WO2019069844A1 - Heterocyclic compound - Google Patents

Heterocyclic compound Download PDF

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Publication number
WO2019069844A1
WO2019069844A1 PCT/JP2018/036660 JP2018036660W WO2019069844A1 WO 2019069844 A1 WO2019069844 A1 WO 2019069844A1 JP 2018036660 W JP2018036660 W JP 2018036660W WO 2019069844 A1 WO2019069844 A1 WO 2019069844A1
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group
imidazole
thieno
oxo
amino
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PCT/JP2018/036660
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French (fr)
Japanese (ja)
Inventor
祐己 半矢
隆史 一川
伸行 根来
武 吉川
広美 福田
稔博 今枝
啓 海江田
紀雄 大籔
善右 塩川
史朗 菊地
昌紀 川崎
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武田薬品工業株式会社
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Publication of WO2019069844A1 publication Critical patent/WO2019069844A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention may have an inhibitory action on Janus kinase (which may be abbreviated as “JAK” in the present specification), and an autoimmune disease (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple disease Heterocyclic compounds which may be useful for the treatment of sclerosis, systemic lupus erythematosus etc., cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis etc.), containing them Pharmaceutical composition and the like.
  • autoimmune disease rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple disease Heterocyclic compounds which may be useful for the treatment of sclerosis, systemic lupus erythematosus etc., cancer (leukemia, uterine lei
  • Cytokines are proteins secreted from cells of the immune system that transmit signals to specific cells. There are many types of cytokines, but many of them are particularly related to immunity and inflammation, and also to cell proliferation, differentiation, cell death, wound healing and the like (Non-patent Document 1).
  • the Janus kinase (JAK) family plays a role in the cytokine-dependent control of cellular functions involved in proliferation and immune responses.
  • the JAK family includes four types of Janus kinases (JAK1 (Janus kinase 1), JAK2 (Janus kinase 2), JAK3 (Janus kinase 3) and TYK2 (tyrosine kinase 2)).
  • JAK1 is IL (interleukin) -2, IL-4, IL-7, IL-15, IL-21, IL-6, OSM (oncostatin M), IL-10 family, IFN (interferon) 2.
  • IL interleukin
  • OSM oncostatin M
  • IL-10 family
  • IFN interferon
  • TYK2 is an IFN- ⁇ , IFN- ⁇ , IL-6, IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-28, IL-29), IL-12, IL It is known to be involved in the signal transduction of cytokines such as -23 (Non-patent document 2, Non-patent document 3).
  • cytokines play an important role in the immune response when present in appropriate amounts, but excessive production is associated with rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, and whole body It is involved in many autoimmune diseases such as sexual lupus erythematosus (Non-patent document 4, Non-patent document 5, Non-patent document 6, Non-patent document 7).
  • Tocilizumab The anti-IL-6 receptor monoclonal antibody Tocilizumab (Tocilizumab) has been approved in Japan, Europe and the United States for the treatment of rheumatoid arthritis, and clinical trials have been conducted in various diseases that are suggested to be involved in the IL-6 signaling pathway. ing. From the above, JAK1 inhibitors can be used as therapeutic agents for various autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis and systemic lupus erythematosus (non-patent literature) 8).
  • autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis and systemic lupus erythematosus (non-patent literature) 8).
  • JAK signaling is also involved in the differentiation and proliferation of many cancer cells (Non-patent Document 9), and in particular, JAK1 is constitutively activated in leukemia and uterine leiomyosarcoma and is involved in pathological conditions ( Non-Patent Document 10, Non-Patent Document 11).
  • JAK1 inhibitors can be therapeutic agents for cancer diseases such as leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like.
  • the anti-IL-12 / 23 monoclonal antibody ustekinumab (Ustekinumab) is approved in Europe as a treatment for patients with moderate to severe psoriasis and suggests the involvement of the IL-12 / 23 signaling pathway Clinical trials have been conducted in various diseases (Non-patent Document 14).
  • the IL-23 signaling pathway has also been suggested to be involved in central diseases such as Alzheimer's disease (eg, Alzheimer's disease etc.) (Non-patent Document 15).
  • TYK2 inhibitors include various autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, and Alzheimer's disease (eg, Alzheimer's disease) It can be used as a therapeutic drug for central diseases such as dementia (Non-patent Document 16).
  • Examples of compounds having JAK1 inhibition include the compounds described in Patent Documents 1 to 7.
  • the object of the present invention is to have excellent JAK inhibitory action, autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, etc. It is an object of the present invention to provide a compound which can be useful as a preventive or therapeutic agent for cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like) and the like.
  • R 1 , R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a substituent. Or a salt thereof (which may be abbreviated as “compound (I)” in the present specification).
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is (a) (i) substituted with a cyano group, (ii) hydroxy group, (iii) a C 6-14 aryl group, (iv) a C 1-6 alkyl-carbonyl group which may be substituted with a cyano group 3-8 membered monocyclic non-aromatic heterocyclic group, (v) (i ') cyano group and (ii') C 6-14 aryl optionally substituted by 1 to 3 cyano groups 1 to 3 selected from 3 to 8 membered monocyclic non-aromatic heterocyclic carbonyl group optionally substituted by 1 to 3 substituents selected from groups, and (vi) di C
  • a medicament comprising the compound of the above-mentioned [1] or a salt thereof.
  • the medicine according to [6], wherein the autoimmune disease is atopic dermatitis.
  • the compound (I) can have excellent JAK inhibitory action, and autoimmune diseases (systemic lupus erythematosus, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease, It may be useful as a preventive or therapeutic agent for multiple sclerosis, atopic dermatitis and the like, cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like) and the like.
  • autoimmune diseases systemic lupus erythematosus, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease
  • It may be useful as a preventive or therapeutic agent for multiple sclerosis,
  • substituted refers to the following groups. (1) halogen atom; (2) cyano group; (3) nitro group; (4) hydroxy group; (5) (a) halogen atom, (b) a cyano group, and (c) a C 1-6 alkyl group which may be substituted by 1 to 3 halogen atoms, and (d) a C 1 optionally substituted by 1 to 3 halogen atoms A C 3-8 cycloalkyl group which may be substituted by 1 to 3 substituents selected from 1-6 alkoxy groups; (6) (a) halogen atom, (b) cyano group, (c) 1 to selected from the three may be substituted by a halogen atom C 1-6 alkyl group, and (d) 1 to 3 of a C 1-6 alkoxy group optionally substituted by a halogen atom C 6-14 aryl group optionally substituted by 1 to 3 substituents; (7) (a) halogen atom; (2) cyano group; (3) nitro group
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • C 1-6 alkyl group means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like.
  • C 1-6 alkoxy group means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and the like Show.
  • C 2-6 alkenyloxy group is, for example, vinyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3- Butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexenyloxy, 5 -Hexenyloxy etc. are shown.
  • C 2-6 alkynyloxy group means, for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy, 2-butynyloxy, 3-butynyloxy, 1-pentynyloxy, 2-Pentynyloxy, 3-Pentynyloxy, 4-Pentynyloxy, 1,1-Dimethylprop-2-yn-1-yloxy, 1-Hexynyloxy, 2-Hexynyloxy, 3-Hexynyloxy, 4-Hexynyloxy, 5 -Hexynyloxy etc. are shown.
  • the “C 1-6 alkoxy-carbonyl group” means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.
  • examples of the “C 2-6 alkenyloxy-carbonyl group” include vinyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl and the like.
  • examples of the "C 2-6 alkynyloxy-carbonyl group” include ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl and the like.
  • examples of the “C 3-8 cycloalkyloxy-carbonyl group” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like.
  • examples of the “C 3-8 cycloalkenyloxy-carbonyl group” include cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl and the like.
  • examples of the “C 6-14 aryloxy-carbonyl group” include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
  • examples of the "C 3-8 cycloalkyl-C 1-6 alkoxy-carbonyl group” include cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, And cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl and the like.
  • examples of the “C 3-8 cycloalkenyl-C 1-6 alkoxy-carbonyl group” include cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl Etc.
  • examples of the "C 7-14 aralkyloxy-carbonyl group” include benzyloxycarbonyl, phenethyloxycarbonyl and the like.
  • examples of the “mono C 1-6 alkylthiocarbamoyl group” include methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl and the like.
  • examples of the “di C 1-6 alkylthiocarbamoyl group” include dimethylthiocarbamoyl, diethylthiocarbamoyl, dipropylthiocarbamoyl and the like.
  • examples of “C 1-6 alkyl-carbonyloxy group” include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy and the like.
  • C 1-6 alkylenedioxy group for example, methylenedioxy, ethylenedioxy and the like are shown.
  • C 1-6 alkyl-carbonyl group means, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl and the like.
  • C 1-6 alkylsulfonyl group means, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl and the like.
  • C 2-6 alkenylsulfonyl group means, for example, vinylsulfonyl, propenylsulfonyl and the like.
  • the “C 2-6 alkynylsulfonyl group” means, for example, ethynylsulfonyl, propynylsulfonyl and the like.
  • the “C 3-8 cycloalkylsulfonyl group” means, for example, cyclopropylsulfonyl, cyclobutylsulfonyl and the like.
  • the “C 3-8 cycloalkenylsulfonyl group” means, for example, cyclopropenylsulfonyl, cyclobutenylsulfonyl and the like.
  • C 6-14 arylsulfonyl group for example, phenylsulfonyl and the like are shown.
  • C 3-8 cycloalkyl-C 1-6 alkylsulfonyl group for example, cyclopropylmethylsulfonyl and the like are shown.
  • C 3-8 cycloalkenyl-C 1-6 alkylsulfonyl group for example, cyclopentenylmethylsulfonyl and the like are shown.
  • C 6-14 aryl-C 1-6 alkylsulfonyl group for example, benzylsulfonyl and the like are shown.
  • examples of "5- or 6-membered monocyclic aromatic heterocyclic sulfonyl group” include furyl sulfonyl, thienyl sulfonyl, pyridyl sulfonyl and the like.
  • examples of the “8 to 12-membered fused aromatic heterocyclic sulfonyl group” include benzofuranylsulfonyl, isobenzofuranylsulfonyl and the like.
  • examples of “3- to 8-membered monocyclic non-aromatic heterocyclic sulfonyl group” include oxiranyl sulfonyl, azetidinyl sulfonyl and the like.
  • examples of the “8 to 12-membered fused non-aromatic heterocyclic sulfonyl group” include dihydrobenzofuranylsulfonyl and the like.
  • C 1-6 alkylsulfanyl group for example, methylsulfanyl, ethylsulfanyl and the like are shown.
  • C 2-6 alkenylsulfanyl group for example, vinylsulfanyl, propenylsulfanyl and the like are shown.
  • C 2-6 alkynylsulfanyl group for example, ethynylsulfanyl, propynylsulfanyl and the like are shown.
  • C 3-8 cycloalkylsulfanyl group for example, cyclopropylsulfanyl, cyclobutylsulfanyl and the like are shown.
  • C 3-8 cycloalkenylsulfanyl group for example, cyclopropenylsulfanyl, cyclobutenylsulfanyl and the like are shown.
  • C 6-14 arylsulfanyl group for example, phenylsulfanyl and the like are shown.
  • C 3-8 cycloalkyl-C 1-6 alkylsulfanyl group for example, cyclopropylmethylsulfanyl and the like are shown.
  • C 3-8 cycloalkenyl-C 1-6 alkylsulfanyl group for example, cyclopentenylmethylsulfanyl and the like are shown.
  • C 1-6 alkylsulfinyl group for example, methylsulfinyl, ethylsulfinyl and the like are shown.
  • examples of the "C 2-6 alkenylsulfinyl group” include vinylsulfinyl, propenylsulfinyl and the like.
  • examples of the “C 2-6 alkynylsulfinyl group” for example, ethynylsulfinyl, propynylsulfinyl and the like are shown.
  • examples of the "C 3-8 cycloalkylsulfinyl group” include cyclopropylsulfinyl, cyclobutylsulfinyl and the like.
  • examples of the "C 3-8 cycloalkenylsulfinyl group” for example, cyclopropenylsulfinyl, cyclobutenylsulfinyl and the like are shown.
  • C 6-14 arylsulfinyl group for example, phenylsulfinyl and the like are shown.
  • C 3-8 cycloalkyl-C 1-6 alkylsulfinyl group for example, cyclopropylmethylsulfinyl and the like are shown.
  • C 3-8 cycloalkenyl-C 1-6 alkylsulfinyl group for example, cyclopentenylmethylsulfinyl and the like are shown.
  • C 3-8 cycloalkyl group means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • a C 3-6 cycloalkyl group eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is preferable.
  • C 3-8 cycloalkenyl group means, for example, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclopentenyl (eg, 2-cyclobuten-1-yl)
  • 2-cyclopenten-1-yl, 3-cyclopenten-1-yl 2-cyclopenten-1-yl, 3-cyclopenten-1-yl
  • cyclohexenyl eg, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl
  • cycloheptenyl eg, 2-cycloheptene-1) -Yl, 3-cyclohepten-1-yl
  • cyclooctenyl eg, 2-cycloocten-1-yl, 3-cycloocten-1-yl
  • C 3-6 cycloalkenyl group eg, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclopentenyl (eg, 2-cyclopentene) -1-yl, 3-cyclopenten-1-yl) and cyclohexenyl (eg, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl)
  • cycloalkenyl group eg, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclopentenyl (eg, 2-cyclopentene) -1-yl, 3-cyclopenten-1-yl)
  • cyclohexenyl eg, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl
  • C 3-8 cycloalkyloxy group means, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
  • the “C 3-8 cycloalkenyloxy group” is, for example, cyclopropenyloxy (eg, 2-cyclopropen-1-yloxy), cyclobutenyloxy (eg, 2-cyclobuten-1-yloxy) And cyclopentenyloxy (eg, 2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy), cyclohexenyloxy (eg, 2-cyclohexen-1-yloxy, 3-cyclohexen-1-yloxy), etc. .
  • cyclopropenyloxy eg, 2-cyclopropen-1-yloxy
  • cyclobutenyloxy eg, 2-cyclobuten-1-yloxy
  • cyclopentenyloxy eg, 2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy
  • cyclohexenyloxy eg, 2-cyclohexen-1-yloxy, 3-cyclohexen-1-
  • the “C 6-14 aryl group” means, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. Among them, a C 6-10 aryl group is preferable.
  • the “C 6-14 aryloxy group” means, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • the “C 7-14 aralkyloxy group” means, for example, benzyloxy, phenethyloxy and the like.
  • examples of the “5- or 6-membered monocyclic aromatic heterocyclic group” include, as ring-constituting atoms, an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom (other than carbon atoms) 5 or 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a group that may be oxidized, for example, furyl (eg, 2-furyl, 3-furyl), thienyl (Eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl (eg,
  • the “8 to 10-membered fused aromatic heterocyclic group” is, for example, a ring formed by condensing a ring corresponding to the 5- or 6-membered monocyclic aromatic heterocyclic group and a benzene ring Derived group; a group derived from a ring formed by condensation of the rings corresponding to the 5 or 6-membered monocyclic aromatic heterocyclic group, for example, quinolyl (eg, 2-quinolyl, 3-quinolyl, 4- 4- Quinolyl, 6-quinolyl), isoquinolyl (eg 3-isoquinolyl), quinazolyl (eg 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (eg 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e
  • examples of the “3- to 8-membered monocyclic non-aromatic heterocyclic group” include, as ring-constituting atoms, an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to carbon atoms.
  • the “8 to 12-membered fused non-aromatic heterocyclic group” for example, a ring corresponding to the above-mentioned 3- to 8-membered monocyclic non-aromatic heterocyclic group and a benzene ring fused A group derived from a ring; a group derived from a ring formed by condensation of the rings corresponding to the above 3- to 8-membered monocyclic non-aromatic heterocyclic group; the above 3- to 8-membered monocyclic non-aromatic hetero ring A group derived from a ring formed by condensation of a ring corresponding to a ring group and a ring corresponding to the 5- or 6-membered monocyclic aromatic heterocyclic group; a group obtained by partial saturation of these groups, for example, dihydro Indolyl (eg, 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-di), dihydrois
  • examples of the "C 2-6 alkenyl-carbonyl group” include acryloyl, butenoyl, pentenoyl, hexenoyl, heptenoyl and the like.
  • examples of the "C 2-6 alkynyl-carbonyl group” include propioloyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl and the like.
  • examples of the "C 3-8 cycloalkyl-carbonyl group” include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
  • examples of the "C 3-8 cycloalkenyl-carbonyl group” include cyclopropenyl carbonyl, cyclobutenyl carbonyl, cyclopentenyl carbonyl, cyclohexenyl carbonyl and the like.
  • examples of the "C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.
  • examples of the "C 3-8 cycloalkyl-C 1-6 alkyl-carbonyl group” include cyclopropylacetyl, 3-cyclopropylpropionyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, 3-cyclohexyl Propionyl and the like can be mentioned.
  • examples of the “C 3-8 cycloalkenyl-C 1-6 alkyl-carbonyl group” include cyclopentenyl acetyl, cyclohexenyl acetyl, 3-cyclohexenyl propionyl, 3-cyclohexenyl propionyl and the like.
  • examples of the “C 7-14 aralkyl-carbonyl group” include phenylacetyl, 3-phenylpropionyl and the like.
  • examples of “5- or 6-membered monocyclic aromatic heterocyclic carbonyl group” include, for example, furyl carbonyl, thienyl carbonyl, pyrrolyl carbonyl, oxazolyl carbonyl, isoxazolyl carbonyl, thiazolyl And carbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl and the like.
  • examples of the “8 to 12-membered fused aromatic heterocyclic carbonyl group” include benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl, isoin Examples include drill carbonyl, indazolyl carbonyl, benzimidazolyl carbonyl, benzoxazolyl carbonyl and the like.
  • examples of “3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group” include oxiranyl carbonyl, azetidinyl carbonyl, oxetanyl carbonyl, thietanyl carbonyl, pyrrolidinyl carbonyl, tetrahydro Furyl carbonyl, thioranyl carbonyl, piperidyl carbonyl and the like.
  • examples of the “8 to 12-membered fused non-aromatic heterocyclic carbonyl group” include dihydrobenzofuranyl carbonyl and the like.
  • examples of “5 or 6-membered monocyclic aromatic heterocyclic oxy group” include, for example, furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyl And oxy, imidazolyloxy, pyridyloxy, pyrazolyloxy and the like.
  • the “8 to 12-membered fused aromatic heterocyclic oxy group” for example, benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy, isobenzothienyloxy, indolyloxy, isoin Examples include doryloxy, indazolyloxy, benzimidazolyloxy, benzoxazolyloxy and the like.
  • examples of the “3- to 8-membered monocyclic non-aromatic heterocyclic oxy group” include oxiranyloxy, azetidinyloxy, oxetanyloxy, thiethanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy , Thioranyloxy, piperidyl oxy and the like.
  • examples of the “8 to 12-membered fused non-aromatic heterocyclic oxy group” include dihydrobenzofuranyloxy and the like.
  • R 1 in Formula (I) represents a hydrogen atom or a substituent.
  • R 1 a hydrogen atom is preferable.
  • R 2 in the formula (I) represents a hydrogen atom or a substituent.
  • R 2 a hydrogen atom is preferable.
  • R 3 in Formula (I) represents a hydrogen atom or a substituent.
  • R 3 (a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidinyl
  • R 3 (a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidinyl carbonyl, piperazinyl carbonyl), and (
  • R 4 in the formula (I) represents a hydrogen atom or a substituent.
  • R 4 (1) cyano group; (2) (a) (i) C 3-8 cycloalkyl group (eg, cyclopentyl), (ii) C 1-6 alkoxy group (eg, methoxy) and (iii) 1 to 3 C 1-6 alkyls C 1 to C optionally substituted by 1 to 3 substituents selected from 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl) optionally substituted by a group (eg, methyl) 1-6 alkyl group (eg, methyl, ethyl, sec-butyl), (b) C 3-8 cycloalkyl group (eg, cyclopentyl), (c) C 6-14 aryl group, (d) C 1-6 alkoxy group, (e) 5- or 6-membered monocyclic aromatic heterocyclic group, (f) 8- to 12-membere
  • R 4 (1) cyano group; (2) (a) (i) C 3-8 cycloalkyl group (eg, cyclopropyl), (ii) C 1-6 alkoxy group (eg, methoxy) and (iii) 1 to 3 C 1-6 It may be substituted by 1 to 3 substituents selected from 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl) which may be substituted by alkyl group (eg, methyl) C 1-6 alkyl group (eg, methyl, ethyl, sec-butyl), (b) C 3-8 cycloalkyl group (eg, cyclopropyl), and (c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl) Or a carbamoyl group optionally mono- or di-substituted with a substituent selected from (3) C 1-6
  • R 5 in Formula (I) represents a hydrogen atom or a substituent.
  • R 5 a hydrogen atom is preferable.
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is (a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from
  • R 1 is a hydrogen atom
  • R 2 is a hydrogen atom
  • R 3 is (a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidin
  • salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids Salt etc. are mentioned.
  • Preferred examples of the metal salt include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzyl And salts with ethylene diamine and the like.
  • Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like Can be mentioned. Among these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts etc.), ammonium salts
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or acetic acid, phthalic acid, fumaric acid, oxalic acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • the compound obtained in each step When the compound obtained in each step is a free compound, it can be converted to a target salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or another type of desired salt by a method known per se.
  • the compound obtained in each step may be used as the reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step may be concentrated from the reaction mixture according to a conventional method It can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually -78 ° C to 300 ° C, preferably -78 ° C to 150 ° C.
  • the pressure may differ depending on the reagent and solvent to be used, but unless otherwise specified, it is usually 1 to 20 atm, preferably 1 to 3 atm.
  • a microwave synthesizer such as Biotage's Initiator may be used.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but is generally room temperature to 300 ° C., preferably 50 ° C. to 250 ° C., unless otherwise specified.
  • the reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.
  • the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate, unless otherwise specified.
  • the reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
  • the reagent also serves as the reaction solvent, the amount of the solvent is used.
  • Inorganic bases sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate etc .
  • Organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine etc .
  • Metal alkoxides sodium ethoxide, potassium tert-butoxide, etc .
  • Alkali metal hydrides sodium hydride etc .
  • Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide etc .
  • Organic lithium n-butyllithium etc.
  • an acid or acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in the examples is used.
  • Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid etc .
  • Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .
  • Lewis acid boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
  • reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Lecture, Volume 13 to Volume 19 (edited by The Chemical Society of Japan); New Experimental Chemistry Lecture, Volume 14 to Volume 15 (Japan) Chemical Society Ed.) Precision Organic Chemistry Rev. 2 (L. F. Tietze, Th. Eicher, Nan-e-do); Revised Organic Personal Name Reactions The Structure and Points (Togo Hideo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII ( John Wiley & Sons Inc .; Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures by Jie Jack Li, OXFORD UN VERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol.
  • Examples of the protecting group of amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzyl carbonyl etc.), C 7-12 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl etc.), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted by C 1-6 alkyl group
  • Optionally substituted silyl eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl etc.
  • C 2-6 alkenyl group eg, 1-allyl etc.
  • These groups may be substituted by 1 to 3 substituents selected from
  • carboxyl-protecting group for example, silyl optionally substituted by C 1-6 alkyl group, C 7-12 aralkyl group (eg, benzyl etc.), phenyl group, trityl group, C 1-6 alkyl group Groups (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl etc.), C 2-6 alkenyl groups (eg, 1-allyl etc.) and the like.
  • Examples of the protecting group for hydroxyl group include C 1-6 alkyl group, phenyl group, trityl group, C 7-12 aralkyl group (eg, benzyl etc.), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group, C 7-12 aralkyl-carbonyl group (eg, benzylcarbonyl etc.), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group optionally substituted by C 1-6 alkyl group (eg, trimethylsilyl, triethyl) Examples thereof include silyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like, C 2-6 alkenyl group (eg, 1-allyl and the like) and the like.
  • These groups may be substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • the removal method of the above-mentioned protective group is a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4 th Ed.” (Theodora W. Greene, Peter GM Wuts) published by Wiley-Interscience 2006. Can be mentioned.
  • the method to use, the reduction method, etc. are used.
  • the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride
  • Metal hydrides such as triacetoxyborohydride and tetramethylammonium hydride; boranes such as borane-tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like.
  • a catalyst such as palladium-carbon or Lindlar catalyst.
  • examples of the oxidizing agent used include m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, peroxides such as tert-butyl hydroperoxide, etc .; tetrabutylammonium perchlorate etc.
  • mCPBA m-chloroperbenzoic acid
  • hydrogen peroxide hydrogen peroxide
  • peroxides such as tert-butyl hydroperoxide, etc .
  • tetrabutylammonium perchlorate etc.
  • Perchlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese dioxide Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), reagents having chromium such as Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as; oxygen; ozone; sulfur trioxide / pyridine complex; Osmium; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • NBS N-bromosuccinimide
  • radical initiator When performing radical cyclization reaction in each process, as a radical initiator used, azo compounds such as azobisisobutyronitrile (AIBN); 4,4'-azobis-4-cyanopentanoic acid (ACPA) Water soluble radical initiators; triethyl boron in the presence of air or oxygen; benzoyl peroxide and the like. Further, as a radical reaction agent to be used, tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like can be mentioned.
  • AIBN azobisisobutyronitrile
  • ACPA 4,4'-azobis-4-cyanopentanoic acid
  • tributylstannane tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iod
  • examples of the Wittig reagent used include alkylidene phosphoranes and the like.
  • the alkylidene phosphoranes can be prepared by methods known per se, for example, by reacting a phosphonium salt with a strong base.
  • phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate
  • bases such as alkali metal hydrides and organic lithiums It can be mentioned.
  • the reagent used is a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (eg, halogenated alkyls, alcohols, olefins, etc.)
  • a Lewis acid an organic acid or inorganic acid can be used, and instead of the acid chloride, an acid anhydride such as acetic anhydride can be used.
  • a nucleophile eg, amines, imidazole etc.
  • a base eg, organic bases etc.
  • nucleophilic addition reaction When performing nucleophilic addition reaction with carbanion, nucleophilic 1,4-addition reaction with carbanion (Michael addition reaction), or nucleophilic substitution reaction with carbanion in each step, a base used to generate carbanion And organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.
  • Grignard reagents When performing Grignard reaction in each process, Grignard reagents include aryl magnesium halides such as phenyl magnesium bromide; and alkyl magnesium halides such as methyl magnesium bromide.
  • the Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with magnesium metal with ether or tetrahydrofuran as a solvent.
  • active methylene compounds eg, malonic acid, diethyl malonate, malononitrile etc.
  • bases eg, organic bases, etc. sandwiched between two electron withdrawing groups Metal alkoxides, inorganic bases
  • examples of the azidation agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like.
  • DPPA diphenylphosphoryl azide
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • the reducing agent used includes sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like.
  • the substrate is an amine compound
  • examples of the carbonyl compound used include paraformaldehyde as well as aldehydes such as acetaldehyde and ketones such as cyclohexanone.
  • the amines to be used include ammonia, primary amines such as methylamine; secondary amines such as dimethylamine, and the like.
  • azodicarboxylic acid esters eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
  • triphenylphosphine eg, triphenylphosphine
  • acyl chloride such as acid chloride and acid bromide
  • acid anhydride active ester
  • sulfuric acid ester And activated carboxylic acids.
  • Carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) as a carboxylic acid activating agent; 4- (4,6-dimethoxy-1,3,5-) Triazine-based condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); Carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Phosphorus azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformic acid such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl)
  • additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be further added to the reaction.
  • HOBt 1-hydroxybenzotriazole
  • HOSu N-hydroxysuccinimide
  • DMAP dimethylaminopyridine
  • the metal catalyst used is palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl) Phosphine compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenyl phosphino) ferrocene palladium (II) chloride; tetrakis (triphenylphosphine) nickel (0) And nickel compounds such as tris (triphenylphosphine) rhodium (III); cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like.
  • a base may be added to the reaction, and such bases include inorganic bases.
  • diphosphorus pentasulfide is used as the thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) ) Reagents with 1,3,2,4-dithiadiphosphetan-2,4-disulfide structure such as 1,3), 2,4-dithiadiphosphetan-2,4-disulfide (Lawesson's reagent) May be used.
  • N-iodosuccinimide N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile or the like to the reaction.
  • an acid halide of a hydrohalic acid and an inorganic acid specifically, in chlorination, hydrochloric acid, thionyl chloride, oxy
  • a method of obtaining a halogenated alkyl from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used.
  • a method may be used in which a halogenated alkyl is synthesized through a two-step reaction in which an alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride or sodium iodide.
  • examples of reagents used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite and tri (isopropyl) phosphite.
  • examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.
  • an acid or a base is used as a reagent.
  • formic acid, triethylsilane, etc. may be added to reductively trap the by-produced tert-butyl cation.
  • examples of the dehydrating agent used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.
  • the compound obtained in each step can be used as the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.
  • Compound (I) can be produced from compound (II) by the following method.
  • Compound (V) can be produced by cyclization reaction of compound (IV) with a halogenating reagent.
  • a halogenating reagent phosphoric acid trichloride and the like can be mentioned.
  • R 1 , R 2 , R 3 , R 4 and R 5 can also be converted using methods known per se.
  • the compounds of the present invention obtained by the above-mentioned respective production methods can be isolated and purified by known means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above.
  • they may be used as they are as a reaction mixture and starting materials for the next step.
  • Compound (I) produced by such a method can be isolated and purified by a conventional separation means such as, for example, recrystallization, distillation, chromatography and the like.
  • the compound (I) contains an optical isomer, stereoisomer, regioisomer, rotamer, these are also contained as the compound (I), and a synthesis method known per se, a separation method (for example, , Concentration, solvent extraction, column chromatography, recrystallization etc.) to obtain each as a single product.
  • a separation method for example, , Concentration, solvent extraction, column chromatography, recrystallization etc.
  • Optical isomers can be produced by methods known per se. Specifically, an optically active synthetic intermediate is used, or an optical isomer is obtained by optically resolving the racemate of the final product according to a conventional method.
  • an optical resolution method a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method or the like is used.
  • Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine), (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine etc.
  • Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine), (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine etc.
  • Racemic and optically active compounds eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine), (-)-1-phenethylamine, cinchonine,
  • Chiral column method A method of separating racemate or a salt thereof by applying a column for optical isomer separation (chiral column).
  • a column for optical isomer separation chiral column
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), water, various buffers (eg, phosphate buffer
  • the optical isomers are separated by developing them as a solution obtained by mixing a liquid or the like), an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine etc.) alone or in combination.
  • separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science Inc.).
  • Diastereomer method A mixture of racemates is converted to a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance via ordinary separation means (eg, fractional recrystallization, chromatography etc.) A method of obtaining an optical isomer by cleaving an optically active reagent site by chemical treatment such as hydrolysis reaction.
  • an organic acid which is optically active with the compound eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid]
  • MTPA ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid
  • diastereomers of ester or amide can be obtained.
  • the compound (I) has a carboxylic acid group
  • the compound and an optically active amine or alcohol reagent are subjected to a condensation reaction to obtain diastereomers of an amide form or an ester form, respectively.
  • the separated diastereomers are converted to the optical isomers of the original compound by acid hydrolysis or basic hydrolysis.
  • Compound (I) may be a crystal.
  • the crystals of compound (I) can be produced by crystallizing compound (I) by applying a crystallization method known per se.
  • a crystallization method for example, a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like can be mentioned.
  • the “crystallization from solution” is a state not saturated by changing the factor related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent.
  • the transition from the above to the supersaturated state is general, and specific examples include a concentration method, a slow cooling method, a reaction method (a diffusion method, an electrolytic method), a hydrothermal growth method, a flux agent method and the like.
  • solvent to be used for example, aromatic hydrocarbons (eg, benzene, toluene, xylene etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane) Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane etc.), nitriles (eg, acetonitrile etc.), ketones (eg, acetone etc.), sulfoxides (eg, dimethyl sulfoxide etc.) And acid amides (eg, N, N-dimethylformamide and the like), esters (eg, ethyl acetate and the like), alcohols (eg, methanol, ethanol, isopropyl alcohol and the like), water and the like.
  • Examples of the “crystallization from vapor” include a vaporization method (a sealed tube method, a gas flow method), a gas phase reaction method, a chemical transport method and the like.
  • crystallization method from a melt examples include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method) And liquid phase epitaxy methods).
  • compound (I) is dissolved in an appropriate solvent (eg, alcohols such as methanol, ethanol etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved
  • an appropriate solvent eg, alcohols such as methanol, ethanol etc.
  • a method of cooling to a temperature or lower for example, 0 to 50 ° C., preferably 0 to 20 ° C.
  • the crystals of the present invention thus obtained can be isolated, for example, by filtration and the like.
  • a method of crystal analysis by powder X-ray diffraction is generally used.
  • a method of determining the orientation of the crystal for example, a mechanical method or an optical method may be mentioned.
  • the crystals of the compound (I) obtained by the above production method have high purity and high quality, low hygroscopicity, and are stored for a long time under ordinary conditions It does not deteriorate nor is extremely excellent in stability. It is also expected to be excellent in biological properties (eg, in vivo pharmacokinetics (absorptivity, distribution, metabolism, excretion), medicinal effect etc.), and may be useful as a medicine.
  • the specific rotation ([ ⁇ ] D ) is, for example, a ratio measured using an optical polarimeter (JASCO (JASCO), P-1030 polarimeter (No. AP-2)) or the like.
  • the melting point means, for example, a melting point measured using a micro melting point apparatus (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR 6000) or the like.
  • Compound (I) may be used as a prodrug.
  • the prodrug of compound (I) is a compound which is converted to compound (I) by reaction with an enzyme or gastric acid under physiological conditions in vivo, that is, enzymatically causes oxidation, reduction, hydrolysis and the like to produce compound (I) Or a compound which is converted to a compound (I) by hydrolysis or the like by gastric acid or the like.
  • a prodrug of compound (I) for example, (1) Compound (I) wherein the amino is acylated, alkylated and phosphorylated (for example, the amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-carbonylated) Oxo-1,3-dioxolene-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropyl carbonylated compounds etc.); (2) Compound (I) hydroxy is acylated, alkylated, phosphorylated, borated (for example, compound (I) hydroxy is acetylated, palmitoylated, propanoylated, pivaloylated, succinyl
  • prodrugs of Compound (I) are those which change into Compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, pages 163 to 198. It may be.
  • compound (I) and a prodrug thereof may be collectively referred to as “the compound of the present invention”.
  • Compound (I) may be any of hydrate, non-hydrate, solvate, non-solvate.
  • Compounds labeled with isotopes eg, 3 H, 14 C, 35 S, 125 I, etc.
  • a deuterium converter wherein 1 H is converted to 2 H (D) is also encompassed in compound (I).
  • Tautomers are also encompassed in compound (I).
  • Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.) Mean crystalline substance composed of solid.
  • Co-crystals or co-crystal salts can be prepared according to co-crystallization methods known per se.
  • Compound (I) may be used as a PET tracer.
  • the compounds of the present invention may have excellent JAK (JAK1, JAK2, JAK3, TYK2) inhibitory activity, and may be useful as safe medicines based on this activity.
  • the compounds of the present invention can also be used to inhibit IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , IL-2 inhibitor, IL-4 inhibitor, IL-7 inhibitor, IL-15 inhibitor, IL- 21 inhibitor, IL-6 inhibitory action, OSM inhibitor, IL-10 inhibitory action, IL-19 inhibitory action, IL-20 inhibitory action, IL-22 inhibitory action, IL-28 inhibitory action, IL-29 inhibitory action, Since it may have an IL-12 inhibitory action and / or an IL-23 inhibitory action (preferably, an IL-23 inhibitory action), it may also be useful as a safe medicine based on this action.
  • the medicament of the present invention comprising the compound of the present invention is a JAK-related disease for a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) More specifically, it can be used as a preventive or therapeutic agent for the diseases described in (1) to (6) below.
  • a mammal eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.
  • inflammatory diseases eg, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis , Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia (such as spontaneous interstitial pneumonia including idiopathic pulmonary fibrosis (IPF)), nephritis, meningitis, cystitis, laryngopharyngitis , Gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, uveitis, suppurative sweat adenosis, ischemia reperfusion injury, gout (eg , Acute gout etc.), hay fever, acute kidney injury, Cliopyrin related periodic
  • Tumorous diseases eg, malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, multiple myeloma, metastatic melanoma, Kaposi sarcoma, vascular growth , Cachexia, metastasis of breast cancer, cancer (eg, colon cancer (eg, familial colorectal cancer, hereditary non-polyposis colon cancer, gastrointestinal stromal tumor etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, etc) Lung cancer, malignant mesothelial glaucoma, infantile hemangioma, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, multiple myeloma, metastatic melanoma, Kaposi sarcoma, vascular growth , Cachexia, metastasis of breast cancer, cancer (
  • the medicament of the present invention is preferably an autoimmune disease, an inflammatory disease, a bone / joint degeneration disease, a central disease or a neoplastic disease, more preferably a systemic lupus erythematosus, an inflammatory bowel disease (preferably Crohn's disease or preferably) Ulcerative colitis), rheumatoid arthritis, psoriasis, Sjogren's syndrome, Behcet's disease, multiple sclerosis, atopic dermatitis, Alzheimer's disease (preferably Alzheimer's disease), Castleman's disease, leukemia, uterine leiomyosarcoma It can be used as a prophylactic or therapeutic agent for prostate cancer, multiple myeloma, cachexia, or myelofibrosis.
  • prevention of the above-mentioned disease refers to, for example, a patient who does not develop the disease or who has developed the disease which is expected to have a high risk of onset due to any factor related to the disease. It means administering a drug containing the compound of the present invention to a non-patient, or administering a drug containing the compound of the present invention to a patient who is concerned about recurrence of the disease after treatment of the disease.
  • the medicament of the present invention is excellent in pharmacokinetics (eg, drug half-life in blood), low in toxicity (eg, HERG inhibition, CYP inhibition, CYP induction), alleviation of cytotoxicity, and side effects based on JAK selectivity improvement Reduction and reduction of drug interactions are noted.
  • the compound of the present invention is used as it is or as a pharmaceutical composition by mixing it with a pharmacologically acceptable carrier according to a means known per se generally used in the method of producing a pharmaceutical preparation, and used as a medicament of the present invention obtain.
  • the medicament of the present invention is orally or parenterally to mammals (eg, humans, monkeys, cattle, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) It can be administered safely.
  • the pharmaceutical composition containing the compound of the present invention may be a compound of the present invention alone or pharmacologically acceptable with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, the method described in Japanese Pharmacopoeia etc.) Can be used as a pharmaceutical composition mixed with the carrier.
  • the medicaments containing the compound of the present invention are, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets and the like), pills, powders, granules, capsules (soft capsules, micro capsules Capsules, troches, syrups, solutions, emulsions, suspensions, controlled release formulations (eg, immediate release formulations, sustained release formulations, sustained release microcapsules), aerosols, films (including capsules)
  • orally disintegrating film, oral mucous membrane adhering film injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, cream, Orally or parenterally as an ointment, lotion, patch, suppository (eg, anal suppository, vaginal suppository), pellet, transnasal agent, pulmonary agent (eg, inhalant), eye drops, etc.
  • the content of the compound of the present invention in the medicament of the present invention is about 0.01% by weight to about 100% by weight of the whole medicament.
  • the dose may vary depending on the administration subject, administration route, disease, etc.
  • rheumatoid arthritis For example, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, atopic dermatitis, systemic lupus erythematosus, Active ingredient per day as an oral agent for patients with Castleman's disease (Castleman's disease), leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis etc.
  • the pharmacologically acceptable carrier which may be used for producing the medicament of the present invention may contain various organic or inorganic carrier substances commonly used as a pharmaceutical material, for example, an excipient in a solid preparation, a lubricant Binders and disintegrants, or solvents in liquid formulations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents may be used. Furthermore, as necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like may be suitably used in appropriate amounts.
  • excipient for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned.
  • lubricant for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be mentioned.
  • binder for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like can be mentioned.
  • disintegrant for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, L-hydroxypropylcellulose and the like
  • solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agents examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc .; for example, polyvinyl alcohol, polyvinyl pyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
  • surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc .
  • polyvinyl alcohol polyvinyl pyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxyprop
  • Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
  • As the soothing agent for example, benzyl alcohol and the like can be mentioned.
  • Examples of preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention can be used together with other agents.
  • a drug used in combination of the compound of the present invention and another drug is referred to as "combination drug of the present invention”.
  • the compound of the present invention is a JAK family inhibitor, IFN- ⁇ inhibitor, IFN- ⁇ inhibitor, IFN- ⁇ inhibitor, IL-2 inhibitor, IL-4 inhibitor, IL-7 inhibitor, IL-15 Inhibitor, IL-21 inhibitor, IL-6 inhibitor, OSM inhibitor, IL-10 inhibitor, IL-19 inhibitor, IL-20 inhibitor, IL-22 inhibitor, IL-28 inhibitor, IL
  • -29 inhibitor, IL-12 inhibitor, and / or IL-23 inhibitor it may be used in combination with the following drugs.
  • Non-steroidal anti-inflammatory drugs (I) Classical NSAIDs Alcofenac, Aceclofenac, Sulindac, Tolmetin, Etodolac, Fenoprofen, Thiaprofenic Acid, Meclofenamic Acid, Meloxicam, Texicam, Lonoxycam, Nabumetone, Acetaminophen, Phenacetin, Etenzamide, Supilin, Antipyrin, Migrenin, Aspirin, Mefenamic Acid, Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctachenine, piroxicam, epirisol, tiaramide hydrochloride, saltoprofen, gabexate mesilate camostat,
  • Cyclooxygenase inhibitors COX-1 selective inhibitors, COX-2 selective inhibitors, etc.
  • Salicylic acid derivatives eg celecoxib, aspirin
  • etoricoxib etoricoxib
  • valdecoxib diclofenac
  • indomethacin loxoprofen etc.
  • Nitric oxide free type NSAIDs Iv
  • JAK inhibitors Tofacitinib Tofacitinib
  • luxolitinib Rosolitinib
  • DMARDs Disease-modifying anti-rheumatic drugs
  • antimalarial drug chloroquine etc. V
  • Pyrimidine synthesis inhibitor leflunomide etc. Vi) Prograph
  • Anti-cytokine drug protein preparation
  • TNF inhibitor etanercept TNF inhibitor etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASTNF- ⁇ , soluble TNF- ⁇ receptor, TNF- ⁇ binding protein, anti-TNF- ⁇ antibody etc.
  • Interleukin-1 inhibitor Anakinra Interleukin-1 receptor antagonist
  • soluble interleukin-1 receptor and the like.
  • Interleukin-6 inhibitor Tocilizumab anti-interleukin-6 receptor antibody
  • anti-interleukin-6 antibody anti-interleukin-6 antibody
  • Iv Interleukin-10 Drug Interleukin-10 and the like.
  • V Interleukin-12 / 23 inhibitors Ustekinumab, Briaquinumab (anti-interleukin-12 / 23 antibody) and the like.
  • II Non-protein preparation
  • Gene regulatory agents Inhibitors of molecules involved in signal transduction such as NF- ⁇ , NF- ⁇ ⁇ B, IKK-1, IKK-2, AP-1.
  • Iv TNF- ⁇ converting enzyme inhibitor
  • VX-765 interleukin-1 ⁇ converting enzyme inhibitor
  • Vi interleukin-6 antagonist HMPL-004 and the like.
  • interleukin-8 inhibitor IL-8 antagonist interleukin-8 inhibitor, CXCR1 & CXCR2 antagonist, repalexin and the like.
  • Chemokine antagonists CCR9 antagonists (CCX-282, CCX-025), MCP-1 antagonists and the like.
  • interleukin-2 receptor antagonist denileukin, diftitox and the like.
  • Therapeutic vaccines TNF- ⁇ vaccine etc.
  • Gene therapeutic agent A gene therapeutic agent aiming to enhance the expression of a gene having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF- ⁇ receptor .
  • antisense compound ISIS-104838 and the like.
  • Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol and the like.
  • Angiotensin converting enzyme inhibitors Enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
  • Angiotensin II receptor antagonist candesartan, cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan and the like.
  • Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopentiazide etc.
  • Cardiotonics Digoxin, dobutamine etc. (11) ⁇ receptor antagonist carvedilol, metoprolol, atenolol and the like. (12) Ca sensitivity enhancer MCC-135 and the like.
  • Contraceptive Sex hormone or derivative thereof Luteinizing hormone or derivative thereof (progesterone, 17 ⁇ -hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodorone, levonorgestrel , Norgestrel, ethinodiol diacetate, desogestrel, norgestimate, gestodene, progestin, etonogestrel, drospirenone, dienogest, diemegeston, nestreone, chromazinone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or Luteinizing hormone or its derivative and follicle hormone or its derivative (Estradiol, Estradiol Benzoate Estradio
  • T cell inhibitor ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil etc.
  • thalidomide v) cathepsin inhibitors
  • MMPs matrix metalloproteinase inhibitors V-85546 and the like.
  • Xvii CD23 antagonist
  • xviii LTB4 receptor antagonist DW-1305 and the like.
  • Xix 5-lipoxygenase inhibitors zileuton etc.
  • Xx Cholinesterase inhibitor galantamine etc.
  • Xxi Tyrosine kinase inhibitor TYK2 inhibitor (WO 2010/142752) and the like.
  • Xxii Cathepsin B inhibitor
  • xxiii Adenosine deaminase inhibitor Pentostatin and the like.
  • osteogenic stimulant xxv
  • dipeptidyl peptidase inhibitor xxvi
  • collagen agonist xxviii
  • hyaluronic acid derivative synbisque hylan GF 20
  • ortho bisque etc.
  • glucosamine sulfate xxx
  • amiprirose xxxi
  • BAFF inhibitors belimumab, tavarumab, atacicept, A-623 and the like.
  • antibacterial drugs for example, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, antihypertensive diuretics, anticoagulants Drugs, tranquilizers, antipsychotics, antineoplastics, antihyperlipidemics, muscle relaxants, antiepileptics, antidepressants, antiallergics, inotropics, antiarrhythmics, vasodilators, vasoconstrictors Drugs, antihypertensive diuretics, antidiabetic drugs, narcotic antagonists, vitamins, vitamin derivatives, antiasthmatic drugs, anti- urinary and urinary incontinence drugs, antidiarrheal drugs, anti-atopic dermatitis drugs, anti-allergic rhinitis drugs, vasopressor Drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory fibros,
  • Antimicrobial agents Sulfa drug sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.
  • Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, freloxacin and the like.
  • Antituberculosis drug isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylic acid), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
  • Acid-fast fungicides such as diaphenyl sulfone and rifampicillin.
  • antiviral agents idoxuridine, acyclovir, vitarabine, ganciclovir and the like.
  • Anti-spirochetes (viii) Antibiotics Tetracycline hydrochloride, Ampicillin, Piperacillin, Gentamycin, Dibekacin, Kanendomycin, Lividomycin, Tobramycin, Amikacin, Fradiomycin, Sisomycin, Tetracycline, Oxytetracycline, Loritetracycline, Doxycycline, Ticarcillin, Cepharotin, Cephapirin, Cepharolizine , Cefaclor, cephalexin, cefloxazine, cefadroxil, cefaamdol, cefatoam, cefuroxime, cefotiam, cefotiam hexetil, cefroxim akicetyl, cefdoxime, cefdinir
  • Antifungal drug Polyethylene antibiotics (eg, amphotericin B, nystatin, trichomycin) (ii) griseofulvin, pyrrolnitrin, etc. (iii) Cytosine Antagonists (eg Flucytosine) (iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) (v) Triazole derivatives (eg fluconazole, itraconazole) (vi) Thiocarbamic acid derivatives (eg, trinaphthol) and the like. (3) Antiprotozoal metronidazole, tinidazole, diethylcarbamidine citrate, quinine hydrochloride, quinine sulfate and the like.
  • Anesthetics (6-1) Local anesthetics cocaine hydrochloride, procaine hydrochloride, lidocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein and the like.
  • Arrhythmic drug eg, Sodium channel blockers (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin), (ii) ⁇ -blockers (eg, propranolol, alprenolol, bufetrol, hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride), (iii) potassium channel blockers (eg, amiodarone), (iv) calcium channel blockers (eg, verapamil, diltiazem) and the like.
  • Sodium channel blockers eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin
  • ⁇ -blockers eg
  • Antipsychotic drug chlorpromazine hydrochloride prochlorperazine, trifluoroperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine etc.
  • Muscle relaxant Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone, eperisone, tizanidine and the like.
  • Anti-epileptic drug phenytoin, etoxacimide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
  • Anti-allergic agents Diphenhydramine, chlorpheniramine, metoperamine, metziramine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast, repirinast, anrexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride , Pranlukast hydrate, seratrodust, etc.
  • Cardiotonics Transbioxocamphor telephilol, aminophylline, ethyephrine, dopamine, dobutamine, denopamin, becinaline, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyl digoxin, ranatoside C, G-strophantin and the like.
  • Vasodilators Oxyphedrine, diltiazem, trazoline, hexobenzin, bamethane, clonidine, methyldopa, guanabenz etc.
  • Vasoconstrictor Dopamine, dobutamine denopamine and the like.
  • Antihypertensive diuretics Hexamethonium bromide, pentrinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
  • Vitamin A Vitamin A 1 , Vitamin A 2 and Retinol Palmitate
  • Vitamin D Vitamin D 1 , D 2 , D 3 , D 4 and D 5
  • Vitamin E ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, nicotinic acid dl- ⁇ -tocopherol
  • Vitamins K Vitamins K 1 , K 2 , K 3 and K 4 (v) folic acid (vitamin M) and the like.
  • vitamin derivative various derivatives of vitamins, for example, 5,6-trans - cholecalciferol, 2,5-hydroxycholecalciferol, 1-alpha-hydroxy cholecalciferol shea vitamin D 3 derivatives such as fellows Le, 5,6 Vitamin D 2 derivatives such as trans-ergocalciferol.
  • Anti-asthmatic drug isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciplanaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, anlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisolate , Beclomethasone prop
  • Pressor agents Dopamin, dobutamine, denopamine, digitoxin, digoxin, methyl digoxin, ranatoside C, G-strophantin and the like.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject or may be administered at time intervals.
  • the dose of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the combination is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • dosage forms for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) obtained by separately formulating the compound of the present invention and the concomitant drug Simultaneous administration of two preparations by the same administration route, (3) Administration with time difference between two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, by the same administration route, (4) Simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, and (5) different two formulations obtained by separately formulating the compound of the present invention and the concomitant drug Examples include administration with a time lag depending on the administration route (for example, administration of the combination drug after administration of the compound of the present invention, or administration in the reverse order) and the like.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of preparation, but usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but it is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably It is about 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the whole preparation. .
  • the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.
  • the dose may vary depending on the type of compound of the present invention, administration route, symptoms, age of patients, etc., for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, atopic When administered orally to a patient (body weight about 60 kg) with dermatitis, systemic lupus erythematosus, leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.
  • the free form of Compound (I) may be administered at a dose of about 0.1 mg / kg body weight to about 50 mg / kg body weight, preferably about 1 mg / kg body weight to 30 mg / kg body weight once to several times a day .
  • the dosage is the type and content of compound (I), dosage form, duration of drug release, target animal (eg, mouse, rat, hamster, guinea pig (A rabbit, a cat, a dog, a cow, a horse, a pig, a sheep, a monkey, a human, a mammal such as a human) and the like, depending on the administration purpose, for example, when applied by parenteral administration, about 0.1 per week.
  • target animal eg, mouse, rat, hamster, guinea pig (A rabbit, a cat, a dog, a cow, a horse, a pig, a sheep, a monkey, a human, a mammal such as a human
  • target animal eg, mouse, rat, hamster, guinea pig (A rabbit, a cat, a dog, a cow, a horse, a pig, a sheep, a monkey, a human, a mammal such as
  • the concomitant drug can be set in any amount as long as side effects do not cause a problem.
  • the daily dose as a concomitant drug may vary depending on the degree of symptoms, age, sex, body weight, difference in sensitivity, administration timing, interval, nature of pharmaceutical preparation, preparation, type of active ingredient, etc.
  • the amount of the drug is usually, for example, about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, and more preferably about 0.1 to 100 mg per kg body weight of a mammal when orally administered. It can be administered, usually divided into 1 to 4 times a day.
  • the compound of the present invention and the concomitant drug may be administered at the same time or may be administered at different times.
  • timed administration the time difference varies depending on the active ingredient, dosage form and administration method to be administered, but for example, when the concomitant drug is administered first, within 1 minute to 3 days after administering the concomitant drug, preferably The method includes administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the method of administering the concomitant drug within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administering the compound of the present invention Can be mentioned.
  • silica gel column chromatography when stated as NH, aminopropylsilane-bonded silica gel was used, and when described as Diol, 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used.
  • NH aminopropylsilane-bonded silica gel
  • Diol 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used.
  • octadecyl-bonded silica gel When described as C18 in preparative HPLC (high performance liquid chromatography), octadecyl-bonded silica gel was used.
  • the ratios shown in the elution solvent indicate volume ratios unless otherwise specified.
  • ACD / SpecManager (trade name) software etc. were used for the analysis of 1 H NMR. There is a case in which a very mild peak such as a hydroxyl group or an amino group is not described. MS was measured by LC / MS.
  • ESI method As the ionization method, ESI method or APCI method was used. The data show the actual value (found). Usually, molecular ion peaks are observed, but sometimes as fragment ions. In the case of a salt, a free molecular ion peak or fragment ion peak is usually observed.
  • the unit of sample concentration (c) in optical rotation ([ ⁇ ] D ) is g / 100 mL. Elemental analysis values (Anal.) Are shown as calculated values (Calcd) and actual values (Found).
  • the powder X-ray diffraction peaks in the examples mean peaks measured at room temperature using Ultima IV (Rigaku Corporation, Japan) using Cu K ⁇ radiation as a radiation source. The measurement conditions are as follows.
  • Example 1 2- (4-((4-hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile
  • 4-iodo-2-methoxynicotinic acid (5.02 g) and methyl HOBt (3.16 g) and WSC.HCl (4.49 g) were added at 0 ° C.
  • Example compounds are shown in Table 1 below. MS in the table indicates the measured value.
  • the compounds of Examples 2 to 23 in the following table were prepared according to the methods described in the above examples or methods analogous thereto.
  • Formulation Example 2 (tablet production) 1) 30 g of the compound of Example 1 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets total 140 g The whole of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried under vacuum and then sized. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and compressed with a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
  • Test Example 1 JAK1 Enzyme Inhibition Test The JAK1 enzyme inhibitory activity of a test compound was measured by the LANCE method (Perkin Elmer). First, 2 ⁇ L each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate .
  • assay buffer 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA
  • Test Example 2 JAK2 Enzyme Inhibition Test The JAK2 enzyme inhibitory activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 ⁇ L each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate .
  • assay buffer 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA
  • Test Example 3 JAK3 Enzyme Inhibition Test The JAK3 enzyme inhibitory activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 ⁇ L each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate .
  • assay buffer 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA
  • Test Example 4 TYK2 Enzyme Inhibition Test
  • the TYK2 enzyme inhibitory activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 ⁇ L each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate .
  • assay buffer 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA
  • the compound of the present invention can have excellent JAK inhibitory action, and autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, etc.) And cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like) and the like can be useful as preventive or therapeutic agents.
  • autoimmune diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, etc.
  • cancer leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibro

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Abstract

Provided is a compound or salt thereof that may have excellent JAK inhibitory action and that may be useful as an agent for preventing or treating an autoimmune disease (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, or the like), cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis, and the like), or the like. The present invention relates to a compound represented by formula (I) (In formula (I), the reference symbols are as defined in the specification.), or a salt thereof.

Description

複素環化合物Heterocyclic compounds
　本発明は、ヤヌスキナーゼ（本明細書中「ＪＡＫ」と略記する場合がある）阻害作用を有し得、自己免疫疾患（関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス等）、癌（白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等）等の治療に有用であり得る複素環化合物、それらを含有する医薬組成物などに関する。 The present invention may have an inhibitory action on Janus kinase (which may be abbreviated as “JAK” in the present specification), and an autoimmune disease (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple disease Heterocyclic compounds which may be useful for the treatment of sclerosis, systemic lupus erythematosus etc., cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis etc.), containing them Pharmaceutical composition and the like.
（発明の背景）
　サイトカインとは免疫システムの細胞から分泌されるタンパク質で、特定の細胞に情報伝達を行う。サイトカインは、多くの種類があるが特に免疫、炎症に関係したものが多く、細胞の増殖、分化、細胞死、あるいは創傷治癒などにも関係する（非特許文献１）。 BACKGROUND OF THE INVENTION
Cytokines are proteins secreted from cells of the immune system that transmit signals to specific cells. There are many types of cytokines, but many of them are particularly related to immunity and inflammation, and also to cell proliferation, differentiation, cell death, wound healing and the like (Non-patent Document 1).
　ヤヌスキナーゼ（ＪＡＫ）ファミリーは増殖および免疫応答に関与する細胞の機能のサイトカイン-依存的制御において役割を果たしている。ＪＡＫファミリーには、４種類のヤヌスキナーゼ（ＪＡＫ１（ヤヌスキナーゼ１）、ＪＡＫ２（ヤヌスキナーゼ２）、ＪＡＫ３（ヤヌスキナーゼ３）およびＴＹＫ２（チロシンキナーゼ２））がある。その中で、ＪＡＫ１は、ＩＬ（インターロイキン）－２、ＩＬ－４、ＩＬ－７、ＩＬ－１５、ＩＬ－２１、ＩＬ－６、ＯＳＭ（オンコスタチンＭ）、ＩＬ－１０ファミリー、ＩＦＮ（インターフェロン）－α、ＩＦＮ－β、ＩＦＮ－γなどのサイトカインシグナル伝達に関与することが知られている（非特許文献２）。ＴＹＫ２は、ＩＦＮ－α、ＩＦＮ－β、ＩＬ－６、ＩＬ－１０ファミリー（ＩＬ－１０、ＩＬ－１９、ＩＬ－２０、ＩＬ－２２、ＩＬ－２８、ＩＬ－２９）、ＩＬ－１２、ＩＬ－２３ などのサイトカインのシグナル伝達に関与することが知られている（非特許文献２、非特許文献３）。また、これらのサイトカイン類は、適量存在するときには免疫反応において重要な役割を担っているものの、過剰な産生は関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス等の多くの自己免疫疾患に関わっている(非特許文献４、非特許文献５、非特許文献６、非特許文献７)。 The Janus kinase (JAK) family plays a role in the cytokine-dependent control of cellular functions involved in proliferation and immune responses. The JAK family includes four types of Janus kinases (JAK1 (Janus kinase 1), JAK2 (Janus kinase 2), JAK3 (Janus kinase 3) and TYK2 (tyrosine kinase 2)). Among them, JAK1 is IL (interleukin) -2, IL-4, IL-7, IL-15, IL-21, IL-6, OSM (oncostatin M), IL-10 family, IFN (interferon) 2.) It is known to be involved in cytokine signal transduction such as -α, IFN-β, IFN-γ and the like (Non-patent Document 2). TYK2 is an IFN-α, IFN-β, IL-6, IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-28, IL-29), IL-12, IL It is known to be involved in the signal transduction of cytokines such as -23 (Non-patent document 2, Non-patent document 3). In addition, these cytokines play an important role in the immune response when present in appropriate amounts, but excessive production is associated with rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, and whole body It is involved in many autoimmune diseases such as sexual lupus erythematosus (Non-patent document 4, Non-patent document 5, Non-patent document 6, Non-patent document 7).
　抗ＩＬ－６受容体モノクローナル抗体であるトシリズマブ（Ｔｏｃｉｌｉｚｕｍａｂ）は関節リウマチの治療薬として日本や欧米で承認されており、ＩＬ－６シグナル経路に関与が示唆されるさまざまな疾患において臨床試験が行われている。以上のことから、ＪＡＫ１阻害薬は、関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス等の様々な自己免疫疾患の治療薬となり得る（非特許文献８）。 The anti-IL-6 receptor monoclonal antibody Tocilizumab (Tocilizumab) has been approved in Japan, Europe and the United States for the treatment of rheumatoid arthritis, and clinical trials have been conducted in various diseases that are suggested to be involved in the IL-6 signaling pathway. ing. From the above, JAK1 inhibitors can be used as therapeutic agents for various autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis and systemic lupus erythematosus (non-patent literature) 8).
　また、ＪＡＫシグナルは多くの癌細胞の分化や増殖にも関与しており（非特許文献９）、特にＪＡＫ１は白血病や子宮平滑筋肉腫で恒常的に活性化しており病態に関与している（非特許文献１０、非特許文献１１）。また、ＩＬ－６を標的にした抗体や低分子化合物は前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等の癌疾患において臨床試験が行われている（非特許文献１２、非特許文献１３）。よってＪＡＫ１阻害薬は白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等の癌疾患の治療薬になり得る。 JAK signaling is also involved in the differentiation and proliferation of many cancer cells (Non-patent Document 9), and in particular, JAK1 is constitutively activated in leukemia and uterine leiomyosarcoma and is involved in pathological conditions ( Non-Patent Document 10, Non-Patent Document 11). In addition, antibodies and low-molecular compounds targeting IL-6 have been clinically tested in cancer diseases such as prostate cancer, multiple myeloma, cachexia, and myelofibrosis (Non-patent Document 12, Non-patent Literature 13). Therefore, JAK1 inhibitors can be therapeutic agents for cancer diseases such as leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like.
　一方、抗ＩＬ－１２/２３モノクローナル抗体であるウステキヌマブ（Ｕｓｔｅｋｉｎｕｍａｂ）は中等症から重等症の乾癬患者への治療薬として欧州で承認され、さらにＩＬ－１２/２３シグナル経路の関与が示唆される様々な疾患において臨床試験が行われている（非特許文献１４）。またＩＬ－２３シグナル経路は、アルツハイマー病（例、アルツハイマー型認知症など）などの中枢性疾患との関与も示唆されている（非特許文献１５）。以上のことからＴＹＫ２阻害剤は、関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス等の様々な自己免疫疾患治療薬やアルツハイマー病（例、アルツハイマー型認知症など）などの中枢性疾患治療薬となり得る（非特許文献１６）。 On the other hand, the anti-IL-12 / 23 monoclonal antibody ustekinumab (Ustekinumab) is approved in Europe as a treatment for patients with moderate to severe psoriasis and suggests the involvement of the IL-12 / 23 signaling pathway Clinical trials have been conducted in various diseases (Non-patent Document 14). The IL-23 signaling pathway has also been suggested to be involved in central diseases such as Alzheimer's disease (eg, Alzheimer's disease etc.) (Non-patent Document 15). From the above, TYK2 inhibitors include various autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, and Alzheimer's disease (eg, Alzheimer's disease) It can be used as a therapeutic drug for central diseases such as dementia (Non-patent Document 16).
　ＪＡＫ１阻害を有する化合物としては、例えば、特許文献１～特許文献７に記載の化合物等挙げられる。 Examples of compounds having JAK1 inhibition include the compounds described in Patent Documents 1 to 7.
米国特許公報第9085578号明細書U.S. Pat. No. 9,085,578 米国特許公報第9371320号明細書U.S. Pat. No. 9,371,320 米国特許出願公報第2016/0251352号明細書U.S. Patent Application Publication No. 2016/0251352 米国特許公報第9187453号明細書U.S. Patent Publication No. 9187453 米国特許出願公報第2016/0159773号明細書US Patent Application Publication No. 2016/0159773 米国特許公報第9637483号明細書U.S. Patent Publication No. 9637483 米国特許出願公報第2017/0174682号明細書US Patent Application Publication No. 2017/0174682
　本発明の目的は、優れたＪＡＫ阻害作用を有し得、自己免疫疾患（関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス、アトピー性皮膚炎等）、癌（白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等）等の予防または治療剤として有用であり得る化合物を提供することである。 The object of the present invention is to have excellent JAK inhibitory action, autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, etc. It is an object of the present invention to provide a compound which can be useful as a preventive or therapeutic agent for cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like) and the like.
　本発明者らは、上記課題を解決すべく鋭意検討した結果、下記の式で示される化合物（Ｉ）が、優れたＪＡＫ阻害作用を有し得ることを見出し、本発明を完成するに至った。
　すなわち、本発明は以下の通りである。
［１］　式 MEANS TO SOLVE THE PROBLEM As a result of earnestly examining that the present inventors should solve the said subject, it discovers that compound (I) shown by a following formula may have the outstanding JAK inhibitory effect, and came to complete this invention. .
That is, the present invention is as follows.
[1]
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
〔式中、R1、R2、R3、R4およびR5は、それぞれ独立して水素原子または置換基を示す。〕で表される化合物またはその塩（本明細書中、「化合物（Ｉ）」と略記する場合がある）。
［２］　Ｒ１が、水素原子であり；
　Ｒ２が、水素原子であり；
　Ｒ３が、
(a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基で置換されていてもよい３ないし８員の単環式非芳香族複素環基、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基、および(vi) ジＣ１－６アルキルアミノ基から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基、
(b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および(iii) Ｃ６－１４アリール基から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基、および
(c) ３ないし８員の単環式非芳香族複素環基
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基であり；
　Ｒ４が、
(1) シアノ基；
(2) (a) (i) Ｃ３－８シクロアルキル基、(ii) Ｃ１－６アルコキシ基および(iii) １ないし3個のＣ１－６アルキル基
で置換されていてもよい３ないし８員の単環式非芳香族複素環基から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基、
　　(b) Ｃ３－８シクロアルキル基、および、
　　(c) ３ないし８員の単環式非芳香族複素環基
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；または、
(3) Ｃ１－６アルコキシ－カルボニル基であり；
　Ｒ５が、水素原子である、［１］記載の化合物またはその塩。
［３］　2-(4-((4-ヒドロキシ-4-フェニルシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル、
　（RまたはS)-2-(2-オキソ-4-(テトラヒドロ-2H-ピラン-3-イルアミノ)-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル、
　2-(4-((trans-4-(ヒドロキシメチル)シクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル、
　メチル 2-(4-(((2R)-1-(3-シアノアゼチジン-1-イル)-1-オキソブタン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート、
　メチル 2-(4-(((2R)-1-(3-シアノアゼチジン-1-イル)-3-メチル-1-オキソブタン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート、
　メチル 2-(4-(シクロペンチルアミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート、
　2-(4-((1-ヒドロキシプロパン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　（RまたはS）-2-(4-((1-ヒドロキシプロパン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　（RまたはS）-2-(4-((1-ヒドロキシプロパン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(1-メトキシブタン-2-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(1-メトキシブタン-2-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(テトラヒドロ-2H-ピラン-4-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　N-(シクロプロピルメチル)-2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(2-メトキシエチル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-((3-メチルオキセタン-3-イル)メチル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-メチル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　N-シクロプロピル-2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　N-シクロプロピル-2-(4-((cis-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　N-シクロプロピル-2-(4-((2-(ジメチルアミノ)-1-フェニルエチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-((シアノメチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-シクロプロピル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
　2-(4-(((1-(シアノアセチル)ピロリジン-3-イル)メチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-シクロプロピル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミドおよび
　2-(4-((2-(4-(2-シアノフェニル)ピペラジン-1-イル)-2-オキソエチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-シクロプロピル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド
からなる群より選ばれる化合物またはその塩。
［４］　上記［１］記載の化合物またはその塩を含有してなる医薬。
［５］　ヤヌスキナーゼ阻害剤である、上記［４］記載の医薬。
［６］　自己免疫疾患の予防または治療剤である、上記［４］記載の医薬。
［７］　自己免疫疾患が全身性エリテマトーデス、炎症性腸疾患、乾癬、関節リウマチ、シェーグレン症候群、ベーチェット病、または多発性硬化症である、上記［６］記載の医薬。
［８］自己免疫疾患がアトピー性皮膚炎である、［６］記載の医薬。 [Wherein, R 1 , R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a substituent. Or a salt thereof (which may be abbreviated as “compound (I)” in the present specification).
[2] R 1 is a hydrogen atom;
R 2 is a hydrogen atom;
R 3 is
(a) (i) substituted with a cyano group, (ii) hydroxy group, (iii) a C 6-14 aryl group, (iv) a C 1-6 alkyl-carbonyl group which may be substituted with a cyano group 3-8 membered monocyclic non-aromatic heterocyclic group, (v) (i ') cyano group and (ii') C 6-14 aryl optionally substituted by 1 to 3 cyano groups 1 to 3 selected from 3 to 8 membered monocyclic non-aromatic heterocyclic carbonyl group optionally substituted by 1 to 3 substituents selected from groups, and (vi) di C 1-6 alkylamino group C 1-6 alkyl group which may be substituted by 1 to 3 substituents,
1 to 3 selected from (b) (i) hydroxy group, (ii) C 1-6 alkyl group optionally substituted with 1 to 3 hydroxy group, and (iii) C 6-14 aryl group C 3-8 cycloalkyl group which may be substituted with a substituent of
(c) an amino group which may be mono- or di-substituted with a substituent selected from 3- to 8-membered monocyclic non-aromatic heterocyclic groups;
R 4 is
(1) cyano group;
(2) (a) (i) 3 to 8 optionally substituted with a C 3-8 cycloalkyl group, (ii) a C 1-6 alkoxy group and (iii) 1 to 3 C 1-6 alkyl groups A C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 8-membered monocyclic non-aromatic heterocyclic groups,
(b) a C 3-8 cycloalkyl group, and
(c) a carbamoyl group which may be mono- or di-substituted with a substituent selected from 3- to 8-membered monocyclic non-aromatic heterocyclic groups; or
(3) C 1-6 alkoxy-carbonyl group;
The compound or a salt thereof according to [1], wherein R 5 is a hydrogen atom.
[3] 2- (4-((4-hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5 -Carbonitrile,
(R or S) -2- (2-oxo-4- (tetrahydro-2H-pyran-3-ylamino) -1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole- 5-carbonitrile,
2- (4-((trans-4- (hydroxymethyl) cyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbo Nitrile,
Methyl 2- (4-(((2R) -1- (3-cyanoazetidin-1-yl) -1-oxobutan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl)- 1H-thieno [2,3-d] imidazole-5-carboxylate,
Methyl 2- (4-(((2R) -1- (3-cyanoazetidin-1-yl) -3-methyl-1-oxobutan-2-yl) amino) -2-oxo-1,2-dihydropyridine-3 -Yl) -1H-thieno [2,3-d] imidazole-5-carboxylate,
Methyl 2- (4- (cyclopentylamino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylate,
2- (4-((1-hydroxypropan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide,
(R or S) -2- (4-((1-hydroxypropan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] Imidazole-5-carboxamide,
(R or S) -2- (4-((1-hydroxypropan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] Imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (1-methoxybutan-2-yl) -1H-thieno [2 , 3-d] Imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (1-methoxybutan-2-yl) -1H-thieno [2 , 3-d] Imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-thieno [ 2,3-d] imidazole-5-carboxamide,
N- (Cyclopropylmethyl) -2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] Imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (2-methoxyethyl) -1H-thieno [2,3-d ] Imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-((3-methyloxetan-3-yl) methyl) -1H- Thieno [2,3-d] imidazole-5-carboxamide,
2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-methyl-1H-thieno [2,3-d] imidazole-5- Carboxamide,
N-Cyclopropyl-2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5 -Carboxamide,
N-Cyclopropyl-2- (4-((cis-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5 -Carboxamide,
N-Cyclopropyl-2- (4-((2- (dimethylamino) -1-phenylethyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3- d] imidazole-5-carboxamide,
2- (4-((Cyanomethyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-cyclopropyl-1H-thieno [2,3-d] imidazole-5-carboxamide,
2- (4-(((1- (cyanoacetyl) pyrrolidin-3-yl) methyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-cyclopropyl-1H-thieno [2 , 3-d] imidazole-5-carboxamide and 2- (4-((2- (4- (2-cyanophenyl) piperazin-1-yl) -2-oxoethyl) amino) -2-oxo-1,2 A compound selected from the group consisting of -dihydropyridin-3-yl) -N-cyclopropyl-1H-thieno [2,3-d] imidazole-5-carboxamide or a salt thereof.
[4] A medicament comprising the compound of the above-mentioned [1] or a salt thereof.
[5] The medicine according to the above-mentioned [4], which is a Janus kinase inhibitor.
[6] The medicine according to the above-mentioned [4], which is an agent for the prophylaxis or treatment of an autoimmune disease.
[7] The medicament according to the above-mentioned [6], wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease, or multiple sclerosis.
[8] The medicine according to [6], wherein the autoimmune disease is atopic dermatitis.
　化合物（Ｉ）は、優れたＪＡＫ阻害作用を有し得、自己免疫疾患（全身性エリテマトーデス、炎症性腸疾患（クローン病、潰瘍性大腸炎等）、乾癬、関節リウマチ、シェーグレン症候群、ベーチェット病、多発性硬化症、アトピー性皮膚炎等）、癌（白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等）等の予防または治療剤として有用であり得る。 The compound (I) can have excellent JAK inhibitory action, and autoimmune diseases (systemic lupus erythematosus, inflammatory bowel disease (Crohn's disease, ulcerative colitis, etc.), psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease, It may be useful as a preventive or therapeutic agent for multiple sclerosis, atopic dermatitis and the like, cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like) and the like.
（発明の詳細な説明）
　本明細書中、「置換基」とは、以下の基を示す。
(1) ハロゲン原子；
(2) シアノ基；
(3) ニトロ基；
(4) ヒドロキシ基；
(5) (a) ハロゲン原子、
　　(b) シアノ基、および
　　(c) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、および
　　(d) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ基
から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基；
(6) (a) ハロゲン原子、
　　(b) シアノ基、
　　(c) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、および
　　(d) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ基
から選ばれる１ないし３個の置換基で置換されていてもよいＣ６－１４アリール基；
(7) (a) ハロゲン原子、
　　(b) シアノ基、
　　(c) １ないし３個のハロゲン原子で置換されていてもよいＣ３－８シクロアルキル基、
　　(d) １ないし３個のハロゲン原子で置換されていてもよいＣ３－８シクロアルケニル基、
　　(e) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール基、および
　　(f) ５または６員の単環式芳香族複素環基
から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルコキシ基；
(8) １ないし３個のハロゲン原子で置換されていてもよいＣ２－６アルケニルオキシ基；
(9) １ないし３個のハロゲン原子で置換されていてもよいＣ２－６アルキニルオキシ基；
(10) １ないし３個のハロゲン原子で置換されていてもよいＣ３－８シクロアルキルオキシ基；
(11) １ないし３個のハロゲン原子で置換されていてもよいＣ３－８シクロアルケニルオキシ基；
(12) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリールオキシ基；
(13) １ないし３個のハロゲン原子で置換されていてもよいＣ７－１４アラルキルオキシ基；
(14) (a) (i) Ｃ３－８シクロアルキル基、(ii) Ｃ１－６アルコキシ基および(iii) １ないし3個のＣ１－６アルキル基で置換されていてもよい３ないし８員の単環式非芳香族複素環基から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基、
　　 (b) Ｃ３－８シクロアルキル基、
　　 (c) Ｃ６－１４アリール基、
　　 (d) Ｃ１－６アルコキシ基、
　　 (e) ５または６員の単環式芳香族複素環基、
　　 (f) ８ないし１２員の縮合芳香族複素環基、
　　 (g) ３ないし８員の単環式非芳香族複素環基、および
　　 (h) ８ないし１２員の縮合非芳香族複素環基
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；
(15) (a) Ｃ１－６アルキル基、
　　 (b) Ｃ３－８シクロアルキル基、
　　 (c) Ｃ６－１４アリール基、
　　 (d) Ｃ１－６アルコキシ基、
　　 (e) ５または６員の単環式芳香族複素環基、
　　 (f) ８ないし１２員の縮合芳香族複素環基、
　　 (g) ３ないし８員の単環式非芳香族複素環基、および
　　 (h) ８ないし１２員の縮合非芳香族複素環基
から選ばれる置換基でモノまたはジ置換されていてもよいスルファモイル基；
(16) ホルミル；
(17) １ないし３個のＣ１－６アルコキシ基で置換されていてもよいＣ１－６アルキル－カルボニル基；
(18) Ｃ２－６アルケニル－カルボニル基；
(19) Ｃ２－６アルキニル－カルボニル基；
(20) Ｃ３－８シクロアルキル－カルボニル基；
(21) Ｃ３－８シクロアルケニル－カルボニル基；
(22) Ｃ６－１４アリール－カルボニル基；
(23) Ｃ３－８シクロアルキル－Ｃ１－６アルキル－カルボニル基；
(24) Ｃ３－８シクロアルケニル－Ｃ１－６アルキル－カルボニル基；
(25) Ｃ７－１４アラルキル－カルボニル基；
(26) ５または６員の単環式芳香族複素環カルボニル基；
(27) ８ないし１２員の縮合芳香族複素環カルボニル基；
(28) ３ないし８員の単環式非芳香族複素環カルボニル基；
(29) ８ないし１２員の縮合非芳香族複素環カルボニル基（例、ジヒドロベンゾフラニルカルボニル）；
(30) (a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基で置換されていてもよい３ないし８員の単環式非芳香族複素環基、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基、および(vi) ジＣ１－６アルキルアミノ基から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基、
　　 (b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および(iii) Ｃ６－１４アリール基から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基、
　　 (c) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール基、
　　 (d) ５または６員の単環式芳香族複素環基、
　　 (e) ８ないし１２員の縮合芳香族複素環基、
　　 (f) ３ないし８員の単環式非芳香族複素環基、
　　 (g) ８ないし１２員の縮合非芳香族複素環基、
　　 (h) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル－カルボニル基、
　　 (i) Ｃ３－８シクロアルキル－カルボニル基、
　　 (j) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール－カルボニル基、
　　 (k) ５または６員の単環式芳香族複素環カルボニル基、
　　 (l) ８ないし１２員の縮合芳香族複素環カルボニル基、
　　 (m) ３ないし８員の単環式非芳香族複素環カルボニル基、および
　　 (n) ８ないし１２員の縮合非芳香族複素環カルボニル基
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基；
(31) スルファニル基；
(32) Ｃ１－６アルキルスルファニル基；
(33) Ｃ２－６アルケニルスルファニル基；
(34) Ｃ２－６アルキニルスルファニル基；
(35) Ｃ３－８シクロアルキルスルファニル基；
(36) Ｃ３－８シクロアルケニルスルファニル基；
(37) Ｃ６－１４アリールスルファニル基；
(38) Ｃ３－８シクロアルキル－Ｃ１－６アルキルスルファニル基；
(39) Ｃ３－８シクロアルケニル－Ｃ１－６アルキルスルファニル基；
(40) Ｃ１－６アルキルスルフィニル基；
(41) Ｃ２－６アルケニルスルフィニル基；
(42) Ｃ２－６アルキニルスルフィニル基；
(43) Ｃ３－８シクロアルキルスルフィニル基；
(44) Ｃ３－８シクロアルケニルスルフィニル基；
(45) Ｃ６－１４アリールスルフィニル基；
(46) Ｃ３－８シクロアルキル－Ｃ１－６アルキルスルフィニル基；
(47) Ｃ３－８シクロアルケニル－Ｃ１－６アルキルスルフィニル基；
(48) Ｃ１－６アルキルスルホニル基；
(49) Ｃ２－６アルケニルスルホニル基；
(50) Ｃ２－６アルキニルスルホニル基；
(51) Ｃ３－８シクロアルキルスルホニル基；
(52) Ｃ３－８シクロアルケニルスルホニル基；
(53) Ｃ６－１４アリールスルホニル基；
(54) Ｃ３－８シクロアルキル－Ｃ１－６アルキルスルホニル基；
(55) Ｃ３－８シクロアルケニル－Ｃ１－６アルキルスルホニル基；
(56) Ｃ６－１４アリール－Ｃ１－６アルキルスルホニル基；
(57) ５または６員の単環式芳香族複素環スルホニル基；
(58) ８ないし１２員の縮合芳香族複素環スルホニル基；
(59) ３ないし８員の単環式非芳香族複素環スルホニル基；
(60) ８ないし１２員の縮合非芳香族複素環スルホニル基；
(61) (a) ハロゲン原子、
　　 (b) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、および
　　 (c) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ基
から選ばれる１ないし３個の置換基で置換されていてもよい５または６員の単環式芳香族複素環基；
(62) (a) ハロゲン原子、
　　 (b) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、および
　　 (c) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ基
から選ばれる１ないし３個の置換基で置換されていてもよい８ないし１２員の縮合芳香族複素環基；
(63) (a) ハロゲン原子、
　　 (b) １ないし３個のハロゲン原子またはヒドロキシ基で置換されていてもよいＣ１－６アルキル基、
　　 (c) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ基、および
　　 (d) オキソ基
から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環基；
(64) (a) ハロゲン原子、
　　 (b) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル基、
　　 (c) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルコキシ基、および
　　 (d) オキソ基
から選ばれる１ないし３個の置換基で置換されていてもよい８ないし１２員の縮合非芳香族複素環基；
(65) ５または６員の単環式芳香族複素環オキシ基；
(66) ８ないし１２員の縮合芳香族複素環オキシ基；
(67) ３ないし８員の単環式非芳香族複素環オキシ基；
(68) ８ないし１２員の縮合非芳香族複素環オキシ基；
(69) カルボキシ基；
(70) Ｃ１－６アルコキシ－カルボニル基；
(71) Ｃ２－６アルケニルオキシ－カルボニル基；
(72) Ｃ２－６アルキニルオキシ－カルボニル基；
(73) Ｃ３－８シクロアルキルオキシ－カルボニル基；
(74) Ｃ３－８シクロアルケニルオキシ－カルボニル基；
(75) Ｃ６－１４アリールオキシ－カルボニル基；
(76) Ｃ３－８シクロアルキル－Ｃ１－６アルコキシ－カルボニル基；
(77) Ｃ３－８シクロアルケニル－Ｃ１－６アルコキシ－カルボニル基；
(78) Ｃ７－１４アラルキルオキシ－カルボニル基；
(79) モノＣ１－６アルキルチオカルバモイル基；
(80) ジＣ１－６アルキルチオカルバモイル基；
(81) Ｃ１－６アルキル－カルボニルオキシ基；
(82) ヒドロキシ基で置換されていてもよいイミノ基；
(83) Ｃ１－６アルキレンジオキシ基。 (Detailed Description of the Invention)
In the present specification, “substituent” refers to the following groups.
(1) halogen atom;
(2) cyano group;
(3) nitro group;
(4) hydroxy group;
(5) (a) halogen atom,
(b) a cyano group, and (c) a C 1-6 alkyl group which may be substituted by 1 to 3 halogen atoms, and (d) a C 1 optionally substituted by 1 to 3 halogen atoms A C 3-8 cycloalkyl group which may be substituted by 1 to 3 substituents selected from 1-6 alkoxy groups;
(6) (a) halogen atom,
(b) cyano group,
(c) 1 to selected from the three may be substituted by a halogen atom C 1-6 alkyl group, and (d) 1 to 3 of a C 1-6 alkoxy group optionally substituted by a halogen atom C 6-14 aryl group optionally substituted by 1 to 3 substituents;
(7) (a) halogen atom,
(b) cyano group,
(c) a C 3-8 cycloalkyl group which may be substituted by 1 to 3 halogen atoms,
(d) a C 3-8 cycloalkenyl group which may be substituted by 1 to 3 halogen atoms,
(e) 1 to 3 substituents selected from a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, and (f) a 5- or 6-membered monocyclic aromatic heterocyclic group A C 1-6 alkoxy group which may be substituted by a group;
(8) a C 2-6 alkenyloxy group optionally substituted by 1 to 3 halogen atoms;
(9) a C 2-6 alkynyloxy group optionally substituted by 1 to 3 halogen atoms;
(10) a C 3-8 cycloalkyloxy group which may be substituted by 1 to 3 halogen atoms;
(11) a C 3-8 cycloalkenyloxy group which may be substituted by 1 to 3 halogen atoms;
(12) a C 6-14 aryloxy group which may be substituted by 1 to 3 halogen atoms;
(13) a C 7-14 aralkyloxy group optionally substituted with 1 to 3 halogen atoms;
(14) (a) (i) 3 to 8 optionally substituted with a C 3-8 cycloalkyl group, (ii) a C 1-6 alkoxy group and (iii) 1 to 3 C 1-6 alkyl groups A C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 8-membered monocyclic non-aromatic heterocyclic groups,
(b) C 3-8 cycloalkyl group,
(c) C 6-14 aryl group,
(d) C 1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered fused aromatic heterocyclic groups,
(g) 3- to 8-membered monocyclic non-aromatic heterocyclic group, and (h) carbamoyl optionally mono- or di-substituted with a substituent selected from 8- to 12-membered fused non-aromatic heterocyclic group Group;
(15) (a) C 1-6 alkyl group,
(b) C 3-8 cycloalkyl group,
(c) C 6-14 aryl group,
(d) C 1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered fused aromatic heterocyclic groups,
A sulfamoyl which may be mono- or di-substituted with a substituent selected from (g) a 3- to 8-membered monocyclic non-aromatic heterocyclic group and (h) a 8- to 12-membered fused non-aromatic heterocyclic group Group;
(16) formyl;
(17) a C 1-6 alkyl-carbonyl group which may be substituted by 1 to 3 C 1-6 alkoxy groups;
(18) C 2-6 alkenyl-carbonyl group;
(19) C 2-6 alkynyl-carbonyl group;
(20) C 3-8 cycloalkyl-carbonyl group;
(21) C 3-8 cycloalkenyl-carbonyl group;
(22) C 6-14 aryl-carbonyl group;
(23) C 3-8 cycloalkyl-C 1-6 alkyl-carbonyl group;
(24) C 3-8 cycloalkenyl-C 1-6 alkyl-carbonyl group;
(25) C 7-14 aralkyl-carbonyl group;
(26) 5 or 6 membered monocyclic aromatic heterocyclic carbonyl group;
(27) 8- to 12-membered fused aromatic heterocyclic carbonyl group;
(28) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group;
(29) 8- to 12-membered fused non-aromatic heterocyclic carbonyl group (eg, dihydrobenzofuranyl carbonyl);
(30) (a) (i) substituted with a cyano group, (ii) a hydroxy group, (iii) a C 6-14 aryl group, (iv) a C 1-6 alkyl-carbonyl group which may be substituted with a cyano group 3-8 membered monocyclic non-aromatic heterocyclic group which may be substituted, (v) C 6 optionally substituted by (i ′) cyano group and (ii ′) 1 to 3 cyano group A 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group which may be substituted by 1 to 3 substituents selected from -14 aryl group, and (vi) a diC 1-6 alkylamino group A C 1-6 alkyl group which may be substituted by 1 to 3 substituents selected;
1 to 3 selected from (b) (i) hydroxy group, (ii) C 1-6 alkyl group optionally substituted with 1 to 3 hydroxy group, and (iii) C 6-14 aryl group C 3-8 cycloalkyl group which may be substituted by the substituent of
(c) a C 6-14 aryl group which may be substituted by 1 to 3 halogen atoms,
(d) 5- or 6-membered monocyclic aromatic heterocyclic group,
(e) 8- to 12-membered fused aromatic heterocyclic groups,
(f) 3- to 8-membered monocyclic non-aromatic heterocyclic group,
(g) 8- to 12-membered fused non-aromatic heterocyclic groups,
(h) a C 1-6 alkyl-carbonyl group which may be substituted by 1 to 3 halogen atoms,
(i) C 3-8 cycloalkyl-carbonyl group,
(j) a C 6-14 aryl-carbonyl group which may be substituted by 1 to 3 halogen atoms,
(k) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(l) 8- to 12-membered fused aromatic heterocyclic carbonyl group,
(m) Mono- or di-substituted with a substituent selected from (m) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group, and (n) 8- to 12-membered fused non-aromatic heterocyclic carbonyl group Good amino group;
(31) sulfanyl group;
(32) a C 1-6 alkylsulfanyl group;
(33) C 2-6 alkenylsulfanyl group;
(34) C 2-6 alkynylsulfanyl group;
(35) C 3-8 cycloalkylsulfanyl group;
(36) C 3-8 cycloalkenyl sulfanyl group;
(37) C 6-14 arylsulfanyl group;
(38) C 3-8 cycloalkyl-C 1-6 alkylsulfanyl group;
(39) C 3-8 cycloalkenyl-C 1-6 alkylsulfanyl group;
(40) C 1-6 alkylsulfinyl group;
(41) C 2-6 alkenylsulfinyl group;
(42) C 2-6 alkynylsulfinyl group;
(43) C 3-8 cycloalkyl sulfinyl group;
(44) C 3-8 cycloalkenylsulfinyl group;
(45) C 6-14 arylsulfinyl group;
(46) C 3-8 cycloalkyl-C 1-6 alkylsulfinyl group;
(47) C 3-8 cycloalkenyl-C 1-6 alkylsulfinyl group;
(48) C 1-6 alkylsulfonyl group;
(49) C 2-6 alkenylsulfonyl group;
(50) C 2-6 alkynylsulfonyl group;
(51) C 3-8 cycloalkyl sulfonyl group;
(52) C 3-8 cycloalkenyl sulfonyl group;
(53) C 6-14 arylsulfonyl group;
(54) C 3-8 cycloalkyl-C 1-6 alkylsulfonyl group;
(55) C 3-8 cycloalkenyl-C 1-6 alkylsulfonyl group;
(56) C 6-14 aryl-C 1-6 alkylsulfonyl group;
(57) 5 or 6 membered monocyclic aromatic heterocyclic sulfonyl group;
(58) 8- to 12-membered fused aromatic heterocyclic sulfonyl group;
(59) 3- to 8-membered monocyclic non-aromatic heterocyclic sulfonyl group;
(60) 8- to 12-membered fused non-aromatic heterocyclic sulfonyl group;
(61) (a) a halogen atom,
(b) 1 to selected from the three may be substituted by a halogen atom C 1-6 alkyl group, and (c) 1 to 3 of a C 1-6 alkoxy group optionally substituted by a halogen atom 5 or 6 membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents;
(62) (a) a halogen atom,
(b) 1 to selected from the three may be substituted by a halogen atom C 1-6 alkyl group, and (c) 1 to 3 of a C 1-6 alkoxy group optionally substituted by a halogen atom 8 to 12-membered fused aromatic heterocyclic group optionally substituted with 1 to 3 substituents;
(63) (a) a halogen atom,
(b) a C 1-6 alkyl group which may be substituted by 1 to 3 halogen atoms or hydroxy group,
(c) 3 to 8 optionally substituted by 1 to 3 substituents selected from C 1-6 alkoxy groups optionally substituted by 1 to 3 halogen atoms, and (d) oxo group -Membered monocyclic non-aromatic heterocyclic group;
(64) (a) a halogen atom,
(b) a C 1-6 alkyl group which may be substituted by 1 to 3 halogen atoms,
(c) 8 to 12 optionally substituted by 1 to 3 substituents selected from C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, and (d) oxo group Membered fused non-aromatic heterocyclic groups;
(65) 5- or 6-membered monocyclic aromatic heterocyclic oxy group;
(66) 8- to 12-membered fused aromatic heterocyclic oxy group;
(67) 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group;
(68) 8- to 12-membered fused non-aromatic heterocyclic oxy group;
(69) a carboxy group;
(70) C 1-6 alkoxy-carbonyl group;
(71) C 2-6 alkenyloxy-carbonyl group;
(72) C 2-6 alkynyloxy-carbonyl group;
(73) C 3-8 cycloalkyloxy-carbonyl group;
(74) C 3-8 cycloalkenyloxy-carbonyl group;
(75) C 6-14 aryloxy-carbonyl group;
(76) C 3-8 cycloalkyl-C 1-6 alkoxy-carbonyl group;
(77) C 3-8 cycloalkenyl-C 1-6 alkoxy-carbonyl group;
(78) C 7-14 aralkyloxy-carbonyl group;
(79) mono C 1-6 alkylthiocarbamoyl group;
(80) di C 1-6 alkylthiocarbamoyl group;
(81) C 1-6 alkyl-carbonyloxy group;
(82) an imino group which may be substituted with a hydroxy group;
(83) C 1-6 alkylenedioxy group.
　本明細書中、「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。 In the present specification, the "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
　本明細書中、「Ｃ１－６アルキル基」とは、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、イソペンチル、ネオペンチル、１－エチルプロピル、ヘキシル、イソヘキシル、１，１－ジメチルブチル、２，２－ジメチルブチル、３，３－ジメチルブチル、２－エチルブチル、１，２－ジメチルプロピル等を示す。 In the present specification, the “C 1-6 alkyl group” means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like.
　本明細書中、「Ｃ１－６アルコキシ基」とは、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ｔｅｒｔ－ブトキシ、ペンチルオキシ、イソペンチルオキシ、へキシルオキシ等を示す。
　本明細書中、「Ｃ２－６アルケニルオキシ基」とは、例えば、ビニルオキシ、１－プロペニルオキシ、２－プロペニルオキシ、２－メチル－１－プロペニルオキシ、１－ブテニルオキシ、２－ブテニルオキシ、３－ブテニルオキシ、３－メチル－２－ブテニルオキシ、１－ペンテニルオキシ、２－ペンテニルオキシ、３－ペンテニルオキシ、４－ペンテニルオキシ、４－メチル－３－ペンテニルオキシ、１－ヘキセニルオキシ、３－ヘキセニルオキシ、５－ヘキセニルオキシ等を示す。
　本明細書中、「Ｃ２－６アルキニルオキシ基」とは、例えば、エチニルオキシ、１－プロピニルオキシ、２－プロピニルオキシ、１－ブチニルオキシ、２－ブチニルオキシ、３－ブチニルオキシ、１－ペンチニルオキシ、２－ペンチニルオキシ、３－ペンチニルオキシ、４－ペンチニルオキシ、１，１－ジメチルプロプ－２－イン－１－イルオキシ、１－ヘキシニルオキシ、２－ヘキシニルオキシ、３－ヘキシニルオキシ、４－ヘキシニルオキシ、５－ヘキシニルオキシ等を示す。 In the present specification, “C 1-6 alkoxy group” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and the like Show.
In the present specification, the “C 2-6 alkenyloxy group” is, for example, vinyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3- Butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexenyloxy, 5 -Hexenyloxy etc. are shown.
In the present specification, the “C 2-6 alkynyloxy group” means, for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy, 2-butynyloxy, 3-butynyloxy, 1-pentynyloxy, 2-Pentynyloxy, 3-Pentynyloxy, 4-Pentynyloxy, 1,1-Dimethylprop-2-yn-1-yloxy, 1-Hexynyloxy, 2-Hexynyloxy, 3-Hexynyloxy, 4-Hexynyloxy, 5 -Hexynyloxy etc. are shown.
　本明細書中、「Ｃ１－６アルコキシ－カルボニル基」とは、例えば、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等を示す。
　本明細書中、「Ｃ２－６アルケニルオキシ－カルボニル基」としては、例えば、ビニルオキシカルボニル、プロペニルオキシカルボニル、ブテニルオキシカルボニル、ペンテニルオキシカルボニル、へキセニルオキシカルボニル等を示す。
　本明細書中、「Ｃ２－６アルキニルオキシ－カルボニル基」としては、例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル、ブチニルオキシカルボニル、ペンチニルオキシカルボニル、ヘキシニルオキシカルボニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキルオキシ－カルボニル基」としては、例えば、シクロプロピルオキシカルボニル、シクロブチルオキシカルボニル、シクロペンチルオキシカルボニル、シクロヘキシルオキシカルボニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニルオキシ－カルボニル基」としては、例えば、シクロプロペニルオキシカルボニル、シクロブテニルオキシカルボニル、シクロペンテニルオキシカルボニル、シクロヘキセニルオキシカルボニル等を示す。
　本明細書中、「Ｃ６－１４アリールオキシ－カルボニル基」としては、例えば、フェノキシカルボニル、１－ナフチルオキシカルボニル、２－ナフチルオキシカルボニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキル－Ｃ１－６アルコキシ－カルボニル基」としては、例えば、シクロプロピルメチルオキシカルボニル、シクロプロピルエチルオキシカルボニル、シクロブチルメチルオキシカルボニル、シクロペンチルメチルオキシカルボニル、シクロヘキシルメチルオキシカルボニル、シクロヘキシルエチルオキシカルボニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニル－Ｃ１－６アルコキシ－カルボニル基」としては、例えば、シクロペンテニルメチルオキシカルボニル、シクロヘキセニルメチルオキシカルボニル、シクロヘキセニルエチルオキシカルボニル、シクロヘキセニルプロピルオキシカルボニル等を示す。
　本明細書中、「Ｃ７－１４アラルキルオキシ－カルボニル基」としては、例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル等を示す。
　本明細書中、「モノＣ１－６アルキルチオカルバモイル基」としては、例えば、メチルチオカルバモイル、エチルチオカルバモイル、プロピルチオカルバモイル等を示す。
　本明細書中、「ジＣ１－６アルキルチオカルバモイル基」としては、例えば、ジメチルチオカルバモイル、ジエチルチオカルバモイル、ジプロピルチオカルバモイル等を示す。
　本明細書中、「Ｃ１－６アルキル－カルボニルオキシ基」としては、例えば、アセチルオキシ、プロパノイルオキシ、ブタノイルオキシ、２－メチルプロパノイルオキシ等を示す。
　本明細書中、「Ｃ１－６アルキレンジオキシ基」としては、例えば、メチレンジオキシ、エチレンジオキシ等を示す。
　本明細書中、「Ｃ１－６アルキル－カルボニル基」とは、例えば、アセチル、プロパノイル、ブタノイル、２－メチルプロパノイル等を示す。 In the present specification, the “C 1-6 alkoxy-carbonyl group” means, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.
In the present specification, examples of the “C 2-6 alkenyloxy-carbonyl group” include vinyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl and the like.
In the present specification, examples of the "C 2-6 alkynyloxy-carbonyl group" include ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl and the like.
In the present specification, examples of the “C 3-8 cycloalkyloxy-carbonyl group” include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like.
In the present specification, examples of the “C 3-8 cycloalkenyloxy-carbonyl group” include cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl and the like.
In the present specification, examples of the “C 6-14 aryloxy-carbonyl group” include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
In the present specification, examples of the "C 3-8 cycloalkyl-C 1-6 alkoxy-carbonyl group" include cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, And cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl and the like.
In the present specification, examples of the “C 3-8 cycloalkenyl-C 1-6 alkoxy-carbonyl group” include cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl Etc.
In the present specification, examples of the "C 7-14 aralkyloxy-carbonyl group" include benzyloxycarbonyl, phenethyloxycarbonyl and the like.
In the present specification, examples of the “mono C 1-6 alkylthiocarbamoyl group” include methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl and the like.
In the present specification, examples of the “di C 1-6 alkylthiocarbamoyl group” include dimethylthiocarbamoyl, diethylthiocarbamoyl, dipropylthiocarbamoyl and the like.
In the present specification, examples of “C 1-6 alkyl-carbonyloxy group” include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy and the like.
In the present specification, as the "C 1-6 alkylenedioxy group", for example, methylenedioxy, ethylenedioxy and the like are shown.
In the present specification, the “C 1-6 alkyl-carbonyl group” means, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl and the like.
　本明細書中、「Ｃ１－６アルキルスルホニル基」とは、例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、イソブチルスルホニル、ｔｅｒｔ－ブチルスルホニル等を示す。
　本明細書中、「Ｃ２－６アルケニルスルホニル基」とは、例えば、ビニルスルホニル、プロペニルスルホニル等を示す。
　本明細書中、「Ｃ２－６アルキニルスルホニル基」とは、例えば、エチニルスルホニル、プロピニルスルホニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキルスルホニル基」とは、例えば、シクロプロピルスルホニル、シクロブチルスルホニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニルスルホニル基」とは、例えば、シクロプロペニルスルホニル、シクロブテニルスルホニル等を示す。
　本明細書中、「Ｃ６－１４アリールスルホニル基」としては、例えば、フェニルスルホニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキル－Ｃ１－６アルキルスルホニル基」としては、例えば、シクロプロピルメチルスルホニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニル－Ｃ１－６アルキルスルホニル基」としては、例えば、シクロペンテニルメチルスルホニル等を示す。
　本明細書中、「Ｃ６－１４アリール－Ｃ１－６アルキルスルホニル基」としては、例えば、ベンジルスルホニル等を示す。
　本明細書中、「５または６員の単環式芳香族複素環スルホニル基」としては、例えば、フリルスルホニル、チエニルスルホニル、ピリジルスルホニル等を示す。
　本明細書中、「８ないし１２員の縮合芳香族複素環スルホニル基」としては、例えば、ベンゾフラニルスルホニル、イソベンゾフラニルスルホニル等を示す。
　本明細書中、「３ないし８員の単環式非芳香族複素環スルホニル基」としては、例えば、オキシラニルスルホニル、アゼチジニルスルホニル等を示す。
　本明細書中、「８ないし１２員の縮合非芳香族複素環スルホニル基」としては、例えば、ジヒドロベンゾフラニルスルホニル等を示す。 In the present specification, the “C 1-6 alkylsulfonyl group” means, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl and the like.
In the present specification, the “C 2-6 alkenylsulfonyl group” means, for example, vinylsulfonyl, propenylsulfonyl and the like.
In the present specification, the “C 2-6 alkynylsulfonyl group” means, for example, ethynylsulfonyl, propynylsulfonyl and the like.
In the present specification, the “C 3-8 cycloalkylsulfonyl group” means, for example, cyclopropylsulfonyl, cyclobutylsulfonyl and the like.
In the present specification, the “C 3-8 cycloalkenylsulfonyl group” means, for example, cyclopropenylsulfonyl, cyclobutenylsulfonyl and the like.
In the present specification, as the "C 6-14 arylsulfonyl group", for example, phenylsulfonyl and the like are shown.
In the present specification, as the "C 3-8 cycloalkyl-C 1-6 alkylsulfonyl group", for example, cyclopropylmethylsulfonyl and the like are shown.
In the present specification, as the "C 3-8 cycloalkenyl-C 1-6 alkylsulfonyl group", for example, cyclopentenylmethylsulfonyl and the like are shown.
In the present specification, as the "C 6-14 aryl-C 1-6 alkylsulfonyl group", for example, benzylsulfonyl and the like are shown.
In the present specification, examples of "5- or 6-membered monocyclic aromatic heterocyclic sulfonyl group" include furyl sulfonyl, thienyl sulfonyl, pyridyl sulfonyl and the like.
In the present specification, examples of the “8 to 12-membered fused aromatic heterocyclic sulfonyl group” include benzofuranylsulfonyl, isobenzofuranylsulfonyl and the like.
In the present specification, examples of “3- to 8-membered monocyclic non-aromatic heterocyclic sulfonyl group” include oxiranyl sulfonyl, azetidinyl sulfonyl and the like.
In the present specification, examples of the “8 to 12-membered fused non-aromatic heterocyclic sulfonyl group” include dihydrobenzofuranylsulfonyl and the like.
　本明細書中、「Ｃ１－６アルキルスルファニル基」としては、例えば、メチルスルファニル、エチルスルファニル等を示す。
　本明細書中、「Ｃ２－６アルケニルスルファニル基」としては、例えば、ビニルスルファニル、プロペニルスルファニル等を示す。
　本明細書中、「Ｃ２－６アルキニルスルファニル基」としては、例えば、エチニルスルファニル、プロピニルスルファニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキルスルファニル基」としては、例えば、シクロプロピルスルファニル、シクロブチルスルファニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニルスルファニル基」としては、例えば、シクロプロペニルスルファニル、シクロブテニルスルファニル等を示す。
　本明細書中、「Ｃ６－１４アリールスルファニル基」としては、例えば、フェニルスルファニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキル－Ｃ１－６アルキルスルファニル基」としては、例えば、シクロプロピルメチルスルファニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニル－Ｃ１－６アルキルスルファニル基」としては、例えば、シクロペンテニルメチルスルファニル等を示す。 In the present specification, as the "C 1-6 alkylsulfanyl group", for example, methylsulfanyl, ethylsulfanyl and the like are shown.
In the present specification, as the "C 2-6 alkenylsulfanyl group", for example, vinylsulfanyl, propenylsulfanyl and the like are shown.
In the present specification, as the "C 2-6 alkynylsulfanyl group", for example, ethynylsulfanyl, propynylsulfanyl and the like are shown.
In the present specification, as the “C 3-8 cycloalkylsulfanyl group”, for example, cyclopropylsulfanyl, cyclobutylsulfanyl and the like are shown.
In the present specification, as the "C 3-8 cycloalkenylsulfanyl group", for example, cyclopropenylsulfanyl, cyclobutenylsulfanyl and the like are shown.
In the present specification, as the "C 6-14 arylsulfanyl group", for example, phenylsulfanyl and the like are shown.
In the present specification, as the "C 3-8 cycloalkyl-C 1-6 alkylsulfanyl group", for example, cyclopropylmethylsulfanyl and the like are shown.
In the present specification, as the "C 3-8 cycloalkenyl-C 1-6 alkylsulfanyl group", for example, cyclopentenylmethylsulfanyl and the like are shown.
　本明細書中、「Ｃ１－６アルキルスルフィニル基」としては、例えば、メチルスルフィニル、エチルスルフィニル等を示す。
　本明細書中、「Ｃ２－６アルケニルスルフィニル基」としては、例えば、ビニルスルフィニル、プロペニルスルフィニル等を示す。
　本明細書中、「Ｃ２－６アルキニルスルフィニル基」としては、例えば、エチニルスルフィニル、プロピニルスルフィニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキルスルフィニル基」としては、例えば、シクロプロピルスルフィニル、シクロブチルスルフィニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニルスルフィニル基」としては、例えば、シクロプロペニルスルフィニル、シクロブテニルスルフィニル等を示す。
　本明細書中、「Ｃ６－１４アリールスルフィニル基」としては、例えば、フェニルスルフィニル等を示す。
　本明細書中、「Ｃ３－８シクロアルキル－Ｃ１－６アルキルスルフィニル基」としては、例えば、シクロプロピルメチルスルフィニル等を示す。
　本明細書中、「Ｃ３－８シクロアルケニル－Ｃ１－６アルキルスルフィニル基」としては、例えば、シクロペンテニルメチルスルフィニル等を示す。 In the present specification, as the “C 1-6 alkylsulfinyl group”, for example, methylsulfinyl, ethylsulfinyl and the like are shown.
In the present specification, examples of the "C 2-6 alkenylsulfinyl group" include vinylsulfinyl, propenylsulfinyl and the like.
In the present specification, as the “C 2-6 alkynylsulfinyl group”, for example, ethynylsulfinyl, propynylsulfinyl and the like are shown.
In the present specification, examples of the "C 3-8 cycloalkylsulfinyl group" include cyclopropylsulfinyl, cyclobutylsulfinyl and the like.
In the present specification, as the "C 3-8 cycloalkenylsulfinyl group", for example, cyclopropenylsulfinyl, cyclobutenylsulfinyl and the like are shown.
In the present specification, as the "C 6-14 arylsulfinyl group", for example, phenylsulfinyl and the like are shown.
In the present specification, as the "C 3-8 cycloalkyl-C 1-6 alkylsulfinyl group", for example, cyclopropylmethylsulfinyl and the like are shown.
In the present specification, as the “C 3-8 cycloalkenyl-C 1-6 alkylsulfinyl group”, for example, cyclopentenylmethylsulfinyl and the like are shown.
　本明細書中、「Ｃ３－８シクロアルキル基」とは、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等を示す。なかでも、Ｃ３－６シクロアルキル基（例、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル）が好ましい。 In the present specification, the “C 3-8 cycloalkyl group” means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Among them, a C 3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) is preferable.
　本明細書中、「Ｃ３－８シクロアルケニル基」とは、例えば、シクロプロペニル（例、２－シクロプロペン－１－イル）、シクロブテニル（例、２－シクロブテン－１－イル）、シクロペンテニル（例、２－シクロペンテン－１－イル、３－シクロペンテン－１－イル）、シクロヘキセニル（例、２－シクロヘキセン－１－イル、３－シクロヘキセン－１－イル）、シクロヘプテニル（例、２－シクロヘプテン－１－イル、３－シクロヘプテン－１－イル）、シクロオクテニル（例、２－シクロオクテン－１－イル、３－シクロオクテン－１－イル）等を示す。なかでも、Ｃ３－６シクロアルケニル基（例、、シクロプロペニル（例、２－シクロプロペン－１－イル）、シクロブテニル（例、２－シクロブテン－１－イル）、シクロペンテニル（例、２－シクロペンテン－１－イル、３－シクロペンテン－１－イル）、シクロヘキセニル（例、２－シクロヘキセン－１－イル、３－シクロヘキセン－１－イル））が好ましい。 In the present specification, the “C 3-8 cycloalkenyl group” means, for example, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclopentenyl (eg, 2-cyclobuten-1-yl) For example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (eg, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl), cycloheptenyl (eg, 2-cycloheptene-1) -Yl, 3-cyclohepten-1-yl), cyclooctenyl (eg, 2-cycloocten-1-yl, 3-cycloocten-1-yl) and the like. Among them, C 3-6 cycloalkenyl group (eg, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobuten-1-yl), cyclopentenyl (eg, 2-cyclopentene) -1-yl, 3-cyclopenten-1-yl) and cyclohexenyl (eg, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl)) are preferred.
　本明細書中、「Ｃ３－８シクロアルキルオキシ基」とは、例えば、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシ等を示す。
　本明細書中、「Ｃ３－８シクロアルケニルオキシ基」とは、例えば、シクロプロペニルオキシ（例、２－シクロプロペン－１－イルオキシ）、シクロブテニルオキシ（例、２－シクロブテン－１－イルオキシ）、シクロペンテニルオキシ（例、２－シクロペンテン－１－イルオキシ、３－シクロペンテン－１－イルオキシ）、シクロヘキセニルオキシ（例、２－シクロヘキセン－１－イルオキシ、３－シクロヘキセン－１－イルオキシ）等を示す。 In the present specification, the “C 3-8 cycloalkyloxy group” means, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
In the present specification, the “C 3-8 cycloalkenyloxy group” is, for example, cyclopropenyloxy (eg, 2-cyclopropen-1-yloxy), cyclobutenyloxy (eg, 2-cyclobuten-1-yloxy) And cyclopentenyloxy (eg, 2-cyclopenten-1-yloxy, 3-cyclopenten-1-yloxy), cyclohexenyloxy (eg, 2-cyclohexen-1-yloxy, 3-cyclohexen-1-yloxy), etc. .
　本明細書中、「Ｃ６－１４アリール基」とは、例えば、フェニル、１－ナフチル、２－ナフチル等を示す。なかでも、Ｃ６－１０アリール基が好ましい。
　本明細書中、「Ｃ６－１４アリールオキシ基」とは、例えば、フェノキシ、１－ナフチルオキシ、２－ナフチルオキシ等を示す。
　本明細書中、「Ｃ７－１４アラルキルオキシ基」とは、例えば、ベンジルオキシ、フェネチルオキシ等を示す。 In the present specification, the “C 6-14 aryl group” means, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. Among them, a C 6-10 aryl group is preferable.
In the present specification, the “C 6-14 aryloxy group” means, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
In the present specification, the “C 7-14 aralkyloxy group” means, for example, benzyloxy, phenethyloxy and the like.
　本明細書中、「５または６員の単環式芳香族複素環基」としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子（酸化されていてもよい）および窒素原子（酸化されていてもよい）から選ばれるヘテロ原子を１ないし４個含有する、５または６員の単環式芳香族複素環基、例えば、フリル（例、２－フリル、３－フリル）、チエニル（例、２－チエニル、３－チエニル）、ピリジル（例、２－ピリジル、３－ピリジル、４－ピリジル）、ピリミジニル（例、２－ピリミジニル、４－ピリミジニル、５－ピリミジニル）、ピリダジニル（例、３－ピリダジニル、４－ピリダジニル）、ピラジニル（例、２－ピラジニル）、ピロリル（例、１－ピロリル、２－ピロリル、３－ピロリル）、イミダゾリル（例、１－イミダゾリル、２－イミダゾリル、４－イミダゾリル、５－イミダゾリル）、ピラゾリル（例、１－ピラゾリル、３－ピラゾリル、４－ピラゾリル）、チアゾリル（例、２－チアゾリル、４－チアゾリル、５－チアゾリル）、イソチアゾリル（例、３－イソチアゾリル、４－イソチアゾリル、５－イソチアゾリル）、オキサゾリル（例、２－オキサゾリル、４－オキサゾリル、５－オキサゾリル）、イソオキサゾリル（例、３－イソオキサゾリル、４－イソオキサゾリル、５－イソオキサゾリル）、オキサジアゾリル（例、１，２，４－オキサジアゾール－５－イル、１，３，４－オキサジアゾール－２－イル）、チアジアゾリル（例、１，３，４－チアジアゾール－２－イル）、トリアゾリル（例、１，２，４－トリアゾール－１－イル、１，２，４－トリアゾール－３－イル、１，２，３－トリアゾール－１－イル、１，２，３－トリアゾール－２－イル、１，２，３－トリアゾール－４－イル）、テトラゾリル（例、テトラゾール－１－イル、テトラゾール－５－イル）、トリアジニル（例、１，２，４－トリアジン－１－イル、１，２，４－トリアジン－３－イル）等が挙げられる。 In the present specification, examples of the “5- or 6-membered monocyclic aromatic heterocyclic group” include, as ring-constituting atoms, an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom (other than carbon atoms) 5 or 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a group that may be oxidized, for example, furyl (eg, 2-furyl, 3-furyl), thienyl (Eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl) 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g. , 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg For example, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg Eg 1,2,4-triazol-1-yl, 1,2,4- Liazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (eg, tetrazole-1) -Yl, tetrazol-5-yl), triazinyl (eg, 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and the like.
　本明細書中、「８ないし１０員の縮合芳香族複素環基」としては、例えば、上記５または６員の単環式芳香族複素環基に対応する環とベンゼン環とが縮合した環から誘導される基；上記５または６員の単環式芳香族複素環基に対応する環同士が縮合した環から誘導される基、例えば、キノリル（例、２－キノリル、３－キノリル、４－キノリル、６－キノリル）、イソキノリル（例、３－イソキノリル）、キナゾリル（例、２－キナゾリル、４－キナゾリル）、キノキサリル（例、２－キノキサリル、６－キノキサリル）、ベンゾフラニル（例、２－ベンゾフラニル、３－ベンゾフラニル）、ベンゾチエニル（例、２－ベンゾチエニル、３－ベンゾチエニル）、ベンズオキサゾリル（例、２－ベンズオキサゾリル）、ベンズイソオキサゾリル（例、７－ベンズイソオキサゾリル）、ベンゾチアゾリル（例、２－ベンゾチアゾリル）、ベンズイミダゾリル（例、ベンズイミダゾール－１－イル、ベンズイミダゾール－２－イル、ベンズイミダゾール－５－イル）、ベンゾトリアゾリル（例、１Ｈ－１，２，３－ベンゾトリアゾール－５－イル）、インドリル（例、インドール－１－イル、インドール－２－イル、インドール－３－イル、インドール－５－イル）、インダゾリル（例、１Ｈ－インダゾール－３－イル）、ピロロピラジニル（例、１Ｈ－ピロロ［２，３－ｂ］ピラジン－２－イル、１Ｈ－ピロロ［２，３－ｂ］ピラジン－６－イル）、イミダゾピリジル（例、１Ｈ－イミダゾ［４，５－ｂ］ピリジン－２－イル、１Ｈ－イミダゾ［４，５－ｃ］ピリジン－２－イル、２Ｈ－イミダゾ［１，２－ａ］ピリジン－３－イル）、チエノピリジル（例、チエノ［２，３－ｂ］ピリジン－３－イル）、イミダゾピラジニル（例、１Ｈ－イミダゾ［４，５－ｂ］ピラジン－２－イル）、ピラゾロピリジル（例、１Ｈ－ピラゾロ［４，３－ｃ］ピリジン－３－イル）、ピラゾロチエニル（例、２Ｈ－ピラゾロ［３，４－ｂ］チオフェン－２－イル）、ピラゾロトリアジニル（例、ピラゾロ［５，１－ｃ］［１，２，４］トリアジン－３－イル）等が挙げられる。 In the present specification, the “8 to 10-membered fused aromatic heterocyclic group” is, for example, a ring formed by condensing a ring corresponding to the 5- or 6-membered monocyclic aromatic heterocyclic group and a benzene ring Derived group; a group derived from a ring formed by condensation of the rings corresponding to the 5 or 6-membered monocyclic aromatic heterocyclic group, for example, quinolyl (eg, 2-quinolyl, 3-quinolyl, 4- 4- Quinolyl, 6-quinolyl), isoquinolyl (eg 3-isoquinolyl), quinazolyl (eg 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (eg 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), benzisoxazolyl (Eg 7-benzisoxazolyl), benzothiazolyl (eg 2-benzothiazolyl), benzimidazolyl (eg benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotria Soryl (eg, 1H-1,2,3-benzotriazol-5-yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), Indazolyl (eg, 1H-indazol-3-yl), pyrrolopyrazinyl (eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), Imidazopyridyl (eg, 1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2 -Imidazo [1,2-a] pyridin-3-yl), thienopyridyl (eg, thieno [2,3-b] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5- b) Pyrazin-2-yl), pyrazolopyridyl (eg, 1H-pyrazolo [4,3-c] pyridin-3-yl), pyrazolothienyl (eg, 2H-pyrazolo [3,4-b] thiophene-2-) And pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazin-3-yl) and the like.
　本明細書中、「３ないし８員の単環式非芳香族複素環基」としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子（酸化されていてもよい）および窒素原子（酸化されていてもよい）から選ばれるヘテロ原子を１ないし４個含有する、３ないし８員（好ましくは、５または６員）の単環式非芳香族複素環基、例えば、アゼチジニル（例、１－アゼチジニル、２－アゼチジニル）、ピロリジニル（例、１－ピロリジニル、２－ピロリジニル）、ピペリジル（例、ピペリジノ、２－ピペリジル、３－ピペリジル、４－ピペリジル）、モルホリニル（例、モルホリノ）、チオモルホリニル（例、チオモルホリノ）、ピペラジニル（例、１－ピペラジニル、２－ピペラジニル、３－ピペラジニル）、オキサゾリジニル（例、オキサゾリジン－２－イル）、チアゾリジニル（例、チアゾリジン－２－イル）、ジヒドロチオピラニル（例、ジヒドロチオピラン－３－イル、ジヒドロチオピラン－４－イル）、イミダゾリジニル（例、イミダゾリジン－２－イル、イミダゾリジン－３－イル）、オキサゾリニル（例、オキサゾリン－２－イル）、チアゾリニル（例、チアゾリン－２－イル）、イミダゾリニル（例、イミダゾリン－２－イル、イミダゾリン－３－イル）、ジオキソリル（例、１，３－ジオキソール－４－イル）、ジオキソラニル（例、１，３－ジオキソラン－４－イル）、ジヒドロオキサジアゾリル（例、４，５－ジヒドロ－１，２，４－オキサジアゾール－３－イル）、ピラニル（例、２－ピラニル、４－ピラニル）、ジヒドロピラニル（例、ジヒドロピラン－３－イル、ジヒドロピラン－４－イル）、テトラヒドロピラニル（例、２－テトラヒドロピラニル、３－テトラヒドロピラニル、４－テトラヒドロピラニル）、チオピラニル（例、４－チオピラニル）、テトラヒドロチオピラニル（例、２－テトラヒドロチオピラニル、３－テトラヒドロチオピラニル、４－テトラヒドロチオピラニル）、１－オキシドテトラヒドロチオピラニル（例、１－オキシドテトラヒドロチオピラン－４－イル）、１，１－ジオキシドテトラヒドロチオピラニル（例、１，１－ジオキシドテトラヒドロチオピラン－４－イル）、テトラヒドロフリル（例、テトラヒドロフラン－３－イル、テトラヒドロフラン－２－イル）、オキセタニル（例、オキセタン－２－イル、オキセタン－３－イル）、ピラゾリジニル（例、ピラゾリジン－１－イル、ピラゾリジン－３－イル）、ピラゾリニル（例、ピラゾリン－１－イル）、テトラヒドロピリミジニル（例、テトラヒドロピリミジン－１－イル）、ジヒドロトリアゾリル（例、２，３－ジヒドロ－１Ｈ－１，２，３－トリアゾール－１－イル）、テトラヒドロトリアゾリル（例、２，３，４，５－テトラヒドロ－１Ｈ－１，２，３－トリアゾール－１－イル）、アゼパニル（例、１－アゼパニル、２－アゼパニル、３－アゼパニル、４－アゼパニル）、ジヒドロピリジル（例、ジヒドロピリジン－１－イル、ジヒドロピリジン－２－イル、ジヒドロピリジン－３－イル、ジヒドロピリジン－４－イル）、テトラヒドロピリジル（例、１，２，３，４－テトラヒドロピリジン－１－イル、１，２，３，４－テトラヒドロピリジン－２－イル、１，２，３，４－テトラヒドロピリジン－３－イル、１，２，３，４－テトラヒドロピリジン－４－イル）等が挙げられる。 In the present specification, examples of the “3- to 8-membered monocyclic non-aromatic heterocyclic group” include, as ring-constituting atoms, an oxygen atom, a sulfur atom (which may be oxidized) and a nitrogen atom in addition to carbon atoms. 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing 1 to 4 hetero atoms selected from (which may be oxidized), for example, azetidinyl (eg 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidyl (eg, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), morpholinyl (eg, morpholino), thiomorpholinyl (Eg thiomorpholino), piperazinyl (eg 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), oxazolidinyl (eg oxa Lysine-2-yl), thiazolidinyl (eg thiazolidin-2-yl), dihydrothiopyranyl (eg dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazolidinyl (eg imidazolidine-2) -Yl, imidazolidin-3-yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazolin-2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), Dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxaxyl) Diazol-3-yl), pyranyl (eg, 2-pyranyl, 4-pyranyl), dihydropyranyl (eg, dihydropyran) 3-yl, dihydropyran-4-yl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), tetrahydrothiopyranyl (Eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxide tetrahydrothiopyranyl (eg, 1-oxide tetrahydrothiopyran-4-yl), 1,1 -Dioxide tetrahydrothiopyranyl (eg, 1,1-dioxide tetrahydrothiopyran-4-yl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), oxetanyl (eg, oxetane-2 -Yl, oxetan-3-yl), pyrazolidinyl (eg, Pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, tetrahydropyrimidin-1-yl), dihydrotriazolyl (eg, 2,3-dihydro-) 1H-1,2,3-triazol-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl), azepanyl (eg, , 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (eg, dihydropyridin-1-yl, dihydropyridin-2-yl, dihydropyridin-3-yl, dihydropyridin-4-yl), tetrahydropyridyl (Eg, 1,2,3,4-tetrahydropyridin-1-yl, 1,2,3,4-tetraphenyl) Ropirijin 2-yl, 1,2,3,4-tetrahydropyridin-3-yl, 4-1,2,3,4-tetrahydropyridin-yl), and the like.
　本明細書中、「８ないし１２員の縮合非芳香族複素環基」としては、例えば、上記３ないし８員の単環式非芳香族複素環基に対応する環とベンゼン環とが縮合した環から誘導される基；上記３ないし８員の単環式非芳香族複素環基に対応する環同士が縮合した環から誘導される基；上記３ないし８員の単環式非芳香族複素環基に対応する環と上記５または６員の単環式芳香族複素環基に対応する環とが縮合した環から誘導される基；これらの基の部分飽和により得られる基、例えば、ジヒドロインドリル（例、２，３－ジヒドロ－１Ｈ－インドール－１－イル）、ジヒドロイソインドリル（例、１，３－ジヒドロ－２Ｈ－イソインドール－２－イル）、ジヒドロベンゾフラニル（例、２，３－ジヒドロ－１－ベンゾフラン－５－イル）、テトラヒドロベンゾフラニル（例、４，５，６，７－テトラヒドロ－１－ベンゾフラン－３－イル）、ジヒドロベンゾジオキシニル（例、２，３－ジヒドロ－１，４－ベンゾジオキシン－２－イル）、ジヒドロベンゾジオキセピニル（例、３，４－ジヒドロ－２Ｈ－１，５－ベンゾジオキセピン－２－イル）、クロメニル（例、４Ｈ－クロメン－２－イル、２Ｈ－クロメン－３－イル）、ジヒドロクロメニル（例、３，４－ジヒドロ－２Ｈ－クロメン－２－イル）、ジヒドロキノリニル（例、１，２－ジヒドロキノリン－４－イル）、テトラヒドロキノリニル（例、１，２，３，４－テトラヒドロキノリン－４－イル）、ジヒドロイソキノリニル（例、１，２－ジヒドロイソキノリン－４－イル）、テトラヒドロイソキノリニル（例、１，２，３，４－テトラヒドロイソキノリン－４－イル）、ジヒドロフタラジニル（例、１，４－ジヒドロフタラジン－４－イル）等が挙げられる。 In the present specification, as the “8 to 12-membered fused non-aromatic heterocyclic group”, for example, a ring corresponding to the above-mentioned 3- to 8-membered monocyclic non-aromatic heterocyclic group and a benzene ring fused A group derived from a ring; a group derived from a ring formed by condensation of the rings corresponding to the above 3- to 8-membered monocyclic non-aromatic heterocyclic group; the above 3- to 8-membered monocyclic non-aromatic hetero ring A group derived from a ring formed by condensation of a ring corresponding to a ring group and a ring corresponding to the 5- or 6-membered monocyclic aromatic heterocyclic group; a group obtained by partial saturation of these groups, for example, dihydro Indolyl (eg, 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (eg, 2,3-dihydro-1-benzofuran-5-yl), Rahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4-benzodioxine-2) ), Dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5-benzodioxepin-2-yl), chromenyl (eg, 4H-chromen-2-yl, 2H-chromen- 3-yl), dihydrochromenyl (eg, 3,4-dihydro-2H-chromen-2-yl), dihydroquinolinyl (eg, 1,2-dihydroquinolin-4-yl), tetrahydroquinolinyl (eg, Examples: 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (eg 1,2,3, , 4-4-tetrahydroisoquinoline-yl), dihydrophthalazinyl (e.g., 1,4-dihydro-phthalazine-4-yl), and the like.
　本明細書中、「Ｃ２－６アルケニル－カルボニル基」としては、例えば、アクリロイル、ブテノイル、ペンテノイル、ヘキセノイル、ヘプテノイル等が挙げられる。
　本明細書中、「Ｃ２－６アルキニル－カルボニル基」としては、例えば、プロピオロイル、プロピニルカルボニル、ブチニルカルボニル、ペンチニルカルボニル、ヘキシニルカルボニル等が挙げられる。
　本明細書中、「Ｃ３－８シクロアルキル－カルボニル基」としては、例えば、シクロプロピルカルボニル、シクロブチルカルボニル、シクロペンチルカルボニル、シクロヘキシルカルボニル等が挙げられる。
　本明細書中、「Ｃ３－８シクロアルケニル－カルボニル基」としては、例えば、シクロプロペニルカルボニル、シクロブテニルカルボニル、シクロペンテニルカルボニル、シクロヘキセニルカルボニル等が挙げられる。
　本明細書中、「Ｃ６－１４アリール－カルボニル基」としては、例えば、ベンゾイル、１－ナフチルカルボニル、２－ナフチルカルボニル等が挙げられる。
　本明細書中、「Ｃ３－８シクロアルキル－Ｃ１－６アルキル－カルボニル基」としては、例えば、シクロプロピルアセチル、３－シクロプロピルプロピオニル、シクロブチルアセチル、シクロペンチルアセチル、シクロヘキシルアセチル、３－シクロヘキシルプロピオニル等が挙げられる。
　本明細書中、「Ｃ３－８シクロアルケニル－Ｃ１－６アルキル－カルボニル基」としては、例えば、シクロペンテニルアセチル、シクロヘキセニルアセチル、３－シクロヘキセニルプロピオニル、３－シクロヘキセニルプロピオニル等が挙げられる。
　本明細書中、「Ｃ７－１４アラルキル－カルボニル基」としては、例えば、フェニルアセチル、３－フェニルプロピオニル等が挙げられる。
　本明細書中、「５または６員の単環式芳香族複素環カルボニル基」としては、例えば、フリルカルボニル、チエニルカルボニル、ピロリルカルボニル、オキサゾリルカルボニル、イソオキサゾリルカルボニル、チアゾリルカルボニル、イソチアゾリルカルボニル、イミダゾリルカルボニル、ピリジルカルボニル、ピラゾリルカルボニル等が挙げられる。
　本明細書中、「８ないし１２員の縮合芳香族複素環カルボニル基」としては、例えば、ベンゾフラニルカルボニル、イソベンゾフラニルカルボニル、ベンゾチエニルカルボニル、イソベンゾチエニルカルボニル、インドリルカルボニル、イソインドリルカルボニル、インダゾリルカルボニル、ベンズイミダゾリルカルボニル、ベンズオキサゾリルカルボニル等が挙げられる。
　本明細書中、「３ないし８員の単環式非芳香族複素環カルボニル基」としては、例えば、オキシラニルカルボニル、アゼチジニルカルボニル、オキセタニルカルボニル、チエタニルカルボニル、ピロリジニルカルボニル、テトラヒドロフリルカルボニル、チオラニルカルボニル、ピペリジルカルボニル等が挙げられる。
　本明細書中、「８ないし１２員の縮合非芳香族複素環カルボニル基」としては、例えば、ジヒドロベンゾフラニルカルボニル等が挙げられる。
　本明細書中、「５または６員の単環式芳香族複素環オキシ基」としては、例えば、フリルオキシ、チエニルオキシ、ピロリルオキシ、オキサゾリルオキシ、イソオキサゾリルオキシ、チアゾリルオキシ、イソチアゾリルオキシ、イミダゾリルオキシ、ピリジルオキシ、ピラゾリルオキシ等が挙げられる。
　本明細書中、「８ないし１２員の縮合芳香族複素環オキシ基」としては、例えば、ベンゾフラニルオキシ、イソベンゾフラニルオキシ、ベンゾチエニルオキシ、イソベンゾチエニルオキシ、インドリルオキシ、イソインドリルオキシ、インダゾリルオキシ、ベンズイミダゾリルオキシ、ベンズオキサゾリルオキシ等が挙げられる。
　本明細書中、「３ないし８員の単環式非芳香族複素環オキシ基」としては、例えば、オキシラニルオキシ、アゼチジニルオキシ、オキセタニルオキシ、チエタニルオキシ、ピロリジニルオキシ、テトラヒドロフリルオキシ、チオラニルオキシ、ピペリジルオキシ等が挙げられる。
　本明細書中、「８ないし１２員の縮合非芳香族複素環オキシ基」としては、例えば、ジヒドロベンゾフラニルオキシ等が挙げられる。 In the present specification, examples of the "C 2-6 alkenyl-carbonyl group" include acryloyl, butenoyl, pentenoyl, hexenoyl, heptenoyl and the like.
In the present specification, examples of the "C 2-6 alkynyl-carbonyl group" include propioloyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl and the like.
In the present specification, examples of the "C 3-8 cycloalkyl-carbonyl group" include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
In the present specification, examples of the "C 3-8 cycloalkenyl-carbonyl group" include cyclopropenyl carbonyl, cyclobutenyl carbonyl, cyclopentenyl carbonyl, cyclohexenyl carbonyl and the like.
In the present specification, examples of the "C 6-14 aryl-carbonyl group" include benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.
In the present specification, examples of the "C 3-8 cycloalkyl-C 1-6 alkyl-carbonyl group" include cyclopropylacetyl, 3-cyclopropylpropionyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, 3-cyclohexyl Propionyl and the like can be mentioned.
In the present specification, examples of the “C 3-8 cycloalkenyl-C 1-6 alkyl-carbonyl group” include cyclopentenyl acetyl, cyclohexenyl acetyl, 3-cyclohexenyl propionyl, 3-cyclohexenyl propionyl and the like. .
In the present specification, examples of the “C 7-14 aralkyl-carbonyl group” include phenylacetyl, 3-phenylpropionyl and the like.
In the present specification, examples of “5- or 6-membered monocyclic aromatic heterocyclic carbonyl group” include, for example, furyl carbonyl, thienyl carbonyl, pyrrolyl carbonyl, oxazolyl carbonyl, isoxazolyl carbonyl, thiazolyl And carbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl and the like.
In the present specification, examples of the “8 to 12-membered fused aromatic heterocyclic carbonyl group” include benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl, isoin Examples include drill carbonyl, indazolyl carbonyl, benzimidazolyl carbonyl, benzoxazolyl carbonyl and the like.
In the present specification, examples of “3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group” include oxiranyl carbonyl, azetidinyl carbonyl, oxetanyl carbonyl, thietanyl carbonyl, pyrrolidinyl carbonyl, tetrahydro Furyl carbonyl, thioranyl carbonyl, piperidyl carbonyl and the like.
In the present specification, examples of the “8 to 12-membered fused non-aromatic heterocyclic carbonyl group” include dihydrobenzofuranyl carbonyl and the like.
In the present specification, examples of “5 or 6-membered monocyclic aromatic heterocyclic oxy group” include, for example, furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyl And oxy, imidazolyloxy, pyridyloxy, pyrazolyloxy and the like.
In the present specification, as the “8 to 12-membered fused aromatic heterocyclic oxy group”, for example, benzofuranyloxy, isobenzofuranyloxy, benzothienyloxy, isobenzothienyloxy, indolyloxy, isoin Examples include doryloxy, indazolyloxy, benzimidazolyloxy, benzoxazolyloxy and the like.
In the present specification, examples of the “3- to 8-membered monocyclic non-aromatic heterocyclic oxy group” include oxiranyloxy, azetidinyloxy, oxetanyloxy, thiethanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy , Thioranyloxy, piperidyl oxy and the like.
In the present specification, examples of the “8 to 12-membered fused non-aromatic heterocyclic oxy group” include dihydrobenzofuranyloxy and the like.
　以下、式（Ｉ）の各記号について説明する。 Hereinafter, each symbol of Formula (I) is demonstrated.
　式（Ｉ）におけるＲ１は、水素原子または置換基を示す。Ｒ１としては、水素原子が好ましい。 R 1 in Formula (I) represents a hydrogen atom or a substituent. As R 1 , a hydrogen atom is preferable.
　式（Ｉ）におけるＲ２は、水素原子または置換基を示す。Ｒ２としては、水素原子が好ましい。 R 2 in the formula (I) represents a hydrogen atom or a substituent. As R 2 , a hydrogen atom is preferable.
　式（Ｉ）におけるＲ３は、水素原子または置換基を示す。Ｒ３としては、
(a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基（例、フェニル）、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基（例、アセチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、ピロリジニル）、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基（例、アゼチジニルカルボニル、ピペラジニルカルボニル）、および(vi) ジＣ１－６アルキルアミノ基（例、ジメチルアミノ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、イソブチル）、
(b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基（例、メチル）、および(iii) Ｃ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基（例、シクロペンチル、シクロヘキシル）、
(c) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール基、
(d) ５または６員の単環式芳香族複素環基、
(e) ８ないし１２員の縮合芳香族複素環基、
(f) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）、
(g) ８ないし１２員の縮合非芳香族複素環基、
(h) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル－カルボニル基、
(i) Ｃ３－８シクロアルキル－カルボニル基、
(j) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール－カルボニル基、
(k) ５または６員の単環式芳香族複素環カルボニル基、
(l) ８ないし１２員の縮合芳香族複素環カルボニル基、
(m) ３ないし８員の単環式非芳香族複素環カルボニル基、および
(n) ８ないし１２員の縮合非芳香族複素環カルボニル基
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基が好ましい。
　なかでも、Ｒ３としては、
(a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基（例、フェニル）、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基（例、アセチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、ピロリジニル）、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基（例、アゼチジニルカルボニル、ピペラジニルカルボニル）、および(vi) ジＣ１－６アルキルアミノ基（例、ジメチルアミノ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、イソブチル）、
(b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基（例、メチル）、および(iii) Ｃ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基（例、シクロペンチル、シクロヘキシル）、および
(c) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基が好ましい。 R 3 in Formula (I) represents a hydrogen atom or a substituent. As R 3 ,
(a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidinyl carbonyl, piperazinyl carbonyl), and (vi) di C 1-6 alkylamino group (eg, dimethylamino) a C 1-6 alkyl group (e.g. also methyl, ethyl, propyl, isopropyl Le, isobutyl),
(b) (i) a hydroxy group, (ii) a C 1-6 alkyl group (eg, methyl) which may be substituted by 1 to 3 hydroxy groups, and (iii) a C 6-14 aryl group (eg C 3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from
(c) a C 6-14 aryl group which may be substituted by 1 to 3 halogen atoms,
(d) 5- or 6-membered monocyclic aromatic heterocyclic group,
(e) 8- to 12-membered fused aromatic heterocyclic groups,
(f) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl),
(g) 8- to 12-membered fused non-aromatic heterocyclic groups,
(h) a C 1-6 alkyl-carbonyl group which may be substituted by 1 to 3 halogen atoms,
(i) C 3-8 cycloalkyl-carbonyl group,
(j) a C 6-14 aryl-carbonyl group which may be substituted by 1 to 3 halogen atoms,
(k) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(l) 8- to 12-membered fused aromatic heterocyclic carbonyl group,
(m) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group, and
(n) Preferred is an amino group which may be mono- or di-substituted with a substituent selected from 8- to 12-membered fused non-aromatic heterocyclic carbonyl groups.
Among them, as R 3 ,
(a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidinyl carbonyl, piperazinyl carbonyl), and (vi) di C 1-6 alkylamino group (eg, dimethylamino) a C 1-6 alkyl group (e.g. also methyl, ethyl, propyl, isopropyl Le, isobutyl),
(b) (i) a hydroxy group, (ii) a C 1-6 alkyl group (eg, methyl) which may be substituted by 1 to 3 hydroxy groups, and (iii) a C 6-14 aryl group (eg And C 3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from phenyl, and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
Preferred is an amino group which may be mono- or di-substituted with a substituent selected from
　式（Ｉ）におけるＲ４は、水素原子または置換基を示す。Ｒ４としては、
(1) シアノ基；
(2) (a) (i) Ｃ３－８シクロアルキル基（例、シクロペンチル）、(ii) Ｃ１－６アルコキシ基（例、メトキシ）および(iii) １ないし3個のＣ１－６アルキル基（例、メチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、オキセタニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、sec-ブチル）、
　　(b) Ｃ３－８シクロアルキル基（例、シクロペンチル）、
　　(c) Ｃ６－１４アリール基、
　　(d) Ｃ１－６アルコキシ基、
　　(e) ５または６員の単環式芳香族複素環基、
　　(f) ８ないし１２員の縮合芳香族複素環基、
　　(g) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）、および
　　(h) ８ないし１２員の縮合非芳香族複素環基
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；または、
(3) Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル）が好ましい。
　なかでも、Ｒ４としては、
(1) シアノ基；
(2) (a) (i) Ｃ３－８シクロアルキル基（例、シクロプロピル）、(ii) Ｃ１－６アルコキシ基（例、メトキシ）および(iii) １ないし3個のＣ１－６アルキル基（例、メチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、オキセタニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、sec-ブチル）、
　　(b) Ｃ３－８シクロアルキル基（例、シクロプロピル）、および、
　　(c) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；または、
(3) Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル）が好ましい。 R 4 in the formula (I) represents a hydrogen atom or a substituent. As R 4 ,
(1) cyano group;
(2) (a) (i) C 3-8 cycloalkyl group (eg, cyclopentyl), (ii) C 1-6 alkoxy group (eg, methoxy) and (iii) 1 to 3 C 1-6 alkyls C 1 to C optionally substituted by 1 to 3 substituents selected from 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl) optionally substituted by a group (eg, methyl) 1-6 alkyl group (eg, methyl, ethyl, sec-butyl),
(b) C 3-8 cycloalkyl group (eg, cyclopentyl),
(c) C 6-14 aryl group,
(d) C 1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered fused aromatic heterocyclic groups,
(g) a substituent selected from a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl) and (h) a 8- to 12-membered fused non-aromatic heterocyclic group; A carbamoyl group which may be substituted; or
(3) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) is preferable.
Among them, as R 4 ,
(1) cyano group;
(2) (a) (i) C 3-8 cycloalkyl group (eg, cyclopropyl), (ii) C 1-6 alkoxy group (eg, methoxy) and (iii) 1 to 3 C 1-6 It may be substituted by 1 to 3 substituents selected from 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl) which may be substituted by alkyl group (eg, methyl) C 1-6 alkyl group (eg, methyl, ethyl, sec-butyl),
(b) C 3-8 cycloalkyl group (eg, cyclopropyl), and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
Or a carbamoyl group optionally mono- or di-substituted with a substituent selected from
(3) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) is preferable.
　式（Ｉ）におけるＲ５は、水素原子または置換基を示す。Ｒ５としては、水素原子が好ましい。 R 5 in Formula (I) represents a hydrogen atom or a substituent. As R 5 , a hydrogen atom is preferable.
　化合物（Ｉ）の好適な具体例としては、以下が挙げられる。
［化合物Ａ］
　Ｒ１が、水素原子であり；
　Ｒ２が、水素原子であり；
　Ｒ３が、
(a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基（例、フェニル）、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基（例、アセチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、ピロリジニル）、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基（例、アゼチジニルカルボニル、ピペラジニルカルボニル）、および(vi) ジＣ１－６アルキルアミノ基（例、ジメチルアミノ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、イソブチル）、
(b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基（例、メチル）、および(iii) Ｃ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基（例、シクロペンチル、シクロヘキシル）、
(c) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール基、
(d) ５または６員の単環式芳香族複素環基、
(e) ８ないし１２員の縮合芳香族複素環基、
(f) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）、
(g) ８ないし１２員の縮合非芳香族複素環基、
(h) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキル－カルボニル基、
(i) Ｃ３－８シクロアルキル－カルボニル基、
(j) １ないし３個のハロゲン原子で置換されていてもよいＣ６－１４アリール－カルボニル基、
(k) ５または６員の単環式芳香族複素環カルボニル基、
(l) ８ないし１２員の縮合芳香族複素環カルボニル基、
(m) ３ないし８員の単環式非芳香族複素環カルボニル基、および
(n) ８ないし１２員の縮合非芳香族複素環カルボニル基
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基であり；
　Ｒ４が、
(1) シアノ基；
(2) (a) (i) Ｃ３－８シクロアルキル基（例、シクロペンチル）、(ii) Ｃ１－６アルコキシ基（例、メトキシ）および(iii) １ないし3個のＣ１－６アルキル基（例、メチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、オキセタニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、sec-ブチル）、
　　(b) Ｃ３－８シクロアルキル基（例、シクロペンチル）、
　　(c) Ｃ６－１４アリール基、
　　(d) Ｃ１－６アルコキシ基、
　　(e) ５または６員の単環式芳香族複素環基、
　　(f) ８ないし１２員の縮合芳香族複素環基、
　　(g) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）、および
　　(h) ８ないし１２員の縮合非芳香族複素環基
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；または、
(3) Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル）であり；
　Ｒ５が、水素原子である、化合物（Ｉ）。 Preferable specific examples of the compound (I) include the following.
[Compound A]
R 1 is a hydrogen atom;
R 2 is a hydrogen atom;
R 3 is
(a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidinyl carbonyl, piperazinyl carbonyl), and (vi) di C 1-6 alkylamino group (eg, dimethylamino) a C 1-6 alkyl group (e.g. also methyl, ethyl, propyl, isopropyl Le, isobutyl),
(b) (i) a hydroxy group, (ii) a C 1-6 alkyl group (eg, methyl) which may be substituted by 1 to 3 hydroxy groups, and (iii) a C 6-14 aryl group (eg C 3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from
(c) a C 6-14 aryl group which may be substituted by 1 to 3 halogen atoms,
(d) 5- or 6-membered monocyclic aromatic heterocyclic group,
(e) 8- to 12-membered fused aromatic heterocyclic groups,
(f) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl),
(g) 8- to 12-membered fused non-aromatic heterocyclic groups,
(h) a C 1-6 alkyl-carbonyl group which may be substituted by 1 to 3 halogen atoms,
(i) C 3-8 cycloalkyl-carbonyl group,
(j) a C 6-14 aryl-carbonyl group which may be substituted by 1 to 3 halogen atoms,
(k) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(l) 8- to 12-membered fused aromatic heterocyclic carbonyl group,
(m) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group, and
(n) an amino group which may be mono- or di-substituted with a substituent selected from 8- to 12-membered fused non-aromatic heterocyclic carbonyl groups;
R 4 is
(1) cyano group;
(2) (a) (i) C 3-8 cycloalkyl group (eg, cyclopentyl), (ii) C 1-6 alkoxy group (eg, methoxy) and (iii) 1 to 3 C 1-6 alkyls C 1 to C optionally substituted by 1 to 3 substituents selected from 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl) optionally substituted by a group (eg, methyl) 1-6 alkyl group (eg, methyl, ethyl, sec-butyl),
(b) C 3-8 cycloalkyl group (eg, cyclopentyl),
(c) C 6-14 aryl group,
(d) C 1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered fused aromatic heterocyclic groups,
(g) a substituent selected from a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl) and (h) a 8- to 12-membered fused non-aromatic heterocyclic group; A carbamoyl group which may be substituted; or
(3) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl);
Compound (I), wherein R 5 is a hydrogen atom.
［化合物Ｂ］
　Ｒ１が、水素原子であり；
　Ｒ２が、水素原子であり；
　Ｒ３が、
(a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基（例、フェニル）、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基（例、アセチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、ピロリジニル）、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基（例、アゼチジニルカルボニル、ピペラジニルカルボニル）、および(vi) ジＣ１－６アルキルアミノ基（例、ジメチルアミノ）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、プロピル、イソプロピル、イソブチル）、
(b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基（例、メチル）、および(iii) Ｃ６－１４アリール基（例、フェニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基（例、シクロペンチル、シクロヘキシル）、および
(c) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基であり；
　Ｒ４が、
(1) シアノ基；
(2) (a) (i) Ｃ３－８シクロアルキル基（例、シクロプロピル）、(ii) Ｃ１－６アルコキシ基（例、メトキシ）および(iii) １ないし3個のＣ１－６アルキル基（例、メチル）で置換されていてもよい３ないし８員の単環式非芳香族複素環基（例、オキセタニル）から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、sec-ブチル）、
　　(b) Ｃ３－８シクロアルキル基（例、シクロプロピル）、および、
　　(c) ３ないし８員の単環式非芳香族複素環基（例、テトラヒドロピラニル）
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；または、
(3) Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル）であり；
　Ｒ５が、水素原子である、化合物（Ｉ）。 [Compound B]
R 1 is a hydrogen atom;
R 2 is a hydrogen atom;
R 3 is
(a) (i) cyano group, (ii) hydroxy group, (iii) C 6-14 aryl group (eg, phenyl), (iv) C 1-6 alkyl-carbonyl group optionally substituted by cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, pyrrolidinyl) which may be substituted with (eg, acetyl) (eg, pyrrolidinyl), (v) (i ') cyano group and (ii') 1 to 3 3 to 8 membered monocyclic non-aromatic heterocycle optionally substituted by 1 to 3 substituents selected from C 6-14 aryl groups (eg, phenyl) optionally substituted by cyano group of Substituted with 1 to 3 substituents selected from ring carbonyl group (eg, azetidinyl carbonyl, piperazinyl carbonyl), and (vi) di C 1-6 alkylamino group (eg, dimethylamino) a C 1-6 alkyl group (e.g. also, methyl, propyl, isopropyl, Lee Butyl),
(b) (i) a hydroxy group, (ii) a C 1-6 alkyl group (eg, methyl) which may be substituted by 1 to 3 hydroxy groups, and (iii) a C 6-14 aryl group (eg And C 3-8 cycloalkyl group (eg, cyclopentyl, cyclohexyl) optionally substituted by 1 to 3 substituents selected from phenyl, and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
An amino group which may be mono- or di-substituted with a substituent selected from
R 4 is
(1) cyano group;
(2) (a) (i) C 3-8 cycloalkyl group (eg, cyclopropyl), (ii) C 1-6 alkoxy group (eg, methoxy) and (iii) 1 to 3 C 1-6 It may be substituted by 1 to 3 substituents selected from 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl) which may be substituted by alkyl group (eg, methyl) C 1-6 alkyl group (eg, methyl, ethyl, sec-butyl),
(b) C 3-8 cycloalkyl group (eg, cyclopropyl), and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
Or a carbamoyl group optionally mono- or di-substituted with a substituent selected from
(3) C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl);
Compound (I), wherein R 5 is a hydrogen atom.
［化合物Ｃ］
　実施例１～２３に記載の化合物またはその塩。 [Compound C]
Compounds or salts thereof described in Examples 1 to 23.
　化合物（Ｉ）が塩である場合、そのような塩としては、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。金属塩の好適な例としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩等のアルカリ土類金属塩；アルミニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ'－ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、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等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸等との塩が挙げられる。
　このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩等）等の無機塩、アンモニウム塩等、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、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等の有機酸との塩が挙げられる。 When the compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids Salt etc. are mentioned. Preferred examples of the metal salt include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferred examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzyl And salts with ethylene diamine and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like Can be mentioned.
Among these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts etc.), ammonium salts Also, in the case where the compound has a basic functional group, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or acetic acid, phthalic acid, fumaric acid, oxalic acid Examples thereof include salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
［製造方法］
　以下に、本発明の化合物（Ｉ）の製造法を説明する。
　化合物（Ｉ）およびその原料化合物は、自体公知の手段を用いて、例えば、以下のスキームで示される方法などによって製造できる。以下の製造法の各工程において、「室温」は通常１０ないし３０℃を示し、スキーム中に記載されている化学構造式中の各記号は、特記しない限り前記と同意義を示す。なお、式中の化合物は、塩を形成している場合も含み、このような塩としては、例えば、化合物（Ｉ）の塩と同様のもの等が挙げられる。 [Production method]
Below, the manufacturing method of compound (I) of this invention is demonstrated.
Compound (I) and a raw material compound thereof can be produced using a method known per se, for example, by a method shown in the following scheme and the like. In each step of the following production methods, "room temperature" usually indicates 10 to 30 ° C, and each symbol in a chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified. In addition, the compound in a formula also includes the case where the salt is formed, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example.
　各工程で得られた化合物が遊離化合物である場合には、自体公知の方法により、目的とする塩に変換することができる。逆に各工程で得られた化合物が塩である場合には、自体公知の方法により、遊離体または目的とする他の種類の塩に変換することができる。 When the compound obtained in each step is a free compound, it can be converted to a target salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or another type of desired salt by a method known per se.
　各工程で得られた化合物は反応液のままか、または粗生成物として得た後に、次反応に用いることもできる、あるいは、各工程で得られた化合物を、常法に従って、反応混合物から濃縮、晶出、再結晶、蒸留、溶媒抽出、分溜、クロマトグラフィーなどの分離手段により単離および／または精製することができる。 The compound obtained in each step may be used as the reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step may be concentrated from the reaction mixture according to a conventional method It can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like.
　各工程の原料や試薬の化合物が市販されている場合には、市販品をそのまま用いることができる。 When the raw material of each process and the compound of a reagent are marketed, a commercial item can be used as it is.
　各工程の反応において、反応時間は、用いる試薬や溶媒により異なり得るが、特に記載の無い場合、通常１分～４８時間、好ましくは１０分～８時間である。 In the reaction of each step, the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.
　各工程の反応において、反応温度は、用いる試薬や溶媒により異なり得るが、特に記載が無い場合、通常－７８℃～３００℃、好ましくは－７８℃～１５０℃である。 In the reaction of each step, the reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, it is usually -78 ° C to 300 ° C, preferably -78 ° C to 150 ° C.
　各工程の反応において、圧力は、用いる試薬や溶媒により異なり得るが、特に記載が無い場合、通常１気圧～２０気圧、好ましくは１気圧～３気圧である。 In the reaction of each step, the pressure may differ depending on the reagent and solvent to be used, but unless otherwise specified, it is usually 1 to 20 atm, preferably 1 to 3 atm.
　各工程の反応において、例えば、Ｂｉｏｔａｇｅ社製ＩｎｉｔｉａｔｏｒなどのＭｉｃｒｏｗａｖｅ合成装置を用いることがある。反応温度は、用いる試薬や溶媒により異なり得るが、特に記載がない場合、通常室温～３００℃、好ましくは５０℃～２５０℃である。反応時間は、用いる試薬や溶媒により異なり得るが、特に記載の無い場合、通常１分～４８時間、好ましくは１分～８時間である。 In the reaction of each step, for example, a microwave synthesizer such as Biotage's Initiator may be used. The reaction temperature may vary depending on the reagent and solvent to be used, but is generally room temperature to 300 ° C., preferably 50 ° C. to 250 ° C., unless otherwise specified. The reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.
　各工程の反応において、試薬は、特に記載が無い場合、基質に対して０．５当量～２０当量、好ましくは０．８当量～５当量が用いられる。試薬を触媒として使用する場合、試薬は基質に対して０．００１当量～１当量、好ましくは０．０１当量～０．２当量が用いられる。試薬が反応溶媒を兼ねる場合、試薬は溶媒量が用いられる。 In the reaction of each step, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent also serves as the reaction solvent, the amount of the solvent is used.
　各工程の反応において、特に記載が無い場合、これらの反応は、無溶媒、あるいは適当な溶媒に溶解または懸濁して行われる。溶媒の具体例としては、実施例に記載されている溶媒、あるいは以下が挙げられる。
アルコール類：メタノール、エタノール、ｔｅｒｔ－ブチルアルコール、２－メトキシエタノールなど；
エーテル類：ジエチルエーテル、ジフェニルエーテル、テトラヒドロフラン、１，２－ジメトキシエタンなど；
芳香族炭化水素類：クロロベンゼン、トルエン、キシレンなど；
飽和炭化水素類：シクロヘキサン、ヘキサンなど；
アミド類：Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドンなど；
ハロゲン化炭化水素類：ジクロロメタン、四塩化炭素など；
ニトリル類：アセトニトリルなど；
スルホキシド類：ジメチルスルホキシドなど；
芳香族有機塩基類：ピリジンなど；
酸無水物類：無水酢酸など；
有機酸類：ギ酸、酢酸、トリフルオロ酢酸など；
無機酸類：塩酸、硫酸など；
エステル類：酢酸エチルなど；
ケトン類：アセトン、メチルエチルケトンなど；
水。
　上記溶媒は、二種以上を適宜の割合で混合して用いてもよい。 In the reaction of each step, unless otherwise specified, these reactions are carried out without solvent, or dissolved or suspended in a suitable solvent. Specific examples of the solvent include the solvents described in the examples, or the following.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol etc .;
Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene etc .;
Saturated hydrocarbons: cyclohexane, hexane etc .;
Amides: N, N-dimethylformamide, N-methylpyrrolidone and the like;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: dimethyl sulfoxide and the like;
Aromatic organic bases: pyridine and the like;
Acid anhydrides: acetic anhydride etc .;
Organic acids: Formic acid, acetic acid, trifluoroacetic acid etc .;
Inorganic acids: hydrochloric acid, sulfuric acid etc .;
Esters: Ethyl acetate etc .;
Ketones: acetone, methyl ethyl ketone etc .;
water.
The above solvents may be used as a mixture of two or more at an appropriate ratio.
　各工程の反応において塩基を用いる場合、例えば、以下に示す塩基、あるいは実施例に記載されている塩基が用いられる。
無機塩基類：水酸化ナトリウム、水酸化マグネシウム、炭酸ナトリウム、炭酸カルシウム、炭酸水素ナトリウムなど；
有機塩基類：トリエチルアミン、ジエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、１，４－ジアザビシクロ［２.２.２］オクタン、１，８－ジアザビシクロ［５.４.０］－７－ウンデセン、イミダゾール、ピペリジンなど；
金属アルコキシド類：ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシドなど；
アルカリ金属水素化物類：水素化ナトリウムなど；
金属アミド類：ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジドなど；
有機リチウム類：ｎ－ブチルリチウムなど。 When a base is used in the reaction of each step, for example, the bases shown below or the bases described in the examples are used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine etc .;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide etc .;
Organic lithium: n-butyllithium etc.
　各工程の反応において酸または酸性触媒を用いる場合、例えば、以下に示す酸や酸性触媒、あるいは実施例に記載されている酸や酸性触媒が用いられる。
無機酸類：塩酸、硫酸、硝酸、臭化水素酸、リン酸など；
有機酸類：酢酸、トリフルオロ酢酸、クエン酸、ｐ－トルエンスルホン酸、１０－カンファースルホン酸など；
ルイス酸：三フッ化ホウ素ジエチルエーテル錯体、ヨウ化亜鉛、無水塩化アルミニウム、無水塩化亜鉛、無水塩化鉄など。 When an acid or acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in the examples is used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
　各工程の反応は、特に記載の無い限り、自体公知の方法、例えば、第５版実験化学講座、１３巻～１９巻（日本化学会編）；新実験化学講座、１４巻～１５巻（日本化学会編）；精密有機化学　改訂第２版（Ｌ．　Ｆ．　Ｔｉｅｔｚｅ，Ｔｈ．　Ｅｉｃｈｅｒ、南江堂）；改訂　有機人名反応　そのしくみとポイント（東郷秀雄著、講談社）；ＯＲＧＡＮＩＣ　ＳＹＮＴＨＥＳＥＳ　Ｃｏｌｌｅｃｔｉｖｅ　Ｖｏｌｕｍｅ　Ｉ～ＶＩＩ（Ｊｏｈｎ　Ｗｉｌｅｙ　＆　ＳｏｎｓＩｎｃ）；Ｍｏｄｅｒｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　ｉｎ　ｔｈｅ　Ｌａｂｏｒａｔｏｒｙ　Ａ　Ｃｏｌｌｅｃｔｉｏｎ　ｏｆ　Ｓｔａｎｄａｒｄ　Ｅｘｐｅｒｉｍｅｎｔａｌ　Ｐｒｏｃｅｄｕｒｅｓ（Ｊｉｅ　Ｊａｃｋ　Ｌｉ著、ＯＸＦＯＲＤ　ＵＮＩＶＥＲＳＩＴＹ出版）；Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｈｅｔｅｒｏｃｙｃｌｉｃ　Ｃｈｅｍｉｓｔｒｙ　ＩＩＩ、Ｖｏｌ．１～Ｖｏｌ．１４（エルゼビア・ジャパン株式会社）；人名反応に学ぶ有機合成戦略（富岡清監訳、化学同人発行）；コンプリヘンシブ・オーガニック・トランスフォーメーションズ（ＶＣＨ　Ｐｕｂｌｉｓｈｅｒｓ　Ｉｎｃ．）１９８９年刊などに記載された方法、あるいは実施例に記載された方法に準じて行われる。 Unless otherwise specified, the reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Lecture, Volume 13 to Volume 19 (edited by The Chemical Society of Japan); New Experimental Chemistry Lecture, Volume 14 to Volume 15 (Japan) Chemical Society Ed.) Precision Organic Chemistry Rev. 2 (L. F. Tietze, Th. Eicher, Nan-e-do); Revised Organic Personal Name Reactions The Structure and Points (Togo Hideo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII ( John Wiley & Sons Inc .; Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures by Jie Jack Li, OXFORD UN VERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan Co., Ltd.); Organic synthesis strategy learned from personal name reaction (translated by Kiyoshi Tomioka, published by Chemical Doujinshi); Method described in Comprehensive Organic Transformations (VCH Publishers Inc.) 1989, etc. Alternatively, it is carried out according to the method described in the examples.
　また、以下の各反応において、原料化合物や中間体が置換基としてアミノ基、カルボキシル基または水酸基を有する場合、これらの基は、ペプチド化学等で一般的に用いられるような保護基で保護されていてもよい。この場合、反応後に、必要に応じて保護基を除去することにより目的化合物を得ることができる。これらの保護基の導入あるいは除去は、自体公知の方法、例えば、Wiley-Interscience社2006年刊「Protective Groups in Organic Synthesis, 4th Ed.」（Theodora W. Greene, Peter G. M. Wuts著）に記載の方法等に準じて行えばよい。 In each of the following reactions, when the starting compound or the intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups are protected by a protecting group generally used in peptide chemistry and the like. May be In this case, after the reaction, the target compound can be obtained by removing the protecting group as necessary. The introduction or removal of these protective groups can be carried out according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4 th Ed." (Theodora W. Greene, Peter GM Wuts) published by Wiley-Interscience 2006. It may be performed according to the like.
　アミノ基の保護基としては、例えば、ホルミル基、Ｃ１－６アルキル－カルボニル基、Ｃ１－６アルコキシ－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル等）、Ｃ７－１２アラルキルオキシ－カルボニル基（例、ベンジルオキシカルボニル、９－フルオレニルメトキシカルボニル等）、トリチル基、フタロイル基、Ｎ，Ｎ－ジメチルアミノメチレン基、Ｃ１－６アルキル基で置換されていてもよいシリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル等）、Ｃ２－６アルケニル基（例、１－アリル等）等が挙げられる。これらの基は、ハロゲン原子、Ｃ１－６アルコキシ基およびニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。 Examples of the protecting group of amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzyl carbonyl etc.), C 7-12 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl etc.), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted by C 1-6 alkyl group Optionally substituted silyl (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl etc.), C 2-6 alkenyl group (eg, 1-allyl etc.), etc. . These groups may be substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
　カルボキシル基の保護基としては、例えば、Ｃ１－６アルキル基、Ｃ７－１２アラルキル基（例、ベンジル等）、フェニル基、トリチル基、Ｃ１－６アルキル基で置換されていてもよいシリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル等）、Ｃ２－６アルケニル基（例、１－アリル等）等が挙げられる。 As a carboxyl-protecting group, for example, silyl optionally substituted by C 1-6 alkyl group, C 7-12 aralkyl group (eg, benzyl etc.), phenyl group, trityl group, C 1-6 alkyl group Groups (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl etc.), C 2-6 alkenyl groups (eg, 1-allyl etc.) and the like.
　水酸基の保護基としては、例えば、Ｃ１－６アルキル基、フェニル基、トリチル基、Ｃ７－１２アラルキル基（例、ベンジル等）、ホルミル基、Ｃ１－６アルキル－カルボニル基、ベンゾイル基、Ｃ７－１２アラルキル－カルボニル基（例、ベンジルカルボニル等）、２－テトラヒドロピラニル基、２－テトラヒドロフラニル基、Ｃ１－６アルキル基で置換されていてもよいシリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル等）、Ｃ２－６アルケニル基（例、１－アリル等）等が挙げられる。 Examples of the protecting group for hydroxyl group include C 1-6 alkyl group, phenyl group, trityl group, C 7-12 aralkyl group (eg, benzyl etc.), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group, C 7-12 aralkyl-carbonyl group (eg, benzylcarbonyl etc.), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group optionally substituted by C 1-6 alkyl group (eg, trimethylsilyl, triethyl) Examples thereof include silyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like, C 2-6 alkenyl group (eg, 1-allyl and the like) and the like.
　これらの基は、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基またはニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。
　上記した保護基の除去方法は、自体公知の方法、例えば、Wiley-Interscience社2006年刊「Protective Groups in Organic Synthesis, 4th Ed.」（Theodora W. Greene, Peter G. M. Wuts著）に記載の方法等が挙げられる。具体的には、酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、N-メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウム、トリアルキルシリルハライド(例えば、トリメチルシリルヨージド、トリメチルシリルブロミド等)等を使用する方法や還元法等が用いられる。 These groups may be substituted by 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
The removal method of the above-mentioned protective group is a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4 th Ed." (Theodora W. Greene, Peter GM Wuts) published by Wiley-Interscience 2006. Can be mentioned. Specifically, acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (eg, trimethylsilyl iodide, trimethylsilyl bromide etc.), etc. The method to use, the reduction method, etc. are used.
　各工程において、還元反応を行う場合、使用される還元剤としては、水素化アルミニウムリチウム、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化ジイソブチルアルミニウム（ＤＩＢＡＬ－Ｈ）、水素化ホウ素ナトリウム、水素化トリアセトキシホウ素テトラメチルアンモニウムなどの金属水素化物類；ボランテトラヒドロフラン錯体などのボラン類；ラネーニッケル；ラネーコバルト；水素；ギ酸；トリエチルシランなどが挙げられる。炭素－炭素二重結合あるいは三重結合を還元する場合は、パラジウム－カーボンやＬｉｎｄｌａｒ触媒などの触媒を用いる方法がある。 When the reduction reaction is carried out in each step, the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride Metal hydrides such as triacetoxyborohydride and tetramethylammonium hydride; boranes such as borane-tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like. In the case of reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as palladium-carbon or Lindlar catalyst.
　各工程において、酸化反応を行う場合、使用される酸化剤としては、ｍ－クロロ過安息香酸（ｍＣＰＢＡ）、過酸化水素、ｔｅｒｔ－ブチルヒドロペルオキシドなどの過酸類；過塩素酸テトラブチルアンモニウムなどの過塩素酸塩類；塩素酸ナトリウムなどの塩素酸塩類；亜塩素酸ナトリウムなどの亜塩素酸塩類；過ヨウ素酸ナトリウムなどの過ヨウ素酸類；ヨードシルベンゼンなどの高原子価ヨウ素試薬；二酸化マンガン、過マンガン酸カリウムなどのマンガンを有する試薬；四酢酸鉛などの鉛類；クロロクロム酸ピリジニウム（ＰＣＣ）、二クロム酸ピリジニウム（ＰＤＣ）、ジョーンズ試薬などのクロムを有する試薬；Ｎ－ブロモスクシンイミド（ＮＢＳ）などのハロゲン化合物類；酸素；オゾン；三酸化硫黄・ピリジン錯体；四酸化オスミウム；二酸化セレン；２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（ＤＤＱ）などが挙げられる。 When an oxidation reaction is carried out in each step, examples of the oxidizing agent used include m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, peroxides such as tert-butyl hydroperoxide, etc .; tetrabutylammonium perchlorate etc. Perchlorates; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodic acids such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese dioxide Reagents having manganese such as potassium manganate; Leads such as lead tetraacetate; pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), reagents having chromium such as Jones reagent; N-bromosuccinimide (NBS) Halogen compounds such as; oxygen; ozone; sulfur trioxide / pyridine complex; Osmium; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.
　各工程において、ラジカル環化反応を行う場合、使用されるラジカル開始剤としては、アゾビスイソブチロニトリル（ＡＩＢＮ）などのアゾ化合物；４，４’－アゾビス－４－シアノペンタン酸（ＡＣＰＡ）などの水溶性ラジカル開始剤；空気あるいは酸素存在下でのトリエチルホウ素；過酸化ベンゾイルなどが挙げられる。また、使用されるラジカル反応試剤としては、トリブチルスタナン、トリストリメチルシリルシラン、１，１，２，２－テトラフェニルジシラン、ジフェニルシラン、ヨウ化サマリウムなどが挙げられる。 When performing radical cyclization reaction in each process, as a radical initiator used, azo compounds such as azobisisobutyronitrile (AIBN); 4,4'-azobis-4-cyanopentanoic acid (ACPA) Water soluble radical initiators; triethyl boron in the presence of air or oxygen; benzoyl peroxide and the like. Further, as a radical reaction agent to be used, tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and the like can be mentioned.
　各工程において、Ｗｉｔｔｉｇ反応を行う場合、使用されるＷｉｔｔｉｇ試薬としては、アルキリデンホスホラン類などが挙げられる。アルキリデンホスホラン類は、自体公知の方法、例えば、ホスホニウム塩と強塩基を反応させることで調製することができる。 When carrying out a Wittig reaction in each step, examples of the Wittig reagent used include alkylidene phosphoranes and the like. The alkylidene phosphoranes can be prepared by methods known per se, for example, by reacting a phosphonium salt with a strong base.
　各工程において、Ｈｏｒｎｅｒ－Ｅｍｍｏｎｓ反応を行う場合、使用される試薬としては、ジメチルホスホノ酢酸メチル、ジエチルホスホノ酢酸エチルなどのホスホノ酢酸エステル類；アルカリ金属水素化物類、有機リチウム類などの塩基が挙げられる。 When performing the Horner-Emmons reaction in each step, as reagents used, phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organic lithiums It can be mentioned.
　各工程において、Ｆｒｉｅｄｅｌ－Ｃｒａｆｔｓ反応を行う場合、使用される試薬としては、ルイス酸と酸クロリドとの組み合せ、あるいはルイス酸とアルキル化剤（例、ハロゲン化アルキル類、アルコール、オレフィン類など）との組み合わせが挙げられる。あるいは、ルイス酸の代わりに、有機酸や無機酸を用いることもでき、酸クロリドの代わりに、無水酢酸などの酸無水物を用いることもできる。 When carrying out the Friedel-Crafts reaction in each step, the reagent used is a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (eg, halogenated alkyls, alcohols, olefins, etc.) A combination of Alternatively, instead of the Lewis acid, an organic acid or inorganic acid can be used, and instead of the acid chloride, an acid anhydride such as acetic anhydride can be used.
　各工程において、芳香族求核置換反応を行う場合、試薬としては、求核剤（例、アミン類、イミダゾールなど）と塩基（例、有機塩基類など）が用いられる。 When performing an aromatic nucleophilic substitution reaction in each step, a nucleophile (eg, amines, imidazole etc.) and a base (eg, organic bases etc.) are used as reagents.
　各工程において、カルボアニオンによる求核付加反応、カルボアニオンによる求核１，４－付加反応（Ｍｉｃｈａｅｌ付加反応）、あるいはカルボアニオンによる求核置換反応を行う場合、カルボアニオンを発生するために用いる塩基としては、有機リチウム類、金属アルコキシド類、無機塩基類、有機塩基類などが挙げられる。 When performing nucleophilic addition reaction with carbanion, nucleophilic 1,4-addition reaction with carbanion (Michael addition reaction), or nucleophilic substitution reaction with carbanion in each step, a base used to generate carbanion And organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.
　各工程において、Ｇｒｉｇｎａｒｄ反応を行う場合、Ｇｒｉｇｎａｒｄ試薬としては、フェニルマグネシウムブロミドなどのアリールマグネシウムハライド類；メチルマグネシウムブロミドなどのアルキルマグネシウムハライド類が挙げられる。Ｇｒｉｇｎａｒｄ試薬は、自体公知の方法、例えばエーテルあるいはテトラヒドロフランを溶媒として、ハロゲン化アルキルまたはハロゲン化アリールと、金属マグネシウムとを反応させることにより調製することができる。 When performing Grignard reaction in each process, Grignard reagents include aryl magnesium halides such as phenyl magnesium bromide; and alkyl magnesium halides such as methyl magnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with magnesium metal with ether or tetrahydrofuran as a solvent.
　各工程において、Ｋｎｏｅｖｅｎａｇｅｌ縮合反応を行う場合、試薬としては、二つの電子求引基に挟まれた活性メチレン化合物（例、マロン酸、マロン酸ジエチル、マロノニトリルなど）および塩基（例、有機塩基類、金属アルコキシド類、無機塩基類）が用いられる。 When performing Knoevenagel condensation reaction in each step, as reagents, active methylene compounds (eg, malonic acid, diethyl malonate, malononitrile etc.) and bases (eg, organic bases, etc.) sandwiched between two electron withdrawing groups Metal alkoxides, inorganic bases) are used.
　各工程において、Ｖｉｌｓｍｅｉｅｒ－Ｈａａｃｋ反応を行う場合、試薬としては、塩化ホスホリルとアミド誘導体（例、Ｎ，Ｎ－ジメチルホルムアミドなど）が用いられる。 When Vilsmeier-Haack reaction is performed in each step, phosphoryl chloride and an amide derivative (eg, N, N-dimethylformamide, etc.) are used as reagents.
　各工程において、アルコール類、アルキルハライド類、スルホン酸エステル類のアジド化反応を行う場合、使用されるアジド化剤としては、ジフェニルホスホリルアジド（ＤＰＰＡ）、トリメチルシリルアジド、アジ化ナトリウムなどが挙げられる。例えば、アルコール類をアジド化する場合、ジフェニルホスホリルアジドと１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）を用いる方法やトリメチルシリルアジドとルイス酸を用いる方法などがある。 When carrying out the azidation reaction of alcohols, alkyl halides and sulfonic acid esters in each step, examples of the azidation agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like. For example, in the case of azide alcohol, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, and the like.
　各工程において、還元的アミノ化反応を行う場合、使用される還元剤としては、水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素、ギ酸などが挙げられる。基質がアミン化合物の場合は、使用されるカルボニル化合物としては、パラホルムアルデヒドの他、アセトアルデヒドなどのアルデヒド類、シクロヘキサノンなどのケトン類が挙げられる。基質がカルボニル化合物の場合は、使用されるアミン類としては、アンモニア、メチルアミンなどの１級アミン；ジメチルアミンなどの２級アミンなどが挙げられる。 When the reductive amination reaction is carried out in each step, the reducing agent used includes sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde as well as aldehydes such as acetaldehyde and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines to be used include ammonia, primary amines such as methylamine; secondary amines such as dimethylamine, and the like.
　各工程において、光延反応を行う場合、試薬としては、アゾジカルボン酸エステル類（例、アゾジカルボン酸ジエチル（ＤＥＡＤ）、アゾジカルボン酸ジイソプロピル（ＤＩＡＤ）など）およびトリフェニルホスフィンが用いられる。 When the Mitsunobu reaction is performed in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.
　各工程において、エステル化反応、アミド化反応、あるいはウレア化反応を行う場合、使用される試薬としては、酸クロリド、酸ブロミドなどのハロゲン化アシル体；酸無水物、活性エステル体、硫酸エステル体など活性化されたカルボン酸類が挙げられる。カルボン酸の活性化剤としては、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣＤ）などのカルボジイミド系縮合剤；４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロライド－ｎ－ハイドレート（ＤＭＴ－ＭＭ）などのトリアジン系縮合剤；１，１－カルボニルジイミダゾール（ＣＤＩ）などの炭酸エステル系縮合剤；ジフェニルリン酸アジド（ＤＰＰＡ）；ベンゾトリアゾール－１－イルオキシ-トリスジメチルアミノホスホニウム塩（ＢＯＰ試薬）；ヨウ化２－クロロ－１－メチル－ピリジニウム（向山試薬）；塩化チオニル；クロロギ酸エチルなどのハロギ酸低級アルキル；Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム ヘキサフルオロリン酸塩（ＨＡＴＵ）；硫酸；あるいはこれらの組み合わせなどが挙げられる。カルボジイミド系縮合剤を用いる場合、１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、Ｎ－ヒドロキシコハク酸イミド（ＨＯＳｕ）、ジメチルアミノピリジン（ＤＭＡＰ）などの添加剤をさらに反応に加えてもよい。 When performing esterification reaction, amidation reaction, or urea conversion reaction in each step, as reagents used, acyl chloride such as acid chloride and acid bromide; acid anhydride, active ester, sulfuric acid ester And activated carboxylic acids. Carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD) as a carboxylic acid activating agent; 4- (4,6-dimethoxy-1,3,5-) Triazine-based condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); Carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Phosphorus azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformic acid such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-te Tramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide type condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like may be further added to the reaction.
　各工程において、カップリング反応を行う場合、使用される金属触媒としては、酢酸パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、ジクロロビス（トリエチルホスフィン）パラジウム（ＩＩ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、塩化１，１’－ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＩＩ）などのパラジウム化合物；テトラキス（トリフェニルホスフィン）ニッケル（０）などのニッケル化合物；塩化トリス（トリフェニルホスフィン）ロジウム（ＩＩＩ）などのロジウム化合物；コバルト化合物；酸化銅、ヨウ化銅（Ｉ）などの銅化合物；白金化合物などが挙げられる。さらに反応に塩基を加えてもよく、このような塩基としては、無機塩基類などが挙げられる。 When a coupling reaction is carried out in each step, the metal catalyst used is palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl) Phosphine compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenyl phosphino) ferrocene palladium (II) chloride; tetrakis (triphenylphosphine) nickel (0) And nickel compounds such as tris (triphenylphosphine) rhodium (III); cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like. Furthermore, a base may be added to the reaction, and such bases include inorganic bases.
　各工程において、チオカルボニル化反応を行う場合、チオカルボニル化剤としては、代表的には五硫化二リンが用いられるが、五硫化二リンの他に、２，４－ビス（４－メトキシフェニル）－１，３，２，４－ジチアジホスフェタン－２，４－ジスルフィド（Ｌａｗｅｓｓｏｎ試薬）などの１，３，２，４－ジチアジホスフェタン－２，４－ジスルフィド構造を持つ試薬を用いてもよい。 When thiocarbonylation reaction is carried out in each step, typically, diphosphorus pentasulfide is used as the thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) ) Reagents with 1,3,2,4-dithiadiphosphetan-2,4-disulfide structure such as 1,3), 2,4-dithiadiphosphetan-2,4-disulfide (Lawesson's reagent) May be used.
　各工程において、Ｗｏｈｌ－Ｚｉｅｇｌｅｒ反応を行う場合、使用されるハロゲン化剤としては、Ｎ－ヨードコハク酸イミド、Ｎ－ブロモコハク酸イミド（ＮＢＳ）、Ｎ－クロロコハク酸イミド（ＮＣＳ）、臭素、塩化スルフリルなどが挙げられる。さらに、熱、光、過酸化ベンゾイル、アゾビスイソブチロニトリルなどのラジカル開始剤を反応に加えることで、反応を加速させることができる。 When performing the Wohl-Ziegler reaction in each step, as a halogenating agent to be used, N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like Can be mentioned. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile or the like to the reaction.
　各工程において、ヒドロキシ基のハロゲン化反応を行う場合、使用されるハロゲン化剤としては、ハロゲン化水素酸と無機酸の酸ハロゲン化物、具体的には、塩素化では、塩酸、塩化チオニル、オキシ塩化リンなど、臭素化では、４８％臭化水素酸などが挙げられる。また、トリフェニルホスフィンと四塩化炭素または四臭化炭素などとの作用により、アルコールからハロゲン化アルキル体を得る方法を用いてもよい。あるいは、アルコールをスルホン酸エステルに変換の後、臭化リチウム、塩化リチウムまたはヨウ化ナトリウムと反応させるような２段階の反応を経てハロゲン化アルキル体を合成する方法を用いてもよい。 When performing a halogenation reaction of a hydroxy group in each step, as a halogenating agent to be used, an acid halide of a hydrohalic acid and an inorganic acid, specifically, in chlorination, hydrochloric acid, thionyl chloride, oxy For bromination, such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned. Alternatively, a method of obtaining a halogenated alkyl from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method may be used in which a halogenated alkyl is synthesized through a two-step reaction in which an alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride or sodium iodide.
　各工程において、Ａｒｂｕｚｏｖ反応を行う場合、使用される試薬としては、ブロモ酢酸エチルなどのハロゲン化アルキル類；トリエチルホスファイトやトリ（イソプロピル）ホスファイトなどのホスファイト類が挙げられる。 When the Arbuzov reaction is carried out in each step, examples of reagents used include alkyl halides such as ethyl bromoacetate; and phosphites such as triethyl phosphite and tri (isopropyl) phosphite.
　各工程において、スルホン酸エステル化反応を行う場合、使用されるスルホニル化剤としては、メタンスルホニルクロリド、ｐ－トルエンスルホニルクロリド、メタンスルホン酸無水物、ｐ－トルエンスルホン酸無水物などが挙げられる。 When a sulfonic acid esterification reaction is performed in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.
　各工程において、加水分解反応を行う場合、試薬としては、酸または塩基が用いられる。また、ｔｅｒｔ－ブチルエステルの酸加水分解反応を行う場合、副生するｔｅｒｔ－ブチルカチオンを還元的にトラップするためにギ酸やトリエチルシランなどを加えることがある。 When performing a hydrolysis reaction in each step, an acid or a base is used as a reagent. When the acid hydrolysis reaction of tert-butyl ester is carried out, formic acid, triethylsilane, etc. may be added to reductively trap the by-produced tert-butyl cation.
　各工程において、脱水反応を行う場合、使用される脱水剤としては、硫酸、五酸化二リン、オキシ塩化リン、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、アルミナ、ポリリン酸などが挙げられる。 When dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.
　また、各工程で得られた化合物は反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、再結晶、蒸留、クロマトグラフィー等の分離手段により容易に精製することができる。 The compound obtained in each step can be used as the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.
　化合物（I）は、化合物（II）より以下の方法で製造することができる。 Compound (I) can be produced from compound (II) by the following method.
[規則26に基づく補充 26.10.2018]　
Figure WO-DOC-CHEMICAL-2
 [Repletion based on rule 26. 26.10.2018]
Figure WO-DOC-CHEMICAL-2
〔式中、Xはハロゲン原子を示し、その他の記号は本明細書中で定義した通りである。〕 [Wherein, X represents a halogen atom, and the other symbols are as defined herein. ]
　化合物（V）は、化合物（IV）のハロゲン化試薬による環化反応により製造することができる。ハロゲン化試薬としては、リン酸トリクロリド等が挙げられる。R1、R２、R３、R４、R5は自体公知の方法を用いて、変換することもできる。 Compound (V) can be produced by cyclization reaction of compound (IV) with a halogenating reagent. As the halogenating reagent, phosphoric acid trichloride and the like can be mentioned. R 1 , R 2 , R 3 , R 4 and R 5 can also be converted using methods known per se.
　上記の各製造法により得られる本発明化合物は、濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィー等の公知の手段により単離精製することができる。また、上記の各製造法において用いられる各原料化合物は、前記と同様の公知の手段によって単離精製することができる。一方、これら原料化合物を単離することなく、そのまま反応混合物として、次の工程の原料として用いてもよい。
　このような方法により生成した化合物（Ｉ）は、例えば、再結晶、蒸留、クロマトグラフィー等の通常の分離手段により単離、精製することができる。
　化合物（Ｉ）が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物（Ｉ）として含有されるとともに、自体公知の合成手法、分離手法（例えば、濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶等）によりそれぞれを単品として得ることができる。例えば、化合物（Ｉ）に光学異性体が存在する場合には、該化合物から分割された光学異性体も化合物（Ｉ）に包含される。 The compounds of the present invention obtained by the above-mentioned respective production methods can be isolated and purified by known means such as concentration, reduced pressure concentration, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In addition, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, without isolating these starting compounds, they may be used as they are as a reaction mixture and starting materials for the next step.
Compound (I) produced by such a method can be isolated and purified by a conventional separation means such as, for example, recrystallization, distillation, chromatography and the like.
When the compound (I) contains an optical isomer, stereoisomer, regioisomer, rotamer, these are also contained as the compound (I), and a synthesis method known per se, a separation method (for example, , Concentration, solvent extraction, column chromatography, recrystallization etc.) to obtain each as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
　光学異性体は自体公知の方法により製造することができる。具体的には、光学活性な合成中間体を用いる、または、最終物のラセミ体を常法に従って光学分割することにより光学異性体を得る。
　光学分割法としては、自体公知の方法、例えば、分別再結晶法、キラルカラム法、ジアステレオマー法等が用いられる。 Optical isomers can be produced by methods known per se. Specifically, an optically active synthetic intermediate is used, or an optical isomer is obtained by optically resolving the racemate of the final product according to a conventional method.
As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method or the like is used.
　1)分別再結晶法
　ラセミ体と光学活性な化合物(例えば、(＋)－マンデル酸、(－)－マンデル酸、(＋)－酒石酸、(－)－酒石酸、(＋)－1－フェネチルアミン、(－)－1－フェネチルアミン、シンコニン、(－)－シンコニジン、ブルシン等)と塩を形成させ、これを分別再結晶法によって分離し、所望により、中和工程を経てフリーの光学異性体を得る方法。 1) Fractional Recrystallization Method Racemic and optically active compounds (eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine), (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine etc.) form a salt, which is separated by a fractional recrystallization method, and optionally, it is subjected to a neutralization step to obtain a free optical isomer Method.
　2)キラルカラム法
　ラセミ体またはその塩を光学異性体分離用カラム(キラルカラム)にかけて分離する方法。例えば、液体クロマトグラフィーの場合、ENANTIO－OVM(東ソー社製)あるいは、CHIRALシリーズ(ダイセル社製)等のキラルカラムに光学異性体の混合物を添加し、水、種々の緩衝液(例、リン酸緩衝液等)、有機溶媒(例、エタノール、メタノール、イソプロパノール、アセトニトリル、トリフルオロ酢酸、ジエチルアミン等)を単独あるいは混合した溶液として展開させることにより、光学異性体を分離する。また、例えば、ガスクロマトグラフィーの場合、CP－Chirasil－DeX　CB(ジーエルサイエンス社製)等のキラルカラムを使用して分離する。 2) Chiral column method A method of separating racemate or a salt thereof by applying a column for optical isomer separation (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Corporation), water, various buffers (eg, phosphate buffer The optical isomers are separated by developing them as a solution obtained by mixing a liquid or the like), an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine etc.) alone or in combination. Also, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science Inc.).
　3)ジアステレオマー法
　ラセミ体の混合物を光学活性な試薬と化学反応によってジアステレオマーの混合物とし、これを通常の分離手段(例えば、分別再結晶、クロマトグラフィー法等)等を経て単一物質とした後、加水分解反応等の化学的な処理により光学活性な試薬部位を切り離すことにより光学異性体を得る方法。例えば、化合物（Ｉ）が分子内にヒドロキシまたは1，2級アミノを有する場合、該化合物と光学活性な有機酸(例えば、MTPA〔α－メトキシ－α－(トリフルオロメチル)フェニル酢酸〕、(－)－メントキシ酢酸等)等とを縮合反応に付すことにより、それぞれエステル体またはアミド体のジアステレオマーが得られる。一方、化合物（Ｉ）がカルボン酸基を有する場合、該化合物と光学活性アミンまたはアルコール試薬とを縮合反応に付すことにより、それぞれアミド体またはエステル体のジアステレオマーが得られる。分離されたジアステレオマーは、酸加水分解あるいは塩基性加水分解反応に付すことにより、元の化合物の光学異性体に変換される。 3) Diastereomer method A mixture of racemates is converted to a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance via ordinary separation means (eg, fractional recrystallization, chromatography etc.) A method of obtaining an optical isomer by cleaving an optically active reagent site by chemical treatment such as hydrolysis reaction. For example, when compound (I) has hydroxy or 1,2 secondary amino in the molecule, an organic acid which is optically active with the compound (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid], By subjecting it to a condensation reaction with —) — menthoxyacetic acid etc., diastereomers of ester or amide can be obtained. On the other hand, when the compound (I) has a carboxylic acid group, the compound and an optically active amine or alcohol reagent are subjected to a condensation reaction to obtain diastereomers of an amide form or an ester form, respectively. The separated diastereomers are converted to the optical isomers of the original compound by acid hydrolysis or basic hydrolysis.
　化合物（Ｉ）は、結晶であってもよい。
　化合物（Ｉ）の結晶は、化合物（Ｉ）に自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　ここで、結晶化法としては、例えば、溶液からの結晶化法、蒸気からの結晶化法、溶融体からの結晶化法等が挙げられる。 Compound (I) may be a crystal.
The crystals of compound (I) can be produced by crystallizing compound (I) by applying a crystallization method known per se.
Here, as a crystallization method, for example, a crystallization method from a solution, a crystallization method from a vapor, a crystallization method from a melt, and the like can be mentioned.
　該「溶液からの結晶化法」としては、化合物の溶解度に関係する因子(溶媒組成、pH、温度、イオン強度、酸化還元状態等)または溶媒の量を変化させることによって、飽和していない状態から過飽和状態に移行させる方法が一般的であり、具体的には、例えば、濃縮法、徐冷法、反応法(拡散法、電解法)、水熱育成法、融剤法等が挙げられる。用いられる溶媒としては、例えば、芳香族炭化水素類(例、ベンゼン、トルエン、キシレン等)、ハロゲン化炭化水素類(例、ジクロロメタン、クロロホルム等)、飽和炭化水素類(例、ヘキサン、ヘプタン、シクロヘキサン等)、エーテル類(例、ジエチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン等)、ニトリル類(例、アセトニトリル等)、ケトン類(例、アセトン等)、スルホキシド類(例、ジメチルスルホキシド等)、酸アミド類(例、N，N－ジメチルホルムアミド等)、エステル類(例、酢酸エチル等)、アルコール類(例、メタノール、エタノール、イソプロピルアルコール等)、水等が挙げられる。これらの溶媒は単独あるいは二種以上を適当な割合(例、1：1ないし1：100(容積比))で混合して用いられる。必要に応じて種晶を使用することもできる。 The “crystallization from solution” is a state not saturated by changing the factor related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of solvent. The transition from the above to the supersaturated state is general, and specific examples include a concentration method, a slow cooling method, a reaction method (a diffusion method, an electrolytic method), a hydrothermal growth method, a flux agent method and the like. As the solvent to be used, for example, aromatic hydrocarbons (eg, benzene, toluene, xylene etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane) Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane etc.), nitriles (eg, acetonitrile etc.), ketones (eg, acetone etc.), sulfoxides (eg, dimethyl sulfoxide etc.) And acid amides (eg, N, N-dimethylformamide and the like), esters (eg, ethyl acetate and the like), alcohols (eg, methanol, ethanol, isopropyl alcohol and the like), water and the like. These solvents may be used alone or in combination of two or more kinds in an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). Seed crystals can also be used as needed.
　該「蒸気からの結晶化法」としては、例えば、気化法(封管法、気流法)、気相反応法、化学輸送法等が挙げられる。 Examples of the “crystallization from vapor” include a vaporization method (a sealed tube method, a gas flow method), a gas phase reaction method, a chemical transport method and the like.
　該「溶融体からの結晶化法」としては、例えば、ノルマルフリージング法(引上げ法、温度傾斜法、ブリッジマン法)、帯溶融法(ゾーンレベリング法、フロートゾーン法)、特殊成長法(VLS法、液相エピタキシー法)等が挙げられる。 Examples of the “crystallization method from a melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method) And liquid phase epitaxy methods).
　結晶化法の好適な例としては、化合物（Ｉ）を20～120℃の温度下において、適当な溶媒(例、メタノール、エタノール等のアルコール類等)に溶解し、得られる溶液を溶解時の温度以下(例えば、0～50℃、好ましくは0～20℃)に冷却する方法等が挙げられる。
　このようにして得られる本発明の結晶は、例えば、ろ過等によって単離することができる。
　得られた結晶の解析方法としては、粉末X線回折による結晶解析の方法が一般的である。さらに、結晶の方位を決定する方法としては、例えば、機械的な方法または光学的な方法等も挙げられる。 As a suitable example of the crystallization method, compound (I) is dissolved in an appropriate solvent (eg, alcohols such as methanol, ethanol etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved A method of cooling to a temperature or lower (for example, 0 to 50 ° C., preferably 0 to 20 ° C.), and the like can be mentioned.
The crystals of the present invention thus obtained can be isolated, for example, by filtration and the like.
As an analysis method of the obtained crystals, a method of crystal analysis by powder X-ray diffraction is generally used. Furthermore, as a method of determining the orientation of the crystal, for example, a mechanical method or an optical method may be mentioned.
　上記の製造法で得られる化合物（Ｉ）の結晶（以下、「本発明の結晶」と略記する）は、高純度、高品質であり、吸湿性が低く、通常条件下で長期間保存しても変質せず、安定性に極めて優れている。また、生物学的性質（例、体内動態（吸収性、分布、代謝、排泄）、薬効発現等）にも優れることが期待され、医薬として有用であり得る。 The crystals of the compound (I) obtained by the above production method (hereinafter abbreviated as "the crystals of the present invention") have high purity and high quality, low hygroscopicity, and are stored for a long time under ordinary conditions It does not deteriorate nor is extremely excellent in stability. It is also expected to be excellent in biological properties (eg, in vivo pharmacokinetics (absorptivity, distribution, metabolism, excretion), medicinal effect etc.), and may be useful as a medicine.
　本明細書中、比旋光度([α]Ｄ)は、例えば、旋光度計(日本分光(JASCO)、P－1030型旋光計(No．AP－2))等を用いて測定される比旋光度を意味する。
　本明細書中、融点は、例えば、微量融点測定器(ヤナコ、MP－500D型)またはDSC(示差走査熱量分析)装置(SEIKO，EXSTAR6000)等を用いて測定される融点を意味する。 In the present specification, the specific rotation ([α] D ) is, for example, a ratio measured using an optical polarimeter (JASCO (JASCO), P-1030 polarimeter (No. AP-2)) or the like. Means optical rotation.
In the present specification, the melting point means, for example, a melting point measured using a micro melting point apparatus (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR 6000) or the like.
　化合物（Ｉ）はプロドラッグとして用いてもよい。化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）に変化する化合物、胃酸等により加水分解等を起こして化合物（Ｉ）に変化する化合物をいう。 Compound (I) may be used as a prodrug. The prodrug of compound (I) is a compound which is converted to compound (I) by reaction with an enzyme or gastric acid under physiological conditions in vivo, that is, enzymatically causes oxidation, reduction, hydrolysis and the like to produce compound (I) Or a compound which is converted to a compound (I) by hydrolysis or the like by gastric acid or the like.
　化合物（Ｉ）のプロドラッグとしては、例えば、
(1) 化合物（Ｉ）のアミノがアシル化、アルキル化、りん酸化された化合物（例えば、化合物（Ｉ）のアミノが、エイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、tert-ブチル化、エトキシカルボニル化、tert-ブトキシカルボニル化、アセチル化、シクロプロピルカルボニル化された化合物等）；
(2) 化合物（Ｉ）のヒドロキシが、アシル化、アルキル化、りん酸化、ホウ酸化された化合物（例えば、化合物（Ｉ）のヒドロキシが、アセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等）；
(3) 化合物（Ｉ）のカルボキシが、エステル化、アミド化された化合物（例えば、化合物（Ｉ）のカルボキシが、エチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等）；
等が挙げられる。これらの化合物は、自体公知の方法によって化合物（Ｉ）から製造することができる。 As a prodrug of compound (I), for example,
(1) Compound (I) wherein the amino is acylated, alkylated and phosphorylated (for example, the amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-carbonylated) Oxo-1,3-dioxolene-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropyl carbonylated compounds etc.);
(2) Compound (I) hydroxy is acylated, alkylated, phosphorylated, borated (for example, compound (I) hydroxy is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated , Fumarylation, alanylation, dimethylaminomethylcarbonylated compounds, etc.);
(3) Compounds in which the carboxy of compound (I) is esterified or amidated (eg, the carboxy of compound (I) is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethylesterified, pi Baroyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methyl amide Compounds etc.);
Etc. These compounds can be produced from compound (I) by a method known per se.
　また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような生理的条件で化合物（Ｉ）に変化するものであってもよい。 In addition, prodrugs of Compound (I) are those which change into Compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals,” Volume 7, Molecular Design, pages 163 to 198. It may be.
　本明細書中、化合物（Ｉ）、およびそのプロドラッグを纏めて「本発明化合物」と略記する場合がある。 In the present specification, compound (I) and a prodrug thereof may be collectively referred to as “the compound of the present invention”.
　化合物（Ｉ）は、水和物、非水和物、溶媒和物、無溶媒和物のいずれであってもよい。
　同位元素（例、３Ｈ、１４Ｃ、３５Ｓ、１２５Ｉ等）等で標識された化合物も、化合物（Ｉ）に包含される。
　さらに、１Ｈを２Ｈ（Ｄ）に変換した重水素変換体も、化合物（Ｉ）に包含される。
　互変異性体も、化合物（Ｉ）に包含される。
　化合物（Ｉ）は、薬学的に許容され得る共結晶または共結晶塩であってもよい。ここで、共結晶または共結晶塩とは、各々が異なる物理的特性（例えば、構造、融点、融解熱、吸湿性、溶解性および安定性等）を持つ、室温で二種またはそれ以上の独特な固体から構成される結晶性物質を意味する。共結晶または共結晶塩は、自体公知の共結晶化法に従い製造することができる。
　化合物（Ｉ）は、ＰＥＴトレーサーとして用いてもよい。 Compound (I) may be any of hydrate, non-hydrate, solvate, non-solvate.
Compounds labeled with isotopes (eg, 3 H, 14 C, 35 S, 125 I, etc.) are also encompassed in compound (I).
Furthermore, a deuterium converter wherein 1 H is converted to 2 H (D) is also encompassed in compound (I).
Tautomers are also encompassed in compound (I).
Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.) Mean crystalline substance composed of solid. Co-crystals or co-crystal salts can be prepared according to co-crystallization methods known per se.
Compound (I) may be used as a PET tracer.
　本発明化合物は、優れたＪＡＫ（ＪＡＫ１、ＪＡＫ２、ＪＡＫ３、ＴＹＫ２）阻害作用を有し得ることから、この作用に基づく安全な医薬としても有用であり得る。
　本発明化合物はまた、ＩＦＮ－α阻害作用、ＩＦＮ－β阻害作用、ＩＦＮ－γ阻害剤、ＩＬ－２阻害剤、ＩＬ－４阻害剤、ＩＬ－７阻害剤、ＩＬ－１５阻害剤、ＩＬ－２１阻害剤、ＩＬ－６阻害作用、ＯＳＭ阻害剤、ＩＬ－１０阻害作用、ＩＬ－１９阻害作用、ＩＬ－２０阻害作用、ＩＬ－２２阻害作用、ＩＬ－２８阻害作用、ＩＬ－２９阻害作用、ＩＬ－１２阻害作用、および／又はＩＬ－２３阻害作用（好ましくは、ＩＬ－２３阻害作用）を有し得ることから、この作用に基づく安全な医薬としても有用であり得る。
　例えば、本発明化合物を含有してなる本発明の医薬は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト等）に対して、ＪＡＫ関連疾患、より具体的には、以下（１）～（６）に記載の疾患の予防または治療剤として用い得る。
（１）炎症性疾患（例、急性膵炎、慢性膵炎、喘息、成人呼吸困難症候群、慢性閉塞性肺疾患（ＣＯＰＤ）、炎症性骨疾患、炎症性肺疾患、炎症性腸疾患、セリアック病、肝炎、全身性炎症反応症候群（ＳＩＲＳ）、手術または外傷後の炎症、肺炎（突発性肺繊維症（ＩＰＦ）を含む突発性間質性肺炎など）、腎炎、髄膜炎、膀胱炎、咽喉頭炎、胃粘膜損傷、髄膜炎、脊椎炎、関節炎、皮膚炎、慢性肺炎、気管支炎、肺梗塞、珪肺症、肺サルコイドーシス、ブドウ膜炎、化膿性汗腺炎、虚血再灌流障害、痛風（例、急性痛風等）、花粉症、急性腎傷害、クリオピリン関連周期性症候群（ＣＡＰＳ）、円形脱毛症、白斑等）、
（２）自己免疫疾患（例、関節リウマチ、乾癬、炎症性腸疾患（例、クローン病、潰瘍性大腸炎等）、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス、ループス腎炎、円板状紅斑性狼瘡、キャッスルマン病、強直性脊椎炎、多発性筋炎、皮膚筋炎（ＤＭ）、結節性多発性動脈炎（ＰＮ）、混合性結合性組織症（ＭＣＴＤ）、強皮症、深在性紅斑性狼瘡、慢性甲状腺炎、橋本甲状腺炎、グレーブス病、自己免疫性胃炎、Ｉ型およびＩＩ型糖尿病、自己免疫性溶血性貧血、自己免疫性好中球減少症、血小板減少症、アトピー性皮膚炎、慢性活動性肝炎、重症筋無力症、臓器移植拒絶、移植片対宿主疾患、アジソン病、異常免疫応答、関節炎、皮膚炎、放射線皮膚炎、原発性胆汁性肝硬変、酒さ等）、
（３）骨・関節変性疾患（例、関節リウマチ、骨粗鬆症、変形性関節症等）、
（４）腫瘍性疾患〔例、悪性腫瘍、血管新生緑内障、幼児性血管腫、多発性骨髄腫、急性骨髄芽球性白血病、慢性肉腫、多発性骨髄腫、転移黒色腫、カポジ肉腫、血管増殖、悪液質、乳癌の転移等、癌（例、大腸癌（例、家族性大腸癌、遺伝性非ポリポーシス大腸癌、消化管間質腫瘍など）、肺癌（例、非小細胞肺癌、小細胞肺癌、悪性中皮腫など）、中皮腫、膵臓癌（例、膵管癌など）、胃癌（例、乳頭腺癌、粘液性腺癌、腺扁平上皮癌など）、乳癌（例、浸潤性乳管癌、非浸潤性乳管癌、炎症性乳癌など）、卵巣癌（例、上皮性卵巣癌、性腺外胚細胞腫瘍、卵巣性胚細胞腫瘍、卵巣低悪性度腫瘍など）、前立腺癌（例、ホルモン依存性前立腺癌、ホルモン非依存性前立腺癌など）、肝臓癌（例、原発性肝癌、肝外胆管癌など）、甲状腺癌（例、甲状腺髄様癌など）、腎臓癌（例、腎細胞癌、腎盂と尿管の移行上皮癌など）、子宮癌、脳腫瘍（例、松果体星細胞腫瘍、毛様細胞性星細胞腫、びまん性星細胞腫、退形成性星細胞腫など）、黒色腫（メラノーマ）、肉腫、膀胱癌、多発性骨髄腫を含む血液癌等、下垂体腺腫、神経膠腫、聴神経鞘腫、網膜肉腫、咽頭癌、喉頭癌、舌癌、胸腺腫、食道癌、十二指腸癌、結腸癌、直腸癌、肝細胞癌、膵内分泌腫瘍、胆管癌、胆嚢癌、陰茎癌、尿管癌、精巣腫瘍、外陰癌、子宮頚部癌、子宮体部癌、子宮肉腫、絨毛性疾患、膣癌、皮膚癌、菌状息肉症、基底細胞腫、軟部肉腫、悪性リンパ腫、ホジキン病、骨髄異形成症候群、成人Ｔ細胞白血病、慢性骨髄増殖性疾患、膵内分泌腫瘍、線維性組織球腫、平滑筋肉腫、横紋筋肉腫、原発不明癌など）、活性化Ｂ細胞様びまん性大細胞型Ｂ細胞性リンパ腫（ＡＢＣ－ＤＬＢＣＬ）、白血病（例、急性白血病（例、急性リンパ性白血病、急性骨髄性白血病など）、慢性白血病（例、慢性リンパ性白血病、慢性骨髄性白血病など）、骨髄形成症候群など）、子宮肉腫（例、子宮中胚葉性混合腫瘍、子宮平滑筋肉腫、子宮内膜間質腫瘍など）、骨髄線維症など〕、
（５）中枢性疾患（例、統合失調症、アルツハイマー病（例、アルツハイマー型認知症））、
（６）疼痛（例、神経因性疼痛、糖尿病性疼痛、筋線維症、術後疼痛、癌性疼痛、炎症性疼痛、偏頭痛、神経痛、筋肉痛等）。 The compounds of the present invention may have excellent JAK (JAK1, JAK2, JAK3, TYK2) inhibitory activity, and may be useful as safe medicines based on this activity.
The compounds of the present invention can also be used to inhibit IFN-α, IFN-β, IFN-γ, IL-2 inhibitor, IL-4 inhibitor, IL-7 inhibitor, IL-15 inhibitor, IL- 21 inhibitor, IL-6 inhibitory action, OSM inhibitor, IL-10 inhibitory action, IL-19 inhibitory action, IL-20 inhibitory action, IL-22 inhibitory action, IL-28 inhibitory action, IL-29 inhibitory action, Since it may have an IL-12 inhibitory action and / or an IL-23 inhibitory action (preferably, an IL-23 inhibitory action), it may also be useful as a safe medicine based on this action.
For example, the medicament of the present invention comprising the compound of the present invention is a JAK-related disease for a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.) More specifically, it can be used as a preventive or therapeutic agent for the diseases described in (1) to (6) below.
(1) inflammatory diseases (eg, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis , Systemic inflammatory response syndrome (SIRS), inflammation after surgery or trauma, pneumonia (such as spontaneous interstitial pneumonia including idiopathic pulmonary fibrosis (IPF)), nephritis, meningitis, cystitis, laryngopharyngitis , Gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, uveitis, suppurative sweat adenosis, ischemia reperfusion injury, gout (eg , Acute gout etc.), hay fever, acute kidney injury, Cliopyrin related periodic syndrome (CAPS), alopecia areata, vitiligo etc),
(2) Autoimmune disease (eg, rheumatoid arthritis, psoriasis, inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis etc.), Sjögren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, yen Platelet erythematous plaque, Castleman's disease, ankylosing spondylitis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, deep Spotted lupus erythema, chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, autoimmune gastritis, type I and II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy Dermatitis, chronic active hepatitis, myasthenia gravis, organ transplant rejection, graft vs. host disease, Addison's disease, abnormal immune response, arthritis, dermatitis, radiation dermatitis, primary biliary cirrhosis, rosacea etc.) ,
(3) Bone and joint degenerative diseases (eg, rheumatoid arthritis, osteoporosis, osteoarthritis, etc.),
(4) Tumorous diseases [eg, malignant tumors, neovascular glaucoma, infantile hemangioma, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, multiple myeloma, metastatic melanoma, Kaposi sarcoma, vascular growth , Cachexia, metastasis of breast cancer, cancer (eg, colon cancer (eg, familial colorectal cancer, hereditary non-polyposis colon cancer, gastrointestinal stromal tumor etc.), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, etc) Lung cancer, malignant mesothelioma etc.), mesothelioma, pancreatic cancer (eg, pancreatic ductal cancer etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma etc.), breast cancer (eg, invasive breast ducts) Cancer, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low grade tumor), prostate cancer (eg, Hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), liver cancer (eg, primary liver cancer, extrahepatic cholangiocarcinoma, etc.), thyroid cancer For example, medullary thyroid carcinoma, etc., kidney cancer (eg, renal cell carcinoma, transitional cell carcinoma of the renal pelvis and ureter), uterine cancer, brain tumor (eg, pineal astrocytic tumor, cholecystic astrocytoma) , Diffuse astrocytoma, anaplastic astrocytoma etc.), melanoma (melanoma), sarcoma, bladder cancer, hematologic cancer including multiple myeloma, etc., pituitary adenoma, glioma, auditory schwannoma, retina Sarcoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thymoma, esophagus cancer, duodenal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic endocrine cancer, cholangiocarcinoma, gallbladder cancer, penile cancer, ureteral cancer, testicular cancer, Vulvar cancer, cervical cancer, endometrial cancer, uterine sarcoma, chorionic disease, vaginal cancer, skin cancer, mycosis fungoides, basal cell carcinoma, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T Cell leukemia, chronic myeloproliferative disorder, pancreatic endocrine tumor, fibrotic histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary origin Etc.) activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), leukemia (eg acute leukemia (eg acute lymphocytic leukemia, acute myeloid leukemia etc.), chronic leukemia (eg chronic) Lymphoid leukemia, chronic myelogenous leukemia etc.), myelogenesis syndrome etc.), uterine sarcoma (eg, uterine mesodermal mixed tumor, uterine leiomyosarcoma, endometrial stromal tumor etc), myelofibrosis etc.),
(5) central diseases (eg, schizophrenia, Alzheimer's disease (eg, Alzheimer's disease)),
(6) Pain (eg, neuropathic pain, diabetic pain, myofibrosis, post-operative pain, cancer pain, inflammatory pain, migraine headache, neuralgia, myalgia etc.).
　本発明の医薬は、好ましくは、自己免疫疾患、炎症性疾患、骨・関節変性疾患、中枢性疾患または腫瘍性疾患、さらに好ましくは、全身性エリテマトーデス、炎症性腸疾患（好ましくは、クローン病または潰瘍性大腸炎）、関節リウマチ、乾癬、シェーグレン症候群、ベーチェット病、多発性硬化症、、アトピー性皮膚炎、アルツハイマー病（好ましくは、アルツハイマー型認知症）、キャッスルマン病、白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、または骨髄線維症の予防または治療剤として用い得る。
　ここで、上記疾患の「予防」とは、例えば、当該疾患に関連する何らかの因子により、発症の危険性が高いと予想される当該疾患を発症していない患者あるいは発症しているが自覚症状のない患者に対し、本発明の化合物を含む医薬を投与すること、あるいは当該疾患治療後、当該疾患の再発が懸念される患者に対し、本発明の化合物を含む医薬を投与することを意味する。 The medicament of the present invention is preferably an autoimmune disease, an inflammatory disease, a bone / joint degeneration disease, a central disease or a neoplastic disease, more preferably a systemic lupus erythematosus, an inflammatory bowel disease (preferably Crohn's disease or preferably) Ulcerative colitis), rheumatoid arthritis, psoriasis, Sjogren's syndrome, Behcet's disease, multiple sclerosis, atopic dermatitis, Alzheimer's disease (preferably Alzheimer's disease), Castleman's disease, leukemia, uterine leiomyosarcoma It can be used as a prophylactic or therapeutic agent for prostate cancer, multiple myeloma, cachexia, or myelofibrosis.
Here, “prevention” of the above-mentioned disease refers to, for example, a patient who does not develop the disease or who has developed the disease which is expected to have a high risk of onset due to any factor related to the disease. It means administering a drug containing the compound of the present invention to a non-patient, or administering a drug containing the compound of the present invention to a patient who is concerned about recurrence of the disease after treatment of the disease.
　本発明の医薬は、体内動態（例、血中薬物半減期）に優れ、毒性が低く（例、ＨＥＲＧ阻害、ＣＹＰ阻害、ＣＹＰ誘導）、細胞傷害性の軽減、ＪＡＫ選択性向上に基づく副作用の軽減および薬物相互作用の軽減が認められる。本発明化合物をそのまま、あるいは医薬製剤の製造法で一般的に用いられている自体公知の手段に従って、薬理学的に許容される担体と混合して医薬組成物とし、本発明の医薬として使用し得る。本発明の医薬は、哺乳動物（例えば、ヒト、サル、ウシ、ウマ、ブタ、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ヒツジ、ヤギ等）に対して、経口的、または非経口的に安全に投与し得る。
　本発明の化合物を含有する医薬は、医薬製剤の製造法として自体公知の方法（例、日本薬局方記載の方法等）に従って、本発明化合物を単独で、または本発明化合物と薬理学的に許容される担体とを混合した医薬組成物として使用し得る。本発明の化合物を含有する医薬は、例えば錠剤（糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む）、丸剤、散剤、顆粒剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤（例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤）、エアゾール剤、フィルム剤（例、口腔内崩壊フィルム、口腔粘膜貼付フィルム）、注射剤（例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤）、点滴剤、経皮吸収型製剤、クリーム剤、軟膏剤、ローション剤、貼付剤、坐剤（例、肛門坐剤、膣坐剤）、ペレット、経鼻剤、経肺剤（例、吸入剤）、点眼剤等として、経口的または非経口的（例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位、病巣等）に安全に投与し得る。
　本発明化合物の、本発明の医薬中の含有量は、医薬全体の約０．０１重量％～約１００重量％である。該投与量は、投与対象、投与ルート、疾患等により異なり得るが、例えば、関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、アトピー性皮膚炎、全身性エリテマトーデス、キャッスルマン病（Castleman’s disease）、白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等の患者（体重約６０ｋｇ）に対し、経口剤として、１日当たり、有効成分（化合物（Ｉ）のフリー体）として約０．０１ｍｇ／ｋｇ体重～約５００ｍｇ／ｋｇ体重、好ましくは約０．１ｍｇ／ｋｇ体重～約５０ｍｇ／ｋｇ体重、さらに好ましくは約１ｍｇ／ｋｇ体重～３０ｍｇ／ｋｇ体重を、１日１回～数回に分けて投与すればよい。
　本発明の医薬の製造に用いられてもよい薬理学的に許容される担体としては、医薬素材として慣用の各種有機あるいは無機担体物質を含み得、例えば、固形製剤における賦形剤、滑沢剤、結合剤および崩壊剤、あるいは液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤および無痛化剤を用い得る。更に必要に応じ、通常の防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加物を適宜、適量用い得る。 The medicament of the present invention is excellent in pharmacokinetics (eg, drug half-life in blood), low in toxicity (eg, HERG inhibition, CYP inhibition, CYP induction), alleviation of cytotoxicity, and side effects based on JAK selectivity improvement Reduction and reduction of drug interactions are noted. The compound of the present invention is used as it is or as a pharmaceutical composition by mixing it with a pharmacologically acceptable carrier according to a means known per se generally used in the method of producing a pharmaceutical preparation, and used as a medicament of the present invention obtain. The medicament of the present invention is orally or parenterally to mammals (eg, humans, monkeys, cattle, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) It can be administered safely.
The pharmaceutical composition containing the compound of the present invention may be a compound of the present invention alone or pharmacologically acceptable with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, the method described in Japanese Pharmacopoeia etc.) Can be used as a pharmaceutical composition mixed with the carrier. The medicaments containing the compound of the present invention are, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets and the like), pills, powders, granules, capsules (soft capsules, micro capsules Capsules, troches, syrups, solutions, emulsions, suspensions, controlled release formulations (eg, immediate release formulations, sustained release formulations, sustained release microcapsules), aerosols, films (including capsules) For example, orally disintegrating film, oral mucous membrane adhering film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, cream, Orally or parenterally as an ointment, lotion, patch, suppository (eg, anal suppository, vaginal suppository), pellet, transnasal agent, pulmonary agent (eg, inhalant), eye drops, etc. (Eg, intravenous, intramuscular, subcutaneous, in organs, nasal cavity , Intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, tumor interior, proximal tumors may be safely administered into a lesion, etc.).
The content of the compound of the present invention in the medicament of the present invention is about 0.01% by weight to about 100% by weight of the whole medicament. The dose may vary depending on the administration subject, administration route, disease, etc. For example, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, atopic dermatitis, systemic lupus erythematosus, Active ingredient per day as an oral agent for patients with Castleman's disease (Castleman's disease), leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis etc. (body weight about 60 kg) (Free compound of Compound (I)) about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 50 mg / kg body weight, more preferably about 1 mg / kg body weight to 30 mg The / kg body weight may be divided and administered once to several times a day.
The pharmacologically acceptable carrier which may be used for producing the medicament of the present invention may contain various organic or inorganic carrier substances commonly used as a pharmaceutical material, for example, an excipient in a solid preparation, a lubricant Binders and disintegrants, or solvents in liquid formulations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents may be used. Furthermore, as necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like may be suitably used in appropriate amounts.
　賦形剤としては、例えば、乳糖、白糖、Ｄ－マンニトール、デンプン、コーンスターチ、結晶セルロース、軽質無水ケイ酸等が挙げられる。
　滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。
　結合剤としては、例えば、結晶セルロース、白糖、Ｄ－マンニトール、デキストリン、ヒドロキシプロピルセルロース、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、デンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム等が挙げられる。
　崩壊剤としては、例えば、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、Ｌ－ヒドロキシプロピルセルロース等が挙げられる。
　溶剤としては、例えば、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、オリーブ油等が挙げられる。
　溶解補助剤としては、例えば、ポリエチレングリコール、プロピレングリコール、Ｄ－マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。
　懸濁化剤としては、例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤；例えば、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等が挙げられる。 As the excipient, for example, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned.
As the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be mentioned.
As the binder, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like can be mentioned.
As the disintegrant, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, L-hydroxypropylcellulose and the like can be mentioned.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc .; for example, polyvinyl alcohol, polyvinyl pyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.
　等張化剤としては、例えば、ブドウ糖、Ｄ－ソルビトール、塩化ナトリウム、グリセリン、Ｄ－マンニトール等が挙げられる。
　緩衝剤としては、例えば、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液等が挙げられる。
　無痛化剤としては、例えば、ベンジルアルコール等が挙げられる。
　防腐剤としては、例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェニルエチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。
　抗酸化剤としては、例えば、亜硫酸塩、アスコルビン酸、α－トコフェロール等が挙げられる。 Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
As the soothing agent, for example, benzyl alcohol and the like can be mentioned.
Examples of preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.
　各種疾患の予防・治療に際し、本発明化合物は、他の薬剤と共に用い得る。以下、本発明化合物と他の薬物の併用時に使用する医薬を「本発明の併用剤」と称する。
　例えば、本発明化合物がＪＡＫファミリー阻害剤、ＩＦＮ－α阻害剤、ＩＦＮ－β阻害剤、ＩＦＮ－γ阻害剤、ＩＬ－２阻害剤、ＩＬ－４阻害剤、ＩＬ－７阻害剤、ＩＬ－１５阻害剤、ＩＬ－２１阻害剤、ＩＬ－６阻害剤、ＯＳＭ阻害剤、ＩＬ－１０阻害剤、ＩＬ－１９阻害剤、ＩＬ－２０阻害剤、ＩＬ－２２阻害剤、ＩＬ－２８阻害剤、ＩＬ－２９阻害剤、ＩＬ－１２阻害剤、および／またはＩＬ－２３阻害剤として用いられる場合、以下の薬物と併用し得る。
（１）非ステロイド性抗炎症薬（ＮＳＡＩＤｓ）
（i）Ｃｌａｓｓｉｃａｌ　ＮＳＡＩＤｓ
　アルコフェナク、アセクロフェナク、スリンダク、トルメチン、エトドラク、フェノプロフェン、チアプロフェン酸、メクロフェナム酸、メロキシカム、テオキシカム、ロルノキシカム、ナブメトン、アセトアミノフェン、フェナセチン、エテンザミド、スルピリン、アンチピリン、ミグレニン、アスピリン、メフェナム酸、フルフェナム酸、ジクロフェナックナトリウム、ロキソプロフェンナトリウム、フェニルブタゾン、インドメタシン、イブプロフェン、ケトプロフェン、ナプロキセン、オキサプロジン、フルルビプロフェン、フェンブフェン、プラノプロフェン、フロクタフェニン、ピロキシカム、エピリゾール、塩酸チアラミド、ザルトプロフェン、メシル酸ガベキサート、メシル酸カモスタット、ウリナスタチン、コルヒチン、プロベネシド、スルフィンピラゾン、ベンズブロマロン、アロプリノール、金チオリンゴ酸ナトリウム、ヒアルロン酸ナトリウム、サリチル酸ナトリウム、塩酸モルヒネ、サリチル酸、アトロピン、スコポラミン、モルヒネ、ペチジン、レボルファノール、オキシモルフォンまたはその塩等。
（ii）シクロオキシゲナーゼ抑制薬（ＣＯＸ－１選択的阻害薬、ＣＯＸ－２選択的阻害薬等）
　サリチル酸誘導体（例、セレコキシブ、アスピリン）、エトリコキシブ、バルデコキシブ、ジクロフェナック、インドメタシン、ロキソプロフェン等。
（iii）Ｎｉｔｒｉｃ　ｏｘｉｄｅ遊離型　ＮＳＡＩＤｓ
（iv）ＪＡＫ阻害薬
　トファシチニブ（Ｔｏｆａｃｉｔｉｎｉｂ）、ルキソリチニブ（Ｒｕｘｏｌｉｔｉｎｉｂ）等。 In the prevention and treatment of various diseases, the compound of the present invention can be used together with other agents. Hereinafter, a drug used in combination of the compound of the present invention and another drug is referred to as "combination drug of the present invention".
For example, the compound of the present invention is a JAK family inhibitor, IFN-α inhibitor, IFN-β inhibitor, IFN-γ inhibitor, IL-2 inhibitor, IL-4 inhibitor, IL-7 inhibitor, IL-15 Inhibitor, IL-21 inhibitor, IL-6 inhibitor, OSM inhibitor, IL-10 inhibitor, IL-19 inhibitor, IL-20 inhibitor, IL-22 inhibitor, IL-28 inhibitor, IL When used as -29 inhibitor, IL-12 inhibitor, and / or IL-23 inhibitor, it may be used in combination with the following drugs.
(1) Non-steroidal anti-inflammatory drugs (NSAIDs)
(I) Classical NSAIDs
Alcofenac, Aceclofenac, Sulindac, Tolmetin, Etodolac, Fenoprofen, Thiaprofenic Acid, Meclofenamic Acid, Meloxicam, Texicam, Lonoxycam, Nabumetone, Acetaminophen, Phenacetin, Etenzamide, Supilin, Antipyrin, Migrenin, Aspirin, Mefenamic Acid, Diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctachenine, piroxicam, epirisol, tiaramide hydrochloride, saltoprofen, gabexate mesilate camostat, camostat for mesilate Urinastatin, colchicine, Robeneshido, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof.
(Ii) Cyclooxygenase inhibitors (COX-1 selective inhibitors, COX-2 selective inhibitors, etc.)
Salicylic acid derivatives (eg celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen etc.
(Iii) Nitric oxide free type NSAIDs
(Iv) JAK inhibitors Tofacitinib (Tofacitinib), luxolitinib (Ruxolitinib) and the like.
（２）疾患修飾性抗リウマチ薬（ＤＭＡＲＤｓ）
（i）金製剤
　Ａｕｒａｎｏｆｉｎ等。
（ii）ペニシラミン
　Ｄ－ペニシラミン。
（iii）アミノサルチル酸製剤
　スルファサラジン、メサラミン、オルサラジン、バルサラジド。
（iv）抗マラリア薬
　クロロキン等。
（v）ピリミジン合成阻害薬
　レフルノマイド等。
（vi）プログラフ (2) Disease-modifying anti-rheumatic drugs (DMARDs)
(I) Gold preparation Auranofin et al.
(Ii) Penicillamine D-Penicillamine.
(Iii) Aminosalicylic acid preparation sulfasalazine, mesalamine, olsalazine, balsalazide.
(Iv) antimalarial drug chloroquine etc.
(V) Pyrimidine synthesis inhibitor leflunomide etc.
(Vi) Prograph
（３）抗サイトカイン薬
（I）タンパク質製剤
（i）ＴＮＦ阻害薬
　エタナーセプト、インフリキシマブ、アダリムマブ、セルトリズマブ　ペゴール、ゴリムマブ、PASSTNF-α、可溶性TNF-α受容体、TNF-α結合蛋白、抗TNF-α抗体等。
（ii）インターロイキン－１阻害薬
　アナキンラ(インターロイキン-1受容体拮抗薬)、可溶性インターロイキン-1受容体等。
（iii）インターロイキン－６阻害薬
　トシリズマブ (抗インターロイキン-6受容体抗体)、抗インターロイキン-6抗体等。
（iv）インターロイキン－１０薬
　インターロイキン-１０等。
（v）インターロイキン－１２/２３阻害薬
　ウステキヌマブ、ブリアキヌマブ（抗インターロイキン-12/23抗体）等。
（II）非タンパク質製剤
（i）ＭＡＰＫ阻害薬
　BMS-582949等。
（ii）遺伝子調節薬
　NF-κ, NF-κB, IKK-1, IKK-2, AP-1等シグナル伝達に関係する分子の阻害薬等。
（iii）サイトカイン産生抑制薬
　イグラチモド、テトミラスト等。
（iv）ＴＮＦ－α変換酵素阻害薬
（v）インターロイキン-1β変換酵素阻害薬
　VX-765等。
（vi）インターロイキン－６拮抗薬
　HMPL-004等。
（vii）インターロイキン－８阻害薬
　IL-8拮抗薬、CXCR1 & CXCR2拮抗薬、レパレキシン等。
（viii）ケモカイン拮抗薬
　CCR9拮抗薬（CCX-282, CCX-025）、MCP-1拮抗薬等。
（ix）インターロイキン－２受容体拮抗薬
　デニロイキン、ディフチトックス等。
（x）Ｔｈｅｒａｐｅｕｔｉｃ　ｖａｃｃｉｎｅｓ
　TNF-αワクチン等。
（xi）遺伝子治療薬
　インターロイキン-4、インターロイキン-10、可溶性インターロイキン-1受容体、可溶性TNF-α受容体等抗炎症作用を有する遺伝子の発現を亢進させることを目的とした遺伝子治療薬。
（xii）アンチセンス化合物
　ISIS-104838等。 (3) Anti-cytokine drug (I) protein preparation (i) TNF inhibitor etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α antibody etc.
(Ii) Interleukin-1 inhibitor Anakinra (Interleukin-1 receptor antagonist), soluble interleukin-1 receptor and the like.
(Iii) Interleukin-6 inhibitor Tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody, etc.
(Iv) Interleukin-10 Drug Interleukin-10 and the like.
(V) Interleukin-12 / 23 inhibitors Ustekinumab, Briaquinumab (anti-interleukin-12 / 23 antibody) and the like.
(II) Non-protein preparation (i) MAPK inhibitor BMS-582949 and the like.
(Ii) Gene regulatory agents Inhibitors of molecules involved in signal transduction such as NF-κ, NF- 阻 害 B, IKK-1, IKK-2, AP-1.
(Iii) Cytokine production inhibitor Igratimod, tetomilast and the like.
(Iv) TNF-α converting enzyme inhibitor (v) interleukin-1β converting enzyme inhibitor VX-765 and the like.
(Vi) interleukin-6 antagonist HMPL-004 and the like.
(Vii) interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist, repalexin and the like.
(Viii) Chemokine antagonists CCR9 antagonists (CCX-282, CCX-025), MCP-1 antagonists and the like.
(Ix) interleukin-2 receptor antagonist denileukin, diftitox and the like.
(X) Therapeutic vaccines
TNF-α vaccine etc.
(Xi) Gene therapeutic agent A gene therapeutic agent aiming to enhance the expression of a gene having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF-α receptor .
(Xii) antisense compound ISIS-104838 and the like.
（４）インテグリン阻害薬
　ナタリズマブ、ベドリズマブ、AJM300、TRK-170、E-6007等。
（５）免疫調節薬（免疫抑制薬）
　メトトレキサート、シクロフォスファミド、MX-68、アチプリモド ディハイドロクロライド、BMS-188667、CKD-461、リメクソロン、シクロスポリン、タクロリムス、グスペリムス、アザチオプリン、抗リンパ血清、乾燥スルホ化免疫グロブリン、エリスロポイエチン、コロニー刺激因子、インターロイキン、インターフェロン等。
（６）ステロイド薬
　デキサメサゾン、ヘキセストロール、メチマゾール、ベタメサゾン、トリアムシノロン、トリアムシノロンアセトニド、フルオシノニド、フルオシノロンアセトニド、プレドニゾロン、メチルプレドニゾロン、酢酸コルチゾン、ヒドロコルチゾン、フルオロメトロン、プロピオン酸ベクロメタゾン、エストリオール等。
（７）アンジオテンシン変換酵素阻害薬
　エナラプリル、カプトプリル、ラミプリル、リシノプリル、シラザプリル、ペリンドプリル等。 (4) Integrin inhibitors natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like.
(5) Immunomodulatory drug (immunosuppressive drug)
Methotrexate, cyclophosphamide, MX-68, atipurimodo hydrochloride, BMS-188667, CKD-461, limexolone, cyclosporin, tacrolimus, gusperimus, azathioprine, antilymphatic serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulation Factors, interleukins, interferons etc.
(6) Steroid drugs Dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol and the like.
(7) Angiotensin converting enzyme inhibitors Enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
（８）アンジオテンシンII受容体拮抗薬
　カンデサルタン、シレキセチル（ＴＣＶ－１１６）、バルサルタン、イルベサルタン、オルメサルタン、エプロサルタン等。
（９）利尿薬
　ヒドロクロロチアジド、スピロノラクトン、フロセミド、インダパミド、ベンドロフルアジド、シクロペンチアジド等。
（１０）強心薬
　ジゴキシン、ドブタミン等。
（１１）β受容体拮抗薬
　カルベジロール、メトプロロール、アテノロール等。
（１２）Ｃａ感受性増強薬
　ＭＣＣ－１３５等。
（１３）Ｃａチャネル拮抗薬
　ニフェジピン、ジルチアゼム、ベラパミル等。
（１４）抗血小板薬、抗凝固薬
　ヘパリン、アスピリン、ワルファリン等。
（１５）ＨＭＧ－ＣｏＡ還元酵素阻害薬
　アトロバスタチン、シンバスタチン等。 (8) Angiotensin II receptor antagonist candesartan, cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan and the like.
(9) Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopentiazide etc.
(10) Cardiotonics Digoxin, dobutamine etc.
(11) β receptor antagonist carvedilol, metoprolol, atenolol and the like.
(12) Ca sensitivity enhancer MCC-135 and the like.
(13) Ca channel antagonist nifedipine, diltiazem, verapamil and the like.
(14) Antiplatelet drug, anticoagulant heparin, aspirin, warfarin etc.
(15) HMG-CoA reductase inhibitor atorvastatin, simvastatin and the like.
（１６）避妊薬
（i）性ホルモンまたはその誘導体
　黄体ホルモンまたはその誘導体（プロゲステロン、17α-ヒドロキシプロゲステロン、メドロキシプロゲステロン、酢酸メドロキシプロゲステロン、ノルエチステロン、ノルエチステロンエナンタート、ノルエチンドロン、酢酸ノルエチンドロン、ノルエチノドレル、レボノルゲストレル、ノルゲストレル、二酢酸エチノジオール、デソゲストレル、ノルゲスチメート、ゲストデン、プロゲスチン、エトノゲストレル、ドロスピレノン、ジエノゲスト、トリメゲストン、ネストロン、酢酸クロマジノン、ミフェプリストン、酢酸ノメゲストロル、Org-30659、TX-525、EMM-310525）あるいは黄体ホルモンまたはその誘導体と卵胞ホルモンまたはその誘導体（エストラジオール、安息香酸エストラジオール、エストラジオールシピオネート、エストラジオールジプロピオナート、エストラジオールエナンタート、エストラジオールヘキサヒドロベンゾアート、エストラジオールフェニルプロピオナート、エストラジオールウンデカノアート、吉草酸エストラジオール、エストロン、エチニルエストラジオール、メストラノール）との合剤等。
（ii）抗卵胞ホルモン薬
　オルメロキシフェン、ミフェプリストン、Org-33628等。
（iii）殺精子薬
　ウシェルセル等。 (16) Contraceptive (i) Sex hormone or derivative thereof Luteinizing hormone or derivative thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate, norethindrone, norethindrone acetate, norethinodorone, levonorgestrel , Norgestrel, ethinodiol diacetate, desogestrel, norgestimate, gestodene, progestin, etonogestrel, drospirenone, dienogest, diemegeston, nestreone, chromazinone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM-310525) or Luteinizing hormone or its derivative and follicle hormone or its derivative (Estradiol, Estradiol Benzoate Estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol-hexahydrobenzo art, estradiol phenylpropionate Honor DOO, estradiol undecanoate, estradiol valerate, estrone, a fixed combination or the like of the ethinyl estradiol, mestranol).
(Ii) Anti-Estrogen Drugs Ormeroxifene, Mifepristone, Org-33628 and the like.
(Iii) Spermicidal agents
（１７）その他
（i）Ｔ細胞阻害薬
（ii）イノシン一リン酸脱水素酵素（ＩＭＰＤＨ）阻害薬
　マイコフェノレート モフェチル等。
（iii）接着分子阻害薬
　ISIS-2302、セレクチン阻害薬、ELAM-1、VCAM-1、ICAM-1等。
（iv）サリドマイド
（v）カテプシン阻害薬
（vi）マトリックスメタロプロテアーゼ（ＭＭＰｓ）阻害薬
　V-85546等。
（vii）グルコース－６－リン酸脱水素酵素阻害薬
（viii）Dihydroorotate脱水素酵素（ＤＨＯＤＨ）阻害薬
（ix）ホスホジエステラーゼIV（ＰＤＥIV）阻害薬
　ロフルミラスト、CG-1088等。
（x）ホスホリパーゼＡ2阻害薬
（xi）ｉＮＯＳ阻害薬
　VAS-203等。
（xii）Microtuble刺激薬
　パクリタキセル等。
（xiii）Microtuble阻害薬
　リューマコン等。
（xiv）ＭＨＣクラスII拮抗薬
（xv）Prostacyclin作働薬
　イロプロスト等。
（xvi）ＣＤ４拮抗薬
　ザノリムマブ等。
（xvii）ＣＤ２３拮抗薬
（xviii）ＬＴＢ４受容体拮抗薬
　DW-1305等。
（xix）５－リポキシゲナーゼ阻害薬
　ジリュートン等。
（xx）コリンエステラーゼ阻害薬
　ガランタミン等。
（xxi）チロシンキナーゼ阻害薬
　TYK2阻害薬（WO2010/142752）等。
（xxii）カテプシンＢ阻害薬
（xxiii）Adenosine deaminase阻害薬
　ペントスタチン等。
（xxiv）骨形成刺激薬
（xxv）ジペプチジルペプチダーゼ阻害薬
（xxvi）コラーゲン作働薬
（xxvii）Ｃａｐｓａｉｃｉｎクリーム
（xxviii）ヒアルロン酸誘導体
　シンビスク(hylan G-F 20)、オルソビスク等。
（xxix）硫酸グルコサミン
（xxx）アミプリローゼ
（xxxi）CD-20阻害薬
　リツキシマブ、イブリツモマブ、トシツモマブ、オファツマブ等。
（xxxii）BAFF阻害薬
　ベリムマブ、タバルマブ、アタシセプト、A-623等。
（xxxiii）CD52阻害薬
　アレムツズマブ等。
（xxxiv） ＩＬ－１７阻害薬
　セクキヌマブ（ＡＩＮ－４５７）、ＬＹ－２４３９８２１、ＡＭＧ８２７等。
（xxxv） PDE4阻害薬
　ロフルミラスト(Roflumilast)、アプレミラスト(Apremilast)等。 (17) Others (i) T cell inhibitor (ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil etc.
(Iii) Adhesion molecule inhibitor ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1 and the like.
(Iv) thalidomide (v) cathepsin inhibitors (vi) matrix metalloproteinase (MMPs) inhibitors V-85546 and the like.
(Vii) Glucose-6-phosphate dehydrogenase inhibitor (viii) Dihydrorotate dehydrogenase (DHODH) inhibitor (ix) phosphodiesterase IV (PDE IV) inhibitor roflumilast, CG-1088 and the like.
(X) Phospholipase A 2 inhibitor (xi) iNOS inhibitor VAS-203 and the like.
(Xii) Microtable stimulator paclitaxel and the like.
(Xiii) Microtable inhibitor Rhumacon etc.
(Xiv) MHC class II antagonist (xv) Prostacyclin agonist iloprost and the like.
(Xvi) CD4 antagonist Zanolimumab and the like.
(Xvii) CD23 antagonist (xviii) LTB4 receptor antagonist DW-1305 and the like.
(Xix) 5-lipoxygenase inhibitors zileuton etc.
(Xx) Cholinesterase inhibitor galantamine etc.
(Xxi) Tyrosine kinase inhibitor TYK2 inhibitor (WO 2010/142752) and the like.
(Xxii) Cathepsin B inhibitor (xxiii) Adenosine deaminase inhibitor Pentostatin and the like.
(Xxiv) osteogenic stimulant (xxv) dipeptidyl peptidase inhibitor (xxvi) collagen agonist (xxvii) Capsaicin cream (xxviii) hyaluronic acid derivative synbisque (hylan GF 20), ortho bisque, etc.
(Xxix) glucosamine sulfate (xxx) amiprirose (xxxi) CD-20 inhibitor rituximab, ibritumomab, tositumomab, ofatumumab and the like.
(Xxxii) BAFF inhibitors belimumab, tavarumab, atacicept, A-623 and the like.
(Xxxiii) CD52 inhibitor alemtuzumab etc.
(Xxxiv) IL-17 inhibitor secquinumab (AIN-457), LY-2439821, AMG 827 and the like.
(Xxxv) PDE4 inhibitor Roflumilast (Roflumilast), apremilast (Apremilast) and the like.
　上記以外の併用薬物としては、例えば、抗菌薬、抗真菌薬、抗原虫薬、抗生物質、鎮咳・去たん薬、鎮静薬、麻酔薬、抗潰瘍薬、不整脈治療薬、降圧利尿薬、抗凝血薬、精神安定薬、抗精神病薬、抗腫瘍薬、抗高脂血症薬、筋弛緩薬、抗てんかん薬、抗うつ薬、抗アレルギー薬、強心薬、不整脈治療薬、血管拡張薬、血管収縮薬、降圧利尿薬、糖尿病治療薬、麻薬拮抗薬、ビタミン薬、ビタミン誘導体、抗喘息薬、頻尿・尿失禁治療薬、止痒薬、アトピー性皮膚炎治療薬、アレルギー性鼻炎治療薬、昇圧薬、エンドトキシン拮抗薬あるいは抗体、シグナル伝達阻害薬、炎症性メディエーター作用抑制薬、炎症性メディエーター作用抑制抗体、抗炎症性メディエーター作用抑制薬、抗炎症性メディエーター作用抑制抗体等が挙げられる。具体的には、以下のものが挙げられる。 As combined drugs other than the above, for example, antibacterial drugs, antifungal drugs, antiprotozoal drugs, antibiotics, antitussives and expectorants, sedatives, anesthetics, antiulcer drugs, antiarrhythmic drugs, antihypertensive diuretics, anticoagulants Drugs, tranquilizers, antipsychotics, antineoplastics, antihyperlipidemics, muscle relaxants, antiepileptics, antidepressants, antiallergics, inotropics, antiarrhythmics, vasodilators, vasoconstrictors Drugs, antihypertensive diuretics, antidiabetic drugs, narcotic antagonists, vitamins, vitamin derivatives, antiasthmatic drugs, anti- urinary and urinary incontinence drugs, antidiarrheal drugs, anti-atopic dermatitis drugs, anti-allergic rhinitis drugs, vasopressor Drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator action antibodies, etc. may be mentioned. Specifically, the following may be mentioned.
（１）抗菌薬
(i)サルファ剤
　スルファメチゾール、スルフィソキサゾール、スルファモノメトキシン、スルファメチゾール、サラゾスルファピリジン、スルファジアジン銀等。
(ii)キノリン系抗菌薬
　ナリジクス酸、ピペミド酸三水和物、エノキサシン、ノルフロキサシン、オフロキサシン、トシル酸トスフロキサシン、塩酸シプロフロキサシン、塩酸ロメフロキサシン、スパルフロキサシン、フレロキサシン等。
(iii)抗結核薬
　イソニアジド、エタンブトール（塩酸エタンブトール）、パラアミノサリチル酸（パラアミノサリチル酸カルシウム）、ピラジナミド、エチオナミド、プロチオナミド、リファンピシン、硫酸ストレプトマイシン、硫酸カナマイシン、サイクロセリン等。
(iv)抗酸菌薬
　ジアフェニルスルホン、リファンピシリン等。
(v)抗ウイルス薬
　イドクスウリジン、アシクロビル、ビタラビン、ガンシクロビル等。 (1) Antimicrobial agents
(i) Sulfa drug sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.
(ii) Quinoline antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, freloxacin and the like.
(iii) Antituberculosis drug isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylic acid), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
(iv) Acid-fast fungicides such as diaphenyl sulfone and rifampicillin.
(v) antiviral agents idoxuridine, acyclovir, vitarabine, ganciclovir and the like.
(vi)抗ＨＩＶ薬
　ジドブジン、ジダノシン、ザルシタビン、硫酸インジナビルエタノール付加物、リトナビル等。
(vii)抗スピロヘータ薬
(viii)抗生物質
　塩酸テトラサイクリン、アンピシリン、ピペラシリン、ゲンタマイシン、ジベカシン、カネンドマイシン、リビドマイシン、トブラマイシン、アミカシン、フラジオマイシン、シソマイシン、テトラサイクリン、オキシテトラサイクリン、ロリテトラサイクリン、ドキシサイクリン、チカルシリン、セファロチン、セファピリン、セファロリジン、セファクロル、セファレキシン、セフロキサジン、セファドロキシル、セファマンドール、セフォトアム、セフロキシム、セフォチアム、セフォチアムヘキセチル、セフロキシムアキセチル、セフジニル、セフジトレンピボキシル、セフタジジム、セフピラミド、セフスロジン、セフメノキシム、セフポドキシムプロキセチル、セフピロム、セファゾプラン、セフェピム、セフスロジン、セフメノキシム、セフメタゾール、セフミノクス、セフォキシチン、セフブペラゾン、ラタモキナセフ、フロモキセフ、セファゾリン、セフォタキシム、セフォペラゾン、セフチゾキシム、モキサラクタム、チエナマイシン、スルファゼシン、アズスレオナムまたはそれらの塩、グリセオフルビン、ランカシジン類〔ジャーナル・オブ・アンチバイオティックス（J．Antibiotics），３８，８７７－８８５（１９８５）〕、アゾール系化合物〔２－〔（１Ｒ，２Ｒ）－２－（２，４－ジフルオロフェニル）－２－ヒドロキシ－１－メチル－３－（１Ｈ－１，２，４－トリアゾール－１－イル）プロピル〕－４－〔４－（２，２，３，３－テトラフルオロプロポキシ）フェニル〕－３－（２Ｈ，４Ｈ）－１，２，４－トリアゾロン、フルコナゾール、イトラコナゾール等〕等。 (vi) Anti-HIV drug zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir and the like.
(vii) Anti-spirochetes
(viii) Antibiotics Tetracycline hydrochloride, Ampicillin, Piperacillin, Gentamycin, Dibekacin, Kanendomycin, Lividomycin, Tobramycin, Amikacin, Fradiomycin, Sisomycin, Tetracycline, Oxytetracycline, Loritetracycline, Doxycycline, Ticarcillin, Cepharotin, Cephapirin, Cepharolizine , Cefaclor, cephalexin, cefloxazine, cefadroxil, cefaamdol, cefatoam, cefuroxime, cefotiam, cefotiam hexetil, cefroxim akicetyl, cefdoxime, cefdinir pivoxil, ceftazidime, cefpyramide, cefsulosin, cefmenoxime, cefupoxime xe Cefpirome, Cefazoplan, Cefepime, Cefuro Gin, cefmenoxim, cefmetazole, cefmetox, cefoxitin, cefbuperazone, latamoquinaef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxim, moxalactam, thiazemine, azusleonam or salts thereof, griseofulvin [[a] Antibiotics), 38, 877-885 (1985)], azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H)]. -1,2,4-Triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3- (2H, 4H) -1,2,4 -Triazolone, Flucona Lumpur, itraconazole, etc.] and the like.
（２）抗真菌薬
(i)ポリエチレン系抗生物質（例、アムホテリシンＢ、ナイスタチン、トリコマイシン）
(ii)グリセオフルビン、ピロールニトリン等
(iii)シトシン代謝拮抗薬（例、フルシトシン）
(iv)イミダゾール誘導体（例、エコナゾール、クロトリマゾール、硝酸ミコナゾール、ビホナゾール、クロコナゾール）
(v)トリアゾール誘導体（例、フルコナゾール、イトラコナゾール）
(vi)チオカルバミン酸誘導体（例、トリナフトール）等。
（３）抗原虫薬
　メトロニダゾール、チニダゾール、クエン酸ジエチルカルバマジン、塩酸キニーネ、硫酸キニーネ等。 (2) Antifungal drug
(i) Polyethylene antibiotics (eg, amphotericin B, nystatin, trichomycin)
(ii) griseofulvin, pyrrolnitrin, etc.
(iii) Cytosine Antagonists (eg Flucytosine)
(iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole)
(v) Triazole derivatives (eg fluconazole, itraconazole)
(vi) Thiocarbamic acid derivatives (eg, trinaphthol) and the like.
(3) Antiprotozoal metronidazole, tinidazole, diethylcarbamidine citrate, quinine hydrochloride, quinine sulfate and the like.
（４）鎮咳・去たん薬
　塩酸エフェドリン、塩酸ノスカピン、リン酸コデイン、リン酸ジヒドロコデイン、塩酸イソプロテレノール、塩酸メチルエフェドリン、アロクラマイド、クロルフェジアノール、ピコペリダミン、クロペラスチン、プロトキロール、イソプロテレノール、サルブタモール、テレプタリン、オキシペテバノール、塩酸モルヒネ、臭化水素酸デキストロペトルファン、塩酸オキシコドン、リン酸ジモルファン、ヒベンズ酸チペピジン、クエン酸ペントキシベリン、塩酸クロフェダノール、ベンゾナテート、グアイフェネシン、塩酸ブロムヘキシン、塩酸アンブロキソール、アセチルシステイン、塩酸エチルシステイン、カルボシステイン等。
（５）鎮静薬
　塩酸クロルプロマジン、硫酸アトロピン、フェノバルビタール、バルビタール、アモバルビタール、ペントバルビタール、チオペンタールナトリウム、チアミラールナトリウム、ニトラゼパム、エスタゾラム、フルラザパム、ハロキサゾラム、トリアゾラム、フルニトラゼパム、ブロムワレリル尿素、抱水クロラール、トリクロホスナトリウム等。 (4) Antitussive and expectorant ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, methyl ephedrine hydrochloride, alloclamide, chlorphedianol, picoperidamine, cloperastine, protochlorol, isoproterenol, salbutamol , Tereptalin, oxypetebanol, morphine hydrochloride, dextropetorphate hydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipepidine hybenzate, pentoxivelin citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxyl hydrochloride Sole, acetylcysteine, ethylcysteine hydrochloride, carbocysteine etc.
(5) Sedatives chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamiral sodium, nitrazepam, estazolam, flurazapam, haloxazolam, trinitrazepam, brom valeril urea, chloral triclofoss, Sodium etc.
（６）麻酔薬
（６－１）局所麻酔薬
　塩酸コカイン、塩酸プロカイン、リドカイン、塩酸ジブカイン、塩酸テトラカイン、塩酸メピバカイン、塩酸ブピバカイン、塩酸オキシブプロカイン、アミノ安息香酸エチル、オキセサゼイン等。
（６－２）全身麻酔薬
(i)吸入麻酔薬（例、エーテル、ハロタン、亜酸化窒素、インフルラン、エンフルラン）、
(ii)静脈麻酔薬（例、塩酸ケタミン、ドロペリドール、チオペンタールナトリウム、チアミラールナトリウム、ペントバルビタール）等。
（７）抗潰瘍薬
　塩酸ヒスチジン、ランソプラゾール、メトクロプラミド、ピレンゼピン、シメチジン、ラニチジン、ファモチジン、ウロガストリン、オキセサゼイン、プログルミド、オメプラゾール、スクラルファート、スルピリド、セトラキサート、ゲファルナート、アルジオキサ、テプレノン、プロスタグランジン等。
（８）不整脈治療薬
(i)ナトリウムチャンネル遮断薬（例、キニジン、プロカインアミド、ジソピラミド、アジマリン、リドカイン、メキシレチン、フェニトイン）、
(ii)β遮断薬（例、プロプラノロール、アルプレノロール、塩酸ブフェトロール、オクスプレノロール、アテノロール、アセブトロール、メトプロロール、ビソプロロール、ピンドロール、カルテオロール、塩酸アロチノロール）、
(iii)カリウムチャンネル遮断薬（例、アミオダロン）、
(iv)カルシウムチャンネル遮断薬（例、ベラパミル、ジルチアゼム）等。 (6) Anesthetics (6-1) Local anesthetics cocaine hydrochloride, procaine hydrochloride, lidocaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein and the like.
(6-2) General anesthetic
(i) Inhalation anesthetics (eg, ether, halothane, nitrous oxide, influrane, enflurane),
(ii) Intravenous anesthetics (eg, ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital) and the like.
(7) Anti-ulcer drug Histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranotidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.
(8) Arrhythmic drug
(i) Sodium channel blockers (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin),
(ii) β-blockers (eg, propranolol, alprenolol, bufetrol, hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride),
(iii) potassium channel blockers (eg, amiodarone),
(iv) calcium channel blockers (eg, verapamil, diltiazem) and the like.
（９）降圧利尿薬
　ヘキサメトニウムブロミド、塩酸クロニジン、ヒドロクロロチアジド、トリクロルメチアジド、フロセミド、エタクリン酸、ブメタニド、メフルシド、アゾセミド、スピロノラクトン、カンレノ酸カリウム、トリアムテレン、アミロリド、アセタゾラミド、Ｄ－マンニトール、イソソルビド、アミノフィリン等。
（１０）抗凝血薬
　ヘパリンナトリウム、クエン酸ナトリウム、活性化プロテインC、組織因子経路阻害剤、アンチトロンビンIII、ダルテパリンナトリウム、ワルファリンカリウム、アルガトロバン、ガベキサート、オザグレルナトリウム、イコサペンタ酸エチル、ベラプロストナトリウム、アルプロスタジル、塩酸チクロピジン、ペントキシフィリン、ジピリダモール、チソキナーゼ、ウロキナーゼ、ストレプトキナーゼ等。
（１１）精神安定薬
　ジアゼパム、ロラゼパム、オキサゼパム、クロルジアゼポキシド、メダゼパム、オキサゾラム、クロキサゾラム、クロチアゼパム、ブロマゼパム、エチゾラム、フルジアゼパム、ヒドロキシジン等。
（１２）抗精神病薬
　塩酸クロルプロマジン、プロクロルペラジン、トリフロペラジン、塩酸チオリダジン、マレイン酸ペルフェナジン、エナント酸フルフェナジン、マレイン酸プロクロルペラジン、マレイン酸レボメプロマジン、塩酸プロメタジン、ハロペリドール、ブロムペリドール、スピペロン、レセルピン、塩酸クロカプラミン、スルピリド、ゾテピン等。 (9) Antihypertensive diuretic hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichloromethiazide, furosemide, ethacrynic acid, bumetanide, mefluside, azosemide, spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminophylline etc.
(10) Anticoagulant Heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, ozagrel sodium, ethyl icosapentanate, beraprost sodium, al Prostidyl, ticlopidine hydrochloride, pentoxifylline, dipyridamole, thysokinase, urokinase, streptokinase etc.
(11) Mental Stabilizer Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, crothiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.
(12) Antipsychotic drug chlorpromazine hydrochloride, prochlorperazine, trifluoroperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine etc.
（１３）抗腫瘍薬
　６－Ｏ－（Ｎ－クロロアセチルカルバモイル）フマギロール、ブレオマイシン、メトトレキサート、アクチノマイシンＤ、マイトマイシンＣ、ダウノルビシン、アドリアマイシン、ネオカルチノスタチン、シトシンアラビノシド、フルオロウラシル、テトラヒドロフリル－５－フルオロウラシル、ピシバニール、レンチナン、レバミゾール、ベスタチン、アジメキソン、グリチルリチン、塩酸ドキソルビシン、塩酸アクラルビシン、塩酸ブレオマイシン、硫酸ヘプロマイシン、硫酸ビンクリスチン、硫酸ビンブラスチン、塩酸イリノテカン、シクロフォスファミド、メルファラン、ズスルファン、チオテパ、塩酸プロカルバジン、シスプラチン、アザチオプリン、メルカプトプリン、テガフール、カルモフール、シタラビン、メチルテストステロン、プロピオン酸テストステロン、エナント酸テストステロン、メピチオスタン、ホスフェストロール、酢酸クロルマジノン、酢酸リュープロレリン、酢酸ブセレリン等。
（１４）抗高脂血症薬
　クロフィブラート、２－クロロ－３－〔４－（２－メチル－２－フェニルプロポキシ）フェニル〕プロピオン酸エチル〔Chem. Pharm. Bull，３８，２７９２－２７９６（１９９０）〕、プラバスタチン、シンバスタチン、プロブコール、ベザフィブラート、クリノフィブラート、ニコモール、コレスチラミン、デキストラン硫酸ナトリウム等。
（１５）筋弛緩薬
　プリジノール、ツボクラリン、パンクロニウム、塩酸トルペリゾン、カルバミン酸クロルフェネシン、バクロフェン、クロルメザノン、メフェネシン、クロゾキサゾン、エペリゾン、チザニジン等。
（１６）抗てんかん薬
　フェニトイン、エトサクシミド、アセタゾラミド、クロルジアゼポキシド、トリペタジオン、カルバマゼピン、フェノバルビタール、プリミドン、スルチアム、バルプロ酸ナトリウム、クロナゼパム、ジアゼパム、ニトラゼパム等。 (13) Antitumor agents 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, picibanil, lentinan, levamizole, bestatin, azimexone, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, hepromycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, zusulfan thiotepa, procarbazine hydrochloride Cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine Methyltestosterone, testosterone propionate, testosterone enanthate, mepithiostan, phosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like.
(14) Antihyperlipidemic drug clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chem. Pharm. Bull, 38, 2792-2796 (1990 ], Pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.
(15) Muscle relaxant Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone, eperisone, tizanidine and the like.
(16) Anti-epileptic drug phenytoin, etoxacimide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine, phenobarbital, primidone, sultiam, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
（１７）抗うつ薬
　イミプラミン、クロミプラミン、ノキシプチリン、フェネルジン、塩酸アミトリプチリン、塩酸ノルトリプチリン、アモキサピン、塩酸ミアンセリン、塩酸マプロチリン、スルピリド、マレイン酸フルボキサミン、塩酸トラゾドン等。
（１８）抗アレルギー薬
　ジフェンヒドラミン、クロルフェニラミン、トリペレナミン、メトジラミン、クレミゾール、ジフェニルピラリン、メトキシフェナミン、クロモグリク酸ナトリウム、トラニラスト、レピリナスト、アンレキサノクス、イブジラスト、ケトチフェン、テルフェナジン、メキタジン、塩酸アゼラスチン、エピナスチン、塩酸オザグレル、プランルカスト水和物、セラトロダスト等。
（１９）強心薬
　トランスバイオキソカンファー、テレフィロール、アミノフィリン、エチレフリン、ドパミン、ドブタミン、デノパミン、ベシナリン、アムリノン、ピモベンダン、ユビデカレノン、ジギトキシン、ジゴキシン、メチルジゴキシン、ラナトシドＣ、Ｇ－ストロファンチン等。
（２０）血管拡張薬
　オキシフェドリン、ジルチアゼム、トラゾリン、ヘキソベンジン、バメタン、クロニジン、メチルドパ、グアナベンズ等。
（２１）血管収縮薬
　ドパミン、ドブタミンデノパミン等。
（２２）降圧利尿薬
　ヘキサメトニウムブロミド、ペントリニウム、メカミルアミン、エカラジン、クロニジン、ジルチアゼム、ニフェジピン等。
（２３）糖尿病治療薬
　トルブタミド、クロルプロパミド、アセトヘキサミド、グリベンクラミド、トラザミド、アカルボース、エパルレスタット、トログリタゾン、グルカゴン、グリミジン、グリプジド、フェンフォルミン、プフォルミン、メトフォルミン等。 (17) Antidepressants Imipramine, clomipramine, noxiptiline, pheneldine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like.
(18) Anti-allergic agents Diphenhydramine, chlorpheniramine, metoperamine, metziramine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast, repirinast, anrexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride , Pranlukast hydrate, seratrodust, etc.
(19) Cardiotonics Transbioxocamphor, telephilol, aminophylline, ethyephrine, dopamine, dobutamine, denopamin, becinaline, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyl digoxin, ranatoside C, G-strophantin and the like.
(20) Vasodilators Oxyphedrine, diltiazem, trazoline, hexobenzin, bamethane, clonidine, methyldopa, guanabenz etc.
(21) Vasoconstrictor Dopamine, dobutamine denopamine and the like.
(22) Antihypertensive diuretics Hexamethonium bromide, pentrinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
(23) Drugs for treating diabetes Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide, phenformin, pformin, metformin and the like.
（２４）麻薬拮抗薬
　レバロルファン、ナロルフィン、ナロキソンまたはその塩等。
（２５）脂溶性ビタミン薬
(i)ビタミンＡ類：ビタミンＡ１、ビタミンＡ２およびパルミチン酸レチノール
(ii)ビタミンＤ類：ビタミンＤ１、Ｄ２、Ｄ３、Ｄ４およびＤ５
(iii)ビタミンＥ類：α－トコフェロール、β－トコフェロール、γ－トコフェロール、δ－トコフェロール、ニコチン酸dl－α－トコフェロール
(iv)ビタミンＫ類：ビタミンＫ１、Ｋ２、Ｋ３およびＫ４
(v)葉酸（ビタミンＭ）等。
（２６）ビタミン誘導体
　ビタミンの各種誘導体、例えば、５，６－トランス－コレカルシフェロール、２，５－ヒドロキシコレカルシフェロール、１－α－ヒドロキシコレカルシフェロール等のビタミンＤ3誘導体、５，６－トランス－エルゴカルシフェロール等のビタミンＤ2誘導体等。
（２７）抗喘息薬
　塩酸イソプレナリン、硫酸サルブタモール、塩酸プロカテロール、硫酸テルブタリン、塩酸トリメトキノール、塩酸ツロブテロール、硫酸オルシプレナリン、臭化水素酸フェノテロール、塩酸エフェドリン、臭化イプロトロピウム、臭化オキシトロピウム、臭化フルトロピウム、テオフィリン、アミノフィリン、クロモグリク酸ナトリウム、トラニラスト、レピリナスト、アンレキサノン、イブジラスト、ケトチフェン、テルフェナジン、メキタジン、アゼラスチン、エピナスチン、塩酸オザグレル、プランルカスト水和物、セラトロダスト、デキサメタゾン、プレドニゾロン、ヒドロコルチゾン、コハク酸ヒドロコルチゾンナトリウム、プロピオン酸ベクロメタゾン等。
（２８）頻尿・尿失禁治療薬
　塩酸フラボキサート等。
（２９）アトピー性皮膚炎治療薬
　クロモグリク酸ナトリウム等。 (24) Narcotic antagonist levallorphan, nalorphine, naloxone or a salt thereof and the like.
(25) Fat-soluble vitamin drugs
(i) Vitamin A: Vitamin A 1 , Vitamin A 2 and Retinol Palmitate
(ii) Vitamin D: Vitamin D 1 , D 2 , D 3 , D 4 and D 5
(iii) Vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, nicotinic acid dl-α-tocopherol
(iv) Vitamins K: Vitamins K 1 , K 2 , K 3 and K 4
(v) folic acid (vitamin M) and the like.
(26) vitamin derivative various derivatives of vitamins, for example, 5,6-trans - cholecalciferol, 2,5-hydroxycholecalciferol, 1-alpha-hydroxy cholecalciferol shea vitamin D 3 derivatives such as fellows Le, 5,6 Vitamin D 2 derivatives such as trans-ergocalciferol.
(27) Anti-asthmatic drug isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciplanaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, anlexanone, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisolate , Beclomethasone propionate, etc.
(28) Remedies for frequent urination and urinary incontinence Flavoxate hydrochloride etc.
(29) Atopic dermatitis remedy sodium cromoglycate etc.
（３０）アレルギー性鼻炎治療薬
　クロモグリク酸ナトリウム、マレイン酸クロルフェニラミン、酒石酸アリメマジン、フマル酸クレマスチン、塩酸ホモクロルシクリジン、フェキソフェナジン、メキタジン等。
（３１）昇圧薬
　ドパミン、ドブタミン、デノパミン、ジギトキシン、ジゴキシン、メチルジゴキシン、ラナトシドＣ、Ｇ－ストロファンチン等。
（３２）その他
　ヒドロキシカム、ダイアセリン、メゲストロール酢酸、ニセロゴリン、プロスタグランジン類等。 (30) Therapeutic agent for allergic rhinitis sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, fexofenadine, mequitadine etc.
(31) Pressor agents Dopamin, dobutamine, denopamine, digitoxin, digoxin, methyl digoxin, ranatoside C, G-strophantin and the like.
(32) Others Hydroxycam, diacelin, megestrol acetate, nicerogoline, prostaglandins and the like.
　併用に際しては、本発明化合物と併用薬物の投与時期は限定されず、本発明化合物および併用薬物を、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。
　併用の投与形態は、特に限定されず、投与時に、本発明化合物と併用薬物とが組み合わされていればよい。このような投与形態としては、例えば、（１）本発明化合物および併用薬物を同時に製剤化して得られる単一の製剤の投与、（２）本発明化合物および併用薬物を別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、（３）本発明化合物および併用薬物を別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、（４）本発明化合物および併用薬物を別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、（５）本発明化合物および併用薬物を別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、本発明化合物を投与した後の併用薬物の投与、またはその逆の順序での投与）等が挙げられる。
　本発明の併用剤における本発明化合物および併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択し得る。
　例えば、本発明の併用剤における本発明化合物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１～１００重量％、好ましくは約０．１～５０重量％、さらに好ましくは約０．５～２０重量％程度である。 When used in combination, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject or may be administered at time intervals. The dose of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
The administration mode of the combination is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. As such dosage forms, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, (2) obtained by separately formulating the compound of the present invention and the concomitant drug Simultaneous administration of two preparations by the same administration route, (3) Administration with time difference between two preparations obtained by separately formulating the compound of the present invention and the concomitant drug, by the same administration route, (4) Simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, and (5) different two formulations obtained by separately formulating the compound of the present invention and the concomitant drug Examples include administration with a time lag depending on the administration route (for example, administration of the combination drug after administration of the compound of the present invention, or administration in the reverse order) and the like.
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of preparation, but usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
　本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１～１００重量％、好ましくは約０．１～５０重量％、さらに好ましくは約０．５～２０重量％程度である。
　本発明の併用剤における担体等の添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１～９９．９９重量％、好ましくは約１０～９０重量％程度である。
　また、本発明化合物および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。
　投与量は本発明化合物の種類、投与ルート、症状、患者の年令等によっても異なり得るが、例えば、関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、アトピー性皮膚炎、全身性エリテマトーデス、白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等の患者（体重約６０ｋｇ）に経口的に投与する場合、１日当たり体重１ｋｇあたり化合物（Ｉ）のフリー体として約０．１ｍｇ／ｋｇ体重～約５０ｍｇ／ｋｇ体重、好ましくは約１ｍｇ／ｋｇ体重～３０ｍｇ／ｋｇ体重を、１日１回～数回に分けて投与すればよい。
　本発明の医薬組成物が徐放性製剤である場合の投与量は、化合物（Ｉ）の種類と含量、剤形、薬物放出の持続時間、投与対象動物（例えば、マウス、ラット、ハムスター、モルモット、ウサギ、ネコ、イヌ、ウシ、ウマ、ブタ、ヒツジ、サル、ヒト等の哺乳動物）、投与目的により種々異なるが、例えば、非経口投与により適用する場合には、１週間に約０．１から約１００ｍｇの化合物（Ｉ）が投与製剤から放出されるようにすればよい。 The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but it is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably It is about 0.5 to 20% by weight.
The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight based on the whole preparation. .
In addition, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.
Although the dose may vary depending on the type of compound of the present invention, administration route, symptoms, age of patients, etc., for example, rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, atopic When administered orally to a patient (body weight about 60 kg) with dermatitis, systemic lupus erythematosus, leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc. per kg body weight per day The free form of Compound (I) may be administered at a dose of about 0.1 mg / kg body weight to about 50 mg / kg body weight, preferably about 1 mg / kg body weight to 30 mg / kg body weight once to several times a day .
When the pharmaceutical composition of the present invention is a sustained release preparation, the dosage is the type and content of compound (I), dosage form, duration of drug release, target animal (eg, mouse, rat, hamster, guinea pig (A rabbit, a cat, a dog, a cow, a horse, a pig, a sheep, a monkey, a human, a mammal such as a human) and the like, depending on the administration purpose, for example, when applied by parenteral administration, about 0.1 per week. To about 100 mg of Compound (I) may be released from the dosage formulation.
　併用薬物は、副作用が問題とならない範囲でどのような量を設定することも可能である。併用薬物としての一日投与量は、症状の程度、投与対象の年齢、性別、体重、感受性差、投与の時期、間隔、医薬製剤の性質、調剤、種類、有効成分の種類等によって異なり得、特に限定されないが、薬物の量として通常、例えば、経口投与で哺乳動物１ｋｇ体重あたり約０．００１～２０００ｍｇ、好ましくは約０．０１～５００ｍｇ、さらに好ましくは、約０．１～１００ｍｇ程度であり得、これを通常１日１～４回に分けて投与し得る。
　本発明の併用剤を投与するに際しては、本発明化合物と併用薬物とを同時期に投与してもよいし、時間差をおいて投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後１分～３日以内、好ましくは１０分～１日以内、より好ましくは１５分～１時間以内に本発明化合物を投与する方法が挙げられる。本発明化合物を先に投与する場合、本発明化合物を投与した後、１分～１日以内、好ましくは１０分～６時間以内、より好ましくは１５分～１時間以内に併用薬物を投与する方法が挙げられる。 The concomitant drug can be set in any amount as long as side effects do not cause a problem. The daily dose as a concomitant drug may vary depending on the degree of symptoms, age, sex, body weight, difference in sensitivity, administration timing, interval, nature of pharmaceutical preparation, preparation, type of active ingredient, etc. Although not particularly limited, the amount of the drug is usually, for example, about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, and more preferably about 0.1 to 100 mg per kg body weight of a mammal when orally administered. It can be administered, usually divided into 1 to 4 times a day.
When administering the concomitant drug of the present invention, the compound of the present invention and the concomitant drug may be administered at the same time or may be administered at different times. In the case of timed administration, the time difference varies depending on the active ingredient, dosage form and administration method to be administered, but for example, when the concomitant drug is administered first, within 1 minute to 3 days after administering the concomitant drug, preferably The method includes administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, the method of administering the concomitant drug within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administering the compound of the present invention Can be mentioned.
　本発明は、更に以下の実施例、試験例および製剤例によって詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
　以下の実施例中の「室温」は通常約10℃ないし約35℃を示す。混合溶媒において示した比は、特に断らない限り容量比を示す。%は、特に断らない限り重量%を示す。
　実施例のカラムクロマトグラフィーにおける溶出は、特に言及しない限り、ＴＬＣ（Ｔｈｉｎ　Ｌａｙｅｒ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，薄層クロマトグラフィー）による観察下に行った。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍｅｒｃｋ）社製の６０　Ｆ２５４を用い、展開溶媒として、カラムクロマトグラフィーで溶出溶媒として用いた溶媒を用いた。また、検出にはＵＶ検出器を採用した。シリカゲルカラムクロマトグラフィーにおいて、ＮＨと記載した場合はアミノプロピルシラン結合シリカゲルを、Ｄｉｏｌと記載した場合は３－（２，３－ジヒドロキシプロポキシ）プロピルシラン結合シリカゲルを用いた。分取ＨＰＬＣ（高速液体クロマトグラフィー）において、Ｃ１８と記載した場合はオクタデシル結合シリカゲルを用いた。溶出溶媒において示した比は、特に断らない限り容量比を示す。
　１Ｈ　ＮＭＲの解析にはＡＣＤ／ＳｐｅｃＭａｎａｇｅｒ（商品名）ソフトウエアなどを用いた。水酸基やアミノ基などのプロトンピークが非常に緩やかなピークについては記載していないことがある。
　ＭＳは、ＬＣ／ＭＳにより測定した。イオン化法としては、ＥＳＩ法、または、ＡＰＣＩ法を用いた。データは実測値（ｆｏｕｎｄ）を示す。通常、分子イオンピークが観測されるがフラグメントイオンとして観測されることがある。塩の場合は、通常、フリー体の分子イオンピークもしくはフラグメントイオンピークが観測される。
　旋光度（［α］Ｄ）における試料濃度（ｃ）の単位はｇ／１００　ｍＬである。
　元素分析値（Ａｎａｌ．）は計算値（Ｃａｌｃｄ）と実測値（Ｆｏｕｎｄ）として示す。
　実施例の粉末Ｘ線回折によるピークは、線源としてＣｕ　Ｋα線を用い、Ｕｌｔｉｍａ　ＩＶ（Ｒｉｇａｋｕ　Ｃｏｒｐｏｒａｔｉｏｎ，Ｊａｐａｎ）を使って室温において測定されるピークを意味する。測定条件は以下のとおりである。
　Ｅｌｅｃｔｒｉｃ　ｐｒｅｓｓｕｒｅ／Ｅｌｅｃｔｒｉｃ　ｃｕｒｒｅｎｔ：４０　ｋＶ／５０　ｍＡ
　Ｓｃａｎ　ｓｐｅｅｄ：６　ｄｅｇｒｅｅ／ｍｉｎ
　Ｓｃａｎ　ｒａｎｇｅ　ｏｆ　２　Ｔｈｅｔａ：２－３５　ｄｅｇｒｅｅ
　実施例の粉末Ｘ線回折による結晶化度はＨｅｒｍａｎｓ法により算出した。 The present invention is further described in detail by the following examples, test examples and formulation examples, which are not intended to limit the present invention and may be varied within the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates weight% unless otherwise specified.
Elution in column chromatography in the examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography) unless otherwise stated. In TLC observation, 60 F 254 manufactured by Merck (Merck) was used as a TLC plate, and the solvent used as an elution solvent in column chromatography was used as a developing solvent. Also, a UV detector was adopted for detection. In the silica gel column chromatography, when stated as NH, aminopropylsilane-bonded silica gel was used, and when described as Diol, 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used. When described as C18 in preparative HPLC (high performance liquid chromatography), octadecyl-bonded silica gel was used. The ratios shown in the elution solvent indicate volume ratios unless otherwise specified.
ACD / SpecManager (trade name) software etc. were used for the analysis of 1 H NMR. There is a case in which a very mild peak such as a hydroxyl group or an amino group is not described.
MS was measured by LC / MS. As the ionization method, ESI method or APCI method was used. The data show the actual value (found). Usually, molecular ion peaks are observed, but sometimes as fragment ions. In the case of a salt, a free molecular ion peak or fragment ion peak is usually observed.
The unit of sample concentration (c) in optical rotation ([α] D ) is g / 100 mL.
Elemental analysis values (Anal.) Are shown as calculated values (Calcd) and actual values (Found).
The powder X-ray diffraction peaks in the examples mean peaks measured at room temperature using Ultima IV (Rigaku Corporation, Japan) using Cu Kα radiation as a radiation source. The measurement conditions are as follows.
Electric pressure / electric current: 40 kV / 50 mA
Scan speed: 6 degree / min
Scan range of 2 Theta: 2-35 degree
The crystallinity degree by powder X-ray diffraction of an Example was computed by the Hermans method.
　以下の実施例においては下記の略号を使用する。
ＭＳ：マススペクトル
Ｎ：規定度
ＣＤＣｌ３：重クロロホルム
ＤＭＳＯ－ｄ６：重ジメチルスルホキシド
１Ｈ　ＮＭＲ：プロトン核磁気共鳴
ＬＣ／ＭＳ：液体クロマトグラフ質量分析計
ＥＳＩ：ｅｌｅｃｔｒｏｓｐｒａｙ　ｉｏｎｉｚａｔｉｏｎ、エレクトロスプレーイオン化
ＡＰＣＩ：ａｔｏｍｏｓｐｈｅｒｉｃ　ｐｒｅｓｓｕｒｅ　ｃｈｅｍｉｃａｌ　ｉｏｎｉｚａｔｉｏｎ、大気圧化学イオン化
WSC : N-(3-(ジメチルアミノ)プロピル)-N'-エチルカルボジイミド
IPE : 2-イソプロポキシプロパン
DIPEA : N-エチル-N-イソプロピルプロパン-2-アミン
DMF : N,N-ジメチルホルムアミド
HOBt : 1H-ベンゾトリアゾール-1-オール
THF : テトラヒドロフラン
MeOH : メタノール
WSC・HCl : N-(3-(ジメチルアミノ)プロピル)-N'-エチルカルボジイミド ヒドロクロリド(1:1)
DMSO : ジメチルスルホキシド
TEA : トリエチルアミン
TMSCl : トリメチルシリルクロリド The following abbreviations are used in the following examples.
MS: mass spectrum N: Normality CDCl 3: deuterated chloroform DMSO-d 6: deuterated dimethyl sulfoxide
1 H NMR: proton nuclear magnetic resonance LC / MS: liquid chromatograph mass spectrometer ESI: electrospray ionization, electrospray ionization APCI: atomic pressure pressure chemical ionization, atmospheric pressure chemical ionization
WSC: N- (3- (dimethylamino) propyl) -N'-ethyl carbodiimide
IPE: 2-Isopropoxypropane
DIPEA: N-ethyl-N-isopropylpropan-2-amine
DMF: N, N-dimethylformamide
HOBt: 1H-benzotriazol-1-ol
THF: tetrahydrofuran
MeOH: methanol
WSC · HCl: N- (3- (dimethylamino) propyl) -N'-ethylcarbodiimide hydrochloride (1: 1)
DMSO: Dimethyl sulfoxide
TEA: Triethylamine
TMSCl: trimethylsilyl chloride
実施例1
2-(4-((4-ヒドロキシ-4-フェニルシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル
A) メチル 5-アミノ-4-(((4-ヨード-2-メトキシピリジン-3-イル)カルボニル)アミノ)チオフェン-2-カルボキシラート
　4-ヨード-2-メトキシニコチン酸 (5.02 g)とメチル 4,5-ジアミノチオフェン-2-カルボキシラート (3.72 g)とDMF(dry) (90 ml)の混合物にHOBt (3.16 g)とWSC・HCl (4.49 g)を0 ℃で加えた。混合物をアルゴン雰囲気下、室温で終夜撹拌した。混合物に室温で水を加え、酢酸エチルで2回抽出した。有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（NH、酢酸エチル/ヘキサン）で精製し、標題化合物 (5.81 g)を得た。
MS: [M+H]+ 434.0. Example 1
2- (4-((4-hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile
A) Methyl 5-amino-4-(((4-iodo-2-methoxypyridin-3-yl) carbonyl) amino) thiophene-2-carboxylate 4-iodo-2-methoxynicotinic acid (5.02 g) and methyl HOBt (3.16 g) and WSC.HCl (4.49 g) were added at 0 ° C. to a mixture of 4,5-diaminothiophene-2-carboxylate (3.72 g) and DMF (dry) (90 ml). The mixture was stirred at room temperature overnight under an argon atmosphere. To the mixture was added water at room temperature and extracted twice with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (5.81 g).
MS: [M + H] < +> 434.0.
B) メチル 2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート
　メチル 5-アミノ-4-(((4-ヨード-2-メトキシピリジン-3-イル)カルボニル)アミノ)チオフェン-2-カルボキシラート(3.80 g)とピリジン (17 ml)の混合物にリン酸 トリクロリド (28.0 g)を0 ℃で加えた。混合物を窒素雰囲気下、80 ℃で2.5時間撹拌した。混合物を氷水に注ぎ、生じた固体をろ取し、水で洗浄後、乾燥し、標題化合物 (3.14 g)を得た。
MS: [M+H]+ 415.9. B) Methyl 2- (4-iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylate Methyl 5-amino-4-(((4-iodo-) To a mixture of 2-methoxypyridin-3-yl) carbonyl) amino) thiophene-2-carboxylate (3.80 g) and pyridine (17 ml) was added phosphoric acid trichloride (28.0 g) at 0 ° C. The mixture was stirred at 80 ° C. for 2.5 hours under nitrogen atmosphere. The mixture was poured into ice water, and the resulting solid was collected by filtration, washed with water and dried to give the title compound (3.14 g).
MS: [M + H] < +> 415.9.
C) 2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボン酸
　メチル 2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート (20 g)とTHF (410 ml)と水 (164 ml)の混合物にリチウム ヒドロキシド 水和物 (1:1:1) (10.11 g)を室温で加えた。混合物を80 ℃で2時間撹拌した。混合物に室温で水を加え、THFを留去した。混合物を0 ℃にて2N塩酸で中和し、0 ℃で5分間撹拌した。生じた固体をろ取し、水で洗浄後、乾燥し、標題化合物 (18.52 g)を得た。
MS: [M+H]+ 402.0. C) 2- (4-iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylate methyl 2- (4-iodo-2-methoxypyridine-3-) Lithium hydroxide hydrate (1: 1: 1) in a mixture of (I) -1H-thieno [2,3-d] imidazole-5-carboxylate (20 g) with THF (410 ml) and water (164 ml) ) (10.11 g) was added at room temperature. The mixture is stirred at 80 ° C. for 2 hours. To the mixture was added water at room temperature and THF was distilled off. The mixture was neutralized at 0 ° C. with 2N hydrochloric acid and stirred at 0 ° C. for 5 minutes. The resulting solid was collected by filtration, washed with water and dried to give the title compound (18.52 g).
MS: [M + H] < +> 402.0.
D) 2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド
　2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボン酸 (16.87 g)とDMF (340 ml)の混合物に1H-ベンゾトリアゾール-1-オール アンモニア和物 (1:1) (12.80 g)とWSC・HCl (16.12 g)を室温で加えた。混合物を室温で2.5時間撹拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を分離し、飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。得られた固体をDMF/酢酸エチル/IPEから結晶化し、標題化合物 (12.14 g)を得た。
MS: [M+H]+ 401.1. D) 2- (4-Iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide 2- (4-iodo-2-methoxypyridin-3-yl) 1H-benzotriazol-1-ol ammonia solvate (1: 1) (12.80 g) in a mixture of -1H-thieno [2,3-d] imidazole-5-carboxylic acid (16.87 g) and DMF (340 ml) And WSC.HCl (16.12 g) were added at room temperature. The mixture was stirred at room temperature for 2.5 hours. To the mixture was added water and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was crystallized from DMF / ethyl acetate / IPE to give the title compound (12.14 g).
MS: [M + H] + 401.1.
E) 2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル
　2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド (12.14 g)とピリジン (9.60 g)とTHF (240 ml)の混合物にトリフルオロ酢酸 無水物 (17.20 g)を0 ℃で加えた。混合物を室温で1時間撹拌した。混合物を飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出した。有機層を分離し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（NH、酢酸エチル/ヘキサン）で精製し、標題化合物 (10.46 g)を得た。
MS: [M+H]+ 383.0. E) 2- (4-iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile 2- (4-iodo-2-methoxypyridin-3-yl) Trifluoroacetic anhydride (17.20 g) is added at 0 ° C to a mixture of -1H-thieno [2,3-d] imidazole-5-carboxamide (12.14 g), pyridine (9.60 g) and THF (240 ml) The The mixture was stirred at room temperature for 1 hour. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (10.46 g).
MS: [M + H] < +> 383.0.
F) 2-(4-ヨード-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル
　2-(4-ヨード-2-メトキシピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル (14.3 g)とCH3CN (340 ml)の混合物にTMSCl (32.5 g)とナトリウム ヨージド (11.22 g)を室温で加えた。混合物をアルゴン雰囲気下、60 ℃で15時間撹拌した。混合物に室温で水 (150 ml)を加え、生じた固体をろ取し、水 とIPEで洗浄し、標題化合物 (12.3 g)を得た。
MS: [M+H]+ 369.0. F) 2- (4-Iodo-2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile 2- (4-iodo-2-methoxy) pyridin-3-yl)-1H-thieno [2,3-d] TMSCl mixture of imidazole-5-carbonitrile (14.3 g) and CH 3 CN (340 ml) ( 32.5 g) and sodium iodide (11.22 g) Was added at room temperature. The mixture was stirred at 60 ° C. for 15 hours under an argon atmosphere. To the mixture was added water (150 ml) at room temperature, and the resulting solid was collected by filtration and washed with water and IPE to give the title compound (12.3 g).
MS: [M + H] < +> 369.0.
G) tert-ブチル (4-ヒドロキシ-4-フェニルシクロヘキシル)カルバマート
　tert-ブチル (4-オキソシクロヘキシル)カルバマート (4.97 g)とTHF(dry) (150 ml)の混合物にフェニルリチウムのブチルエーテル溶液 (30.6 ml)を-78 ℃で加えた。混合物をアルゴン雰囲気下、-78 ℃で1.5時間撹拌した。混合物に水を加え、酢酸エチルで抽出した。有機層を分離し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧下濃縮した。得られた固体をジエチルエーテル/ヘキサンで洗浄し、標題化合物 (2.5 g)を得た。
1H NMR (300 MHz, CDCl3) δ 1.46 (9H, s), 1.59-2.06 (9H, m), 3.29-3.75 (1H, m), 4.48 (1H, brs), 7.21-7.29 (1H, m), 7.31-7.40 (2H, m), 7.44-7.52 (2H, m). G) tert-Butyl (4-hydroxy-4-phenylcyclohexyl) carbamate tert-Butyl (4-oxocyclohexyl) carbamate (4.97 g) in THF (dry) (150 ml) in a solution of phenyllithium in butyl ether (30.6 ml) ) At -78 ° C. The mixture was stirred at −78 ° C. for 1.5 hours under an argon atmosphere. To the mixture was added water and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was washed with diethyl ether / hexane to give the title compound (2.5 g).
1 H NMR (300 MHz, CDCl 3 ) δ 1.46 (9 H, s), 1.59-2.06 (9 H, m), 3.29-3. 75 (1 H, m), 4.48 (1 H, brs), 7.21-7. 29 (1 H, m) ), 7.31-7.40 (2H, m), 7.44-7.52 (2H, m).
H) 4-アミノ-1-フェニルシクロヘキサノール塩酸塩
　tert-ブチル (4-ヒドロキシ-4-フェニルシクロヘキシル)カルバマート (500 mg)とMeOH(12 ml)の混合物に2 N 塩化水素メタノール溶液 (12.87 ml)を0 ℃で加えた。混合物を室温で7時間撹拌した。混合物に酢酸エチル (150 ml)とヘプタン (150 ml)を加え、生じた固体を酢酸エチル/ヘプタン (1/1)で洗浄し、標題化合物 (257 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.51-2.08 (8H, m), 2.95-3.21 (1H, m), 4.94 (1H, s), 7.15-7.25 (1H, m), 7.25-7.37 (2H, m), 7.42-7.55 (2H, m), 8.17 (3H, brs). H) 4-Amino-1-phenylcyclohexanol hydrochloride tert-butyl (4-hydroxy-4-phenylcyclohexyl) carbamate (500 mg) in MeOH (12 ml) 2 N hydrogen chloride in methanol (12.87 ml) Was added at 0 ° C. The mixture was stirred at room temperature for 7 hours. Ethyl acetate (150 ml) and heptane (150 ml) were added to the mixture, and the resulting solid was washed with ethyl acetate / heptane (1/1) to give the title compound (257 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.51-2.08 (8 H, m), 2.95-3.21 (1 H, m), 4.94 (1 H, s), 7.15-7.25 (1 H, m), 7.25-7.37 (2H, m), 7.42-7.55 (2H, m), 8.17 (3H, brs).
I) 2-(4-((4-ヒドロキシ-4-フェニルシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル
　2-(4-ヨード-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル (86.6 mg)とDMF(dry) (1.8 ml)の混合物にTEA (95 mg)と4-アミノ-1-フェニルシクロヘキサノール ヒドロクロリド (1:1) (94 mg)を室温で加えた。混合物をアルゴン雰囲気下、80 ℃で1時間撹拌した。さらに混合物をアルゴン雰囲気下、60 ℃で15時間撹拌した。混合物に80 ℃でDMF (3.6 ml)を加えた。さらに混合物に水 (0.5 ml)を加え、生じた固体をろ取し、DMF/水 (1/1)、IPEで洗浄した。得られた固体をDMF/酢酸エチル/ヘプタンから結晶化し、標題化合物 (31 mg)を得た。
1H NMR (300 MHz, DMSO-d6) δ 1.63-2.11 (8H, m), 3.75 (1H, d, J = 7.2 Hz), 4.95 (1H, s), 6.25 (1H, d, J = 7.6 Hz), 7.15-7.27 (1H, m), 7.28-7.42 (3H, m), 7.53 (2H, d, J = 7.2 Hz), 7.85 (1H, brs), 9.90-10.41 (1H, m), 11.28 (1H, brs), 13.43 (1H, brs). I) 2- (4-((4-hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5- Carbonitrile 2- (4-Iodo-2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile (86.6 mg) and DMF (dry) ( To a mixture of 1.8 ml) TEA (95 mg) and 4-amino-1-phenylcyclohexanol hydrochloride (1: 1) (94 mg) were added at room temperature. The mixture was stirred at 80 ° C. for 1 hour under an argon atmosphere. The mixture was further stirred at 60 ° C. for 15 hours under an argon atmosphere. To the mixture was added DMF (3.6 ml) at 80 ° C. To the mixture was further added water (0.5 ml), and the resulting solid was collected by filtration and washed with DMF / water (1/1), IPE. The obtained solid was crystallized from DMF / ethyl acetate / heptane to give the title compound (31 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ 1.63-2.11 (8 H, m), 3.75 (1 H, d, J = 7.2 Hz), 4.95 (1 H, s), 6.25 (1 H, d, J = 7.6 Hz), 7.15-7.27 (1 H, m), 7. 28-7. 42 (3 H, m), 7.53 (2 H, d, J = 7.2 Hz), 7.55 (1 H, brs), 9. 90-10. 41 (1 H, m), 11.28 (1H, brs), 13.43 (1H, brs).
　実施例化合物を以下の表１に示す。表中のMSは実測値を示す。上記の実施例に示した方法またはそれらに準じた方法に従って、以下の表中の実施例2～23 の化合物を製造した。 Example compounds are shown in Table 1 below. MS in the table indicates the measured value. The compounds of Examples 2 to 23 in the following table were prepared according to the methods described in the above examples or methods analogous thereto.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
製剤例１（カプセルの製造）
　１）実施例１の化合物　　　　　　　　　　 ３０　ｍｇ
　２）微粉末セルロース　　　　　　　　　　 １０　ｍｇ
　３）乳糖　　　　　　　　　　　　　　　　 １９　ｍｇ
　４）ステアリン酸マグネシウム　　　　　　　 １　ｍｇ
　　　　　　　　　　　　　　計　　　　　　 ６０　ｍｇ
　１）、２）、３）および４）を混合して、ゼラチンカプセルに充填する。 Formulation Example 1 (Manufacture of Capsule)
1) Compound of Example 1 30 mg
2) fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg in total
Mix 1), 2), 3) and 4) and fill in gelatin capsules.
製剤例２（錠剤の製造）
　１）実施例１の化合物　　　　　　　　　　　３０　ｇ
　２）乳糖　　　　　　　　　　　　　　　　　５０　ｇ
　３）トウモロコシデンプン　　　　　　　　　１５　ｇ
　４）カルボキシメチルセルロースカルシウム　４４　ｇ
　５）ステアリン酸マグネシウム　　　　　　　　１　ｇ
　　　　　　　　　　　　１０００錠　 計　１４０　ｇ
　１）、２）、３）の全量および３０ｇの４）を水で練合し、真空乾燥後、整粒を行う。この整粒末に１４ｇの４）および１ｇの５）を混合し、打錠機により打錠する。このようにして、１錠あたり実施例１の化合物３０ｍｇを含有する錠剤１０００錠を得る。 Formulation Example 2 (tablet production)
1) 30 g of the compound of Example 1
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The whole of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried under vacuum and then sized. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and compressed with a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
試験例１　ＪＡＫ１酵素阻害試験
　被検化合物のＪＡＫ１酵素阻害活性はＬＡＮＣＥ法（パーキンエルマー）にて測定した。まず、アッセイバッファー（５０ｍＭ　ＨＥＰＥＳ　（ｐＨ７．５）、１０ｍＭ　ＭｇＣｌ２、１ｍＭ　ＥＧＴＡ、２ｍＭ　ＤＴＴ、０．０１％　Ｔｗｅｅｎ２０、０．０１％　ＢＳＡ）で希釈した被検化合物を３８４ウェルプレートに２μＬずつ添加した。次に、ＪＡＫ１（インビトロジェン）を１８７．５ｎｇ／ｍＬ、蛍光標識ペプチド基質（ＵＬｉｇｈｔ－ＪＡＫ１、パーキンエルマー）を３００ｎＭとなるようアッセイバッファーで希釈した溶液を２μＬずつ添加し、その後、１５０μＭとなるようアッセイバッファーで調製したＡＴＰ溶液を２μＬずつ添加することにより酵素反応を開始した。室温にて１時間反応させた後、２０ｍＭ　ＥＤＴＡ、４ｎＭ　ユーロピウム標識抗リン酸化チロシン抗体（パーキンエルマー）となるよう調製したＤｅｔｅｃｔｉｏｎ　Ｂｕｆｆｅｒ（パーキンエルマー）を６μＬずつ添加した。室温にて１時間静置した後、プレートリーダーＥｎｖｉｓｉｏｎ（パーキンエルマー）にて蛍光強度（励起波長３４０ｎｍ、蛍光波長６６５ｎｍ、ｄｅｌａｙ　ｔｉｍｅ　１００マイクロ秒）を測定した。各化合物の阻害活性は、酵素なしのウェルの蛍光強度を１００％阻害とする相対活性値として算出した。その結果を表２に示す。 Test Example 1 JAK1 Enzyme Inhibition Test The JAK1 enzyme inhibitory activity of a test compound was measured by the LANCE method (Perkin Elmer). First, 2 μL each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate . Next, add 2 μL each of a solution diluted with 187.5 ng / mL of JAK1 (Invitrogen) and 300 nM of a fluorescence-labeled peptide substrate (ULight-JAK1, Perkin-Elmer) in assay buffer, and then assay to 150 μM The enzyme reaction was initiated by adding 2 μL each of the ATP solution prepared in buffer. After reacting for 1 hour at room temperature, 6 μL each of Detection Buffer (Perkin Elmer) prepared to be 20 mM EDTA, 4 nM europium-labeled anti-phosphotyrosine antibody (Perkin Elmer) was added. After standing at room temperature for 1 hour, fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (Perkin Elmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the wells without enzyme. The results are shown in Table 2.
試験例２　ＪＡＫ２酵素阻害試験
　被検化合物のＪＡＫ２酵素阻害活性はＬＡＮＣＥ法（パーキンエルマー）にて測定した。まず、アッセイバッファー（５０ｍＭ　ＨＥＰＥＳ　（ｐＨ７．５）、１０ｍＭ　ＭｇＣｌ２、１ｍＭ　ＥＧＴＡ、２ｍＭ　ＤＴＴ、０．０１％　Ｔｗｅｅｎ２０、０．０１％　ＢＳＡ）で希釈した被検化合物を３８４ウェルプレートに２μＬずつ添加した。次に、ＪＡＫ２（インビトロジェン）を６ｎｇ／ｍＬ、蛍光標識ペプチド基質（ＵＬｉｇｈｔ－ＪＡＫ１、パーキンエルマー）を３００ｎＭとなるようアッセイバッファーで希釈した溶液を２μＬずつ添加し、その後、４５μＭとなるようアッセイバッファーで調製したＡＴＰ溶液を２μＬずつ添加することにより酵素反応を開始した。室温にて１時間反応させた後、２０ｍＭ　ＥＤＴＡ、４ｎＭ　ユーロピウム標識抗リン酸化チロシン抗体（パーキンエルマー）となるよう調製したＤｅｔｅｃｔｉｏｎ　Ｂｕｆｆｅｒ（パーキンエルマー）を６μＬずつ添加した。室温にて１時間静置した後、プレートリーダーＥｎｖｉｓｉｏｎ（パーキンエルマー）にて蛍光強度（励起波長３４０ｎｍ、蛍光波長６６５ｎｍ、ｄｅｌａｙ　ｔｉｍｅ　１００マイクロ秒）を測定した。各化合物の阻害活性は、酵素なしのウェルの蛍光強度を１００％阻害とする相対活性値として算出した。その結果を表２に示す。 Test Example 2 JAK2 Enzyme Inhibition Test The JAK2 enzyme inhibitory activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 μL each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate . Next, add 2 μL each of a solution diluted with 6 ng / mL of JAK2 (Invitrogen) and 300 nM of a fluorescence-labeled peptide substrate (ULight-JAK1, Perkin Elmer) in assay buffer, and then add 45 μM in assay buffer. The enzyme reaction was initiated by adding 2 μL each of the prepared ATP solution. After reacting for 1 hour at room temperature, 6 μL each of Detection Buffer (Perkin Elmer) prepared to be 20 mM EDTA, 4 nM europium-labeled anti-phosphotyrosine antibody (Perkin Elmer) was added. After standing at room temperature for 1 hour, fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (Perkin Elmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the wells without enzyme. The results are shown in Table 2.
試験例３　ＪＡＫ３酵素阻害試験
　被検化合物のＪＡＫ３酵素阻害活性はＬＡＮＣＥ法（パーキンエルマー）にて測定した。まず、アッセイバッファー（５０ｍＭ　ＨＥＰＥＳ　（ｐＨ７．５）、１０ｍＭ　ＭｇＣｌ２、１ｍＭ　ＥＧＴＡ、２ｍＭ　ＤＴＴ、０．０１％　Ｔｗｅｅｎ２０、０．０１％　ＢＳＡ）で希釈した被検化合物を３８４ウェルプレートに２μＬずつ添加した。次に、ＪＡＫ３（インビトロジェン）を１２ｎｇ／ｍＬ、蛍光標識ペプチド基質（ＵＬｉｇｈｔ－ＪＡＫ１、パーキンエルマー）を３００ｎＭとなるようアッセイバッファーで希釈した溶液を２μＬずつ添加し、その後、１５μＭとなるようアッセイバッファーで調製したＡＴＰ溶液を２μＬずつ添加することにより酵素反応を開始した。室温にて１時間反応させた後、２０ｍＭ　ＥＤＴＡ、４ｎＭ　ユーロピウム標識抗リン酸化チロシン抗体（パーキンエルマー）となるよう調製したＤｅｔｅｃｔｉｏｎ　Ｂｕｆｆｅｒ（パーキンエルマー）を６μＬずつ添加した。室温にて１時間静置した後、プレートリーダーＥｎｖｉｓｉｏｎ（パーキンエルマー）にて蛍光強度（励起波長３４０ｎｍ、蛍光波長６６５ｎｍ、ｄｅｌａｙ　ｔｉｍｅ　１００マイクロ秒）を測定した。各化合物の阻害活性は、酵素なしのウェルの蛍光強度を１００％阻害とする相対活性値として算出した。その結果を表２に示す。 Test Example 3 JAK3 Enzyme Inhibition Test The JAK3 enzyme inhibitory activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 μL each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate . Next, add 2 μL each of a solution in which JAK3 (Invitrogen) is diluted to 12 ng / mL, and a fluorescently labeled peptide substrate (ULight-JAK1, Perkin Elmer) to 300 nM, and then add 15 μM to the assay buffer. The enzyme reaction was initiated by adding 2 μL each of the prepared ATP solution. After reacting for 1 hour at room temperature, 6 μL each of Detection Buffer (Perkin Elmer) prepared to be 20 mM EDTA, 4 nM europium-labeled anti-phosphotyrosine antibody (Perkin Elmer) was added. After standing at room temperature for 1 hour, fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (Perkin Elmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the wells without enzyme. The results are shown in Table 2.
試験例４　ＴＹＫ２酵素阻害試験
　被検化合物のＴＹＫ２酵素阻害活性はＬＡＮＣＥ法（パーキンエルマー）にて測定した。まず、アッセイバッファー（５０ｍＭ　ＨＥＰＥＳ　（ｐＨ７．５）、１０ｍＭ　ＭｇＣｌ２、１ｍＭ　ＥＧＴＡ、２ｍＭ　ＤＴＴ、０．０１％　Ｔｗｅｅｎ２０、０．０１％　ＢＳＡ）で希釈した被検化合物を３８４ウェルプレートに２μＬずつ添加した。次に、ＴＹＫ２（インビトロジェン）を３７５ｎｇ／ｍＬ、蛍光標識ペプチド基質（ＵＬｉｇｈｔ－ＪＡＫ１、パーキンエルマー）を３００ｎＭとなるようアッセイバッファーで希釈した溶液を２μＬずつ添加し、その後、３０μＭとなるようアッセイバッファーで調製したＡＴＰ溶液を２μＬずつ添加することにより酵素反応を開始した。室温にて１時間反応させた後、２０ｍＭ　ＥＤＴＡ、４ｎＭ　ユーロピウム標識抗リン酸化チロシン抗体（パーキンエルマー）となるよう調製したＤｅｔｅｃｔｉｏｎ　Ｂｕｆｆｅｒ（パーキンエルマー）を６μＬずつ添加した。室温にて１時間静置した後、プレートリーダーＥｎｖｉｓｉｏｎ（パーキンエルマー）にて蛍光強度（励起波長３４０ｎｍ、蛍光波長６６５ｎｍ、ｄｅｌａｙ　ｔｉｍｅ　１００マイクロ秒）を測定した。各化合物の阻害活性は、酵素なしのウェルの蛍光強度を１００％阻害とする相対活性値として算出した。その結果を表２に示す。 Test Example 4 TYK2 Enzyme Inhibition Test The TYK2 enzyme inhibitory activity of the test compound was measured by the LANCE method (Perkin Elmer). First, 2 μL each of the test compound diluted in assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to the 384 well plate . Next, add 2 μL each of a solution diluted with assay buffer to 375 ng / mL of TYK2 (Invitrogen) and 300 nM of fluorescence-labeled peptide substrate (ULight-JAK1, Perkin Elmer), and then add 30 μM of assay buffer The enzyme reaction was initiated by adding 2 μL each of the prepared ATP solution. After reacting for 1 hour at room temperature, 6 μL each of Detection Buffer (Perkin Elmer) prepared to be 20 mM EDTA, 4 nM europium-labeled anti-phosphotyrosine antibody (Perkin Elmer) was added. After standing at room temperature for 1 hour, fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (Perkin Elmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the wells without enzyme. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
　本発明化合物は、優れたＪＡＫ阻害作用を有し得、自己免疫疾患（関節リウマチ、乾癬、炎症性腸疾患、シェーグレン症候群、ベーチェット病、多発性硬化症、全身性エリテマトーデス、アトピー性皮膚炎等）、癌（白血病、子宮平滑筋肉腫、前立腺癌、多発性骨髄腫、悪液質、骨髄線維症等）等の予防または治療剤として有用であり得る。 The compound of the present invention can have excellent JAK inhibitory action, and autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, atopic dermatitis, etc.) And cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis and the like) and the like can be useful as preventive or therapeutic agents.
　本出願は、日本で出願された特願２０１７－１９３０８７を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on patent application No. 2017-193087 filed in Japan, the contents of which are incorporated in full herein.

Claims (8)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     〔式中、R1、R2、R3、R4およびR5は、それぞれ独立して水素原子または置換基を示す。〕で表される化合物またはその塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, R 1 , R 2 , R 3 , R 4 and R 5 each independently represent a hydrogen atom or a substituent. Or a salt thereof.
  2. 　Ｒ１が、水素原子であり；
    　Ｒ２が、水素原子であり；
    　Ｒ３が、
    (a) (i) シアノ基、(ii) ヒドロキシ基、(iii) Ｃ６－１４アリール基、(iv) シアノ基で置換されていてもよいＣ１－６アルキル-カルボニル基で置換されていてもよい３ないし８員の単環式非芳香族複素環基、(v) (i') シアノ基および(ii') １ないし３個のシアノ基で置換されていてもよいＣ６－１４アリール基から選ばれる１ないし３個の置換基で置換されていてもよい３ないし８員の単環式非芳香族複素環カルボニル基、および(vi) ジＣ１－６アルキルアミノ基から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基、
    (b) (i) ヒドロキシ基、(ii) １ないし3個のヒドロキシ基で置換されていてもよいＣ１－６アルキル基、および(iii) Ｃ６－１４アリール基から選ばれる１ないし３個の置換基で置換されていてもよいＣ３－８シクロアルキル基、および
    (c) ３ないし８員の単環式非芳香族複素環基
    から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基であり；
    　Ｒ４が、
    (1) シアノ基；
    (2) (a) (i) Ｃ３－８シクロアルキル基、(ii) Ｃ１－６アルコキシ基および(iii) １ないし3個のＣ１－６アルキル基
    で置換されていてもよい３ないし８員の単環式非芳香族複素環基から選ばれる１ないし３個の置換基で置換されていてもよいＣ１－６アルキル基、
    　　(b) Ｃ３－８シクロアルキル基、および、
    　　(c) ３ないし８員の単環式非芳香族複素環基
    から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基；または、
    (3) Ｃ１－６アルコキシ－カルボニル基であり；
    　Ｒ５が、水素原子である、請求項１記載の化合物またはその塩。     R 1 is a hydrogen atom;
    R 2 is a hydrogen atom;
    R 3 is
    (a) (i) substituted with a cyano group, (ii) hydroxy group, (iii) a C 6-14 aryl group, (iv) a C 1-6 alkyl-carbonyl group which may be substituted with a cyano group 3-8 membered monocyclic non-aromatic heterocyclic group, (v) (i ') cyano group and (ii') C 6-14 aryl optionally substituted by 1 to 3 cyano groups 1 to 3 selected from 3 to 8 membered monocyclic non-aromatic heterocyclic carbonyl group optionally substituted by 1 to 3 substituents selected from groups, and (vi) di C 1-6 alkylamino group C 1-6 alkyl group which may be substituted by 1 to 3 substituents,
    1 to 3 selected from (b) (i) hydroxy group, (ii) C 1-6 alkyl group optionally substituted with 1 to 3 hydroxy group, and (iii) C 6-14 aryl group C 3-8 cycloalkyl group which may be substituted with a substituent of
    (c) an amino group which may be mono- or di-substituted with a substituent selected from 3- to 8-membered monocyclic non-aromatic heterocyclic groups;
    R 4 is
    (1) cyano group;
    (2) (a) (i) 3 to 8 optionally substituted with a C 3-8 cycloalkyl group, (ii) a C 1-6 alkoxy group and (iii) 1 to 3 C 1-6 alkyl groups A C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 8-membered monocyclic non-aromatic heterocyclic groups,
    (b) a C 3-8 cycloalkyl group, and
    (c) a carbamoyl group which may be mono- or di-substituted with a substituent selected from 3- to 8-membered monocyclic non-aromatic heterocyclic groups; or
    (3) C 1-6 alkoxy-carbonyl group;
    The compound or a salt thereof according to claim 1, wherein R 5 is a hydrogen atom.
  3. 　2-(4-((4-ヒドロキシ-4-フェニルシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル、
    　（RまたはS)-2-(2-オキソ-4-(テトラヒドロ-2H-ピラン-3-イルアミノ)-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル、
    　2-(4-((trans-4-(ヒドロキシメチル)シクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボニトリル、
    　メチル 2-(4-(((2R)-1-(3-シアノアゼチジン-1-イル)-1-オキソブタン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート、
    　メチル 2-(4-(((2R)-1-(3-シアノアゼチジン-1-イル)-3-メチル-1-オキソブタン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート、
    　メチル 2-(4-(シクロペンチルアミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキシラート、
    　2-(4-((1-ヒドロキシプロパン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　（RまたはS）-2-(4-((1-ヒドロキシプロパン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　（RまたはS）-2-(4-((1-ヒドロキシプロパン-2-イル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(1-メトキシブタン-2-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(1-メトキシブタン-2-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(テトラヒドロ-2H-ピラン-4-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　N-(シクロプロピルメチル)-2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-(2-メトキシエチル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-((3-メチルオキセタン-3-イル)メチル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-メチル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　N-シクロプロピル-2-(4-((trans-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　N-シクロプロピル-2-(4-((cis-4-ヒドロキシシクロヘキシル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　N-シクロプロピル-2-(4-((2-(ジメチルアミノ)-1-フェニルエチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-((シアノメチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-シクロプロピル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド、
    　2-(4-(((1-(シアノアセチル)ピロリジン-3-イル)メチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-シクロプロピル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミドおよび
    　2-(4-((2-(4-(2-シアノフェニル)ピペラジン-1-イル)-2-オキソエチル)アミノ)-2-オキソ-1,2-ジヒドロピリジン-3-イル)-N-シクロプロピル-1H-チエノ[2,3-d]イミダゾール-5-カルボキサミド
    からなる群より選ばれる化合物またはその塩。     2- (4-((4-hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile ,
    (R or S) -2- (2-oxo-4- (tetrahydro-2H-pyran-3-ylamino) -1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole- 5-carbonitrile,
    2- (4-((trans-4- (hydroxymethyl) cyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbo Nitrile,
    Methyl 2- (4-(((2R) -1- (3-cyanoazetidin-1-yl) -1-oxobutan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl)- 1H-thieno [2,3-d] imidazole-5-carboxylate,
    Methyl 2- (4-(((2R) -1- (3-cyanoazetidin-1-yl) -3-methyl-1-oxobutan-2-yl) amino) -2-oxo-1,2-dihydropyridine-3 -Yl) -1H-thieno [2,3-d] imidazole-5-carboxylate,
    Methyl 2- (4- (cyclopentylamino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylate,
    2- (4-((1-hydroxypropan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide,
    (R or S) -2- (4-((1-hydroxypropan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] Imidazole-5-carboxamide,
    (R or S) -2- (4-((1-hydroxypropan-2-yl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] Imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (1-methoxybutan-2-yl) -1H-thieno [2 , 3-d] Imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (1-methoxybutan-2-yl) -1H-thieno [2 , 3-d] Imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (tetrahydro-2H-pyran-4-yl) -1H-thieno [ 2,3-d] imidazole-5-carboxamide,
    N- (Cyclopropylmethyl) -2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] Imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N- (2-methoxyethyl) -1H-thieno [2,3-d ] Imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-((3-methyloxetan-3-yl) methyl) -1H- Thieno [2,3-d] imidazole-5-carboxamide,
    2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-methyl-1H-thieno [2,3-d] imidazole-5- Carboxamide,
    N-Cyclopropyl-2- (4-((trans-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5 -Carboxamide,
    N-Cyclopropyl-2- (4-((cis-4-hydroxycyclohexyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3-d] imidazole-5 -Carboxamide,
    N-Cyclopropyl-2- (4-((2- (dimethylamino) -1-phenylethyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -1H-thieno [2,3- d] imidazole-5-carboxamide,
    2- (4-((Cyanomethyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-cyclopropyl-1H-thieno [2,3-d] imidazole-5-carboxamide,
    2- (4-(((1- (cyanoacetyl) pyrrolidin-3-yl) methyl) amino) -2-oxo-1,2-dihydropyridin-3-yl) -N-cyclopropyl-1H-thieno [2 , 3-d] imidazole-5-carboxamide and 2- (4-((2- (4- (2-cyanophenyl) piperazin-1-yl) -2-oxoethyl) amino) -2-oxo-1,2 A compound selected from the group consisting of -dihydropyridin-3-yl) -N-cyclopropyl-1H-thieno [2,3-d] imidazole-5-carboxamide or a salt thereof.
  4. 　請求項１記載の化合物またはその塩を含有してなる医薬。 A medicament comprising the compound according to claim 1 or a salt thereof.
  5. 　ヤヌスキナーゼ阻害剤である、請求項４記載の医薬。 The medicine according to claim 4, which is a Janus kinase inhibitor.
  6. 　自己免疫疾患の予防または治療剤である、請求項４記載の医薬。 The medicine according to claim 4, which is a preventive or therapeutic agent for an autoimmune disease.
  7. 　自己免疫疾患が全身性エリテマトーデス、炎症性腸疾患、乾癬、関節リウマチ、シェーグレン症候群、ベーチェット病、または多発性硬化症である、請求項６記載の医薬。 The pharmaceutical composition according to claim 6, wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjögren's syndrome, Behcet's disease, or multiple sclerosis.
  8. 　自己免疫疾患がアトピー性皮膚炎である、請求項６記載の医薬。 The medicine according to claim 6, wherein the autoimmune disease is atopic dermatitis.
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