WO2014175370A1 - Pyrrolidine derivative and pharmaceutical composition containing same - Google Patents

Pyrrolidine derivative and pharmaceutical composition containing same Download PDF

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WO2014175370A1
WO2014175370A1 PCT/JP2014/061530 JP2014061530W WO2014175370A1 WO 2014175370 A1 WO2014175370 A1 WO 2014175370A1 JP 2014061530 W JP2014061530 W JP 2014061530W WO 2014175370 A1 WO2014175370 A1 WO 2014175370A1
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substituted
unsubstituted
aromatic
aromatic heterocyclic
group
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PCT/JP2014/061530
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French (fr)
Japanese (ja)
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一也 鹿野
輝和 加藤
千明 藤越
佑介 酒匂
彩枝 直原
太一 上田
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塩野義製薬株式会社
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Publication of WO2014175370A1 publication Critical patent/WO2014175370A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound useful for treating a disease or condition involving interleukin-2 inducible T cell kinase (hereinafter referred to as ITK), and a pharmaceutical composition containing the compound.
  • ITK interleukin-2 inducible T cell kinase
  • ITK is a non-receptor tyrosine kinase belonging to the TEC family, and is mainly expressed in T cells, NK cells, and mast cells. Stimulation of the T cell receptor (TCR) expressed on the T cell surface induces activation of lymphocyte-specific protein tyrosine kinase (LCK) that functions downstream of the TCR, followed by activation of ITK (Non-Patent Document 1). In mast cells, ITK functions downstream of the high affinity immunoglobulin E (IgE) receptor and is activated by stimulation of a complex of antigen and IgE (Non-patent Document 2).
  • TCR T cell receptor
  • LCK lymphocyte-specific protein tyrosine kinase
  • ITK functions downstream of the high affinity immunoglobulin E (IgE) receptor and is activated by stimulation of a complex of antigen and IgE (Non-patent Document 2).
  • Activated ITK phosphorylates phospholipase C ⁇ (PLC ⁇ ), which is an intracellular substrate.
  • PLC ⁇ phospholipase C ⁇
  • Phosphorylated PLC ⁇ breaks phosphoinositol diphosphate into inositol triphosphate and diacylglycerol, leading to an increase in intracellular calcium concentration and activation of protein kinase C.
  • T cells play an important role in the immune response. It is known that abnormalities of T cells are observed in many diseases including autoimmune diseases and allergic diseases. Mast cells are also involved in the pathogenesis and development of allergic diseases by releasing chemical mediators such as histamine.
  • ITK-deficient mice activation and differentiation of T cells, production of cytokines including interleukin (IL) -2, IL-4, IL-5, IL-13, and cell proliferation have been reported to be suppressed.
  • Non-Patent Documents 3, 4, and 5 It has also been observed that degranulation is inhibited in mast cells lacking ITK (Non-patent Document 6). Therefore, it is considered that inhibition of ITK can suppress T cell activation, cytokine production, suppression of proliferation, and suppression of mast cell degranulation. From the above, it is considered that the ITK inhibitor is useful as a therapeutic and / or prophylactic agent for autoimmune diseases, allergic diseases and inflammatory diseases involving T cells or mast cells.
  • Patent Documents 1 and 2 describe compounds having an ITK inhibitory action, but differ in structure from the compounds of the present invention.
  • Patent Documents 3 to 15 describe compounds similar in structure to the compounds of the present invention, but there is no description or suggestion regarding ITK inhibitory action.
  • An object of the present invention is to provide a compound and a pharmaceutical composition having an ITK inhibitory action.
  • the present invention relates to the following (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (21).
  • Each R 2 is independently halogen, hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted alkynylcarbonyl, substituted or unsubstituted substituted alkynylcarbonyl, substituted or unsubstituted substituted alkynylcarbon
  • Ring B is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle
  • Ring C is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle
  • Ring D is a 5-membered aromatic heterocycle
  • Ring E is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle
  • Ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle
  • Ring G is a 5-membered aromatic heterocycle
  • Each R 2 is independently halogen, hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Alkynylcarbonyl, substituted or unsubstituted monoalkylamino,
  • —L— is —C ( ⁇ O) C (R 5a ) (R 5b ) —, —S ( ⁇ O) C (R 5a ) (R 5b ) —, or —SO 2 C (R 5a ) (R 5b ) -when R 5a and R 1 together with adjacent carbon atoms form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group
  • Each Ra is independently carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted
  • Each Ra independently represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-substituted group; Aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic hetero Ring carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, or substituted or unsubstituted non-aromatic heterocyclic carbamoy
  • Each Ra independently represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted
  • the compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′) and (2) to (5), which is a non-aromatic heterocyclic group.
  • Each Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted Substituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or unsubstituted Monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbo
  • (9) —L— is —C ( ⁇ O) N (R 4 ) —, —N (R 4 ) C ( ⁇ O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -
  • R 4 , R 5a and R 5b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, (1), (1 ′), And (2) to (6), (6a), (6b), and the compound according to any one of (7) to (9) or a pharmaceutically acceptable salt thereof.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or an unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group
  • Each R 2 is independently halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Monoalkylureido, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic
  • the compound according to the present invention has an inhibitory effect on ITK, and is useful as a therapeutic and / or prophylactic agent for diseases or conditions involving ITK.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • “Aromatic carbocycle” means a monocyclic or two or more cyclic aromatic hydrocarbon rings. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned. A preferred embodiment of the “aromatic carbocycle” includes a benzene ring.
  • the “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
  • non-aromatic carbocycle means a monocyclic ring or two or more cyclic saturated hydrocarbon rings or cyclic non-aromatic unsaturated hydrocarbon rings.
  • the two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
  • the “non-aromatic carbocycle” includes a ring that is bridged or a spiro ring.
  • the monocyclic non-aromatic carbocycle preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
  • the two or more non-aromatic carbocycles include indane, indene, acenaphthalene, tetrahydronaphthalene, and fluorene.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the non-aromatic carbocyclic group having 2 or more rings includes a monocyclic ring or a non-aromatic carbocyclic group having 2 or more rings condensed with the ring in the above “aromatic carbocyclic group”.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • Aromatic heterocycle means a single ring or two or more aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
  • Two or more aromatic heterocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more aromatic heterocycles.
  • the monocyclic aromatic heterocycle is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples thereof include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
  • bicyclic aromatic heterocyclic group examples include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benz Oxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophore, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolo Examples include pyridine.
  • aromatic heterocyclic group having 3 or more rings examples include carbazole, acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, and dibenzofuran.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocycle means a monocyclic or bicyclic or more cyclic non-aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring .
  • a non-aromatic heterocycle having two or more rings is a monocyclic ring or a non-aromatic heterocycle having two or more rings. Also included are those in which each ring is condensed.
  • the “non-aromatic heterocycle” includes a ring that is bridged or a spiro ring.
  • the monocyclic non-aromatic heterocyclic ring is preferably 3 to 8 members, more preferably 5 or 6 members.
  • Examples include dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thio
  • non-aromatic heterocyclic group having two or more rings examples include indoline, isoindoline, chroman, isochroman and the like.
  • “Non-aromatic heterocyclic group” means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • non-aromatic heterocyclic group includes a group which forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Preferred embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned. Preferable embodiments of “monoalkylamino” include methylamino and ethylamino.
  • Dialkylamino means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like. Preferred embodiments of “dialkylamino” include dimethylamino and diethylamino.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
  • Preferable embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Preferred embodiments of “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
  • “Monoalkenylcarbonylamino” means a group in which the above “alkenylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkenylcarbonyl For example, ethylenylcarbonylamino, propenylcarbonylamino and the like can be mentioned.
  • “Monoalkynylcarbonylamino” means a group in which the above “alkynylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • alkynylcarbonyl For example, ethynylcarbonylamino, propynylcarbonylamino and the like can be mentioned.
  • “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
  • Preferable embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Dialkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned. Preferred embodiments of “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like. Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
  • Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
  • Dialkylcarbamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.
  • Dialkylsulfamoyl means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
  • “Monoalkyloxycarbonylamino” means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • methyloxycarbonylamino, ethyloxycarbonylamino, propyloxycarbonylamino and the like can be mentioned.
  • Dialkyloxycarbonylamino means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • Two alkylcarbonyl groups may be the same or different. Examples thereof include dimethyloxycarbonylamino, diethyloxycarbonylamino and the like.
  • “Monoalkylureido” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the ureido group.
  • the group shown below Etc the group shown below Etc.
  • Dialkylureido means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the ureido group.
  • Two alkyl groups may be the same or different. For example, the group shown below Etc.
  • Trialkylsilyl means a group in which the above three “alkyls” are bonded to a silicon atom.
  • the three alkyls may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • non-aromatic heterocyclic alkyloxy means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”.
  • non-aromatic heterocyclic alkyloxyalkyl substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • “Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group.
  • phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • “Aromatic carbocyclic carbamoyl” means a group in which “aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to a nitrogen atom of a carbamoyl group.
  • “Aromatic carbocyclic amino” means a group in which “aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • phenylamino, naphthylamino and the like can be mentioned.
  • “Aromatic carbocyclic carbonylamino” means a group in which “aromatic carbocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic carbocyclic ureido means a group in which the “aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group.
  • Etc the group shown below Etc.
  • Non-aromatic carbocyclic oxy "non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, “non-aromatic carbocyclic sulfonyl”, “non-aromatic
  • the “non-aromatic carbocycle” portion of “carbocyclic carbamoyl”, “non-aromatic carbocyclic amino”, “non-aromatic carbocyclic carbonylamino” and “non-aromatic carbocyclic ureido” is The same as “formula”.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocycle carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
  • non-aromatic carbocyclic oxycarbonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group.
  • cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • non-aromatic carbocyclic carbamoyl means a group in which the “non-aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like can be mentioned.
  • Non-aromatic carbocyclic amino means a group in which “non-aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Non-aromatic carbocyclic carbonylamino means a group in which “non-aromatic carbocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylcarbonylamino, cyclohexylcarbonylamino, cyclohexenylcarbonylamino and the like can be mentioned.
  • non-aromatic carbocyclic ureido means a group in which the “non-aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group.
  • the group shown below Etc the group shown below Etc.
  • Aromatic heterocyclic oxy means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
  • “Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • “Aromatic heterocycle carbamoyl” means a group in which “aromatic heterocycle” is replaced with one or two hydrogen atoms bonded to a nitrogen atom of a carbamoyl group.
  • “Aromatic heterocycle amino” means a group in which “aromatic heterocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • “Aromatic heterocyclic carbonylamino” means a group in which “aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • pyridylcarbonylamino, oxazolylcarbonylamino and the like can be mentioned.
  • aromatic heterocyclic ureido means a group in which the “aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group.
  • the group shown below Etc the group shown below Etc.
  • Non-aromatic heterocyclic oxy "Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic sulfanyl”, “Non-aromatic heterocyclic sulfonyl”, “Non-aromatic
  • the “non-aromatic heterocycle” portion of “heterocyclic carbamoyl”, “non-aromatic heterocyclic amino”, “non-aromatic heterocyclic carbonylamino” and “non-aromatic heterocyclic ureido” is The same as “formula”.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • the “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • non-aromatic heterocyclic carbamoyl means a group in which the “non-aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • non-aromatic heterocyclic amino means a group in which the “non-aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Non-aromatic heterocyclic carbonylamino means a group in which “non-aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and the like can be mentioned.
  • the “non-aromatic heterocyclic ureido” means a group in which the “non-aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group.
  • Etc For example, piperidinyl ureido, tetrahydrofuryl ureido, etc. are mentioned.
  • the carbon atom at any position may be bonded to one or more groups selected from the substituent group A.
  • Substituent group A halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, al
  • Rings such as “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, “non-aromatic heterocycle” and the like in Substituent Group A are those in which the atom at any position in the ring is the Substituent Group It may be substituted with one or more groups selected from ⁇ .
  • Substituent group ⁇ halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkenyl Carbonyl, alkynylcarbonyl, monoalkylamino, dialkyla
  • substituted group ⁇ is halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyl.
  • substituted group ⁇ includes halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy.
  • the atom at any position on the ring may be bonded to one or more groups selected from the substituent group B.
  • Substituent group B halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alky
  • Rings such as “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle” and “non-aromatic heterocycle” in Substituent Group B are those in which the atom at any position in the ring is the Substituent Group It may be substituted with one or more groups selected from ⁇ .
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • the atom a means an atom adjacent to -X- and constituting only the ring C.
  • a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom can be mentioned.
  • Atom b is adjacent to —X— and is a ring member atom of both ring B and ring C.
  • the atom b includes a carbon atom or a nitrogen atom.
  • the atom c is an atom adjacent to -X- and constituting only the ring E.
  • a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom can be mentioned.
  • the atom d is adjacent to —X— and is a ring atom of both ring D and ring E.
  • the atom d includes a carbon atom or a nitrogen atom.
  • the left bond is bonded to the carbon atom of the pyrrolidine ring, and the right bond is bonded to R1.
  • ring A is assumed to be A1 (Wherein p is as defined above). (Hereinafter, ring A is assumed to be A2) (Wherein p is as defined above). (Hereinafter, ring A is assumed to be A3)
  • R 2a is halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted fragrance Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-
  • ring A is assumed to be A6) (Wherein R 2a and p ′ are as defined above). (Hereinafter, ring A is assumed to be A7) (Wherein R 2a has the same meaning as above). (Hereinafter, ring A is assumed to be A8) (Wherein R 2a has the same meaning as above). (Hereinafter, ring A is assumed to be A9)
  • Each Ra is independently carboxy, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, Substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or Unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl
  • Each Ra is independently carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or Unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbon
  • Each Ra is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic Carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbon Ring carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted Or an unsubstituted non-aromatic heterocycl
  • Each Ra independently represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted Non-aromatic heterocyclic group is mentioned. (Hereafter, Ra is assumed to be Ra4)
  • Rb each independently represents hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or un
  • Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted Or unsubstituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or unsubstituted Substituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbocyclic
  • Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted Or unsubstituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbocyclic carbonylamino , Substituted or unsubstituted aromatic heterocyclic carbonylamino, or substituted or unsubstituted nonaromatic heterocyclic carbonylamino.
  • Rc includes a hydrogen atom.
  • —L— includes —C ( ⁇ O) N (R 4 ) —, —N (R 4 ) C ( ⁇ O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO. 2- .
  • L is assumed to be L1
  • Examples of —L— include —C ( ⁇ O) N (R 4 ) — or —N (R 4 ) C ( ⁇ O) —.
  • L is assumed to be L2
  • R 4 , R 5a and R 5b each independently include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
  • R 4 , R 5a and R 5b include a hydrogen atom.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, Substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group Is mentioned.
  • R 1 is R11
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group.
  • Group heterocyclic groups (Hereafter, R 1 is assumed to be R12)
  • R 1 includes a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group.
  • R 1 is assumed to be R13)
  • R 2 is each independently halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-
  • n is 1 or 2; n is 1. m is 0, and n is 1 or 2. (Hereafter, nm is assumed to be nm1) m is 0 and n is 1. (Hereafter, nm is assumed to be nm2)
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof includes a compound or a pharmaceutically acceptable salt thereof generated by a combination of a part or all of the definition of each substituent shown above. It is done. More specifically, a compound or a pharmaceutically acceptable salt thereof in which the combination of ring A, Ra, L, R 1 and nm (ring A, Ra, L, R 1 , nm) is the following combination, respectively. It is done.
  • One embodiment of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof includes the following compound or a pharmaceutically acceptable salt thereof. 1) n and m are both 0; Rc is a hydrogen atom; Is; —L— is —C ( ⁇ O) N (R 4 ) —, —N (R 4 ) C ( ⁇ O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is; R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubsti
  • Rc is a hydrogen atom
  • Is R 6 is substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl;
  • —L— is —C ( ⁇ O) N (R 4 ) —, —N (R 4 ) C ( ⁇ O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is
  • R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group
  • Rc is a hydrogen atom
  • R 2a is as defined above
  • —L— is —C ( ⁇ O) N (R 4 ) —, —N (R 4 ) C ( ⁇ O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is
  • R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
  • Rc is a hydrogen atom
  • R 2a is as defined above
  • —L— is —C ( ⁇ O) N (R 4 ) —, —N (R 4 ) C ( ⁇ O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is
  • R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 2 when the substituent represented by R 2 is represented as follows: R 2 can be substituted with p at all substitutable ring atoms of ring B or ring C. Similarly in other rings, R 2 can be substituted with p at all substitutable ring atoms of multiple or single rings.
  • the compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fum
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph.
  • a solvate for example, a hydrate etc.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • the compound represented by the above general formula (I) has an inhibitory action on ITK, and is useful as a therapeutic and / or prophylactic agent for diseases and / or conditions involving ITK.
  • ITK is considered to be involved in autoimmune diseases, allergic diseases, inflammatory diseases, immune diseases and the like.
  • ITK Intradermatitis fibrosis .
  • ITK inflammatory or allergic airway diseases
  • allergic rhinitis asthma, etc.
  • COPD chronic obstructive pulmonary disease
  • inflammatory or allergic skin diseases contact dermatitis
  • food allergy psoriasis
  • rheumatoid arthritis multiple sclerosis
  • conjunctivitis allergic conjunctivitis, spring keratoconjunctivitis, etc.
  • type I diabetes T cell mediated hypersensitivity, Guillain-Barre syndrome, Hashimoto Thyroiditis, graft rejection (organ transplant rejection, bone marrow transplant rejection, etc.), graft-versus-host disease, inflammatory bowel disease, chronic inflammation, HIV, aplastic anemia, pain, inflammatory pain, cancer, etc.
  • a more preferred compound of the present invention is a pharmaceutical composition having selective ITK inhibitory activity.
  • ITK inhibitors that have no inhibitory activity or weak inhibitory activity against other kinases that have physiologically important functions, such as autoimmune diseases, inflammatory diseases, and allergic diseases that have overcome safety concerns It is considered very useful as a preventive or therapeutic agent.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. All of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment. The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
  • Hal is a halogen atom; —M— is —C ( ⁇ O) —, —S ( ⁇ O) — or —SO 2 —; Pg A is a suitable protecting group for an amino group ; , Ra, Rb, Rc, R 1 , n and m are the same as defined in (1) above.
  • Compound (A-iii) can be obtained by reacting compound (Ai) with compound (A-ii) in the presence of a base.
  • the base include potassium carbonate, cesium carbonate, sodium hydride and the like.
  • the reaction solvent include DMSO, DMF, DMA, DMI, THF, dioxane and the like.
  • reaction temperature is 60 to 180 ° C, preferably 100 to 120 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 3 hours.
  • compound (A-iii) can be obtained by a coupling reaction using a catalyst. Specifically, the compound (A-iii) is reacted with the compound (A-ii) in the presence or absence of a base and in the presence of a catalyst and a phosphine ligand. Obtainable.
  • the catalyst include palladium catalysts such as Pd (Ac) 2 and Pd 2 (dba) 3 , copper catalysts such as copper iodide, and the like.
  • Examples of the phosphine ligand include Xantphos, BINAP, X-phos, S-phos and the like.
  • Examples of the base include sodium tert-butoxide, cesium carbonate and the like.
  • As the reaction solvent for example, toluene, DMF, DMA, dioxane or the like can be used, but it is not particularly limited as long as it is a solvent other than the solvent that hinders the reaction under the present conditions.
  • the reaction temperature is not particularly limited, it can be carried out at room temperature to 200 ° C. If the reactivity is low, it may be appropriately heated.
  • Compound (A-iv) can be obtained by deprotecting the protecting group of the amino group of compound (A-iii) by an appropriate method.
  • Appropriate deprotection in this case is, for example, deprotection by catalytic hydrogenation reduction method for Cbz or deprotection by acid such as hydrochloric acid, and deprotection by acid such as TFA or hydrochloric acid if it is Boc group. It is protection.
  • the reaction solvent include DMF, THF, dichloromethane and the like.
  • Compound (Av) can be obtained by reacting compound (A-iv) with corresponding carboxylic acid or corresponding sulfonic acid in the presence of HOBt or HOAt, a base, and a condensing agent.
  • the base include triethylamine, DIEA and the like.
  • the condensing agent include EDC / HCl, HATU, PyBOP, and the like.
  • the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • the reaction solvent include dichloromethane, THF, DMF, DMA, NMP, dioxane and the like.
  • compound (Av) can be obtained by reacting compound (A-iv) with a corresponding acid chloride or corresponding sulfonyl chloride in the presence of a base.
  • a base include DIEA, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 0.5 hour to 120 hours, preferably 1 hour to 72 hours.
  • the reaction solvent include acetonitrile, THF, toluene, dichloromethane and the like.
  • the compound (Av) can be obtained by condensing the corresponding aldehyde derivative, the corresponding ketone derivative and the compound (A-iv) or a salt thereof in the presence or absence of a condensing agent and then reducing with a reducing agent.
  • a condensing agent examples include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, molecular sieves, etc.
  • the compound (A-iv) has 1 to 10 molar equivalents can be used.
  • Compound (A-iv) or a salt thereof can be used at 1 to 10 molar equivalents relative to the aldehyde derivative or ketone derivative to be reacted.
  • the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride, and the like. 1 to 10 molar equivalents can be used with respect to the ketone derivative.
  • the reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably 0 to 25 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
  • the reaction solvent include THF, toluene, dichloromethane, chloroform, methanol, ethanol and the like, and these can be used alone or in combination.
  • the compound (B-iv) can be obtained by deprotecting the protecting group for the hydroxyl group by a suitable method in a solvent such as dichloromethane, DMF, or THF.
  • a suitable method such as dichloromethane, DMF, or THF.
  • Appropriate deprotection in this case is, for example, deprotection with a fluorine ion such as TBAF or deprotection with an acid such as hydrochloric acid if it is a silyl protecting group such as a TBS group, and dilute hydrochloric acid if it is a THP group. Deprotection with acid.
  • Compound (Bv) in which Nr is a phthalimide group or an azide group can be obtained by reacting compound (B-iv) with potassium phthalimide or DPPA in the presence of triphenylphosphine and a condensing agent.
  • the condensing agent include DEAD, DIAD and the like, and 1 to 5 molar equivalents can be used with respect to the compound (B-iv).
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 10 ° C. to 40 ° C.
  • the reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.
  • reaction solvent examples include THF, dioxane, ethyl acetate, toluene, acetonitrile and the like, and these can be used alone or in combination.
  • the hydroxyl group of compound (Bv) can be sulfonylated with mesyl chloride, tosyl chloride or the like to obtain compound (Bv) in which Nr is a sulfonyl protecting group.
  • the reaction temperature includes ⁇ 20 ° C. to room temperature, preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • the reaction solvent include dichloromethane, chloroform, toluene and the like.
  • compound (Bv) in which Nr is an azido group can be obtained by reacting compound (Bv) in which Nr is a sulfonyl protecting group with NaN 3 .
  • the reaction temperature is ⁇ 20 to 180 ° C., preferably room temperature to 120 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • the reaction solvent include dichloromethane, chloroform, acetonitrile, THF, dioxane, toluene, DMF, DMA and the like.
  • the reaction temperature is 0 to 120 ° C., preferably room temperature to 60 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 24 hours.
  • the reaction solvent include THF, dioxane and the like.
  • diastereomers of compound (B-vi) can be separated by silica gel chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • Nr of compound (Bv) is an azide group
  • compound (B-vi) can be obtained by reacting with a reducing agent.
  • the reducing agent examples include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and 1 to 10 molar equivalents can be used with respect to the compound.
  • the reaction temperature includes 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature.
  • the reaction time may be 0.2 to 48 hours, preferably 1 to 24 hours.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, dichloromethane, water and the like, and these can be used alone or in combination.
  • Nr of compound (Bv) is a sulfonyl protecting group
  • compound (B-vi) can be obtained by reacting with ammonia.
  • the reaction temperature is ⁇ 20 to 120 ° C., preferably room temperature to 100 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
  • the reaction solvent include alcohols such as methanol and ethanol, DMF, DMA, THF, dioxane, acetonitrile and the like.
  • Pg C1 and Pg C3 are suitable protecting groups for amino groups, and it is desirable that Pg C3 does not leave under the elimination conditions of Pg C1 .
  • Pg C2 is a suitable protecting group for hydroxyl groups. And is preferably a protecting group that is not accompanied by elimination of Pg C1 Hal is a halogen atom;
  • Metal is a metal atom;
  • Nr is an amino group such as an azide group, a phthalimide group, or a sulfonyl-type protecting group.
  • Nucleophiles (C-xiii) include lithium reagents such as methyl lithium and ethyl lithium, and Grignard reagents such as methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, ethyl magnesium bromide, ethyl magnesium chloride, and ethyl magnesium iodide. And a mixed reagent of these and a metal salt, and the compound (Ci) can be used at 1 to 5 molar equivalents.
  • the reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably -45 ° C to 0 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 6 hours.
  • reaction solvent examples include tetrahydrofuran, hexane, diethyl ether, methyl tert-butyl ether, toluene, dichloromethane and the like, and these can be used alone or in combination.
  • the nucleophilic agent (C-xiii) can be adjusted by lithiating a halide represented by Ra-Hal using n-butyllithium, LDA, LHMDS or the like.
  • the reaction solvent is not particularly limited as long as it does not react with alkyl lithium such as tetrahydrofuran, dioxane, diethyl ether and the like.
  • the temperature of the lithiation reaction is preferably about ⁇ 78 ° C. to 0 ° C.
  • Compound (C-iii) can be obtained by reacting compound (C-ii) with a reducing agent.
  • the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (C-ii).
  • the reaction temperature includes 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature.
  • the reaction time may be 0.2 to 48 hours, preferably 1 to 24 hours.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, dichloromethane, water and the like, and these can be used alone or in combination.
  • Compound (C-iv) can be obtained by adding a base and an acid chloride to compound (C-iii).
  • the base include pyridine, triethylamine, DIEA and the like.
  • the acid chloride include mesyl chloride, tosyl chloride, and the like, and 1 to 5 molar equivalents can be used with respect to compound (C-iii).
  • the reaction temperature is ⁇ 40 to 80 ° C., preferably 0 to 40 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 5 hours.
  • the reaction solvent include dichloromethane, chloroform, THF, DMF and the like.
  • the compound (Cv) can be obtained using a fluorine reagent.
  • the fluorine reagent include TBAF.
  • the reaction temperature is ⁇ 20 to 50 ° C., preferably 0 to 40 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.
  • the reaction solvent include THF, dioxane, diethyl ether, methanol, ethanol and the like.
  • Compound (Cv) can be separated into diastereomers using silica gel chromatography and amino silica gel column chromatography.
  • diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • compound (Cv) can be obtained by the method described in the third step of Method B.
  • compound (C-vi) can be obtained by the method described in the fourth step of Method B.
  • Compound (C-viii) can be obtained by adding a base and an acid chloride to compound (C-vii). Examples of the base include pyridine, triethylamine, DIEA and the like.
  • Examples of the acid chloride include carbonate chloride, tosyl chloride, o-nitrosulfonyl chloride and the like. Preferred is o-nitrosulfonyl chloride.
  • Examples of the reaction temperature include ⁇ 40 to 70 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 6 hours.
  • Examples of the reaction solvent include dichloromethane, chloroform, THF, dioxane and the like.
  • Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, TFA, and the like.
  • Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O). Etc.
  • the acid or Lewis acid can be used in an amount of 1 to 10 molar equivalents relative to compound (C-viii).
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • reaction solvent examples include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
  • Pg C1 of the compound (C-viii) is an oxycarbonyl-based protecting group, an aminocarbonyl-based protecting group, an oxysulfonyl-based protecting group or an aminosulfonyl-based protecting group
  • a compound (C-- ix) can be obtained.
  • the acid include hydrochloric acid and the like.
  • Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), and the like.
  • the acid or Lewis acid can be used in an amount of 1 to 10 molar equivalents relative to compound (C-viii).
  • the reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is 0.5 hour to 120 hours, preferably 1 hour to 6 hours.
  • the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
  • Compound (Cx) can be obtained by reacting compound (Ai) with compound (C-ix) in the presence of a base. If the reactivity is low, 1 equivalent of potassium fluoride may be added.
  • Examples of the base include triethylamine, DIEA, potassium carbonate, cesium carbonate and the like.
  • the reaction solvent include DMF, DMSO, NMP, DMI and the like.
  • the reaction temperature is 0 to 200 ° C., preferably room temperature to 160 ° C.
  • the reaction time is 0.5 to 240 hours, preferably 0.5 to 36 hours.
  • compound (Cx) can be obtained by a catalytic coupling reaction described in the first step of Method A using compound (Ai) and compound (C-ix). (10th step)
  • Compound (C-xi) can be obtained by reacting compound (Cx) with n-dodecanethiol or the like.
  • the reaction temperature is 0 to 160 ° C., preferably room temperature to 60 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 24 hours.
  • Examples of the reaction solvent include DMF, dioxane, THF and the like.
  • Compound (D-vii) can be separated into diastereomers using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • compound (D-viii) can be obtained by the method described in the fourth step of Method B.
  • compound (D-ix) can be obtained by the method described in the third step of Method A.
  • diastereomers of compound (D-ix) can be separated using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • the reaction temperature is -78 to 0 ° C, preferably -10 to 10 ° C.
  • the reaction solvent include dichloromethane and chloroform.
  • the reaction time is 0.5 to 240 hours, preferably 0.5 to 36 hours.
  • Compound (E-iii) can be reacted with a protecting group such as silyl chloride in the presence of a base to give compound (E-iii).
  • Examples of the base include imidazole and triethylamine.
  • the solvent include DMF, THF, acetonitrile, dichloromethane, chloroform and the like.
  • the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 120 hours, preferably 4 to 24 hours.
  • compound (E-iii) and nucleophile (C-xiii) can be obtained by the method described in the first step of Method C.
  • compound (E-iv) can be obtained by the method described in the fourth step of Method C.
  • Compound (E-vi) can be obtained by subjecting compound (Ev) to an appropriate oxidation reaction. As the oxidation reaction, Dess-Matin oxidation, Swan oxidation and the like are preferable.
  • the compound (E-vi) is desirably used for the next reaction promptly without purification.
  • compound (E-vi) can be obtained by reacting compound (Ev) with Dess-Matin reagent.
  • the reaction solvent include dichloromethane and chloroform.
  • the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 120 hours, preferably 6 to 48 hours.
  • dimethyl sulfoxide and oxalyl chloride or trifluoroacetic anhydride are reacted, then reacted with compound (Ev) and treated with amine to give compound (E-vii).
  • Swan oxidation specifically, dimethyl sulfoxide and oxalyl chloride or trifluoroacetic anhydride are reacted, then reacted with compound (Ev) and treated with amine to give compound (E-vii).
  • the reaction temperature is -78 ° C to -15 ° C, preferably -78 ° C to -40 ° C.
  • the reaction time is 0.1 to 4 hours, preferably 0.5 to 2 hours.
  • the amine include trimethylamine, triethylamine, tripropylamine, and tributylamine.
  • Examples of the reaction solvent include dichloromethane, THF, dioxane, benzene and the like.
  • condensing agent examples include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, molecular sieves, and the like. 10 molar equivalents can be used. Compound (Ex) or a salt thereof can be used at 1 to 10 molar equivalents relative to compound (E-vi).
  • Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride and the like (E 1 to 10 molar equivalents can be used with respect to -vi).
  • the reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably 0 to 25 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
  • Examples of the reaction solvent include THF, toluene, dichloromethane, chloroform, methanol, ethanol and the like, and they can be used alone or in combination.
  • cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, or the like can also be used.
  • the reaction temperature is 0 ° C. to 40 ° C., preferably 10 ° C. to 30 ° C.
  • the reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
  • the reaction solvent include methanol, ethanol, water, THF, ethyl acetate and the like, and these can be used alone or in combination.
  • Compound (E-vii) can be separated into diastereomers using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • Pg F1 and Pg F2 are suitable protecting group for a hydroxyl group
  • Pg F2 is .Nr a protecting group that does not affect the Pg F1 as desorption conditions, azide group, phthalimide group, a sulfonyl type protecting A functional group that can be easily converted to an amino group such as a group
  • —M— is —C ( ⁇ O) —, —S ( ⁇ O) —, or —SO 2 —
  • Ra, Rb, Rc, R 1 and m are as defined in (1) above.
  • compound (F-xi) can be obtained by the method described in the third step of Method A.
  • diastereomers of compound (Fx) can be separated using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • R G is a silyl protecting group such as a hydrogen atom or a TBS group; Nr is a functional group that can be easily converted to an amino group such as an azide group, a phthalimide group, or a sulfonyl protecting group; M— is —C ( ⁇ O) —, —S ( ⁇ O) — or —SO 2 —; , Ra, R 1 and m are as defined above (1).
  • Compound (G-ii) can be obtained by reductive amination reaction.
  • compound (G-iii) and compound (Gi) or a salt thereof are condensed in the presence or absence of a condensing agent, and reduced with a reducing agent, to thereby reduce compound (G-ii).
  • a condensing agent examples include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, and molecular sieve.
  • Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride and the like.
  • the reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably 0 to 25 ° C.
  • the reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
  • Examples of the reaction solvent include THF, toluene, dichloromethane, chloroform, methanol, ethanol and the like, and these can be used alone or in combination.
  • Compound (G-iii) can be obtained by reacting compound (G-ii) with excess compound (G-ix) in the presence of a Lewis acid.
  • a Lewis acid include Ti (Cl) 4 , Ti (isopropoxyl) 4 , tetramethylaluminum, diethylaluminum chloride and the like.
  • the reaction solvent include acetic acid, dichloroethane, dichloromethane, toluene and the like.
  • the reaction temperature is ⁇ 40 to 160 ° C., preferably 0 to 60 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 48 hours.
  • the compound (G-iv) can be obtained by reacting the compound (G-iii) in the presence of a base.
  • the base include LHMDS.
  • the reaction solvent include THF.
  • the reaction temperature may be -78 ° C to room temperature, preferably -78 to 0 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 24 hours.
  • the compound can be obtained by reacting the compound (G-iii) in the presence of a base and then deprotecting the TBS group using TBAF or the like.
  • the base include NaHMDS.
  • the reaction solvent include THF, dioxane and the like.
  • the reaction temperature is -78 to 120 ° C, preferably -40 ° C to room temperature.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 48 hours.
  • diastereomers of compound (G-iv) can be separated using silica gel chromatography and amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase. (4th process) Using compound (G-iv), compound (Gv) can be obtained by the method described in the third step of Method B.
  • compound (G-vi) can be obtained by the method described in the fourth step of Method B.
  • diastereomers of compound (G-vi) can be separated using silica gel chromatography and amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
  • compound (G-vii) can be obtained by the method described in the third step of Method A.
  • Hal is a halogen atom
  • —M 1 — is —C ( ⁇ O) —, —S ( ⁇ O) — or —SO 2 —
  • —M 2 — is —N (R 4 ) — Or —C (R 5a ) (R 5b ) —
  • Pg H1 is a suitable protecting group for a carboxyl group, a sulfinyl group, or a sulfo group
  • Ra, Rb, Rc, R 1 , R 4 , R 5a , R 5b , n and m are as defined above (1).
  • compound (H-ii) can be obtained by the method described in the first step of Method A.
  • Compound (H-iv) can be obtained by deprotecting the protecting group of compound (H-iii) by an appropriate method.
  • the compound (H-iv) can be obtained by performing deprotection under the conditions of alkaline hydrolysis.
  • the alkali include aqueous solutions of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • the reaction solvent include methanol, ethanol, THF, dioxane and the like.
  • the reaction temperature is 0 to 120 ° C., preferably room temperature to 70 ° C.
  • the reaction time is 0.5 to 120 hours, preferably 0.5 to 48 hours.
  • Pg H1 is a Boc group
  • compound (H-iv) can be obtained by deprotection in the presence of an acid such as TFA.
  • the reaction solvent include dichloromethane and chloroform.
  • the reaction temperature is 0 to 80 ° C., preferably room temperature to 60 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • reaction solvent examples include dichloromethane, THF, DMF, DMA, NMP, dioxane and the like.
  • the compound (H-iv) is activated with CDI or the like, and then reacted with a corresponding nucleophile to thereby react the compound (H) with —M 2 — being —C (R 5a ) (R 5b ) —. -V) can be obtained.
  • the reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is 0.5 hour to 120 hours, preferably 1 hour to 72 hours.
  • the reaction solvent include acetonitrile, THF, toluene, DMF, DMA, dichloromethane and the like.
  • optically active form of the compound represented by the formula (I) is an optically active starting material, an asymmetric synthesis is carried out at an appropriate stage to obtain an optically active intermediate, or an intermediate or final product that is a racemate. It can be manufactured by optical resolution at an appropriate stage.
  • Optical resolution methods include separation of optical isomers using an optically active column, kinetic optical resolution using enzymatic reactions, etc., diastereomers by salt formation using chiral acids and chiral bases. There are crystallization division, preferential crystallization method and the like.
  • the more preferred compound of the present invention has not only an ITK inhibitory action but also a usefulness as a medicine, and has any or all of the following excellent characteristics.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
  • d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • parenteral administration any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • Example 1 Synthesis of Compound I-253 Process 1 To a solution of compound 1 (51.4 g, 0.20 mol) in acetonitrile (500 mL) was added potassium carbonate (55.2 g, 0.40 mol) and benzyl bromide (37.6 g, 0.22 mol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate 15: 1) to obtain Compound 2 (35 g, yield 50%).
  • Example 2 Process 1 Compound 7 (10 g, 36 mmol) obtained in the same manner as Compound 2 was heated to reflux in concentrated hydrochloric acid (50 mL). After 2 hours, the reaction solution was concentrated under reduced pressure to obtain Compound 8 (4.0 g, yield 43%).
  • Process 2 Compound 8 (3.5 g, 25.8 mmol), Boc 2 O (6.8 g, 31 mmol), sodium hydroxide (2.18 g, 54.2 mmol) dissolved in tert-butanol / water (20 mL, 20 mL) And stirred at 30 ° C. for 16 hours. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • Example 3 Process 1 Compound 14 (16.7 g, 34.4 mmol) obtained in the same manner as Compound 4 and lithium hydroxide monohydrate (4.4 g, 103 mg) were added to methanol / water (100 mL: 10 mL), Stir at 30 ° C. for 16 hours. The pH was adjusted to around 5 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound 15 (15.7 g, 100%).
  • Example 5 A solution of 3-amino-6-chloropyridazine (100 g, 0.77 mol) in 2-chloroacetaldehyde (668.5 g, 35% aqueous solution, 2.67 mol) in ethanol (1 L) was heated to reflux for 4 hours under a nitrogen atmosphere. . The reaction mixture was concentrated to 100 mL and then cooled to room temperature. The produced solid was collected by filtration, washed with ethanol and dried to obtain compound 22 (100 g, yield 84%).
  • Example 6 Process 1 2-Bromo-6-fluoropyridine (2.6 g, 14.8 mmol), 3-methoxyazetidine hydrochloride (18 g, 14.8 mmol), potassium carbonate (8.2 g, 59.1 mmol) were added to DMF (30 mL). The mixture was stirred at room temperature for 15 hours and then at 60 ° C. for 8 hours. After cooling to room temperature, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 26 (2.8 g, yield 78%) as an oil.
  • Example 7 Synthesis of Compounds I-539 and I-545 Process 1 A DMF solution (2 mL) of compound 29 (235 mg, 0.843 mmol), compound 28 (258 mg, 0.76 mmol), DIEA (400 ⁇ L, 2.29 mmol) obtained in the same manner as compound 24 was added at 125 ° C. Stir for hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-539 (87 mg, yield). 21%) was obtained.
  • Example 8 Synthesis of Compound I-540 Process 1 A DMF solution (2 mL) of compound 28 (258 mg, 0.76 mmol), compound 30 (described in WO2012 / 034091A1, 90 mg, 0.843 mmol), DIEA (400 ⁇ L, 2.29 mmol) was stirred at 125 ° C. for 2 hours. . After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-540 (210 mg, yield). 56%). MS (ESI) m / z 490 [M + H] +
  • Example 12 Synthesis of Compound I-258 Process 1
  • Compound 37 (410 mg, 1.67 mmol) was dissolved in 10 mL of DMF, HATU (633 mg, 1.67 mmol), DIEA (0.606 mL, 3.47 mmol), compound 36 (300 mg, 1.39 mmol) were added, and 30 minutes at room temperature. Stir and let stand overnight. Water was added and the mixture was extracted with chloroform and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 38 (631 mg, yield 100%).
  • Example 13 Synthesis of Compounds I-423 and I-424 Process 1 4-Methoxybenzyl alcohol (3.88 mL, 31.3 mmol) was dissolved in DMF (50 mL), 60% sodium hydride (1.4 g, 34.1 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 20 minutes. did. Next, 4-bromo-2-fluoropyridine (5 g, 28.4 mmol) was added under ice cooling, and then the mixture was warmed to room temperature and stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 6 Compound 45 (100 mL, 0.24 mmol) is dissolved in DMF (1 mL), DIEA (0.38 mL, 2.16 mmol) and methanesulfonyl chloride (0.056 mL, 0.72 mmol) are added, and the mixture is stirred at room temperature for 3 hours. did. Next, sodium azide (78 mg, 1.20 mmol) was added, and the mixture was stirred at 70 ° C. for 6 and a half hours. After allowing to cool, water was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 10 Compound I-163 (116 mg, 0.20 mmol) was dissolved in DMF (1 mL), potassium carbonate (136 mg, 0.98 mmol) and dodecane-1-thiol (0.14 mL, 0.59 mmol) were added, and the mixture was heated to 50 ° C. And stirred for 3 hours. After allowing to cool, the solid was filtered and concentrated under reduced pressure to obtain a crude product 56.
  • Example 15 Synthesis of Compound I-070 Process 1
  • Compound 57 24 g, 72.2 mmol was dissolved in THF (240 mL), and 1 mol / L 3-fluorophenylmagnesium bromide-hexane solution (87 mL, 87 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 2 hours. did.
  • methanol 144 mL
  • sodium borohydride (4 g, 108 mmol) was added in small portions and stirred at 0 ° C. for 1 hour.
  • reaction solution was added little by little to a mixed solution of saturated aqueous ammonium chloride and water, and the mixture was warmed and stirred at room temperature for 30 minutes.
  • the mixture was concentrated under reduced pressure, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 58 (28 g, yield 90%).
  • Example 16 Synthesis of Compound 65 Process 1
  • Compound 60 (323 mg, 1.08 mmol) was dissolved in 6 mL of THF, and triethylamine (0.33 mL, 2.38 mmol) was added. The mixture was cooled to 0 ° C., 4-nitrobenzenesulfonyl chloride (360 mg, 1.62 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hr and at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Example 17 Compound 66 (241 mg, 1.12 mmol), Compound 34 (200 mg, 0.93 mmol), cesium carbonate (424 mg, 1.30 mmol), Xantphos (81 mg, 0.14 mmol), Pd (OAc) 2 (21 mg, 0.093 mmol) ) was added with 4 mL of dioxane and stirred at 85 ° C. for 30 minutes. Water was added to the reaction solution and extracted with chloroform, and then the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain Compound 67 (215 mg, 66% yield). MS (ESI) m / z 350 [M + H] + Example compounds described in the following table were synthesized by using Compound 67 instead of Compound 57 in Example 15.
  • Example 18 Synthesis of Compounds I-376 and I-374 Process 1
  • Compound 68 (described in WO2010 / 110231, 820 mg, 3.00 mol), potassium carbonate (829 mg, 6.00 mmol) was dissolved in DMF (5 mL), and iodomethane (0.225 mL, 3.6 mmol) was added with stirring. And stirred at 40 ° C. for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol 3%) to obtain Compound 69 (571 mg, yield 66.2%).
  • Step 5 Synthesis of Compound 77
  • Compound 76 (about 1.0 g, 2.5 mmol), 3-amino-6- (benzhydroxy) pyridine (829 mg, 3.0 mmol), acetic acid (172 ⁇ L, 3.0 mmol) was added to anhydrous dichloromethane (25 mL) at room temperature.
  • NaBH (OAc) 3 (3.18 g, 15 mmol) was added and stirred at room temperature overnight.
  • the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate.
  • Step 6 Compound 77 (47 mg, 0.106 mmol), Compound 37 (26 mg, 0.106 mmol), HOBt (19 mg, 0.138 mmol) in DMF solution (1.5 mL), EDC.HCl (24 mg, 0.127 mmol) and DIEA (46 ⁇ L, 0.265 mmol) was added and stirred at room temperature. After 16 hours, water (1.5 mL) and dichloromethane were added to the reaction solution, and the mixture was vigorously stirred.
  • Example 20 Process 1 Step 1-1 Trimethylaluminum (575 mL, 2 mol / L toluene solution) was added dropwise at 0 ° C. to a suspension of methoxymethylamine hydrochloride (115 g, 1.15 mmol) in anhydrous dichloromethane (900 mL). After stirring at 25 ° C. for 30 minutes, an anhydrous dichloromethane solution (180 mL) of (S) -3-Cbz-amino- ⁇ -butyrolactone (90 g, 0.383 mmol) was added dropwise at 0 ° C. After stirring at room temperature for 15 hours, saturated aqueous ammonium chloride (100 mL) was added.
  • Step 1-5 To a solution of compound 82 (800 mg, 2.55 mmol) in anhydrous dichloromethane (35 mL) was added dropwise an anhydrous dichloromethane solution (15 mL) of Dess Martin reagent (3.24 g, 7.64 mmol) at 0 ° C. After the addition, the reaction solution was stirred for 4 hours at room temperature. The mixture was diluted with a mixed solution of a saturated Na 2 S 2 SO 3 solution (40 mL) and a saturated aqueous sodium hydrogen carbonate solution (20 mL), and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate.
  • anhydrous dichloromethane solution 15 mL
  • Dess Martin reagent 3.24 g, 7.64 mmol
  • Step 3-2 Compound 88 (95 mg, 0.20 mmol) was dissolved in ethanol / aqueous ammonia (10 mL, 0.2 mL), and palladium on carbon (10 mg, water content 50%) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered through celite, washed with methanol, and concentrated under reduced pressure.
  • Example 21 Synthesis of Compound I-432 Process 1 A solution of 1,4-dichloropyridazine (7.6 g, 510 mmol), benzenesulfonamide (8.42 g, 53.55 mmol) and potassium carbonate (15.51 g, 112 mmol) in DMF (75 mL) at 120 ° C. for 2 hours. Stir. After cooling to room temperature, bromoacetamide (7.74 g, 56.1 mmol) was added and stirred at room temperature for 2.5 hours. After adding ethyl acetate and filtering, the mixture was extracted with ethyl acetate.
  • Process 3 Compound 92 (128 mg, 0.309 mmol) was dissolved in THF (2 mL), 2 mol / L aqueous sodium hydroxide solution (0.309 mL, 0.618 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. After standing overnight, 2 mol / L hydrochloric acid aqueous solution (0.160 mL, 0.800 mmol) was added, and then the solvent was concentrated under reduced pressure. THF (2.6 mL) and ethyl isocyanate (0.049 mL mg, 0.618 mmol) were added to the residue, and the mixture was stirred at 60 ° C. for 4 hours.
  • Example 22 Process 1 6-Bromo-2H-1,4-benzoxazin-3 (4H) -one (200 mg, 0.88 mmol) was dissolved in DMF (2 mL), sodium hydride (39 mg, 0.97 mmol), 2-bromoethyl Methyl ether (0.109 mL, 1.14 mmol) was added and stirred at 60 ° C. for 2 hours. The reaction solution was allowed to cool, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 96 (214 mg, yield 85%).
  • Example 23 Process 1 6-Iodo-3,4-dihydro-2H-pyrido (3,2-B) (1,4) oxazine (1 g, 3.82 mmol) was dissolved in THF (10 mL) and phenyl isocyanate (0.54 mL, 4 .96 mmol) and triethylamine (0.79 mL, 5.72 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The precipitated solid was collected by filtration and washed with diethyl ether and water. The obtained solid was dried to obtain Compound 99 (1.2 g, yield 85%).
  • Example 25 Process 1 Compound 107 (846 mg, 3.2 mmol) and Compound 108 (784 mg, 3.2 mmol), copper iodide (122 mg, 0.64 mmol), potassium carbonate (663 mg, 4.8 mmol) obtained in the same manner as Compound 22 were added. Dissolved in DMA (4 mL) and stirred at 90 ° C. overnight. Purification by silica gel column chromatography (chloroform-methanol) gave compound 109 (510 mg, yield 42%).
  • Example 26 Process 1
  • Compound 112 (901 mg, 2.87 mmol) obtained in the same manner as in the method described in WO2012 / 034091A1 was dissolved in DMSO (9.0 mL), and compound 111 (the synthesis method is described in WO2012 / 034091A1) (970 mg, 4 .3 mmol) and potassium fluoride (833 mg, 14.33 mmol) were added, and the mixture was stirred at 120 ° C. for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Example 27 Process 1 Compound 91 (150 mg, 0.57 mmol), 3-ethoxycarbonyl-4- (benzyloxycarbonylamino) pyrrolidine (331 mg, 1.13 mmol) was dissolved in NMP (1.5 mL), and DIEA (0.50 mL, 2. 83 mmol) was added and stirred at 150 ° C. for 2 hours under microwave. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-THF) to obtain Compound 116 (87 mg, yield 30%).
  • Example 28 Synthesis of Compounds I-252, I-265 and I-235 Process 1
  • Compound 103 400 mg, 1.14 mmol
  • phthalimide 202 mg, 1.37 mmol
  • triphenylphosphine 359 mg, 1.37 mmol
  • a 2.2 mol / L diethyl azodicarboxylate-toluene solution 0.52 mL, 1.14 mmol
  • Example 29 Synthesis of Compound I-607 Process 1
  • Compound 123 (27 mg, 0.20 mmol) was dissolved in DMSO (1 mL), compound 55 (70 mg, 0.18 mmol) and cesium carbonate (207 mg, 0.64 mmol) were added, and it was microwaved at 120 ° C. for 1 hour. Stir. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave Compound 124 (64 mg, 76% yield).
  • Example 30 Process 1 Compound 111 (described in WO2012 / 034091A1) (114 mg, 0.51 mmol) was dissolved in DMSO (1.3 mL), compound 55 (130 mg, 0.34 mmol), cesium carbonate (550 mg, 1.69 mmol) were added, and 120 Stir at 0 ° C. for 3 hours. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a crude product 127 (200 mg).
  • Example 31 Process 1 Compound 129 (1.8 g, 10 mmol) was dissolved in dichloromethane (100 mL), sulfatrifluoride diethylamine complex (6.61 mL, 50 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was added little by little to a mixture of saturated aqueous sodium hydrogen carbonate solution and ice, and the mixture was stirred at the same temperature. The resulting solution was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave Compound 130 (2.02 g, yield 99%).
  • Example 32 Synthesis of Compound I-465 Process 1
  • Compound 91 (30.0 g, 113 mmol), 3-carboxymethyl ester pyrrolidine (43.9 g, 340 mmol), DIEA (43.9 g, 340 mmol) were added to NMP (200 mL) and at 160 ° C. under nitrogen atmosphere. Stir for 1.5 hours.
  • the produced solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain a crude product 133 (35 g, yield 87%).
  • Example 32 Synthesis of Compound I-225
  • Compound I-166 (16 mg, 0.03 mmol) was dissolved in 1 mL of toluene, and (1-ethoxyethenyl) tributylstannane (53.4 mg, 0.15 mmol), Pd (PPh 3 ) 4 (10.3 mg, 0 0.009 mmol) and stirred at 110 ° C. for 2 hours.
  • the reaction solution was returned to room temperature, 2 mol / L hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with chloroform and concentrated under reduced pressure.
  • Example 35 6-Iodo-3,4-dihydro-2H-pyrido (3,2-B) (1,4) oxazine (200 mg, 0.76 mmol) was dissolved in THF (2 mL) and 60% sodium hydride (46 mg, 1.15 mmol) and bromoethyl (0.068 mL, 0.92 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours. After allowing to cool, water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 139 (69 mg, yield 31%). MS (ESI) m / z 291 [M + H] + Example compounds described in the following table were synthesized by using compound 139 instead of compound 96 of example 22 or compound 99 of example 23.
  • Example 36 6-iodo-3,4-dihydro-2H-pyrido (3,2-B) (1,4) oxazine (100 mg, 0.38 mmol) was dissolved in dichloromethane (1 mL) and cyclopropanecarboxylic acid chloride (0. (052 mL, 0.57 mmol) and triethylamine (0.106 mL, 0.76 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 140 (95 mg, yield 75%). MS (ESI) m / z 331 [M + H] + Example compounds described in the following table were synthesized by using Compound 140 instead of Compound 96 of Example 22 or Compound 99 of Example 23.
  • Example 37 Process 1 Manganese chloride (MgCl 2 , 59.4 g, 625 mmol) and triethylamine (126 g, 1.25 mol) were added to diethylmalonic acid (100 g, 625 mmol) in acetonitrile (500 mL) at 5-15 ° C. After stirring for 5 minutes, acetyl chloride (49.0 g, 625 mmol) was added dropwise while maintaining 10 to 20 ° C. The reaction solution was stirred at 16-22 ° C. for 17 hours. The pH was adjusted to 2-3 with an aqueous hydrochloric acid solution, followed by extraction with ethyl acetate.
  • MgCl 2 59.4 g, 625 mmol
  • triethylamine 126 g, 1.25 mol
  • Step 2-2 To a methanol solution (30 mL) of the crude product 144 (6 g), a 4 mol / L hydrochloric acid methanol solution (20 mL) was added dropwise. The mixture was stirred at 12-16 ° C. for 4 hours, and concentrated to 20 mL under reduced pressure. The solution was added dropwise into ethyl acetate (80 mL) with stirring. The resulting solid was collected and collected by filtration and washed with ethyl acetate. The obtained solid was dried to obtain Compound 145 (1.01 g, yield 25%). Compound 145 was used in the reaction of Step 3 shown below.
  • Step 3 Synthesis of Compound 148 Step 3-1
  • Compound 142 (1.67 g, 8.28 mmol) was added to a solution of compound 145 (1.01 g, 8.28 mmol) in ethanol (50 mL).
  • the reaction solution was stirred at 13-16 ° C. for 4 hours.
  • Step 3-2 Compound 146 (310 mg, 1.38 mmol) was dissolved in iodomethane (24.6 g) and potassium carbonate (382 mg, 2.77 mmol) was added at 10-15 ° C.
  • Test Example 1 Evaluation of ITK Inhibitory Activity (Ki Value)
  • the ITK inhibitory activity (Ki value) of the compound according to the present invention was evaluated by performing a reaction under any one of the reaction conditions 1 to 4.
  • reaction condition 1 Each well of the test plate was diluted with 0.5 ⁇ L of the compound of the present invention (DMSO solution) and enzyme reaction solution (100 mM HEPES, 0.003% Brij-35, 0.004% Tween 20, 1 mM DTT, 10 mM MgCl 2). 4.5 ⁇ L of 2.2 ⁇ g / mL ITK (manufactured by Carna Biosciences) was added and allowed to stand for 15 minutes.
  • DMSO solution the compound of the present invention
  • enzyme reaction solution 100 mM HEPES, 0.003% Brij-35, 0.004% Tween 20, 1 mM DTT, 10 mM MgCl 2).
  • reaction condition 2 a mixed solution of 3 ⁇ M substrate peptide (FAM-EFPIYDFLPAKKK) and 20 ⁇ M ATP diluted with an enzyme reaction solution is added and reacted at room temperature for 90 minutes, and then 10 ⁇ L of a reaction stop solution containing EDTA is added to stop the reaction. I let you. (Reaction condition 2)
  • DMSO solution a compound according to the present invention
  • 14 ⁇ L of 1.5 ⁇ g / mL ITK diluted with an enzyme reaction solution were added and allowed to stand for 15 minutes.
  • reaction condition 3 To each well of the test plate, 0.1 ⁇ L of the compound according to the present invention (DMSO solution) and 5 ⁇ L of 25 ⁇ g / mL ITK diluted with an enzyme reaction solution were added and allowed to stand for 15 minutes.
  • reaction condition 4 in the presence of 0.1% BSA
  • an enzyme reaction solution 100 mM HEPES, 0.003% Brij-35, 0.004% Tween 20, 1 mM
  • DMSO solution 0.1 ⁇ L of the compound of the present invention
  • the fluorescence intensity of the phosphorylated substrate and the unphosphorylated substrate contained in the reaction stopped solution obtained based on the reaction conditions 1 to 4 was measured using Caliper EZ Reader 2 (Perkin Elmer).
  • the substrate phosphorylation rate was calculated by the following formula. (Phosphorylated fluorescence intensity / (phosphorylated fluorescence intensity + unphosphorylated fluorescence intensity)) ⁇ 100.
  • the ITK inhibition rate of the compound of the present invention was calculated from the following formula using a well added with DMSO, which is a solvent of the compound of the present invention, as a negative control and a well not added with ITK as a positive control.
  • Inhibition rate (1 ⁇ (substrate phosphorylation rate of the compound of the present invention ⁇ substrate phosphorylation rate of positive control) / (substrate phosphorylation rate of negative control ⁇ substrate phosphorylation rate of positive target)) ⁇ 100.
  • IC50 which is a concentration of a compound showing 50% inhibitory activity, was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
  • the ATP concentration during the reaction was changed to 80, 40, 20, 10, 5, 2.5, 1.25, 0.625 ⁇ M, and the substrate phosphorylation rate was measured by the same method.
  • the Michaelis-Menten constant Km was calculated by the Lineweaver-Burk plot method using the value obtained by subtracting the substrate phosphorylation rate in the absence of ITK from the substrate phosphorylation rate at each ATP concentration as a constant multiple of the reaction rate v. The value was calculated by the following formula.
  • Ki IC50 value / (1 + test ATP concentration ( ⁇ M) / Km ( ⁇ M))
  • the Ki value of Compound I-004 is 210 nM (Reaction Condition 4)
  • the Ki value of Compound I-036 is 640 nM (Reaction Condition 3)
  • the Ki value of Compound I-154 is 15 nM.
  • Ki value of compound I-155 is 24 nM (reaction condition 3)
  • Ki value of compound I-175 is 50 nM (reaction condition 3)
  • Ki value of compound I-219 is 18 nM (Reaction condition 3)
  • the Ki value of compound I-258 is 110 nM (reaction condition 4)
  • the Ki value of compound I-414 is 32 nM (reaction condition 3)
  • the Ki value of compound I-445 is Compound I-488 has a Ki value of 7.3 nM (Reaction condition 2)
  • Compound I-510 has a Ki value of 530 nM (Reaction condition 4)
  • Compound I-516 has a Ki value of 21 nM (Reaction condition 2).
  • K Value is 62 nM (reaction condition 3)
  • Ki values of the compounds I-546 was 51 nM (reaction condition 3).
  • the evaluation results and reaction condition numbers regarding the ITK inhibitory activity of the compounds of the present invention other than the above are shown in the following table.
  • the Ki value is “A” for 0 nM to less than 100 nM, “B” for 100 nM to less than 500 nM, and “C” for 500 nM to less than 1000 nM.
  • kinase inhibitory activity other than ITK When measuring kinase inhibitory activity other than ITK, kinase inhibitory activity other than ITK can be evaluated by using the same method as the method for measuring ITK inhibitory activity, various kinases, and corresponding substrate peptides.
  • Test Example 2 Evaluation of PLC ⁇ 1 phosphorylation inhibitory activity The measurement of the PLC ⁇ 1 phosphorylation inhibitory activity of the compound according to the present invention is evaluated by the following procedure.
  • the human T cell line Jurkat is washed with Hank's balanced salt solution (HBSS), adjusted to a cell concentration of 1.5 ⁇ 10 7 / mL, and used for experiments. Pre-incubate 40 ⁇ L of the cell suspension at 37 ° C. for 5 minutes, mix 10 ⁇ L of HBSS solution of each compound containing 2% DMSO, and pre-incubate at 37 ° C. for another 10 minutes.
  • HBSS Hank's balanced salt solution
  • HBSS containing 20 ⁇ g / mL anti-human CD3 ⁇ • antibody
  • 50 ⁇ L of HBSS containing 20 ⁇ g / mL anti-human CD3 ⁇ • antibody is added and incubated at 37 ° C. for 3 minutes.
  • Cells are lysed by adding 25 ⁇ L of a mixed solution of 20 mM sodium tartrate, 5 ⁇ g / mL leupeptin and a protease inhibitor cocktail adjusted to a 5-fold concentration.
  • the amount of PLC ⁇ 1 phosphorylation in the cell solution is measured by ELISA. Tris-buffered saline containing 0.05% Tween-20 was added to a microwell plate on which anti-PLC ⁇ 1 antibody (clone 2B1, derived from mouse) was solidified, and 50 ⁇ L of the prepared cell lysate was added and allowed to stand at room temperature for 2 hours. Wash 4 times with (Tris-Buffered Saline). Anti-phosphorylated PLC ⁇ 1 antibody (pTyr783, derived from rabbit) is added and left to stand at room temperature for 2 hours. After washing in the same manner, HRP-labeled anti-rabbit IgG antibody is reacted.
  • the protease inhibitor cocktail uses: Product name: cComplete, Mini, EDTA-free Product number: 4 693 159 Company: Roche Diagnostics Co., Ltd.
  • Test Example 3 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively.
  • the degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction.
  • NADPH a coenzyme
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified with a fluorescent multi-label counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
  • Test Example 4 CYP3A4 fluorescence MBI test
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate.
  • a part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated.
  • Intravenous administration is performed from the tail vein using a syringe with a needle.
  • the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio of the group and the AUC ratio.
  • Test Example 6 Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution. 7.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate:
  • the cells are suspended in 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL) To the MicroF buffer).
  • TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (under the metabolic activation conditions, 498 ⁇ L of the test bacterial solution and S9 mix 90 ⁇ L of the mixture) and incubate with shaking at 37 ° C.
  • Test Example 7 hERG Test
  • hERG human ether-a-go-related gene
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • Test Example 9 Metabolic stability test A commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
  • Test Example 10 Powder solubility test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution are added to each container. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Lactose 15mg Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g Are mixed well, compression molded, pulverized, sized, and sieved to obtain granules of appropriate size.
  • the compound according to the present invention has an inhibitory action on ITK and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving ITK.

Abstract

A compound represented by formula (I) and a pharmaceutically acceptable salt thereof. (In the formula, AA represents BB or the like; ring B represents a six-membered aromatic carbon ring or the like; ring C represents a five-membered or six-membered aromatic heterocyclic ring or the like; -X- represents =N- or the like; R1 represents a substituted or unsubstituted alkyl group or the like; each R2 independently represents a halogen atom or the like; R3 represents a hydrogen atom or the like; each Ra independently represents a substituted or unsubstituted alkyl group or the like; each Rb independently represents a substituted or unsubstituted alkyl group or the like; Rc represents a hydrogen atom or the like; -L- represents -C(=O)NR4- or the like; R4 represents a hydrogen atom or the like; p represents an integer of 0-3; and each of n and m independently represents an integer of 0-2.)

Description

ピロリジン誘導体およびそれらを含有する医薬組成物Pyrrolidine derivatives and pharmaceutical compositions containing them
　本発明は、インターロイキン－２誘導性Ｔ細胞キナーゼ（以下、ＩＴＫと示す。）が関与する疾患または状態を治療するのに有用な化合物、および該化合物を含有する医薬組成物に関する。 The present invention relates to a compound useful for treating a disease or condition involving interleukin-2 inducible T cell kinase (hereinafter referred to as ITK), and a pharmaceutical composition containing the compound.
　プロテインキナーゼは、細胞の活性化、分化、増殖を含む多くのイベントに関与するタンパク質であり、生理的、病態形成に重要な役割を担っている。
　ＩＴＫは、ＴＥＣファミリーに属する非受容体型チロシンキナーゼであり、主に、Ｔ細胞、ＮＫ細胞、肥満細胞に発現している。
　Ｔ細胞表面に発現しているＴ細胞受容体（ＴＣＲ）への抗原刺激により、ＴＣＲの下流で機能するリンパ球特異的タンパク質チロシンキナーゼ（ＬＣＫ）の活性化が誘導され、それに続いてＩＴＫが活性化される（非特許文献１）。肥満細胞において、ＩＴＫは高親和性免疫グロブリンＥ（ＩｇＥ）受容体の下流で機能し、抗原とＩｇＥの複合体刺激により活性化される（非特許文献２）。活性化したＩＴＫは、細胞内基質であるホスホリパーゼＣγ（ＰＬＣγ）をリン酸化する。リン酸化されたＰＬＣγは、ホスホイノシトール二リン酸を、イノシトール三リン酸およびジアシルグリセロールへ分解し、その結果、細胞内カルシウム濃度の上昇およびプロテインキナーゼＣの活性化が誘導される。これらの一連の現象は、Ｔ細胞においては、サイトカイン産生、細胞増殖、肥満細胞においては、脱顆粒に重要である。
　Ｔ細胞は、免疫反応において重要な役割を担っている。Ｔ細胞の異常は、自己免疫疾患、アレルギー性疾患を含む多くの疾患で認められることが知られている。また、肥満細胞は、ヒスタミンなどのケミカルメディエーターを放出することにより、アレルギー性疾患の病態形成および進展に関与している。
　ＩＴＫ欠損マウスにおいて、Ｔ細胞の活性化および分化、インターロイキン（ＩＬ）－２、ＩＬ－４、ＩＬ－５、ＩＬ－１３を含むサイトカインの産生、ならびに細胞増殖が抑制されていることが報告されている（非特許文献３、４、５）。また、ＩＴＫを欠損した肥満細胞は、脱顆粒が阻害されていることも観察されている （非特許文献６）。したがって、ＩＴＫを阻害することにより、Ｔ細胞の活性化、サイトカイン産生、増殖の抑制、肥満細胞の脱顆粒の抑制が可能であると考えられる。
　以上より、ＩＴＫ 阻害剤は、Ｔ細胞または肥満細胞が関与している自己免疫疾患、アレルギー性疾患、炎症性疾患の治療薬および／または予防薬として有用であると考えられる。 Protein kinases are proteins involved in many events including cell activation, differentiation and proliferation, and play an important role in physiological and pathogenesis.
ITK is a non-receptor tyrosine kinase belonging to the TEC family, and is mainly expressed in T cells, NK cells, and mast cells.
Stimulation of the T cell receptor (TCR) expressed on the T cell surface induces activation of lymphocyte-specific protein tyrosine kinase (LCK) that functions downstream of the TCR, followed by activation of ITK (Non-Patent Document 1). In mast cells, ITK functions downstream of the high affinity immunoglobulin E (IgE) receptor and is activated by stimulation of a complex of antigen and IgE (Non-patent Document 2). Activated ITK phosphorylates phospholipase Cγ (PLCγ), which is an intracellular substrate. Phosphorylated PLCγ breaks phosphoinositol diphosphate into inositol triphosphate and diacylglycerol, leading to an increase in intracellular calcium concentration and activation of protein kinase C. These series of phenomena are important for cytokine production, cell proliferation in T cells, and degranulation in mast cells.
T cells play an important role in the immune response. It is known that abnormalities of T cells are observed in many diseases including autoimmune diseases and allergic diseases. Mast cells are also involved in the pathogenesis and development of allergic diseases by releasing chemical mediators such as histamine.
In ITK-deficient mice, activation and differentiation of T cells, production of cytokines including interleukin (IL) -2, IL-4, IL-5, IL-13, and cell proliferation have been reported to be suppressed. (Non-Patent Documents 3, 4, and 5). It has also been observed that degranulation is inhibited in mast cells lacking ITK (Non-patent Document 6). Therefore, it is considered that inhibition of ITK can suppress T cell activation, cytokine production, suppression of proliferation, and suppression of mast cell degranulation.
From the above, it is considered that the ITK inhibitor is useful as a therapeutic and / or prophylactic agent for autoimmune diseases, allergic diseases and inflammatory diseases involving T cells or mast cells.
　特許文献１および２には、ＩＴＫ阻害作用を有する化合物が記載されているが、本発明化合物とは構造が異なる。
　特許文献３～１５には、本発明化合物と構造が類似した化合物が記載されているが、ＩＴＫ阻害作用に関する記載も示唆もない。 Patent Documents 1 and 2 describe compounds having an ITK inhibitory action, but differ in structure from the compounds of the present invention.
Patent Documents 3 to 15 describe compounds similar in structure to the compounds of the present invention, but there is no description or suggestion regarding ITK inhibitory action.
国際公開第２０１１／０６５４０２号International Publication No. 2011-0665402 国際公開第２０１２／１２１９３９号International Publication No. 2012/121939 国際公開第２０１１／００６０７４号International Publication No. 2011/006074 国際公開第２０１２／０３４０９１号International Publication No. 2012/034091 国際公開第２０１２／１２３５６３号International Publication No. 2012/123563 国際公開第２００８／０７５１７２号International Publication No. 2008/075172 国際公開第２０１０／０５６０２２号International Publication No. 2010/056022 国際公開第２００４／００４６６５号International Publication No. 2004/004665 国際公開第９９／４５００９号International Publication No. 99/45009 国際公開第２００９／１０６４４１号International Publication No. 2009/106441 米国公開第２００７／００７８１２１号US Publication No. 2007/0078121 国際公開第２００７／１０６２３６号International Publication No. 2007/106236 国際公開第２００８／０１６１３１号International Publication No. 2008/016131 国際公開第２０１３／０８２４２９号International Publication No. 2013/082429 国際公開第２０１３／１７８５９１号International Publication No. 2013/178591
　本発明の目的は、ＩＴＫ阻害作用を有する化合物および医薬組成物を提供することにある。 An object of the present invention is to provide a compound and a pharmaceutical composition having an ITK inhibitory action.
　本発明は、以下の（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～～（２１）に関する。
（１）
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000016
（式中、
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
であり；
　環Ｂは、６員の芳香族炭素環または６員の芳香族複素環であり；
　環Ｃは、５もしくは６員の芳香族複素環または５もしくは６員の非芳香族複素環であり；
　環Ｄは、５員の芳香族複素環であり；
　環Ｅは、５もしくは６員の芳香族複素環または５もしくは６員の非芳香族複素環であり；
　環Ｆは、６員の芳香族炭素環または６員の芳香族複素環であり；
　環Ｇは、５員の芳香族複素環であり；
　－Ｘ－は、＝Ｎ－、－Ｎ＝、－Ｏ－、または－Ｓ－（ここで、左の結合手は原子ａに結合し、右の結合手は原子ｂに結合する）であり；
　－Ｙ－は、＝Ｎ－ＣＨ２－、＝Ｎ－ＣＨ＝、－Ｎ＝ＣＨ－、－Ｎ＝Ｎ－、＝Ｎ－ＮＨ－、＝Ｎ－Ｎ＝、＝Ｎ－Ｓ－、＝Ｎ－Ｏ－、－Ｏ－ＣＨ２－、－Ｏ－ＣＨ＝、－Ｏ－ＮＨ－、－Ｏ－Ｎ＝、－Ｓ－ＮＨ－、－Ｓ－Ｎ＝、－Ｓ－ＣＨ２－または－Ｓ－ＣＨ＝（ここで、左の結合手は原子ｃに結合し、右の結合手は原子ｄに結合する）であり；
　Ｒ２は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルケニルカルボニルアミノ、置換もしくは非置換のモノアルキニルカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換のモノアルキルウレイド、置換もしくは非置換のジアルキルウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、置換もしくは非置換の芳香族炭素環アミノ、置換もしくは非置換の非芳香族炭素環アミノ、置換もしくは非置換の芳香族複素環アミノ、置換もしくは非置換の非芳香族複素環アミノ、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環ウレイド、置換もしくは非置換の非芳香族炭素環ウレイド、置換もしくは非置換の芳香族複素環ウレイド、または置換もしくは非置換の非芳香族複素環ウレイドであり；
　ｐは、０から３の整数であり；
　Ｒ３は、水素原子、ヒドロキシ、アミノ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基であり；
　Ｒａは、それぞれ独立して、カルボキシ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、もしくは置換もしくは非置換の非芳香族複素環カルバモイル；または２つのＲａは、隣接する炭素原子と一緒になって、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し；
　Ｒｂは、それぞれ独立して、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、もしくは置換もしくは非置換の非芳香族複素環カルバモイル；または、２つのＲｂは、隣接する炭素原子と一緒になって、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し；
　Ｒｃは、水素原子またはハロゲンであり；
　ｎおよびｍは、それぞれ独立して、０から２の整数であり；
　－Ｌ－は、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｓ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、－Ｎ（Ｒ４）ＳＯ２－、－Ｃ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｓ（＝Ｏ）－、－ＳＯ２Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）ＳＯ２－であり；
　Ｒ４、Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、もしくは置換若しくは非置換のアルキニル；または
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｓ（＝Ｏ）Ｎ（Ｒ４）－、または－ＳＯ２Ｎ（Ｒ４）－であるとき、Ｒ４とＲ1が、隣接する窒素原子と一緒になって、置換若しくは非置換の芳香族複素環、または置換若しくは非置換の非芳香族複素環を形成するか；
　－Ｌ－が、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－Ｎ（Ｒ４）Ｓ（＝Ｏ）－、または－Ｎ（Ｒ４）ＳＯ２－であるとき、Ｒ４とＲ1が、Ｒ４の隣接する窒素原子およびＲ1が隣接する炭素原子または硫黄原子と一緒になって、置換若しくは非置換の非芳香族複素環を形成するか；、
　－Ｌ－が、－Ｃ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｓ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、または－ＳＯ２Ｃ（Ｒ５ａ）（Ｒ５ｂ）－であるとき、Ｒ５ａとＲ1が、隣接する炭素原子と一緒になって、置換若しくは非置換の芳香族複素環、または置換若しくは非置換の非芳香族複素環を形成するか；もしくは、
　－Ｌ－が、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｃ（＝Ｏ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｓ（＝Ｏ）－、または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）ＳＯ２－であるとき、Ｒ５ａとＲ１が、Ｒ５ａの隣接する炭素原子およびＲ1が隣接する炭素原子または硫黄原子と一緒になって、置換若しくは非置換の非芳香族複素環を形成し；
　Ｒ１は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである）で示される化合物
（ただし、
　Ｒ１は、メチルまたはｔｅｒｔ－ブチルオキシではなく；
　ｎおよびｍが共に０であるとき、
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
（式中、
　環Ｈは、６員の芳香族複素環または６員の非芳香族複素環であり；
　Ｒ６は、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルであり；
ｐ’は０から２の整数であり；
Figure JPOXMLDOC01-appb-C000021
であるとき、
Ｒ１は、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基（ただし、置換もしくは非置換のピロリジルではない）である）であり；
　以下の化合物を除く
Figure JPOXMLDOC01-appb-C000022
）、またはその製薬上許容される塩。 The present invention relates to the following (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (21).
(1)
Formula (I):
Figure JPOXMLDOC01-appb-C000016
(Where
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Is;
Ring B is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle;
Ring C is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle;
Ring D is a 5-membered aromatic heterocycle;
Ring E is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle;
Ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle;
Ring G is a 5-membered aromatic heterocycle;
-X- is = N-, -N =, -O-, or -S- (where the left bond is bonded to atom a and the right bond is bonded to atom b);
-Y- is = N-CH 2- , = N-CH =, -N = CH-, -N = N-, = N-NH-, = NN =, = NS-, = N —O—, —O—CH 2 —, —O—CH═, —O—NH—, —O—N═, —S—NH—, —S—N═, —S—CH 2 — or —S. -CH = (where the left bond is bonded to atom c and the right bond is bonded to atom d);
Each R 2 is independently halogen, hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, Substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkenylcarbonylamino, substituted or unsubstituted monoalkynylcarbonylamino, substituted or unsubstituted Substituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted Or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or Unsubstituted monoalkylureido, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted Or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted Aromatic heterocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, substituted or unsubstituted aromatic carbocyclic amino, substituted or unsubstituted non-aromatic carbocyclic amino, substituted or unsubstituted aromatic heterocyclic Ring amino, substituted or unsubstituted non-aromatic heterocyclic amino, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic carbonyl Amino, substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic A carbocyclic ureido, a substituted or unsubstituted non-aromatic carbocyclic ureido, a substituted or unsubstituted aromatic heterocyclic ureido, or a substituted or unsubstituted non-aromatic heterocyclic ureido;
p is an integer from 0 to 3;
R 3 is a hydrogen atom, hydroxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
Each Ra is independently carboxy, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted Or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Substituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted Is an unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic Heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, Substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted A non-aromatic carbocyclic carbamoyl, a substituted or unsubstituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl; or two Ra, together with adjacent carbon atoms, are substituted or non-substituted Forming a substituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
Rb independently represents hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, hydrazino, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynyl Carbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Or substituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or Unsubstituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, Substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or Unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted fragrance Aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl Substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or Unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic carbonylamino, Substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted aromatic heterocyclic carbamoyl, or substituted or An unsubstituted non-aromatic heterocyclic carbamoyl; or two Rb together with adjacent carbon atoms form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring And
Rc is a hydrogen atom or halogen;
n and m are each independently an integer from 0 to 2;
-L- is -C (= O) N (R 4 )-, -N (R 4 ) C (= O)-, -S (= O) N (R 4 )-, -N (R 4 ) S (═O) —, —SO 2 N (R 4 ) —, —N (R 4 ) SO 2 —, —C (═O) C (R 5a ) (R 5b ) —, —C (R 5a ) (R 5b ) C (═O) —, —S (═O) C (R 5a ) (R 5b ) —, —C (R 5a ) (R 5b ) S (═O) —, —SO 2 C ( R 5a ) (R 5b ) —, or —C (R 5a ) (R 5b ) SO 2 —;
R 4 , R 5a and R 5b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or -L- is -C (= When O) N (R 4 ) —, —S (═O) N (R 4 ) —, or —SO 2 N (R 4 ) —, R 4 and R 1 together with the adjacent nitrogen atom Forming a substituted or unsubstituted aromatic heterocycle, or a substituted or unsubstituted nonaromatic heterocycle;
When —L— is —N (R 4 ) C (═O) —, —N (R 4 ) S (═O) —, or —N (R 4 ) SO 2 —, R 4 and R 1 Wherein R 4 together with the adjacent nitrogen atom and R 1 of the adjacent carbon or sulfur atom form a substituted or unsubstituted non-aromatic heterocycle;
—L— is —C (═O) C (R 5a ) (R 5b ) —, —S (═O) C (R 5a ) (R 5b ) —, or —SO 2 C (R 5a ) (R 5b ) -when R 5a and R 1 together with adjacent carbon atoms form a substituted or unsubstituted aromatic heterocycle or substituted or unsubstituted non-aromatic heterocycle; Or
—L— is —C (R 5a ) (R 5b ) C (═O) —, —C (R 5a ) (R 5b ) S (═O) —, or —C (R 5a ) (R 5b ) When SO 2 —, R 5a and R 1 together with the adjacent carbon atom of R 5a and R 1 adjacent carbon atom or sulfur atom form a substituted or unsubstituted non-aromatic heterocycle And
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or Unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoal Killsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted Dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted A non-aromatic heterocyclic carbonyl, a substituted or unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted aromatic heterocyclic sulfonyl, or a substituted or unsubstituted non-aromatic A compound represented by a heterocyclic group sulfonyl)
R 1 is not methyl or tert-butyloxy;
When n and m are both 0,
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000020
(Where
Ring H is a 6-membered aromatic heterocycle or a 6-membered non-aromatic heterocycle;
R 6 represents substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocycle Carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or non-substituted A substituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl;
p ′ is an integer from 0 to 2;
Figure JPOXMLDOC01-appb-C000021
When
R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group. A heterocyclic group (but not a substituted or unsubstituted pyrrolidyl);
Excluding the following compounds
Figure JPOXMLDOC01-appb-C000022
) Or a pharmaceutically acceptable salt thereof.
（１’）
　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000023
（式中、
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
であり；
　環Ｂは、６員の芳香族炭素環または６員の芳香族複素環であり；
　環Ｃは、５もしくは６員の芳香族複素環または５もしくは６員の非芳香族複素環であり；
　環Ｄは、５員の芳香族複素環であり；
　環Ｅは、５もしくは６員の芳香族複素環または５もしくは６員の非芳香族複素環であり；
　環Ｆは、６員の芳香族炭素環または６員の芳香族複素環であり；
　環Ｇは、５員の芳香族複素環であり；
　－Ｘ－は、＝Ｎ－、－Ｎ＝、－Ｏ－、または－Ｓ－（ここで、左の結合手は原子ａに結合し、右の結合手は原子ｂに結合する）であり；
　－Ｙ－は、＝Ｎ－ＣＨ２－、＝Ｎ－ＣＨ＝、－Ｎ＝ＣＨ－、－Ｎ＝Ｎ－、＝Ｎ－ＮＨ－、＝Ｎ－Ｎ＝、＝Ｎ－Ｓ－、＝Ｎ－Ｏ－、－Ｏ－ＣＨ２－、－Ｏ－ＣＨ＝、－Ｏ－ＮＨ－、－Ｏ－Ｎ＝、－Ｓ－ＮＨ－、－Ｓ－Ｎ＝、－Ｓ－ＣＨ２－または－Ｓ－ＣＨ＝（ここで、左の結合手は原子ｃに結合し、右の結合手は原子ｄに結合する）であり；
　Ｒ２はそれぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルケニルカルボニルアミノ、置換もしくは非置換のモノアルキニルカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換のモノアルキルウレイド、置換もしくは非置換のジアルキルウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、置換もしくは非置換の芳香族炭素環アミノ、置換もしくは非置換の非芳香族炭素環アミノ、置換もしくは非置換の芳香族複素環アミノ、置換もしくは非置換の非芳香族複素環アミノ、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環ウレイド、置換もしくは非置換の非芳香族炭素環ウレイド、置換もしくは非置換の芳香族複素環ウレイド、または置換もしくは非置換の非芳香族複素環ウレイドであり；
　ｐは、０から３の整数であり；
　Ｒ３は、水素原子、ヒドロキシ、アミノ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基であり；
　Ｒａはそれぞれ独立して、カルボキシ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、もしくは置換もしくは非置換の非芳香族複素環カルバモイル；または２つのＲａは、隣接する炭素原子と一緒になって、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し；
　Ｒｂはそれぞれ独立して、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、もしくは置換もしくは非置換の非芳香族複素環カルバモイル；または、２つのＲｂは、隣接する炭素原子と一緒になって、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し；
　Ｒｃは水素原子、またはハロゲンであり；
　ｎおよびｍはそれぞれ独立して、０から２の整数であり；
　－Ｌ－は、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｓ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、－Ｎ（Ｒ４）ＳＯ２－、－Ｃ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｓ（＝Ｏ）－、－ＳＯ２Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）ＳＯ２－であり；
　Ｒ４、Ｒ５ａおよびＲ５ｂはそれぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、もしくは置換若しくは非置換のアルキニル；または
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｓ（＝Ｏ）Ｎ（Ｒ４）－、または－ＳＯ２Ｎ（Ｒ４）－であるとき、Ｒ４とＲ1が、隣接する窒素原子と一緒になって、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環を形成するか；
　－Ｌ－が、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－Ｎ（Ｒ４）Ｓ（＝Ｏ）－、または－Ｎ（Ｒ４）ＳＯ２－であるとき、Ｒ４とＲ1が、Ｒ４の隣接する窒素原子およびＲ1が隣接する炭素原子または硫黄原子と一緒になって、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環を形成するか；、
　－Ｌ－が、－Ｃ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｓ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、または－ＳＯ２Ｃ（Ｒ５ａ）（Ｒ５ｂ）－であるとき、Ｒ５ａとＲ1が、隣接する炭素原子と一緒になって、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環式基を形成するか；もしくは
　－Ｌ－が、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｃ（＝Ｏ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｓ（＝Ｏ）－、または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）ＳＯ２－であるとき、Ｒ５ａとＲ１が、Ｒ５ａの隣接する炭素原子およびＲ1が隣接する炭素原子または硫黄原子と一緒になって、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環を形成し；
　Ｒ１は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである）で示される化合物
（ただし、
　Ｒ１は、メチルまたはｔｅｒｔ－ブチルオキシではなく；
　ｎおよびｍが共に０であるとき、
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
（式中、
　環Ｈは、６員の芳香族複素環または６員の非芳香族複素環であり；
　Ｒ６は、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルであり；
ｐ’は０から２の整数である）であり；
　以下の化合物を除く
Figure JPOXMLDOC01-appb-C000028
）、またはその製薬上許容される塩。 (1 ')
Formula (I):
Figure JPOXMLDOC01-appb-C000023
(Where
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Is;
Ring B is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle;
Ring C is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle;
Ring D is a 5-membered aromatic heterocycle;
Ring E is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle;
Ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle;
Ring G is a 5-membered aromatic heterocycle;
-X- is = N-, -N =, -O-, or -S- (where the left bond is bonded to atom a and the right bond is bonded to atom b);
-Y- is = N-CH 2- , = N-CH =, -N = CH-, -N = N-, = N-NH-, = NN =, = NS-, = N —O—, —O—CH 2 —, —O—CH═, —O—NH—, —O—N═, —S—NH—, —S—N═, —S—CH 2 — or —S. -CH = (where the left bond is bonded to atom c and the right bond is bonded to atom d);
Each R 2 is independently halogen, hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, Substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkenylcarbonylamino, substituted or unsubstituted monoalkynylcarbonylamino, substituted or unsubstituted Substituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted Or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or Substituted monoalkylureido, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or Unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-substituted Aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted Or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted Aromatic heterocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, substituted or unsubstituted aromatic carbocyclic amino, substituted or unsubstituted non-aromatic carbocyclic amino, substituted or unsubstituted aromatic heterocyclic Ring amino, substituted or unsubstituted non-aromatic heterocyclic amino, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic carbonyl Amino, substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic charcoal A prime ring ureido, a substituted or unsubstituted non-aromatic carbocyclic ureido, a substituted or unsubstituted aromatic heterocyclic ureido, or a substituted or unsubstituted non-aromatic heterocyclic ureido;
p is an integer from 0 to 3;
R 3 is a hydrogen atom, hydroxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
Each Ra is independently carboxy, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or Unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or Unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted Or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted Aromatic carbocyclic carbamoyl, substituted or unsubstituted aromatic heterocyclic carbamoyl, or substituted or unsubstituted non-aromatic heterocyclic carbamoyl; or two Ra together with adjacent carbon atoms, substituted or unsubstituted A non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle;
Each Rb is independently hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, Substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or Unsubstituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, Substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted Or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted Aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, Substituted or unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic carbonyl amino , Substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted aromatic heterocyclic carbamoyl, or A substituted or unsubstituted non-aromatic heterocyclic carbamoyl; or two Rb together with adjacent carbon atoms, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring Forming;
Rc is a hydrogen atom or halogen;
n and m are each independently an integer from 0 to 2;
-L- is -C (= O) N (R 4 )-, -N (R 4 ) C (= O)-, -S (= O) N (R 4 )-, -N (R 4 ) S (═O) —, —SO 2 N (R 4 ) —, —N (R 4 ) SO 2 —, —C (═O) C (R 5a ) (R 5b ) —, —C (R 5a ) (R 5b ) C (═O) —, —S (═O) C (R 5a ) (R 5b ) —, —C (R 5a ) (R 5b ) S (═O) —, —SO 2 C ( R 5a ) (R 5b ) —, or —C (R 5a ) (R 5b ) SO 2 —;
R 4 , R 5a and R 5b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or —L— is —C (═O ) N (R 4 ) —, —S (═O) N (R 4 ) —, or —SO 2 N (R 4 ) —, R 4 and R 1 are combined with the adjacent nitrogen atom. Forming a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted nonaromatic heterocycle;
When —L— is —N (R 4 ) C (═O) —, —N (R 4 ) S (═O) —, or —N (R 4 ) SO 2 —, R 4 and R 1 In combination with the adjacent nitrogen atom of R 4 and R 1 with the adjacent carbon or sulfur atom to form a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring? ;
—L— is —C (═O) C (R 5a ) (R 5b ) —, —S (═O) C (R 5a ) (R 5b ) —, or —SO 2 C (R 5a ) (R 5b ) -when R 5a and R 1 together with adjacent carbon atoms form a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group Or -L- is -C (R 5a ) (R 5b ) C (= O)-, -C (R 5a ) (R 5b ) S (= O)-, or -C (R 5a ) (R 5b) SO 2 - when a, R 5a and R 1 together with the carbon atom or sulfur atom which carbon atom and R 1 adjacent R 5a are adjacent, a substituted or unsubstituted aromatic heterocyclic or Forming a substituted or unsubstituted non-aromatic heterocycle;
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or Unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoal Killsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted Dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted A non-aromatic heterocyclic carbonyl, a substituted or unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted aromatic heterocyclic sulfonyl, or a substituted or unsubstituted non-aromatic A compound represented by a heterocyclic group sulfonyl)
R 1 is not methyl or tert-butyloxy;
When n and m are both 0,
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
(Where
Ring H is a 6-membered aromatic heterocycle or a 6-membered non-aromatic heterocycle;
R 6 represents substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocycle Carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or non-substituted A substituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl;
p ′ is an integer from 0 to 2);
Excluding the following compounds
Figure JPOXMLDOC01-appb-C000028
) Or a pharmaceutically acceptable salt thereof.
（２）
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
である、上記（１）または（１’）記載の化合物またはその製薬上許容される塩。
（３）
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
である、上記（１）または（１’）記載の化合物またはその製薬上許容される塩。
（４）
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
である、上記（１）または（１’）記載の化合物またはその製薬上許容される塩。
（５）
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000036
である、上記（１）または（１’）記載の化合物またはその製薬上許容される塩。 (2)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
The compound according to (1) or (1 ′) above or a pharmaceutically acceptable salt thereof.
(3)
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
The compound according to (1) or (1 ′) above or a pharmaceutically acceptable salt thereof.
(4)
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
The compound according to (1) or (1 ′) above or a pharmaceutically acceptable salt thereof.
(5)
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000036
The compound according to (1) or (1 ′) above or a pharmaceutically acceptable salt thereof.
（６）
　Ｒａがそれぞれ独立して、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルである、上記（１）、（１’）、および（２）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（６ａ）
　Ｒａがそれぞれ独立して、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルである、上記（１）、（１’）、および（２）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（６ｂ）
　Ｒａがそれぞれ独立して、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である、上記（１）、（１’）、および（２）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（７）
　Ｒｂがそれぞれ独立して、ヒドロキシ、カルボキシ、アミノ、カルバモイル、ウレイド、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルである、上記（１）、（１’）、（２）～（６）、（６ａ）、および（６ｂ）のいずれかに記載の化合物またはその製薬上許容される塩。
（８）
　Ｒｃが水素原子である、上記（１）、（１’）、（２）～（６）、（６ａ）、（６ｂ）、および（７）のいずれかに記載の化合物またはその製薬上許容される塩。 (6)
Each Ra is independently carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted fragrance Heterocyclic carbonyl, substituted or unsubstituted non-aromatic compound Ring carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, or substituted or unsubstituted non-aromatic heterocyclic carbamoyl The compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′) and (2) to (5) above.
(6a)
Each Ra independently represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-substituted group; Aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic hetero Ring carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, or substituted or unsubstituted non-aromatic heterocyclic carbamoyl The compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′) and (2) to (5) above.
(6b)
Each Ra independently represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′) and (2) to (5), which is a non-aromatic heterocyclic group.
(7)
Each Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted Substituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or unsubstituted Monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbocyclic carbonylamino, substituted or non-substituted Substituted aromatic heterocyclic carbonylamino, substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted Any one of the above (1), (1 ′), (2) to (6), (6a), and (6b), which is an aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl Or a pharmaceutically acceptable salt thereof.
(8)
The compound according to any one of the above (1), (1 ′), (2) to (6), (6a), (6b), and (7), wherein Rc is a hydrogen atom, or a pharmaceutically acceptable salt thereof Salt.
（９）
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－である、上記（１）、（１’）、（２）～（６）、（６ａ）、（６ｂ）、および（７）～（８）のいずれかに記載の化合物またはその製薬上許容される塩。
（１０）
　Ｒ４、Ｒ５ａおよびＲ５ｂがそれぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルである、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（９）のいずれかに記載の化合物またはその製薬上許容される塩。　 (9)
—L— is —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -The compound according to any one of (1), (1 '), (2) to (6), (6a), (6b), and (7) to (8), or a pharmaceutically acceptable salt thereof Salt.
(10)
R 4 , R 5a and R 5b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, (1), (1 ′), And (2) to (6), (6a), (6b), and the compound according to any one of (7) to (9) or a pharmaceutically acceptable salt thereof.
（１１）
　Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１０）のいずれかに記載の化合物またはその製薬上許容される塩。
（１２）
　Ｒ１が、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１０）のいずれかに記載の化合物またはその製薬上許容される塩。 (11)
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or an unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group The compound according to any one of the above (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (10) or a pharmaceutically acceptable salt thereof Salt.
(12)
R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group The compound according to any one of the above (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (10), which is a heterocyclic group, or Its pharmaceutically acceptable salt.
（１３）
　Ｒ２がそれぞれ独立して、ハロゲン、カルボキシ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルウレイド、置換もしくは非置換のジアルキルウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、または置換もしくは非置換の芳香族複素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイルである、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１２）のいずれかに記載の化合物またはその製薬上許容される塩。 (13)
Each R 2 is independently halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Monoalkylureido, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, A substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic carbamoyl, a substituted or unsubstituted non-aromatic carbocyclic carbamoyl, or a substituted or unsubstituted aromatic heterocyclic carbamoyl, substituted or Any of the above (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (12), which is an unsubstituted non-aromatic heterocyclic carbamoyl Or a pharmaceutically acceptable salt thereof.
（１４）
　ｎが１または２である、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１３）のいずれかに記載の化合物またはその製薬上許容される塩。
（１５）
　ｍが０である、請求項（１４）に記載の化合物またはその製薬上許容される塩。
（１６）
　ｍが１または２である、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１３）のいずれかに記載の化合物またはその製薬上許容される塩。
（１７）
　ｎが０である、（１６）に記載の化合物またはその製薬上許容される塩。 (14)
The compound according to any one of (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (13), wherein n is 1 or 2 Or a pharmaceutically acceptable salt thereof.
(15)
The compound or a pharmaceutically acceptable salt thereof according to claim (14), wherein m is 0.
(16)
The compound according to any one of (1), (1 ′), and (2) to (6), (6a), (6b), and (7) to (13), wherein m is 1 or 2 Or a pharmaceutically acceptable salt thereof.
(17)
The compound or a pharmaceutically acceptable salt thereof according to (16), wherein n is 0.
（１８）上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１７）のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
（１９）ＩＴＫ阻害作用を有する上記（１８）に記載の医薬組成物。
（２０）ＩＴＫが関与する疾患の治療および／または予防に使用するための、上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１７）のいずれかに記載の化合物またはその製薬上許容される塩。
（２１）上記（１）、（１’）、および（２）～（６）、（６ａ）、（６ｂ）、および（７）～（１７）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、ＩＴＫが関与する疾患の治療および／または予防方法。 (18) The compound according to any one of (1), (1 ′) and (2) to (6), (6a), (6b) and (7) to (17) or a pharmaceutically acceptable salt thereof The pharmaceutical composition containing the salt made.
(19) The pharmaceutical composition according to the above (18), which has an ITK inhibitory action.
(20) The above (1), (1 ′), and (2) to (6), (6a), (6b), and (7) for use in the treatment and / or prevention of diseases involving ITK ) To (17) or a pharmaceutically acceptable salt thereof.
(21) The compound according to any one of (1), (1 ′) and (2) to (6), (6a), (6b) and (7) to (17) or a pharmaceutically acceptable salt thereof A method for treating and / or preventing a disease involving ITK, which comprises administering a salt to be treated.
　本発明に係る化合物は、ＩＴＫに対する阻害作用を有し、ＩＴＫが関与する疾患または状態の治療剤および／または予防剤として有用である。 The compound according to the present invention has an inhibitory effect on ITK, and is useful as a therapeutic and / or prophylactic agent for diseases or conditions involving ITK.
　以下に本明細書において用いられる各用語の意味を説明する。各用語は特に断りのない限り、単独で用いられる場合も、または他の用語と組み合わせて用いられる場合も、同一の意味で用いられる。 The meaning of each term used in this specification is explained below. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、およびヨウ素原子を包含する。特にフッ素原子、および塩素原子が好ましい。 “Halogen” includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状の炭化水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　「アルキル」の好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 “Alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
Preferred embodiments of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
　「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
　「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 “Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。これらはさらに任意の位置に二重結合を有していてもよい。
　「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
　「芳香族炭素環」とは、単環または２環以上の、環状芳香族炭化水素環を意味する。例えば、ベンゼン環、ナフタレン環、アントラセン環、フェナントレン環等が挙げられる。
　「芳香族炭素環」の好ましい態様として、ベンゼン環が挙げられる。
　「芳香族炭素環式基」とは、単環または２環以上の、環状芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
　「芳香族炭素環式基」の好ましい態様として、フェニルが挙げられる。 “Aromatic carbocycle” means a monocyclic or two or more cyclic aromatic hydrocarbon rings. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned.
A preferred embodiment of the “aromatic carbocycle” includes a benzene ring.
The “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
　「非芳香族炭素環」とは、単環または２環以上の、環状飽和炭化水素環または環状非芳香族不飽和炭化水素環を意味する。２環以上の非芳香族炭素環は、単環または２環以上の非芳香族炭素環に、上記「芳香族炭素環」における環が縮合したものも包含する。
　さらに、「非芳香族炭素環」は、架橋している環、またはスピロ環も包含する。
　単環の非芳香族炭素環としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン、シクロプロペン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロヘキサジエン等が挙げられる。
　２環以上の非芳香族炭素環としては、例えば、インダン、インデン、アセナフタレン、テトラヒドロナフタレン、フルオレン等が挙げられる。
　「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の非芳香族炭素環式基は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000037
　単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。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、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
　２環以上の非芳香族炭素環式基としては、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocycle” means a monocyclic ring or two or more cyclic saturated hydrocarbon rings or cyclic non-aromatic unsaturated hydrocarbon rings. The two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
Furthermore, the “non-aromatic carbocycle” includes a ring that is bridged or a spiro ring.
The monocyclic non-aromatic carbocycle preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
Examples of the two or more non-aromatic carbocycles include indane, indene, acenaphthalene, tetrahydronaphthalene, and fluorene.
The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The non-aromatic carbocyclic group having 2 or more rings includes a monocyclic ring or a non-aromatic carbocyclic group having 2 or more rings condensed with the ring in the above “aromatic carbocyclic group”.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000037
The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
　「芳香族複素環」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環を意味する。
　２環以上の芳香族複素環は、単環または２環以上の芳香族複素環に、上記「芳香族炭素環」における環が縮合したものも包含する。
　単環の芳香族複素環としては、５～８員が好ましく、より好ましくは５員または６員である。例えば、ピロール、イミダゾール、ピラゾール、ピリジン、ピリダジン、ピリミジン、ピラジン、トリアゾール、トリアジン、テトラゾール、フラン、チオフェン、イソオキサゾール、オキサゾール、オキサジアゾール、イソチアゾール、チアゾール、チアジアゾール等が挙げられる。
　２環の芳香族複素環式基としては、例えば、インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンズイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチフォフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、オキサゾロピリジン、チアゾロピリジン等が挙げられる。
　３環以上の芳香族複素環式基としては、例えば、カルバゾール、アクリジン、キサンテン、フェノチアジン、フェノキサチイン、フェノキサジン、ジベンゾフラン等が挙げられる。
　「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。
　２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられる。
　２環の芳香族複素環式基としては、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。
　３環以上の芳香族複素環式基としては、例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “Aromatic heterocycle” means a single ring or two or more aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
Two or more aromatic heterocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more aromatic heterocycles.
The monocyclic aromatic heterocycle is preferably 5 to 8 members, more preferably 5 or 6 members. Examples thereof include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
Examples of the bicyclic aromatic heterocyclic group include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benz Oxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophore, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolo Examples include pyridine.
Examples of the aromatic heterocyclic group having 3 or more rings include carbazole, acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, and dibenzofuran.
“Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
Examples of the bicyclic aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
Examples of the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
　「非芳香族複素環」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、環状非芳香族環を意味する。
　２環以上の非芳香族複素環は、単環または２環以上の非芳香族複素環に、上記「芳香族炭素環」、「非芳香族炭素環」、および／または「芳香族複素環」におけるそれぞれの環が縮合したものも包含する。
　さらに、「非芳香族複素環」は、架橋している環、またはスピロ環も包含する。
　単環の非芳香族複素環としては、３～８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサン、チイラン、オキシラン、オキセタン、オキサチオラン、アゼチジン、チアン、チアゾリジン、ピロリジン、ピロリン、イミダゾリジン、イミダゾリン、ピラゾリジン、ピラゾリン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、ジヒドロピリジン、テトラヒドロピリジン、テトラヒドロフラン、テトラヒドロピラン、ジヒドロチアゾール、テトラヒドロチアゾール、テトラヒドロイソチアゾール、ジヒドロオキサジン、ヘキサヒドロアゼピン、テトラヒドロジアゼピン、テトラヒドロピリダジン、ヘキサヒドロピリミジン、ジオキソラン、ジオキサジン、アジリジン、ジオキソリン、オキセパン、チオラン、チイン、チアジン等が挙げられる。
　２環以上の非芳香族複素環式基としては、例えば、インドリン、イソインドリン、クロマン、イソクロマン等が挙げられる。
　「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、環状非芳香族環式基を意味する。
　２環以上の非芳香族複素環式基は、単環または２環以上の非芳香族複素環式基に、上記「芳香族炭素環式基」、「非芳香族炭素環式基」、および／または「芳香族複素環式基」におけるそれぞれの環が縮合したものも包含する。
　さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000038
　単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル等が挙げられる。
　２環以上の非芳香族複素環式基としては、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 “Non-aromatic heterocycle” means a monocyclic or bicyclic or more cyclic non-aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring .
A non-aromatic heterocycle having two or more rings is a monocyclic ring or a non-aromatic heterocycle having two or more rings. Also included are those in which each ring is condensed.
Furthermore, the “non-aromatic heterocycle” includes a ring that is bridged or a spiro ring.
The monocyclic non-aromatic heterocyclic ring is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, Examples include dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thiolane, thiyne, thiazine and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include indoline, isoindoline, chroman, isochroman and the like.
“Non-aromatic heterocyclic group” means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
The non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
Furthermore, the “non-aromatic heterocyclic group” includes a group which forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000038
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl Furyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl Aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thii Le, triazinyl, and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
　「ヒドロキシアルキル」とは、１以上のヒドロキシ基が、上記「アルキル」の炭素原子に結合している水素原子と置き換わった基を意味する。例えば、ヒドロキシメチル、１－ヒドロキシエチル、２－ヒドロキシエチル、１－ヒドロキシプロピル、２－ヒドロキシプロピル、１，２－ヒドロキシエチル等が挙げられる。
　「ヒドロキシアルキル」の好ましい態様として、ヒドロキシメチルが挙げられる。 “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
　「アルキルオキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。例えば、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｎ－ブチルオキシ、ｔｅｒｔ－ブチルオキシ、イソブチルオキシ、ｓｅｃ－ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、へキシルオキシ等が挙げられる。
　「アルキルオキシ」の好ましい態様として、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｔｅｒｔ－ブチルオキシが挙げられる。 “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
　「アルケニルオキシ」とは、上記「アルケニル」が酸素原子に結合した基を意味する。
例えば、ビニルオキシ、アリルオキシ、１－プロペニルオキシ、２－ブテニルオキシ、２－ペンテニルオキシ、２－ヘキセニルオキシ、２－ヘプテニルオキシ、２－オクテニルオキシ等が挙げられる。 “Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom.
Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
　「アルキニルオキシ」とは、上記「アルキニル」が酸素原子に結合した基を意味する。
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、２－ブチニルオキシ、２－ペンチニルオキシ、２－ヘキシニルオキシ、２－ヘプチニルオキシ、２－オクチニルオキシ等が挙げられる。 “Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
　「ハロアルキル」とは、１以上の上記「ハロゲン」が上記「アルキル」に結合した基を意味する。例えば、モノフルオロメチル、モノフルオロエチル、モノフルオロプロピル、２，２，３，３，３－ペンタフルオロプロピル、モノクロロメチル、トリフルオロメチル、トリクロロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、１，２－ジブロモエチル、１，１，１－トリフルオロプロパン－２－イル等が挙げられる。
　「ハロアルキル」の好ましい態様として、トリフルオロメチル、トリクロロメチルが挙げられる。 “Haloalkyl” means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
　「ハロアルキルオキシ」とは、上記「ハロアルキル」が酸素原子に結合した基を意味する。例えば、モノフルオロメトキシ、モノフルオロエトキシ、トリフルオロメトキシ、トリクロロメトキシ、トリフルオロエトキシ、トリクロロエトキシ等が挙げられる。
　「ハロアルキルオキシ」の好ましい態様として、トリフルオロメトキシ、トリクロロメトキシが挙げられる。 “Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
　「アルキルオキシアルキル」とは、上記「アルキルオキシ」が上記「アルキル」に結合した基を意味する。例えば、メトキシメチル、メトキシエチル、エトキシメチル等が挙げられる。 “Alkyloxyalkyl” means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
　「アルキルオキシアルキルオキシ」とは、上記「アルキルオキシ」が上記「アルキルオキシ」に結合した基を意味する。例えば、メトキシメトキシ、メトキシエトキシ、エトキシメトキシ、エトキシエトキシ等が挙げられる。 “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
　「アルキルカルボニル」とは、上記「アルキル」がカルボニル基に結合した基を意味する。例えば、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ｔｅｒｔ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ペンチルカルボニル、イソペンチルカルボニル、へキシルカルボニル等が挙げられる。
　「アルキルカルボニル」の好ましい態様として、メチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニルが挙げられる。 “Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
Preferred embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
　「アルケニルカルボニル」とは、上記「アルケニル」がカルボニル基に結合した基を意味する。例えば、エチレニルカルボニル、プロペニルカルボニル等が挙げられる。 “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
　「アルキニルカルボニル」とは、上記「アルキニル」がカルボニル基に結合した基を意味する。例えば、エチニルカルボニル、プロピニルカルボニル等が挙げられる。 “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
　「モノアルキルアミノ」とは、上記「アルキル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルアミノ、エチルアミノ、イソプロピルアミノ等が挙げられる。
　「モノアルキルアミノ」の好ましい態様として、メチルアミノ、エチルアミノが挙げられる。 “Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
Preferable embodiments of “monoalkylamino” include methylamino and ethylamino.
　「ジアルキルアミノ」とは、上記「アルキル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルアミノ、ジエチルアミノ、Ｎ，Ｎ－ジイソプロピルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、Ｎ－イソプロピル－Ｎ－エチルアミノ等が挙げられる。
　「ジアルキルアミノ」の好ましい態様として、ジメチルアミノ、ジエチルアミノが挙げられる。 “Dialkylamino” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
Preferred embodiments of “dialkylamino” include dimethylamino and diethylamino.
　「アルキルスルホニル」とは、上記「アルキル」がスルホニル基に結合した基を意味する。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、ｔｅｒｔ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル等が挙げられる。
　「アルキルスルホニル」の好ましい態様として、メチルスルホニル、エチルスルホニルが挙げられる。 “Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
　「アルケニルスルホニル」とは、上記「アルケニル」がスルホニル基に結合した基を意味する。例えば、エチレニルスルホニル、プロペニルスルホニル等が挙げられる。 “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
　「アルキニルスルホニル」とは、上記「アルキニル」がスルホニル基に結合した基を意味する。例えば、エチニルスルホニル、プロピニルスルホニル等が挙げられる。 “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
　「モノアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルボニルアミノ、エチルカルボニルアミノ、プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ｔｅｒｔ－ブチルカルボニルアミノ、イソブチルカルボニルアミノ、ｓｅｃ－ブチルカルボニルアミノ等が挙げられる。
　「モノアルキルカルボニルアミノ」の好ましい態様としては、メチルカルボニルアミノ、エチルカルボニルアミノが挙げられる。 “Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned.
Preferable embodiments of “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.
　「ジアルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルカルボニル基は、同一でも異なっていてもよい。例えば、ジメチルカルボニルアミノ、ジエチルカルボニルアミノ、Ｎ，Ｎ－ジイソプロピルカルボニルアミノ等が挙げられる。
　「ジアルキルカルボニルアミノ」の好ましい態様として、ジメチルカルボニルアミノ、ジエチルカルボニルアミノが挙げられる。 “Dialkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
Preferred embodiments of “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
　「モノアルケニルカルボニルアミノ」とは、上記「アルケニルカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、エチレニルカルボニルアミノ、プロペニルカルボニルアミノ等が挙げられる。 “Monoalkenylcarbonylamino” means a group in which the above “alkenylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, ethylenylcarbonylamino, propenylcarbonylamino and the like can be mentioned.
　「モノアルキニルカルボニルアミノ」とは、上記「アルキニルカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、エチニルカルボニルアミノ、プロピニルカルボニルアミノ等が挙げられる。 “Monoalkynylcarbonylamino” means a group in which the above “alkynylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, ethynylcarbonylamino, propynylcarbonylamino and the like can be mentioned.
　「モノアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルホニルアミノ、エチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｓｅｃ－ブチルスルホニルアミノ等が挙げられる。
　「モノアルキルスルホニルアミノ」の好ましい態様としては、メチルスルホニルアミノ、エチルスルホニルアミノが挙げられる。 “Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
Preferable embodiments of “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
　「ジアルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキルスルホニル基は、同一でも異なっていてもよい。例えば、ジメチルスルホニルアミノ、ジエチルスルホニルアミノ、Ｎ，Ｎ－ジイソプロピルスルホニルアミノ等が挙げられる。
　「ジアルキルカルボニルアミノ」の好ましい態様として、ジメチルスルホニルアミノ、ジエチルスルホニルアミノが挙げられる。 “Dialkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
Preferred embodiments of “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.
　「アルキルイミノ」とは、上記「アルキル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルイミノ、エチルイミノ、ｎ－プロピルイミノ、イソプロピルイミノ等が挙げられる。 “Alkylimino” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
　「アルケニルイミノ」とは、上記「アルケニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルイミノ、プロペニルイミノ等が挙げられる。 “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
　「アルキニルイミノ」とは、上記「アルキニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルイミノ、プロピニルイミノ等が挙げられる。 “Alkynylimino” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.
　「アルキルカルボニルイミノ」とは、上記「アルキルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルカルボニルイミノ、エチルカルボニルイミノ、ｎ－プロピルカルボニルイミノ、イソプロピルカルボニルイミノ等が挙げられる。 “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
　「アルケニルカルボニルイミノ」とは、上記「アルケニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルカルボニルイミノ、プロペニルカルボニルイミノ等が挙げられる。 “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
　「アルキニルカルボニルイミノ」とは、上記「アルキニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルカルボニルイミノ、プロピニルカルボニルイミノ等が挙げられる。 “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
　「アルキルオキシイミノ」とは、上記「アルキルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルオキシイミノ、エチルオキシイミノ、ｎ－プロピルオキシイミノ、イソプロピルオキシイミノ等が挙げられる。 “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
　「アルケニルオキシイミノ」とは、上記「アルケニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルオキシイミノ、プロペニルオキシイミノ等が挙げられる。 “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
　「アルキニルオキシイミノ」とは、上記「アルキニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルオキシイミノ、プロピニルオキシイミノ等が挙げられる。 “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.
　「アルキルカルボニルオキシ」とは、上記「アルキルカルボニル」が酸素原子に結合した基を意味する。例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ、イソブチルカルボニルオキシ、ｓｅｃ－ブチルカルボニルオキシ等が挙げられる。
　「アルキルカルボニルオキシ」の好ましい態様としては、メチルカルボニルオキシ、エチルカルボニルオキシが挙げられる。 “Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
　「アルケニルカルボニルオキシ」とは、上記「アルケニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチレニルカルボニルオキシ、プロペニルカルボニルオキシ等が挙げられる。 “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
　「アルキニルカルボニルオキシ」とは、上記「アルキニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチニルカルボニルオキシ、プロピニルカルボニルオキシ等が挙げられる。 “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
　「アルキルオキシカルボニル」とは、上記「アルキルオキシ」がカルボニル基に結合した基を意味する。例えば、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニル、イソプロピルオキシカルボニル、ｔｅｒｔ－ブチルオキシカルボニル、イソブチルオキシカルボニル、ｓｅｃ－ブチルオキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、へキシルオキシカルボニル等が挙げられる。
　「アルキルオキシカルボニル」の好ましい態様としては、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニルが挙げられる。 “Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.
　「アルケニルオキシカルボニル」とは、上記「アルケニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチレニルオキシカルボニル、プロペニルオキシカルボニル等が挙げられる。 “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
　「アルキニルオキシカルボニル」とは、上記「アルキニルオキシ」がカルボニル基に結合した基を意味する。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等が挙げられる。 “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
　「アルキルスルファニル」とは、上記「アルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル等が挙げられる。 “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
　「アルケニルスルファニル」とは、上記「アルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルスルファニル、プロペニルスルファニル等が挙げられる。 “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
　「アルキニルスルファニル」とは、上記「アルキニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。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が挙げられる。 “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
　「アルキルスルフィニル」とは、上記「アルキル」がスルフィニル基に結合した基を意味する。例えば、メチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル等が挙げられる。 “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
　「アルケニルスルフィニル」とは、上記「アルケニル」がスルフィニル基に結合した基を意味する。例えば、エチレニルスルフィニル、プロペニルスルフィニル等が挙げられる。 “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
　「アルキニルスルフィニル」とは、上記「アルキニル」がスルフィニル基に結合した基を意味する。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が挙げられる。 “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
　「モノアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルカルバモイル、エチルカルバモイル等が挙げられる。 “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
　「ジアルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
　「モノアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルスルファモイル、ジメチルスルファモイル等が挙げられる。 “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.
　「ジアルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、ジメチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.
　「モノアルキルオキシカルボニルアミノ」とは、上記「アルキルオキシカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、メチルオキシカルボニルアミノ、エチルオキシカルボニルアミノ、プロピルオキシカルボニルアミノ等が挙げられる。 “Monoalkyloxycarbonylamino” means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methyloxycarbonylamino, ethyloxycarbonylamino, propyloxycarbonylamino and the like can be mentioned.
　「ジアルキルオキシカルボニルアミノ」とは、上記「アルキルオキシカルボニル」がアミノ基の窒素原子と結合している水素原子１個と置き換わった基を意味する。２個のアルキルカルボニル基は、同一でも異なっていてもよい。例えば、ジメチルオキシカルボニルアミノ、ジエチルオキシカルボニルアミノ等が挙げられる。 “Dialkyloxycarbonylamino” means a group in which the above “alkyloxycarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. Examples thereof include dimethyloxycarbonylamino, diethyloxycarbonylamino and the like.
　「モノアルキルウレイド」とは、上記「アルキル」がウレイド基の窒素原子と結合している水素原子１個と置き換わった基を意味する。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000039
等が挙げられる。 “Monoalkylureido” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the ureido group. For example, the group shown below
Figure JPOXMLDOC01-appb-C000039
Etc.
　「ジアルキルウレイド」とは、上記「アルキル」がウレイド基の窒素原子と結合している水素原子２個と置き換わった基を意味する。２個のアルキル基は、同一でも異なっていてもよい。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000040
等が挙げられる。 “Dialkylureido” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the ureido group. Two alkyl groups may be the same or different. For example, the group shown below
Figure JPOXMLDOC01-appb-C000040
Etc.
　「トリアルキルシリル」とは、上記「アルキル」３個がケイ素原子に結合している基を意味する。３個のアルキルは同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル等が挙げられる。 “Trialkylsilyl” means a group in which the above three “alkyls” are bonded to a silicon atom. The three alkyls may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
　「芳香族炭素環アルキル」、「非芳香族炭素環アルキル」、「芳香族複素環アルキル」、および「非芳香族複素環アルキル」、
「芳香族炭素環アルキルオキシ」、「非芳香族炭素環アルキルオキシ」、「芳香族複素環アルキルオキシ」、および「非芳香族複素環アルキルオキシ」、
「芳香族炭素環アルキルオキシカルボニル」、「非芳香族炭素環アルキルオキシカルボニル」、「芳香族複素環アルキルオキシカルボニル」、および「非芳香族複素環アルキルオキシカルボニル」、
「芳香族炭素環アルキルオキシアルキル」、「非芳香族炭素環アルキルオキシアルキル」、「芳香族複素環アルキルオキシアルキル」、および「非芳香族複素環アルキルオキシアルキル」、ならびに
「芳香族炭素環アルキルアミノ」、「非芳香族炭素環アルキルアミノ」、「芳香族複素環アルキルアミノ」、および「非芳香族複素環アルキルアミノ」のアルキル部分も、上記「アルキル」と同様である。 “Aromatic carbocyclic alkyl”, “non-aromatic carbocyclic alkyl”, “aromatic heterocyclic alkyl”, and “non-aromatic heterocyclic alkyl”,
“Aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, and “non-aromatic heterocyclic alkyloxy”,
“Aromatic carbocyclic alkyloxycarbonyl”, “non-aromatic carbocyclic alkyloxycarbonyl”, “aromatic heterocyclic alkyloxycarbonyl”, and “non-aromatic heterocyclic alkyloxycarbonyl”,
“Aromatic carbocyclic alkyloxyalkyl”, “non-aromatic carbocyclic alkyloxyalkyl”, “aromatic heterocyclic alkyloxyalkyl”, and “non-aromatic heterocyclic alkyloxyalkyl”, and “aromatic carbocyclic alkyl” The alkyl part of “amino”, “non-aromatic carbocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “nonaromatic heterocyclic alkylamino” is the same as the above “alkyl”.
　「芳香族炭素環アルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルを意味する。例えば、ベンジル、フェネチル、フェニルプロピニル、ベンズヒドリル、トリチル、ナフチルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000041
等が挙げられる。
　「芳香族炭素環アルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリルが挙げられる。 “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000041
Etc.
Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl and benzhydryl.
　「非芳香族炭素環アルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルを意味する。また、「非芳香族炭素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキル」も包含する。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロへキシルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000042
等が挙げられる。 “Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000042
Etc.
　「芳香族複素環アルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルを意味する。また、「芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキル」も包含する。例えば、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000043
等が挙げられる。 “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
Figure JPOXMLDOC01-appb-C000043
Etc.
　「非芳香族複素環アルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルを意味する。また、「非芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキル」も包含する。例えば、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000044
等が挙げられる。 The “non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000044
Etc.
　「芳香族炭素環アルキルオキシ」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシを意味する。例えば、ベンジルオキシ、フェネチルオキシ、フェニルプロピニルオキシ、ベンズヒドリルオキシ、トリチルオキシ、ナフチルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000045
等が挙げられる。 “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000045
Etc.
　「非芳香族炭素環アルキルオキシ」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族炭素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロへキシルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000046
等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000046
Etc.
　「芳香族複素環アルキルオキシ」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシ」も包含する。例えば、ピリジルメチルオキシ、フラニルメチルオキシ、イミダゾリルメチルオキシ、インドリルメチルオキシ、ベンゾチオフェニルメチルオキシ、オキサゾリルメチルオキシ、イソキサゾリルメチルオキシ、チアゾリルメチルオキシ、イソチアゾリルメチルオキシ、ピラゾリルメチルオキシ、イソピラゾリルメチルオキシ、ピロリジニルメチルオキシ、ベンズオキサゾリルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000047
等が挙げられる。 “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000047
Etc.
　「非芳香族複素環アルキルオキシ」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシ」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000048
等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000048
Etc.
　「芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。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、フェニルプロピニルオキシカルボニル、ベンズヒドリルオキシカルボニル、トリチルオキシカルボニル、ナフチルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000049
等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000049
Etc.
　「非芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族炭素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシカルボニル」も包含する。例えば、シクロプロピルメ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、シクロへキシルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000050
等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000050
Etc.
　「芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシカルボニル」も包含する。例えば、ピリジルメチルオキシカルボニル、フラニルメチルオキシカルボニル、イミダゾリルメチルオキシカルボニル、インドリルメチルオキシカルボニル、ベンゾチオフェニルメチルオキシカルボニル、オキサゾリルメチルオキシカルボニル、イソキサゾリルメチルオキシカルボニル、チアゾリルメチルオキシカルボニル、イソチアゾリルメチルオキシカルボニル、ピラゾリルメチルオキシカルボニル、イソピラゾリルメチルオキシカルボニル、ピロリジニルメチルオキシカルボニル、ベンズオキサゾリルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000051
等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000051
Etc.
　「非芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシカルボニル」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000052
等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000052
Etc.
　「芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。例えば、ベンジルオキシメチル、フェネチルオキシメチル、フェニルプロピニルオキシメチル、ベンズヒドリルオキシメチル、トリチルオキシメチル、ナフチルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000053
等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000053
Etc.
　「非芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族炭素環アルキルオキシアルキル」は、非芳香族炭素環が結合しているアルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシアルキル」も包含する。例えば、シクロプロピルメチルオキシメチル、シクロブチルメチルオキシメチル、シクロペンチルメチルオキシメチル、シクロへキシルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000054
等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000054
Etc.
　「芳香族複素環アルキルオキシアルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「芳香族複素環アルキルオキシアルキル」は、芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシアルキル」も包含する。例えば、ピリジルメチルオキシメチル、フラニルメチルオキシメチル、イミダゾリルメチルオキシメチル、インドリルメチルオキシメチル、ベンゾチオフェニルメチルオキシメチル、オキサゾリルメチルオキシメチル、イソキサゾリルメチルオキシメチル、チアゾリルメチルオキシメチル、イソチアゾリルメチルオキシメチル、ピラゾリルメチルオキシメチル、イソピラゾリルメチルオキシメチル、ピロリジニルメチルオキシメチル、ベンズオキサゾリルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000055
等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000055
Etc.
　「非芳香族複素環アルキルオキシアルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族複素環アルキルオキシ」は、非芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシアルキル」も包含する。例えば、テトラヒドロピラニルメチルオキシメチル、モルホリニルエチルオキシメチル、ピペリジニルメチルオキシメチル、ピペラジニルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000056
等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In addition, “non-aromatic heterocyclic alkyloxy” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”. Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000056
Etc.
　「芳香族炭素環アルキルアミノ」とは、上記「芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ベンジルアミノ、フェネチルアミノ、フェニルプロピニルアミノ、ベンズヒドリルアミノ、トリチルアミノ、ナフチルメチルアミノ、ジベンジルアミノ等が挙げられる。 “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
　「非芳香族炭素環アルキルアミノ」とは、上記「非芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルメチルアミノ、シクロブチルメチルアミノ、シクロペンチルメチルアミノ、シクロへキシルメチルアミノ等が挙げられる。 “Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
　「芳香族複素環アルキルアミノ」とは、上記「芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルメチルアミノ、フラニルメチルアミノ、イミダゾリルメチルアミノ、インドリルメチルアミノ、ベンゾチオフェニルメチルアミノ、オキサゾリルメチルアミノ、イソキサゾリルメチルアミノ、チアゾリルメチルアミノ、イソチアゾリルメチルアミノ、ピラゾリルメチルアミノ、イソピラゾリルメチルアミノ、ピロリジニルメチルアミノ、ベンズオキサゾリルメチルアミノ等が挙げられる。 “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
　「非芳香族複素環アルキルアミノ」とは、上記「非芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、テトラヒドロピラニルメチルアミノ、モルホリニルエチルアミノ、ピペリジニルメチルアミノ、ピペラジニルメチルアミノ等が挙げられる。 “Non-aromatic heterocyclic alkylamino” means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
　「芳香族炭素環オキシ」、「芳香族炭素環カルボニル」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環スルファニル」、「芳香族炭素環スルホニル」、「芳香族炭素環カルバモイル」、「芳香族炭素環アミノ」、「芳香族炭素環カルボニルアミノ」および「芳香族炭素環ウレイド」の「芳香族炭素環」部分も、上記「芳香族炭素環式基」と同様である。
　「芳香族炭素環オキシ」とは、「芳香族炭素環」が酸素原子に結合した基を意味する。例えば、フェニルオキシ、ナフチルオキシ等が挙げられる。
　「芳香族炭素環カルボニル」とは、「芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、フェニルカルボニル、ナフチルカルボニル等が挙げられる。
　「芳香族炭素環オキシカルボニル」とは、上記「芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、フェニルオキシカルボニル、ナフチルオキシカルボニル等が挙げられる。
　「芳香族炭素環スルファニル」とは、「芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、フェニルスルファニル、ナフチルスルファニル等が挙げられる。
　「芳香族炭素環スルホニル」とは、「芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。
　「芳香族炭素環カルバモイル」とは、「芳香族炭素環」がカルバモイル基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、フェニルカルバモイル、ナフチルカルバモイル等が挙げられる。
　「芳香族炭素環アミノ」とは、「芳香族炭素環」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、フェニルアミノ、ナフチルアミノ等が挙げられる。
　「芳香族炭素環カルボニルアミノ」とは、「芳香族炭素環カルボニル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、フェニルカルボニルアミノ、ナフチルカルボニルアミノ等が挙げられる。
　「芳香族炭素環ウレイド」とは、「芳香族炭素環」がウレイド基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000057
等が挙げられる。 “Aromatic carbocyclic oxy”, “Aromatic carbocyclic carbonyl”, “Aromatic carbocyclic oxycarbonyl”, “Aromatic carbocyclic sulfanyl”, “Aromatic carbocyclic sulfonyl”, “Aromatic carbocyclic carbamoyl”, “ The “aromatic carbocyclic” moiety of “aromatic carbocyclic amino”, “aromatic carbocyclic carbonylamino” and “aromatic carbocyclic ureido” is the same as the above “aromatic carbocyclic group”.
“Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
“Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
“Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
“Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
“Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
“Aromatic carbocyclic carbamoyl” means a group in which “aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to a nitrogen atom of a carbamoyl group. For example, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.
“Aromatic carbocyclic amino” means a group in which “aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, phenylamino, naphthylamino and the like can be mentioned.
“Aromatic carbocyclic carbonylamino” means a group in which “aromatic carbocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, phenylcarbonylamino, naphthylcarbonylamino and the like can be mentioned.
The “aromatic carbocyclic ureido” means a group in which the “aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group. For example, the group shown below
Figure JPOXMLDOC01-appb-C000057
Etc.
　「非芳香族炭素環オキシ」、「非芳香族炭素環カルボニル」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環スルファニル」、「非芳香族炭素環スルホニル」、「非芳香族炭素環カルバモイル」、「非芳香族炭素環アミノ」、「非芳香族炭素環カルボニルアミノ」および「非芳香族炭素環ウレイド」の「非芳香族炭素環」部分も、上記「非芳香族炭素環式基」と同様である。
　「非芳香族炭素環オキシ」とは、「非芳香族炭素環」が酸素原子に結合した基を意味する。例えば、シクロプロピルオキシ、シクロヘキシルオキシ、シクロへキセニルオキシ等が挙げられる。
　「非芳香族炭素環カルボニル」とは、「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロへキセニルカルボニル等が挙げられる。
　「非芳香族炭素環オキシカルボニル」とは、上記「非芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロピルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロへキセニルオキシカルボニル等が挙げられる。
　「非芳香族炭素環スルファニル」とは、「非芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロピルスルファニル、シクロヘキシルスルファニル、シクロヘキセニルスルファニル等が挙げられる。
　「非芳香族炭素環スルホニル」とは、「非芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル等が挙げられる。
　「非芳香族炭素環カルバモイル」とは、「非芳香族炭素環」がカルバモイル基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルカルバモイル、シクロヘキシルカルバモイル、シクロへキセニルカルバモイル等が挙げられる。
　「非芳香族炭素環アミノ」とは、「非芳香族炭素環」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルアミノ、シクロヘキシルアミノ、シクロへキセニルアミノ等が挙げられる。
　「非芳香族炭素環カルボニルアミノ」とは、「非芳香族炭素環カルボニル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルカルボニルアミノ、シクロヘキシルカルボニルアミノ、シクロへキセニルカルボニルアミノ等が挙げられる。
　「非芳香族炭素環ウレイド」とは、「非芳香族炭素環」がウレイド基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000058
等が挙げられる。 "Non-aromatic carbocyclic oxy", "non-aromatic carbocyclic carbonyl", "non-aromatic carbocyclic oxycarbonyl", "non-aromatic carbocyclic sulfanyl", "non-aromatic carbocyclic sulfonyl", "non-aromatic The “non-aromatic carbocycle” portion of “carbocyclic carbamoyl”, “non-aromatic carbocyclic amino”, “non-aromatic carbocyclic carbonylamino” and “non-aromatic carbocyclic ureido” is The same as “formula”.
“Non-aromatic carbocyclic oxy” means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
“Non-aromatic carbocycle carbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
“Non-aromatic carbocyclic sulfanyl” means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
“Non-aromatic carbocycle sulfonyl” means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
The “non-aromatic carbocyclic carbamoyl” means a group in which the “non-aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like can be mentioned.
“Non-aromatic carbocyclic amino” means a group in which “non-aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylamino, cyclohexylamino, cyclohexenylamino and the like can be mentioned.
“Non-aromatic carbocyclic carbonylamino” means a group in which “non-aromatic carbocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylcarbonylamino, cyclohexylcarbonylamino, cyclohexenylcarbonylamino and the like can be mentioned.
The “non-aromatic carbocyclic ureido” means a group in which the “non-aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group. For example, the group shown below
Figure JPOXMLDOC01-appb-C000058
Etc.
　「芳香族複素環オキシ」、「芳香族複素環カルボニル」、「芳香族複素環オキシカルボニル」、「芳香族複素環スルファニル」、「芳香族複素環スルホニル」、「芳香族複素環カルバモイル」、「芳香族複素環アミノ」、「芳香族複素環カルボニルアミノ」および「芳香族複素環ウレイド」の「芳香族複素環」部分も、上記「芳香族複素環式基」と同様である。
　「芳香族複素環オキシ」とは、「芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピリジルオキシ、オキサゾリルオキシ等が挙げられる。
　「芳香族複素環カルボニル」とは、「芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピリジルカルボニル、オキサゾリルカルボニル等が挙げられる。
　「芳香族複素環オキシカルボニル」とは、上記「芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピリジルオキシカルボニル、オキサゾリルオキシカルボニル等が挙げられる。
　「芳香族複素環スルファニル」とは、「芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピリジルスルファニル、オキサゾリルスルファニル等が挙げられる。
　「芳香族複素環スルホニル」とは、「芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピリジルスルホニル、オキサゾリルスルホニル等が挙げられる。
　「芳香族複素環カルバモイル」とは、「芳香族複素環」がカルバモイル基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルカルバモイル、オキサゾリルカルバモイル等が挙げられる。
　「芳香族複素環アミノ」とは、「芳香族複素環」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルアミノ、オキサゾリルアミノ等が挙げられる。
　「芳香族複素環カルボニルアミノ」とは、「芳香族複素環カルボニル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルカルボニルアミノ、オキサゾリルカルボニルアミノ等が挙げられる。
　「芳香族複素環ウレイド」とは、「芳香族複素環」がウレイド基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000059
等が挙げられる。 "Aromatic heterocyclic oxy", "aromatic heterocyclic carbonyl", "aromatic heterocyclic oxycarbonyl", "aromatic heterocyclic sulfanyl", "aromatic heterocyclic sulfonyl", "aromatic heterocyclic carbamoyl", " The “aromatic heterocycle” moiety of “aromatic heterocycle amino”, “aromatic heterocycle carbonylamino” and “aromatic heterocycle ureido” is the same as the above “aromatic heterocycle”.
“Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
“Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
“Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
“Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
“Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
“Aromatic heterocycle carbamoyl” means a group in which “aromatic heterocycle” is replaced with one or two hydrogen atoms bonded to a nitrogen atom of a carbamoyl group. For example, pyridylcarbamoyl, oxazolylcarbamoyl and the like can be mentioned.
“Aromatic heterocycle amino” means a group in which “aromatic heterocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylamino, oxazolylamino and the like can be mentioned.
“Aromatic heterocyclic carbonylamino” means a group in which “aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylcarbonylamino, oxazolylcarbonylamino and the like can be mentioned.
The “aromatic heterocyclic ureido” means a group in which the “aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group. For example, the group shown below
Figure JPOXMLDOC01-appb-C000059
Etc.
　「非芳香族複素環オキシ」、「非芳香族複素環カルボニル」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環スルファニル」、「非芳香族複素環スルホニル」、「非芳香族複素環カルバモイル」、「非芳香族複素環アミノ」、「非芳香族複素環カルボニルアミノ」および「非芳香族複素環ウレイド」の「非芳香族複素環」部分も、上記「非芳香族複素環式基」と同様である。
　「非芳香族複素環オキシ」とは、「非芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピペリジニルオキシ、テトラヒドロフリルオキシ等が挙げられる。
　「非芳香族複素環カルボニル」とは、「非芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピペリジニルカルボニル、テトラヒドロフリルカルボニル等が挙げられる。
　「非芳香族複素環オキシカルボニル」とは、上記「非芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピペリジニルオキシカルボニル、テトラヒドロフリルオキシカルボニル等が挙げられる。
　「非芳香族複素環スルファニル」とは、「非芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピペリジニルスルファニル、テトラヒドロフリルスルファニル等が挙げられる。
　「非芳香族複素環スルホニル」とは、「非芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。
　「非芳香族複素環カルバモイル」とは、「非芳香族複素環」がカルバモイル基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピペリジニルカルバモイル、テトラヒドロフリルカルバモイル等が挙げられる。
　「非芳香族複素環アミノ」とは、「非芳香族複素環」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピペリジニルアミノ、テトラヒドロフリルアミノ等が挙げられる。
　「非芳香族複素環カルボニルアミノ」とは、「非芳香族複素環カルボニル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピペリジニルカルボニルアミノ、テトラヒドロフリルカルボニルアミノ等が挙げられる。
　「非芳香族複素環ウレイド」とは、「非芳香族複素環」がウレイド基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、以下に示される基
Figure JPOXMLDOC01-appb-C000060
等が挙げられる。
例えば、ピペリジニルウレイド、テトラヒドロフリルウレイド等が挙げられる。 "Non-aromatic heterocyclic oxy", "Non-aromatic heterocyclic carbonyl", "Non-aromatic heterocyclic oxycarbonyl", "Non-aromatic heterocyclic sulfanyl", "Non-aromatic heterocyclic sulfonyl", "Non-aromatic The “non-aromatic heterocycle” portion of “heterocyclic carbamoyl”, “non-aromatic heterocyclic amino”, “non-aromatic heterocyclic carbonylamino” and “non-aromatic heterocyclic ureido” is The same as “formula”.
“Non-aromatic heterocyclic oxy” means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
“Non-aromatic heterocyclic carbonyl” means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group. For example, piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfanyl” means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfonyl” means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
The “non-aromatic heterocyclic carbamoyl” means a group in which the “non-aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, piperidinylcarbamoyl, tetrahydrofurylcarbamoyl and the like can be mentioned.
The “non-aromatic heterocyclic amino” means a group in which the “non-aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, piperidinylamino, tetrahydrofurylamino and the like can be mentioned.
“Non-aromatic heterocyclic carbonylamino” means a group in which “non-aromatic heterocyclic carbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, piperidinylcarbonylamino, tetrahydrofurylcarbonylamino and the like can be mentioned.
The “non-aromatic heterocyclic ureido” means a group in which the “non-aromatic heterocyclic ring” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the ureido group. For example, the group shown below
Figure JPOXMLDOC01-appb-C000060
Etc.
For example, piperidinyl ureido, tetrahydrofuryl ureido, etc. are mentioned.
　「置換若しくは非置換のアルキル」、「置換若しくは非置換のアルケニル」、「置換若しくは非置換のアルキニル」、「置換若しくは非置換のアルキルオキシ」、「置換若しくは非置換のアルケニルオキシ」、「置換若しくは非置換のアルキニルオキシ」、「置換若しくは非置換のアルキルカルボニル」、「置換若しくは非置換のアルケニルカルボニル」、「置換若しくは非置換のアルキニルカルボニル」、「置換若しくは非置換のモノアルキルアミノ」、「置換若しくは非置換のジアルキルアミノ」、「置換若しくは非置換のアルキルスルホニル」、「置換若しくは非置換のアルケニルスルホニル」、「置換若しくは非置換のアルキニルスルホニル」、「置換若しくは非置換のモノアルキルカルボニルアミノ」、「置換若しくは非置換のジアルキルカルボニルアミノ」、「置換もしくは非置換のモノアルケニルカルボニルアミノ」、「置換もしくは非置換のモノアルキニルカルボニルアミノ」、「置換若しくは非置換のモノアルキルスルホニルアミノ」、「置換若しくは非置換のジアルキルスルホニルアミノ」、「置換若しくは非置換のアルキルスルフィニル」、「置換若しくは非置換のアルケニルスルフィニル」、「置換若しくは非置換のアルキニルスルフィニル」、「置換若しくは非置換のモノアルキルカルバモイル」、「置換若しくは非置換のジアルキルカルバモイル」、「置換若しくは非置換のモノアルキルスルファモイル」、「置換若しくは非置換のジアルキルスルファモイル」、「置換もしくは非置換のモノアルキルウレイド」、「置換もしくは非置換のジアルキルウレイド」、「置換もしくは非置換のモノアルキルオキシカルボニルアミノ」、および「置換もしくは非置換のジアルキルカルボニルアミノ」の置換基としては、置換基群Ａが挙げられる。任意の位置の炭素原子が置換基群Ａから選択される１以上の基と結合していてもよい。
　置換基群Ａ：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、非芳香族複素環スルホニル、芳香族炭素環オキシイミノ、非芳香族炭素環オキシイミノ、芳香族複素環オキシイミノ、および非芳香族複素環オキシイミノ。
　置換基群Ａにおける「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、「非芳香族複素環」等の環は、環状の任意の位置の原子が置換基群αから選択される１以上の基で置換されていてもよい。
　置換基群α：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキル、非芳香族炭素環アルキル、芳香族複素環アルキル、非芳香族複素環アルキル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルオキシアルキル、非芳香族炭素環アルキルオキシアルキル、芳香族複素環アルキルオキシアルキル、非芳香族複素環アルキルオキシアルキル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。
　「置換基群α」の一つの態様としては、ハロゲン、ヒドロキシ、カルボキシ、アミノ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、およびジアルキルスルファモイルが挙げられる。
　「置換基群α」の一つの態様としては、ハロゲン、シアノ、ニトロ、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、およびハロアルキルオキシが挙げられる。 “Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted or "Unsubstituted alkynyloxy", "substituted or unsubstituted alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted monoalkylamino", "substituted Or “unsubstituted dialkylamino”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted monoalkylcarbonylamino”, "Substituted or unsubstituted di- ”Alkylcarbonylamino”, “substituted or unsubstituted monoalkenylcarbonylamino”, “substituted or unsubstituted monoalkynylcarbonylamino”, “substituted or unsubstituted monoalkylsulfonylamino”, “substituted or unsubstituted dialkylsulfonylamino” ”,“ Substituted or unsubstituted alkylsulfinyl ”,“ substituted or unsubstituted alkenylsulfinyl ”,“ substituted or unsubstituted alkynylsulfinyl ”,“ substituted or unsubstituted monoalkylcarbamoyl ”,“ substituted or unsubstituted dialkyl ” Carbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted monoalkylureido, substituted or unsubstituted dialkyl Raid ", the substituent of the" substituted or unsubstituted mono alkyloxycarbonylamino ", and" substituted or unsubstituted dialkylamino carbonyl amino "include the substituent group A. The carbon atom at any position may be bonded to one or more groups selected from the substituent group A.
Substituent group A: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl , Alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfo Ruamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic Group carbocyclic , Non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, Aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic Aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyl Oxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino , Non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, Non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, non-aromatic heterocyclic sulfonyl, aromatic carbocyclic oxyimino, non-aromatic carbocyclic oxyimino, aromatic heterocyclic oxyimino, and non-aromatic hetero Ring oxyimino.
Rings such as “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, “non-aromatic heterocycle” and the like in Substituent Group A are those in which the atom at any position in the ring is the Substituent Group It may be substituted with one or more groups selected from α.
Substituent group α: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenyl Carbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfoni , Alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino Alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarba Moyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocycle Oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic Carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic Heterocyclic alkyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic al Ruoxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyl Oxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, Aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic hetero Ring sulfonyl.
One embodiment of the “substituent group α” is halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyl. Oxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkyl Sulfonylamino, dialkylsulfonylamino, alkylsulfanyl, alkenylsulfanyl, alkyl Rusurufaniru, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, mono alkylsulfamoyl and dialkylsulfamoyl, and the like.
One embodiment of the “substituent group α” includes halogen, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, and haloalkyloxy.
　「置換若しくは非置換の非芳香族炭素環」、「置換若しくは非置換の非芳香族複素環」、および「置換若しくは非置換の芳香族複素環」
「置換若しくは非置換の芳香族炭素環式基」、「置換若しくは非置換の非芳香族炭素環式基」、「置換若しくは非置換の芳香族複素環式基」、および「置換若しくは非置換の非芳香族複素環式基」、
「置換若しくは非置換の芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の芳香族複素環オキシ」、および「置換若しくは非置換の非芳香族複素環オキシ」、
「置換若しくは非置換の芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の芳香族複素環カルボニル」、および「置換若しくは非置換の非芳香族複素環カルボニル」、
「置換若しくは非置換の芳香族炭素環スルホニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、「置換若しくは非置換の芳香族複素環スルホニル」、および「置換若しくは非置換の非芳香族複素環スルホニル」、
「置換もしくは非置換の芳香族炭素環カルバモイル」、「置換もしくは非置換の非芳香族炭素環カルバモイル」、「置換もしくは非置換の芳香族複素環カルバモイル」、および「置換もしくは非置換の非芳香族複素環カルバモイル」、
「置換もしくは非置換の芳香族炭素環アミノ」、「置換もしくは非置換の非芳香族炭素環アミノ」、「置換もしくは非置換の芳香族複素環アミノ」、および「置換もしくは非置換の非芳香族複素環アミノ」、
「置換もしくは非置換の芳香族炭素環カルボニルアミノ」、「置換もしくは非置換の非芳香族炭素環カルボニルアミノ」、「置換もしくは非置換の芳香族複素環カルボニルアミノ」および「置換もしくは非置換の非芳香族複素環カルボニルアミノ」、ならびに
「置換もしくは非置換の芳香族炭素環ウレイド」、「置換もしくは非置換の非芳香族炭素環ウレイド」、「置換もしくは非置換の芳香族複素環ウレイド」、および「置換もしくは非置換の非芳香族複素環ウレイド」
の「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、および「非芳香族複素環」の環上の置換基としては、置換基群Ｂが挙げられる。環上の任意の位置の原子が置換基群Ｂから選択される１以上の基と結合していてもよい。
　置換基群Ｂ：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、シアノアルキル、ヒドロキシアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、ジアルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、ジアルキルカルボニルアミノ、モノアルキルスルホニルアミノ、ジアルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、ジアルキルカルバモイル、モノアルキルスルファモイル、ジアルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環カルボニルアミノ、非芳香族炭素環カルボニルアミノ、芳香族複素環カルボニルアミノ、非芳香族複素環カルボニルアミノ、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキル、非芳香族炭素環アルキル、芳香族複素環アルキル、非芳香族複素環アルキル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルオキシアルキル、非芳香族炭素環アルキルオキシアルキル、芳香族複素環アルキルオキシアルキル、非芳香族複素環アルキルオキシアルキル、芳香族炭素環カルボニルオキシアルキル、非芳香族炭素環カルボニルオキシアルキル、芳香族複素環カルボニルオキシアルキル、非芳香族複素環カルボニルオキシアルキル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。
　置換基群Ｂにおける「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、「非芳香族複素環」等の環は、環状の任意の位置の原子が置換基群αから選択される１以上の基で置換されていてもよい。 “Substituted or unsubstituted non-aromatic carbocycle”, “Substituted or unsubstituted non-aromatic heterocycle”, and “Substituted or unsubstituted aromatic heterocycle”
“Substituted or unsubstituted aromatic carbocyclic group”, “Substituted or unsubstituted nonaromatic carbocyclic group”, “Substituted or unsubstituted aromatic heterocyclic group”, and “Substituted or unsubstituted aromatic carbocyclic group” Non-aromatic heterocyclic group ",
"Substituted or unsubstituted aromatic carbocyclic oxy", "Substituted or unsubstituted non-aromatic carbocyclic oxy", "Substituted or unsubstituted aromatic heterocyclic oxy", and "Substituted or unsubstituted non-aromatic Heterocyclic oxy ",
"Substituted or unsubstituted aromatic carbocyclic carbonyl", "Substituted or unsubstituted non-aromatic carbocyclic carbonyl", "Substituted or unsubstituted aromatic heterocyclic carbonyl", and "Substituted or unsubstituted non-aromatic Heterocyclic carbonyl ",
"Substituted or unsubstituted aromatic carbocyclic sulfonyl", "Substituted or unsubstituted non-aromatic carbocyclic sulfonyl", "Substituted or unsubstituted aromatic heterocyclic sulfonyl", and "Substituted or unsubstituted non-aromatic Heterocyclic sulfonyl ",
"Substituted or unsubstituted aromatic carbocyclic carbamoyl", "Substituted or unsubstituted non-aromatic carbocyclic carbamoyl", "Substituted or unsubstituted aromatic heterocyclic carbamoyl", and "Substituted or unsubstituted non-aromatic `` Heterocyclic carbamoyl '',
“Substituted or unsubstituted aromatic carbocyclic amino”, “Substituted or unsubstituted non-aromatic carbocyclic amino”, “Substituted or unsubstituted aromatic heterocyclic amino”, and “Substituted or unsubstituted non-aromatic Heterocyclic amino ",
"Substituted or unsubstituted aromatic carbocyclic carbonylamino", "Substituted or unsubstituted non-aromatic carbocyclic carbonylamino", "Substituted or unsubstituted aromatic heterocyclic carbonylamino" and "Substituted or unsubstituted non-substituted carbocyclic amino" “Aromatic heterocyclic carbonylamino”, and “substituted or unsubstituted aromatic carbocyclic ureido”, “substituted or unsubstituted nonaromatic carbocyclic ureido”, “substituted or unsubstituted aromatic heterocyclic ureido”, and "Substituted or unsubstituted non-aromatic heterocyclic ureido"
Substituent group B may be mentioned as the substituent on the “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle”. The atom at any position on the ring may be bonded to one or more groups selected from the substituent group B.
Substituent group B: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyl Oxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, Killylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxy Imino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, al Nylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group , Aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic hetero Ring carbonyl, aromatic carbocyclic carbonylamino, non-aromatic carbocyclic carbonylamino, aromatic heterocyclic carbonylamino, non-aromatic heterocyclic carbonylamino, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic Heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocycle Alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyl Oxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic Alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic carbonyloxyalkyl, non-aromatic carbocyclic carbonyloxyalkyl, aromatic heterocyclic carbonyloxyalkyl, non-aromatic heterocyclic carbonyloxyalkyl, aromatic carbon Ring alkylamino, non-aromatic Carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbon Ring sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
Rings such as “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle” and “non-aromatic heterocycle” in Substituent Group B are those in which the atom at any position in the ring is the Substituent Group It may be substituted with one or more groups selected from α.
　また、「置換若しくは非置換の非芳香族炭素環式基」および「置換若しくは非置換の非芳香族複素環式基」は「オキソ」で置換されていてもよい。この場合、以下のように炭素原子上の２個の水素原子が置換されている基を意味する。
Figure JPOXMLDOC01-appb-C000061
 Further, the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
Figure JPOXMLDOC01-appb-C000061
　上記、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族複素環オキシカルボニル」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、「置換若しくは非置換の非芳香族複素環スルホニル」、「置換もしくは非置換の非芳香族炭素環カルバモイル」、「置換もしくは非置換の非芳香族複素環カルバモイル」、「置換もしくは非置換の非芳香族炭素環アミノ」、「置換もしくは非置換の非芳香族複素環アミノ」、「置換もしくは非置換の非芳香族炭素環カルボニルアミノ」、「置換もしくは非置換の非芳香族複素環カルボニルアミノ」、「置換もしくは非置換の非芳香族炭素環ウレイド」、および「置換もしくは非置換の非芳香族複素環ウレイド」の非芳香族炭素環、および非芳香族複素環部分も上記と同様に「オキソ」で置換されていてもよい。 The above-mentioned “substituted or unsubstituted non-aromatic carbocyclic oxy”, “substituted or unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted “Non-aromatic heterocyclic carbonyl”, “Substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl”, “Substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl”, “Substituted or unsubstituted non-aromatic carbocyclic sulfanyl” ”,“ Substituted or unsubstituted non-aromatic heterocyclic sulfanyl ”,“ substituted or unsubstituted non-aromatic carbocyclic sulfonyl ”,“ substituted or unsubstituted non-aromatic heterocyclic sulfonyl ”,“ substituted or unsubstituted “Non-aromatic carbocyclic carbamoyl”, “substituted or unsubstituted non-aromatic heterocyclic carbamoyl”, “substituted or unsubstituted non-aromatic carbocyclic amino”, Substituted or unsubstituted non-aromatic heterocyclic amino ”,“ substituted or unsubstituted non-aromatic carbocyclic amino ”,“ substituted or unsubstituted non-aromatic heterocyclic carbonyl amino ”,“ substituted or unsubstituted non-substituted Aromatic carbocyclic ureido ”and non-aromatic carbocyclic and non-aromatic heterocyclic moieties of“ substituted or unsubstituted non-aromatic heterocyclic ureido ”may also be substituted with“ oxo ”in the same manner as described above. .
原子ａは、－Ｘ－に隣接し、環Ｃのみを構成する原子を意味する。原子ａとしては、炭素原子、窒素原子、酸素原子または硫黄原子が挙げられる。
原子ｂは、－Ｘ－に隣接し、環Ｂおよび環Ｃ両方の環構成原子である。原子ｂとしては、炭素原子または窒素原子が挙げられる。
原子ｃは、－Ｘ－に隣接し、環Ｅのみを構成する原子を意味する。原子ｃとしては、炭素原子、窒素原子、酸素原子または硫黄原子が挙げられる。
原子ｄは、－Ｘ－に隣接し、環Ｄおよび環Ｅ両方の環構成原子である。原子ｄとしては、炭素原子または窒素原子が挙げられる。
－Ｌ－において、左の結合手はピロリジン環の炭素原子に結合し、右の結合手はＲ１に結合する。 The atom a means an atom adjacent to -X- and constituting only the ring C. As the atom a, a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom can be mentioned.
Atom b is adjacent to —X— and is a ring member atom of both ring B and ring C. The atom b includes a carbon atom or a nitrogen atom.
The atom c is an atom adjacent to -X- and constituting only the ring E. As the atom c, a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom can be mentioned.
The atom d is adjacent to —X— and is a ring atom of both ring D and ring E. The atom d includes a carbon atom or a nitrogen atom.
In -L-, the left bond is bonded to the carbon atom of the pyrrolidine ring, and the right bond is bonded to R1.
　式（Ｉ）で示される化合物またはその製薬上許容される塩における、各置換基の具体例を以下に示す。 Specific examples of each substituent in the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof are shown below.
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000063
（式中、ｐは０から３の整数である）が挙げられる。（以下、環ＡがＡ１であるとする）
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
（式中、ｐは上記と同意義である）が挙げられる。（以下、環ＡがＡ２であるとする）
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000067
（式中、ｐは上記と同意義である）が挙げられる。（以下、環ＡがＡ３であるとする）
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000063
(Wherein p is an integer from 0 to 3). (Hereinafter, ring A is assumed to be A1)
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000065
(Wherein p is as defined above). (Hereinafter, ring A is assumed to be A2)
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000067
(Wherein p is as defined above). (Hereinafter, ring A is assumed to be A3)
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
（式中、ｐは上記と同意義である）が挙げられる。（以下、環ＡがＡ４であるとする）
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000071
（式中、ｐは上記と同意義である）が挙げられる。（以下、環ＡがＡ５であるとする）
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000069
(Wherein p is as defined above). (Hereinafter, ring A is assumed to be A4)
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000071
(Wherein p is as defined above). (Hereinafter, ring A is assumed to be A5)
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
（式中、Ｒ２ａはハロゲン、カルボキシ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルであり；ｐ’は０から２の整数である）が挙げられる。（以下、環ＡがＡ６であるとする）
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000075
（式中、Ｒ２ａおよびｐ’は上記と同意義である）が挙げられる。（以下、環ＡがＡ７であるとする）
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000077
（式中、Ｒ２ａは上記と同意義である）が挙げられる。（以下、環ＡがＡ８であるとする）
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000079
（式中、Ｒ２ａは上記と同意義である）が挙げられる。（以下、環ＡがＡ９であるとする）
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000073
Wherein R 2a is halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted fragrance Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-substituted Aromatic carbocyclic carbamoyl, substituted Or an unsubstituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl; p ′ is an integer of 0 to 2. (Hereinafter, ring A is assumed to be A6)
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000075
(Wherein R 2a and p ′ are as defined above). (Hereinafter, ring A is assumed to be A7)
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000077
(Wherein R 2a has the same meaning as above). (Hereinafter, ring A is assumed to be A8)
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000079
(Wherein R 2a has the same meaning as above). (Hereinafter, ring A is assumed to be A9)
　Ｒａとしては、それぞれ独立して、カルボキシ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルが挙げられる。（以下、ＲａがＲａ１であるとする） Each Ra is independently carboxy, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, Substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or Unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, Substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted fragrance Aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl Substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or Non-aromatic carbocyclic carbamoyl unsubstituted, substituted or unsubstituted aromatic heterocyclic carbamoyl, or substituted or non-aromatic heterocyclic ring-carbamoyl unsubstituted thereof. (Hereafter, Ra is assumed to be Ra1)
　Ｒａとしては、それぞれ独立して、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルが挙げられる。（以下、ＲａがＲａ２であるとする） Each Ra is independently carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or Unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted Aromatic heterocyclic carbonyl, substituted or unsubstituted Aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, or substituted or unsubstituted non-aromatic Heterocyclic carbamoyl is mentioned. (Hereafter, Ra is assumed to be Ra2)
　Ｒａとしては、それぞれ独立して、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルが挙げられる。（以下、ＲａがＲａ３であるとする） Each Ra is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic Carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbon Ring carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted Or an unsubstituted non-aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl. That. (Hereafter, Ra is assumed to be Ra3)
　Ｒａがそれぞれ独立して、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基が挙げられる。（以下、ＲａがＲａ４であるとする） Each Ra independently represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted Non-aromatic heterocyclic group is mentioned. (Hereafter, Ra is assumed to be Ra4)
　Ｒｂとしては、それぞれ独立して、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルが挙げられる。 Rb each independently represents hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, hydrazino, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyls Phonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, Substituted or unsubstituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkyl Carbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamo , Substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted fragrance Aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl Amino, substituted or unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic ring Bonylamino, substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted aromatic heterocyclic carbamoyl, or Examples thereof include substituted or unsubstituted non-aromatic heterocyclic carbamoyl.
　Ｒｂとしては、それぞれ独立して、ヒドロキシ、カルボキシ、アミノ、カルバモイル、ウレイド、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルが挙げられる。 Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted Or unsubstituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or unsubstituted Substituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbocyclic carbonylamino, substituted Or unsubstituted aromatic heterocyclic carbonylamino, substituted or unsubstituted nonaromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted nonaromatic carbocyclic carbamoyl, substituted or An unsubstituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl can be mentioned.
　Ｒｂとしては、それぞれ独立して、ヒドロキシ、カルボキシ、アミノ、カルバモイル、ウレイド、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、または置換もしくは非置換の非芳香族複素環カルボニルアミノが挙げられる。 Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted Or unsubstituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbocyclic carbonylamino , Substituted or unsubstituted aromatic heterocyclic carbonylamino, or substituted or unsubstituted nonaromatic heterocyclic carbonylamino.
　Ｒｃとしては、水素原子が挙げられる。 Rc includes a hydrogen atom.
　－Ｌ－としては、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－が挙げられる。（以下、ＬがＬ１であるとする）
　－Ｌ－としては、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）Ｃ（＝Ｏ）－が挙げられる。（以下、ＬがＬ２であるとする） —L— includes —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO. 2- . (Hereafter, L is assumed to be L1)
Examples of —L— include —C (═O) N (R 4 ) — or —N (R 4 ) C (═O) —. (Hereafter, L is assumed to be L2)
　Ｒ４、Ｒ５ａおよびＲ５ｂとしては、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルが挙げられる。
　Ｒ４、Ｒ５ａおよびＲ５ｂとしては、水素原子が挙げられる。 R 4 , R 5a and R 5b each independently include a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
Examples of R 4 , R 5a and R 5b include a hydrogen atom.
　Ｒ１としては、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基が挙げられる。（以下、Ｒ１がＲ１１であるとする）
　Ｒ１としては、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基が挙げられる。（以下、Ｒ１がＲ１２であるとする）
　Ｒ１としては、置換もしくは非置換の芳香族炭素環式基、または置換もしくは非置換の芳香族複素環式基が挙げられる。（以下、Ｒ１がＲ１３であるとする）　 R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, Substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group Is mentioned. (Hereinafter referred to as R 1 is R11)
R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group. Group heterocyclic groups. (Hereafter, R 1 is assumed to be R12)
R 1 includes a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group. (Hereinafter, R 1 is assumed to be R13)
　Ｒ２としては、それぞれ独立して、ハロゲン、カルボキシ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のモノアルキルウレイド、置換もしくは非置換のジアルキルウレイド、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルが挙げられる。　 R 2 is each independently halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or non-substituted Substituted monoalkyluree Id, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted aromatic heterocyclic carbamoyl, or substituted or unsubstituted Non-aromatic heterocyclic carbamoyl is mentioned.
　ｎが１または２である。
　ｎが１である。
　ｍが０であり、かつｎが１または２である。（以下、ｎｍがｎｍ１であるとする）
　ｍが０であり、かつｎが１である。（以下、ｎｍがｎｍ２であるとする） n is 1 or 2;
n is 1.
m is 0, and n is 1 or 2. (Hereafter, nm is assumed to be nm1)
m is 0 and n is 1. (Hereafter, nm is assumed to be nm2)
　ｍが１または２である。
　ｍが１である。
　ｎが０であり、かつｍが１または２である。
　ｎが０であり、かつｍが１である。 m is 1 or 2;
m is 1.
n is 0, and m is 1 or 2.
n is 0 and m is 1.
　また、式（Ｉ）で示される化合物またはその製薬上許容される塩としては、上記で示した各置換基の定義の一部または全部の組み合わせにより生じる化合物またはその製薬上許容される塩が挙げられる。
　さらに具体的には、環Ａ、Ｒａ、Ｌ、Ｒ１およびｎｍの組み合わせ（環Ａ、Ｒａ、Ｌ、Ｒ１、ｎｍ）がそれぞれ以下の組み合わせである化合物またはその製薬上許容される塩が挙げられる。
(A1, Ra1, L1, R11, nm1)、(A1, Ra1, L1, R11, nm2)、(A1, Ra1, L1, R12, nm1)、(A1, Ra1, L1, R12, nm2)、(A1, Ra1, L1, R13, nm1)、(A1, Ra1, L1, R13, nm2)、(A1, Ra1, L2, R11, nm1)、(A1, Ra1, L2, R11, nm2)、(A1, Ra1, L2, R12, nm1)、(A1, Ra1, L2, R12, nm2)、(A1, Ra1, L2, R13, nm1)、(A1, Ra1, L2, R13, nm2)、(A1, Ra2, L1, R11, nm1)、(A1, Ra2, L1, R11, nm2)、(A1, Ra2, L1, R12, nm1)、(A1, Ra2, L1, R12, nm2)、(A1, Ra2, L1, R13, nm1)、(A1, Ra2, L1, R13, nm2)、(A1, Ra2, L2, R11, nm1)、(A1, Ra2, L2, R11, nm2)、(A1, Ra2, L2, R12, nm1)、(A1, Ra2, L2, R12, nm2)、(A1, Ra2, L2, R13, nm1)、(A1, Ra2, L2, R13, nm2)、(A1, Ra3, L1, R11, nm1)、(A1, Ra3, L1, R11, nm2)、(A1, Ra3, L1, R12, nm1)、(A1, Ra3, L1, R12, nm2)、(A1, Ra3, L1, R13, nm1)、(A1, Ra3, L1, R13, nm2)、(A1, Ra3, L2, R11, nm1)、(A1, Ra3, L2, R11, nm2)、(A1, Ra3, L2, R12, nm1)、(A1, Ra3, L2, R12, nm2)、(A1, Ra3, L2, R13, nm1)、(A1, Ra3, L2, R13, nm2)、(A1, Ra4, L1, R11, nm1)、(A1, Ra4, L1, R11, nm2)、(A1, Ra4, L1, R12, nm1)、(A1, Ra4, L1, R12, nm2)、(A1, Ra4, L1, R13, nm1)、(A1, Ra4, L1, R13, nm2)、(A1, Ra4, L2, R11, nm1)、(A1, Ra4, L2, R11, nm2)、(A1, Ra4, L2, R12, nm1)、(A1, Ra4, L2, R12, nm2)、(A1, Ra4, L2, R13, nm1)、(A1, Ra4, L2, R13, nm2)、(A2, Ra1, L1, R11, nm1)、(A2, Ra1, L1, R11, nm2)、(A2, Ra1, L1, R12, nm1)、(A2, Ra1, L1, R12, nm2)、(A2, Ra1, L1, R13, nm1)、(A2, Ra1, L1, R13, nm2)、(A2, Ra1, L2, R11, nm1)、(A2, Ra1, L2, R11, nm2)、(A2, Ra1, L2, R12, nm1)、(A2, Ra1, L2, R12, nm2)、(A2, Ra1, L2, R13, nm1)、(A2, Ra1, L2, R13, nm2)、(A2, Ra2, L1, R11, nm1)、(A2, Ra2, L1, R11, nm2)、(A2, Ra2, L1, R12, nm1)、(A2, Ra2, L1, R12, nm2)、(A2, Ra2, L1, R13, nm1)、(A2, Ra2, L1, R13, nm2)、(A2, Ra2, L2, R11, nm1)、(A2, Ra2, L2, R11, nm2)、(A2, Ra2, L2, R12, nm1)、(A2, Ra2, L2, R12, nm2)、(A2, Ra2, L2, R13, nm1)、(A2, Ra2, L2, R13, nm2)、(A2, Ra3, L1, R11, nm1)、(A2, Ra3, L1, R11, nm2)、(A2, Ra3, L1, R12, nm1)、(A2, Ra3, L1, R12, nm2)、(A2, Ra3, L1, R13, nm1)、(A2, Ra3, L1, R13, nm2)、(A2, Ra3, L2, R11, nm1)、(A2, Ra3, L2, R11, nm2)、(A2, Ra3, L2, R12, nm1)、(A2, Ra3, L2, R12, nm2)、(A2, Ra3, L2, R13, nm1)、(A2, Ra3, L2, R13, nm2)、(A2, Ra4, L1, R11, nm1)、(A2, Ra4, L1, R11, nm2)、(A2, Ra4, L1, R12, nm1)、(A2, Ra4, L1, R12, nm2)、(A2, Ra4, L1, R13, nm1)、(A2, Ra4, L1, R13, nm2)、(A2, Ra4, L2, R11, nm1)、(A2, Ra4, L2, R11, nm2)、(A2, Ra4, L2, R12, nm1)、(A2, Ra4, L2, R12, nm2)、(A2, Ra4, L2, R13, nm1)、(A2, Ra4, L2, R13, nm2)、(A3, Ra1, L1, R11, nm1)、(A3, Ra1, L1, R11, nm2)、(A3, Ra1, L1, R12, nm1)、(A3, Ra1, L1, R12, nm2)、(A3, Ra1, L1, R13, nm1)、(A3, Ra1, L1, R13, nm2)、(A3, Ra1, L2, R11, nm1)、(A3, Ra1, L2, R11, nm2)、(A3, Ra1, L2, R12, nm1)、(A3, Ra1, L2, R12, nm2)、(A3, Ra1, L2, R13, nm1)、(A3, Ra1, L2, R13, nm2)、(A3, Ra2, L1, R11, nm1)、(A3, Ra2, L1, R11, nm2)、(A3, Ra2, L1, R12, nm1)、(A3, Ra2, L1, R12, nm2)、(A3, Ra2, L1, R13, nm1)、(A3, Ra2, L1, R13, nm2)、(A3, Ra2, L2, R11, nm1)、(A3, Ra2, L2, R11, nm2)、(A3, Ra2, L2, R12, nm1)、(A3, Ra2, L2, R12, nm2)、(A3, Ra2, L2, R13, nm1)、(A3, Ra2, L2, R13, nm2)、(A3, Ra3, L1, R11, nm1)、(A3, Ra3, L1, R11, nm2)、(A3, Ra3, L1, R12, nm1)、(A3, Ra3, L1, R12, nm2)、(A3, Ra3, L1, R13, nm1)、(A3, Ra3, L1, R13, nm2)、(A3, Ra3, L2, R11, nm1)、(A3, Ra3, L2, R11, nm2)、(A3, Ra3, L2, R12, nm1)、(A3, Ra3, L2, R12, nm2)、(A3, Ra3, L2, R13, nm1)、(A3, Ra3, L2, R13, nm2)、(A3, Ra4, L1, R11, nm1)、(A3, Ra4, L1, R11, nm2)、(A3, Ra4, L1, R12, nm1)、(A3, Ra4, L1, R12, nm2)、(A3, Ra4, L1, R13, nm1)、(A3, Ra4, L1, R13, nm2)、(A3, Ra4, L2, R11, nm1)、(A3, Ra4, L2, R11, nm2)、(A3, Ra4, L2, R12, nm1)、(A3, Ra4, L2, R12, nm2)、(A3, Ra4, L2, R13, nm1)、(A3, Ra4, L2, R13, nm2)、(A4, Ra1, L1, R11, nm1)、(A4, Ra1, L1, R11, nm2)、(A4, Ra1, L1, R12, nm1)、(A4, Ra1, L1, R12, nm2)、(A4, Ra1, L1, R13, nm1)、(A4, Ra1, L1, R13, nm2)、(A4, Ra1, L2, R11, nm1)、(A4, Ra1, L2, R11, nm2)、(A4, Ra1, L2, R12, nm1)、(A4, Ra1, L2, R12, nm2)、(A4, Ra1, L2, R13, nm1)、(A4, Ra1, L2, R13, nm2)、(A4, Ra2, L1, R11, nm1)、(A4, Ra2, L1, R11, nm2)、(A4, Ra2, L1, R12, nm1)、(A4, Ra2, L1, R12, nm2)、(A4, Ra2, L1, R13, nm1)、(A4, Ra2, L1, R13, nm2)、(A4, Ra2, L2, R11, nm1)、(A4, Ra2, L2, R11, nm2)、(A4, Ra2, L2, R12, nm1)、(A4, Ra2, L2, R12, nm2)、(A4, Ra2, L2, R13, nm1)、(A4, Ra2, L2, R13, nm2)、(A4, Ra3, L1, R11, nm1)、(A4, Ra3, L1, R11, nm2)、(A4, Ra3, L1, R12, nm1)、(A4, Ra3, L1, R12, nm2)、(A4, Ra3, L1, R13, nm1)、(A4, Ra3, L1, R13, nm2)、(A4, Ra3, L2, R11, nm1)、(A4, Ra3, L2, R11, nm2)、(A4, Ra3, L2, R12, nm1)、(A4, Ra3, L2, R12, nm2)、(A4, Ra3, L2, R13, nm1)、(A4, Ra3, L2, R13, nm2)、(A4, Ra4, L1, R11, nm1)、(A4, Ra4, L1, R11, nm2)、(A4, Ra4, L1, R12, nm1)、(A4, Ra4, L1, R12, nm2)、(A4, Ra4, L1, R13, nm1)、(A4, Ra4, L1, R13, nm2)、(A4, Ra4, L2, R11, nm1)、(A4, Ra4, L2, R11, nm2)、(A4, Ra4, L2, R12, nm1)、(A4, Ra4, L2, R12, nm2)、(A4, Ra4, L2, R13, nm1)、(A4, Ra4, L2, R13, nm2)、(A5, Ra1, L1, R11, nm1)、(A5, Ra1, L1, R11, nm2)、(A5, Ra1, L1, R12, nm1)、(A5, Ra1, L1, R12, nm2)、(A5, Ra1, L1, R13, nm1)、(A5, Ra1, L1, R13, nm2)、(A5, Ra1, L2, R11, nm1)、(A5, Ra1, L2, R11, nm2)、(A5, Ra1, L2, R12, nm1)、(A5, Ra1, L2, R12, nm2)、(A5, Ra1, L2, R13, nm1)、(A5, Ra1, L2, R13, nm2)、(A5, Ra2, L1, R11, nm1)、(A5, Ra2, L1, R11, nm2)、(A5, Ra2, L1, R12, nm1)、(A5, Ra2, L1, R12, nm2)、(A5, Ra2, L1, R13, nm1)、(A5, Ra2, L1, R13, nm2)、(A5, Ra2, L2, R11, nm1)、(A5, Ra2, L2, R11, nm2)、(A5, Ra2, L2, R12, nm1)、(A5, Ra2, L2, R12, nm2)、(A5, Ra2, L2, R13, nm1)、(A5, Ra2, L2, R13, nm2)、(A5, Ra3, L1, R11, nm1)、(A5, Ra3, L1, R11, nm2)、(A5, Ra3, L1, R12, nm1)、(A5, Ra3, L1, R12, nm2)、(A5, Ra3, L1, R13, nm1)、(A5, Ra3, L1, R13, nm2)、(A5, Ra3, L2, R11, nm1)、(A5, Ra3, L2, R11, nm2)、(A5, Ra3, L2, R12, nm1)、(A5, Ra3, L2, R12, nm2)、(A5, Ra3, L2, R13, nm1)、(A5, Ra3, L2, R13, nm2)、(A5, Ra4, L1, R11, nm1)、(A5, Ra4, L1, R11, nm2)、(A5, Ra4, L1, R12, nm1)、(A5, Ra4, L1, R12, nm2)、(A5, Ra4, L1, R13, nm1)、(A5, Ra4, L1, R13, nm2)、(A5, Ra4, L2, R11, nm1)、(A5, Ra4, L2, R11, nm2)、(A5, Ra4, L2, R12, nm1)、(A5, Ra4, L2, R12, nm2)、(A5, Ra4, L2, R13, nm1)、(A5, Ra4, L2, R13, nm2)、(A6, Ra1, L1, R11, nm1)、(A6, Ra1, L1, R11, nm2)、(A6, Ra1, L1, R12, nm1)、(A6, Ra1, L1, R12, nm2)、(A6, Ra1, L1, R13, nm1)、(A6, Ra1, L1, R13, nm2)、(A6, Ra1, L2, R11, nm1)、(A6, Ra1, L2, R11, nm2)、(A6, Ra1, L2, R12, nm1)、(A6, Ra1, L2, R12, nm2)、(A6, Ra1, L2, R13, nm1)、(A6, Ra1, L2, R13, nm2)、(A6, Ra2, L1, R11, nm1)、(A6, Ra2, L1, R11, nm2)、(A6, Ra2, L1, R12, nm1)、(A6, Ra2, L1, R12, nm2)、(A6, Ra2, L1, R13, nm1)、(A6, Ra2, L1, R13, nm2)、(A6, Ra2, L2, R11, nm1)、(A6, Ra2, L2, R11, nm2)、(A6, Ra2, L2, R12, nm1)、(A6, Ra2, L2, R12, nm2)、(A6, Ra2, L2, R13, nm1)、(A6, Ra2, L2, R13, nm2)、(A6, Ra3, L1, R11, nm1)、(A6, Ra3, L1, R11, nm2)、(A6, Ra3, L1, R12, nm1)、(A6, Ra3, L1, R12, nm2)、(A6, Ra3, L1, R13, nm1)、(A6, Ra3, L1, R13, nm2)、(A6, Ra3, L2, R11, nm1)、(A6, Ra3, L2, R11, nm2)、(A6, Ra3, L2, R12, nm1)、(A6, Ra3, L2, R12, nm2)、(A6, Ra3, L2, R13, nm1)、(A6, Ra3, L2, R13, nm2)、(A6, Ra4, L1, R11, nm1)、(A6, Ra4, L1, R11, nm2)、(A6, Ra4, L1, R12, nm1)、(A6, Ra4, L1, R12, nm2)、(A6, Ra4, L1, R13, nm1)、(A6, Ra4, L1, R13, nm2)、(A6, Ra4, L2, R11, nm1)、(A6, Ra4, L2, R11, nm2)、(A6, Ra4, L2, R12, nm1)、(A6, Ra4, L2, R12, nm2)、(A6, Ra4, L2, R13, nm1)、(A6, Ra4, L2, R13, nm2)、(A7, Ra1, L1, R11, nm1)、(A7, Ra1, L1, R11, nm2)、(A7, Ra1, L1, R12, nm1)、(A7, Ra1, L1, R12, nm2)、(A7, Ra1, L1, R13, nm1)、(A7, Ra1, L1, R13, nm2)、(A7, Ra1, L2, R11, nm1)、(A7, Ra1, L2, R11, nm2)、(A7, Ra1, L2, R12, nm1)、(A7, Ra1, L2, R12, nm2)、(A7, Ra1, L2, R13, nm1)、(A7, Ra1, L2, R13, nm2)、(A7, Ra2, L1, R11, nm1)、(A7, Ra2, L1, R11, nm2)、(A7, Ra2, L1, R12, nm1)、(A7, Ra2, L1, R12, nm2)、(A7, Ra2, L1, R13, nm1)、(A7, Ra2, L1, R13, nm2)、(A7, Ra2, L2, R11, nm1)、(A7, Ra2, L2, R11, nm2)、(A7, Ra2, L2, R12, nm1)、(A7, Ra2, L2, R12, nm2)、(A7, Ra2, L2, R13, nm1)、(A7, Ra2, L2, R13, nm2)、(A7, Ra3, L1, R11, nm1)、(A7, Ra3, L1, R11, nm2)、(A7, Ra3, L1, R12, nm1)、(A7, Ra3, L1, R12, nm2)、(A7, Ra3, L1, R13, nm1)、(A7, Ra3, L1, R13, nm2)、(A7, Ra3, L2, R11, nm1)、(A7, Ra3, L2, R11, nm2)、(A7, Ra3, L2, R12, nm1)、(A7, Ra3, L2, R12, nm2)、(A7, Ra3, L2, R13, nm1)、(A7, Ra3, L2, R13, nm2)、(A7, Ra4, L1, R11, nm1)、(A7, Ra4, L1, R11, nm2)、(A7, Ra4, L1, R12, nm1)、(A7, Ra4, L1, R12, nm2)、(A7, Ra4, L1, R13, nm1)、(A7, Ra4, L1, R13, nm2)、(A7, Ra4, L2, R11, nm1)、(A7, Ra4, L2, R11, nm2)、(A7, Ra4, L2, R12, nm1)、(A7, Ra4, L2, R12, nm2)、(A7, Ra4, L2, R13, nm1)、(A7, Ra4, L2, R13, nm2)、(A8, Ra1, L1, R11, nm1)、(A8, Ra1, L1, R11, nm2)、(A8, Ra1, L1, R12, nm1)、(A8, Ra1, L1, R12, nm2)、(A8, Ra1, L1, R13, nm1)、(A8, Ra1, L1, R13, nm2)、(A8, Ra1, L2, R11, nm1)、(A8, Ra1, L2, R11, nm2)、(A8, Ra1, L2, R12, nm1)、(A8, Ra1, L2, R12, nm2)、(A8, Ra1, L2, R13, nm1)、(A8, Ra1, L2, R13, nm2)、(A8, Ra2, L1, R11, nm1)、(A8, Ra2, L1, R11, nm2)、(A8, Ra2, L1, R12, nm1)、(A8, Ra2, L1, R12, nm2)、(A8, Ra2, L1, R13, nm1)、(A8, Ra2, L1, R13, nm2)、(A8, Ra2, L2, R11, nm1)、(A8, Ra2, L2, R11, nm2)、(A8, Ra2, L2, R12, nm1)、(A8, Ra2, L2, R12, nm2)、(A8, Ra2, L2, R13, nm1)、(A8, Ra2, L2, R13, nm2)、(A8, Ra3, L1, R11, nm1)、(A8, Ra3, L1, R11, nm2)、(A8, Ra3, L1, R12, nm1)、(A8, Ra3, L1, R12, nm2)、(A8, Ra3, L1, R13, nm1)、(A8, Ra3, L1, R13, nm2)、(A8, Ra3, L2, R11, nm1)、(A8, Ra3, L2, R11, nm2)、(A8, Ra3, L2, R12, nm1)、(A8, Ra3, L2, R12, nm2)、(A8, Ra3, L2, R13, nm1)、(A8, Ra3, L2, R13, nm2)、(A8, Ra4, L1, R11, nm1)、(A8, Ra4, L1, R11, nm2)、(A8, Ra4, L1, R12, nm1)、(A8, Ra4, L1, R12, nm2)、(A8, Ra4, L1, R13, nm1)、(A8, Ra4, L1, R13, nm2)、(A8, Ra4, L2, R11, nm1)、(A8, Ra4, L2, R11, nm2)、(A8, Ra4, L2, R12, nm1)、(A8, Ra4, L2, R12, nm2)、(A8, Ra4, L2, R13, nm1)、(A8, Ra4, L2, R13, nm2)、(A9, Ra1, L1, R11, nm1)、(A9, Ra1, L1, R11, nm2)、(A9, Ra1, L1, R12, nm1)、(A9, Ra1, L1, R12, nm2)、(A9, Ra1, L1, R13, nm1)、(A9, Ra1, L1, R13, nm2)、(A9, Ra1, L2, R11, nm1)、(A9, Ra1, L2, R11, nm2)、(A9, Ra1, L2, R12, nm1)、(A9, Ra1, L2, R12, nm2)、(A9, Ra1, L2, R13, nm1)、(A9, Ra1, L2, R13, nm2)、(A9, Ra2, L1, R11, nm1)、(A9, Ra2, L1, R11, nm2)、(A9, Ra2, L1, R12, nm1)、(A9, Ra2, L1, R12, nm2)、(A9, Ra2, L1, R13, nm1)、(A9, Ra2, L1, R13, nm2)、(A9, Ra2, L2, R11, nm1)、(A9, Ra2, L2, R11, nm2)、(A9, Ra2, L2, R12, nm1)、(A9, Ra2, L2, R12, nm2)、(A9, Ra2, L2, R13, nm1)、(A9, Ra2, L2, R13, nm2)、(A9, Ra3, L1, R11, nm1)、(A9, Ra3, L1, R1
1, nm2)、(A9, Ra3, L1, R12, nm1)、(A9, Ra3, L1, R12, nm2)、(A9, Ra3, L1, R13, nm1)、(A9, Ra3, L1, R13, nm2)、(A9, Ra3, L2, R11, nm1)、(A9, Ra3, L2, R11, nm2)、(A9, Ra3, L2, R12, nm1)、(A9, Ra3, L2, R12, nm2)、(A9, Ra3, L2, R13, nm1)、(A9, Ra3, L2, R13, nm2)、(A9, Ra4, L1, R11, nm1)、(A9, Ra4, L1, R11, nm2)、(A9, Ra4, L1, R12, nm1)、(A9, Ra4, L1, R12, nm2)、(A9, Ra4, L1, R13, nm1)、(A9, Ra4, L1, R13, nm2)、(A9, Ra4, L2, R11, nm1)、(A9, Ra4, L2, R11, nm2)、(A9, Ra4, L2, R12, nm1)、(A9, Ra4, L2, R12, nm2)、(A9, Ra4, L2, R13, nm1)、(A9, Ra4, L2, R13, nm2) In addition, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof includes a compound or a pharmaceutically acceptable salt thereof generated by a combination of a part or all of the definition of each substituent shown above. It is done.
More specifically, a compound or a pharmaceutically acceptable salt thereof in which the combination of ring A, Ra, L, R 1 and nm (ring A, Ra, L, R 1 , nm) is the following combination, respectively. It is done.
(A1, Ra1, L1, R11, nm1), (A1, Ra1, L1, R11, nm2), (A1, Ra1, L1, R12, nm1), (A1, Ra1, L1, R12, nm2), (A1 , Ra1, L1, R13, nm1), (A1, Ra1, L1, R13, nm2), (A1, Ra1, L2, R11, nm1), (A1, Ra1, L2, R11, nm2), (A1, Ra1 , L2, R12, nm1), (A1, Ra1, L2, R12, nm2), (A1, Ra1, L2, R13, nm1), (A1, Ra1, L2, R13, nm2), (A1, Ra2, L1 , R11, nm1), (A1, Ra2, L1, R11, nm2), (A1, Ra2, L1, R12, nm1), (A1, Ra2, L1, R12, nm2), (A1, Ra2, L1, R13) , nm1), (A1, Ra2, L1, R13, nm2), (A1, Ra2, L2, R11, nm1), (A1, Ra2, L2, R11, nm2), (A1, Ra2, L2, R12, nm1 ), (A1, Ra2, L2, R12, nm2), (A1, Ra2, L2, R13, nm1), (A1, Ra2, L2, R13, nm2), (A1, Ra3, L1, R11, nm1), (A1, Ra3, L1, R11, nm2), (A1, Ra3, L1, R12, nm1), (A1, Ra3, L1, R12, nm2), (A1, Ra3, L1, R13, nm1), (A1 , Ra3, L1, R13, nm2), (A1, Ra3, L2, R11, nm1), (A1, Ra3, L2, R11, nm2), (A1, Ra3, L2, R12, nm1), (A1, Ra3 , L2, R12, nm2), (A1, Ra3, L2, R13, nm1), (A1, Ra3, L2, R13, nm2), (A1, Ra4, L1, R11, nm1), (A1, Ra4, L1 , R11, nm2), (A1, Ra4, L1 , R12, nm1), (A1, Ra4, L1, R12, nm2), (A1, Ra4, L1, R13, nm1), (A1, Ra4, L1, R13, nm2), (A1, Ra4, L2, R11 , nm1), (A1, Ra4, L2, R11, nm2), (A1, Ra4, L2, R12, nm1), (A1, Ra4, L2, R12, nm2), (A1, Ra4, L2, R13, nm1 ), (A1, Ra4, L2, R13, nm2), (A2, Ra1, L1, R11, nm1), (A2, Ra1, L1, R11, nm2), (A2, Ra1, L1, R12, nm1), (A2, Ra1, L1, R12, nm2), (A2, Ra1, L1, R13, nm1), (A2, Ra1, L1, R13, nm2), (A2, Ra1, L2, R11, nm1), (A2 , Ra1, L2, R11, nm2), (A2, Ra1, L2, R12, nm1), (A2, Ra1, L2, R12, nm2), (A2, Ra1, L2, R13, nm1), (A2, Ra1 , L2, R13, nm2), (A2, Ra2, L1, R11, nm1), (A2, Ra2, L1, R11, nm2), (A2, Ra2, L1, R12, nm1), (A2, Ra2, L1 , R12, nm2), (A2, Ra2, L1, R13, nm1), (A2, Ra2, L1, R13, nm2), (A2, Ra2, L2, R11, nm1), (A2, Ra2, L2, R11 , nm2), (A2, Ra2, L2, R12, nm1), (A2, Ra2, L2, R12, nm2), (A2, Ra2, L2, R13, nm1), (A2, Ra2, L2, R13, nm2 ), (A2, Ra3, L1, R11, nm1), (A2, Ra3, L1, R11, nm2), (A2, Ra3, L1, R12, nm1), (A2, Ra3, L1, R12, nm2), (A2, Ra3, L1, R13, nm1) (A2, Ra3, L1, R13, nm2), (A2, Ra3, L2, R11, nm1), (A2, Ra3, L2, R11, nm2), (A2, Ra3, L2, R12, nm1), (A2 , Ra3, L2, R12, nm2), (A2, Ra3, L2, R13, nm1), (A2, Ra3, L2, R13, nm2), (A2, Ra4, L1, R11, nm1), (A2, Ra4 , L1, R11, nm2), (A2, Ra4, L1, R12, nm1), (A2, Ra4, L1, R12, nm2), (A2, Ra4, L1, R13, nm1), (A2, Ra4, L1 , R13, nm2), (A2, Ra4, L2, R11, nm1), (A2, Ra4, L2, R11, nm2), (A2, Ra4, L2, R12, nm1), (A2, Ra4, L2, R12 , nm2), (A2, Ra4, L2, R13, nm1), (A2, Ra4, L2, R13, nm2), (A3, Ra1, L1, R11, nm1), (A3, Ra1, L1, R11, nm2 ), (A3, Ra1, L1, R12, nm1), (A3, Ra1, L1, R12, nm2), (A3, Ra1, L1, R13, nm1), (A3, Ra1, L1, R13, nm2), (A3, Ra1, L2, R11, nm1), (A3, Ra1, L2, R11, nm2), (A3, Ra1, L2, R12, nm1), (A3, Ra1, L2, R12, nm2), (A3 , Ra1, L2, R13, nm1), (A3, Ra1, L2, R13, nm2), (A3, Ra2, L1, R11, nm1), (A3, Ra2, L1, R11, nm2), (A3, Ra2 , L1, R12, nm1), (A3, Ra2, L1, R12, nm2), (A3, Ra2, L1, R13, nm1), (A3, Ra2, L1, R13, nm2), (A3, Ra2, L2 , R11, nm1), (A3, Ra2, L2, R11, nm2), (A3, Ra2, L2, R12, nm1), (A3, Ra2, L2, R12, nm2), (A3, Ra2, L2, R13, nm1), (A3, Ra2, L2, R13, nm2), (A3, Ra3, L1, R11, nm1), (A3, Ra3, L1, R11, nm2), (A3, Ra3, L1, R12, nm1), (A3, Ra3, L1, R12, nm2), (A3, Ra3, L1, R13, nm1), (A3, Ra3, L1, R13, nm2), (A3, Ra3, L2, R11, nm1), (A3, Ra3, L2, R11, nm2) , (A3, Ra3, L2, R12, nm1), (A3, Ra3, L2, R12, nm2), (A3, Ra3, L2, R13, nm1), (A3, Ra3, L2, R13, nm2), ( (A3, Ra4, L1, R11, nm1), (A3, Ra4, L1, R11, nm2), (A3, Ra4, L1, R12, nm1), (A3, Ra4, L1, R12, nm2), (A3, Ra4, L1, R13, nm1), (A3, Ra4, L1, R13, nm2), (A3, Ra4, L2, R11, nm1), (A3, Ra4, L2, R11, nm2), (A3, Ra4, L2, R12, nm1), (A3, Ra4, L2, R12, nm2), (A3, Ra4, L2, R13, nm1), (A3, Ra4, L2, R13, nm2), (A4, Ra1, L1, R11, nm1), (A4, Ra1, L1, R11, nm2), (A4, Ra1, L1, R12, nm1), (A4, Ra1, L1, R12, nm2), (A4, Ra1, L1, R13, nm1), (A4, Ra1, L1, R13, nm2), (A4, Ra1, L2, R11, nm1), (A4, Ra1, L2, R11, nm2), (A4, Ra1, L2, R12, nm1) , (A4, Ra1, L2, R12, nm2 ), (A4, Ra1, L2, R13, nm1), (A4, Ra1, L2, R13, nm2), (A4, Ra2, L1, R11, nm1), (A4, Ra2, L1, R11, nm2), (A4, Ra2, L1, R12, nm1), (A4, Ra2, L1, R12, nm2), (A4, Ra2, L1, R13, nm1), (A4, Ra2, L1, R13, nm2), (A4 , Ra2, L2, R11, nm1), (A4, Ra2, L2, R11, nm2), (A4, Ra2, L2, R12, nm1), (A4, Ra2, L2, R12, nm2), (A4, Ra2 , L2, R13, nm1), (A4, Ra2, L2, R13, nm2), (A4, Ra3, L1, R11, nm1), (A4, Ra3, L1, R11, nm2), (A4, Ra3, L1 , R12, nm1), (A4, Ra3, L1, R12, nm2), (A4, Ra3, L1, R13, nm1), (A4, Ra3, L1, R13, nm2), (A4, Ra3, L2, R11 , nm1), (A4, Ra3, L2, R11, nm2), (A4, Ra3, L2, R12, nm1), (A4, Ra3, L2, R12, nm2), (A4, Ra3, L2, R13, nm1 ), (A4, Ra3, L2, R13, nm2), (A4, Ra4, L1, R11, nm1), (A4, Ra4, L1, R11, nm2), (A4, Ra4, L1, R12, nm1), (A4, Ra4, L1, R12, nm2), (A4, Ra4, L1, R13, nm1), (A4, Ra4, L1, R13, nm2), (A4, Ra4, L2, R11, nm1), (A4 , Ra4, L2, R11, nm2), (A4, Ra4, L2, R12, nm1), (A4, Ra4, L2, R12, nm2), (A4, Ra4, L2, R13, nm1), (A4, Ra4 , L2, R13, nm2), (A5, Ra1 , L1, R11, nm1), (A5, Ra1, L1, R11, nm2), (A5, Ra1, L1, R12, nm1), (A5, Ra1, L1, R12, nm2), (A5, Ra1, L1 , R13, nm1), (A5, Ra1, L1, R13, nm2), (A5, Ra1, L2, R11, nm1), (A5, Ra1, L2, R11, nm2), (A5, Ra1, L2, R12 , nm1), (A5, Ra1, L2, R12, nm2), (A5, Ra1, L2, R13, nm1), (A5, Ra1, L2, R13, nm2), (A5, Ra2, L1, R11, nm1 ), (A5, Ra2, L1, R11, nm2), (A5, Ra2, L1, R12, nm1), (A5, Ra2, L1, R12, nm2), (A5, Ra2, L1, R13, nm1), (A5, Ra2, L1, R13, nm2), (A5, Ra2, L2, R11, nm1), (A5, Ra2, L2, R11, nm2), (A5, Ra2, L2, R12, nm1), (A5 , Ra2, L2, R12, nm2), (A5, Ra2, L2, R13, nm1), (A5, Ra2, L2, R13, nm2), (A5, Ra3, L1, R11, nm1), (A5, Ra3 , L1, R11, nm2), (A5, Ra3, L1, R12, nm1), (A5, Ra3, L1, R12, nm2), (A5, Ra3, L1, R13, nm1), (A5, Ra3, L1 , R13, nm2), (A5, Ra3, L2, R11, nm1), (A5, Ra3, L2, R11, nm2), (A5, Ra3, L2, R12, nm1), (A5, Ra3, L2, R12 , nm2), (A5, Ra3, L2, R13, nm1), (A5, Ra3, L2, R13, nm2), (A5, Ra4, L1, R11, nm1), (A5, Ra4, L1, R11, nm2 ), (A5, Ra4, L1, R12, n m1), (A5, Ra4, L1, R12, nm2), (A5, Ra4, L1, R13, nm1), (A5, Ra4, L1, R13, nm2), (A5, Ra4, L2, R11, nm1) , (A5, Ra4, L2, R11, nm2), (A5, Ra4, L2, R12, nm1), (A5, Ra4, L2, R12, nm2), (A5, Ra4, L2, R13, nm1), ( (A5, Ra4, L2, R13, nm2), (A6, Ra1, L1, R11, nm1), (A6, Ra1, L1, R11, nm2), (A6, Ra1, L1, R12, nm1), (A6, Ra1, L1, R12, nm2), (A6, Ra1, L1, R13, nm1), (A6, Ra1, L1, R13, nm2), (A6, Ra1, L2, R11, nm1), (A6, Ra1, L2, R11, nm2), (A6, Ra1, L2, R12, nm1), (A6, Ra1, L2, R12, nm2), (A6, Ra1, L2, R13, nm1), (A6, Ra1, L2, R13, nm2), (A6, Ra2, L1, R11, nm1), (A6, Ra2, L1, R11, nm2), (A6, Ra2, L1, R12, nm1), (A6, Ra2, L1, R12, nm2), (A6, Ra2, L1, R13, nm1), (A6, Ra2, L1, R13, nm2), (A6, Ra2, L2, R11, nm1), (A6, Ra2, L2, R11, nm2) , (A6, Ra2, L2, R12, nm1), (A6, Ra2, L2, R12, nm2), (A6, Ra2, L2, R13, nm1), (A6, Ra2, L2, R13, nm2), ( (A6, Ra3, L1, R11, nm1), (A6, Ra3, L1, R11, nm2), (A6, Ra3, L1, R12, nm1), (A6, Ra3, L1, R12, nm2), (A6, Ra3, L1, R13, nm1), (A6, R a3, L1, R13, nm2), (A6, Ra3, L2, R11, nm1), (A6, Ra3, L2, R11, nm2), (A6, Ra3, L2, R12, nm1), (A6, Ra3, L2, R12, nm2), (A6, Ra3, L2, R13, nm1), (A6, Ra3, L2, R13, nm2), (A6, Ra4, L1, R11, nm1), (A6, Ra4, L1, R11, nm2), (A6, Ra4, L1, R12, nm1), (A6, Ra4, L1, R12, nm2), (A6, Ra4, L1, R13, nm1), (A6, Ra4, L1, R13, nm2), (A6, Ra4, L2, R11, nm1), (A6, Ra4, L2, R11, nm2), (A6, Ra4, L2, R12, nm1), (A6, Ra4, L2, R12, nm2) (A6, Ra4, L2, R13, nm1), (A6, Ra4, L2, R13, nm2), (A7, Ra1, L1, R11, nm1), (A7, Ra1, L1, R11, nm2), ( (A7, Ra1, L1, R12, nm1), (A7, Ra1, L1, R12, nm2), (A7, Ra1, L1, R13, nm1), (A7, Ra1, L1, R13, nm2), (A7, Ra1, L2, R11, nm1), (A7, Ra1, L2, R11, nm2), (A7, Ra1, L2, R12, nm1), (A7, Ra1, L2, R12, nm2), (A7, Ra1, L2, R13, nm1), (A7, Ra1, L2, R13, nm2), (A7, Ra2, L1, R11, nm1), (A7, Ra2, L1, R11, nm2), (A7, Ra2, L1, R12, nm1), (A7, Ra2, L1, R12, nm2), (A7, Ra2, L1, R13, nm1), (A7, Ra2, L1, R13, nm2), (A7, Ra2, L2, R11, nm1), (A7, Ra2, L2, R11, nm2), (A7, Ra2, L2, R12, nm1), (A7, Ra2, L2, R12, nm2), (A7, Ra2, L2, R13, nm1), (A7, Ra2, L2, R13, nm2) , (A7, Ra3, L1, R11, nm1), (A7, Ra3, L1, R11, nm2), (A7, Ra3, L1, R12, nm1), (A7, Ra3, L1, R12, nm2), ( (A7, Ra3, L1, R13, nm1), (A7, Ra3, L1, R13, nm2), (A7, Ra3, L2, R11, nm1), (A7, Ra3, L2, R11, nm2), (A7, Ra3, L2, R12, nm1), (A7, Ra3, L2, R12, nm2), (A7, Ra3, L2, R13, nm1), (A7, Ra3, L2, R13, nm2), (A7, Ra4, L1, R11, nm1), (A7, Ra4, L1, R11, nm2), (A7, Ra4, L1, R12, nm1), (A7, Ra4, L1, R12, nm2), (A7, Ra4, L1, R13, nm1), (A7, Ra4, L1, R13, nm2), (A7, Ra4, L2, R11, nm1), (A7, Ra4, L2, R11, nm2), (A7, Ra4, L2, R12, nm1), (A7, Ra4, L2, R12, nm2), (A7, Ra4, L2, R13, nm1), (A7, Ra4, L2, R13, nm2), (A8, Ra1, L1, R11, nm1) (A8, Ra1, L1, R11, nm2), (A8, Ra1, L1, R12, nm1), (A8, Ra1, L1, R12, nm2), (A8, Ra1, L1, R13, nm1), ( (A8, Ra1, L1, R13, nm2), (A8, Ra1, L2, R11, nm1), (A8, Ra1, L2, R11, nm2), (A8, Ra1, L2, R12, nm1), (A8, Ra1, L2, R12, nm2), (A8, Ra1, L2, R13, nm1), (A8, Ra1, L2, R13, nm2), (A8, Ra2, L1, R11, nm1), (A8, Ra2, L1, R11, nm2), (A8, Ra2, L1, R12, nm1), (A8, Ra2, L1, R12, nm2), (A8, Ra2, L1, R13, nm1), (A8, Ra2, L1, R13, nm2), (A8, Ra2, L2, R11, nm1), (A8, Ra2, L2, R11, nm2), (A8, Ra2, L2, R12, nm1), (A8, Ra2, L2, R12, nm2), (A8, Ra2, L2, R13, nm1), (A8, Ra2, L2, R13, nm2), (A8, Ra3, L1, R11, nm1), (A8, Ra3, L1, R11, nm2), (A8, Ra3, L1, R12, nm1) , (A8, Ra3, L1, R12, nm2), (A8, Ra3, L1, R13, nm1), (A8, Ra3, L1, R13, nm2), (A8, Ra3, L2, R11, nm1), ( (A8, Ra3, L2, R11, nm2), (A8, Ra3, L2, R12, nm1), (A8, Ra3, L2, R12, nm2), (A8, Ra3, L2, R13, nm1), (A8, Ra3, L2, R13, nm2), (A8, Ra4, L1, R11, nm1), (A8, Ra4, L1, R11, nm2), (A8, Ra4, L1, R12, nm1), (A8, Ra4, L1, R12, nm2), (A8, Ra4, L1, R13, nm1), (A8, Ra4, L1, R13, nm2), (A8, Ra4, L2, R11, nm1), (A8, Ra4, L2, R11, nm2), (A8, Ra4, L2, R12, nm1), (A8, Ra4, L2, R12, nm2), (A8, Ra4, L2, R13, nm1), (A8, Ra4, L2, R13, nm2), (A9, Ra1, L1, R1 1, nm1), (A9, Ra1, L1, R11, nm2), (A9, Ra1, L1, R12, nm1), (A9, Ra1, L1, R12, nm2), (A9, Ra1, L1, R13, nm1), (A9, Ra1, L1, R13, nm2), (A9, Ra1, L2, R11, nm1), (A9, Ra1, L2, R11, nm2), (A9, Ra1, L2, R12, nm1) , (A9, Ra1, L2, R12, nm2), (A9, Ra1, L2, R13, nm1), (A9, Ra1, L2, R13, nm2), (A9, Ra2, L1, R11, nm1), ( (A9, Ra2, L1, R11, nm2), (A9, Ra2, L1, R12, nm1), (A9, Ra2, L1, R12, nm2), (A9, Ra2, L1, R13, nm1), (A9, Ra2, L1, R13, nm2), (A9, Ra2, L2, R11, nm1), (A9, Ra2, L2, R11, nm2), (A9, Ra2, L2, R12, nm1), (A9, Ra2, L2, R12, nm2), (A9, Ra2, L2, R13, nm1), (A9, Ra2, L2, R13, nm2), (A9, Ra3, L1, R11, nm1), (A9, Ra3, L1, R1
1, nm2), (A9, Ra3, L1, R12, nm1), (A9, Ra3, L1, R12, nm2), (A9, Ra3, L1, R13, nm1), (A9, Ra3, L1, R13, nm2), (A9, Ra3, L2, R11, nm1), (A9, Ra3, L2, R11, nm2), (A9, Ra3, L2, R12, nm1), (A9, Ra3, L2, R12, nm2) (A9, Ra3, L2, R13, nm1), (A9, Ra3, L2, R13, nm2), (A9, Ra4, L1, R11, nm1), (A9, Ra4, L1, R11, nm2), ( (A9, Ra4, L1, R12, nm1), (A9, Ra4, L1, R12, nm2), (A9, Ra4, L1, R13, nm1), (A9, Ra4, L1, R13, nm2), (A9, Ra4, L2, R11, nm1), (A9, Ra4, L2, R11, nm2), (A9, Ra4, L2, R12, nm1), (A9, Ra4, L2, R12, nm2), (A9, Ra4, L2, R13, nm1), (A9, Ra4, L2, R13, nm2)
　式（Ｉ）で示される化合物またはその製薬上許容される塩の一つの態様としては、以下の化合物またはその製薬上許容される塩が挙げられる。
１）　ｎおよびｍが共に０であり；
　Ｒｃが水素原子であり；
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000081
であり；
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－であり；
　Ｒ４が水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり；かつ
　Ｒ１が、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である化合物またはその製薬上許容される塩。
２）　ｎおよびｍが共に０であり；
　Ｒｃが水素原子であり；
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000083
であり；
　Ｒ６が、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイルであり；
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－であり；
　Ｒ４が水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり；かつ
　Ｒ１が、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である化合物またはその製薬上許容される塩。
３）　ｎおよびｍが共に０であり；
　Ｒｃが水素原子であり；
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000085
（式中、Ｒ２ａは上記と同意義である）であり；
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－であり；
　Ｒ４が水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり；かつ
　Ｒ１が、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である化合物またはその製薬上許容される塩。
４）　ｎおよびｍが共に０であり；
　Ｒｃが水素原子であり；
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
（式中、Ｒ２ａは上記と同意義である）であり；
　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－であり；
　Ｒ４が水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり；かつ
　Ｒ１が、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である化合物またはその製薬上許容される塩。 One embodiment of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof includes the following compound or a pharmaceutically acceptable salt thereof.
1) n and m are both 0;
Rc is a hydrogen atom;
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000081
Is;
—L— is —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is;
R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
2) n and m are both 0;
Rc is a hydrogen atom;
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000083
Is;
R 6 is substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl;
—L— is —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is;
R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
3) n and m are both 0;
Rc is a hydrogen atom;
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000085
Wherein R 2a is as defined above;
—L— is —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is;
R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
4) n and m are both 0;
Rc is a hydrogen atom;
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000087
Wherein R 2a is as defined above;
—L— is —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 -Is;
R 4 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and R 1 is a substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Or a pharmaceutically acceptable salt thereof, which is a non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group.
　式（Ｉ）で示される化合物の絶対配置としては、
Figure JPOXMLDOC01-appb-C000088
が挙げられる。
　式（Ｉ）で示される化合物の絶対配置としては、
Figure JPOXMLDOC01-appb-C000089
が挙げられる。 As the absolute configuration of the compound represented by the formula (I),
Figure JPOXMLDOC01-appb-C000088
Is mentioned.
As the absolute configuration of the compound represented by the formula (I),
Figure JPOXMLDOC01-appb-C000089
Is mentioned.
　式（Ｉ）で示される化合物において、例えば、Ｒ２で示される置換基が以下のように表されている場合、
Figure JPOXMLDOC01-appb-C000090
Ｒ２は、環Ｂまたは環Ｃの、全ての置換可能な環構成原子にｐ個置換することができる。他の環においても同様に、Ｒ２は、複数のまたは１つの環の、全ての置換可能な環構成原子にｐ個置換することができる。 In the compound represented by the formula (I), for example, when the substituent represented by R 2 is represented as follows:
Figure JPOXMLDOC01-appb-C000090
R 2 can be substituted with p at all substitutable ring atoms of ring B or ring C. Similarly in other rings, R 2 can be substituted with p at all substitutable ring atoms of multiple or single rings.
　式（Ｉ）で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等）、ラセミ体またはそれらの混合物を含む。 The compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof.
　式（Ｉ）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
　式（Ｉ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）を参照にできる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
　式（Ｉ）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、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、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等）との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、式（Ｉ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）で示される化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph. Various solvates and crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
　式（Ｉ）で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロリド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent. For example, CH 3 COO—, C 2 H 5 COO—, tert-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3- , PhSO 3- , p-CH 3 PhSO 3 -can be mentioned.
　上記一般式（Ｉ）で表される化合物は、ＩＴＫに対する阻害作用を有し、ＩＴＫが関与する疾患および／または状態の治療剤および／または予防剤として有用である。ＩＴＫは自己免疫疾患、アレルギー性疾患、炎症性疾患、免疫性疾患等に関与すると考えられている。ＩＴＫが関与する疾患および／または状態として、例えば、炎症性もしくはアレルギー性気道疾患（アレルギー性鼻炎、喘息など）、慢性閉塞性肺疾患（ＣＯＰＤ）、炎症性もしくはアレルギー性皮膚疾患（接触性皮膚炎、アトピー性皮膚炎など）、食物アレルギー、乾癬、関節リウマチ、多発性硬化症、結膜炎（アレルギー性結膜炎、春季角結膜炎など）、Ｉ型糖尿病、Ｔ細胞媒介性過敏症、ギラン・バレー症候群、橋本甲状腺炎、移植片拒絶（臓器移植拒絶、骨髄移植拒絶など）、移植片対宿主病、炎症性腸疾患、慢性炎症、ＨＩＶ、再生不良性貧血、疼痛、炎症性疼痛、がん等が挙げられる The compound represented by the above general formula (I) has an inhibitory action on ITK, and is useful as a therapeutic and / or prophylactic agent for diseases and / or conditions involving ITK. ITK is considered to be involved in autoimmune diseases, allergic diseases, inflammatory diseases, immune diseases and the like. Diseases and / or conditions involving ITK include, for example, inflammatory or allergic airway diseases (allergic rhinitis, asthma, etc.), chronic obstructive pulmonary disease (COPD), inflammatory or allergic skin diseases (contact dermatitis) Atopic dermatitis), food allergy, psoriasis, rheumatoid arthritis, multiple sclerosis, conjunctivitis (allergic conjunctivitis, spring keratoconjunctivitis, etc.), type I diabetes, T cell mediated hypersensitivity, Guillain-Barre syndrome, Hashimoto Thyroiditis, graft rejection (organ transplant rejection, bone marrow transplant rejection, etc.), graft-versus-host disease, inflammatory bowel disease, chronic inflammation, HIV, aplastic anemia, pain, inflammatory pain, cancer, etc.
　より好ましい本発明化合物は、選択的なＩＴＫ阻害活性を有する医薬組成物である。生理的に重要な機能を有する他のキナーゼに対して阻害活性を有しない、または阻害活性が弱いＩＴＫ阻害剤は、安全性の懸念を克服した自己免疫疾患、炎症性疾患、アレルギー性疾患等の予防薬または治療薬として非常に有用であると考えられる。
　例えば、AKT1、AKT2、ROCK2、ADRBK1、PRKACA、PRKCA、PRKCB1、PRKCB2、PRKCD、PRKCE、PRKCI、PRKCZ、RPS6KB1、RPS6KA3、CAMK4、PRKAA1、PRKAA2、CDK4、CDK6、CDK5、DYRK1A、GSK3B、CHUK、IKBKA、IKBKE、TBK1、PLK5、MAP3K14、MAPK14、ABL1、EGFR、ERBB2、ERBB4、EPHA4、PTK2、PTK2B、FGFR1、FGFR2、FGFR3、IGF1R、INSR、JAK2、JAK3、MET、MST1R、PDGFRA、PDGFRB、RET、LCK、SRC、TEK、NTRK2、FLT1、KDR、BRAF、RAF1、TGFBR1、PIK3CA、PIK3CB、BTKおよび／またはTXKに対するＩＴＫ阻害選択性を有することが好ましい。 A more preferred compound of the present invention is a pharmaceutical composition having selective ITK inhibitory activity. ITK inhibitors that have no inhibitory activity or weak inhibitory activity against other kinases that have physiologically important functions, such as autoimmune diseases, inflammatory diseases, and allergic diseases that have overcome safety concerns It is considered very useful as a preventive or therapeutic agent.
For example, AKT1, AKT2, ROCK2, ADRBK1, PRKACA, PRKCA, PRKCB1, PRKCB1, PRKCD, PRKCE, PRKCI, PRKCZ, RPS6KB1, RPS6KA3, CAMK4, PRKAA1, PRKAA2, CDK4, CDK6, CDK5, DYRK1A IKBKE, TBK1, PLK5, MAP3K14, MAPK14, ABL1, EGFR, ERBB2, ERBB4, EPHA4, PTK2, PTK2B, FGFR1, FGFR2, FGFR3, IGF1R, INSR, JAK2, JAK3, MET, MST1R, PDGFRA, PDGFRB, RET, LCK, Preferably, it has ITK inhibitory selectivity for SRC, TEK, NTRK2, FLT1, KDR, BRAF, RAF1, TGFBR1, PIK3CA, PIK3CB, BTK and / or TXK.
（本発明の化合物の製造法）
　本発明に係る式（Ｉ）で示される化合物は、例えば、下記に示す一般的合成法によって製造することができる。これら合成に用いる出発物質および反応試薬はいずれも、商業的に入手可能であるか、または商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。また、抽出、精製等は、通常の有機化学の実験で行う処理を行えばよい。
　本発明の化合物の合成は、当該分野において公知の手法を参酌しながら実施することができる。
　下記すべての工程において、反応の障害となる置換基（例えば、ヒドロキシ、メルカプト、アミノ、ホルミル、カルボニル、カルボキシル等）を有する場合には、Protective　Groups　in　Organic　Synthesis,　Theodora　W　Greene(John　Wiley　&　Sons)等に記載の方法で予め保護し、望ましい段階でその保護基を除去すればよい。
　また、下記すべての工程について、実施する工程の順序を適宜変更することができ、各中間体を単離して次の工程に用いてもよい。 (Method for producing the compound of the present invention)
The compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. All of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons) when all of the following steps have substituents that interfere with the reaction (eg, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.) Or the like, and the protecting group may be removed at a desired stage.
Moreover, about all the following processes, the order of the process to implement can be changed suitably, and each intermediate body may be isolated and used for the following process.
　また、本明細書中で用いる略語は以下の意味を表す。
Ａｃ：アセチル
ＢＩＮＡＰ：２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル
Ｂｎ：ベンジル
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
Ｂｏｃ２Ｏ：ジ－ｔｅｒｔ－ブチルジカーボネート
Ｃｂｚ：ベンジルオキシカルボニル
ＤＡＳＴ：Ｎ，Ｎ－ジエチルアミノスルファー　トリフルオライド
ＣＤＩ：カルボニルジイミダゾールＤＥＡＤ：ジエチルアゾジカルボキシレート
ＤＩＡＤ：ジイソプロピルアゾジカルボキシレート
ＤＩＥＡ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＤＭＡ：Ｎ，Ｎ－ジメチルアセトアミド
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＩ：１，３－ジメチル－２－イミダゾリジノン
ＤＭＳＯ：ジメチルスルホキシド
ＤＰＰＡ：ジフェニルリン酸アジド
ＥＤＣ：１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド
Ｅｔ：エチル
ＨＡＴＵ：Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスフェート
ＨＯＡｔ：１－ヒドロキシ－７－アザベンゾトリアゾール
ＨＯＢｔ：１－ヒドロキシベンゾトリアゾール
ｉ－Ｐｒ：イソプロピル
ＬＤＡ：リチウムジイソプロピルアミド
ＬＨＭＤＳ：リチウムヘキサメチルジシラジドＭｅ：メチル
ＮａＨＭＤＳ：ナトリウムヘキサメチルジシラジド
ＮＩＳ：Ｎ－ヨードスクシンイミド
ＮＭＰ：Ｎ－メチルピロリドン
Ｎｓ：２－ニトロ－ベンゼンスルホニル
ＯＤＳ：オクタデシルシリル
Ｐｄ（ＯＡｃ）２：酢酸パラジウム
Ｐｄ（ＰＰｈ３）４：テトラキス（トリフェニルホスフィン）パラジウム
Ｐｄ２（ｄｂａ）３：トリス（ジベンジリデンアセトン）ビスパラジウム
Ｐｈ：フェニル
ＰｙＢＯＰ：ヘキサフルオロリン酸（ベンゾトリアゾール－１－イルオキシ）トリピロリジノホスホニウム
ＲｕＰｈｏｓ：２－ジシクロへキシルホスフィノ-２’,６’-ジイソプロポキシビフェニル
Ｓ－Ｐｈｏｓ：２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル
ＴＢＡＦ：テトラブチルアンモニウムフルオリド
ＴＢＳ：ｔｅｒｔ－ブチルジメチルシリル
ｔ－Ｂｕ：ｔｅｒｔ－ブチル
ＴＦＡ：トリフルオロ酢酸
ＴＨＦ：テトラヒドロフラン
ＴＨＰ：テトラヒドロピラニル
Ｘａｎｔｐｈｏｓ：４，５’－ビス（ジフェニルホスフィノ）－９，９’－ジメチルキサンテンＸ－Ｐｈｏｓ：２，４，６－トリイソプロピル－２’－（ジシクロヘキシルホスフィノ）ビフェニルＮ，Ｎ－ジエチルアミノスルファー　トリフルオライド Moreover, the abbreviation used in this specification represents the following meaning.
Ac: Acetyl BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl Bn: benzyl Boc: tert-butoxycarbonyl Boc 2 O: di-tert-butyl dicarbonate Cbz: benzyloxycarbonyl DAST: N, N-diethylaminosulfur trifluoride CDI: carbonyldiimidazole DEAD: diethyl azodicarboxylate DIAD: diisopropyl azodicarboxylate DIEA: N, N-diisopropylethylamine DMA: N, N-dimethylacetamide DMF: N, N- Dimethylformamide DMI: 1,3-dimethyl-2-imidazolidinone DMSO: Dimethyl sulfoxide DPPA: Diphenyl phosphate azide EDC: 1-ethyl-3- (3-dimethylaminopropyl Carbodiimide Et: ethyl HATU: O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOBt: 1- Hydroxybenzotriazole i-Pr: isopropyl LDA: lithium diisopropylamide LHMDS: lithium hexamethyldisilazide Me: methyl NaHMDS: sodium hexamethyldisilazide NIS: N-iodosuccinimide NMP: N-methylpyrrolidone Ns: 2-nitro- benzenesulfonyl ODS: octadecylsilyl Pd (OAc) 2: palladium acetate Pd (PPh 3) 4: tetrakis (triphenylphosphine) palladium Pd 2 (dba) 3: tris (Jibenjiride Acetone) Bispalladium Ph: Phenyl PyBOP: Hexafluorophosphoric acid (benzotriazol-1-yloxy) tripyrrolidinophosphonium RuPhos: 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl S-Phos: 2-dicyclohexyl Phosphino-2 ′, 6′-dimethoxybiphenyl TBAF: tetrabutylammonium fluoride TBS: tert-butyldimethylsilyl t-Bu: tert-butyl TFA: trifluoroacetic acid THF: tetrahydrofuran THP: tetrahydropyranyl Xanthphos: 4, 5 '-Bis (diphenylphosphino) -9,9'-dimethylxanthene X-Phos: 2,4,6-triisopropyl-2'-(dicyclohexylphosphino) biphenyl N, N-diethylamino Surufa trifluoride
［Ａ法］
Figure JPOXMLDOC01-appb-C000091
（式中、Ｈａｌはハロゲン原子であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；ＰｇＡはアミノ基の適切な保護基であり；
Figure JPOXMLDOC01-appb-C000092
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１、ｎおよびｍは、上記（１）と同意義である。）

（第１工程）
　塩基の存在下、化合物（Ａ－ｉ）と化合物（Ａ－ｉｉ）を反応させることにより、化合物（Ａ－ｉｉｉ）を得ることができる。
　塩基としては、炭酸カリウム、炭酸セシウム、水素化ナトリウム等が挙げられる。
　反応溶媒としては、ＤＭＳＯ、ＤＭＦ、ＤＭＡ、ＤＭＩ、ＴＨＦ、ジオキサン等が挙げられる。
　反応温度としては、６０～１８０℃、好ましくは１００～１２０℃が挙げられる。
　反応時間としては、０．５～１２時間、好ましくは１～３時間が挙げられる。

または、触媒によるカップリング反応により、化合物（Ａ－ｉｉｉ）を得ることができる。具体的には、塩基の存在下または非存在下、触媒およびホスフィン配位子の存在下、化合物（Ａ－ｉ）と化合物（Ａ－ｉｉ）を反応させることにより、化合物（Ａ－ｉｉｉ）を得ることができる。
　触媒としては、Ｐｄ（Ａｃ）２、Ｐｄ２（ｄｂａ）３等のパラジウム触媒、ヨウ化銅等の銅触媒等が挙げられる。
　ホスフィン配位子としては、Ｘａｎｔｐｈｏｓ、ＢＩＮＡＰ、Ｘ－ｐｈｏｓ、Ｓ－ｐｈｏｓ等が挙げられる。
　塩基としては、ナトリウム　ｔｅｒｔ－ブトキシド、炭酸セシウム等が挙げられる。
　反応溶媒としては、例えば、トルエン、ＤＭＦ、ＤＭＡ、ジオキサン等を用いることができるが、本条件下で反応に支障をきたす溶媒以外であれば特に限定されない。
　反応温度は、特に限定されないが、室温～２００℃で行うことができ、反応性の低い場合は適宜加温すればよい。

（第２工程）
　化合物（Ａ－ｉｉｉ）のアミノ基の保護基を、適切な方法により脱保護を行うことにより、化合物（Ａ－ｉｖ）を得ることができる。この場合の適切な脱保護とは、例えば、Ｃｂｚであれば接触水素化還元法による脱保護、または塩酸等の酸による脱保護であり、Ｂｏｃ基であれば、ＴＦＡや塩酸等の酸による脱保護である。
　反応溶媒としては、ＤＭＦ、ＴＨＦ、ジクロロメタン等が挙げられる。

（第３工程）
　化合物（Ａ－ｉｖ）に、ＨＯＢｔまたはＨＯＡｔ、塩基、および縮合剤の存在下、対応するカルボン酸または対応するスルホン酸を反応させることにより、化合物（Ａ－ｖ）を得ることができる。
　塩基としては、トリエチルアミン、ＤＩＥＡ等が挙げられる。
　縮合剤としては、ＥＤＣ・ＨＣｌ、ＨＡＴＵ、ＰｙＢＯＰ等が挙げられる。
　反応温度としては、０～６０℃、好ましくは０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは１～７２時間が挙げられる。
　反応溶媒としては、ジクロロメタン、ＴＨＦ、ＤＭＦ、ＤＭＡ、ＮＭＰ、ジオキサン等が挙げられる。

　または、化合物（Ａ－ｉｖ）に、塩基の存在下、対応する酸クロリドまたは対応するスルホニルクロリドを反応させることにより、化合物（Ａ－ｖ）を得ることができる。
　塩基としては、ＤＩＥＡ、炭酸カリウム、炭酸水素ナトリウム、水素化ナトリウム、水酸化ナトリウム等が挙げられる。
　反応温度としては、０℃～１５０℃、好ましくは２０℃～１００℃が挙げられる。
　反応時間としては、０．５時間～１２０時間、好ましくは１時間～７２時間が挙げられる。
　反応溶媒としては、アセトニトリル、ＴＨＦ、トルエン、ジクロロメタン等が挙げられる。

または、縮合剤の存在下または非存在下、対応するアルデヒド誘導体、対応するケトン誘導体と化合物（Ａ－ｉｖ）またはその塩を縮合した後、還元剤により還元することにより、化合物（Ａ－ｖ）を得ることができる。
　縮合剤としては、４－トルエンスルホン酸、メタンスルホン酸、酢酸、無水硫酸マグネシウム、オルトチタン酸テトライソプロピル、四塩化チタン、モレキュラーシーブ等が挙げられ、化合物（Ａ－ｉｖ）に対して、１～１０モル当量用いることができる。
　化合物（Ａ－ｉｖ）またはその塩は、反応させるアルデヒド誘導体またはケトン誘導体に対して、１～１０モル当量用いることができる。
　還元剤としては、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、ボランおよびその錯体、水素化ホウ素リチウム、水素化ホウ素カリウム、水素化ジイソブチルアルミニウム等が挙げられ、反応させるアルデヒド、ケトン誘導体に対して、１～１０モル当量用いることができる。
　反応温度としては、－７８℃～溶媒の還流温度、好ましくは０～２５℃が挙げられる。
　反応時間としては、０．５～４８時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、ＴＨＦ、トルエン、ジクロロメタン、クロロホルム、メタノール、エタノール等が挙げられ、単独または混合して用いることができる。
[Method A]
Figure JPOXMLDOC01-appb-C000091
Wherein Hal is a halogen atom; —M— is —C (═O) —, —S (═O) — or —SO 2 —; Pg A is a suitable protecting group for an amino group ;
Figure JPOXMLDOC01-appb-C000092
, Ra, Rb, Rc, R 1 , n and m are the same as defined in (1) above. )

(First step)
Compound (A-iii) can be obtained by reacting compound (Ai) with compound (A-ii) in the presence of a base.
Examples of the base include potassium carbonate, cesium carbonate, sodium hydride and the like.
Examples of the reaction solvent include DMSO, DMF, DMA, DMI, THF, dioxane and the like.
The reaction temperature is 60 to 180 ° C, preferably 100 to 120 ° C.
The reaction time is 0.5 to 12 hours, preferably 1 to 3 hours.

Alternatively, compound (A-iii) can be obtained by a coupling reaction using a catalyst. Specifically, the compound (A-iii) is reacted with the compound (A-ii) in the presence or absence of a base and in the presence of a catalyst and a phosphine ligand. Obtainable.
Examples of the catalyst include palladium catalysts such as Pd (Ac) 2 and Pd 2 (dba) 3 , copper catalysts such as copper iodide, and the like.
Examples of the phosphine ligand include Xantphos, BINAP, X-phos, S-phos and the like.
Examples of the base include sodium tert-butoxide, cesium carbonate and the like.
As the reaction solvent, for example, toluene, DMF, DMA, dioxane or the like can be used, but it is not particularly limited as long as it is a solvent other than the solvent that hinders the reaction under the present conditions.
Although the reaction temperature is not particularly limited, it can be carried out at room temperature to 200 ° C. If the reactivity is low, it may be appropriately heated.

(Second step)
Compound (A-iv) can be obtained by deprotecting the protecting group of the amino group of compound (A-iii) by an appropriate method. Appropriate deprotection in this case is, for example, deprotection by catalytic hydrogenation reduction method for Cbz or deprotection by acid such as hydrochloric acid, and deprotection by acid such as TFA or hydrochloric acid if it is Boc group. It is protection.
Examples of the reaction solvent include DMF, THF, dichloromethane and the like.

(Third step)
Compound (Av) can be obtained by reacting compound (A-iv) with corresponding carboxylic acid or corresponding sulfonic acid in the presence of HOBt or HOAt, a base, and a condensing agent.
Examples of the base include triethylamine, DIEA and the like.
Examples of the condensing agent include EDC / HCl, HATU, PyBOP, and the like.
Examples of the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
Examples of the reaction solvent include dichloromethane, THF, DMF, DMA, NMP, dioxane and the like.

Alternatively, compound (Av) can be obtained by reacting compound (A-iv) with a corresponding acid chloride or corresponding sulfonyl chloride in the presence of a base.
Examples of the base include DIEA, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like.
The reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
The reaction time is 0.5 hour to 120 hours, preferably 1 hour to 72 hours.
Examples of the reaction solvent include acetonitrile, THF, toluene, dichloromethane and the like.

Alternatively, the compound (Av) can be obtained by condensing the corresponding aldehyde derivative, the corresponding ketone derivative and the compound (A-iv) or a salt thereof in the presence or absence of a condensing agent and then reducing with a reducing agent. Can be obtained.
Examples of the condensing agent include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, molecular sieves, etc., and the compound (A-iv) has 1 to 10 molar equivalents can be used.
Compound (A-iv) or a salt thereof can be used at 1 to 10 molar equivalents relative to the aldehyde derivative or ketone derivative to be reacted.
Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride, and the like. 1 to 10 molar equivalents can be used with respect to the ketone derivative.
The reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably 0 to 25 ° C.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include THF, toluene, dichloromethane, chloroform, methanol, ethanol and the like, and these can be used alone or in combination.
［Ｂ法］
Figure JPOXMLDOC01-appb-C000093
（式中、Ｈａｌはハロゲン原子であり；ＰｇＢは水酸基の適切な保護基であり；Ｎｒはアジド基、フタルイミド基、スルホニル系保護基等のアミノ基に容易に変換できる官能基であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；
Figure JPOXMLDOC01-appb-C000094
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１、ｎおよびｍは、上記（１）と同意義である。）

（第１工程）
　化合物（Ｂ－ｉ）と化合物（Ｂ－ｉｉ）を用いて、Ａ法の第１工程に記載の方法により、化合物（Ｂ－ｉｉｉ）を得ることができる。

（第２工程）
　水酸基の保護基を、ジクロロメタン、ＤＭＦ、ＴＨＦ等の溶媒中、適切な方法により脱保護を行うことで、化合物（Ｂ－ｉｖ）を得ることができる。この場合の適切な脱保護とは、例えば、ＴＢＳ基等のシリル系保護基であれば、ＴＢＡＦ等のフッ素イオンによる脱保護、または塩酸等の酸による脱保護であり、ＴＨＰ基であれば希塩酸等の酸による脱保護である。

（第３工程）
　化合物（Ｂ－ｉｖ）に、トリフェニルホスフィン、および縮合剤の存在下、フタルイミドカリウムまたはＤＰＰＡを反応させることにより、Ｎｒがフタルイミド基またはアジド基である化合物（Ｂ－ｖ）を得ることができる。
　縮合剤としては、ＤＥＡＤ、ＤＩＡＤ等が挙げられ、化合物（Ｂ－ｉｖ）に対して１～５モル当量用いることができる。
　反応温度としては、０℃～６０℃、好ましくは１０℃～４０℃が挙げられる。
　反応時間としては、０．１時間～１２時間、好ましくは０．２時間～６時間が挙げられる。
　反応溶媒としては、ＴＨＦ、ジオキサン、酢酸エチル、トルエン、アセトニトリル等が挙げられ、単独または混合して用いることができる。

または、化合物（Ｂ－ｖ）の水酸基を、メシルクロリド、トシルクロリド等でスルホニル化を行い、Ｎｒがスルホニル系保護基である化合物（Ｂ－ｖ）を得ることができる。
　反応温度としては、－２０℃～室温、好ましくは０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは１～７２時間が挙げられる。
　反応溶媒としては、ジクロロメタン、クロロホルム、トルエン等が挙げられる。

また、Ｎｒがスルホニル系保護基である化合物（Ｂ－ｖ）に、ＮａＮ３を反応させ、Ｎｒがアジド基である化合物（Ｂ－ｖ）を得ることもできる。
　反応温度としては、－２０～１８０℃、好ましくは室温～１２０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは１～７２時間が挙げられる。
　反応溶媒としては、ジクロロメタン、クロロホルム、アセトニトリル、ＴＨＦ、ジオキサン、トルエン、ＤＭＦ、ＤＭＡ等が挙げられる。

（第４工程）
　化合物（Ｂ－ｖ）のＮｒがフタルイミド基である場合には、化合物（Ｂ－ｖｉ）にヒドラジン、メチルアミン等を加えることにより、化合物（Ｂ－ｖｉ）を得ることができる。
　反応温度としては、０～１２０℃、好ましくは室温～６０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～２４時間が挙げられる。
　反応溶媒としては、ＴＨＦ、ジオキサン等が挙げられる。

　また、化合物（Ｂ－ｖｉ）は、シリカゲルクロマドグラフィーにてジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。

　化合物（Ｂ－ｖ）のＮｒがアジド基である場合には、還元剤を反応させることにより、化合物（Ｂ－ｖｉ）を得ることができる。
　還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化アルミニウムリチウム等が挙げられ、化合物に対して、１～１０モル当量用いることができる。
　反応温度としては、０℃～還流温度、好ましくは２０℃～還流温度が挙げられる。
　反応時間としては、０．２時間～４８時間、好ましくは１時間～２４時間が挙げられる。
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ＴＨＦ、ジエチルエーテル、ジクロロメタン、水等が挙げられ、単独または混合して用いることができる。

　化合物（Ｂ－ｖ）のＮｒがスルホニル系保護基である場合には、アンモニアを反応させることにより、化合物（Ｂ－ｖｉ）を得ることができる。
　反応温度としては、－２０～１２０℃、好ましくは室温～１００℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは１～７２時間が挙げられる。
　反応溶媒としては、メタノール、エタノール等のアルコール類、ＤＭＦ、ＤＭＡ、ＴＨＦ、ジオキサン、アセトニトリル等が挙げられる。

（第５工程）
　化合物（Ｂ－ｖｉ）を用いて、Ａ法の第３工程に記載の方法により、化合物（Ｂ－ｖｉｉ）を得ることができる。
[Method B]
Figure JPOXMLDOC01-appb-C000093
(Wherein Hal is a halogen atom; Pg B is a suitable protecting group for a hydroxyl group; Nr is a functional group that can be easily converted to an amino group such as an azide group, a phthalimide group, a sulfonyl-type protecting group; M— is —C (═O) —, —S (═O) — or —SO 2 —;
Figure JPOXMLDOC01-appb-C000094
, Ra, Rb, Rc, R 1 , n and m are the same as defined in (1) above. )

(First step)
Using compound (Bi) and compound (B-ii), compound (B-iii) can be obtained by the method described in the first step of Method A.

(Second step)
The compound (B-iv) can be obtained by deprotecting the protecting group for the hydroxyl group by a suitable method in a solvent such as dichloromethane, DMF, or THF. Appropriate deprotection in this case is, for example, deprotection with a fluorine ion such as TBAF or deprotection with an acid such as hydrochloric acid if it is a silyl protecting group such as a TBS group, and dilute hydrochloric acid if it is a THP group. Deprotection with acid.

(Third step)
Compound (Bv) in which Nr is a phthalimide group or an azide group can be obtained by reacting compound (B-iv) with potassium phthalimide or DPPA in the presence of triphenylphosphine and a condensing agent.
Examples of the condensing agent include DEAD, DIAD and the like, and 1 to 5 molar equivalents can be used with respect to the compound (B-iv).
The reaction temperature is 0 ° C. to 60 ° C., preferably 10 ° C. to 40 ° C.
The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.
Examples of the reaction solvent include THF, dioxane, ethyl acetate, toluene, acetonitrile and the like, and these can be used alone or in combination.

Alternatively, the hydroxyl group of compound (Bv) can be sulfonylated with mesyl chloride, tosyl chloride or the like to obtain compound (Bv) in which Nr is a sulfonyl protecting group.
The reaction temperature includes −20 ° C. to room temperature, preferably 0 ° C. to room temperature.
The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
Examples of the reaction solvent include dichloromethane, chloroform, toluene and the like.

Alternatively, compound (Bv) in which Nr is an azido group can be obtained by reacting compound (Bv) in which Nr is a sulfonyl protecting group with NaN 3 .
The reaction temperature is −20 to 180 ° C., preferably room temperature to 120 ° C.
The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
Examples of the reaction solvent include dichloromethane, chloroform, acetonitrile, THF, dioxane, toluene, DMF, DMA and the like.

(4th process)
When Nr of the compound (Bv) is a phthalimide group, the compound (B-vi) can be obtained by adding hydrazine, methylamine or the like to the compound (B-vi).
The reaction temperature is 0 to 120 ° C., preferably room temperature to 60 ° C.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 24 hours.
Examples of the reaction solvent include THF, dioxane and the like.

In addition, diastereomers of compound (B-vi) can be separated by silica gel chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.

When Nr of compound (Bv) is an azide group, compound (B-vi) can be obtained by reacting with a reducing agent.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and 1 to 10 molar equivalents can be used with respect to the compound.
The reaction temperature includes 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature.
The reaction time may be 0.2 to 48 hours, preferably 1 to 24 hours.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, dichloromethane, water and the like, and these can be used alone or in combination.

When Nr of compound (Bv) is a sulfonyl protecting group, compound (B-vi) can be obtained by reacting with ammonia.
The reaction temperature is −20 to 120 ° C., preferably room temperature to 100 ° C.
The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
Examples of the reaction solvent include alcohols such as methanol and ethanol, DMF, DMA, THF, dioxane, acetonitrile and the like.

(5th process)
Using compound (B-vi), compound (B-vii) can be obtained by the method described in the third step of Method A.
［Ｃ法］
Figure JPOXMLDOC01-appb-C000095
（式中、ＰｇＣ１およびＰｇＣ３は、アミノ基の適切な保護基であり、ＰｇＣ１の脱離条件下において、ＰｇＣ３が脱離しないことが望ましい。ＰｇＣ２は水酸基の適切な保護基であり、ＰｇＣ１の脱離を伴わない保護基であることが望ましい。Ｈａｌはハロゲン原子であり；Ｍｅｔａｌは金属原子であり；Ｎｒは、アジド基、フタルイミド基、スルホニル系保護基等のアミノ基に容易に変換できる官能基であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；
Figure JPOXMLDOC01-appb-C000096
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１およびｍは、上記（１）と同意義である。）

（第１工程）
　化合物（Ｃ－ｉ）と求核剤（Ｃ－ｘｉｉｉ）を反応させることにより、化合物（Ｃ－ｉｉ）を得ることができる。
　求核剤（Ｃ－ｘｉｉｉ）としては、メチルリチウム、エチルリチウム等のリチウム試薬やメチル臭化マグネシウム、メチル塩化マグネシウム、メチルヨウ化マグネシウム、エチル臭化マグネシウム、エチル塩化マグネシウム、エチルヨウ化マグネシウム等のグリニャール試薬およびこれらと金属塩の混合試薬が挙げられ、化合物（Ｃ－ｉ）に対して、１～５モル当量用いることができる。
　反応温度としては、－７８℃～溶媒の還流温度、好ましくは－４５℃～０℃が挙げられる。
　反応時間としては、０．５～２４時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、テトラヒドロフラン、ヘキサン、ジエチルエーテル、メチルｔｅｒｔ－ブチルエーテル、トルエン、ジクロロメタン等が挙げられ、単独または混合して用いることができる。
　求核剤（Ｃ－ｘｉｉｉ）は、Ｒａ－Ｈａｌで示されるハロゲン化物をｎ－ブチルリチウム、ＬＤＡ、ＬＨＭＤＳ等を用いてリチオ化することにより、調整することができる。
　反応溶媒としては、テトラヒドロフラン、ジオキサン、ジエチルエーテル等のアルキルリチウムと反応しない溶媒でなければ特に限定されない。リチオ化反応の温度は、－７８℃～０℃程度が好ましい。

（第２工程）
　化合物（Ｃ－ｉｉ）に還元剤を反応させることにより、化合物（Ｃ－ｉｉｉ）を得ることができる。
　還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化アルミニウムリチウム等が挙げられ、化合物（Ｃ－ｉｉ）に対して、１～１０モル当量用いることができる。
　反応温度としては、０℃～還流温度、好ましくは２０℃～還流温度が挙げられる。
　反応時間としては、０．２時間～４８時間、好ましくは１時間～２４時間が挙げられる。
　反応溶媒としては、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、ＴＨＦ、ジエチルエーテル、ジクロロメタン、水等が挙げられ、単独または混合して用いることができる。

（第３工程）
　化合物（Ｃ－ｉｉｉ）に塩基および酸塩化物を加えることにより、化合物（Ｃ－ｉｖ）を得ることができる。
　塩基としては、ピリジン、トリエチルアミン、ＤＩＥＡ等が挙げられる。
　酸塩化物としては、メシルクロリド、トシルクロリド等が挙げられ、化合物（Ｃ－ｉｉｉ）に対して、１～５モル当量用いることができる。
　反応温度としては、－４０～８０℃、好ましくは０～４０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～５時間が挙げられる。
　反応溶媒としては、ジクロロメタン、クロロホルム、ＴＨＦ、ＤＭＦ等が挙げられる。

（第４工程）
　ＰｇＣ２がＴＢＳ基等のシリル系保護基である場合には、フッ素試薬を用いて化合物（Ｃ－ｖ）を得ることができる。
　フッ素試薬としては、例えばＴＢＡＦ等が挙げられる。
　反応温度としては、－２０～５０℃、好ましくは０～４０℃が挙げられる。
　反応時間としては、０．５～２４時間、好ましくは１～５時間が挙げられる。
　反応溶媒としては、ＴＨＦ、ジオキサン、ジエチルエーテル、メタノール、エタノール等が挙げられる。

　また、化合物（Ｃ－ｖ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。

（第５工程）
　化合物（Ｃ－ｖ）を用いて、Ｂ法の第３工程に記載の方法により、化合物（Ｃ－ｖｉ）を得ることができる。

（第６工程）
　化合物（Ｃ－ｖｉ）を用いて、Ｂ法の第４工程に記載の方法により、化合物（Ｃ－ｖｉｉ）を得ることができる。

（第７工程）
　化合物（Ｃ－ｖｉｉ）に塩基および酸塩化物を加えることにより、化合物（Ｃ－ｖｉｉｉ）を得ることができる。
　塩基としては、ピリジン、トリエチルアミン、ＤＩＥＡ等が挙げられる。
　酸塩化物としては、炭酸クロリド、トシルクロリド、ｏ－ニトロスルホニルクロリド等が挙げられる。好ましくは、ｏ－ニトロスルホニルクロリドである。
　反応温度としては、－４０～７０℃、好ましくは０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～６時間が挙げられる。
　反応溶媒としては、ジクロロメタン、クロロホルム、ＴＨＦ、ジオキサン等が挙げられる。

（第８工程）
　化合物（Ｃ－ｖｉｉｉ）のＰｇＣ１がＢｏｃ基である場合、酸またはルイス酸を反応させることにより、化合物（Ｃ－ｉｘ）を得ることができる。
　酸としては、塩酸－酢酸エチル、塩酸－メタノール、塩酸－ジオキサン、硫酸、ギ酸、ＴＦＡ等が挙げられ、ルイス酸としては、ヨウ化トリメチルシリル、ＢＢｒ３、ＡｌＣｌ３、ＢＦ３・（Ｅｔ２Ｏ）等が挙げられる。酸またはルイス酸は、化合物（Ｃ－ｖｉｉｉ）に対して１～１０モル当量用いることができる。
　反応温度としては、０℃～６０℃、好ましくは０℃～２０℃が挙げられる。
　反応時間としては、０．５時間～１２時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、メタノール、エタノール、水、アセトン、アセトニトリル、ＤＭＦ等が挙げられ、単独または混合して用いることができる。

　化合物（Ｃ－ｖｉｉｉ）のＰｇＣ１がオキシカルボニル系保護基、アミノカルボニル系保護基、オキシスルホニル系保護基またはアミノスルホニル系保護基の場合、酸またはルイス酸を反応させることにより、化合物（Ｃ－ｉｘ）を得ることができる。
　酸としては、塩酸等が挙げられる。ルイス酸としては、ヨウ化トリメチルシリル、ＢＢｒ３、ＡｌＣｌ３、ＢＦ３・（Ｅｔ２Ｏ）等が挙げられる。酸またはルイス酸は、化合物（Ｃ－ｖｉｉｉ）に対して１～１０モル当量用いることができる。
　反応温度としては、０℃～６０℃、好ましくは０℃～１００℃が挙げられる。
　反応時間としては、０．５時間～１２０時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、メタノール、エタノール、水、アセトン、アセトニトリル、ＤＭＦ等が挙げられ、単独または混合して用いることができる。

（第９工程）
　塩基の存在下、化合物（Ａ－ｉ）と化合物（Ｃ－ｉｘ）を反応させることにより、化合物（Ｃ－ｘ）を得ることができる。反応性の低い場合はフッ化カリウムを１当量加えても良い。
　塩基としては、トリエチルアミン、ＤＩＥＡ、炭酸カリウム、炭酸セシウム等が挙げられる。
　反応溶媒としては、ＤＭＦ、ＤＭＳＯ、ＮＭＰ、ＤＭＩ等が挙げられる。
　反応温度としては、０～２００℃、好ましくは室温～１６０℃が挙げられる。
　反応時間としては、０．５～２４０時間、好ましくは０．５～３６時間が挙げられる。

　または、化合物（Ａ－ｉ）と化合物（Ｃ－ｉｘ）を用いて、Ａ法の第１工程に記載の、触媒によるカップリング反応により、化合物（Ｃ－ｘ）を得ることができる。

（第１０工程）
　化合物（Ｃ－ｘ）にｎ－ドデカンチオール等を反応させることにより、化合物（Ｃ－ｘｉ）を得ることができる。
　反応温度としては、０～１６０℃、好ましくは室温～６０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～２４時間が挙げられる。
　反応溶媒としては、ＤＭＦ、ジオキサン、ＴＨＦ等が挙げられる。

（第１１工程）
　化合物（Ｃ－ｘｉ）を用いて、Ａ法の第３工程に記載の方法により、化合物（Ｃ－ｘｉｉ）を得ることができる。
[Method C]
Figure JPOXMLDOC01-appb-C000095
(In the formula, Pg C1 and Pg C3 are suitable protecting groups for amino groups, and it is desirable that Pg C3 does not leave under the elimination conditions of Pg C1 . Pg C2 is a suitable protecting group for hydroxyl groups. And is preferably a protecting group that is not accompanied by elimination of Pg C1 Hal is a halogen atom; Metal is a metal atom; Nr is an amino group such as an azide group, a phthalimide group, or a sulfonyl-type protecting group. An easily convertible functional group; —M— is —C (═O) —, —S (═O) — or —SO 2 —;
Figure JPOXMLDOC01-appb-C000096
, Ra, Rb, Rc, R 1 and m are as defined in (1) above. )

(First step)
Compound (C-ii) can be obtained by reacting compound (Ci) with nucleophile (C-xiii).
Nucleophiles (C-xiii) include lithium reagents such as methyl lithium and ethyl lithium, and Grignard reagents such as methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, ethyl magnesium bromide, ethyl magnesium chloride, and ethyl magnesium iodide. And a mixed reagent of these and a metal salt, and the compound (Ci) can be used at 1 to 5 molar equivalents.
The reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably -45 ° C to 0 ° C.
The reaction time is 0.5 to 24 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include tetrahydrofuran, hexane, diethyl ether, methyl tert-butyl ether, toluene, dichloromethane and the like, and these can be used alone or in combination.
The nucleophilic agent (C-xiii) can be adjusted by lithiating a halide represented by Ra-Hal using n-butyllithium, LDA, LHMDS or the like.
The reaction solvent is not particularly limited as long as it does not react with alkyl lithium such as tetrahydrofuran, dioxane, diethyl ether and the like. The temperature of the lithiation reaction is preferably about −78 ° C. to 0 ° C.

(Second step)
Compound (C-iii) can be obtained by reacting compound (C-ii) with a reducing agent.
Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (C-ii).
The reaction temperature includes 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature.
The reaction time may be 0.2 to 48 hours, preferably 1 to 24 hours.
Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, dichloromethane, water and the like, and these can be used alone or in combination.

(Third step)
Compound (C-iv) can be obtained by adding a base and an acid chloride to compound (C-iii).
Examples of the base include pyridine, triethylamine, DIEA and the like.
Examples of the acid chloride include mesyl chloride, tosyl chloride, and the like, and 1 to 5 molar equivalents can be used with respect to compound (C-iii).
The reaction temperature is −40 to 80 ° C., preferably 0 to 40 ° C.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 5 hours.
Examples of the reaction solvent include dichloromethane, chloroform, THF, DMF and the like.

(4th process)
When Pg C2 is a silyl protecting group such as a TBS group, the compound (Cv) can be obtained using a fluorine reagent.
Examples of the fluorine reagent include TBAF.
The reaction temperature is −20 to 50 ° C., preferably 0 to 40 ° C.
The reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.
Examples of the reaction solvent include THF, dioxane, diethyl ether, methanol, ethanol and the like.

Compound (Cv) can be separated into diastereomers using silica gel chromatography and amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.

(5th process)
Using compound (Cv), compound (C-vi) can be obtained by the method described in the third step of Method B.

(6th process)
Using compound (C-vi), compound (C-vii) can be obtained by the method described in the fourth step of Method B.

(Seventh step)
Compound (C-viii) can be obtained by adding a base and an acid chloride to compound (C-vii).
Examples of the base include pyridine, triethylamine, DIEA and the like.
Examples of the acid chloride include carbonate chloride, tosyl chloride, o-nitrosulfonyl chloride and the like. Preferred is o-nitrosulfonyl chloride.
Examples of the reaction temperature include −40 to 70 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 6 hours.
Examples of the reaction solvent include dichloromethane, chloroform, THF, dioxane and the like.

(8th step)
When Pg C1 of the compound (C-viii) is a Boc group, the compound (C-ix) can be obtained by reacting an acid or a Lewis acid.
Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, TFA, and the like. Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O). Etc. The acid or Lewis acid can be used in an amount of 1 to 10 molar equivalents relative to compound (C-viii).
The reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.

When Pg C1 of the compound (C-viii) is an oxycarbonyl-based protecting group, an aminocarbonyl-based protecting group, an oxysulfonyl-based protecting group or an aminosulfonyl-based protecting group, a compound (C-- ix) can be obtained.
Examples of the acid include hydrochloric acid and the like. Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), and the like. The acid or Lewis acid can be used in an amount of 1 to 10 molar equivalents relative to compound (C-viii).
The reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 100 ° C.
The reaction time is 0.5 hour to 120 hours, preferably 1 hour to 6 hours.
Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.

(9th step)
Compound (Cx) can be obtained by reacting compound (Ai) with compound (C-ix) in the presence of a base. If the reactivity is low, 1 equivalent of potassium fluoride may be added.
Examples of the base include triethylamine, DIEA, potassium carbonate, cesium carbonate and the like.
Examples of the reaction solvent include DMF, DMSO, NMP, DMI and the like.
The reaction temperature is 0 to 200 ° C., preferably room temperature to 160 ° C.
The reaction time is 0.5 to 240 hours, preferably 0.5 to 36 hours.

Alternatively, compound (Cx) can be obtained by a catalytic coupling reaction described in the first step of Method A using compound (Ai) and compound (C-ix).

(10th step)
Compound (C-xi) can be obtained by reacting compound (Cx) with n-dodecanethiol or the like.
The reaction temperature is 0 to 160 ° C., preferably room temperature to 60 ° C.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 24 hours.
Examples of the reaction solvent include DMF, dioxane, THF and the like.

(11th step)
Using compound (C-xi), compound (C-xi) can be obtained by the method described in the third step of Method A.
［Ｄ法］
Figure JPOXMLDOC01-appb-C000097
（式中、Ｈａｌはハロゲン原子であり；ＰｇＤ１は水酸基の適切な保護基であり；Ｎｒはアジド基、フタルイミド基、スルホニル系保護基等のアミノ基に容易に変換できる官能基であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；
Figure JPOXMLDOC01-appb-C000098
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１およびｍは、上記（１）と同意義である。）

（第１工程）
　化合物（Ｄ－ｉ）と化合物（Ｄ－ｉｉ）を用いて、Ａ法の第１工程に記載の、触媒によるカップリング反応により、化合物（Ｄ－ｉｉｉ）を得ることができる。

（第２工程）
　化合物（Ｄ－ｉｉｉ）を用いて、Ｃ法の第１工程に記載の方法により、化合物（Ｄ－ｉｖ）を得ることができる。

（第３工程）
　化合物（Ｄ－ｉｖ）を用いて、Ｃ法の第２工程に記載の方法により、化合物（Ｄ－ｖ）を得ることができる。

（第４工程）
　化合物（Ｄ－ｖ）を用いて、Ｃ法の第３工程に記載の方法により、化合物（Ｄ－ｖｉ）を得ることができる。

（第５工程）
　化合物（Ｄ－ｖｉ）を用いて、Ｃ法の第４工程に記載の方法により、化合物（Ｄ－ｖｉｉ）を得ることができる。

（第６工程）
　化合物（Ｄ－ｖｉｉ）を用いて、Ｂ法の第３工程に記載の方法により、化合物（Ｄ－ｖｉｉｉ）を得ることができる。

　また、化合物（Ｄ－ｖｉｉ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。

（第７工程）
　化合物（Ｄ－ｖｉｉｉ）を用いて、Ｂ法の第４工程に記載の方法により、化合物（Ｄ－ｉｘ）を得ることができる。

（第８工程）
　化合物（Ｄ－ｉｘ）を用いて、Ａ法の第３工程に記載の方法により、化合物（Ｄ－ｘ）を得ることができる。

　また、化合物（Ｄ－ｉｘ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。
[Method D]
Figure JPOXMLDOC01-appb-C000097
(Wherein Hal is a halogen atom; Pg D1 is a suitable protecting group for a hydroxyl group; Nr is a functional group that can be easily converted to an amino group such as an azide group, a phthalimide group, or a sulfonyl-type protecting group; M— is —C (═O) —, —S (═O) — or —SO 2 —;
Figure JPOXMLDOC01-appb-C000098
, Ra, Rb, Rc, R 1 and m are as defined in (1) above. )

(First step)
The compound (D-iii) can be obtained by the catalytic coupling reaction described in the first step of Method A using the compound (Di) and the compound (D-ii).

(Second step)
Using compound (D-iii), compound (D-iv) can be obtained by the method described in the first step of Method C.

(Third step)
Using compound (D-iv), compound (Dv) can be obtained by the method described in the second step of Method C.

(4th process)
Using compound (Dv), compound (D-vi) can be obtained by the method described in the third step of Method C.

(5th process)
Using compound (D-vi), compound (D-vii) can be obtained by the method described in the fourth step of Method C.

(6th process)
Using compound (D-vii), compound (D-viii) can be obtained by the method described in the third step of Method B.

Compound (D-vii) can be separated into diastereomers using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.

(Seventh step)
Using compound (D-viii), compound (D-ix) can be obtained by the method described in the fourth step of Method B.

(8th step)
Using compound (D-ix), compound (Dx) can be obtained by the method described in the third step of Method A.

In addition, diastereomers of compound (D-ix) can be separated using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
［Ｅ法］
Figure JPOXMLDOC01-appb-C000099
（式中、ＰｇＥ１はアミノ基の適切な保護基である。ＰｇＥ２は、水酸基の適切な保護基であり、脱離条件としてＰｇＥ１に影響を与えない保護基である。Ｍｅｔａｌは金属原子であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；
Figure JPOXMLDOC01-appb-C000100
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１およびｍは、上記（１）と同意義である。）

（第１工程）
　メトキシメチルアミンとルイス酸を反応させた後、化合物（Ｅ－ｉ）を反応させることにより、化合物（Ｅ－ｉｉ）を得ることができる。
　ルイス酸としては、トリメチルアルミニウム、ジメチルアルミニウムクロリド等が挙げられる。
　反応温度としては、－７８～０℃、好ましくは－１０～１０℃が挙げられる。
　反応溶媒としては、ジクロロメタン、クロロホルム等が挙げられる。
　反応時間としては、０．５～２４０時間、好ましくは０．５～３６時間が挙げられる。

（第２工程）
　化合物（Ｅ－ｉｉ）を、塩基の存在下、塩化シリル等の保護基と反応させ、化合物（Ｅ－ｉｉｉ）を得ることができる。
　塩基としては、イミダゾール、トリエチルアミン等が挙げられる。
　溶媒としては、ＤＭＦ、ＴＨＦ、アセトニトリル、ジクロロメタン、クロロホルム等が挙げられる。
　反応温度としては、０～６０℃、好ましくは０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは４～２４時間が挙げられる。

（第３工程）
　化合物（Ｅ－ｉｉｉ）およびと求核剤（Ｃ－ｘｉｉｉ）を用いて、Ｃ法の第１工程に記載の方法により、化合物（Ｅ－ｉｖ）を得ることができる。

（第４工程）
　化合物（Ｅ－ｉｖ）を用いて、Ｃ法の第４工程に記載の方法により、化合物（Ｅ－ｖ）を得ることができる。

（第５工程）
　化合物（Ｅ－ｖ）を適切な酸化反応によって、化合物（Ｅ－ｖｉ）を得ることができる。酸化反応として、Ｄｅｓｓ－Ｍａｔｉｎ酸化、Ｓｗａｎ酸化等が好ましい。化合物（Ｅ－ｖｉ）は、精製することなく、速やかに次の反応に用いるのが望ましい。
　Ｄｅｓｓ－Ｍａｔｉｎ酸化を用いる場合、具体的には、化合物（Ｅ－ｖ）をＤｅｓｓ－Ｍａｔｉｎ試薬と反応させることにより、化合物（Ｅ－ｖｉ）を得ることができる。
　反応溶媒としてはジクロロメタン、クロロホルム等が挙げられる。
　反応温度としては、０～６０℃、好ましくは０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは６～４８時間が挙げられる。

　Ｓｗａｎ酸化を用いる場合、具体的には、ジメチルスルホキシドと塩化オキサリルまたはトリフルオロ酢酸無水物を反応させた後、化合物（Ｅ－ｖ）と反応させ、アミンで処理することにより、化合物（Ｅ－ｖｉ）を得ることができる。
　反応温度としては、－７８℃～－１５℃、好ましくは－７８℃～－４０℃が挙げられる。
　反応時間としては、０．１時間～４時間、好ましくは０．５時間～２時間が挙げられる。
　アミンとしては、トリメチルアミン、トリエチルアミン、トリプロピルアミン、トリブチルアミン等が挙げられる。
　反応溶媒としては、ジクロロメタン、ＴＨＦ、ジオキサン、ベンゼン等が挙げられる。

（第６工程）
　縮合剤の存在下または非存在下、化合物（Ｅ－ｖｉ）と化合物（Ｅ－ｘ）またはその塩を縮合しした後、還元剤により還元することにより、化合物（Ｅ－ｖｉｉ）を得ることができる。
　縮合剤としては、４－トルエンスルホン酸、メタンスルホン酸、酢酸、無水硫酸マグネシウム、オルトチタン酸テトライソプロピル、四塩化チタン、モレキュラーシーブ等が挙げられ、化合物（Ｅ－ｘ）に対して、１～１０モル当量用いることができる。
　化合物（Ｅ－ｘ）またはその塩は、化合物（Ｅ－ｖｉ）に対して、１～１０モル当量用いることができる。
　還元剤としては、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、ボランおよびその錯体、水素化ホウ素リチウム、水素化ホウ素カリウム、水素化ジイソブチルアルミニウム等が挙げられ、化合物（Ｅ－ｖｉ）に対して、１～１０モル当量用いることができる。
　反応温度としては、－７８℃～溶媒の還流温度、好ましくは０～２５℃が挙げられる。
　反応時間としては、０．５～４８時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、ＴＨＦ、トルエン、ジクロロメタン、クロロホルム、メタノール、エタノール等が挙げられ、単独または混合して用いることができる

（第７工程）
　ＰｇＥ１がベンジルオキシカルボニルオキシ基の場合、化合物（Ｅ－ｖｉｉ）にＰｄ－炭素を加え、水素ガスを反応させることにより、または、化合物（Ｅ－ｖｉｉ）をルイス酸を反応させることにより、化合物（Ｅ－ｖｉｉｉ）を得ることができる。
　Ｐｄ－炭素は、化合物（Ｅ－ｖｉｉ）に対して、０．０１～１００重量パーセント用いることができる。
　ルイス酸としては、ヨウ化トリメチルシリル、ＢＢｒ３、ＡｌＣｌ３、ＢＦ３・（Ｅｔ２Ｏ）等が挙げられ、化合物ｏ１に対して１～１０モル当量用いることができる。
　水素気圧は、１～５０気圧が挙げられる。なお、水素源として、シクロへキセン、１，４－シクロヘキサジエン、ギ酸、ギ酸アンモニウム等も用いることができる。
　反応温度としては、０℃～４０℃、好ましくは１０℃～３０℃が挙げられる。
　反応時間としては、０．５時間～１２時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、メタノール、エタノール、水、ＴＨＦ、酢酸エチル等が挙げられ、単独または混合して用いることができる。

（第８工程）
　化合物（Ｅ－ｖｉｉｉ）を用いて、Ａ法の第３工程に記載の方法により、化合物（Ｅ－ｉｘ）を得ることができる。

　また、化合物（Ｅ－ｖｉｉ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。
[E method]
Figure JPOXMLDOC01-appb-C000099
(Wherein Pg E1 is a suitable protecting group for an amino group. Pg E2 is a suitable protecting group for a hydroxyl group and is a protecting group that does not affect Pg E1 as a leaving condition. Metal is a metal atom. -M- is -C (= O)-, -S (= O)-or -SO 2- ;
Figure JPOXMLDOC01-appb-C000100
, Ra, Rb, Rc, R 1 and m are as defined in (1) above. )

(First step)
Compound (E-ii) can be obtained by reacting methoxymethylamine and Lewis acid and then reacting compound (Ei).
Examples of the Lewis acid include trimethylaluminum and dimethylaluminum chloride.
The reaction temperature is -78 to 0 ° C, preferably -10 to 10 ° C.
Examples of the reaction solvent include dichloromethane and chloroform.
The reaction time is 0.5 to 240 hours, preferably 0.5 to 36 hours.

(Second step)
Compound (E-iii) can be reacted with a protecting group such as silyl chloride in the presence of a base to give compound (E-iii).
Examples of the base include imidazole and triethylamine.
Examples of the solvent include DMF, THF, acetonitrile, dichloromethane, chloroform and the like.
Examples of the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.5 to 120 hours, preferably 4 to 24 hours.

(Third step)
Using compound (E-iii) and nucleophile (C-xiii), compound (E-iv) can be obtained by the method described in the first step of Method C.

(4th process)
Using compound (E-iv), compound (Ev) can be obtained by the method described in the fourth step of Method C.

(5th process)
Compound (E-vi) can be obtained by subjecting compound (Ev) to an appropriate oxidation reaction. As the oxidation reaction, Dess-Matin oxidation, Swan oxidation and the like are preferable. The compound (E-vi) is desirably used for the next reaction promptly without purification.
When using Dess-Matin oxidation, specifically, compound (E-vi) can be obtained by reacting compound (Ev) with Dess-Matin reagent.
Examples of the reaction solvent include dichloromethane and chloroform.
Examples of the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.5 to 120 hours, preferably 6 to 48 hours.

In the case of using Swan oxidation, specifically, dimethyl sulfoxide and oxalyl chloride or trifluoroacetic anhydride are reacted, then reacted with compound (Ev) and treated with amine to give compound (E-vii). ) Can be obtained.
The reaction temperature is -78 ° C to -15 ° C, preferably -78 ° C to -40 ° C.
The reaction time is 0.1 to 4 hours, preferably 0.5 to 2 hours.
Examples of the amine include trimethylamine, triethylamine, tripropylamine, and tributylamine.
Examples of the reaction solvent include dichloromethane, THF, dioxane, benzene and the like.

(6th process)
Compound (E-vii) can be obtained by condensing compound (E-vi) with compound (Ex) or a salt thereof in the presence or absence of a condensing agent and then reducing with a reducing agent. it can.
Examples of the condensing agent include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, molecular sieves, and the like. 10 molar equivalents can be used.
Compound (Ex) or a salt thereof can be used at 1 to 10 molar equivalents relative to compound (E-vi).
Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride and the like (E 1 to 10 molar equivalents can be used with respect to -vi).
The reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably 0 to 25 ° C.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include THF, toluene, dichloromethane, chloroform, methanol, ethanol and the like, and they can be used alone or in combination.

(Seventh step)
When Pg E1 is a benzyloxycarbonyloxy group, the compound (E-vii) is added with Pd-carbon and reacted with hydrogen gas, or the compound (E-vii) is reacted with a Lewis acid. (E-viii) can be obtained.
Pd-carbon can be used in an amount of 0.01 to 100 weight percent based on compound (E-vii).
Examples of the Lewis acid include trimethylsilyl iodide, BBr 3 , AlCl 3 , BF 3. (Et 2 O), and the like, and 1 to 10 molar equivalents can be used with respect to the compound o1.
The hydrogen pressure is 1 to 50 atm. As a hydrogen source, cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, or the like can also be used.
The reaction temperature is 0 ° C. to 40 ° C., preferably 10 ° C. to 30 ° C.
The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include methanol, ethanol, water, THF, ethyl acetate and the like, and these can be used alone or in combination.

(8th step)
Using compound (E-viii), compound (E-ix) can be obtained by the method described in the third step of Method A.

Compound (E-vii) can be separated into diastereomers using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
［Ｆ法］
Figure JPOXMLDOC01-appb-C000101
（式中、ＰｇＦ１およびＰｇＦ２は水酸基の適切な保護基であり、ＰｇＦ２は脱離条件としてＰｇＦ１に影響を与えない保護基である。Ｎｒは、アジド基、フタルイミド基、スルホニル系保護基等のアミノ基に容易に変換できる官能基であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；
Figure JPOXMLDOC01-appb-C000102
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１およびｍは、上記（１）と同意義である。）

（第１工程）
　化合物（Ｆ－ｉ）を用いて、Ｅ法の第１工程に記載の方法により、化合物（Ｆ－ｉｉ）を得ることができる。

（第２工程）
　化合物（Ｆ－ｉｉ）を用いて、Ｅ法の第２工程に記載の方法により、化合物（Ｆ－ｉｉｉ）を得ることができる。

（第３工程）
　化合物（Ｆ－ｉｉｉ）を用いて、Ｃ法の第１工程に記載の方法により、化合物（Ｆ－ｉｖ）を得ることができる。

（第４工程）
　ギ酸等の弱酸を用いて、化合物（Ｆ－ｉｖ）のＰｇＦ２のみを選択的に脱保護し、化合物（Ｆ－ｖ）を得ることができる。

（第５工程）
　化合物（Ｆ－ｖ）を用いて、Ｅ法の第５工程に記載の方法により、化合物（Ｆ－ｖｉ）を得ることができる。

（第６工程）
　化合物（Ｆ－ｖｉ）を用いて、Ｅ法の第６工程に記載の方法により、化合物（Ｆ－ｖｉｉ）を得ることができる。

（第７工程）
　化合物（Ｆ－ｖｉｉ）を用いて、Ｃ法の第４工程に記載の方法により、化合物（Ｆ－ｖｉｉｉ）を得ることができる。

（第８工程）
　化合物（Ｆ－ｖｉｉｉ）を用いて、Ｂ法の第３工程に記載の方法により、化合物（Ｆ－ｉｘ）を得ることができる。

　また、化合物（Ｆ－ｖｉｉｉ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。

（第９工程）
　化合物（Ｆ－ｉｘ）を用いて、Ｂ法の第４工程に記載の方法により、化合物（Ｆ－ｘ）を得ることができる。

（第１０工程）
　化合物（Ｆ－ｘ）を用いて、Ａ法の第３工程に記載の方法により、化合物（Ｆ－ｘｉ）を得ることができる。

　また、化合物（Ｆ－ｘ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。
[F method]
Figure JPOXMLDOC01-appb-C000101
(Wherein, Pg F1 and Pg F2 are suitable protecting group for a hydroxyl group, Pg F2 is .Nr a protecting group that does not affect the Pg F1 as desorption conditions, azide group, phthalimide group, a sulfonyl type protecting A functional group that can be easily converted to an amino group such as a group; —M— is —C (═O) —, —S (═O) —, or —SO 2 —;
Figure JPOXMLDOC01-appb-C000102
, Ra, Rb, Rc, R 1 and m are as defined in (1) above. )

(First step)
Using compound (Fi), compound (F-ii) can be obtained by the method described in the first step of Method E.

(Second step)
Using compound (F-ii), compound (F-iii) can be obtained by the method described in the second step of Method E.

(Third step)
Using compound (F-iii), compound (F-iv) can be obtained by the method described in the first step of Method C.

(4th process)
Using a weak acid such as formic acid, only Pg F2 of compound (F-iv) can be selectively deprotected to obtain compound (Fv).

(5th process)
Using compound (Fv), compound (F-vi) can be obtained by the method described in the fifth step of Method E.

(6th process)
Using compound (F-vi), compound (F-vii) can be obtained by the method described in Step 6 of Method E.

(Seventh step)
Using compound (F-vii), compound (F-viii) can be obtained by the method described in Step 4 of Method C.

(8th step)
Using compound (F-viii), compound (F-ix) can be obtained by the method described in the third step of Method B.

Compound (F-viii) can be separated into diastereomers using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.

(9th step)
Using compound (F-ix), compound (Fx) can be obtained by the method described in the fourth step of Method B.

(10th step)
Using compound (Fx), compound (F-xi) can be obtained by the method described in the third step of Method A.

In addition, diastereomers of compound (Fx) can be separated using silica gel chromatography or amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.
［Ｇ法］
Figure JPOXMLDOC01-appb-C000103
（式中、ＲＧは、水素原子またはＴＢＳ基等のシリル系保護基であり；Ｎｒは、アジド基、フタルイミド基、スルホニル系保護基等のアミノ基に容易に変換できる官能基であり；－Ｍ－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；
Figure JPOXMLDOC01-appb-C000104
、Ｒａ、Ｒ１およびｍは、上記（１）と同意義である。）

（第１工程）
　還元的アミノ化反応により、化合物（Ｇ－ｉｉ）を得ることができる。具体的には、縮合剤の存在下または非存在下、化合物（Ｇ－ｖｉｉｉ）と化合物（Ｇ－ｉ）またはその塩を縮合し、還元剤により還元することにより、化合物（Ｇ－ｉｉ）を得ることができる。
　縮合剤としては、４－トルエンスルホン酸、メタンスルホン酸、酢酸、無水硫酸マグネシウム、オルトチタン酸テトライソプロピル、四塩化チタン、モレキュラーシーブ等が挙げられる。
　還元剤としては、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化トリアセトキシホウ素ナトリウム、ボランおよびその錯体、水素化ホウ素リチウム、水素化ホウ素カリウム、水素化ジイソブチルアルミニウム等が挙げられる。
　反応温度としては、－７８℃～溶媒の還流温度、好ましくは０～２５℃が挙げられる。
　反応時間としては、０．５～４８時間、好ましくは１時間～６時間が挙げられる。
　反応溶媒としては、ＴＨＦ、トルエン、ジクロロメタン、クロロホルム、メタノール、エタノール等が挙げられ、単独または混合して用いることができる。

（第２工程）
　ルイス酸の存在下、化合物（Ｇ－ｉｉ）と過剰の化合物（Ｇ－ｉｘ）を反応させることにより、化合物（Ｇ－ｉｉｉ）を得ることができる。
　ルイス酸としては、Ｔｉ（Ｃｌ）４、Ｔｉ（イソプロポキシル）４、テトラメチルアルミニウム、ジエチルアルミニウムクロリド等が挙げられる。
　反応溶媒としては、酢酸、ジクロロエタン、ジクロロメタン、トルエン等が挙げられる。
　反応温度としては、－４０～１６０℃、好ましくは０～６０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～４８時間が挙げられる。

（第３工程）
　ＲＧが水素原子の場合には、塩基存在下、化合物（Ｇ－ｉｉｉ）を反応させることにより、化合物（Ｇ－ｉｖ）を得ることができる。
　塩基としては、ＬＨＭＤＳ等が挙げられる。
　反応溶媒としては、ＴＨＦ等が挙げられる。
　反応温度としては、－７８℃～室温、好ましくは－７８～０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～２４時間が挙げられる。

　また、ＲＧがＴＢＳ基の場合には、塩基存在下、化合物（Ｇ－ｉｉｉ）を反応させた後、ＴＢＡＦ等を用いてＴＢＳ基を脱保護することにより、化合物を得ることができる。
　塩基としては、ＮａＨＭＤＳ等が挙げられる。
　反応溶媒としては、ＴＨＦ、ジオキサン等が挙げられる。
　反応温度としては、－７８～１２０℃、好ましくは－４０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～４８時間が挙げられる。

　また、化合物（Ｇ－ｉｖ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。

（第４工程）
　化合物（Ｇ－ｉｖ）を用いて、Ｂ法の第３工程に記載の方法により、化合物（Ｇ－ｖ）を得ることができる。

（第５工程）
　化合物（Ｇ－ｖ）を用いて、Ｂ法の第４工程に記載の方法により、化合物（Ｇ－ｖｉ）を得ることができる。

　また、化合物（Ｇ－ｖｉ）は、シリカゲルクロマドグラフィー、アミノシリカゲルカラムクロマトグラフィーを用い、ジアステレオマーを分離することができる。具体的には、移動相としてヘキサン－酢酸エチル、クロロホルム－メタノール、ジクロロメタン－メタノール等を用い展開することにより、ジアステレオマーを分離、精製することができる。

（第１０工程）
　化合物（Ｇ－ｖｉ）を用いて、Ａ法の第３工程に記載の方法により、化合物（Ｇ－ｖｉｉ）を得ることができる。
[G method]
Figure JPOXMLDOC01-appb-C000103
(Wherein R G is a silyl protecting group such as a hydrogen atom or a TBS group; Nr is a functional group that can be easily converted to an amino group such as an azide group, a phthalimide group, or a sulfonyl protecting group; M— is —C (═O) —, —S (═O) — or —SO 2 —;
Figure JPOXMLDOC01-appb-C000104
, Ra, R 1 and m are as defined above (1). )

(First step)
Compound (G-ii) can be obtained by reductive amination reaction. Specifically, compound (G-iii) and compound (Gi) or a salt thereof are condensed in the presence or absence of a condensing agent, and reduced with a reducing agent, to thereby reduce compound (G-ii). Obtainable.
Examples of the condensing agent include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, and molecular sieve.
Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride and the like.
The reaction temperature may be -78 ° C to the reflux temperature of the solvent, preferably 0 to 25 ° C.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include THF, toluene, dichloromethane, chloroform, methanol, ethanol and the like, and these can be used alone or in combination.

(Second step)
Compound (G-iii) can be obtained by reacting compound (G-ii) with excess compound (G-ix) in the presence of a Lewis acid.
Examples of the Lewis acid include Ti (Cl) 4 , Ti (isopropoxyl) 4 , tetramethylaluminum, diethylaluminum chloride and the like.
Examples of the reaction solvent include acetic acid, dichloroethane, dichloromethane, toluene and the like.
The reaction temperature is −40 to 160 ° C., preferably 0 to 60 ° C.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 48 hours.

(Third step)
When R G is a hydrogen atom, the compound (G-iv) can be obtained by reacting the compound (G-iii) in the presence of a base.
Examples of the base include LHMDS.
Examples of the reaction solvent include THF.
The reaction temperature may be -78 ° C to room temperature, preferably -78 to 0 ° C.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 24 hours.

When R G is a TBS group, the compound can be obtained by reacting the compound (G-iii) in the presence of a base and then deprotecting the TBS group using TBAF or the like.
Examples of the base include NaHMDS.
Examples of the reaction solvent include THF, dioxane and the like.
The reaction temperature is -78 to 120 ° C, preferably -40 ° C to room temperature.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 48 hours.

In addition, diastereomers of compound (G-iv) can be separated using silica gel chromatography and amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.

(4th process)
Using compound (G-iv), compound (Gv) can be obtained by the method described in the third step of Method B.

(5th process)
Using compound (Gv), compound (G-vi) can be obtained by the method described in the fourth step of Method B.

In addition, diastereomers of compound (G-vi) can be separated using silica gel chromatography and amino silica gel column chromatography. Specifically, diastereomers can be separated and purified by developing using hexane-ethyl acetate, chloroform-methanol, dichloromethane-methanol or the like as the mobile phase.

(10th step)
Using compound (G-vi), compound (G-vii) can be obtained by the method described in the third step of Method A.
［Ｈ法］
Figure JPOXMLDOC01-appb-C000105
（式中、Ｈａｌはハロゲン原子であり；－Ｍ１－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；－Ｍ２－は、－Ｎ（Ｒ４）－または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）－であり；ＰｇＨ１はカルボキシル基、スルフィニル基、またはスルホ基の適切な保護基であり；
Figure JPOXMLDOC01-appb-C000106
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１、Ｒ４、Ｒ５ａ、Ｒ５ｂ、ｎおよびｍは、上記（１）と同意義である。）

（第１工程）
　化合物（Ｈ－ｉ）を用いて、Ａ法の第１工程に記載の方法により、化合物（Ｈ－ｉｉ）を得ることができる。

（第２工程）
　化合物（Ｈ－ｉｉｉ）の保護基を、適切な方法により脱保護を行うことにより、化合物（Ｈ－ｉｖ）を得ることができる。例えば、カルボキシル基の保護基であれば、アルカリ加水分解の条件下、脱保護を行うことにより、化合物（Ｈ－ｉｖ）を得ることができる。
　アルカリとしては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水溶液が挙げられる。
　反応溶媒としては、メタノール、エタノール、ＴＨＦ、ジオキサン等が挙げられる。
　反応温度としては、０～１２０℃、好ましくは室温～７０℃が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは０．５～４８時間が挙げられる。

また、ＰｇＨ１がＢｏｃ基の場合であれば、ＴＦＡなどの酸の存在下、脱保護を行うことにより、化合物（Ｈ－ｉｖ）を得ることができる。
　反応溶媒としては、ジクロロメタン、クロロホルム等が挙げられる。
　反応温度としては、０～８０℃、好ましくは室温～６０℃が挙げられる。
　反応時間としては、０．５～２４時間、好ましくは０．５～６時間が挙げられる。

（第３工程）
　化合物（Ｈ－ｉｖ）に、ＨＯＢｔまたはＨＯＡｔ、塩基、および縮合剤の存在下、対応するアミンを反応させることにより、－Ｍ２－が－Ｎ（Ｒ４）－である化合物（Ｈ－ｖ）を得ることができる。
　塩基としては、トリエチルアミン、ＤＩＥＡ等が挙げられる。
　縮合剤としては、ＥＤＣ・ＨＣｌ、ＨＡＴＵ、ＰｙＢＯＰ等が挙げられる。
　反応温度としては、０～６０℃、好ましくは０℃～室温が挙げられる。
　反応時間としては、０．５～１２０時間、好ましくは１～７２時間が挙げられる。
　反応溶媒としては、ジクロロメタン、ＴＨＦ、ＤＭＦ、ＤＭＡ、ＮＭＰ、ジオキサン等が挙げられる。

　または、化合物（Ｈ－ｉｖ）に、ＣＤＩなどで活性化した後に、対応する求核試薬を反応させることにより、－Ｍ２－が－Ｃ（Ｒ５ａ）（Ｒ５ｂ）－である化合物（Ｈ－ｖ）を得ることができる。
　反応温度としては、０℃～１５０℃、好ましくは２０℃～１００℃が挙げられる。
　反応時間としては、０．５時間～１２０時間、好ましくは１時間～７２時間が挙げられる。
　反応溶媒としては、アセトニトリル、ＴＨＦ、トルエン、ＤＭＦ、ＤＭＡ、ジクロロメタン等が挙げられる。
[Method H]
Figure JPOXMLDOC01-appb-C000105
(Wherein Hal is a halogen atom; —M 1 — is —C (═O) —, —S (═O) — or —SO 2 —; —M 2 — is —N (R 4 ) — Or —C (R 5a ) (R 5b ) —; Pg H1 is a suitable protecting group for a carboxyl group, a sulfinyl group, or a sulfo group;
Figure JPOXMLDOC01-appb-C000106
, Ra, Rb, Rc, R 1 , R 4 , R 5a , R 5b , n and m are as defined above (1). )

(First step)
Using compound (Hi), compound (H-ii) can be obtained by the method described in the first step of Method A.

(Second step)
Compound (H-iv) can be obtained by deprotecting the protecting group of compound (H-iii) by an appropriate method. For example, in the case of a protecting group for a carboxyl group, the compound (H-iv) can be obtained by performing deprotection under the conditions of alkaline hydrolysis.
Examples of the alkali include aqueous solutions of lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
Examples of the reaction solvent include methanol, ethanol, THF, dioxane and the like.
The reaction temperature is 0 to 120 ° C., preferably room temperature to 70 ° C.
The reaction time is 0.5 to 120 hours, preferably 0.5 to 48 hours.

When Pg H1 is a Boc group, compound (H-iv) can be obtained by deprotection in the presence of an acid such as TFA.
Examples of the reaction solvent include dichloromethane and chloroform.
The reaction temperature is 0 to 80 ° C., preferably room temperature to 60 ° C.
The reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.

(Third step)
Compound (Hv) in which —M 2 — is —N (R 4 ) — is reacted with compound (H-iv) in the presence of HOBt or HOAt, a base, and a condensing agent. Can be obtained.
Examples of the base include triethylamine, DIEA and the like.
Examples of the condensing agent include EDC / HCl, HATU, PyBOP, and the like.
Examples of the reaction temperature include 0 to 60 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
Examples of the reaction solvent include dichloromethane, THF, DMF, DMA, NMP, dioxane and the like.

Alternatively, the compound (H-iv) is activated with CDI or the like, and then reacted with a corresponding nucleophile to thereby react the compound (H) with —M 2 — being —C (R 5a ) (R 5b ) —. -V) can be obtained.
The reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
The reaction time is 0.5 hour to 120 hours, preferably 1 hour to 72 hours.
Examples of the reaction solvent include acetonitrile, THF, toluene, DMF, DMA, dichloromethane and the like.
　また、化合物（Ｈ－ｉ）の代わりに、以下に示す化合物（Ｈ－ｖｉ）を用いてＨ法と同様の合成を行うことが可能である。
Figure JPOXMLDOC01-appb-C000107
（式中、－Ｍ１－は－Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）－または－ＳＯ２－であり；ＰｇＨ１はカルボキシル基、スルフィニル基、またはスルホ基の適切な保護基であり；
Figure JPOXMLDOC01-appb-C000108
、Ｒａ、Ｒｂ、Ｒｃ、Ｒ５ａ、Ｒ５ｂ、ｎおよびｍは、上記（１）と同意義である。） Further, instead of the compound (Hi), it is possible to carry out the same synthesis as the method H using the compound (H-vi) shown below.
Figure JPOXMLDOC01-appb-C000107
Wherein —M 1 — is —C (═O) —, —S (═O) — or —SO 2 —; Pg H1 is a suitable protecting group for a carboxyl group, sulfinyl group or sulfo group Yes;
Figure JPOXMLDOC01-appb-C000108
, Ra, Rb, Rc, R 5a , R 5b , n and m have the same meanings as (1) above. )
　式（Ｉ）で示される化合物の光学活性体は、光学活性な出発原料を用いる、適当な段階で不斉合成を行い光学活性な中間体を得る、またはラセミ体である中間体若しくは最終物を適当な段階で光学分割することにより製造することができる。光学分割の手法としては、光学活性カラムを用いて光学異性体を分離する方法、酵素反応等を利用した速度論的光学分割、キラルな酸、キラルな塩基を用いての塩形成によるジアステレオマーの晶析分割、優先晶出法等がある。 The optically active form of the compound represented by the formula (I) is an optically active starting material, an asymmetric synthesis is carried out at an appropriate stage to obtain an optically active intermediate, or an intermediate or final product that is a racemate. It can be manufactured by optical resolution at an appropriate stage. Optical resolution methods include separation of optical isomers using an optically active column, kinetic optical resolution using enzymatic reactions, etc., diastereomers by salt formation using chiral acids and chiral bases. There are crystallization division, preferential crystallization method and the like.
　より好ましい本発明化合物は、ＩＴＫ阻害作用のみならず、医薬としての有用性を備えており、下記いずれか、あるいは全ての優れた特徴を有する。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
ｂ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｃ）代謝安定性が高い。
ｄ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、本明細書に記載する測定条件の濃度範囲内で不可逆的阻害作用を示さない。
ｅ）変異原性を有さない。
ｆ）心血管系のリスクが低い。
ｇ）高い溶解性を示す。
ｈ）ＩＴＫに対する高い選択性を有している。 The more preferred compound of the present invention has not only an ITK inhibitory action but also a usefulness as a medicine, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
h) High selectivity for ITK.
　本発明の医薬組成物を投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、注射剤等の通常用いられるいずれの剤型でも好適に投与することができる。本発明に係る化合物は経口吸収性が高いため、経口剤として好適に使用できる。 When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。 Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
　以下に本発明の実施例および参考例、ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples of the present invention, but the present invention is not limited thereto.
　各実施例で得られたＮＭＲ分析は、４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３を用いて測定した。
　下記表に示された化合物のＬＣ／ＭＳ：分析液体クロマトグラフィー／質量分析は、以下の分析条件にて測定した。また、ＬＣ／ＭＳの分析結果を［Ｍ＋Ｈ］、保持時間（分）および分析条件番号として、以下の別表に示した。 The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d 6 and CDCl 3 .
LC / MS: Analytical liquid chromatography / mass spectrometry of the compounds shown in the table below was measured under the following analytical conditions. The LC / MS analysis results are shown in the following table as [M + H], retention time (minutes), and analysis condition number.
分析条件（１）
　カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
　流速：０．８　ｍＬ／分
　ＵＶ検出波長：２５４ｎｍ
　移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
　グラジェント：３．５分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した

分析条件（２）
　カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
　流速：０．８　ｍＬ／分
　ＵＶ検出波長：２５４ｎｍ
　移動相：［Ａ］は１０ｍＭ炭酸アンモニウム含有水溶液、［Ｂ］はアセトニトリル
　グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した

分析条件（３）
　カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）　（Ｓｈｉｍａｄｚｕ）
　流速：１．６　ｍＬ／分
　ＵＶ検出波長：２５４ｎｍ
　移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
　グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した

分析条件（４）
　カラム：Ｇｅｍｉｎｉ－ＮＸ　（５μｍ、ｉ．ｄ．４．６ｘ５０ｍｍ）（Ｐｈｅｎｏｍｅｎｅｘ）
　流速：３　ｍＬ／分
　ＵＶ検出波長：２５４ｎｍ
　移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
　グラジェント：３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した Analysis conditions (1)
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: A linear gradient of 10% -100% solvent [B] is performed in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.

Analysis conditions (2)
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile. Gradient: Linear gradient of 5% -100% solvent [B] is performed for 3.5 minutes, and 100% solvent [B] is added for 0.5 minutes. B] was maintained

Analysis conditions (3)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: A linear gradient of 10% -100% solvent [B] is performed in 3 minutes. Maintained 100% solvent [B] for 5 minutes

Analysis conditions (4)
Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Perform a linear gradient of 5% -100% solvent [B] in 3.5 minutes. 100% solvent [B] was maintained for 0.5 minutes.
実施例１　化合物Ｉ－２５３の合成
Figure JPOXMLDOC01-appb-C000109
工程１
　化合物１（５１．４ｇ、０．２０ｍｏｌ）のアセトニトリル（５００ｍＬ）溶液に、炭酸カリウム（５５．２ｇ、０．４０ｍｏｌ）とベンジルブロミド（３７．６ｇ、０．２２ｍｏｌ）を加えた。室温にて、終夜で攪拌後、減圧濃縮した。残渣に、水を加え、酢酸エチルで抽出を行なった。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル－酢酸エチル　１５：１）により精製して化合物２（３５ｇ、収率５０％）を得た。

工程２
　化合物２（３５ｇ、０．１ｍｏｌ）のジクロロメタン（５００ｍＬ）溶液に、ＤＩＥＡ（２５．８ｇ、０．２０ｍｍｏｌ）と、ヒドロキシルアミン塩酸塩（１３．８ｇ、０．２０ｍｏｌ）を加えた。反応混合物を室温にて、終夜で攪拌後、水と飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をエタノール（３００ｍＬ）に溶解し、ラネーニッケル（５ｇ）を加え、水素雰囲気下、室温で撹拌した。反応後、濾過し、減圧濃縮し、粗生成物３（１０ｇ、収率２８．７％）を得た。

工程３
　粗生成物３（６００ｍｇ、２．０７ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液に、ＨＡＴＵ（１．１８ｇ、　３．１０ｍｍｏｌ）とＤＭＦ（８０１ｍｇ、６．２１ｍｍｏｌ）を加え室温にて、攪拌した。３０分後、１－（２－ヒドロキシ－２－メチルプロピル）－５－メチル－３－オキソ－２－フェニル－２，３－ジヒドロ－１Ｈ－ピラゾール－４－カルボン酸（７２０ｍｇ、２．０７ｍｍｏｌ）を加えた。終夜にて攪拌後、反応混合液を水（１５ｍＬ）に加えた。酢酸エチルで抽出を行い、有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物４を得た。
MS (ESI) m/z 621.3 [M+H]+、MS (ESI) m/z 643.3 [M+Na]+

工程４
　化合物４（２３７ｍｇ、０．３８ｍｍｏｌ）の酢酸エチル（２ｍＬ）溶液に、４ｍｏｌ／Ｌ　塩化水素－酢酸エチル溶液（１０ｍＬ）を加え、３０分室温にて攪拌した。反応溶液を減圧濃縮し、塩酸塩を固体で得た。得られた個体を、酢酸エチル（１０ｍＬ）に懸濁した溶液を、飽和炭酸水素ナトリウム溶液で洗浄した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。化合物５を黄色固体（１８５ｍｇ、収率９３％）として得た。

工程５
　化合物５（１８０ｍｇ、０．３５ｍｍｏｌ）のトルエン（５ｍＬ）溶液に、６－ブロモベンズチアゾール（８１ｍｇ、　０．３８ｍｍｏｌ）、炭酸セシウム（３４１ｍｇ、　１．０５ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（５ｍｇ）、Ｐｄ２（ｄｂａ）３（５ｍｇ）を加え、窒素雰囲気下、１１０℃にて攪拌した。３時間後、減圧濃縮し、酢酸エチルに溶解した。水で洗浄後、有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（ＴＦＡ－アセトニトリル）により精製し、化合物６を得た。
MS (ESI) m/z 654.4 [M+H]+、MS (ESI) m/z 643.3 [M+Na]+

工程６
　化合物６（３９２ｍｇ、０．０６ｍｍｏｌ）の、エタノール（５ｍＬ）と水（５ｍＬ）の混合溶液に、水酸化リチウム（１５ｍｇ、０．６ｍｍｏｌ）を加え、室温にて２時間攪拌し、さらに、６０℃にて１時間撹拌した。減圧濃縮し、塩酸水溶液でｐＨ＝２～３付近に調整した。酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（ＴＦＡ－アセトニトリル）により精製し、ジアステレオマーとして、化合物Ｉ－２５３および化合物Ｉ－２５４を得た。
Example 1 Synthesis of Compound I-253
Figure JPOXMLDOC01-appb-C000109
Process 1
To a solution of compound 1 (51.4 g, 0.20 mol) in acetonitrile (500 mL) was added potassium carbonate (55.2 g, 0.40 mol) and benzyl bromide (37.6 g, 0.22 mol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. Water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate 15: 1) to obtain Compound 2 (35 g, yield 50%).

Process 2
To a solution of compound 2 (35 g, 0.1 mol) in dichloromethane (500 mL) was added DIEA (25.8 g, 0.20 mmol) and hydroxylamine hydrochloride (13.8 g, 0.20 mol). The reaction mixture was stirred at room temperature overnight and then washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (300 mL), Raney nickel (5 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After the reaction, the mixture was filtered and concentrated under reduced pressure to obtain a crude product 3 (10 g, yield 28.7%).

Process 3
HATU (1.18 g, 3.10 mmol) and DMF (801 mg, 6.21 mmol) were added to a solution of crude product 3 (600 mg, 2.07 mmol) in DMF (10 mL), and the mixture was stirred at room temperature. After 30 minutes, 1- (2-hydroxy-2-methylpropyl) -5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (720 mg, 2.07 mmol) Was added. After stirring overnight, the reaction mixture was added to water (15 mL). Extraction was performed with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase liquid chromatography (10 mmol / L ammonium carbonate-containing aqueous solution-acetonitrile) to obtain compound 4.
MS (ESI) m / z 621.3 [M + H] +, MS (ESI) m / z 643.3 [M + Na] +

Process 4
To a solution of compound 4 (237 mg, 0.38 mmol) in ethyl acetate (2 mL) was added 4 mol / L hydrogen chloride-ethyl acetate solution (10 mL), and the mixture was stirred for 30 minutes at room temperature. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride as a solid. A solution obtained by suspending the obtained solid in ethyl acetate (10 mL) was washed with a saturated sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Compound 5 was obtained as a yellow solid (185 mg, 93% yield).

Process 5
To a solution of compound 5 (180 mg, 0.35 mmol) in toluene (5 mL), 6-bromobenzthiazole (81 mg, 0.38 mmol), cesium carbonate (341 mg, 1.05 mmol), Xantphos (5 mg), Pd 2 (dba) 3 (5 mg) was added, and the mixture was stirred at 110 ° C. under a nitrogen atmosphere. After 3 hours, the solution was concentrated under reduced pressure and dissolved in ethyl acetate. After washing with water, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase liquid chromatography (TFA-acetonitrile) to give compound 6.
MS (ESI) m / z 654.4 [M + H] +, MS (ESI) m / z 643.3 [M + Na] +

Step 6
Lithium hydroxide (15 mg, 0.6 mmol) was added to a mixed solution of compound 6 (392 mg, 0.06 mmol) in ethanol (5 mL) and water (5 mL), and the mixture was stirred at room temperature for 2 hours. For 1 hour. The mixture was concentrated under reduced pressure, and adjusted to pH = 2 to 3 with an aqueous hydrochloric acid solution. Extraction was performed with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (TFA-acetonitrile) to give Compound I-253 and Compound I-254 as diastereomers.
実施例２
Figure JPOXMLDOC01-appb-C000110
工程１
　化合物２と同様にして得られた化合物７（１０ｇ、３６ｍｍｏｌ）を、濃塩酸（５０ｍＬ）中、加熱還流した。２時間後、反応溶液を減圧濃縮し、化合物８（４．０ｇ、収率４３％）を得た。

工程２
　化合物８（３．５ｇ、２５．８ｍｍｏｌ）と、Ｂｏｃ２Ｏ（６．８ｇ、３１ｍｍｏｌ）、水酸化ナトリウム（２．１８ｇ、５４．２ｍｍｏｌ）を、ｔｅｒｔ－ブタノール・水（２０ｍＬ、２０ｍＬ）に溶解し、３０℃にて１６時間攪拌した。酢酸エチルで抽出後、有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル－酢酸エチル　１０：１）により精製して化合物９（２．５ｇ、収率４０％）をオイルとして得た。

工程３
　化合物９（２．５ｇ、１２．５ｍｏｌ）のジクロロメタン（２０ｍＬ）溶液に、ピリジン（３．９ｇ、５０ｍｍｏｌ）、ヒドロキシルアミン塩酸塩（２．６ｇ、３７．３ｍｍｏｌ）を加え、室温で４時間攪拌した。反応溶液をｐＨ＝５付近まで塩酸水溶液で中和し、有機層を減圧濃縮し、化合物１０を得た（２ｇ、収率８０％）。

工程４
　化合物１０（２ｇ）をメタノール（３０ｍＬ）に溶解し、ラネーニッケル（０．５ｇ、wet）を加え、水素雰囲気下、室温で撹拌した。反応終了後、反応液を濾過し、減圧濃縮し、化合物１１（２ｇ、収率１００％）をラセミ体として得た。得られた化合物１１は、精製することなく、次の反応に用いた。

　実施例１における化合物３の代わりに化合物１１を用い、実施例１と同様の反応を行うことにより、下記表に記載の実施例化合物を合成した。
Example 2
Figure JPOXMLDOC01-appb-C000110
Process 1
Compound 7 (10 g, 36 mmol) obtained in the same manner as Compound 2 was heated to reflux in concentrated hydrochloric acid (50 mL). After 2 hours, the reaction solution was concentrated under reduced pressure to obtain Compound 8 (4.0 g, yield 43%).

Process 2
Compound 8 (3.5 g, 25.8 mmol), Boc 2 O (6.8 g, 31 mmol), sodium hydroxide (2.18 g, 54.2 mmol) dissolved in tert-butanol / water (20 mL, 20 mL) And stirred at 30 ° C. for 16 hours. After extraction with ethyl acetate, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether-ethyl acetate 10: 1) to obtain Compound 9 (2.5 g, yield 40%) as an oil.

Process 3
Pyridine (3.9 g, 50 mmol) and hydroxylamine hydrochloride (2.6 g, 37.3 mmol) were added to a solution of compound 9 (2.5 g, 12.5 mol) in dichloromethane (20 mL), and the mixture was stirred at room temperature for 4 hours. . The reaction solution was neutralized with an aqueous hydrochloric acid solution to near pH = 5, and the organic layer was concentrated under reduced pressure to obtain Compound 10 (2 g, yield 80%).

Process 4
Compound 10 (2 g) was dissolved in methanol (30 mL), Raney nickel (0.5 g, wet) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure to obtain Compound 11 (2 g, yield 100%) as a racemate. The obtained compound 11 was used for the next reaction without purification.

Example compounds described in the following table were synthesized by performing the same reaction as in Example 1 using Compound 11 instead of Compound 3 in Example 1.
実施例３
Figure JPOXMLDOC01-appb-I000111

工程１
　化合物４と同様にして得られた化合物１４（１６．７ｇ、３４．４ｍｍｏｌ）と、水酸化リチウム・１水和物（４．４ｇ、１０３ｍｇ）を、メタノール・水（１００ｍＬ：１０ｍＬ）に加え、３０℃にて１６時間攪拌した。ｐＨを５付近とし、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、化合物１５（１５．７ｇ、１００％）を得た。
MS (ESI) m/z 459.2 [M+H]+

工程２
　化合物１５（１０．０ｇ、２１．８ｍｍｏｌ）と、ＤＰＰＡ（１８ｇ、６５．５ｍｍｏｌ）、トリエチルアミン（８．８３ｇ、８７．４ｍｍｏｌ）をＴＨＦ（２００ｍＬ）に溶解し、６０℃にて８時間攪拌した。水を加えて、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロロメタン－メタノール　２０：１）により精製して化合物１６（５．０ｇ、収率４７％）を得た。
MS (ESI) m/z 499.2 [M+H]+

工程３
　化合物１６（４．５ｇ、９．０４ｍｍｏｌ）と、水酸化ナトリウム（１．０８ｇ、　２７．１ｍｇ）を、ジオキサン・水（３０ｍＬ：５ｍＬ）に加え、４０℃にて３時間撹拌した。混合物に水を加えて、ジクロロメタンで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、化合物１７（３．６ｇ、　９０％）を得た。
MS (ESI) m/z 430.2 [M+H]+

工程４
　化合物１７（１００ｍｇ、０．２３ｍｍｏｌ）、トリエチルアミン（４６ｍｇ、０．４６ｍｍｏｌ）を、ジクロロメタン（５ｍＬ）に溶解し、ｔｅｒｔ－ブチルイソシアナート（３５ｍｇ、０．３５ｍｍｏｌ）を加え、３０℃にて８時間攪拌した。減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物１８（５０ｍｇ、収率４０％）を得た。
MS (ESI) m/z 529.3 [M+H]+

工程５
　化合物１８（５０ｍｇ、０．１７ｍｍｏｌ）のジクロロメタン（６ｍＬ）に溶液に、ＴＦＡ（２ｍＬ）を加え、加熱還流した。１６時間後、減圧濃縮し、化合物１９（３０ｍｇ、収率７５％）を得た。
MS (ESI) m/z 373.19 [M+H]+

　実施例４における化合物２０の代わりに化合物１９を用い、実施例４と同様の反応を行うことにより、下記表に記載の実施例化合物を合成した。
Example 3
Figure JPOXMLDOC01-appb-I000111

Process 1
Compound 14 (16.7 g, 34.4 mmol) obtained in the same manner as Compound 4 and lithium hydroxide monohydrate (4.4 g, 103 mg) were added to methanol / water (100 mL: 10 mL), Stir at 30 ° C. for 16 hours. The pH was adjusted to around 5 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound 15 (15.7 g, 100%).
MS (ESI) m / z 459.2 [M + H] +

Process 2
Compound 15 (10.0 g, 21.8 mmol), DPPA (18 g, 65.5 mmol) and triethylamine (8.83 g, 87.4 mmol) were dissolved in THF (200 mL), and the mixture was stirred at 60 ° C. for 8 hours. Water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane-methanol 20: 1) to obtain Compound 16 (5.0 g, yield 47%).
MS (ESI) m / z 499.2 [M + H] +

Process 3
Compound 16 (4.5 g, 9.04 mmol) and sodium hydroxide (1.08 g, 27.1 mg) were added to dioxane / water (30 mL: 5 mL), and the mixture was stirred at 40 ° C. for 3 hours. Water was added to the mixture and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound 17 (3.6 g, 90%).
MS (ESI) m / z 430.2 [M + H] +

Process 4
Compound 17 (100 mg, 0.23 mmol) and triethylamine (46 mg, 0.46 mmol) are dissolved in dichloromethane (5 mL), tert-butyl isocyanate (35 mg, 0.35 mmol) is added, and the mixture is stirred at 30 ° C. for 8 hours. did. The residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to obtain Compound 18 (50 mg, 40% yield).
MS (ESI) m / z 529.3 [M + H] +

Process 5
To a solution of compound 18 (50 mg, 0.17 mmol) in dichloromethane (6 mL) was added TFA (2 mL) and heated to reflux. After 16 hours, the mixture was concentrated under reduced pressure to obtain Compound 19 (30 mg, yield 75%).
MS (ESI) m / z 373.19 [M + H] +

Example compounds described in the following table were synthesized by performing the same reaction as in Example 4 using Compound 19 in place of Compound 20 in Example 4.
実施例４　化合物Ｉ－２４２の合成
Figure JPOXMLDOC01-appb-C000112
　化合物１９と同様にして得られた化合物２０（５００ｍｇ、１．３ｍｍｏｌ）と５－ブロモチアゾロ[５，４－Ｂ]ピリジン－２－アミンと炭酸カリウム（３１ｍｇ、０．２２ｍｍｏｌ）をＤＭＦ（３ｍＬ）に溶解し１４０℃にて撹拌した。４時間後、水を加えて、ジクロロメタンで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（ＴＦＡ－アセトニトリル）により精製して化合物Ｉ－２４２（１４３ｍｇ、収率１４％）を得た。
MS (ESI) m/z 464.31[M+H]+
Example 4 Synthesis of Compound I-242
Figure JPOXMLDOC01-appb-C000112
Compound 20 (500 mg, 1.3 mmol), 5-bromothiazolo [5,4-B] pyridin-2-amine and potassium carbonate (31 mg, 0.22 mmol) obtained in the same manner as Compound 19 were added to DMF (3 mL). Dissolved and stirred at 140 ° C. After 4 hours, water was added and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (TFA-acetonitrile) to obtain Compound I-242 (143 mg, yield 14%).
MS (ESI) m / z 464.31 [M + H] +
実施例５
Figure JPOXMLDOC01-appb-C000113
工程１
　３－アミノ－６－クロロピリダジン（１００ｇ、０．７７ｍｏｌ）を２－クロロアセトアルデヒド（６６８．５ｇ、３５％水溶液、２．６７ｍｏｌ）のエタノール（１Ｌ）溶液を、窒素雰囲気下、４時間加熱還流した。反応混合物を１００ｍＬまで濃縮後、室温まで冷却した。生成した固体を濾取し、エタノールで洗浄・乾燥し、化合物２２（１００ｇ、収率８４％）を得た。
MS (ESI) m/z 154[M+H]+

工程２
　化合物２２（１０ｇ、６４ｍｍｏｌ）のＤＭＳＯ（６５ｍＬ）溶液に、１８―クラウン―６（２０．６ｇ、７８ｍｍｏｌ）とフッ化カリウム（１１．４ｇ、１９６ｍｍｏｌ）を加えた。得られた混合物を、窒素気流中下、２００℃にて３時間撹拌した。濾過後、逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物２３を得た。
MS (ESI) m/z 138[M+H]+

工程３
　化合物２３（２００ｍｇ、１．４６ｍｍｏｌ）をＤＭＦ（４ｍＬ）に溶解し、ＮＩＳ（４９２ｍｇ、２．１９ｍｍｏｌ）を加え、室温にて４時間撹拌した。反応溶液に水を加えクロロホルムで抽出、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物２４（１０２ｍｇ、収率２７％）を得た。
MS (ESI) m/z 264 [M+H]+ 

　実施例７における化合物２９の代わりに化合物２４を用いることにより、下記表に記載の実施例化合物を合成した。
Example 5
Figure JPOXMLDOC01-appb-C000113
Process 1
A solution of 3-amino-6-chloropyridazine (100 g, 0.77 mol) in 2-chloroacetaldehyde (668.5 g, 35% aqueous solution, 2.67 mol) in ethanol (1 L) was heated to reflux for 4 hours under a nitrogen atmosphere. . The reaction mixture was concentrated to 100 mL and then cooled to room temperature. The produced solid was collected by filtration, washed with ethanol and dried to obtain compound 22 (100 g, yield 84%).
MS (ESI) m / z 154 [M + H] +

Process 2
To a solution of compound 22 (10 g, 64 mmol) in DMSO (65 mL), 18-crown-6 (20.6 g, 78 mmol) and potassium fluoride (11.4 g, 196 mmol) were added. The resulting mixture was stirred at 200 ° C. for 3 hours in a nitrogen stream. After filtration, the compound 23 was obtained by purification by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile).
MS (ESI) m / z 138 [M + H] +

Process 3
Compound 23 (200 mg, 1.46 mmol) was dissolved in DMF (4 mL), NIS (492 mg, 2.19 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 24 (102 mg, yield 27%).
MS (ESI) m / z 264 [M + H] +

Example compounds described in the following table were synthesized by using compound 24 instead of compound 29 in example 7.
実施例６
Figure JPOXMLDOC01-appb-C000114
工程１
　２－ブロモ－６－フルオロピリジン（２．６ｇ、１４．８ｍｍｏｌ）、３－メトキシアゼチジン・塩酸塩（１８ｇ、１４．８ｍｍｏｌ）、炭酸カリウム（８．２ｇ、５９．１ｍｍｏｌ）を、ＤＭＦ（３０ｍＬ）中、室温にて１５時間攪拌後、６０℃にて８時間撹拌した。室温に冷却後、反応混合液を水（３００ｍＬ）に注ぎ、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物２６（２．８ｇ、収率７８％）をオイルとして得た。

工程２
　化合物２６（２．２ｇ、２９．３ｍｍｏｌ）の無水ＴＨＦ（４０ｍＬ）溶液に、ｎ－ブチルリチウム（４．４ｇ、１１ｍｍｏｌ、２．５Ｍ　ＴＨＦ溶液）を－７８℃にて、滴下した。３０分間、－７８℃にて攪拌後、トリブチルチンクロリド（３．９ｇ、１１．０ｍｍｏｌ）を、同温を保ちつつ加えた。－７８℃にて３０分攪拌後、フッ化カリウム水溶液（１０ｍＬ）を加え、室温で３０分攪拌した。混合物をセライトで濾過し、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝１０：１～５：１）で精製し、化合物２７（３．２ｇ、収率７８％）をオイルとして得た。

　実施例７における工程２の反応を行うことにより、下記表に記載の実施例化合物を合成した。
Example 6
Figure JPOXMLDOC01-appb-C000114
Process 1
2-Bromo-6-fluoropyridine (2.6 g, 14.8 mmol), 3-methoxyazetidine hydrochloride (18 g, 14.8 mmol), potassium carbonate (8.2 g, 59.1 mmol) were added to DMF (30 mL). The mixture was stirred at room temperature for 15 hours and then at 60 ° C. for 8 hours. After cooling to room temperature, the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 26 (2.8 g, yield 78%) as an oil.

Process 2
To a solution of compound 26 (2.2 g, 29.3 mmol) in anhydrous THF (40 mL), n-butyllithium (4.4 g, 11 mmol, 2.5 M THF solution) was added dropwise at −78 ° C. After stirring at −78 ° C. for 30 minutes, tributyltin chloride (3.9 g, 11.0 mmol) was added while maintaining the same temperature. After stirring at −78 ° C. for 30 minutes, an aqueous potassium fluoride solution (10 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through celite and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain Compound 27 (3.2 g, yield 78%) as an oil.

Example compounds described in the following table were synthesized by carrying out the reaction in Step 2 of Example 7.
実施例７　化合物Ｉ－５３９およびＩ－５４５の合成
Figure JPOXMLDOC01-appb-C000115
工程１
　化合物２４と同様にして得られた化合物２９（２３５ｍｇ、　０．８４３ｍｍｏｌ）と化合物２８（２５８ｍｇ、０．７６ｍｍｏｌ）、ＤＩＥＡ（４００μＬ、２．２９ｍｍｏｌ）のＤＭＦ溶液（２ｍＬ）を、１２５℃にて４時間撹拌した。室温に冷却後、水を加えて、酢酸エチルで抽出した。有機層を、有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－５３９（８７ｍｇ、収率２１％）を得た。
MS (ESI) m/z 544[M+H]+

工程２
　窒素雰囲気下、化合物Ｉ－５３９（２７ｍｇ、０．０５ｍｍｏｌ）、化合物２７（３４ｍｇ、　０．０７５ｍｍｏｌ）、Ｐｄ（ＰＰｈ３）４６ｍｇ、１０ｍｏｌ％）のＤＭＦ溶液（１．５ｍＬ）を、９０℃にて８時間撹拌した。室温に冷却後、酢酸エチルを加えて、セライトで濾過した。硫酸ナトリウムで乾燥し、減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－５４５（８ｍｇ、収率２６％）を得た。
MS (ESI) m/z 580[M+H]+
Example 7 Synthesis of Compounds I-539 and I-545
Figure JPOXMLDOC01-appb-C000115
Process 1
A DMF solution (2 mL) of compound 29 (235 mg, 0.843 mmol), compound 28 (258 mg, 0.76 mmol), DIEA (400 μL, 2.29 mmol) obtained in the same manner as compound 24 was added at 125 ° C. Stir for hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-539 (87 mg, yield). 21%) was obtained.
MS (ESI) m / z 544 [M + H] +

Process 2
Under a nitrogen atmosphere, a DMF solution (1.5 mL) of compound I-539 (27 mg, 0.05 mmol), compound 27 (34 mg, 0.075 mmol), Pd (PPh 3 ) 4 6 mg, 10 mol%) was heated to 90 ° C. And stirred for 8 hours. After cooling to room temperature, ethyl acetate was added and filtered through celite. The extract was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse-phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to obtain Compound I-545 (8 mg, 26% yield). .
MS (ESI) m / z 580 [M + H] +
実施例８　化合物Ｉ－５４０の合成
Figure JPOXMLDOC01-appb-C000116
工程１
　化合物２８（２５８ｍｇ、０．７６ｍｍｏｌ）、化合物３０（ＷＯ２０１２／０３４０９１Ａ１に記載、９０ｍｇ、　０．８４３ｍｍｏｌ）、ＤＩＥＡ（４００μＬ、２．２９ｍｍｏｌ）のＤＭＦ溶液（２ｍＬ）を、１２５℃にて２時間撹拌した。室温に冷却後、水を加えて、酢酸エチルで抽出した。有機層を、有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－５４０（２１０ｍｇ、収率５６％）を得た。
MS (ESI) m/z 490[M+H]+
Example 8 Synthesis of Compound I-540
Figure JPOXMLDOC01-appb-C000116
Process 1
A DMF solution (2 mL) of compound 28 (258 mg, 0.76 mmol), compound 30 (described in WO2012 / 034091A1, 90 mg, 0.843 mmol), DIEA (400 μL, 2.29 mmol) was stirred at 125 ° C. for 2 hours. . After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-540 (210 mg, yield). 56%).
MS (ESI) m / z 490 [M + H] +
実施例９　化合物Ｉ－２５５、Ｉ－２３０、およびＩ－２５９の合成
Figure JPOXMLDOC01-appb-C000117
工程１
　化合物３１（１．４ｇ、６．９６ｍｍｏｌ）、１、５－ジメチル－３－オキソ－２－フェニル－２，３－ジヒドロ－１Ｈ－ピラゾール－４－カルボン酸（９６９ｍｇ、４．１７ｍｍｏｌ）をＤＭＦ１５ｍＬに溶解し、ＨＡＴＵ（１．５９ｇ、４．１７ｍｍｏｌ）、ＤＩＥＡ（３．０４ｍＬ、１７．４ｍｍｏｌ）を加え、室温で撹拌した。２時間後、Ｎ－（ベンジルオキシカルボニルオキシ）スクシイミド（３．７４ｇ、１３．９ｍｍｏｌ）を加え、室温で終夜反応させた。水を加えクロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物３２（１．６８ｇ、収率４４％）を得た。
MS (ESI) m/z 550 [M+H]+

工程２
　化合物３２（１．６８ｇ、０．７５ｍｍｏｌ）を酢酸エチル２０ｍＬに溶解し、４ｍｏｌ／Ｌ　塩化水素－酢酸エチル溶液（１５．３ｍＬ）を加え、室温で３０分撹拌した。減圧濃縮し、得られた残渣に酢酸エチル－ヘキサンを加え固体を析出させた後、濾取することにより化合物３３（１．３０ｇ、収率９５％）を得た。
MS (ESI) m/z 450 [M+H]+

工程３
　化合物３３（７００ｍｇ、１．５６ｍｍｏｌ）、化合物２２（５９８ｍｇ、３．８９ｍｍｏｌ）をＮＭＰ（３ｍＬ）に溶解し、ＤＩＥＡ（０．６８ｍＬ、３．８９ｍｍｏｌ）を加え、マイクロウェーブ下、１５０℃にて２．５時間撹拌した。水を加えクロロホルムで抽出し、有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２５５（４１５ｍｇ、収率４７％）を得た。
MS (ESI) m/z ５６７ [M+H]+

工程４
　化合物Ｉ－２５５（４１５ｍｇ、０．７３ｍｍｏｌ）をメタノール２０ｍＬに溶解し、１０％パラジウムカーボンを加え、水素雰囲気下、室温で７時間撹拌した。濾過し、得られた残渣を再度メタノール２０ｍＬに溶解し、１０％パラジウムカーボンを加え、水素雰囲気下、室温で７時間撹拌した。濾過し、化合物Ｉ－２３０（２６０ｍｇ、収率８２％）を得た。
MS (ESI) m/z ４３３ [M+H]+

工程５
　化合物Ｉ－２３０（１５ｍｇ、０．０３５ｍｍｏｌ）をジクロロメタン（１ｍＬ）に溶解し、プロピオニルクロリド（３．８ｍｇ、０．０４２ｍｍｏｌ）、トリエチルアミン（０．０１４ｍＬ、０．１０ｍｍｏｌ）を加え、室温で１時間撹拌した。水を加えクロロホルムで抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－２５９（１３．４ｍｇ、収率７９％）を得た。
MS (ESI) m/z ４８９ [M+H]+
Example 9 Synthesis of Compounds I-255, I-230, and I-259
Figure JPOXMLDOC01-appb-C000117
Process 1
Compound 31 (1.4 g, 6.96 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (969 mg, 4.17 mmol) in 15 mL DMF Dissolved, HATU (1.59 g, 4.17 mmol), DIEA (3.04 mL, 17.4 mmol) were added and stirred at room temperature. After 2 hours, N- (benzyloxycarbonyloxy) succinimide (3.74 g, 13.9 mmol) was added and allowed to react overnight at room temperature. Water was added and extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 32 (1.68 g, yield 44%).
MS (ESI) m / z 550 [M + H] +

Process 2
Compound 32 (1.68 g, 0.75 mmol) was dissolved in 20 mL of ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate solution (15.3 mL) was added, and the mixture was stirred at room temperature for 30 min. After concentration under reduced pressure, ethyl acetate-hexane was added to the resulting residue to precipitate a solid, which was then collected by filtration to obtain Compound 33 (1.30 g, yield 95%).
MS (ESI) m / z 450 [M + H] +

Process 3
Compound 33 (700 mg, 1.56 mmol) and compound 22 (598 mg, 3.89 mmol) were dissolved in NMP (3 mL), DIEA (0.68 mL, 3.89 mmol) was added, and 2 microwaves at 150 ° C. were added. Stir for 5 hours. Water was added and the mixture was extracted with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-255 (415 mg, yield 47%).
MS (ESI) m / z 567 [M + H] +

Process 4
Compound I-255 (415 mg, 0.73 mmol) was dissolved in 20 mL of methanol, 10% palladium carbon was added, and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. The residue obtained by filtration was dissolved again in 20 mL of methanol, 10% palladium carbon was added, and the mixture was stirred at room temperature for 7 hours in a hydrogen atmosphere. Filtration gave compound I-230 (260 mg, 82% yield).
MS (ESI) m / z 433 [M + H] +

Process 5
Compound I-230 (15 mg, 0.035 mmol) is dissolved in dichloromethane (1 mL), propionyl chloride (3.8 mg, 0.042 mmol) and triethylamine (0.014 mL, 0.10 mmol) are added, and the mixture is stirred at room temperature for 1 hour. did. Water was added, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to obtain Compound I-259 (13.4 mg, yield 79%).
MS (ESI) m / z 489 [M + H] +
実施例１０　化合物Ｉ－２３３の合成
Figure JPOXMLDOC01-appb-C000118
　化合物Ｉ－２３０（３４ｍｇ、０．０７９ｍｍｏｌ）をメタノール（０．９ｍＬ）に溶解し、酢酸（０．１ｍＬ）、アセトアルデヒド（０．００７ｍＬ、０．１２ｍｍｏｌ）を加え、室温で撹拌した。３０分後０℃に冷却し、水素化ホウ素ナトリウム（９ｍｇ、０．２４ｍｍｏｌ）を加え、室温で２．５時間攪拌した。飽和重曹水を加えクロロホルムで抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－２３３（７．２ｍｇ、収率２０％）を得た。
MS (ESI) m/z ４６１ [M+H]+
Example 10 Synthesis of Compound I-233
Figure JPOXMLDOC01-appb-C000118
Compound I-230 (34 mg, 0.079 mmol) was dissolved in methanol (0.9 mL), acetic acid (0.1 mL) and acetaldehyde (0.007 mL, 0.12 mmol) were added, and the mixture was stirred at room temperature. After 30 minutes, the mixture was cooled to 0 ° C., sodium borohydride (9 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate was added, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to obtain Compound I-233 (7.2 mg, yield 20%).
MS (ESI) m / z 461 [M + H] +
実施例１１　化合物Ｉ－２３７およびＩ－２３８の合成
Figure JPOXMLDOC01-appb-C000119
工程１
　化合物３３（２００ｍｇ、０．４５ｍｍｏｌ）、化合物３４（２８７ｍｇ、１．３４ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、炭酸カリウム（１８４ｍｇ、１．３４ｍｍｏｌ）を加え、１４０℃にて１．５時間撹拌した。水を加えクロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、さらにシリカゲルカラムクロマトグラフィー（酢酸エチル－ヘキサン）により精製して化合物３５（３２ｍｇ、収率１２％）を得た。
MS (ESI) m/z ５８４ [M+H]+

工程２
　化合物３５（２２ｍｇ、０．０３８ｍｍｏｌ）を酢酸０．４ｍＬに溶解し、２５％臭化水素－酢酸溶液（０．０８２ｍＬ、０．３８ｍｍｏｌ）を加え室温で３０分撹拌した。さらに２５％臭化水素－酢酸溶液（０．０４１ｍＬ、０．１９ｍｍｏｌ）を追加し、室温で４０分撹拌した後、減圧濃縮し、化合物Ｉ－２３７の粗生成物を得た。
MS (ESI) m/z 450 [M+H]+

工程３
　化合物Ｉ－２３７（１８ｍｇ、０．０４０ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、ＤＩＥＡ（０．０１７ｍＬ、０．１０ｍｍｏｌ）、無水酢酸（０．００５ｍＬ、０．０４８ｍｍｏｌ）を加え、室温で３０分攪拌した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物Ｉ－２３８（４．１ｍｇ、収率２１％）を得た。
MS (ESI) m/z 492 [M+H]+
Example 11 Synthesis of Compounds I-237 and I-238
Figure JPOXMLDOC01-appb-C000119
Process 1
Compound 33 (200 mg, 0.45 mmol) and compound 34 (287 mg, 1.34 mmol) were dissolved in DMF (1 mL), potassium carbonate (184 mg, 1.34 mmol) was added, and the mixture was stirred at 140 ° C. for 1.5 hours. . Water was added, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol), and further purified by silica gel column chromatography (ethyl acetate-hexane) to obtain Compound 35 (32 mg, 12% yield).
MS (ESI) m / z 584 [M + H] +

Process 2
Compound 35 (22 mg, 0.038 mmol) was dissolved in 0.4 mL of acetic acid, 25% hydrogen bromide-acetic acid solution (0.082 mL, 0.38 mmol) was added, and the mixture was stirred at room temperature for 30 min. Further, a 25% hydrogen bromide-acetic acid solution (0.041 mL, 0.19 mmol) was added, and the mixture was stirred at room temperature for 40 minutes and then concentrated under reduced pressure to obtain a crude product of compound I-237.
MS (ESI) m / z 450 [M + H] +

Process 3
Compound I-237 (18 mg, 0.040 mmol) was dissolved in DMF (1 mL), DIEA (0.017 mL, 0.10 mmol) and acetic anhydride (0.005 mL, 0.048 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. did. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-238 (4.1 mg, yield 21%).
MS (ESI) m / z 492 [M + H] +
実施例１２　化合物Ｉ－２５８の合成
Figure JPOXMLDOC01-appb-C000120
工程１
　化合物３７（４１０ｍｇ、１．６７ｍｍｏｌ）をＤＭＦ１０ｍＬに溶解し、ＨＡＴＵ（６３３ｍｇ、１．６７ｍｍｏｌ）、ＤＩＥＡ（０．６０６ｍＬ、３．４７ｍｍｏｌ）、化合物３６（３００ｍｇ、１．３９ｍｍｏｌ）を加え室温で３０分攪拌し、終夜で静置した。水を加えクロロホルムで抽出した後、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物３８（６３１ｍｇ、収率１００％）を得た。
MS (ESI) m/z ４４５ [M+H]+

工程２
　化合物３８（６３１ｍｇ、１．４２ｍｍｏｌ）を酢酸エチル１０ｍＬに溶解し、４ｍｏｌ／Ｌ　塩化水素－酢酸エチル溶液（７．１ｍＬ）を加え、室温で２時間撹拌した。減圧濃縮し、化合物３９（４４７ｍｇ、収率９１％）を得た。
MS (ESI) m/z ３４５ [M+H]+

工程３
　化合物３９（１５０ｍｇ、０．４４ｍｍｏｌ）、化合物３４（２８１ｍｇ、１．３１ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、炭酸カリウム（１８１ｍｇ、１．３１ｍｍｏｌ）を加え、１４０℃にて３０分撹拌した。水を加えクロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）、および逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－２５８（５６ｍｇ、収率２７％）を得た。
MS (ESI) m/z ４７９ [M+H]+
Example 12 Synthesis of Compound I-258
Figure JPOXMLDOC01-appb-C000120
Process 1
Compound 37 (410 mg, 1.67 mmol) was dissolved in 10 mL of DMF, HATU (633 mg, 1.67 mmol), DIEA (0.606 mL, 3.47 mmol), compound 36 (300 mg, 1.39 mmol) were added, and 30 minutes at room temperature. Stir and let stand overnight. Water was added and the mixture was extracted with chloroform and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 38 (631 mg, yield 100%).
MS (ESI) m / z 445 [M + H] +

Process 2
Compound 38 (631 mg, 1.42 mmol) was dissolved in 10 mL of ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate solution (7.1 mL) was added, and the mixture was stirred at room temperature for 2 hr. Concentration under reduced pressure gave Compound 39 (447 mg, 91% yield).
MS (ESI) m / z 345 [M + H] +

Process 3
Compound 39 (150 mg, 0.44 mmol) and compound 34 (281 mg, 1.31 mmol) were dissolved in DMF (1 mL), potassium carbonate (181 mg, 1.31 mmol) was added, and the mixture was stirred at 140 ° C. for 30 minutes. Water was added, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) and reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-258 (56 mg, yield 27%). It was.
MS (ESI) m / z 479 [M + H] +
実施例１３　化合物Ｉ－４２３およびＩ－４２４の合成
Figure JPOXMLDOC01-appb-C000121
工程１
　４－メトキシベンジルアルコール（３．８８ｍＬ、３１．３ｍｍｏｌ）をＤＭＦ（５０ｍＬ）に溶解し、氷冷下、６０％水素化ナトリウム（１．４ｇ、３４．１ｍｍｏｌ）を加え０℃にて２０分撹拌した。次に、氷冷下４－ブロモ－２－フルオロピリジン（５ｇ、２８．４ｍｍｏｌ）を加えた後室温へ昇温し、１時間半撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物４１（５．１１ｇ、収率６１％）を得た。
MS (ESI) m/z 294 [M+H]+ 

工程２
　化合物４１（８８ｍｇ、０．３０ｍｍｏｌ）をジエチルエーテル（１ｍＬ）に溶解し、－７４℃にて、１．６５ｍｏｌ／Ｌ　ｎ－ブチルリチウム－ヘキサン溶液（０．１８２ｍＬ、０．３０ｍｍｏｌ）を滴下し３０分撹拌した。次に、ＴＨＦ（０．６ｍＬ）に溶解した、化合物６７と同様にして得られた化合物５７（１００ｍｇ、０．３０ｍｍｏｌ）を－７４℃にて滴下し、－７８℃にて２時間撹拌した。反応溶液に２ｍｏｌ／Ｌ　塩酸水溶液（０．１８ｍＬ、０．３６ｍｍｏｌ）を加えジエチルエーテルとＴＨＦの混合溶液で抽出、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、粗生成物４２（２１２ｍｇ）を得た。
MS (ESI) m/z 548 [M+H]+ 

工程３
　粗生成物４２（１６５ｍＬ、０．３０ｍｍｏｌ）をメタノール（２ｍＬ）に溶解し、氷冷下、水素化ホウ素ナトリウム（１４ｍｇ、０．３６ｍｍｏｌ）を加え０℃にて１時間半撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、粗生成物４３（２０１ｍｇ）を得た。
MS (ESI) m/z 550 [M+H]+ 

工程４
　粗生成物４３（１６６ｍＬ、０．３０ｍｍｏｌ）をジクロロメタン（４ｍＬ）に溶解し、氷冷下、ＤＩＥＡ（０．１６ｍＬ、０．９１ｍｍｏｌ）、メタンスルホニルクロリド（０．０３５ｍＬ、０．４５ｍｍｏｌ）を加え、０℃にて２時間撹拌した。室温へ昇温後、更に２時間撹拌した。反応溶液に水を加えジクロロメタンで抽出、減圧濃縮し、粗生成物４４（１８５ｍｇ）を得た。
MS (ESI) m/z 532 [M+H]+ 

工程５
　粗生成物４４（１６１ｍＬ、０．３０ｍｍｏｌ）をジクロロメタン（１．５ｍＬ）に溶解し、１ｍｏｌ／Ｌ　ＴＢＡＦ－ＴＨＦ溶液（１．５１ｍＬ、１．５１ｍｍｏｌ）を加え、室温にて２時間半撹拌した。反応溶液に水を加えジクロロメタンで抽出、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物４５（４１ｍｇ、収率３２％）を得た。
MS (ESI) m/z 418 [M+H]+ 
1H-NMR (CDCl3) δ: 8.13 (1.0H, d, J = 5.3 Hz), 7.62 (2.0H, d, J = 9.4 Hz), 7.51 (1.0H, s), 7.37 (2.0H, d, J = 8.7 Hz), 6.89 (3.0H, d, J = 8.7 Hz), 6.89-6.84 (3.0H, m), 6.74 (1.0H, s), 6.38 (1.0H, d, J = 9.8 Hz), 5.27 (2.0H, s), 5.00 (1.0H, dd, J = 9.3, 2.3 Hz), 4.66 (1.0H, s), 3.92-3.80 (5.0H, m), 2.72 (1.0H, ddd, J = 13.8, 9.3, 4.7 Hz), 2.19 (1.0H, d, J = 13.8 Hz).

工程６
　化合物４５（１００ｍＬ、０．２４ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、ＤＩＥＡ（０．３８ｍＬ、２．１６ｍｍｏｌ）、メタンスルホニルクロリド（０．０５６ｍＬ、０．７２ｍｍｏｌ）を加え、室温にて３時間撹拌した。次に、アジ化ナトリウム（７８ｍｇ、１．２０ｍｍｏｌ）を加え、７０℃にて６時間半撹拌した。放冷後、反応溶液に水を加え酢酸エチルで抽出、有機層を水洗し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮した後、残留物をメタノール（１ｍＬ）に溶解し、１０％パラジウムカーボン（５０ｍｇ、０．４７ｍｍｏｌ）を加え、水素雰囲気下室温にて２６時間撹拌した。反応液を濾過し、減圧濃縮し、化合物４６（８９ｍｇ、収率８９％）を得た。
MS (ESI) m/z 417 [M+H]+ 

工程７
　化合物４６（２０ｍｇ、０．０４８ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、ＨＡＴＵ（２２ｍｇ、０．０５８ｍｍｏｌ）、化合物３７（１４ｍｇ、０．０５８ｍｍｏｌ）、ＤＩＥＡ（０．０１７ｍＬ、０．０９６ｍｍｏｌ）を加え、室温にて４時間撹拌した。反応溶液に水を加えクロロホルムで抽出、減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－４２３（１１ｍｇ、収率３７％）を得た。
MS (ESI) m/z 645 [M+H]+ 

工程８
　化合物Ｉ－４２３（１０ｍｇ、０．０１６ｍｍｏｌ）をクロロホルム（０．１ｍＬ）に溶解し、トリフルオロ酢酸（０．１ｍＬ、１．３０ｍｍｏｌ）を加え、室温にて１時間撹拌した。減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－４２４（５ｍｇ、収率６６％）を得た。
MS (ESI) m/z 525 [M+H]+
Example 13 Synthesis of Compounds I-423 and I-424
Figure JPOXMLDOC01-appb-C000121
Process 1
4-Methoxybenzyl alcohol (3.88 mL, 31.3 mmol) was dissolved in DMF (50 mL), 60% sodium hydride (1.4 g, 34.1 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 20 minutes. did. Next, 4-bromo-2-fluoropyridine (5 g, 28.4 mmol) was added under ice cooling, and then the mixture was warmed to room temperature and stirred for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 41 (5.11 g, yield 61%).
MS (ESI) m / z 294 [M + H] +

Process 2
Compound 41 (88 mg, 0.30 mmol) was dissolved in diethyl ether (1 mL), and a 1.65 mol / L n-butyllithium-hexane solution (0.182 mL, 0.30 mmol) was added dropwise at -74 ° C. Stir for minutes. Next, Compound 57 (100 mg, 0.30 mmol) obtained in the same manner as Compound 67 dissolved in THF (0.6 mL) was added dropwise at −74 ° C., and the mixture was stirred at −78 ° C. for 2 hours. A 2 mol / L hydrochloric acid aqueous solution (0.18 mL, 0.36 mmol) was added to the reaction solution, followed by extraction with a mixed solution of diethyl ether and THF. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude product 42 (212 mg).
MS (ESI) m / z 548 [M + H] +

Process 3
The crude product 42 (165 mL, 0.30 mmol) was dissolved in methanol (2 mL), sodium borohydride (14 mg, 0.36 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 1.5 hr. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude product 43 (201 mg).
MS (ESI) m / z 550 [M + H] +

Process 4
The crude product 43 (166 mL, 0.30 mmol) was dissolved in dichloromethane (4 mL), and DIEA (0.16 mL, 0.91 mmol) and methanesulfonyl chloride (0.035 mL, 0.45 mmol) were added under ice cooling, Stir at 0 ° C. for 2 hours. After raising the temperature to room temperature, the mixture was further stirred for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure to obtain a crude product 44 (185 mg).
MS (ESI) m / z 532 [M + H] +

Process 5
The crude product 44 (161 mL, 0.30 mmol) was dissolved in dichloromethane (1.5 mL), 1 mol / L TBAF-THF solution (1.51 mL, 1.51 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 45 (41 mg, yield 32%).
MS (ESI) m / z 418 [M + H] +
1 H-NMR (CDCl 3 ) δ: 8.13 (1.0H, d, J = 5.3 Hz), 7.62 (2.0H, d, J = 9.4 Hz), 7.51 (1.0H, s), 7.37 (2.0H, d , J = 8.7 Hz), 6.89 (3.0H, d, J = 8.7 Hz), 6.89-6.84 (3.0H, m), 6.74 (1.0H, s), 6.38 (1.0H, d, J = 9.8 Hz) , 5.27 (2.0H, s), 5.00 (1.0H, dd, J = 9.3, 2.3 Hz), 4.66 (1.0H, s), 3.92-3.80 (5.0H, m), 2.72 (1.0H, ddd, J = 13.8, 9.3, 4.7 Hz), 2.19 (1.0H, d, J = 13.8 Hz).

Step 6
Compound 45 (100 mL, 0.24 mmol) is dissolved in DMF (1 mL), DIEA (0.38 mL, 2.16 mmol) and methanesulfonyl chloride (0.056 mL, 0.72 mmol) are added, and the mixture is stirred at room temperature for 3 hours. did. Next, sodium azide (78 mg, 1.20 mmol) was added, and the mixture was stirred at 70 ° C. for 6 and a half hours. After allowing to cool, water was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was dissolved in methanol (1 mL), 10% palladium carbon (50 mg, 0.47 mmol) was added, and the mixture was stirred at room temperature for 26 hours in a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain Compound 46 (89 mg, yield 89%).
MS (ESI) m / z 417 [M + H] +

Step 7
Compound 46 (20 mg, 0.048 mmol) was dissolved in DMF (1 mL), HATU (22 mg, 0.058 mmol), compound 37 (14 mg, 0.058 mmol), DIEA (0.017 mL, 0.096 mmol) were added, Stir at room temperature for 4 hours. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The resulting residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-423 (11 mg, yield 37%).
MS (ESI) m / z 645 [M + H] +

Process 8
Compound I-423 (10 mg, 0.016 mmol) was dissolved in chloroform (0.1 mL), trifluoroacetic acid (0.1 mL, 1.30 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the resulting residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-424 (5 mg, 66% yield).
MS (ESI) m / z 525 [M + H] +
実施例１４　化合物Ｉ－１６３およびＩ－１４５の合成
Figure JPOXMLDOC01-appb-C000122
工程１
　２－ブロモピリジン（５０１ｍｇ、３．１７ｍｍｏｌ）をジエチルエーテル（１０ｍＬ）に溶解し、－７４℃にて１．６５ｍｏｌ／Ｌ　ブチルリチウム－ヘキサン溶液（１．９２ｍＬ、３．１７ｍｍｏｌ）を滴下し、同温下３０分撹拌した。次に、化合物４７（合成法はＷＯ２０１２０３４０９１Ａ１に記載）（１ｇ、３．１７ｍｍｏｌ）のＴＨＦ（４ｍＬ）溶液を－７４℃にて滴下し、－７８℃にて３時間半撹拌した。反応溶液に２ｍｏｌ／Ｌ　塩酸水溶液（１．９０ｍＬ、３．８０ｍｍｏｌ）を加え、室温に昇温し、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥、減圧濃縮し、粗生成物４８（１．３ｇ）を得た。
MS (ESI) m/z 395 [M+H]+ 

工程２
　粗生成物４８（１．３ｇ、３．１７ｍｍｏｌ）をメタノール（１２ｍＬ）に溶解し、氷冷下、水素化ホウ素ナトリウム（１４４ｍｇ、３．８０ｍｍｏｌ）を加え、０℃にて３０分撹拌した。水を加え、酢酸エチルで抽出、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、粗生成物４９（１．３ｇ）を得た。
MS (ESI) m/z 397 [M+H]+ 

工程３
　粗生成物４９（１．３ｇ、３．１７ｍｍｏｌ）をジクロロメタン（２４ｍＬ）に溶解し、ＤＩＥＡ（１．６６ｍＬ、９．５１ｍｍｏｌ）を加え、室温にてメタンスルホニルクロリド（０．３７ｍＬ、４．７５ｍｍｏｌ）を滴下し、１時間撹拌した。反応溶液に水を加え、クロロホルムで抽出、減圧濃縮した。得られた残渣をＤＭＦ（１２ｍＬ）に溶解し、氷冷下、６０％水素化ナトリウム（１３９ｍｇ、３．４９ｍｍｏｌ）を加え、室温にて１時間半撹拌した。反応溶液に水、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出、有機層を水、飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、粗生成物５０（１．０８ｇ）を得た。
MS (ESI) m/z 379 [M+H]+ 

工程４
　粗生成物５０（９８０ｍｇ、２．５９ｍｍｏｌ）をジクロロメタン（１０ｍＬ）に溶解し、１ｍｏｌ／Ｌ　ＴＢＡＦ－ＴＨＦ溶液（１３ｍＬ、１３ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応溶液に水を加えジクロロメタンで抽出、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５１（２１５ｍｇ、収率３１％）を得た。
MS (ESI) m/z 265 [M+H]+  
1H-NMR (CDCl3) δ: 8.53-8.49 (1.0H, m), 7.72-7.66 (1.0H, m), 7.52 (0.5H, d, J = 7.8 Hz), 7.31 (0.5H, d, J = 7.8 Hz), 7.21 (1.0H, dd, J = 12.2, 7.0 Hz), 4.97 (0.5H, d, J = 9.7 Hz), 4.84 (0.5H, d, J = 9.7 Hz), 4.43-4.40 (1.0H, m), 3.82-3.55 (2.0H, m), 2.57-2.45 (1.0H, m), 2.14 (1.0H, dd, J = 13.9, 4.5 Hz), 1.39 (4.5H, s), 1.27 (4.5H, s).

工程５
　化合物５１（２１５ｍｇ、０．８１ｍｍｏｌ）をＴＨＦ（２ｍＬ）に溶解し、フタルイミド（１８０ｍｇ、１．２２ｍｍｏｌ）、トリフェニルホスフィン（３２０ｍｇ、１．２２ｍｍｏｌ）を加え、室温にて、２．２ｍｏｌ／Ｌ　ＤＥＡＤ－トルエン溶液（０．５６ｍＬ、１．２２ｍｍｏｌ）を加えた後、室温にて１時間半撹拌した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して粗生成物５２（３４５ｍｇ）を得た。
MS (ESI) m/z 394 [M+H]+ 

工程６
　粗生成物５２（３２０ｍｇ、０．８１ｍｍｏｌ）をメタノール（３ｍＬ）に溶解し、４０％メチルアミン－メタノール溶液（３．５１ｍＬ、４０．７ｍｍｏｌ）を加え、６５℃にて２時間半撹拌した。放冷後、減圧濃縮し、粗生成物５３（３６８ｍｇ）を得た。
MS (ESI) m/z 264 [M+H]+ 

工程７
　粗生成物５３（３３８ｍｇ、１．２８ｍｍｏｌ）をジクロロメタン（３．５ｍＬ）に溶解し、ＤＩＥＡ（０．２６９ｍＬ、１．５４ｍｍｏｌ）、２－ニトロベンゼンスルホニルクロリド（３１３ｍｇ、１．４１ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応溶液に水を加えジクロロメタンで抽出、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物５４（９６ｍｇ、収率１７％）を得た。
MS (ESI) m/z 449 [M+H]+ 

工程８
　化合物５４（９６ｍｇ、０．２１ｍｍｏｌ）に４ｍｏｌ／Ｌ　塩酸－ジオキサン溶液（１ｍＬ、４ｍｍｏｌ）を加え、室温にて１９時間撹拌した。反応液を減圧濃縮し、粗生成物５５（１０５ｍｇ）を得た。
MS (ESI) m/z 349 [M+H]+ 

工程９
　粗生成物５５（８２ｍｇ、０．２１ｍｍｏｌ）をＤＭＳＯ（１．５ｍＬ）に溶解し、化合物２４（６２ｍｇ、０．２３ｍｍｏｌ）、炭酸セシウム（２４３ｍｇ、０．７５ｍｍｏｌ）を加え、マイクロウェーブ下、１２０℃にて３０分撹拌した。反応溶液に水を加え酢酸エチルで抽出し、有機層を水、飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、化合物Ｉ－１６３（１２１ｍｇ、収率９６％）を得た。
MS (ESI) m/z 592 [M+H]+ 
1H-NMR (DMSO-D6) δ: 8.71-8.68 (1.0H, m), 8.48 (1.0H, d, J = 4.4 Hz), 8.07-8.03 (1.0H, m), 7.98-7.95 (1.0H, m), 7.87-7.84 (2.0H, m), 7.75-7.69 (2.0H, m), 7.42 (1.0H, d, J = 8.0 Hz), 7.26-7.22 (1.0H, m), 6.58 (1.0H, d, J = 8.9 Hz), 5.25 (1.0H, dd, J = 8.0, 3.8 Hz), 4.29-4.24 (1.0H, m), 3.93 (1.0H, dd, J = 10.8, 6.9 Hz), 3.53 (1.0H, dd, J = 10.8, 5.9 Hz), 2.47-2.42 (1.0H, m), 2.19-2.12 (1.0H, m).

工程１０
　化合物Ｉ－１６３（１１６ｍｇ、０．２０ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、炭酸カリウム（１３６ｍｇ、０．９８ｍｍｏｌ）、ドデカン－１－チオール（０．１４ｍＬ、０．５９ｍｍｏｌ）を加え、５０℃にて３時間撹拌した。放冷後、固体を濾過し、減圧濃縮し、粗生成物５６を得た。
MS (ESI) m/z 407 [M+H]+ 

工程１１
　粗生成物５６（１１ｍｇ、０．０２７ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、ＥＤＣ（６ｍｇ、０．０３２ｍｍｏｌ）、化合物３７（８ｍｇ、０．０３２ｍｍｏｌ）、ＨＯＢｔ（４ｍｇ、０．０３２ｍｍｏｌ）、ＤＩＥＡ（０．０１４ｍＬ、０．０８１ｍｍｏｌ）を加え、室温にて１７時間撹拌した。反応溶液に水を加えジクロロメタンで抽出、減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－１４５（９ｍｇ、収率５３％）を得た。
MS (ESI) m/z 635 [M+H]+ 
1H-NMR (CDCl3) δ: 8.88 (1.0H, d, J = 7.0 Hz), 8.50 (1.0H, dd, J = 4.7, 0.8 Hz), 7.56 (1.0H, td, J = 7.7, 1.7 Hz), 7.48-7.43 (4.0H, m), 7.39-7.33 (1.0H, m), 7.33-7.25 (3.0H, m), 7.10 (1.0H, ddd, J = 7.4, 4.7, 0.8 Hz), 6.38 (1.0H, d, J = 9.8 Hz), 5.21 (1.0H, dd, J = 7.9, 4.4 Hz), 4.91 (1.0H, td, J = 13.6, 6.7 Hz), 4.29 (1.0H, dd, J = 10.7, 6.7 Hz), 3.72 (2.0H, q, J = 7.0 Hz), 3.63 (1.0H, dd, J = 10.7, 6.4 Hz), 2.69 (3.0H, s), 2.54-2.41 (2.0H, m), 0.96 (3.0H, t, J = 7.0 Hz).
Example 14 Synthesis of Compounds I-163 and I-145
Figure JPOXMLDOC01-appb-C000122
Process 1
2-Bromopyridine (501 mg, 3.17 mmol) was dissolved in diethyl ether (10 mL), and a 1.65 mol / L butyllithium-hexane solution (1.92 mL, 3.17 mmol) was added dropwise at -74 ° C. Stir for 30 minutes under warm. Next, a THF (4 mL) solution of compound 47 (the synthesis method is described in WO2012034091A1) (1 g, 3.17 mmol) was added dropwise at −74 ° C., and the mixture was stirred at −78 ° C. for 3.5 hours. A 2 mol / L aqueous hydrochloric acid solution (1.90 mL, 3.80 mmol) was added to the reaction solution, and the mixture was warmed to room temperature and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 48 (1.3 g).
MS (ESI) m / z 395 [M + H] +

Process 2
The crude product 48 (1.3 g, 3.17 mmol) was dissolved in methanol (12 mL), sodium borohydride (144 mg, 3.80 mmol) was added under ice cooling, and the mixture was stirred at 0 ° C. for 30 min. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude product 49 (1.3 g).
MS (ESI) m / z 397 [M + H] +

Process 3
The crude product 49 (1.3 g, 3.17 mmol) was dissolved in dichloromethane (24 mL), DIEA (1.66 mL, 9.51 mmol) was added, and methanesulfonyl chloride (0.37 mL, 4.75 mmol) was added at room temperature. Was added dropwise and stirred for 1 hour. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was dissolved in DMF (12 mL), 60% sodium hydride (139 mg, 3.49 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. Concentration under reduced pressure gave crude product 50 (1.08 g).
MS (ESI) m / z 379 [M + H] +

Process 4
The crude product 50 (980 mg, 2.59 mmol) was dissolved in dichloromethane (10 mL), 1 mol / L TBAF-THF solution (13 mL, 13 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 51 (215 mg, 31% yield).
MS (ESI) m / z 265 [M + H] +
1 H-NMR (CDCl 3 ) δ: 8.53-8.49 (1.0H, m), 7.72-7.66 (1.0H, m), 7.52 (0.5H, d, J = 7.8 Hz), 7.31 (0.5H, d, J = 7.8 Hz), 7.21 (1.0H, dd, J = 12.2, 7.0 Hz), 4.97 (0.5H, d, J = 9.7 Hz), 4.84 (0.5H, d, J = 9.7 Hz), 4.43-4.40 (1.0H, m), 3.82-3.55 (2.0H, m), 2.57-2.45 (1.0H, m), 2.14 (1.0H, dd, J = 13.9, 4.5 Hz), 1.39 (4.5H, s), 1.27 (4.5H, s).

Process 5
Compound 51 (215 mg, 0.81 mmol) was dissolved in THF (2 mL), phthalimide (180 mg, 1.22 mmol) and triphenylphosphine (320 mg, 1.22 mmol) were added, and 2.2 mol / L DEAD at room temperature. -Toluene solution (0.56 mL, 1.22 mmol) was added and stirred at room temperature for 1.5 hours. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give a crude product 52 (345 mg).
MS (ESI) m / z 394 [M + H] +

Step 6
The crude product 52 (320 mg, 0.81 mmol) was dissolved in methanol (3 mL), 40% methylamine-methanol solution (3.51 mL, 40.7 mmol) was added, and the mixture was stirred at 65 ° C. for 2.5 hr. After allowing to cool, the mixture was concentrated under reduced pressure to obtain a crude product 53 (368 mg).
MS (ESI) m / z 264 [M + H] +

Step 7
The crude product 53 (338 mg, 1.28 mmol) was dissolved in dichloromethane (3.5 mL), DIEA (0.269 mL, 1.54 mmol), 2-nitrobenzenesulfonyl chloride (313 mg, 1.41 mmol) were added and brought to room temperature. And stirred for 1 hour. Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 54 (96 mg, 17% yield).
MS (ESI) m / z 449 [M + H] +

Process 8
A 4 mol / L hydrochloric acid-dioxane solution (1 mL, 4 mmol) was added to compound 54 (96 mg, 0.21 mmol), and the mixture was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product 55 (105 mg).
MS (ESI) m / z 349 [M + H] +

Step 9
Crude product 55 (82 mg, 0.21 mmol) was dissolved in DMSO (1.5 mL), compound 24 (62 mg, 0.23 mmol), cesium carbonate (243 mg, 0.75 mmol) were added, and 120 ° C. under microwave. For 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave Compound I-163 (121 mg, 96% yield).
MS (ESI) m / z 592 [M + H] +
1 H-NMR (DMSO-D 6 ) δ: 8.71-8.68 (1.0H, m), 8.48 (1.0H, d, J = 4.4 Hz), 8.07-8.03 (1.0H, m), 7.98-7.95 (1.0 H, m), 7.87-7.84 (2.0H, m), 7.75-7.69 (2.0H, m), 7.42 (1.0H, d, J = 8.0 Hz), 7.26-7.22 (1.0H, m), 6.58 ( 1.0H, d, J = 8.9 Hz), 5.25 (1.0H, dd, J = 8.0, 3.8 Hz), 4.29-4.24 (1.0H, m), 3.93 (1.0H, dd, J = 10.8, 6.9 Hz) , 3.53 (1.0H, dd, J = 10.8, 5.9 Hz), 2.47-2.42 (1.0H, m), 2.19-2.12 (1.0H, m).

Step 10
Compound I-163 (116 mg, 0.20 mmol) was dissolved in DMF (1 mL), potassium carbonate (136 mg, 0.98 mmol) and dodecane-1-thiol (0.14 mL, 0.59 mmol) were added, and the mixture was heated to 50 ° C. And stirred for 3 hours. After allowing to cool, the solid was filtered and concentrated under reduced pressure to obtain a crude product 56.
MS (ESI) m / z 407 [M + H] +

Step 11
The crude product 56 (11 mg, 0.027 mmol) was dissolved in DMF (1 mL) and EDC (6 mg, 0.032 mmol), compound 37 (8 mg, 0.032 mmol), HOBt (4 mg, 0.032 mmol), DIEA ( 0.014 mL, 0.081 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The resulting residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-145 (9 mg, 53% yield).
MS (ESI) m / z 635 [M + H] +
1 H-NMR (CDCl 3 ) δ: 8.88 (1.0H, d, J = 7.0 Hz), 8.50 (1.0H, dd, J = 4.7, 0.8 Hz), 7.56 (1.0H, td, J = 7.7, 1.7 Hz), 7.48-7.43 (4.0H, m), 7.39-7.33 (1.0H, m), 7.33-7.25 (3.0H, m), 7.10 (1.0H, ddd, J = 7.4, 4.7, 0.8 Hz), 6.38 (1.0H, d, J = 9.8 Hz), 5.21 (1.0H, dd, J = 7.9, 4.4 Hz), 4.91 (1.0H, td, J = 13.6, 6.7 Hz), 4.29 (1.0H, dd, J = 10.7, 6.7 Hz), 3.72 (2.0H, q, J = 7.0 Hz), 3.63 (1.0H, dd, J = 10.7, 6.4 Hz), 2.69 (3.0H, s), 2.54-2.41 (2.0H , m), 0.96 (3.0H, t, J = 7.0 Hz).
実施例１５　化合物Ｉ－０７０の合成
Figure JPOXMLDOC01-appb-C000123
工程１
　化合物５７（２４ｇ、７２．２ｍｍｏｌ）をＴＨＦ（２４０ｍＬ）に溶解し、氷冷下、１ｍｏｌ／Ｌ　３－フルオロフェニルマグネシウムブロミド－ヘキサン溶液（８７ｍＬ、８７ｍｍｏｌ）を滴下し、０℃にて２時間撹拌した。次に、氷冷下メタノール（１４４ｍＬ）を滴下し、０℃にて１０分撹拌した。続いて、水素化ホウ素ナトリウム（４ｇ、１０８ｍｍｏｌ）を少量ずつ加え、０℃にて１時間撹拌した。氷冷下、飽和塩化アンモニウム水溶液と水の混合溶液に、反応溶液を少しずつ加え、昇温後室温にて３０分撹拌した。減圧濃縮し、酢酸エチルで抽出、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物５８（２８ｇ、収率９０％）を得た。
MS (ESI) m/z 431 [M+H]+ 

工程２
　化合物５８（２８ｇ、６４．１ｍｍｏｌ）をジクロロメタン（５６０ｍＬ）に溶解し、－７２℃にて、トリエチルアミン（２７ｍＬ、１９２ｍｍｏｌ）を加えた。次に、メタンスルホニルクロリド（７．５ｍＬ、９６ｍｍｏｌ）を－７４℃にて滴下し、１時間半撹拌した。０℃へ昇温後、反応溶液に飽和炭酸水素ナトリウム水溶液と水の混合溶液を加え、室温へ昇温し、１０分撹拌した。溶液をジクロロメタンで抽出、有機層を飽和食塩水、飽和塩化アンモニウム水溶液、水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製した。活性炭にて色素を除去後ヘキサンで固化し、化合物５９（９．９ｇ、収率３８％）を得た。
MS (ESI) m/z 413 [M+H]+ 

工程３
　化合物５９（１．５ｇ、３．６４ｍｍｏｌ）をジクロロメタン（１５ｍＬ）に溶解し、１ｍｏｌ／Ｌ　ＴＢＡＦ－ＴＨＦ溶液（１８ｍＬ、１８ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応溶液に水を加えクロロホルムで抽出、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物６０（１ｇ、収率９２％）を得た。
MS (ESI) m/z 299 [M+H]+ 

工程４
　化合物６０（１ｇ、３．３５ｍｍｏｌ）をＴＨＦ（１０ｍＬ）に溶解し、フタルイミド（５９２ｍｇ、４．０２ｍｍｏｌ）、トリフェニルホスフィン（１．０６ｇ、４．０２ｍｍｏｌ）を加え、氷冷下、２．２ｍｏｌ／Ｌ　ＤＥＡＤ－トルエン溶液（１．６８ｍＬ、３．６９ｍｍｏｌ）を加えた後、室温にて１５時間撹拌した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物６１（１．４ｇ、収率９８％）を得た。
MS (ESI) m/z 428 [M+H]+ 

工程５
　化合物６１（１．４ｇ、３．２８ｍｍｏｌ）をＤＭＦ（２８ｍＬ）に溶解し、ＮＩＳ（９２１ｍｇ、４．０９ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応溶液に水を加えクロロホルムで抽出、有機層を飽和食塩水にて洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物６２（１．８ｇ、収率９９％）を得た。
MS (ESI) m/z 554 [M+H]+ 

工程６
　化合物６２（１．８ｇ、３．２５ｍｍｏｌ）をメタノール（２０ｍＬ）に溶解し、４０％メチルアミン－メタノール溶液（１４ｍＬ、１６３ｍｍｏｌ）を加え、６５℃にて１時間半撹拌した。反応液を、放冷後、減圧濃縮し、粗生成物６３（１．６ｇ）を得た。
MS (ESI) m/z 424 [M+H]+ 

工程７
　粗生成物６３（２５ｍｇ、０．０５９ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、ＨＡＴＵ（２７ｍｇ、０．０７１ｍｍｏｌ）、４－メトキシ－２－キノリンカルボン酸（１４ｍｇ、０．０７１ｍｍｏｌ）、ＤＩＥＡ（０．０５２ｍＬ、０．２９５ｍｍｏｌ）を加え、室温にて５時間撹拌した。反応溶液に水、飽和食塩水を加えクロロホルムとメタノールの混合溶媒で抽出、減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－０７０（１４ｍｇ、収率３９％）を得た。
MS (ESI) m/z 609 [M+H]+
Example 15 Synthesis of Compound I-070
Figure JPOXMLDOC01-appb-C000123
Process 1
Compound 57 (24 g, 72.2 mmol) was dissolved in THF (240 mL), and 1 mol / L 3-fluorophenylmagnesium bromide-hexane solution (87 mL, 87 mmol) was added dropwise under ice cooling, followed by stirring at 0 ° C. for 2 hours. did. Next, methanol (144 mL) was added dropwise under ice cooling, and the mixture was stirred at 0 ° C. for 10 minutes. Subsequently, sodium borohydride (4 g, 108 mmol) was added in small portions and stirred at 0 ° C. for 1 hour. Under ice-cooling, the reaction solution was added little by little to a mixed solution of saturated aqueous ammonium chloride and water, and the mixture was warmed and stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 58 (28 g, yield 90%).
MS (ESI) m / z 431 [M + H] +

Process 2
Compound 58 (28 g, 64.1 mmol) was dissolved in dichloromethane (560 mL), and triethylamine (27 mL, 192 mmol) was added at -72 ° C. Next, methanesulfonyl chloride (7.5 mL, 96 mmol) was added dropwise at −74 ° C. and stirred for 1.5 hours. After the temperature was raised to 0 ° C., a mixed solution of saturated aqueous sodium hydrogen carbonate and water was added to the reaction solution, the temperature was raised to room temperature, and the mixture was stirred for 10 minutes. The solution was extracted with dichloromethane, and the organic layer was washed with saturated brine, saturated aqueous ammonium chloride solution and water, and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform-methanol). The pigment was removed with activated carbon and then solidified with hexane to obtain Compound 59 (9.9 g, yield 38%).
MS (ESI) m / z 413 [M + H] +

Process 3
Compound 59 (1.5 g, 3.64 mmol) was dissolved in dichloromethane (15 mL), 1 mol / L TBAF-THF solution (18 mL, 18 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with chloroform and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 60 (1 g, yield 92%).
MS (ESI) m / z 299 [M + H] +

Process 4
Compound 60 (1 g, 3.35 mmol) was dissolved in THF (10 mL), and phthalimide (592 mg, 4.02 mmol) and triphenylphosphine (1.06 g, 4.02 mmol) were added. After adding L DEAD-toluene solution (1.68 mL, 3.69 mmol), the mixture was stirred at room temperature for 15 hours. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 61 (1.4 g, yield 98%).
MS (ESI) m / z 428 [M + H] +

Process 5
Compound 61 (1.4 g, 3.28 mmol) was dissolved in DMF (28 mL), NIS (921 mg, 4.09 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 62 (1.8 g, yield 99%).
MS (ESI) m / z 554 [M + H] +

Step 6
Compound 62 (1.8 g, 3.25 mmol) was dissolved in methanol (20 mL), 40% methylamine-methanol solution (14 mL, 163 mmol) was added, and the mixture was stirred at 65 ° C. for 1.5 hr. The reaction solution was allowed to cool and then concentrated under reduced pressure to obtain a crude product 63 (1.6 g).
MS (ESI) m / z 424 [M + H] +

Step 7
The crude product 63 (25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and HATU (27 mg, 0.071 mmol), 4-methoxy-2-quinolinecarboxylic acid (14 mg, 0.071 mmol), DIEA (0. (052 mL, 0.295 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Water and saturated brine were added to the reaction solution, extracted with a mixed solvent of chloroform and methanol and concentrated under reduced pressure. The resulting residue was purified by reverse phase liquid chromatography (water-acetonitrile) to give compound I-070 (14 mg, yield). 39%).
MS (ESI) m / z 609 [M + H] +
実施例１６　化合物６５の合成
Figure JPOXMLDOC01-appb-C000124
工程１
　化合物６０（３２３ｍｇ、１．０８ｍｍｏｌ）をＴＨＦ６ｍＬに溶解し、トリエチルアミン（０．３３ｍＬ、２．３８ｍｍｏｌ）を加えた。混合液を０℃に冷却し、４－ニトロベンゼンスルホニルクロリド（３６０ｍｇ、１．６２ｍｍｏｌ）を加え、０℃にて２時間、室温で１時間攪拌した。飽和重曹水を加えクロロホルムで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、化合物６４（５１１ｍｇ、収率９８％）を得た。
MS (ESI) m/z ４８４ [M+H]+

工程２
　化合物６４（４８６ｍｇ、１．０１ｍｍｏｌ）をＴＨＦ５ｍＬに溶解し、４０％メチルアミン水溶液（３．４７ｍＬ、４０ｍｍｏｌ）を加えた。６０℃にて６時間攪拌したクロロホルムで抽出した後、有機層を無水硫酸ナトリウムで乾燥し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物６５（１４０ｍｇ、収率４５％）を得た。
MS (ESI) m/z ３１２ [M+H]+

　実施例１５における化合物６３の代わりに化合物６５を用いることにより、下記表に記載の実施例化合物を合成した。
Example 16 Synthesis of Compound 65
Figure JPOXMLDOC01-appb-C000124
Process 1
Compound 60 (323 mg, 1.08 mmol) was dissolved in 6 mL of THF, and triethylamine (0.33 mL, 2.38 mmol) was added. The mixture was cooled to 0 ° C., 4-nitrobenzenesulfonyl chloride (360 mg, 1.62 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hr and at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain Compound 64 (511 mg, yield 98%).
MS (ESI) m / z 484 [M + H] +

Process 2
Compound 64 (486 mg, 1.01 mmol) was dissolved in 5 mL of THF, and 40% aqueous methylamine solution (3.47 mL, 40 mmol) was added. After extraction with chloroform stirred at 60 ° C. for 6 hours, the organic layer was dried over anhydrous sodium sulfate, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 65 (140 mg, yield). 45%).
MS (ESI) m / z 312 [M + H] +

Example compounds described in the following table were synthesized by using compound 65 instead of compound 63 in example 15.
実施例１７
Figure JPOXMLDOC01-appb-C000125
　化合物６６（２４１ｍｇ、１．１２ｍｍｏｌ）、化合物３４（２００ｍｇ、０．９３ｍｍｏｌ）、炭酸セシウム（４２４ｍｇ、１．３０ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（８１ｍｇ、０．１４ｍｍｏｌ）、Ｐｄ（ＯＡｃ）２（２１ｍｇ、０．０９３ｍｍｏｌ）にジオキサン４ｍＬを加え、８５℃にて３０分攪拌した。反応液に水を加え、クロロホルムで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル－ヘキサン）により精製して、化合物６７（２１５ｍｇ、収率６６％）を得た。
MS (ESI) m/z ３５０ [M+H]+

　実施例１５における化合物５７の代わりに化合物６７を用いることにより、下記表に記載の実施例化合物を合成した。
Example 17
Figure JPOXMLDOC01-appb-C000125
Compound 66 (241 mg, 1.12 mmol), Compound 34 (200 mg, 0.93 mmol), cesium carbonate (424 mg, 1.30 mmol), Xantphos (81 mg, 0.14 mmol), Pd (OAc) 2 (21 mg, 0.093 mmol) ) Was added with 4 mL of dioxane and stirred at 85 ° C. for 30 minutes. Water was added to the reaction solution and extracted with chloroform, and then the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain Compound 67 (215 mg, 66% yield).
MS (ESI) m / z 350 [M + H] +

Example compounds described in the following table were synthesized by using Compound 67 instead of Compound 57 in Example 15.
実施例１８　化合物Ｉ－３７６およびＩ－３７４の合成
Figure JPOXMLDOC01-appb-C000126
工程１
　化合物６８（ＷＯ２０１０／１１０２３１に記載、８２０ｍｇ、３．００ｍｏｌ）、炭酸カリウム（８２９ｍｇ、６．００ｍｍｏｌ）を、ＤＭＦ（５ｍＬ）に溶解し、撹拌下、ヨードメタン（０．２２５ｍＬ、３．６ｍｍｏｌ）を加え、４０℃にて２時間撹拌した。反応液に水を加え、ジクロロメタンで抽出し、有機層を硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール３％）により精製して化合物６９（５７１ｍｇ、収率６６．２％）を得た。
MS (ESI) m/z 288 [M+H]+

工程２
　化合物６９（３５０ｍｇ、１．２ｍｍｏｌ）をメタノール（２５ｍＬ）に溶解し、１０％水酸化パラジウムカーボン（１００ｍｇ）を加え、水素雰囲気下、室温で３時間撹拌した。反応液を濾過し、化合物７０（２０４ｍｇ、収率８５％）を得た。
MS (ESI) m/z 198 [M+H]+

工程３
　化合物７０（１２６ｍｇ、０．６４ｍｍｏｌ）、炭酸カリウム（１７７ｍｇ、１．２８ｍｍｏｌ）を、ＤＭＦ（２ｍＬ）に溶解し、撹拌下、ヨードメタン（０．１９５ｍＬ、０．７７ｍｍｏｌ）を加え、４０℃にて５時間撹拌した。反応液に水を加え、ジクロロメタンで抽出し、減圧濃縮した。得られた残渣（１１０ｍｇ）をメタノール（２ｍＬ）に溶解し、４ｍｏｌ／Ｌ　水酸化リチウム（０．１４３ｍＬ）を加え、室温で撹拌した。２時間後、反応溶液を濃縮し乾燥し、得られた化合物７１を、次の反応に用いた。
MS (ESI) m/z 184 [M+H]+

工程４
　化合物７１（１００ｍｇ、０．５３ｍｍｏｌ）を、ＤＭＦ（１ｍＬ）と１，３－ジメチル－２－イミダゾリジノン（１ｍＬ）に溶解し、ＤＩＥＡ（３７０ｍｇ、２．１２ｍｍｏｌ）を加えた。氷冷下、イソブチルクロロホルメート（０．０７０ｍＬ、０．５３ｍｍｏｌ）を加え、４５分攪拌した。反応溶液に、化合物６３と同様に得られる化合物１４９を加え、室温まで昇温した。５時間後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。抽出液を減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－３７６（４．５ｍｇ、収率１．８％）、化合物Ｉ－３７４（３ｍｇ、収率１．４％）を得た。
MS (ESI) m/z 480 [M+H]+、MS (ESI) m/z 415 [M+H]+　
Example 18 Synthesis of Compounds I-376 and I-374
Figure JPOXMLDOC01-appb-C000126
Process 1
Compound 68 (described in WO2010 / 110231, 820 mg, 3.00 mol), potassium carbonate (829 mg, 6.00 mmol) was dissolved in DMF (5 mL), and iodomethane (0.225 mL, 3.6 mmol) was added with stirring. And stirred at 40 ° C. for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, and the organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol 3%) to obtain Compound 69 (571 mg, yield 66.2%).
MS (ESI) m / z 288 [M + H] +

Process 2
Compound 69 (350 mg, 1.2 mmol) was dissolved in methanol (25 mL), 10% palladium hydroxide carbon (100 mg) was added, and the mixture was stirred at room temperature for 3 hr in a hydrogen atmosphere. The reaction solution was filtered to obtain Compound 70 (204 mg, yield 85%).
MS (ESI) m / z 198 [M + H] +

Process 3
Compound 70 (126 mg, 0.64 mmol) and potassium carbonate (177 mg, 1.28 mmol) were dissolved in DMF (2 mL), and iodomethane (0.195 mL, 0.77 mmol) was added with stirring. Stir for hours. Water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The obtained residue (110 mg) was dissolved in methanol (2 mL), 4 mol / L lithium hydroxide (0.143 mL) was added, and the mixture was stirred at room temperature. After 2 hours, the reaction solution was concentrated and dried, and the resulting compound 71 was used in the next reaction.
MS (ESI) m / z 184 [M + H] +

Process 4
Compound 71 (100 mg, 0.53 mmol) was dissolved in DMF (1 mL) and 1,3-dimethyl-2-imidazolidinone (1 mL), and DIEA (370 mg, 2.12 mmol) was added. Under ice-cooling, isobutyl chloroformate (0.070 mL, 0.53 mmol) was added and stirred for 45 minutes. Compound 149 obtained in the same manner as Compound 63 was added to the reaction solution, and the temperature was raised to room temperature. After 5 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-376 (4.5 mg, yield 1.8%), compound I-374 (3 mg, 1.4% yield) was obtained.
MS (ESI) m / z 480 [M + H] +, MS (ESI) m / z 415 [M + H] +
実施例１９　化合物Ｉ－０２２の合成
Figure JPOXMLDOC01-appb-C000127
工程１
　氷冷下、（Ｒ）－（＋）－ヒドロキシ－γ－ブチロラクトン（５ｇ、４９ｍｍｏｌ）のＤＭＦ（１００ｍＬ）溶液に、ＴＢＳ－Ｃｌ（１４．８１ｇ、５８．８ｍｍｏｌ）とイミダゾール（４ｇ、５８．８ｍｍｏｌ）を加えた。室温にて、４時間攪拌した後、水（２００ｍＬ）へ反応溶液を注いだ、ジクロロメタンで抽出した後、有機層を、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５０：１）にて精製し、化合物７３（１５．９ｇ、収率９５％）を得た。

工程２
　窒素雰囲気下、Ｎ，Ｏ－ジメチルヒドロキシルアミン（８６．３ｇ、８８０ｍｍｏｌ）の無水ジクロロメタン懸濁溶液に、トリメチルアルミニウムのトルエン溶液（２ｍｍｏｌ／Ｌ、４４０ｍＬ、８８０ｍｍｏｌ）を－１０℃にて加えた。反応溶液を２４℃にて３０分攪拌し、再び０℃に冷却した。この反応溶液に、化合物７３（１００ｇ、２９０ｍｍｏｌ）のジクロロメタン（２００ｍＬ　＋　４００ｍＬのリンス）溶液を加え、反応溶液を１８～２４℃にて、１２時間攪拌した。ＫＨＳＯ４（１．０Ｍ、１．０Ｌ）を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣に、ｎ－ヘキサン（６００ｍＬ）を加え、室温で１時間攪拌した。生成した無色固体を濾取した。酢酸エチル（６０ｍＬ）とｎ－ヘキサン（４００ｍＬ）から固化し、化合物７４（５０．０ｇ、収率４３．１％）を無色固体として得た。
MS (ESI) m/z 402.1 [M+H]+, 424.1 [M+Na]+

工程３
　窒素雰囲気下、無水ＴＨＦ（１００ｍＬ）を０℃に冷却し、３－フルオロフェニルマグネシウムブロミドのＴＨＦ溶液（１．０Ｍ、７４．８ｍＬ）を滴下した。反応溶液に、０℃にて化合物７４（１０ｇ、２４．９ｍｍｏｌ）の無水ＴＨＦ（２０ｍＬ）を滴下した。０℃にて４時間反応させた後、反応溶液を水（１００ｍＬ）に注ぎ、酢酸エチルで抽出した。有機層を、硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝１０：１）にて精製し、化合物７５（８．９２ｇ、収率８２％）を無色オイルとして得た。
MS (ESI) m/z 459.0 [M+H]+ 

工程４
　ＤＭＳＯ（１．７７ｇ、２２．０ｍｍｏｌ）の無水ジクロロメタン（６ｍＬ）を、オギザリルクロリド（１．４０ｇ、１１ｍｍｏｌ）の無水ジクロロメタン溶液（１３ｍＬ）に－７８℃にて加えた。１５分後、化合物７５（１．０９ｇ、２．５０ｍｍｏｌ）のジクロロメタン（９ｍＬ）溶液を滴下した。－７８℃にて１５分反応させた後、－４０～－５０℃に昇温して１時間攪拌し、再び－７８℃に冷却した。反応溶液に、－７８℃にてトリエチルアミン（３．７９ｇ、３７．５ｍｍｏｌ）を加えた。この後、昇温し室温で１時間攪拌した。反応液に飽和塩化アンモニウム水溶液（１００ｍＬ）を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥した。分取ＴＬＣで精製（石油エーテル：酢酸エチル＝１０：１）し、化合物７６（６７６ｍｇ、収率６２％）を得た。

工程５　化合物７７の合成
　化合物７６（約１．０ｇ、２．５ｍｍｏｌ）、３－アミノ－６－（ベンズヒドロキシ）ピリジン（８２９ｍｇ、３．０ｍｍｏｌ）、酢酸（１７２μＬ、３．０ｍｍｏｌ）を、無水ジクロロメタン（２５ｍＬ）中で室温にて、攪拌した。ＮａＢＨ（ＯＡｃ）３（３．１８ｇ、１５ｍｍｏｌ）を加えた後、室温にて、終夜で攪拌した。反応溶液を、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）に注ぎ、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製し、化合物７７（cis体、７０４ｍｇ、収率４２％）を得た。

工程６
　化合物７７（４７ｍｇ、０．１０６ｍｍｏｌ）、化合物３７（２６ｍｇ、０．１０６ｍｍｏｌ）、ＨＯＢｔ（１９ｍｇ、０．１３８ｍｍｏｌ）のＤＭＦ溶液（１．５ｍＬ）に、ＥＤＣ・ＨＣｌ（２４ｍｇ、０．１２７ｍｍｏｌ）とＤＩＥＡ（４６μＬ、０．２６５ｍｍｏｌ）を加え、室温にて攪拌した。１６時間後、反応溶液に水（１．５ｍＬ）とジクロロメタンを加えて、激しく攪拌した。有機層を取り出し、飽和塩化アンモニウム水
、水で洗浄した。得られた有機層に、ギ酸（０．１ｍＬ）を加え、室温で１時間攪拌した。減圧濃縮し、得られた残渣を、逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－０２２を得た。
Example 19 Synthesis of Compound I-022
Figure JPOXMLDOC01-appb-C000127
Process 1
Under ice cooling, a solution of (R)-(+)-hydroxy-γ-butyrolactone (5 g, 49 mmol) in DMF (100 mL) was mixed with TBS-Cl (14.81 g, 58.8 mmol) and imidazole (4 g, 58.8 mmol). ) Was added. After stirring at room temperature for 4 hours, the reaction solution was poured into water (200 mL) and extracted with dichloromethane, and then the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to obtain Compound 73 (15.9 g, yield 95%).

Process 2
Under a nitrogen atmosphere, a toluene solution of trimethylaluminum (2 mmol / L, 440 mL, 880 mmol) was added at −10 ° C. to a suspension of N, O-dimethylhydroxylamine (86.3 g, 880 mmol) in anhydrous dichloromethane. The reaction solution was stirred at 24 ° C. for 30 minutes and cooled again to 0 ° C. To this reaction solution was added a solution of compound 73 (100 g, 290 mmol) in dichloromethane (200 mL + 400 mL rinse), and the reaction solution was stirred at 18-24 ° C. for 12 hours. KHSO 4 (1.0 M, 1.0 L) was added and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, n-hexane (600 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The formed colorless solid was collected by filtration. Solidification from ethyl acetate (60 mL) and n-hexane (400 mL) gave Compound 74 (50.0 g, yield 43.1%) as a colorless solid.
MS (ESI) m / z 402.1 [M + H] +, 424.1 [M + Na] +

Process 3
Under a nitrogen atmosphere, anhydrous THF (100 mL) was cooled to 0 ° C., and a solution of 3-fluorophenylmagnesium bromide in THF (1.0 M, 74.8 mL) was added dropwise. To the reaction solution, anhydrous THF (20 mL) of Compound 74 (10 g, 24.9 mmol) was added dropwise at 0 ° C. After reacting at 0 ° C. for 4 hours, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain Compound 75 (8.92 g, yield 82%) as a colorless oil.
MS (ESI) m / z 459.0 [M + H] +

Process 4
DMSO (1.77 g, 22.0 mmol) in anhydrous dichloromethane (6 mL) was added to a solution of oxalyl chloride (1.40 g, 11 mmol) in anhydrous dichloromethane (13 mL) at −78 ° C. After 15 minutes, a solution of compound 75 (1.09 g, 2.50 mmol) in dichloromethane (9 mL) was added dropwise. After reacting at −78 ° C. for 15 minutes, the temperature was raised to −40 to −50 ° C., stirred for 1 hour, and cooled again to −78 ° C. Triethylamine (3.79 g, 37.5 mmol) was added to the reaction solution at −78 ° C. Then, it heated up and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Purification by preparative TLC (petroleum ether: ethyl acetate = 10: 1) gave Compound 76 (676 mg, 62% yield).

Step 5 Synthesis of Compound 77 Compound 76 (about 1.0 g, 2.5 mmol), 3-amino-6- (benzhydroxy) pyridine (829 mg, 3.0 mmol), acetic acid (172 μL, 3.0 mmol) was added to anhydrous dichloromethane (25 mL) at room temperature. NaBH (OAc) 3 (3.18 g, 15 mmol) was added and stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain Compound 77 (cis form, 704 mg, yield 42%).

Step 6
Compound 77 (47 mg, 0.106 mmol), Compound 37 (26 mg, 0.106 mmol), HOBt (19 mg, 0.138 mmol) in DMF solution (1.5 mL), EDC.HCl (24 mg, 0.127 mmol) and DIEA (46 μL, 0.265 mmol) was added and stirred at room temperature. After 16 hours, water (1.5 mL) and dichloromethane were added to the reaction solution, and the mixture was vigorously stirred. The organic layer was taken out and washed with saturated aqueous ammonium chloride and water. Formic acid (0.1 mL) was added to the obtained organic layer, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the resulting residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to give compound I-022.
実施例２０
工程１
Figure JPOXMLDOC01-appb-C000128
工程１－１
　メトキシメチルアミン塩酸塩（１１５ｇ、１．１５ｍｍｏｌ）の無水ジクロロメタン（９００ｍＬ）懸濁液に、トリメチルアルミニウム（５７５ｍＬ、２ｍｏｌ／Ｌ　トルエン溶液）を０℃にて滴下した。２５℃にて３０分攪拌後、（Ｓ）－３－Ｃｂｚ－アミノ－γ－ブチロラクトン（９０ｇ、０．３８３ｍｍｏｌ）の無水ジクロロメタン溶液（１８０ｍＬ）を、０℃にて滴下した。室温にて１５時間攪拌後、飽和塩化アンモニア水（１００ｍＬ）を加えた。生成した固体を濾過し、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝１０：１）で精製し、化合物７９（９６．３ｇ、収率８５％）を無色個体として得た。
MS (ESI) m/z 297.1 [M+H]+ 

工程１－２
　化合物７９（８６．０ｇ、２９１ｍｍｏｌ）とイミダゾール（７８．９ｇ、１．１６ｍｏｌ）のＤＭＦ溶液（４００ｍＬ）に、ｔｅｒｔ－ブチルジフェニルシリルクロリド（１６０ｇ、５８２ｍｍｏｌ）を加えた。室温で１５時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝５：１）で精製し、化合物８０（１３１ｇ、収率８５％）を無色個体として得た。
MS (ESI) m/z 535.1 [M+H]+ 

工程１－３
　化合物８０（８６．０ｇ、２９１ｍｍｏｌ）の無水ＴＨＦ溶液（７０ｍＬ）に、－７８℃にて、ｎ－ブチルリチウム（８．８ｍＬ、２２ｍｍｏｌ、２．５ｍｏｌ／Ｌヘキサン溶液）を滴下した。－７８℃で１時間攪拌後、化合物８０（３．８１ｇ、７．２５ｍｍｏｌ）の無水ＴＨＦ（２３ｍＬ）を滴下した。－７８℃で１時間攪拌後、室温に昇温し１０時間攪拌した。飽和塩化アンモニア水（１００ｍＬ）に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、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（石油エーテル：酢酸エチル＝５０：１～１０：１）で精製し、化合物８１（２．４１ｇ、収率６１％）をオイルとして得た。
MS (ESI) m/z 553 [M+H]+

工程１－４
　化合物８１（２．０ｇ、３．６２ｍｍｏｌ）の無水ジクロロメタン溶液（５０ｍＬ）に、テトラブチルアンモニウムフロライド・３水和物（３．４３ｇ、５．４０ｍｍｏｌ）を加え室温にて、攪拌した。８時間後、水を加えて、ジクロロメタンで抽出した。有機層を、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝１０：１～１：１）で精製し、化合物８２（１．０ｇ、収率８８％）を無色個体として得た。

工程１－５
　化合物８２（８００ｍｇ、２．５５ｍｍｏｌ）の無水ジクロロメタン（３５ｍＬ）溶液に、０℃にて、Ｄｅｓｓ　Ｍａｒｔｉｎ試薬（３．２４ｇ、７．６４ｍｍｏｌ）の無水ジクロロメタン溶液（１５ｍＬ）を滴下した。滴下後、反応溶液を４時間室温で攪拌した。飽和Ｎａ２Ｓ２ＳＯ３溶液（４０ｍＬ）と飽和炭酸水素ナトリウム水溶液（２０ｍＬ）の混合溶液で希釈後、ジクロロメタンで抽出した。有機層を、飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝４：１～１：１）で精製し、粗生成物８３（５００ｍｇ）を得た。粗生成物８３は、精製することなく以下に示す工程３の反応に用いた。
Example 20
Process 1
Figure JPOXMLDOC01-appb-C000128
Step 1-1
Trimethylaluminum (575 mL, 2 mol / L toluene solution) was added dropwise at 0 ° C. to a suspension of methoxymethylamine hydrochloride (115 g, 1.15 mmol) in anhydrous dichloromethane (900 mL). After stirring at 25 ° C. for 30 minutes, an anhydrous dichloromethane solution (180 mL) of (S) -3-Cbz-amino-γ-butyrolactone (90 g, 0.383 mmol) was added dropwise at 0 ° C. After stirring at room temperature for 15 hours, saturated aqueous ammonium chloride (100 mL) was added. The resulting solid was filtered and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain Compound 79 (96.3 g, yield 85%) as a colorless solid.
MS (ESI) m / z 297.1 [M + H] +

Step 1-2
To a DMF solution (400 mL) of compound 79 (86.0 g, 291 mmol) and imidazole (78.9 g, 1.16 mol) was added tert-butyldiphenylsilyl chloride (160 g, 582 mmol). After stirring at room temperature for 15 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain Compound 80 (131 g, yield 85%) as a colorless solid.
MS (ESI) m / z 535.1 [M + H] +

Step 1-3
N-Butyllithium (8.8 mL, 22 mmol, 2.5 mol / L hexane solution) was added dropwise to a solution of compound 80 (86.0 g, 291 mmol) in anhydrous THF (70 mL) at −78 ° C. After stirring at −78 ° C. for 1 hour, Compound 80 (3.81 g, 7.25 mmol) in anhydrous THF (23 mL) was added dropwise. After stirring at −78 ° C. for 1 hour, the mixture was warmed to room temperature and stirred for 10 hours. The mixture was poured into saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1 to 10: 1) to obtain Compound 81 (2.41 g, yield 61%) as an oil.
MS (ESI) m / z 553 [M + H] +

Step 1-4
Tetrabutylammonium fluoride trihydrate (3.43 g, 5.40 mmol) was added to an anhydrous dichloromethane solution (50 mL) of compound 81 (2.0 g, 3.62 mmol), and the mixture was stirred at room temperature. After 8 hours, water was added and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1) to obtain Compound 82 (1.0 g, yield 88%) as a colorless solid.

Step 1-5
To a solution of compound 82 (800 mg, 2.55 mmol) in anhydrous dichloromethane (35 mL) was added dropwise an anhydrous dichloromethane solution (15 mL) of Dess Martin reagent (3.24 g, 7.64 mmol) at 0 ° C. After the addition, the reaction solution was stirred for 4 hours at room temperature. The mixture was diluted with a mixed solution of a saturated Na 2 S 2 SO 3 solution (40 mL) and a saturated aqueous sodium hydrogen carbonate solution (20 mL), and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1 to 1: 1) to obtain a crude product 83 (500 mg). The crude product 83 was used for the reaction in Step 3 shown below without purification.
工程２
Figure JPOXMLDOC01-appb-C000129
工程２－１
　クロマン－４－オン（１０ｇ、６７．５ｍｍｏｌ）の濃硫酸（１００ｍＬ）溶液に、氷冷下、硝酸カリウム（７．５１ｇ、７４．３ｍｍｏｌ）の濃硫酸（４０ｍＬ）溶液を滴下し、氷冷下で２時間攪拌した。反応溶液を氷水（３００ｍＬ）に注ぎ、生成した固体を濾取し、水で洗浄した。メタノールから固化し、化合物８５（１０．４ｇ、収率８０％）を得た。

工程２－２
　化合物８５（１．５ｇ、７．７７ｍｍｏｌ）とＤＡＳＴ（６．８７ｇ、３１．１ｍｍｏｌ）を、ジクロロメタン（２０ｍＬ）・エタノール（０．１８ｍＬ）の混合溶媒に溶解した後、密栓し、４０℃にて２４時間攪拌した。反応液を飽和炭酸水素ナトリウム溶液（５０ｍＬ）に注ぎ、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝２０：１～１０：１）で精製し、化合物８６（１．１４ｇ、収率６８％）を得た。

工程２－３
　化合物８６（１．９０ｇ、８．８３ｍｍｏｌ）、鉄粉（２．９６ｇ、５３．０ｍｍｏｌ）、塩化鉄（８５９ｍｇ、５．３０ｍｍｏｌ）、エタノール（３０ｍＬ）、酢酸（３ｍＬ）の混合液を８０℃にて撹拌した。４０分後、混合物を濾過し、濃縮した。飽和炭酸水素ナトリウム溶液を加えて、酢酸エチルで抽出した。有機層を、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝２０：１～１０：１）で精製し、化合物８７（１．５０ｇ、収率９２％）を得た。化合物８７は、以下に示す工程３の反応に用いた。
Process 2
Figure JPOXMLDOC01-appb-C000129
Step 2-1
To a concentrated sulfuric acid (100 mL) solution of chroman-4-one (10 g, 67.5 mmol) was added dropwise a concentrated sulfuric acid (40 mL) solution of potassium nitrate (7.51 g, 74.3 mmol) under ice cooling. Stir for 2 hours. The reaction solution was poured into ice water (300 mL), and the generated solid was collected by filtration and washed with water. Solidification from methanol gave compound 85 (10.4 g, 80% yield).

Step 2-2
Compound 85 (1.5 g, 7.77 mmol) and DAST (6.87 g, 31.1 mmol) were dissolved in a mixed solvent of dichloromethane (20 mL) and ethanol (0.18 mL), then sealed and sealed at 40 ° C. Stir for 24 hours. The reaction mixture was poured into saturated sodium hydrogen carbonate solution (50 mL) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain Compound 86 (1.14 g, yield 68%).

Step 2-3
A mixture of compound 86 (1.90 g, 8.83 mmol), iron powder (2.96 g, 53.0 mmol), iron chloride (859 mg, 5.30 mmol), ethanol (30 mL), acetic acid (3 mL) was heated to 80 ° C. And stirred. After 40 minutes, the mixture was filtered and concentrated. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1 to 10: 1) to obtain Compound 87 (1.50 g, yield 92%). Compound 87 was used in the reaction of Step 3 shown below.
工程３
Figure JPOXMLDOC01-appb-C000130
工程３－１
　化合物８３（５００ｍｇ）のジクロロメタン溶液（３０ｍＬ）に、化合物８７（４７１ｍｇ、２．５５ｍｍｏｌ）と酢酸（１５３ｍｇ、２．５５ｍｍｏｌ）を加えた。室温で１時間攪拌後、ＮａＢＨ（ＯＡｃ）３（１．６２ｇ、７．６４ｍｍｏｌ）を加え、室温で１８時間攪拌した。反応液を飽和炭酸水素ナトリウム溶液で希釈し、ジクロロメタンで抽出した。有機層を、飽和炭酸水素ナトリウム水溶液で洗浄し、硫酸ナトリウムで乾燥した。減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（石油エーテル：酢酸エチル＝５：１）で精製した。更に、分取ＴＬＣ（石油エーテル：酢酸エチル＝２：１）にて再度精製し、化合物８８（９５ｍｇ、収率８．０％）を無色オイルとして得た。

工程３－２
　化合物８８（９５ｍｇ、０．２０ｍｍｏｌ）を、エタノール・アンモニア水（１０ｍＬ、　０．２ｍＬ）に溶解し、パラジウム炭素（１０ｍｇ、含水率５０％）を加えた。水素雰囲気下、室温で１時間撹拌した。セライトで濾過し、メタノールで洗浄し、減圧下濃縮した。得られた残渣（約６０ｍｇ）を酢酸エチル（１０ｍＬ）に溶解し、４ｍｏｌ／Ｌ　塩化水素－酢酸エチル溶液（２ｍＬ）を加えた。室温にて、３０分攪拌し、減圧下濃縮した。得られた残渣は、メチル・ｔｅｒｔ－ブチルエーテル（１５ｍＬ）から固化し、化合物８９（６２ｍｇ、収率７５％）を得た。

　実施例１５における化合物６３の代わりに化合物８９を用いることにより、下記表に記載の実施例化合物を合成することができる。
Process 3
Figure JPOXMLDOC01-appb-C000130
Step 3-1
Compound 87 (471 mg, 2.55 mmol) and acetic acid (153 mg, 2.55 mmol) were added to a dichloromethane solution (30 mL) of compound 83 (500 mg). After stirring at room temperature for 1 hour, NaBH (OAc) 3 (1.62 g, 7.64 mmol) was added and stirred at room temperature for 18 hours. The reaction was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1). Further, the product was purified again by preparative TLC (petroleum ether: ethyl acetate = 2: 1) to obtain Compound 88 (95 mg, yield 8.0%) as a colorless oil.

Step 3-2
Compound 88 (95 mg, 0.20 mmol) was dissolved in ethanol / aqueous ammonia (10 mL, 0.2 mL), and palladium on carbon (10 mg, water content 50%) was added. The mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixture was filtered through celite, washed with methanol, and concentrated under reduced pressure. The obtained residue (about 60 mg) was dissolved in ethyl acetate (10 mL), and a 4 mol / L hydrogen chloride-ethyl acetate solution (2 mL) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The obtained residue was solidified from methyl tert-butyl ether (15 mL) to obtain Compound 89 (62 mg, yield 75%).

Example compounds described in the following table can be synthesized by using compound 89 instead of compound 63 in example 15.
実施例２１　化合物Ｉ－４３２の合成
Figure JPOXMLDOC01-appb-C000131
工程１
　１，４－ジクロロピリダジン（７．６ｇ、５１０ｍｍｏｌ）、ベンゼンスルホンアミド（８．４２ｇ、５３．５５ｍｍｏｌ）、炭酸カリウム（１５．５１ｇ、１１２ｍｍｏｌ）のＤＭＦ（７５ｍＬ）溶液を、１２０℃にて２時間撹拌した。室温へ冷却後、ブロモアセトアミド（７．７４ｇ、５６．１ｍｍｏｌ）を加え、室温で２．５時間攪拌した。酢酸エチルを加えて濾過した後、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール３％）により精製して化合物９１（１．５８ｇ、収率１１．７％）を得た。
MS (ESI) m/z 265. [M+H]+

工程２
　窒素雰囲気下、化合物９１（２００ｍｇ、０．７５６ｍｍｏｌ）を１，４－ジオキサン（８ｍＬ）に溶解し、３－Ｂｏｃ－アミノピロリジン（２８２ｍｇ、１．５１２ｍｍｏｌ）、Ｐｄ２（ｄｂａ）３（６９．２ｍｇ、０．０７６ｍｍｏｌ）、ＲｕＰｈｏｓ（７０．５ｍｇ、０．１５１ｍｍｏｌ）、ｔｅｒｔ－ブトキシナトリウム（１４５ｍｇ、１．５１２ｍｍｏｌ）を加え、１００℃にて２時間撹拌した。水を加え、クロロホルム－メタノール（９：１）で抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物９２（２１１ｍｇ、収率６７％）を得た。
1H-NMR (CDCl3) δ: 1.46 (s, 9H), 1.96-2.05 (m, 1H), 2.26-2.36 (m, 1H), 3.37 (dd, J = 10.6, 4.1 Hz, 1H), 3.53-3.62 (m, 2H), 3.73-3.79 (m, 1H), 4.37 (br, 1H), 4.72 (br, 1H), 6.59 (d, J = 10.1 Hz, 1H), 7.54 (d, J = 10.1 Hz, 1H), 8.17 (s, 1H), 9.44 (br, 1H).

工程３
　化合物９２（１２８ｍｇ、０．３０９ｍｍｏｌ）をＴＨＦ（２ｍＬ）に溶解し、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．３０９ｍＬ、０．６１８ｍｍｏｌ）を加え６０℃にて２時間攪拌した。一晩静置後、２ｍｏｌ／Ｌ塩酸水溶液（０．１６０ｍＬ、０．８００ｍｍｏｌ）を加えた後、溶媒を減圧濃縮した。残渣にＴＨＦ（２．６ｍＬ）、エチルイソシアネート（０．０４９ｍＬｍｇ、０．６１８ｍｍｏｌ）を加え６０℃にて４時間攪拌した。水を加え、クロロホルム－メタノール（９：１）で抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物９３（６０ｍｇ、収率５０％）を得た。
1H-NMR (CDCl3) δ: 1.24 (t, J = 7.4 Hz, 3H), 1.46 (s, 9H), 1.94-2.03 (m, 1H), 2.25-2.35 (m, 1H), 3.32-3.43 (m, 3H), 3.49-3.61 (m, 2H), 3.73 (dd, J = 10.6, 6.1 Hz, 1H), 4.36 (br, 1H), 4.71 (d, J = 7.1 Hz, 1H), 6.48 (d, J = 9.6 Hz, 1H), 6.90 (s, 1H), 7.31 (s, 1H), 7.50 (d, J = 9.6 Hz, 1H), 7.83 (br, 1H).

工程４
　化合物９３（５９ｍｇ、０．１５１ｍｍｏｌ）にＴＦＡ（０．５ｍＬ）を加え、室温で１時間撹拌し、減圧濃縮した。得られた残渣に４ｍｏｌ／Ｌ塩化水素－酢酸エチル溶液（０．５ｍＬ）を加え、室温で１０分間撹拌した後、減圧濃縮し、化合物９４（５５ｍｇ、収率１００％）を得た。
MS (ESI) m/z 290 [M+H]+ 

工程５
　化合物９４（５ｍｇ、０．０１４ｍｍｏｌ）をＤＭＦ（０．３ｍＬ）に溶解し、１－（２－ヒドロキシ－２－メチルプロピル）－５－メチル－３－オキソ－２－フェニル－２，３－ジヒドロ－１Ｈ－ピラゾール－４－カルボン酸（４．８ｍｇ、０．０１７ｍｍｏｌ）、トリエチルアミン（９．６μＬ、０．０６９ｍｍｏｌ）、ＨＡＴＵ（６．３ｍｇ、０．０１７ｍｍｏｌ）のＤＭＦ溶液（０．１５ｍＬ）を加え、室温で２時間攪拌した。反応液に水を加え、クロロホルム－メタノール（９：１）で抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（１０ｍｍｏｌ／Ｌ炭酸アンモニウム含有水溶液－アセトニトリル）により精製して化合物Ｉ－４３２（５．６ｍｇ、収率７１％）を得た。
MS (ESI) m/z 562 [M+H]+ 
Example 21 Synthesis of Compound I-432
Figure JPOXMLDOC01-appb-C000131
Process 1
A solution of 1,4-dichloropyridazine (7.6 g, 510 mmol), benzenesulfonamide (8.42 g, 53.55 mmol) and potassium carbonate (15.51 g, 112 mmol) in DMF (75 mL) at 120 ° C. for 2 hours. Stir. After cooling to room temperature, bromoacetamide (7.74 g, 56.1 mmol) was added and stirred at room temperature for 2.5 hours. After adding ethyl acetate and filtering, the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol 3%) to obtain compound 91 (1.58 g, yield 11.7%). .
MS (ESI) m / z 265. [M + H] +

Process 2
Under a nitrogen atmosphere, compound 91 (200 mg, 0.756 mmol) was dissolved in 1,4-dioxane (8 mL), and 3-Boc-aminopyrrolidine (282 mg, 1.512 mmol), Pd 2 (dba) 3 (69.2 mg). 0.076 mmol), RuPhos (70.5 mg, 0.151 mmol) and sodium tert-butoxy (145 mg, 1.512 mmol) were added, and the mixture was stirred at 100 ° C. for 2 hours. Water was added, extraction was performed with chloroform-methanol (9: 1), and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 92 (211 mg, 67% yield).
1 H-NMR (CDCl 3 ) δ: 1.46 (s, 9H), 1.96-2.05 (m, 1H), 2.26-2.36 (m, 1H), 3.37 (dd, J = 10.6, 4.1 Hz, 1H), 3.53 -3.62 (m, 2H), 3.73-3.79 (m, 1H), 4.37 (br, 1H), 4.72 (br, 1H), 6.59 (d, J = 10.1 Hz, 1H), 7.54 (d, J = 10.1 Hz, 1H), 8.17 (s, 1H), 9.44 (br, 1H).

Process 3
Compound 92 (128 mg, 0.309 mmol) was dissolved in THF (2 mL), 2 mol / L aqueous sodium hydroxide solution (0.309 mL, 0.618 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. After standing overnight, 2 mol / L hydrochloric acid aqueous solution (0.160 mL, 0.800 mmol) was added, and then the solvent was concentrated under reduced pressure. THF (2.6 mL) and ethyl isocyanate (0.049 mL mg, 0.618 mmol) were added to the residue, and the mixture was stirred at 60 ° C. for 4 hours. Water was added, extracted with chloroform-methanol (9: 1), and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (10 mmol / L ammonium carbonate-containing aqueous solution-acetonitrile) to obtain Compound 93 (60 mg, yield 50%).
1 H-NMR (CDCl 3 ) δ: 1.24 (t, J = 7.4 Hz, 3H), 1.46 (s, 9H), 1.94-2.03 (m, 1H), 2.25-2.35 (m, 1H), 3.32-3.43 (m, 3H), 3.49-3.61 (m, 2H), 3.73 (dd, J = 10.6, 6.1 Hz, 1H), 4.36 (br, 1H), 4.71 (d, J = 7.1 Hz, 1H), 6.48 ( d, J = 9.6 Hz, 1H), 6.90 (s, 1H), 7.31 (s, 1H), 7.50 (d, J = 9.6 Hz, 1H), 7.83 (br, 1H).

Process 4
TFA (0.5 mL) was added to compound 93 (59 mg, 0.151 mmol), stirred at room temperature for 1 hour, and concentrated under reduced pressure. To the obtained residue was added 4 mol / L hydrogen chloride-ethyl acetate solution (0.5 mL), and the mixture was stirred at room temperature for 10 minutes and concentrated under reduced pressure to give compound 94 (55 mg, yield 100%).
MS (ESI) m / z 290 [M + H] +

Process 5
Compound 94 (5 mg, 0.014 mmol) was dissolved in DMF (0.3 mL) to give 1- (2-hydroxy-2-methylpropyl) -5-methyl-3-oxo-2-phenyl-2,3-dihydro -1H-pyrazole-4-carboxylic acid (4.8 mg, 0.017 mmol), triethylamine (9.6 μL, 0.069 mmol), HATU (6.3 mg, 0.017 mmol) in DMF (0.15 mL) were added. And stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform-methanol (9: 1) and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (10 mmol / L aqueous solution containing ammonium carbonate-acetonitrile) to obtain Compound I-432 (5.6 mg, 71% yield).
MS (ESI) m / z 562 [M + H] +
実施例２２
Figure JPOXMLDOC01-appb-C000132
工程１
　６－ブロモ－２Ｈ－１，４－ベンズオキサジン－３（４Ｈ）－オン（２００ｍｇ、０．８８ｍｍｏｌ）をＤＭＦ（２ｍＬ）に溶解し、水素化ナトリウム（３９ｍｇ、０．９７ｍｍｏｌ）、２－ブロモエチルメチルエーテル（０．１０９ｍＬ、１．１４ｍｍｏｌ）を加え、６０℃にて２時間撹拌した。反応液を放冷後、反応溶液に水を加えクロロホルムで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物９６（２１４ｍｇ、収率８５％）を得た。
MS (ESI) m/z 286 [M+H]+ 

工程２
　窒素雰囲気下、化合物９６（２００ｍｇ、０．７０ｍｍｏｌ）をＤＭＡ（４ｍＬ）に溶解し、（Ｓ）－（－）－３－（Ｂｏｃアミノ）ピロリジン（１３０ｍｇ、０．７０ｍｍｏｌ）、Ｐｄ（ＯＡｃ）２（３１ｍｇ、０．１４ｍｍｏｌ）、ジシクロヘキシル（２’，６’－ジイソプロポキシビフェニル－２－イル）ホスフィン（９８ｍｇ、０．２１ｍｍｏｌ）、炭酸セシウム（４５５ｍｇ、１．４０ｍｍｏｌ）を加え、１２０℃にて４時間半撹拌した。反応液を放冷後濾過し、水を加えクロロホルムで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して粗生成物９７（３１５ｍｇ）を得た。
MS (ESI) m/z 392 [M+H]+ 

　実施例２１における化合物９３の代わりに化合物９７を用いることにより、下記表に記載の実施例化合物を合成した。
Example 22
Figure JPOXMLDOC01-appb-C000132
Process 1
6-Bromo-2H-1,4-benzoxazin-3 (4H) -one (200 mg, 0.88 mmol) was dissolved in DMF (2 mL), sodium hydride (39 mg, 0.97 mmol), 2-bromoethyl Methyl ether (0.109 mL, 1.14 mmol) was added and stirred at 60 ° C. for 2 hours. The reaction solution was allowed to cool, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 96 (214 mg, yield 85%).
MS (ESI) m / z 286 [M + H] +

Process 2
Under a nitrogen atmosphere, compound 96 (200 mg, 0.70 mmol) was dissolved in DMA (4 mL), and (S)-(−)-3- (Boc amino) pyrrolidine (130 mg, 0.70 mmol), Pd (OAc) 2 (31 mg, 0.14 mmol), dicyclohexyl (2 ′, 6′-diisopropoxybiphenyl-2-yl) phosphine (98 mg, 0.21 mmol), cesium carbonate (455 mg, 1.40 mmol) were added at 120 ° C. Stir for 4 and a half hours. The reaction solution was allowed to cool and then filtered, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a crude product 97 (315 mg).
MS (ESI) m / z 392 [M + H] +

Example compounds described in the following table were synthesized by using compound 97 instead of compound 93 in example 21.
実施例２３
Figure JPOXMLDOC01-appb-C000133
工程１
　６－ヨード－３，４－ジヒドロ－２Ｈ－ピリド（３，２－Ｂ）（１，４）オキサジン（１ｇ、３．８２ｍｍｏｌ）をＴＨＦ（１０ｍＬ）に溶解し、フェニルイソシアネート（０．５４ｍＬ、４．９６ｍｍｏｌ）、トリエチルアミン（０．７９ｍＬ、５．７２ｍｍｏｌ）を加え、室温で２４時間撹拌した。析出した固体を濾取し、ジエチルエーテル、水で洗浄した。得られた個体を乾燥し、化合物９９（１．２ｇ、収率８５％）を得た。
MS (ESI) m/z 382 [M+H]+ 

工程２
　窒素雰囲気下、化合物９９（５００ｍｇ、１．３１ｍｍｏｌ）をジオキサン（５ｍＬ）に溶解し、（Ｓ）－（－）－３－（Ｂｏｃアミノ）ピロリジン（２６９ｍｇ、１．４４ｍｍｏｌ）、Ｐｄ２（ｄｂａ）３（１２０ｍｇ、０．１３ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（１１４ｍｇ、０．２０ｍｍｏｌ）、炭酸セシウム（１．２８ｇ、３．９４ｍｍｏｌ）を加え、１２０℃にてマイクロウェーブ下、２時間撹拌した。放冷後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１００（１３７ｍｇ、収率２４％）を得た。
MS (ESI) m/z 440 [M+H]+ 

工程３
　化合物１００（１３７ｍｇ、０．３１ｍｍｏｌ）をクロロホルム（２ｍＬ）に溶解し、トリフルオロ酢酸（１．０４ｍＬ、１３．５ｍｍｏｌ）を加え、室温にて２時間撹拌した。反応液を減圧濃縮し、得られた残渣に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水、水で洗浄した後、無硫酸ナトリウムで乾燥した。減圧濃縮し、化合物１０１（１００ｍｇ、収率９５％）を得た。
MS (ESI) m/z 340 [M+H]+ 

　実施例２１における化合物９４の代わりに化合物１０１を用いることにより、下記表に記載の実施例化合物を合成した。
Example 23
Figure JPOXMLDOC01-appb-C000133
Process 1
6-Iodo-3,4-dihydro-2H-pyrido (3,2-B) (1,4) oxazine (1 g, 3.82 mmol) was dissolved in THF (10 mL) and phenyl isocyanate (0.54 mL, 4 .96 mmol) and triethylamine (0.79 mL, 5.72 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The precipitated solid was collected by filtration and washed with diethyl ether and water. The obtained solid was dried to obtain Compound 99 (1.2 g, yield 85%).
MS (ESI) m / z 382 [M + H] +

Process 2
Under a nitrogen atmosphere, compound 99 (500 mg, 1.31 mmol) was dissolved in dioxane (5 mL), and (S)-(−)-3- (Boc amino) pyrrolidine (269 mg, 1.44 mmol), Pd 2 (dba) 3 (120 mg, 0.13 mmol), Xantphos (114 mg, 0.20 mmol) and cesium carbonate (1.28 g, 3.94 mmol) were added and stirred at 120 ° C. under microwave for 2 hours. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 100 (137 mg, yield 24%).
MS (ESI) m / z 440 [M + H] +

Process 3
Compound 100 (137 mg, 0.31 mmol) was dissolved in chloroform (2 mL), trifluoroacetic acid (1.04 mL, 13.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and water and then dried over sodium sulfate free. Concentration under reduced pressure gave Compound 101 (100 mg, 95% yield).
MS (ESI) m / z 340 [M + H] +

Example compounds described in the following table were synthesized by using Compound 101 instead of Compound 94 in Example 21.
実施例２４　化合物Ｉ－２５０およびＩ－２４７の合成
Figure JPOXMLDOC01-appb-C000134
工程１
　３－エトキシカルボニル－４－（ベンジルオキシカルボニルアミノ）－１－Ｂｏｃ－ピロリジン（１．１５ｇ、２．９ｍｍｏｌ）をＴＨＦ（２５ｍＬ）に溶解し、０℃に冷却して水素化ホウ素リチウム（９６ｍｇ、４．４ｍｍｏｌ）を加えた。室温で１．５時間攪拌した後、６０℃にて１．５時間撹拌した。室温に冷却し、塩化アンモニウム水溶液に注ぎ入れ、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１０３（８７０ｍｇ、収率８５％）を得た。
MS (ESI) m/z ３５１ [M+H]+

工程２
　化合物１０３（３００ｍｇ、０．７５ｍｍｏｌ）を酢酸エチル５ｍＬに溶解し、４ｍｏｌ／Ｌ　塩化水素－酢酸エチル溶液（４．３ｍＬ）を加え、室温で１時間撹拌した。反応液を減圧濃縮し、得られた残渣にヘキサンを加え固体を析出させた後、濾取することにより化合物１０４（１９３ｍｇ、収率９０％）を得た。
MS (ESI) m/z ２５１ [M+H]+

工程３
　化合物１０４（５９０ｍｇ、２．０６ｍｍｏｌ）、化合物２２（７９０ｍｇ、５．１４ｍｍｏｌ）をＮＭＰ（３．５ｍＬ）に溶解し、得られた溶液にＤＩＥＡ（０．９０ｍＬ、５．１４ｍｍｏｌ）を加え、マイクロウェーブ下、１５０℃にて２時間撹拌した。反応液に水を加え、クロロホルムで抽出し、有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１０５（４５５ｍｇ、収率６０％）を得た。
MS (ESI) m/z ３６８ [M+H]+

工程４
　化合物１０５（２００ｍｇ、０．５４ｍｍｏｌ）をＴＨＦ／メタノール（１：１）の混合溶媒２０ｍＬに懸濁し、１０％パラジウムカーボンを加え、水素雰囲気下、室温で５．５時間撹拌した。反応液を濾過し、化合物１０６（１２５ｍｇ、収率９８％）を得た。

工程５
　化合物１０６（１５．５ｍｇ、０．０６６ｍｍｏｌ）、１、５－ジメチル－３－オキソ－２－フェニル－２，３－ジヒドロ－１Ｈ－ピラゾール－４－カルボン酸（１８．５ｍｇ、０．０８ｍｍｏｌ）をＤＭＦ１ｍＬに溶解し、ＨＡＴＵ（３０ｍｇ、０．０８ｍｍｏｌ）、ＤＩＥＡ（０．０２９ｍＬ、０．１７ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液に飽和重曹水を加え、クロロホルム－メタノール（１０：１）で抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２５０（７．６ｍｇ、収率２６％）を得た。
MS (ESI) m/z ４４８ [M+H]+

工程６
　化合物Ｉ－２５０（２２ｍｇ、０．０５ｍｍｏｌ）をジクロロメタン１ｍＬに溶解し、ＤＩＥＡ（０．０２６ｍＬ、０．１５ｍｍｏｌ）、メタンスルホニルクロリド（０．００８ｍＬ、０．１０ｍｍｏｌ）を加え、０℃で１時間攪拌した。反応液に水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をＤＭＦ１ｍＬに溶解し、２ｍｏｌ／Ｌ ジメチルアミン－ＴＨＦ溶液（１．２３ｍＬ、２．５ｍｍｏｌ）を加え５０℃にて１０時間攪拌し、さらに２ｍｏｌ／Ｌ ジメチルアミン－ＴＨＦ溶液（１．２３ｍＬ、２．５ｍｍｏｌ）を加え７０℃にて５時間攪拌した。反応液を減圧濃縮し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２４７（８．７ｍｇ、収率３７％）を得た。
MS (ESI) m/z ４７５ [M+H]+
Example 24 Synthesis of Compounds I-250 and I-247
Figure JPOXMLDOC01-appb-C000134
Process 1
3-Ethoxycarbonyl-4- (benzyloxycarbonylamino) -1-Boc-pyrrolidine (1.15 g, 2.9 mmol) was dissolved in THF (25 mL), cooled to 0 ° C. and cooled to lithium borohydride (96 mg, 4.4 mmol) was added. After stirring at room temperature for 1.5 hours, the mixture was stirred at 60 ° C for 1.5 hours. The mixture was cooled to room temperature, poured into an aqueous ammonium chloride solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 103 (870 mg, yield 85%).
MS (ESI) m / z 351 [M + H] +

Process 2
Compound 103 (300 mg, 0.75 mmol) was dissolved in 5 mL of ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate solution (4.3 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, hexane was added to the resulting residue to precipitate a solid, and then collected by filtration to obtain Compound 104 (193 mg, yield 90%).
MS (ESI) m / z 251 [M + H] +

Process 3
Compound 104 (590 mg, 2.06 mmol) and compound 22 (790 mg, 5.14 mmol) were dissolved in NMP (3.5 mL), DIEA (0.90 mL, 5.14 mmol) was added to the resulting solution, and microwaves were added. The mixture was stirred at 150 ° C. for 2 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 105 (455 mg, yield 60%).
MS (ESI) m / z 368 [M + H] +

Process 4
Compound 105 (200 mg, 0.54 mmol) was suspended in 20 mL of a mixed solvent of THF / methanol (1: 1), 10% palladium carbon was added, and the mixture was stirred at room temperature for 5.5 hours under a hydrogen atmosphere. The reaction solution was filtered to obtain Compound 106 (125 mg, yield 98%).

Process 5
Compound 106 (15.5 mg, 0.066 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (18.5 mg, 0.08 mmol) It melt | dissolved in DMF1mL, HATU (30mg, 0.08mmol) and DIEA (0.029mL, 0.17mmol) were added, and it stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform-methanol (10: 1) and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-250 (7.6 mg, yield 26%).
MS (ESI) m / z 448 [M + H] +

Step 6
Compound I-250 (22 mg, 0.05 mmol) was dissolved in 1 mL of dichloromethane, DIEA (0.026 mL, 0.15 mmol) and methanesulfonyl chloride (0.008 mL, 0.10 mmol) were added, and the mixture was stirred at 0 ° C. for 1 hour. did. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 1 mL of DMF, 2 mol / L dimethylamine-THF solution (1.23 mL, 2.5 mmol) was added, and the mixture was stirred at 50 ° C. for 10 hours, and further 2 mol / L dimethylamine-THF solution (1. 23 mL, 2.5 mmol) was added and stirred at 70 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography (chloroform-methanol) to obtain Compound I-247 (8.7 mg, yield 37%).
MS (ESI) m / z 475 [M + H] +
実施例２５
Figure JPOXMLDOC01-appb-C000135
工程１
　化合物１０７（８４６ｍｇ、３．２ｍｍｏｌ）および化合物２２と同様にして得られた化合物１０８（７８４ｍｇ、３．２ｍｍｏｌ）、ヨウ化銅（１２２ｍｇ、０．６４ｍｍｏｌ）、炭酸カリウム（６６３ｍｇ、４．８ｍｍｏｌ）をＤＭＡ（４ｍＬ）に溶解し、９０℃にて終夜で撹拌した。シリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１０９（５１０ｍｇ、収率４２％）を得た。
MS (ESI) m/z ３８２ [M+H]+

工程２
　化合物１０９（５６ｍｇ、０．１５ｍｍｏｌ）をＤＭＦ２ｍＬに溶解し、ＨＡＴＵ（６７ｍｇ、０．１８ｍｍｏｌ）、ＤＩＥＡ（０．０６４ｍＬ、０．３７ｍｍｏｌ）、塩化アンモニウム（９ｍｇ、０．１８ｍｍｏｌ）を加え室温で１．５時間攪拌した。反応液に水を加え、クロロホルムで抽出した後、減圧濃縮し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して、化合物１１０（２４ｍｇ、収率４３％）を得た。
MS (ESI) m/z ３８１ [M+H]+

　実施例２４における化合物１０５の代わりに化合物１１０を用いることにより、下記表に記載の実施例化合物を合成した。
Example 25
Figure JPOXMLDOC01-appb-C000135
Process 1
Compound 107 (846 mg, 3.2 mmol) and Compound 108 (784 mg, 3.2 mmol), copper iodide (122 mg, 0.64 mmol), potassium carbonate (663 mg, 4.8 mmol) obtained in the same manner as Compound 22 were added. Dissolved in DMA (4 mL) and stirred at 90 ° C. overnight. Purification by silica gel column chromatography (chloroform-methanol) gave compound 109 (510 mg, yield 42%).
MS (ESI) m / z 382 [M + H] +

Process 2
Compound 109 (56 mg, 0.15 mmol) was dissolved in 2 mL of DMF, HATU (67 mg, 0.18 mmol), DIEA (0.064 mL, 0.37 mmol), ammonium chloride (9 mg, 0.18 mmol) were added, and 1. Stir for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (chloroform-methanol) to obtain Compound 110 (24 mg, 43% yield). .
MS (ESI) m / z 381 [M + H] +

Example compounds described in the following table were synthesized by using compound 110 instead of compound 105 in example 24.
実施例２６
Figure JPOXMLDOC01-appb-C000136
工程１
　ＷＯ２０１２／０３４０９１Ａ１に記載の方法と同様にして得られた化合物１１２（９０１ｍｇ、２．８７ｍｍｏｌ）をＤＭＳＯ（９．０ｍＬ）に溶解し、化合物１１１（合成法はＷＯ２０１２／０３４０９１Ａ１に記載）（９７０ｍｇ、４．３ｍｍｏｌ）、フッ化カリウム（８３３ｍｇ、１４．３３ｍｍｏｌ）を加え、１２０℃にて６時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して粗生成物１１３（８００ｍｇ、収率５５％）を得た。
MS (ESI) m/z 504 [M+H]+ 

工程２
　０℃に冷却したＴＨＦ５ｍＬに、水素化アルミニウムリチウム（１０．２ｍｇ、０．２７ｍｍｏｌ）、ＴＨＦ５ｍＬに溶解した化合物１１３（９０ｍｇ、０．１８ｍｍｏｌ）を加え、室温で６時間攪拌した。０℃に冷却し、水素化アルミニウムリチウム（３０．６ｍｇ、０．８１ｍｍｏｌ）を追加し、さらに室温で３０分攪拌した。反応液を０℃に冷却し、水、クエン酸水溶液を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、化合物１１４（７６ｍｇ、収率９２％）を得た。
MS (ESI) m/z ４６２ [M+H]+

　実施例２４における化合物１０５の代わりに化合物１１４を用いることにより、下記表に記載の実施例化合物を合成した。
Example 26
Figure JPOXMLDOC01-appb-C000136
Process 1
Compound 112 (901 mg, 2.87 mmol) obtained in the same manner as in the method described in WO2012 / 034091A1 was dissolved in DMSO (9.0 mL), and compound 111 (the synthesis method is described in WO2012 / 034091A1) (970 mg, 4 .3 mmol) and potassium fluoride (833 mg, 14.33 mmol) were added, and the mixture was stirred at 120 ° C. for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain a crude product 113 (800 mg, yield 55%).
MS (ESI) m / z 504 [M + H] +

Process 2
To 5 mL of THF cooled to 0 ° C., lithium aluminum hydride (10.2 mg, 0.27 mmol) and compound 113 (90 mg, 0.18 mmol) dissolved in 5 mL of THF were added and stirred at room temperature for 6 hours. The mixture was cooled to 0 ° C., lithium aluminum hydride (30.6 mg, 0.81 mmol) was added, and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C., water and aqueous citric acid solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain Compound 114 (76 mg, yield 92%).
MS (ESI) m / z 462 [M + H] +

Example compounds described in the following table were synthesized by using compound 114 instead of compound 105 in example 24.
実施例２７
Figure JPOXMLDOC01-appb-C000137
工程１
　化合物９１（１５０ｍｇ、０．５７ｍｍｏｌ）、３－エトキシカルボニル－４－（ベンジルオキシカルボニルアミノ）ピロリジン（３３１ｍｇ、１．１３ｍｍｏｌ）をＮＭＰ（１．５ｍＬ）に溶解し、ＤＩＥＡ（０．５０ｍＬ、２．８３ｍｍｏｌ）を加え、マイクロウェーブ下、１５０℃にて２時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－ＴＨＦ）により精製して化合物１１６（８７ｍｇ、収率３０％）を得た。
MS (ESI) m/z 521 [M+H]+

工程２
　化合物１１６（２９７ｍｇ、０．１６ｍｍｏｌ）をＴＨＦ／メタノール（１：１）の混合溶媒（２０ｍＬ）に溶解し、１０％パラジウムカーボンを加え、水素雰囲気下、室温で４時間撹拌した。反応液を濾過し、化合物１１７（２４９ｍｇ、収率１００％）を得た。
MS (ESI) m/z 387 [M+H]+

　実施例２４における化合物１０６の代わりに化合物１１７を用いることにより、下記表に記載の実施例化合物を合成した。
Example 27
Figure JPOXMLDOC01-appb-C000137
Process 1
Compound 91 (150 mg, 0.57 mmol), 3-ethoxycarbonyl-4- (benzyloxycarbonylamino) pyrrolidine (331 mg, 1.13 mmol) was dissolved in NMP (1.5 mL), and DIEA (0.50 mL, 2. 83 mmol) was added and stirred at 150 ° C. for 2 hours under microwave. Water was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-THF) to obtain Compound 116 (87 mg, yield 30%).
MS (ESI) m / z 521 [M + H] +

Process 2
Compound 116 (297 mg, 0.16 mmol) was dissolved in a mixed solvent (20 mL) of THF / methanol (1: 1), 10% palladium carbon was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction solution was filtered to obtain Compound 117 (249 mg, yield 100%).
MS (ESI) m / z 387 [M + H] +

Example compounds described in the following table were synthesized by using Compound 117 instead of Compound 106 in Example 24.
実施例２８　化合物Ｉ－２５２、Ｉ－２６５およびＩ－２３５の合成
Figure JPOXMLDOC01-appb-C000138
工程１
　化合物１０３（４００ｍｇ、１．１４ｍｍｏｌ）をＴＨＦ８ｍＬに溶解し、フタルイミド（２０２ｍｇ、１．３７ｍｍｏｌ）、トリフェニルホスフィン（３５９ｍｇ、１．３７ｍｍｏｌ）を加えた。反応液を０℃に冷却した後、２．２ｍｏｌ／Ｌアゾジカルボン酸ジエチル－トルエン溶液（０．５２ｍＬ、１．１４ｍｍｏｌ）を加え、室温で４時間攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル－ヘキサン）により精製して化合物１１８（５９０ｍｇ、収率１００％）を得た。
MS (ESI) m/z ４８０ [M+H]+

工程２
　化合物１１８（２４０ｍｇ、０．５０ｍｍｏｌ）を酢酸エチル８ｍＬに溶解し、４ｍｏｌ／Ｌ　塩化水素－酢酸エチル溶液（２．５ｍＬ）を加え、室温で１時間撹拌した。反応液を減圧濃縮し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１１９（１２５ｍｇ、収率６６％）を得た。
MS (ESI) m/z ３８０ [M+H]+

工程３
　化合物１１９（１１５ｍｇ、０．３０ｍｍｏｌ）、化合物２２（１１６ｍｇ、０．７６ｍｍｏｌ）をＮＭＰ（２ｍＬ）に溶解し、ＤＩＥＡ（０．１３ｍＬ、０．７６ｍｍｏｌ）を加え、マイクロウェーブ下、１５０℃にて２時間撹拌した。反応液に水を加え、クロロホルムで抽出し、有機層を水で洗浄した後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１２０（８８ｍｇ、収率５９％）を得た。
MS (ESI) m/z ４９７ [M+H]+

工程４
　化合物１２０（１３５ｍｇ、０．２７ｍｍｏｌ）をＴＨＦ／メタノール（１：１）の混合溶媒６ｍＬに懸濁し、２０％水酸化パラジウムカーボンを加え、水素雰囲気下、室温で５日間撹拌した。反応液を濾過し、化合物１２１（８５ｍｇ、８６％）を得た。
MS (ESI) m/z ３６３ [M+H]+

工程５
　化合物１２１（８５ｍｇ、０．２４ｍｍｏｌ）、１、５－ジメチル－３－オキソ－２－フェニル－２，３－ジヒドロ－１Ｈ－ピラゾール－４－カルボン酸（６５ｍｇ、０．２８ｍｍｏｌ）をＤＭＦ２ｍＬに溶解し、ＨＡＴＵ（１０７ｍｇ、０．２８ｍｍｏｌ）、ＤＩＥＡ（０．１０２ｍＬ、０．５９ｍｍｏｌ）を加え室温で９時間攪拌した。反応液に水を加え、クロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２５２（７３ｍｇ、収率５４％）を得た。
MS (ESI) m/z ５７７ [M+H]+

工程６
　化合物Ｉ－２５２（７３ｍｇ、０．１３ｍｍｏｌ）をメタノール２ｍＬに溶解し、４０％メチルアミン－メタノール溶液 (１．３ｍＬ、１２．７ｍｍｏｌ)を加え、６５℃にて２．５時間攪拌した。反応液を減圧濃縮し、化合物Ｉ－２６５を含む混合物を得た。
MS (ESI) m/z ４４７ [M+H]+

工程７
　化合物Ｉ－２６５（０．０６３ｍｍｏｌ）をＤＭＦ１ｍＬに溶解し、ＤＩＥＡ（０．０２８ｍＬ、０．１５８ｍｍｏｌ）、トリメチルシリルイソシアネート（０．０１０ｍＬ、０．０７６ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液に水、飽和重曹水を加え、クロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）、およびアミノシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物Ｉ－２３５（７．２ｍｇ、収率２３％）を得た。
MS (ESI) m/z ４９０ [M+H]+
Example 28 Synthesis of Compounds I-252, I-265 and I-235
Figure JPOXMLDOC01-appb-C000138
Process 1
Compound 103 (400 mg, 1.14 mmol) was dissolved in 8 mL of THF, and phthalimide (202 mg, 1.37 mmol) and triphenylphosphine (359 mg, 1.37 mmol) were added. After the reaction solution was cooled to 0 ° C., a 2.2 mol / L diethyl azodicarboxylate-toluene solution (0.52 mL, 1.14 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain Compound 118 (590 mg, yield 100%).
MS (ESI) m / z 480 [M + H] +

Process 2
Compound 118 (240 mg, 0.50 mmol) was dissolved in 8 mL of ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate solution (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (chloroform-methanol) to obtain Compound 119 (125 mg, yield 66%).
MS (ESI) m / z 380 [M + H] +

Process 3
Compound 119 (115 mg, 0.30 mmol) and compound 22 (116 mg, 0.76 mmol) were dissolved in NMP (2 mL), DIEA (0.13 mL, 0.76 mmol) was added, and 2 microwaves at 150 ° C. were added. Stir for hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 120 (88 mg, yield 59%).
MS (ESI) m / z 497 [M + H] +

Process 4
Compound 120 (135 mg, 0.27 mmol) was suspended in 6 mL of a mixed solvent of THF / methanol (1: 1), 20% palladium hydroxide carbon was added, and the mixture was stirred at room temperature for 5 days in a hydrogen atmosphere. The reaction solution was filtered to obtain Compound 121 (85 mg, 86%).
MS (ESI) m / z 363 [M + H] +

Process 5
Compound 121 (85 mg, 0.24 mmol), 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (65 mg, 0.28 mmol) was dissolved in 2 mL of DMF. , HATU (107 mg, 0.28 mmol) and DIEA (0.102 mL, 0.59 mmol) were added and stirred at room temperature for 9 hours. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound I-252 (73 mg, yield 54%).
MS (ESI) m / z 577 [M + H] +

Step 6
Compound I-252 (73 mg, 0.13 mmol) was dissolved in 2 mL of methanol, 40% methylamine-methanol solution (1.3 mL, 12.7 mmol) was added, and the mixture was stirred at 65 ° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain a mixture containing Compound I-265.
MS (ESI) m / z 447 [M + H] +

Step 7
Compound I-265 (0.063 mmol) was dissolved in 1 mL of DMF, DIEA (0.028 mL, 0.158 mmol) and trimethylsilyl isocyanate (0.010 mL, 0.076 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) and amino silica gel column chromatography (chloroform-methanol) to obtain compound I-235 (7.2 mg, yield 23%).
MS (ESI) m / z 490 [M + H] +
実施例２９　化合物Ｉ－６０７の合成
Figure JPOXMLDOC01-appb-C000139
工程１
　化合物１２３（２７ｍｇ、０．２０ｍｍｏｌ）をＤＭＳＯ（１ｍＬ）に溶解し、化合物５５（７０ｍｇ、０．１８ｍｍｏｌ）、炭酸セシウム（２０７ｍｇ、０．６４ｍｍｏｌ）を加え、マイクロウェーブ下、１２０℃にて１時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、化合物１２４（６４ｍｇ、収率７６％）を得た。
MS (ESI) m/z 466 [M+H]+ 

工程２
　窒素雰囲気下、化合物１２４（１４７ｍｇ、０．３２ｍｍｏｌ）をクロロホルム（３ｍＬ）に溶解し、１－トリフルオロメチル－３，３－ジメチル－１，２－ベンズヨードオキソール（１５６ｍｇ、０．４７ｍｍｏｌ）、７価メチルトリオキソレニウム（６ｍｇ、０．０２５ｍｍｏｌ）を加え、７０℃にて８時間撹拌した。反応液を放冷後、水を加え、クロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１２５（２５ｍｇ、収率１５％）を得た。
MS (ESI) m/z 534 [M+H]+ 

工程３
　化合物１２５（２５ｍｇ、０．０４７ｍｍｏｌ）をＤＭＦ（０．５ｍＬ）に溶解し、炭酸カリウム（３２ｍｇ、０．２３ｍｍｏｌ）、ドデカン－１－チオール（０．０３４ｍＬ、０．１４ｍｍｏｌ）を加え、５０℃にて２時間半撹拌した。反応液を放冷後、生じた固体を濾過し、ＨＡＴＵ（２７ｍｇ、０．０７０ｍｍｏｌ）、化合物３７（１４ｍｇ、０．０５６ｍｍｏｌ）、ＤＩＥＡ（０．０２５ｍＬ、０．１４ｍｍｏｌ）を加え、室温にて３時間撹拌した。反応溶液に水を加え、クロロホルムで抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－６０７（１１ｍｇ、収率４１％）を得た。
MS (ESI) m/z 577 [M+H]+ 
1H-NMR (CDCl3) δ: 8.93 (1.0H, d, J = 7.2 Hz), 8.55 (1.0H, d, J = 4.5 Hz), 7.71 (1.0H, s), 7.65-7.59 (2.0H, m), 7.52 (2.0H, t, J = 7.7 Hz), 7.42 (1.0H, t, J = 7.3 Hz), 7.35-7.29 (3.0H, m), 7.14 (1.0H, dd, J = 7.0, 5.3 Hz), 6.60 (1.0H, d, J = 9.9 Hz), 5.22 (1.0H, dd, J = 7.8, 4.3 Hz), 5.00 (1.0H, dd, J = 13.6, 6.7 Hz), 4.32 (1.0H, dd, J = 10.4, 6.7 Hz), 3.78 (2.0H, q, J = 7.0 Hz), 3.64 (1.0H, dd, J = 10.4, 6.2 Hz), 2.74 (3.0H, s), 2.60-2.45 (2.0H, m), 1.02 (3.0H, t, J = 7.0 Hz).
Example 29 Synthesis of Compound I-607
Figure JPOXMLDOC01-appb-C000139
Process 1
Compound 123 (27 mg, 0.20 mmol) was dissolved in DMSO (1 mL), compound 55 (70 mg, 0.18 mmol) and cesium carbonate (207 mg, 0.64 mmol) were added, and it was microwaved at 120 ° C. for 1 hour. Stir. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave Compound 124 (64 mg, 76% yield).
MS (ESI) m / z 466 [M + H] +

Process 2
Under a nitrogen atmosphere, compound 124 (147 mg, 0.32 mmol) was dissolved in chloroform (3 mL), 1-trifluoromethyl-3,3-dimethyl-1,2-benziodooxol (156 mg, 0.47 mmol), Hexavalent methyltrioxorhenium (6 mg, 0.025 mmol) was added, and the mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was allowed to cool, water was added, the mixture was extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 125 (25 mg, yield 15%).
MS (ESI) m / z 534 [M + H] +

Process 3
Compound 125 (25 mg, 0.047 mmol) was dissolved in DMF (0.5 mL), potassium carbonate (32 mg, 0.23 mmol) and dodecane-1-thiol (0.034 mL, 0.14 mmol) were added, and the mixture was heated to 50 ° C. And stirred for 2.5 hours. The reaction mixture was allowed to cool, and the resulting solid was filtered, and HATU (27 mg, 0.070 mmol), compound 37 (14 mg, 0.056 mmol), DIEA (0.025 mL, 0.14 mmol) were added, and the mixture was stirred at room temperature. Stir for hours. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-607 (11 mg, yield 41%).
MS (ESI) m / z 577 [M + H] +
1 H-NMR (CDCl 3 ) δ: 8.93 (1.0H, d, J = 7.2 Hz), 8.55 (1.0H, d, J = 4.5 Hz), 7.71 (1.0H, s), 7.65-7.59 (2.0H , m), 7.52 (2.0H, t, J = 7.7 Hz), 7.42 (1.0H, t, J = 7.3 Hz), 7.35-7.29 (3.0H, m), 7.14 (1.0H, dd, J = 7.0 , 5.3 Hz), 6.60 (1.0H, d, J = 9.9 Hz), 5.22 (1.0H, dd, J = 7.8, 4.3 Hz), 5.00 (1.0H, dd, J = 13.6, 6.7 Hz), 4.32 ( 1.0H, dd, J = 10.4, 6.7 Hz), 3.78 (2.0H, q, J = 7.0 Hz), 3.64 (1.0H, dd, J = 10.4, 6.2 Hz), 2.74 (3.0H, s), 2.60 -2.45 (2.0H, m), 1.02 (3.0H, t, J = 7.0 Hz).
実施例３０
Figure JPOXMLDOC01-appb-C000140
工程１
　化合物１１１（ＷＯ２０１２／０３４０９１Ａ１に記載）（１１４ｍｇ、０．５１ｍｍｏｌ）をＤＭＳＯ（１．３ｍＬ）に溶解し、化合物５５（１３０ｍｇ、０．３４ｍｍｏｌ）、炭酸セシウム（５５０ｍｇ、１．６９ｍｍｏｌ）を加え、１２０℃にて３時間撹拌した。反応溶液に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して粗生成物１２７（２００ｍｇ）を得た。
MS (ESI) m/z 538 [M+H]+ 

工程２
　粗生成物１２７（１８２ｍｇ、０．３４ｍｍｏｌ）をＴＨＦ（２ｍＬ）、メタノール（２ｍＬ）、水（１ｍＬ）の混合溶液に溶解し、４ｍｏｌ／Ｌ　水酸化リチウム水溶液（０．３４ｍＬ、１．３５ｍｍｏｌ）を加え、室温にて１時間撹拌した。反応溶液に２ｍｏｌ／Ｌ　塩酸水溶液（０．５１ｍＬ、１．０１ｍｍｏｌ）を加え、撹拌後減圧濃縮した。得られた残渣をＤＭＦ（５ｍＬ）に溶解し、ＨＡＴＵ（１５４ｍｇ、０．４１ｍｍｏｌ）、２，２－ジフルオロエタナミン（６９ｍｇ、０．８５ｍｍｏｌ）、ＤＩＥＡ（０．１８ｍＬ、１．０１ｍｍｏｌ）を加え、室温にて３０分撹拌した。反応溶液に水を加え、クロロホルムで抽出、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム－メタノール）により精製して化合物１２８（８９ｍｇ、収率４６％）を得た。
MS (ESI) m/z 573 [M+H]+ 

　実施例２９における化合物１２５の代わりに化合物１２８を用いることにより、下記表に記載の実施例化合物を合成した。
Example 30
Figure JPOXMLDOC01-appb-C000140
Process 1
Compound 111 (described in WO2012 / 034091A1) (114 mg, 0.51 mmol) was dissolved in DMSO (1.3 mL), compound 55 (130 mg, 0.34 mmol), cesium carbonate (550 mg, 1.69 mmol) were added, and 120 Stir at 0 ° C. for 3 hours. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain a crude product 127 (200 mg).
MS (ESI) m / z 538 [M + H] +

Process 2
The crude product 127 (182 mg, 0.34 mmol) was dissolved in a mixed solution of THF (2 mL), methanol (2 mL), and water (1 mL), and 4 mol / L lithium hydroxide aqueous solution (0.34 mL, 1.35 mmol) was added. The mixture was further stirred at room temperature for 1 hour. A 2 mol / L aqueous hydrochloric acid solution (0.51 mL, 1.01 mmol) was added to the reaction solution, and the mixture was stirred and concentrated under reduced pressure. The obtained residue was dissolved in DMF (5 mL), HATU (154 mg, 0.41 mmol), 2,2-difluoroethanamine (69 mg, 0.85 mmol), DIEA (0.18 mL, 1.01 mmol) were added, Stir at room temperature for 30 minutes. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 128 (89 mg, yield 46%).
MS (ESI) m / z 573 [M + H] +

Example compounds described in the following table were synthesized by using Compound 128 instead of Compound 125 in Example 29.
実施例３１
Figure JPOXMLDOC01-appb-C000141
工程１
　化合物１２９（１．８ｇ、１０ｍｍｏｌ）をジクロロメタン（１００ｍＬ）に溶解し、スルファ　トリフルオリド　ジエチルアミン　コンプレックス（６．６１ｍＬ、５０ｍｍｏｌ）を加え、室温にて終夜撹拌した。飽和炭酸水素ナトリウム水溶液と氷の混合液に、反応溶液を少しずつ加え、同温下にて撹拌した。得られた溶液をジクロロメタンで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、化合物１３０（２．０２ｇ、収率９９％）を得た。
MS (ESI) m/z 204 [M+H]+ 

工程２
　化合物１３０（１５５ｍｇ、０．７６ｍｍｏｌ）をＤＭＳＯ（２ｍＬ）に溶解し、化合物５５（２００ｍｇ、０．４８ｍｍｏｌ）、炭酸セシウム（７７３ｍｇ、２．３７ｍｍｏｌ）を加え、マイクロウェーブ下、１２０℃にて１時間半撹拌した。反応溶液に水を加え酢酸エチルで抽出し、水、飽和食塩水にて洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、化合物１３１（２４０ｍｇ、収率９８％）を得た。
MS (ESI) m/z 516 [M+H]+ 

　実施例２９における化合物１２５の代わりに化合物１３１を用いることにより、下記表に記載の実施例化合物を合成した。
Example 31
Figure JPOXMLDOC01-appb-C000141
Process 1
Compound 129 (1.8 g, 10 mmol) was dissolved in dichloromethane (100 mL), sulfatrifluoride diethylamine complex (6.61 mL, 50 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was added little by little to a mixture of saturated aqueous sodium hydrogen carbonate solution and ice, and the mixture was stirred at the same temperature. The resulting solution was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave Compound 130 (2.02 g, yield 99%).
MS (ESI) m / z 204 [M + H] +

Process 2
Compound 130 (155 mg, 0.76 mmol) was dissolved in DMSO (2 mL), compound 55 (200 mg, 0.48 mmol), cesium carbonate (773 mg, 2.37 mmol) were added, and microwaved at 120 ° C. for 1 hour. Half stirred. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave Compound 131 (240 mg, 98% yield).
MS (ESI) m / z 516 [M + H] +

Example compounds shown in the following table were synthesized by using compound 131 instead of compound 125 in example 29.
実施例３２　化合物Ｉ－４６５の合成
Figure JPOXMLDOC01-appb-C000142
工程１
　化合物９１（３０．０ｇ、１１３ｍｍｏｌ）、３－カルボキシメチルエステルピロリジン（４３．９ｇ、３４０ｍｍｏｌ）、ＤＩＥＡ（４３．９ｇ、３４０ｍｍｏｌ）を、ＮＭＰ（２００ｍＬ）に加え、窒素雰囲気下、１６０℃にて、１．５時間撹拌した。反応溶液を室温まで冷却した後、１ｍｏｌ／Ｌ塩酸水溶液（５００ｍＬ）に注ぎ、水酸化ナトリウム水溶液にてｐＨ＝６まで、中和した。生成した固体を濾取し、水で洗浄した後、減圧乾燥して粗生成物１３３（３５ｇ、収率８７％）を得た。

工程２
　粗生成物１３３（１１ｇ、３１ｍｍｏｌ）のメタノール（１５０ｍＬ）溶液に、１ｍｏｌ／Ｌ水酸化カリウム（１５０ｍＬ）を加えた。その反応溶液を窒素雰囲気下、６０℃にて２時間撹拌した。反応液に塩酸水溶液を加え、ｐＨ＝３まで酸性化した。減圧濃縮し、粗生成物１３４（３．５ｇ、１４ｍｍｏｌ）を得た。
MS (ESI) m/z 248.0 [M+H]+

工程３
　粗生成物１３４（１４．０ｇ、３１ｍｍｏｌ）のメタノール（３００ｍＬ）溶液に、濃塩酸（１０ｍＬ）を加えた。その反応溶液を窒素雰囲気下、６０℃にて２時間撹拌した。反応液を減圧濃縮し、炭酸水素ナトリウムで中和（ｐＨ＝７）し、ジクロロメタンで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、粗生成物１３５（１３．６ｇ）を得た。
MS (ESI) m/z 262.0 [M+H]+

工程４
　粗生成物１３５（１３．６ｇ、５２ｍｍｏｌ）のＴＨＦ（３００ｍＬ）溶液に、エチルイソシアナート（５．５５ｇ、７８ｍｍｏｌ）とＤＩＥＡ（８．１ｇ、６３ｍｍｏｌ）を加え、６０℃にて撹拌した。４時間後、さらにエチルイソシアナート（５．５５ｇ、７８ｍｍｏｌ）を加え、反応を６０℃にて１６時間撹拌した。反応液を減圧濃縮し、得られた残渣を逆相液体クロマトグラフィー（０．１％ＴＦＡ－アセトニトリル）により精製して化合物１３６（６．２３ｇ、収率３５％）を得た。

工程５
　化合物１３６（６．２ｇ、１８．７ｍｍｏｌ）のメタノール（１３０ｍＬ）・水（５６ｍＬ）の混合溶液に、水酸化リチウム・１水和物（２．３５ｇ、５６ｍｍｏｌ）を加え、室温にて１６時間攪拌した。反応液を減圧濃縮し、生成した固体を濾取した。得られた固体を水（３０ｍＬ）に溶解した後、塩酸水溶液でｐＨ＝２にした。この状態で、５時間攪拌し、生成した固体を濾取した。ｐＨ＝７になるまで、水で洗浄し、減圧乾燥し化合物１３７（４．６６ｇ、収率７６％）を得た。
MS (ESI) m/z 319.2 [M+H]+

工程６
　化合物１３７（１５ｍｇ、０．０４７ｍｍｏｌ）をＤＭＦ（１ｍＬ）に溶解し、ＨＡＴＵ（２２ｍｇ、０．０５７ｍｍｏｌ）、３－アミノビフェニル（１０ｍｇ、０．０５７ｍｍｏｌ）、トリエチルアミン（０．０１０ｍＬ、０．０７１ｍｍｏｌ）を加え、室温にて５時間撹拌した。反応溶液に水、飽和炭酸水素ナトリウム水溶液を加えクロロホルムとメタノールの混合溶媒で抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－４６５（１０ｍｇ、収率４７％）を得た。
MS (ESI) m/z 470 [M+H]+ 
Example 32 Synthesis of Compound I-465
Figure JPOXMLDOC01-appb-C000142
Process 1
Compound 91 (30.0 g, 113 mmol), 3-carboxymethyl ester pyrrolidine (43.9 g, 340 mmol), DIEA (43.9 g, 340 mmol) were added to NMP (200 mL) and at 160 ° C. under nitrogen atmosphere. Stir for 1.5 hours. The reaction solution was cooled to room temperature, poured into a 1 mol / L hydrochloric acid aqueous solution (500 mL), and neutralized with an aqueous sodium hydroxide solution to pH = 6. The produced solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain a crude product 133 (35 g, yield 87%).

Process 2
1 mol / L potassium hydroxide (150 mL) was added to a solution of the crude product 133 (11 g, 31 mmol) in methanol (150 mL). The reaction solution was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. A hydrochloric acid aqueous solution was added to the reaction solution to acidify to pH = 3. Concentration under reduced pressure gave the crude product 134 (3.5 g, 14 mmol).
MS (ESI) m / z 248.0 [M + H] +

Process 3
To a solution of the crude product 134 (14.0 g, 31 mmol) in methanol (300 mL) was added concentrated hydrochloric acid (10 mL). The reaction solution was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, neutralized with sodium bicarbonate (pH = 7), and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude product 135 (13.6 g).
MS (ESI) m / z 262.0 [M + H] +

Process 4
Ethyl isocyanate (5.55 g, 78 mmol) and DIEA (8.1 g, 63 mmol) were added to a solution of the crude product 135 (13.6 g, 52 mmol) in THF (300 mL), and the mixture was stirred at 60 ° C. After 4 hours, more ethyl isocyanate (5.55 g, 78 mmol) was added and the reaction was stirred at 60 ° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (0.1% TFA-acetonitrile) to obtain Compound 136 (6.23 g, yield 35%).

Process 5
To a mixed solution of compound 136 (6.2 g, 18.7 mmol) in methanol (130 mL) and water (56 mL) was added lithium hydroxide monohydrate (2.35 g, 56 mmol), and the mixture was stirred at room temperature for 16 hours. did. The reaction solution was concentrated under reduced pressure, and the resulting solid was collected by filtration. The obtained solid was dissolved in water (30 mL) and adjusted to pH = 2 with an aqueous hydrochloric acid solution. In this state, the mixture was stirred for 5 hours, and the produced solid was collected by filtration. Washing with water until pH = 7 and drying under reduced pressure gave Compound 137 (4.66 g, yield 76%).
MS (ESI) m / z 319.2 [M + H] +

Step 6
Compound 137 (15 mg, 0.047 mmol) was dissolved in DMF (1 mL), HATU (22 mg, 0.057 mmol), 3-aminobiphenyl (10 mg, 0.057 mmol), triethylamine (0.010 mL, 0.071 mmol) were added. The mixture was further stirred at room temperature for 5 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted with a mixed solvent of chloroform and methanol and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-465 (10 mg, 47% yield).
MS (ESI) m / z 470 [M + H] +
実施例３２　化合物Ｉ－２２５の合成
Figure JPOXMLDOC01-appb-C000143
　化合物Ｉ－１６６（１６ｍｇ、０．０３ｍｍｏｌ）をトルエン１ｍＬに溶解し、(1－エトキシエテニル)トリブチルスタンナン（５３．４ｍｇ、０．１５ｍｍｏｌ）、Ｐｄ（ＰＰｈ３）４（１０．３ｍｇ、０．００９ｍｍｏｌ）を加え、１１０℃にて２時間攪拌した。反応液を室温に戻し、２ｍｏｌ／Ｌ塩酸（０．５ｍＬ）を加え、室温で２時間攪拌した。水を加えクロロホルムで抽出した後、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（０．１％ギ酸水溶液－０．１％ギ酸アセトニトリル溶液）により精製して化合物Ｉ－２２５（３．５ｍｇ、収率２６％）を得た。

MS (ESI) m/z ４５８ [M+H]+
Example 32 Synthesis of Compound I-225
Figure JPOXMLDOC01-appb-C000143
Compound I-166 (16 mg, 0.03 mmol) was dissolved in 1 mL of toluene, and (1-ethoxyethenyl) tributylstannane (53.4 mg, 0.15 mmol), Pd (PPh 3 ) 4 (10.3 mg, 0 0.009 mmol) and stirred at 110 ° C. for 2 hours. The reaction solution was returned to room temperature, 2 mol / L hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with chloroform and concentrated under reduced pressure. The obtained residue was purified by reverse-phase liquid chromatography (0.1% formic acid aqueous solution-0.1% formic acid acetonitrile solution) to obtain Compound I-225 (3.5 mg, yield 26%).

MS (ESI) m / z 458 [M + H] +
実施例３３　化合物Ｉ－１７４の合成
Figure JPOXMLDOC01-appb-C000144
　窒素雰囲気下、化合物Ｉ－１６６（４ｍｇ、０．００７４ｍｍｏｌ）をジオキサン（０．１ｍＬ）に溶解し、ビニルボロン酸ピナコールシクロエステル（０．００２ｍＬ、０．０１１ｍｍｏｌ）、Ｐｄ（ＰＰｈ３）４（１ｍｇ、０．０００７４ｍｍｏｌ）、炭酸ナトリウム（３ｍｇ、０．０２２ｍｍｏｌ）を加え、１００℃にて４時間撹拌した。放冷後、反応溶液に水を加え、ジクロロメタンで抽出し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－１７４（２．３ｍｇ、収率７１％）を得た。
MS (ESI) m/z 442 [M+H]+ 
Example 33 Synthesis of Compound I-174
Figure JPOXMLDOC01-appb-C000144
Compound I-166 (4 mg, 0.0074 mmol) was dissolved in dioxane (0.1 mL) under a nitrogen atmosphere, and vinylboronic acid pinacol cycloester (0.002 mL, 0.011 mmol), Pd (PPh 3 ) 4 (1 mg, 0.00074 mmol) and sodium carbonate (3 mg, 0.022 mmol) were added, and the mixture was stirred at 100 ° C. for 4 hours. After allowing to cool, water was added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-174 (2.3 mg, 71% yield).
MS (ESI) m / z 442 [M + H] +
実施例３４　化合物Ｉ－５４３の合成
Figure JPOXMLDOC01-appb-C000145
　窒素雰囲気下、化合物Ｉ－５１５（８ｍｇ、０．０１４ｍｍｏｌ）をトルエン（０．５ｍＬ）と水（０．０５ｍＬ）の混合溶液に溶解し、シクロプロピルトリフルオロボロン酸カリウム（３ｍｇ、０．０２１ｍｍｏｌ）、Ｐｄ（ＯＡｃ）２（１ｍｇ、０．００１４ｍｍｏｌ）、ブチルジ－１－アダマンチルホスフィン（１ｍｇ、０．００２１ｍｍｏｌ）、炭酸セシウム（１３ｍｇ、０．０４１ｍｍｏｌ）を加え、１００℃にて８時間撹拌した。放冷後、固体を濾過し、減圧濃縮した。得られた残渣を逆相液体クロマトグラフィー（水－アセトニトリル）により精製して化合物Ｉ－５４３（０．９ｍｇ、収率１３％）を得た。
MS (ESI) m/z 498 [M+H]+ 
Example 34 Synthesis of Compound I-543
Figure JPOXMLDOC01-appb-C000145
In a nitrogen atmosphere, Compound I-515 (8 mg, 0.014 mmol) was dissolved in a mixed solution of toluene (0.5 mL) and water (0.05 mL), and potassium cyclopropyltrifluoroboronate (3 mg, 0.021 mmol). , Pd (OAc) 2 (1 mg, 0.0014 mmol), butyldi-1-adamantylphosphine (1 mg, 0.0021 mmol) and cesium carbonate (13 mg, 0.041 mmol) were added, and the mixture was stirred at 100 ° C. for 8 hours. After allowing to cool, the solid was filtered and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (water-acetonitrile) to obtain Compound I-543 (0.9 mg, 13% yield).
MS (ESI) m / z 498 [M + H] +
実施例３５
Figure JPOXMLDOC01-appb-C000146
　６－ヨード－３，４－ジヒドロ－２Ｈ－ピリド（３，２－Ｂ）（１，４）オキサジン（２００ｍｇ、０．７６ｍｍｏｌ）をＴＨＦ（２ｍＬ）に溶解し、６０％水素化ナトリウム（４６ｍｇ、１．１５ｍｍｏｌ）、ブロモエチル（０．０６８ｍＬ、０．９２ｍｍｏｌ）を加え、５０℃にて３時間撹拌した。放冷後、反応溶液に水を加え、クロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１３９（６９ｍｇ、収率３１％）を得た。
MS (ESI) m/z 291 [M+H]+

　実施例２２の化合物９６、または実施例２３の化合物９９の代わりに化合物１３９を用いることにより、下記表に記載の実施例化合物を合成した。
Example 35
Figure JPOXMLDOC01-appb-C000146
6-Iodo-3,4-dihydro-2H-pyrido (3,2-B) (1,4) oxazine (200 mg, 0.76 mmol) was dissolved in THF (2 mL) and 60% sodium hydride (46 mg, 1.15 mmol) and bromoethyl (0.068 mL, 0.92 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours. After allowing to cool, water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 139 (69 mg, yield 31%).
MS (ESI) m / z 291 [M + H] +

Example compounds described in the following table were synthesized by using compound 139 instead of compound 96 of example 22 or compound 99 of example 23.
実施例３６
Figure JPOXMLDOC01-appb-C000147
　６－ヨード－３，４－ジヒドロ－２Ｈ－ピリド（３，２－Ｂ）（１，４）オキサジン（１００ｍｇ、０．３８ｍｍｏｌ）をジクロロメタン（１ｍＬ）に溶解し、シクロプロパンカルボン酸クロリド（０．０５２ｍＬ、０．５７ｍｍｏｌ）、トリエチルアミン（０．１０６ｍＬ、０．７６ｍｍｏｌ）を加え、室温にて４時間撹拌した。反応溶液に水を加え、クロロホルムで抽出し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル）により精製して化合物１４０（９５ｍｇ、収率７５％）を得た。
MS (ESI) m/z 331 [M+H]+ 

　実施例２２の化合物９６、または実施例２３の化合物９９の代わりに化合物１４０を用いることにより、下記表に記載の実施例化合物を合成した。
Example 36
Figure JPOXMLDOC01-appb-C000147
6-iodo-3,4-dihydro-2H-pyrido (3,2-B) (1,4) oxazine (100 mg, 0.38 mmol) was dissolved in dichloromethane (1 mL) and cyclopropanecarboxylic acid chloride (0. (052 mL, 0.57 mmol) and triethylamine (0.106 mL, 0.76 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, extracted with chloroform, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 140 (95 mg, yield 75%).
MS (ESI) m / z 331 [M + H] +

Example compounds described in the following table were synthesized by using Compound 140 instead of Compound 96 of Example 22 or Compound 99 of Example 23.
実施例３７
工程１
Figure JPOXMLDOC01-appb-C000148
　ジエチルマロン酸（１００ｇ、６２５ｍｍｏｌ）のアセトニトリル（５００ｍＬ）に、５～１５℃にて、塩化マンガン（ＭｇＣｌ２、５９．４ｇ、６２５ｍｍｏｌ）と、トリエチルアミン（１２６ｇ、１．２５ｍｏｌ）を加えた。５分間、攪拌した後、塩化アセチル（４９．０ｇ、６２５ｍｍｏｌ）を、１０～２０℃を保ちながら滴下した。反応溶液を、１６～２２℃にて、１７時間攪拌した。塩酸水溶液で、ｐＨ＝２～３にした後、酢酸エチルで抽出した。有機層を、１ｍｏｌ／Ｌ塩酸水溶液で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮し、化合物１４２（１１０ｇ、収率８７％）をオイルとして得た。化合物１４２は、以下に示す工程３の反応に用いた。
Example 37
Process 1
Figure JPOXMLDOC01-appb-C000148
Manganese chloride (MgCl 2 , 59.4 g, 625 mmol) and triethylamine (126 g, 1.25 mol) were added to diethylmalonic acid (100 g, 625 mmol) in acetonitrile (500 mL) at 5-15 ° C. After stirring for 5 minutes, acetyl chloride (49.0 g, 625 mmol) was added dropwise while maintaining 10 to 20 ° C. The reaction solution was stirred at 16-22 ° C. for 17 hours. The pH was adjusted to 2-3 with an aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a 1 mol / L hydrochloric acid aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure to obtain Compound 142 (110 g, yield 87%) as an oil. Compound 142 was used in the reaction of Step 3 shown below.
工程２
Figure JPOXMLDOC01-appb-C000149
工程２－１
　シクロブタノン（３．００ｇ、４２．８ｍｍｏｌ）とｔｅｒｔ－ブトキシカルボニルヒドラジン（５．０１ｇ、３８．６ｍｍｏｌ）のジクロロメタン（６０ｍＬ）溶液に、酢酸（２．５７ｇ、４２．８ｍｍｏｌ）を加えた。反応液を１０～１５℃にて、２時間攪拌した後、ＮａＢＨ３（ＣＮ）（３．３４ｇ、６４．２ｍｍｏｌ）を加え、１２～１６℃にて１８時間、攪拌した。反応溶液に飽和炭酸水素ナトリウム溶液を加えて、ジクロロメタンで抽出した。有機層を、飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、減圧下濃縮し、粗生成物１４４（６ｇ）を得た。この化合物は精製せず、次の反応に用いた。

工程２－２
　粗生成物１４４（６ｇ）のメタノール溶液（３０ｍＬ）に、４ｍｏｌ／Ｌ　塩酸メタノール溶液（２０ｍＬ）を滴下した。１２～１６℃にて、４時間攪拌し、減圧下２０ｍＬまで濃縮した。その溶液を、酢酸エチル（８０ｍＬ）の中に、攪拌下滴下した。生成した固体を集め濾取し、酢酸エチルで洗浄した。得られた個体を乾燥し、化合物１４５（１．０１ｇ、収率２５％）を得た。化合物１４５は、以下に示す工程３の反応に用いた。
Process 2
Figure JPOXMLDOC01-appb-C000149
Step 2-1
Acetic acid (2.57 g, 42.8 mmol) was added to a solution of cyclobutanone (3.00 g, 42.8 mmol) and tert-butoxycarbonylhydrazine (5.01 g, 38.6 mmol) in dichloromethane (60 mL). The reaction solution was stirred at 10 to 15 ° C. for 2 hours, NaBH 3 (CN) (3.34 g, 64.2 mmol) was added, and the mixture was stirred at 12 to 16 ° C. for 18 hours. Saturated sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude product 144 (6 g). This compound was used for the next reaction without purification.

Step 2-2
To a methanol solution (30 mL) of the crude product 144 (6 g), a 4 mol / L hydrochloric acid methanol solution (20 mL) was added dropwise. The mixture was stirred at 12-16 ° C. for 4 hours, and concentrated to 20 mL under reduced pressure. The solution was added dropwise into ethyl acetate (80 mL) with stirring. The resulting solid was collected and collected by filtration and washed with ethyl acetate. The obtained solid was dried to obtain Compound 145 (1.01 g, yield 25%). Compound 145 was used in the reaction of Step 3 shown below.
工程３　化合物１４８の合成
Figure JPOXMLDOC01-appb-C000150
工程３－１
　化合物１４５（１．０１ｇ、８．２８ｍｍｏｌ）のエタノール（５０ｍＬ）溶液に、化合物１４２（１．６７ｇ、８．２８ｍｍｏｌ）を加えた。反応溶液を１３～１６℃にて、４時間攪拌した。反応溶液を減圧下濃縮し、分取ＴＬＣ（ジクロロメタン：メタノール＝２０：１）で精製後、化合物１４６（３１０ｍｇ、収率１５％）を茶褐色固体として得た。

工程３－２
　化合物１４６（３１０ｍｇ、１．３８ｍｍｏｌ）をヨードメタン（２４．６ｇ）に溶解し、炭酸カリウム（３８２ｍｇ、２．７７ｍｍｏｌ）を、１０～１５℃にて加えた。反応混合物を、４０～４５℃にて１８時間攪拌した。反応溶液を飽和塩化アンモニウム水溶液（６０ｍＬ）に注ぎ、ジクロロメタンで抽出した。有機層を、硫酸ナトリウムで乾燥し、減圧下濃縮し、分取ＴＬＣ（ジクロロメタン：メタノール＝２０：１）で精製し、化合物１４７（１２０ｍｇ、収率３６％）を無色固体として得た。

工程３－３
　化合物１４７（１２０ｍｇ、０．５０４ｍｍｏｌ）のＴＨＦ（３０ｍＬ）溶液に、水酸化リチウム・１水和物（３７ｍｇ、１．５ｍｍｏｌ）を加え、室温にて攪拌した。２４時間後、反応溶液に飽和食塩水を加えて、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥、減圧下濃縮して化合物１４８（８０ｍｇ、収率７５％）を得た。
MS (ESI) m/z 210.8 [M+H]+

　実施例９、実施例２４および実施例２８における１、５－ジメチル－３－オキソ－２－フェニル－２，３－ジヒドロ－１Ｈ－ピラゾール－４－カルボン酸、または実施例３２における３－アミノビフェニル等の代わりに化合物１４８を用いることにより、下記表に記載の実施例化合物を合成した。
Step 3 Synthesis of Compound 148
Figure JPOXMLDOC01-appb-C000150
Step 3-1
Compound 142 (1.67 g, 8.28 mmol) was added to a solution of compound 145 (1.01 g, 8.28 mmol) in ethanol (50 mL). The reaction solution was stirred at 13-16 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure and purified by preparative TLC (dichloromethane: methanol = 20: 1) to obtain compound 146 (310 mg, yield 15%) as a brown solid.

Step 3-2
Compound 146 (310 mg, 1.38 mmol) was dissolved in iodomethane (24.6 g) and potassium carbonate (382 mg, 2.77 mmol) was added at 10-15 ° C. The reaction mixture was stirred at 40-45 ° C. for 18 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (60 mL) and extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC (dichloromethane: methanol = 20: 1) to obtain compound 147 (120 mg, yield 36%) as a colorless solid.

Step 3-3
To a solution of compound 147 (120 mg, 0.504 mmol) in THF (30 mL) was added lithium hydroxide monohydrate (37 mg, 1.5 mmol), and the mixture was stirred at room temperature. After 24 hours, saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain Compound 148 (80 mg, yield 75%).
MS (ESI) m / z 210.8 [M + H] +

1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid in Example 9, Example 24 and Example 28, or 3-aminobiphenyl in Example 32 Example compounds described in the following table were synthesized by using Compound 148 instead of etc.
　上記の実施例に従い、以下の化合物を合成した。化学構造式および物性（ＬＣ／ＭＳデータ）を以下に示す。 The following compounds were synthesized according to the above examples. The chemical structural formula and physical properties (LC / MS data) are shown below.
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000276
実施例化合物のＮＭＲスペクトルデータを以下に示す。
Figure JPOXMLDOC01-appb-T000277
 The NMR spectrum data of the example compounds are shown below.
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000279
　以下に、本発明化合物に関する生物試験例を記載する。 Hereinafter, biological test examples relating to the compounds of the present invention will be described.
試験例１：ＩＴＫ阻害活性（Ｋｉ値）の評価
　本発明に係る化合物のＩＴＫ阻害活性（Ｋｉ値）は、反応条件１～４のいずれかの条件で反応を行い、評価した。 Test Example 1: Evaluation of ITK Inhibitory Activity (Ki Value) The ITK inhibitory activity (Ki value) of the compound according to the present invention was evaluated by performing a reaction under any one of the reaction conditions 1 to 4.
（反応条件１）
　試験プレートの各ウェルに、本発明に係る化合物０．５μＬ（ＤＭＳＯ溶液）および酵素反応溶液（１００ｍＭ　ＨＥＰＥＳ、０．００３％　Ｂｒｉｊ－３５、０．００４％　Ｔｗｅｅｎ２０、１ｍＭ　ＤＴＴ、１０ｍＭ　ＭｇＣｌ２）で希釈した２．２μｇ／ｍＬ　ＩＴＫ（カルナバイオサイエンス製）４．５μＬを加え、１５分間静置した。その後、酵素反応溶液で希釈した、３μＭ　基質ペプチド（ＦＡＭ－ＥＦＰＩＹＤＦＬＰＡＫＫＫ）および２０μＭ　ＡＴＰの混合溶液を５μＬ添加し、９０分間室温で反応させた後、ＥＤＴＡを含む反応停止溶液を１０μＬ加え、反応を停止させた。
（反応条件２）
　試験プレートの各ウェルに、本発明に係る化合物１μＬ（ＤＭＳＯ溶液）および酵素反応溶液で希釈した１．５μｇ／ｍＬ　ＩＴＫ１４μＬを加え、１５分間静置した。その後、酵素反応溶液で希釈した、３．７５μＭ　基質ペプチドおよび２５μＭ　ＡＴＰの混合溶液を１０μＬ添加し、９０分間室温で反応させた後、ＥＤＴＡを含む反応停止溶液を２０μＬ加え、反応を停止させた。
（反応条件３）
　試験プレートの各ウェルに、本発明に係る化合物０．１μＬ（ＤＭＳＯ溶液）および酵素反応溶液で希釈した２５μｇ／ｍＬ　ＩＴＫ５μＬを加え、１５分間静置した。その後、酵素反応溶液で希釈した、３μＭ　基質ペプチドおよび１０μＭ　ＡＴＰの混合溶液を４．９μＬ添加し、９０分間室温で反応させた後、ＥＤＴＡを含む反応停止溶液を１０μＬ加え、反応を停止させた。
（反応条件４　０．１％ＢＳＡ存在下）
　試験プレートの各ウェルに、本発明に係る化合物０．１μＬ（ＤＭＳＯ溶液）および０．１％のＢＳＡを含む酵素反応溶液（１００ｍＭ　ＨＥＰＥＳ、０．００３％　Ｂｒｉｊ－３５、０．００４％　Ｔｗｅｅｎ２０、１ｍＭ　ＤＴＴ、１０ｍＭ　ＭｇＣｌ２、０．１％　ＢＳＡ）で希釈した２５μｇ／ｍＬ　ＩＴＫ５μＬを加え、１５分間静置した。その後、０．１％のＢＳＡを含む酵素反応溶液で希釈した、３μＭ　基質ペプチドおよび１０μＭ　ＡＴＰの混合溶液を４．９μＬ添加し、９０分間室温で反応させた後、ＥＤＴＡを含む反応停止溶液を１０μＬ加え、反応を停止させた。 (Reaction condition 1)
Each well of the test plate was diluted with 0.5 μL of the compound of the present invention (DMSO solution) and enzyme reaction solution (100 mM HEPES, 0.003% Brij-35, 0.004% Tween 20, 1 mM DTT, 10 mM MgCl 2). 4.5 μL of 2.2 μg / mL ITK (manufactured by Carna Biosciences) was added and allowed to stand for 15 minutes. Thereafter, 5 μL of a mixed solution of 3 μM substrate peptide (FAM-EFPIYDFLPAKKK) and 20 μM ATP diluted with an enzyme reaction solution is added and reacted at room temperature for 90 minutes, and then 10 μL of a reaction stop solution containing EDTA is added to stop the reaction. I let you.
(Reaction condition 2)
To each well of the test plate, 1 μL of the compound according to the present invention (DMSO solution) and 14 μL of 1.5 μg / mL ITK diluted with an enzyme reaction solution were added and allowed to stand for 15 minutes. Thereafter, 10 μL of a mixed solution of 3.75 μM substrate peptide and 25 μM ATP diluted with an enzyme reaction solution was added and reacted at room temperature for 90 minutes, and then 20 μL of a reaction stop solution containing EDTA was added to stop the reaction.
(Reaction condition 3)
To each well of the test plate, 0.1 μL of the compound according to the present invention (DMSO solution) and 5 μL of 25 μg / mL ITK diluted with an enzyme reaction solution were added and allowed to stand for 15 minutes. Thereafter, 4.9 μL of a mixed solution of 3 μM substrate peptide and 10 μM ATP diluted with an enzyme reaction solution was added and reacted at room temperature for 90 minutes, and then 10 μL of a reaction stop solution containing EDTA was added to stop the reaction.
(Reaction condition 4 in the presence of 0.1% BSA)
In each well of the test plate, an enzyme reaction solution (100 mM HEPES, 0.003% Brij-35, 0.004% Tween 20, 1 mM) containing 0.1 μL of the compound of the present invention (DMSO solution) and 0.1% BSA 5 μL of 25 μg / mL ITK diluted with DTT, 10 mM MgCl 2, 0.1% BSA) was added and allowed to stand for 15 minutes. Thereafter, 4.9 μL of a mixed solution of 3 μM substrate peptide and 10 μM ATP diluted with an enzyme reaction solution containing 0.1% BSA was added and reacted at room temperature for 90 minutes, followed by 10 μL of a reaction stop solution containing EDTA. In addition, the reaction was stopped.
　反応条件１～４に基づき得られた反応停止済溶液中に含まれるリン酸化基質および未リン酸化基質の蛍光強度を、Ｃａｌｉｐｅｒ　ＥＺ　Ｒｅａｄｅｒ　２　（パーキンエルマー社製）を用いて測定した。基質リン酸化率を次式により算出した。
　（リン酸化質蛍光強度／（リン酸化質蛍光強度＋未リン酸化質蛍光強度））ｘ１００。
　次に、本発明化合物のＩＴＫ阻害率を、本発明化合物の溶媒であるＤＭＳＯを添加したウェルを陰性対照とし、ＩＴＫ未添加のウェルを陽性対照として次式より算出した。
　阻害率＝（１－（本発明化合物の基質リン酸化率－陽性対照の基質リン酸化率）／（陰性対照の基質リン酸化率－陽性対象の基質リン酸化率））ｘ１００。
５０％の阻害活性を示す化合物濃度であるＩＣ５０の算出は、マイクロソフト・エクセル（Ｍｉｃｒｏｓｏｆｔ社）およびＸＬｆｉｔ（ｉｄｂｓ社）のソフトウェアを用いて行った。 The fluorescence intensity of the phosphorylated substrate and the unphosphorylated substrate contained in the reaction stopped solution obtained based on the reaction conditions 1 to 4 was measured using Caliper EZ Reader 2 (Perkin Elmer). The substrate phosphorylation rate was calculated by the following formula.
(Phosphorylated fluorescence intensity / (phosphorylated fluorescence intensity + unphosphorylated fluorescence intensity)) × 100.
Next, the ITK inhibition rate of the compound of the present invention was calculated from the following formula using a well added with DMSO, which is a solvent of the compound of the present invention, as a negative control and a well not added with ITK as a positive control.
Inhibition rate = (1− (substrate phosphorylation rate of the compound of the present invention−substrate phosphorylation rate of positive control) / (substrate phosphorylation rate of negative control−substrate phosphorylation rate of positive target)) × 100.
IC50, which is a concentration of a compound showing 50% inhibitory activity, was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
　化合物非存在下において、反応中のＡＴＰ濃度を、８０、４０、２０、１０、５、２．５、１．２５、０．６２５μＭに変更し、同様の方法にて基質リン酸化率を測定した。各ＡＴＰ濃度での基質リン酸化率からＩＴＫ非存在下の基質リン酸化率を差し引いた値を反応速度ｖの定数倍としてラインウィーバー・バークプロット法によりミカエリス・メンテン定数Ｋｍを算出し、化合物のＫｉ値を次式によって算出した。
　Ｋｉ＝ＩＣ５０値／（１＋試験ＡＴＰ濃度（μＭ）／Ｋｍ（μＭ））
　本発明化合物のうち、化合物Ｉ－００４のＫｉ値は２１０ｎＭであり（反応条件４）、化合物Ｉ－０３６のＫｉ値は６４０ｎＭであり（反応条件３）、化合物Ｉ－１５４のＫｉ値は１５ｎＭであり（反応条件３）、化合物Ｉ－１５５のＫｉ値は２４ｎＭであり（反応条件３）、化合物Ｉ－１７５のＫｉ値は５０ｎＭであり（反応条件３）、化合物Ｉ－２１９のＫｉ値は１８ｎＭであり（反応条件３）、化合物Ｉ－２５８のＫｉ値は１１０ｎＭであり（反応条件４）、化合物Ｉ－４１４のＫｉ値は３２ｎＭであり（反応条件３）、化合物Ｉ－４４５のＫｉ値は２１ｎＭであり（反応条件２）、化合物Ｉ－４８８のＫｉ値は７．３ｎＭであり（反応条件２）、化合物Ｉ－５１０のＫｉ値は５３０ｎＭ（反応条件４）であり、化合物Ｉ－５１６のＫｉ値は６２ｎＭ（反応条件３）であり、化合物Ｉ－５４６のＫｉ値は５１ｎＭ（反応条件３）であった。
　上記以外の本発明化合物のＩＴＫ阻害活性に関する評価結果および反応条件番号を以下の表に示す。なお、Ｋｉ値は、０ｎＭ以上～１００ｎＭ未満を「Ａ」、１００ｎＭ以上～５００ｎＭ未満を「Ｂ」、５００ｎＭ以上～１０００ｎＭ未満を「Ｃ」とする。 In the absence of the compound, the ATP concentration during the reaction was changed to 80, 40, 20, 10, 5, 2.5, 1.25, 0.625 μM, and the substrate phosphorylation rate was measured by the same method. . The Michaelis-Menten constant Km was calculated by the Lineweaver-Burk plot method using the value obtained by subtracting the substrate phosphorylation rate in the absence of ITK from the substrate phosphorylation rate at each ATP concentration as a constant multiple of the reaction rate v. The value was calculated by the following formula.
Ki = IC50 value / (1 + test ATP concentration (μM) / Km (μM))
Among the compounds of the present invention, the Ki value of Compound I-004 is 210 nM (Reaction Condition 4), the Ki value of Compound I-036 is 640 nM (Reaction Condition 3), and the Ki value of Compound I-154 is 15 nM. Yes (reaction condition 3), Ki value of compound I-155 is 24 nM (reaction condition 3), Ki value of compound I-175 is 50 nM (reaction condition 3), and Ki value of compound I-219 is 18 nM (Reaction condition 3), the Ki value of compound I-258 is 110 nM (reaction condition 4), the Ki value of compound I-414 is 32 nM (reaction condition 3), and the Ki value of compound I-445 is Compound I-488 has a Ki value of 7.3 nM (Reaction condition 2), Compound I-510 has a Ki value of 530 nM (Reaction condition 4), and Compound I-516 has a Ki value of 21 nM (Reaction condition 2). K Value is 62 nM (reaction condition 3), Ki values of the compounds I-546 was 51 nM (reaction condition 3).
The evaluation results and reaction condition numbers regarding the ITK inhibitory activity of the compounds of the present invention other than the above are shown in the following table. The Ki value is “A” for 0 nM to less than 100 nM, “B” for 100 nM to less than 500 nM, and “C” for 500 nM to less than 1000 nM.
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000281
（ＩＴＫ以外のキナーゼ阻害活性の測定）
　ＩＴＫ以外のキナーゼ阻害活性の測定する場合は、ＩＴＫ阻害活性の測定方法と同様の方法、各種キナーゼ、対応する基質ペプチドを用いることにより、ＩＴＫ以外のキナーゼ阻害活性を評価可能である。 (Measurement of kinase inhibitory activity other than ITK)
When measuring kinase inhibitory activity other than ITK, kinase inhibitory activity other than ITK can be evaluated by using the same method as the method for measuring ITK inhibitory activity, various kinases, and corresponding substrate peptides.
試験例２：ＰＬＣγ１リン酸化阻害活性の評価
本発明に係る化合物のＰＬＣγ１リン酸化阻害活性の測定は、以下の手順で評価する。
ヒトＴ細胞株　Ｊｕｒｋａｔをハンクス平衡化塩溶液（Ｈａｎｋ’ｓ　ｂａｌａｎｃｅｄ　ｓａｌｔ　ｓｏｌｕｔｉｏｎ、ＨＢＳＳ）で洗浄後、１．５ｘ１０７／ｍＬの細胞濃度に調製し、実験に使用する。細胞懸濁液４０μＬを３７度で５分間予備保温した後、２％　ＤＭＳＯを含む各化合物のＨＢＳＳ溶液１０μＬを混和し、３７度でさらに１０分間予備保温する。その後、２０μｇ／ｍＬ　抗ヒトＣＤ３ε・抗体を含むＨＢＳＳを５０μＬ加え、３分間、３７度で保温する。１００ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ７．５）、７５０ｍＭ　ＮａＣｌ、５ｍＭ　Ｎａ２ＥＤＴＡ、５ｍＭ　ＥＧＴＡ、５％　Ｔｒｉｔｏｎ、１２．５ｍＭ　ピロリン酸ナトリウム、５ｍＭ　β－グリセロホスフェート、１０ｍＭ　Ｎａ３ＶＯ４、１０ｍＭ　イミダゾール、５ｍＭ　ＮａＦ、５．７５ｍМ　Ｎａ２ＭｏＯ４、２０ｍＭ　酒石酸ナトリウム、５μｇ／ｍＬ　ロイペプチンおよび５倍濃度に調整したプロテアーゼインヒビターカクテルの混合溶液を２５μＬ加えて細胞を溶解させる。細胞溶液中のＰＬＣγ１リン酸化量はＥＬＩＳＡ法にて測定する。抗ＰＬＣγ１抗体（クローン２Ｂ１、マウス由来）を固層化したマイクロウェルプレートに調整した細胞溶解液５０μＬを加え２時間室温に静置し、０．０５％　Ｔｗｅｅｎ－２０を含有するトリス緩衝生理食塩水（Ｔｒｉｓ－Ｂｕｆｆｅｒｅｄ　Ｓａｌｉｎｅ）で４回洗浄する。抗リン酸化ＰＬＣγ１抗体（ｐＴｙｒ７８３、ウサギ由来）を加え、２時間室温で静置し、同様に洗浄後、ＨＲＰ標識した抗ウサギＩｇＧ抗体を反応させる。室温で１時間静置し、同様に洗浄後、５０μＬのＴＭＢ（３、３’、５、５”－テトラメチルベンジジン）を加えて室温にて３０分間反応させる。５０μＬの１ｍｏｌ／Ｌ　硫酸を加えて呈色反応を停止させた後、４５０ｎｍの吸光度を測定する。陽性対照（ＩＴＫによりリン酸化したリコンビナントヒトＰＬＣγ１）の希釈列を検量として用い、抗ヒトＣＤ３ε・抗体非存在下のサンプル中のリン酸化量を０％活性として阻害率を算出する。
プロテアーゼインヒビターカクテルは、以下を用いる。
　品名：ｃＯｍｐｌｅｔｅ,　Ｍｉｎｉ,　ＥＤＴＡ－ｆｒｅｅ
　品番：４　６９３　１５９
　会社：ロシュ・ダイアグノスティックス株式会社
　上記にしたがってＩＴＫ以外のキナーゼ阻害活性を確認することで、本発明化合物のＩＴＫに対する選択性を確認することができる。 Test Example 2: Evaluation of PLCγ1 phosphorylation inhibitory activity The measurement of the PLCγ1 phosphorylation inhibitory activity of the compound according to the present invention is evaluated by the following procedure.
The human T cell line Jurkat is washed with Hank's balanced salt solution (HBSS), adjusted to a cell concentration of 1.5 × 10 7 / mL, and used for experiments. Pre-incubate 40 μL of the cell suspension at 37 ° C. for 5 minutes, mix 10 μL of HBSS solution of each compound containing 2% DMSO, and pre-incubate at 37 ° C. for another 10 minutes. Thereafter, 50 μL of HBSS containing 20 μg / mL anti-human CD3ε • antibody is added and incubated at 37 ° C. for 3 minutes. 100 mM Tris-HCl (pH 7.5), 750 mM NaCl, 5 mM Na2EDTA, 5 mM EGTA, 5% Triton, 12.5 mM sodium pyrophosphate, 5 mM β-glycerophosphate, 10 mM Na3VO4, 10 mM imidazole, 5 mM NaF, 5.75 mM М Na2MoO4, Cells are lysed by adding 25 μL of a mixed solution of 20 mM sodium tartrate, 5 μg / mL leupeptin and a protease inhibitor cocktail adjusted to a 5-fold concentration. The amount of PLCγ1 phosphorylation in the cell solution is measured by ELISA. Tris-buffered saline containing 0.05% Tween-20 was added to a microwell plate on which anti-PLCγ1 antibody (clone 2B1, derived from mouse) was solidified, and 50 μL of the prepared cell lysate was added and allowed to stand at room temperature for 2 hours. Wash 4 times with (Tris-Buffered Saline). Anti-phosphorylated PLCγ1 antibody (pTyr783, derived from rabbit) is added and left to stand at room temperature for 2 hours. After washing in the same manner, HRP-labeled anti-rabbit IgG antibody is reacted. Allow to stand at room temperature for 1 hour, and after washing in the same manner, add 50 μL of TMB (3, 3 ′, 5, 5 ″ -tetramethylbenzidine) and react for 30 minutes at room temperature. Add 50 μL of 1 mol / L sulfuric acid. After stopping the color reaction, the absorbance at 450 nm is measured, and a dilution series of positive control (recombinant human PLCγ1 phosphorylated by ITK) is used as a calibration, and phosphorous in the sample in the absence of anti-human CD3ε antibody is detected. The inhibition rate is calculated with the amount of oxidation as 0% activity.
The protease inhibitor cocktail uses:
Product name: cComplete, Mini, EDTA-free
Product number: 4 693 159
Company: Roche Diagnostics Co., Ltd. By confirming kinase inhibitory activity other than ITK according to the above, the selectivity of the compound of the present invention for ITK can be confirmed.
試験例３：ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価する。 Test Example 3: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
　９６穴プレートに反応溶液として、５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始する。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止する。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量する。 As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction. To start. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) , Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
　薬物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。 The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
試験例４：ＣＹＰ３Ａ４蛍光ＭＢＩ試験
　ＣＹＰ３Ａ４蛍光ＭＢＩ試験は、代謝反応による本発明化合物のＣＹＰ３Ａ４阻害の増強を調べる試験である。ＣＹＰ３Ａ４酵素（大腸菌発現酵素）により７－ベンジルオキシトリフルオロメチルクマリン（７－ＢＦＣ）が脱ベンジル化されて、蛍光を発する代謝物７－ハイドロキシトリフルオロメチルクマリン（７－ＨＦＣ）が生じる。７－ＨＦＣ生成反応を指標としてＣＹＰ３Ａ４阻害を評価する。 Test Example 4: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
　反応条件は以下のとおり：基質、５．６μｍｏｌ／Ｌ　７－ＢＦＣ；プレ反応時間、０または３０分；反応時間、１５分；反応温度、２５℃（室温）；ＣＹＰ３Ａ４含量（大腸菌発現酵素）、プレ反応時６２．５ｐｍｏｌ／ｍＬ、反応時６．２５ｐｍｏｌ／ｍＬ（１０倍希釈時）；本発明化合物濃度、０．６２５、１．２５、２．５、５、１０、２０μｍｏｌ／Ｌ（６点）。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中に酵素、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（プレ反応無）、所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止する。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（プレ反応有）、所定時間プレ反応後、別のプレートに基質とＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始する。所定の時間反応後、アセトニトリル／０．５ｍｏｌ／Ｌ　Ｔｒｉｓ（トリスヒドロキシアミノメタン）＝４／１（Ｖ／Ｖ）を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である７－ＨＦＣの蛍光値を測定する。（Ｅｘ＝４２０ｎｍ、Ｅｍ＝５３５ｎｍ） The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)
　本発明化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。ＩＣ５０値の差が５μｍｏｌ／Ｌ以上の場合を（＋）とし、３μｍｏｌ／Ｌ以下の場合を（－）とする。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Is used to calculate IC 50 by inverse estimation using a logistic model. The case where the difference in IC 50 value is 5 μmol / L or more is (+), and the case where it is 3 μmol / L or less is (−).
試験例５：ＢＡ試験
経口吸収性の検討実験材料と方法
（１）使用動物：マウスあるいはＳＤラットを使用する。
（２）飼育条件：マウスあるいはＳＤラットは、固形飼料および滅菌水道水を自由摂取させる。
（３）投与量、群分けの設定：所定の投与量で経口投与および静脈内投与する。以下のように群を設定する。（化合物ごとで投与量は変更有）
　経口投与　１～３０ｍｇ／ｋｇ（ｎ＝２～３）
　静脈内投与　０．５～１０ｍｇ／ｋｇ（ｎ＝２～３）
（４）投与液の調製：経口投与は溶液または懸濁液として投与する。静脈内投与は可溶化して投与する。
（５）投与方法：経口投与は、経口ゾンデにより強制的に胃内に投与する。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与する。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定する。
（７）統計解析：血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムＷｉｎＮｏｎｌｉｎ（登録商標）を用いて血漿中濃度‐時間曲線下面積（ＡＵＣ）を算出し、経口投与群と静脈内投与群の投与量比およびＡＵＣ比から本発明化合物のバイオアベイラビリティ（ＢＡ）を算出する。 Test Example 5: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice or SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with a needle.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the dose ratio of the group and the AUC ratio.
試験例６：Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価する。
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養した。ＴＡ９８株は７．７０ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去する。７．７０ｍＬのＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１２０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加する。ＴＡ１００株は３．４２ｍＬ菌液に対しＥｘｐｏｓｕｒｅ培地１３０ｍＬに添加し試験菌液を調製する。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養する。本発明化合物を曝露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し、５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養する。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。 Test Example 6: Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 7. 70 mL Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: The cells are suspended in 0.25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) To the MicroF buffer). TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under the metabolic activation conditions, 498 μL of the test bacterial solution and S9 mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added to 2300 μL of indicator medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL aliquots into 48 wells / dose of the microplate and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).
試験例７：ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャネルを発現させたＣＨＯ細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討する。
　全自動パッチクランプシステム（ＱＰａｔｃｈ；Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ　Ａ／Ｓ）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持し、－５０ｍＶのリーク電位を与えた後、＋２０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録する。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液（ＮａＣｌ：１４５　ｍｍｏｌ／Ｌ、ＫＣｌ：４　ｍｍｏｌ／Ｌ、ＣａＣｌ２：２　ｍｍｏｌ／Ｌ、ＭｇＣｌ２：１　ｍｍｏｌ／Ｌ、グルコース：１０　ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－１－ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｅｓｕｌｆｏｎｉｃ　ａｃｉｄ、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を室温条件下で、１０分間細胞に適用させる。得られたＩＫｒから、解析ソフト（Ｆａｌｓｔｅｒ　Ｐａｔｃｈ；Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ　Ａ／Ｓ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群（０．１％ジメチルスルホキシド溶液）と比較して、本発明化合物のＩＫｒへの影響を評価する。 Test Example 7: hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, it is important for the ventricular repolarization process using CHO cells in which human ether-a-go-related gene (hERG) channels are expressed. Consider the action of the compounds of the present invention on the delayed rectifier K + current (I Kr ) that plays a role.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cell was held at a membrane potential of −80 mV by a whole cell patch clamp method, and after applying a leak potential of −50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV. After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol) in which the compound of the present invention is dissolved at a desired concentration. / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7. 4) is applied to the cells for 10 minutes at room temperature. The absolute value of the maximum tail current is measured from the obtained I Kr using analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
試験例８：溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定する。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液６　μＬをｐＨ６．８人工腸液（０．２ｍｏｌ／Ｌ　リン酸二水素カリウム試液　２５０ｍＬに０．２ｍｏｌ／Ｌ　ＮａＯＨ試液１１８ｍＬ、水を加えて１０００ｍＬとした）５９４μＬに添加する。２５℃で１６時間静置させた後、混液を吸引濾過する。濾液をメタノール／水＝１／１（Ｖ／Ｖ）にて２倍希釈し、絶対検量線法によりＨＰＬＣまたはＬＣ／ＭＳ／ＭＳを用いて濾液中濃度を測定する。 Test Example 8: Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) To 594 μL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. The filtrate is diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate is measured by HPLC or LC / MS / MS by the absolute calibration method.
試験例９：代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価する。 Test Example 9: Metabolic stability test A commercially available pooled human liver microsome is reacted with the compound of the present invention for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させる（酸化的反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心する。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳにて定量し、反応後の本発明化合物の残存量を０分反応時の化合物量を１００％として計算する。 In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%.
試験例１０：粉末溶解度試験
　適当な容器に本発明化合物を適量入れ、各容器にＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとする）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加える）、２０ｍｍｏｌ／Ｌ　タウロコール酸ナトリウム（ＴＣＡ）／ＪＰ－２液（ＴＣＡ１．０８ｇにＪＰ－２液を加え１００ｍＬとする）を２００μＬずつ添加する。試験液添加後に全量溶解した場合には、適宜、本発明化合物を追加する。密閉して３７℃で１時間振とう後に濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないかを確認し、密閉して振とうする。絶対検量線法によりＨＰＬＣを用いて本発明化合物を定量する。 Test Example 10: Powder solubility test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution are added to each container. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１　錠剤
　　本発明化合物　　　　　　　　　１５ｍｇ
　　乳糖　　　　　　　　　　　　　１５ｍｇ
　　ステアリン酸カルシウム　　　　　３ｍｇ
　ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例２　カプセル剤
　　本発明化合物　　　　　　　　　１０ｍｇ
　　ステアリン酸マグネシウム　　　１０ｍｇ
　　乳糖　　　　　　　　　　　　　８０ｍｇ
を均一に混合して粉末又は細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
製剤例３　顆粒剤
　　本発明化合物　　　　　　　　　　　３０ｇ
　　乳糖　　　　　　　　　　　　　　２６５ｇ
　　ステアリン酸マグネシウム　　　　　　５ｇ
をよく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
Are mixed well, compression molded, pulverized, sized, and sieved to obtain granules of appropriate size.
　本発明に係る化合物は、ＩＴＫに対する阻害作用を有し、ＩＴＫが関与する疾患または状態の治療剤および／または予防剤として有用であると考えられる。 The compound according to the present invention has an inhibitory action on ITK and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving ITK.

Claims (21)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    であり；
    　環Ｂは、６員の芳香族炭素環または６員の芳香族複素環であり；
    　環Ｃは、５もしくは６員の芳香族複素環または５もしくは６員の非芳香族複素環であり；
    　環Ｄは、５員の芳香族複素環であり；
    　環Ｅは、５もしくは６員の芳香族複素環または５もしくは６員の非芳香族複素環であり；
    　環Ｆは、６員の芳香族炭素環または６員の芳香族複素環であり；
    　環Ｇは、５員の芳香族複素環であり；
    　－Ｘ－は、＝Ｎ－、－Ｎ＝、－Ｏ－、または－Ｓ－（ここで、左の結合手は原子ａに結合し、右の結合手は原子ｂに結合する）であり；
    　－Ｙ－は、＝Ｎ－ＣＨ２－、＝Ｎ－ＣＨ＝、－Ｎ＝ＣＨ－、－Ｎ＝Ｎ－、＝Ｎ－ＮＨ－、＝Ｎ－Ｎ＝、＝Ｎ－Ｓ－、＝Ｎ－Ｏ－、－Ｏ－ＣＨ２－、－Ｏ－ＣＨ＝、－Ｏ－ＮＨ－、－Ｏ－Ｎ＝、－Ｓ－ＮＨ－、－Ｓ－Ｎ＝、－Ｓ－ＣＨ２－または－Ｓ－ＣＨ＝（ここで、左の結合手は原子ｃに結合し、右の結合手は原子ｄに結合する）であり；
    　Ｒ２は、それぞれ独立して、ハロゲン、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルケニルカルボニルアミノ、置換もしくは非置換のモノアルキニルカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換のモノアルキルウレイド、置換もしくは非置換のジアルキルウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、置換もしくは非置換の芳香族炭素環アミノ、置換もしくは非置換の非芳香族炭素環アミノ、置換もしくは非置換の芳香族複素環アミノ、置換もしくは非置換の非芳香族複素環アミノ、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環ウレイド、置換もしくは非置換の非芳香族炭素環ウレイド、置換もしくは非置換の芳香族複素環ウレイド、または置換もしくは非置換の非芳香族複素環ウレイドであり；
    　ｐは、０から３の整数であり；
    　Ｒ３は、水素原子、ヒドロキシ、アミノ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基であり；
    　Ｒａは、それぞれ独立して、カルボキシ、カルバモイル、スルファモイル、スルフィノ、スルホ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、もしくは置換もしくは非置換の非芳香族複素環カルバモイル；または２つのＲａは、隣接する炭素原子と一緒になって、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し；
    　Ｒｂは、それぞれ独立して、ヒドロキシ、カルボキシ、アミノ、ヒドロキシアミノ、カルバモイル、スルファモイル、スルフィノ、スルホ、ヒドラジノ、ウレイド、アミジノ、グアニジノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、もしくは置換もしくは非置換の非芳香族複素環カルバモイル；または、２つのＲｂは、隣接する炭素原子と一緒になって、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し；
    　Ｒｃは、水素原子またはハロゲンであり；
    　ｎおよびｍは、それぞれ独立して、０から２の整数であり；
    　－Ｌ－は、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｓ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、－Ｎ（Ｒ４）ＳＯ２－、－Ｃ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｃ（＝Ｏ）－、－Ｓ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｓ（＝Ｏ）－、－ＳＯ２Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）ＳＯ２－であり；
    　Ｒ４、Ｒ５ａおよびＲ５ｂは、それぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、もしくは置換若しくは非置換のアルキニル；または
    　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｓ（＝Ｏ）Ｎ（Ｒ４）－、または－ＳＯ２Ｎ（Ｒ４）－であるとき、Ｒ４とＲ1が、隣接する窒素原子と一緒になって、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環を形成するか；
    　－Ｌ－が、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－Ｎ（Ｒ４）Ｓ（＝Ｏ）－、または－Ｎ（Ｒ４）ＳＯ２－であるとき、Ｒ４とＲ1が、Ｒ４の隣接する窒素原子およびＲ1が隣接する炭素原子または硫黄原子と一緒になって、置換若しくは非置換の非芳香族複素環を形成するか；、
    　－Ｌ－が、－Ｃ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、－Ｓ（＝Ｏ）Ｃ（Ｒ５ａ）（Ｒ５ｂ）－、または－ＳＯ２Ｃ（Ｒ５ａ）（Ｒ５ｂ）－であるとき、Ｒ５ａとＲ1が、隣接する炭素原子と一緒になって、置換若しくは非置換の芳香族複素環または置換若しくは非置換の非芳香族複素環を形成するか；もしくは、
    　－Ｌ－が、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｃ（＝Ｏ）－、－Ｃ（Ｒ５ａ）（Ｒ５ｂ）Ｓ（＝Ｏ）－、または－Ｃ（Ｒ５ａ）（Ｒ５ｂ）ＳＯ２－であるとき、Ｒ５ａとＲ１が、Ｒ５ａの隣接する炭素原子およびＲ1が隣接する炭素原子または硫黄原子と一緒になって、置換若しくは非置換の非芳香族複素環を形成し；
    　Ｒ１は、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルスルホニルアミノ、置換もしくは非置換のジアルキルスルホニルアミノ、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルスルファモイル、置換もしくは非置換のジアルキルスルファモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、または置換もしくは非置換の非芳香族複素環スルホニルである）で示される化合物
    （ただし、
    　Ｒ１は、メチルまたはｔｅｒｔ－ブチルオキシではなく；
    　ｎおよびｍが共に０であるとき、
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
    （式中、
    　環Ｈは、６員の芳香族複素環または６員の非芳香族複素環であり；
    　Ｒ６は、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルであり；
    ｐ’は０から２の整数であり；
    Figure JPOXMLDOC01-appb-C000006
    であるとき、
    Ｒ１は、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基（ただし、置換もしくは非置換のピロリジルではない）である）であり；
    　以下の化合物を除く
    Figure JPOXMLDOC01-appb-C000007
    ）、またはその製薬上許容される塩。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (Where
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
    Is;
    Ring B is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle;
    Ring C is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle;
    Ring D is a 5-membered aromatic heterocycle;
    Ring E is a 5- or 6-membered aromatic heterocycle or a 5- or 6-membered non-aromatic heterocycle;
    Ring F is a 6-membered aromatic carbocycle or 6-membered aromatic heterocycle;
    Ring G is a 5-membered aromatic heterocycle;
    -X- is = N-, -N =, -O-, or -S- (where the left bond is bonded to atom a and the right bond is bonded to atom b);
    -Y- is = N-CH 2- , = N-CH =, -N = CH-, -N = N-, = N-NH-, = NN =, = NS-, = N —O—, —O—CH 2 —, —O—CH═, —O—NH—, —O—N═, —S—NH—, —S—N═, —S—CH 2 — or —S. -CH = (where the left bond is bonded to atom c and the right bond is bonded to atom d);
    Each R 2 is independently halogen, hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Substituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, Substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkenylcarbonylamino, substituted or unsubstituted monoalkynylcarbonylamino, substituted or unsubstituted Substituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted Or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or Unsubstituted monoalkylureido, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group Group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted Or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted Aromatic heterocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, substituted or unsubstituted aromatic carbocyclic amino, substituted or unsubstituted non-aromatic carbocyclic amino, substituted or unsubstituted aromatic heterocyclic Ring amino, substituted or unsubstituted non-aromatic heterocyclic amino, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic carbonyl Amino, substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic A carbocyclic ureido, a substituted or unsubstituted non-aromatic carbocyclic ureido, a substituted or unsubstituted aromatic heterocyclic ureido, or a substituted or unsubstituted non-aromatic heterocyclic ureido;
    p is an integer from 0 to 3;
    R 3 is a hydrogen atom, hydroxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group;
    Each Ra is independently carboxy, carbamoyl, sulfamoyl, sulfino, sulfo, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted Or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted Substituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted Is an unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic Heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, Substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted A non-aromatic carbocyclic carbamoyl, a substituted or unsubstituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl; or two Ra, together with adjacent carbon atoms, are substituted or non-substituted Forming a substituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
    Rb independently represents hydroxy, carboxy, amino, hydroxyamino, carbamoyl, sulfamoyl, sulfino, sulfo, hydrazino, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynyl Carbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Or substituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or Unsubstituted monoalkylsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, Substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or Unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted fragrance Aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl Substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or Unsubstituted non-aromatic carbocyclic carbonylamino, substituted or unsubstituted aromatic heterocyclic carbonylamino, Substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted aromatic heterocyclic carbamoyl, or substituted or An unsubstituted non-aromatic heterocyclic carbamoyl; or two Rb together with adjacent carbon atoms form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring And
    Rc is a hydrogen atom or halogen;
    n and m are each independently an integer from 0 to 2;
    -L- is -C (= O) N (R 4 )-, -N (R 4 ) C (= O)-, -S (= O) N (R 4 )-, -N (R 4 ) S (═O) —, —SO 2 N (R 4 ) —, —N (R 4 ) SO 2 —, —C (═O) C (R 5a ) (R 5b ) —, —C (R 5a ) (R 5b ) C (═O) —, —S (═O) C (R 5a ) (R 5b ) —, —C (R 5a ) (R 5b ) S (═O) —, —SO 2 C ( R 5a ) (R 5b ) —, or —C (R 5a ) (R 5b ) SO 2 —;
    R 4 , R 5a and R 5b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or -L- is -C (= When O) N (R 4 ) —, —S (═O) N (R 4 ) —, or —SO 2 N (R 4 ) —, R 4 and R 1 together with the adjacent nitrogen atom Form a substituted or unsubstituted aromatic heterocycle or a substituted or unsubstituted nonaromatic heterocycle;
    When —L— is —N (R 4 ) C (═O) —, —N (R 4 ) S (═O) —, or —N (R 4 ) SO 2 —, R 4 and R 1 Wherein R 4 together with the adjacent nitrogen atom and R 1 of the adjacent carbon or sulfur atom form a substituted or unsubstituted non-aromatic heterocycle;
    —L— is —C (═O) C (R 5a ) (R 5b ) —, —S (═O) C (R 5a ) (R 5b ) —, or —SO 2 C (R 5a ) (R 5b )-, when R 5a and R 1 are taken together with adjacent carbon atoms to form a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; or ,
    —L— is —C (R 5a ) (R 5b ) C (═O) —, —C (R 5a ) (R 5b ) S (═O) —, or —C (R 5a ) (R 5b ) When SO 2 —, R 5a and R 1 together with the adjacent carbon atom of R 5a and R 1 adjacent carbon atom or sulfur atom form a substituted or unsubstituted non-aromatic heterocycle And
    R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or Unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoal Killsulfonylamino, substituted or unsubstituted dialkylsulfonylamino, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted Dialkylcarbamoyl, substituted or unsubstituted monoalkylsulfamoyl, substituted or unsubstituted dialkylsulfamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted A non-aromatic heterocyclic carbonyl, a substituted or unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted aromatic heterocyclic sulfonyl, or a substituted or unsubstituted non-aromatic A compound represented by a heterocyclic group sulfonyl)
    R 1 is not methyl or tert-butyloxy;
    When n and m are both 0,
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
    (Where
    Ring H is a 6-membered aromatic heterocycle or a 6-membered non-aromatic heterocycle;
    R 6 represents substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocycle Carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or non-substituted A substituted aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl;
    p ′ is an integer from 0 to 2;
    Figure JPOXMLDOC01-appb-C000006
    When
    R 1 represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group. A heterocyclic group (but not a substituted or unsubstituted pyrrolidyl);
    Excluding the following compounds
    Figure JPOXMLDOC01-appb-C000007
    ) Or a pharmaceutically acceptable salt thereof.
  2. Figure JPOXMLDOC01-appb-C000008
    Figure JPOXMLDOC01-appb-C000009
    である、請求項１記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000008
    Figure JPOXMLDOC01-appb-C000009
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. Figure JPOXMLDOC01-appb-C000010
    Figure JPOXMLDOC01-appb-C000011
    である、請求項１記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000010
    Figure JPOXMLDOC01-appb-C000011
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  4. Figure JPOXMLDOC01-appb-C000012
    Figure JPOXMLDOC01-appb-C000013
    である、請求項１記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000012
    Figure JPOXMLDOC01-appb-C000013
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  5. Figure JPOXMLDOC01-appb-C000014
    Figure JPOXMLDOC01-appb-C000015
    である、請求項１記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000014
    Figure JPOXMLDOC01-appb-C000015
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  6. 　Ｒａがそれぞれ独立して、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルである、請求項１～５のいずれかに記載の化合物またはその製薬上許容される塩。
    Each Ra is independently carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted Alkynylcarbonyl, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted fragrance Heterocyclic carbonyl, substituted or unsubstituted non-aromatic compound Ring carbonyl, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic heterocyclic carbamoyl, or substituted or unsubstituted non-aromatic heterocyclic carbamoyl The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
  7. 　Ｒｂがそれぞれ独立して、ヒドロキシ、カルボキシ、アミノ、カルバモイル、ウレイド、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のモノアルキルアミノ、置換もしくは非置換のジアルキルアミノ、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルオキシカルボニルアミノ、置換もしくは非置換のジアルキルオキシカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換の芳香族炭素環カルボニルアミノ、置換もしくは非置換の非芳香族炭素環カルボニルアミノ、置換もしくは非置換の芳香族複素環カルボニルアミノ、置換もしくは非置換の非芳香族複素環カルボニルアミノ、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、置換もしくは非置換の芳香族複素環カルバモイル、または置換もしくは非置換の非芳香族複素環カルバモイルである、請求項１～６のいずれかに記載の化合物またはその製薬上許容される塩。
    Each Rb is independently hydroxy, carboxy, amino, carbamoyl, ureido, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted Substituted dialkylamino, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkyloxycarbonylamino, substituted or unsubstituted dialkyloxycarbonylamino, substituted or unsubstituted Monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted aromatic carbocyclic carbonylamino, substituted or unsubstituted nonaromatic carbocyclic carbonylamino, substituted or non-substituted Substituted aromatic heterocyclic carbonylamino, substituted or unsubstituted non-aromatic heterocyclic carbonylamino, substituted or unsubstituted aromatic carbocyclic carbamoyl, substituted or unsubstituted non-aromatic carbocyclic carbamoyl, substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is an aromatic heterocyclic carbamoyl, or a substituted or unsubstituted non-aromatic heterocyclic carbamoyl.
  8. 　Ｒｃが水素原子である、請求項１～７のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein Rc is a hydrogen atom.
  9. 　－Ｌ－が、－Ｃ（＝Ｏ）Ｎ（Ｒ４）－、－Ｎ（Ｒ４）Ｃ（＝Ｏ）－、－ＳＯ２Ｎ（Ｒ４）－、または－Ｎ（Ｒ４）ＳＯ２－である、請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩。
    —L— is —C (═O) N (R 4 ) —, —N (R 4 ) C (═O) —, —SO 2 N (R 4 ) —, or —N (R 4 ) SO 2 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, which is-.
  10. 　Ｒ４、Ｒ５ａおよびＲ５ｂがそれぞれ独立して、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルである、請求項１～９のいずれかに記載の化合物またはその製薬上許容される塩。
    The R 4 , R 5a and R 5b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl. Or a pharmaceutically acceptable salt thereof.
  11. 　Ｒ１が、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である、請求項１～１０のいずれかに記載の化合物またはその製薬上許容される塩。
    R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted Or an unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.
  12. 　Ｒ１が、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、または置換もしくは非置換の非芳香族複素環式基である、請求項１～１０のいずれかに記載の化合物またはその製薬上許容される塩。
    R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic group The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is a heterocyclic group.
  13. 　Ｒ２がそれぞれ独立して、ハロゲン、カルボキシ、カルバモイル、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のモノアルキルカルボニルアミノ、置換もしくは非置換のジアルキルカルボニルアミノ、置換もしくは非置換のモノアルキルカルバモイル、置換もしくは非置換のジアルキルカルバモイル、置換もしくは非置換のモノアルキルウレイド、置換もしくは非置換のジアルキルウレイド、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環カルバモイル、置換もしくは非置換の非芳香族炭素環カルバモイル、または置換もしくは非置換の芳香族複素環カルバモイル、置換もしくは非置換の非芳香族複素環カルバモイルである、請求項１～１２のいずれかに記載の化合物またはその製薬上許容される塩。
    Each R 2 is independently halogen, carboxy, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted monoalkylcarbonylamino, substituted or unsubstituted dialkylcarbonylamino, substituted or unsubstituted monoalkylcarbamoyl, substituted or unsubstituted dialkylcarbamoyl, substituted or unsubstituted Monoalkylureido, substituted or unsubstituted dialkylureido, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, A substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic carbamoyl, a substituted or unsubstituted non-aromatic carbocyclic carbamoyl, or a substituted or unsubstituted aromatic heterocyclic carbamoyl, substituted or The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is an unsubstituted non-aromatic heterocyclic carbamoyl.
  14. 　ｎが１または２である、請求項１～１３のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein n is 1 or 2.
  15. 　ｍが０である、請求項１４に記載の化合物またはその製薬上許容される塩。
    15. The compound or pharmaceutically acceptable salt thereof according to claim 14, wherein m is 0.
  16. 　ｍが１または２である、請求項１～１３のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein m is 1 or 2.
  17. 　ｎが０である、請求項１６に記載の化合物またはその製薬上許容される塩。
    The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein n is 0.
  18. 　請求項１～１７のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
    A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.
  19. 　ＩＴＫ阻害作用を有する請求項１８に記載の医薬組成物。
    The pharmaceutical composition according to claim 18, which has an ITK inhibitory action.
  20. 　ＩＴＫが関与する疾患の治療および／または予防に使用するための、請求項１～１７のいずれかに記載の化合物またはその製薬上許容される塩。
    The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving ITK.
  21. 　請求項１～１７のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、ＩＴＫが関与する疾患の治療および／または予防方法。 A method for treating and / or preventing a disease associated with ITK, comprising administering the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.
PCT/JP2014/061530 2013-04-25 2014-04-24 Pyrrolidine derivative and pharmaceutical composition containing same WO2014175370A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016010108A1 (en) * 2014-07-18 2016-01-21 塩野義製薬株式会社 Nitrogen-containing heterocyclic derivatives and medicinal compositions comprising same
EP3193604A4 (en) * 2014-09-10 2018-02-21 Epizyme, Inc. Substituted pyrrolidine compounds
JP2020525413A (en) * 2018-05-25 2020-08-27 日本たばこ産業株式会社 Method for treating pain or interstitial cystitis using indole compound
JP2021535125A (en) * 2018-08-23 2021-12-16 ベネボレントエーアイ バイオ リミティド Imidazo [1,2-b] pyridazine as a Trk inhibitor
CN115297863A (en) * 2020-01-22 2022-11-04 博善人工智能生物科技有限公司 Topical pharmaceutical compositions comprising imidazo [1,2-b ] pyridazine compounds
WO2023099561A1 (en) * 2021-12-01 2023-06-08 Mission Therapeutics Limited Substituted n-cyanopyrrolidines with activity as usp30 inhibitors

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10505078A (en) * 1994-09-07 1998-05-19 ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング Pyrimido [5,4-d] pyrimidines, medicaments containing these compounds, their use and methods for their preparation
JP2000506153A (en) * 1996-03-06 2000-05-23 ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング Pyrimido [5,4-d] pyrimidines, pharmaceuticals containing these compounds, their use and methods for their preparation
JP2006503010A (en) * 2002-08-14 2006-01-26 アストラゼネカ・アクチエボラーグ Some novel imidazopyridines and their use
JP2008519059A (en) * 2004-11-04 2008-06-05 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrazolo [1,5-α] pyrimidines useful as inhibitors of protein kinases
JP2008524233A (en) * 2004-12-16 2008-07-10 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrid-2-ones useful as inhibitors of TEC family protein kinases for the treatment of inflammatory, proliferative and immune-mediated diseases
JP2010513458A (en) * 2006-12-19 2010-04-30 ファイザー・プロダクツ・インク Nicotinamide derivatives as inhibitors of H-PGDS and their use to treat prostaglandin D2-mediated diseases
JP2011524894A (en) * 2008-06-18 2011-09-08 ファイザー・リミテッド Nicotinamide derivatives
JP2011528025A (en) * 2008-07-16 2011-11-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New chemical compounds
JP2011528026A (en) * 2008-07-16 2011-11-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New chemical compounds
WO2011163518A1 (en) * 2010-06-24 2011-12-29 Gilead Sciences, Inc. Pyrazolo [1, 5 -a] pyrimidines as antiviral agents
WO2011162515A2 (en) * 2010-06-23 2011-12-29 Hanmi Holdings Co. , Ltd. Novel fused pyrimidine derivatives for inhd3ition of tyrosine kinase activity
JP2012526113A (en) * 2009-05-05 2012-10-25 ダナ ファーバー キャンサー インスティテュート インコーポレイテッド EGFR inhibitor and disease treatment method
US20130165423A1 (en) * 2011-12-01 2013-06-27 Chemocentryx, Inc. Substituted benzimidazoles and benzopyrazoles as ccr(4) antagonists
WO2013134336A2 (en) * 2012-03-09 2013-09-12 Lexicon Pharmaceuticals, Inc. Inhibition of adaptor associated kinase 1 for the treatment of pain

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10505078A (en) * 1994-09-07 1998-05-19 ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング Pyrimido [5,4-d] pyrimidines, medicaments containing these compounds, their use and methods for their preparation
JP2000506153A (en) * 1996-03-06 2000-05-23 ドクトル カルル トーマエ ゲゼルシャフト ミット ベシュレンクテル ハフツング Pyrimido [5,4-d] pyrimidines, pharmaceuticals containing these compounds, their use and methods for their preparation
JP2006503010A (en) * 2002-08-14 2006-01-26 アストラゼネカ・アクチエボラーグ Some novel imidazopyridines and their use
JP2008519059A (en) * 2004-11-04 2008-06-05 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrazolo [1,5-α] pyrimidines useful as inhibitors of protein kinases
JP2008524233A (en) * 2004-12-16 2008-07-10 バーテックス ファーマシューティカルズ インコーポレイテッド Pyrid-2-ones useful as inhibitors of TEC family protein kinases for the treatment of inflammatory, proliferative and immune-mediated diseases
JP2010513458A (en) * 2006-12-19 2010-04-30 ファイザー・プロダクツ・インク Nicotinamide derivatives as inhibitors of H-PGDS and their use to treat prostaglandin D2-mediated diseases
JP2011524894A (en) * 2008-06-18 2011-09-08 ファイザー・リミテッド Nicotinamide derivatives
JP2011528025A (en) * 2008-07-16 2011-11-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New chemical compounds
JP2011528026A (en) * 2008-07-16 2011-11-10 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング New chemical compounds
JP2012526113A (en) * 2009-05-05 2012-10-25 ダナ ファーバー キャンサー インスティテュート インコーポレイテッド EGFR inhibitor and disease treatment method
WO2011162515A2 (en) * 2010-06-23 2011-12-29 Hanmi Holdings Co. , Ltd. Novel fused pyrimidine derivatives for inhd3ition of tyrosine kinase activity
WO2011163518A1 (en) * 2010-06-24 2011-12-29 Gilead Sciences, Inc. Pyrazolo [1, 5 -a] pyrimidines as antiviral agents
US20130165423A1 (en) * 2011-12-01 2013-06-27 Chemocentryx, Inc. Substituted benzimidazoles and benzopyrazoles as ccr(4) antagonists
WO2013134336A2 (en) * 2012-03-09 2013-09-12 Lexicon Pharmaceuticals, Inc. Inhibition of adaptor associated kinase 1 for the treatment of pain

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016010108A1 (en) * 2014-07-18 2016-01-21 塩野義製薬株式会社 Nitrogen-containing heterocyclic derivatives and medicinal compositions comprising same
EP3193604A4 (en) * 2014-09-10 2018-02-21 Epizyme, Inc. Substituted pyrrolidine compounds
JP2020525413A (en) * 2018-05-25 2020-08-27 日本たばこ産業株式会社 Method for treating pain or interstitial cystitis using indole compound
CN112118843A (en) * 2018-05-25 2020-12-22 日本烟草产业株式会社 Methods of treating pain or interstitial cystitis using indole compounds
JP2021008496A (en) * 2018-05-25 2021-01-28 日本たばこ産業株式会社 Method of treating pain or interstitial cystitis using indole compound
CN112118843B (en) * 2018-05-25 2023-09-29 日本烟草产业株式会社 Methods of treating pain or interstitial cystitis using indole compounds
JP2021535125A (en) * 2018-08-23 2021-12-16 ベネボレントエーアイ バイオ リミティド Imidazo [1,2-b] pyridazine as a Trk inhibitor
JP7417594B2 (en) 2018-08-23 2024-01-18 ベネボレントエーアイ バイオ リミティド Imidazo[1,2-b]pyridazine as a Trk inhibitor
CN115297863A (en) * 2020-01-22 2022-11-04 博善人工智能生物科技有限公司 Topical pharmaceutical compositions comprising imidazo [1,2-b ] pyridazine compounds
WO2023099561A1 (en) * 2021-12-01 2023-06-08 Mission Therapeutics Limited Substituted n-cyanopyrrolidines with activity as usp30 inhibitors

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