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WO2014175370A1 - Dérivé de pyrrolidine et composition pharmaceutique en contenant - Google Patents

Dérivé de pyrrolidine et composition pharmaceutique en contenant Download PDF

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Publication number
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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Japanese (ja)
Inventor
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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Shionogi and Co Ltd
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Shionogi and Co Ltd
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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.

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Abstract

La présente invention concerne un composé représenté par la formule (I) et son sel pharmaceutiquement acceptable. Dans la formule, AA représente BB ou équivalent ; le cycle B représente un cycle carboné aromatique à six chaînons ou équivalent ; le cycle C représente un cycle hétérocyclique aromatique à cinq ou six chaînons ou équivalent ; -X- représente =N- ou équivalent ; R1 représente un groupe alkyle substitué ou non substitué ou équivalent ; chaque R2 représente indépendamment un atome d'halogène ou équivalent ; R3 représente un atome d'hydrogène ou équivalent ; chaque Ra représente indépendamment un groupe alkyle substitué ou non substitué ou équivalent ; chaque Rb représente indépendamment un groupe alkyle substitué ou non substitué ou équivalent ; Rc représente un atome d'hydrogène ou équivalent ; -L- représente -C(=O)NR4 ou équivalent ; R4 représente un atome d'hydrogène ou équivalent ; p représente un nombre entier de 0 à 3 ; et chaque n et m représente indépendamment un nombre entier de 0 à 2.
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KR102725563B1 (ko) * 2018-05-25 2024-11-05 니뽄 다바코 산교 가부시키가이샤 인돌 화합물을 사용한 통증 또는 간질성 방광염의 치료 방법
JP2024096817A (ja) * 2018-05-25 2024-07-17 日本たばこ産業株式会社 インドール化合物を用いた疼痛又は間質性膀胱炎の治療方法
JP2021535125A (ja) * 2018-08-23 2021-12-16 ベネボレントエーアイ バイオ リミティド Ｔｒｋ阻害剤としてのイミダゾ［１，２−ｂ］ピリダジン
JP7417594B2 (ja) 2018-08-23 2024-01-18 ベネボレントエーアイ バイオ リミティド Ｔｒｋ阻害剤としてのイミダゾ［１，２－ｂ］ピリダジン
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WO2023099561A1 (fr) * 2021-12-01 2023-06-08 Mission Therapeutics Limited N-cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30

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