WO2017213210A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2017213210A1
WO2017213210A1 PCT/JP2017/021264 JP2017021264W WO2017213210A1 WO 2017213210 A1 WO2017213210 A1 WO 2017213210A1 JP 2017021264 W JP2017021264 W JP 2017021264W WO 2017213210 A1 WO2017213210 A1 WO 2017213210A1
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Prior art keywords
group
optionally substituted
aromatic heterocyclic
membered
alkyl
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PCT/JP2017/021264
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English (en)
Japanese (ja)
Inventor
山本　哲史
淳也 白井
光功 ▲高▼野
伸行 根来
智也 湯川
小田　恒夫
岐 今田
佐々木　聡
歩 佐藤
石井　直樹
善右 塩川
章人 渋谷
泰男 中川
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武田薬品工業株式会社
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Publication of WO2017213210A1 publication Critical patent/WO2017213210A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound that can have a ROR ⁇ t-regulating action and can be useful as a preventive or therapeutic agent for cancer, and a medicament containing the compound.
  • Th17 cells and inflammatory cytokines (IL-17A, IL-17F, etc.) produced by them are deeply involved in the pathology of various cancers by immunologically modifying cancer tissues and surrounding tissues.
  • Th17 cells and inflammatory cytokines (IL-17A, IL-17F, etc.) produced by T cells have attracted attention in the pathogenesis of cancer via these immune mechanisms.
  • ROR Retinic acid-related Orphan Receptor
  • Patent Document 1 Is described as having a ROR ⁇ t activity promoting action and an IL-17 increasing action.
  • Patent Document 2 as a condensed heterocyclic compound,
  • An object of the present invention is to provide a compound that has ROR ⁇ t regulating action and is expected to be useful as a preventive or therapeutic agent for cancer.
  • R 1 represents a group via a carbon atom, a group via an oxygen atom or a group via a nitrogen atom
  • X represents a carbon atom or a nitrogen atom
  • Ring A represents a 6-membered nitrogen-containing aromatic ring which may be further substituted
  • Y represents a carbon atom, an oxygen atom, a nitrogen atom or a sulfur atom
  • Ring B represents a 7-membered nitrogen-containing heterocyclic ring which may be further substituted
  • L represents a bond, an optionally substituted methylene group, an oxygen atom or —N (R 3 ) —
  • R 3 represents a hydrogen atom or a substituent
  • R 2 represents an optionally substituted cyclic group.
  • R 1 is (1) mono- or di-C 1-6 alkylamino group (wherein the C 1-6 alkyl may be substituted), (2) mono- or di-C 6-14 arylamino group (wherein the C 6-14 aryl may be substituted), (3) mono- or di-C 7-16 aralkylamino group (the C 7-16 aralkyl may be substituted), (4) 5- to 14-membered aromatic heterocyclic amino group (the 5- to 14-membered aromatic heterocyclic ring may be substituted), (5) an optionally substituted heterocyclic group through a nitrogen atom, (6) an optionally substituted C 2-6 alkenyl group, (7) an optionally substituted C 1-6 alkoxy - carbonyl group, (8) mono- or di-C 1-6 alkyl-carbamoyl group (wherein the C 1-6 alkyl may be substituted), (9) an optionally substituted 3- to 14-
  • ring B is, in addition to the -SO 2 -L-R 2, (i) a hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) carboxy, and (b) C 1-6 alkoxy - 1 to 3 substituents optionally substituted by C 1-6 alkoxy group selected from a carbonyl group, (vi) a C 1-6 alkoxy-carbonyl group, (vii) a 5- to 14-membered aromatic heterocyclic group, (viii) a 3 to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 oxo groups, (ix) a mono- or di-C 1-6 alkylamino group optionally substituted with 1 to 3 carboxy groups, and (x) a C 3 optionally substituted with 1 to 3 carboxy groups A 7-membered nitrogen-containing heterocyclic ring which may be further substituted
  • [5] (((2R) -4-((3-chloro-4-cyanophenyl) sulfonyl) -7- (cis-3,5-dimethylpiperidin-1-yl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetic acid or a salt thereof.
  • a medicament comprising the compound or salt thereof according to any one of [1] to [5] above.
  • a method for regulating ROR ⁇ t in a mammal comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [5] to a mammal.
  • a method for preventing or treating cancer in a mammal comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [5] to a mammal.
  • examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl.
  • the "optionally halogenated C 1-6 alkyl group" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkyl group is mentioned.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
  • the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- A 10 cycloalkyl group.
  • examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the "optionally halogenated C 1-6 alkoxy group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
  • Examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
  • Examples include oxy and hexyloxy.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkylthio group is mentioned.
  • examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
  • examples of the “ optionally halogenated C 1-6 alkyl-carbonyl group” include C 1 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
  • a -6 alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
  • examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
  • examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
  • examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
  • examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
  • examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
  • the "optionally halogenated C 1-6 alkyl sulfonyl group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1- 6 alkylsulfonyl group is mentioned.
  • examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
  • examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
  • An optionally substituted amino group an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
  • examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a C 7-16 aralkyl group.
  • examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
  • substituent group A (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbony
  • the number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • examples of the “heterocyclic group” include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
  • an aromatic heterocyclic group (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .
  • the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
  • non-aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl Thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, t
  • preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
  • examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
  • examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
  • the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • acyl group is, for example, “1 selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group.
  • the “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
  • the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded
  • the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded
  • the hydrocarbon-sulfinyl group is a hydrocarbon group.
  • a sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
  • the “acyl group” a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered
  • Diallylcarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C 7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di -C 2-6 alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di cycl
  • examples of the “optionally substituted amino group” include, for example, a C 1-6 alkyl group each having 1 to 3 substituents selected from the substituent group A, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7- 16- aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group Mono- or di-C 1-6 alkyl-carbamoyl group, mono- or di-C 7-16 aralkyl-carbamoyl group, C 1-6 alkylsulfonyl group and C 6-1 And an amino group optional
  • Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C 1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino groups (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C 1-6 alkyl) - carbonyl amino group (e.g., a Chiru
  • examples of the “optionally substituted carbamoyl group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
  • Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group).
  • Mono- or di-C 3-10 cycloalkyl-carbamoyl groups eg cyclopropylcarbamoyl, cyclohexylcarbamoyl
  • mono- or di-C 6-14 aryl-carbamoyl groups eg phenylcarbamoyl
  • mono- or Di-C 7-16 aralkyl-carbamoyl group mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl)
  • a 5- to 14-membered aromatic heterocyclic carbamoyl group eg, pyridylcarbamoyl
  • pyridylcarbamoyl pyridylcarb
  • examples of the “optionally substituted thiocarbamoyl group” include, for example, “C 1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - one or two location selected from a carbamoyl
  • thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
  • examples of the “optionally substituted sulfamoyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl).
  • examples of the “optionally substituted hydroxy group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy).
  • C 3-10 cycloalkyloxy group eg, cyclohexyloxy
  • C 6-14 aryloxy group eg, phenoxy, naphthyloxy
  • C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
  • C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • C 6-14 aryl-carbonyloxy group eg, benzoyloxy
  • C 7-16 aralkyl- A carbonyloxy group eg benzylcarbonyloxy)
  • 5 to 14-membered aromatic heterocyclic carbonyloxy group e.g., nicotinoyl oxy
  • 3 to 14-membered non-aromatic heterocyclic carbonyloxy group e.g., piperidinylcarbonyl oxy
  • examples of the “optionally substituted sulfanyl group” include a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”.
  • C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
  • the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio), 5-
  • examples of the “optionally substituted silyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”
  • a silyl group optionally having 1 to 3 substituents selected from a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group ” Can be mentioned.
  • Preferable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
  • examples of the “C 1-6 alkylene group” include —CH 2 —, — (CH 2 ) 2 —, — (CH 2 ) 3 —, — (CH 2 ) 4 —, — (CH 2 ) 5 —, — (CH 2 ) 6 —, —CH (CH 3 ) —, —C (CH 3 ) 2 —, —CH (C 2 H 5 ) —, —CH (C 3 H 7 ) —, —CH (CH (CH 3 ) 2 ) —, — (CH (CH 3 )) 2 —, —CH 2 —CH (CH 3 ) —, —CH (CH 3 ) —CH 2 —, —CH 2 —CH 2 -C (CH 3) 2 - , - C (CH 3) 2 -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -C (CH 3) 2 -, - C (CH 3) 2
  • examples of the “C 2-6 alkenylene group” include —CH ⁇ CH—, —CH 2 —CH ⁇ CH—, —CH ⁇ CH—CH 2 —, —C (CH 3 ) 2 —.
  • examples of the “C 2-6 alkynylene group” include —C ⁇ C—, —CH 2 —C ⁇ C—, —C ⁇ C—CH 2 —, —C (CH 3 ) 2 —.
  • ring B is a ring containing a double bond of a condensed moiety as in formula (B).
  • R 1 represents a group via a carbon atom, a group via an oxygen atom, or a group via a nitrogen atom.
  • the “group having a carbon atom” represented by R 1 means a group having a bond on a carbon atom, and the bond is bonded to a carbon atom of ring A.
  • Examples of the “group via a carbon atom” represented by R 1 include an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group via a carbon atom, an acyl group via a carbon atom, and a substituent. And an optionally substituted carbamoyl group and an optionally substituted thiocarbamoyl group.
  • heterocyclic group via a carbon atom in the “optionally substituted heterocyclic group via a carbon atom” includes a heterocyclic group having a bond on the carbon atom in the “heterocyclic group”.
  • acyl group via a carbon atom examples include an acyl group having a bond on a carbon atom in the “acyl group”.
  • halogen atom optionally halogenated C 1-6 alkoxy
  • the “group having an oxygen atom” represented by R 1 means a group having a bond on the oxygen atom, and the bond is bonded to the carbon atom of ring A.
  • Examples of the “group through an oxygen atom” represented by R 1 include an optionally substituted hydroxy group.
  • the “group through the nitrogen atom” represented by R 1 means a group having a bond on the nitrogen atom, and the bond is bonded to the carbon atom of ring A.
  • Examples of the “group through the nitrogen atom” represented by R 1 include an optionally substituted amino group and an optionally substituted heterocyclic group through the nitrogen atom (that is, an optionally substituted cyclic group). Amino group).
  • the “heterocyclic group via a nitrogen atom” of the “optionally substituted heterocyclic group via a nitrogen atom” includes a heterocyclic group having a bond on the nitrogen atom in the “heterocyclic group”. It is done.
  • R 1 is preferably (1) a mono- or di-C 1-6 alkylamino group (wherein the C 1-6 alkyl may be substituted), (2) mono- or di-C 6-14 arylamino group (the C 6-14 aryl may be substituted), (3) mono- or di-C 7-16 aralkylamino group (the C 7-16 aralkyl may be substituted), (4) a 5- to 14-membered aromatic heterocyclic amino group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic amino group) (the 5- to 14-membered aromatic heterocyclic ring may be substituted), (5) An optionally substituted heterocyclic group via a nitrogen atom (ie, an optionally substituted cyclic amino group), (6) an optionally substituted C 2-6 alkenyl group, (7) an optionally substituted C 1-6 alkoxy - carbonyl group, (8) mono- or di-C 1-6 alkyl-carbamoyl group (wherein the C 1-6 alkyl may
  • R 1 is more preferably (1) Mono- or di-C 1-6 alkylamino group (eg, isobutylamino, N-isobutyl-N-methylamino, N, N-diethylamino) (wherein the C 1-6 alkyl is 1 to 3 C 1-6 alkoxy group (eg, optionally substituted with methoxy)), (2) Mono- or di-C 6-14 arylamino group (eg, phenylamino) (the C 6-14 aryl may be condensed with C 3-10 cycloalkane (eg, cyclopentane)) (Eg, indan-4-ylamino), (3) mono- or di-C 7-16 aralkylamino group (eg, 2-phenylethylamino), (4) 5- to 14-membered aromatic heterocyclic amino group (preferably 5- or 6-membered monocyclic aromatic heterocyclic amino group (eg, pyridylamino, pyrazolylamino)) (
  • R 1 is more preferably (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy) A C 1-6 alkyl group (eg, methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from: (b) a C 1-6 alkoxy group (eg, methoxy), and (c) a cyclic amino group (eg, morpholino, piperidine-1-) optionally substituted with 1 to 3 substituents selected from an oxo group Yl, pyrrolidin-1-yl, dihydroisoindoline-2-yl, 5-azaspiro [2.5] oct-5-yl, 6-azaspiro [3.5] non-6-yl, 2-oxa-6- Azaspiro [3.5] non-6-yl, 6-azaspiro [3.5] non-6-yl, 5-ox
  • R 1 is more preferably (1) Mono- or di-C 1-6 alkylamino group (eg, isobutylamino, N-isobutyl-N-methylamino, N, N-diethylamino) (wherein the C 1-6 alkyl is 1 to 3 C 1-6 alkoxy group (eg, optionally substituted with methoxy)), (2) Mono- or di-C 6-14 arylamino group (eg, phenylamino) (the C 6-14 aryl may be condensed with C 3-10 cycloalkane (eg, cyclopentane)) (Eg, indan-4-ylamino), (3) mono- or di-C 7-16 aralkylamino group (eg, 2-phenylethylamino), (4) 5- to 14-membered aromatic heterocyclic amino group (preferably 5- or 6-membered monocyclic aromatic heterocyclic amino group (eg, pyridylamino, pyrazolylamino),
  • R 1 is more preferably (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy) A C 1-6 alkyl group (eg, methyl, ethyl, isopropyl) optionally substituted with 1 to 3 substituents selected from: (b) a C 1-6 alkoxy group (eg, methoxy), and (c) a cyclic amino group (eg, morpholino, piperidine-1-) optionally substituted with 1 to 3 substituents selected from an oxo group Yl, pyrrolidin-1-yl, dihydroisoindoline-2-yl, 5-azaspiro [2.5] oct-5-yl, 6-azaspiro [3.5] non-6-yl, 2-oxa-6- Azaspiro [3.5] non-6-yl, 6-azaspiro [3.5] non-6-yl, 6-azas
  • X represents a carbon atom or a nitrogen atom.
  • Ring A represents a 6-membered nitrogen-containing aromatic ring which may be further substituted.
  • Examples of the “6-membered nitrogen-containing aromatic ring” of the “optionally substituted 6-membered nitrogen-containing aromatic ring” represented by ring A include a pyridine ring and a pyrimidine ring.
  • the “6-membered nitrogen-containing aromatic ring” of the “optionally substituted 6-membered nitrogen-containing aromatic ring” represented by ring A is, for example, further substituted with a substituent selected from the substituent group A described above.
  • the number of substituents is, for example, 1 or 2. When the number of substituents is 2, each substituent may be the same or different.
  • Ring A is preferably a pyridine ring or a pyrimidine ring having no substituent other than R 1 .
  • Y represents a carbon atom, an oxygen atom, a nitrogen atom (N (R ′) (wherein R ′ represents a hydrogen atom or a substituent)) or a sulfur atom.
  • sulfur atom also includes oxidized sulfur atoms, that is, SO and SO 2 .
  • Y is preferably an oxygen atom.
  • Ring B represents a 7-membered nitrogen-containing heterocyclic ring which may be further substituted.
  • the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B includes 2,3,4,7-tetrahydroazepine, 2,3,4,5 -Tetrahydro [1,4] diazepine, 2,3,4,5-tetrahydro [1,4] oxazepine and 2,3,4,5-tetrahydro [1,4] thiazepine. Preferred is 2,3,4,5-tetrahydro [1,4] oxazepine.
  • the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B is, for example, further substituted with a substituent selected from the substituent group A described above.
  • the number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • the position of the substituent is not particularly limited as long as it can be substituted, but is preferably on the carbon atom next to Y, that is, the position of the following arrow.
  • substituent of the “7-membered nitrogen-containing heterocyclic ring” of the “optionally substituted 7-membered nitrogen-containing heterocyclic ring” represented by ring B more preferably, (1) a carboxy group, (2) (i) hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl)), and (
  • substituent of the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B more preferably, (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups A C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (eg, methyl, ethyl) Is mentioned.
  • Ring B is more preferably in addition to —SO 2 —LR 2 , (1) a carboxy group, (2) (i) hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl)), and (viii) substituted with 1 to 3 oxo groups 3- to 14-membered non-aromatic heterocyclic group (preferably
  • Ring B is more preferably in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups 1 to 3 further optionally substituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from 2,3,4,5 -Tetrahydro [1,4] oxazepine.
  • a 1-6 alkoxy group eg, methoxy
  • a C 1-6 alkyl group eg, methyl, ethyl
  • C 1-6 alkyl group eg, methyl, ethyl
  • the substituent of the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B is more preferably, (1) a carboxy group, (2) (i) hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropyloxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg,
  • the substituent of the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B is more preferably (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups
  • a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (eg, methyl, ethyl) Is mentioned.
  • ring B is more preferably in addition to —SO 2 —LR 2 , (1) a carboxy group, (2) (i) hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropyloxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl)), (viii) a 3- to 14-membered non-
  • ring B is more preferably in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups 1 to 3 further optionally substituted by a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from 2,3,4,5 -Tetrahydro [1,4] oxazepine.
  • the substituent of “7-membered nitrogen-containing heterocycle” of “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B is preferably substituted.
  • Good C 1-6 alkyl groups eg, methyl, ethyl
  • the substituent of the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B is more preferably, (i) a hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropyloxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazoly
  • the substituent of the “7-membered nitrogen-containing heterocycle” of the “optionally substituted 7-membered nitrogen-containing heterocycle” represented by ring B is more preferably (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups
  • a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from (eg, methyl, ethyl) Is mentioned.
  • ring B is preferably 1 to 3 optionally substituted C 1-6 alkyl groups (eg, methyl, ethyl) in addition to —SO 2 —LR 2.
  • C 1-6 alkyl groups eg, methyl, ethyl
  • a 7-membered nitrogen-containing heterocyclic ring preferably 2,3,4,5-tetrahydro [1,4] oxazepine which may be further substituted.
  • ring B is more preferably in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropyloxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl)), (viii) a 3- to 14-membered non-aromatic heterocyclic
  • ring B is more preferably in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups
  • a 7-membered nitrogen-containing heterocycle optionally substituted with 1 to 3 C 1-6 alkyl groups (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from 2,3,4,5-tetrahydro [1,4] oxazepine) is preferred.
  • the ring A part and the ring B part may each be further substituted
  • the ring B moiety is in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups 1 to 3 each optionally further substituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from:
  • the ring B moiety is in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups 1 to 3 each optionally further substituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from:
  • the ring B moiety has 1 to 3 optionally substituted C 1-6 alkyl groups (eg, methyl) in addition to —SO 2 —LR 2. , Ethyl) each may be further substituted,
  • the ring B moiety is in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a cyano group, (iv) a carbamoyl group, (v) (a) a carboxy group, and (b) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) A C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropyloxy) optionally substituted with 1 to 3 substituents selected from: (vi) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl), (vii) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, tetrazolyl)), (viii) a 3- to 14-membere
  • the ring B moiety is in addition to —SO 2 —LR 2 , (i) a hydroxy group, (ii) a carboxy group, (iii) a carbamoyl group, and (iv) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 carboxy groups 1 to 3 each optionally further substituted with a C 1-6 alkyl group (eg, methyl, ethyl) optionally substituted with 1 to 3 substituents selected from:
  • L represents a bond, an optionally substituted methylene group, an oxygen atom or —N (R 3 ) —.
  • R 3 represents a hydrogen atom or a substituent.
  • the “methylene group” of the “optionally substituted methylene group” represented by L may be further substituted with a substituent selected from the above-mentioned substituent group A, for example, and the number of substituents is, for example, One or two. When the number of substituents is 2, each substituent may be the same or different.
  • L is preferably a bond or an optionally substituted methylene group.
  • L is more preferably a bond or a methylene group.
  • L is particularly preferably a bond.
  • R 2 represents an optionally substituted cyclic group.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R 2 includes a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a heterocyclic group. Can be mentioned.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R 2 is preferably a C 6-14 aryl group, a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered single group).
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R 2 may be further substituted with a substituent selected from the above-mentioned substituent group A, for example, For example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • R 2 is preferably (1) an optionally substituted C 6-14 aryl group, (2) optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably 5- or 6-membered monocyclic aromatic heterocyclic group or 8- to 14-membered condensed polycyclic group (preferably 2- or 3-ring) Formula) aromatic heterocyclic group), or (3) An optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 9- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) non-aromatic heterocyclic group) It is.
  • R 2 is more preferably (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) a carbamoyl group, (d) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), (e) an optionally halogenated C 1-6 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), and (h) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl)) ) A C 6-14 aryl group (eg, phenyl, naphthyl) optionally substituted with 1 to 3 substitu
  • R 2 is more preferably (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), and (d) an optionally halogenated C 1-6 alkoxy group (eg, Difluoromethoxy, trifluoromethoxy) A C 6-14 aryl group (eg, phenyl, naphthyl) optionally substituted with 1 to 3 substituents selected from: (2) (a) an optionally halogenated C 1-6 alkyl group (eg, trifluoromethyl), and (b) (i) a hydroxy group, and (ii) a C 1-6 alkyl-carbonyloxy group (Eg, acetyloxy) A C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from (eg, ethoxy) A
  • Preferred examples of compound (I) include the following compounds.
  • R 1 is (1) a mono- or di-C 1-6 alkylamino group (wherein the C 1-6 alkyl may be substituted), (2) mono- or di-C 6-14 arylamino group (the C 6-14 aryl may be substituted), (3) mono- or di-C 7-16 aralkylamino group (the C 7-16 aralkyl may be substituted), (4) a 5- to 14-membered aromatic heterocyclic amino group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic amino group) (the 5- to 14-membered aromatic heterocyclic ring may be substituted), (5) An optionally substituted heterocyclic group via a nitrogen atom (ie, an optionally substituted cyclic amino group), (6) an optionally substituted C 2-6 alkenyl group, (7) an optionally substituted C 1-6 alkoxy - carbonyl group, (8) mono- or di-C 1-6 alkyl-carbamoyl group (wherein the C 1-6 alkyl may be substitute
  • L is a bond or an optionally substituted methylene group
  • R 2 is (1) an optionally substituted C 6-14 aryl group, (2) optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably 5- or 6-membered monocyclic aromatic heterocyclic group or 8- to 14-membered condensed polycyclic group (preferably 2- or 3-ring) Formula) aromatic heterocyclic group), or (3) An optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 9- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) non-aromatic heterocyclic group) Is, Compound (I).
  • R 1 is (1) Mono- or di-C 1-6 alkylamino group (eg, isobutylamino, N-isobutyl-N-methylamino, N, N-diethylamino) (wherein the C 1-6 alkyl is 1 to 3 C 1-6 alkoxy group (eg, optionally substituted with methoxy)), (2) Mono- or di-C 6-14 arylamino group (eg, phenylamino) (the C 6-14 aryl may be condensed with C 3-10 cycloalkane (eg, cyclopentane)) (Eg, indan-4-ylamino), (3) mono- or di-C 7-16 aralkylamino group (eg, 2-phenylethylamino), (4) 5- to 14-membered aromatic heterocyclic amino group (preferably 5- or 6-membered monocyclic aromatic heterocyclic amino group (eg, pyridylamino, pyrazolylamino)
  • L is a bond or a methylene group
  • R 2 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) a carbamoyl group, (d) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), (e) an optionally halogenated C 1-6 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), and (h) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl)) ) A C 6-14 aryl group (eg, phenyl
  • R 1 is (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy)
  • a C 1-6 alkyl group eg, methyl, ethyl, isopropyl
  • substituents selected from:
  • a C 1-6 alkoxy group eg, methoxy
  • a cyclic amino group eg, morpholino, piperidine-1-
  • R 1 is (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy)
  • a C 1-6 alkyl group eg, methyl, ethyl, isopropyl
  • a cyclic amino group eg, morpholino, piperidine-1-
  • substituents selected from an oxo group Yl, pyrrolidin-1-yl
  • L is a bond
  • R 2 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), and (d) an optionally halogenated C 1-6 alkoxy group (eg, Difluoromethoxy, trifluoromethoxy)
  • a C 6-14 aryl group eg, phenyl, naphthyl
  • substituents selected from: (2) (a) an optionally halogenated C 1-6 alkyl group (eg, trifluoromethyl), and (b) (i) a hydroxy group, and (ii) a C 1-6 alkyl-carbonyloxy group (Eg, acetyloxy)
  • a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from (
  • R 1 is (1) a mono- or di-C 1-6 alkylamino group (wherein the C 1-6 alkyl may be substituted), (2) mono- or di-C 6-14 arylamino group (the C 6-14 aryl may be substituted), (3) mono- or di-C 7-16 aralkylamino group (the C 7-16 aralkyl may be substituted), (4) a 5- to 14-membered aromatic heterocyclic amino group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic amino group) (the 5- to 14-membered aromatic heterocyclic ring may be substituted), (5) An optionally substituted heterocyclic group via a nitrogen atom (ie, an optionally substituted cyclic amino group), (6) an optionally substituted C 2-6 alkenyl group, (7) an optionally substituted C 1-6 alkoxy - carbonyl group, (8) mono- or di-C 1-6 alkyl-carbamoyl group (wherein the C 1-6 alkyl may be substitute
  • Ring B moiety in the partial structure represented by, in addition to SO 2 -L-R 2, (1) a carboxy group, (2) an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl), (3) a C 1-6 alkylidene group (eg, methylene ( CH 2 )), and (4) Mono- or di-C 1-6 alkyl-carbamoyl group (eg, methylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, isobutylcarbamoyl) which may be substituted Each of which may be further substituted with 1 to 3 substituents selected from:
  • the position of the substituent is preferably on the carbon atom next to the oxygen atom (ie 2,3,4,5-tetrahydropyrido [2,3-f ] [1,4] oxazepine 2-position or 6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine 6-position)).
  • L is a bond or an optionally substituted methylene group
  • R 2 is (1) an optionally substituted C 6-14 aryl group, (2) optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably 5- or 6-membered monocyclic aromatic heterocyclic group or 8- to 14-membered condensed polycyclic group (preferably 2- or 3-ring) Formula) aromatic heterocyclic group), or (3) An optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 9- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) non-aromatic heterocyclic group) Is, Compound (I).
  • R 1 is (1) Mono- or di-C 1-6 alkylamino group (eg, isobutylamino, N-isobutyl-N-methylamino, N, N-diethylamino) (wherein the C 1-6 alkyl is 1 to 3 C 1-6 alkoxy group (eg, optionally substituted with methoxy)), (2) Mono- or di-C 6-14 arylamino group (eg, phenylamino) (the C 6-14 aryl may be condensed with C 3-10 cycloalkane (eg, cyclopentane)) (Eg, indan-4-ylamino), (3) mono- or di-C 7-16 aralkylamino group (eg, 2-phenylethylamino), (4) 5- to 14-membered aromatic heterocyclic amino group (preferably 5- or 6-membered monocyclic aromatic heterocyclic amino group (eg, pyridylamino, pyrazolylamino)
  • the position of the substituent is preferably on the carbon atom next to the oxygen atom (ie 2,3,4,5-tetrahydropyrido [2,3-f ] [1,4] oxazepine 2-position or 6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine 6-position)).
  • L is a bond or a methylene group
  • R 2 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) a carbamoyl group, (d) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), (e) an optionally halogenated C 1-6 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), and (h) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl)) ) A C 6-14 aryl group (eg, phenyl, naph
  • R 1 is (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy)
  • a C 1-6 alkyl group eg, methyl, ethyl, isopropyl
  • substituents selected from:
  • a C 1-6 alkoxy group eg, methoxy
  • a cyclic amino group eg, morpholino, piperidine-1-
  • R 1 is (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy)
  • a C 1-6 alkyl group eg, methyl, ethyl, isopropyl
  • a cyclic amino group eg, morpholino, piperidine-1-
  • substituents selected from an oxo group Yl, pyrrolidin-1-yl
  • the position of the substituent is preferably on the carbon atom next to the oxygen atom (ie 2,3,4,5-tetrahydropyrido [2,3-f ] [1,4] oxazepine 2-position or 6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine 6-position)).
  • R 2 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), and (d) an optionally halogenated C 1-6 alkoxy group (eg, Difluoromethoxy, trifluoromethoxy)
  • a C 6-14 aryl group eg, phenyl, naphthyl
  • substituents selected from: (2) (a) an optionally halogenated C 1-6 alkyl group (eg, trifluoromethyl), and (b) (i) a hydroxy group, and (ii) a C 1-6 alkyl-carbonyloxy group (Eg, acetyloxy)
  • a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from (eg,
  • R 1 is (1) a mono- or di-C 1-6 alkylamino group (wherein the C 1-6 alkyl may be substituted), (2) mono- or di-C 6-14 arylamino group (the C 6-14 aryl may be substituted), (3) mono- or di-C 7-16 aralkylamino group (the C 7-16 aralkyl may be substituted), (4) a 5- to 14-membered aromatic heterocyclic amino group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic amino group) (the 5- to 14-membered aromatic heterocyclic ring may be substituted), (5) An optionally substituted heterocyclic group via a nitrogen atom (ie, an optionally substituted cyclic amino group), (6) an optionally substituted C 2-6 alkenyl group, (7) an optionally substituted C 1-6 alkoxy - carbonyl group, (8) mono- or di-C 1-6 alkyl-carbamoyl group (wherein the C 1-6 alkyl may be substitute
  • Ring B moiety in the represented part structure in addition to the -SO 2 -L-R 2, respectively with 1 to 3 substituents which may be C 1-6 alkyl group (e.g., methyl, ethyl) May be further substituted,
  • the position of the substituent is preferably on the carbon atom next to the oxygen atom (ie 2,3,4,5-tetrahydropyrido [2,3-f ] [1,4] oxazepine 2-position or 6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine 6-position)).
  • L is a bond or an optionally substituted methylene group
  • R 2 is (1) an optionally substituted C 6-14 aryl group, (2) optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably 5- or 6-membered monocyclic aromatic heterocyclic group or 8- to 14-membered condensed polycyclic group (preferably 2- or 3-ring) Formula) aromatic heterocyclic group), or (3) An optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 9- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) non-aromatic heterocyclic group) Is, Compound (I).
  • R 1 is (1) Mono- or di-C 1-6 alkylamino group (eg, isobutylamino, N-isobutyl-N-methylamino, N, N-diethylamino) (wherein the C 1-6 alkyl is 1 to 3 C 1-6 alkoxy group (eg, optionally substituted with methoxy)), (2) Mono- or di-C 6-14 arylamino group (eg, phenylamino) (the C 6-14 aryl may be condensed with C 3-10 cycloalkane (eg, cyclopentane)) (Eg, indan-4-ylamino), (3) mono- or di-C 7-16 aralkylamino group (eg, 2-phenylethylamino), (4) 5- to 14-membered aromatic heterocyclic amino group (preferably 5- or 6-membered monocyclic aromatic heterocyclic amino group (eg, pyridylamino, pyrazolylamino)
  • the position of the substituent is preferably on the carbon atom next to the oxygen atom (ie 2,3,4,5-tetrahydropyrido [2,3-f ] [1,4] oxazepine 2-position or 6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine 6-position)).
  • L is a bond or a methylene group
  • R 2 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) a carbamoyl group, (d) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), (e) an optionally halogenated C 1-6 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), and (h) a 5- to 14-membered aromatic heterocyclic group (preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, oxazolyl)) ) A C 6-14 aryl group (eg, phenyl, naph
  • R 1 is (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy)
  • a C 1-6 alkyl group eg, methyl, ethyl, isopropyl
  • substituents selected from:
  • a C 1-6 alkoxy group eg, methoxy
  • a cyclic amino group eg, morpholino, piperidine-1-
  • R 1 is (1) (a) (i) a halogen atom (eg, fluorine atom), and (ii) a C 1-6 alkoxy group (eg, methoxy)
  • a C 1-6 alkyl group eg, methyl, ethyl, isopropyl
  • a cyclic amino group eg, morpholino, piperidine-1-
  • substituents selected from an oxo group Yl, pyrrolidin-1-yl
  • the position of the substituent is preferably on the carbon atom next to the oxygen atom (ie 2,3,4,5-tetrahydropyrido [2,3-f ] [1,4] oxazepine 2-position or 6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine 6-position)).
  • R 2 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, tert-butyl, trifluoromethyl), and (d) an optionally halogenated C 1-6 alkoxy group (eg, Difluoromethoxy, trifluoromethoxy)
  • a C 6-14 aryl group eg, phenyl, naphthyl
  • substituents selected from: (2) (a) an optionally halogenated C 1-6 alkyl group (eg, trifluoromethyl), and (b) (i) a hydroxy group, and (ii) a C 1-6 alkyl-carbonyloxy group (Eg, acetyloxy)
  • a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from (eg,
  • Specific examples of the compound (I) include the compounds of Examples 1 to 74, 76 to 287, 289 to 312 or salts thereof.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; and aluminum salt.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include sulfonic acid and salts with p-toluenesulfonic acid.
  • the salt with basic amino acid include salts with arginine, lysine and ornithine
  • preferable examples of the salt with acidic amino acid include salts with aspartic acid and glutamic acid. It is done. Of these, pharmaceutically acceptable salts are preferred.
  • the pharmaceutically acceptable salt include an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.) when the compound has an acidic functional group.
  • Inorganic salts such as barium salts), ammonium salts, and the like, and when having a basic functional group in the compound, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or Examples thereof include salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid
  • organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
  • compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
  • the production method of compound (I) will be described below.
  • the intermediate produced in the following production method may be isolated and purified using methods such as column chromatography, recrystallization, distillation, etc., or may be used as it is in the next step without isolation.
  • the intermediate may be a salt, and examples of such a salt include the same as those exemplified as the salt of compound (I).
  • room temperature usually indicates 10 to 35 ° C., and each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • the introduction or removal of these protecting groups is a method known per se, for example, the method described in Wiley-Interscience 2006 “Protective Groups in Organic Synthesis, 4th Ed.” (By Theodora W. Greene, Peter GM Wuts). It may be done according to this.
  • each step described below can be carried out without solvent or by dissolving or suspending the reactants in an appropriate solvent. Moreover, each process can also be performed using the solution which mixed the 2 or more types of solvent in the appropriate ratio.
  • the solvent used in each step include the following solutions: Alcohols: methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol, etc.
  • Ethers diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc.
  • Aromatic hydrocarbons benzene, chlorobenzene, toluene, xylene, etc.
  • Saturated hydrocarbons cyclohexane, hexane, etc.
  • Amides N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, etc.
  • Halogenated hydrocarbons dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.
  • Nitriles acetonitrile, propionitrile, etc.
  • Sulfoxides dimethyl sulfoxide, etc.
  • Aromatic organic bases pyridine, lutidine, etc.
  • Acid anhydrides acetic anhydride, etc.
  • Organic acids formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.
  • Inorganic acids hydrochloric acid, sulfuric acid, etc.
  • Esters methyl acetate, ethyl acetate, butyl acetate, etc.
  • Ketones acetone, methyl ethyl ketone, and the like.
  • Examples of the base or deoxidizing agent used in the production method of the compound of the present invention include the following: Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, magnesium hydroxide, etc.
  • Basic salts sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, etc.
  • Organic bases triethylamine, diethylamine, diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, imidazole, etc.
  • Metal alkoxides sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • Alkali metal hydrides sodium hydride, potassium hydride, etc.
  • Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.
  • Organic lithiums methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, etc.
  • Examples of the acid or acidic catalyst used in the production method of compound (I) include the following: Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.
  • Organic acids acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.
  • Lewis acid boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
  • Compound (I) can be produced using, for example, the following Method A, Method B or Method C.
  • the raw material compound of each method may be a commercially available product as it is, or may be produced by a method known per se or a method analogous thereto.
  • the starting compound may be a salt, and examples of such a salt include the same as those exemplified as the salt of compound (I).
  • compound (Ia) wherein Y is an oxygen atom, a nitrogen atom (specifically, —N (R ′)) or a sulfur atom (S) is produced by the following method A or method B can do.
  • Ya represents an oxygen atom, —N (R ′), or a sulfur atom (S);
  • R ′ represents a hydrogen atom or a substituent, PG 1 and PG 2 each independently represent a protecting group;
  • LG 1 represents a leaving group,
  • LG 2 represents a leaving group,
  • R 4 -R 9 and R 12 each independently represent a hydrogen atom or a substituent,
  • Other symbols are as defined above.
  • Examples of the protecting group represented by PG 1 or PG 2 include a C 1-6 alkyl group and a C 7-14 aralkyl group optionally substituted with a C 1-6 alkoxy group (eg, benzyl, 4-methoxybenzyl).
  • Silyl groups eg,
  • the leaving group represented by LG 1 includes, for example, a halogen atom (for example, a chlorine atom, a bromine atom, and an iodine atom), an optionally substituted sulfonyloxy group (for example, 1 to 3 halogen atoms).
  • a halogen atom for example, a chlorine atom, a bromine atom, and an iodine atom
  • an optionally substituted sulfonyloxy group for example, 1 to 3 halogen atoms.
  • C 1-6 alkylsulfonyloxy group e.g., methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group
  • 1 may be substituted with 3 C 1-6 alkyl groups C 6-14 arylsulfonyloxy group (eg benzenesulfonyloxy group, p-toluenesulfonyloxy group); C 7-14 aralkylsulfonyloxy group (eg benzylsulfonyloxy group)), [(oxide) phenyl- ⁇ 4- Sulfanylidene] dimethylammonium group.
  • C 6-14 arylsulfonyloxy group eg benzenesulfonyloxy group, p-toluenesulfonyloxy group
  • C 7-14 aralkylsulfonyloxy group eg benz
  • the leaving group represented by LG 2 includes, for example, a halogen atom (eg, chlorine atom), an optionally substituted sulfonyloxy group (eg, C 1-6 optionally substituted with 1 to 3 halogen atoms).
  • Alkylsulfonyloxy group for example, methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group
  • C 6-14 arylsulfonyloxy group optionally substituted by 1 to 3 C 1-6 alkyl groups
  • benzenesulfonyloxy group, p-toluenesulfonyloxy group C 7-14 aralkylsulfonyloxy group (for example, benzylsulfonyloxy group)).
  • This step is a step of converting compound (III) by protecting Ya of compound (II). If necessary, this step can be carried out in the presence of a base or acid, without solvent, or in a solvent that does not adversely influence the reaction.
  • the introduction of the protective group can be carried out by selecting from the methods described in Greene's protective groups in organic synthesis 4 th edition (Wiley-International Publication).
  • reaction temperature is usually about ⁇ 200 to 40 ° C., preferably about ⁇ 80 to 0 ° C.
  • the reaction time is usually about 0.5 to 48 hours, preferably about 0.5 to 12 hours.
  • Step A-3 This step is a step of converting compound (IV) to compound (V) by reductive alkylation reaction with an amine.
  • the reducing agent in the reductive alkylation reaction include metal hydrides (sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride). And dibutylaluminum hydride, aluminum hydride, lithium aluminum hydride, etc.) and borane complexes (borane-THF complex, catecholborane, 2-picolineborane, etc.).
  • the amount of the reducing agent to be used is about 1-50 mol, preferably about 1-5 mol, per 1 mol of compound (IV).
  • This reaction can be carried out in a solvent inert to the reaction.
  • solvents include aromatic hydrocarbons (toluene, xylene, etc.), aliphatic hydrocarbons (heptane, hexane, etc.), halogenated hydrocarbons (chloroform, dichloromethane, etc.), ethers (diethyl ether).
  • this reaction can also be performed in presence of an acid (acetic acid, hydrochloric acid, etc.). While the reaction temperature varies depending on the type of solvent, it is generally about ⁇ 80 to 80 ° C., preferably about ⁇ 40 to 40 ° C., and the reaction time is usually about 5 minutes to 48 hours, preferably about 1 to 24 hours. It is.
  • the amount of the amine to be used is about 2-50 mol, preferably about 2-5 mol, per 1 mol of compound (IV).
  • Step A-4 In this step, compound (V) is converted to compound (VI) by deprotection.
  • “Deprotection” can be carried out according to a method described for example in Greene's protective groups in organic synthesis 4 th edition (Wiley-International Publication).
  • This step is a step of converting compound (VI) to compound (VII).
  • This reaction can be carried out in the presence of a base and a sulfonylating agent.
  • the base used in this reaction include inorganic bases (alkali metal hydrides such as sodium hydride and lithium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and sodium hydrogen carbonate.
  • Alkali metal hydrogen carbonates such as potassium hydrogen carbonate, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate) or organic bases (trimethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5, Amines such as 4,0] undec-7-ene, and cyclic amines such as pyridine and 4-dimethylaminopyridine.
  • the amount of the base used varies depending on the type of solvent and other reaction conditions, but is usually about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, relative to 1 mol of compound (VI).
  • the sulfonylating agent used in this reaction includes sulfonic acid chloride (eg, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-tosyl chloride), sulfonic acid anhydride (eg, trifluoromethanesulfonic acid anhydride, p-toluenesulfone). Acid anhydride), sulfonimide (eg, N-phenylbis (trifluoromethanesulfonimide), N- (5-chloro-2-pyridyl) triflimide) and the like.
  • sulfonic acid chloride eg, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-tosyl chloride
  • sulfonic acid anhydride eg, trifluoromethanesulfonic acid anhydride, p-toluenes
  • the amount of the sulfonylating agent to be used varies depending on the type of solvent and other reaction conditions, but is usually about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents, per 1 mol of compound (VI).
  • This reaction can be carried out in a solvent inert to the reaction.
  • the solvent include aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (hexane, heptane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, etc.), ethers (diethyl ether).
  • reaction temperature is, for example, about ⁇ 10 to 250 ° C., and the reaction time varies depending on the type of salt of compound (VI), the reaction temperature, etc. About 5 to 50 hours.
  • compound (VII) is converted to compound (VIII) by an intramolecular cyclization reaction.
  • the “intramolecular cyclization reaction” is generally performed in the presence of a base, no solvent, or a solvent that does not adversely influence the reaction.
  • the amount of the base to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (VII).
  • This reaction can be carried out using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds, and examples thereof include solvents such as ethers, aromatic hydrocarbons, saturated hydrocarbons and amides, or a mixed solvent thereof.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 10 to 150 ° C.
  • This step is a step of converting compound (IX) to compound (X) containing a part of compound (Ia) by subjecting compound (IX) to sulfonamidation.
  • “Sulfonamidation” can be carried out according to a method known per se or according thereto, for example, by reacting compound (IX) with sulfonyl chloride in the presence of a base.
  • a base a tertiary amine such as triethylamine is preferable. This step is usually performed in a solvent that does not adversely influence the reaction.
  • the solvent examples include hydrocarbons (benzene, toluene, etc.), ethers (diethyl ether, dioxane, tetrahydrofuran, etc.) or a mixture thereof.
  • hydrocarbons benzene, toluene, etc.
  • ethers diethyl ether, dioxane, tetrahydrofuran, etc.
  • tetrahydrofuran is preferred.
  • This step is a step of converting compound (X) to compound (Ia) by a nucleophilic substitution reaction with an amine or a coupling reaction with a boronic acid derivative.
  • the “nucleophilic substitution reaction” can be carried out in the presence of a base.
  • the amount of amine used in the “nucleophilic substitution reaction” is about 0.5 to 20 mol, preferably about 1 to 10 mol, per 1 mol of compound (X).
  • the amount of these bases to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (X).
  • This reaction can be carried out using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.
  • reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 150 to 250 ° C. This reaction can also be performed under microwave irradiation.
  • the “coupling reaction” can be carried out according to a method known per se [eg, Chemical Science, 2011, Vol. 2, page 27, etc.], for example, in the presence of a transition metal catalyst and a base, The reaction can be performed in the absence of a solvent or in a solvent that does not adversely influence the reaction.
  • transition metal catalyst examples include palladium catalysts (for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), ( 1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II)), nickel catalyst (for example, nickel chloride).
  • palladium catalysts for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium (II) chloride, tetrakis (triphenylphosphine) palladium (0), ( 1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II)
  • nickel catalyst for example, nickel chloride
  • This reaction may be carried out according to necessity with a ligand (for example, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, , 2′-bis (di-p-tolylphosphino) -1,1′-binaphthyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, triphenylphosphine, tri -Tert-butylphosphine) can also be added.
  • a ligand for example, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, , 2′-bis (di-
  • the amount of transition metal catalyst used is about 0.0001 to 5 mol, preferably about 0.001 to 1 mol, relative to 1 mol of compound (X), and the amount of ligand used is 1 mol of compound (X).
  • the amount of the boronic acid derivative to be used is about 0.5 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound (X).
  • This reaction is preferably performed in the presence of a base.
  • the base include alkali metal salts (sodium carbonate, potassium carbonate, cesium carbonate, etc.) and the like.
  • the amount of these bases to be used is about 0.1 to about 100 molar equivalents, preferably about 1 to about 10 molar equivalents, relative to compound (X).
  • This reaction can be carried out using a solvent inert to the reaction. Examples of such solvents are not particularly limited as long as the reaction proceeds. For example, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, nitriles, sulfoxides, esters, water Or a mixed solvent thereof.
  • the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 150 to 250 ° C. This reaction can also be performed under microwave irradiation.
  • This step is a step of converting compound (VIa) to compound (VIIIa) by Mitsunobu reaction.
  • the “Mitsunobu reaction” is a method known per se [eg, Synthesis, page 1-27, 1981, Tetrahedron Lett. 36, 6373-6374, 1995, Tetrahedron Lett. 38, 5831-5834, 1997, etc.], and examples thereof include azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and 1,1 ′-(azodicarbonyl) dipiperidine.
  • the reaction can be carried out in the presence of a carboxylate and a phosphine such as triphenylphosphine or tributylphosphine without solvent or in a solvent that does not adversely influence the reaction.
  • This reaction can be performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane; benzene, toluene and the like
  • Aromatic hydrocarbons saturated hydrocarbons such as cyclohexane and hexane
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoryltriamide
  • Halogenated hydrocarbons such as 1,2-dichloroethane
  • nitriles such as acetonitrile and propionitrile
  • ketones such as acetone and ethyl methyl ketone
  • esters such as ethyl acetate and tert-butyl acetate
  • dimethyl sulfoxide What sulfoxides include
  • the reaction time is 5 minutes to 100 hours, preferably 30 minutes to 72 hours.
  • the reaction temperature is ⁇ 20 to 200 ° C., preferably 0 to 100 ° C.
  • the amount of azodicarboxylates and phosphines to be used is about 1-5 mol, preferably about 1-2 mol, per 1 mol of compound (VIa).
  • Step A-11 This step is a step of converting compound (Ib) to compound (Ic) by an oxidation reaction.
  • the oxidizing agent used in the “oxidation reaction” include 3-chlorophenyl perbenzoic acid, sodium periodate, hydrogen peroxide solution, peracetic acid, and Oxone (trademark).
  • This step can be performed in a solvent that does not adversely influence the reaction, and examples of such a solvent include dichloromethane.
  • This step is a step of converting compound (VIII) to compound (XI). This step can be performed, for example, according to Step A-10.
  • This step is a step of converting compound (XI) to compound (XII). This step can be performed, for example, according to Step A-8.
  • This step is a step of converting compound (XII) to compound (I). This step can be performed, for example, according to Step A-9.
  • Compound (Id) in which Y is a carbon atom (CR 10 R 11 ) among compounds (I) can be produced by the following method C.
  • R 10 and R 11 each independently represent a hydrogen atom or a substituent, Other symbols are as defined above. ]
  • This step is a step of converting compound (XIII) to compound (XIV). This step can be performed, for example, according to Step A-9.
  • This step is a step of converting compound (XIV) to compound (XV). This step can be performed, for example, according to Step A-11.
  • reaction time varies depending on the solvent to be used, it is generally 10 min-100 hr, preferably 30 min-50 hr.
  • the reaction temperature is ⁇ 10 to 250 ° C., preferably 10 to 150 ° C.
  • This step is a step of converting compound (XVI) to compound (Id). This step can be performed, for example, according to Step A-10.
  • the target compound In each reaction of the target compound and the raw material synthesis, when the raw material compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, these groups are protected with a protecting group that is generally used in peptide chemistry or the like. May be. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of such protecting groups, for example, include those described in Wiley-Interscience, 1999, “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter G. M. Wuts Author) It is done.
  • protecting groups for amino groups include formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl group), phenylcarbonyl group, C 1-6 alkyl-oxycarbonyl group (eg, methoxycarbonyl, ethoxy Carbonyl group), aryloxycarbonyl group (eg phenyloxycarbonyl group), C 7-10 aralkyl-carbonyl group (eg benzyloxycarbonyl group), benzyl group, benzhydryl group, trityl group, phthaloyl group, and the like These protecting groups may have a substituent.
  • substituents examples include halogen atoms (eg, fluorine, chlorine, bromine, iodine atoms), C 1-6 alkyl-carbonyl groups (eg, acetyl, propionyl, butylcarbonyl groups), and nitro groups.
  • the number of substituents is about 1 to 3.
  • Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl group), phenyl group, trityl group, and silyl group. These protecting groups may have a substituent. Examples of these substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms), formyl groups, C 1-6 alkyl-carbonyl groups (eg acetyl, propionyl, butylcarbonyl groups), and nitro groups. The number of substituents is about 1 to 3.
  • hydroxyl-protecting group examples include a C 1-6 alkyl group (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl group), phenyl group, C 7-10 aralkyl group.
  • benzyl group formyl group, C 1-6 alkyl-carbonyl group (eg acetyl, propionyl group), aryloxycarbonyl group (eg phenyloxycarbonyl group), C 7-10 aralkyl-carbonyl group (eg Benzyloxycarbonyl group), pyranyl group, furanyl group, silyl group, and the like, and these protecting groups may have a substituent.
  • substituents include halogen atoms (fluorine, chlorine, bromine, iodine atoms), C 1-6 alkyl groups, phenyl groups, C 7-10 aralkyl groups, and nitro groups. About 1 to 4 pieces.
  • the desired product When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method. You can also.
  • the compound (I) thus obtained can be isolated and purified from the reaction solution by known means (for example, phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography).
  • compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included.
  • an optical isomer an optical isomer resolved from a racemate is also encompassed in compound (I).
  • the optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemate according to a conventional method.
  • a method known per se for example, a fractional recrystallization method, a chiral column method, or a diastereomer method is used.
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine
  • Racemate and optically active compound for example, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column).
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffers (eg, phosphoric acid)
  • the optical isomers are separated by developing as a single or mixed solution of a buffer solution) and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine).
  • Diastereomer method A mixture of racemates is made into a mixture of diastereomers by chemical reaction with an optically active reagent, and this is converted into a single substance through ordinary separation means (for example, fractional recrystallization, chromatography method). Then, the optical isomer is obtained by separating the optically active reagent site by chemical treatment such as hydrolysis reaction.
  • the compound (I) when the compound (I) has a hydroxy or a primary or secondary amino in the molecule, the compound and an optically active organic acid (for example, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], ( A diastereomer in an ester form or an amide form can be obtained by subjecting it to a condensation reaction with-)-menthoxyacetic acid) or the like.
  • an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. The separated diastereomer is converted into the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each with different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se. Crystals of compound (I) can be produced by applying crystallization methods known per se to compound (I) for crystallization.
  • examples of the crystallization method include a crystallization method from a solution, a crystallization method from a vapor, and a crystallization method from a melt.
  • the “crystallization from solution” includes a state in which the compound is not saturated by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ionic strength, redox state, etc.) or the amount of the solvent.
  • a method of shifting from a supersaturated state to a supersaturated state is exemplified, and specific examples include a concentration method, a slow cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method.
  • solvent used examples include aromatic hydrocarbons (eg, benzene, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane, chloroform), saturated hydrocarbons (eg, hexane, heptane, cyclohexane), Ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane), nitriles (eg, acetonitrile), ketones (eg, acetone), sulfoxides (eg, dimethyl sulfoxide), acid amides (eg, N, N -Dimethylformamide), esters (eg, ethyl acetate), alcohols (eg, methanol, ethanol, isopropyl alcohol), and water.
  • aromatic hydrocarbons eg, benzene, toluene, xylene
  • halogenated hydrocarbons eg, dich
  • a seed crystal can also be used as needed.
  • Examples of the “crystallization method from vapor” include a vaporization method (sealed tube method, air flow method), a gas phase reaction method, and a chemical transport method.
  • Examples of the “crystallization from melt” include normal freezing method (pulling method, temperature gradient method, Bridgman method), zone melting method (zone leveling method, float zone method), special growth method (VLS method, Liquid phase epitaxy method).
  • compound (I) is dissolved in an appropriate solvent (eg, alcohols such as methanol, ethanol, etc.) at a temperature of 20 to 120 ° C., and the resulting solution is dissolved at a temperature at the time of dissolution.
  • an appropriate solvent eg, alcohols such as methanol, ethanol, etc.
  • the method include cooling to the following (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
  • the crystals of the present invention thus obtained can be isolated by, for example, filtration.
  • a method for analyzing the obtained crystal a crystal analysis method by powder X-ray diffraction is generally used. Further, examples of the method for determining the crystal orientation include a mechanical method and an optical method.
  • the peak by powder X-ray diffraction is measured using, for example, a Cu—K ⁇ 1 line (tube voltage: 40 KV; tube current: 50 mA) as a radiation source and using a RINT2100 type (Rigaku Denki) or the like. Means a peak.
  • the melting point and the peak due to powder X-ray diffraction may vary depending on the measuring instrument, measurement conditions, and the like.
  • the crystal in the present specification may be a crystal having a value different from the melting point or the peak by powder X-ray diffraction described in the present specification as long as it is within a normal error range.
  • Crystals of compound (I) obtained by the above production method have physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, It is expected to be excellent in pharmacokinetics (absorbability, distribution, metabolism, excretion) and drug efficacy), and may be useful as a medicine.
  • the specific rotation ([ ⁇ ] D ) is, for example, a specific rotation measured using a polarimeter (JASCO, P-1030 polarimeter (No. AP-2)). Means.
  • the melting point means a melting point measured using, for example, a trace melting point measuring device (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000).
  • Compound (I) may be a solvate (eg, a hydrate such as a 0.5 hydrate, a monohydrate, a dihydrate, etc.) or a solvate (eg, a non-hydrate) And may be included in the compound (I).
  • a deuterium conversion form in which 1 H is converted to 2 H (D) is also encompassed in compound (I).
  • a compound labeled or substituted with an isotope eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I
  • Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis. obtain.
  • the prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated eg, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds
  • compounds (I ) In which the hydroxy is acylated, alkylated, phosphorylated or borated eg, the hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethyl Aminomethylcarbonylated compound); the carboxy of compound (I)
  • Compound (I) is expected to be excellent in physical properties (solubility, cytotoxicity, membrane permeability, protein binding rate, etc.).
  • Compound (I) and prodrugs thereof (hereinafter sometimes abbreviated as compounds of the present invention) exhibit ROR ⁇ t-modulating activity, and thus can be useful as safe pharmaceuticals based on this action.
  • the medicament of the present invention comprising the compound of the present invention is used for mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans) against ROR ⁇ t-related diseases, Th17.
  • Inflammatory diseases eg, rheumatoid arthritis, acute pancreatitis, chronic pancreatitis, asthma, bronchial asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel Disease, celiac disease, Behcet's disease, hepatitis, alcoholic liver fibrosis, alcoholic hepatitis, alcoholic cirrhosis, hepatitis B viral hepatopathy, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) , Transient ischemic attack (TIA), systemic inflammatory response syndrome (SIRS), dry eye, glaucoma, uveitis, orbital cellulitis, idiopathic orbit
  • inflammatory diseases eg, rheumatoid arthritis, acute pancreatitis, chronic pancreatitis, asthma, bronchial asthma, adult respiratory distress syndrome,
  • Cancer eg, colon cancer (eg, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small cell) Lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), breast cancer (eg, invasive milk) Duct cancer, non-invasive breast cancer, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-grade tumor), prostate cancer (eg, hormone) Dependent prostate cancer, hormone-independent prostate cancer), liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (eg, medullary
  • the medicament of the present invention can be preferably used as a preventive or therapeutic agent for neoplastic diseases.
  • the medicament of the present invention is preferably an autoimmune disease, inflammatory disease, bone / joint disease or neoplastic disease, particularly preferably psoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylosing spondylitis, systemic lupus erythematosus (SLE), chronic obstructive pulmonary disease, colon cancer, kidney cancer, black It can be used as a prophylactic or therapeutic agent for melanoma, pharyngeal cancer, laryngeal cancer, tongue cancer, esophageal cancer, ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, head and neck cancer, prostate cancer or endometrial cancer.
  • IBD inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • rheumatoid arthritis multiple sclerosis
  • prevention of the disease refers to, for example, a patient who has not developed the disease, which is expected to have a high risk of onset due to some factor related to the disease, or who has developed the subjective symptom. This means that a drug containing the compound of the present invention is administered to a patient who is not, or that a drug containing the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.
  • the medicament of the present invention can be expected to have low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), and the compound of the present invention is generally used as it is or in a method for producing a pharmaceutical preparation. According to known means used per se, it can be mixed with a pharmacologically acceptable carrier to obtain a pharmaceutical composition, which can be used as the medicament of the present invention.
  • the medicament of the present invention is safe orally or parenterally for mammals (eg, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats). Can be administered.
  • the medicament containing the compound of the present invention is pharmacologically acceptable with the compound of the present invention alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier.
  • Examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, film-forms (eg , Orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion As an agent, patch, suppository (eg, anal suppository, vaginal suppository), pellet, nasal agent, pulmonary agent (inhalant), eye drops, etc., orally or parenterally (eg, intravenously, Intramuscular, subcutaneous,
  • the content of the compound of the present invention in the medicament of the present invention is about 0.01% to about 100% by weight of the whole medicament.
  • the dose varies depending on the administration subject, administration route, disease and the like, but for example, about 0.1 mg as an active ingredient (compound (I)) per day as an oral agent for cancer patients (body weight: about 60 kg).
  • / Kg body weight to about 30 mg / kg body weight, preferably about 1 mg / kg body weight to 20 mg / kg body weight can be administered once to several times a day, preferably once or twice or three times a day.
  • the pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials.
  • excipients and lubricants in solid preparations Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
  • examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
  • Examples of the buffer include phosphate, acetate, carbonate, citrate buffer and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Examples of the antioxidant include sulfite, ascorbic acid, and ⁇ -tocopherol.
  • the compound of the present invention can be used in combination with other drugs.
  • the compound of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and drugs that inhibit the action of the receptors.
  • drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or cell growth factors and drugs that inhibit the action of the receptors.
  • a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.
  • ⁇ hormone therapeutic agent '' examples include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin acetate) Leuprorelin acetate), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozo
  • chemotherapeutic agent for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents are used.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, ado
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbpyramide, pendant Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and their DS formulation is used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT, doxyfluridine,
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations (eg, doxorubicin-encapsulated PEG ribosomes).
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine and their DDS preparations are used.
  • immunotherapeutic agent examples include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum , Levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody (eg, ipilimumab, tremelimumab), anti-PD-1 antibody (eg, nivolumab, pembrolizumab), and anti-PD-L1 antibody.
  • CTLA4 antibody eg, ipilimumab, tremelimumab
  • anti-PD-1 antibody eg, nivolumab, pembrolizumab
  • anti-PD-L1 antibody examples include picibanil, krestin, schizophyllan, lentinan, uben
  • the “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less.
  • Examples of the peptide include a factor that exerts an action at a low concentration by binding to a receptor.
  • EGF epidermal growth factor
  • IGF insulin receptor ase B
  • IGF insulin receptor ase B
  • FGF fibroblast growth factor
  • Substances having substantially the same activity eg, acidic FGF, Basic FGF, KGF (keratinocyte growth factor), FGF-10]
  • Other cell growth factors eg, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF ( next growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF (hepatocyte growth factor), GFth (hethocycle growth factor), VEGF (v).
  • the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (eg, HER3 ), Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (eg, Tie2), PDGF receptor, etc. .
  • EGF receptor heregulin receptor (eg, HER3 )
  • Insulin receptor eg, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2
  • VEGF receptor eg, angiopoietin receptor (eg, Tie2), PDGF receptor, etc.
  • agents that inhibit the action of cell growth factors and their receptors include EGF inhibitors, TGF ⁇ inhibitors, harregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGF ⁇ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor Agent, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor , Src inhibitor, PKC inhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor
  • an anti-VEGF antibody eg, Bevacizumab, Ramucurumab
  • an anti-HER2 antibody eg, Trastuzumab, Pertuzumab
  • an anti-EGFR antibody eg, Cetuximab, Panitumab, Matuzumab, Nimotumumab, Antimothumab, Emototumumab, Antimothumab, Emototumub , Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib, Actinib, Visodegib b, Motesanib, Nilotinib, 6- [4- (4-Ethylpiperazin-1-ylmethyl) phenyl] -N- [1 (R) -phenylethyl] -7H-pyrrolo
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the combination is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) obtained by separately formulating the compound of the present invention and the concomitant drug.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . The same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • the dose varies depending on the type of the compound of the present invention, administration route, symptom, patient age, etc.
  • IBD inflammatory bowel disease
  • the dosage is the type and content of compound (I), the dosage form, the duration of drug release, the animal to be administered (for example, mouse, rat, hamster, guinea pig, rabbit) Mammals such as cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.), which may vary depending on the purpose of administration, for example, from about 0.1 per week when applied parenterally About 100 mg of compound (I) may be released from the dosage formulation.
  • the animal to be administered for example, mouse, rat, hamster, guinea pig, rabbit
  • Mammals such as cats, dogs, cows, horses, pigs, sheep, monkeys, humans, etc.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc.
  • the amount of the drug is usually about 0.001 to 2000 mg per kg body weight of the mammal by oral administration, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg. This is usually administered in 1 to 4 divided doses per day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, or may be administered with a time difference.
  • the time difference varies depending on the active ingredient, dosage form, and administration method to be administered.
  • the concomitant drug when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably Examples include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour.
  • the concomitant drug is administered within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. Is mentioned.
  • silica gel column chromatography aminopropylsilane-bonded silica gel was used when NH was described, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when Diol was described.
  • preparative HPLC high performance liquid chromatography
  • octadecyl-bonded silica gel was used.
  • the elution solvent indicates a volume ratio unless otherwise specified.
  • Room temperature usually means a temperature of about 10 ° C to 35 ° C.
  • sodium sulfate or magnesium sulfate was used for drying the extract.
  • 6-chloro-2-iodo-3- (methoxymethoxy) pyridine 6-chloro-2-iodopyridin-3-ol (160 g, 626.37 mmol) in DMF (482 ml) solution in potassium carbonate (260 g, 1879.10 mmol) and bromo (methoxy) methane (100 g, 800.23 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Distilled water was added to the reaction mixture, followed by extraction with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 2 7- (3,5-Dimethylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [ 1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine ( 100 mg, 0.25 mmol), 3,5-dimethylpiperidine cis-trans mixture (0.169 mL, 1.27 mmol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl ) [2- (2-Aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether
  • Example 6 4-((3- (Difluoromethoxy) phenyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4]
  • oxazepine (15 mg , 0.06 mmol) in THF solution (285 ⁇ l) were added triethylamine (23.82 ⁇ l, 0.17 mmol) and 3- (difluoromethoxy) benzenesulfonyl chloride (13.82 ⁇ l, 0.09 mmol) and stirred overnight. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (hexane / ethyl
  • Example 7 7- (cis-2,6-dimethylmorpholin-4-yl) -4-((5- (trifluoromethyl) pyridin-3-yl) sulfonyl) -2,3,4,5-tetrahydropyrido [2 , 3-f] [1,4] oxazepine 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4 ] To a THF solution (285 ⁇ l) of oxazepine (20 mg, 0.08 mmol), add triethylamine (0.021 ml, 0.15 mmol) and 5- (trifluoromethyl) pyridine-3-sulfonyl chloride (28.0 mg, 0.11 mmol).
  • Example 11 7- (1,3-Dihydro-2H-isoindol-2-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3 -f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4] Oxazepine (31.4 mg, 80 ⁇ mol), Isoindoline (400 ⁇ mol), Chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- (2- Aminoethyl) phenyl] palladium (II) (5.83 mg, 8.00 ⁇ mol), dicyclohexyl (2
  • Example 13 7- (5-Azaspiro [2.5] oct-5-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31.4 mg, 80 ⁇ mol), 5-azaspiro [2.5] octane (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- ( 2-Aminoethyl) phenyl] palladium (II) (5.83 mg, 8.00 ⁇ mol), dicyclohex
  • Example 15 7- (2-Ethylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • oxazepine (31.4 mg , 80 ⁇ mol), 2-ethylpiperidine (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- (2-aminoethyl) phenyl ] Palladium (II) (5.83 mg, 8.00 ⁇ mol), dicyclohexyl (2 ', 6'
  • Example 29 2- (3,5-Dimethylpiperidin-1-yl) -8-((3- (trifluoromethyl) phenyl) sulfonyl) -6,7,8,9-tetrahydropyrimido [4,5-f] [ 1,4]
  • Oxazepine (“Short retention time") 2-Chloro-8-((3- (trifluoromethyl) phenyl) sulfonyl) -6,7,8,9-tetrahydropyrimido [4,5-f] [1,4] oxazepine (50 mg, 0.13 mmol )
  • NMP solution (2 mL) was added 3,5-dimethylpiperidine cis-trans mixture (0.067 ml, 0.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.133 ml, 0.76 mmol).
  • Example 30 2- (3,5-Dimethylpiperidin-1-yl) -8-((3- (trifluoromethyl) phenyl) sulfonyl) -6,7,8,9-tetrahydropyrimido [4,5-f] [ 1,4]
  • Oxazepine (“Long retention time")
  • oxazepine 50 mg, 0.13 mmol
  • NMP solution (2 mL) was added 3,5-dimethylpiperidine cis-trans mixture (0.067 ml, 0.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.133 ml, 0.76 mmol).
  • Example 32 7- (cis-2,6-dimethylmorpholin-4-yl) -4-((2- (trifluoromethyl) pyridin-4-yl) sulfonyl) -2,3,4,5-tetrahydropyrido [2 , 3-f] [1,4] oxazepine 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4 ] To a THF solution (2 ml) of oxazepine (20 mg, 0.08 mmol), add triethylamine (0.021 ml, 0.15 mmol) and 2- (trifluoromethyl) pyridine-4-sulfonyl chloride (28.0 mg, 0.11 mmol).
  • Example 34 7- (cis-2,6-dimethylmorpholin-4-yl) -4-((4- (trifluoromethyl) pyridin-2-yl) sulfonyl) -2,3,4,5-tetrahydropyrido [2 , 3-f] [1,4] oxazepine 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4 ] To a THF solution (2 ml) of oxazepine (33.2 mg, 0.13 mmol), add triethylamine (0.018 ml, 0.13 mmol) and 4- (trifluoromethyl) pyridine-2-sulfonyl chloride (31 mg, 0.13 mmol).
  • Example 36 2-((3-((7- (cis-2,6-dimethylmorpholin-4-yl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepin-4 (5H) -yl ) Sulfonyl) -5- (trifluoromethyl) pyridin-2-yl) oxy) ethanol 2-((3-((7- (cis-2,6-dimethylmorpholin-4-yl) -2,3-dihydropyrido) [2,3-f] [1,4] Oxazepine-4 (5H) -yl) sulfonyl) -5- (trifluoromethyl) pyridin-2-yl) oxy) ethyl acetate (60 mg, 0.10 mmol) in THF 4N lithium hydroxide (2 ml, 8.00 mmol) was added to the solution (2 ml), and the mixture was stirred for 4 hours.
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the diluted solution was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by preparative HPLC, and the obtained solid was pulverized and washed with diisopropyl ether-heptane to obtain the title compound (38.0 mg, 0.071 mmol, 68.3%).
  • Example 40 4-((3-Chlorophenyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4 ]
  • ethyldiisopropylamine 0.028 ml, 0.16 mmol
  • 3-chlorobenzenesulfonyl chloride (0.16 mmol
  • Example 47 7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3-methylphenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • ethyldiisopropylamine 0.028 ml, 0.16 mmol
  • 3-methylbenzenesulfonyl chloride (0.16 mmol
  • Example 53 7- (cis-2,6-dimethylmorpholin-4-yl) -4-((4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) sulfonyl) -2,3 , 4,5-Tetrahydropyrido [2,3-f] [1,4] oxazepine 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [ 2,3-f] [1,4] oxazepine (21 mg, 0.08 mmol) in THF (1 ml) and ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 4-methyl-3,4-dihydro-2H- 1,4-Benzoxazine-7-sulfonyl chloride (0.16 mmol) was added and stirred overnight. After the solvent was distilled off, the residue was purified by preparat
  • Example 60 4-((5-Chloro-1-naphthyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (21 mg , 0.08 mmol) in THF (1 ml) were added ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 5-chloronaphthalene-1-sulfonyl chloride (0.16 mmol) and stirred overnight. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (58.4 ⁇ mol).
  • Example 61 7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethoxy) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • oxazepine 21 To a THF solution (1 ml) of mg, 0.08 mmol), ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 3-trifluoromethoxybenzenesulfonyl chloride (0.16 mmol) were added and stirred overnight. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (56.4 ⁇ mol).
  • Example 63 4- (2,3-Dihydro-1-benzofuran-5-ylsulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepine 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4]
  • Add ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 2,3-dihydro-1-benzofuran-5-sulfonyl chloride (0.16 mmol) to THF solution (1 ml) of oxazepine (21 mg, 0.08 mmol) and stir overnight. did. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (53.9 ⁇ mol).
  • Example 65 2-Chloro-4-((7- (cis-2,6-dimethylmorpholin-4-yl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepin-4 (5H) -yl ) Sulfonyl) benzonitrile 7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (21 mg, Ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 3-chloro-4-cyanobenzenesulfonyl chloride (0.16 mmol) were added to a THF solution (1 ml) of 0.08 mmol) and stirred overnight. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (54.6 ⁇ mol).
  • Example 68 7- (cis-2,6-Dimethylmorpholin-4-yl) -4- (2-naphthylsulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7- (cis-2,6-Dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (21 mg, 0.08 mmol) in THF Ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 2-naphthalenesulfonyl chloride (0.16 mmol) were added to the solution (1 ml) and stirred overnight. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (58.2 ⁇ mol).
  • Example 70 4-((3,4-Difluorophenyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [ 1,4]
  • oxazepine 21 mg, Ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 3,4-difluorobenzenesulfonyl chloride (0.16 mmol) were added to a THF solution (1 ml) of 0.08 mmol) and stirred overnight. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (53.9 ⁇ mol).
  • Example 71 4-((3-tert-butylphenyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [ 1,4]
  • oxazepine 21 mg, Ethyldiisopropylamine (0.028 ml, 0.16 mmol) and 3-tertbutylbenzenesulfonyl chloride (0.16 mmol) were added to a THF solution (1 ml) of 0.08 mmol) and stirred overnight. After the solvent was distilled off, the residue was purified by preparative HPLC to obtain the title compound (55.9 ⁇ mol).
  • Example 78 7-((E) -2- (2-chloro-6- (trifluoromethyl) phenyl) vinyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepine (25 mg, 0.06 mmol), 2-((E) -2- (2-chloro-6- (trifluoromethyl) phenyl) vinyl) -4,4,5, To a solution of 5-tetramethyl-1,3,2-dioxaborolane (36.0 mg, 0.11 mmol) and cesium carbonate (95 mg, 0.19 mmol) in dimethoxyethane (318
  • Example 84 7- (2-Methylphenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7 -Chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol) , 2-methylphenylboronic acid (0.16 mmol), cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) in bis4-di-tert-butylphosphanyl-N, N-dimethylaniline dichloropalladium ( 5.66 mg, 8 ⁇ mol) was added, and the mixture was stirred at 150 ° C.
  • Example 85 7- (3-Methylphenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7 -Chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol) , 3-Methylphenylboronic acid (0.16 mmol), Cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) solution in bis4-di-tert-butylphosphanyl-N, N-dimethylaniline dichloropalladium ( 5.66 mg, 8 ⁇ mol) was added, and the mixture was stirred at 150 ° C.
  • Example 89 7- (3-Ethylphenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7 -Chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol) , 3-Ethylphenylboronic acid (0.16 mmol), cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) in bis4-di-tert-butylphosphanyl-N, N-dimethylaniline dichloropalladium ( 5.66 mg, 8 ⁇ mol) was added, and the mixture was stirred at 150 ° C.
  • Example 92 7- (3-Chlorophenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7- Chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol), Bis4-di-tert-butylphosphanyl-N, N-dimethylaniline dichloropalladium (5.66 mg) in a solution of 3-chlorophenylboronic acid (0.16 mmol) and cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) , 8 ⁇ mol), and stirred in a microwave reactor at 150 ° C
  • Example 93 7- (3-Cyclopropylphenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7-Chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol ), 3-cyclopropylphenylboronic acid (0.16 mmol), cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) in bis 4-di-tert-butylphosphanyl-N, N-dimethylaniline dichloro Palladium (5.66 mg, 8 ⁇ mol) was added and stirred in a microwave reactor at 150 ° C
  • Example 99 7- (3,5-Dimethoxyphenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4]
  • Example 101 7- (3- (trifluoromethyl) phenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • Example 102 7- (3,5-dichlorophenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7-Chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol ), 3,5-dichlorophenylboronic acid (0.16 mmol), cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) solution in bis 4-di-tert-butylphosphanyl-N, N-dimethylaniline dichloro Palladium (5.66 mg, 8 ⁇ mol) was added and stirred in a microwave reactor at 150 °
  • Distilled water was added to the reaction mixture, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate-THF. The extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Pyridine (1 mL) was added to the residue and stirred at 100 ° C. for 2 hours. Distilled water was added to the reaction mixture, neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 106 3- (7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4]
  • Oxazepin-2-yl) propanamide 3- (7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) Sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) propanoic acid (48 mg, 0.09 mmol), ammonium chloride (7.09 mg, 0.13 mmol) ), 1H-benzotriazol-1-ol (13.13 mg, 0.10 mmol) and triethylamine (14.77 ⁇ l, 0.11 mmol) in DMF (0.3
  • Example 119 7- (3-methoxypiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • oxazepine (31.4 mg , 80 ⁇ mol), 3-methoxypiperidine (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- (2-aminoethyl) phenyl ] Palladium (II) -methyl-t-butyl ether adduct (6.53 mg, 8.00 ⁇ mol
  • Example 121 7- (6-Azaspiro [3.5] non-6-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31.4 mg, 80 ⁇ mol), 6-azaspiro [3.5] nonane (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- ( 2-Aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether adduct (6.53 mg, 8
  • Example 122 4-((3- (trifluoromethyl) phenyl) sulfonyl) -7- (3- (trifluoromethyl) piperidin-1-yl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • Example 123 7- (3,3-Dimethylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [ 1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine ( 31.4 mg, 80 ⁇ mol), 3,3-Dimethylpiperidine (400 ⁇ mol), Chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- (2- Aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether adduct (6.53 mg, 8.00
  • Example 133 7-((2R) -2- (methoxymethyl) pyrrolidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1 , 4] oxazepine (31.4 mg, 80 ⁇ mol), (R) -2-methoxymethylpyrrolidine (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'- Biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether
  • Example 137 7- (cis-3,5-dimethylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • Oxazepine (31.4 mg, 80 ⁇ mol), cis-3,5-dimethylpiperidine (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2 -(2-Aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether adduct
  • Example 138 ((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [ 2,3-f] [1,4] oxazepin-2-yl) methanol
  • Example 145 7- (2-Isopropylpyrrolidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • oxazepine (31.4 mg , 80 ⁇ mol), 2-isopropylpyrrolidine (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2- (2-aminoethyl) phenyl ] Palladium (II) -methyl-t-butyl ether adduct (6.53 mg
  • Example 146 7- (2-Oxa-6-azaspiro [3.5] non-6-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1 , 4] Oxazepine (31.4 mg, 80 ⁇ mol), 2-oxa-6-azaspiro [3.5] nonane (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1 '-Biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether
  • Example 148 7-((2S) -2-methylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • Oxazepine (31.4 mg, 80 ⁇ mol), (S) -2-methylpiperidine (400 ⁇ mol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2 -(2-Aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether adduct (6.53 mg
  • Example 151 Ethyl (((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyri Do [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetate ((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (Trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (80 mg, 0.16 mmol) in toluene ( To the solution, add rhodium acetate dimer (0.705 mg, 1.60 ⁇ mol) and ethyl diazoacetate in toluene (447
  • Example 152 (((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4]
  • Oxazepin-2-yl) methoxy) ethyl acetate (((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3 -(Trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4]
  • oxazepin-2-yl) methoxy) acetate 33 mg, 0.06 mmol) 2N aqueous lithium hydroxide solution (84 ⁇ l, 0.34 mmol) was added to a THF (187 ⁇ l) -ethanol (187
  • reaction mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (27.5 mg, 0.049 mmol, 88%).
  • Example 154 ((7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3 -f] [1,4] oxazepin-3-yl) methoxy) acetic acid ethyl ((7- (cis-2,6-dimethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) (Sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-3-yl) methoxy) acetate (25 mg, 0.04 mmol) in ethanol (1.5 ml) 8N Aqueous sodium hydroxide solution (1.563 ml, 12.50 mmol) was added, and the mixture was stirred at 60 ° C.
  • Benzenesulfonyl chloride (486 ⁇ l, 3.03 mmol) was added and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (1 g, 1.690 mmol, 84%).
  • the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate.
  • the diluted solution was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (545 mg, 1.087 mmol, 67.7%).
  • Example 164 ((2R) -7- (3,5-dimethylphenyl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepin-2-yl) methanol ((2R) -7- (3,5-dimethylphenyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4]
  • Oxazepin-2-yl) methanol dihydrochloride (310 mg, 0.87 mmol) in THF (10 ml) and triethylamine (0.629 ml, 4.52 mmol) and 4-fluoro-3- (trifluoromethyl) Benzenesulfonyl chloride (239 mg, 0.91 mmol) was added and stirred for 1 hour.
  • Example 168 (((2R) -4-((4-cyano-3- (trifluoromethyl) phenyl) sulfonyl) -7- (3,5-dimethylphenyl) -2,3,4,5-tetrahydropyrido [2 , 3-f] [1,4] Oxazepin-2-yl) methoxy) acetic acid
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (17.10 mg, 0.030 mmol, 85%).
  • Example 170 Ethyl (((2R) -7- (3,5-dimethylphenyl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [ 2,3-f] [1,4] oxazepin-2-yl) methoxy) acetate ((2R) -7- (3,5-dimethylphenyl) -4-((4-fluoro-3- (trifluoromethyl ) Phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (80 mg, 0.16 mmol) in toluene (1567 ⁇ l) To the solution were added rhodium acetate dimer (0.693 mg, 1.57 ⁇ mol) and a toluene solution of eth
  • Example 171 (((2R) -4-((4-Fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -7- (2-methylphenyl) -2,3,4,5-tetrahydropyrido [2,3 -f] [1,4] oxazepin-2-yl) methoxy) acetic acid
  • Example 172 ((((2R) -7- (3,5-dimethylphenyl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2 , 3-f] [1,4]
  • oxazepin-2-yl) methoxy) acetate 40 mg, 0.07 mmol
  • ethanol 2 ml
  • 8N aqueous sodium hydroxide solution 8.38 ⁇ l, 0.07 mmol
  • Example 173 ((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol ((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4, 5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (50 mg, 0.17 mmol) in THF (5 ml) and triethylamine (0.071 ml, 0.51 mmol) and 4-fluoro -3- (Trifluoromethyl) benzenesulfonyl chloride (44.8 mg, 0.17 mmol) was added and stirred for 1 hour.
  • Example 174 4-(((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -2- (hydroxymethyl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepine -4 (5H) -yl) sulfonyl) -2- (trifluoromethyl) benzonitrile ((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (61 mg, 0.21 mmol) in THF (5 ml) and triethylamine (0.087 ml, 0.62 mmol) and 4-cyano-3 -(Trifluoromethyl) benzenesulfonyl chloride (76 mg, 0.28 mmol) was added and stirred for 1 hour.
  • Example 175 ((2R) -7- (cis-3,5-dimethylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [ 2,3-f] [1,4] oxazepin-2-yl) methanol
  • Example 176 Ethyl (((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4, 5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetate ((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4- ((4-Fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (80 mg, 0.15 mmol) in toluene (770 ⁇ l), rhodium acetate dimer (3.40 mg, 7.70 ⁇ mol) and ethy
  • Example 177 ((2R) -7- (cis-3,5-dimethylpiperidin-1-yl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol ((2R) -7- (cis-3,5-dimethylpiperidin-1-yl) -2,3,4, 5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (86 mg, 0.30 mmol) in THF (2 ml) and triethylamine (123 ⁇ l, 0.89 mmol) and 4- Fluoro-3- (trifluoromethyl) benzenesulfonyl chloride (79 mg, 0.30 mmol) was added and stirred for 1 hour.
  • Example 178 4-(((2R) -7- (cis-3,5-dimethylpiperidin-1-yl) -2- (hydroxymethyl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepine -4 (5H) -yl) sulfonyl) -2- (trifluoromethyl) benzonitrile ((2R) -7- (cis-3,5-dimethylpiperidin-1-yl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methanol (86 mg, 0.30 mmol) in THF (2 ml) and triethylamine (123 ⁇ l, 0.89 mmol) and 4-cyano- 3- (Trifluoromethyl) benzenesulfonyl chloride (103 mg, 0.38 mmol) was added and stirred for 1 hour.
  • Example 196 7- (5-Fluoro-2-methylphenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • Example 199 4-Methyl-3- (4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine-7- Yl) benzonitrile 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (31 mg, 0.08 mmol), 2-methyl-5-cyanophenylboronic acid pinacol ester (0.16 mmol), cesium carbonate (120 mg, 0.24 mmol) in dimethoxyethane (1 ml) in bis 4-di-tert-butylphosphine Fanyl-N, N-dimethylaniline dichloropalladium (5.66 mg, 8 ⁇ mol) was added and stirred in
  • Example 224 7- (3-Methyl-5- (trifluoromethyl) phenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • Example 228 7- (3-methoxy-5- (trifluoromethyl) phenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • oxazepine 31 mg, 0.08 mmol
  • 3-methoxy-5-trifluoromethylphenylboronic acid (0.16 mmol)
  • cesium carbonate 120 mg, 0.24 mmol
  • dimethoxyethane (1 ml) bis 4-di-tert -Butylphosphanyl-N, N-dimethylaniline dichloropalladium
  • Example 230 7- (3-Chloro-5- (trifluoromethyl) phenyl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f ] [1,4]
  • oxazepine 31 mg, 0.08 mmol
  • 3-chloro-5-trifluoromethylphenylboronic acid (0.16 mmol)
  • cesium carbonate 120 mg, 0.24 mmol
  • dimethoxyethane (1 ml) bis 4-di-tert -Butylphosphanyl-N, N-dimethylaniline dichloropalladium
  • Example 235 (((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4-((4-fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5 -Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) ethyl acetate (((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -4 -((4-Fluoro-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) To a solution of acetate (39 mg, 0.06 mmol) in THF (2 ml) -ethanol (2 ml) was added 2N aqueous lithium
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (15.00 mg, 0.026 mmol, 40.3%).
  • Example 236 (((2R) -4-((4-cyano-3- (trifluoromethyl) phenyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5 -Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) ethyl acetate (((2R) -4-((4-cyano-3- (trifluoromethyl) phenyl) sulfonyl ) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) To a solution of acetate (15 mg, 0.02 mmol) in THF (2 ml) -ethanol (2 ml) was added 2N aqueous lithium hydroxide solution (
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by preparative HPLC to give the title compound (10.00 mg, 0.017 mmol, 69.9%).
  • Example 238 (((2R) -7- (cis-3,5-dimethylpiperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetic acid
  • the reaction mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography (diol, hexane / ethyl acetate) to give the title compound (19.5 mg, 0.035 mmol, 52.5%).
  • the reaction mixture was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel chromatography (diol, hexane / ethyl acetate) to give the title compound (25.6 mg, 0.044 mmol, 62.4%).
  • Example 240 (((2R) -4-((4-cyano-3- (trifluoromethyl) phenyl) sulfonyl) -7- (cis-3,5-dimethylpiperidin-1-yl) -2,3,4,5 -Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetic acid
  • Example 241 (((2R) -4-((3-Chloro-4-cyanophenyl) sulfonyl) -7- (cis-3,5-dimethylpiperidin-1-yl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetic acid
  • Example 243 Ethyl (((2R) -4-((4-cyano-3- (trifluoromethyl) phenyl) sulfonyl) -7- (cis-2,6-dimethylmorpholin-4-yl) -2,3,4, 5-tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetate 4-(((2R) -7- (cis-2,6-dimethylmorpholin-4-yl) -2- (hydroxymethyl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepine-4 (5H) -yl) sulfonyl) -2- (trifluoromethyl) benzonitrile (78 mg, 0.15 mmol) in toluene (741 ⁇ l), rhodium acetate dimer (3.27 mg, 7.41 ⁇ mol) and ethyl diazo
  • Example 248 4-(((2R) -7- (6-azaspiro [3.5] non-6-yl) -2- (hydroxymethyl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepine- 4 (5H) -yl) sulfonyl) -2-chlorobenzonitrile ((2R) -7- (6-azaspiro [3.5] non-6-yl) -2,3,4,5-tetrahydropyrido [2, 3-F] [1,4] Oxazepin-2-yl) methanol dihydrochloride (80 mg, 0.21 mmol) in THF (10 ml) and triethylamine (0.148 ml, 1.06 mmol) and 3-chloro-4-cyano Benzenesulfonyl chloride (52.7 mg, 0.22 mmol) was added and stirred for 1 hour.
  • Example 250 (((2R) -7- (6-azaspiro [3.5] non-6-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [ 2,3-f] [1,4] Oxazepin-2-yl) methoxy) acetic acid
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (9 mg, 0.016 mmol, 94%).
  • Example 251 (((2R) -7- (6-Azaspiro [3.5] non-6-yl) -4-((3-chloro-4-cyanophenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [ 2,3-f] [1,4] Oxazepin-2-yl) methoxy) acetic acid
  • Example 253 4-(((2R) -7- (6-azaspiro [3.5] non-6-yl) -2- (hydroxymethyl) -2,3-dihydropyrido [2,3-f] [1,4] oxazepine- 4 (5H) -yl) sulfonyl) -2- (trifluoromethyl) benzonitrile ((2R) -7- (6-azaspiro [3.5] non-6-yl) -2,3,4,5-tetrahydropyri
  • [2,3-f] [1,4] oxazepin-2-yl) methanol dihydrochloride 80 mg, 0.21 mmol
  • THF 10 ml
  • triethylamine (0.148 ml, 1.06 mmol
  • 4-cyano -3- (Trifluoromethyl) benzenesulfonyl chloride 93 mg, 0.35 mmol
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.60 mg, 6.23 ⁇ mol, 20.86%).
  • Example 256 (((2R) -7- (6-Azaspiro [3.5] non-6-yl) -4-((4-cyano-3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5- Tetrahydropyrido [2,3-f] [1,4] oxazepin-2-yl) methoxy) acetic acid
  • the reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with distilled water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (15.00 mg, 0.025 mmol, 84%).
  • Example 259 7- (3- (methoxymethyl) piperidin-1-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1,4] oxazepine (100 mg, 0.25 mmol), 3- (methoxymethyl) piperidine (0.149 mL, 1.02 mmol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [ 2- (2-Aminoethyl) phenyl] palladium (II) -methyl-t-butyl ether ad
  • Example 261 7- (2-Ethylmorpholin-4-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1, 4]
  • Example 268 7- (5-oxa-8-azaspiro [3.5] non-8-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1 , 4] oxazepine (100 mg, 0.25 mmol), 5-oxa-8-azaspiro [3.5] nonane (50 mg, 0.39 mmol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy- 1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) -methyl-t-
  • Example 270 7- (1-Oxa-6-azaspiro [3.5] non-6-yl) -4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2, 3-f] [1,4] oxazepine 7-chloro-4-((3- (trifluoromethyl) phenyl) sulfonyl) -2,3,4,5-tetrahydropyrido [2,3-f] [1 , 4] oxazepine (100 mg, 0.25 mmol), 1-oxa-6-azaspiro [3.5] nonane (0.057 mL, 0.39 mmol), chloro- (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy- 1,1'-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) -methyl
  • Example 4 8 to 10, 12, 14, 16 to 28, 37 to 39, 41 to 46, 49 to 52, 54 to 59, 62, 64, 66, 67, 69, 72 to 74, 76, 77, 79-83, 86-88, 90, 91, 94-96, 98, 100, 103, 104, 107-114, 116-118, 120, 124-132, 134-136, 139-144, 147, 149, 150,153,156-162,166,167,169,180-195,197,198,200-223,225-227,229,231-234,237,242,244-246,249,252-254, 256 to 258, 260, 262 to 267, 269, 271 to 287, and 289 to 312 are the same as the methods shown in the above-mentioned examples or a method according to them. It was prepared me. Example compounds are shown in Tables 1-1 to 1-32. MS in the table indicates actual measurement values.
  • Test example 1 ROR ⁇ t binding test using a fluorescently labeled synthetic ligand The binding activity of a test compound to ROR ⁇ t was determined according to ROR ⁇ t with a histidine tag, a fluorescently labeled synthetic ligand (specifically, 5-((2Z) -2-((1 -(Difluoroboryl) -3,5-dimethyl-1H-pyrrol-2-yl) methylene) -2H-pyrrol-5-yl) -N- (2-((3,5-difluoro-4- (trimethylsilyl) Phenyl) amino) -1- (4- (methoxymethyl) phenyl) -2-oxoethyl) pentanamide), a time-resolved fluorescence resonance energy transfer method (TR-FRET) using a terbium-labeled anti-histidine tag antibody (Invitrogen) Measured.
  • TR-FRET time-resolved fluorescence resonance energy transfer method
  • test compound diluted with an assay buffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM DTT, 0.1% BSA) was added to each 384 well plate.
  • assay buffer 20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM DTT, 0.1% BSA
  • 4 ⁇ L each of ROR ⁇ t and terbium-labeled anti-histidine tag antibody mixed solution final concentration 2 nM, 1 nM
  • fluorescent-labeled synthetic ligand final concentration 120 nM
  • Test example 2 Jurkat reporter test
  • the cells used in the reporter test were prepared by inserting a reporter vector in which the ROR response element of human IL-17 was inserted upstream of luciferase of pGL4.28 (Promega) and a vector in which the sequence of ROR ⁇ t was inserted downstream of the CMV promoter.
  • the leukemia T cell line Jurkat cell (Clontech) was stably expressed.
  • the cells were cultured in culture medium (RPMI-1640 (Invitrogen), 10% FCS (AusGeneX), 100 U / mL penicillin, 100 ⁇ g / mL streptomycin).
  • Doxocycline (final concentration 1.25 ⁇ g / mL) was added to a suspension with a cell density of 1 ⁇ 10 6 cells / mL, and 20 ⁇ L was seeded in 384 well plates (final density 20,000 cells / well). Thereafter, 5 ⁇ L of a test compound diluted with a reaction medium was added and cultured overnight in an incubator. After adding 25 ⁇ L of Bright-Glo (Promega) and stirring at room temperature for 10 minutes, the amount of luminescence was measured with Envision (Perkin Elmer). Table 2 shows the results measured by the above method (ratio of the amount of luminescence in the test compound 3 ⁇ M to the control group). Test Example 2 showed that the compound of the present invention has an activity to regulate the transcription of ROR ⁇ t.
  • Test example 3 Compound Evaluation Test Using Mouse Th17 Differentiation Induction Method naive CD4 + T cells were collected from spleen cells of BALB / c mice ( ⁇ , 7-12W) using CD4 + CD62L + T cell isolation kit (Miltenyi Biotec). This naive CD4 + T cell is seeded in a 96-well U-bottom plate (2 x 10 5 cells / well), anti-CD3 antibody, anti-CD28 antibody, anti-IFN ⁇ antibody, anti-IL-2 antibody, anti-IL-4 antibody, IL -6, IL-23 and TGF ⁇ were cultured for 4 days (5% CO 2 , 37 ° C). A compound prepared with DMSO at the start of the culture was also added at the same time.
  • Test Example 3 showed that the compound of the present invention has an activity of regulating IL-17A production of mouse spleen-derived cells.
  • Formulation Example A pharmaceutical containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
  • Tablet (1) 10 mg of the compound obtained in Example 1 (2) Lactose 35mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30mg (5) Magnesium stearate 5mg 1 tablet 230mg The total amount of (1), (2) and (3) above was mixed with 20 mg of (4) and 2.5 mg of (5), and then granulated, and the remaining (4) was added to 10 mg and (5) in this granule. Of 2.5 mg and pressure-molded to obtain tablets.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé potentiellement utile en tant que médicament prophylactique ou thérapeutique contre le cancer.
PCT/JP2017/021264 2016-06-10 2017-06-08 Composé hétérocyclique WO2017213210A1 (fr)

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CN112119065A (zh) * 2018-07-13 2020-12-22 四川科伦博泰生物医药股份有限公司 苯并二氮杂环类化合物、其制备方法及用途

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JP2002507989A (ja) * 1997-07-02 2002-03-12 ブリストル−マイヤーズ・スクイブ・カンパニー ファルネシルたんぱく転移酵素のインヒビター
JP2004502635A (ja) * 1999-09-27 2004-01-29 アムジエン・インコーポレーテツド 縮合シクロヘプタンおよび縮合アザシクロヘプタン化合物ならびにそれらの使用方法
WO2013064231A1 (fr) * 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3)
WO2015035278A1 (fr) * 2013-09-09 2015-03-12 Bristol-Myers Squibb Company Modulateurs de rorγ
WO2015042212A1 (fr) * 2013-09-20 2015-03-26 Bristol-Myers Squibb Company Modulateurs de rorγ
JP2015516428A (ja) * 2012-05-08 2015-06-11 リセラ・コーポレイションＬｙｃｅｒａ Ｃｏｒｐｏｒａｔｉｏｎ ＲＯＲγのアゴニストとしての使用のためおよび疾患の処置のためのテトラヒドロ［１，８］ナフチリジンスルホンアミドおよび関連化合物

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WO2013064231A1 (fr) * 2011-10-31 2013-05-10 Phenex Pharmaceuticals Ag Sulfonamides à sept chaînons comme modulateurs des récepteurs gamma orphelins associés à un récepteur de l'acide rétinoïque (rorγ, nr1f3)
JP2015516428A (ja) * 2012-05-08 2015-06-11 リセラ・コーポレイションＬｙｃｅｒａ Ｃｏｒｐｏｒａｔｉｏｎ ＲＯＲγのアゴニストとしての使用のためおよび疾患の処置のためのテトラヒドロ［１，８］ナフチリジンスルホンアミドおよび関連化合物
WO2015035278A1 (fr) * 2013-09-09 2015-03-12 Bristol-Myers Squibb Company Modulateurs de rorγ
WO2015042212A1 (fr) * 2013-09-20 2015-03-26 Bristol-Myers Squibb Company Modulateurs de rorγ

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112119065A (zh) * 2018-07-13 2020-12-22 四川科伦博泰生物医药股份有限公司 苯并二氮杂环类化合物、其制备方法及用途
CN112119065B (zh) * 2018-07-13 2024-01-23 四川科伦博泰生物医药股份有限公司 苯并二氮杂环类化合物、其制备方法及用途

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