning to room temperature, the mixture was stirred for 3 hours. Ethyl acetate (150 ml) was added to the reaction mixture, and the mixture was washed with water (70 ml) and saturated brine (150 ml). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the y-reference compound (2.89 g) as a pale orange solid. (quantitative)
Figure imgf000047_0001
以下、参考化合物 20— 2と市販化合物を使用し、参考化合物 5—1の製造方法に準じ て、参考化合物 5— 2を得た。 ビス [4ー（1一 tert—ブトキシカルボニルピロリジン一 1H-N R (500 MHz, DMSO - d6) 2—ィルカルボニルァミノ）フエニル]ジスルフイド（参 δ 1.25, 1.39 (s, 18Η), 1.77-1.
Figure imgf000048_0001
参考例 6
Figure imgf000047_0001
Reference compound 20-2 and a commercially available compound were used below to obtain reference compound 5-2 according to the production method of reference compound 5-1. Bis [4- (1 tert-butoxycarbonylpyrrolidine- 1 HNR (500 MHz, DMSO-d 6 ) 2-ylcarbonylamino) phenyl] disulfide (reference δ 1.25, 1.39 (s, 18Η), 1.77- 1.
Figure imgf000048_0001
Reference Example 6
4—ベンゾィルアミノー 1—ニトロベンゼン（参考化合物 6— 1)  4-Benzylamino-1-nitrobenzene (Reference compound 6- 1)
4—二卜ロア二リン（692mg、 5. 01 mmol)を塩 ίヒメチレン（ 1 Oml)に溶角军し、 N, N_ ジイソプロピルェチルァミン（4.'4ml、 25. Ommol)、塩化ベンゾィル（0， 88mし 7. 5 m mol)を加え、室温で 1. 5時間攪拌した。析出物をクロ口ホルムで濾取することによリ標 記参考化合物（651 mg)を淡黄色固体として得た。（収率 54%)  4-Dichloroaniline (692 mg, 5. 01 mmol) is dissolved in salt Himethylene (1 Oml), N, N_diisopropylethylamine (4.'4 ml, 25. Ommol), benzoyl chloride (0, 88 m and 7.5 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The precipitate was collected by filtration with black mouthform to give the reference compound (651 mg) as a pale yellow solid. (Yield 54%)
Figure imgf000048_0002
以下、市販化合物を使用し、参考化合物 6— 1の製造方法に準じて、参考化合物 6 を得た。
Figure imgf000048_0002
Hereafter, the reference compound 6 was obtained according to the manufacturing method of the reference compound 6-1 using a commercially available compound.
Figure imgf000048_0003
参考例 7
Figure imgf000048_0003
Reference Example 7
4—ベンゾィルアミノア二リン（参考化合物 7— 1)  4-Benzylaminoaniline (Reference compound 7-1)
4一べンゾィルァミノ一 1—ニトロベンゼン（参考化合物 6—1、 607mg、 2. 51mmoI) をメタノール（10ml)に溶解し、 5%パラジウム一炭素（触媒量）を加え、水素雰囲気下、 室温で一晚攪拌した。反応液をセライト濾過し、減圧下溶媒を留去した後、析出物をへ キサンで濾取することにより標記参考化合物（518mg)を白色固体として得た。（収率 9 7%) 4 Benzoylamino 1-nitrobenzene (reference compound 6-1, 607 mg, 2.51 mmoI) is dissolved in methanol (10 ml), 5% palladium on carbon (catalytic amount) is added, and the mixture is stirred at room temperature under a hydrogen atmosphere. Stir. The reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. The title reference compound (518 mg) was obtained as a white solid by filtration with xane. (Yield 9 7%)
Figure imgf000049_0001
以下、参考化合物 6— 2を使用し、参考化合物フー 1の製造方法に準じて、参考化合物 フー 2を得た。
Figure imgf000049_0001
Hereinafter, Reference Compound Fu-2 was obtained using Reference Compound 6-2 in accordance with the production method of Reference Compound Fu-1.
4一ベンゾィル（メチル）アミノア二リン（参考 1H-NMR (500 MHz, DMSO-d6) 4 Monobenzoyl (methyl) aminoaniline (Reference 1 H-NMR (500 MHz, DMSO-d 6 )
化合物 7— 2) δ 3.26 (s, 3Η), 5.32 (br s, 2H)， 6.41  Compound 7— 2) δ 3.26 (s, 3Η), 5.32 (br s, 2H), 6.41
(d, J = 8.6 Hz, 2H), 6.78 (d, J = 8. 6 Hz, 2H), 7.18-7.24 (m， 5H) (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.6 Hz, 2H), 7.18-7.24 (m, 5H)
Figure imgf000049_0002
参考例 8
Figure imgf000049_0002
Reference Example 8
4— tert—ブトキシカルボニルァミノ安息香酸（参考化合物 8)  4-tert-Butoxycarbonylaminobenzoic acid (Reference compound 8)
4ーァミノ安息香酸（1. 01g、 7. 36mmol)を 1 , 4一ジォキサン（5ml)—水（5ml)に 溶解し、トリェチルァミン（1. 5mし 10. 8mmol)、二炭酸ジ一 tert—ブチル（2· 10g、 9. 4-aminobenzoic acid (1.01 g, 7.36 mmol) was dissolved in 1,4-dioxane (5 ml) —water (5 ml), triethylamine (1.5 m, 10.8 mmol), di-tert-butyl dicarbonate (1.5 ml). 2 · 10g, 9.
62mmol)を加え、室温でー晚攪拌した。反応液に水（30ml)および酢酸ェチル（30ml62 mmol) was added and stirred at room temperature. Water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution.
)を加え分配した後、水層を 5 %クェン酸水溶液で酸性とし、酢酸ェチル（ 50 m I )で抽出 した。有機層を飽和食塩水（50ml)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下 溶媒を留去することにより標記参考化合物（1. 66g)を白色固体として得た。（収率 96The aqueous layer was acidified with a 5% aqueous citrate solution and extracted with ethyl acetate (50 ml). The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the titled reference compound (1.66 g) as a white solid. (Yield 96
%) 1H-NMR (500 MHz, DMSO - d6) %) 1 H-NMR (500 MHz, DMSO-d 6 )
δ 1.49 (s, 9H), 7.56 (d, J = 9.0 Hz 2H), 7.83 (d, J = 9.0 Hz, 2H), 9.73 (s, 1H), 12.56 (br s, 1H)  δ 1.49 (s, 9H), 7.56 (d, J = 9.0 Hz 2H), 7.83 (d, J = 9.0 Hz, 2H), 9.73 (s, 1H), 12.56 (br s, 1H)
参考例 9 Reference Example 9
1—(4_tert—ブトキシカルポニルァミノべンゾィル）ピロリジン（参考化合物 9— 1 )  1— (4_tert-Butoxycarbonylaminobenzoyl) pyrrolidine (Reference compound 9— 1)
4一 tert—ブトキシカルポニルァミノ安息香酸（参考化合物 8、 1 · OOg、 4. 21mmol) 、ピロリジン（310mg、 4. 36mmol)を塩化メチレン（10ml)に溶解し、 N—メチルモルホ リン（0. 46ml、4. 21mmol)、 7—ヒドロキシベンゾ卜リアゾーノレ（578mg、 4. 28mmol )および 1一（3—ジメチルァミノプロピル）一 3—ェチルカルポジイミド 塩酸塩（891mg、 4. 65mmol)を加え、室温で一晚攪拌した。反応液にクロ口ホルム（30ml)を加え、水（ 50ml、 2回）、飽和食塩水（50ml)で洗浄した。有機層を無水硫酸マグネシウムで乾燥 後、減圧下溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィ一（へキサ ンー酢酸ェチル）で精製することにより、標記参考化合物（1. 24g)を白色固体として得 た。（収率 1000/0)  4-1 tert-Butoxycarbonylaminobenzoic acid (reference compound 8, 1 · OOg, 4.21 mmol) and pyrrolidine (310 mg, 4.36 mmol) are dissolved in methylene chloride (10 ml), and N-methylmorpholine (0.46 ml) is dissolved. 4.21 mmol), 7-hydroxybenzotriazolenore (578 mg, 4.28 mmol) and 1- (3-dimethylaminopropyl) -1-3-ethyl carpositimide hydrochloride (891 mg, 4.65 mmol) were added at room temperature. Was stirred for a while. To the reaction solution, black mouth form (30 ml) was added and washed with water (50 ml, twice) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.24 g). Obtained as a white solid. (Yield 1000/0)
Figure imgf000050_0001
以下、参考化合物 8および市販化合物を使用し、参考化合物 9—1の製造方法に準じて 、参考化合物 9— 2〜9— 4を得た。
Figure imgf000050_0001
Reference compounds 8-2 to 9-4 were obtained using Reference Compound 8 and commercially available compounds according to the production method of Reference Compound 9-1.
1一（4— tert—ブトキシカルボニルァミノべ 1H-N R (500 MHz, CDCI3) 1 (4— tert-butoxycarbonylamino) 1 HN R (500 MHz, CDCI 3 )
ンゾィル）一 4—メチルビペリジン（参考化合 δ 0.97 (d, J = 6.2 Hz, 3H), 1.52 (s, 物 9— 2) 9H), 1.16 (br s, 2H), 1,64 (br s, 3H)  1-methylbiperidine (reference compound δ 0.97 (d, J = 6.2 Hz, 3H), 1.52 (s, product 9— 2) 9H), 1.16 (br s, 2H), 1,64 (br s, 3H )
, 2.80 (br s, 2H), 3.79 (br s, 1H), 4.6 2 (br s, 1H), 6.59 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz , 2H)
Figure imgf000051_0001
参考例 10 , 2.80 (br s, 2H), 3.79 (br s, 1H), 4.6 2 (br s, 1H), 6.59 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H)
Figure imgf000051_0001
Reference Example 10
N—メチル一N—フエ二ルー 4— tert—ブトキシカルポニルァミノべンズアミド（参考化合物 10)  N-Methyl-1-N-phenol 4--tert-Butoxycarbonylaminobenzamide (Reference Compound 10)
4— tert—ブトキシカルボニルァミノ安息香酸（参考化合物 8、 500mg、 2. 11 mmol) と N—メチルァニリン（304〃し 2. 11 mmol)を N, N—ジメチルホルムアミド（5ml)に溶 解し、 N, N—ジイソプロピルェチルァミン（734jUし 4. 22mmol)と O— (7—ァザべンゾ トリァゾール一 1—ィル）一 N, N, N, N—テトラメチルゥロニゥムへキサフルォロホスフエ —ト（802mg、 2. 11 mmol)を加え、室温で 4日間攪拌した。反応液に水（30ml)およ び酢酸ェチル（30ml)を加え分配した後、有機層を水（30ml)、飽和食塩水（30ml)で 洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた 固体を酢酸ェチルで濾取することにより標記参考化合物（401 mg)を白色固体として得 た。（収率 58%) 1H-N R (500 MHz, DMSO - d6) 4-tert-butoxycarbonylaminobenzoic acid (reference compound 8, 500 mg, 2.11 mmol) and N-methylaniline (304 〃 2.11 mmol) are dissolved in N, N-dimethylformamide (5 ml). N, N-diisopropylethylamine (734jU 4.22mmol) and O- (7-azabenzotriazole 1-yl) one N, N, N, N-tetramethyluronium Xafluorophosphite (802 mg, 2.11 mmol) was added, and the mixture was stirred at room temperature for 4 days. Water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution for partitioning, and the organic layer was washed with water (30 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was collected by filtration with ethyl acetate to give the titled reference compound (401 mg) as a white solid. (Yield 58%) 1 HN R (500 MHz, DMSO-d 6 )
δ 1.44 (s, 9H), 3.34 (s, 3H), 7.11-7. 17 (m, 5H), 7.25-7.28 (m, 4H), 9.44 ( s, 1H)  δ 1.44 (s, 9H), 3.34 (s, 3H), 7.11-7.17 (m, 5H), 7.25-7.28 (m, 4H), 9.44 (s, 1H)
参考例 11 Reference Example 11
1一（4ーァミノべンゾィル）ピロリジン 塩酸塩（参考化合物 11—1)  1- (4-aminobenzoyl) pyrrolidine hydrochloride (reference compound 11-1)
1一（4一 tert—ブトキシカルポニルァミノべンゾィル）ピロリジン（参考化合物 9一 1、 1. 13g、3. 89mmol)を 1 , 4一ジォキサン（ 15ml)に溶解し、 4規定塩化水素一 1 · 4ージ ォキサン溶液い Oml)を加え、室温で 1. 5時間攪拌した。減圧下溶媒を留去することに より標記参考化合物（720mg)を無色油状物として得た。（収率 820/0). 1 (4 tert-butoxycarbonylaminobenzoyl) pyrrolidine (reference compound 91-1, 1.13 g, 3.89 mmol) is dissolved in 1,4 monodioxane (15 ml), and 4N hydrogen chloride 4-Dioxane solution (Oml) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure to obtain the title reference compound (720 mg) as a colorless oil. (Yield 820/0).
Figure imgf000052_0001
以下、参考化合物 9_2〜9— 4および 10から選択される化合物を使用し、参考化合物 11一 1の製造方法に準じて、参考化合物 11— 2〜11—5を得た。
Figure imgf000052_0001
Hereinafter, reference compounds 11-2 to 11-5 were obtained using a compound selected from reference compounds 9_2 to 9-4 and 10 according to the production method of reference compound 11-11.
1一（4ーァミノべンゾィル）ー4ーメチルピぺ 'H-NMR (500 MHz, DMSO - d6) 1- (4-aminobenzoyl) -4-methyl pipette 'H-NMR (500 MHz, DMSO-d 6 )
リジン 2) δ 0.92 (d, J = 6.1 Hz, 3H)， 1.04-1.0  Lysine 2) δ 0.92 (d, J = 6.1 Hz, 3H), 1.04-1.0
9 (m， 3H), 1.59-1.63 (m, 3H), 2.52-2. 54 (m, 1H), 2.88 (br s, 2H), 7.20 (br s， 2H), 7.38 (d, J = 8.0 Hz, 2H)
Figure imgf000052_0002
9 (m, 3H), 1.59-1.63 (m, 3H), 2.52-2. 54 (m, 1H), 2.88 (br s, 2H), 7.20 (br s, 2H), 7.38 (d, J = 8.0 (Hz, 2H)
Figure imgf000052_0002
N— (n—ペンチル）一4ーァミノべンズアミド 1H-NMR (500 MHz, DMSO - d6) N— (n-pentyl) -4-aminoaminoamide 1 H-NMR (500 MHz, DMSO-d 6 )
塩酸塩（参考化合物 11一 3) δ 0.87 (t, J = 6.9 Hz, 3H), 1.26-1.3  Hydrochloride (reference compound 11 1 3) δ 0.87 (t, J = 6.9 Hz, 3H), 1.26-1.3
3 (m， 4H), 1.48-1.54 (m, 2H), 3.28—3. 24 (m, 2H), 7,16 (d, J = 7.8 Hz, 2H)， 7.81 (d, J = 7.8 Hz, 2H), 8.36 (s, 1 3 (m, 4H), 1.48-1.54 (m, 2H), 3.28—3.24 (m, 2H), 7,16 (d, J = 7.8 Hz, 2H), 7.81 (d, J = 7.8 Hz, 2H), 8.36 (s, 1
HCI H2N^^ ー H) HCI H 2 N ^^ ー H)
N—フエ二ルー 4—ァミノべンズアミド 塩酸 1H-NMR (500 MHz, DMSO' - d6) N-phenyl 4-Haminobenzamide Hydrochloride 1 H-NMR (500 MHz, DMSO '-d 6 )
塩（参考化合物 11一 4) δ 7.08 (t, J = 7.3 Hz, 1H), 7.12 (d,  Salt (reference compound 11 1 4) δ 7.08 (t, J = 7.3 Hz, 1H), 7.12 (d,
J = 8.5 Hz, 2H), 7.33 (dd J = 8.5, 7.3 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H)
Figure imgf000053_0001
参考例 1 2 J = 8.5 Hz, 2H), 7.33 (dd J = 8.5, 7.3 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H)
Figure imgf000053_0001
Reference example 1 2
4ー（2—メチルフエニル）ァニリン（参考化合物 1 2— 1 )  4- (2-Methylphenyl) aniline (Reference compound 1 2— 1)
4ーョ一ドア二リシ（876mg、 4. OOmmol)および 2—メチルフエニルボロン酸（81 7 m g、 6. OOmmol)、卜リー O—卜りノレホスフィン（246mg、 0. 80mmol )、 / ラジウム（ Π ) ジベンジリデンアセテート（232mg、 0. 40mmol)に亍トラヒドロフラン（8ml)— 1 2規定 水酸化ナトリウム水溶液（ 1 m I )の混合溶液を加え 80度で一晩攪拌した。放冷後、不溶 物をセライトで濾去し、酢酸ェチル（30m l)および水（30ml)を加えて分配した。有機層 を水（30ml )、飽和食塩水（30ml)で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下 溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸 ェチル）で精製することにより標記参考化合物（588mg)を淡黄色油状物として得た。（ 収率 80%)  4-methylanisyl (876 mg, 4. OOmmol) and 2-methylphenylboronic acid (81 7 mg, 6. OOmmol), 卜 -O-phosphorus norephosphine (246 mg, 0.80 mmol), radium ( )) To dibenzylidene acetate (232 mg, 0.40 mmol) was added a mixed solution of 亍 trahydrofuran (8 ml) —12N aqueous sodium hydroxide (1 ml) and stirred at 80 ° C. overnight. After allowing to cool, the insoluble material was filtered off through celite, and the mixture was partitioned by adding ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the titled reference compound (588 mg) as a pale yellow oil. (Yield 80%)
Figure imgf000053_0002
以下、市販化合物を使用し、参考化合物 1 2— 1の製造方法に準じて、参考化合物 1 2 — 2 ~ 1 2— 28を得た。
Figure imgf000053_0002
Hereinafter, reference compounds 1 2-2 to 1 2-28 were obtained using commercially available compounds according to the production method of Reference compound 1 2-1.
4—フエ二ルァニリン（参考化合物 1 2— 2) 1H-NMR (500 MHz, DMSO - d6)
Figure imgf000054_0001
4一（3—フルオロフェニル）ァニリン（参考化 1H -國 R (500 MHz, DMSO - d6) 4-phenylaniline (reference compound 1 2— 2) 1 H-NMR (500 MHz, DMSO-d 6 )
Figure imgf000054_0001
4- (3-Fluorophenyl) aniline (reference 1 H-country R (500 MHz, DMSO-d 6 )
合物 12— 11) δ 5.32 (s, 2H), 6.64 (d, J = 8.6 Hz, Compound 12— 11) δ 5.32 (s, 2H), 6.64 (d, J = 8.6 Hz,
2H)， 6.98-7.03 (m, 1H), 7.33-7.35 (m 2H), 6.98-7.03 (m, 1H), 7.33-7.35 (m
H2N ^F , 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.3 H2N ^ F , 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.3
7-7.40 (m， 2H)  7-7.40 (m, 2H)
4一（4—フルオロフェニル）ァニリン（参考化 1H - NMR (500 MHz, DMSO - d6) 4-one (4-fluorophenyl) aniline (referenced 1 H-NMR (500 MHz, DMSO-d 6 )
合物 12— 12) δ 5,21 (s, 2H)， 6.63 (d, J = 8.6 Hz, Compound 12— 12) δ 5,21 (s, 2H), 6.63 (d, J = 8.6 Hz,
2H), 7.18 (t, J = 8.9 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 8. 9, 5.5 Hz, 2H)  2H), 7.18 (t, J = 8.9 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.54 (dd, J = 8. 9, 5.5 Hz, 2H)
4— (3—メチルフエニル）ァニリン（参考化合 fH-N R (500 MHz, DMSO - d6) 4— (3-Methylphenyl) aniline (reference compound f HNR (500 MHz, DMSO-d 6 )
物 12— 13) δ 2,33 (s, 3H)， 5.19 (br s, 2H), 6.63 Object 12—13) δ 2,33 (s, 3H), 5.19 (br s, 2H), 6.63
(d, J = 8.4 Hz, 2H), 7.02 (d, J = 7. 3 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.31-7.34 ( m, 2H)  (d, J = 8.4 Hz, 2H), 7.02 (d, J = 7.3 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.31 -7.34 (m, 2H)
4一（4—メチルフエニル）ァニリン（参考化合 1H-N R (500 MHz, DMSO - d6) 4- (4-methylphenyl) aniline (reference compound 1 HN R (500 MHz, DMSO-d 6 )
物 12— 14) 6 2.29 (s, 3H), 5.16 (br s， 2H)， 6.62 Object 12—14) 6 2.29 (s, 3H), 5.16 (br s, 2H), 6.62
(d， J = 8,5 Hz, 2H), 7.17 (d, J = 8. 0 Hz, 2H), 7.31 (d, J - 8.5 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H)  (d, J = 8,5 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.31 (d, J-8.5 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H)
4— (2—トリフルォロメチルフエニル）ァニリ - NMR (500 MHz, DMSO-d6) ン（参考化合物 12— 15) δ 5.22 (s, 2H), 6.60 (d, J = 8.4 Hz, 4- (2-Trifluoromethylphenyl) anilyl-NMR (500 MHz, DMSO-d 6 ) (reference compound 12-15) δ 5.22 (s, 2H), 6.60 (d, J = 8.4 Hz,
2H), 6.97 (d, J = 8.4 Hz, 2H)， 7.34 (d， J = 7,6 Hz, 1H), 7.50 (t, J = 7.6 2H), 6.97 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 7,6 Hz, 1H), 7.50 (t, J = 7.6
Hz, 1H)， 7.64 (t, J = 7.6 Hz, 1H), 7 • 75 (d, J = 7.6 Hz, 1H) Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7 • 75 (d, J = 7.6 Hz, 1H)
4一（3—トリフルォロメチルフエニル）ァニリ 'H-NMR (500 MHz, DMSO - d6) ン（参考化合物 12— 16) δ 5.36 (s, 2H)， 6.66 (d, J = 8,6 Hz, 4- (3-trifluoromethylphenyl) aniline 'H-NMR (500 MHz, DMSO-d 6 ) (Reference compound 12— 16) δ 5.36 (s, 2H), 6.66 (d, J = 8, 6 Hz,
2H), 7.44 (d， J = 8.6 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.59 (t, J = 7.6
Hz, 1H), 7.80 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H) Hz, 1H), 7.80 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H)
4— (4—トリフルォロメチルフエニル）ァニリ H-N R (500 MHz, DMSO - d6) ン（参考化合物 12— 17) 6 5,40 (s, 2H), 6.66 (d, J = 8.6 Hz, 4- (4-Trifluoromethylphenyl) aniline HN R (500 MHz, DMSO-d 6 ) (Reference compound 12— 17) 6 5,40 (s, 2H), 6.66 (d, J = 8.6 Hz ,
2H), 7.45 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2
Hz, 2H) (Hz, 2H)
F  F
1—(4ーァミノフエニル）ナフタレン（参考化 1H-NMR (500 MHz, DMSO - d6) 合物 12— 18) δ 5.25 (s, 2H), 6.71 (d, J = 8.4 Hz, 1— (4-Aminophenyl) naphthalene (referenced 1 H-NMR (500 MHz, DMSO-d 6 ) compound 12— 18) δ 5.25 (s, 2H), 6.71 (d, J = 8.4 Hz,
2H), 7.14 (d, J = 8.4 Hz, 2H), 7.35
Figure imgf000056_0001
Figure imgf000057_0001
参考例 13 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.35
Figure imgf000056_0001
Figure imgf000057_0001
Reference Example 13
2 _( 4—ニトロフエニル）ベンゾチアゾ一ル（参考化合物 13— 1 )  2 _ (4-Nitrophenyl) benzothiazol (reference compound 13-1)
4—ニトロべンズアルデヒド（1. 51g、 10. Ommol)、 2—ァミノベンゼンチオール（1. 0 7mU 10. Ommol)をトルエン（20ml)に懸濁し、 60度で 4時間攪拌した。放冷後、析出 物をトルエンで濾取することにより標記参考化合物（224mg)を淡黄色固体として得た。 (収率 9%)  4-Nitrobenzaldehyde (1.51 g, 10. Ommol) and 2-aminobenzenethiol (1.07 mU 10. Ommol) were suspended in toluene (20 ml) and stirred at 60 degrees for 4 hours. After allowing to cool, the precipitate was collected by filtration with toluene to give the titled reference compound (224 mg) as a pale yellow solid. (Yield 9%)
Figure imgf000057_0002
以下、市販化合物を使用し、参考化合物 13— 1の製造方法に準じて、参考化合物 13 _2~13— 6を得た。
Figure imgf000057_0002
Hereinafter, using a commercially available compound, according to the production method of Reference Compound 13-1, Reference Compound 13 _2 ~ 13-6 was obtained.
Figure imgf000058_0001
参考例 14
Figure imgf000058_0001
Reference Example 14
2— (4—ァミノフエニル）ベンゾチアゾ一ル（参考化合物 14—1 )  2 -— (4-Aminophenyl) benzothiazol (reference compound 14-1)
2- (4一二トロフエニル）ベンゾチアゾ一ル（参考化合物 13— 1、 202mg、 0. 78mm ol)をエタノール（4ml)に溶解し、二酸化白金（触媒量）を加え、水素雰囲気下、室温で 2時間攪拌した。反応液をセライト濾過し、減圧下溶媒を留去することにより標記参考化 合物（178mg)を灰色固体として得た。（収率 100%)  2- (4-12 trophenyl) benzothiazol (reference compound 13-1, 202 mg, 0.78 mmol) is dissolved in ethanol (4 ml), platinum dioxide (catalytic amount) is added, and hydrogen is added at room temperature under room temperature. Stir for hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain the title reference compound (178 mg) as a gray solid. (Yield 100%)
H-NMR (500 MHz, DMS0-d6) H-NMR (500 MHz, DMS0-d 6 )
δ 5.89 (s, 2H), 6.67 (d, J = 8.6 Hz 2H), 7.34 (t, J = 7,9 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.76 (d, J = 8.6 δ 5.89 (s, 2H), 6.67 (d, J = 8.6 Hz 2H), 7.34 (t, J = 7,9 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.76 (d, J = 8.6
Hz, 2H), 7.89 (d， J = 7.9 Hz, 1H), 8 .02 (d, J = 7.9 Hz, 1H) 以下、参考化合物 13— 2〜13— 6を使用し、参考化合物 14—1の製造方法に準じて、 参考化合物 14一 2〜 14一 6を得た。  Hz, 2H), 7.89 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H) Hereafter, reference compounds 13-2 to 13-6 were used and reference compounds 14-1 According to the production method of Reference Compound 14 1-2 2-14 16 were obtained.
Figure imgf000059_0001
参考例 15
Figure imgf000059_0001
Reference Example 15
2—メチル一4— (2 _フエ二ルー 1—ェチニル）ァニリン（参考化合物 15—1 )  2-Methyl-1-4- (2_Phenylu 1-ethynyl) aniline (Reference compound 15-1)
4ーョードー 2—メチルァニリン（470mg、 2. 02mmol)、フエニルアセチレン（220 I 、2. OOmmol)を N， N—ジメチノレホ レムアミド（4ml)に;、容角军し、卜リエチソレアミン（8ml)、 よう化銅（ I ) (47. 1mg、0. 25mmol)、テトラキス（トリフエニルホスフィン）パラジウム（ 0) (230mg, 0. 20mmol)を加え、室温で 2曰間攪拌した。反応液に酢酸ェチル（100 ml)および水（100ml)を加えて分配し、有機層を飽和食塩水（ 120ml)で洗浄した。有 機層を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、得られた残留物をシリカゲ ルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することにより標記参考化合 物（182mg)を橙色固体として得た。（収率 43%) 4-methyl 2-methylaniline (470 mg, 2.02 mmol) and phenylacetylene (220 I, 2. OOmmol) into N, N-dimethylenoreformamide (4 ml); Copper (I) (47.1 mg, 0.25 mmol), tetrakis (triphenylphosphine) palladium ( 0) (230 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction solution for partitioning, and the organic layer was washed with saturated brine (120 ml). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the titled reference compound (182 mg). Obtained as an orange solid. (Yield 43%)
1H-NMR (400 MHz, DMSO - d6) 1 H-NMR (400 MHz, DMSO-d 6 )
δ 2.05 (s, 3Η), 5,32 (br s, 2H)， 6.59 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.
Figure imgf000060_0001
δ 2.05 (s, 3Η), 5,32 (br s, 2H), 6.59 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.
Figure imgf000060_0001
3, 2.0 Hz, 1H), 7.12 (s, 1H), 7.31-7.4 0 (m， 3H)， 7.43-7.46 (m, 2H) 以下、化合物 1一 83、参考化合物 17— 18および市販化合物から選択される化合物を 使用し、参考化合物 15—1の製造方法に準じて、参考化合物 15— 2〜 15— 9を得た。 3, 2.0 Hz, 1H), 7.12 (s, 1H), 7.31-7.4 0 (m, 3H), 7.43-7.46 (m, 2H) Below, selected from Compound 1 83, Reference Compound 17-18 and commercially available compounds using the compounds, according to the production method of reference compound 15-1 to give reference compound 15 2 - 15 9.
Figure imgf000060_0002
Figure imgf000061_0001
参考例 16
Figure imgf000060_0002
Figure imgf000061_0001
Reference Example 16
4—イソプロポキシ一1ーェチニルベンゼン（参考化合物 16— 1)  4-Isopropoxy-1-ethynylbenzene (Reference compound 16-1)
4_イソプロポキシ一 1—(2—トリメチルシリル一 1ーェチニル）ベンゼン（参考化合物 1 5— 7、 871mg、 3. 75mmol)をテトラヒドロフラン（1 Oml)に溶解し、テトラプチルアンモ ニゥムフルオリド 三水和物（1. 79g、5. 64mmol)を加え、室温で 4. 5時間攪拌した。 減圧下溶媒を留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン一 酢酸ェチル）で精製することにより標記参考化合物（431 mg)を無色油状物として得た。 (収率 71 <½) 'H— NMR (400 MHz, CDCI3) 4_Isopropoxy mono 1- (2-trimethylsilyl mono 1-ethynyl) benzene (reference compound 15-7, 871 mg, 3.75 mmol) is dissolved in tetrahydrofuran (1 Oml), and tetraptylammonium fluoride trihydrate (1 79 g, 5.64 mmol) was added and stirred at room temperature for 4.5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane monoethyl acetate) to give the titled reference compound (431 mg) as a colorless oil. (Yield 71 <½) 'H— NMR (400 MHz, CDCI 3 )
υ0 δ 1.33 (d, J = 6.1 Hz, 6H), 2.98 (s, υ 0 δ 1.33 (d, J = 6.1 Hz, 6H), 2.98 (s,
1H), 4.52-4.59 (m, 1H), 6.81 (d, J = 1H), 4.52-4.59 (m, 1H), 6.81 (d, J =
8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2 H) 以下、参考化合物 15— 9を使用し、参考化合物 16— 1の製造方法に準じて、参考化合 物 16— 2を得た。 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2 H) Reference compound 15-2 was used below, and reference compound 16-2 was obtained according to the production method of reference compound 16-1 .
2—ェチルー 1 —ェチ二ルベンゼン（参考化 1H-NMR (500 MHz, CDCI3) 2-Ethyl 1-ethenylbenzene (referenced 1 H-NMR (500 MHz, CDCI 3 )
合物 16— 2) δ 1.25 (t, J = 7.5 Hz, 3H)， 2.83 (q,  Compound 16— 2) δ 1.25 (t, J = 7.5 Hz, 3H), 2.83 (q,
J = 7.5 Hz, 2H), 3.24 (s, 1H), 7 14 J = 7.5 Hz, 2H), 3.24 (s, 1H), 7 14
(t, J = 7.6 HZ, 1H), 7.13-7.30 (m, 2H(t, J = 7.6 HZ, 1H), 7.13-7.30 (m, 2H
), 7.47 (d, J = 7.6 Hz, 1H) ), 7.47 (d, J = 7.6 Hz, 1H)
参考例 17 Reference Example 17
4— n—ブトキシ _1—ョ一ドベンゼン（参考化合物 17— 1)  4— n-Butoxy _1— iodide benzene (Reference compound 17— 1)
4一ョ一ドフエノール（1. 01g、4. 55mmol)を N, N—ジメチルホルムアミド（1 Oml)に ；'容角军し、炭酸カリウム（1. 92g、 13. 7mmol)、 n—ブチノレブロミド（1. 46mし 13. 7m mol)を加え、 60度で 2時間攪拌した。放冷後、反応液に酢酸ェチル（50ml)と水（50m I)を加え分配し、有機層を水（50ml)、飽和食塩水（50ml)で順次洗浄した。有機層を 無水硫酸マグネシウムで乾燥後、溶媒を留去し、得られた残留物をシリカゲルカラムクロ マトグラフィー（へキサン一酢酸ェチル）で精製することにより標記参考化合物（1. 16g) を無色油状物として得た。（収率 88%)  4 Monophenol (1.01 g, 4.55 mmol) in N, N-dimethylformamide (1 Oml); 'Correct, potassium carbonate (1.92 g, 13.7 mmol), n-butinolevromide (1 46m and 13.7mmol) were added and stirred at 60 degrees for 2 hours. After allowing to cool, ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution for partitioning, and the organic layer was washed successively with water (50 ml) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane ethyl acetate) to give the titled reference compound (1.16 g) as a colorless oil. Obtained as a thing. (Yield 88%)
Figure imgf000062_0001
以下、参考化合物 24および市販化合物を使用し、参考化合物 17—1の製造方法に準 じて、参考化合物 17— 2~17— 29を得た。
Figure imgf000063_0001
Figure imgf000064_0001
。
Figure imgf000062_0001
Reference compounds 17-2 to 17-29 were obtained using reference compound 24 and commercially available compounds according to the production method of reference compound 17-1.
Figure imgf000063_0001
Figure imgf000064_0001
.
1ーョードー 4一（2— tert—ブトキシカルボ 1H-N R (400 MHz, DMSO - d6) ニルアミノエトキシ）ベンゼン（参考化合物 1 δ 1.38 (s, 9Η), 3.27 (dt, J = 5.9 HZ 7-19) , 2H)， 3.93 (t, J = 5.9 Hz, 2H), 6.78 1-4- (2-tert-butoxycarbo 1 HN R (400 MHz, DMSO-d 6 ) nylaminoethoxy) benzene (reference compound 1 δ 1.38 (s, 9Η), 3.27 (dt, J = 5.9 HZ 7- 19), 2H), 3.93 (t, J = 5.9 Hz, 2H), 6.78
(d, J = 9.0 Hz, 2H), 6.99 (t, J= 5.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H)
Figure imgf000065_0001
(d, J = 9.0 Hz, 2H), 6.99 (t, J = 5.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H)
Figure imgf000065_0001
4—ベンジルォキシー 3， 5—ジメチル一 1— 1H-N R (400 MHz, DMSO - d6) ョ一ドベンゼン（参考化合物 17— 20) δ 2.20 (s, 6H), 4.78 (s, 2H), 7.34-7. 4-Benzyloxy 3,5-dimethyl-1- 1 HNR (400 MHz, DMSO-d 6 ) iodide benzene (reference compound 17-20) δ 2.20 (s, 6H), 4.78 (s, 2H), 7.34- 7.
43 (m, 5H), 7.46-7.48 (m, 2H)  43 (m, 5H), 7.46-7.48 (m, 2H)
4—シクロペンチルメトキシー 1一ョ一ドベン 1H-NMR (400 MHz, CDCI3) 4-Cyclopentylmethoxy-mono-benzone 1 H-NMR (400 MHz, CDCI 3 )
ゼン（参考化合物 17— 21 ) δ 1.29-1.38 (m， 2H), 1.55-1.67 (m, 4 Zen (reference compound 17-21) δ 1.29-1.38 (m, 2H), 1.55-1.67 (m, 4
H), 1.78-1.86 (m, 2H), 2.30-2.38 (m, 1H), 3.78 (d, J = 7.1Hz, 2H)， 6.67 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 9.0 H z, 2H)  H), 1.78-1.86 (m, 2H), 2.30-2.38 (m, 1H), 3.78 (d, J = 7.1Hz, 2H), 6.67 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 9.0 H z, 2H)
4-(1一ェチルプロポキシ）一1—ョードベン 'H-NMR (500 MHz, CDCI3) 4- (1 ethylpropoxy) 1-yodoben 'H-NMR (500 MHz, CDCI 3 )
ゼン（参考化合物 17— 22) δ 0.94 (t, J = 7.3 Hz, 6H)， 1.66 (qd Zen (reference compound 17-22) δ 0.94 (t, J = 7.3 Hz, 6H), 1.66 (qd
, J = 7.3, 5.8 Hz, 4H), 4.06 (quintet, J = 5,8 Hz, 1H), 6.67 (d, J = 8.9 H z ，2H), 7.52 (d, J = 8.9 Hz, 2H) , J = 7.3, 5.8 Hz, 4H), 4.06 (quintet, J = 5,8 Hz, 1H), 6.67 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H)
3, 5—ジメチルー 1ーョ一ド一 4一イソプロポ 1H-NMR (500 MHz, D SO-d6) キシベンゼン（参考化合物 17— 23) δ 1.21 (d, J = 6.1 Hz, 6H), 2.16 (s, 3, 5-Dimethyl 1 -mono 4- 1 Isoprop 1 H-NMR (500 MHz, D SO-d 6 ) Xylbenzene (Reference compound 17— 23) δ 1.21 (d, J = 6.1 Hz, 6H), 2.16 ( s,
6H), 4.09-4.19 (m, 1H), 7.37 (s, 2H)  6H), 4.09-4.19 (m, 1H), 7.37 (s, 2H)
'H-NMR (400 MHz, DMSO-d6) 考化合物 17— 24) δ 1.29 (d, J = 6.1 Hz, 6H)， 4.64 (se ptet, J = 6,1 Hz, 1H), 6.72 (td, J = 7.4, 1.2 Hz, 1H), 7.02 (dd, J = 8.4, 1 •2 Hz, 1H), 7.33 (ddd, J = 8.4, 7.4, 1 .5 Hz, 1H), 7.76 (dd, J = 7.4, 1.5 Hz, 1H) 'H-NMR (400 MHz, DMSO-d 6 ) Compound 17— 24) δ 1.29 (d, J = 6.1 Hz, 6H), 4.64 (se ptet, J = 6,1 Hz, 1H), 6.72 (td , J = 7.4, 1.2 Hz, 1H), 7.02 (dd, J = 8.4, 1 • 2 Hz, 1H), 7.33 (ddd, J = 8.4, 7.4, 1.5 Hz, 1H), 7.76 (dd, J = 7.4, 1.5 Hz, 1H)
し  Shi
2—ベンジルォキシ一 1一ョ一ドベンゼン（参 1H-NMR (400 MHz, DMSO - d6) 考化合物 17— 25) δ 5.20 (s, 2H), 6.76 (td, J = 7.6, 1. 2-Benzyloxy 1-monobenzene (Reference 1 H-NMR (400 MHz, DMSO-d 6 ) Compound 17— 25) δ 5.20 (s, 2H), 6.76 (td, J = 7.6, 1.
2 Hz, 1H), 7.10 (dd, J = 8.3, 1.2 Hz, 2 Hz, 1H), 7.10 (dd, J = 8.3, 1.2 Hz,
1H), 7.31-7.38 (m, 2H), 7.39-7.43 (m , 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.791H), 7.31-7.38 (m, 2H), 7.39-7.43 (m, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.79
(dd, J = 7.7, 1.6 Hz, 1H)
Figure imgf000066_0001
参考例 18 (dd, J = 7.7, 1.6 Hz, 1H)
Figure imgf000066_0001
Reference Example 18
4ーァセチルァミノ一 1一ョードベンゼン（参考化合物 18— 1 )  4-Acetylamino-1 1-iodobenzene (Reference compound 18-1)
4ーョードア二リン（1. OOg、 4. 57mmol)を塩ィ匕メチレン（10ml)に溶角 し、 N, N— ジイソプロピルェチルァミン（3. 98mし 22. 9mmol)、塩化ァセチル（488〃 I、 6. 86m mol)を加え、室温で 3時間攪拌した。反応液にクロ口ホルム（30ml)を加え、水（30ml) 、 1規定塩酸（30ml)、飽和重曹水（30ml)、飽和食塩水（30ml)で洗浄した。有機層 を無水硫酸マグネシゥムで乾燥後、減圧下溶媒を留去し得られた固体を酢酸ェチル ί: て濾取することにより標記参考化合物（71 Omg)を白色固体として得た。（収率 59%) 4-Cyanodiline (1.OOg, 4.57 mmol) was dissolved in salt methylene (10 ml), and N, N-diisopropylethylamine (3.98 m, 22.9 mmol), acetyl chloride (488 I, 6.86 mmol) was added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added black mouth form (30 ml), and the mixture was washed with water (30 ml), 1N hydrochloric acid (30 ml), saturated aqueous sodium hydrogen carbonate (30 ml), and saturated brine (30 ml). Organic layer After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting solid was filtered to obtain the title reference compound (71 Omg) as a white solid. (Yield 59%)
Figure imgf000067_0001
以下、市販化合物を使用し、参考化合物 18—1の製造方法に準じて、参考化合物 18 一 2を得た。
Figure imgf000067_0001
Hereinafter, using the commercially available compound, Reference Compound 18-12 was obtained according to the production method of Reference Compound 18-1.
Figure imgf000067_0002
参考例 19
Figure imgf000067_0002
Reference Example 19
1一ョ一ド一4ーフヱノキシカルボニルォキシベンゼン（参考化合物 19)  1 1 4- 1 4-phenoxycarbonyloxybenzene (Reference compound 19)
4一ョ一ドフエノール.（1. 00g、 4. 55mmol)を塩化メチレン（20ml)に溶解し、氷冷下 4 Monophenol (1.00 g, 4.55 mmol) was dissolved in methylene chloride (20 ml) and cooled with ice.
、 N, N—ジイソプロピルェチルァミン（1. 60mU 9. 19mmol)、クロ口炭酸フエニル（0., N, N-diisopropylethylamine (1.60 mU 9. 19 mmol), phenyl carbonate carbonate (0.
850ml、 6. 78mmol)を加えた。室温で 3日間攪袢した後、反応液に酢酸ェチル（200 ml)を加え、水（200ml)、飽和食塩水（150ml)で洗浄した。有機層を無水硫酸ナトリ ゥムで乾燥後、減圧下溶媒を留去し得られた固体をへキサンにて濾取することによリ標 記参考化合物（1. 40g)を淡桃色固体として得た。（収率 90%) 850 ml, 6.78 mmol) was added. After stirring at room temperature for 3 days, ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water (200 ml) and saturated brine (150 ml). After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the solid obtained was filtered with hexane to obtain the reference compound (1.40 g) as a pale pink solid. It was. (Yield 90%)
1H-NMR (500 MHz, DMSO-d6) δ 7.23 (d, J = 8.9 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 8.6 H z, 2H), 7.48 (dd, J = 8.S, 7.3 Hz, 2H ), 7.82 (d, J = 8.9 Hz, 2H) 参考例 20 1 H-NMR (500 MHz, DMSO-d 6 ) δ 7.23 (d, J = 8.9 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.38 (d, J = 8.6 H z, 2H) , 7.48 (dd, J = 8.S, 7.3 Hz, 2H), 7.82 (d, J = 8.9 Hz, 2H) Reference Example 20
N— tert—ブトキシカルポ二ルー 2, 5—ジヒドロピロ一ルー 2_カルボン酸（参考化合物 2 0-1)  N-tert-butoxycarbonyl 2,5-dihydropyrrole 2_carboxylic acid (reference compound 2 0-1)
3, 4—デヒドロプロリン（455mg、 4. 02mmol)をテトラヒドロフラン（12ml)—水（4m I)に溶解し、炭酸カリウム（1. 34g、9. 70mmol)、二炭酸ジー tert—ブチル（1 · 14g、 5. 22mmol)を加え、室温でー晚攪拌した。反応液に 10<½クェン酸水溶液を加えて酸 性とし、酢酸ェチル（ 15 mし 3回）で抽出した。有機層を無水硫酸マグネシウムで乾燥後 、減圧下溶媒を留去することにより標記参考化合物を無色油状物として得た。（定量的）  3, 4-Dehydroproline (455 mg, 4.02 mmol) was dissolved in tetrahydrofuran (12 ml) -water (4 ml), potassium carbonate (1.34 g, 9.70 mmol), di-tert-butyl dicarbonate (1.14 g) 5.22 mmol) and stirred at room temperature. The reaction mixture was acidified with 10 <½ citrate aqueous solution and extracted with ethyl acetate (15 m, 3 times). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title reference compound as a colorless oil. (quantitative)
Figure imgf000068_0001
以下、市販化合物を使用し、参考化合物 20— 1の製造方法に準じて、参考化合物 20 一 2を得た。
Figure imgf000068_0001
Hereafter, the reference compound 20 1-2 was obtained according to the manufacturing method of the reference compound 20-1 using the commercially available compound.
Figure imgf000068_0002
参考例 21
Figure imgf000068_0002
Reference Example 21
(2R, 4R)— 1—tert—ブトキシカルボ二ルー 4ーァセトキシピロリジン一2 _カルボン酸（ 参考化合物 21— 1)  (2R, 4R) — 1-tert-Butoxycarbonyl 4-acetoxypyrrolidine 1-2 carboxylic acid (Reference compound 21— 1)
(2R, 4R)— 1—tert—ブトキシカルポ二ルー 4ーヒドロキシピロリジン一 2—カルポン酸 (765mg、 3. 31 mmol)をピリジン（2ml)に溶解し、無水酢酸（ 1 ml)を加え、室温で 7 時間攪拌した。反応液に水（10ml)を加え、酢酸ェチル（10ml、 2回）で抽出し、有機層 を飽和食塩水（ 10 m I )で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留 去し、得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精 製することにより標記参考化合物（258mg)を無色アモルファスとして得た。（収率 290/0(2R, 4R) — 1-tert-Butoxycarbonyl 4-hydroxypyrrolidine mono 2-carbonic acid (765 mg, 3.31 mmol) was dissolved in pyridine (2 ml), acetic anhydride (1 ml) was added, and Stir for 7 hours. Water (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml, twice), and the organic layer was washed with saturated brine (10 m I). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane monoacetate) to give the titled reference compound (258 mg) as a colorless amorphous product. (Yield 290/0
) )
Figure imgf000069_0001
以下、市販化合物を使用し、参考化合物 21—1の製造方法に準じて、参考化合物 21 一 2を得た。
Figure imgf000069_0001
Hereinafter, using a commercially available compound, Reference Compound 21-12 was obtained according to the production method of Reference Compound 21-1.
Figure imgf000069_0002
参考例 22
Figure imgf000069_0002
Reference Example 22
4一（2—アミノエトキシ）— 1一ョ一ドベンゼン（参考化合物 22)  4- (2-aminoethoxy) -1-monobenzene (Reference compound 22)
1—ョ一ドー 4— (2— tert—ブトキシカルボニルアミノエトキシ）ベンゼン（参考化合物 1 7— 19、 501 mg、 1. 38mmol)を 1， 4一ジォキサン（5ml)に;、容角军し、 4規定塩^ (匕水素 — 1, 4一ジォキサン溶液（15ml、 60mmol)を加え、室温で 2時間 30分攪拌した。減圧 下溶媒を留去して得られた固体を酢酸ェチルにて濾取することにより標記参考化合物（ 344mg)を白色固体として得た。（収率 83%) 1H-NMR (500 MHz, D SO-d6) 1-yodo 4- ( 2 -tert-butoxycarbonylaminoethoxy) benzene (reference compound 1 7-19, 501 mg, 1.38 mmol) into 1,4-dioxane (5 ml); 4N salt ^ (hydrogen--1,4-dioxane solution (15 ml, 60 mmol) was added, and the mixture was stirred at room temperature for 2 hours 30 minutes. The solvent was distilled off under reduced pressure, and the resulting solid was collected by filtration with ethyl acetate. The title reference compound (344 mg) was obtained as a white solid (yield 83%). 1 H-NMR (500 MHz, D SO-d 6 )
δ 3.18 (t, J = 4.9 HZ, 2H 4,17 (t, NH2 HCI J = 4.9 Hz, 2H), 6.84 (d, J = 8.7Hz δ 3.18 (t, J = 4.9 HZ, 2H 4,17 (t, NH 2 HCI J = 4.9 Hz, 2H), 6.84 (d, J = 8.7 Hz
2H), 7.63 (d, J = 8,7 Hz, 2H 8.29 (br s 3H) 参考例 23  2H), 7.63 (d, J = 8,7 Hz, 2H 8.29 (br s 3H) Reference Example 23
4— (ヒドロキシメチル）キノリン（参考化合物 23)  4- (Hydroxymethyl) quinoline (Reference compound 23)
ラ K冷下、水素化ホウ素ナトリウム（5· 3g 140mmol)の亍トラヒドロフラン（300ml) 懸濁液に 4_キノリンカルポキシアルデヒド（20, Og 130mmol)のテトラヒドロフラン（2 00ml)溶液を滴下し、室温で 1時間攪拌した。水（300ml)を加えた後、酢酸ェチル（40 Omし 1回， 100ml 3回）で抽出し、有機層を飽和食塩水（200mし 3回）で洗浄し、無 水硫酸マグネシウムで乾燥した。減圧下溶媒を留去して得られた固体をジェチルェ一テ ルでろ取することにより、標記参考化合物（13. 8g)を橙白色固体として得た。（収率 69 %)  While cooling with La K, a solution of 4_quinoline carboxyaldehyde (20, Og 130 mmol) in tetrahydrofuran (200 ml) was added dropwise to a suspension of sodium borohydride (5.3 g 140 mmol) in 亍 trahydrofuran (300 ml). Stir at room temperature for 1 hour. Water (300 ml) was added, followed by extraction with ethyl acetate (40 Om, once, 100 ml, 3 times). The organic layer was washed with saturated brine (200 m, 3 times) and dried over anhydrous magnesium sulfate. The solid obtained by evaporating the solvent under reduced pressure was collected by filtration with jetyl ether to give the titled reference compound (13.8 g) as an orange-white solid. (Yield 69%)
Figure imgf000070_0001
参考例 24
Figure imgf000070_0001
Reference Example 24
4一（クロロメチル）キノリン（参考化合物 24)  4 mono (chloromethyl) quinoline (Reference Compound 24)
氷冷下、 4一（ヒドロキシメチル）キノリン（参考化合物 23 13. 0g 81. 7mmol)のジ クロロメタン（200ml)溶液に塩化チォニル（12. Omし 165mmol)を滴下し、室温で 5 時間攪拌した。減圧下溶媒を留去して得られた固体を酢酸ェチルでろ取することにより 標記参考化合物を含む混合物（17. 2g)を黄白色固体として得た。（定量的）
Figure imgf000071_0001
参考例 25 Under ice-cooling, thionyl chloride (12. Om and 165 mmol) was added dropwise to a solution of 41 (hydroxymethyl) quinoline (reference compound 23 13.0 g 81.7 mmol) in dichloromethane (200 ml), and the mixture was stirred at room temperature for 5 hours. . The solid obtained by evaporating the solvent under reduced pressure was collected by filtration with ethyl acetate to obtain a mixture (17.2 g) containing the title reference compound as a pale yellow solid. (quantitative)
Figure imgf000071_0001
Reference Example 25
1—ョ一ドー 4ースルファモイルベンゼン（参考化合物 25)  1-yodo 4-sulfamoylbenzene (Reference compound 25)
氷冷下、 28%アンモニア水（10ml)に 4一ョードベンゼンスルホニルクロリド (2. 01 g、 6. 64mmol)の酢酸ェチル（10ml)溶液を滴下し 1時間撹袢した。反応液に水（50ml) および酢酸ェチル（50ml)を加えて分配し、有機層を 1規定塩酸（30ml)、飽和炭酸水 素ナトリウム水溶液（30ml)、飽和食塩水（30ml)で洗浄した。有機層を無水硫酸マグ ネシゥムで乾燥後、減圧下溶媒を留去し得られた固体をへキサン一酢酸ェチル（ 20： 1 ) の溶液で濾取することにより標記参考化合物（1. 75g)を白色固体として得た。（収率 9 Under ice cooling, a solution of 4-iodobenzenesulfonyl chloride (2.01 g, 6.64 mmol) in ethyl acetate (10 ml) was added dropwise to 28% aqueous ammonia (10 ml) and stirred for 1 hour. Water (50 ml) and ethyl acetate (50 ml) were added to the reaction solution for partitioning, and the organic layer was washed with 1N hydrochloric acid (30 ml), saturated aqueous sodium hydrogen carbonate solution (30 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the solid obtained was collected by filtration with a solution of hexyl monoacetate (20: 1) to give the title reference compound (1.75 g). Obtained as a white solid. (Yield 9
3%) (3%)
Figure imgf000071_0002
参考例 26
Figure imgf000071_0002
Reference Example 26
1—ョ一ドー 4一イソプロピルスルファモイルベンゼン（参考化合物 26— 1)  1-yodo 4-1-isopropylsulfamoylbenzene (reference compound 26-1)
窒素雰囲気下、イソプロピルアミン（619 し 7. 27mmol)のテトラヒドロフラン（10m I)溶液にトリェチルァミン（1. 84mし 13. 2mmol)を加えた後、 4—ョ一ドベンゼンスル ホニルクロリド（2. 01g、 6. 64mmol)のテトラヒドロフラン溶液（10ml)を滴下し 4. 5時 間撹拌した。反応液に水（50ml)および酢酸ェチル（50ml)を加え分配し、有機層を水（ 50ml)、飽和食塩水（30ml)で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減 圧下溶媒を留去した。得られた固体をへキサンで濾取することにより標記参考化合物（2. 01 g)を白色固体として得た。（収率 93%) H-NMR (500 MHz, GD〇I3) Under a nitrogen atmosphere, triethylamine (1.84m and 13.2mmol) was added to a solution of isopropylamine (619 and 7.27mmol) in tetrahydrofuran (10mI), followed by 4-iodobenzenesulfonyl chloride (2.01g, 6.64mmol). ) In tetrahydrofuran (10 ml) was added dropwise and stirred for 4.5 hours. Water (50 ml) and ethyl acetate (50 ml) were added to the reaction solution for partitioning, and the organic layer was washed with water (50 ml) and saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was filtered with hexane to give the titled reference compound (2.01 g) as a white solid. (Yield 93%) H-NMR (500 MHz, GD〇I 3 )
δ 1.10 (d, J = 6.7 Hz, 6H), 3.43-3.5 3 (m, 1H), 4.29 (d, J = 7.6 Hz, 1H)， 7.59 (d, J = 8.6 Hz, 2H)， 7.87 (d, J = 8.6 Hz, 2H) 以下、市販化合物を使用し、参 化合物 26— 1の製造方法に準じて、参考化合物 26 —2を得た。  δ 1.10 (d, J = 6.7 Hz, 6H), 3.43-3.5 3 (m, 1H), 4.29 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.87 (d , J = 8.6 Hz, 2H) Hereinafter, using a commercially available compound, Reference Compound 26-2 was obtained according to the production method of Reference Compound 26-1.
1—ョードー 4—フエニルスルファモイルべ 1H-NMR (500 MHz, DMSO - d6) 1-Edodo 4-phenylsulfamoyl 1 H-NMR (500 MHz, DMSO-d 6 )
ンゼン（参考化合物 26— 2) δ 7.04 (t, J = 7.5 Hz, 1H), 7.07 (d,  (Reference compound 26-2) δ 7.04 (t, J = 7.5 Hz, 1H), 7.07 (d,
J - 7.5 Hz, 2H), 7.23 (t, J = 7.5 H z, 2H), 7.48 (d, J = 8.6 Hz, 2H)， 7.9 3 (d, J = 8.6 Hz, 2H)， 10.33 (s， 1H)
Figure imgf000072_0001
J-7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.9 3 (d, J = 8.6 Hz, 2H), 10.33 (s, 1H)
Figure imgf000072_0001
参考例 27 Reference Example 27
4ーシクロペンチルォキシー 1—ョ一ドベンゼン（参考化合物 27— 1)  4-Cyclopentyloxy 1-yodobenzene (Reference compound 27-1)
4—ョ一ドフエノ一ゾレ（3. 32g、 15. 1 mmol)、トリフエ二ノレホスフィン（8. 07g、 30. 8 mmol)のテトラヒドロフラン（80ml)溶液にシクロペンタノ一ル（1. 7mし 18. 7mmol)を 加え、氷冷下、 2, 2M ジェチルァゾジカルポキシレート トルエン溶液（13· 6mし 29. 9mmol)を滴下した。滴下後、室温に戻し一晩攪拌した。反応液に水（ 1 OOml)を加え た後、酢酸ェチル（100ml、 2回）で抽出し、有機層を飽和食塩水（100ml)で洗浄し、 無水硫酸マグネシウムで乾燥した。減圧下溶媒留去して得られた残留物をシリカゲル力 ラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することにより標記参考化合物（3. 2g)を淡桃色固体として得た。（収率 74%)  4-tetrafluorophenol (3.32 g, 15.1 mmol) and triphenylenophosphine (8.07 g, 30.8 mmol) in tetrahydrofuran (80 ml) in cyclopentanol (1.7 m and 18. 7 mmol) was added, and 2,2M Jetylazodicarboxylate in toluene (13.6 m, 29.9 mmol) was added dropwise under ice cooling. After dropping, the mixture was returned to room temperature and stirred overnight. Water (1 OO ml) was added to the reaction solution, followed by extraction with ethyl acetate (100 ml, twice). The organic layer was washed with saturated brine (100 ml) and dried over anhydrous magnesium sulfate. The title compound (3.2 g) was obtained as a pale pink solid by purifying the residue obtained by distilling off the solvent under reduced pressure by silica gel chromatography (hexane ethyl acetate). (Yield 74%)
Figure imgf000072_0002
以下、市販化合物を使用し、参考化合物 27— 1の製造方法に準じて、参考化合物 27 一 2を得た。
Figure imgf000072_0002
Hereinafter, using a commercially available compound, according to the production method of Reference Compound 27-1, Reference Compound 27 I got two.
4—シクロへキシルォキシ一1 1H-NMR (500 MHz, CDCI3) 4-Cyclohexyloxy 1 1 H-NMR (500 MHz, CDCI 3 )
ン（参考化合物 2フ一 2) δ 1.29-1.39 (m, 3Η), 1.47-1.58 (m， 3 (Reference compound 2 1) δ 1.29-1.39 (m, 3Η), 1.47-1.58 (m, 3
H), 1.78-1.80 (m, 2H), 1.94-1.97 (m, 2H)， 4.17-4.21 (m, 1H), 6,67 (d, J = .
Figure imgf000073_0001
8.9 Hz. 2H), 7.52 (d, J = 8.9 Hz, 2H H), 1.78-1.80 (m, 2H), 1.94-1.97 (m, 2H), 4.17-4.21 (m, 1H), 6,67 (d, J =.
Figure imgf000073_0001
8.9 Hz. 2H), 7.52 (d, J = 8.9 Hz, 2H
実施例 1 Example 1
(R)-N— tert—ブトキシカルポニル一 N' - (4—トリフルォロメチルフエニル）ピロリジン —2—カルボキサミド（化合物 1—1) (R) -N— tert-Butoxycarbonyl N ′-(4-Trifluoromethylphenyl) pyrrolidine —2-carboxamide (Compound 1-1)
(R)— N—tert「ブトキシカルボニルピロリジン一 2—カルポン酸（2· 15g、 1 Ommol) と 4_トリフルォロメチルァ二リン（1. 93g、 12mmol)を N， N—ジメチルホルムアミド（30 ml)に溶解し、氷冷下、 N, N—ジイソプロピルェチルァミン（4. 2ml、 24mmol)と 0 (7 ーァザべンゾトリァゾ一ルー 1 _ィル） _N, N, N, N—テトラメチルゥロニゥ厶へキサフル ォロホスフェート（4. 57g、 12mmol)を加え、室温に戻した後、一晚攪拌した。反応液 に酢酸ェチル（1 OOml)を加え、水（100ml, 2回）、飽和食塩水（100ml)で洗浄した。 有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物を シリカゲルカラムクロマトグラフィーで精製することにより標記化合物（2. 69g)を白色固 体として得た。（収率 75%)  (R) —N-tert ”butoxycarbonylpyrrolidine mono-2-carboponic acid (2.15 g, 1 Ommol) and 4_trifluoromethylaniline (1.93 g, 12 mmol) were mixed with N, N-dimethylformamide (30 N, N-diisopropylethylamine (4.2 ml, 24 mmol) and 0 (7-azabenzotriazol 1 _il) _N, N, N, N-tetramethyl After adding uronium hexafluorophosphate (4.57 g, 12 mmol), the mixture was warmed to room temperature and stirred for a while.Ethyl acetate (1 OOml) was added to the reaction mixture, water (100 ml, 2 times), The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to purify the title compound (2.69 g). Was obtained as a white solid (yield 75%).
1H-NMR (500 MHz, DMSO-d6) δ 1.26, 1.40 (s, 9Η), 1.77-1.91 (m, 3H), 2.15-2.26 (m, 1H), 3.29-3.44 (m, 2H), 4.19-4.30 (m, 1H), 7.66-7. 70 (m, 2H), 7.80-7.83 (m， 2H), 10.3 5 (s, 1H) 以下、参考化合物 2、 4、 7-1、7— 2、"— 1 11 -5、 12— 1〜 12— 28、 14— 1〜 14— 6、 15— 1〜15— 5、15— 8、20—1、20_2、21—1、21— 2および市販化合 物から選択される化合物を使用し、化合物 1一 1の製造方法に準じて、化合物 1一 2〜1 — 177を得た。 1 H-NMR (500 MHz, DMSO-d 6 ) δ 1.26, 1.40 (s, 9Η), 1.77-1.91 (m, 3H), 2.15-2.26 (m, 1H), 3.29-3.44 (m, 2H), 4.19-4.30 (m, 1H), 7.66-7. 70 (m, 2H), 7.80-7.83 (m, 2H), 10.3 5 (s, 1H) Reference compounds 2, 4, 7-1, 7— 2, “— 1 11 -5, 12— 1 to 12— 28, 14— 1 to 14— 6, 15— 1 to 15— 5, 15— 8, 20—1, 20_2, 21—1, 21— 2 And a compound selected from commercially available compounds, and in accordance with the production method of Compound 1-11, — Obtained 177.
(m, (m,
d6) d 6 )
(m， 7.  (m, 7.
- 1,88 (m, -1,88 (m,
d6) d 6 )
(m，  (m,
(s, 9H), (s, 9H),
- d6) -d 6 )
(m,
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
(m, (m,
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
(m,
(m， (m,
(m, (m,
(m, (m,
- d6) -d 6 )
(m，  (m,
(m,
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
一ペンチルカルバモイルフエニル）ピロリジンー2— δ 0.87 (t, J = 7.0 Hz, 3H), 1.26, カルボキサミド（化合物 1一 44) 1.40 (s, 9H), 1.27-1.34 (m, 4H), 1. (m,
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
1-pentylcarbamoylphenyl) pyrrolidine-2— δ 0.87 (t, J = 7.0 Hz, 3H), 1.26, carboxamide (compound 1 1 44) 1.40 (s, 9H), 1.27-1.34 (m, 4H), 1.
48-1.54 (m, 2H), 1.78-1.93 (m, 3H), 48-1.54 (m, 2H), 1.78-1.93 (m, 3H),
2.18-2.23 (m, 1H), 3.20-3.24 (m, 2H), 3.31-3.36 (m, 1H), 3.40-3.45 ( z 0 O m, 1H)， 4.19-4.28 (m, 1H), 7.64-7.6 2.18-2.23 (m, 1H), 3.20-3.24 (m, 2H), 3.31-3.36 (m, 1H), 3.40-3.45 (z 0 O m, 1H), 4.19-4.28 (m, 1H), 7.64- 7.6
7 (m, 2H)， 7.78-7.80 (m, 2H), 8.29 7 (m, 2H), 7.78-7.80 (m, 2H), 8.29
(t, J = 5.5 Hz, 1H), 10.17 (s, 1H)(t, J = 5.5 Hz, 1H), 10.17 (s, 1H)
(R)—N— tert—ブトキシカルボニル— N'—（4一 1H-NMR (500 MHz, DMSO - d6) フエ二ルカルバモイルフエニル）ピロリジン— 2—力 δ 1.27, 1.41 (s， 9H), 1.79-1.94 (m, ルポキサミド（化合物 1一 45) 3H), 2.20-2.23 (m, 1H)， 3.33-3.38 (R) —N—tert-butoxycarbonyl—N ′ — (4 1 H-NMR (500 MHz, DMSO-d 6 ) phenylcarbamoylphenyl) pyrrolidine—2—force δ 1.27, 1.41 (s, 9H) , 1.79-1.94 (m, lupoxamide (Compound 1-145) 3H), 2.20-2.23 (m, 1H), 3.33-3.38
(m, 1H), 3.41-3.46 (m, 1H), 4.21-4. 31 (m, 1H), 7.07-7.10 (m, 1H), 7.3 2-7.36 (m, 2H), 7.73-7.77 (m, 4H),
Figure imgf000081_0001
7.93-7.96 (m， 2H), 10.10 (s, 1H), (m, 1H), 3.41-3.46 (m, 1H), 4.21-4.31 (m, 1H), 7.07-7.10 (m, 1H), 7.3 2-7.36 (m, 2H), 7.73-7.77 (m , 4H),
Figure imgf000081_0001
7.93-7.96 (m, 2H), 10.10 (s, 1H),
10.27 (s， 1H)  10.27 (s, 1H)
(R)—Ν— tert—ブトキシカルボニル一 N'— [4ーメ 1H - NMR (500 MHz, DMSO - d6) チル（フエニル）力ルバモイルフエニル]ピロリジン一 δ 1.22, 1.38 (s, 9H), 1.74-1.87 (m， 2—カルボキサミド（化合物 1—46) 3H), 2.13-2.17 (m， 1H), 3.29-3.39 (R) —Ν— tert-butoxycarbonyl 1 N′— [4-Me 1 H -NMR (500 MHz, DMSO -d 6 ) til (phenyl) force ruberamoyl phenyl] pyrrolidine 1 δ 1.22, 1.38 (s, 9H), 1.74-1.87 (m, 2-carboxamide (compound 1-46) 3H), 2.13-2.17 (m, 1H), 3.29-3.39
(m, 2H), 3.35 (s, 3H), 4.12-4.21 (m , 1H), 7.13 (d, J = 8.2 Hz, 2H), 7. 19 (d, J = 8.8 Hz, 2H), 7.12-7.19
Figure imgf000081_0002
(m, 1H)， 7.24-7.29 (m, 2H)， 7.42 (d (m, 2H), 3.35 (s, 3H), 4.12-4.21 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.12- 7.19
Figure imgf000081_0002
(m, 1H), 7.24-7.29 (m, 2H), 7.42 (d
, J = 8.5 Hz, 2H), 10.02(s, 1H) , J = 8.5 Hz, 2H), 10.02 (s, 1H)
(R)— N— tert—ブトキシカルボ二ルー N'— (4— 1H-N R (400 MHz, DMSO - d6) モルホリノフエニル）ピロリジン一 2—カルポキサミド δ 1.27, 1.40 (s, 9H), 1.77 - 1.90 (m, (化合物 1一 47) 3H), 2.15-2.18 (m, 1H), 3.04 (t, J (R) — N— tert-Butoxycarboluro N′— (4— 1 HN R (400 MHz, DMSO-d 6 ) morpholinophenyl) pyrrolidine mono 2-carboxamide δ 1.27, 1.40 (s, 9H), 1.77 -1.90 (m, (compound 1 1 47) 3H), 2.15-2.18 (m, 1H), 3.04 (t, J
= 4.5 Hz, 4H), 3.35-3.42 (m, 2H), 3.72 (t, J = 4.5 Hz, 4H), 4.12-4.2 3 (m, 1H), 6.89 (d, J = 9.0 Hz, 2H ), 7.45 (d, J = 9.0 Hz, 2H), 9.74 ( s, 1H)  = 4.5 Hz, 4H), 3.35-3.42 (m, 2H), 3.72 (t, J = 4.5 Hz, 4H), 4.12-4.2 3 (m, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 9.0 Hz, 2H), 9.74 (s, 1H)
(R)—N—tert—ブトキシカルポ二ルー N' - (4一 'H-N R (400 MHz, DMSO - d6) ァセチルァミノフエニル）ピロリジン一 2—力ルポキ δ 1.27, 1.40 (s, 9H), 1.77-1.91 (m, サミド（化合物 1一 48) 3H), 2,01 (s, 3H), 2.17-2.19 (m, 1 (R) —N—tert-Butoxycarbonyl N '-(4 1' HN R (400 MHz, DMSO-d 6 ) Acetylaminophenyl) pyrrolidine 1 2-Power Lupoki δ 1.27, 1.40 (s, 9H) , 1.77-1.91 (m, samide (compound 1 1 48) 3H), 2,01 (s, 3H), 2.17-2.19 (m, 1
H), 3.30 - 3.42 (m, 2H), 4.14-4.25 (m , 1H), 7.49 (s, 4H), 9.85 (s, 1H), 9 .88 (s, 1H) H), 3.30-3.42 (m, 2H), 4.14-4.25 (m, 1H), 7.49 (s, 4H), 9.85 (s, 1H), 9.88 (s, 1H)
Figure imgf000081_0003
Figure imgf000081_0003
(R)— N— tert—ブトキシカルボ二ルー N'— (4— 1H - NMR (500 MHz, DMSO- d6) ジメチルァミノフエニル）ピ口リジン一 2—カルボキサ δ 1.28, 1.40 (s, 9H), 1.75-1.92 (m, ミド（化合物 1一 49) 3H), 2.12-2.19 (m, 1H), 2.84 (s, 6 (R) — N— tert-butoxycarbonyl N'— (4 — 1 H-NMR (500 MHz, DMSO-d 6 ) dimethylaminophenyl) pi-lysine 1-carboxa δ 1.28, 1.40 (s, 9H), 1.75-1.92 (m, Mido (Compound 1-149) 3H), 2.12-2.19 (m, 1H), 2.84 (s, 6
H), 3.38-3.42 (m, 2H)， 4.12-4.21 (m , 1H), 6.68 (d, J = 9.0 Hz, 2H), 7. 39 (d, J = 9.0 Hz, 2H), 9.62 (s, 1
Figure imgf000081_0004
H) H), 3.38-3.42 (m, 2H), 4.12-4.21 (m, 1H), 6.68 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 2H), 9.62 (s , 1
Figure imgf000081_0004
H)
(R)—Ν— tert—ブトキシカルボニル一 N'—（4一 1H-NMR (500 MHz, DMSO - d6) フエニルァミノフエニル）ピロリジン一 2—カルボキサ δ 1.29, 1.40 (s, 9H), 1.76-1.92 (m, ミド（化合物 1 -50) 3H), 2.14-2.21 (m， 1 H), 3.28-3.43
Figure imgf000082_0001
Figure imgf000083_0001
(m, (R) —Ν— tert-butoxycarbonyl 1 N ′ — (4 1 1 H-NMR (500 MHz, DMSO -d 6 ) phenylaminophenyl) pyrrolidine 1 2-carboxa δ 1.29, 1.40 (s, 9H) , 1.76-1.92 (m, amide (compound 1-50) 3H), 2.14-2.21 (m, 1 H), 3.28-3.43
Figure imgf000082_0001
Figure imgf000083_0001
(m,
(m, (m,
(m, (m,
(m, (m,
- d6) -d 6 )
(m,  (m,
(m,
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
(m,
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
8t"09I0/S00 df/ェ) d ひ t而 9002： O
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
(s, 3 8t "09I0 / S00 df / e) d ひ t meta 9002: O
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
(s, 3
(m, (m,
1.93 (m, 1.93 (m,
(m， (m,
d6) 3H), 2. d 6 ) 3H), 2.
d6) d 6 )
(m,  (m,
Figure imgf000093_0001
Figure imgf000093_0001
9 (m, 9 (m,
d6) d 6 )
(m, (s, 6  (m, (s, 6
(m, (m,
(m， (m,
(m, (m,
Figure imgf000094_0001
Figure imgf000095_0001
(m,
Figure imgf000094_0001
Figure imgf000095_0001
(m,
(m, (m， (m,
Figure imgf000096_0001
Figure imgf000097_0001
(m, (m， (m， (m, (s, (m,
Figure imgf000098_0001
(m, 2H), 4.20-4.29 (m, 1H), 6.46 (s (m, (m, (m,
Figure imgf000096_0001
Figure imgf000097_0001
(m, (m, (m, (m, (s, (m,
Figure imgf000098_0001
(m, 2H), 4.20-4.29 (m, 1H), 6.46 (s
, 1Η), 7.35-7.38 (m, 2Η), 7.44 (d, J = 8.6 Hz, 1H), 7,61 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H)，
Figure imgf000099_0001
, 1Η), 7.35-7.38 (m, 2Η), 7.44 (d, J = 8.6 Hz, 1H), 7,61 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H) ,
Figure imgf000099_0001
7.78 (s, 1H), 10.00 (s, 1H), 11.10 7.78 (s, 1H), 10.00 (s, 1H), 11.10
(s, 1H) (s, 1H)
(R)—Ν— tert—ブトキシカルボニル— Ν'—[4— ( H-NMR (500 MHz, DMSO-d6) 1—メチルインドール一 5—ィル）ラエニル]ピロリジ δ 1.30, 1.41 (s, 9H), 1.79-1.96 (m, ンー 2—カルボキサミド（化合物 1—151 ) 3H), 2.14-2.26 (m, 1H)， 3.34-3.46 (R) —Ν— tert-butoxycarbonyl— Ν ′ — [4— (1 H-NMR (500 MHz, DMSO-d 6 ) 1-methylindole-5-yl) laenyl] pyrrolid δ 1.30, 1.41 (s, 9H), 1.79-1.96 (m, n-2-carboxamide (compound 1-151) 3H), 2.14-2.26 (m, 1H), 3.34-3.46
(m, 2H), 3.81 (s, 3H), 4.20-4.29 (m (m, 2H), 3.81 (s, 3H), 4.20-4.29 (m
, 1H), 6.46 (d, J = 3.1 Hz, 1H), 7., 1H), 6.46 (d, J = 3.1 Hz, 1H), 7.
34 (d, J = 3,1 Hz, 1H)， 7,44 (d, J
Figure imgf000099_0002
= 8,6， Hz, 1H)， 7.49 (d, J = 8.6 34 (d, J = 3,1 Hz, 1H), 7,44 (d, J
Figure imgf000099_0002
= 8,6, Hz, 1H), 7.49 (d, J = 8.6
Hz, 1H)， 7.62 (d, J = 8.9 Hz, 2H) Hz, 1H), 7.62 (d, J = 8.9 Hz, 2H)
， 7.67 (d, J = 8,9 Hz, 2H), 7.79 (s, 7.67 (d, J = 8,9 Hz, 2H), 7.79 (s
， 1H), 10.01 (s, 1H) , 1H), 10.01 (s, 1H)
(R)—N— tert—ブトキシカルボニル一 N' — [4— ( 1H-NMR (500 MHz, DMSO-d6) キノリン一 3—ィル）フエニル]ピロリジン一 2—カル δ 1.30, 1.41 (s, 9H), 1.80-1.95 (m, ボキサミド（化合物 1一 152) 3H), 2.18-2.26 (m, 1H), 3.34-3.47 (R) —N— tert-butoxycarbonyl 1 N ′ — [4— ( 1 H-NMR (500 MHz, DMSO-d 6 ) quinoline 1-yl) phenyl] pyrrolidine 1 2-cal δ 1.30, 1.41 ( s, 9H), 1.80-1.95 (m, boxamide (compound 1 1 152) 3H), 2.18-2.26 (m, 1H), 3.34-3.47
(m, 2H), 4.22-4.31 (m, 1 H), 7.64 (t, J = 8.1 Hz, 1H), 7.76 (t, J = 8.4 (m, 2H), 4.22-4.31 (m, 1 H), 7.64 (t, J = 8.1 Hz, 1H), 7.76 (t, J = 8.4
4 Hz, 1H)， 7.80 (d， J = 8.9 Hz, 2H) 4 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H)
0 ノ  0
Ο Ο Ν , 7.88 (d， J = 8.6 Hz, 2H), 8.04 (d Ο Ο Ν , 7.88 (d, J = 8.6 Hz, 2H), 8.04 (d
, J = 8.6 Hz, 2H), 8.62 (d, J = 2. , J = 8.6 Hz, 2H), 8.62 (d, J = 2.
3 Hz, 1H), 9.26 (d， J = 2.3 Hz, 13 Hz, 1H), 9.26 (d, J = 2.3 Hz, 1
H), 10.16 (s, 1H) H), 10.16 (s, 1H)
(R)—N— tert—ブトキシカルポ二ルー N'— [4— ( H-NMR (500 MHz, DMSO - d6) キノリン一 6—ィル）フエニル]ピロリジン一 2—カル δ 1.30, 1.41 (s, 9H), 1.80-1.96 (m, ボキサミド（化合物 1—153) 3H), 2.16 - 2.26 (m, 1H), 3.34 - 3.47 n H へ (m, 2H), 4.22-4.31 (m, 1H), 7.55 (d d, J = 8.2, 4.3 Hz, 1H), 7.77 (d, J(R) —N— tert-Butoxycarbonyl N′— [4— (H-NMR (500 MHz, DMSO-d 6 ) quinoline 6-yl) phenyl] pyrrolidine 1 2-cal δ 1.30, 1.41 (s , 9H), 1.80-1.96 (m, boxamide (compound 1-153) 3H), 2.16-2.26 (m, 1H), 3.34-3.47 n H (m, 2H), 4.22-4.31 (m, 1H), 7.55 (dd, J = 8.2, 4.3 Hz, 1H), 7.77 (d, J
I N I N
人。' \ V  Man. '\ V
^。 。 = 8.7 Hz, 2H), 7.82 (d, J = 8.7 H i N z, 2H), 8.07 (d, J = 8.9 Hz, 1H), 8  ^. . = 8.7 Hz, 2H), 7.82 (d, J = 8.7 H i N z, 2H), 8.07 (d, J = 8.9 Hz, 1H), 8
.10 (d, J = 8,9 Hz, 1H), 8.26 (d, J .10 (d, J = 8,9 Hz, 1H), 8.26 (d, J
= 1.8 Hz, 1H)， 8.41 (d, J = 8.2 H z, 1H), 8.89 (dd, J = 4.3, 1. & Hz, 1H)， 10.13 (s, 1H) = 1.8 Hz, 1H), 8.41 (d, J = 8.2 H z, 1H), 8.89 (dd, J = 4.3, 1. & Hz, 1H), 10.13 (s, 1H)
(R)—N— tert—ブトキシカルボニル— N'— [4一（ 1H-NMR (400 MHz, DMSO- d6) ベンゾチアゾールー 2—ィル）フエニル]ピロリジン一 δ 1,28， 1.41 (s, 9H), 1.81-1.93 (m, 2—力ルポキサミド（化合物 1—154) 3H), 2.23-2.33 (m, 1H), 3.30-3.45 (R) —N— tert-butoxycarbonyl—N′— [4 1 ( 1 H-NMR (400 MHz, DMSO-d 6 ) benzothiazol-2-yl) phenyl] pyrrolidine mono δ 1,28, 1.41 ( s, 9H), 1.81-1.93 (m, 2-force lupoxamide (compound 1-154) 3H), 2.23-2.33 (m, 1H), 3.30-3.45
(m, 2H)， 4.22-4.31 (m, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H),
Figure imgf000099_0003
8.02 (d, J = 8.1 Hz, 1H), 8.07 (d, (m, 2H), 4.22-4.31 (m, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.53 (t, J = 8.1 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H) ,
Figure imgf000099_0003
8.02 (d, J = 8.1 Hz, 1H), 8.07 (d,
J = 8.7 Hz, 2H), 8.13 (d, J = 8.1 Hz, 1H), 10.32 (s; 1H)  J = 8.7 Hz, 2H), 8.13 (d, J = 8.1 Hz, 1H), 10.32 (s; 1H)
(R)—N— tert—ブトキシカルボニル一 N' — [4—（ 1H-刚 R (500 MHz, DMSO - d6) 5—クロ口べンゾチアゾールー 2—ィル）フエニル]ピ δ 1.28, 1.41 (s, 9H), 1.79-1.94 (m, 口リジン一 2—カルポキサミド（化合物 1—155) 3H)， 2.18-2.26 (m, 1H), 3.33-3.46 (d (R) —N— tert-Butoxycarbonyl 1 N ′ — [4— ( 1 H- 刚 R (500 MHz, DMSO-d 6 ) 5—Clo-benzophenazol-2-yl) phenyl] pi δ 1.28, 1.41 (s, 9H), 1.79-1.94 (m, oral lysine 2-carboxamide (compound 1-155) 3H), 2.18-2.26 (m, 1H), 3.33-3.46 (d
(m， (m,
(m, (m,
(m, (m,
(m, (m,
(m, (m,
d6) d 6 )
(m,
Figure imgf000100_0001
d6) (m,
Figure imgf000100_0001
d 6 )
(m,  (m,
d6) d 6 )
(m,  (m,
(m, J (m, J
3H), 3H),
d6) d 6 )
(m,  (m,
(s
Figure imgf000101_0001
W (s
Figure imgf000101_0001
W
Figure imgf000102_0001
Figure imgf000103_0001
実施例 2
Figure imgf000102_0001
Figure imgf000103_0001
Example 2
(2R, 4R)— N— tert—ブトキシカルボ二ルー N'一 (4一クロ口フエニル）一4—ヒドロキシ ピロリジン一 2—カルポキサミド（化合物 2— 1)  (2R, 4R) — N-tert-Butoxycarbolulu N′-one (4-monophenyl) 4-hydroxypyrrolidine-one 2-carboxamide (compound 2-1)
(2R, 4R)— N—tert—ブトキシカルポニル一 N'— (4—クロ口フエニル）一 4ーァセトキ シピロリジン一 2—カルボキサミド（化合物 1—170、 140mg、 0. 37mmol)をメタノール (2ml)に溶解し、炭酸カリウム（106mg、 0. 77mmol)を加え、 60度で 3時間攪拌した 。減圧下溶媒を留去し、水（20ml)と酢酸ェチル（20ml)を加えて分配後、有機層を飽 和食塩水（ 20 m I )で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去す ることにより標記化合物（132mg)を無色アモルファスとして得た。（定量的） (2R, 4R) — N-tert-butoxycarbonyl-N′— (4-phenyl) -4-acetopyrrolidine-one 2-carboxamide (Compound 1-170, 140 mg, 0.37 mmol) in methanol Dissolved in (2 ml), potassium carbonate (106 mg, 0.77 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. The solvent was distilled off under reduced pressure, water (20 ml) and ethyl acetate (20 ml) were added and partitioned, and the organic layer was washed with saturated brine (20 m I). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (132 mg) as a colorless amorphous. (quantitative)
Figure imgf000104_0001
以下、化合物 1一 171を使用し、化合物 2—1の製造方法に準じて、化合物 2— 2を得た
Figure imgf000104_0001
Hereinafter, Compound 2-1 171 was used, and Compound 2-2 was obtained according to the production method of Compound 2-1.
(2R, 4S)— N— tert—ブトキシカルボニル一 1H-NMR (400 MHz, DMSO - d6) (2R, 4S) — N— tert-Butoxycarbonyl 1 H-NMR (400 MHz, DMSO-d 6 )
N'—(4一クロ口フエニル）一4ーヒドロキシピロ δ 1.25, 1.39 (s, 9Η), 1.88-1.94 (m, 1 リジン一 2—カルボキサミド（化合物 2— 2) H), 2.08-2.14 (m, 1H), 3.42 (dd, J = 1  N ′ — (4 monophenyl) 1-4-hydroxypyrrole δ 1.25, 1.39 (s, 9Η), 1.88-1.94 (m, 1 lysine 1-carboxamide (compound 2-2) H), 2.08-2.14 (m, 1H), 3.42 (dd, J = 1
1.0, 4.0 Hz, 1H)， 4.27—4.34 (m, 2H)， 5. 06-5.07 (m， 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H) 1.0, 4.0 Hz, 1H), 4.27—4.34 (m, 2H), 5. 06-5.07 (m, 1H), 7.36 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H )
Figure imgf000104_0002
実施例 3
Figure imgf000104_0002
Example 3
(R)— N— tert—ブトキシカルボニル一 N'— [4一 [(E)— 2—（4—トリフルォロメチルフエ ニル）一 1—ェテニル]フエニル]ピロリジン一2—カルポキサミド（化合物 3— 1)  (R) — N— tert-butoxycarbonyl 1 N′— [4 1 [(E) — 2— (4-trifluoromethylphenyl) 1 1-ethenyl] phenyl] pyrrolidine 1 2-carboxamide (compound 3— 1)
(R)— N— tert—ブトキシカルボニル一 N'— (4—ビニルフエニル）ピロリジン一 2—カル ボキサミド（ィ匕合物 1一 119、 802mg、 2. 53mmol)および 4一ョードベンゾ卜リフ レ才リ ド（837〃し5. 70mmol)を N, N—ジメチルホルムアミド（5ml)に溶解し、 N , N—ジイソ プロピ レエチノレアミン（1. 10mし 6. 31mmol)、酔酸ノ ラジウム（H) ('168mg、0. 75 Ommol)、トリー O—トリルホスフィン（468mg、 1. 54mmol)を加え、マイクロ波を照射 (100度、 30分）（マイルスト一ンゼネラル社製 MicroSYNTH)した。放冷後、反応液に 酢酸ェチル（50ml)およびジェチルエーテル（50ml)を加え、水（100mし 2回）、飽和食 塩水（ 50 m I )で洗浄した。さらに無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し(R) — N— tert-butoxycarbonyl 1 N′— (4-vinylphenyl) pyrrolidine 1 2-carboxamide (compound 1 119, 802 mg, 2.53 mmol) and 4-iodobenzoyl fluoride (837 83 5.70 mmol) was dissolved in N, N-dimethylformamide (5 ml), and N, N-diisopropyleneethylamine (1.10 m, 6.31 mmol), noradium disulfate (H) ('168 mg, 0.775 mmol) and tri-O-tolylphosphine (468 mg, 1.54 mmol) were added, and microwave irradiation (100 ° C., 30 minutes) (MicroSYNTH manufactured by Milest General Co., Ltd.) was performed. After standing to cool, Ethyl acetate (50 ml) and jetyl ether (50 ml) were added, and the mixture was washed with water (100 ml, twice) and saturated saline (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
、得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製す ることにより標記化合物（170mg)を淡黄色固体として得た（収率 150/0)。 , Resulting residue gave the title compound Rukoto be purified by silica gel column chromatography (hexane monoacetate Echiru to) a (170 mg) as a pale yellow solid (yield: 150/0).
Figure imgf000105_0001
以下、化合物 1一 119および市販化合物から選択される化合物を使用し、化合物 3—1 の製造方法に準じて、化合物 3— 2~3— 29を得た。
Figure imgf000105_0001
Hereinafter, using compounds selected from Compound 1-119 and commercially available compounds, compounds 3-2-3 to 29 were obtained according to the production method of compound 3-1.
Figure imgf000105_0002
z, 2H), 7.46 (d, J = 8.0 Hz, 2H), -,
Figure imgf000105_0002
z, 2H), 7.46 (d, J = 8.0 Hz, 2H),-,
52 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 10.03 (s, 1H)  52 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 10.03 (s, 1H)
(R)— N—tert—ブトキシカルポ二ルー N'—[4 1H-NMR (500 MHz, DMSO- d6) — [(E)— 2—（2—メトキシフエ二ル）一 1—ェテ二 δ 1.28, 1.40 (s, 9H), 1.78—1.92 (m， ル]フエニル]ピロリジン一 2—力ルポキサミド（化 3H), 2.17-2.21 (m, 1H)， 3.29-3.45 (m 合物 3— 5) , 2H), 3.85 (s, 3H)， 4.18-4.27 (m, 1H (R) — N-tert-Butoxycarbonyl N '— [4 1 H-NMR (500 MHz, DMSO-d 6 ) — [(E) — 2— (2-methoxyphenyl) 1 1-et δ 1.28, 1.40 (s, 9H), 1.78—1.92 (m, ru] phenyl] pyrrolidine 1-strength lupoxamide (Chemical 3H), 2.17-2.21 (m, 1H), 3.29-3.45 (m Compound 3-5 ), 2H), 3.85 (s, 3H), 4.18-4.27 (m, 1H
), 6.98 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H)， 7.15 (d, J = 16.5 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 16.5 Hz, 1H), 7.51 (d,
Figure imgf000106_0001
J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 H z, 2H), 7.62 (d, J = 7.8 Hz, 1H), 10 •04 (s, 1H) ), 6.98 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 16.5 Hz, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 16.5 Hz, 1H), 7.51 (d,
Figure imgf000106_0001
J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 H z, 2H), 7.62 (d, J = 7.8 Hz, 1H), 10 • 04 (s, 1H)
(R)—N— tert—ブトキシカルボニル— N'— L4 1H-NMR (500 MHz, DMSO - d6) — [(E)— 2— (3—メトキシフエ二ル）一 1一ェテニ δ 1.27, 1.40 (s, 9H), 1.78-1.92 (m, ル]フエニル]ピロリジン一 2—カルボキサミド（化 3H), 2.18-2.23 (m, 1H), 3.33-3.45 (m 合物 3— 6) ， 2H)， 3.79 (s, 3H), 4.18-4.27 (m, 1H (R) —N— tert-butoxycarbonyl— N′— L4 1 H-NMR (500 MHz, DMSO-d 6 ) — [(E) — 2— (3-methoxyphenyl) 1 1 1 etheni δ 1.27, 1.40 (s, 9H), 1.78-1.92 (m, ru] phenyl] pyrrolidine 1-carboxamide (Chemical 3H), 2.18-2.23 (m, 1H), 3.33-3.45 (m Compound 3-6), 2H) , 3.79 (s, 3H), 4.18-4.27 (m, 1H
), 6,83 (dd, J = 8.6, 1.8 Hz, 1H), 7. 12 (d, J 二 16.4 Hz, 1H), 7.14 (s, 1 H), 7.14-7.15 (m， 1H), 7.21 (d, J =
Figure imgf000106_0002
16.4 Hz, 1H)， 7.28 (t, J = 8.1 Hz, 1 ), 6,83 (dd, J = 8.6, 1.8 Hz, 1H), 7.12 (d, J 2 16.4 Hz, 1H), 7.14 (s, 1 H), 7.14-7.15 (m, 1H), 7.21 (d, J =
Figure imgf000106_0002
16.4 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1
H), 7.55 (d, J = 8.7 Hz, 2H), 7.62 ( d, J = 8.7 Hz, 2H), 10.05 (s, 1H) H), 7.55 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 10.05 (s, 1H)
(R)— N—tert—ブトキシカルボ二ルー N' - [4 1H-NMR (500 MHz, DMSO - d6) -[(E)一 2— (2—クロ口フエニル）一1—ェ亍二 δ 1.27, 1.40 (s， 9Η), 1.78-1.94 (m, ル]フエニル]ピロリジン一 2—カルボキサミド（化 3H)， 2.17-2.23 (m, 1H), 3.29-3.45 (m 合物 3— 7) , 2H), 4.19-4.28 (m, 1H), 7.25 (d, J (R) — N—tert-Butoxycarbonyl N '-[4 1 H-NMR (500 MHz, DMSO-d 6 )-[(E) One 2— (2-Chlorophenyl) -1-one 2 δ 1.27, 1.40 (s, 9Η), 1.78-1.94 (m, Ru] phenyl] pyrrolidine 1-carboxamide (Chemical 3H), 2.17-2.23 (m, 1H), 3.29-3.45 (m Compound 3-7 ), 2H), 4.19-4.28 (m, 1H), 7.25 (d, J
= 16.2 Hz, 1H)， 7.29 (t, J = 7.7 Hz, = 16.2 Hz, 1H), 7.29 (t, J = 7.7 Hz,
1H), 7.35-7.38 (m， 1H), 7.36 (d, J = 16.2 Hz, 1H), 7.48 (dd, J = 7,7, 1 ,0 Hz, 1H), 7.58 (d, J = 8.6 Hz, 2H)
Figure imgf000106_0003
1H), 7.35-7.38 (m, 1H), 7.36 (d, J = 16.2 Hz, 1H), 7.48 (dd, J = 7,7, 1, 0 Hz, 1H), 7.58 (d, J = 8.6 Hz , 2H)
Figure imgf000106_0003
， 7.66 (d, J = 8.6 Hz, 2H)， 7.84-7.8 6 (m, 1H)， 10.10 (s, 1H)  7.66 (d, J = 8.6 Hz, 2H), 7.84-7.8 6 (m, 1H), 10.10 (s, 1H)
(R)—N— tert—ブトキシカルボニル— N'― [4 1H-NMR (500 MHz, DMSO - d6) — [(E)—2— (3—クロ口フエ二ル）一 1—ェ亍二 δ 1.27, 1.40 (s, 9Η), 1.78-1.93 (m, ル]フエニル]ピロリジン一 2—力ルポキサミド（化 3H), 2.17-2.23 (m, 1H), 3.32-3.45 (m 合物 3— 8) , 2H)， 4.18-4.28 (m, 1H), 7.15 (d, J (R) —N— tert-Butoxycarbonyl— N′— [4 1 H-NMR (500 MHz, DMSO-d 6 ) — [(E) —2— (3—Black mouth phenyl) 1 1—亍 δ 1.27, 1.40 (s, 9Η), 1.78-1.93 (m, ru] phenyl] pyrrolidine 1-strength lupoxamide (Chemical 3H), 2.17-2.23 (m, 1H), 3.32-3.45 (m Compound 3 — 8), 2H), 4.18-4.28 (m, 1H), 7.15 (d, J
= 16.1 Hz, 1H), 7.29 (d, J = 16.1 H z, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7. 39 (t, J = 7.8 Hz, 1H)， 7.53 (d, J =
Figure imgf000106_0004
7.8 Hz, 1H), 7.56 (d, J = 8.7 Hz, = 16.1 Hz, 1H), 7.29 (d, J = 16.1 H z, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.53 (d, J =
Figure imgf000106_0004
7.8 Hz, 1H), 7.56 (d, J = 8.7 Hz,
2H), 7.64 (d, J = 8.7 Hz, 2H), 7.66 (s, 1H), 10.05 (s, 1H)  2H), 7.64 (d, J = 8.7 Hz, 2H), 7.66 (s, 1H), 10.05 (s, 1H)
(R)—N— tert—ブトキシカルボ二ルー N' - [4 1H-N R (400 MHz, DMSO - d6) 一 [(E)— 2—（4一クロ口フエ二ル）一 1—ェ亍二 δ 1.27, 1.40 (s, 9Η), 1.77-1.94 (m, ル]フエニル]ピロリジン一 2—カルボキサミド（化 3H), 2.17-2.23 (m, 1H), 3.31-3.45 (m 合物 3— 9) , 2H)， 4.18-4.28 (m, 1H), 7.15 (d, J (R) —N— tert-Butoxycarbonyl N '-[4 1 HN R (400 MHz, DMSO-d 6 ) ONE [(E) — 2— (4 single-mouthed phenol) ONE 1—亍 δ 1.27, 1.40 (s, 9Η), 1.77-1.94 (m, ru] phenyl] pyrrolidine mono 2-carboxamide (Chemical 3H), 2.17-2.23 (m, 1H), 3.31-3.45 (m Compound 3— 9), 2H), 4.18-4.28 (m, 1H), 7.15 (d, J
04 (m, 04 (m,
(m  (m
(m, (m (m, (m
(m (m
(m, (m (m, (m
(m, (m
Figure imgf000107_0001
(m, (m
Figure imgf000107_0001
05
Figure imgf000108_0001
05
Figure imgf000108_0001
0 6
Figure imgf000109_0001
0 6
Figure imgf000109_0001
0 7
Figure imgf000110_0001
実施例 4 (R)_N— tert—ブトキシカルポ二ルー N' _[4— [(E)— 2— (4—エトキシフエ二ル）一 1 ーェテニル]フエニル]ピロリジン一 2—力ルポキサミド（化合物 4一 1) 0 7
Figure imgf000110_0001
Example 4 (R) _N— tert-Butoxycarbonyl N ′ _ [4— [(E) — 2— (4-Ethoxyphenyl) -1-ethyl] phenyl] pyrrolidine-1-2-Lupoxamide (Compound 4-11)
(R)— N-tert—ブトキシカルボニル一N'— (4—ョ一ドフエニル）ピロリジン一 2—カル ポキサミド（化合物 1—30、 804mg、 1. 9mmol)および 4ーェトキシスチレン（580〃 I、 3. 9mmol)を N， N—ジメチルホルムアミド（ 8ml)に溶解し、 N , N—ジイソプロピルェチ ノレァミン（830〃し 4. 8mmol)、酔酸ノ ラジウム（ Π ) (44mg、 0. 19mmol)、卜リ一 O —トリルホスフィン（126mg、0. 39mmol)を加え、 80度で 6. 5時間攪拌した。放冷後 、反応液に酢酸ェチル（100ml)および水（120ml)を加えて分配し、有機層を飽和食塩 水（120ml)で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去し、 得られた残留物を.シリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製す ることにより標記化合物（400mg)を黄色固体として得た（収率 480/0)。 (R) — N-tert-butoxycarbonyl 1 N′— (4-iodophenyl) pyrrolidine 1 2-carboxamide (compound 1-30, 804 mg, 1.9 mmol) and 4-ethoxystyrene (580〃I, 3.9 mmol) is dissolved in N, N-dimethylformamide (8 ml), and N, N-diisopropylethylamine (830 to 4.8 mmol), noradium disulfate (44 mg, 0.19 mmol),卜 Li-O-tolylphosphine (126 mg, 0.39 mmol) was added and stirred at 80 degrees for 6.5 hours. After allowing to cool, ethyl acetate (100 ml) and water (120 ml) were added to the reaction solution for partitioning, and the organic layer was washed with saturated brine (120 ml). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the title compound (400 mg ) as yellow. It was obtained as a solid (yield 480/0).
Figure imgf000111_0001
以下、化合物 1一 13、 1—30、 1—81 ~1 _84および市販化合物から選択される化合 物を使用し、化合物 4—1の製造方法に準じて、化合物 4_2〜4— 19を得た。
Figure imgf000111_0001
Hereinafter, compounds 4_2 to 4-19 were obtained according to the production method of compound 4-1, using compounds selected from compounds 1-13, 1-30, 1-81 to 1_84, and commercially available compounds. .
Figure imgf000111_0002
Figure imgf000111_0002
09
Figure imgf000112_0001
(m, 1 09
Figure imgf000112_0001
(m, 1
(m, - 3.45 (m,-3.45
(m, (m,
d6) d 6 )
(m,  (m,
- d6) -d 6 )
(m,  (m,
Figure imgf000113_0001
(s, 1H)
Figure imgf000113_0001
(s, 1H)
(R)—N—tert—ブトキシカルボ二ルー N'— [4— [ 1H-NMR (500 MHz, DMSO - d6) (E)— 2— (4—スルファモイルフエ二ル）一 1ーェテ δ 1.27, 1.40 (s, 9H), 1.78-1.92 (m, ニル]フ Iニル]ピロリジン一 2—力ルポキサミド（化 3H), 2.18-2.23 (m， 1H), 3.32-3.45 合物 4—14) (m, 2H), 4.18-4.28 (m， 1H)， 7.23 (d, (R) —N—tert-Butoxycarbonyl N'— [4— [ 1 H-NMR (500 MHz, DMSO-d 6 ) (E) — 2— (4-sulfamoylphenol) 1 Δ 1.27, 1.40 (s, 9H), 1.78-1.92 (m, Nil] F i Nyl] pyrrolidine I 2—Power lupoxamide (Chemical 3H), 2.18-2.23 (m, 1H), 3.32-3.45 Compound 4— 14) (m, 2H), 4.18-4.28 (m, 1H), 7.23 (d,
J = 16.5 Hz, 1H), 7.33 (br s, 2H)， 7.35 (d, J = 16.5 Hz, 1H), 7.59 (d J = 16.5 Hz, 1H), 7.33 (br s, 2H), 7.35 (d, J = 16.5 Hz, 1H), 7.59 (d
, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 ο ο ° 60 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H)， , J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 ο ο ° 60 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H),
7.80 (d, J = 8.6 Hz, 2H), 10.09 (s 7.80 (d, J = 8.6 Hz, 2H), 10.09 (s
， 1H) , 1H)
(R)—N— tert—ブトキシカルボ二ルー N'— [4— [ 1H - NMR (400 MHz, DMSO - d6) (E)— 2—（4—シァノフエニル）一 1—ェテニル]フ δ 1.27, 1.40 (s, 9H), 1.79-1.90 (m, ェニル]ピロリジン一 2—力ルポキサミド（化合物 4 3H), 2.20-2.24 (m, 1H), 3.30 - 3.45 一 15) (m, 2H), 4.18-4.27 (m, 1H), 7.24 (d, n H へ J = 16.4 Hz, 1H), 7.41 (d, J = 16 • 4 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2 H), 7.66 (d, J = 8.7 Hz, 2H)， 7.76 ス OAO (d, J = 8.5 Hz, 2H)， 7.82 (d, J = (R) —N— tert-Butoxycarbonyl N'— [4— [ 1 H -NMR (400 MHz, DMSO -d 6 ) (E) — 2— (4-Cyanophenyl) -1-etenyl] fur δ 1.27, 1.40 (s, 9H), 1.79-1.90 (m, enyl) pyrrolidine 1-strength lupoxamide (compound 4 3H), 2.20-2.24 (m, 1H), 3.30-3.45 1 15) (m, 2H), 4.18-4.27 (m, 1H), 7.24 (d, n to H J = 16.4 Hz, 1H), 7.41 (d, J = 16 • 4 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2 H) , 7.66 (d, J = 8.7 Hz, 2H), 7.76 S O A O (d, J = 8.5 Hz, 2H), 7.82 (d, J =
8.5 Hz, 2H), 10.11 (s, 1H)  8.5 Hz, 2H), 10.11 (s, 1H)
(R)— N— tert—ブトキシカルボ二ルー N'— [4— [ 1H-N R (500 MHz, DMSO - d6) (E)—2— (2—ピリジル）一 1一ェ亍ニル]フエ二 δ 1,27, 1.40 (s, 9H), 1,78—1.93 (m, ル]ピロリジン一 2—力ルポキサミド（化合物 4—16 3H), 2.14-2.23 (m, 1H), 3.32-3.45 ) (m, 2H), 4.18-4.28 (m, 1H), 7.21-7. (R) — N— tert—Butoxycarbonyl N'— [4— [ 1 HN R (500 MHz, DMSO-d 6 ) (E) —2— (2-Pyridyl) 1 1 2 δ 1,27, 1.40 (s, 9H), 1,78—1.93 (m, ru) pyrrolidine 1-strength lupoxamide (compound 4-16 3H), 2.14-2.23 (m, 1H), 3.32-3.45) (m, 2H), 4.18-4.28 (m, 1H), 7.21-7.
24 (m， 1H), 7.22 (d, J = 16.2 Hz, 24 (m, 1H), 7.22 (d, J = 16.2 Hz,
1H), 7,51 (d, J = 7.6 Hz, 1H), 7.61 0 。 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 0 N 1H), 7,51 (d, J = 7.6 Hz, 1H), 7.61 0. (d, J = 8.9 Hz, 2H), 7.61 (d, J = 0 N
16.2 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 8.5 16.2 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.77 (t, J = 7.6 Hz, 1H), 8.5
5 (dd, J = 4.9, 0.9 Hz, 1H), 10.095 (dd, J = 4.9, 0.9 Hz, 1H), 10.09
(s, 1H) (s, 1H)
(R)— N— tert—ブトキシカルボ二ルー N'— [4一 [ 1H - NMR (500 MHz, DMSO - d6) (E)—2—（4—ピリジル）一 1—ェテニル]フエ二 δ 1.27, 1.40 (s, 9H), 1.78-1.93 (m, ル]ピロリジン一 2—カルボキサミド（化合物 4一 17 3H), 2.15-2.23 (m， 1H), 3.33-3.45 ) (m, 2H), 4.19-4.28 (m， 1H)， 7.15 (d, (R) — N— tert-butoxycarbonyl N′— [4 1 [ 1 H-NMR (500 MHz, DMSO-d 6 ) (E) —2— (4-Pyridyl) 1 1-ethenyl] δ 1.27, 1.40 (s, 9H), 1.78-1.93 (m, ru) pyrrolidine 1-carboxamide (compound 4 1 17 3H), 2.15-2.23 (m, 1H), 3.33-3.45) (m, 2H), 4.19-4.28 (m, 1H), 7.15 (d,
J = 16,5 Hz, 1H)， 7.48 (d, J = 16 .5 Hz, 1H), 7.53 (d, J = 4.6 Hz, 2 H), 7.61 (d, J = 8.7 Hz, 2H), 7.66
Figure imgf000114_0001
(d, J = 8.7 Hz, 2H), 8.52 (dd, J = J = 16,5 Hz, 1H), 7.48 (d, J = 16.5 Hz, 1H), 7.53 (d, J = 4.6 Hz, 2 H), 7.61 (d, J = 8.7 Hz, 2H), 7.66
Figure imgf000114_0001
(d, J = 8.7 Hz, 2H), 8.52 (dd, J =
4.6, 1.2 Hz, 2H), 10.11 (s, 1H) 4.6, 1.2 Hz, 2H), 10.11 (s, 1H)
(R)—N— tert—ブトキシカルボ二ルー N'— [4— [ 'H— NMR (500 MHz, DMSO - d6) (E)—2—シクロへキシルー 1—ェ亍ニル]フエ二 δ 1.11-1.33 (m, 5H), 1.26, 1.40 (s, ル]ピロリジン一 2—カルボキサミド（化合物 4一 18 9H), 1.62—1.81 (m, 5H)， 1.84-1.89 ) (m, 3H), 2.09-2.20 (m, 2H), 3.25 - 3. (R) —N— tert-butoxycarbonyl N'— [4— ['H— NMR (500 MHz, DMSO-d 6 ) (E) —2-cyclohexyloxy 1-enyl] phenyl δ 1.11-1.33 (m, 5H), 1.26, 1.40 (s, ru) pyrrolidine 1-carboxamide (compound 4 1 18 9H), 1.62—1.81 (m, 5H), 1.84-1.89) (m, 3H), 2.09 -2.20 (m, 2H), 3.25-3.
41 (m, 2H), 4.16-4.24 (m, 1H), 6.15 41 (m, 2H), 4.16-4.24 (m, 1H), 6.15
(dd, J = 15.9, 6.7' Hz, 1 H), 6.29 ( d, J = 15.9 Hz, 1H), 7.31 (d, J = z、O 0 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2 (dd, J = 15.9, 6.7 'Hz, 1 H), 6.29 (d, J = 15.9 Hz, 1H), 7.31 (d, J = z, O 0 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2
H), 9.95 (s, 1H) (R)—N— tert—ブトキシカルポニル— N'—[3— [ 1H-N R (400 MHz, DMSO-d6) (E)— 2—フエニル一 1ーェテニル]フエニル]ピロリ δ 1.29, 1.41 (s, 9Η), 1.78-1.90 (m, ジンー2—力ルポキサミド（化合物 4— 19) 3H), 2.16-2.22 (m, 1H), 3.30-3.46 H), 9.95 (s, 1H) (R) —N— tert-butoxycarbonyl—N ′ — [3— [ 1 HN R (400 MHz, DMSO-d 6 ) (E) — 2-phenyl-1-ethyl] phenyl] pyrrole δ 1.29, 1.41 (s , 9Η), 1.78-1.90 (m, Jin-2-force lupoxamide (compound 4-19) 3H), 2.16-2.22 (m, 1H), 3.30-3.46
(m, 2H), 4.17-4.29 (m, 1H), 7.15 (d, (m, 2H), 4.17-4.29 (m, 1H), 7.15 (d,
J = 16.6 Hz, 1H), 7.24 (d, J = 16 ■ 6 Hz, 1H), 7.26-7.34 (m, 3H), 7.38J = 16.6 Hz, 1H), 7.24 (d, J = 16 ∎ 6 Hz, 1H), 7.26-7.34 (m, 3H), 7.38
(t, J = 7.6 Hz, 2H), 7.45-7.49 (m,(t, J = 7.6 Hz, 2H), 7.45-7.49 (m,
1H), 7.62 (d, J = 7.6 Hz, 2H), 7.8 5, 7.89 (s, 1H)， 10.02 (s, 1H)
Figure imgf000115_0001
実施例 5 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.8 5, 7.89 (s, 1H), 10.02 (s, 1H)
Figure imgf000115_0001
Example 5
(R)— N— tert_ブトキシカルポ二ルー N'— (4—ヒドロキシフエニル）ピロリジン一 2—力 ルポキサミド（化合物 5)  (R) — N— tert_Butoxycarbonyl N'— (4-Hydroxyphenyl) pyrrolidine 1- 2 force Lupoxamide (Compound 5)
(R)— N— tert—ブトキシカルボニル一 N' - (4—ベンジルォキシフエニル）ピロリジン一 2—カノレポキサミド（化合物 1—87、 5. OOg、 12. 6mmol)をエタノール（25ml)に;'容角军 し、パラジウム一炭素（500mg)を加え、水素雰囲気下、室温で一晩攪拌した。テトラヒ ドロフラン（ 50m I )を加えて、セライトで不溶物を濾去した後、減圧下溶媒を留去した。得 られた残留物をジイソプロピルェ一テルで濾取することにより標記化合物（3· 63g)を淡 紫色固体として得た。（収率 94%) H-NMR (500 MHz, DMSO - d6) (R) —N-tert-butoxycarbonyl 1 N ′-(4-benzyloxyphenyl) pyrrolidine 1 2-canolepoxamide (Compound 1-87, 5. OOg, 12.6 mmol) in ethanol (25 ml); Then, palladium on carbon (500 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. Tetrahydrofuran (50 ml) was added, insoluble material was filtered off through celite, and the solvent was evaporated under reduced pressure. The obtained residue was collected by filtration with diisopropyl ether to give the title compound (3.63 g) as a pale purple solid. (Yield 94%) H-NMR (500 MHz, DMSO-d 6 )
δ 1,28， 1.39 (s, 9H), 1.75-1.91 (m, 3 δ 1,28, 1.39 (s, 9H), 1.75-1.91 (m, 3
H), 2.13-2.19 (m, 1H), 3.30-3.42 (m, 2
Figure imgf000115_0002
H), 4.12-4.21 (m, 1H), 6.68 (d, J = 8. H), 2.13-2.19 (m, 1H), 3.30-3.42 (m, 2
Figure imgf000115_0002
H), 4.12-4.21 (m, 1H), 6.68 (d, J = 8.
6 Hz, 2H), 7.35 (d, J = 8,6 Hz, 2H), 9 .15 (s， 1H), 9.67(s, 1H) 実施例 6  6 Hz, 2H), 7.35 (d, J = 8,6 Hz, 2H), 9.15 (s, 1H), 9.67 (s, 1H) Example 6
(R)-N— tert—ブトキシカルポニル一 N'—[4— (4—クロ口ベンジルォキシ）フエニル]ピ 口リジン一 2—カルポキサミド（化合物 6— 1)  (R) -N— tert-Butoxycarbonyl 1 N ′ — [4- (4-Chronobenzyloxy) phenyl] pi-lysine 1 2-Carboxamide (Compound 6-1)
(R)—N— tert—ブトキシカルボ二ルー N' - (4—ヒドロキシフエニル）ピロリジン一 2— カルポキサミド（化合物 5、 201 mg、0. 653mmol)を N, N—ジメチルホルムアミド（4ml )に溶解し、炭酸カリウム（280mg、 2. O3mmol)、 4—クロ口ベンジルブロミド（270mg 、 1. 31mmol)を加え、 60度で 4時間攪拌した。放冷後、反応液に酢酸ェチル（20ml) と水（20ml)を加え分配し、有機層を飽和食塩水（20ml)で洗浄した。有機層を無水硫 酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲルカラムク 口マトグラフィ一（へキサン一酢酸ェチル）で精製することにより標記化合物（260mg)を 白色固体として得た。（収率 93%) (R) —N— tert-Butoxycarbolulu N ′-(4-Hydroxyphenyl) pyrrolidine 1-carboxamide (compound 5, 201 mg, 0.653 mmol) dissolved in N, N-dimethylformamide (4 ml) Potassium carbonate (280 mg, 2. O3 mmol), 4-clonal benzyl bromide (270 mg) 1.31 mmol) was added and stirred at 60 degrees for 4 hours. After allowing to cool, ethyl acetate (20 ml) and water (20 ml) were added to the reaction solution for partitioning, and the organic layer was washed with saturated brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl hexyl acetate) to give the title compound (260 mg) as a white solid. (Yield 93%)
Figure imgf000116_0001
以下、化合物 5および市販化合物から選択される化合物を使用し、化合物 6—1の製造 方法に準じて、化合物 6— 2~6— 12を得た。
Figure imgf000116_0001
Hereinafter, compounds 6-2 to 6-12 were obtained according to the production method of compound 6-1 using a compound selected from compound 5 and commercially available compounds.
Figure imgf000116_0002
Figure imgf000116_0002
14 (m, 3 14 (m, 3
(m, (m, 3 (m, 3 (m, 3 (m， 3 (m, 3
Figure imgf000117_0001
5.00 (s, 2H), 6.94 (d, J = 9.1 Hz, 2H (m, (m, 3 (m, 3 (m, 3 (m, 3 (m, 3
Figure imgf000117_0001
5.00 (s, 2H), 6.94 (d, J = 9.1 Hz, 2H
), 7.19 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H)， 7.48 (d, J = 9.1 Hz , 2H)， 9.79 (s, 1H)  ), 7.19 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 7.48 (d, J = 9.1 Hz, 2H), 9.79 (s, 1H)
(R)— N— tert—ブトキシカルボ二ルー N' -[4 1H-NMR (500 MHz, DMSO-d6) (R) — N— tert-Butoxycarbonyl N '-[4 1 H-NMR (500 MHz, DMSO-d 6 )
一（2—ピリジル）メトキシフエ二ル]ピロリジン一 δ 1.28, 1.40 (s, 9H), 1.76-1.91 (m, 3 2—カルボキサミド（化合物 6— 11.) H), 2.15-2.20 (m, 1H)， 3.29-3.43 (m, Mono (2-pyridyl) methoxyphenyl] pyrrolidine mono δ 1.28, 1.40 (s, 9H), 1.76-1.91 (m, 3 2-carboxamide (compound 6— 11.) H), 2.15-2.20 (m, 1H) , 3.29-3.43 (m,
2H), 4.14-4.23 (m, 1H), 5,13 (s, 2H), 6.98 (d, J = 8.9 Hz, 2H), 7.32—7,35 ( 丄 O m, 1H), 7.50 (m, 3H)， 7.81-7.85 (m, 1 0 0 H), 8.57 (d, J = 4.3 Hz, 1H), 9.82 (s,  2H), 4.14-4.23 (m, 1H), 5,13 (s, 2H), 6.98 (d, J = 8.9 Hz, 2H), 7.32—7,35 (丄 O m, 1H), 7.50 (m, 3H), 7.81-7.85 (m, 1 0 0 H), 8.57 (d, J = 4.3 Hz, 1H), 9.82 (s,
1H)  1H)
(R)— N— tert—ブトキシカルポ二ルー N' - [4 1H-NM (400 MHz, D SO-d6) —(3—ピリジル）メトキシフエ二ル]ピロリジン一 δ 1.27, 1.40 (s, 9H), 1.76—1.92 (m, 3 2—カルボキサミド（化合物 6— 12) H), 2.14-2.21 (m， 1H), 3.29-3.43 (m, (R) — N— tert-Butoxycarbonyl N '-[4 1 H-NM (400 MHz, D SO-d 6 ) — (3-Pyridyl) methoxyphenyl] pyrrolidine δ 1.27, 1.40 (s, 9H ), 1.76—1.92 (m, 3 2-carboxamide (compound 6—12) H), 2.14-2.21 (m, 1H), 3.29-3.43 (m,
2H)， 4.13-4.22 (m, 1H), 5.11 (s, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.40-7.44 ( 2H), 4.13-4.22 (m, 1H), 5.11 (s, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.40-7.44 (
I V 。1 ) m， 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.8 人。 ° N 6 (d, J = 7.8 Hz, 1H), 8.54 (d, J = IV. 1) m, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.8 people. ° N 6 (d, J = 7.8 Hz, 1H), 8.54 (d, J =
4.9 Hz, 1H), 8.66 (d, J = 1.7 Hz, 1H) , 9.82 (s, 1H) 実施例 7  4.9 Hz, 1H), 8.66 (d, J = 1.7 Hz, 1H), 9.82 (s, 1H) Example 7
(R)—N— tert—ブトキシカルボ二ルー N' - (4一メルカプトフエニル）ピロリジン一 2—カル ポキサミド（化合物 7— 1)  (R) —N— tert-butoxycarbonyl N '-(4 mercaptophenyl) pyrrolidine 1 2-carboxamide (compound 7-1)
ビス [4— [(R)— (1—tert—ブトキシカルポニル）ピロリジン一 2-ィルカルポニルァミノ ]フエ二ノレ]ジス レフイド（参考 ί匕合物 5—1、 2. 50g、 3. 9mmol)をアセトン（30ml)、水 (8ml)、テトラヒドロフラン（8ml)および 1 , 4一ジォキサン（4ml)の混合溶液に溶解させ 、トリ一 n—ブチルホスフィン（1. 88mしフ. 6mmol)を加え、室温で 1時間攪拌した。減 圧下溶媒を留去した後、酢酸ェチル（100ml)および 5%クェン酸水溶液（200ml)を加 えて分配し、有機層を飽和食塩水（150ml)で洗浄した。有機層を無水硫酸ナトリウム で乾燥後、減圧下溶媒を留去した。得られた固体をへキサン一酢酸ェチル（2:1)の混 合溶媒で濾取することにより標記化合物（1. 86g)を白色固体として得た。（収率 74%) 1H-NMR (500 MHz, DMSO - d6) Bis [4 — [(R) — (1-tert-Butoxycarbonyl) pyrrolidine-1-ylcarbonylamino] phenenoyl] disreflex (reference compound 5–1, 2. 50 g, 3.9 mmol ) Is dissolved in a mixed solution of acetone (30 ml), water (8 ml), tetrahydrofuran (8 ml) and 1,4-dioxane (4 ml), tri-n-butylphosphine (1.88 m and 6 mmol) is added, Stir at room temperature for 1 hour. After distilling off the solvent under reduced pressure, ethyl acetate (100 ml) and 5% aqueous citrate solution (200 ml) were added and partitioned, and the organic layer was washed with saturated brine (150 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was filtered off with a mixed solvent of hexane monoethyl acetate (2: 1) to obtain the title compound (1.86 g) as a white solid. (Yield 74%) 1 H-NMR (500 MHz, DMSO-d 6 )
δ 1.26, 1.39 (s, 9H)， 1.76-1.91 (m, 3H) ， 2.12-2.21 (m, 1H), 3.32-3.43 (m, 2H), 4.14-4.24 (m, 1H), 5.23 (s, 1H), 7.23 (d, δ 1.26, 1.39 (s, 9H), 1.76-1.91 (m, 3H), 2.12-2.21 (m, 1H), 3.32-3.43 (m, 2H), 4.14-4.24 (m, 1H), 5.23 (s, 1H), 7.23 (d,
J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz,J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz,
2H), 9.94 (s, 1H) 以下、参考化合物 5— 2を使用し、化合物 7— 1の製造方法に準じて、化合物 7— 2を得 た。 2H), 9.94 (s, 1H) Hereinafter, Reference Compound 5-2 was used, and Compound 7-2 was obtained according to the production method of Compound 7-1.
Figure imgf000119_0001
実施例 8
Figure imgf000119_0001
Example 8
(R)— N— tert—ブトキシカルボニル一 N'— [4— (4—メトキシベンジルチオ）フエニル]ピ 口リジン一 2—力ルポキサミド（化合物 8— 1 )  (R) — N— tert-Butoxycarbonyl 1 N′— [4- (4-Methoxybenzylthio) phenyl] pi-lysine 1— Power Lupoxamide (Compound 8-1)
(R)— N_tert—ブトキシカルポニル一N'—（4—メルカプトフエニル）ピロリジン一 2 _ カルポキサミド（化合物 7— 1、 202mg、 0. 62mmol)を N， N—ジメチルホルムアミド（3 ml)に溶解し、炭酸カリウム（264mg, 1. 9mmol)、 4ーメトキシベンジルクロリド（170 l、 1. 3mmol)を加え、 60度で 1. 5時間攪拌した。放冷後、反応液に酢酸ェチル（70 ml)および水（100ml)を加え分配し、有機層を飽和食塩水（ 1 OOml)で洗浄した。有機 層を無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残留物をシリカゲ ルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することにより標記化合物を 無色油状物（262mg)として得た。（収率 94%) (R) — N_tert-butoxycarbonyl-1-N ′-(4-mercaptophenyl) pyrrolidine-1-2_carboxamide (compound 7-1, 202 mg, 0.62 mmol) was dissolved in N, N-dimethylformamide (3 ml). , Potassium carbonate (264 mg, 1.9 mmol) and 4-methoxybenzyl chloride (170 l, 1.3 mmol) were added, and the mixture was stirred at 60 ° C. for 1.5 hours. After allowing to cool, ethyl acetate (70 ml) and water (100 ml) were added to the reaction solution for partitioning, and the organic layer was washed with saturated brine (1 OOml). The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the title compound as a colorless oil (262 mg). (Yield 94%)
1H-N R (500 MHz, DMSO-d6) 1 HN R (500 MHz, DMSO-d 6 )
δ 1.26, 1.39 (s, 9Η), 1.76-1.91 (m, 3 H), 2.15-2.21 (m, 1H), 3.29 - 3.43 (m, 2H), 3.71 (s, 3H), 4.09, 4.10 (s, 2H), 4.14-4.24 (m, 1 H)， 6.83 (d, J = 8.6 H z, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.2 7 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8 J Hz, 2H)， 9.98, 9.99 (s, 1 H) 以下、化合物 7— 1、 7— 2および市販化合物から選択される化合物を使用し、化合物 8 —1の製造方法に準じて、化合物 8— 2 ~ 8— 22を得た。 δ 1.26, 1.39 (s, 9Η), 1.76-1.91 (m, 3 H), 2.15-2.21 (m, 1H), 3.29-3.43 (m, 2H), 3.71 (s, 3H), 4.09, 4.10 (s , 2H), 4.14-4.24 (m, 1 H), 6.83 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.2 7 (d, J = 8.7 Hz, 2H), 7.53 ( d, J = 8 J Hz, 2H), 9.98, 9.99 (s, 1 H) or less, and using a compound selected from Compound 7-1, 7-2 and a commercially available compound, Accordingly, compounds 8-2 to 8-22 were obtained.
Figure imgf000120_0001
Figure imgf000120_0001
8 6.97 (d, J = 8.1 Hz, 1H), 7.14 (d, J 8 6.97 (d, J = 8.1 Hz, 1H), 7.14 (d, J
= 7.3 Hz, 1H), 7.19-7.25 (m, 1H), 7. 27 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H)， 9.99 (s, 1H) = 7.3 Hz, 1H), 7.19-7.25 (m, 1H), 7.27 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 9.99 (s, 1H)
Figure imgf000121_0001
Figure imgf000121_0001
(R) N— tert—ブトキシカルボ二ルー N' -[4 'Η - NMR (500 MHz, DMSO-d6) —(3—メトキシベンジルチオ）フエ.ニル]ピロリジ δ 1.26, 1.39 (s, 9H), 1,76 - 1.91 (m, 3 ンー 2—カルボキサミド（化合物 8— 7) H)， 2.10-2.21 (m, 1H), 3.29-3.43 (m, (R) N— tert-Butoxycarbonyl N '-[4' Η-NMR (500 MHz, DMSO-d 6 ) — (3-Methoxybenzylthio) phenyl.pyrrolid δ 1.26, 1.39 (s, 9H ), 1,76-1.91 (m, 3-2-carboxamide (compound 8-7) H), 2.10-2.21 (m, 1H), 3.29-3.43 (m,
2H), 3.69 (s, 3H), 4.13 (s, 2H)， 4.14— 4.24 (m, 1H), 6.78 (d, J = 7.6 Hz, 1 H), 6.83-6.86 (m, 2H), 7.18 (t, J = 7.
Figure imgf000121_0002
6 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 2H), 3.69 (s, 3H), 4.13 (s, 2H), 4.14— 4.24 (m, 1H), 6.78 (d, J = 7.6 Hz, 1 H), 6.83-6.86 (m, 2H), 7.18 ( t, J = 7.
Figure imgf000121_0002
6 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H),
7.53 (d, J = 8.7 Hz, 2H), 9.99 (s, 1H )  7.53 (d, J = 8.7 Hz, 2H), 9.99 (s, 1H)
(R)— N— tert—ブトキシカルポ二ルー N' -[4 1H - NMR (500 MHz, D SO-d6) —(2—ピリジルメチルチオ）フエニル]ピロリジン δ 1,25， 1.39 (s, 9H), 1.76-1.91 (m, 3 —2—力ルポキサミド（化合物 8— 8) H), 2.15-2.21 (m, 1H), 3.29-3.43 (m, (R) — N— tert-Butoxycarbonyl N '-[4 1 H -NMR (500 MHz, D SO-d 6 ) — (2-Pyridylmethylthio) phenyl] pyrrolidine δ 1,25, 1.39 (s, 9H ), 1.76-1.91 (m, 3 —2—force lupoxamide (compound 8—8) H), 2.15-2.21 (m, 1H), 3.29-3.43 (m,
2H), 4.14-4.25 (m, 3H), 7.21-7.24 (m, 2H), 4.14-4.25 (m, 3H), 7.21-7.24 (m,
1H)， 7.29 (d, J = 8.6 Hz, 2H), 7.32- 7.35 (m, 1H), 7,52 (d, J = 8.6 Hz, 2
Figure imgf000121_0003
H), 7.70 (t, J = 7.6 Hz, 1H)， 8,46 (d, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.32- 7.35 (m, 1H), 7,52 (d, J = 8.6 Hz, 2
Figure imgf000121_0003
H), 7.70 (t, J = 7.6 Hz, 1H), 8,46 (d,
J = 4.9 Hz, 1H), 9.98 (s, 1 H) J = 4.9 Hz, 1H), 9.98 (s, 1 H)
(R)—N— tert—ブトキシカルポ二ルー N'— [4 1H-N R (500 MHz, DMSO-d6) 一（3—ピリジルメチルチオ）フエニル]ピロリジン δ 1.25, 1.39 (s, 9Η)， 1.77-1.91 (m, 3 一 2—カルボキサミド（化合物 8— 9) Η), 2.13-2.21 (m, 1Η), 3.28-3.43 (m, (R) —N— tert-butoxycarbonyl N′— [4 1 HN R (500 MHz, DMSO-d 6 ) mono (3-pyridylmethylthio) phenyl] pyrrolidine δ 1.25, 1.39 (s, 9Η), 1.77- 1.91 (m, 3 1 2-carboxamide (compound 8-9) Η), 2.13-2.21 (m, 1Η), 3.28-3.43 (m,
2H)， 4.02-4.24 (m, 3H)， 7.28 (d, J = 8.7 Hz, 2H), 7.26-7.30 (m, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 7.9
Figure imgf000121_0004
Hz, 1H), 8.39 (dd, J = 4.9, 1.8 Hz, 2H), 4.02-4.24 (m, 3H), 7.28 (d, J = 8.7 Hz, 2H), 7.26-7.30 (m, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 7.9
Figure imgf000121_0004
Hz, 1H), 8.39 (dd, J = 4.9, 1.8 Hz,
1H), 8.41 (d, J = 1.8 Hz, 1H)， 10.00 (s, 1H)  1H), 8.41 (d, J = 1.8 Hz, 1H), 10.00 (s, 1H)
(R)—N— tert—ブトキシカルポニル一 N'—[4 1H-NMR (400 MHz, DMSO - d6) —(4一ピリジルメチルチオ）フエニル]ピロリジン 6 1.25, 1.39 (ε, 9Η)， 1.75 - 1.90 (m, 3 —2—力ルポキサミド（化合物 8— 10) Η), 2.14-2.21 (m, 1Η), 3.29-3.43 (m， (R) —N— tert-butoxycarbonyl 1 N ′ — [4 1 H-NMR (400 MHz, DMSO-d 6 ) — (4 monopyridylmethylthio) phenyl] pyrrolidine 6 1.25, 1.39 (ε, 9Η), 1.75 -1.90 (m, 3 -2—force lupoxamide (compound 8-10) Η), 2.14-2.21 (m, 1Η), 3.29-3.43 (m,
2H)， 4.13-4.23 (m, 3H), 7.24-7.29 (m, 4H), 7.53 (d, J = 8.8 Hz, 2H), 8.42- 8.45 (m, 2H), 10.01 (s, 1H) 2H), 4.13-4.23 (m, 3H), 7.24-7.29 (m, 4H), 7.53 (d, J = 8.8 Hz, 2H), 8.42-8.45 (m, 2H), 10.01 (s, 1H)
Figure imgf000121_0005
Figure imgf000121_0005
(R)—N— tert—ブトキシカルボ二ルー N'—[4 1H-N R (400 MHz, DMSO - d6) (R) —N— tert—Butoxycarbonyl N '— [4 1 HN R (400 MHz, DMSO-d 6 )
一（キノリン一 4ーィルメチルチオ）フエニル]ピロ δ 1.26, 1.39 (s, 9Η), 1.75—1.90 (m, 3 リジン一 2—カルポキサミド（化合物 8—11) H), 2.15-2.21 (m, 1H)， 3.32-3.44 (m, Mono (quinoline-4-ylmethylthio) phenyl] pyro δ 1.26, 1.39 (s, 9Η), 1.75—1.90 (m, 3 lysine 2-carboxamide (compound 8-11) H), 2.15-2.21 (m, 1H), 3.32-3.44 (m,
2H), 4.13 - 4,23 (m, 1H), 4.64, 4.65 (s, 2H), 7.25-7.30 (m, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2 H), 7.62-7.68 (m, 1H), 7.75-7.79 (m,
Figure imgf000121_0006
1H), 8.02 (d, J = 8.3 Hz, 1H), 8.26 ( d, J = 8.1 Hz, 1H)， 8.70-8.73 (m, 1H ), 10.02, 10,03 (s, 1H) 2H), 4.13-4,23 (m, 1H), 4.64, 4.65 (s, 2H), 7.25-7.30 (m, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2 H), 7.62-7.68 (m, 1H), 7.75-7.79 (m,
Figure imgf000121_0006
1H), 8.02 (d, J = 8.3 Hz, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.70-8.73 (m, 1H), 10.02, 10,03 (s, 1H)
19 3 19 Three
(s,  (s,
3 Three
= 7. = 7.
1.9 3.3 1.9 3.3
(m, 5 7. (m, 5 7.
Figure imgf000122_0001
Figure imgf000122_0001
20
Figure imgf000123_0001
実施例 9 20
Figure imgf000123_0001
Example 9
(R)— N— tert—ブトキシカルポ二ルー N'—（6—ベンジルチオ一 3—ピリジル）ピロリジン 一 2—カルポキサミド（化合物 9— 1)  (R) — N— tert-Butoxycarbonyl N ′ — (6-Benzylthio-1-3-pyridyl) pyrrolidine 1-2-carboxamide (Compound 9-1)
(R)—N— tert—ブトキシカルボ二ルー N'—（6—クロロー 3—ピリジル）ピロリジン一 2 —カルポキサミド（化合物 1一 54、 298mg, 0. 915mmol)の N, N—ジメチルホルムァ ミド（5ml)溶液を 10分間窒素バブリングした後、窒素雰囲気下、炭酸カリウム（304mg , 2. 20mmol)、ベンジルメルカプタン（129 il, 1. 1 Ommol)をカロえ、 100度でー晚撹 拌した。反応液に酢酸ェチル（50ml)、ジェチルエーテル（50ml)を加え、水（100mし 3 回）、飽和食塩水（ 150 m I )で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を 留去し、得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で 精製することにより標記化合物（118mg)を無色固体で得た。（収率 31%) (R) —N— tert-Butoxycarbonyl N '— (6-Chloro-3-pyridyl) pyrrolidine 1 2 —Carpoxamide (Compound 1-154, 298 mg, 0.915 mmol) in N, N-dimethylformamide (5 ml) was bubbled with nitrogen for 10 minutes, then potassium carbonate (304 mg , 2.20 mmol) under a nitrogen atmosphere, Benzyl mercaptan (129 il, 1.1 Ommol) was added and stirred at 100 degrees. Ethyl acetate (50 ml) and jetyl ether (50 ml) were added to the reaction solution, washed with water (100 ml, 3 times) and saturated brine (150 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the title compound (118 mg) as a colorless solid. (Yield 31%)
Figure imgf000124_0001
以下、化合物 1一 54および市販化合物から選択される化合物を使用し、化合物 9—1の 製造方法に準じて、化合物 9_2〜9— 3を得た。
Figure imgf000124_0001
Hereinafter, compounds 9_2 to 9-3 were obtained according to the production method of compound 9-1 using compounds selected from Compound 1-154 and commercially available compounds.
Figure imgf000124_0002
Figure imgf000124_0002
22 実施例 10 twenty two Example 10
(R)— N— tert—ブトキシカルポ二ルー N'— [4— [2— (4—トリフルォロメチルフエニル） 一 1—ェチニル]フエニル]ピロリジン一 2—カルポキサミド（化合物 10— 1)  (R) — N— tert-Butoxycarbonyl N′— [4— [2— (4-Trifluoromethylphenyl) 1-ethynyl] phenyl] pyrrolidine 1 2-carboxamide (Compound 10-1)
(R)— N— tert—ブトキシカルポニル一 N'—（4—ェチニルフエニル）一ピロリジン一 2— カ レボキサミド（化合物 1—113、 315mg、 1 - OOmmol)、 4—ョ一ドベンゾ卜リフ レオリ ド（273mg、 1. OOmmol)を N, N—ジメチノレホノレムアミド（3, 5ml)に;、容角 し、トリェチ レ ァミン（3. 5ml)、'ようィ匕銅（ I ) (20. 4mg、 0. 1 Ommol)、テ卜ラキス（卜リフエニノレホスフ イン）パラジウム（0) (116mg, 0. 1 Ommol)を加え、室温で一晩攪拌した。反応液に酢 酸ェチル（80ml)、エーテル（80ml)と水（160ml)を加えて分配し、有機層を水（160m I )、飽和食塩水（ 160 m I )で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥後、 減圧下溶媒を留去した。得られた残留物をシリカゲルカラムク口マトグラフィ一（へキサン 一酢酸ェチル）で精製することにより標記化合物（419mg)を白色固体として得た。（収 率 92%)  (R) — N-tert-butoxycarbonyl 1 N ′ — (4-ethynylphenyl) 1 pyrrolidine 1 2-carboxamide (compound 1-113, 315 mg, 1-OOmmol), 4-iodobenzoyl fluoride (273 mg) 1. OOmmol) into N, N-Dimethinorephonolemamide (3, 5ml); Diagonal, Tolyreamine (3.5ml), 'Iodine Copper (I) (20.4mg, 0 0.1 Ommol), tetrakis (卜 lienorephosphine) palladium (0) (116 mg, 0.1 Ommol) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (80 ml), ether (80 ml) and water (160 ml) were added to the reaction solution for partitioning, and the organic layer was washed successively with water (160 ml) and saturated brine (160 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate) to give the title compound (419 mg) as a white solid. (Yield 92%)
Figure imgf000125_0001
以下、化合物 1一 56、 1一 57、 1—113、 1一 173、 14、參考ィ匕合物 17— 1〜27、 18 — 1、 18— 2、 19、 22、 25、 26— 1、 26— 2、 27— 1、 27— 2および市販化合物から選 択される化合物を使用し、化合物 10— 1の製造方法に準じて、化合物 10— 2~10— 1 45を得た。
Figure imgf000125_0001
Compounds 1-56, 1-157, 1-113, 1-173, 14, Considered compounds 17-1-27, 18--1, 18-2, 19, 22, 25, 26-1, Using compounds selected from 26-2, 27-1, 27-2 and commercially available compounds, compounds 10-2 to 10-145 were obtained according to the production method of compound 10-1.
(R)—N— tert—ブトキシカルボ二ルー N'— [4— ( H-N R (500MHz, DMSO-d6) 2—フエ二ルー 1—ェチニル）フエニル]ピロリジン一 δ 1.27, 1.40 (s, 9Η), 1.76-1.94 (m 2—カルボキサミド（化合物 10— 2) (R) —N— tert-butoxycarbonyl N'— [4— (HN R (500 MHz, DMSO-d 6 ) 2-phenyl-2-phenyl) pyrrolidine δ 1.27, 1.40 (s, 9Η ), 1.76-1.94 (m 2 -carboxamide (compound 10-2))
23 (m, twenty three (m,
(m, (m,
(m, (m,
1.94 (m, 1.94 (m,
(m, (m,
(m 3.41
Figure imgf000126_0001
Figure imgf000127_0001
(m 3.41
Figure imgf000126_0001
Figure imgf000127_0001
2 5
Figure imgf000128_0001
Figure imgf000129_0001
-25) 3-2.25 (m, 1H), 2.88-2.95 (m, 1H), twenty five
Figure imgf000128_0001
Figure imgf000129_0001
-25) 3-2.25 (m, 1H), 2.88-2.95 (m, 1H),
3.30-3.45 (m, 2H), 4.18-4.27 (m, 1H H へ  3.30-3.45 (m, 2H), 4.18-4.27 (m, to 1H H
), 7.29 (d, J = 8.2 Hz, 2H), 7.45 ( d, J = 8.2 Hz, 2H), 7.48 (d, J = 8. 7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H ), 10.17, 10.18 (s, 1H)  ), 7.29 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H) ), 10.17, 10.18 (s, 1H)
(R)—N—tert—ブトキシカルポ二ルー Ν'— [4— [ 1H-NMR (500 MHz, DMSO-d6) 2—（4一べンジルフエ二ル）一 1ーェチニル]フエ二 δ 1.26, 1.40 (s, 9H), 1.78-1.92 (m, ル]ピロリジン一2—カルボキサミド（化合物 10— 2 3H), 2.17-2.23 (m, 1H), 3.29-3.44 6) (m, 2H), 3.97 (s, 2H), 4.18-4.27 (m, (R) —N—tert-Butoxycarbonyl Ν'— [4— [ 1 H-NMR (500 MHz, DMSO-d 6 ) 2— (4 monophenyl) 1 1-ethynyl] phen δ 1.26, 1.40 (s, 9H), 1.78-1.92 (m, ru] pyrrolidine 2-carboxamide (compound 10— 2 3H), 2.17-2.23 (m, 1H), 3.29-3.44 6) (m, 2H), 3.97 ( s, 2H), 4.18-4.27 (m,
1H)， 7.20 (t, J = 7.2 Hz, 1H)， 7.2 3-7.31 (m, 6H), 7.44 (d, J = 7.9 H z， 2H), 7.48 (d, J = 8.6 Hz, 2H), 7 .66 (d, J = 8.6 Hz, 2H), 10.16 (s, 1H)  1H), 7.20 (t, J = 7.2 Hz, 1H), 7.2 3-7.31 (m, 6H), 7.44 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 10.16 (s, 1H)
(R)— N—tert—ブトキシカルボニル一 N'— [4_[ 1H-NMR (400 MHz, DMSO - d6) 2—（4— n—プロポキシフエニル）一 1ーェチニル] 0 0.98 (t， J = 6.9 Hz, 3H), 1.27, フエニル]ピロリジン一 2—カルボキサミド（化合物 1 1.40 (s, 9H)， 1.73 (sextet, J = 6.9 0— 2フ） Hz, 2H), 1.84 - 1.95 (m, 3H), 2.18-2. (R) — N—tert-butoxycarbonyl 1 N′— [4_ [ 1 H-NMR (400 MHz, DMSO-d 6 ) 2— (4-n-propoxyphenyl) 1 1-ethynyl] 0 0.98 (t, J = 6.9 Hz, 3H), 1.27, phenyl] pyrrolidine 1-carboxamide (compound 1 1.40 (s, 9H), 1.73 (sextet, J = 6.9 0—2F) Hz, 2H), 1.84-1.95 (m, 3H), 2.18-2.
H へ 22 (m, 1H), 3.30-3.45 (m, 2H), 3.96  H to 22 (m, 1H), 3.30-3.45 (m, 2H), 3.96
(t, J = 6.9 Hz, 2H), 4.18-4.27 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.4 4 (d, J = 8.5 Hz, 2H)， 7.46 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 10.15, 10.16 (s, 1H)  (t, J = 6.9 Hz, 2H), 4.18-4.27 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.4 4 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 10.15, 10.16 (s, 1H)
(R)—N—tert—ブトキシカルポニル一 N'— [4一 [ 'H-NMR (400 MHz, DMSO - d6) 2— (4— n—ブトキシフエ二ル）一 1—ェチニル]フエ δ 0.93 (t, J = 7.3 Hz, 3H), 1.27, ニル]ピロリジン一 2—カルボキサミド（化合物 10— 1.40 (s, 9H), 1.40-1.48 (m, 2H), 1.6 28) 7-1.74 (m, 2H)， 1.79-1.89 (m， 3H), (R) —N—tert-Butoxycarbonyl N′— [4 I ['H-NMR (400 MHz, DMSO-d 6 ) 2— (4- n-Butoxyphenyl) mono 1-ethynyl] Hue δ 0.93 (t, J = 7.3 Hz, 3H), 1.27, nyl] pyrrolidine mono 2-carboxamide (compound 10— 1.40 (s, 9H), 1.40-1.48 (m, 2H), 1.6 28) 7-1.74 (m, 2H ), 1.79-1.89 (m, 3H),
2.15-2.22 (m, 1H), 3.30-3.45 (m， 2H ), 4.00 (t, J = 6.5 Hz, 2H), 4.18-4. 26 (m, 1H), 6.96 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H)， 7.65 (d, J = 8.5 Hz, 2H), 10.15, 10.16 (s, 1H) 2.15-2.22 (m, 1H), 3.30-3.45 (m, 2H), 4.00 (t, J = 6.5 Hz, 2H), 4.18-4. 26 (m, 1H), 6.96 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 10.15, 10.16 (s, 1H)
(R)—N—tert—ブトキシカルポ二ルー N'—[4— [ H-NMR (400 MHz, DMSO - d6) 2— (4— n—ペンチルォキシフエニル）一 1一ェチニ δ 0.89 (t, J = 7.2 Hz, 3H), 1.27， ル]フエニル]ピロリジン一 2—カルボキサミド（化合 1.40 (s, 9H), 1.25-1.40 (m， 4H), 1.6 物 10— 29) 8-1.90 (m, 5H), 2.15-2.25 (m, 1H), (R) —N—tert-butoxycarbonyl N '— [4— [H-NMR (400 MHz, DMSO-d 6 ) 2— (4— n-pentyloxyphenyl) 1 1 1 echini δ 0.89 ( t, J = 7.2 Hz, 3H), 1.27, Ru] phenyl] pyrrolidine 1-carboxamide (compound 1.40 (s, 9H), 1.25-1.40 (m, 4H), 1.6 compound 10-29) 8-1.90 (m , 5H), 2.15-2.25 (m, 1H),
3.29-3.45 (m, 2H), 3.99 (t, J = 6.6 Hz, 2H), 4.18-4.27 (m, 1H), 6.96 ( d, J = 8.8 Hz, 2H), 7.44 (d, J = 8. 8 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H )， 7.65 (d, J = 8.5 Hz, 2H), 10.15, 10.16 (s, 1H)  3.29-3.45 (m, 2H), 3.99 (t, J = 6.6 Hz, 2H), 4.18-4.27 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8. 8 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 10.15, 10.16 (s, 1H)
(R)—N—tert—ブトキシカルポ二ルー N'— [4— [ 1H-NMR (500 MHz, DMSO - d6) 2—（4一 n—へキシルォキシフエニル）一 1—ェチ二 δ 0.88 (t, J = 7.2 Hz, 3H)， 1.23—1 ル]フエニル]ピロリジン一 2—力ルポキサミド（化合 ■43 (m, 6H), 1.27, 1,40 (s, 9H), 1.6 物 10— 30) 8-1.74 (m, 2H)， 1.77-1.93 (m, 3H), (R) —N—tert-Butoxycarbonyl N'— [4— [ 1 H-NMR (500 MHz, DMSO -d 6 ) 2— (4 n-Hexyloxyphenyl) 1 1 -eth 2 δ 0.88 (t, J = 7.2 Hz, 3H), 1.23-1 ru] phenyl] pyrrolidine 1-strength lupoxamide (compound ■ 43 (m, 6H), 1.27, 1,40 (s, 9H), 1.6 10—30) 8-1.74 (m, 2H), 1.77-1.93 (m, 3H),
28
Figure imgf000131_0001
28
Figure imgf000131_0001
2 9
Figure imgf000132_0001
2 9
Figure imgf000132_0001
3 0 (m, 3 0 (m,
(m， 3 (m, 3
(m, (m,
(m， (m,
） )
1.89 (m,  1.89 (m,
— —
(m,
Figure imgf000133_0001
(m,
Figure imgf000133_0001
31 (m, 31 (m,
3  Three
(m, (s, 3 (m, (s, 3
d6) d 6 )
(m, (s, 3  (m, (s, 3
1.35, ， 2.1 1.35,, 2.1
d6) d 6 )
(m,  (m,
Figure imgf000134_0001
Figure imgf000134_0001
3 2 8.5 Hz, 2H), 10.19 (s, 1H)
Figure imgf000135_0001
3 2 8.5 Hz, 2H), 10.19 (s, 1H)
Figure imgf000135_0001
(R)— N— tert—ブトキシカルボニル一 N'— [4— [ H-NMR (400 MHz, DMSO - d6) 2—（4ーメトキシメトキシフエ二ル）ー1ーェチニル] δ 1.27, 1.40 (s, 9H), 1.78-1.89 (m, フエニル]ピロリジン一 2—力ルポキサミド（化合物 1 3H), 2.15-2.24 (m, 1H), 3.30-3,45 0-52) (m, 2H), 3.32 (s, 3H), 4.18-4.27 (m, (R) — N— tert-butoxycarbonyl 1 N′— [4— [1 H-NMR (400 MHz, DMSO-d 6 ) 2— (4-methoxymethoxyphenyl) -1-ethynyl] δ 1.27, 1.40 ( s, 9H), 1.78-1.89 (m, phenyl) pyrrolidine 1-2-streptoxamide (compound 1 3H), 2.15-2.24 (m, 1H), 3.30-3,45 0-52) (m, 2H), 3.32 (s, 3H), 4.18-4.27 (m,
1H)， 5.23 (s, 2H)， 7.05 (d, J = 8. 7 Hz, 2H), 7,47 (d, J = 8.7 Hz, 2H ), 7.47 (d, J = 8.8 Hz, 2H), 7.65 ( 。 ° l cT° d, J = 8,8 Hz, 2H)， 10.16 (s, 1H)  1H), 5.23 (s, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7,47 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.65 (. ° l cT ° d, J = 8,8 Hz, 2H), 10.16 (s, 1H)
(R)—N—tert—ブトキシカルポニル一 N'—[4一 [ 1H-NMR (400 MHz, DMSO— d6 ) 2— (4—イソプロポキシ一3—メチルフエ二ル）一 1 δ 1.27, 1.40 (s, 9H), 1,28 (d, J = ーェチニル]フエニル]ピロリジン一 2—カルボキサ 5.9 Hz, 6H), 1.78-1.89 (m, 3H), 2. ミド（化合物 10— 53) 12 (s, 3H)， 2.20-2.22 (m, 1H), 3.2 (R) —N—tert-butoxycarbonyl 1 N ′ — [4 1 [ 1 H-NMR (400 MHz, DMSO—d 6 ) 2— (4-Isopropoxy 3-methylphenyl) 1 1 δ 1.27, 1.40 (s, 9H), 1,28 (d, J = ethynyl] phenyl] pyrrolidine 1-carboxa 5.9 Hz, 6H), 1.78-1.89 (m, 3H), 2. Mido (compound 10- 53) 12 ( s, 3H), 2.20-2.22 (m, 1H), 3.2
9-3.45 (m， 2H), 4.17-4.27 (m, 1H)， 9-3.45 (m, 2H), 4.17-4.27 (m, 1H),
, " ^^ 4.60-4.67 (m, 1H), 6.97 (d， J = 9.3 , "^^ 4.60-4.67 (m, 1H), 6.97 (d, J = 9.3
Hz, 1H), 7.29-7.32 (m, 2H), 7.45 ( Hz, 1H), 7.29-7.32 (m, 2H), 7.45 (
^0人。。 \ ο d, J = 8.8 Hz, 2H), 7.65 (d, J = 8. ^ 0 people. . \ ο d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.
8 Hz, 2H), 10.15, 10.16 (s, 1H) 8 Hz, 2H), 10.15, 10.16 (s, 1H)
(R)— N— tert—ブトキシカルボ二ルー N'— [4一 [ 1H-N R (500 MHz, DMSO - d6 ) 2— (4—べンジルォキシ _3—メチルフエニル）一 1 δ 1.27, 1.40 (s, 9H), 1.78-1.93 (m, ーェチニル]フエニル]ピロリジン一 2—カルボキサ 3H), 2.17-2.23 (m, 1H), 2.20 (s, 3 ミド（化合物 10— 54) H), 3.30-3.45 (m, 2H), 4.18-4.27 (m (R) — N— tert-butoxycarbonyl N'— [4 1 [ 1 HN R (500 MHz, DMSO-d 6 ) 2— (4-Benzyloxy _3-methylphenyl) 1 δ 1.27, 1.40 (s , 9H), 1.78-1.93 (m, ethynyl] phenyl] pyrrolidine mono 2-carboxa 3H), 2.17-2.23 (m, 1H), 2.20 (s, 3 amide (compound 10-54) H), 3.30-3.45 ( m, 2H), 4.18-4.27 (m
， 1H), 5.17 (s, 2H)， 7.05 (d, J = 8. 6 Hz, 1H), 7.32-7.35 (m, 3H)， 7.41 (t, J = 7.5 Hz, 2H), 7.43-7.48 (m,
Figure imgf000135_0002
4H), 7.65 (dd, J = 8.7, 2.0 Hz, 2H) , 1H), 5.17 (s, 2H), 7.05 (d, J = 8.6 Hz, 1H), 7.32-7.35 (m, 3H), 7.41 (t, J = 7.5 Hz, 2H), 7.43-7.48 ( m,
Figure imgf000135_0002
4H), 7.65 (dd, J = 8.7, 2.0 Hz, 2H)
， 10.15, 10.16 (s, 1H)  , 10.15, 10.16 (s, 1H)
(R)—N—tert—ブトキシカルボ二ルー N'— [4— [ 1H - NMR (400 MHz, DMSO - d6) 2— [4— (キノリン _4一ィルメトキシ）フエニル]一 δ 1.27, 1.40 (s, 9H), 1.79-1.89 (m， 1ーェチニル]フエニル]ピロリジン一 2—カルボキ 3H), 2.17 - 2.22 (m, 1H), 3.30-3.43 サ Sド"匕合物 10— 55) (m, 2H), 4.18-4.28 (m, 1H), 5.73 ( s, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7 .48 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.64-7.71 (m, 2H),
Figure imgf000135_0003
7.66 (d, J = 8.9 Hz, 2H)， 7.79-7.84 (R) —N—tert-Butoxycarbonyl N'— [4— [ 1 H-NMR (400 MHz, DMSO-d 6 ) 2— [4— (Quinolin_4 monomethoxy) phenyl] δ 1.27, 1.40 (s, 9H), 1.79-1.89 (m, 1-ethynyl] phenyl] pyrrolidine 1-carboxy 3H), 2.17-2.22 (m, 1H), 3.30-3.43 S compound "10- 55) (m , 2H), 4.18-4.28 (m, 1H), 5.73 (s, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.64-7.71 (m, 2H),
Figure imgf000135_0003
7.66 (d, J = 8.9 Hz, 2H), 7.79-7.84
(m, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.93 (d, J = 4.2 Hz, 1H), 10.16 (s, 1H) (m, 1H), 8.09 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.93 (d, J = 4.2 Hz, 1H), 10.16 (s, 1H)
(R)— N—tert—ブトキシカルボ二ルー N'— [4— [ 1H-NMR (500 MHz, DMSO - d6) 2—（4—フエノキシカルボニルォキシフエ二ル）一 1 δ 1.27, 1.40 (s, 9H), 1.78-1.93 (m, ーェチニル]フエニル]ピロリジン一 2—カルボキサ 3H), 2.15-2.24 (m，. 1H), 3.28-3.45 Sド、（化合物 10— 56) (m, 2H), 4.18-4.28 (m, 1H), 7.34 ( t, J = 7.3 Hz, 1H), 7.40 (d, J = 8. 7 Hz, 2H), 7.44-7.53 (m, 6H), 7.63 (d, J = 8.9 Hz, 2H), 7.68 (d, J =
Figure imgf000136_0001
2— (3—べンジルォキシフエ二ル）一 1—ェチニル] δ 1.27, 1.40, (s, 9H), 1.79-1.99 (m フエニル]ピロリジン一 2—カルボキサミド（化合物 1 ， 3H), 2.21-2.22 (m， 1H), 3.35-3.45 0-62) (m, 2H), 4.18-4.28 (m, 1H), 5.15 ( s, 2H), 7.06 (d, J = 8.3 Hz, 1H)， 7 .11 (d, J = 6.4 Hz, 1H), 7.16 (s, 1 H)， 7.31-7.36 (m, 2H), 7.40 (t, J =(R) — N—tert-butoxycarbonyl N′— [4— [ 1 H-NMR (500 MHz, DMSO-d 6 ) 2— (4-phenoxycarbonyloxyphenyl) 1 1 δ 1.27, 1.40 (s, 9H), 1.78-1.93 (m, ethynyl] phenyl] pyrrolidine 1-carboxa 3H), 2.15-2.24 (m, .1H), 3.28-3.45 S, (compound 10-56) ( m, 2H), 4.18-4.28 (m, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.44-7.53 (m, 6H), 7.63 (d, J = 8.9 Hz, 2H), 7.68 (d, J =
Figure imgf000136_0001
2- (3-Benzyloxyphenyl) 1-ethynyl] δ 1.27, 1.40, (s, 9H), 1.79-1.99 (m phenyl) pyrrolidine 1 2-carboxamide (compound 1, 3H), 2.21-2.22 (m , 1H), 3.35-3.45 0-62) (m, 2H), 4.18-4.28 (m, 1H), 5.15 (s, 2H), 7.06 (d, J = 8.3 Hz, 1H), 7.11 (d , J = 6.4 Hz, 1H), 7.16 (s, 1 H), 7.31-7.36 (m, 2H), 7.40 (t, J =
7.3 Hz, 2H), 7.45-7.48 (m ,2H), 7.
Figure imgf000137_0001
50 (d, J = 8.8 Hz, 2H), 7.67 (d， J 7.3 Hz, 2H), 7.45-7.48 (m 2H), 7.
Figure imgf000137_0001
50 (d, J = 8.8 Hz, 2H), 7.67 (d, J
= 8.8 Hz, 2H), 10.19 (s, 1H) = 8.8 Hz, 2H), 10.19 (s, 1H)
(R)—N—tert—ブトキシカルボ二ルー N'— [4一 [ 1H-NMR (500 MHz, DMSO - d6) 2— [3— (4—フルオロフエノキシ）フエニル ]一 1一 δ 1.26, 1.40 (s, 9H)， 1.78-1.92 (m, ェチニル]フエニル]ピロリジン一 2—カルボキサミド 3H), 2.17-2.23 (m, 1H), 3.30-3.44 (化合物 10— 63) (m, 2H), 4.18-4.27 (m, 1H), 7.03-7. (R) —N—tert-butoxycarbonyl N′— [4 1 [ 1 H-NMR (500 MHz, DMSO -d 6 ) 2— [3— (4-Fluorophenoxy) phenyl] 1 1 1 δ 1.26, 1.40 (s, 9H), 1.78-1.92 (m, ethynyl] phenyl] pyrrolidine mono 2-carboxamide 3H), 2.17-2.23 (m, 1H), 3.30-3.44 (compound 10- 63) (m, 2H ), 4.18-4.27 (m, 1H), 7.03-7.
05 (m， 2H), 7.12-7.16 (m， 2H)， 7.2 4—7,29 (m, 3H), 7.42 (t, J = 7.8 H 。 z, 1H)， 7.49 (d, J = 8.6 Hz, 2H)， 7 • 66 (d, J = 8.6 Hz, 2H), 10.18, 10. 19 (s, 1H)  05 (m, 2H), 7.12-7.16 (m, 2H), 7.2 4—7, 29 (m, 3H), 7.42 (t, J = 7.8 H. z, 1H), 7.49 (d, J = 8.6 Hz , 2H), 7 • 66 (d, J = 8.6 Hz, 2H), 10.18, 10. 19 (s, 1H)
(R)一 N—tert—ブトキシカルボ二ルー N'— [4— [ 1H-N R (500 MHz, DMSO - d6) 2—（4—ァセチルァミノフエニル）一 1—ェチニル] δ 1.27, 1.40 (s, 9H), 1.78-1.95 (m, フエニル]ピロリジン一 2—カルポキサミド（化合物 1 3H)， 2.06 (s, 3H), 2,15 - 2.22 (m, 1 0-64) H), 3.30-3.45 (m, 2H)， 4.18-4.27 (m n H , 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.(R) -N-tert-Butoxycarbonyl N'— [4— [ 1 HN R (500 MHz, DMSO -d 6 ) 2— (4-acetylaminophenyl) -1-1-ethynyl] δ 1.27, 1.40 (s, 9H), 1.78-1.95 (m, phenyl) pyrrolidine 1-carboxamide (compound 1 3H), 2.06 (s, 3H), 2,15-2.22 (m, 1 0-64) H), 3.30 -3.45 (m, 2H), 4.18-4.27 (mn H , 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.
' ^^ 47 (d, J = 8.6 Hz, 2H), 7.63 (d， J 广 0  '^^ 47 (d, J = 8.6 Hz, 2H), 7.63 (d, J 广 0
。。 = 8.6 Hz, 2H), 7.66 (d, J = 8.6 H z, 2H), 10.11 (s, 1H), 10.16 (s, 1H) . . = 8.6 Hz, 2H), 7.66 (d, J = 8.6 H z, 2H), 10.11 (s, 1H), 10.16 (s, 1H)
(R)一 N—tert—ブトキシカルボニル一 N'— [4一 [ 1H-NMR (500 MHz, DMSO-d6) 2—（4一べンゾィルァミノフエニル）一 1一ェチニ <5 1.27, 1.40 (s, 9H)， 1.77-1.93 (m, ル]フエニル]ピロリジン一 2—カルボキサミド（化合 3H), 2.13-2.28 (m, 1H), 3.32-3.43 物 10— 65) (m， 2H), 4.25 - 4.32 (m， 1H), 7.49 (d, (R) One N-tert-Butoxycarbonyl One N'— [4 One [ 1 H-NMR (500 MHz, DMSO-d 6 ) 2— (4 One-Benzylaminophenyl) One 1 One Ethini <5 1.27, 1.40 (s, 9H), 1.77-1.93 (m, ru] phenyl] pyrrolidine mono 2-carboxamide (compound 3H), 2.13-2.28 (m, 1H), 3.32-3.43 compound 10-65) (m, 2H ), 4.25-4.32 (m, 1H), 7.49 (d,
J = 8.6 Hz, 2H), 7,52 (d, J = 8.6 Hz, 2H), 7.55 (d， J = 7.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6
Figure imgf000137_0002
J = 8.6 Hz, 2H), 7,52 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6
Figure imgf000137_0002
Hz, 2H)， 7.99 (d, J = 7.5 Hz, 2H), 10.40 (s， 1H), 10.52 (s, 1H) Hz, 2H), 7.99 (d, J = 7.5 Hz, 2H), 10.40 (s, 1H), 10.52 (s, 1H)
(R)一 N—tert—ブトキシカルボ二ルー N'— [4— [ 'H - NMR (500 MHz, DMSO - d6) 2— [3, 5—ビス（トリフルォロメチル）フエ二ル]— 1 δ 1.27, 1.40 (s, 9H), 1.79-1.93 (m, —ェチニル]フエニル]ピロリジン一 2—力ルポキサ 3H), 2.17-2.24 (m， 1H), 3.30-3.45 ミド（化合物 10— 66) (m, 2H), 4.20-4.28 (m, 1H)， 7.59 (d, (R) -N-tert-Butoxycarbonyl N'— [4— ['H-NMR (500 MHz, DMSO-d 6 ) 2— [3,5-bis (trifluoromethyl) phenyl] — 1 δ 1.27, 1.40 (s, 9H), 1.79-1.93 (m, —ethynyl] phenyl] pyrrolidine 1-power lupoxa 3H), 2.17-2.24 (m, 1H), 3.30-3.45 amide (compound 10—66 ) (m, 2H), 4.20-4.28 (m, 1H), 7.59 (d,
J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 8.13 (s, 1H), 8.25, 8.26 ( s, 2H), 10.24, 10.26 (s, 1H)
Figure imgf000137_0003
J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 8.13 (s, 1H), 8.25, 8.26 (s, 2H), 10.24, 10.26 (s, 1H)
Figure imgf000137_0003
(R)— N—tert—ブトキシカルポニル一 N'— [4— [ 'H-NMR (400 MHz, DMSO - d6) 2— (3, 4—ジクロ口フエ二ル）一 1—ェチニル]フエ 6 1,27, 1.40 (s, 9H)， 1.78-1.92 (m,
Figure imgf000138_0001
(R) — N-tert-Butoxycarbonyl N'— [4— ['H-NMR (400 MHz, DMSO-d 6 ) 2— (3, 4-Dichlorophenyl) -1- 1-ethynyl] 6 1,27, 1.40 (s, 9H), 1.78-1.92 (m,
Figure imgf000138_0001
3 6
Figure imgf000139_0001
3 6
Figure imgf000139_0001
3 7
Figure imgf000140_0001
Figure imgf000141_0001
3 7
Figure imgf000140_0001
Figure imgf000141_0001
3 9 (m, 3 9 (m,
( (
(m, (m,
(m, (m,
(m, (s, 3 (m, (s, 3
(m, (m,
Figure imgf000142_0001
Figure imgf000142_0001
4 0
Figure imgf000143_0001
Figure imgf000144_0001
4 0
Figure imgf000143_0001
Figure imgf000144_0001
4 2 (m, 4 2 (m,
(m, (s, 3 (m, (s, 3
(m， (s, 3 (m, (s, 3
2.1 2.1
(m, (m,
Figure imgf000145_0001
Figure imgf000145_0001
4 3 (m, 4 3 (m,
d6) d 6 )
(m,  (m,
(m, (m,
d6) d 6 )
(m,  (m,
d6) 3H), 2.1 d 6 ) 3H), 2.1
d6) d 6 )
(m,
Figure imgf000146_0001
(m,
Figure imgf000146_0001
4 4
Figure imgf000147_0001
Figure imgf000148_0001
4 4
Figure imgf000147_0001
Figure imgf000148_0001
4 6
Figure imgf000149_0001
Figure imgf000150_0001
4 6
Figure imgf000149_0001
Figure imgf000150_0001
4 8
Figure imgf000151_0001
4 8
Figure imgf000151_0001
4 9
Figure imgf000152_0001
実施例 11 4 9
Figure imgf000152_0001
Example 11
(R)—N -tert—ブトキシ.カルボニル一NT— [4 - [2—（2—ナフチル）一 1—ェチニル]フ ェニル]ピロリジン一 2—力ルポキサミド（化合物 11—1) (R) —N-tert-butoxy.carbonyl mono-NT— [4- [2- (2-naphthyl)-1-ethynyl] fur Enyl] pyrrolidine 1-strength lupoxamide (compound 11-1)
(R)— N— tert—ブトキシカルボ二ルー N'— (4—ェチニルフエニル）ピロリジン一 2—力 ルポキサミド（化合物 1—113、 1. 00g、 3. 18mmol)、 2—ブロモナフタレン（658mg、 3. 18mmol)、ァリルノ ラジウム（H)クロリドダイマ—（58, 2mg 0. 159mmol)をァ セトニトリ レ（6ml)に容角 し、トリ一 tert—ブチノレホスフィン（129mg、 0. 638mmol)、ト リエチレンジァミン（713mg、 6. 36mmol)を加え、窒素雰囲気下、室温で 5時間撹拌し た。反応液に酢酸ェチル（200ml)を加え、水（50ml、 2回）、飽和食塩水（50ml)で洗 浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去した。得られた残 留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することにより 標記化合物（632mg)を白色固体として得た。（収率 45%) (R) —N—tert-butoxycarbonyl N ′ — (4-ethynylphenyl) pyrrolidine 1- 2 force lupoxamide (compound 1-113, 1.00 g, 3.18 mmol), 2-bromonaphthalene (658 mg, 3. 18 mmol), arrylnoradium (H) chloride dimer (58, 2 mg 0.159 mmol) was adjusted to acetonitrile (6 ml), tri-tert-butinorephosphine (129 mg, 0.638 mmol), triethylenediamine. Min (713 mg , 6.36 mmol) was added, and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water (50 ml, twice) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the title compound (632 mg) as a white solid. (Yield 45%)
1H-NMR (500 MHz, DMSO - d6) 1 H-NMR (500 MHz, DMSO-d 6 )
H ハ  H
δ 1.28, 1.41 (s， 9H)， 1.78-1.95 (m, 3H) δ 1.28, 1.41 (s, 9H), 1.78-1.95 (m, 3H)
, 2.15-2.25 (m, 1H), 3.30-3.45 (m, 2H), 人。。 4.20-4.29 (m, 1H), 7.55-7.60 (m, 5H), , 2.15-2.25 (m, 1H), 3.30-3.45 (m, 2H), person. . 4.20-4.29 (m, 1H), 7.55-7.60 (m, 5H),
7.70 (d, J = 8.6 Hz, 2H), 7.94-7.96 (m， 3H), 8.16 (s, 1H), 10.20 (s, 1 H) 以下、參考ィ匕合物 17— 28、 17— 29、ィ匕合物 1一 113、 1一 176およぴ市,販ィ匕合物カヽ ら選択される化合物を使用し、化合物 11—1の製造方法に準じて、化合物 11一 2~11 —32を得た。  7.70 (d, J = 8.6 Hz, 2H), 7.94-7.96 (m, 3H), 8.16 (s, 1H), 10.20 (s, 1 H) Compound 11 1 113, 1 1 176 and the compound selected from the following: Got.
Figure imgf000153_0001
Figure imgf000153_0001
5
Figure imgf000154_0001
(m, Five
Figure imgf000154_0001
(m,
(m, (s， 3 (m, (s, 3
(m, (m,
d6) d 6 )
(m,  (m,
d6) d 6 )
(m,
Figure imgf000155_0001
- d6) (m,
Figure imgf000155_0001
-d 6 )
1.78-1.94 (m，  1.78-1.94 (m,
(s, 3  (s, 3
(m, (s, 3 (m, (s, 3
(m, (s, 3 (m, (s, 3
(m, (s, 3 (m, (s, 3
(m， (s, 6
Figure imgf000156_0001
(m, (m, (s, 6
Figure imgf000156_0001
(m,
(m, (m,
2 2
(m, (m,
d6) d 6 )
(m,  (m,
(m, (s, 3
Figure imgf000157_0001
Figure imgf000158_0001
(m, (s, 3
Figure imgf000157_0001
Figure imgf000158_0001
5 6 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 5 6 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H),
10.21 (s, 1H)  10.21 (s, 1H)
〇 t 〇 t
(R)— N— tert—ブリトェ zキシカルボ二ルー N'— [4一 [ 1H-N R (400 MHz, DMSO - d6) 2—（2— " < Tソプロポキシ一 1—ナフチル）一 1ーェチ δ 1.28, 1.41 (s, 9H)， 1.38 (d, J = ニル]フエニル]ピロリジン一 2—カルボキサミド（化 6.1 Hz, 6H), 1.78-1.93 (m, 3H), 2. 合物 11—29) 14-2.23 (m, 1H), 3.30-3.44 (m, 2H)， (R) — N— tert—Brité z xycarbonyl N'— [4 1 [ 1 HN R (400 MHz, DMSO-d 6 ) 2— (2— “<T Sopropoxy 1 1-naphthyl) 1 1 δ 1.28, 1.41 (s, 9H), 1.38 (d, J = nyl] phenyl] pyrrolidine 1 2-carboxamide (Chemical 6.1 Hz, 6H), 1.78-1.93 (m, 3H), 2. Compound 11-29) 14 -2.23 (m, 1H), 3.30-3.44 (m, 2H),
4.20-4.29 (m, 1H), 4.82-4.88 (m, 1H), 7.43-7.47 (m, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.57-7.63 (m, 1H), 7.59 (d, J = 8.7 Hz, 2H)， 7.72 (d, 4.20-4.29 (m, 1H), 4.82-4.88 (m, 1H), 7.43-7.47 (m, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.57-7.63 (m, 1H), 7.59 ( d, J = 8.7 Hz, 2H), 7.72 (d,
O J = 8.7 Hz, 2H)， 7.92 (d， J = 8.3O J = 8.7 Hz, 2H), 7.92 (d, J = 8.3
. Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H), Hz, 1H), 7.95 (d, J = 8.9 Hz, 1H),
8.23 (d, J = 8.5 Hz, 1H), 10.21 ( s, 1H)  8.23 (d, J = 8.5 Hz, 1H), 10.21 (s, 1H)
(R)—N— tert—ブトキシカルボ二ルー N'— [6— 1H-NMR (500 MHz, DMSO-d6) メチルー 5—（2—フエ二ルー 1ーェチニル）ー2—ピ δ 1.26, 1.39 (s, 9H), 1.76-1.90 (m， リジル]ピロリジン一 2—力ルポキサミド（化合物 11 3H), 2.17-2.21 (m, 1H), 2.60 (s, 3 -30) H), 3.36 - 3.43 (m, 2H), 4.38-4.43 (m (R) —N— tert-Butoxycarbonyl N'— [6 — 1 H-NMR (500 MHz, DMSO-d 6 ) Methyl-5- (2-phenyl-2-ethynyl) -2-pi δ 1.26, 1.39 (s, 9H), 1.76-1.90 (m, lysyl) pyrrolidine 1-strength lupoxamide (compound 11 3H), 2.17-2.21 (m, 1H), 2.60 (s, 3 -30) H), 3.36-3.43 (m, 2H), 4.38-4.43 (m
， 1H), 7.42-7.47 (m, 3H)， 7.56-7.58 , 1H), 7.42-7.47 (m, 3H), 7.56-7.58
(m， 2H)， 7.87-7.91 (m, 1H), 7.95-8 .01 (m, 1H), 10.71, 10.76 (s, 1H)
Figure imgf000159_0001
(m, 2H), 7.87-7.91 (m, 1H), 7.95-8 .01 (m, 1H), 10.71, 10.76 (s, 1H)
Figure imgf000159_0001
(R) tert—ブトキシカルポ二ルー N'— [6— 1H-N R (500 MHz, DMSO - d6) メチルー 5— [2—（1一ナフチル）一1ーェチニル] δ 1.27, 1.40 (s, 9H), 1.77-1.92 (m, 一 2—ピリジル]ピロリジン一 2—カルボキサミド（化 3H), 2.19-2.23 (m, 1H), 2.72 (s, 3 合物 11— 31 ) H), 3.34-3.44 (m, 2H)， 4.38 - 4.45 (m (R) tert-Butoxycarbonyl N'— [6— 1 HN R (500 MHz, DMSO-d 6 ) Methyl-5— [2— (1 naphthyl) 1 1-ethynyl] δ 1.27, 1.40 (s, 9H) , 1.77-1.92 (m, 1-2-pyridyl) pyrrolidine 1-carboxamide (Chemical 3H), 2.19-2.23 (m, 1H), 2.72 (s, 3 Compound 11- 31) H), 3.34-3.44 (m , 2H), 4.38-4.45 (m
, 1H), 7.58 (dd， J = 8.2, 7.0 Hz, 1 H), 7.63 (dd, J = 7.9, 7.0 Hz, 1H), 7.70 (dd, J = 8.2, 7.0 Hz, 1H)， 人0 ° 7.84 (d, J = 7.0 Hz, 1H), 8.01-8.05 , 1H), 7.58 (dd, J = 8.2, 7.0 Hz, 1 H), 7.63 (dd, J = 7.9, 7.0 Hz, 1H), 7.70 (dd, J = 8.2, 7.0 Hz, 1H), person 0 ° 7.84 (d, J = 7.0 Hz, 1H), 8.01-8.05
(m, 4H), 8.37 (d, J = 8.2 Hz, 1H) , 10.81 (s, 1H)  (m, 4H), 8.37 (d, J = 8.2 Hz, 1H), 10.81 (s, 1H)
(R)—N— tert—ブトキシカルポ二ルー N'— [6— H-NMR (500 MHz, DMSO-d6) メチルー 5— [2— (4—トリフルォロメチルフエニル） δ 1.26, 1.40 (s, 9H), 1.76-1.91 (m, -1一ェチニル]— 2—ピリジル]ピロリジン一 2—力 3H)， 2.13-2.24 (m, 1H), 2.64 (s, 3 ルボキサミド（化合物 11—32) H), 3.32-3.43 (m, 2H), 4.37-4.44 (m (R) —N— tert-Butoxycarbonyl N'— [6— H-NMR (500 MHz, DMSO-d 6 ) Methyl-5— [2— (4-Trifluoromethylphenyl) δ 1.26, 1.40 ( s, 9H), 1.76-1.91 (m, -1 monoethyl)]-2-pyridyl] pyrrolidine 1 2-force 3H), 2.13-2.24 (m, 1H), 2.64 (s, 3 ruboxamide (compound 11-32) H), 3.32-3.43 (m, 2H), 4.37-4.44 (m
, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7. 81 (d, J = 9,0 Hz, 2H), 7.92-8.03 (m, 2H), 10.77, 10.82 (s, 1H)
Figure imgf000159_0002
実施例 12 , 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.81 (d, J = 9,0 Hz, 2H), 7.92-8.03 (m, 2H), 10.77, 10.82 (s, 1H)
Figure imgf000159_0002
Example 12
(R)— N— tert—ブトキシカルポ二ルー N'— [4— [(E)—2—（4ーァセチルァミノフエニル )-1ーェテニル]フエニル]ピロリジン一 2—カルポキサミド（化合物 12— 1)  (R) — N— tert-Butoxycarbonyl N′— [4— [(E) -2 -— (4-Acetylaminophenyl) -1-ethenyl] phenyl] pyrrolidine-1-2-carboxamide (Compound 12— 1)
(R)—N— tert—ブトキシカルボ二ルー N'— [4— [(E)— 2-(4—ァミノフエニル）一 1 _ ェ亍ニル]フエニル]ピロリジン一 2—力ルポキサミド（化合物 3— 18、 148mg、 0. 363m mol)をテトラヒドロフラン（3ml)に溶解し、 N, N—ジイソプロピルェチルァミン（253〃 I、 1. 45mmol)、塩化ァセチル（52〃し 0. 726mmol)を加え、室温で 1時間攪拌した。 反応液に酢酸ェチル（100ml)を加え、水（100ml)、飽和食塩水（100ml)で洗浄した (R) —N— tert-Butoxycarbonyl N'— [4— [(E) — 2- (4-Aminophenyl) -1- 1-enyl] phenyl] pyrrolidine-1-2—Lupoxamide (Compound 3-18) , 148 mg, 0.363 mmol) dissolved in tetrahydrofuran (3 ml), N, N-diisopropylethylamine (253〃I, 1.45 mmol), acetylyl chloride (52〃0.6726 mmol) were added, and room temperature was added. For 1 hour. Ethyl acetate (100 ml) was added to the reaction solution and washed with water (100 ml) and saturated brine (100 ml).
。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより標記化合 物（158mg)を淡茶色固体として得た。（収率 97%) . The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (158 mg) as a light brown solid. (Yield 97%)
1H-NMR (500 MHz, DMSO - d6) 1 H-NMR (500 MHz, DMSO-d 6 )
δ 1.27, 1.40 (s, 9Η), 1.78-1.95 (m, 3 H), 2.05 (s, 3H), 2.16-2.23 (m, 1H), 3 .33-3.45 (m, 2H), 4.18-4.27 (m, 1H), 7.08 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H ), 7.51 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz , 2H)， 9.98 (s, 1H)， 10.03 (s, 1H) 以下、化合物 10— 85および市販化合物を使用し、化合物 12— 1の製造方法に準じて 、化合物 12— 2、 12-3を得た。  δ 1.27, 1.40 (s, 9Η), 1.78-1.95 (m, 3 H), 2.05 (s, 3H), 2.16-2.23 (m, 1H), 3.33-3.45 (m, 2H), 4.18-4.27 (m, 1H), 7.08 (s, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 9.98 (s, 1H), 10.03 (s, 1H) Hereinafter, using Compound 10-85 and a commercially available compound, Compound 12-12 was prepared according to the production method of Compound 12-1. — 2, 12-3 was obtained.
Figure imgf000160_0001
Figure imgf000160_0001
58
Figure imgf000161_0001
実施例 13 58
Figure imgf000161_0001
Example 13
(R)— N— tert—ブトキシカルポ二ルー N'— [4_[(E)_2— (4—イソプロポキシフエニル )ー1ーェテニル]フエニル]ピロリジン一 2—カルボキサミド（化合物 13— 1)  (R) — N— tert-Butoxycarbonyl N′— [4 _ [(E) _2— (4-Isopropoxyphenyl) -1-ethenyl] phenyl] pyrrolidine-1-2-carboxamide (Compound 13-1)
(R)— N— tert—ブトキシカルポニル一 N'— [4— [(E)— 2— (4—ヒドロキシフエ二ル）一 1—ェテニル]フエニル]ピロリジン一 2—力ルポキサミド（化合物 3— 15、 190mg、 0. 46 5mmol)を N, N—ジメチリレホレムアミド（3ml)にミ容角 し、炭酸カリウム（260mg、 1. 88 mmol)、 2—ョ一ド'プロパン（140/ l、 1. 40mmol)を加え、 60度で 4時間攪拌した。放 冷後、反応液に酢酸ェチル（80ml)を加え水（50ml、 2回）、飽和食塩水（50ml)で洗 浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去し、得られた残留 物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することによリ標 記化合物（ 165 m g )を白色固体として得た。（収率 79 % )  (R) — N— tert-butoxycarbonyl 1 N′— [4— [(E) — 2— (4-hydroxyphenyl) 1 1-ethenyl] phenyl] pyrrolidine 1 2—power lupoxamide (compound 3— 15 , 190 mg, 0.46 5 mmol) was mixed with N, N-dimethylethyleneformamide (3 ml), potassium carbonate (260 mg, 1.88 mmol), 2- iodide propane (140 / l, 1. 40 mmol) was added and stirred at 60 degrees for 4 hours. After allowing to cool, ethyl acetate (80 ml) was added to the reaction mixture, and the mixture was washed with water (50 ml, twice) and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane monoacetate) to obtain the labeled compound (165 mg). Obtained as a white solid. (Yield 79%)
Figure imgf000161_0002
以下、化合物 10— 85および市販化合物を使用し、化合物 13— 1の製造方法に準じて 、化合物 13— 2〜13— 4を得た。
Figure imgf000161_0002
Hereinafter, using Compound 10-85 and a commercially available compound, Compounds 13-2 to 13-4 were obtained according to the production method of Compound 13-1.
(R)—N— tert—フトキシカルボニル一 N'— [4一 [2— 1H-NMR (500 MHz, DMSO-d6) (4一エトキシフエ二ル）一 1—ェチニル]フエニル]一ピロ S 1.27, 1.40 (s, 9H), 1.33 (t, J リジン一 2—カルポキサミド（化合物 13— 2) I = 7.0 Hz, 3H), 1.78-1.93 (m, 3 (R) —N— tert-Futoxycarbonyl 1 N′— [4 1 [2 — 1 H-NMR (500 MHz, DMSO-d 6 ) (4 1 ethoxyphenyl) 1 1-ethynyl] phenyl] 1 pyro S 1.27, 1.40 (s, 9H), 1.33 (t, J lysine 2-carpoxamide (compound 13-2) I = 7.0 Hz, 3H), 1.78-1.93 (m, 3
59
Figure imgf000162_0001
実施例 14 59
Figure imgf000162_0001
Example 14
(R)—N— tert—ブトキシカルポ二ルー N'—（2—メチルー 4ーェチニルフエニル）ピロリジ ンー 2—カルボキサミド（化合物 14)  (R) —N— tert-butoxycarbonyl N ′ — (2-methyl-4-ethynylphenyl) pyrrolidine-2-carboxamide (compound 14)
(R)— N— tert—ブトキシカルポ二ルー NT— [2—メチル一4一（2—トリメチルシリル一 1—ェチニル）フエニル]ピロリジン一 2—カルボキサミド（参考化合物 15— 6、 466mg、 1. 16mmol)をテトラヒドロフラン（5ml)に溶解し、テトラプチルアンモニゥムフルオリド 三 水和物（550mg、 mmol)を加え、室温で 3時間攪拌した。減圧下溶媒を留去し、得られ た残留物をシリカゲルカラムクロマトグラフィー（へキサン一酢酸ェチル）で精製することに より標記化合物（477mg)を無色油状物として得た。（定量的） (R) —N—tert-butoxycarbonyl-NT— [2-methyl-4- (2-trimethylsilyl-1-1-ethynyl) phenyl] pyrrolidine-1-2-carboxamide (reference compounds 15-6, 466 mg, 1.16 mmol) It melt | dissolved in tetrahydrofuran (5 ml), Tetraptylammonium fluoride trihydrate (550 mg , mmol) was added, and it stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane monoacetate) to give the title compound (477 mg) as a colorless oil. (quantitative)
60 1H-NMR (400 MHz, DMS( 6) 60 1 H-NMR (400 MHz, DMS ( 6 )
δ 1.34, 1.41 (s, 9H), 1.80-1.92 (m, 3H) ， 2.10-2.25 (m, 1H), 2.19 (s, 3H), 3.30- 3.45 (m, 2H)， 4.10 (s, 1H), 4.30-4.33 ( m, 1H), 7.28-7.30 (m， 1H), 7.34 (s, 1H), 7.42-7.50 (m, 1H), 9.36, 9.40 (s, 1H) 実施例 15  δ 1.34, 1.41 (s, 9H), 1.80-1.92 (m, 3H), 2.10-2.25 (m, 1H), 2.19 (s, 3H), 3.30-3.45 (m, 2H), 4.10 (s, 1H) , 4.30-4.33 (m, 1H), 7.28-7.30 (m, 1H), 7.34 (s, 1H), 7.42-7.50 (m, 1H), 9.36, 9.40 (s, 1H) Example 15
(R)— NT—(4—トリフルォロメチルフエニル）ピロリジン一 2—力ルポキサミド 塩酸塩（化 合物 15— 1)  (R) —NT— (4-Trifluoromethylphenyl) pyrrolidine mono-2-streptoxamide hydrochloride (Compound 15— 1)
(R)— N_tert-ブトキシカルポ二ルー N'—（4—トリフルォロメチルフエニル）ピロリジ ン一 2—力ルポキサミド（化合物 1—1、 2.69g、 7. 51mmol)を 1 , 4一ジォキサン（20 ml)—メタノール（5ml)の混合溶液に懸濁し、 4規定塩化水素一 1, 4一ジォキサン溶液 (30ml)を加え、室温で一晚攪拌した。減圧下溶媒を留去した後、得られた残留物を酢 酸ェチルージェチルエーテルの混合溶液で濾取することにより標記化合物（1. 76g)を 白色固体として得た。（収率 80%)  (R) —N_tert-butoxycarbonyl N ′ — (4-trifluoromethylphenyl) pyrrolidine-1 2-streptoxamide (compound 1-1, 2.69 g, 7.51 mmol) was converted to 1,4-dioxane (20 ml) -methanol (5 ml), 4N hydrogen chloride-1,4-dioxane solution (30 ml) was added, and the mixture was stirred at room temperature. After evaporating the solvent under reduced pressure, the obtained residue was collected by filtration with a mixed solution of ethyl acetate-jetyl ether to obtain the title compound (1.76 g) as a white solid. (Yield 80%)
1 H 'Η- NMR (500 MHz, DMSO— d6) 1 H 'Η- NMR (500 MHz, DMSO— d 6 )
δ 1.92-2.03 (m, 3H), 2.42-2.47 (m, 1 δ 1.92-2.03 (m, 3H), 2.42-2.47 (m, 1
" FF Η), 3.75 (br s, 2H), 4.44-4.47 (m, 1 H)" F F Η), 3.75 (br s, 2H), 4.44-4.47 (m, 1 H)
H 〇 F ， 7 .74 (d, J = 8.6 Hz, 2H), 7,88 (d,H ○ F, 7.74 (d, J = 8.6 Hz, 2H), 7,88 (d,
HCI J = ： 8,6 Hz, 2H), 8.72 (br s, 1H), 10. HCI J =: 8,6 Hz, 2H), 8.72 (br s, 1H), 10.
02 (br s, 1H), 10.38 (br s, 1H) 以下、化合物 1 - 2~1 - 55、 1— 58〜1一 78、 1— 80、 1 - 82、 1 - 85〜1 -112、 1 — " 4~ 1-118、 1—120~1—148、 1一 152〜 1-172、 1—174、 1—175、 1— 177、 2— 1、2— 2、3— 1〜3_24、3— 26〜3— 29、4—1~4ー6、4ー8〜4ー19、 5、6—1〜6—12、7— 1、8— 1〜8— 22、9—1~9ー3、 10—1~10— 51、 10— 54 〜10— 119、 10—123〜10-126、 10-128~139、 10-144、 10—145、 "一 1〜11-15、 "一17〜27、 11— 30~11— 32、 12— 1〜12— 3、 13— 1〜13— 4 から選択される化合物を使用し、化合物 15—1の製造方法に準じて、化合物 15— 2〜 15 - 424を得た。  02 (br s, 1H), 10.38 (br s, 1H) Compound 1-2-1-55, 1-58-1-78, 1-80, 1-82, 1-85-1 -112, 1 — “4 to 1-118, 1 to 120 to 1 to 148, 1 to 152 to 1-172, 1 to 174, 1 to 175, 1 to 177, 2 to 1, 2 to 2, 3 to 1 to 3_24 , 3-26-3-29, 4-1-4-6, 4-8-4-19, 5, 6-1-6-12, 7-1, 8-1-8-22, 22-9-1 ~ 9-3, 10-1 ~ 10-51, 10-54 ~ 10-119, 10-123 ~ 10-126, 10-128 ~ 139, 10-144, 10-145, "1 1-11-15 , "1-17-27, 11-30-30-11-32, 12-1-12-3, 13-1-13-13, in accordance with the production method of compound 15-1 Compounds 15-2 to 15-424 were obtained.
6
Figure imgf000164_0001
= 8.3 Hz, 1H), 7.16 (d, J = 8.3 H z, 1H), 7.26 (t, J = 8.3 Hz, 1H), 7.31 (s， 1H), 8.67 (br s, 1H), 9.77
Figure imgf000165_0001
(br s, 1H), 10.76 (s, 1H) HCI 6
Figure imgf000164_0001
= 8.3 Hz, 1H), 7.16 (d, J = 8.3 H z, 1H), 7.26 (t, J = 8.3 Hz, 1H), 7.31 (s, 1H), 8.67 (br s, 1H), 9.77
Figure imgf000165_0001
(br s, 1H), 10.76 (s, 1H) HCI
(R) -N'— (3—メチルフエニル）ピロリジン一 2 - NMR (500 MHz, DMSO-d6) 一カルボキサミド 塩酸塩（化合物 15— 8) δ 1.91-1.98 (m， 3H), 2,29 (s, 3H), (R) -N'— (3-Methylphenyl) pyrrolidine 1 2-NMR (500 MHz, DMSO-d 6 ) monocarboxamide hydrochloride (Compound 15— 8) δ 1.91-1.98 (m, 3H), 2,29 ( s, 3H),
2.41-2.48 (m, 1H), 3.23-3.32 (m,. 2H), 4.42-4.47 (m, 1H), 6.93 (d, J 2.41-2.48 (m, 1H), 3.23-3.32 (m, .2H), 4.42-4.47 (m, 1H), 6.93 (d, J
= 7.6 Hz, 1H), 7.23 (d, J = 7.9= 7.6 Hz, 1H), 7.23 (d, J = 7.9
H O Hz, 1H), 7.48-7.49 (m, 2H), 8.68 ( HCI br s, 1H), 10.30 (br s, 1H), 11.02 H O Hz, 1H), 7.48-7.49 (m, 2H), 8.68 (HCI br s, 1H), 10.30 (br s, 1H), 11.02
(s, 1H)  (s, 1H)
(R) -N'一（3—べンジルォキシフエニル）ピロり 1H-NMR (500 MHz, DMSO-d6) ジン一 2—カルボキサミド 塩酸塩（化合物 15 δ 1.90 - 1.98 (m, 3H), 2.39-2.46 ( 一 9) m， 1H)， 3.25-3.27 (m, 2H), 4.40 - 4. (R) -N '-(3-Benzyloxyphenyl) pyrrole 1 H-NMR (500 MHz, DMSO-d 6 ) Gin mono 2-carboxamide hydrochloride (compound 15 δ 1.90-1.98 (m, 3H ), 2.39-2.46 (9) m, 1H), 3.25-3.27 (m, 2H), 4.40-4.
41 (m, 1H), 5.08 (s, 2H)， 6.78 (d, J = 8.0 Hz, 1H), 7.20-7.27 (m, 2H )' 7.33 (t, J = 7.3 Hz, 1H)， 7.39 ( t, J = 7.3 Hz, 2H), 7.43-7.46 (m, 3H), 8.67 (br s, 1H), 10.16 (br s,
Figure imgf000165_0002
1H), 11.00 (s， 1H) 41 (m, 1H), 5.08 (s, 2H), 6.78 (d, J = 8.0 Hz, 1H), 7.20-7.27 (m, 2H) '7.33 (t, J = 7.3 Hz, 1H), 7.39 (t , J = 7.3 Hz, 2H), 7.43-7.46 (m, 3H), 8.67 (br s, 1H), 10.16 (br s,
Figure imgf000165_0002
1H), 11.00 (s, 1H)
HCI  HCI
(R)— N' —（3—フエノキシフエニル）ピロリジン 1H-N R (400 MHz, D SO-d6) 一 2—カルボキサミド 塩酸塩（化合物 15— 10 δ 1.88-1.99 (m， 3H), 2.32-2.41 ( m, 1H)， 3.23-3.24 (m, 2H)， 4.33 (b r s, 1H), 6.79 (d, J = 7.8 Hz, 1H) , 7.05 (d, J = 7.5 Hz, 2H), 7.18 ( t, J = 7.5 Hz, 1H), 7.31-7.44 (m,(R) — N ′ — (3-phenoxyphenyl) pyrrolidine 1 HN R (400 MHz, D SO-d 6 ) mono 2-carboxamide hydrochloride (compound 15— 10 δ 1.88-1.99 (m, 3H), 2.32-2.41 (m, 1H), 3.23-3.24 (m, 2H), 4.33 (brs, 1H), 6.79 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.31-7.44 (m,
H 0 。 5H), 8.65 (br s, 1H), 9.75 (br s, 1 HCI H), 10.86 (br s, 1H) H 0. 5H), 8.65 (br s, 1H), 9.75 (br s, 1 HCI H), 10.86 (br s, 1H)
(R) -Ν' — (3—ジメチルァミノフエニル）ピロリ 1H-NMR (400 MHz, DMSO-d6) ジンー2—力ルポキサミド 塩酸塩（化合物 15 δ 1.92-1.98 (m, 3H), 2.38-2.48 ( -11 ) m, 1H)， 2.98 (s, 6H), 3.24-3.29 (m， (R) -Ν '— (3-Dimethylaminophenyl) pyrrole 1 H-NMR (400 MHz, DMSO-d 6 ) Din-2-force lupoxamide hydrochloride (compound 15 δ 1.92-1.98 (m, 3H), 2.38 -2.48 (-11) m, 1H), 2.98 (s, 6H), 3.24-3.29 (m,
2H), 4.37-4.40 (m, 1H)， 6.98 (br s, 1H)， 7.37 (br s, 2H), 7.53 (br s , 1H), 8.69 (br s, 1H), 10.03 (br s ， 1H), 10.94 (br s, 1H)  2H), 4.37-4.40 (m, 1H), 6.98 (br s, 1H), 7.37 (br s, 2H), 7.53 (br s, 1H), 8.69 (br s, 1H), 10.03 (br s, 1H ), 10.94 (br s, 1H)
Η 0  Η 0
HCI  HCI
(R) -Ν'—(3—力ルバモイルフエ二ル）ピロリジ H-NMR (500 MHz, DMSO - d6) ンー 2—力ルポキサミド 塩酸塩（化合物 15— 1 δ 1.92-2.02 (m， 3H), 2.36-2.47 ( 2) m, 1H), 3.23-3.39 (m, 2H), 4.37-4. (R) -Ν '— (3-Strong rubermoylphenyl) pyrrolidi-H-NMR (500 MHz, DMSO-d 6 ) N-2-Streptoxamide hydrochloride (compound 15— 1 δ 1.92-2.02 (m, 3H), 2.36-2.47 (2) m, 1H), 3.23-3.39 (m, 2H), 4.37-4.
41 (m, 1H), 7.38 (br s, 1H)， 7.43 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.78 (dd, J = 7.9, 1. 5 Hz, 1H), 7.98 (br s, 1H), 8.08 ( 41 (m, 1H), 7.38 (br s, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.78 (dd, J = 7.9, 1.5 Hz, 1H), 7.98 (br s, 1H), 8.08 (
H O t, J = 1.8 Hz, 1H), 8.67 (d, J = HCI 5.2 Hz, 1H), 9.89 (d, J = 5.5 Hz, H O t, J = 1.8 Hz, 1H), 8.67 (d, J = HCI 5.2 Hz, 1H), 9.89 (d, J = 5.5 Hz,
63
Figure imgf000166_0001
63
Figure imgf000166_0001
6 4 一 2—カルボキサミド 塩酸塩（化合物 15— 19 δ 0.89 (t, J = 7.3 Hz, 3H), 1.25- ) 1.32 (m, 2H)， 1.49-1.55 (m, 2H)， 1 6 4 1 2-Carboxamide hydrochloride (compound 15—19 δ 0.89 (t, J = 7.3 Hz, 3H), 1.25-) 1.32 (m, 2H), 1.49-1.55 (m, 2H), 1
.91-1.97 (m, 3H), 2.39-2.44 (m, 1H ), 2.54 (t, J = 7.3 Hz, 2H), 3,25— 3.27 (m, 2H), 4.39 (br s, 1H), 7.16 .91-1.97 (m, 3H), 2.39-2.44 (m, 1H), 2.54 (t, J = 7.3 Hz, 2H), 3,25— 3.27 (m, 2H), 4.39 (br s, 1H), 7.16
H' O (d, J = 8.4 Hz, 2H), 7.54 (d, J HCI = 8.4 Hz, 2H), 8.65 (br s, 1H), 10 H 'O (d, J = 8.4 Hz, 2H), 7.54 (d, J HCI = 8.4 Hz, 2H), 8.65 (br s, 1H), 10
.12 (br s, 1H), 10.85 (br s, 1H) .12 (br s, 1H), 10.85 (br s, 1H)
(R) -N'— (4— n—ペンチルフエ二ル）ピロリジ 1H-NMR (500 MHz, DMSO - d6) ン一 2—カルボキサミド 塩酸塩（化合物 15— 2 δ 0,86 (t, J = 7.2 Hz, 3H)， 1.21 - 0) 1.32 (m, 4H), 1.51-1.57 (m, 2H), 1 (R) -N'— (4— n-pentylphenyl) pyrrolidi 1 H-NMR (500 MHz, DMSO-d 6 ) -one 2-carboxamide hydrochloride (compound 15— 2 δ 0,86 (t, J = 7.2 Hz, 3H), 1.21-0) 1.32 (m, 4H), 1.51-1.57 (m, 2H), 1
.90-1.97 (m, 3H), 2,39 - 2.44 (m, 1H ), 2.50-2.54 (m, 2H), 3.23-3.35 (m, .90-1.97 (m, 3H), 2,39-2.44 (m, 1H), 2.50-2.54 (m, 2H), 3.23-3.35 (m,
2H), 4.36-4.39 (m, 1H), 7.16 (d,2H), 4.36-4.39 (m, 1H), 7.16 (d,
H O. H O.
J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 HCI Hz, 2H), 8.65 (br s, 1H), 10.05 ( br s, 1H)， 10.80 (s, 1H)  J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 HCI Hz, 2H), 8.65 (br s, 1H), 10.05 (br s, 1H), 10.80 (s, 1H)
(R)一 N'一（4— n—へキシルフェニル）ピロリジ H-N R (500 MHz, DMSO - d6) ン一 2—力ルポキザミド 塩酸塩（化合物 15— 2 δ 0.85 (t, J = 7.0 Hz, 3H)， 1.26 1) (s, 6H), 1.52-1.55 (m, 2H), 1.91-1. (R) -N '-(4-N-Hexylphenyl) pyrrolidi HN R (500 MHz, DMSO-d 6 ) -N-2-Lupoxamide hydrochloride (Compound 15— 2 δ 0.85 (t, J = 7.0 Hz , 3H), 1.26 1) (s, 6H), 1.52-1.55 (m, 2H), 1.91-1.
97 (m， 3H)， 2.36-2.43 (m， 1H), 2.5 1-2.55 (m, 2H), 3.22-3.29 (m, 2H), 97 (m, 3H), 2.36-2.43 (m, 1H), 2.5 1-2.55 (m, 2H), 3.22-3.29 (m, 2H),
4.34-4.37 (m, 1H), 7.16 (d, J =4.34-4.37 (m, 1H), 7.16 (d, J =
H 0 H 0
8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, HCI 2H)， 8.67 (br s, 1H), 9.80 (br s, 1  8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, HCI 2H), 8.67 (br s, 1H), 9.80 (br s, 1
H)， 10.68 (s, 1H)  H), 10.68 (s, 1H)
(R)— N'— (4— n—ォクチルフエ二ル）ピロリジ 1H-NMR (500 MHz, DMSO- d6) ンー 2—カルボキサミド 塩酸塩（化合物 15— 2 δ 0.85 (t, J = 7.1 Hz, 3H)， 1.23- 2) 1.28 (m, 10H), 1.52-1.56 (m, 2H), (R) — N′— (4— n-octylphenyl) pyrrolidi 1 H-NMR (500 MHz, DMSO-d 6 ) N-2-carboxamide hydrochloride (compound 15— 2 δ 0.85 (t, J = 7.1 Hz , 3H), 1.23- 2) 1.28 (m, 10H), 1.52-1.56 (m, 2H),
1.91-1.97 (m, 3H), 2.38-2.41 (m, 1 H), 2.51 (t, J = 7.9 Hz, 2H), 3.2 3-3.30 (m, 2H), 4.35-4.38 (m, 1H)， 1.91-1.97 (m, 3H), 2.38-2.41 (m, 1 H), 2.51 (t, J = 7.9 Hz, 2H), 3.2 3-3.30 (m, 2H), 4.35-4.38 (m, 1H),
H O 7.16 (d, J = 8.6 Hz, 2H), 7,52 (d HCI , J = 8.6 Hz, 2H), 10.76 (br s, 1 H O 7.16 (d, J = 8.6 Hz, 2H), 7,52 (d HCI, J = 8.6 Hz, 2H), 10.76 (br s, 1
H)  H)
(R)— N'—(4—イソプロピルフエニル）ピロリジ H-N R (500 MHz, DMSO - d6) ン一 2—カルボキサミド 塩酸塩（化合物 15— 2 δ 1,18 (d, J = 7.0 Hz, 6H), 1.9 (R) — N ′ — (4-Isopropylphenyl) pyrrolidi HN R (500 MHz, DMSO-d 6 ) 2-Carboxamide hydrochloride (compound 15— 2 δ 1,18 (d, J = 7.0 Hz, 6H), 1.9
0-1.97 (m, 3H), 2.38-2.44 (m, 1H)， 0-1.97 (m, 3H), 2.38-2.44 (m, 1H),
2.83-2.88 (m, 1H), 3.24-3.29 (m, 2H), 4.36-4.38 (m, 1H), 7.22 (d, J2.83-2.88 (m, 1H), 3.24-3.29 (m, 2H), 4.36-4.38 (m, 1H), 7.22 (d, J
= 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H)， 8.65 (br s, 1H), 10.04 (br= 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 8.65 (br s, 1H), 10.04 (br
HCI s, 1H)， 10,79 (s, 1H)HCI s, 1H), 10,79 (s, 1H)
(R)— N'—（4— tert—ブチルフエニル）ピロリジ 1H-N R (500 MHz, DMSO - d6) ンー 2—力ルポキサミド 塩酸塩（化合物 15— 2 δ 1.26 (s, 9H), 1.92-1.95 (m, 3H), 4) 2.35-2.42 (m, 1H), 3.20-3.40 (m, (R) — N ′ — (4— tert-Butylphenyl) pyrrolidi- 1 HN R (500 MHz, DMSO-d 6 ) N—2 Lupoxamide hydrochloride (compound 15— 2 δ 1.26 (s, 9H), 1.92-1.95 (m, 3H), 4) 2.35-2.42 (m, 1H), 3.20-3.40 (m,
2H), 4.34 (br s, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 8.65 (br s, 1H), 9.65 (br s,
Figure imgf000168_0001
2H), 4.34 (br s, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.9 Hz, 2H), 8.65 (br s, 1H), 9.65 (br s,
Figure imgf000168_0001
6 6
Figure imgf000169_0001
6 6
Figure imgf000169_0001
6 7 Hz, 2H), 7.92—7,95 (m， 1H), 8.70 6 7 Hz, 2H), 7.92-7,95 (m, 1H), 8.70
(d, J = 4.9 Hz, 1H), 10.06 (d, J = ΐ ΤΗ2 4.9 Hz, 1H), 11.22 (s, 1H)(d, J = 4.9 Hz, 1H), 10.06 (d, J = ΐ Τ Η 2 4.9 Hz, 1H), 11.22 (s, 1H)
Η 0 ο Η 0 ο
HCI  HCI
(R)-N'一（4—ァセチルフエニル）ピロリジン一 1H-NMR (500 MHz, DMSO - d6) 2—力ルポキサミド 塩酸塩（化合物 15— 37) δ 1.92-2.03 (m， 3H), 2.36-2.45 ( m, 1H), 2.54 (s, 3H)， 3.27-3.40 (m,(R) -N '-(4-acetylphenyl) pyrrolidine 1 H-NMR (500 MHz, DMSO-d 6 ) 2-force lupoxamide hydrochloride (compound 15-37) δ 1.92-2.03 (m, 3H), 2.36 -2.45 (m, 1H), 2.54 (s, 3H), 3.27-3.40 (m,
2H), 4,41 (br s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.7 H z, 2H), 8.71 (br s, 1H)， 9.66 (br s2H), 4,41 (br s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.7 H z, 2H), 8.71 (br s, 1H), 9.66 (br s
HCI , 1H), 11.07 (s, 1H) HCI, 1H), 11.07 (s, 1H)
(R)-N'一（4一プロピオニルフエニル）ピロリジ 1H-NMR (500 MHz, DMSO - d6) ンー 2—力ルポキ γミド 塩酸塩（化合物 15— 3 δ 1.08 (t, J = 7.3 Hz, 3H)， 1.90- 2.02 (m, 3H), 2.42-2.48 (m, 1H), 3 • 00 (q, J = 7.3 Hz, 2H), 3.23—3.32(R) -N '-(4-propionylphenyl) pyrrolidi 1 H-NMR (500 MHz, DMSO-d 6 ) N-2—force l-gamma imide hydrochloride (compound 15-3 δ 1.08 (t, J = 7.3 Hz, 3H), 1.90- 2.02 (m, 3H), 2.42-2.48 (m, 1H), 3 • 00 (q, J = 7.3 Hz, 2H), 3.23—3.32
(m, 2H), 4.44-4.48 (m, 1H), 7.79 (d, J = 8.7 Hz, 2H),. 7.98 (d, J =(m, 2H), 4.44-4.48 (m, 1H), 7.79 (d, J = 8.7 Hz, 2H) ,. 7.98 (d, J =
8.7 Hz, 2H), 8.72 (br s, 1H), 10.8.7 Hz, 2H), 8.72 (br s, 1H), 10.
HCI 07 (br s, 1H)， 11,34 (s, 1 H)HCI 07 (br s, 1H), 11,34 (s, 1 H)
(R)— N' - (4—ベンゾィルフエニル）ピロリジン 1H-NMR (500 MHz, DMSO - d6) —2—カルボキサミド 塩酸塩（化合物 15— 39 δ 1.93-2.04 (m, 3H), 2.43-2.50 ( ) m, 1H), 3.25-3.32 (m, 2H), 4.44-4. (R) — N ′-(4-Benzylphenyl) pyrrolidine 1 H-NMR (500 MHz, DMSO-d 6 ) —2-carboxamide hydrochloride (compound 15—39 δ 1.93-2.04 (m, 3H), 2.43-2.50 () m, 1H), 3.25-3.32 (m, 2H), 4.44-4.
49 (m， 1H), 7.51-7.85 (m, 9H), 8.7 3 (br s, 1H), 9.94 (br s, 1H), 11.2 9 (s, 1H) 49 (m, 1H), 7.51-7.85 (m, 9H), 8.7 3 (br s, 1H), 9.94 (br s, 1H), 11.2 9 (s, 1H)
Figure imgf000170_0001
Figure imgf000170_0001
HCI  HCI
(R)— Ν'—（4一シァノメチルフエニル）ピロリジ 1H - NMR (500 MHz, DMSO - d6) ン一 2—力ルポキサミド 塩酸塩（化合物 15— 4 δ 1.91-1.99 (m， 3H), 2.39-2.45 ( 0) m, 1H), 3.23-3.31 (m, 2H), 4.00 (s, (R) — Ν ′ — (4-Cyanomethylphenyl) pyrrolidi 1 H-NMR (500 MHz, DMSO-d 6 ) -I-2-Lupoxamide hydrochloride (Compound 15—4 δ 1.91-1.99 (m, 3H), 2.39-2.45 (0) m, 1H), 3.23-3.31 (m, 2H), 4.00 (s,
2H), 4.38-4.41 (m, 1H), 7.34 (d, ' J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 ^ CN  2H), 4.38-4.41 (m, 1H), 7.34 (d, 'J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 ^ CN
H 0 Hz, 2H), 8,68 (br s， 1H), 9.95 (br s, 1H), 10.95 (s, 1H)  H 0 Hz, 2H), 8,68 (br s, 1H), 9.95 (br s, 1H), 10.95 (s, 1H)
HCI  HCI
(R)— N'—（4一シァノフエニル）ピロリジン一 2 1H-N R (500 MHz, DMSO - d6) 一力ルポキサミド 塩酸塩（化合物 15— 41) δ 1.91-2.01 (m, 3H), 2.42-2.46 ( m, 1H), 3.24-3.30 (m, 2H), 4.45-4 .48 (m, 1H)， 7.82-7.87 (m, 4H), 8, 75 (br s, 1H), 9.95 (br s, 1H)， 11.
Figure imgf000170_0002
(R) — N ′ — (4 Cyanophenyl) pyrrolidine 1 2 1 HN R (500 MHz, DMSO-d 6 ) One strength lupoxamide hydrochloride (Compound 15—41) δ 1.91-2.01 (m, 3H), 2.42- 2.46 (m, 1H), 3.24-3.30 (m, 2H), 4.45-4 .48 (m, 1H), 7.82-7.87 (m, 4H), 8, 75 (br s, 1H), 9.95 (br s , 1H), 11.
Figure imgf000170_0002
48 (s， 1H)  48 (s, 1H)
HCI  HCI
(R)— N'—（4—アミノメチルフエニル）ピロリジ 1H - NMR (500 MHz, DMSO - d6) ンー 2—カルボキサミド 2塩酸塩（化合物 15— δ 1.91-1.98 (m, 3H), 2.41-2.47 ( 42) m, 1H)， 3.24-3.30 (m, 2H), 3.96-3. (R) — N ′ — (4-Aminomethylphenyl) pyrrolidi 1 H-NMR (500 MHz, DMSO-d 6 ) N-2-carboxamide dihydrochloride (compound 15—δ 1.91-1.98 (m, 3H), 2.41-2.47 (42) m, 1H), 3.24-3.30 (m, 2H), 3.96-3.
98 (m， 2H), 4.40-4.42 (m, 1H), 7.4 7 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 8.35 (br s, 3H)， 8 .66 (br s, 1H), 9.95 (br s, 1H), 11  98 (m, 2H), 4.40-4.42 (m, 1H), 7.4 7 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 8.35 (br s, 3H), 8 .66 (br s, 1H), 9.95 (br s, 1H), 11
68
Figure imgf000171_0001
68
Figure imgf000171_0001
6 9
Figure imgf000172_0001
6 9
Figure imgf000172_0001
7 0 ( 7 0 (
( (
( (
- d6) -d 6 )
(  (
d6) d 6 )
(  (
Figure imgf000173_0001
3Η)，
Figure imgf000173_0001
3Η),
d6) d6) - d6) d6) (
Figure imgf000174_0001
- d6)
Figure imgf000175_0001
(. d 6 ) d 6 )-d 6 ) d 6 ) (
Figure imgf000174_0001
-d 6 )
Figure imgf000175_0001
(.
( 1 (1
d6) d 6 )
(  (
- d6) -d 6 )
(  (
d6) d 6 )
(  (
d6) d 6 )
(
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
(
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
7 6
Figure imgf000179_0001
7 6
Figure imgf000179_0001
7 7
Figure imgf000180_0001
, 1H), 7.19 (d, J = 7,9 Hz, 2H), 77 7
Figure imgf000180_0001
, 1H), 7.19 (d, J = 7,9 Hz, 2H), 7
？ 。 .• 33 (d, J = 7.9 Ηζ,. 2H), 7.39 (s, ? . . • 33 (d, J = 7.9 Ηζ ,. 2H), 7.39 (s,
1H), 7.40 (d, J = 8.8 Hz, 1H), 8.6 1H), 7.40 (d, J = 8.8 Hz, 1H), 8.6
2 (br s, 1H), 9.97 (br s, 1H), 10.62 (br s, 1H), 9.97 (br s, 1H), 10.6
HCI 3 (s， 1H) HCI 3 (s, 1H)
(R) - '— [4-(2—ピリジルメチルォキシ）フ 1H -画 R (500 MHz, DMSO-de) ェニル]ピロリジン一 2—カルボキサミド 塩酸塩 δ 1.90-1.97 (m, 3H), 2.39—2.44 ( (化合物 15— 101) m, 1H), 3.22-3.29 (m, 2H), 4.36-4. (R) - '- [4- (2- pyridylmethyl O carboxymethyl) off 1 H - field R (500 MHz, DMSO-d e) Eniru] pyrrolidine one 2-carboxamide hydrochloride δ 1.90-1.97 (m, 3H) , 2.39-2.44 ((Compound 15- 101) m, 1H), 3.22-3.29 (m, 2H), 4.36-4.
39 (m, 1H), 5.35 (s, 2H), 7.07 (d, J = 9.0 Hz, 2H)， 7.59 (d, J = 9.0 39 (m, 1H), 5.35 (s, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 9.0
V Hz, 2H), 7.69-7.72 (m, 1H), 7.83 -V Hz, 2H), 7.69-7.72 (m, 1H), 7.83-
H ' 0 。u 7.85 (m, 1H), 8.23-8.26 (m， 1H), 8 HCI .64-8.66 (m， 1H), 8.76 (d, J = 5.2 H '0. u 7.85 (m, 1H), 8.23-8.26 (m, 1H), 8 HCI .64-8.66 (m, 1H), 8.76 (d, J = 5.2
Hz, 1H), 10.11 (s, 1H), 10.89 (s， 1H)  Hz, 1H), 10.11 (s, 1H), 10.89 (s, 1H)
(R)— N'— [4_(3—ピリジルメチルォキシ）フ 1H - NMR (500 MHz, DMSO - d6) ェニル]ピロリジン一 2—力ルポキサミド 塩酸塩 δ 1.90-1.98 (m, 3H)， 2.36-2.47 ( (化合物 15— 102) m, 1H), 3.22-3.28 (m, 2H), 4.37 (s, (R) — N′— [4_ (3-Pyridylmethyloxy) 1 H-NMR (500 MHz, DMSO-d 6 ) enyl] pyrrolidine mono 2-power lupoxamide hydrochloride δ 1.90-1.98 (m, 3H) , 2.36-2.47 ((compound 15—102) m, 1H), 3.22-3.28 (m, 2H), 4.37 (s,
1H), 5.28 (s, 2H), 7.06 (d, J = 8 .7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2 1H), 5.28 (s, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2
V H)， 7.94 (br s， 1H)， 8.45 (br s, 1V H), 7.94 (br s, 1H), 8.45 (br s, 1
H i 0 。1N ) H i 0. 1N)
H), 8,64 (br s， 1H), 8.82 (s， 1H), HCI 8.93 (s, 1H)， 10.04 (br s, 1H)， 10.  H), 8,64 (br s, 1H), 8.82 (s, 1H), HCI 8.93 (s, 1H), 10.04 (br s, 1H), 10.
85 (br s, 1H)  85 (br s, 1H)
(R)— N'—（4一フエノキシフエニル）ピロリジン - NMR (500 MHz, DMSO - d6) 一 2—カルボキサミド 塩酸塩（化合物 15— 10 δ 1.91一 2.01 (m, 3H)， 2.36-2.47 ( m, 1H), 3.17-3.28 (m, 2H), 4.38 (b r s, 1H), 6.98 (dd, J = 8,7, 1.1 H z, 2H), 7.04 (d, J = 8.9 Hz, 2H),
Figure imgf000181_0001
(R) — N ′ — (4 monophenoxyphenyl) pyrrolidine-NMR (500 MHz, DMSO -d 6 ) 1 2-carboxamide hydrochloride (compound 15—10 δ 1.91 one 2.01 (m, 3H), 2.36- 2.47 (m, 1H), 3.17-3.28 (m, 2H), 4.38 (brs, 1H), 6.98 (dd, J = 8,7, 1.1 H z, 2H), 7.04 (d, J = 8.9 Hz, 2H ),
Figure imgf000181_0001
7.12 (t, J = 7.3 Hz, 1H), 7.36-7.4 7.12 (t, J = 7.3 Hz, 1H), 7.36-7.4
H 0 0 (m, 2H), 7.65 (dd, J = 7.0, 2.1 H 0 0 (m, 2H), 7.65 (dd, J = 7.0, 2.1
Hz, 2H), 8.67 (br s, 1H), 9.93 (br HCI  Hz, 2H), 8.67 (br s, 1H), 9.93 (br HCI
s, 1H), 10.89 (s, 1H)  s, 1H), 10.89 (s, 1H)
(R)— N'— [4一（3—メチルフ ίノキシ）フエ二 1H-NMR (400 MHz, DMSO - d6) ル]ピロリジン一 2—カルボキサミド 塩酸塩（化 δ 1.91-1.99 (m, 3H), 2.28 (s, 3H), 合物 15— 104) 2.38-2.48 (m, 1H), 3.25-3.33 (m, (R) - N'[4 i (3 Mechirufu ί phenoxy) phenylene 1 H-NMR (400 MHz, DMSO - d 6) Le] pyrrolidine one 2-carboxamide hydrochloride (Formula δ 1.91-1.99 (m, 3H), 2.28 (s, 3H), Compound 15-104) 2.38-2.48 (m, 1H), 3.25-3.33 (m,
2H), 4.36-4.38 (m, 1H), 6.74-7.27 (m, 6H), 7.56-7.66 (m, 2H), 8.66 ( br s, 1H), 9.93 (br s, 1H), 10.87, 2H), 4.36-4.38 (m, 1H), 6.74-7.27 (m, 6H), 7.56-7.66 (m, 2H), 8.66 (br s, 1H), 9.93 (br s, 1H), 10.87,
Η 0 10.90 (s, 1H) Η 0 10.90 (s, 1H)
HCI  HCI
(R)— N'— (3—クロロー 4一トリフルォロメトキ 'H - NMR (400 MHz, DMSO - d6) シフ： cニル）ピロリジン一 2—カルボキサミド 塩 δ 1.91-2.04 (m, 3H), 2.33-2.47 ( 酸塩（化合物 15— 105) m, 1H), 3.27 (br s, 2H), 4.42 (br r~\ H CI F F s, 1H), 7.59 (d, J = 9,0 Hz, 1 H), ' 7.67 (dd, J = 9.0, 2.4 Hz, 1H), 8. (R) — N′— (3-Chloro-4 monotrifluorometho'H-NMR (400 MHz, DMSO-d 6 ) Schiff: cnyl) pyrrolidine mono 2-carboxamide salt δ 1.91-2.04 (m, 3H) , 2.33-2.47 (acid salt (compound 15—105) m, 1H), 3.27 (br s, 2H), 4.42 (br r ~ \ H CI FF s, 1H), 7.59 (d, J = 9,0 Hz , 1 H), '7.67 (dd, J = 9.0, 2.4 Hz, 1H), 8.
02 (d, J = 2.4 Hz, 1H), 8.72 (br H 0 s, 1H), 9.85 (br s, 1H), 11.38 (s, 02 (d, J = 2.4 Hz, 1H), 8.72 (br H 0 s, 1H), 9.85 (br s, 1H), 11.38 (s,
HCI 1H) HCI 1H)
79
Figure imgf000182_0001
79
Figure imgf000182_0001
8 0
Figure imgf000183_0001
- d6) 8 0
Figure imgf000183_0001
-d 6 )
(  (
( (
( (
d6) d 6 )
d6) ( d 6 ) (
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000184_0001
Figure imgf000185_0001
8 3 1Η), 3.22-3.29 (m, 2H), 4.35-4.38 8 3 1Η), 3.22-3.29 (m, 2H), 4.35-4.38
(m, 1H), 4.85 (s, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 (m, 1H), 4.85 (s, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6
Hz, 2H), 7.60 (d, J = 4.6 Hz, 1H)， 7.85-7.89 (m, 1H), 8.02-8.05 (m,
Figure imgf000186_0001
1H), 8.28 (d, J = 8.6 Hz, 1H), 8.4 Hz, 2H), 7.60 (d, J = 4.6 Hz, 1H), 7.85-7.89 (m, 1H), 8.02-8.05 (m,
Figure imgf000186_0001
1H), 8.28 (d, J = 8.6 Hz, 1H), 8.4
7 (d, J = 8,6 Hz, 1H), 8.66 (br s, 1H), 9.01 (d, J = 4.6 Hz, 1H), 9, 7 (d, J = 8,6 Hz, 1H), 8.66 (br s, 1H), 9.01 (d, J = 4.6 Hz, 1H), 9,
88 (br s, 1H), 10.98 (s, 1H)88 (br s, 1H), 10.98 (s, 1H)
(R) -N' - [4- (1—フエ二ルェチルチオ）フエ 1H-NMR (500 MHz, DMSO - d6) ニル]ピロリジン一 2—カルボキサミド 塩酸塩（ δ 1.52 (d, J = 7.0 Hz, 3H), 1.9 化合物 15— 130) 1-1.97 (m, 3H), 2.37-2.40 (m, 1H), (R) -N '- [4- (1- phenylene Ruechiruchio) Hue 1 H-NMR (500 MHz, DMSO - d 6) sulfonyl] pyrrolidine one 2-carboxamide hydrochloride (δ 1.52 (d, J = 7.0 Hz , 3H), 1.9 Compound 15- 130) 1-1.97 (m, 3H), 2.37-2.40 (m, 1H),
3.22-3.29 (m, 2H), 4.35-4.39 (m， 1H), 4.51 (q, J = 7.0 Hz, 1H), 7.2 1 (t, J = 7.2 Hz, 1H), 7.26-7.34 (
Figure imgf000186_0002
m， 6H), 7.55 (d, J = 8.6 Hz, 2H),3.22-3.29 (m, 2H), 4.35-4.39 (m, 1H), 4.51 (q, J = 7.0 Hz, 1H), 7.2 1 (t, J = 7.2 Hz, 1H), 7.26-7.34 (
Figure imgf000186_0002
m, 6H), 7.55 (d, J = 8.6 Hz, 2H),
HCI 8.77 (br s, 1H), 9.82 (br s， 1H), HCI 8.77 (br s, 1H), 9.82 (br s, 1H),
10.94 (s, 1H)  10.94 (s, 1H)
(R) -N'ー[4— (1ーメチルー 1一フエ二ルェチ 1H-NMR (500 MHz, DMSO-d6) ルチオ）フエニル]ピロリジン一 2—力ルポキサミ δ 1.61 (s, 6H)， 1.90-1.97 (m， 3H), ド 塩酸塩（化合物 15— 131 ) 2.35-2.39 (m, 1H), 3.22-3.33 (m, (R) -N '-[4— (1-Methyl- 1 monophenyl 1 H-NMR (500 MHz, DMSO-d 6 ) ruthio) phenyl] pyrrolidine mono 2-force lupoxami δ 1.61 (s, 6H), 1.90 -1.97 (m, 3H), dehydrochloride (compound 15—131) 2.35-2.39 (m, 1H), 3.22-3.33 (m,
2H), 4.33-4.36 (m, 1H), 7.12 (d, J 2H), 4.33-4.36 (m, 1H), 7.12 (d, J
= 8.7 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H)， 7.30 (dd, J = 8.6 Hz, 7.3
Figure imgf000186_0003
= 8.7 Hz, 2H), 7.22 (t, J = 7.3 Hz, 1H), 7.30 (dd, J = 8.6 Hz, 7.3
Figure imgf000186_0003
Hz, 2H)， 7.41 (d, J = 8.6 Hz, 2H Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H
HCI ), 7.51 (d, J = 8.7 Hz, 2H), 8.70 ( br s, 1H), 9.58 (br s, 1H), 10.84 ( s, 1H) HCI), 7.51 (d, J = 8.7 Hz, 2H), 8.70 (br s, 1H), 9.58 (br s, 1H), 10.84 (s, 1H)
(R)— N' —（4一フエネチルチオフエ二ル])ピロ 1H-NMR (500 MHz, DMSO - d6) リジン一 2—カルボキサミド 塩酸塩（化合物 15 δ 1.90-1.99 (m, 3H)， 2.36-2.40 ( -132) m, 1H)， 2.83 (t, J = 7.9 Hz, 2H), (R) — N ′ — (4 phenethylthiophenyl)) pyro 1 H-NMR (500 MHz, DMSO-d 6 ) lysine mono 2-carboxamide hydrochloride (compound 15 δ 1.90-1.99 (m, 3H ), 2.36-2.40 (-132) m, 1H), 2.83 (t, J = 7.9 Hz, 2H),
3.19 (t, J = 7.9 Hz, 2H)， 3.23-3.3 2 (m， 2H)， 4.33-4.36 (m, 1H)， 7.1 9-7.25 (m, 3H)， 7.29 (t, J = 7.3 Hz, 2H)， 7.38 (d, J = 8.9 Hz, 2H),
Figure imgf000186_0004
3.19 (t, J = 7.9 Hz, 2H), 3.23-3.3 2 (m, 2H), 4.33-4.36 (m, 1H), 7.1 9-7.25 (m, 3H), 7.29 (t, J = 7.3 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H),
Figure imgf000186_0004
7.60 (d, J = 8.9 Hz, 2H), 9.03 (b HCI r s, 2H), 10.77 (s, 1H)  7.60 (d, J = 8.9 Hz, 2H), 9.03 (b HCI r s, 2H), 10.77 (s, 1H)
(R)— N' — [4— (3—フエニルプロピルチオ）フ 1H - NMR (500 MHz, DMSO - d6) ェニル]ピロリジン一 2—カルボキサミド 塩酸塩 δ 1.82 (quintet, J = 7.3 Hz, 2H), (化合物 15— 133) 1.90-1.98 (m, 3H), 2.36-2.39 (m, (R) — N ′ — [4— (3-Phenylpropylthio) ph 1 H -NMR (500 MHz, DMSO -d 6 ) enyl] pyrrolidine mono 2-carboxamide hydrochloride δ 1.82 (quintet, J = 7.3 Hz , 2H), (Compound 15- 133) 1.90-1.98 (m, 3H), 2.36-2.39 (m,
1H), 2.69 (t, J = 7.3 Hz, 2H), 2.9 1 (t, J = 7.3 Hz, 2H)， 3.22-3.32 ( m, 2H), 4.32-4.35 (m, 1H), 7.16-7.
Figure imgf000186_0005
1H), 2.69 (t, J = 7.3 Hz, 2H), 2.9 1 (t, J = 7.3 Hz, 2H), 3.22-3.32 (m, 2H), 4.32-4.35 (m, 1H), 7.16-7.
Figure imgf000186_0005
19 (m, 3H), 7.27 (t, J = 7.5 Hz, HCI 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.5  19 (m, 3H), 7.27 (t, J = 7.5 Hz, HCI 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.5
7 (d, J = 8.9 Hz, 2H)， 9.05 (br s, 7 (d, J = 8.9 Hz, 2H), 9.05 (br s,
2H)， 10.74 (s, 1H) 2H), 10.74 (s, 1H)
(R) -Ν'ー（4一 η—プチルチオフエニル）ピロリ 1H-NMR (500 MHz, DMSO - d6) ジン一 2—力ルポキサミド 塩酸塩（化合物 15 δ 0.87 (t, J = 7.3 Hz, 3H), 1.35- (R) -Ν '-(4 η-Ptylthiophenyl) Pyrrol 1 H-NMR (500 MHz, DMSO-d 6 ) Gin -1-2-Lupoxamide hydrochloride (Compound 15 δ 0.87 (t, J = 7.3 Hz, 3H), 1.35-
84 ■134) 1.44 (m, 2H)， 1.49一 1.60 (m, 2H), 1 84 ■ 134) 1.44 (m, 2H), 1.49 one 1.60 (m, 2H), 1
.91-2.00 (m, 3H), 2.36 - 2.42 (m, 1H )， 2.91 (t, J = 7.2 Hz, 2H), 3.22- 3.30 (m, 2H), 4.35-4.40 (m, 1H), 7
Figure imgf000187_0001
• 33 (d, J = 8.6 Hz, 2H)， 7.59 (d,.91-2.00 (m, 3H), 2.36-2.42 (m, 1H), 2.91 (t, J = 7.2 Hz, 2H), 3.22- 3.30 (m, 2H), 4.35-4.40 (m, 1H), 7
Figure imgf000187_0001
• 33 (d, J = 8.6 Hz, 2H), 7.59 (d,
HCI J = 8.6 Hz, 2H)， 8.72 (br s, 1H), HCI J = 8.6 Hz, 2H), 8.72 (br s, 1H),
9,79 (br s, 1H), 10.84 (s, 1H)  9,79 (br s, 1H), 10.84 (s, 1H)
(R)— NT— (4—シクロへキシルメチルチオフエ 1H-N R (400 MHz, DMSO-d6) 二ル])ピロリジン一 2—カルボキサミド 塩酸塩 δ 0.91-1.01 (m, 2H), 1.09-1.21 ( (化合物 15— 135) m, 3H), 1.39-1.46 (m, 1H), 1.58-1. (R) — NT— (4-cyclohexylmethylthiophene 1 HN R (400 MHz, DMSO-d 6 ) dil]) pyrrolidine mono 2-carboxamide hydrochloride δ 0.91-1.01 (m, 2H), 1.09-1.21 ((Compound 15- 135) m, 3H), 1.39-1.46 (m, 1H), 1.58-1.
68 (m, 3H), 1.79-1.83 (m, 2H), 1.8 9-1.98 (m, 3H)， 2.37-2.44 (m, 1H), 68 (m, 3H), 1.79-1.83 (m, 2H), 1.8 9-1.98 (m, 3H), 2.37-2.44 (m, 1H),
2.82 (d, J = 6.8 Hz, 2H), 3.20-3.
Figure imgf000187_0002
2.82 (d, J = 6.8 Hz, 2H), 3.20-3.
Figure imgf000187_0002
30 (m, 2H), 4.35-4.39 (m, 1H)， 7.3 30 (m, 2H), 4.35-4.39 (m, 1H), 7.3
HCI 2 (d, J = 8.5 Hz, 2H), 7.58 (d, J HCI 2 (d, J = 8.5 Hz, 2H), 7.58 (d, J
= 8.5 Hz, 2H), 8.70 (br s, 1H), 9 .78 (br s, 1H), 10.86 (s, 1H)  = 8.5 Hz, 2H), 8.70 (br s, 1H), 9.78 (br s, 1H), 10.86 (s, 1H)
(R)-N' -[4-(2, 6—ジメチルペンジルチオ 1H-NMR (400 MHz, DMSO - d6) )フエニル]ピロリジン一 2—カルボキサミド 塩 δ 1.90-1.99 (m, 3Η), 2.31 (s, 6H), 酸塩（化合物 15— 136) 2.34-2.47 (m, 1H), 3.23-3.31 (m, (R) -N '-[4- (2,6-Dimethylpentylthio 1 H-NMR (400 MHz, DMSO-d 6 )) phenyl] pyrrolidine mono 2-carboxamide salt δ 1.90-1.99 (m, 3Η), 2.31 (s, 6H), acid salt (compound 15—136) 2.34-2.47 (m, 1H), 3.23-3.31 (m,
2H)， 4.16 (s, 2H), 4.37-4.39 (m, 1 H), 7.00-7.09 (m, 3H)， 7.40 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 H
Figure imgf000187_0003
z, 2H)， 8.69 (br s， 1H), 9.88 (br s HCI , 1H), 10.95 (s， 1H) 2H), 4.16 (s, 2H), 4.37-4.39 (m, 1 H), 7.00-7.09 (m, 3H), 7.40 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 H
Figure imgf000187_0003
z, 2H), 8.69 (br s, 1H), 9.88 (br s HCI, 1H), 10.95 (s, 1H)
(R) -N'一 [4一（2, 6—ジクロロべンジルチオ 1H - NMR (500 MHz, DMSO - d6) )フエニル]ピロリジン一 2—力ルポキサミド 塩 δ 1.90-1.99 (m, 3H), 2.36-2.42 ( 酸塩（化合物 15— 137) m, 1H), 3.23-3.30 (m, 2H), 4.34 (s, (R) -N '-[4- (2,6-dichlorobenzylthiol 1 H-NMR (500 MHz, DMSO-d 6 )) phenyl] pyrrolidine mono-2-lupoxamide salt δ 1.90-1.99 (m, 3H) , 2.36-2.42 (acid salt (compound 15—137) m, 1H), 3.23-3.30 (m, 2H), 4.34 (s,
2H)， 4.37-4.40 (m, 1H), 7.30-7.34 (m, 1H), 7.39 (d, J = 8.7 Hz, 2H )， 7.46 (d, J = 7.9 Hz, 2H), 7.60 (
Figure imgf000187_0004
d, J = 8.7 Hz, 2H), 8.68 (br s, 12H), 4.37-4.40 (m, 1H), 7.30-7.34 (m, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.60 (
Figure imgf000187_0004
d, J = 8.7 Hz, 2H), 8.68 (br s, 1
HCI H), 9.82 (br s, 1H)， 10.94 (s, 1H)HCI H), 9.82 (br s, 1H), 10.94 (s, 1H)
(R)-N'ー[4一（2—ピリジルチオ）フエニル]ピ 1H-NMR (500 MHz, DMSO - d6) 口リジン一 2—カルボキサミド 塩酸塩（化合物 δ 1.90-2.03 (m, 3Η), 2.41-2.54 ( 15-138) m, 1H), 3.23-3.33 (m, 2H), 4.39-4. (R) -N '-[4 (2-Pyridylthio) phenyl] pi 1 H-NMR (500 MHz, DMSO-d 6 ) Oral lysine mono 2-carboxamide hydrochloride (compound δ 1.90-2.03 (m, 3Η) , 2.41-2.54 (15-138) m, 1H), 3.23-3.33 (m, 2H), 4.39-4.
44 (m, 1H), 6.90 (dd, J = 7.6, 0.9 Hz, 1H)， 7.15 (ddd, J = 7.6, 4.9, 0,9 Hz, 1H), 7.59 (d, J = 8.7 Hz,
Figure imgf000187_0005
2H)， 7,65 (td, J = 7.6, 2,1 Hz, 144 (m, 1H), 6.90 (dd, J = 7.6, 0.9 Hz, 1H), 7.15 (ddd, J = 7.6, 4.9, 0,9 Hz, 1H), 7.59 (d, J = 8.7 Hz,
Figure imgf000187_0005
2H), 7,65 (td, J = 7.6, 2,1 Hz, 1
HCI H), 7.77 (d, J = 8.7 Hz, 2H), 8,39 HCI H), 7.77 (d, J = 8.7 Hz, 2H), 8,39
(ddd, J = 4.9, 2.1, 0.9 Hz, 1H), (ddd, J = 4.9, 2.1, 0.9 Hz, 1H),
8.71 (br s, 1H), 9.88 (br s, 1H), 18.71 (br s, 1H), 9.88 (br s, 1H), 1
1.12 (s, 1H) 1.12 (s, 1H)
(R)-N'—[4一（4—ピリジルチオ）フエニル]ピ 1H-NMR (500 MHz, DMSO- d6) 口リジン一 2—力ルポキサミド 塩酸塩（化合物 δ 1.90-2.02 (m, 3H), 2.42-2.54 ( 15-139) m, 1H), 3.24-3.29 (m, 2H), 4.45-4. (R) -N '— [4 (4-Pyridylthio) phenyl] pi 1 H-NMR (500 MHz, DMSO-d 6 ) Oral lysine mono-2-power lupoxamide hydrochloride (compound δ 1.90-2.02 (m, 3H ), 2.42-2.54 (15-139) m, 1H), 3.24-3.29 (m, 2H), 4.45-4.
49 (m, 1H), 7.47 (d, J = 6.9 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.9  49 (m, 1H), 7.47 (d, J = 6.9 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.9
85 d6) 85 d 6 )
( ( (
Figure imgf000188_0001
(((
Figure imgf000188_0001
8 6 d6) 8 6 d 6 )
(  (
d6) d 6 )
- d6) -d 6 )
(  (
- d6) -d 6 )
( (
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000189_0001
Figure imgf000190_0001
8 8 ( 8 8 (
( (
d6) d 6 )
(  (
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000191_0001
Figure imgf000192_0001
9 0
Figure imgf000193_0001
9 0
Figure imgf000193_0001
1 9 ピロリジン一 2—力ルポキサミド 塩酸塩（化合 δ 1.94-2.04 (m, 3H)， 2.44-2.48 ( 物 15— 1フ3) m, 1H), 3.25-3.34 (m, 2H), 4.43-4. 1 9 Pyrrolidine 1-strength lupoxamide hydrochloride (compound δ 1.94-2.04 (m, 3H), 2.44-2.48 (compound 15-1 f3) m, 1H), 3.25-3.34 (m, 2H), 4.43-4.
47 (m, 1H), 7.85 (d, J = 8,7 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.9 1-7.95 (m, 1H), 8.35 (d, J = 9.5 47 (m, 1H), 7.85 (d, J = 8,7 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.9 1-7.95 (m, 1H), 8.35 (d, J = 9.5
H 0 Hz, 1H), 8.39 (d, J = 9.5 Hz, 1H), HCI 8.55 (s, 1H), 8.72 (br s, 1H), 8.9 H 0 Hz, 1H), 8.39 (d, J = 9.5 Hz, 1H), HCI 8.55 (s, 1H), 8.72 (br s, 1H), 8.9
3 (d, J = 7.9 Hz, 1H), 9.16 (d, J = 4.6 Hz, 1H)， 9.96 (s， 1H)， 11.1 3 (d, J = 7.9 Hz, 1H), 9.16 (d, J = 4.6 Hz, 1H), 9.96 (s, 1H), 11.1
4 (s, 1H) 4 (s, 1H)
(R)一 N'—[4— (ベンゾチアゾールー 2—ィル） 1H-NMR (500 MHz, DMSO-d6) フエニル]ピロリジン一 2—カルボキサミド 塩酸 δ 1.91-2.04 (m, 3H), 2.41-2.48 ( 塩（化合物 15— 174) m, 1H), 3.25-3.33 (m, 2H), 4.43-4. (R) -N '— [4- (Benzothiazol-2-yl) 1 H-NMR (500 MHz, DMSO-d 6 ) phenyl] pyrrolidine mono 2-carboxamide hydrochloride δ 1.91-2.04 (m, 3H), 2.41-2.48 (Salt (compound 15—174) m, 1H), 3.25-3.33 (m, 2H), 4.43-4.
46 (m, 1H), 7.46 (t, J = 8,0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H)， 7.8 5 (d, J = 8.6 Hz, 2H), 8.04 (d, J 46 (m, 1H), 7.46 (t, J = 8,0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.8 5 (d, J = 8.6 Hz, 2H), 8.04 (d, J
= 8.0 Hz, 1H), 8.11 (d, J = 8.6= 8.0 Hz, 1H), 8.11 (d, J = 8.6
HCI Hz, 2H)， 8.14 (d, J = 8.0 Hz, 1H), HCI Hz, 2H), 8.14 (d, J = 8.0 Hz, 1H),
8.72-8.74 (m, 1H)， 9.85 (br s, 1H ), 11.20 (s, 1H)  8.72-8.74 (m, 1H), 9.85 (br s, 1H), 11.20 (s, 1H)
(R)-N'—[4— (5—クロ口べンゾチアゾ一ルー 1H-NMR (500 MHz, DMSO - d6) 2—ィル)フエニル]ピロリジン一 2—力ルポキサミ δ 1.91-2.05 (m, 3H), 2.41-2.47 ( ド 塩酸塩（化合物 15— 1フ5) m, 1H), 3.25-3.34 (m, 2H), 4.43-4. (R) -N '— [4— (5-Chronobenzothiazo-Lu 1 H-NMR (500 MHz, DMSO-d 6 ) 2-yl) phenyl] pyrrolidine-I 2—Power Lupoxami δ 1.91-2.05 ( m, 3H), 2.41-2.47 (dehydrochloride (compound 15-1 f5) m, 1H), 3.25-3.34 (m, 2H), 4.43-4.
49 (m， 1H), 7.51 (dd, J = 8.6, 2.1 49 (m, 1H), 7.51 (dd, J = 8.6, 2.1
Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H ), 8.10-8.12 (m, 3H), 8.19 (d， J =Hz, 1H), 7.87 (d, J = 8.6 Hz, 2H), 8.10-8.12 (m, 3H), 8.19 (d, J =
8.6 Hz, 1H), 8.72-8.73 (m, 1H), 9
Figure imgf000194_0001
.92-9.94 (m， 1H), 11.27, 11.28 (s, 8.6 Hz, 1H), 8.72-8.73 (m, 1H), 9
Figure imgf000194_0001
.92-9.94 (m, 1H), 11.27, 11.28 (s,
1H)  1H)
(R) -N'—[4一（6—トリフルォロメチルベンゾ 1H-N R (400 MHz, DMSO - d6) チアゾ一ル一2—ィル)フエニル]ピロリジン一 2— 6 1.93-2.06 (m, 3H), 2.46-2.52 ( カルボキサミド 塩酸塩（化合物 15— 176) m, 1H), 3.27-3.32 (m， 2H), 4.46-4. (R) -N '- [4 one (6-triflate Ruo b methylbenzoyl 1 HN R (400 MHz, DMSO - d 6) thiazole Ichiru one 2-I le) phenyl] pyrrolidine one 2- 6 1.93-2.06 ( m, 3H), 2.46-2.52 (carboxamide hydrochloride (compound 15—176) m, 1H), 3.27-3.32 (m, 2H), 4.46-4.
51 (m, 1H), 7.78 (dd, J = 8.4, 1.6 51 (m, 1H), 7.78 (dd, J = 8.4, 1.6
Hz, 1H), 7.90 (d, J = 8.8 Hz, 2HHz, 1H), 7.90 (d, J = 8.8 Hz, 2H
？ ), 8.15 (d, J = 8.8 Hz, 2H), 8.37 ( ? ), 8.15 (d, J = 8.8 Hz, 2H), 8.37 (
FF s， 1H), 8.41 (d, J = 8.4 Hz, 1H), HCI 8.73-8.74 (m, 1H), 10.08 - 10.09 (m, F F s, 1H), 8.41 (d, J = 8.4 Hz, 1H), HCI 8.73-8.74 (m, 1H), 10.08-10.09 (m,
1H), 11.41 (s, 1H)  1H), 11.41 (s, 1H)
(R) -N' - [4— (6—クロ口べンゾチアゾ一ルー 1H-N R (500 MHz, DMSO - d6) 2—ィル)フエニル]ピロリジン一 2—カルボキサミ δ 1.91-2.04 (m, 3H), 2.41-2.46 ( ド 塩酸塩（化合物 15— 177) m, 1H), 3.26-3.3.3 (m, 2H), 4.41-4. (R) -N '-[4— (6—Black-headed Benzothiazo-Lu 1 HN R (500 MHz, DMSO-d 6 ) 2-yl) phenyl] pyrrolidine-I 2-Carboxami δ 1.91-2.04 (m, 3H), 2.41-2.46 (dehydrochloride (compound 15—177) m, 1H), 3.26-3.3.3 (m, 2H), 4.41-4.
44 (m, 1H), 7.57 (dd, J = 8.9, 2.1 44 (m, 1H), 7.57 (dd, J = 8.9, 2.1
Hz, 1H), 7.84 (d, J = 8.9 Hz, 2H ), 8,03 (d, J = 8.9 Hz, 1H), 8.11 ( d, J = 8.9 Hz, 2H), 8.31 (d, J =Hz, 1H), 7.84 (d, J = 8.9 Hz, 2H), 8,03 (d, J = 8.9 Hz, 1H), 8.11 (d, J = 8.9 Hz, 2H), 8.31 (d, J =
HCI 2.1 Hz, 1H), 8,73 (br s, 1H), 9.65 HCI 2.1 Hz, 1H), 8,73 (br s, 1H), 9.65
(br s, 1H), 10.34 (s, 1H)  (br s, 1H), 10.34 (s, 1H)
(R) -N'一 [4一（ベンゾイミダゾ一ルー 2—ィル 1H-N R (500 MHz, DMSO - d6) (R) -N 'One [4 One (Benzimidazo One-Lou 2-Yil 1 HN R (500 MHz, DMSO-d 6 )
)フエニル]ピロリジン一 2—カルボキサミド 二塩 δ 1.91-2.06 (m, 3H), 2.43-2.47 ( ) Phenyl] pyrrolidine mono 2-carboxamide disalt δ 1.91-2.06 (m, 3H), 2.43-2.47 (
92 酸塩（化合物 15— 178) m, 1H)， 3.25-3.33 (m, 2H), 4.46 - 4. 92 Acid salt (compound 15—178) m, 1H), 3.25-3.33 (m, 2H), 4.46-4.
51 (m， 1H), 7.51 - 7.53 (m, 2H)， 7.8 0-7.82 (m, 2H), 7.96 (d, J = 8.8 Hz, 2H), 8.35 (d, J = 8.8 Hz, 2H), 8.73-8.75 (m, 1H), 9.84 (br s, 1H 51 (m, 1H), 7.51-7.53 (m, 2H), 7.8 0-7.82 (m, 2H), 7.96 (d, J = 8.8 Hz, 2H), 8.35 (d, J = 8.8 Hz, 2H), 8.73-8.75 (m, 1H), 9.84 (br s, 1H
2HCI Π )， 11.45 (s， 1H), 15.40 (br s, 2H) 2HCI Π), 11.45 (s, 1H), 15.40 (br s, 2H)
(R) -N'一 [4一（ベンゾォキサゾール一2—ィ 1H-NMR (500 MHz, DMSO - d6) ル)フエニル]ピロリジン一 2—カルボキサミド 塩 8 1,90-2,05 (m, 3H)， 2.42-2.54 ( 酸塩（化合物 15— 179) m, 1H)， 3.24-3.34 (m, 2H), 4.44-4. (R) -N 'one [4 one (benzo O benzoxazole one 2 I 1 H-NMR (500 MHz, DMSO - d 6) Le) phenyl] pyrrolidine one 2-carboxamide salt 8 1,90-2,05 (m, 3H), 2.42-2.54 (acid salt (compound 15—179) m, 1H), 3.24-3.34 (m, 2H), 4.44-4.
49 (m, 1H), 7.40-7.44 (m， 2H), 7.7 6-7.81 (m, 2H), 7.90 (d， J = 8,9 Hz, 2H), 8.21 (d, J = 8.9 Hz, 2H)， 8.72-8.73 (m, 1H), 9.89 (br s, 1H 49 (m, 1H), 7.40-7.44 (m, 2H), 7.7 6-7.81 (m, 2H), 7.90 (d, J = 8,9 Hz, 2H), 8.21 (d, J = 8.9 Hz, 2H ), 8.72-8.73 (m, 1H), 9.89 (br s, 1H
HCI )， 11.28 (s, 1H) HCI), 11.28 (s, 1H)
(R) -N'—[4— [(E)— 2—エトキシカルボ二 'H-NMR (400 MHz, DMSO- d6) ルー 1ーェテニル]フエニル]ピロリジンー2—力 δ 1.25 (t, J = 7.1 Hz, 3H)， 1.90- ルポキサミド 塩酸塩（化合物 15— 180) 2.02 (m, 3H), 2.32-2.54 (m, 1H), 3 (R) -N '— [4— [(E) — 2-Ethoxycarbodi'H-NMR (400 MHz, DMSO-d 6 ) Ru 1-ethenyl] phenyl] pyrrolidine-2—force δ 1.25 (t, J = 7.1 Hz, 3H), 1.90-Lupoxamide hydrochloride (compound 15—180) 2.02 (m, 3H), 2.32-2.54 (m, 1H), 3
.26-3.30 (m， 2H), 4.18 (q, J = 7.1 ο., 。 Hz, 2H)t 4.38-4.40 (m, 1H), 6.56 .26-3.30 (m, 2H), 4.18 (q, J = 7.1 ο., Hz, 2H) t 4.38-4.40 (m, 1H), 6.56
(d, J = 16.1 Hz, 1H), 7.60 (d, J = (d, J = 16.1 Hz, 1H), 7.60 (d, J =
H 0 0 H 0 0
16.1 Hz, 1H), 7.68 (d, J = 8.8 H HCI z, 2H), 7.73 (d, J = 8.8 Hz, 2H),  16.1 Hz, 1H), 7.68 (d, J = 8.8 H HCI z, 2H), 7.73 (d, J = 8.8 Hz, 2H),
9.20 (br s, 2H), 10.99 (s, 1H) 9.20 (br s, 2H), 10.99 (s, 1H)
(R) - '—【3— [(E)—2—フ； r二ルー 1ーェ亍 1H-NMR (400 MHz, DMSO - d6) ニル]フエニル]ピロリジン一 2—カルボキサミド δ 1.91-2.04 (m， 3H), 2.39-2.45 ( 塩酸塩（化合物 15— 181) m, 1H), 3.23-3.31 (m, 2H), 4.37-4. (R)-'— 【3— [(E) —2—F; r 2-ru 1- ー1 H-NMR (400 MHz, DMSO-d 6 ) Nyl] phenyl] pyrrolidine 1 2-carboxamide δ 1.91- 2.04 (m, 3H), 2.39-2.45 (hydrochloride (compound 15—181) m, 1H), 3.23-3.31 (m, 2H), 4.37-4.
41 (m, 1H), 7.17 (d, J = 16.5 Hz, 41 (m, 1H), 7.17 (d, J = 16.5 Hz,
1H)， 7.26 (d, J = 16.5 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.35-7.4 1 (m, 4H), 7.53 (dt, J = 6.6, 2.3 Hz, 1H), 7,62 (d, J = 7.1 Hz, 2H),1H), 7.26 (d, J = 16.5 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.35-7.4 1 (m, 4H), 7.53 (dt, J = 6.6, 2.3 Hz, 1H) , 7,62 (d, J = 7.1 Hz, 2H),
H" 0 7.85 (s, 1H), 10.81 (s, 1H) HCI H "0 7.85 (s, 1H), 10.81 (s, 1H) HCI
(R) - '— [4一 [(E)— 2—フ王ニルー 1—ェ亍 1H - NMR (500 MHz, DMSO- d6) ニル]フエニル]ピロリジン一 2—カルボキサミド δ 1.93-2.00 (m, 3H), 2.41-2.45 ( 塩酸塩（化合物 15— 182) m, 1H), 3.27-3.29 (m, 2H)， 4.42 (b r s, 1H), 7.19 (d, J = 16.5 Hz, 1 H), 7.23 (d, J = 16.5 Hz, 1H), 7.2(R)-'— [4 1 [(E) 2 2-Fu Nyl 1- H 1 NMR-(500 MHz, DMSO-d 6 ) Nyl] phenyl] pyrrolidine 1 2-carboxamide δ 1.93-2.00 ( m, 3H), 2.41-2.45 (hydrochloride (compound 15—182) m, 1H), 3.27-3.29 (m, 2H), 4.42 (brs, 1H), 7.19 (d, J = 16.5 Hz, 1 H) , 7.23 (d, J = 16.5 Hz, 1H), 7.2
Η' Ο 6 (t, J = 7.4 Hz, 1H), 7.38 (t, J Η 'Ο 6 (t, J = 7.4 Hz, 1H), 7.38 (t, J
~  ~
= 7.4 Hz, 2H)， 7.58-7.61 (m, 2H), HCI 7.66 (d, J = 8.9 Hz, 2H), 7.68 (d,  = 7.4 Hz, 2H), 7.58-7.61 (m, 2H), HCI 7.66 (d, J = 8.9 Hz, 2H), 7.68 (d,
J = 8,9 Hz, 2H)， 8.68 (br s, 1H), 10.03 (br s, 1H), 11.01 (s， 1H) J = 8,9 Hz, 2H), 8.68 (br s, 1H), 10.03 (br s, 1H), 11.01 (s, 1H)
(R)-N'一 [4— [(E)— 2— (4—カルボキシフ 1H-NMR (400 MHz, DMSO - d6) ェニル）一 1ーェ亍ニル]フエニル]ピロリジン一 2 δ 1.91-2.02 (m， 3H), 2.38 - 2.48 ( 一力ルポキサミド 塩酸塩（化合物 15— 183) m, 1H), 3.24-3.29 (m, 2H), 4.36-4. (R) -N ′-[4 — [(E) — 2— (4-Carboxyph 1 H-NMR (400 MHz, DMSO -d 6 ) enyl) -1-enyl] phenyl] pyrrolidine 1 2 δ 1.91-2.02 (m, 3H), 2.38-2.48 (strength lupoxamide hydrochloride (compound 15-183) m, 1H), 3.24-3.29 (m, 2H), 4.36-4.
38 (m, 1H), 7.27 (d, J = 16.5 Hz, 1H), 7.38 (d, J = 16.5 Hz, 1H), 7.42-7.71 (m， 6H), 7.93 (d, J = 8.
Figure imgf000196_0001
38 (m, 1H), 7.27 (d, J = 16.5 Hz, 1H), 7.38 (d, J = 16.5 Hz, 1H), 7.42-7.71 (m, 6H), 7.93 (d, J = 8.
Figure imgf000196_0001
9 4 Hz, 1H), 7.20 (d, J = 16.3 Hz, 1 9 4 Hz, 1H), 7.20 (d, J = 16.3 Hz, 1
H), 7.26 (t， J = 7.5 Hz, 1H), 7.37 H), 7.26 (t, J = 7.5 Hz, 1H), 7.37
(d, J = 7,5 Hz, 1H), 7.41 (s, 1H)(d, J = 7,5 Hz, 1H), 7.41 (s, 1H)
H' 0 , 7.59 (d, J = 8.7 Hz, 2H), 7.66 ( HCI d, J = 8.7 Hz, 2H), 8.69 (br s, 1 H '0, 7.59 (d, J = 8.7 Hz, 2H), 7.66 (HCI d, J = 8.7 Hz, 2H), 8.69 (br s, 1
H), 9.93 (br s, 1H)， 10.96 (s, 1 H) H), 9.93 (br s, 1H), 10.96 (s, 1 H)
(R)— N' —[4— [(E)—2— (4—メチルフエ二 - NMR (500 MHz, DMSO - d6) ル）一 1ーェ亍ニル]フエニル]ピロリジン一 2—力 δ 1.91-2.02 (m, 3H), 2.31 (s, 3H)，. ルポキサミド 塩酸塩（化合物 15— 189) 2.34-2.47 (m, 1H), 3.23-3.30 (m, (R) — N ′ — [4— [(E) —2— (4-Methylphenyl-NMR (500 MHz, DMSO -d 6 ))) 1-phenyl] phenyl] pyrrolidine 1- 2 force δ 1.91-2.02 (m, 3H), 2.31 (s, 3H),. Lupoxamide hydrochloride (compound 15—189) 2.34-2.47 (m, 1H), 3.23-3.30 (m,
2H), 4.37-4.40 (m, 1H), 7.15 (s, 2 H)， 7.18 (d, J = 8,1 Hz, 2H), 7.47 2H), 4.37-4.40 (m, 1H), 7.15 (s, 2 H), 7.18 (d, J = 8,1 Hz, 2H), 7.47
(d, J = 8.1 Hz, 2H), 7.58 (d, J(d, J = 8.1 Hz, 2H), 7.58 (d, J
H 0 H 0
= 8.7 Hz, 2H), 7.64 (d， J = 8.7 H HCI z, 2H), 8.66 (br s, 1H), 9.83 (br s  = 8.7 Hz, 2H), 7.64 (d, J = 8.7 H HCI z, 2H), 8.66 (br s, 1H), 9.83 (br s
, 1H), 10.87 (s, 1H)  , 1H), 10.87 (s, 1H)
(R)— N' — [4— [(E)— 2— (2—クロ口フエ二 1H -國 R (500 MHz, DMSO - d6) ル）ー1ーェ亍ニル]フエニル]ピロリジン一 2—力 δ 1.92-2.01 (m, 3H), 2.40-2.45 ( ルポキサミド 塩酸塩（化合物 15— 190) . m, 1H), 3.25-3.31 (m, 2H), 4.40-4. (R) - N '- [ 4- [(E) - 2- (2- Black port phenylene 1 H - kingdom R (500 MHz, DMSO - d 6) Le) -1-E亍sulfonyl] phenyl] pyrrolidine 1 2—Force δ 1.92-2.01 (m, 3H), 2.40-2.45 (Lupoxamide hydrochloride (compound 15—190) .m, 1H), 3.25-3.31 (m, 2H), 4.40-4.
H CI 43 (m, 1H)， 7.28 (d, J = 16,3 Hz,  H CI 43 (m, 1H), 7.28 (d, J = 16,3 Hz,
1H), 7.29-7.32 (m, 1H)， 7.36 - 7.39 (m, 1H), 7.39 (d, J = 16.3 Hz, 1 1H), 7.29-7.32 (m, 1H), 7.36-7.39 (m, 1H), 7.39 (d, J = 16.3 Hz, 1
H 0 H)， 7.48 (dd, J = 7.9， 1.5 Hz, 1H)， HCI 7.63 (d, J = 8.7 Hz, 2H)， 7.70 (d H 0 H), 7.48 (dd, J = 7.9, 1.5 Hz, 1H), HCI 7.63 (d, J = 8.7 Hz, 2H), 7.70 (d
, J = 8.7 Hz, 2H), 7.86 (dd, J = 7.9， 1.5 Hz, 1H), 8.70 (br s, 1H), 9.94 (br s， 1H), 10.99， 11.00 (s， 1 H)  , J = 8.7 Hz, 2H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 8.70 (br s, 1H), 9.94 (br s, 1H), 10.99, 11.00 (s, 1 H)
(R) -N' 一 [4— [(E)— 2— (3—クロ口フエ二 1H-NMR (400 MHz, DMS0-d6) ル）一 1ーェテニル]フエニル]ピロリジン一 2—力 δ 1.91-2.03 (m, 3H), 2.39-2.47 ( ルボキサミド 塩酸塩（化合物 15— 191 ) m, 1H)， 3.25-3.31 (m, 2H), 4.41 (b r s, 1H), 7.19 (d, J = 16.4 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1H), 7.32(R) -N 'one [4- [(E) - 2- (3- black port phenylene 1 H-NMR (400 MHz, DMS0-d 6) Le) Single 1 Eteniru] phenyl] pyrrolidine one 2- force δ 1.91-2.03 (m, 3H), 2.39-2.47 (ruboxamide hydrochloride (compound 15—191) m, 1H), 3.25-3.31 (m, 2H), 4.41 (brs, 1H), 7.19 (d, J = 16.4 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1H), 7.32
H 0 (d, J = 16.4 Hz, 1H), 7.40 (t, J H 0 (d, J = 16.4 Hz, 1H), 7.40 (t, J
= 7.8 Hz, 1H), 7.54 (d, J = 7.8 H HCI z, 1H), 7.61 (d, J = 8.8 Hz, 2H),  = 7.8 Hz, 1H), 7.54 (d, J = 7.8 H HCI z, 1H), 7.61 (d, J = 8.8 Hz, 2H),
7.64-7.68 (m， 3H), 8.69 (br s, 1H), 7.64-7.68 (m, 3H), 8.69 (br s, 1H),
9.90 (br s, 1H), 10.94, 10.97 (s, 1H) 9.90 (br s, 1H), 10.94, 10.97 (s, 1H)
(R) -N' 一 [4— [(E)—2—（4一クロ口フエ二 1H-NMR (500 MHz, DMSO - d6) ル）一 1ーェ亍ニル]フエニル]ピロリジン一 2—力 δ 1.92-2.02 (m, 3H), 2.36-2.47 ( ルポキサミド 塩酸塩（化合物 15— 192) m, 1H), 3.27-3.28 (m, 2H), 4.40 (b (R) -N 'one [4- [(E) -2- ( 4 one black port phenylene 1 H-NMR (500 MHz, DMSO - d 6) Le) one 1 over E亍sulfonyl] phenyl] pyrrolidine one 2—Force δ 1.92-2.02 (m, 3H), 2.36-2.47 (Lupoxamide hydrochloride (compound 15—192) m, 1H), 3.27-3.28 (m, 2H), 4.40 (b
H へ r s, 1H), 7.19 (d, J = 16.5 Hz, 1  H to r s, 1H), 7.19 (d, J = 16.5 Hz, 1
H), 7.25 (d, J = 16.5 Hz, 1H), 7.4 H), 7.25 (d, J = 16.5 Hz, 1H), 7.4
K o V ci 2-7.44 (m, 2H), 7.59-7.64 (m, 2H), K o V ci 2-7.44 (m, 2H), 7.59-7.64 (m, 2H),
7.61 (d, J = 8.6 Hz, 2H), 7.66 (d 7.61 (d, J = 8.6 Hz, 2H), 7.66 (d
HCI , J = 8.6 Hz, 2H)， 8.69 (br s, 1H) HCI, J = 8.6 Hz, 2H), 8.69 (br s, 1H)
, 9.85 (br s, 1H), 10.92 (s, 1H) , 9.85 (br s, 1H), 10.92 (s, 1H)
(R)-N'—[4— [(E)— 2—（2—トリフルォロメ H-NMR (400 MHz, DMSO - d6) チルフエ二ル）一 1ーェ亍ニル]フエニル]ピロリジ δ 1.91-2.02 (m, 3H)， 2.38-2.44 ( (R) -N '— [4— [(E) — 2— (2-trifluoromethyl-H-NMR (400 MHz, DMSO-d 6 ) tylfenyl) 1-enyl] phenyl] pyrrolidi δ 1.91- 2.02 (m, 3H), 2.38-2.44 (
95
Figure imgf000198_0001
Figure imgf000199_0001
95
Figure imgf000198_0001
Figure imgf000199_0001
9 7
Figure imgf000200_0001
( 9 7
Figure imgf000200_0001
(
(m,  (m,
2.45 ( 2.45 (
3H), 3H),
( (
( (s,
Figure imgf000201_0001
((s,
Figure imgf000201_0001
9 9
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
( ( ( ( (
Figure imgf000205_0001
d6) 9 9
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
(((((
Figure imgf000205_0001
d 6 )
(  (
d6) d 6 )
(  (
d6) d 6 )
(  (
d6) d 6 )
(  (
( (
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
(
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
(
- d6) -d 6 )
(  (
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
d6)
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
d 6 )
( (s,  ((s,
- de) -d e )
( (t,  ((t,
de) d e )
( (s，  ((s,
d6) (s, 3H), d 6 ) (s, 3H),
1 d6) 1 d 6 )
3H), (m,  3H), (m,
Figure imgf000216_0001
3H),
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
3H),
Figure imgf000216_0001
3H),
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
3H),
( ( ((
( (
- d6) -d 6 )
(  (
3H), 3H),
(
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
( (
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
(
( 7.5 (7.5
( 4.46 (b (4.46 (b
d6) d 6 )
(  (
d6) d 6 )
(  (
- d6)
Figure imgf000223_0001
-d 6 )
Figure imgf000223_0001
2 2
Figure imgf000224_0001
4.28 twenty two
Figure imgf000224_0001
4.28
- d6) -d 6 )
(  (
- d6) -d 6 )
=  =
d6) d 6 )
，  ,
d6)
Figure imgf000225_0001
Figure imgf000226_0001
( d 6 )
Figure imgf000225_0001
Figure imgf000226_0001
(
( (
( (
6H), 6H),
( (b ((b
(
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
( (
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
(
( 4.43 (b (4.43 (b
( (m, ((m,
( (
(
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
(
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
2 3
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
, 7.96-8.03 (m, 2H), 8.71 (br s, 1twenty three
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
, 7.96-8.03 (m, 2H), 8.71 (br s, 1
ΓΛ ィ H), 10.32 (br s, 1H), 11.37 (s, 1H) ΓΛ i H), 10.32 (br s, 1H), 11.37 (s, 1H)
HCI F HCI F
(R) -N'一 [4一 [2— (2—メトキシー 1一ナフ 1H-NMR (400 MHz, DMSO - d6) チル）一1ーェチニル]フエニル]ピロリジン一 2— δ 1.94-2.02 (m, 3H), 2.41-2.47 (. カルポキサミド 塩酸塩（化合物 15— 401) m, 1H), 3.26-3.32 (m, 2H), 4.01 (s, (R) -N 'one [4 one [2- (2-methoxy 1 one naphthoquinone 1 H-NMR (400 MHz, DMSO - d 6) chill) Single 1 Echiniru] phenyl] pyrrolidine one 2- [delta] 1.94-2.02 ( m, 3H), 2.41-2.47 (. Carpoxamide hydrochloride (compound 15—401) m, 1H), 3.26-3.32 (m, 2H), 4.01 (s,
3H), 4.38-4.42 (m， 1H), 7.42-7.46 (m, 1H), 7.52 (d, J = 9.0 Hz, 1H 3H), 4.38-4.42 (m, 1H), 7.42-7.46 (m, 1H), 7.52 (d, J = 9.0 Hz, 1H
), 7.60-7.63 (m, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8,7 Hz, 2H), 7.94 (d, J = 8.3 Hz, 1H), 8.
Figure imgf000238_0001
02 (d, J = 9.0 Hz, 1H), 8,22 (d, J ), 7.60-7.63 (m, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8,7 Hz, 2H), 7.94 (d, J = 8.3 Hz, 1H), 8 .
Figure imgf000238_0001
02 (d, J = 9.0 Hz, 1H), 8,22 (d, J
= 8,8 Hz, 1H), 8.73 (br s, 1H)， 9 = 8,8 Hz, 1H), 8.73 (br s, 1H), 9
.62 (br s, 1H), 10.96 (s， 1H).62 (br s, 1H), 10.96 (s, 1H)
(R) -N'—[4— [2— (2—ァセチルフ: cニル） 'H-NMR (400 MHz, DMSO-d6) -1—ェチニル]フエニル]ピロリジン一 2—カル δ 1.93-2.00 (m, 3H), 2.41-2.45 ( ポキサミド 塩酸塩（化合物 15— 402) m, 1H), 2.69 (s, 3H), 3.27-3.28 (m, (R) -N '— [4— [2— (2-acetylyl: cnyl)' H-NMR (400 MHz, DMSO-d 6 ) -1-ethynyl] phenyl] pyrrolidine mono 2-cal δ 1.93-2.00 (m, 3H), 2.41-2.45 (poxamide hydrochloride (compound 15-402) m, 1H), 2.69 (s, 3H), 3.27-3.28 (m,
2H), 4.42 (br s, 1H), 7.50-7.55 ( m， 1H), 7.57 (d, J = 8.8 Hz, 2H)， 2H), 4.42 (br s, 1H), 7.50-7.55 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H),
7.60 (td, J = 7.5, 1.4 Hz, 1H)， 7.7.60 (td, J = 7.5, 1.4 Hz, 1H), 7.
H O 67 (dd， J = 7.7, 1.1 Hz, 1H), 7,73 HCI (d, J = 8.8 Hz, 2H), 7,83 (dd, J H O 67 (dd, J = 7.7, 1.1 Hz, 1H), 7,73 HCI (d, J = 8.8 Hz, 2H), 7,83 (dd, J
= 7.8， 1.0 Hz, 1H), 8.70 (br s, 1 H), 9,80 (br s, 1H), 11.08 (s, 1H) = 7.8, 1.0 Hz, 1H), 8.70 (br s, 1 H), 9,80 (br s, 1H), 11.08 (s, 1H)
(R) -N'一 [4— [2— (キノリン一 6—ィル）一1 1H-NMR (500 MHz, DMSO - d6) ーェチニル]フエニル]ピロリジン一 2—カルボキ δ 1.91-2.02 (m, 3H), 2.41-2.44 ( サミド 塩酸塩（化合物 15— 403) m, 1H), 3.25-3.32 (m, 2H), 4.39-4. (R) -N '1 [4— [2— (Quinolin 6-yl) 1 1 1 H-NMR (500 MHz, DMSO-d 6 ) -ethynyl] phenyl] pyrrolidine 1 2-carboki δ 1.91-2.02 ( m, 3H), 2.41-2.44 (samide hydrochloride (compound 15-403) m, 1H), 3.25-3.32 (m, 2H), 4.39-4.
41 (m, 1H), 7.63 (d, J = 8,9 Hz, 2H)， 7.70-7.72 (m, 1H), 7.74 (d, J 41 (m, 1H), 7.63 (d, J = 8,9 Hz, 2H), 7.70-7.72 (m, 1H), 7.74 (d, J
= 8.9 Hz, 2H)， 7.93 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H),
Figure imgf000238_0002
8.31 (s, 1H), 8.56 (d, J = 7.9 Hz ， 1H), 8.68-8.75 (m, 1H), 9.02 (d, J = 4.3 Hz, 1H), 9.61 (br s, 1H), 10.99 (s, 1H) = 8.9 Hz, 2H), 7.93 (d, J = 8.6 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H),
Figure imgf000238_0002
8.31 (s, 1H), 8.56 (d, J = 7.9 Hz, 1H), 8.68-8.75 (m, 1H), 9.02 (d, J = 4.3 Hz, 1H), 9.61 (br s, 1H), 10.99 ( s, 1H)
(R) -N'—[4一 [2— (2—シァノメチルフエ二 (H-NMR (500 MHz, D SO-d6) ル）一 1ーェチニル]フエニル]ピロリジン一 2—力 δ 1.91-2.03 (m, 3H), 2.39-2.45 ( ルポキサミド 塩酸塩（化合物 15— 404) m, 1H), 3.23-3.31 (m, 2H), 4.18 (s, (R) -N '— [4 1 [2— (2-Cyanomethylphenyl ( H-NMR (500 MHz, D SO-d 6 )) 1 1-ethynyl] phenyl] pyrrolidine 1 2—force δ 1.91-2.03 ( m, 3H), 2.39-2.45 (Lupoxamide hydrochloride (compound 15-404) m, 1H), 3.23-3.31 (m, 2H), 4.18 (s,
H CN 2H), 4.40 (br s, 1H), 7.42 (t, J = ' 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz,  H CN 2H), 4.40 (br s, 1H), 7.42 (t, J = '7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz,
1H), 7.53 (d, J = 7.5 Hz, 1H), 7. 60 (d, J = 7.5 Hz, 1H), 7,63 (d, J 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7,63 (d, J
HCI = 8.7 Hz, 2H), 7.72 (d, J = 8.7 HCI = 8.7 Hz, 2H), 7.72 (d, J = 8.7
Hz, 2H)， 8.72 (br s, 1H), 9.70 (br s, 1H), 10,99, 11.01 (s, 1H) Hz, 2H), 8.72 (br s, 1H), 9.70 (br s, 1H), 10,99, 11.01 (s, 1H)
(R)-N'—[4— [2— (2—メチルチオフエニル） 1H-NMR (500 MHz, DMSO - d6) 一 1—ェチニル]フエニル]ピロリジン一 2—カル δ 1.91-2.03 (m, 3H), 2.38-2.45 ( ボキサミド 塩酸塩（化合物 15— 405) m, 1H), 2.49 (s, 3H), 3.29-3.40 (m, (R) -N '— [4— [2— (2-Methylthiophenenyl) 1 H-NMR (500 MHz, DMSO -d 6 ) 1-ethynyl] phenyl] pyrrolidine 1 2-cal δ 1.91-2.03 ( m, 3H), 2.38-2.45 ( Boxamide hydrochloride (compound 15—405) m, 1H), 2.49 (s, 3H), 3.29-3.40 (m,
2H), 4.39 (br s, 1H), 7.17 (t, J = 1.1 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H)， 7.41 (t, J = 7.7 Hz, 1H), 7. 2H), 4.39 (br s, 1H), 7.17 (t, J = 1.1 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.
H 0 48 (d, J = 7.7 Hz, 1H), 7.55 (d， J HCI = 8.7 Hz, 2H), 7.71 (d, J = 8.7 H 0 48 (d, J = 7.7 Hz, 1H), 7.55 (d, J HCI = 8.7 Hz, 2H), 7.71 (d, J = 8.7
Hz, 2H), 8.71 (br s, 1H), 9.65 (br s, 1H), 10.93—10.96 (m, 1 H)  Hz, 2H), 8.71 (br s, 1H), 9.65 (br s, 1H), 10.93—10.96 (m, 1 H)
(R) -N'一 [4— [2—（4—シァノ一2—メチル H-NMR (400 MHz, DMSO-d6) フエ二ル）一 1ーェチニル]フエニル]ピロリジン一 < 1.91-2.03 (m， 3H)， 2.40-2.47 ( 2—カルボキサミド 塩酸塩（化合物 15— 406 m, 1H)， 2.50 (s, 3H), 3.25—3.30 (m, ) 2H)， 4.42-4.43 (m， 1H), 7.61 (d, (R) -N '-[4— [2- (4-Cyano-2-methyl) H-NMR (400 MHz, DMSO-d 6 ) phenyl) -1-etynyl] phenyl] pyrrolidine <1.91-2.03 ( m, 3H), 2.40-2.47 (2-carboxamide hydrochloride (compound 15—406 m, 1H), 2.50 (s, 3H), 3.25—3.30 (m,) 2H), 4.42-4.43 (m, 1H), 7.61 (d,
J = 8.8 Hz, 2H), 7.66 (d, J = 8.0 J = 8.8 Hz, 2H), 7.66 (d, J = 8.0
Hz, 1H), 7.71 (dd, J = 8.0, 1.1 H z, 1H), 7.75 (d, J = 8.8 Hz, 2H)， 7.83-7.84 (m， 1H), 8.71 (br s, 1H),
Figure imgf000239_0001
9.92 (br s，1H), 11.20 (s, 1H)Hz, 1H), 7.71 (dd, J = 8.0, 1.1 H z, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.83-7.84 (m, 1H), 8.71 (br s, 1H),
Figure imgf000239_0001
9.92 (br s, 1H), 11.20 (s, 1H)
(R)-N'ー[4一 [2— (4—メトキシ一 2—メチル 1H-NMR (400 MHz, DMSO - de) フエ二ル）一 1ーェチニル]フエニル]ピロリジン一 8 1.91-2.03 (m, 3H)， 2.27-2.45 ( 2—カルボキサミド 塩酸塩（化合物 15— 407 m, 1H), 2.43 (s, 3H), 3.22-3.31 (m, ) 2H), 3.78 (s， 3H), 4.38-4.39 (m， (R) -N 'over [4 one [2- (4-methoxy one 2-methyl-1 H-NMR (400 MHz, DMSO - d e) Hue sulfonyl) Single 1 Echiniru] phenyl] pyrrolidine one 8 1.91-2.03 (m, 3H), 2.27-2.45 (2-carboxamide hydrochloride (compound 15—407 m, 1H), 2.43 (s, 3H), 3.22-3.31 (m,) 2H), 3.78 (s, 3H), 4.38 -4.39 (m,
1H), 6.80 (dd, J = 8.4, 2.7 Hz, 1H ), 6.91 (d, J = 1.1 Hz, 1H)， 7.41 ( d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz,
Figure imgf000239_0002
2H), 8.80 (br s, 1H), 9.65 (br s,1H 1H), 6.80 (dd, J = 8.4, 2.7 Hz, 1H), 6.91 (d, J = 1.1 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz,
Figure imgf000239_0002
2H), 8.80 (br s, 1H), 9.65 (br s, 1H
), 10.99 (s， 1H)  ), 10.99 (s, 1H)
(R) -N' - [4— [2— (2—チェニル）一 1—ェ 1H - NMR (500 MHz, DMSO - d6) チニル]フエニル]ピロリジン一 2—力ルポキサミ 6 1.90-2.02 (m, 3H), 2.38-2.45 ( ド 塩酸塩（化合物 15— 408) m, 1H), 3.25-3.32 (m, 2H), 4.39-4. (R) -N '-[4— [2— (2-Chenyl) 1 1- H 1 NMR (500 MHz, DMSO-d 6 ) Tinyl] phenyl] pyrrolidine 1 2-force lupoxami 6 1.90-2.02 ( m, 3H), 2.38-2.45 (dehydrochloride (compound 15-408) m, 1H), 3.25-3.32 (m, 2H), 4.39-4.
41 (m， 1H), 7.13 (dd, J = 5.2, 3.7 Hz, 1H), 7.40 (dd, J = 3.7， 1.2 H z, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.67 (dd, J = 5.2, 1.2 Hz, 1H)， 7.
Figure imgf000239_0003
71 (d, J = 8.9 Hz, 2H), 8.70 (br s, 1H), 9.78 (br s, 1H), 11.06 (s, 1H) 41 (m, 1H), 7.13 (dd, J = 5.2, 3.7 Hz, 1H), 7.40 (dd, J = 3.7, 1.2 Hz, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.67 ( dd, J = 5.2, 1.2 Hz, 1H), 7.
Figure imgf000239_0003
71 (d, J = 8.9 Hz, 2H), 8.70 (br s, 1H), 9.78 (br s, 1H), 11.06 (s, 1H)
(R)— N'— [4— [2— (3—チェニル）一 1ーェ 1H-NMR (500 MHz, DMSO-d6) チニル]フエニル]ピロリジン一 2—カルボキサミ δ 1.90-2.02 (m, 3H), 2.38-2.45 ( ド 塩酸塩（化合物 15— 409) m, 1H), 3.22-3.31 (m, 2H), 4.38-4. (R) - N'- [4- [ 2- (3- thienyl) one 1 over E 1 H-NMR (500 MHz, DMSO-d 6) ethynyl] phenyl] pyrrolidine one 2- Karubokisami δ 1.90-2.02 (m , 3H), 2.38-2.45 (dehydrochloride (compound 15—409) m, 1H), 3.22-3.31 (m, 2H), 4.38-4.
42 (m, 1H)， 7.25 (dd, J = 5.2, 1.2 42 (m, 1H), 7.25 (dd, J = 5.2, 1.2
Hz, 1H), 7.52 (d， J = 8.9 Hz, 2H ), 7.65 (dd, J = 5.2, 3.1 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7,87 (dd
Figure imgf000239_0004
, J = 3.1, 1.2 Hz, 1H), 8.76 (br s, Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.65 (dd, J = 5.2, 3.1 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7,87 (dd
Figure imgf000239_0004
, J = 3.1, 1.2 Hz, 1H), 8.76 (br s,
1H), 9.81 (br s, 1H), 11.04 (s, 1 H)  1H), 9.81 (br s, 1H), 11.04 (s, 1 H)
(R) -N'— [4— [2—（2—シァノフエニル）一 1 1H - NMR (400 MHz, DMSO- d6) ーェチニル]フエニル]ピロリジン一 2—カルボキ δ 1.91-2.05 (m, 3H), 2.39-2.46 ( ( (R) -N'— [4— [2— (2-Cyanophenyl) 1 1 1 H-NMR (400 MHz, DMSO-d 6 ) -ethynyl] phenyl] pyrrolidine 1 2-carboki δ 1.91-2.05 (m, 3H ), 2.39-2.46 ( (
d6) d 6 )
(  (
( (
( (
Figure imgf000240_0001
Figure imgf000241_0001
(R)— N'—[4ー[2— (4—ヒドロキシ一 3—メト 1H-NMR (500 MHz, D SO-d6) キシフエ二ル）一 1—ェチニル]フエニル]ピロリジ δ 1.94-2.00 (m, 3H), 2.36-2.42 ( ンー 2—カルボキサミド 塩酸塩（化合物 15— 4 m, 1H), 3.26-3.30 (m, 2H), 3.80 (s, 20) 3H), 4.33 (br s, 1H), 6.79 (d, J
Figure imgf000240_0001
Figure imgf000241_0001
(R) —N ′ — [4- [2— (4-Hydroxy- 1-3 -meth 1 H-NMR (500 MHz, D SO-d 6 ) xyphenyl) -1- 1-ethynyl] phenyl] pyrrolidi δ 1.94- 2.00 (m, 3H), 2.36-2.42 (N-2-carboxamide hydrochloride (compound 15— 4 m, 1H), 3.26-3.30 (m, 2H), 3.80 (s, 20) 3H), 4.33 (br s, 1H), 6.79 (d, J
= 7.9 Hz, 1H)， 6.97 (d, J = 7.9 H z, 1H), 7.04 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H)， 8.71 (br s, 1H), 9.24 (br s, 1
Figure imgf000242_0001
H), 9.51 (s, 1H), 10.66 (s, 1H)= 7.9 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 7.04 (s, 1H), 7.51 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H) , 8.71 (br s, 1H), 9.24 (br s, 1
Figure imgf000242_0001
H), 9.51 (s, 1H), 10.66 (s, 1H)
(R) -N'—[4一 [2—（ベンゾチォフェン一 3— 1H-NMR (500 MHz, DMSO - d6) ィル）一 1—ェチニル]フエニル]ピロリジン一 2— δ 1.93-2.03 (m, 3H)， 2.40-2.44 ( カルポキサミド 塩酸塩（化合物 15— 421) m, 1H), 3.25-3.31 (m, 2H), 4.38-4. (R) -N '— [4 1 [2— (Benzthiophene 3 1 H-NMR (500 MHz, DMSO -d 6 ) yl) 1 1-ethynyl] phenyl] pyrrolidine 1 2 δ 1.93-2.03 ( m, 3H), 2.40-2.44 (Carpoxamide hydrochloride (compound 15-421) m, 1H), 3.25-3.31 (m, 2H), 4.38-4.
41 (m, 1H), 7.48-7.51 (m, 1H)， 7.5 3-7.56 (m, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8,9 Hz, 2H), 41 (m, 1H), 7.48-7.51 (m, 1H), 7.5 3-7.56 (m, 1H), 7.66 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8,9 Hz, 2H ),
7.99-8.01 (m, 1H), 8.08-8.10 (m,7.99-8.01 (m, 1H), 8.08-8.10 (m,
HCI 1H), 8.16 (s, 1H), 8.71 (br s, 1H), HCI 1H), 8.16 (s, 1H), 8.71 (br s, 1H),
9.61 (br s, 1H), 10.96 (s, 1H) 9.61 (br s, 1H), 10.96 (s, 1H)
(R) -N' -[4-[2-(1 , 3—べンゾジォキソ 1H-NMR (500 MHz, DMSO - d6) —ルー 4一ィル）一 1ーェチニル]フエニル]ピロ δ 1.91-2.03 (m, 3H), 2.37-2.43 ( リジン一 2—力ルポキサミド 塩酸塩（化合物 15 m, 1H), 3.23-3.31 (m， 2H)， 4.35-4. -422) 38 (m, 1H)， 6.12 (s, 2H), 6.87 (dd, (R) -N '-[4- [2- (1,3-Benzenedioxo 1 H-NMR (500 MHz, DMSO-d 6 ) —Lu 4 yl) 1-1 ethynyl] phenyl] pyro δ 1.91- 2.03 (m, 3H), 2.37-2.43 (Lysine 1-strength lupoxamide hydrochloride (compound 15 m, 1H), 3.23-3.31 (m, 2H), 4.35-4. -422) 38 (m, 1H), 6.12 (s, 2H), 6.87 (dd,
J = 8.1, 1.1 Hz, 1H), 6.97 (dd, J = 8.1, 1.2 Hz, 1H), 6.97 (dd, J = 7.7, 1.2 Hz, 1H), 7.54 (d, J = 8. J = 8.1, 1.1 Hz, 1H), 6.97 (dd, J = 8.1, 1.2 Hz, 1H), 6.97 (dd, J = 7.7, 1.2 Hz, 1H), 7.54 (d, J = 8.
H 0 H 0
9 Hz, 2H), 7.69 (d, J = 8.9 Hz, 2 HCI H), 9.00 (br s, 2H), 10.86 (s, 1H) 9 Hz, 2H), 7.69 (d, J = 8.9 Hz, 2 HCI H), 9.00 (br s, 2H), 10.86 (s, 1H)
(R)— N'— [4— [2—（2—シクロへキシルフェ H-NMR (400 MHz, DMSO - d6) ニル）一 1ーェチニル]フエニル]ピロリジン一 2— δ 1.23-1.51 (m, 5H), 1.73-1.85 ( カルボキサミド 塩酸塩（化合物 15— 423) m, 5H), 1.91-2.04 (m, 3H), 2.40-2. (R) — N′— [4— [2— (2-Cyclohexylphe) H-NMR (400 MHz, DMSO-d 6 ) nyl) 1-ethynyl] phenyl] pyrrolidine 1 2— δ 1.23-1.51 (m, 5H), 1.73-1.85 (carboxamide hydrochloride (compound 15-423) m, 5H), 1.91-2.04 (m, 3H), 2.40-2.
46 (m, 1H), 3.05-3.08 (m, 1H), 3.2 3-3.29 (m, 2H), 4.36-4.40 (m, 1H), 46 (m, 1H), 3.05-3.08 (m, 1H), 3.2 3-3.29 (m, 2H), 4.36-4.40 (m, 1H),
7.21-7.25 (m, 1H), 7.33-7.38 (m, 2H), 7.48 (d, J = 7,3 Hz, 1H), 7.5 4 (d, J = 8.7 Hz, 2H), 7.71 (d, J
Figure imgf000242_0002
= 8.7 Hz, 2H), 8.73 (br s, 1H), 9 7.21-7.25 (m, 1H), 7.33-7.38 (m, 2H), 7.48 (d, J = 7,3 Hz, 1H), 7.5 4 (d, J = 8.7 Hz, 2H), 7.71 (d, J
Figure imgf000242_0002
= 8.7 Hz, 2H), 8.73 (br s, 1H), 9
.49 (br s, 1H)， 10.92 (s, 1H) .49 (br s, 1H), 10.92 (s, 1H)
(R) -N'ー[5— [2— (2—ェチルフ: i:ニル）ー1 H-NMR (500 MHz, DMSO - d6) ーェチニル]—2—ピリジル]ピロリジン一 2—力 δ 1.25 (t, J = 7.5 Hz, 3H), 1.91- ルポキサミド 塩酸塩（化合物 15— 424) 2.02 (m, 3H), 2.38-2.44 (m, 1H), 2 (R) -N '-[5— [2— (2-Ethylph: i: nyl) -1 H-NMR (500 MHz, DMSO-d 6 ) -ethynyl] —2-pyridyl] pyrrolidine 1- 2 δ 1.25 (t, J = 7.5 Hz, 3H), 1.91-Lupoxamide hydrochloride (compound 15—424) 2.02 (m, 3H), 2.38-2.44 (m, 1H), 2
.84 (q, J = 7.5 Hz, 2H), 3.26 - 3.31 .84 (q, J = 7.5 Hz, 2H), 3.26-3.31
(m, 2H), 4.45 (br s, 1H), 7.25-7.2 9 (m, 1H), 7.34-7.39 (m, 2H), 7.5 1-7.53 (m, 1H), 7.90-7.93 (m, 1H),
Figure imgf000242_0003
8.03 (br s, 1H), 8.58 (d, J = 2.1 (m, 2H), 4.45 (br s, 1H), 7.25-7.2 9 (m, 1H), 7.34-7.39 (m, 2H), 7.5 1-7.53 (m, 1H), 7.90-7.93 (m, 1H ),
Figure imgf000242_0003
8.03 (br s, 1H), 8.58 (d, J = 2.1
Hz, 1H), 8.70 (br s,.1H), 9.87 (br s， 1H), 11.42 (br s, 1H) 実施例 16 Hz, 1H), 8.70 (br s, .1H), 9.87 (br s, 1H), 11.42 (br s, 1H) Example 16
(R)一 N'—（3—クロロー 4—シァノフエニル）ピロリジン一 2—カルポキサミド トリフルォ 口酢酸塩（化合物 16) (R) -N '-(3-Chloro-4-cyanophenyl) pyrrolidine-2-carpoxamide trifluoroacetate (compound 16)
(R)— N— tert—ブトキシカルボ二ルー N'— (3—クロ口一 4—シァノフエニル）ピロリジ ン一 2—カルポキサミド（化合物 1一 79、 25. Omg、0. 0715mmol)を塩化メチレン（5 ml)に溶解し、トリフルォロ酢酸（250〃し 3. 25mmol)を加え、室温で 6時間撹拌した 。減圧下溶媒を留去することにより標記化合物（25.4mg)を白色固体として得た。（収 率 98%)  (R) —N—tert-Butoxycarbonyl N′— (3-Chroone 1-Cyanophenyl) pyrrolidine 1-Carboxamide (Compound 1 1 79, 25. Omg, 0.0715 mmol) was added to methylene chloride (5 trifluoroacetic acid (250 ml, 3.25 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The solvent was distilled off under reduced pressure to obtain the title compound (25.4 mg) as a white solid. (Yield 98%)
1H-NMR (500 MHz, DMSO-d6) 1 H-NMR (500 MHz, DMSO-d 6 )
δ 1.91-2.06 (m, 3Η), 2.34-2.41 (m, 1 H)， 3.27-3.30 (m， 2H), 4.36-4.37 (m,
Figure imgf000243_0001
1H), 7.64 (dd, J = 8.7, 2.0 Hz, 1H), δ 1.91-2.06 (m, 3Η), 2.34-2.41 (m, 1 H), 3.27-3.30 (m, 2H), 4.36-4.37 (m,
Figure imgf000243_0001
1H), 7.64 (dd, J = 8.7, 2.0 Hz, 1H),
7.98 (d, J = 8.7 Hz, 1H)， 8.01 (d, J = 2.0 Hz, 1H), 8.73 (br s, 1H)， 9.33 (br s, 1H), 11.11 (s, 1H) 実施例 17  7.98 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 8.73 (br s, 1H), 9.33 (br s, 1H), 11.11 (s, 1H) Example 17
(R)-N' -[4-(1一メチルインド一ルー 5—ィル）フエニル]ピロリジン一 2—カルボキサミ ド（化合物 17— 1)  (R) -N '-[4- (1Methylindo1ru 5-yl) phenyl] pyrrolidine 1 2-carboxamide (Compound 17-1)
(R)—N— tert—ブトキシカルボニル一 N'— [4— (1—メチルインド一ルー 5—ィル）フ ェニル]ピロリジン一 2—カルボキサミド（化合物 1— 151、 71mg、 0. 17mmol)を塩化 メチレン（3ml)に溶解し、 2， 6—ルチジン（80〃し 0. 68mmol)、トリフルォロメタンスル ホン酸トリメチソレシリル（65 I, 0.34mmol)を加え、室温でー晚攪拌した。反応液に飽 和炭酸水素ナトリウム水溶液（30ml)を加え、酢酸ェチル（30mし 2回）で抽出した。有 機層を飽和食塩水（30ml)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を 留去し、得られた残留物をへキサンで濾取することにより標記化合物（49. 3mg)を淡褐 色粉末として得た。（収率 91 «½)  (R) —N— tert-butoxycarbonyl 1 N′— [4- (1-methylindo1ru 5-yl) phenyl] pyrrolidine 1 2-carboxamide (Compound 1-151, 71 mg, 0.17 mmol) It was dissolved in methylene chloride (3 ml), 2,6-lutidine (80 to 0.68 mmol) and trimethysolesilyl trifluoromethanesulfonate (65 I, 0.34 mmol) were added, and the mixture was stirred at room temperature. A saturated aqueous sodium hydrogen carbonate solution (30 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml, twice). The organic layer was washed with saturated brine (30 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was collected by filtration with hexane to obtain the title compound (49.3 mg) as a pale brown powder. (Yield 91 «½)
24 1H - NMR (500 MHz, DMSO - d6) twenty four 1 H-NMR (500 MHz, DMSO-d 6 )
δ 1.64-1.83 (m, 3H), 2.02-2.10 (m, 1 H), 2.90-2.93 (m, 2H), 3.70-3.73 (m, 1H), 3.81 (s, 3H), 6.46 (d, J = 3.1 H z, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7,4 4 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.9 Hz, 2H) , 7.72 (d, J = 8.9 Hz, 2H), 7.79 (s, 1H), 9.98 (s, 1H) 以下、化合物 1-1131一 1191—1491-1503— 254一 710-5210— 5310— 12010— 12210-12710— 14010— 14311-16,11 -28, 11—29から選択される化合物を使用し、化合物 17—1の製造方法に準じて、化合物 1 7— 217_20を得た。  δ 1.64-1.83 (m, 3H), 2.02-2.10 (m, 1 H), 2.90-2.93 (m, 2H), 3.70-3.73 (m, 1H), 3.81 (s, 3H), 6.46 (d, J = 3.1 H z, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7,4 4 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.62 (d , J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.79 (s, 1H), 9.98 (s, 1H) The following compounds 1-1131 1191-1491-1503-254-1 710 -5210— 5310— 12010— 12210-12710— 14010— 14311-16,11 -28, 11-29 According to the production method of compound 17-1, compound 1 7-217_20 Obtained.
(R) -N'—[4—(インド一ルー 2—ィル）フエ二 1H - NMR (500 MHz, DMSO - d6) ル]ピロリジンー2—カルボキサミド（化合物 17— δ 1.64-1.83 (m， 3H)， 2.02-2.09 ( 2) m, 1H), 2.88-2.92 (m, 2H), 3.69—3. (R) -N '- [4- ( India one rule 2 I le) phenylene 1 H - NMR (500 MHz, DMSO - d 6) Le] Pirorijin 2- carboxamide (Compound 17- δ 1.64-1.83 (m , 3H), 2.02-2.09 (2) m, 1H), 2.88-2.92 (m, 2H), 3.69-3.
72 (m, 1H), 6,82 (d, J = 1.5 Hz, 72 (m, 1H), 6,82 (d, J = 1.5 Hz,
1H), 6.98 (t, J = 7.9 Hz, 1H), 7. 07 (t, J = 7.9 Hz, 1H)， 7.37 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.9
Figure imgf000244_0001
Hz, 1H)， 7.75 (d, J = 8.9 Hz, 2H 1H), 6.98 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.9
Figure imgf000244_0001
Hz, 1H), 7.75 (d, J = 8.9 Hz, 2H
)， 7.80 (d, J = 8.9 Hz, 2H), 10.03 ), 7.80 (d, J = 8.9 Hz, 2H), 10.03
(s, 1H), 11.43 (s, 1H) (s, 1H), 11.43 (s, 1H)
(R) -N' - [4— (インド一ルー 5—ィル）フエ二 1H - NMR (500 MHz, DMSO-d6) ル]ピロリジンー2—力ルポキサミド（化合物 1フ δ 1.64-1.83 (m， 3H), 2.02 - 2.09 ( 一 3) m, 1H), 2.89-2.92 (m, 2H), 3.68-3. (R) -N '-[4— (Indoluo 5-yl) Phenol 1 H -NMR (500 MHz, DMSO-d 6 ) Ru] pyrrolidine-2-force lupoxamide (Compound 1 δ 1.64-1.83 ( m, 3H), 2.02-2.09 (1) m, 1H), 2.89-2.92 (m, 2H), 3.68-3.
71 (m ,1H), 6.46 (t, J = 2.0 Hz, 1H), 7.35-7.38 (m, 2H), 7.44 (d, J 71 (m, 1H), 6.46 (t, J = 2.0 Hz, 1H), 7.35-7.38 (m, 2H), 7.44 (d, J
= 8.6 Hz, 1H), 7.60 (d, J = 8.9
Figure imgf000244_0002
Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H) = 8.6 Hz, 1H), 7.60 (d, J = 8.9
Figure imgf000244_0002
Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H)
， 7.78 (s, 1H), 9.97 (s, 1H)， 11.10 7.78 (s, 1H), 9.97 (s, 1H), 11.10
(s, 1H) (s, 1H)
(R) -N'ー （4一ビニルフエニル）ピロリジン一 2 1H-NMR (400 MHz, DMSO-d6) —カルポキサミド （化合物 17— 4) δ 1.61-1.68 (m, 2H), 1.73-1.81 ( m, 1H), 2.00-2.06 (m, 1H), 2.86-2. 90 (m, 2H), 3.67 (dd, J = 8.8, 5.6 Hz, 1H), 5.16 (dd, J = 11.0, 1.0
Figure imgf000244_0003
(R) -N'- (4 Monovinylphenyl) pyrrolidine 1 2 1 H-NMR (400 MHz, DMSO-d 6 ) —Carpoxamide (Compound 17— 4) δ 1.61-1.68 (m, 2H), 1.73-1.81 ( m, 1H), 2.00-2.06 (m, 1H), 2.86-2.90 (m, 2H), 3.67 (dd, J = 8.8, 5.6 Hz, 1H), 5.16 (dd, J = 11.0, 1.0
Figure imgf000244_0003
Hz, 1H), 5.73 (dd, J = 17.6, 1.0 Hz, 1H), 6.67 (dd, U = 17.6, 11.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H ), 7.64 (d, J = 8.5 Hz, 2H), 9.96 (s, 1H)
Figure imgf000245_0001
Figure imgf000246_0001
9.2 Hz, 1H), 8.23 (d, J = 8.6 Hz, Hz, 1H), 5.73 (dd, J = 17.6, 1.0 Hz, 1H), 6.67 (dd, U = 17.6, 11.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 9.96 (s, 1H)
Figure imgf000245_0001
Figure imgf000246_0001
9.2 Hz, 1H), 8.23 (d, J = 8.6 Hz,
1H), 8.96 (br s, 1H), 10.92 (s, 1 H)  1H), 8.96 (br s, 1H), 10.92 (s, 1 H)
(R) -N'一 [4一 [2— (4—ヒドロキシ一 3—メチ 1H-NMR (500 MHz, DMSO - d6) ルフエニル）一 1ーェチニル]フエニル]ピロリジン δ 1.61-1.69 (m, 2H), 1.75-1.81 ( —2—カルボキサミド（化合物 17— 15) m， 1H), 2.01-2.08 (m, 1H), 2.11 (s (R) -N '-[4- [2- (4-Hydroxy- 1-3 -Methyl- 1 H-NMR (500 MHz, DMSO-d 6 ) Ruphenyl) -1-etenyl] phenyl] pyrrolidine δ 1.61-1.69 (m, 2H), 1.75-1.81 (—2—carboxamide (compound 17—15) m, 1H), 2.01-2.08 (m, 1H), 2.11 (s
, 3H), 2.89 (t, J = 6.6 Hz, 2H), 3 .14 (br s, 1H), 3.69 (dd， J = 8.9, , 3H), 2.89 (t, J = 6.6 Hz, 2H), 3.14 (br s, 1H), 3.69 (dd, J = 8.9,
5.5 Hz, 1H)， 6,79 (d, J = 8.2 Hz
Figure imgf000247_0001
, 1H)， 7.17 (dd, J = 8.2, 1.8 Hz, 5.5 Hz, 1H), 6,79 (d, J = 8.2 Hz
Figure imgf000247_0001
, 1H), 7.17 (dd, J = 8.2, 1.8 Hz,
1H), 7.25 (d， J = 1.8 Hz, 1H)， 7.4 1 (d, J = 8.9 Hz, 2H)， 7,70 (d， J 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.4 1 (d, J = 8.9 Hz, 2H), 7,70 (d, J
= 8.9 Hz, 2H), 9.81 (br s, 1H)， 10.08 (s, 1H) = 8.9 Hz, 2H), 9.81 (br s, 1H), 10.08 (s, 1H)
(R) -N'— [4— [2— (4—シクロペンチルメトキ 1H-N R (400 MHz, DMSO- d6) シフエニル）一 1ーェチニル]フエニル]ピロリジン δ 1.31-1.35 (m, 2H), 1.52-1.68 ( 一 2—カルボキサミド（化合物 17— 16) m， 6H), 1.76-1.80 (m， 3H), 2.00-2. (R) -N'— [4— [2— (4-Cyclopentylmethoxy 1 HN R (400 MHz, DMSO-d 6 ) cyphenyl)-1-ethynyl] phenyl] pyrrolidine δ 1.31-1.35 (m, 2H), 1.52 -1.68 (1 2-carboxamide (compound 17-16) m, 6H), 1.76-1.80 (m, 3H), 2.00-2.
09 (m, 1H), 2.27-2.34 (m, 1H)， 2.8 9 (t, J = 6.6 Hz, 2H), 3.16 (br s, 09 (m, 1H), 2.27-2.34 (m, 1H), 2.8 9 (t, J = 6.6 Hz, 2H), 3.16 (br s,
1H), 3.68-3.71 (m, 1H), 3.87 (d,
Figure imgf000247_0002
J = 7,1 Hz, 2H), 6.96 (d, J = 8.8 1H), 3.68-3.71 (m, 1H), 3.87 (d,
Figure imgf000247_0002
J = 7,1 Hz, 2H), 6.96 (d, J = 8.8
Hz, 2H)， 7.44 (d, J = 8.8 Hz, 2H ), 7.45 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 10.10 (s， 1H) Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 10.10 (s, 1H)
(R)-N' -[4-[2-[4-(1一ェチルプロポキ 1H-NMR (500 MHz, DMSO- d6) シ）フエ二ル]— 1ーェチニル]フエニル]ピロリジ δ 0.90 (t， J = 7.3 Hz, 6H), 1.5 ン一 2—カルボキサミド（化合物 17— 17) 7-1.68 (m, 6H), 1.75-1.81 (m, 1H)， (R) -N '-[4- [2- [4- (1-Ethylpropoxy 1 H-NMR (500 MHz, DMSO-d 6 ) cis) phenyl]-1-ethynyl] phenyl] pyrrolidi δ 0.90 (t , J = 7.3 Hz, 6H), 1.5-1 2-carboxamide (Compound 17-17) 7-1.68 (m, 6H), 1.75-1.81 (m, 1H),
1.99-2.09 (m, 1H)， 2.89 (t, J = 6.6 Hz, 2H), 3.68-3.71 (m, 1H), 4. 25-4.30 (m， 1H), 6.96 (d, J = 8.6
Figure imgf000247_0003
Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H 1.99-2.09 (m, 1H), 2.89 (t, J = 6.6 Hz, 2H), 3.68-3.71 (m, 1H), 4. 25-4.30 (m, 1H), 6.96 (d, J = 8.6
Figure imgf000247_0003
Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H
), 7.44 (d, J = 8.6 Hz, 2H), 7.71 (d， J = 8.6 Hz, 2H)， 10.09 (s, 1H) ), 7.44 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 10.09 (s, 1H)
(R) -N'一 [4— [2— (4—ヒド'ロキシ一 2—二ト 'Η - NMR (400 MHz, DMSO - d6) 口フエニル）ー1ーェチニル]フエニル]ピロリジン 6 1.63-1.71 (m, 2H), 1.75-1.84 ( —2—カルボキサミド（化合物 1フー 18) m, 1H), 2.02-2.12 (m, 1H), 2.92 (t (R) -N '-[4 -— [2 -— (4-Hydro-oxy-2-2-dito'-NMR (400 MHz, DMSO-d 6 ) Methyl phenyl) -1-ethynyl] phenyl] pyrrolidine 6 1.63- 1.71 (m, 2H), 1.75-1.84 (—2—carboxamide (compound 1 fu 18) m, 1H), 2.02-2.12 (m, 1H), 2.92 (t
, J = 6.6 Hz, 2H)， 3.73-3.77 (m, 1H), 7.16 (dd, J = 8.5, 2.4 Hz, 1 H), 7.45-7.48 (m， 1 H), 7.47 (d, J
Figure imgf000247_0004
= 8.7 Hz, 2H)， 7.63 (d, J = 8.5 H z, 1H), 7.75 (d, J = 8.7 Hz, 2H), 10.19 (s, 1H) , J = 6.6 Hz, 2H), 3.73-3.77 (m, 1H), 7.16 (dd, J = 8.5, 2.4 Hz, 1 H), 7.45-7.48 (m, 1 H), 7.47 (d, J
Figure imgf000247_0004
= 8.7 Hz, 2H), 7.63 (d, J = 8.5 H z, 1H), 7.75 (d, J = 8.7 Hz, 2H), 10.19 (s, 1H)
(R)—N'— [4— [2— (4—ヒドロキシ一 2—メチ 'Η - NMR (500 MHz, DMSO - d6) ルフエ二ル）一 1—ェチニル]フエニル]ピロリジン δ 1.61-1.70 (m, 2H), 1.75-1.81 ( 一 2—力ルポキサミド（化合物 17— 19) m, 1H)， 2.01-2.08 (m, 1H), 2.36 (s (R) —N′— [4— [2— (4-Hydroxy-2-methyl] Η-NMR (500 MHz, DMSO-d 6 ) Ruphenyl) 1-ethynyl] phenyl] pyrrolidine δ 1.61-1.70 (m, 2H), 1.75-1.81 (1-2-power lupoxamide (compound 17-19) m, 1H), 2.01-2.08 (m, 1H), 2.36 (s
, 3H), 2.89 (t, J = 6.6 Hz, 2H), 3 .20 (br s, 1H), 3.69 (dd, J = 8.9, 5.8 Hz, 1H), 6.61 (dd, J = 8.2,
Figure imgf000247_0005
2.2 Hz, 1H), 6.70 (d, J = 2.2 Hz, 寸 , 3H), 2.89 (t, J = 6.6 Hz, 2H), 3.20 (br s, 1H), 3.69 (dd, J = 8.9, 5.8 Hz, 1H), 6.61 (dd, J = 8.2,
Figure imgf000247_0005
2.2 Hz, 1H), 6.70 (d, J = 2.2 Hz, Size
Figure imgf000248_0001
実施例 18
Figure imgf000248_0001
Example 18
(R)— N'—(4-フエネチルフエニル）ピロリジン一 2_カルポキサミド 塩酸塩（化合物 18 一 1)  (R) — N ′ — (4-Phenethylphenyl) pyrrolidine mono 2_caroxamide hydrochloride (Compound 18 1 1)
(R)-N' _[4一 [(E)— 2—フエ二ルー 1—ェテニル]フエニル]ピロリジン一 2—カルボ キサミド塩酸塩（化合物 15—182、 202mg、 0. 614mmol)をエタノール（3ml)に溶角 し、 10%パラジウム一炭素（触媒量）を加え水素雰囲気下、室温で 4時間攪拌した。セラ イトで不溶物を濾去し、減圧下溶媒を留去することにより標記化合物（173mg)を白色 固体として得た。（収率 86%)  (R) -N '_ [4 [[E] -2-phenyl-2-phenyl] pyrrolidine-2-carboxamide hydrochloride (compound 15-182, 202 mg, 0.614 mmol) in ethanol (3 ml ), 10% palladium-carbon (catalytic amount) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The insoluble material was removed by filtration through celite, and the solvent was distilled off under reduced pressure to obtain the title compound (173 mg) as a white solid. (Yield 86%)
Figure imgf000248_0002
以下、化合物 15— 186、 15— 214を使用し、化合物 18— 1の製造方法に準じて、化 合物 18— 2、 18— 3を得た。 メトキシフエネチル）フ 'H- NMR (500 MHz, DMSO -d6)
Figure imgf000248_0002
Hereinafter, compounds 15-186 and 15-214 were used, and compounds 18-2 and 18-3 were obtained according to the production method of compound 18-1. Methoxyphenethyl) 'H-NMR (500 MHz, DMSO -d 6 )
ェニル]ピロリジン一2- -カルボキサミド 1塩 δ 1.91-1.99 (m, 3H), 2.38- -2.43 (m, 1 酸塩（化合物 18— 2) Η), 2.80 (s, 4H), 3.23-3.33 (m, 2H), 3  Enyl] pyrrolidine mono-2-carboxamide monosalt δ 1.91-1.99 (m, 3H), 2.38- -2.43 (m, monoacid salt (compound 18—2))), 2.80 (s, 4H), 3.23-3.33 ( m, 2H), 3
.71 (s, 3H), 4.36-4.39 (m, 1H), 6.82 ( dt, J = 8.7, 2.5 Hz, 2H), 7.10 (dt, J .71 (s, 3H), 4.36-4.39 (m, 1H), 6.82 ( dt, J = 8.7, 2.5 Hz, 2H), 7.10 (dt, J
= 8.7, 2.5 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 8. 64 (br s， 1H), 9.99 (br s, 1H), 10.79 = 8.7, 2.5 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 8. 64 (br s, 1H), 9.99 (br s, 1H) , 10.79
HCI (s, 1H) HCI (s, 1H)
(R)— N'—[4— (4—アミノフエネチル）フエ 1H-N R (500 MHz, DMSO - d6) ニル]ピロリジン一 2—カルポキサミド 1塩 δ 1.91-1.98 (m, 3H), 2.36-2.41 (m, 1 酸塩（化合物 18— 3) H), 2.65-2.68 (m， 2H), 2.74—2.77 (m, (R) — N ′ — [4— (4-Aminophenethyl) Hue 1 HN R (500 MHz, DMSO-d 6 ) nyl] pyrrolidine mono 2-carboxamide monosalt δ 1.91-1.98 (m, 3H), 2.36-2.41 (m, 1 acid salt (compound 18—3) H), 2.65-2.68 (m, 2H), 2.74—2.77 (m,
2H), 3.23-3.30 (m, 2H), 4.33-4.36 (m, 2H), 3.23-3.30 (m, 2H), 4.33-4.36 (m,
1H), 5,00 (br s, 2H), 6.48 (d， J = 8. 3 Hz, 2H), 6.84 (d, J = 8,6 Hz, 2H)，1H), 5,00 (br s, 2H), 6.48 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8,6 Hz, 2H),
7.16 (d, J = 8.3 Hz, 2H)， 7.50 (d, J7.16 (d, J = 8.3 Hz, 2H), 7.50 (d, J
HCI = 8,6 Hz, 2H), 8.70 (br s, 1H), 9.65 HCI = 8,6 Hz, 2H), 8.70 (br s, 1H), 9.65
(br s, 1H), 10.67 (s, 1H) 実施例 19  (br s, 1H), 10.67 (s, 1H) Example 19
(R)— N—ァセチル一 N' - (4一クロ口フエニル）ピロリジン一 2—カルボキサミド（化合物 19-1)  (R) — N-acetylyl N ′-(4 monophenyl) pyrrolidine 1 2-carboxamide (Compound 19-1)
(R)—N'— (4—クロ口フエニル）ピロリジン一 2—カルボキサミド 塩酸塩（化合物 15 — 29、 200mg、 0. 766mmol)を塩化メチレン（1 ml)に力 Qえ、ピリジン（2ml)、塩化ァ セチル（82 l、 1. 15mmol)を加え、室温で 2. 5時間攪拌した。反応液に水（20ml)、 酢酸ェチル（20ml)を加え分配し， 有機層を水（20ml)、飽和食塩水（20ml)で洗浄し た。有機層を無水硫酸マグネシウムで乾燥後、減圧下溶媒を留去することにより標的化 合物（59mg)を乳白色固体として得た。（収率 29%)  (R) —N′— (4-Chlorophenyl) pyrrolidine mono 2-carboxamide hydrochloride (compound 15 — 29, 200 mg, 0.766 mmol) was added to methylene chloride (1 ml), pyridine (2 ml), Acetyl chloride (82 l, 1.15 mmol) was added and stirred at room temperature for 2.5 hours. Water (20 ml) and ethyl acetate (20 ml) were added to the reaction solution for partitioning, and the organic layer was washed with water (20 ml) and saturated brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the target compound (59 mg) as a milky white solid. (Yield 29%)
1H-N R (500 MHz, DMSO - de) 1 HN R (500 MHz, DMSO- de )
δ 1.82-1.92 (m, 3Η)， 1.99 (s, 3Η)， 2. δ 1.82-1.92 (m, 3Η), 1.99 (s, 3Η), 2.
01-2.15 (m, 1Η), 3.49-3.60 (m, 2H), 401-2.15 (m, 1Η), 3.49-3.60 (m, 2H), 4
.36-4.50 (m， 1H), 7.33-7.38 (m, 2H)，.36-4.50 (m, 1H), 7.33-7.38 (m, 2H),
7.60-7.64 (m, 2H), 10.07, 10.25 (s, 17.60-7.64 (m, 2H), 10.07, 10.25 (s, 1
H) 以下、市販化合物を使用し、化合物 19一 1の製造方法に準じて、化合物 19一 2~ 19 一 4を得た。 H) Hereinafter, commercially available compounds were used, and compounds 191-2 to 19-14 were obtained according to the production method of compound 19-11.
(R)—N— (4—クロ口べンゾィル）一 N'—（ 1H-NMR (500 MHz, DMSO - d6) (R) —N— (4—Black mouth Benzoyl) N '— ( 1 H-NMR (500 MHz, DMSO-d 6 )
4—クロ口フエニル）一ピロリジン一 2—カル ボキサミド（化合物 19— 2) δ 1.82-1.99 (m， 3H)， 2.24-2.37 (m, 1 4—Black mouth phenyl) 1 Pyrrolidine 1 2-Cal Boxamide (Compound 19— 2) δ 1.82-1.99 (m, 3H), 2.24-2.37 (m, 1
H), 3.48-3.64 (m， 2H)， 4.35-4.58 (m, 1H), 7.30-8.17 (m， 8H), 9.86, 10.21 (s γ'《0 Ν ， 1H) H), 3.48-3.64 (m, 2H), 4.35-4.58 (m, 1H), 7.30-8.17 (m, 8H), 9.86, 10.21 (s γ '<< 0 Ν , 1H)
(R)— Ν—メチルス。ルホニルー NT—（4ーク 1H-NMR (500 MHz, DMSO - de) (R) —Ν—Methyls. Ruhoniru NT- (4 over click 1 H-NMR (500 MHz, DMSO - d e)
ロロべンゾィル）一ピロリジンー2—力ルポキ δ 1.87-1.99 (m, 3H), 2.23-2.30 (m, 1 サミド（化合物 19一 3) H), 2.99 (s, 3H), 3.37-3.50 (m, 2H), 4 ■29 (dd, J = 8,6, 4.0 Hz, 1 H)， 7.37 (d ， J = 9.0 Hz, 2H), 7.65 (d， J = 9.0 Hz, 2H)， 10.00 (s, 1H)Lolobenzoyl) -Pyrrolidine-2—Power Lupoki δ 1.87-1.99 (m, 3H), 2.23-2.30 (m, 1 Samid (Compound 19-1 3) H), 2.99 (s, 3H), 3.37-3.50 (m, 2H), 4 ■ 29 (dd, J = 8,6, 4.0 Hz, 1 H), 7.37 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 9.0 Hz, 2H), 10.00 (s, 1H)
Figure imgf000250_0001
。
Figure imgf000250_0001
.
(R)—Ν—（4一クロ口フエニルスルホニル） H-NMR (400 MHz, DMSO - d6) (R) —Ν— (4 monophenyl phenylsulfonyl) H-NMR (400 MHz, DMSO-d 6 )
-N' - (4一クロ口フエニル）一ピロリジン一 δ 1.59-1.62 (m, 1H), 1.88-1.95 (m， 3 2—カルボキサミド（化合物 19— 4) H), 3.24-3.31 (m, 1H), .3.47-3.49 (m, -N '-(4 monophenyl) monopyrrolidine 1 δ 1.59-1.62 (m, 1H), 1.88-1.95 (m, 3 2-carboxamide (compound 19-4) H), 3.24-3.31 (m, 1H ), .3.47-3.49 (m,
1H), 4,21 (dd, J = 8.1, 3.9 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H)， 7.72 (d, J = 8.8 Hz, 1H), 4,21 (dd, J = 8.1, 3.9 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz,
2H), 7.88 (d, J = 8.8 Hz, 2H), 10.13 α 。 (s, 1H) 2H), 7.88 (d, J = 8.8 Hz, 2H), 10.13 α. (s, 1H)
実施例 20 Example 20
(R)— N—メチルー N'—（4-クロ口フエニル）一ピロリジン一 2—力ルポキサミド（化合物 2 0-1)  (R) —N-Methyl-N ′ — (4-chlorophenyl) monopyrrolidine 1-2-streptoxamide (Compound 2 0-1)
(R)-N'一（4—クロ口フエニル）ピロリジン一 2—カルボキサミド 塩酸塩（化合物 15 -29, 149mg、 0. 571 mmol)を N, N—ジメチルホルムアミド（3ml)に溶解し、炭酸力 リウム（238mg、1. 72mmol)、ョ一ドメタン（36〃し 0. 578mmol)を力 Qえ、窒素雰囲 気下、室温でー晚攪拌した。反応液に酢酸ェチル（50ml)と水（100ml)を加え分配し、 有機層を飽和食塩水（100ml)で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減 圧下溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（へキサン一 酢酸ェチル）で精製することにより標記化合物（51 mg)を無色油状物として得た。（収率 38%) 1H-NMR (500 MHz, DMSO - d6) Dissolve (R) -N ′-(4-chlorophenyl) pyrrolidine-1-carboxamide hydrochloride (compound 15 -29, 149 mg, 0.571 mmol) in N, N-dimethylformamide (3 ml) Lithium (238 mg, 1.72 mmol) and iodide methane (36 to 0.578 mmol) were vigorously stirred at room temperature in a nitrogen atmosphere. Ethyl acetate (50 ml) and water (100 ml) were added to the reaction solution for partitioning, and the organic layer was washed with saturated brine (100 ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane monoethyl acetate) to give the title compound (51 mg) as a colorless oil. (Yield 38%) 1 H-NMR (500 MHz, DMSO-d 6 )
δ 1.74-1.81 (m, 3H), 2.11-2.16 (m， 1 H), 2.31-2.35 (m， 1H), 2.33 (s, 3H), 2 .88-2.91 (m, 1H), 3.08-3.11 (m, 1H), 7.34 (d, J = 8,9 Hz, 2H), 7.73 (d, J = 8,9 Hz, 2H), 9.79 (s， 1 H) 以下、市販化合物を使用し、化合物 20— 1の製造方法に準じて、化合物 20_2を得た  δ 1.74-1.81 (m, 3H), 2.11-2.16 (m, 1 H), 2.31-2.35 (m, 1H), 2.33 (s, 3H), 2.88-2.91 (m, 1H), 3.08-3.11 (m, 1H), 7.34 (d, J = 8,9 Hz, 2H), 7.73 (d, J = 8,9 Hz, 2H), 9.79 (s, 1 H) Compound 20_2 was obtained according to the production method of 20-1.
(R)— N— (4—クロ口ベンジル）一N' - (4 1H-NMR (400 MHz, D SO-d6) (R) — N— (4-Chlorobenzyl) N '-(4 1 H-NMR (400 MHz, D SO-d 6 )
一クロ口フエニル）一ピロリジンー2—カルボ δ 1.75-1.84 (m， 3Η)， 2.12-2.17 (m， 1 キサミド（化合物 20— 2) Η), 2.32-2.41 (m, 1Η), 3.01 - 3, 04 (m， Monophenyl) monopyrrolidine-2-carbo δ 1.75-1.84 (m, 3Η), 2.12-2.17 (m, 1 xamide (compound 20—2) Η), 2.32-2.41 (m, 1Η), 3.01-3, 04 (m,
1H), 3.19-3.23 (m, 1H), 3.59 (d, J = 13.2 Hz, 1H)， 3.79 (d, J = 13.2 Hz, 1H), 7.31-7.36 (m， 4H)， 7.41 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H) ， 9.75 (br s, 1H) 1H), 3.19-3.23 (m, 1H), 3.59 (d, J = 13.2 Hz, 1H), 3.79 (d, J = 13.2 Hz, 1H), 7.31-7.36 (m, 4H), 7.41 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 9.75 (br s, 1H)
Figure imgf000251_0001
Figure imgf000251_0001
[製剤例] [Formulation example]
本発明化合物の代表的な製剤例を以下に示す。 The typical formulation example of this invention compound is shown below.
1)錠剤（100mg中)  1) Tablet (in 100mg)
本発明化合物 1mg  1 mg of the present compound
乳糖 66.4mg  Lactose 66.4mg
トウモロコシデンプン 20mg  Corn starch 20mg
カルポキシメチルセルロースカルシウム 6mg  Carpoxymethylcellulose calcium 6mg
ヒドロキシプロピルセルロース 4mg ステアリン酸マグネシウム 0.6mg  Hydroxypropyl cellulose 4mg Magnesium stearate 0.6mg
上記処方の錠剤にコーティング剤（例えば、ヒドロキシプロピルメチルセルロース、マク 口ゴール、シリコーン樹脂等の通常のコーティング剤） 2mgを用いてコーティングを施し、目 的とする錠剤を得ることができる。また、本発明化合物並びに添加物の種類及び 又は 量を適宜変更することで、所望の錠剤を得ることもできる。 2)カプセル剤（1 50mg中） A tablet of the above formulation can be coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macaque gall, or silicone resin) to obtain the intended tablet. Moreover, a desired tablet can also be obtained by changing suitably the kind and / or quantity of this invention compound and an additive. 2) Capsule (1 in 50mg)
本発明化合物 5mg Compound of the present invention 5 mg
乳糖 1 45mg  Lactose 1 45mg
本発明化合物並びに乳糖の混合比を適宜変更することで、所望のカプセル剤を得る ことができる。  A desired capsule can be obtained by appropriately changing the mixing ratio of the compound of the present invention and lactose.
3)点眼剤（100ml中） 3) Eye drops (in 100ml)
本発明化合物 100mg Compound of the present invention 100 mg
塩化ナトリウム 900mg Sodium chloride 900m g
ポリソノレべ一卜 80 200mg  Polysonole Ichigo 80 200mg
水酸化ナトリウム 適量  Sodium hydroxide
塩酸 ¾1蓳  Hydrochloric acid ¾1 蓳
滅菌精製水 適量  Sterilized purified water
本発明化合物並びに添加物の種類及び/又は量を適宜変更することで、所望の点 眼剤を得ることができる。  Desired eye drops can be obtained by appropriately changing the type and / or amount of the compound of the present invention and additives.
[薬理試験] [Pharmacological test]
1 .ジヒドロォロテートデヒドロゲナ一ゼ (以下、「DHODH」とする)阻害活性評価試験  1. Dihydrorotate dehydrogenase (hereinafter referred to as “DHODH”) inhibitory activity evaluation test
DHODH阻害活性を評価する方法の一つとして、ニトロブルーテトラゾリゥム（以下、「N BTJとする） の酸化還元反応を用いた評価系がァチ一ブス'ォブ'バイオケミストリー 'ァ ンド-バイオフィジックス、 323巻、 79-86頁（1 995年） [Archives of Biochemistry and Bio physics, 323, 79 - 86(1 995)]に報告されている。そこで、 DHODH標品としてヒト型リコンビ ナント DHODHタンパクを用いて、前記文献記載の方法に準じ試験を実施し、本発明化合 物の DHODH阻害活性を評価した。  As one of the methods for evaluating DHODH inhibitory activity, an evaluation system using a redox reaction of nitro blue tetrazolium (hereinafter referred to as “N BTJ”) is the “Vibs' Ob” Biochemistry “and” -Biophysics, 323, 79-86 (1 995) [Archives of Biochemistry and Bio physics, 323, 79-86 (1 995)], where human-type recombinants are used as DHODH preparations. A test was performed using the DHODH protein according to the method described in the above literature, and the DHODH inhibitory activity of the compound of the present invention was evaluated.
(被験化合物溶液の調製） .  (Preparation of test compound solution)
被験化合物をジメチルスルホキシド (以下、「DMS0Jとする） に溶解後、得られた溶液を 0.1 %トリトン X-1 00含有トリス緩衝液で希釈し、 50 j« g/mLの被験化合物溶液を調製した (試薬の調製） After dissolving the test compound in dimethyl sulfoxide (hereinafter referred to as “DMS0J”), the obtained solution was diluted with Tris buffer containing 0.1% Triton X-100, and a test compound solution of 50 j «g / mL was prepared. (Reagent preparation)
NBT溶液： NBTを 0.1 %トリトン X-1 00含有卜リス緩衝液で希釈し、 1 mMの溶液を調製した デシルュビキノン溶液：デシルュビキノンを DMSOに溶解した後、得られた溶液を 0.1 %ト リトン X- 1 00含有トリス緩衝液で希釈し、 0.5mMの溶液を調製した。  NBT solution: NBT was diluted with 0.1% Triton X-1000 containing squirrel buffer solution to prepare a 1 mM solution. Decylubiquinone solution: After dissolving decylubiquinone in DMSO, the resulting solution was 0.1% Triton X- The solution was diluted with 100-containing Tris buffer to prepare a 0.5 mM solution.
ジヒドロォロト酸（以下、「DHO」とする）溶液： DHOを 0.1 %トリトン X-100含有トリス緩衝液 で希釈し、 5mMの溶液を調製した。  Dihydroorotic acid (hereinafter referred to as “DHO”) solution: DHO was diluted with Tris buffer containing 0.1% Triton X-100 to prepare a 5 mM solution.
(試験方法及び測定方法）  (Test method and measurement method)
1 )384穴プレートに NBT溶液、デシルュビキノン溶液及び DHO溶液を 1穴あたり各々 1 0 し ずつ注入し、次いで、被験化合物溶液及び D H 0 D H溶液をこの順で 1穴あたり各々 1 0〃 L ずつ添加した。 1) Inject NBT solution, decylubiquinone solution, and DHO solution into a 384-well plate at 10 ° each per well, then add test compound solution and DH 0 DH solution in this order, 10 μL each per well. did.
2)得られた混合溶液を空気雰囲気遮光下、 30°Cで、 1時間インキュベーションした。  2) The obtained mixed solution was incubated at 30 ° C for 1 hour under the light shielding of air atmosphere.
3) 1 0%ドデシル硫酸ナトリウム水溶液を 1穴あたり 10 jU Lずつ添加し、反応を停止させた。  3) 10 jU L of 10% sodium dodecyl sulfate aqueous solution was added per well to stop the reaction.
4)吸光光度計（マルチラベルカウンター ARVO)に前記プレートを装着して、 540nmにおけ る各穴の吸光度を測定した。 4) The plate was attached to an absorptiometer (multi-label counter ARVO), and the absorbance of each hole at 540 nm was measured.
5)被験化合物溶液に代えて 2.5%DMSOを用いて、他は前記 1 ~ 4)と同じ操作を行った。そ の結果をコントロールとした。  5) The same procedure as in 1 to 4) above was performed, except that 2.5% DMSO was used instead of the test compound solution. The result was used as a control.
6)被験化合物溶液に代えて 2.5°/。DMSOを、また、 DHO溶液に代えて 0.1 %トリトン X- 1 00含 有トリス緩衝液を用いて、他は前記 1 ~ 5)と同じ操作を行い、その結果をブランクとした。 6) 2.5 ° / in place of the test compound solution. The same procedure as in 1-5) above was performed except that DMSO was used instead of DHO solution, and Tris buffer containing 0.1% Triton X-100 was used, and the result was blank.
(酵素阻害率の計算式） (Formula for enzyme inhibition rate)
酵素阻害率 (％)は以下の式により算出した。  The enzyme inhibition rate (%) was calculated by the following formula.
酵素阻害率 (W = 1 00 X { 1— (被験化合物懸濁液の吸光度一ブランクの吸光度）ノ（コ ントロールの吸光度一ブランクの吸光度） } Enzyme inhibition rate (W = 100 X {1— (absorbance of test compound suspension vs. absorbance of blank) No (absorbance of control minus absorbance of blank)}
.  .
(試験結果及び考察）  (Test results and discussion)
試験結果の一例として、被験化合物（化合物 1 5—1、化合物 1 5— 22、化合物 1 5— 25、ィ匕合物 15— 26、 4匕合物 15— 29、 "(匕合物 15— 31、 ί匕合物" I 5— 32、 4匕合物 15 一 39、ィ匕合物 15— 48、ィ匕合物 15— 87、化合物 15— 88、ィ匕合物 15— 89、化合物 1 5-91 ,化合物 15— 94、化合物 15— 95、化合物 15— 96、化合物 15— 9フ、化合物 15— 98、化合物 15— 99、化合物 15— 100、化合物 15— 102、化合物 15— 103、 化合物 15— 114、化合物 15— 116、ィ匕合物 15— 119、 ·(匕合物 15— 120、ィ匕合物 1 5— 121、化合物 15—123、 4匕台物 15— 124、化合物 15— 125、ィ匕合物 15— 128、 化合物 15— 131、化合物 15— 132、化合物 15— 133、化合物 15— 134、化合物 1 5— 135、化合物 15— 145、ィ匕合物 15— 147、ィ匕合物 15— 16フ、ィ匕合物 15— 169、 ^(匕合物 15— 174、化合物 15— 182、ィ匕合物 15— 187、ィ匕合物 15— 188、化合物 1 5—189、ィ匕合物: I 5— 190、ィ匕合物 15—191、ィ匕合物 15— 192、ィ匕合物 15— 200、 ィ匕合物 15— 202、ィ匕合物 15— 203、 ί匕合物 15— 206、ィ匕合物 15— 209、化合物 1 5— 216、 ί匕合物 15— 225、ィ匕合物 15— 229、化合物 15— 230、ィ匕合物 15— 232、 化合物 15— 239、化合物 15— 240、ィ匕合物 15— 241、化合物 15— 245、化合物 1 5— 246、化合物 15— 247、化合物 15— 250、化合物 15— 257、 ί匕合物 15— 266、 ィ匕合物 15— 267、ィ匕合物 15— 270、ィ匕合物 15— 271、 ί匕合物 15— 273、 4匕合物 1 5— 274、化合物 15— 288、 1匕合物 15— 292、ィ匕合物 15— 293、ィ匕合物 15— 294、 匕合物 15— 323、ィ匕合物 15— 324、ィ匕合物 15— 325、ィ匕合物 15— 334、ィ匕合物 1 5— 338、ィ匕合物 15— 373、ィ匕合物 15— 397、ィ匕合物 15— 407、 4匕合物 15— 408、 化合物 15— 415、ィ匕合物 15— 418、ィ匕合物 15— 417、 1匕合物 15— 421、ィ匕合物 1 7— 1、化合物 17— 3、化合物 17— 5、化合物 17 _9及び化合物 18 - 1 )の酵素阻害 率 (％)を表 1に示す。 As an example of test results, test compounds (compound 1 5-1, compound 1 5-22, compound 1 5— 25, Compound 15—26, 4 Compound 15—29, “(Compound 15—31, Compound” I 5—32, 4 Compound 15 1 39, Compound 15 — 48, Compound 15-87, Compound 15-88, Compound 15-89, Compound 1 5-91, Compound 15-94, Compound 15-95, Compound 15-96, Compound 15-9 , Compound 15-98, Compound 15-99, Compound 15-100, Compound 15-102, Compound 15-103, Compound 15-114, Compound 15-116, Compound 15-119, (Compound 15 — 120, Compound 1 5—121, Compound 15—123, 4 Compound 15—124, Compound 15—125, Compound 15—128, Compound 15—131, Compound 15—132, Compound 15 — 133, Compound 15—134, Compound 1 5—135, Compound 15—145, Compound 15—147, Compound 15—16F, Compound 15—169, ^ (Compound 15 — 174, Compound 15—182, Compound 15—187, Compound 15—188, Compound 1 5-189, Compound: I 5—190 Compound 15-191, Compound 15-192, Compound 15-200, Compound 15-202, Compound 15-203, Compound 15-206, Compound Compound 15—209, Compound 1 5—216, Compound 15—225, Compound 15—229, Compound 15—230, Compound 15—232, Compound 15—239, Compound 15—240 Compound 15-241, Compound 15-245, Compound 15-246, Compound 15-247, Compound 15-250, Compound 15-257, Compound 15-266, Compound 15-267 Compound 15-270, Compound 15-271, Compound 15-273, Compound 4 15-274, Compound 15-288, Compound 15-292, Compound Material 15-293, Compound 15-294, Compound 15-323, Compound 15-324, Compound 15-325, Compound 15-334, Compound 1 5 — 338, Compound 15—373, Compound 15—397, Compound 15—407, Compound Four 15—408, Compound 15—415, Compound 15—418, Compound Compound 15-417, Compound 15-421, Compound 17-1, Compound 17-3, Compound 17-5, Compound 17_9 and Compound 18-1) Table 1 shows.
表 1  table 1
酵素阻害率 酵素阻害率 被験化合物 被験化合物  Enzyme inhibition rate Enzyme inhibition rate Test compound Test compound
(%) (%) 化合物 15— 1 99 化合物 15— 192 100 化合物 15— 22 100 化合物 15— 200 100 化合物 15— 25 98 化合物 15— 202 100 化合物 15— 26 100 化合物 15— 203 99 化合物 15— 29 100 化合物 15— 206 100 化合物 15— 31 97 化合物 15— 209 100 化合物 15— 32 100 96 化合物 15— 39 100 化合物 15-225 98 化合物 15— 48 91 化合物 15-229 97 化合物 15— 87 99 化合物 15— 230 100 化合物 15— 88 99 化合物 15— 232 100 化合物 15— 89 100 化合物 15-239 100 化合物 15— 91 100 化合物 15-240 100 化合物 15— 94 100 化合物 15— 241 100 化合物 15— 95 100 化合物 15— 245 99 化合物 15— 96 100 化合物 15— 246 99 化合物 15— 97 100 化合物 15-247 100 化合物 15— 98 100 化合物 15— 250 95 化合物 15— 99 99 化合物 15-257 96 化合物 15— 100 97 化合物 15— 266 100 化合物 15— 102 67 化合物 15— 267 94 化合物 15-103 100 化合物 15— 270 87 化合物 15— " 4 100 化合物 15— 271 96 化合物 15— 116 98 化合物 15-273 93 化合物 15— 119 99 化合物 15— 274 97 化合物 15— 120 100 化合物 15— 288 96 化合物 15— 121 100 化合物 15— 292 90 化合物 15-123 100 化合物 15-290)3 94 化合物 15-124 99 化合物 15— 294 94 化合物 15-125 100 化合物 15— 323 95 化合物 15— 128 92 化合物 15-324 92 化合物 15-131 100 化合物 15-325 93 化合物 15-132 100 化合物 15-334 63 化合物 15-133 99 化合物 15-338 96 化合物 15— 134 104 化合物 15-373 100 化合物 15— 135 97 化合物 15— 397 99 化合物 15— 145 99 化合物 15— 407 100 化合物 15— 147 98 化合物 15— 408 100 ィ匕 !! ¾15— 167 100 化合物 15— 415 99 化合物 15— 169 100 化合物 15— 417 100 化合物 15-174 100 化合物 15— 418 100 化合物 15— 182 100 化合物 15— 421 98 化合物 15— 187 93 化合物 17— 1 100 化合物 15-188 90 化合物 17— 3 100 化合物 15-189 96 化合物 17— 5 100 化合物 15— 190 96 化合物 17— 9 100 化合物 15-191 100 化合物 18— 1 100 尚、 100%以上の阻害率については 100%と示した (%) (%) Compound 15- 1 99 Compound 15- 192 100 Compound 15- 22 100 Compound 15- 200 100 Compound 15- 25 98 Compound 15- 202 100 Compound 15- 26 100 Compound 15- 203 99 Compound 15- 29 100 Compound 15- 206 100 Compound 15- 31 97 Compound 15- 209 100 Compound 15- 32 100 96 Compound 15- 39 100 Compound 15-225 98 Compound 15- 48 91 Compound 15-229 97 Compound 15- 87 99 Compound 15- 230 100 Compound 15- 88 99 Compound 15- 232 100 Compound 15- 89 100 Compound 15-239 100 Compound 15-91 100 Compound 15-240 100 Compound 15-94 100 Compound 15-241 100 Compound 15-95 100 Compound 15-245 99 Compound 15-96 100 Compound 15-246 99 Compound 15- 97 100 Compound 15-247 100 Compound 15-98 100 Compound 15- 250 95 Compound 15- 99 99 Compound 15-257 96 Compound 15- 100 97 Compound 15- 266 100 Compound 15- 102 67 Compound 15- 267 94 Compound 15-103 100 Compound 15—270 87 Compound 15— “4 100 Compound 15—271 96 Compound 15—116 98 Compound 15-273 93 Compound 15—119 99 Compound 15—274 97 Compound 15—120 100 Compound 15—288 96 Compound 15— 121 100 Compound 15-292 90 Compound 15-123 100 Compound 15-290) 3 94 Compound 15-124 99 Compound 15- 294 94 Compound 15-125 100 Compound 15- 323 95 Compound 15- 128 92 Compound 15-324 92 Compound 15-131 100 Compound 15-325 93 Compound 15-132 100 Compound 15-334 63 Compound 15-133 99 Compound 15-338 96 Compound 15-134 104 Compound 15-373 100 Compound 15- 135 97 Compound 15- 397 99 Compound 15- 145 99 Compound 15- 407 100 Compound 15- 147 98 Compound 15- 408 100 Di 匕 !! ¾15- 167 100 Compound 15- 415 99 Compound 15- 169 100 Compound 15- 417 100 Compound 15-174 100 Compound 15- 418 100 Compound 15- 182 100 Compound 15- 421 98 Compound 15- 187 93 Compound 17- 1 100 Compound 15- 188 90 Compound 17- 3 100 Compound 15-189 96 Compound 17- 5 100 Compound 15- 190 96 Compound 17- 9 100 Compound 15-191 100 Compound 18- 1 100 Note that the inhibition rate over 100% is 100%. Indicated
表 1で示されたとおり、本発明化合物は優れた D H OD Η阻害活性を有し、細胞増碑 破骨細胞分化、過剰な免疫反応（自己免疫反応、アレルギー反応、臓器移植時の拒絶 反応、移植片対宿主疾患（graft versus host disease )等）等が関与する疾患の予防 又は治療剤として有用である。本発明化合物は特に癌、骨'関節疾患（骨粗鬆症、変形 性関節症等）、自己免疫疾患（乾癬、関節リウマチ、多発性硬化症、全身性エリテマトー デス、シエーグレン症候群、ぶどう膜炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎、クロ ーン病等）、アレルギー性疾患（アトピー性皮膚炎、アレルギー性皮膚炎、アレルギー性 鼻炎、アレルギー性結膜炎、気管支喘息）、臓器移植時の拒絶反応、移植片対宿主疾 患等の予防又は治療剤として有用である。 2.マウスタイプ IIコラーゲン誘発関節炎モデルに対する効果 As shown in Table 1, the compound of the present invention has an excellent DH OD Η inhibitory activity, and it has been It is useful as a preventive or therapeutic agent for diseases involving osteoclast differentiation, excessive immune response (autoimmune reaction, allergic reaction, rejection during organ transplantation, graft versus host disease, etc.). is there. The compounds of the present invention are particularly cancer, bone 'joint disease (osteoporosis, osteoarthritis, etc.), autoimmune disease (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, siegren syndrome, uveitis, polymyositis) Type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma), rejection during organ transplantation, It is useful as a preventive or therapeutic agent for graft-versus-host disease. 2.Effects on mouse type II collagen-induced arthritis model
本発明化合物の抗関節炎効果を評価するため、マウスタイプ Πコラーゲン誘発関節 炎モデルを用いて試験を行った。尚、評価指標として、マウスに本発明化合物を経口投 与（10mg/kg又は 30mg/kg)した時の関節炎スコア抑制率を用いた。また、本評価はネィ チヤ一、 283巻、 666- 668頁（1 980年） [N ature 283,666- 668(1 980)]に準じて実施した。 (被験化合物溶液の調製）  In order to evaluate the anti-arthritic effect of the compound of the present invention, a test was conducted using a mouse type Π collagen-induced arthritis model. As an evaluation index, the arthritis score inhibition rate when the compound of the present invention was orally administered (10 mg / kg or 30 mg / kg) to mice was used. This evaluation was conducted according to Nichiya, Vol. 283, 666-668 (1 980) [Nature 283, 666-668 (1 980)]. (Preparation of test compound solution)
被験化合物を適量秤量した後、 1 %メチルセルロース溶液に溶解し、被験化合物溶液 とした。  An appropriate amount of the test compound was weighed and then dissolved in a 1% methylcellulose solution to obtain a test compound solution.
(試験方法及び測定方法） .  (Test method and measurement method).
1 )雄性 DBA/1 J系マウスの尾根部皮内にゥシタイプ Πコラーゲンとフロインド完全アジュ バント (Freund' s complete adjuvant)を一緒に投与し、この日を感作日（0日目）とした。  1) Ushitype Π collagen and Freund's complete adjuvant were administered together into the ridge skin of male DBA / 1 J mice, and this day was designated as the sensitization day (Day 0).
2)感作日から 21日目に再度、ゥシタイプ Πコラーゲンとフロインド完全アジュバントを一緒 に投与して、関節炎を惹起させた。  2) On the 21st day from the sensitization day, ulsitype 、 collagen and Freund's complete adjuvant were administered together to induce arthritis.
3)感作日から 39日目に目視により関節炎の程度を評価しスコア化を行った。  3) On the 39th day after the sensitization, the degree of arthritis was visually evaluated and scored.
4)スコア化は以下表 2に示す評価基準に基づき 5段階で行い、 4肢の各スコアの合計を 関節炎スコアとした。 .  4) Based on the evaluation criteria shown in Table 2 below, scoring was performed in five stages, and the total of the scores for the four limbs was used as the arthritis score. .
5)尚、被験化合物溶液は、感作日から 1日 1回（計 40日間）経口投与した。  5) The test compound solution was orally administered once a day (40 days in total) from the sensitization date.
6)また、被験化合物溶液に代えて 1 %メチルセルロース溶液を用いて、前記 1〜5と同じ操 作を行い、その結果をコントロール群とした。 6) In addition, using the 1% methylcellulose solution instead of the test compound solution, the same operation as in the above 1-5. The result was used as a control group.
表 2  Table 2
Figure imgf000257_0001
Figure imgf000257_0001
(関節炎スコア抑制率の計算式） (Calculation formula for arthritis score suppression rate)
関節炎スコア抑制率 ( は以下の式により算出した。  Arthritis score inhibition rate (was calculated by the following equation.
関節炎スコア抑制率 (％)  Arthritis score suppression rate (%)
= 100 x(1— 験化合物投与群の関節炎スコア/コントロール群の関節炎スコア） (試験結果及び考察）  = 100 x (1— Arthritis score of test compound administration group / arthritis score of control group) (Test results and discussion)
試験結果の一例として、被験化合物（化合物 15— 182、化合物 15— 246、化合物 1 5-247,化合物 15— 267及び化合物 15— 273)の関節炎スコア抑制率を表' 3に示す 表 3  As an example of the test results, the arthritis score inhibition rates of the test compounds (Compound 15-182, Compound 15-246, Compound 1 5-247, Compound 15-267, and Compound 15-273) are shown in Table 3
Figure imgf000257_0002
Figure imgf000257_0002
尚、 100%以上の抑制率については 100%と示した。 表 3で示したとおり、本発明化合物は優れた抗関節炎効果を有し、関節リゥマチ等の 骨'関節疾患の治療剤として有用である。  In addition, the inhibition rate of 100% or more is shown as 100%. As shown in Table 3, the compound of the present invention has an excellent anti-arthritic effect and is useful as a therapeutic agent for bone and joint diseases such as rheumatoid arthritis.
3,マウス遅延型過敏症モデルに対する効果 3, Effects on mouse delayed hypersensitivity model
本発明化合物の細胞性免疫に対する抑制効果を評価するため、マウス遅延型過敏 症モデルを用い試験を行った。尚、評価指標として、マウスに本発明化合物を経口投与 (30mg/kg)した時の遅延型過敏症（以下、「DTH」とする）抑制率を用いた。本評価はァ 一ルツナイミツテル-フォーシュ、 40卷（ Π号）、 1125-1131頁（1990年） [ArzneimH±el Forsc h,40(n ),1125-1131 (1990)]に準じて実施した。 In order to evaluate the inhibitory effect on the cellular immunity of the compound of the present invention, mouse delayed hypersensitivity The test was conducted using a disease model. As an evaluation index, the inhibition rate of delayed hypersensitivity (hereinafter referred to as “DTH”) when the compound of the present invention was orally administered (30 mg / kg) to mice was used. This evaluation was carried out in accordance with Alznai Mitstel-Fausch, 40 卷 (Π), 1125-1131 (1990) [ArzneimH ± el Forsc h, 40 (n), 1125-1131 (1990)].
(被験化合物溶液の調製） (Preparation of test compound solution)
被験化合物を適量秤量した後、 1%メチルセルロース溶液に溶解し、得られた溶液を被 験化合物溶液とした。  An appropriate amount of the test compound was weighed and then dissolved in a 1% methylcellulose solution, and the resulting solution was used as the test compound solution.
(試験方法及び測定方法） (Test method and measurement method)
1)雄性 C57BL/6系マウスの背部皮内にメチル牛血清アルブミン（methyl bovine serum albumin、以下、 mpSAとする）とフロインド完全アジュバント（FreuncT s complete adjuvan t)を一緒に投与し、この日を感作曰（0曰目)とした。  1) Methyl bovine serum albumin (hereinafter referred to as mpSA) and FreundTs complete adjuvan t are administered together in the back skin of male C57BL / 6 mice, and this day is felt. It was set as an operation (0th).
2)感作日から 5日目に mBSAを後肢足躕皮内に投与して DTHを惹起した。  2) On the fifth day from the sensitization day, DTH was induced by administering mBSA into the hind limb footpad.
3) 5曰目の投与から 24時間後の足幅の増加量をシックネスゲージで測定した。  3) The increase in foot width 24 hours after the 5th dose was measured with a thickness gauge.
4 )尚、被験化合物溶液は感作曰から 1日 1回（計 6日間）経口投与した。  4) The test compound solution was orally administered once a day (6 days in total) after the sensitization.
5)また、被験化合物溶液に代えて 1%メチルセルロース溶液を用いて、前記 1〜4と同じ操 作を行い、その結果をコントロール群とした。 5) In addition, a 1% methylcellulose solution was used instead of the test compound solution, and the same operations as in 1 to 4 were performed, and the result was used as a control group.
(DTH抑制率の計算式） (DTH suppression rate calculation formula)
DTH抑制率 (％)は以下の式により算出した。 The DTH inhibition rate (%) was calculated by the following formula.
DTH抑制率 (％) = 100 x(1—被験化合物投与群の足幅の増加量/コントロール群の足幅 の増加量）  DTH inhibition rate (%) = 100 x (1—increase in foot width in test compound administration group / increase in foot width in control group)
(試験結果及び考察） (Test results and discussion)
試験結果の一例として、被験化合物（化合物 15— 1、化合物 15— 182、化合物 15 一 257、化合物 15— 273、ィ匕合物 15— 274、ィ匕合物 15— 325、 4匕合物 15— 326及 び化合物 17— 9)の DTH抑制率を表 4に示す。 表 4 被験化合物 被験化合物用量 DTH抑制率 (％) 化合物 1 5— 1 50mg/kg 50 As an example of the test results, test compounds (compound 15-1, compound 15-182, compound 15 one 257, compound 15-273, compound 15-274, compound 15-325, four compound 15 Table 4 shows the DTH inhibition rates of 326 and Compound 17-9). Table 4 Test compound Test compound dose DTH inhibition rate (%) Compound 1 5— 1 50 mg / kg 50
化合物 1 5— 1 82 50mg/kg 84  Compound 1 5— 1 82 50 mg / kg 84
化合物 1 5— 257 50mg/kg 85  Compound 1 5—257 50mg / kg 85
化合物 1 5— 273 50mg/kg 70  Compound 1 5— 273 50 mg / kg 70
化合物 1 5— 274 50mg/kg 79  Compound 1 5— 274 50 mg / kg 79
化合物 1 5— 325 50mg/kg 71  Compound 1 5— 325 50 mg / kg 71
化合物 1 5— 326 50mg/kg 61  Compound 1 5— 326 50 mg / kg 61
化合物 1 7— 9 50mg/kg 83 表 4に示したとおり、本発明化合物は優れた D T H抑制効果を有し、自己免疫疾患、ァ レルギ一性疾患等の治療剤として有用である。  Compound 17-7-9 50 mg / kg 83 As shown in Table 4, the compound of the present invention has an excellent DTH suppression effect, and is useful as a therapeutic agent for autoimmune diseases, allergic diseases and the like.
4. リンパ球混合反応に対する効果 4. Effects on mixed lymphocyte reaction
本発明化合物の in vitroにおける免疫抑制活性を評価するため、マウス同種異系リン パ球混合反応を用いて試験を行った。すなわち、マイトマイシン Cで処理した異系マウスリ ンパ球を刺激細胞した時の、反応細胞（リンパ球）の増殖率によりリンパ球混合反応（以 下、「M LRJとする)活性を測定した。尚、 MLR抑制効果は 10μΜでの抑制率で示した。 (被験化合物溶液の調製）  In order to evaluate the in vitro immunosuppressive activity of the compounds of the present invention, a test was conducted using a mouse allogeneic lymphocyte mixing reaction. That is, the activity of the mixed lymphocyte reaction (hereinafter referred to as “M LRJ”) was measured by the proliferation rate of the reaction cells (lymphocytes) when differentiated mouse lymphocytes treated with mitomycin C were stimulated. MLR inhibitory effect was shown by the inhibition rate at 10μΜ (Preparation of test compound solution)
被験化合物をジメチルスルホキシド（以下、「DMSO」とする） に溶解後、 1 0%ゥシ胎児 血清含有 RPMI-1 640(以下、「培養液 Jとする)で希釈し、被験化合物溶液とした。  The test compound was dissolved in dimethyl sulfoxide (hereinafter referred to as “DMSO”) and then diluted with RPMI-1 640 (hereinafter referred to as “culture medium J”) containing 10% urine fetal serum to obtain a test compound solution.
(マウスリンパ球の調製） ，. (Preparation of mouse lymphocytes)
BALBん系マウスの脾臓から細胞分画を調製し、溶血処理したものを反応細胞（リンパ 球）として用いた。また、 G57BL/6系マウスの脾臓から細胞分画を調製し、溶血処理及び マイトマイシン C処理したものを刺激細胞 (異系マウスリンパ球)として用いた。  A cell fraction was prepared from the spleen of a BALB mouse and the hemolyzed cell fraction was used as a reaction cell (lymphocyte). In addition, cell fractions were prepared from the spleen of G57BL / 6 mice, and those treated with hemolysis and mitomycin C were used as stimulating cells (heterogeneous mouse lymphocytes).
(試験方法及び測定方法） (Test method and measurement method)
1 )96穴培養プレート (ハーフエリア）に 1 .6 X 1 07cell/mLに調製した反応細胞（リンパ球） 及び刺激細胞 (異系マウスリンパ球)を各々 1 穴あたり 10μΙ_ずつ添加した。 1) was added in 96-well culture plates (1 .6 X 1 0 7 cell / mL to prepare reaction cell (lymphocytes) and stimulated cells (allogeneic mouse lymphocytes) respectively per well in half-area) 10Myuiota_ .
2)被験化合物溶液を 1穴あたり 20μΙ_ずつ添加した。 2) Test compound solution was added at 20 μΙ per well.
3)炭酸ガス培養器内で 3日間培養を行った。 4)細胞増殖能測定試薬 (商品名： Cell Titer Glo;プロメガ社製） 1 穴あたり 20μしずつ 添加し、これを被験化合物処置サンプルとした。 3) The cells were cultured for 3 days in a carbon dioxide incubator. 4) Reagent for measuring cell proliferation (trade name: Cell Titer Glo; manufactured by Promega) 20 μl per well was added, and this was used as a test compound-treated sample.
5)被験化合物処置サンプルからの化学発光強度をルミノメーターにより測定した。  5) The chemiluminescence intensity from the test compound-treated sample was measured with a luminometer.
6)尚、被験化合物溶液に代えて培養液を用いて、前記 1~5 と同じ操作を行い、その 結果をコントロールとした。  6) The same procedure as in 1 to 5 was performed using a culture solution instead of the test compound solution, and the result was used as a control.
7)また、刺激細胞及び被験化合物溶液に代えて培養液を用いて、前記 1〜5と同じ操 作を行い、その結果をブランクとした。  7) In addition, using the culture solution instead of the stimulator cells and the test compound solution, the same operations as in 1 to 5 were performed, and the result was blank.
(MLR抑制率の計算式）  (MLR suppression rate calculation formula)
M LR抑制率 (％)は以下の式により算出した。  The M LR inhibition rate (%) was calculated by the following formula.
MLR抑制率 (。/。). = 100Χ {1— (被験化合物処置サンプルの化学発光強度一ブランク の化学発光強度)/ (コントロールの化学発光強度一ブランクの化学発光強度）}  MLR inhibition rate (./.). = 100 Χ {1— (chemiluminescence intensity of test compound treated sample vs. blank) / (chemiluminescence intensity of control vs. blank)}
(試験結果及び考察） (Test results and discussion)
試験結果の一例として、被験化合物（化合物 15— 1、化合物 15— 22、化合物 15— 90、化合物 15— 93、化合物 15— 96、ィ匕合物 15— 99、化合物 15— 120、ィ匕合物 1 5— 121、ィ匕合物 15— 132、ィ匕合物 15— 135、化合物 15— 182、ィ匕合物 15— 187、 化合物 15— 200、化合物 15— 202、化合物 15— 211、化合物 15— 224、化合物 1 5— 225、化合物 15— 236、化合物 15— 237、化合物 15— 254及び化合物 15— 32 6)の MLR抑制率を表 5に示す。  As an example of test results, test compounds (compound 15-1, compound 15-22, compound 15-90, compound 15-93, compound 15-96, compound 15-99, compound 15-120, compound Compound 15 5-121, Compound 15-132, Compound 15-135, Compound 15-182, Compound 15-187, Compound 15-200, Compound 15-202, Compound 15-211, Table 5 shows the MLR inhibition rates of Compound 15-224, Compound 15-225, Compound 15-236, Compound 15-237, Compound 15-254 and Compound 15-32 6).
表 5  Table 5
被験化合物 抑制率 (％) 化合物 15— 1 55  Test compound inhibition rate (%) Compound 15— 1 55
化合物 15— 22 100  Compound 15—22 100
化合物 15— 90 44  Compound 15—90 44
化合物 15— 93 70  Compound 15- 93 70
化合物 15— 96 42  Compound 15— 96 42
化合物 15— 99 62  Compound 15—99 62
化合物 15—120 74  Compound 15-120 74
化合物 15—121 55  Compound 15-121 55
化合物 15— 132 44  Compound 15—132 44
化合物 15—135 89 化合物 1 5— 1 82 97 Compound 15-135 89 Compound 1 5— 1 82 97
化合物 1 5— 1 87 100  Compound 1 5— 1 87 100
化合物 1 5— 200 98  Compound 1 5—200 98
化合物 1 5 - 202 100  Compound 1 5-202 100
化合物 1 5— 21 1 100  Compound 1 5—21 1 100
化合物 1 5— 224 100  Compound 1 5— 224 100
化合物 1 5 225 100  Compound 1 5 225 100
化合物 1 5— 236 100  Compound 1 5— 236 100
化合物 1 5— 237 100  Compound 1 5— 237 100
化合物 1 5 - 254 100  Compound 1 5-254 100
化合物 1 5— 326 100  Compound 1 5— 326 100
尚、 1 00%以上の抑制率については 1 00%と示した。  In addition, the suppression rate of 100% or more is shown as 100%.
表 5で示したとおり、本発明化合物は優れた M LR活性抑制効果を有し、臓器移植時 の拒絶反応の抑制'剤、移植片対宿主疾患治療剤等として有用である。 As shown in Table 5, the compound of the present invention has an excellent inhibitory effect on MLR activity, and is useful as an agent for suppressing rejection during organ transplantation, a therapeutic agent for graft versus host disease, and the like.
産業上の利用可能性 Industrial applicability
本発明化合物は、細胞増殖、破骨細胞分化、過剰な免疫反応（自己免疫反応、ァレ ルギ一反応、臓器移植時の拒絶反応、移植片対宿主疾患等）等に深く関与している D H O D Hの活性を阻害し、細胞増殖、破骨細胞分化、過剰な免疫反応（自己免疫反応、ァ レルギ一反応、臓器移植時の拒絶反応、移植片対宿主疾患等）等に関与する疾患、よ リ具体的には、癌、骨'関節疾患（骨粗鬆症、変形性関節症等）、自己免疫疾患（乾癬、 関節リウマチ、多発性硬化症、全身性エリテマトーデス、シヱーグレン症候群、ぶどう膜 炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎、クローン病等）、アレルギー性疾患（アト ピー性皮膚炎、アレルギー性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎、気管支 喘息等）、臓器移植時の拒絶反応、移植片対宿主疾患等の予防又は治療剤として有 用である  The compound of the present invention is deeply involved in cell proliferation, osteoclast differentiation, excessive immune response (autoimmune response, allergy response, rejection during organ transplantation, graft-versus-host disease, etc.), etc. DHODH Diseases that inhibit cell activity, such as cell proliferation, osteoclast differentiation, excessive immune response (autoimmune response, allergic response, rejection during organ transplantation, graft-versus-host disease, etc.) Specifically, cancer, bone 'joint diseases (osteoporosis, osteoarthritis, etc.), autoimmune diseases (psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Schiegren's syndrome, uveitis, polymyositis, Type I diabetes, ulcerative colitis, Crohn's disease, etc.), allergic diseases (atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis, bronchial asthma, etc.), rejection during organ transplantation, transplantation One-sided accommodation Is a useful as a prophylactic or therapeutic agent such diseases

Claims

請求の範囲 般式（1 )で表される化合物又はその塩。  A compound represented by the general formula (1) or a salt thereof.
Figure imgf000262_0001
Figure imgf000262_0001
[式中、 X1— X2は S— CH2、 CH2— S、 CH2— CH2、又は CH = CHを示し； [Wherein X 1 — X 2 represents S—CH 2 , CH 2 — S, CH 2 — CH 2 , or CH = CH;
R1は置換基を有してもよい低級アルキル基、置換基を有してもよいァリール基、ヒドロキ シ基、ヒドロキシ基のエステル、置換基を有してもよい低級アルコキシ基、及び置換基を 有してもよいァリールォキシ基から選択される基を示し； R 1 represents a lower alkyl group which may have a substituent, an aryl group which may have a substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, and a substituent. A group selected from an aryloxy group which may have
pは 0〜7を示し、 pが 2 ~ 7である場合、各 R1は同一又は異なってもよく； p represents 0-7, and when p is 2-7, each R 1 may be the same or different;
R2は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよいァリール 基、置換基を有してもよいァラルキル基、ホルミル基、置換基を有してもよい低級アルキ ルカルポニル基、置換基を有してもよいァリールカルボ二ル基、置換基を有してもよい低 級アルコキシカルボニル基、置換基を有してもよいァリールォキシカルボニル基、置換基 を有してもよい低級アルキルスルフィニル基、置換基を有してもよいァリールスルフィニル 基、置換基を有してもよい低級アルキルスルホニル基、又は置換基を有してもよいァリー ルスルホニル基を示し； R 2 may have a hydrogen atom, a lower alkyl group that may have a substituent, an aryl group that may have a substituent, an aralkyl group that may have a substituent, a formyl group, or a substituent. Preferred lower alkylcarbonyl group, optionally substituted arylcarbonyl group, optionally substituted lower alkoxycarbonyl group, optionally substituted aryloxycarbonyl group, substituent A lower alkylsulfinyl group which may have a substituent, an arylsulfinyl group which may have a substituent, a lower alkylsulfonyl group which may have a substituent, or an arylsulfonyl group which may have a substituent Indicates;
R3は水素原子、又は置換基を有してもよい低級アルキル基を示し； R 3 represents a hydrogen atom or an optionally substituted lower alkyl group;
Y1— Y2は CH = CH、 N = CH、又は CH = Nを示し； Y 1 — Y 2 represents CH = CH, N = CH, or CH = N;
R4はハロゲン原子、置換基を有してもよい低級アルキル基、ハロゲノ低級アルキル基、 置換基を有してもよい低級アルケニル基、置換基を有してもよい低級アルキニル基、置 換基を有してもよいァリール基、置換基を有してもよいァラルキル基、ヒドロキシ基、ヒドロ キシ基のエステル、置換基を有してもよい低級アルコキシ基、置換基を有してもよいァリ ールォキシ基、置換基を有してもよいァラルキルォキシ基、アミノ基、ァミノ基のアミド、置 換基を有してもよい低級アルキルアミノ基、置換基を有してもよい低級アルキルアミノ基 のアミド、置換基を有してもよいァリールアミノ基、置換基を有してもよいァリールアミノ基 のアミド、カルポキシ基、カルボキシ基のエステル、カルボキシ基のアミド、及びシァノ基か ら選択される基を示し； R 4 represents a halogen atom, a lower alkyl group which may have a substituent, a halogeno lower alkyl group, a lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, or a substituent. An aryl group that may have a substituent, an aralkyl group that may have a substituent, an ester of a hydroxy group, a hydroxy group, a lower alkoxy group that may have a substituent, and an alkyl group that may have a substituent. Ryloxy group, aralkyloxy group which may have a substituent, amino group, amide of an amino group, lower alkylamino group which may have a substituent, lower alkylamino group which may have a substituent Amido, optionally substituted aryl amino group, optionally substituted aryl amino group A group selected from an amide, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, and a cyan group;
qは 0〜4を示し、 qが 2〜4である場合、各 R4は同一又は異なってもよく； q represents 0-4, and when q is 2-4, each R 4 may be the same or different;
R5はハロゲン原子、水素原子、置換基を有してもよい低級アルキル基、ハロゲノ低級ァ ルキル基、置換基を有してもよい低級シクロアルキル基、置換基を有してもよいァリール 基、置換基を有してもよい複素環基、置換基を有してもよいァラルキル基、ヒドロキシ基、 ヒドロキシ基のエステル、置換基を有してもよい低級アルコキシ基、ハロゲノ低級アルコキ シ基、置換基を有してもよい低級シクロアルキルォキシ基、置換基を有してもよいァリ一 ルォキシ基、置換基を有してもよい複素璟ォキシ基、置換基を有してもよいァラルキルォ キシ基、メルカプト基、メルカプト基のエステル、置換基を有してもよい低級アルキルチオ 基、/、ロゲノ低級アルキルチオ基、置換基を有してもよい低級シクロアルキルチオ基、置 換基を有してもよいァリ一ルチオ基、置換基を有してもよい複素環チォ基、置換基を有し てもよぃァラルキルチオ基、アミノ基、ァミノ基のアミド、置換基を有してもよい低級アルキ ルァミノ基、置換基を有してもよい低級アルキルアミノ基のアミド、置換基を有してもよい ァリールアミノ基、置換基を有してもよいァリ一ルァミノ基のアミド、ホルミル基、置換基を 有してもよい低級アルキルカルポニル基、置換基を有してもよいァリールカルボ二ル基、 カルボキシ基、カルボキシ基のエステル、カルボキシ基のアミド、置換基を有してもよい低 級アルキルスルフィニル基、置換基を有してもよいァリ一ルスルフィニル基、置換基を有し てもよい低級アルキルスルホニル基、置換基を有してもよいァリールスルホニル基、スル フィン酸基、スルフィン酸基のエステル、スルフィン酸基のアミド、スルホン酸基、スルホン 酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ基、 CR6 = CR7 (R8)、 C≡CR9、 又は N = N R1°を示し； R 5 is a halogen atom, a hydrogen atom, a lower alkyl group which may have a substituent, a halogeno lower alkyl group, a lower cycloalkyl group which may have a substituent, or an aryl group which may have a substituent. A heterocyclic group which may have a substituent, an aralkyl group which may have a substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, A lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a heterocyclic group which may have a substituent, and a substituent. An aralkyloxy group, a mercapto group, an ester of a mercapto group, an optionally substituted lower alkylthio group, /, a logeno lower alkylthio group, an optionally substituted lower cycloalkylthio group, and a substituent. Even An arylthio group, an optionally substituted heterocyclic thio group, an optionally substituted aralkylthio group, an amino group, an amide of an amino group, an optionally substituted lower alkylamino Group, an amide of a lower alkylamino group which may have a substituent, an arylamine group which may have a substituent, an amide of an arylamino group which may have a substituent, a formyl group, a substituent A lower alkylcarbonyl group which may have, an arylcarbonyl group which may have a substituent, a carboxy group, an ester of a carboxy group, an amide of a carboxy group, a lower alkylsulfinyl group which may have a substituent, An arylsulfinyl group which may have a substituent, a lower alkylsulfonyl group which may have a substituent, an arylsulfonyl group which may have a substituent, a sulfinic acid group, a sulfinic acid Ester, sulfinic acid group amide, sulfonic acid group, sulfonic acid group ester, sulfonic acid group amide, nitro group, cyano group, CR 6 = CR 7 (R 8 ), C≡CR 9 , or N = Indicates NR 1 °;
R6は水素原子、又は置換基を有してもよい低級アルキル基を示し； R 6 represents a hydrogen atom or an optionally substituted lower alkyl group;
R7と R8は同一又は異なって、水素原子、置換基を有してもよい低級アルキル基、置換基 を有してもよい低級シクロアルキル基、置換基を有してもよいァリール基、置換基を有し てもよい複素環基、カルポキシ基、カルポキシ基のエステル、又はカルポキシ基のアミドを 示し； R9は水素原子、置換基を有してもよい低級アルキル基、置換基を有してもよい低級シク 口アルキル基、置換基を有してもよいァリール基、又は置換基を有してもよい複素璟基を 示し、 R 7 and R 8 are the same or different and are a hydrogen atom, a lower alkyl group that may have a substituent, a lower cycloalkyl group that may have a substituent, an aryl group that may have a substituent, Represents an optionally substituted heterocyclic group, a carboxy group, an ester of a carboxy group, or an amide of a carboxy group; R 9 has a hydrogen atom, a lower alkyl group which may have a substituent, a lower cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a substituent. Indicates a good complex group,
R1 Dが置換基を有してもよいァリール基を示す。 ] R 1 D represents an aryl group which may have a substituent. ]
2. 一般式（1 )において、 X1— X2が S— CH2、 CH2— S、 CH2_ CH2、又は CH = CH を示し； 2. In the general formula (1), X 1 — X 2 represents S—CH 2 , CH 2 — S, CH 2 _CH 2 , or CH = CH;
R1が低級アルキル基、ァリール基、ヒドロキシ基、ヒドロキシ基のエステル、アルコキシ基 、及びァリールォキシ基から選択される基を示し； R 1 represents a group selected from a lower alkyl group, an aryl group, a hydroxy group, an ester of a hydroxy group, an alkoxy group, and an aryloxy group;
pが 0、 1又は 2を示し、 pが 2である場合、各 R1は同一又は異なってもよ When p is 0, 1 or 2, and p is 2, each R 1 may be the same or different.
R2が水素原子、低級アルキル基、ァリール基、ァラルキル基、ホルミル基、低級アルキル カルポニル基、ァリールカルボニル基、低級アルコキシカルボニル基、ァリールォキシカル ポニル基、低級アルキルスルホニル基、又はァリールスルホニル基を示し、 R2がァラルキ ル基、ァリ一ルカルポニル基又はァリールスルホニル基の場合、該ァラルキル基、該ァリ —ルカルポニル基又は該ァリ一ルスルホニル基は 1又は複数個のハロゲン原子を置換 基として有してもよぐ R 2 is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, a formyl group, a lower alkyl carbonyl group, an aryl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, a lower alkylsulfonyl group, or an aryl group. When R 2 is an aralkyl group, an arylcarbonyl group or an arylsulfonyl group, the aralkyl group, the arylcarbonyl group or the arylsulfonyl group is one or more halogen atoms. May have atoms as substituents
が水素原子、又は低級アルキル基を示し；  Represents a hydrogen atom or a lower alkyl group;
Y1 _Y2が CH = CH、 N = CH、又は CH = Nを示し； Y 1 _Y 2 represents CH = CH, N = CH, or CH = N;
R4がハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、低級アルケニル基、低 級アルキニル基、ァリール基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のエステル、低 級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基、アミノ基、ァミノ基のアミド、低 級アルキルアミノ基、低級アルキルアミノ基のアミド、ァリールアミノ基、ァリ一ルァミノ基 のアミド、カルポキシ基、カルボキシ基のエステル、カルポキシ基のアミド、及びシァノ基か ら選択される基を示し、 R4が低級アルケニル基の場合、該低級アルケニル基は 1又は複 数個のァリール基を置換基として有してもよく； R 4 is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower alkenyl group, a lower alkynyl group, an aryl group, an aralkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, an amino group. Group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylamino group, amide of arylamino group, carboxy group, ester of carboxy group, amide of carboxy group, and cyano group When R 4 is a lower alkenyl group, the lower alkenyl group may have one or more aryl groups as a substituent;
qが 0、 1又は 2を示し、 qが 2である場合、各 R4は同一又は異なってもよぐ. When q is 0, 1 or 2, and q is 2, each R 4 may be the same or different.
R5がハロゲン原子、水素原子、低級アルキル基、ハロゲノ低級アルキル基、低級シクロ アルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基、ヒドロキシ基のエステ ル、低級アルコキシ基、ハロゲノ低級アルコキシ基、低級シクロアルキルォキシ基、ァリ一 ルォキシ基、複素環ォキシ基、ァラルキルォキシ基、メルカプト基、メルカプト基のエステ ル、低級アルキルチオ基、ハロゲノ低級アルキルチオ基、低級シクロアルキルチオ基、ァ リールチオ基、複素環チォ基、ァラルキルチオ基、アミノ基、ァミノ基のアミド、低級アルキ ルァミノ基、低級アルキルアミノ基のアミド、ァリ一ルァミノ基、ァリ一ルァミノ基のアミド、 ホルミル基、低級アルキルカルボニル基、ァリールカルボ二ル基、カルボキシ基、カルボキ シ基のエステル、カルポキシ基のアミド、低級アルキルスルホニル基、ァリールスルホニル 基、スルホン酸基、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、シァノ基、 CR6 = CR7 (R8)、 C≡CR9、又は N = NR10を示し、 R5が低級アルキル基の場合、該低級 アルキル基は複素.環 ¾、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキ ルァミノ基のアミド、力ルポキシ基、カルボキシ基のエステル、カルボキシ基のアミド、及び シァノ基から選択される 1又は複数個の基を置換基として有してもよく、 R5がァリール基 の場合、該ァリール基はハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、ヒド ロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、ハロゲノ低級アルコキシ基、ニト 口基、及びシァノ基から選択される 1又は複数個の基を置換基として有してもよ《 R5が 複素環基の場合、該複素環基はハロゲン原子、低級アルキル基、及び低級ハロゲノア ルキル基から選択される 1又は複数個の基を置換基として有してもよく、 R5がァラルキル 基の場合、該ァラルキル基はヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、 アミノ基、ァミノ基のアミド、低級アルキルアミノ基、及び低級アルキルアミノ基のアミドから 選択される 1又は複数個の基を置換基として有してもよく、 R5が低級アルコキシ基の場合 、該低級アルコキシ基は 1又は複数個の複素環基を置換基として有してもよく、 R5がァリ ールォキシ基の場合、該ァリールォキシ基は 1又は複数個の低級アルキル基を置換基と して有してもよく、 R5がァラルキルォキシ基の場合、該ァラルキルォキシ基はハロゲン原 子、低級アルキル基、ハロゲノ低級アルキル基、ヒドロキシ基、ヒドロキシ基のエステル、 低級アルコキシ基、及びハロゲノ低級アルコキシ基から選択される 1又は複数個の基を 置換基として有してもよく、 R5が低級アルキルチオ基の場合、該低級アルキルチオ基は 低級シクロアルキル基、ァリール基、及び複素環基から選択される 1又は複数個の基を 置換基として有してもよ R5がァリールチオ基の場合、該ァリールチオ基はハロゲン原 子、低級アルキル基、ハロゲノ低級アルキル基、アミノ基、ァミノ基のアミド、低級アルキ ルァミノ基、及び低級アルキルアミノ基のアミドから選択される 1又は複数個の基を置換 基として有してもよく、 R5がァラルキルチオ基の場合、該ァラルキルチオ基はハロゲン原 子、低級アルキル基、ハロゲノ低級アルキル基、ヒドロキシ基、ヒドロキシ基のエステル、 低級アルコキシ基、及ぴハロゲノ低級アルコキシ基から選択される 1又は複数個の基を 置換基として有してもよく、 R5がァリ一ルスルホニル基の場合、該ァリールスルホニル基 はァミノ基、ァミノ基のアミド、低級アルキルアミノ基、及び低級アルキルアミノ基のアミド から選択される 1又は複数個の基を置換基として有してもよく； R 5 is a halogen atom, hydrogen atom, lower alkyl group, halogeno lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group or hydroxy group. , Lower alkoxy group, halogeno lower alkoxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, aralkyloxy group, mercapto group, ester of mercapto group, lower alkylthio group, halogeno lower alkylthio group, Lower cycloalkylthio group, arylthio group, heterocyclic thio group, aralkylthio group, amino group, amide of amino group, lower alkylamino group, amide of lower alkylamino group, arylalkylamino group, amide of arylamine group , Formyl group, lower alkylcarbonyl group, arylcarbonyl group, carboxy group, carboxy group ester, carboxy group amide, lower alkylsulfonyl group, arylsulfonyl group, sulfonic acid group, sulfonic acid group ester, sulfonic acid Group amide, nitro group, cyan group, CR 6 = CR 7 (R 8 ), C≡CR 9 , or N = NR 10 and when R 5 is a lower alkyl group, the lower alkyl group is a heterocycle, an amino group, an amide of an amino group, One or more groups selected from a lower alkylamino group, an amide of a lower alkylamino group, a strong lpoxy group, an ester of a carboxy group, an amide of a carboxy group, and a cyano group may be substituted. When 5 is an aryl group, the aryl group is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a halogeno lower alkoxy group, a nitrogen group, and a cyan group. If 1 or "R 5 I have a plurality of groups as substituents of the heterocyclic group, 1 heterocyclic group selected from a halogen atom, a lower alkyl group, and a lower Harogenoa alkyl group It may have a plurality of groups as a substituent, when R 5 is a Ararukiru group, the Ararukiru group hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an amino group, an amide of Amino groups, lower alkylamino Group, and one or more groups selected from amides of lower alkylamino groups as a substituent, and when R 5 is a lower alkoxy group, the lower alkoxy group is one or more heterocycles Group may be substituted as a substituent, and when R 5 is an aryloxy group, the aryloxy group may have one or more lower alkyl groups as a substituent, and R 5 is an aralkyloxy group. In this case, the aralkyloxy group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group, or a halogeno lower group. May have one or more groups selected from Kokishi group as a substituent, when R 5 is a lower alkylthio group selected, said lower alkylthio group is a lower cycloalkyl group, Ariru group, and heterocyclic group One or more groups Optionally substituted as R 5 is an arylothio group, the arylothio group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, an amino group, an amide of an amino group, a lower alkylamino group, and a lower alkylamino group. One or a plurality of groups selected from amides of the group may have as a substituent, and when R 5 is an aralkylthio group, the aralkylthio group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxy group. , An ester of a hydroxy group, a lower alkoxy group, and a halogeno lower alkoxy group may have one or more groups selected as a substituent, and when R 5 is an arylsulfonyl group, The reelsulfonyl group is selected from the group consisting of an amino group, an amide of an amino group, a lower alkylamino group, and an amide of a lower alkylamino group. It may have a plurality of groups as substituents;
R6が水素原子、又 (ま低級アルキル基を示し； R 6 represents a hydrogen atom or (also represents a lower alkyl group;
R7と R8が H一又は異なって、水素原子、低級アルキル基、低級シクロアルキル基、ァリ —ル基、複素環基、カルボキシ基、カルポキシ基のエステル、又はカルポキシ基のアミド を示し、 R7又は R8がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基 、ハロゲノ低級アルキル基、低級シクロアルキル基、ァリール基、複素環基、ァラルキル 基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、ハロゲノ低級アルコキシ 基、低級シクロアルキルォキシ基、ァリールォキシ基、複素環ォキシ基、ァラルキルォキ シ基、メルカプト基、メルカプト基のエステル、低級アルキルチオ基、ァリ一ルチオ基、アミ ノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキルアミノ基のアミド、ァリールァ ミノ基、ァリ一ルァミノ基のアミド、ホルミル基、低級アルキルカルポニル基、ァリ一ルカル ポニル基、カルポキシ基、カルボキシ基のエステル、カルポキシ基のアミド、スルホン酸基 、スルホン酸基のエステル、スルホン酸基のアミド、ニトロ基、及びシァノ基から選択され る 1又は複数個の基を置換基として有してもよぐ R 7 and R 8 are H or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a carboxy group, an ester of a carboxy group, or an amide of a carboxy group, When R 7 or R 8 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, an ester of a hydroxy group, Lower alkoxy group, halogeno lower alkoxy group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group, aralkyloxy group, mercapto group, mercapto group ester, lower alkylthio group, arylthio group, amino group, Amido group, lower alkylamino group, lower alkylamino group amide, arylamino group, aryl Amide of monolumino group, formyl group, lower alkyl carbonyl group, aryl carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, sulfonic acid group, ester of sulfonic acid group, amide of sulfonic acid group, One or more groups selected from a nitro group and a cyan group may be substituted.
R9が水素原子、低級アルキル基、低級シクロアルキル基、ァリール基、又は複素璟基を 示し、 R 9 represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, an aryl group, or a heterocyclic group,
R9がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基、' 1若しくは複数 個のヒドロキシ基で置換された低級アルキル基、 1若しくは複数個のヒドロキシ基のエス テルで置換された低級アルキル基、 1若しくは複数個の低級アルコキシ基で置換された 低級アルキル基、 1若しくは複数個のァリールォキシ基で置換された低級アルキル基、 1 若しくは複数個のカルボキシ基で置換された低級アルキル基、 1若しくは複数個の力ルポ キシ基のエステルで置換された低級アルキル基、 1若しくは複数個のカルポキシ基のアミ ドで置換された低級アルキル基、 1若しくは複数個のシァノ基で置換された低級アルキル 基、ハロゲノ低級アルキル基、低級シクロアルキル基、ァリール基、複素環基、ァラルキ ル基、ヒドロキシ基、ヒドロキシ基のエステル、低級アルコキシ基、 1若しくは複数個の低 級アルキル基で置換された低級アルコキシ基、 1若しくは複数個の低級シクロアルキル 基で置換された低級アルコキシ基、 1若しくは複数個のァリール基で置換された低級アル コキシ基、 1若しくは複数個の複素環基で置換された低級アルコキシ基、 1若しくは複数 個のヒドロキシ基で置換された低級アルコキシ基、 1若しくは複数個のヒドロキシ基のエス テルで置換された低級アルコキシ基、 1若しくは複数個の低級アルコキシ基で置換された 低級アルコキシ基、 1若しくは複数個の低級シクロアルキルォキシ基で置換された低級ァ ルコキシ基、 1若しくは複数個のァリールォキシ基で置換された低級アルコキシ基、 1若し くは複数個の複素環ォキシ基で置換された低級アルコキシ基、 1若しくは複数個のァミノ 基で置換された低級アルコキシ基、 1若しくは複数個のァミノ基のアミドで置換された低 級アルコキシ基、 1若しくは複数個の低級アルキルアミノ基で置換された低級アルコキシ 基、 1若しくは複数個の低級アルキルアミノ基のアミドで置換された低級アルコキシ基、 1 若し ま複数個のァリールァ ノ基で置換された低級アルコキシ基、 1若しくは複数個の ァリ一ルァミノ基のアミドで置換された低級アルコキシ基、 1若し ま複数個のカルボキシ 基で置換された低級アルコキシ基、 1若しくは複数個のカルボキシ基のエステルで置換さ れた低級アルコキシ基、 1若しくは複数個のカルポキシ基のアミドで置換された低級アル コキシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ基、低級アルキニルォキシ 基、低級シクロアルキルォキシ基、ァリールォキシ基、 1若しくは複数個のハロゲン原子 で置換されたァリ一ルォキシ基、複素環ォキシ基、ァラルキルォキシ基、低級アルコキシ カルポニルォキシ基、ァリールォキシカルボニルォキシ基、メルカプト基、メルカプト基のェ ステル、低級アルキルチオ基、ァリ一ルチオ基、アミノ基、ァミノ基のアミド、低級アルキル アミノ基、低級アルキルアミノ基のアミド、ァリールアミノ基、ァリールァミノ基のアミド、ホ ルミル基、低級アルキルカルポニル基、ァリ一ルカルポ二ル基、カルボキシ基、カルボキシ 基のエステル、カルボキシ基のアミド、スルホン酸基、スルホン酸基のエステル、スルホン 酸基のアミド、ニトロ基、及びシァノ基から選択される 1又は複数個の基を置換基として 有してもよぐ When R 9 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with one or more hydroxy groups, a lower alkyl group substituted with one or more hydroxy group esters. An alkyl group, substituted with one or more lower alkoxy groups Lower alkyl group, lower alkyl group substituted with one or more aryloxy groups, lower alkyl group substituted with one or more carboxy groups, lower substituted with ester of one or more force alkoxy groups An alkyl group, a lower alkyl group substituted with an amide of one or more carboxy groups, a lower alkyl group substituted with one or more cyano groups, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a complex Ring group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, lower alkoxy group substituted with one or more lower alkyl groups, lower substituted with one or more lower cycloalkyl groups An alkoxy group, a lower alkoxy group substituted with one or more aryl groups, one or more A lower alkoxy group substituted with a heterocyclic group, a lower alkoxy group substituted with one or more hydroxy groups, a lower alkoxy group substituted with an ester of one or more hydroxy groups, one or more lower groups A lower alkoxy group substituted with an alkoxy group, a lower alkoxy group substituted with one or more lower cycloalkyloxy groups, a lower alkoxy group substituted with one or more aryloxy groups, one or more A lower alkoxy group substituted with a plurality of heterocyclic oxy groups, a lower alkoxy group substituted with one or more amino groups, a lower alkoxy group substituted with an amide of one or more amino groups, 1 or A lower alkoxy group substituted with a plurality of lower alkylamino groups, an amide of one or more lower alkylamino groups A substituted lower alkoxy group, a lower alkoxy group substituted with one or more arylano groups, a lower alkoxy group substituted with an amide of one or more arylamino groups, one or more Lower alkoxy group substituted by one or more carboxy groups, lower alkoxy group substituted by one or more carboxy group esters, lower alkoxy group substituted by one or more carboxy group amides, halogeno lower An alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, an aryloxy group substituted with one or more halogen atoms, a heterocyclic oxy group, an aralkyloxy group, Lower alkoxy carbonyloxy group, aryloxycarbonyloxy group, mercapto group, mercapto group Group E ester, a lower alkylthio group, § Li one thio group, an amino group, an amide of Amino group, a lower alkylamino group, amide of a lower alkylamino group, Ariruamino group, an amide of Ariruamino group, e Rumyl group, lower alkyl carbonyl group, aryl carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, sulfonic acid group, ester of sulfonic acid group, amide of sulfonic acid group, nitro group, and cyano One or more groups selected from the group may be substituted.
R1 Qがァリール基を示す請求項 1記載の化合物又はその塩。 The compound or a salt thereof according to claim 1, wherein R 1 Q represents an aryl group.
3. 一般式（1 )において、 X1— X2が S _ CH2、 CH2— CH2、又は CH = C Hを示し； R1が低級アルキル基、ァリール基、ヒドロキシ基、及びヒドロキシ基のエステルから選択さ れる を示し； 3. In the general formula (1), X 1 — X 2 represents S — CH 2 , CH 2 — CH 2 , or CH = CH; R 1 represents a lower alkyl group, an aryl group, a hydroxy group, or a hydroxy group. Indicates selected from esters;
p力 0、 1又は 2を示し、 pが 2である場合、各 R1は同一であり； p force 0, 1 or 2 when p is 2, each R 1 is the same;
R2が水素原子、低級アルキル基、ァラルキル基、低級アルキルカルボ二ル基、ァリール カルポニル基、低級アルコキシカルボニル基、低級アルキルスルホニル基、又はァリール スルホ二ル基を示し、 R2がァラルキル基、ァリール力ルポニル基又はァリールスルホニル 基の場合、該ァラルキル基、該ァリ一ルカルポニル基又は該ァリールスルホニル基は 1 又は複数個のハロゲン原子を置換基として有してもよく； R 2 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a lower alkyl carbonyl group, an aryl carbonyl group, a lower alkoxycarbonyl group, a lower alkyl sulfonyl group, or an aryl sulfonyl group, and R 2 represents an aralkyl group or an aryl. In the case of a strong sulfonyl group or an arylsulfonyl group, the aralkyl group, the arylcarbonyl group or the arylsulfonyl group may have one or more halogen atoms as substituents;
R3が水素原子を示し； R 3 represents a hydrogen atom;
Y1— Y2力 CH = CH、 N = CH、又は CH = Nを示し； Y 1 — Y 2 force indicates CH = CH, N = CH, or CH = N;
R4がハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、低級アルケニル基、ァラ ルキル基、低級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基、低級アルキルァ ミノ基、カルポキシ基のアミド、及びシァノ基から選択される基を示し、 R4が低級アルケニ ル基の場合、該低級アルケニル基は 1又は複数個のァリール基を置換基として有しても よ R 4 is selected from halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkenyl group, aralkyl group, lower alkoxy group, aryloxy group, aralkyloxy group, lower alkylamino group, carboxy group amide, and cyano group. And when R 4 is a lower alkenyl group, the lower alkenyl group may have one or more aryl groups as a substituent.
qが 0、 1又は 2を示し、 qが 2である場合、各 R4は同一又は異なってもよく； when q represents 0, 1 or 2, and q is 2, each R 4 may be the same or different;
R5がハロゲン原子、水素原子、低級アルキル基、ハロゲノ低級アルキル基、低級シクロ アルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基、低級アルコキシ基、ハ ロゲノ低級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基、メルカプト基、低級ァ ルキルチオ基、ハロゲノ低級アルキルチオ基、ァリールチオ基、複素環チォ基、ァラルキ ルチオ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキルアミノ基のァ ミド、ァリ一ルァミノ基、低級アルキルカルポニル基、ァリールカルポニル基、カルボキシ基 、カルボキシ基のエステル、カルポキシ基のアミド、低級アルキルスルホニル基、ァリール スルホニル基、スルホン酸基のアミ ニトロ基、シァノ基、 CR6 = CR7 (Re)、 C≡CR9、又 は N = NR1 Qを示し、 R5が低級アルキル基の場合、該低級アルキル基は複素環基、ァミノ 基、カルポキシ基のエステル、及びシァノ基から選択される 1又は複数個の基を置換基と して有してもよく、 R5がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル 基、ハロゲノ低級アルキル基、低級アルコキシ基、ニトロ基、及びシァノ基から選択される 1又は複数個の基を置換基として有してもよく、 R5が複素環基の場合、該複素環基はハ ロゲン原子、低級アルキル基、及びハロゲノ低級アルキル基から選択される 1又は複数 個の基を置換基として有してもよく、 R5がァラルキル基の場合、該ァラルキル基は低級ァ ルコキシ基及びアミノ基から選択される 1又は複数個の基を置換基として有してもよく、 RR 5 is a halogen atom, hydrogen atom, lower alkyl group, halogeno lower alkyl group, lower cycloalkyl group, aryl group, heterocyclic group, aralkyl group, hydroxy group, lower alkoxy group, halogeno lower alkoxy group, aryloxy group, aralkyloxy. Group, mercapto group, lower alkylthio group, halogeno lower alkylthio group, arylothio group, heterocyclic thio group, aralkylthio group, amino group, amido amide, lower alkylamino group, lower alkylamino group Amide, arylamine group, lower alkyl carbonyl group, aryl carbonyl group, carboxy group, ester of carboxy group, amide of carboxy group, lower alkyl sulfonyl group, aryl sulfonyl group, aminitro group of sulfonic acid group, cyano group CR 6 = CR 7 (R e ), C≡CR 9 , or N = NR 1 Q, and when R 5 is a lower alkyl group, the lower alkyl group is a heterocyclic group, an amino group, or a carboxy group. One or more groups selected from an ester and a cyano group may be substituted, and when R 5 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, or a halogeno lower alkyl group. , A lower alkoxy group, a nitro group, and a cyan group may have one or more groups as a substituent, and when R 5 is a heterocyclic group, the heterocyclic group is a halogen atom, Al One or more groups selected from a kill group and a halogeno lower alkyl group may be substituted, and when R 5 is an aralkyl group, the aralkyl group is selected from a lower alkoxy group and an amino group. May have one or more groups as substituents, R
5が低級アルコキシ基の場合、該低級アルコキシ基は 1又は複数個の複素環基を置換基 として有してもよく、 R5がァリールォキシ基の場合、該ァリールォキシ基は 1又は複数個 の低級アルキル基を置換基として有してもよく、 R5がァラルキルォキシ基の場合、該ァラ ルキルォキシ基はハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、及び低級 アルコキシ基から選択される 1又は複数個の基を置換基として有してもよぐ R5が低級ァ ルキルチオ基の場合、該低級アルキルチオ基は低級シクロアルキル基、及ぴ複素環基 から選択される 1又は複数個の基を置換基として有してもよ R5がァリールチオ基の場 合、該ァリ一ルチオ基はハロゲン原子、ハロゲノ低級アルキル基、及びアミノ基から選択 される 1又は複数個の基を置換基として有してもよく、 R5がァラルキルチオ基の場合、該 ァラルキルチオ基はハロゲン原子、低級アルキル基、ハロゲノ低級アルキル基、及び低 級アルコキシ基から選択される 1又は複数個の基を置換基として有してもよ《 R5がァリ 一ルスルホニル基の場合、該ァリ一ルスルホニル基は 1又は複数個のアミノ基を置換基 として有してもよぐ When 5 is a lower alkoxy group, the lower alkoxy group may have one or more heterocyclic groups as a substituent, and when R 5 is an aryloxy group, the aryloxy group is one or more lower alkyl groups. And when R 5 is an aralkyloxy group, the aralkyloxy group is selected from a halogen atom, a lower alkyl group, a halogeno lower alkyl group, and a lower alkoxy group. In the case where R 5 is a lower alkylthio group, the lower alkylthio group may be one or more groups selected from a lower cycloalkyl group and a heterocyclic group. If of good R 5 have Ariruchio group, said § Li one Lucio group is a halogen atom, halogeno-lower alkyl group, and one or a plurality of groups selected from an amino group May be, when R 5 is a Ararukiruchio group has the Ararukiruchio group halogen atom, a lower alkyl group, a halogeno-lower alkyl group, and one or a plurality of groups selected from a low-grade alkoxy group as a substituent However, when R 5 is an arylsulfonyl group, the arylsulfonyl group may have one or more amino groups as substituents.
R6が水素原子を示し； . R 6 represents a hydrogen atom;
R7が水素原子を示し； R 7 represents a hydrogen atom;
R8が水素原子、低級シクロアルキル基、ァリール基、複素環基、又はカルポキシ基のェ ス亍ノレを示し、 R 8 is a hydrogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic group, or a carboxy group. Show the snow,
がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基、ハロゲノ低級 アルキル基、低級シクロアルキル基、ァリール基、複素環基、ァラルキル基、ヒドロキシ基 、低級アルコキシ基、ハロゲノ低級アルコキシ基、ァリールォキシ基、ァラルキルォキシ基 、低級アルキルチオ基、アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキル カルポニル基、ァリールカルボニル基、カルボキシ基、スルホン酸基のアミド、ニトロ基、及 びシァノ基から選択される 1又は複数個の基を置換基として有してもよぐ  Is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a lower cycloalkyl group, an aryl group, a heterocyclic group, an aralkyl group, a hydroxy group, a lower alkoxy group, a halogeno lower alkoxy group, an aryloxy group. Group, aralkyloxy group, lower alkylthio group, amino group, amino amide, lower alkylamino group, lower alkyl carbonyl group, arylcarbonyl group, carboxy group, sulfonic acid group amide, nitro group, and cyano group May have one or more groups as substituents
R9が水素原子、ァリール基、又は複素環基を示し、 R 9 represents a hydrogen atom, an aryl group, or a heterocyclic group,
R9がァリール基の場合、該ァリール基はハロゲン原子、低級アルキル基、 1若しくは複数 個のヒドロキシ基で置換された低級アルキル基、 1若しくは複数個の低級アルコキシ基で 置換された低級アルキル基、 1若し〈は複数個のァリールォキシ基で置換された低級ァ ルキル基、 1若しくは複数個のカルポキシ基で置換された低級アルキル基、 1若しくは複 数個のカルボキシ基のエステルで置換された低級アルキル基、 1若しくは複数個のシァノ 基で置換された低級アルキル基、ハロゲノ低級アルキル基、低級シクロアルキル基、ァリ —ル基、ァラルキル基、ヒドロキシ基、ヒドロキジ基のエステル、低級アルコキシ基、 1若し くは複数個の低級シクロアルキル基で置換された低級アルコキシ基、 1若しくは複数個の 複素環基で置換された低級アルコキシ基、 1若しくは複数個のヒドロキシ基で置換された 低級アルコキシ基、 1若しくは複数個の低級アルコキシ基で置換された低級アルコキシ 基、 1若しくは複数個のァミノ基で置換された低級アルコキシ基、 1若しくは複数個のカル ポキシ基で置換された低級アルコキシ基、 1若しくは複数個のカルボキシ基のエステルで 置換された低級アルコキシ基、ハロゲノ低級アルコキシ基、低級アルケニルォキシ基、低 級シクロアルキルォキシ基、 1若しくは複数個のハロゲン原子で置換されたァリールォキ シ基、ァラルキルォキシ基、ァリールォキシカルボニルォキシ基、低級アルキルチオ基、 アミノ基、ァミノ基のアミド、低級アルキルアミノ基、低級アルキルカルポニル基、ァリール カルポニル基、カルボキシ基、カルポキシ基のアミド、スルホン酸基のアミド、ニトロ基、及 びシァノ基から選択される 1又は複数個の基を置換基として有してもよぐ When R 9 is an aryl group, the aryl group is a halogen atom, a lower alkyl group, a lower alkyl group substituted with one or more hydroxy groups, a lower alkyl group substituted with one or more lower alkoxy groups, 1 or <is a lower alkyl group substituted with a plurality of aryloxy groups, a lower alkyl group substituted with one or more carboxy groups, or a lower alkyl substituted with esters of one or more carboxy groups Group, lower alkyl group substituted with one or more cyan groups, halogeno lower alkyl group, lower cycloalkyl group, aryl group, aralkyl group, hydroxy group, ester of hydroxy group, lower alkoxy group, Or a lower alkoxy group substituted with a plurality of lower cycloalkyl groups, or a lower alkoxy group substituted with one or more heterocyclic groups. A ruxoxy group, a lower alkoxy group substituted with one or more hydroxy groups, a lower alkoxy group substituted with one or more lower alkoxy groups, a lower alkoxy group substituted with one or more amino groups, 1 Or a lower alkoxy group substituted with a plurality of carboxy groups, a lower alkoxy group substituted with one or a plurality of esters of carboxy groups, a halogeno lower alkoxy group, a lower alkenyloxy group, a lower cycloalkyloxy group An aryloxy group, an aralkyloxy group, an aryloxycarbonyloxy group, a lower alkylthio group, an amino group, an amide of an amino group, a lower alkylamino group, a lower alkylcarbonyl group substituted with one or more halogen atoms, Aryl carbonyl, carboxy, and carboxy groups And one or more groups selected from amide, nitro group, and cyano group of sulfonic acid group may be substituted.
R1 Qがァリール基を示す請求項 1又は 2記載の化合物又はその塩。 The compound or salt thereof according to claim 1 or 2, wherein R 1 Q represents an aryl group.
4. 一般式（1 )において、 X1— X2が CH 2— C H2を示し； 4. In the general formula (1), X 1 — X 2 represents CH 2 — CH 2 ;
Y1— Y2が CH = CHを示し； Y 1 — Y 2 represents CH = CH;
pが 0を示し； p represents 0;
R2と R3がともに水素原子を示す請求項 1 ~ 3記載の化合物又はその塩。 4. The compound or a salt thereof according to claim 1, wherein R 2 and R 3 both represent a hydrogen atom.
5. 一般式（1 )において、 X1— X2が CH2— CH2を示し； 5. In the general formula (1), X 1 — X 2 represents CH 2 — CH 2 ;
Y1— Y2は N = CH、又は CH = Nを示し； Y 1 — Y 2 represents N = CH or CH = N;
pが 0を示し； p represents 0;
R2と R3がともに水素原子を示す請求項 1〜3記載の化合物又はその塩。 The compound or a salt thereof according to claim 1, wherein R 2 and R 3 both represent a hydrogen atom.
6. 一般式（1 )において、 R5がハロゲン原子、置換基を有してもよい低級アルキル 基、ハロゲノ低級アルキル基、置換基を有してもよい複素環基、置換基を有してもよいァ ラルキル基、ヒドロキシ基、ヒドロキシ基のエステル、置換基を有してもよい低級アルコキ シ基、ハロゲノ低級アルコキシ基、置換基を有してもよい低級シクロアルキルォキシ基、 置換基を有してもよいァリールォキシ基、置換基を有してもよい複素環ォキシ基、置換基 を有してもよいァラルキルォキシ基、メルカプト基、メルカプト基のエステル、置換基を有し てもよい低級アルキルチオ基、ハロゲノ低級アルキルチオ基、置換基を有してもよい低級 シクロアルキルチオ基、置換基を有してもよいァリールチオ基、置換基を有してもよい複 素環チォ基、置換基を有してもよいァラルキルチオ基、アミノ基、ァミノ基のアミド、置換 基を有してもよい低級アルキルアミノ基、置換基を有してもよい低級アルキルアミノ基の アミド、置換基を有してもよいァリ一ルァミノ基、置換基を有してもよいァリールァミノ基の アミド、ホルミル基、置換基を有してもよい低級アルキルカルポニル基、置換基を有しても よいァリ一ルカルポニル基、置換基を有してもよい低級アルキルスルホニル基、置換基を 有してもよいァリールスルホニル基、 CR6 = CR7 ( R8)、又は C三 CR9を示す請求項 1記載 の化合物又はその塩。 6. In the general formula (1), R 5 has a halogen atom, a lower alkyl group which may have a substituent, a halogeno lower alkyl group, a heterocyclic group which may have a substituent, or a substituent. An aralkyl group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, a lower cycloalkyloxy group which may have a substituent, a substituent An aryloxy group which may have, a heterocyclic oxy group which may have a substituent, an aralkyloxy group which may have a substituent, a mercapto group, an ester of a mercapto group, and a lower alkylthio which may have a substituent Group, halogeno lower alkylthio group, optionally substituted lower cycloalkylthio group, optionally substituted arylthio group, optionally substituted bicyclic thio group, substituted May have an aralkylthio group, an amino group, an amide of an amino group, a lower alkylamino group which may have a substituent, an amide of a lower alkylamino group which may have a substituent, or a substituent. An arylamine group, an amide of an arylamine group which may have a substituent, a formyl group, a lower alkylcarbonyl group which may have a substituent, an arylcarbonyl group which may have a substituent, a substituted group The compound according to claim 1, which represents a lower alkylsulfonyl group that may have a group, an arylsulfonyl group that may have a substituent, CR 6 = CR 7 (R 8 ), or C 3 CR 9 salt.
7 . 一般式（1 )において、 R5が置換基を有してもよい複素環基、ヒドロキシ基、ヒド ロキシ基のエス亍ル、置換基を有してもよい低級アルコキシ基、ハロゲノ低級アルコキシ 基、置換基を有してもよい低級シクロアルキルォキシ基、置換基を有してもよいァリール ォキシ基、置換基を有してもよい複素環ォキシ基、置換基を有してもよいァラルキルォキ シ基、メルカプト基、メルカプト基のエステル、置換基を有してもよい低級アルキルチオ基 、ハロゲノ低級アルキルチオ基、置換基を有してもよい低級シクロアルキルチオ基、置換 基を有してもよいァリールチオ基、置換基を有してもよい複素環チォ基、置換基を有して もよぃァラルキルチオ基、 CR6 = CR7 ( R8)、又は C三 CR9を示す請求項 6記載の化合物 又はその塩。 7. In the general formula (1), R 5 may have a heterocyclic group which may have a substituent, a hydroxy group, a hydroxyl group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy. Group, a lower cycloalkyloxy group which may have a substituent, an aryloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, and a substituent. Aralkiroki Ci group, mercapto group, mercapto group ester, optionally substituted lower alkylthio group, halogeno lower alkylthio group, optionally substituted lower cycloalkylthio group, optionally substituted arylthio 7. The compound according to claim 6, which represents a group, a heterocyclic thio group which may have a substituent, an aralkylthio group which may have a substituent, CR 6 = CR 7 (R 8 ), or C 3 CR 9 Or a salt thereof.
8 . 一般式（"において、 R5が置換基を有してもよい複素環基を示す請求項 1記 載の化合物又はその塩。 8. The compound or a salt thereof according to claim 1, wherein in general formula (“, R 5 represents a heterocyclic group which may have a substituent.
9 . 一般式（1 )において、複素環基の複素環が、ピぺラジン、モルホリン、ピロリジ ン、ピリジン、チォフェン、インドール、ベンゾイミダゾ一ル、キノリン、キノキサリン、ベンゾフ ラン、ベンゾチオフ:!:ン、ベンゾォキサゾリン、又はべンゾチアゾリンを示す請求項 8記載の 化合物又はその塩。  9. In the general formula (1), the heterocyclic ring of the heterocyclic group is piperazine, morpholine, pyrrolidine, pyridine, thiophene, indole, benzimidazole, quinoline, quinoxaline, benzofuran, benzothiol :! The compound or a salt thereof according to claim 8, which represents benzoxazoline or benzothiazoline.
1 0. 一般式（1 )において、 R5がヒドロキシ基、ヒドロキシ基のエステル、置換基を有 してもよい低級アルコキシ基、ハロゲノ低級アルコキシ基、置換基を有してもよい低級シ クロアルキルォキシ基、置換基を有してもよいァリールォキシ基、置換基を有してもよい 複素環ォキシ基、又は置換基を有してもよいァラルキルォキシ基を示す請求項 1記載の 化合物又はその塩。 10. In general formula (1), R 5 is a hydroxy group, an ester of a hydroxy group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, or a lower cycloalkyl which may have a substituent. The compound or a salt thereof according to claim 1, which represents an oxy group, an aryloxy group which may have a substituent, a heterocyclic oxy group which may have a substituent, or an aralkyloxy group which may have a substituent. .
1 1 . 一般式（1 )において、 R5がヒドロキシ基、置換基を有してもよい低級アルコキシ 基、ハロゲノ低級アルコキシ基、置換基を有してもよいァリールォキシ基、又は置換基を 有してもよいァラルキルォキシ基を示す請求項 1 0記載の化合物又はその塩。 1 1. In general formula (1), R 5 has a hydroxy group, a lower alkoxy group which may have a substituent, a halogeno lower alkoxy group, an aryloxy group which may have a substituent, or a substituent. The compound or a salt thereof according to claim 10, which may be an aralkyloxy group.
1 2. —般式（1 )において、 R5がメルカプト基、メルカプト基のエステル、置換基を有し てもよい低級アルキルチオ基、ハロゲノ低級アルキルチオ基、置換基を有してもよい低級 シクロアルキルチオ基、置換基を有してもよいァリールチオ基、置換基を有してもよい複 素環チォ基、又は置換基を有してもよいァラルキルチオ基を示す請求項 1記載の化合物 又はその塩。 1 2. —In general formula (1), R 5 represents a mercapto group, an ester of a mercapto group, an optionally substituted lower alkylthio group, a halogeno-lower alkylthio group, or an optionally substituted lower cycloalkylthio group. 2. The compound according to claim 1 or a salt thereof, which represents a group, an arylthio group which may have a substituent, a bicyclic thio group which may have a substituent, or an aralkylthio group which may have a substituent.
1 3. 一般式（1 )において、 R5がメルカプト基、置換基を有してもよい低級アルキルチ ォ基、ハロゲノ低級アルキルチオ基、置換基を有してもよいァリールチオ基、複素環チォ 基、又は置換基を有してもよいァラルキルチオ基を示す請求項 1 2記載の化合物又はそ の塩。 1 3. In the general formula (1), R 5 represents a mercapto group, a lower alkylthio group which may have a substituent, a halogeno lower alkylthio group, an arylylthio group which may have a substituent, a heterocyclic thio group, Or a compound according to claim 12 or an aralkylthio group which may have a substituent. Salt.
14. 一般式（1)において、 R5が CR6 = CR7(Ra)を示す請求項 1記載の化合物又は その塩。 14. The compound or a salt thereof according to claim 1, wherein, in the general formula (1), R 5 represents CR 6 = CR 7 (R a ).
15. 一般式（1)において、 R6が水素原子を示し； 15. In general formula (1), R 6 represents a hydrogen atom;
R7が水素原子を示し； R 7 represents a hydrogen atom;
R8が水素原子、低級シクロアルキル基、置換基を有してもよいァリール基、複素環基、 又はカルポキシ基のエステルを示す請求項 14記載の化合物又はその塩。 15. The compound or a salt thereof according to claim 14, wherein R 8 represents a hydrogen atom, a lower cycloalkyl group, an optionally substituted aryl group, a heterocyclic group, or an ester of a carboxy group.
16. —般式（1)において、 R5が C≡CR9を示す請求項 1記載の化合物又はその塩16. The compound or a salt thereof according to claim 1, wherein in the general formula (1), R 5 represents C≡CR 9
17. 一般式（1 )において、 R9が水素原子、置換基を有してもよいァリール基、又は 複素璟基を示す請求項 16記載の化合物又はその塩。 17. The compound or a salt thereof according to claim 16, wherein in the general formula (1), R 9 represents a hydrogen atom, an aryl group which may have a substituent, or a heterocyclic group.
18. - (R)- -Ν'—(4—トリフルォロメチルフエニル）ピロリジン一 2—力ルポキサミド、 18.-(R)--Ν '— (4-Trifluoromethylphenyl) pyrrolidine 1-strand lupoxamide,
■ (R)一 N'一（4 —η—ォクチルフエニル）ピロリジン一 2—カルポキサミド、 ■ (R) 1 N '1 (4-η-octylphenyl) pyrrolidine 1 2-carboxamide,
■(R)一 N'一（4一ベンジルフ Iニル）ピロリジン一 2—カルボキサミド、  ■ (R) -one N'-one (4-one benzylphenyl) pyrrolidine-one 2-carboxamide,
■ (R) -N' —(4一ョ一ドフエニル）ピロリジン一 2—カルポキサミド、  ■ (R) -N '— (4 -1-dophenyl) pyrrolidine 1-carboxamide,
■(R) -N'一（4 —ベンゾィルフエニル）ピロリジン一 2—力ルポキサミド、  ■ (R) -N '-(4-benzoylphenyl) pyrrolidine-one 2-power lupoxamide,
■ (R) -N'一（6 —クロ口一 3—ピリジル）ピロリジン一 2—力ルポキサミド、  ■ (R) -N'-one (6—Black 1-Pyridyl) pyrrolidine 1-Strong Lupoxamide,
■ ( ) -N'一（4 —トリフルォロメトキシフエニル）ピロリジン一 2—カルボキサミド、 ■ () -N '-(4-Trifluoromethoxyphenyl) pyrrolidine 2-Carboxamide,
■(R) -N'一（4 —ベンジルォキシフエニル）ピロリジン一 2—カルボキサミド、 ■ (R) -N ′-(4-Benzyloxyphenyl) pyrrolidine-1-Carboxamide,
■ (R)一 N'一 [4 —(3—メトキシベンジルォキシ）フエニル]ピロリジン一2—カルポキサミド  ■ (R) -N '-[4 — (3-Methoxybenzyloxy) phenyl] pyrrolidine-2-carbonoxamide
■ (R) — N'一 [4 — (3—メチルベンジルォキシ）フエニル]ピロリジン一 2—力ルポキサミド、■ (R) — N ′ 1 [4 — (3-Methylbenzyloxy) phenyl] pyrrolidine 1 2-strength lupoxamide,
■ ( ) -N'一 [4 — ( 3—クロロベンジルォキシ）フエニル]ピ口リジン― 2—力ルポキサミド、■ () -N '1 [4 — (3 -Chlorobenzyloxy) phenyl] pipinal lysine-2-force lupoxamide,
•(R)一 N'一 [4 — (4—クロ口ベンジルォキシ）フエニル]ピロリジン一 2—力ルポキサミド、• (R) -one N'-one [4 — (4-Chronobenzyloxy) phenyl] pyrrolidine one 2-power lupoxamide,
■ (R)一 N'一 [4一（2—トリフルォロメチルベンジルォキシ）フエニル]ピロリジン一 2—カル ボキサミド、 ■ (R) -N '-[41- (2-trifluoromethylbenzyloxy) phenyl] pyrrolidine-1-2-carboxamide,
■ (R)-N'一 [4— (3—トリフルォロメチルベンジルォキシ）フエニル]ピロリジン一 2—カル ボキサミド、 ■ (R) -N '1 [4- (3-Trifluoromethylbenzyloxy) phenyl] pyrrolidine 1 2-cal Boxamide,
■ (R)-N'一 [4一（4一トリフルォロメチルベンジルォキシ）フエニル]ピロリジン一2—カル ボキサミド、  ■ (R) -N ′-[41- (4-trifluoromethylbenzyloxy) phenyl] pyrrolidine-1-2-carboxamide,
■(R)-N'—(4一べンジルォキシー3—クロ口）フエニルピロリジン一 2_カルポキサミド、 ' (R)— N'— [3—メチル一4— (4—メチルベンジルォキシ）フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) -N '— (4 Benzyloxy 3—Black) Phenylpyrrolidine 1_Carpoxamide,' (R) — N'— [3-Methyl 4- (4-methylbenzyloxy) phenyl ] Pyrrolidine 1-power Lupoxamide,
■(R)_N'—[4—（3—ピリジルメチルォキシ）フエニル]ピロリジン一 2—カルボキサミド、 ' (R)-N' - (4 フエノキシフエニル）ピロリジン一 2—力ルポキサミド、  ■ (R) _N '— [4— (3-Pyridylmethyloxy) phenyl] pyrrolidine-1-carboxamide,' (R) -N '-(4 phenoxyphenyl) pyrrolidine-1-2-lupoxamide,
»( )-N'一（4一トリフルォロメチルチオフエニル）ピロリジン一 2—力ルポキサミド、 ■ (R)-N'一（4一フエ二ルチオフエニル）ピロリジン一 2—カルボキサミド、 »() -N '-(4-trifluoromethylthiophenenyl) pyrrolidine-1-2-lupoxamide, ■ (R) -N'-(4-phenylthiophenyl) pyrrolidine-1-2-carboxamide,
- (R)-N' - (4一べンジルチオフエニル）ピロリジン一 2—力ルポキサミド、 -(R) -N'- (4 benzylthiophenyl) pyrrolidine 1-streptoxoxamide,
■(R)— N'—[4- (2—クロ口べンジルチオ）フエニル]ピロリジン一 2—力ルポキサミド、.■ (R) —N ′ — [4- (2-Chronobensylthio) phenyl] pyrrolidine-1 2-power lupoxamide.
■ (R)-N' - [4一（2—トリフルォロメチルベンジルチオ）フエニル]ピロリジン一 2—カルボ キサミド、 ■ (R) -N '-[4 (2-trifluoromethylbenzylthio) phenyl] pyrrolidine-1 2-carboxamide,
'(R)_N'— [4— (2—メトキシベンジルチオ）フエニル]ピロリジン一 2—力ルポキサミド、'(R) _N'— [4- (2-Methoxybenzylthio) phenyl] pyrrolidine 1-power lupoxamide,
■ (R)-N' _ [4一（3—メトキシベンジルチオ）フエニル]ピロリジン一 2_カルポキサミド、■ (R) -N '_ [4 (3-methoxybenzylthio) phenyl] pyrrolidine-1 2_carboxamide,
■ (R)-N' _ [4一（4ーメトキシベンジルチオ）フエニル]ピロリジン一 2—力ルポキサミド、■ (R) -N '_ [4 (4-Methoxybenzylthio) phenyl] pyrrolidine-1 2-power lupoxamide,
■ (R)_N'—[4— (4—ピリジルメチルチオ）フエニル]ピロリジン一 2—カルボキサミド、 ■(R)-N'— [4— (1ーメチルー 1一フエ二ルェチルチオ）フエニル]ピロリジン一 2—力ルポ キサミド、 ■ (R) _N '— [4— (4-Pyridylmethylthio) phenyl] pyrrolidine-1-carboxamide, ■ (R) -N' — [4 -— (1-Methyl-1-monophenylthio) phenyl] pyrrolidine-2- Force lupoxamide,
- (R)— N' _ (4—フエネチルチオフエニル）ピロリジン一 2—カルポキサミド、  -(R) — N ′ _ (4-phenethylthiophenyl) pyrrolidine 1-carboxamide,
■ (R)-N'—[4一（3—フエニルプロピルチオ）フエニル]ピロリジン _2—力ルポキサミド、 ■ (R) -N '— [4 (3-phenylpropylthio) phenyl] pyrrolidine _2—power lupoxamide,
■ (R)— N '—（4— n _プチルチオフエニル）ピ口リジン― 2—カルボキサミド、 ■ (R) —N ′ — (4—n_Putylthiophenyl) pi-lysine—2-carboxamide,
■ (R)—N'— (4—シクロへキシルメチルチオフエニル）ピロリジン一 2—カルボキサミド、 '(R)_N'—(6—ベンジルチオ一 3—ピリジル）ピロリジン一 2—力ルポキサミド、  ■ (R) —N'— (4-cyclohexylmethylthiophenyl) pyrrolidine-2-carboxamide, '(R) _N' — (6-benzylthio-1-3-pyridyl) pyrrolidine-1-2-lupoxamide,
' (R)—NT _[4— (2—ナフチル）フエニル]ピロリジン一 2—カルボキサミド、  '(R) —NT _ [4— (2-Naphthyl) phenyl] pyrrolidine 1-carboxamide,
' (R)-N'—[4— (ベンゾチォフェン一 2—ィル）フエニル]ピロリジン一 2—カルボキサミド ' (R)-N'ー[4一（ベンゾチアゾ一ルー 2—ィル）フエニル]ピロリジン一 2—カルポキサミド '(R) -N' — [4— (Benzothiophene-2-yl) phenyl] pyrrolidine-2-Carboxamide '(R) -N'-[4 (benzothiazo-l-yl) phenyl] pyrrolidine-l-carboxamide
- (R) -N' _ [4一 [(E)—2—フエニル一 1—ェテニル]フエニル]ピロリジン一2—力ルポ キサミド、 -(R) -N '_ [4 1 [(E) -2-phenyl-1- 1-ethenyl] phenyl] pyrrolidine 1-strength lupoxamide,
■ (R)— N'— [4— [(E)—2— (2—メチルフ; ϋ二ル）一 1—ェテニル]フ Iニル]ピロリジン 一 2—カルボキサミド、  ■ (R) — N′— [4— [(E) —2— (2-Methyl); 1-ethenyl] fur Inyl] pyrrolidine and 1-carboxamide;
■ (R)— N'— [4— [(E)—2— (3—メチルフエニル）一 1—ェテニル]フエニル]ピロリジン 一 2—カルボキサミド、  ■ (R) — N′— [4— [(E) —2— (3-Methylphenyl) 1-ethenyl] phenyl] pyrrolidine 1 2-carboxamide,
■ (R)— N'— [4— [(E)—2— (4—メチルフエニル）一 1—ェテニル]フエニル]ピロリジン —2—カルボキサミド、 ■ (R) — N′— [4— [(E) —2— (4-Methylphenyl)-1-ethenyl] phenyl] pyrrolidine —2-carboxamide,
' (R)-N'一 [4一 [(E)—2— (2—クロ口フエニル）一 1—ェテニル]フエニル]ピロリジン一 2—カルボキサミド、  '(R) -N' 1 [4 1 [(E) -2- (2-Clophenyl) 1 1-ethenyl] phenyl] pyrrolidine 1 2-carboxamide,
■ (R)-N'一 [4— [(E)— 2— (3—クロ口フエニル）一1—ェテニル]フエニル]ピロリジン一 2—カルボキサミド、  ■ (R) -N '-[4 — [(E) — 2-((3-phenyl) phenyl] -1-ethenyl] phenyl] pyrrolidine-1 2-carboxamide,
- (R)-N' _ [4_ [(E)— 2— (4—クロ口フエ二ル）一 1—ェ亍ニル]フエニル]ピロリジン一 2—カルボキサミド、  -(R) -N '_ [4_ [(E) — 2— (4-phenyl) 1-enyl] phenyl] pyrrolidine 1-carboxamide,
■ (R)-N'—[3—メチルー 4— [(E)— 2—フエニル _1—ェテニル]フエニル]ピロリジン一 2—カルボキサミド、  ■ (R) -N '— [3-Methyl-4 — [(E) —2-phenyl_1-ethenyl] phenyl] pyrrolidine-1-2-carboxamide,
- (R)-N'— [3—クロロー 4— [(E)-2—フエニル _1—ェテニル]フエニル]ピロリジン一 2—カルボキサミド、 -(R) -N'— [3-Chloro-4-[[E) -2-phenyl-1-phenyl] pyrrolidine-1-2-carboxamide,
■ (R)—N'—[4— [(E)— 2—シクロへキシル _1—ェテニル]フエニル]ピロリジン一 2— カルポキサミド、  ■ (R) —N ′ — [4 — [(E) —2-cyclohexyl_1-ethenyl] phenyl] pyrrolidine mono 2-carboxamide,
■ (R)— N'— [4_ [(E)— 2— (4—イソプロポキシフエニル）一 1—ェテニル]フエニル]ピ 口リジン一 2—カルボキサミド、  ■ (R) — N′— [4_ [(E) — 2— (4-Isopropoxyphenyl) -1- 1-ethenyl] phenyl] di-lysine 1-carboxamide,
■(R)— N'— [4_ [(E)—2— (4—ニトロフエ二ル）一 1ーェテニル]フヱニル]ピロリジン一 2—カルポキサミド、 ■ (R)— N'— [4— [(E)— 2— (4—べンジルフエ二ル）一 1—ェテニル]フエニル]ピロリジ ン一 2—カルボキサミド、 ■ (R) — N′— [4_ [(E) —2— (4-Nitrophenyl) -1-etenyl] phenyl] pyrrolidine-1-2-carboxamide, ■ (R) — N′— [4— [(E) — 2— (4-Benzylphenyl) -1- 1-ethenyl] phenyl] pyrrolidin-2-carbonamide,
' (R)— N'— [4一 [(E)— 2— (1—ナフチル）一1 -ェ亍ニル]フエニル]ピロリジン一 2— カルボキサミド、  '(R) — N'— [4 1 [(E) 2-(1-Naphthyl) 1 -enyl] phenyl] pyrrolidine 1 2-carboxamide,
-(R)-N'一 [4一 [(E)— 2—（4一ピリジル）一1—ェテニル]フエニル]ピロリジン一 2—力 ルポキサミド、 -(R) -N'one [41] [(E) -2- (4-1pyridyl) 1-1-ethenyl] phenyl] pyrrolidine 1-2-power lupoxamide,
■(R)-N'一 [4— [(E)— 2—（2—チェ二ル）一 1ーェテニル]フエニル]ピロリジン一 2— カルボキサミド、  ■ (R) -N '-[4 — [(E) —2- (2-Chenyl) -1-1-ethenyl] phenyl] pyrrolidine-1-2-carboxamide,
■(R)-N' -[4—（2—フエニル一1ーェチニル）フエニル]ピロリジン一 2—カルポキサミド 、  ■ (R) -N '-[4- (2-phenyl-1-ethynyl) phenyl] pyrrolidine-2-carboxamide,
' (R)-N' -[4-[2- (2—メチルフエ二ル）一 1ーェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、  '(R) -N'-[4- [2- (2-Methylphenyl) -1- 1-ethynyl] phenyl] pyrrolidine-1 2-force lupoxamide,
■(R)-N'—[4- [2—（3—メチルフエニル）一 1ーェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) -N '— [4- [2- (3-Methylphenyl) -1- 1-ethynyl] phenyl] pyrrolidine 1-2-power lupoxamide,
-(R)-N'—[4一 [2—（4—メチルフエニル）一1—ェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、 -(R) -N '-[4 1 [2- (4-methylphenyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2-force lupoxamide,
' (R)-N' -[4-[2- (2—トリフルォロメチルフエニル）一 1—ェチニル]フエニル]ピロリ ジンー2—カルボキサミド、  '(R) -N'-[4- [2- (2-trifluoromethylphenyl)-1-ethynyl] phenyl] pyrrolidine-2-carboxamide,
- (R) -N'—[4一 [2—（3—トリフルォロメチルフエニル）一 1ーェチニル]フエニル]ピロリ ジン _2—力ルポキサミド、  -(R) -N '— [4 1 [2- (3-Trifluoromethylphenyl) 1 1-ethynyl] phenyl] pyrrolidine _2—power lupoxamide,
■(R)-N'—[4一 [2—（4—トリフルォロメチルフエ二ル）一 1ーェチニル]フエニル]ピロリ ジン一 2—カルボキサミド、  ■ (R) -N '— [4 1 [2- (4-Trifluoromethylphenyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2-carboxamide,
■(R)-N'—[4一 [2— (4—ニトロフエニル）一 1ーェチニル]フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) -N '— [4 1 [2— (4-Nitrophenyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2 — force lupoxamide,
- (R)-N'—[4— [2— (4—べンジルフエ二ル）一 1—ェチニル]フエニル]ピロリジン一 2 一力ルポキサミド、 -(R) -N '— [4— [2— (4-Benzylphenyl) -1-ethynyl] phenyl] pyrrolidine-1 2 lupoxamide,
■ (R)-N'—[4— [2— (4—シクロへキシルメトキシフエニル）一 1ーェチニル]フエニル]ピ 口リジン一 2—カルポキサミド、 ■ (R) -N '— [4 -— [2 -— (4-Cyclohexylmethoxyphenyl)-1-ethynyl] phenyl] pi Oral lysine 1-carboxamide,
■(R)— N'— [4— [2— (4—イソプロポキシフエニル）一 1ーェチニル]フエニル]ピロリジン —2—カルボキサミド、  ■ (R) — N′— [4— [2— (4-Isopropoxyphenyl) 1-ethynyl] phenyl] pyrrolidine —2-carboxamide,
' (R)-N'—[4- [2—（4-ベンジルォキシフヱ二ル）一 1—ェチニル]フヱニル]ピロリジ ンー 2—力ルポキサミド、  '(R) -N' — [4- [2- (4-Benzyloxyphenyl) mono-1-ethynyl] phenyl] pyrrolidin-2-power lupoxamide,
■(R)-N'—[4一 [2- (4—ピリジルメチルォキシフエ二ル）一 1ーェチニル]フエニル]ピロ リジン一 2—力ルポキサミド、  ■ (R) -N '— [4 1 [2- (4-Pyridylmethyloxyphenyl) 1 1-ethynyl] phenyl] pyrolysine 1 2 -power lupoxamide,
■ (R)-N' -[4-[2-(1 -ナフチル）一1—ェチニル]フエニル]ピロリジン一 2—力ルポ キサミド、  ■ (R) -N ′-[4- [2- (1- (Naphthyl) -1-1-ethynyl] phenyl] pyrrolidine-1-2-lupoxamide,
-(R)-N'一 [2—メチルー 4一（2—フエ二ルー 1—ェチニル）フエニル]ピロリジン一 2—力 ルポキサミド、 -(R) -N'one [2-Methyl-one (2-phenyl-2-phenyl)] pyrrolidine one-power lupoxamide,
■ (R)— N'— [2—クロ口一 4_ (2—フエ二ルー 1ーェチニル）フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) — N'— [2—Black 1 4_ (2-phenyl 1-ethynyl) phenyl] pyrrolidine 1 2—Lupoxamide,
■(R)-N'一 [3—メチルー 4一（2—フエ二ルー 1—ェチニノレ）フエニル]ピロリジン一 2—力 ルポキサミド、  ■ (R) -N'1 [3-Methyl-4 (2-phenyl-2-phenyl) pyrrolidine-1 2-power lupoxamide,
' (R)— N'— [3—クロロー 4— (2—フエ二ルー 1—工チニノレ）フエニル]ピロリジンー2—力 ルポキサミド、  '(R) — N'— [3—Chloro 4— (2—Phenol, 1—Techninole) Phenyl] pyrrolidine—2—Power
' (R)— N'— [5—（2—フヱニルー 1ーェチニル）一 2—ピリジル]ピロリジン一 2-カルボ キサミド、  '(R) — N'— [5— (2-phenyl-1-ethynyl) -1-2-pyridyl] pyrrolidine-1-2-carboxamide,
' (R) -N'ー[6— (2—フエ二ルー 1ーェチニル）一 3—ピリジル]ピロリジン _2_カルボ キサミド、 '(R) -N'-[6— (2-phenyl-2-ethynyl) -1-3-pyridyl] pyrrolidine _2_carboxamide,
■(R)-N' -[5— [2—（4一トリフルォロメチルフエ二ル）一 1一ェチニル]— 2—ピリジル] ピロリジン一 2—カルボキサミド、  ■ (R) -N '-[5— [2- (4- (Trifluoromethylphenyl) -1-1-1ethynyl] -2-2-pyridyl] pyrrolidine-1-2-carboxamide,
- (S)-N'一 [4 _ [(E)— 2—フエ二ルー 1—ェテニル]フエニル]チアゾリジン一 4—カル ポキサミド、  -(S) -N '1 [4 _ [(E) — 2-phenyl-2-phenyl] thiazolidine 4-carboxamide,
■N' _[4一 [(E)— 2—（4ーメトキシフエ二ル）一 1—ェテニル]フエニル]一 2, 5—ジヒドロ ピロール一2—カルボキサミド、 ' (R)-N'— [4ー（1一メチルインドール一 5—ィル）フエニル]ピロリジン一 2—カルボキサ 5ド、、 ■ N '_ [4 1 [(E) — 2- (4-methoxyphenyl) 1 1-ethenyl] phenyl] 1 2,5-dihydropyrrole 1 2-carboxamide, '(R) -N'— [4- (1 methyl indole 1 5-yl) phenyl] pyrrolidine 1-carboxa 5
■(R)— N'—[4—（インドール一 5—ィル）フエニル]ピロリジン一 2—力ルポキサミド、 ■ (R) — N ′ — [4— (Indole 1-5-yl) phenyl] pyrrolidine 1—2 Lupoxamide,
■ (R)-N'一 [4— [(E)—2— (4-tert—ブトキシフエニル）一 1ーェテニル]フエニル]ピ 口リジン一 2—カルポキサミド、 ■ (R) -N '-[4 — [(E) -2- (4-tert-butoxyphenyl) -1-etenyl] phenyl] pi-lysine-1-2-carboxamide,
■(R)— N'—(4—フエネチルフエニル）ピロリジン一 2—力ルポキサミド、  ■ (R) —N ′ — (4-Phenethylphenyl) pyrrolidine-1-2-Lupoxamide,
' (R)-N'—[4一 [2— (2—フエニルフエニル）一"！ーェチニル]フエニル]ピロリジン一 2— カルボキサミド、  '(R) -N' — [4 1 [2— (2-phenylphenyl) 1 “! -Ethynyl] phenyl] pyrrolidine 1 2 — carboxamide,
■ (R)— N'— [6—メチルー 5— [2—（1—ナフチル）一 1—ェチニル]一 2—ピリジル]ピロ リジン一 2—力ルポキサミド、  ■ (R) —N ′ — [6-Methyl-5- [2- (1-Naphtyl) -1-1-ethynyl] 1-2-pyridyl] pyrolysine 1-2-Lupoxamide,
' (R)-N'—[4一 [2— (4—メトキシー 2—メチルフエニル）一 1ーェチニル]フエニル]ピロ リジン一 2—力ルポキサミド、  '(R) -N' — [4 1 [2- (4-Methoxy-2-methylphenyl) 1 1-ethynyl] phenyl] pyrrolidin 1 2-strength lupoxamide,
'( )-N'— [4— [2— (2—チェ二ル）一 1—ェチニル]フエニル]ピロリジン一 2—力ルポ キサミド、  '() -N'— [4— [2— (2-Chenyl) 1-ethynyl] phenyl] pyrrolidine 1 2-streptoxamide,
-(R)-N'—[4— [2— (5-トリフルォロメチルー 1一ナフチル）一 1—ェチニル]フエニル] ピロリジン一 2—カルボキサミド、 -(R) -N '— [4— [2— (5-trifluoromethyl-1 naphthyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2-carboxamide,
■ (R)-N' -[5-[2-(1一ナフチル）一1ーェチニル] -2—ピリジル]ピロリジン一 2— カルポキサミド、  ■ (R) -N '-[5- [2- (1-Naphtyl) -1-1-1ethynyl] -2-pyridyl] pyrrolidine-1-2-carboxamide,
■(R)-N'一 [4— [2—（4一インドリル）一 1—ェチニル]フエ二ノレ]ピロリジン一 2—力ルポ キサミド、  ■ (R) -N'1 [4— [2— (4 indolyl) 1 1-ethynyl] feninole] pyrrolidine 1 2 force lupoxamide,
■(R)-N' - [4- [2- (ベンゾチォフェンー3—ィル）一 1—ェチニル]フエニル]ピロリジン —2—カルボキサミド、  ■ (R) -N '-[4- [2- (Benzothiophene-3-yl)-1-ethynyl] phenyl] pyrrolidine —2-carboxamide,
, (R)— N'— [4一 [2—（4—アミノー 2—メチルフ I二ル）一 1—ェチニル]フ Iニル]ピロリ ジン一 2—力ルポキサミド、  , (R) — N′— [4 1 [2- (4-Amino-2-methylphenyl) 1 1-ethynyl] furinyl] pyrrolidine 1 2-streptoxamide,
- (R)-N' -[4一 [2—（4一トリフルォロメトキシフエ二ル）一 1—ェチニル]フエニル]ピロ リジン一 2—カルボキサミド、及び -(R) -N '-[4 1 [2- (4 1 trifluoromethoxyphenyl) 1 1-ethynyl] phenyl] pyrrolidine 1 2-carboxamide, and
■ (R)-N' - [4一 [2—（4一イソプロポキシ一 3—メチルフエニル）一 1—ェチニル]フエ二 ル]ピロリジン一 2—カルボキサミドから選択される化合物又はその塩。 ■ (R) -N '-[4 1 [2— (4 1 Isopropoxy 1 3 -methylphenyl) 1 1-ethynyl] phenyl L] pyrrolidine 1 2-carboxamide or a salt thereof.
1 9. 請求項 1〜1 8のいずれか 1記載の化合物又はその塩を含有する医薬組成物  1 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a salt thereof.
20. 請求項 1 ~ 1 8のいずれか 1記載の化合物又はその塩を有効成分とするジヒド ロォロテートデヒドロゲナーゼ阻害剤。 20. A dihydrorotate dehydrogenase inhibitor comprising the compound according to any one of claims 1 to 18 or a salt thereof as an active ingredient.
2 1 . 請求項 1〜1 8のいずれか 1記載の化合物又はその塩を有効成分とする細胞 増殖、破骨細胞分化又は過剰な免疫反応が関与する疾患の予防又は治療剤。  2 1. A prophylactic or therapeutic agent for a disease involving cell proliferation, osteoclast differentiation or excessive immune reaction, comprising the compound according to any one of claims 1 to 18 or a salt thereof as an active ingredient.
22.細胞増殖が関与する疾患が癌であり、破骨細胞分化が関与する疾患が骨 ·関 節疾患であり及び 又は過剰な免疫反応が関与する疾患が自己免疫疾患、アレルギー 性疾患、臓器移植時の拒絶反応若しくは移植片対宿主疾患である請求項 21記載の予 防又は治療剤。 .  22. The disease involving cell proliferation is cancer, the disease involving osteoclast differentiation is a bone-related disease, and / or the disease involving excessive immune response is an autoimmune disease, allergic disease, organ transplantation 22. The prophylactic or therapeutic agent according to claim 21, which is a rejection reaction or graft-versus-host disease. .
23. 骨■関節疾患が骨粗鬆症又は変形性関節症であり、自己免疫疾患が乾癬、 関節リウマチ、多発性硬化症、全身性エリテマトーデス、シ； c—グレン症候群、ぶどう膜 炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎又はクローン病であり、アレルギー性疾患 がアトピー性皮膚炎、アレルギー性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎又 は気管支喘息である請求項 22記載の予防又は治療剤。  23. Bone ■ Joint disease is osteoporosis or osteoarthritis and autoimmune diseases are psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, sy; c-Glen syndrome, uveitis, polymyositis, I 23. The preventive or therapeutic agent according to claim 22, which is type 2 diabetes, ulcerative colitis or Crohn's disease, and the allergic disease is atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis or bronchial asthma.
24. 請求項 1〜1 8のいずれか 1記載の化合物又はその塩を患者に有効な量投与 することからなるジヒドロォロテートデヒドロゲナーゼの阻害方法。  24. A method for inhibiting dihydrorotate dehydrogenase, comprising administering an effective amount of the compound according to any one of claims 1 to 18 or a salt thereof to a patient.
25. 請求項 1〜1 8のいずれか 1記載の化合物又はその塩を患者に有効な量投与 することからなる細胞増殖、破骨細胞分化又は過剰な免疫反応が関与する疾患の予防 又は治療方法。  25. A method for preventing or treating a disease involving cell proliferation, osteoclast differentiation or excessive immune reaction, comprising administering an effective amount of the compound or salt thereof according to any one of claims 1 to 18 to a patient. .
26.細胞増殖が関与する疾患が癌であり、破骨細胞分化が関与する疾患が骨'関 節疾患であり及びノ又は過剰な免疫反応が関与する疾患が自己免疫疾患、アレルギー 性疾患、臓器移植時の拒絶反応若しくは移植片対宿主疾患である請求項 25記載の予 防又は治療方法。 - 26. Cancer-related diseases are cancer, osteoclast differentiation-related diseases are bone-related diseases, and diseases that involve excessive or excessive immune responses are autoimmune diseases, allergic diseases, organs 26. The prophylactic or therapeutic method according to claim 25, which is rejection at the time of transplantation or graft-versus-host disease. -
27 . 骨■関節疾患が骨粗鬆症又は変形性関節症であり、自己免疫疾患が乾癬、 関節リウマチ、多発性硬化症、全身性エリテマトーデス、シエーグレン症候群、ぶどう膜 炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎又はクローン病であり、アレルギー性疾患 がァトビー性皮膚炎、ァレルギー性皮膚炎、ァレルギー性鼻炎、ァレルギー性結膜炎又 は気管支喘息である請求項 26記載の予防又は治療方法。 27. Bone ■ Joint disease is osteoporosis or osteoarthritis and autoimmune diseases are psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Siegren's syndrome, uvea 26. It is inflammation, polymyositis, type I diabetes, ulcerative colitis or Crohn's disease, and the allergic disease is Watby dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis or bronchial asthma The prevention or treatment method described.
28. 医薬組成物の製造のための、請求項 1〜1 8のいずれか 1記載の化合物又は その塩の使用。  28. Use of the compound according to any one of claims 1 to 18 or a salt thereof for the manufacture of a pharmaceutical composition.
29. ジヒドロォロテートデヒドロゲナーゼ阻害剤の製造のための、請求項 1 ~ 1 8の いずれか 1記載の化合物又はその塩の使用。  29. Use of the compound or a salt thereof according to any one of claims 1 to 18 for the production of a dihydrorotate dehydrogenase inhibitor.
30. 細胞増殖、破骨細胞分化又は過剰な免疫反応が関与する疾患の予防又は 治療剤の製造のための、請求項 1 ~ 1 8のいずれか 1記載の化合物又はその塩の使用。  30. Use of the compound or a salt thereof according to any one of claims 1 to 18 for the manufacture of a prophylactic or therapeutic agent for a disease involving cell proliferation, osteoclast differentiation or excessive immune response.
31 .細胞増 が関与する疾患が癌であり、破骨細胞分化が関与する疾患が骨■関 節疾患であリ及び 又は過剰な免疫反応が関与する疾患が自己免疫疾患、アレルギー 性疾患、臓器移植時の拒絶反応若しくは移植片対宿主疾患である請求項 30記載の烤 用。  31. The disease involving cell proliferation is cancer, the disease involving osteoclast differentiation is bone related disease, and / or the disease involving excessive immune response is autoimmune disease, allergic disease, organ 31. The use according to claim 30, which is rejection at the time of transplantation or graft-versus-host disease.
32. 骨'関節疾患が骨粗鬆症又は変形性関節症であり、自己免疫疾患が乾癬、 関節リウマチ、多発性硬化症、全身性エリテマト一デス、シヱ一ダレン症候群、ぶどう膜 炎、多発性筋炎、 I型糖尿病、潰瘍性大腸炎又はクローン病であり、アレルギー性疾患 がアトピー性皮膚炎、アレルギー性皮膚炎、アレルギー性鼻炎、アレルギー性結膜炎又 は気管支喘息である請求項 3 1記載の使用。  32. Bone 'joint disease is osteoporosis or osteoarthritis, and autoimmune diseases are psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, shii-daren syndrome, uveitis, polymyositis, The use according to claim 31, which is type I diabetes, ulcerative colitis or Crohn's disease, and the allergic disease is atopic dermatitis, allergic dermatitis, allergic rhinitis, allergic conjunctivitis or bronchial asthma.
PCT/JP2005/016048 2004-08-24 2005-08-24 Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity WO2006022442A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2004282746 2004-08-24
JP2004-282746 2004-08-24

Publications (1)

Publication Number Publication Date
WO2006022442A1 true WO2006022442A1 (en) 2006-03-02

Family

ID=35967633

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2005/016048 WO2006022442A1 (en) 2004-08-24 2005-08-24 Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity

Country Status (1)

Country Link
WO (1) WO2006022442A1 (en)

Cited By (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006133326A1 (en) * 2005-06-06 2006-12-14 Bristol-Myers Squibb Company Inhibitors of hcv replication
FR2901792A1 (en) * 2006-06-06 2007-12-07 Negma Lerads Soc Par Actions S PPAR ACTIVATOR DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC APPLICATION
WO2008077639A1 (en) * 2006-12-22 2008-07-03 Laboratorios Almirall, S.A. Amino nicotinic and isonicotinic acid derivatives as dhodh inhibitors
EP2100881A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Pyrimidyl- or pyridinylaminobenzoic acid derivatives
ES2327372A1 (en) * 2007-04-23 2009-10-28 Laboratorios Almirall S.A. New derivatives of the acids amino-nicotinico and amino-isonicotinico. (Machine-translation by Google Translate, not legally binding)
US7659270B2 (en) 2006-08-11 2010-02-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010039793A1 (en) * 2008-10-01 2010-04-08 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2010043000A1 (en) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd S1p receptors modulators and their use thereof
US7745636B2 (en) 2006-08-11 2010-06-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2228367A1 (en) 2009-03-13 2010-09-15 Almirall, S.A. Addition salts of amines containing hydroxyl and/or carboxylic groups with amino nicotinic acid derivatives as DHODH inhibitors
WO2010102825A1 (en) 2009-03-13 2010-09-16 Almirall, S.A. Addition salts of tromethamine with azabiphenylaminobenzoic acid derivatives as dhodh inhibitors
WO2010102824A2 (en) 2009-03-13 2010-09-16 Almirall, S.A. Sodium salt of 5-cyclopropyl-2-{[2-(2,6- difluorophenyl)pyrimidin-5-yl]amino}benzoic acid as dhodh inhibitor
EP2253617A1 (en) * 2009-05-20 2010-11-24 Bayer CropScience AG Halogenated compounds as pesticides
US7906655B2 (en) 2008-08-07 2011-03-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2310369A1 (en) * 2008-06-24 2011-04-20 Valeant Pharmaceuticals International Benzyloxy anilide derivatives useful as potassium channel modulators
WO2012025877A1 (en) 2010-08-24 2012-03-01 Actelion Pharmaceuticals Ltd Proline sulfonamide derivatives as orexin receptor antagonists
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8143301B2 (en) 2009-04-09 2012-03-27 Bristol Myers Squibb Company Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2012109329A2 (en) 2011-02-08 2012-08-16 Children's Medical Center Corporation Methods for treatment of melanoma
US8303944B2 (en) 2006-08-11 2012-11-06 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8329159B2 (en) 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8536165B2 (en) 2007-08-10 2013-09-17 Almirall, S.A. Azabiphenylaminobenzoic acid derivatives as DHODH inhibitors
US8552047B2 (en) 2011-02-07 2013-10-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8586607B2 (en) 2008-07-28 2013-11-19 Syddansk Universitet Compounds for the treatment of metabolic diseases
US8598363B2 (en) 2009-10-16 2013-12-03 Almirall, S.A. Process for manufacturing 2-[(3,5-difluoro-3′-methoxy-1,1′biphenyl-4-yl)amino]nicotinic acid
US8618153B2 (en) 2009-11-12 2013-12-31 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8686048B2 (en) 2010-05-06 2014-04-01 Rhizen Pharmaceuticals Sa Immunomodulator and anti-inflammatory compounds
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2014117676A1 (en) * 2013-01-31 2014-08-07 华东理工大学 N- and s-containing heterocyclic compound having dhodh inhibiting activity and preparation and use thereof
US8809548B2 (en) 2009-02-17 2014-08-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8865728B2 (en) 2008-06-20 2014-10-21 Almirall, S.A. Combinations comprising methotrexate and DHODH inhibitors
US9006455B2 (en) 2009-11-11 2015-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2015090122A1 (en) * 2013-12-20 2015-06-25 北京智博高科生物技术有限公司 Phenyl benzyl ether derivative and preparation method and use thereof
US9181182B2 (en) 2008-10-17 2015-11-10 Akaal Pharma Pty Ltd S1P receptors modulators
WO2015169944A1 (en) * 2014-05-08 2015-11-12 Panoptes Pharma Ges.M.B.H. Compounds for treating ophthalmic diseases and disorders
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
US9776981B2 (en) 2009-11-11 2017-10-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2018136009A1 (en) 2017-01-20 2018-07-26 Aslan Pharmaceuticals Pte Ltd Combination therapy
CN109134336A (en) * 2017-10-27 2019-01-04 北京大学深圳研究生院 Two fragrant ether compounds and its preparation method and application
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP3660106A4 (en) * 2017-07-28 2021-08-11 Nippon Kayaku Kabushiki Kaisha Stilbene compound or salt thereof, polarizing film, polarizing plate and display device
US20220298168A1 (en) * 2018-03-23 2022-09-22 Yumanity Therapeutics, Inc. Compounds and uses thereof
EP3941908A4 (en) * 2019-03-22 2023-05-17 Yumanity Therapeutics, Inc. Compounds and uses thereof
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof
WO2024216094A1 (en) * 2023-04-14 2024-10-17 Soley Therapeutics, Inc. Substituted phenyl-piperazinyl based modulators for the treatment of disease

Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6185367A (en) * 1984-09-21 1986-04-30 カセラ・アクチエンゲゼルシヤフト 4,5-dihydro-3(2h)-
JPH02179A (en) * 1987-02-20 1990-01-05 Yamanouchi Pharmaceut Co Ltd Saturated heterocyclic carboxylic acid amide derivative
WO2000062777A1 (en) * 1999-04-20 2000-10-26 Medinox, Inc. Methods for treatment of sickle cell anemia
WO2001036376A1 (en) * 1999-11-18 2001-05-25 Ajinomoto Co., Inc. Novel phenylalanine derivatives
WO2001098272A1 (en) * 2000-06-20 2001-12-27 Astrazeneca Ab Novel compounds
JP2002507965A (en) * 1997-06-20 2002-03-12 ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーシヨン・シヤンテイフイツク・（エス．セー．エール．アー．エス） Novel 2- (iminomethyl) aminophenyl derivatives, their production, use as pharmaceuticals and pharmaceutical compositions containing them
JP2002510679A (en) * 1998-04-08 2002-04-09 アボット・ラボラトリーズ Pyrazole cytokine production inhibitor
JP2002518985A (en) * 1997-05-07 2002-06-25 ユニバーシティー・オブ・ピッツバーグ Protein isoprenyltransferase inhibitors
WO2003000180A2 (en) * 2001-06-20 2003-01-03 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
WO2003006425A2 (en) * 2001-07-10 2003-01-23 4Sc Ag Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
US20030078420A1 (en) * 1997-03-24 2003-04-24 Chabrier De Lassauniere Pierre Etienne New derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
JP2003517424A (en) * 1997-07-31 2003-05-27 エラン・ファーマシューティカルズ・インコーポレーテッド 4-Amino-phenylalanine-type compounds that inhibit leukocyte adhesion mediated by VLA-4
WO2003082186A2 (en) * 2002-03-25 2003-10-09 Avanir Pharmaceuticals Use of benzimidazole analogs in the treatment of cell proliferation
WO2003084949A1 (en) * 2002-03-29 2003-10-16 Eli Lilly And Company Pyridinoylpiperidines as 5-ht1f agonists
JP2004099586A (en) * 2002-05-21 2004-04-02 Sumitomo Pharmaceut Co Ltd Dihydroorotatedehydrogenase inhibitor
WO2004062601A2 (en) * 2003-01-08 2004-07-29 Chiron Corporation Antibacterial agents
WO2004072025A2 (en) * 2003-02-14 2004-08-26 Aventis Pharma Deutschland Gmbh Substituted n-arylheterocycles, method for production and use thereof as medicaments
WO2004087646A2 (en) * 2003-04-03 2004-10-14 Merck Patent Gmbh Pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxo-morpholino-4-yl)-phenylamide) derivatives and related compounds for use as inhibitors of coagulation factor xa in the treatment of thrombo-embolic diseases
US20040237837A1 (en) * 2003-05-27 2004-12-02 Samsung Electronics Co., Ltd. Lightfast additive having UV-absorbing moiety and ink composition including the same

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6185367A (en) * 1984-09-21 1986-04-30 カセラ・アクチエンゲゼルシヤフト 4,5-dihydro-3(2h)-
JPH02179A (en) * 1987-02-20 1990-01-05 Yamanouchi Pharmaceut Co Ltd Saturated heterocyclic carboxylic acid amide derivative
US20030078420A1 (en) * 1997-03-24 2003-04-24 Chabrier De Lassauniere Pierre Etienne New derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
JP2002518985A (en) * 1997-05-07 2002-06-25 ユニバーシティー・オブ・ピッツバーグ Protein isoprenyltransferase inhibitors
JP2002507965A (en) * 1997-06-20 2002-03-12 ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーシヨン・シヤンテイフイツク・（エス．セー．エール．アー．エス） Novel 2- (iminomethyl) aminophenyl derivatives, their production, use as pharmaceuticals and pharmaceutical compositions containing them
JP2003517424A (en) * 1997-07-31 2003-05-27 エラン・ファーマシューティカルズ・インコーポレーテッド 4-Amino-phenylalanine-type compounds that inhibit leukocyte adhesion mediated by VLA-4
JP2002510679A (en) * 1998-04-08 2002-04-09 アボット・ラボラトリーズ Pyrazole cytokine production inhibitor
WO2000062777A1 (en) * 1999-04-20 2000-10-26 Medinox, Inc. Methods for treatment of sickle cell anemia
WO2001036376A1 (en) * 1999-11-18 2001-05-25 Ajinomoto Co., Inc. Novel phenylalanine derivatives
WO2001098272A1 (en) * 2000-06-20 2001-12-27 Astrazeneca Ab Novel compounds
WO2003000180A2 (en) * 2001-06-20 2003-01-03 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
WO2003006425A2 (en) * 2001-07-10 2003-01-23 4Sc Ag Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents
WO2003082186A2 (en) * 2002-03-25 2003-10-09 Avanir Pharmaceuticals Use of benzimidazole analogs in the treatment of cell proliferation
WO2003084949A1 (en) * 2002-03-29 2003-10-16 Eli Lilly And Company Pyridinoylpiperidines as 5-ht1f agonists
JP2004099586A (en) * 2002-05-21 2004-04-02 Sumitomo Pharmaceut Co Ltd Dihydroorotatedehydrogenase inhibitor
WO2004062601A2 (en) * 2003-01-08 2004-07-29 Chiron Corporation Antibacterial agents
WO2004072025A2 (en) * 2003-02-14 2004-08-26 Aventis Pharma Deutschland Gmbh Substituted n-arylheterocycles, method for production and use thereof as medicaments
WO2004087646A2 (en) * 2003-04-03 2004-10-14 Merck Patent Gmbh Pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxo-morpholino-4-yl)-phenylamide) derivatives and related compounds for use as inhibitors of coagulation factor xa in the treatment of thrombo-embolic diseases
US20040237837A1 (en) * 2003-05-27 2004-12-02 Samsung Electronics Co., Ltd. Lightfast additive having UV-absorbing moiety and ink composition including the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 45, no. 1, 1972, pages 195 - 198 *
CHEMICAL ABSTRACTS, vol. 76, 1972, Columbus, Ohio, US; abstract no. 76:127503R, YAMASHITA T.: "Synthesis and asymetric adsorption of an optically-active basic polymer starting from L-proline" page 5; XP002994547 *

Cited By (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006133326A1 (en) * 2005-06-06 2006-12-14 Bristol-Myers Squibb Company Inhibitors of hcv replication
FR2901792A1 (en) * 2006-06-06 2007-12-07 Negma Lerads Soc Par Actions S PPAR ACTIVATOR DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC APPLICATION
US8288562B2 (en) 2006-08-11 2012-10-16 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9421192B2 (en) 2006-08-11 2016-08-23 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8492553B2 (en) 2006-08-11 2013-07-23 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8329159B2 (en) 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7659270B2 (en) 2006-08-11 2010-02-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8303944B2 (en) 2006-08-11 2012-11-06 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9227961B2 (en) 2006-08-11 2016-01-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7745636B2 (en) 2006-08-11 2010-06-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9758487B2 (en) 2006-08-11 2017-09-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8846023B2 (en) 2006-08-11 2014-09-30 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9018390B2 (en) 2006-08-11 2015-04-28 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10047056B2 (en) 2006-08-11 2018-08-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8900566B2 (en) 2006-08-11 2014-12-02 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8642025B2 (en) 2006-08-11 2014-02-04 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
NO341991B1 (en) * 2006-12-22 2018-03-12 Almirall Sa Amino-nicotinic and isonicotinic acid derivatives useful as DHODH inhibitors
KR101435233B1 (en) 2006-12-22 2014-08-28 알미랄 에스.에이. Amino nicotinic and isonicotinic acid derivatives as dhodh inhibitors
AU2007338321B2 (en) * 2006-12-22 2012-01-19 Almirall, S.A. Amino nicotinic and isonicotinic acid derivatives as DHODH inhibitors
US8258308B2 (en) 2006-12-22 2012-09-04 Laboratorios Almirall, S.A. Amino nicotinic and isonicotinic acid derivatives as DHODH inhibitors
ES2319596A1 (en) * 2006-12-22 2009-05-08 Laboratorios Almirall S.A. Amino nicotinic and isonicotinic acid derivatives as dhodh inhibitors
RU2469024C2 (en) * 2006-12-22 2012-12-10 Альмираль, С.А. Aminonicotinic acid and isonicotinic acid derivatives as dhodg (dihydroorotate dehydrogenase) inhibitors
WO2008077639A1 (en) * 2006-12-22 2008-07-03 Laboratorios Almirall, S.A. Amino nicotinic and isonicotinic acid derivatives as dhodh inhibitors
US8691852B2 (en) 2006-12-22 2014-04-08 Amirall, S.A. Amino nicotinic and isonicotinic acid derivatives as DHODH inhibitors
ES2327372A1 (en) * 2007-04-23 2009-10-28 Laboratorios Almirall S.A. New derivatives of the acids amino-nicotinico and amino-isonicotinico. (Machine-translation by Google Translate, not legally binding)
US8536165B2 (en) 2007-08-10 2013-09-17 Almirall, S.A. Azabiphenylaminobenzoic acid derivatives as DHODH inhibitors
EP2100881A1 (en) 2008-03-13 2009-09-16 Laboratorios Almirall, S.A. Pyrimidyl- or pyridinylaminobenzoic acid derivatives
US8865728B2 (en) 2008-06-20 2014-10-21 Almirall, S.A. Combinations comprising methotrexate and DHODH inhibitors
EP2310369A4 (en) * 2008-06-24 2014-02-19 Valeant Pharmaceuticals Int Benzyloxy anilide derivatives useful as potassium channel modulators
EP2310369A1 (en) * 2008-06-24 2011-04-20 Valeant Pharmaceuticals International Benzyloxy anilide derivatives useful as potassium channel modulators
US8586607B2 (en) 2008-07-28 2013-11-19 Syddansk Universitet Compounds for the treatment of metabolic diseases
US7906655B2 (en) 2008-08-07 2011-03-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CN102227407A (en) * 2008-10-01 2011-10-26 百时美施贵宝公司 Hepatitis c virus inhibitors
US8383094B2 (en) 2008-10-01 2013-02-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010039793A1 (en) * 2008-10-01 2010-04-08 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
WO2010043000A1 (en) * 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd S1p receptors modulators and their use thereof
US9707205B2 (en) 2008-10-17 2017-07-18 Akaal Pharma Pty Ltd. S1P receptors modulators and their use thereof
US9181182B2 (en) 2008-10-17 2015-11-10 Akaal Pharma Pty Ltd S1P receptors modulators
US8394968B2 (en) 2009-02-17 2013-03-12 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8809548B2 (en) 2009-02-17 2014-08-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010102826A1 (en) 2009-03-13 2010-09-16 Almirall, S.A. Addition salts of amines containing hydroxyl and/or carboxylic groups with amino nicotinic acid derivatives as dhodh inhibitors
US8501943B2 (en) 2009-03-13 2013-08-06 Almirall, S.A. Sodium salt of 5-cyclopropyl-2-{[2-(2,6-difluorophenyl)pyrimidin-5-yl]amino}benzoic acid as DHODH inhibitor
CN102348689A (en) * 2009-03-13 2012-02-08 奥米罗有限公司 Addition salts of amines containing hydroxyl and/or carboxylic groups with amino nicotinic acid derivatives as DHODH inhibitors
EP2239256A1 (en) 2009-03-13 2010-10-13 Almirall, S.A. Sodium salt of 5-cyclopropyl-2-{[2-(2,6-difluorophenyl)pyrimidin-5-yl]amino}benzoic acid as DHODH inhibitor
EP2230232A1 (en) 2009-03-13 2010-09-22 Almirall, S.A. Addition salts of tromethamine with azabiphenylaminobenzoic acid derivatives as DHODH inhibitors
WO2010102824A2 (en) 2009-03-13 2010-09-16 Almirall, S.A. Sodium salt of 5-cyclopropyl-2-{[2-(2,6- difluorophenyl)pyrimidin-5-yl]amino}benzoic acid as dhodh inhibitor
CN102348689B (en) * 2009-03-13 2014-05-14 奥米罗有限公司 Addition salts of amines containing hydroxyl and/or carboxylic groups with amino nicotinic acid derivatives as DHODH inhibitors
WO2010102825A1 (en) 2009-03-13 2010-09-16 Almirall, S.A. Addition salts of tromethamine with azabiphenylaminobenzoic acid derivatives as dhodh inhibitors
EP2228367A1 (en) 2009-03-13 2010-09-15 Almirall, S.A. Addition salts of amines containing hydroxyl and/or carboxylic groups with amino nicotinic acid derivatives as DHODH inhibitors
US8796466B2 (en) 2009-03-30 2014-08-05 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8143301B2 (en) 2009-04-09 2012-03-27 Bristol Myers Squibb Company Hepatitis C virus inhibitors
US8143414B2 (en) 2009-04-13 2012-03-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2253617A1 (en) * 2009-05-20 2010-11-24 Bayer CropScience AG Halogenated compounds as pesticides
US8138215B2 (en) 2009-05-29 2012-03-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8211928B2 (en) 2009-05-29 2012-07-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8598363B2 (en) 2009-10-16 2013-12-03 Almirall, S.A. Process for manufacturing 2-[(3,5-difluoro-3′-methoxy-1,1′biphenyl-4-yl)amino]nicotinic acid
US9006455B2 (en) 2009-11-11 2015-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9776981B2 (en) 2009-11-11 2017-10-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8618153B2 (en) 2009-11-12 2013-12-31 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8377980B2 (en) 2009-12-16 2013-02-19 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8362020B2 (en) 2009-12-30 2013-01-29 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8735398B2 (en) 2009-12-30 2014-05-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9758474B2 (en) 2010-05-06 2017-09-12 Incozen Therapeutics Pvt. Ltd. Immunomodulator and anti-inflammatory compounds
US8686048B2 (en) 2010-05-06 2014-04-01 Rhizen Pharmaceuticals Sa Immunomodulator and anti-inflammatory compounds
US8895606B2 (en) 2010-08-24 2014-11-25 Actelion Pharmaceuticals Ltd. Proline sulfonamide derivatives as orexin receptor antagonists
US9211279B2 (en) 2010-08-24 2015-12-15 Actelion Pharmaceuticals Ltd. Proline sulfonamide derivatives as orexin receptor antagonists
US9000029B2 (en) 2010-08-24 2015-04-07 Actelion Pharmaceuticals Ltd. Proline sulfonamide derivatives as orexin receptor antagonists
JP2013538206A (en) * 2010-08-24 2013-10-10 アクテリオン ファーマシューティカルズ リミテッド Proline sulfonamide derivatives as orexin receptor antagonists
WO2012025877A1 (en) 2010-08-24 2012-03-01 Actelion Pharmaceuticals Ltd Proline sulfonamide derivatives as orexin receptor antagonists
US8552047B2 (en) 2011-02-07 2013-10-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9340520B2 (en) 2011-02-07 2016-05-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2012109329A2 (en) 2011-02-08 2012-08-16 Children's Medical Center Corporation Methods for treatment of melanoma
US9546160B2 (en) 2011-05-12 2017-01-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2014117676A1 (en) * 2013-01-31 2014-08-07 华东理工大学 N- and s-containing heterocyclic compound having dhodh inhibiting activity and preparation and use thereof
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
JP2017503012A (en) * 2013-12-20 2017-01-26 ベイジン ズィボォ バイオメディカル テクノロジー カンパニー、リミテッド Phenylbenzyl ether derivatives and their preparation and applications
WO2015090122A1 (en) * 2013-12-20 2015-06-25 北京智博高科生物技术有限公司 Phenyl benzyl ether derivative and preparation method and use thereof
WO2015169944A1 (en) * 2014-05-08 2015-11-12 Panoptes Pharma Ges.M.B.H. Compounds for treating ophthalmic diseases and disorders
US11730716B2 (en) 2014-05-08 2023-08-22 Kiora Pharmaceuticals Gmbh Compounds for treating ophthalmic diseases and disorders
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
WO2018136009A1 (en) 2017-01-20 2018-07-26 Aslan Pharmaceuticals Pte Ltd Combination therapy
EP3660106A4 (en) * 2017-07-28 2021-08-11 Nippon Kayaku Kabushiki Kaisha Stilbene compound or salt thereof, polarizing film, polarizing plate and display device
US11802208B2 (en) 2017-07-28 2023-10-31 Nippon Kayaku Kabushiki Kaisha Stilbene-based compound or salt thereof, and polarizing film, polarizing plate, and display device
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof
CN109134336B (en) * 2017-10-27 2021-08-03 北京大学深圳研究生院 Diaryl ether compound, preparation method and application thereof
CN109134336A (en) * 2017-10-27 2019-01-04 北京大学深圳研究生院 Two fragrant ether compounds and its preparation method and application
US20220298168A1 (en) * 2018-03-23 2022-09-22 Yumanity Therapeutics, Inc. Compounds and uses thereof
US12098146B2 (en) 2019-01-24 2024-09-24 Janssen Pharmaceutica Nv Compounds and uses thereof
EP3941908A4 (en) * 2019-03-22 2023-05-17 Yumanity Therapeutics, Inc. Compounds and uses thereof
WO2024216094A1 (en) * 2023-04-14 2024-10-17 Soley Therapeutics, Inc. Substituted phenyl-piperazinyl based modulators for the treatment of disease

Similar Documents

Publication Publication Date Title
WO2006022442A1 (en) Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity
US8193237B2 (en) Indole derivative having IκB kinase β inhibitory activity
AU2006248788B2 (en) Histone deacetylase inhibitors
CN104352492B (en) Extend enzyme inhibitor using arylsulfonyl derivatives as the long chain fatty acids of active ingredient
TWI475020B (en) The substituted nicotine amide as a KCNQ2 / 3 modifier
WO2006036024A1 (en) Proton pump inhibitors
JP5769326B2 (en) Rho kinase inhibitor
EP1717229B1 (en) Novel cyclic compound having 4-pyridylalkylthio group having (un)substituted amino introduced therein
TW200410963A (en) Heterocyclic derivatives
JP6434528B2 (en) Substituted pyridones and pyrazinones and their use as inhibitors of neutrophil elastase activity
WO2020072580A1 (en) Matriptase 2 inhibitors and uses thereof
EP2733144B1 (en) Novel compound having parp inhibitory activity
WO2008053863A1 (en) Novel compound having 1,4-benzothiazin-3-one skeleton or 3,4-dihydroquinolin-2-one skeleton
JP2006089485A (en) New heterocyclic amide derivative having dihydroorotate dehydrogenase inhibitory activity
JP2009235057A (en) New indole derivative having anti-angiogenesis activity
JP2006096739A (en) New cyclocompound having 4-pyridylalkylthio group to which sustituted or unsubstituted amino group is introduced
EP1864977B1 (en) Novel cyclic compound having pyrimidinylalkylthio group
EP1854787B1 (en) Novel cyclic compound having quinolylalkylthio group
WO2006095822A1 (en) Sulfonamide compound and pharmaceutical thereof
JP2006306861A (en) Novel cyclic compound having pyrimidinylalkylthio group
TWI643847B (en) Novel benzoazepine derivatives and their medical uses
JP2024156867A (en) Matriptase 2 inhibitors and uses thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP