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WO2002066454A1 - Derives de chromene - Google Patents

Derives de chromene Download PDF

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Publication number
WO2002066454A1
WO2002066454A1 PCT/JP2002/001501 JP0201501W WO02066454A1 WO 2002066454 A1 WO2002066454 A1 WO 2002066454A1 JP 0201501 W JP0201501 W JP 0201501W WO 02066454 A1 WO02066454 A1 WO 02066454A1
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group
substituent
substituted
atom
optionally substituted
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PCT/JP2002/001501
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English (en)
Japanese (ja)
Inventor
Takashi Fujita
Minoru Oguchi
Tomihisa Yokoyama
Tatsuya Inoue
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Sankyo Company, Limited
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Publication of WO2002066454A1 publication Critical patent/WO2002066454A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a chromene derivative having an excellent preventive or therapeutic activity for diabetic retinopathy, a pharmacologically acceptable salt thereof, and a medicament containing them as an active ingredient.
  • Tranilast is disclosed in WO 98/47504 as a prophylactic or therapeutic agent for diseases associated with hyperproliferation of the vesicle pigment epithelial cells.
  • the activity of tranilast is not sufficient, and a clinically more potent and safe drug for preventing or treating retinopathy is desired.
  • Compounds having a structure similar to that of the compound of the present invention are described in Japanese Patent No. 3076066 (Japanese Patent Application No. 10-502698, WO 98/08836) and WO 00/06085. None has been suggested about its relationship with retinopathy and its angiogenesis inhibitory effect.
  • the present inventors have conducted various studies on chromene derivatives and chroman derivatives, and found that a derivative in which a specific amide was substituted at the 3-position of the chromene or chroman ring was diabetic retinopathy or retinopathy. On the other hand, the present inventors have found that the present invention exhibits excellent prophylactic or therapeutic activity, thereby completing the present invention.
  • the invention relates to the formula
  • R 1 represents a hydrogen atom, which may be substituted ⁇ 6 alkyl group (the substituent is C
  • R 6 is a C 10 Ariru group. ), ⁇ ⁇ ⁇ . Indicates Ariru group or ⁇ ⁇ Ji Ashiru group, R ⁇ RR 4 ⁇ Pi R 5 are the same or different, a hydrogen atom, a halogen atom, ⁇ 6 alkyl group, C 3 -C 6 cycloalkyl group, optionally substituted Good ⁇ .
  • Aryl group (the substituent is selected from the following substituent group), an optionally substituted 5- to 10-membered heterocyclic group (the substituent is selected from the following substituent group 0), a hydroxyl group, C C-alkoxy group which may be substituted ⁇
  • the substituent is a halogen atom and a c 6 -c 10 aryl group which may be substituted (the substituent is selected from the following substituent group J3).
  • C 3 -C 6 cycloalkoxy group may be substituted ⁇ ⁇ .
  • Aryloxy group (the substituent is selected from the following substituent group), ⁇ ⁇ asiloxy group, amino group which may be substituted (the substituent is selected from the following substituent group a), nitro group or Represents a cyano group,
  • R 6 is a hydrogen atom, a halogen atom, - may be substituted ⁇ alkyl group ⁇ said substituent is hydroxyl, ⁇ ⁇ alkoxy, C 3 -C 6 cycloalkyl group ⁇ Pi which may be substituted ⁇ 6 ⁇ ⁇ .
  • Aryl group (the substituent is selected from the following substituent group 3).
  • ⁇ C 2 -C e alkenyl group, C 2 -C 6 alkynyl group, C 3 -C 6 cyclo alkyl group may be substituted
  • a reel group (the substituent is selected from the following substituent group 3), an optionally substituted 5- to 10-membered heterocyclic group (the substituent is selected from the following substituent group ⁇ ), and a substituent C ⁇ Cs alkoxy group
  • the substituent may be a hydroxyl group, a cyano group, a formyl group, a ⁇ - ⁇ alkoxy group or a 5- to 10-membered heterocyclic group which may be substituted (the substituents may be the following substituents) Selected from the group
  • Aryloxy group (the substituent is selected from the following substituent group), an optionally substituted 5- to 10-membered heterocyclic oxy group (the substituent is selected from the following substituent group j3), C 2 A C 7 alkylcarboxy group, a ⁇ alkylthio group or a substituted amino group (the substituent is selected from the following substituent group ⁇ ).
  • R 7 and R 8 are the same or different, a hydrogen atom, a halogen atom, - ⁇ alkyl group, ⁇ 3 ⁇ 6 cycloalkyl group may be substituted Reel group (substituent Is selected from the following substituent group i3. Or a 5- to 10-membered heterocyclic group which may be substituted (the substituent is selected from the following substituent group jS).
  • Ar may be substituted.
  • Aryl group (the substituent is selected from the following substituent group ⁇ ) or an optionally substituted 5- to 10-membered heterocyclic group (the ring is selected from the following substituent group ⁇ . ),
  • Substituent group ⁇ is which may be substituted ⁇ 6 alkyl group ⁇ said substituent is ⁇ 6 ⁇ . It is selected from the group consisting of an aryl group, a hydroxyl group, a substituted amino group (the substituent is an alkyl group) and a 5- to 10-membered heterocyclic group. ⁇ , Which may be replaced ⁇ 6 ⁇ .
  • Aryl group (the substituent is a halogen atom), a hydroxyl group, a C ⁇ Ce alkoxy group, a C 6 -C 1 Q aryloxy group, a 5- to 10-membered heterocyclic oxy group, a C 2 -C 7 alkylcarbonyl group, C 7 -C U arylcarbonyl, 5- to 10-membered heterocyclic carbonyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 7 alkylaminocarbonyl, C 7 -C U arylarylcarbonyl group, a C 2 -C 7 alkylaminocarbonyl (Chio carbonyl) Moto ⁇ Pi C 7 C u Ariruamino group consisting (Chio carbonyl) group,
  • Substituent group 3 includes a halogen atom, an optionally substituted alkyl group (the substituent is a halogen atom), a hydroxyl group, an optionally substituted ⁇ to ⁇ 6 alkoxy group (the substituent is halogen A) a group consisting of a carboxyl group and a C 2 -C 7 alkoxyl group.
  • Substituent group ⁇ represents a halogen atom, a hydroxyl group, which may be substituted ⁇ 6 alkoxy group (those said substituent is ⁇ ⁇ . Ariru group.), ⁇ -. Aryloxy group, amino group which may be substituted (the substituent is selected from the above-mentioned substituent group ⁇ ), and may be substituted A reel group (the substituent is selected from the above substituent group), a 5- to 10-membered heterocyclic group which may be substituted (the substituent is selected from the above substituent group 3), and lipoxyl A group consisting of a C 2 -C 7 alkylcarbonyloxy group, a nitro group and a cyano group,
  • Substituent group ⁇ is a halogen atom, an optionally substituted ⁇ to ⁇ alkyl group (the substituent is selected from the above-mentioned noble substituent group y.), An optionally substituted C 2 -C 6 alkenyl group (eg, The substituent is selected from the above-mentioned substituent group ⁇ .), An optionally substituted C 2 -C 6 alkynyl (The substituent is selected from the above-mentioned substituent group ⁇ ), a C 3 -C 6 cycloalkyl group, a C 2 -C 7 alkylcarbonyl group, an optionally substituted C 7 -C U arylcarbonyl group (The substituent is selected from the above-mentioned substituent group 3)., A 5- to 10-membered heterocyclic carbonyl group which may be substituted (the substituent is selected from the above-mentioned substituent group 3).
  • carboxyl group may be substituted C 2 -C 7 alkoxycarbonyl Cal Poni Le group (said substituent is a C 6 -C i. Ariru group.) may be substituted CTCU ⁇ reel O alkoxycarbonyl group (those said substituent The group is selected from the above substituent group 0), an optionally substituted carbamoyl group (the substituent is selected from the above substituent group), and an optionally substituted CCi.
  • Aryl group (the substituent is the above-mentioned substituent group) 3.
  • a 5- to 10-membered heterocyclic group which may be substituted (the substituent is selected from the above-mentioned substituent group 3), a hydroxyl group, an optionally-substituted ⁇ alkoxy group (the substituent is the above-mentioned substituent Selected from group ⁇ ), an optionally substituted C 2 -C 6 alkenyloxy group (the substituent is selected from the above-mentioned substituent group y), and an optionally substituted C 2 -C 6 alkynylo alkoxy group (said substituents. selected from the location substituent group V), C 3 ⁇ C 6 cycloalkoxy group optionally C 6 -C i which is substituted.
  • Aryloxy group (the substituent is selected from the above-mentioned substituent group j8), a mercapto group, a sulfo group, or a group which may be substituted.
  • a 6- alkylthio group (the substituent is selected from the above-mentioned substituent group ⁇ ), an optionally substituted C 2 -C 6 alkenylthio group (the substituent is selected from the above-mentioned substituent group), may be substituted C 2 -C 6 alkynylthio group (said substituents are selected from the substituent group ⁇ .), C 3 ⁇ C 6 cycloalkyl Ji O group, - which may be substituted.
  • Arylthio group (the substituent is selected from the above substituent group), an optionally substituted ⁇ ⁇ alkylsulfinyl group (the substituent is selected from the above substituent group ⁇ ), and an optionally substituted C 2 -C 6 alkenylsulfinyl two Le group (said substituents are selected from the substituent group gamma.), may be substituted C 2 -C 6 alkylene Nils sulfide El group (said substituents are the above-mentioned substituent group "Choose from V.), C
  • Arylsulfinyl group (the substituent is selected from the above-mentioned substituent group J3), an optionally substituted C 6 alkylsulfonyl group (the substituent is selected from the above-mentioned substituent group ⁇ ), An optionally substituted C 2 -C 6 alkenylsulfonyl group (the substituent is selected from the above-mentioned substituent group y); an optionally substituted C 2 -C 6 alkynylsulfonyl group (the substituent is It is selected from the above substituent group ⁇ .
  • C 3 -C 6 cycloalkylsulfonyl group may be substituted. 6 to.
  • An arylsulfonyl group (the substituent is selected from the above-mentioned substituent group; 8); and a substituted sulfamoyl group (the substituent is selected from the above-mentioned substituent group ⁇ ).
  • a diamino group (the substituent is selected from the above-mentioned substituent group ⁇ ), a nitro group and a cyano group;
  • ⁇ ⁇ 6 alkyl group is a straight or branched chain alkyl group having 1 to 6 carbon atoms, e.g., methyl, Echiru, .eta.
  • propyl isopropyl, eta one butyl, Isobuchinore, sec-butyl, tert-butylinole, n-pentyl, isopentyl, 2-methylbutyl, neopentinole, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3, 3 1,2-Dimethinolebutinole, 1,1-dimethinoleptinole, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, or 2-ethylbutyl group It is preferably a linear or branched alkyl group having 1 to 4 carbon atoms ( ⁇ ⁇ alkyl group), more preferably a linear or branched alkyl group having 1 to 3 carbon atoms. Branch is an alkyl group ( ⁇ alkyl group), more
  • the “reel group” is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and may be, for example, a phenyl group or a naphthyl group, and is preferably a phenyl group.
  • "optionally substituted C ⁇ Cs alkyl group (said substituent is c 6 to c 10 Ariru group.)” May be the same or different 1-3 amino wherein " ⁇ .
  • ⁇ Li one Is a ⁇ - ⁇ ⁇ 6 alkyl group '' which may be substituted, for example, benzyl, a-naphthylmethylinole, ⁇ -naphthinolemethyl, indeninolemethinole, diphenylmethyl, triphenylmethylinole, 1-phenethyl, 2-phenethylenole, 1 1 naphthylechinole, 2 naphthinoleetinolle, 1 1 fuynorepropyl, 2 _ fuynolepropinole, 3 fujinole pill pill, 1 naphthyl pulp pill, 2 napthyl pulp pill, 2 _ nabutyl pulp pill, 3 1-naphthinolepropynole, 1-phenylenolebutinole, 2-phenylenolebutinole, 3-phenylbutyl, 4-phenylinolebutinole, 1-
  • the “ ⁇ to ⁇ 12 acyl group” is an acyl group having 1 to 12 carbon atoms.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or a boron atom, preferably a fluorine atom, a chlorine atom or a bromine atom, and more preferably a substituent group ⁇ .
  • it is a fluorine atom or a chlorine atom, even more preferably a fluorine atom, and in other substituents, more preferably a fluorine atom or a chlorine atom, even more preferably chlorine. Is an atom.
  • the ⁇ C 3 -C 6 cycloalkyl group '' is a 3- to 6-membered saturated cyclic hydrocarbon, and is cyclopropyl, cyclopentyl, cyclopentyl or cyclohexylene, preferably It is a cyclopentyl or cyclohexyl group.
  • the “optionally substituted ⁇ -alkyl group (the substituent is a halogen atom)” is the same as or different from the same or different 1 to 9 “halogen atoms” which may be substituted.
  • ⁇ 6 alkyl group ", for example, triflates Ruo Russia methyl, tri Kuroromechinore, Ziv Honoré Oro methylate Honoré, Jikuroromechinore, jib port Momechinore, Funoreorome chill, 2, 2, 2-Application Benefits Funoreoroechiru, 2, 2, 2- It can be trichloroethynole, 2-bromoethynole, 2-chloroethynole, 2-funoleoloethyl, 2-odoethynole, 3-chloropropyl, 4-fluorobutyl, 6-hexodohexyl or 2,2-dibromoethyl group, which is preferred.
  • ⁇ ⁇ Ri alkyl group der, more preferably, the same or different ivy 1-4 substituents may be substituted C i to C 3 alkyl group selected from the group consisting of fluorine and chlorine atoms, Even more preferably, it is an alkyl group which may be substituted by 1 to 3 fluorine atoms, and particularly preferably a methyl or trifluoromethyl group.
  • the “ ⁇ -alkoxy group” is an oxygen atom bonded to the above-mentioned “ ⁇ - ⁇ alkyl group” by a force S bond, preferably a straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms ( A C 1 -C 4 alkoxy group), more preferably a straight-chain or branched-chain alkoxy group having 1 to 3 carbon atoms (( ⁇ alkoxy group), and still more preferably 1 carbon atom. Or two alkoxy groups (-alkoxy groups), most preferably a methoxy group.
  • the "optionally substituted ⁇ to ⁇ alkoxy group (the substituent is a halogen atom.)" Is the above-mentioned "optionally substituted alkyl group (the substituent is a halogen atom.
  • a group substituted to be ⁇ 4 alkoxy group, and more preferably, have yo same or different 1-4 substituent is substituted selected from the group consisting of fluorine atom ⁇ Pi chlorine atom ⁇
  • the “C 2 -C 7 alkoxycarbonyl group” is a carbonyl group to which the above-mentioned “ ⁇ to 6 alkoxy group” is bonded, and preferably a carbonyl group to which a C ⁇ Ca alkoxy group is bonded ( c 2 to C 5 alkoxycarponyl groups), more preferably c L to C 3 alkoxy groups bonded to a carbonyl group (C 2 to C 4 alkoxycarponyl groups), and even more preferably ⁇ 2 An alkoxy group is bonded to a carbonyl group (c 2
  • Aryl group (the substituent is selected from substituent group 3)” is the same or different 1 to 5 selected from the above “substituent group 3”. number of the that may be substituted by a substituent " ⁇ ⁇ .
  • Ariru group is, preferably, fluorine atom, chlorine atom, bromine atom, which may be substituted ⁇ 4 alkyl group (said substituent is a fluorine atom is selected from the group consisting of chlorine atom and bromine atom.), hydroxyl group, which may be substituted ⁇ 4 alkoxy group (said substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.) And a phenyl group which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of a carboxyl group and a C 2 -C 5 alkoxycarbonyl group.
  • the ⁇ 5- to 10-membered heterocyclic group '' is a 5- to 10-membered saturated ring wherein the heteroatoms in the ring are 1 to 4 heteroatoms consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • an unsaturated heterocyclic group such a heterocyclic ring may be condensed with a benzene ring or a pyridine ring, and may be substituted with a C 3 -C 4 alkylene group, for example, furyl, phenyl, pyrrolyl , Azepinyl, virazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3_oxdiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl aromatic groups such as pyrimidinyl Morpholinyl, thiomorpholin A saturated or partially unsaturated heterocyclic group such as a phenyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl
  • a pyridyl group Is preferably a 3-pyridyl group, and in Ar, preferably a 5- to 6-membered unsaturated heterocyclic group (wherein the heteroatom in the ring is selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) 1 to 3 hetero atoms selected from the same or different, and the ring may be condensed with a benzene ring or a pyridin ring, and may be substituted by a C 3 -C 4 alkylene group.
  • a 5- to 6-membered unsaturated heterocyclic group (1 to 3 identical or different hetero atoms in the ring are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • the ring may be condensed with a pyridine ring and may be substituted with a tetramethylene group.), And still more preferably, a 5-membered unsaturated heterocyclic group (a heterocyclic group in the ring).
  • the ring may be substituted with a tetramethylene group.), Most preferably a tetrahydrobenzozoenyl or imidazolyl group, and in other substituents, preferably a heterocyclic group in the ring.
  • the atom is a 5- or 6-membered saturated or unsaturated heterocyclic group, which is 1 to 3 heteroatoms consisting of a nitrogen atom, an oxygen atom and a sulfur atom, more preferably chenyl, pyrrolyl, pyrazolyl, pyridyl, It is piperidyl or 4,5,6,7-tetrahydro-benz [b] thiophene group.
  • the “optionally substituted 5- to 10-membered heterocyclic group (the substituent is selected from Substituent Group / 3)” is the same or different from the above “Substituent Group] 3”
  • the above-mentioned ⁇ 5- to 10-membered heterocyclic group '' which may be substituted by 1 to 4 substituents, preferably a 5- to 6-membered unsaturated heterocyclic group which may be substituted
  • the atoms are 1 to 4 complex atoms, which are the same or different and are selected from the group consisting of nitrogen, oxygen and sulfur Is an atom.
  • the ring may be fused with a benzene ring or a pyridine ring.
  • the substituent is an optionally substituted- ⁇ alkyl group (the substituent is a halogen atom). ⁇ Or a 5- to 6-membered saturated heterocyclic group (the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen). Is an optionally substituted 5- to 6-membered unsaturated heterocyclic group ⁇ wherein the heteroatoms in the ring are 1-4 nitrogen atoms.
  • the ring may be fused with a benzene ring.
  • the substituent may be substituted ⁇ ⁇ 4 alkyl group (said substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.) It is.
  • a 6-membered saturated heterocyclic group (the same or different 1 or 2 heteroatoms selected from the group consisting of a heterocyclic nuclear S, a nitrogen atom and an oxygen atom in the ring).
  • an optionally substituted 5- to 6-membered unsaturated heterocyclic group ⁇ the heteroatom in the ring is 1-2 nitrogen atoms.
  • the substituent is an alkyl group (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom) which may be substituted.
  • the substituent is a C i -C 3 alkyl group which may be substituted. (The substituent is a fluorine atom. ).
  • the substituent is selected from the group consisting of the above-mentioned "halogen atom” or the above-mentioned "may be substituted with.-Aryl group (the substituent is selected from substituent group j8).
  • substituent group j8 the substituent is selected from substituent group j8.
  • a C i Ce alkoxy group which may be substituted by an aryl group, more preferably 1 to 3 identical or different substituents or 1 or more selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom a of which may be substituted ⁇ 6 alkoxy group by phenyl group, even more preferably more, a C i Cg alkoxy group, particularly preferably a methoxy group.
  • the “C 3 -C 6 cycloalkoxy group” is an oxygen atom to which the above “C 3 -C 6 cycloalkyl group” is bonded, and is cyclopropyloxy, cyclobutoxy, cyclopentyloxy or cycloalkyl.
  • the “C 6 -C 1Q 7 lyloxy group” is an oxygen atom to which the above “-.aryl group” is bonded, and is preferably a phenoxy group.
  • the “optionally substituted C 6 -C 1Q aryloxy group (the substituent is selected from a substituent group)” is the above-mentioned “optionally substituted ⁇ -. selected from the substituent group jS.) "is an oxygen atom bonded in substituent group [delta], preferably, the same or different 1 selected from the group consisting of carboxyl Moto ⁇ Pi 2-0 7 alkoxycarbonyl Cal Poni Le group A phenoxy group substituted with 2 to 2 substituents, and more preferably 1 to 2 identical or different 1 or 2 groups selected from the group consisting of a carboxyl group and a C 2 to C 5 alkoxycarbonyl group.
  • a fluorine atom, a chlorine atom, a bromine atom, a C i -C 4 alkyl group which may be substituted (the substituent is preferably Huh Atom, selected from the group consisting of chlorine atom ⁇ Pi bromine atom.), A hydroxyl group, have good substituted ⁇ to 0, 4 alkoxy group (said substituent is selected from fluorine atom, the group consisting of chlorine and bromine is.), a carboxyl Moto ⁇ Pi C 2 -C 5 alkoxy force Lupo two Le identical selected from groups or Ranaru group or different 1-3 amino substituted by a substituent which may be phenoxy group.
  • ⁇ ⁇ 0 12 Ashiruokishi group the r ⁇ C u Ashiru group "is an oxygen atom bonded, preferably, C 2 -C 7 alkyl force Ruponiruokishi group or ⁇ -C 6 alkylsulfonyl And more preferably a C 2 -C 7 alkylcarbonyloxy group.
  • substituted with Yoi Amino group (the substituent is ⁇ an alkyl group.)" May be the same or different 1-2 amino-alkyl group substituted by yo I Amino groups
  • the term “optionally substituted alkyl group (substituent is C 6 -Ci.
  • Aryl group, hydroxyl group, substituted amino group is an alkyl group. Is selected from the group consisting of a 5- to 10-membered heterocyclic group. "Is the above-mentioned" CeCi.
  • a ⁇ - ⁇ alkyl group which may be substituted by one or two different substituents, more preferably a phenyl group, a hydroxyl group, a di (C i C alkyl) amino group or a 6-membered saturated heterocyclic ring A group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom); preferably a phenyl group, a hydroxyl group, di (-C 3 alkyl) amino group or a piperidyl which may be substituted-alkyl group by group, particularly preferably, phenyl group, Jimechiruamino group, Jie isopropyl ⁇ Mi J groups or by a piperidino group which may be substituted ⁇ a ⁇ 0 4 alkyl group, and most preferably, the force Rubamoiru group, methylcarbamoyl
  • the “optionally substituted CeC ⁇ aryl group (the substituent is a halogen atom.)” May be substituted by 1 to 5 identical or different “halogen atoms”.
  • a "C 6 -C 1Q 7 aryl group” preferably a fluorine atom
  • the same or different 1 to 3 substituent is phenyl which may be substituted selected from the group consisting of chlorine atom ⁇ Pi bromine
  • a phenyl group which may be substituted with one or two same or different substituents selected from the group consisting of a fluorine atom and a chlorine atom.
  • the “5- to 10-membered heterocyclic oxy group” is an oxygen atom to which the “5 to 10-membered heterocyclic group” is bonded, and is preferably a 5- to 6-membered saturated heterocyclic oxy group (
  • the hetero atom in the ring is the same or different 1 or 2 hetero atoms selected from the group consisting of a nitrogen atom and an oxygen atom.)
  • a 6-membered saturated heterocyclic oxy group The heteroatom in the ring is 1 to 2 nitrogen atoms.), And still more preferably a tetrahydropyrael group.
  • C 2 -C 7 alkylcarbonyl group said a “C 2 -C 7 alkyl Le group” bonded carbonyl group, preferably, ⁇ ⁇ 4 alkyl group bonded a carbonyl group (c 2 to c 5 alkyl group), more preferably a ⁇ 3 alkyl group is bonded to a carbonyl group (c 2 to c 4 alkyl group), preferably by a further, ⁇ a ⁇ ⁇ alkyl group is bonded to a carbonyl group (c 2 to c 3 alkylcarbonyl group), most preferably a Asechiru group.
  • the “ ⁇ to reel carbyl group” is a carbonyl group to which the above “C 6 to C 1Q aryl group” is bonded, and is preferably a benzoyl group.
  • the ⁇ 5- to 10-membered heterocyclic carbonyl group '' is a carbonyl group to which the above-mentioned ⁇ 5- to 10-membered heterocyclic group '' is bonded, and may be preferably substituted in the substituent group ⁇ .
  • a 5- or 6-membered saturated heterocyclic carboninole group (wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen atoms and oxygen atoms.
  • a 6-membered saturated heterocyclic carbonyl group which may be substituted, wherein the hetero atom in the ring is the same or different and is selected from the group consisting of a nitrogen atom and an oxygen atom And the substituent is a hydroxyl group.
  • a substituted piperidylcarbonyl group (the substituent is a hydroxyl group.)
  • the substituent group ⁇ preferably, 5 to 6
  • a membered unsaturated heterocyclic alkenyl group (the heteroatoms in the ring are the same or different one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms); More preferably, it is a 6-membered unsaturated heterocyclic carbonyl group (the heteroatom in the ring is 1 to 3 nitrogen atoms).
  • the “C 2 -C 7 alkylaminocarbonyl group” is a canolebamoyl group in which one of the “C i -C 6 alkynole groups” is bonded to a nitrogen atom.
  • a-alkyl group is bound to force Rubamoiru group to the nitrogen atom, more preferably a single-c 3 alkyl group is bonded to force Rubamoiru group to the nitrogen atom, further preferably more, one Is a molybmoyl group in which the ci- 2 alkyl group is bonded to a nitrogen atom, most preferably a methylaminocarbonyl group.
  • ⁇ ⁇ . ⁇ Arylaminocarbonyl group is one of the above “C
  • the aryl group is a canolebamoyl group bonded to a nitrogen atom, preferably a phenylcarbamoyl group.
  • the “C 2 -C 7 alkylamino (thiocarbonyl) group” is a thiocarbamoyl group in which one “-alkyl group” is bonded to a nitrogen atom, and preferably one ⁇ ⁇ are four Chiokarubamoiru group der which an alkyl group is bonded to the nitrogen atom, more preferably a single ⁇ ⁇ ⁇ Chiokarupamo I le group in which an alkyl group is bonded to the nitrogen atom, further preferably more,
  • One C ⁇ Cs alkyl group is a thiocarbamoyl group bonded to a nitrogen atom, most preferably a methylamino (thiocarbonyl) group.
  • C 7 -C U Ariruamino (Chio carbonyl) group one of the r Ce C i.
  • An “aryl group” is a thiocarpamoyl group bonded to a nitrogen atom, preferably a feninole (thiolbamoyl) group.
  • the “substituted amino group (the substituent is selected from the substituent group ⁇ )” is the same or different one or two substituents selected from the “substituent group a”.
  • a substituted or unsubstituted laid group (the substituent is selected from the group consisting of a ⁇ -alkyl group and a phenyl group.) Or a substituted or unsubstituted thioureido group (the substituted group is And more preferably a substituted amino group (the substituent is a C 2 -C 5 alkylcarbonyl group, a benzoyl group, a 6-membered unsaturated heterocyclic carbonyl group (in the ring, Is 1 to 3 nitrogen atoms.) And from the group consisting of C 2 -C 5 alkoxycarbonyl groups To be elected.
  • An optionally substituted ureido group (the substituent is selected from the group consisting of an alkyl group and a phenyl group) or an optionally substituted thioperido group (the substituent is a phenyl group).
  • a substituted amino group (the substituent is a C 2 -C 5 alkoxycarbonyl group), and particularly preferably a substituted amino group ( The substituent is a t-butoxycarbonyl group.
  • ⁇ may be a substituted alkyl group ⁇ said substituent is hydroxyl, ⁇ ⁇ 6 alkoxy group, C 3 -C S cycloalkyl group ⁇ Pi may be substituted ⁇ ⁇ .
  • ⁇ Li Lumpur group The substituent is selected from the group consisting of a substituent group 3).
  • C 6 -C 1 Q aryl group which may be substituted (the substituent is selected from substituent group iS)".
  • the same or different one or two substituents selected from the group consisting of The above-mentioned "-alkyl group” is preferable, and a phenyl group, a hydroxyl group, a di (-alkyl) amino group or a 5- to 6-membered saturated heterocyclic group (a heteroatom 1 nitrogen atom and an oxygen atom in the ring are preferable)
  • By may be substituted ⁇ ⁇ 6 alkyl group, more preferably a phenyl group, a hydroxyl group, di ( ⁇ alkyl) heterocyclic atom of the amino group or a 6-membered saturated Hajime Tamaki (During the said ring, The same or different 1 to 2 hetero atoms selected from the group consisting of a nitrogen atom and an oxygen atom.)
  • a C i -C 6 alkyl group which may be substituted by, and even more preferably a phenyl group
  • the “C 2 -C 6 alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, and includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1 2-methodinol 2-propidinol, 1-methyl-1-propidinole, 2-methidinyl 1-propidinole, 2-methyl-2nd-propidinole, 2-ethyninol 2-propidininol, 1-ptenyl, 2 —Buteninole, 3-butul, 1-methyl-1 1-buteninole, 1-methylinole 2 • 1-buteninole, 1-methyl-3-butenyl, 3-methyl-2-butenyl, 2-methyl 1 3-butenyl, 1-ethyl-1 2-pteninole, 1-ethynorre 3-buteninole, 1-pentininole, 2-penteninole, 1-methinolane 2-penteninole,
  • the “C 2 -C 6 alkynyl group” is a straight-chain or branched-chain alkynyl group having 2 to 6 carbon atoms, and includes, for example, ethur, 1-propynyl, 2-propynyl, 1-methyl-21 Propinyl, 1-methyl-1-probutyl, 2-methinole 1-mouth, 2-methyl-2-propynyl, 2-ethyl-2-propenyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-butul, 1-methyl-2-butul, 1-methyl-1-butynyl, 3-methyl-12-butynyl, 2_methyl —3-butethinole, 1-ethinole 2-petinole, 1-ethynole-1 3-petinole, 1-1 Pentinole, 2-pentinole, 1-methinole 21-pentinole, 2-methyl-2-pentinyl, 3-pentinole, 1-methino
  • the group is selected from the group consisting of a substituent group iS.)).
  • the above-mentioned ⁇ alkoxy group which may be substituted by 1 to 2 same or different substituents selected from Preferably, a hydroxyl group, a cyano group, a forminole Group, to an alkoxy group or a 5- to 6-membered double-ring group (the heteroatoms in the ring are the same or different one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms) Is an alkoxy group which may be substituted by).
  • C 2 -C 6 Arukeniruokishi group said an oxygen atom "C 2 -C 6 alkenyl Le group” is bonded, preferably, bound are C 2 -C 4 alkenyl group an acid atom (C 2 -C 4 alkenyl old alkoxy group), more preferably a Ariruokishi group.
  • c 2 to c 6 Arukiniruokishi group said an oxygen atom "c 2 to c 6 Arukini Le group” is bonded, preferably, c 3 to c 4 alkynyl group is bonded It is an oxygen atom (C 3 -C 4 alkynyloxy group), and more preferably a 2-propynyloxy group.
  • the “optionally substituted 5- to 10-membered heterocyclic oxy group (the substituent is selected from the group of substituents)” is the same or a group selected from the above “substituent group 3”
  • a 5- to 10-membered heterocyclic oxy group which may be substituted by 1 to 4 different substituents, preferably a fluorine atom, a chlorine atom, a bromine atom, and a C i to C which may be substituted.
  • the ⁇ C 2 -C 7 alkylcarbonyl group '' is an oxygen atom to which the ⁇ c 2 -C 7 alkyl carbonyl group '' is bonded, and preferably a C 2 -C 5 alkyl carbonyl group is A bonded oxygen atom (C 2 -C 5 alkylcarbonyloxy group), more preferably an oxygen atom bonded to a c 2 -c 4 alkylcarbonyl group (c 2 -c 4 alkylcarbonyloxy group) And even more preferably an oxygen atom (c 2 -c 3 alkylcarbonyloxy group) to which a c 2 -c 4 alkylcarbonyl group is bonded, and most preferably an acetoxy group.
  • “to (: 6 alkylthio group)” is a sulfur atom to which the above “ ⁇ to 6 alkylthio group” is bonded, preferably a linear or branched alkylthio group having 1 to 4 carbon atoms.
  • the “optionally substituted ⁇ to 6 alkoxy group (the substituent is C 6 to aryl group)” is the above-mentioned “optionally substituted 6 to 6 alkyl group (the substituent is a ⁇ 6 ⁇ .
  • ⁇ Li one Norre group.) is an oxygen atom bonded, preferably a one phenyl group may be substituted ⁇ ⁇ 0 4 alkoxy group, more preferably the , more preferably, methoxy, in the c present invention is Benjiruokishi or 4 one-phenylalanine butyl O alkoxy group "which may be substituted-alkyl group (said substituents are selected from the substituent group gamma.)” is And the above-mentioned “to alkyl group” which may be substituted by the same or different 1 to 3 substituents selected from the above “substituent group ⁇ ”, preferably a halogen atom, a carboxyl group and a C 2 to consisting C 7 alkoxycarbonyl group From the same or different 1-3 - may be substituted by a substituent alkyl group selected, more preferably, fluorine atom, chlorine atom, bromine atom, carboxyl group and a C 2 ⁇ ⁇
  • the “optionally substituted C 2 -C 6 alkenyl group (the substituent is selected from the substituent group y)” is the same as the “substituent group ⁇ ” selected from the same or different ones.
  • the ⁇ C 2 -C 6 alkenyl group '' which may be substituted by up to 3 substituents, preferably a 5- to 6-membered unsaturated heterocyclic group which may be substituted (wherein the heteroatom in the ring is , Nitrogen atoms, oxygen atoms and sulfur atoms; one or three identical or different Elementary atom.
  • the substituent is selected from the group consisting of a halogen atom, a C ⁇ Ce alkyl group and an optionally substituted fuunyl group (the substituent is a halogen atom).
  • ⁇ A C 2 -C 6 alkenyl group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a carboxyl group and a C 2 -C 7 alkoxycarbonyl group, more preferably, 5-membered unsaturated heterocyclic group which may be substituted- ⁇
  • the heteroatom in the ring is 1 to 3 nitrogen atoms.
  • the substituent is selected from a fluorine atom, a chlorine atom, a bromine atom, a C 4 alkyl group and a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom). Selected from the group ⁇ And C
  • the substituent is selected from the group consisting of a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom).
  • ⁇ Or c 2 to c 4 alkoxycarbonyl which may be substituted c 2 to c 4 an alkenyl group by group.
  • the “optionally substituted C 2 -C 6 alkynyl group and the substituent are selected from the substituent group.)” are the same or different 1 to 3 groups selected from the above “substituent group ⁇ ”. a number of the that may be substituted by a substituent "C 2 -C 6 alkynyl group”, the good suitable, fluorine atom, chlorine atom, bromine atom, hydroxyl group, which may be substituted - alkoxy group (said substituent Is a phenyl group.), A phenoxy group, an amino group, a phenyl group, a 5- to 6-membered heterocyclic group (the heteroatoms in the ring are the same selected from the group consisting of nitrogen, oxygen and sulfur atoms) Or different 1 to 3 hetero atoms.) 1 to 2 identical or different 1 or 2 selected from the group consisting of carboxyl group, C 2 -C 5 alkylcarbonyloxy group, nitro group and dicyano group Is
  • the "optionally substituted ⁇ ⁇ . ⁇ Ally ⁇ ; lecarbonyl group (the substituent is selected from a substituent group)" is the aforementioned "optionally substituted ⁇ ⁇ . Aryl group"
  • the substituent is selected from Substituent Group] 3.
  • a hydroxyl group, an optionally substituted alkoxy group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a carboxyl group and a group consisting of a C 2 -C 5 alkoxycarbonyl group It is a benzoyl group which may be substituted by the same or different 1 to 3 substituents selected.
  • the “optionally substituted 5- to 10-membered heterocyclic sulfonic group (the substituent is selected from the substituent group J3)” is the same or the same selected from the above “substituent group” 3 It is substituted with 1 to 4 different substituents, and is the above-mentioned “5 to: L 0 membered heterocyclic group”, preferably a 5 to 6 membered saturated group which may be substituted by a hydroxyl group.
  • a heterocyclic carbonyl group (wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), and more preferably a hydroxyl group
  • a 6-membered saturated heterocyclic carbonyl group which may be substituted by 1 to 2 heterocyclic atoms in the ring being the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom. Even more preferably substituted with a hydroxyl group. It is a ruponyl group.
  • a phenoxycarbonyl group which may be substituted by up to 3 substituents which may be substituted by up to 3 substituents.
  • the “optionally substituted rubamoyl group (the substituent is selected from the substituent group ⁇ )” is the same or different from one or two of the “substituent group ⁇ ”.
  • a carpamoyl group which may be substituted by a substituent, preferably an optionally substituted ⁇ ⁇ alkyl group ⁇ the substituents are a phenyl group, a hydroxyl group, a di ( ⁇ ⁇ alkyl) amino group and a 5- A 6-membered saturated heterocyclic group, wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen atoms and oxygen atoms. .
  • a phenyl group which may be substituted (the substituent is a halogen atom), a hydroxyl group and a 5- to 6-membered saturated heterocyclic oxy group (a heteroatom in the ring is a group consisting of a nitrogen atom and an oxygen atom
  • a heteroatom in the ring is a group consisting of a nitrogen atom and an oxygen atom
  • a carpamoyl group which may be substituted by the same or different 1 to 2 substituents selected from the group consisting of Optionally substituted ⁇ ⁇ alkyl group
  • the substituents are a phenyl group, a hydroxyl group, a di (-alkyl) amino group and a 6-membered saturated heterocyclic group (the heteroatom in the ring is composed of a nitrogen atom and an oxygen atom
  • the group : the substituent is a halogen atom
  • An optionally substituted fuunyl group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), A hydroxyl group or a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is nitrogen 1 to 2 heteroatoms were identical or different dates selected from the group consisting of atoms and oxygen atoms.) by a which may be substituted force Rubamoiru group, preferably by a further, ⁇ may be substituted 4 Alkyl group ⁇
  • the substituent is selected from the group consisting of a phenyl group, a hydroxyl group, a di ( ⁇ Cg phenol) amino group and a piperidyl group.
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), and a carpamoyl group which may be substituted by a hydroxyl group or a tetrahydropyraeroxy group.
  • the substituent is selected from the group consisting of a phenyl group, a dimethylamino group, a diisopropylamino group and a 'piperidino group) or a carbamoyl group which may be substituted by a hydroxyl group .
  • the "optionally substituted ⁇ ⁇ alkoxy group (the substituent is selected from the substituent group ⁇ )" is the above-mentioned "optionally substituted C ⁇ Ce alkyl group (the substituent is a substituted Is selected from the group consisting of:) "is a bonded oxygen atom;
  • substituents Is a ⁇ - ⁇ alkoxy group which may be substituted by one piperidyl group or di (-alkyl) amino group, particularly preferably 1-3 fluorine atoms or one piperidino group, dimethylamino group or An alkoxy group which may be substituted by a diisopropylamino group, and most preferably a methoxy group, a 2-piperidinethoxy group or a 2-diisopropylamino group.
  • the “optionally substituted c 2 -c 6 alkenyl group (the substituent is selected from the substituent group T /)” is the above-mentioned “optionally substituted c 2 -c 6 alkenyl group”.
  • the substituent is selected from the substituent group ⁇ .
  • the “optionally substituted C 2 -C 6 alkynyloxy group (the substituent is selected from the substituent group y.)” Is the above-mentioned “optionally substituted C 2 -C 6 alkynyl group ( The substituent is selected from the group of substituents “Y.)” is an oxygen atom bonded thereto, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, and an optionally substituted ⁇ to ⁇ 4 alkoxy group (The substituent is a phenyl group.), A phenoxy group, an amino group, a phenyl group, a 5- to 6-membered heterocyclic group (the heteroatom in the ring is composed of a nitrogen atom, an oxygen atom and a sulfur atom.
  • the “optionally substituted alkylthio group (the substituent is selected from the substituent group ⁇ )” refers to the above-mentioned “optionally substituted alkyl group” (the substituent group or the substituent group ⁇ ). ) Is a bonded sulfur atom, and is preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted alkoxy group (the substituent is a phenyl group), and phenoxy.
  • the “optionally substituted C 2 -C 6 alkenylthio group (the substituent is selected from the substituent group ⁇ )” is the above-mentioned “optionally substituted C 2 -C 6 alkenyl group”
  • the substituent is selected from a substituent group ⁇ /.)) Is a sulfur atom bonded thereto, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted to alkoxy group (the substituent Is a phenyl group.),
  • the “optionally substituted c 2 -c 6 alkynylthio group (the substituent is selected from the substituent group V.)” refers to the “optionally substituted c 2 -c 6 alkynyl group (the The substituent is selected from substituent group y.)) Is a sulfur atom bonded thereto.
  • Fluorine atom, chlorine atom, bromine atom, hydroxyl group, C i C alkoxy group which may be substituted (the substituent is a phenyl group), fuoxy group, amino group, phenyl group, 5- to 6-membered heterocyclic ring group (hetero atom in the ring is a nitrogen atom, the same or different 1 to 3 heteroatoms selected from the group consisting of oxygen atom and sulfur atom.), carboxyl group, C 2 -C 5 alkyl carbonyl O alkoxy group, a nitro Moto ⁇ Pi Shiano same or different 1 to 2 may be substituted by a substituent C 3 -C 4 Al Kiniruchio group selected the group or al consisting group.
  • the ⁇ C 3 -C 6 cycloalkylthio group '' is a sulfur atom to which the ⁇ C 3 -C 6 cycloalkyl group '' is bonded, and may be cyclopropylthio, cyclobutylthio, cyclopentino, or cyclopentio.
  • an optionally substituted CeC i. Arylsulfinyl group (the substituent is selected from a group of substituents / 3.) J is the aforementioned“ optionally substituted C ⁇ Ci.aryl group (the substituents are selected from substituent group.)
  • "Ri sulfinyl group der bound is, preferably, fluorine atom, chlorine atom, bromine atom, which may be substituted and 0 4 alkyl Le group (the substituent Is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.), A hydroxyl group, and an optionally substituted alkoxy group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.
  • the force Rupokishiru group and c 2 to c 5 alkoxide aryloxycarbonyl same or different 1-3 is substituted by a substituent which may be phenylene thioether group selected from the group consisting of groups.
  • the “optionally substituted ⁇ to ⁇ 6 alkylsulfinyl group is the aforementioned “optionally substituted 6 to 6 alkyl group (substituent Is selected from the group of substituents 1.) is a sulfier group to which is bonded, and is preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, or a substituted or unsubstituted C 4 alkoxy group (the substituent is , A phenyl group, a phenoxy group, an amino group, a phenyl group, a 5- to 6-membered heterocyclic group (the heteroatom in the ring is the same selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) or different 1 to Ru Ah in three hetero atoms.), a carboxyl group, C 2 -C 5 alkyl
  • the “optionally substituted C 2 -C 6 alkenyl sulfier group (the substituent is selected from the substituent group T.)” is the above-mentioned “optionally substituted C 2 -C 6 alkyl”.
  • An alkoxy group (the substituent is a phenyl group), a phenoxy group, an amino group, a phenyl group, a 5- to 6-membered heterocyclic group (the heteroatoms in the ring are nitrogen atom, oxygen atom and sulfur The same or different 1 to 3 heteroatoms selected from the group consisting of: atoms), a carboxyl group, a C 2 -C 5 alkylcarbonyloxy group, a nitro group and a cyano group Or one or two different places A substituted or c 3 to to c 4 ⁇ Luque Nils sulfinyl group by group.
  • the substituent is a phenyl group.
  • a phenoxy group, an amino group, a phenyl group, a 5- to 6-membered heterocyclic group (the heteroatoms in the ring are a nitrogen atom, an oxygen atom and a sulfur atom. identical are selected from the group consisting of or different 1 to a three hetero atoms.
  • a carboxyl group, C 2 -C 5 alkylcarbonyl O alkoxy group the same is selected from the group consisting of nitro Moto ⁇ Pi Shiano group or 1 to 2 different substituents It is more or substituted C 3 -C 4 alkynylsulfinyl group.
  • c 3 to c 6 cycloalkyl sulfide El group is a sulfinyl group, wherein “c 3 to c 6 cycloalkyl group” is bonded, cyclopropyl sulfide alkenyl, cycloalkyl Petit Luz Honoré alkylsulfonyl, cyclopentyl It is a sulfinyl or cyclohexyl sulfier group, preferably a pentyl sulfiel or a hexahexyl sulfinyl group.
  • the “optionally substituted C 6 -C 1 Q arylsulfinyl group (the substituent is selected from a substituent group)” is the above-mentioned “optionally substituted CC i.
  • Aryl group (the substituent Is selected from the substituent group jS.)) Is a sulfinyl group bonded to More preferably, a fluorine atom, a chlorine atom, a bromine atom, and may be substituted.
  • the aforementioned “optionally substituted to ⁇ 6 alkyl ⁇ (the substituent is a substituted Selected from the group ⁇ ) is a sulfonyl group bonded, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted ⁇ ⁇ alkoxy group (the substituent is a phenyl group ),
  • a carboxyl group, C 2 -C 5 alkylcarbonyl O alkoxy group the same or different
  • An alkoxy group (the substituent is a phenyl group), a phenoxy group, an amino group, a phenyl group, a 5- to 6-membered heterocyclic group (a heteroatom in the ring comprises a nitrogen atom, an oxygen atom and a sulfur atom
  • a carboxyl group a C 2 -C 5 alkylcarbonyloxy group, a nitro group and a cyano group
  • Ri is optionally substituted c 3 and to c 4 ⁇ Luque sulfonyl sulfonyl group.
  • C 4 alkoxy group (the substituent is a phenyl group), a phenoxy group, an amino group, a fuunyl group, a 5- to 6-membered heterocyclic group (the heteroatoms in the ring are nitrogen atom, oxygen atom and sulfur Ru Oh by the same or different 1 to 3 heteroatoms selected from the group consisting of atoms.), the force Rupokishiru group, C 2 -C 5 alkylcarbonyl O alkoxy group, the group consisting of nitro Moto ⁇ Pishi ⁇ amino group And C 3 -C 4 alkynylsulfonyl groups which may be substituted by one or two identical or different substituents selected from
  • the “C 3 -C 6 cycloalkylsulfonyl group” is a sulfonyl group to which the “C 3 -C 6 cycloalkyl group” is bonded, and is cyclopropylsulfonyl; It is a quinole or hexinolesulfonyl group, preferably a pentylsulfonyl or a hexylsulfoninole group.
  • the “substituted sulfamoyl group (the substituent is selected from the substituent group A)” is the same or different one or two selected from the “substituent group ⁇ ” force. It is a sulfamoyl group which may be substituted by a substituent, preferably a C Ce alkyl group which may be substituted ⁇ the substituent is a phenyl group, a hydroxyl group, a di (- ⁇ alkyl) amino group and a 5- to 6-membered group.
  • Saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen atoms) selected from the group consisting of ⁇ , A phenyl group which may be substituted (the substituent is a halogen atom), a hydroxyl group and a 5- to 6-membered saturated heterocyclic oxy group (a group in the ring).
  • the elementary atoms are the same or different one or two hetero atoms selected from the group consisting of nitrogen atoms and oxygen atoms.
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group or a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is The same or different one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms.) And further substituted with a sulfamoyl group.
  • Alkyl group ⁇
  • the substituent is selected from the group consisting of a phenyl group, a hydroxyl group, a di (-alkyl) amino group and a piperidyl group.
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), and a sulfamoyl group which is substituted by a hydroxyl group or a tetrahydrobiranyloxy group, and is particularly preferable.
  • “optionally substituted ⁇ 6 to aryl group (the substituent is selected from substituent group ⁇ .) ′” Is the same or different 1 to 4 selected from the above “substituent group ⁇ ”.
  • Aryl group which may be substituted by 5 substituents, preferably, a fluorine atom, a chlorine atom, a bromine atom, an optionally substituted ⁇ ⁇ alkyl group (the substituent is fluorine Selected from the group consisting of an atom, a chlorine atom, a bromine atom, a carboxyl group, and a C 2 -C 5 alkoxycarbonyl group.),
  • An optionally substituted c 2 -c 4 alkenyl group [ Good 5-membered unsaturated heterocyclic group ⁇ The heteroatom in the ring is 1-3 nitrogen atoms.
  • the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C i -C 4 alkyl group and a substituted or unsubstituted phenyl group (the substituent is a group consisting of a fluorine atom, a chlorine atom and a bromine atom. Selected from the group consisting of strength. ⁇ And it is selected from the group consisting of C 2 -C 5 alkoxycarbonyl group.
  • C 2 -C 5 alkyl A carbonyl group, a benzoyl group, an optionally substituted 6-membered saturated heterocyclic carbonyl group (the same or different one or two hetero atoms selected from the group consisting of a heteronuclear nitrogen atom and an oxygen atom in the ring.
  • the substituent is a hydroxyl group.
  • the substituent is an optionally substituted ⁇ - ⁇ 6 alkyl group (the substituent is Phenyl group, hydroxyl group, di-C 4 alkyl) amino group and 6-membered saturated heterocyclic group (the same or different 1 to 2 heteroatoms in the ring are selected from the group consisting of nitrogen atoms and oxygen atoms. ).
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is a nitrogen atom And one or two hetero atoms of the same or different selected from the group consisting of oxygen atoms.)).
  • a phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted ⁇ the heteroatom in the ring is 1-4 nitrogen atoms.
  • the ring may be fused with a benzene ring.
  • the substituent is an alkyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom).
  • a 6-membered saturated heterocyclic group (the same or different 1 or 2 heteroatoms selected from the group consisting of heteronuclear, nitrogen and oxygen atoms in the ring), hydroxyl, substituted Good to alkoxy group
  • the substituents are a fluorine atom, a chlorine atom, a bromine atom, a 6-membered saturated heterocyclic group (the same or different hetero atoms in the ring are selected from the group consisting of nitrogen atom and oxygen atom) 1 or 2 heteroatoms.)
  • di (C i -C 4 alkyl) amino group the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom.
  • C 3 to c 6 cycloalkoxy group which may be substituted phenoxy group (the substituent is a barrel selected from the group consisting of carboxyl Moto ⁇ Pi 0 2 ⁇ 5 alkoxycarbonyl group.), A mercapto group, a sulfo group, Sulfamoyl group, substituted amino group ⁇ the substituent is a C 2 -C 5 alkylcarbonyl group, a benzoyl group, a 6-membered unsaturated bicyclic carbinole group (the heteroatom in the ring is 1 to is three nitrogen atoms.) and selected from C 2 -C 5 alkoxyalkyl group consisting carbonyl group.
  • the substituent is selected from the group consisting of a phenyl group, a hydroxyl group, a di (Cgalkyl) amino group, and a piperidyl group.
  • a substituted phenyl group (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), a hydroxyl group and a tetrahydrobiranyloxy group.
  • a phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted ⁇ the heteroatom in the ring is 1-2 nitrogen atoms.
  • the substituent may be substituted ⁇ ⁇ 0 3 alkyl group (said substituents are selected from the group consisting of fluorine atom ⁇ Pi chlorine atom.) Is.
  • ⁇ Morpholyl group, a hydroxyl group, which may be substituted ⁇ alkoxy group
  • substituent is a fluorine atom, a chlorine atom, selected from the group consisting of Piperi Gilles Moto ⁇ Piji ( ⁇ ⁇ 3 alkyl) Amino group.
  • Phenyl group which may be substituted pyridyl group or a pyrazolyl group ⁇ those ⁇ substituent may be substituted ⁇ ⁇ 0 3 alkyl group (the substituent is a fluorine atom.)
  • a sulfamoyl group and a substituted amino group (the substituent is a t-butoxycarbonyl group), which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of A phenyl group, particularly preferably a methyl group, an ethoxycanolebonylmethyl group, a carbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, 4-phenylbutylcarbamoyl Group, 2-dimethylaminoethylcarbamoyl group, 2-diisopropylaminoethylcarbamoyl group, 2-piberidinoethylcarbamoyl group, 3,5-pisto-trifluoromethyl-11-pyrazolyl group, hydroxyl group, methoxy group, 2-piperidinethoxy Group, 2-diisopropyl
  • the “optionally substituted 5- to 10-membered heterocyclic group (the substituent is selected from the substituent group ⁇ )” is the same or different from the “substituent group ⁇ ”.
  • the ⁇ 5- to 10-membered heterocyclic group '' which may be substituted by 1 to 4 substituents, preferably a Ci Ce alkyl group, a carboxyl group, a C 2 to C 7 alkoxycarbonyl group and
  • the substituent may be a substituted or unsubstituted ⁇ ⁇ ⁇ ⁇ 6 alkyl group ⁇ wherein the substituent is the same or different from one to four selected from the group consisting of a hydroxyl group and a di ((alkyl) amino group.
  • a 5- or 6-membered unsaturated heterocyclic group which may be substituted by a substituent (where the heteroatoms in the ring are the same or different from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms)
  • the ring is a benzene ring or pyridine And condensed well, it may be substituted by C 3 -C 4 alkylene group.
  • ⁇ alkyl group a carboxyl group, C 2 -C 5 alkoxy carbonyl Moto ⁇ Pi which may be substituted force Rubamoyl group
  • the substituent may be substituted to an alkyl group.
  • the substituent is selected from the group consisting of a hydroxyl group and a di ( 4 alkyl) amino group.
  • a 5- or 6-membered unsaturated heterocyclic group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom
  • the ring may be condensed with a pyridine ring, and It may be substituted by a ren group.
  • C 2 -C 4 alkoxycarbonyl Moto ⁇ Pi which may be substituted force Rubamoiru group
  • the substituent group may be substituted (alkyl group ⁇ said substituent, Selected from the group consisting of a hydroxyl group and a di (-alkyl) amino group.
  • the ring may be substituted by a tetramethylene group ), And particularly preferably, a carboxyl group, a C 2 -C 3 alkoxycarbonyl group and an optionally substituted carbamoyl group ⁇ the substituent is an optionally substituted C ⁇ C 2 alkyl group (the substituent Is a hydroxyl group, Selected from the group consisting of a lumino group and a diisopropylamino group.) The same or different 1 or 2 substituents selected from the group consisting of It is an unzochenyl group or an imidazolyl group.
  • the compound represented by the formula (I) of the present invention can have an acidic carboxyl group, it can be converted into a salt by reacting it with a base.
  • the salt with such a base include a salt with an alkaline metal such as a lithium salt, a sodium salt and a potassium salt; a salt with an alkaline earth metal such as a calcium salt and a magnesium salt; or Salts with organic bases such as ammonium salts, triethylamine salts, diisopropylamine salts and cyclohexylamine salts can be mentioned.
  • Examples of the salt with an acid include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; acetate, fumarate, maleate, and oxalate.
  • Salts of carboxylic acids such as sulphonate, malonate, succinate, citrate and malate; salts of sulphonic acids such as methanesulphonate, ethanesulphonate, benzenesulphonate and toluenesulphonate;
  • Examples include salts of amino acids such as glutamate and aspartate, and are preferably salts of inorganic acids or salts of carboxylic acids, and more preferably hydrochloride, nitrate, fumarate, maleate or oxalic acid. Salts may be mentioned.
  • the compound represented by the formula (I) of the present invention may have an asymmetric carbon in the molecule, there are stereoisomers each having S-coordinate and R-coordination. , Each of them And mixtures of these isomers in any ratio.
  • the compound represented by the formula (I) of the present invention When the compound represented by the formula (I) of the present invention is left in the air or recrystallized, it may absorb water, adhere to adsorbed water, or become a hydrate.
  • the compound (I) of the present invention and a salt thereof include such a hydrate.
  • the compound (I) of the present invention may absorb some other solvent and form a solvate.
  • the compound (I) of the present invention and a salt thereof include such a solvate.
  • R 1 is preferably a hydrogen atom, ⁇ ⁇ 6 alkyl group, a C 2 to c 7 alkylcarbonyl group or - an alkylsulfonyl group,
  • a hydrogen atom or. 4 is an alkyl group
  • R 2, R 3, R 4 and R 5 are preferably identical or different dates, a hydrogen atom, a halogen atom, ⁇ ⁇ 6 alkyl group, ⁇ .
  • a hydrogen atom a fluorine atom, a chlorine atom, ⁇ -C 4 alkyl group, a pyridyl group, a hydroxyl group, ⁇ ⁇ ⁇ alkoxy group or a C 2 -C 4 alkylene Honoré force Noreboniruokishi group ,
  • R 2 , R 3 and R 5 are a methyl group and R 4 is an acetyl group; R 2 and R 5 are a hydrogen atom and R 3 and R 4 are a methoxy group; or R 2 , R 3 R 5 is a hydrogen atom and R 4 is a chlorine atom.
  • R 6 is preferably a hydrogen atom.
  • R 7 and R 8 are preferably both hydrogen atoms.
  • Ar is preferably substituted by may phenyl group
  • hose ⁇ substituent is a halogen atom, which may be substituted ⁇ Ji 6 alkyl group (the substituent is a halo gen atom, the force Selected from the group consisting of a ruboxyl group and a C 2 -C 7 alkoxycarbonyl group.)
  • An optionally substituted c 2 -c 6 alkenyl group [the substituent may be a 5- to 6-membered unsubstituted group.
  • Saturated heterocyclic group ⁇ The heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • the substituent is selected from the group consisting of a halogen atom, an alkyl group and a phenyl group which may be substituted (the substituent is a halogen atom).
  • ⁇ It is selected from the group consisting of carboxyl and C 2 -C 7 alkoxycarbonyl group.
  • the substituent is a hydroxyl group.
  • a phenoxycarbonyl group, a carbamoyl group which may be substituted [the substituent may be a Ci-C 6 alkyl group which may be substituted ⁇ the substituent is a phenyl group, a hydroxyl group , di ( ⁇ ⁇ 6 alkyl) same or different 1 to 2 selected from amino groups ⁇ Pi 5 double prime nuclear S 6-membered saturated Hajime Tamaki (in the ring, the group consisting of nitrogen atom and oxygen atom
  • the ring may be fused with a benzene ring or a pyridine ring.
  • the substituent is a Ci Ce alkyl group which may be substituted (the substituent is a halogen atom).
  • a 5- or 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and a substituent C i Cs alkoxy group which may be used ⁇ the substituent is a halogen atom, a 5- to 6-membered saturated heterocyclic group (the same or a hetero atom in the ring is selected from the group consisting of a nitrogen atom and an oxygen atom) It is one or two different heteroatoms.) And selected from the group consisting of di ( ⁇ ⁇ ⁇ alkyl) amino groups.
  • ⁇ which may be substituted ureido group (said substituent is ⁇ ⁇ 6 alkyl Moto ⁇ Pi off We sulfonyl group or Ranaru group forces, et chosen.) And which may be substituted Chioureido group (said substituent is Phenyl) is selected from the group consisting of: Or an optionally substituted 5- to 6-membered unsaturated heterocyclic group [where the hetero atom in the ring is a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; Is an atom.
  • the ring is a benzene ring 'or a pyridine ring fused well, it may be substituted by C 3 -C 4 alkylene group.
  • a phenyl group which may be substituted [the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C i Ca alkyl group which may be substituted (the substituent is a fluorine atom, a chlorine atom, a bromine atom) it is selected from carboxyl Moto ⁇ Pi C 2 -C 5 alkoxycarbonyl group carbonyl group ing), which may be substituted C 2 -C 4 alkenyl -.
  • Le group [the substituent is 5-membered unsaturated been substitution Saturated heterocyclic group (where the heteroatom in the ring is 1 to 3 nitrogen atoms is there.
  • the substituents are fluorine atom, chlorine atom, bromine atom, and 0 4 alkyl Moto ⁇ Pi which may be substituted phenyl group (said substituent is a fluorine atom, selected from chlorine and bromine or Ranaru group.) Selected from the group consisting of ⁇ And 2 to 5 alkoxy forces are selected from the group consisting of luponyl groups.
  • C 2 to c 5 alkyl carboxy group benzo I group, the hetero atoms in which may be substituted 6-membered saturated heterocyclic group (said ring, selected from the group consisting of nitrogen atom ⁇ Pi oxygen atom
  • the substituent is a hydroxyl group.
  • a carboxyl group, a C 2 -C 5 alkoxycarbonyl group, an optionally substituted rubamoyl group [substituted
  • the group may be an optionally substituted ⁇ - ⁇ alkyl group ⁇ the substituents are a fuunyl group, a hydroxyl group, a di (- ⁇ alkyl) amino group and a 6-membered saturated heterocyclic group (where the heteroatom in the ring is a nitrogen atom or The same or different one or two heteroatoms selected from the group consisting of oxygen atoms).
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is And 1 to 2 identical or different heteroatoms selected from the group consisting of nitrogen and oxygen atoms.) ],
  • a phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted ⁇ the heteroatom in the ring is 1-4 nitrogen atoms.
  • the ring may be fused with a benzene ring.
  • the substituent is an alkyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom).
  • ⁇ A 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and may be substituted ⁇ ⁇ Alkoxy group
  • the substituent is a fluorine atom, a chlorine atom, a bromine atom, a 6-membered saturated heterocyclic group (the heteroatoms in the ring are the same or different and are selected from the group consisting of a nitrogen atom and an oxygen atom) And one or two complex atoms.) And di (C i C alkyl) amino group.
  • C 3 -C 6 cycloalkoxy group which may be substituted phenoxy group (said substituents are selected from the group consisting of local Bokishiru Moto ⁇ Pi c 2 to c 5 alkoxycarbonyl group.), Main mercapto group, sulfo Group, a sulfamoyl group, a substituted amino group ⁇ the substituent is a C 2 -C 5 alkylcarbonyl group, a benzoyl group, a 6-membered unsaturated heterocyclic carbonyl group (the heteroatom in the ring is 1 to 3 Nitrogen atoms.) And C 2 -C 5 alkoxy It is selected from the group consisting of a cicarbonyl group.
  • Moto ⁇ Pi is selected from the group consisting of phenyl group) ⁇ Pi which may be substituted Chioureido group (said substituents are off - It is selected from the group consisting of force. Or an optionally substituted 5- to 6-membered unsaturated heterocyclic group [where the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. is there.
  • the ring may be condensed with a pyridine ring and may be substituted with a tetramethylene group.
  • the substituents are C 1 -C 4 alkyl group, carboxyl group, C 2 '-C 5 alkoxycarbonyl group and which may be substituted force Rubamoiru group [the substituent may be substituted ⁇ 4 alkyl group ⁇ said
  • the substituent is selected from the group consisting of a hydroxyl group and a di ( ⁇ to 4 alkyl) amino group. ⁇ . ] Is selected from the group consisting of ]
  • a fuunyl group which may be substituted may be substituted C 2 -C 4 alkenyl group [the substituent is which may be substituted pyromellitic one drill group ⁇ said substituents may be substituted A phenyl group (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom).
  • ⁇ And it is selected from c 2 to c 4 group consisting alkoxide aryloxycarbonyl group. ], Benzoiru group, which may be substituted pin Beri Zirka Lupo sulfonyl group (the substituent is a hydroxyl group.), The force Rupokishiru group, C 2 -C 4 alkoxycarbonyl group, which may be substituted force Rubamoiru group [the substituent Is an optionally substituted ⁇ to ⁇ alkyl group ⁇ wherein the substituent is a phenyl group, a hydroxyl group, a di-C 3 alkyl) amino group and a piperidyl group.
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), a hydroxyl group and a tetrahydrobiranyloxy group.
  • a phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted ⁇ a heteroatom in the ring is 1-2 nitrogen atoms;
  • the substituent is an alkyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom).
  • a 5-membered unsaturated heterocyclic group which may be substituted, wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen atoms and sulfur atoms.
  • the ring may be substituted by a tetramethylene group.
  • the substituent may be a carbonyl group, a C 2 to C 4 alkoxycarbonyl group or a carpamoyl group which may be substituted [the substituent may be a substituted or unsubstituted 3 alkyl group ⁇ the substituent is a hydroxyl group C 3 -alkyl 3 ) selected from the group consisting of amino groups. ⁇ . ] Is selected from the group consisting of ]
  • the substituent is a bromine atom, which may be substituted ⁇ 2 alkyl group (the substituent is a group consisting of fluorine atom or a C 2 -C 3 alkoxy force Ruponiru group selected from.), the force Rupokishiru group, c 2 to c 3 alkoxy force Ruponiru group, which may be substituted Karupamoiru group (said substituent which may be substituted to c 4 alkyl group (the substituent is Hue nil , A dimethylamino group, a diisopropylamino group and a piperidino group.) And a hydroxyl group.
  • a phenyl group, an optionally substituted pyridyl group or a pyrazolyl group the substituent Is an optionally substituted ⁇ to ⁇ alkyl group (the substituent is a fluorine atom).
  • a hydroxyl group A hydroxyl group,
  • Lubamoyl group the substituent is an optionally substituted alkyl group (the substituent is selected from the group consisting of a hydroxyl group, a dimethylamino group and a diisopropylamino group) ⁇ . .]
  • a phenyl group which may be substituted (the substituent may be a methyl group, an ethoxycarbonylmethyl group, a carboxyl group, a methoxycarpo'enyl group, an ethoxycanoleponyl group, a carbamoyl group, a methylcarbamoyl group, a 4-phenyl group) Ninolebutyl butyl canolebamoyl Group, 2-dimethylaminoethyl carbamoyl group, 2-diisopropylaminoethyl carbamoyl group, 2-piperidinoethylcarbamoyl group, 3,5-bistrifluomethyl-1-vinylazolyl group, hydroxyl group, methoxy group, 2-piperidi One or two identical or different substituents selected from the group consisting of a nonethoxy group, a 2-diisopropylaminoaminoethoxy group and a bis-
  • R 1 is a hydrogen atom, an alkyl group, a C 2 -C 7 alkylcarbonyl group or a C i Ce alkylsulfonyl group,
  • R 2 , R 3 , R 4 and R 5 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group, or.
  • R 6 is a hydrogen atom
  • R 7 and R 8 are both hydrogen atoms
  • Ar is a fuunyl group which may be substituted [the substituent is a halogen atom, an optionally substituted alkyl group (the substituent is a halogen atom, a carboxyl group and a c 2 to c 7 alkoxycarbonyl group; selected from the group consisting of.), may be substituted C 2 -C 6 alkenyl group [the substituent is a heterocyclic atom in which may be substituted 5-6 membered unsaturated Hajime Tamaki ⁇ those ring nitrogen 1 to 3 identical or different hetero atoms selected from the group consisting of atoms, oxygen atoms and sulfur atoms.
  • the substituent is selected from the group consisting of a halogen atom, a C 6 alkyl group and a phenyl group which may be substituted (the substituent is a halogen atom).
  • ⁇ It is selected from the group consisting of carboxyl group, and c 2 to c 7 Arukokishikaru Boniru group. ], C 2 to c 7 alkylcarbonyl group, Benzoi group, hetero atoms in which may be substituted 5-6 membered saturated heterocyclic force Ruponiru group (said ring is selected from the group consisting of nitrogen atom ⁇ Pi oxygen atom Same or different 1 or 2 complex Is an atom.
  • the substituent is a hydroxyl group.
  • a carboxyl group may be substituted C 2 -C 7 alkoxycarbonyl group (the substituent is a phenyl group.), Fuweno alkoxycarbonyl group, which may be substituted force Rubamoiru group [the substituent is substituted have good Te ⁇ ⁇ alkyl group ⁇ said substituent is off group, hydroxyl group, di ( ⁇ ⁇ 6 alkyl Le) Amino group ⁇ Pi 5-6 membered saturated Hajime Tamaki (hetero atom in the ring, the nitrogen And one or two identical or different heteroatoms selected from the group consisting of atoms and oxygen atoms.) ⁇ , A phenyl group which may be substituted (the substituent is a halogen atom), a hydroxyl group and a 5- to 6-membered saturated heterocyclic oxy group (a heteroatom in the ring is a group consisting of a nitrogen atom and an oxygen atom 1 or 2 identical or different heteroatoms selected from the group consisting of:
  • the ring may be fused with a benzene ring or a pyridine ring.
  • the substituent is an ⁇ alkyl group which may be substituted (the substituent is a halogen atom).
  • a 5- to 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and a substituted Alkoxy group
  • the substituent may be a halogen atom, a 5- to 6-membered saturated heterocyclic group (wherein the same or different 1- to 4-membered heteroatom is selected from the group consisting of nitrogen and oxygen).
  • An optionally substituted ureido group (the substituent is selected from the group consisting of an alkyl group and a phenyl group.) And an optionally substituted thioperido group (the substituent is a phenyl group.) Selected from the group consisting of Or a 5- or 6-membered unsaturated heterocyclic group which may be substituted The same or different selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom:! To 3 hetero atoms.
  • the ring may be condensed with a benzene ring or a pyridine ring may be substituted by a C 3 -C 4 alkylene group.
  • the substituent may be, for example, an alkyl group, a carboxyl group, a C 2 to C 7 alkoxyl propyl group, and a substituted carbamoyl group (the substituent may be substituted; an alkyl group; Selected from the group consisting of a hydroxyl group and a di (C Cs alkyl) amino group. ⁇ . ] Is selected from the group consisting of ]
  • R 1 is a hydrogen atom or an alkyl group
  • R 2 , R 3 , R 4 and R 5 are the same or different and each represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, a phenyl group, a 6-membered unsaturated heterocyclic group ( The hetero atom in the ring is 1 to 3 nitrogen atoms.), A hydroxyl group, a C alkoxy group which may be substituted (the substituent is a fluorine atom, a chlorine atom, a bromine atom and a phenyl group). Or a C 2 -C 5 alkylcarbonyloxy group, (2c) R 6 is a hydrogen atom,
  • R 7 and R 8 are both hydrogen atoms
  • (2e) ... is a double bond or a single bond
  • Ar is an optionally substituted fuunyl group [the substituent is a fluorine atom, a chlorine atom, a bromine atom, an optionally substituted ⁇ ⁇ alkyl group (the substituent is a fluorine atom, a chlorine atom, a bromine Selected from the group consisting of an atom, a carboxyl group and a C 2 -C 5 alkoxycarbonyl group.), An optionally substituted c 2 -c 4 alkenyl group [the substituent is a 5-membered unsaturated heterocyclic group which may be substituted. Ring group ⁇ The heteroatom in the ring is 1 to 3 nitrogen atoms.
  • the substituent is a group consisting of a fluorine atom, a chlorine atom, a bromine atom, an alkyl group and a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom). Selected from. ⁇ And C 2 -C 5 alkoxy force selected from the group consisting of luponyl groups.
  • C 2 -C 5 alkylcarbonyl group a benzo I group, the hetero atoms in which may be substituted 6-membered saturated heterocyclic force Ruponiru group (said ring, selected from the group consisting of nitrogen atom ⁇ Pi oxygen atom The same or different 1 or 2 heteroatoms, and the substituent is a hydroxyl group.), A carbonyl group, a C 2 -C 5 alkoxy Sicarbonyl group, optionally substituted rubamoyl group [The substituent may be substituted-alkyl group ⁇ The substituent is a fuyl group, a hydroxyl group, a di ( ⁇ 4 alkyl) amino group and a 6-membered saturated group.
  • a group consisting of a heterocyclic group (where the heteroatoms in the ring are the same or different one or two heteroatoms selected from the group consisting of nitrogen atoms and oxygen atoms).
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is The same or different one or two hetero atoms selected from the group consisting of nitrogen atoms and oxygen atoms.
  • a phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted ⁇ the heteroatom in the ring is 1-4 nitrogen atoms.
  • the ring may be fused with a benzene ring.
  • the substituents, which may be substituted Ci ⁇ C 4 alkyl group (said substituent is a fluorine atom, selected from chlorine and bromine or Ranaru group.) It is.
  • a 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and may be substituted C ⁇ Ce alkoxy group ⁇
  • the substituent is a fluorine atom, a chlorine atom, a bromine atom, a 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different and are selected from the group consisting of a nitrogen atom and an oxygen atom. And one or two heteroatoms.) And di (-alkyl) amino groups.
  • C 3 -C 6 cycloalkoxy group which may be substituted off phenoxy group (the substituent is selected from the group consisting of local Bokishiru Moto ⁇ Pi C 2 -C 5 alkoxycarbonyl group.), Main mercapto group, A sulfo group, a sulfamoyl group, a substituted amino group ⁇ the substituents are a C 2 -C 5 alkylcarbonyl group, a benzoyl group, a 6-membered unsaturated heterocyclic carbonyl group (where the heteroatom in the ring is 1 to And three nitrogen atoms.) And selected from the group consisting of C 2 -C 5 alkoxycarbonyl groups.
  • a substituted peridode group (the substituted group is selected from the group consisting of ⁇ to ( ⁇ an alkyl group and a phenyl group)) and an optionally substituted thioperido group (the substituted group is a phenyl group.
  • a 5- or 6-membered unsaturated heterocyclic group which may be substituted, wherein the heteroatoms in the ring are the same or different and are selected from the group consisting of nitrogen, oxygen and sulfur
  • the ring may be condensed with a pyridine ring and may be substituted with a tetramethylene group
  • the substituent may be a ⁇ to ⁇ 4 alkyl group, a carboxyl group, a C 2 -C 5 alkoxycarbonyl group, and which may be substituted force Rubamoiru group [the substituent is which may be substituted-alkyl group ⁇ said substituent from the group consisting of hydroxyl group and di ( ⁇ ⁇ 0 4 Al Kill) Amino group To be elected. ⁇ . ] Is selected from the group consisting of ]
  • R 1 is a hydrogen atom
  • R 2, R 3, R 4 and R 5 are the same or different, a hydrogen atom, a fluorine atom, a chlorine atom, ⁇ ⁇ 4 alkyl group, a pyridyl group, a hydroxyl group, ⁇ alkoxy group or C 2 -C 4 is an alkylcarbonyloxy group,
  • R 6 is a hydrogen atom
  • R 7 and R 8 are both hydrogen atoms
  • Ar is a phenyl group which may be substituted [the substituent is a fluorine atom, a chlorine atom, a bromine atom, an optionally substituted alkyl group (the substituent is a fluorine atom, a chlorine atom and a C atom; Selected from the group consisting of 2 to C 4 alkoxycarbonyl groups.), An optionally substituted c 2 to c 4 alkenyl group [the substituent is an optionally substituted pyromonolyl group ⁇ the substituent is an optionally substituted Phenyl group (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom).
  • ⁇ And is selected from the group consisting of c 2 to c 4 alkoxy carbonyl group.
  • a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), a hydroxyl group and a tetrahydrobilanyloxy group. ], A phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted ⁇ The heteroatom in the ring is 1-2 nitrogen atoms.
  • the substituent may be substituted ⁇ ⁇ 3 alkyl group (said substituents are selected from the group consisting of fluorine atom and chlorine atom.) It is.
  • ⁇ A morpholyl group, a hydroxyl group, an optionally substituted alkoxy group ⁇ the substituent is a fluorine atom, It is selected from the group consisting of a chlorine atom, a piperidyl group and a di (- ⁇ alkyl) amino group.
  • ⁇ Mercapto group, a sulfamoyl group and is substituted Yoi Amino group (those ⁇ substituent is a C 2 -C 5 alkoxycarbonyl group.) Selected from the group consisting of.
  • a 5-membered unsaturated heterocyclic group which may be substituted, wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and a sulfur atom.
  • the ring may be substituted by a tetramethylene group.
  • the substituents are carboxyl group, C 2 ⁇ C 4 alkoxy Cal Poni Le group and which may be substituted force Rubamoiru group [the substituent is which may be substituted and 0 3 alkyl group ⁇ said substituent is hydroxyl ⁇ Pi di ( ⁇ ⁇ Alkyl) selected from the group consisting of amino groups. ⁇ . ] Is selected from the group consisting of: ]
  • R 1 is a hydrogen atom
  • R ⁇ R ⁇ R 4 ⁇ Pi R 5 same or different, a hydrogen atom, a chlorine atom, methylation group, a 3-pin. Lysyl group, a methoxy group or an Asetokishi group,
  • R 6 is a hydrogen atom
  • R 7 and R 8 are both hydrogen atoms
  • Ar is, which may be substituted phenyl group [the substituent is a bromine atom, may be substituted ⁇ ⁇ Ji 2 alkyl group (the substituent is a fluorine atom or a C 2 -C 3 alkoxy force Ruponiru group ), A carboxyl group, a C 2 -C 3 alkoxycarbonyl group, an optionally-substituted rubamoyl group ⁇ the substituent is an optionally substituted ⁇ -alkyl group (the substituent is a phenyl group, a dimethylamino group , A diisopropylamino group and a pyridino group.) And a hydroxyl group.
  • Lahydrobenzozoenyl group or imidazolyl group [The substituent is a carboxyl group, a C 2 -C 3 alkoxycarbonyl group and an optionally substituted carpamoyl group ⁇ the substituent is an optionally substituted alkyl group The group is selected from the group consisting of a hydroxyl group, a dimethylamino group and a diisopropylamino group. ⁇ It is selected from a powerful group.
  • R 1 is a hydrogen atom
  • R 2 , R 3 and R 5 are a methyl group and R 4 is an acetyl group; R 2 and R 5 are a hydrogen atom and R 3 and are a methoxy group; or R 2 , R 3 and R 5 is a hydrogen atom and R 4 is a chlorine atom,
  • R 6 is a hydrogen atom
  • R 7 and R 8 are both hydrogen atoms
  • Ar is a phenyl group which may be substituted (the substituent is a methyl group, an ethoxycarbonylmethyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a canolebamoinole group, a methylcarbamoyl group, Pheninolebutylcanolebamoinole group, 2-dimethylaminoethylcarbamoyl group, 2-diisopropylaminoaminoethyl carbamoyl group, 21-piperidinoethylcarbamoyl group, 3,5-bistrifluomethyl-1- One or two identical or different members selected from the group consisting of a virazolyl group, a hydroxyl group, a methoxy group, a 2-piperidinoethoxy group, a 2-diisopropylpropylaminoethoxy group and a bis-t-
  • H M viP uc; ArO C H -2-C0 MP-1 fi-1 (2-Ovr)
  • (b-1) to (b-16) represent the following substituents.
  • Me is methyl group
  • Et is ethyl group
  • iPr is isopropyl group
  • Bu is butyl group
  • t-Bu is tert-butyl group
  • iPen is isopentyl group
  • Hx is hexyl group
  • Ac is acetyl group
  • cycpen is cyclopentyl.
  • Ph is a phenyl group
  • Bn is a benzyl group
  • pyr is a pyridyl group
  • pip is a pyridyl group
  • pyra is a pyrazolyl group
  • pyrro is a pyrrolyl group
  • mor is a morpholino group
  • thp is a tetrahydrovinylinole group
  • Bimid is 1H - benzimidazolyl group, tez the 1H- tetrazolyl group, C 6 H 4 - 2 - C0 2 H 2 one carboxyphenyl group, C 6 H- 2- C0 2 H- 4, 5, 6- ri- OMe is 2—Ripoxyl—Indicates 4,5,6-trimethoxyphenyl group.
  • preferred compounds are Compound Nos. 1-12, 1-37, 1-38, 1-54, 1-67, G69, 1-70, 1-74, 1-91, G98, 1-99, 1-100, 1-101, 1-102, 1-103, 1-104, 1-108, 1-109, G 114, 1-115, 1-120, 1-122, 1-123 , 1—125, 1—143, 1—168, 1—175, G 179, 1-217, 1—224, 1—225, 1—226, 1-228, 1—229, 1—230, 1— 231, 1-239, 1-240, G 243, 1-257, 1-258, 1-262, 1-263, 1-272, 1-273, 1-286, 1-288, 1-289, G 298, 299, 1-301, 1-302, 1-303, 1-304, 1-305, 1-309, 1-314, 1-315, 1-316, 1-317, 1—319, 1—320, 1-321, 1—325, 1
  • No. 2-15, 2-16, 2-17 or 3-24 more preferably Compound No. 1-12, 1-67, 1-91, 1-98, 1-99, 1- 101, 1-104, 1-108, 1-109, 1-120, 1-224, G 225, 1-228, 1-229, 1-230, 1-239, 1-240, 1-257, 1 -262, 1-263, 1-286, 1-289, 1-298, G 302, 1-303, 1-305, 1-309, 1-315, 1-316, 1-317, 1-319, 1-320, 1-326, 1-331, 1-332, 1-336, 1-348, 1-356, 2-14, 2-15, 2-16 or 2-17.
  • Method A is a method for producing a compound represented by the formula (I-1) in which R 6 , R 7 and R 8 are hydrogen atoms among the compounds (I) of the present invention. Indicated by
  • X represents a halogen atom
  • Z represents a cyano group or an ester group.
  • the dichloromethyl ⁇ -alkyl ether used is preferably dichloromethyl methyl ether or dichloromethyl n-butynole.
  • the ⁇ solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • hydrocarbons such as benzene, toluene, xylene, hexane and heptane; Ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, Halogenated hydrocarbons such as 2-dichloroethane; or mixtures thereof, preferably dichloromethane.
  • the acid used can be, for example, a Lewis acid such as titanium tetrachloride, tin tetrachloride.
  • the amount of the dichloromethyl ⁇ to ⁇ 6 alkyl ether to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (1).
  • the reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range from cooling to heating, preferably from 0 ° C to 100 ° C.
  • the reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hour to several days, preferably 1 hour to 10 hours.
  • the conjugate represented by the formula (2) is reacted with acrylonitrile or an acrylate to close the ring, and the compound represented by the formula (3)
  • the acrylate used may be, for example, tert-butyl acrylate, ethyl acrylate and methyl acrylate, and is preferably tert-butynole acrylate.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane.
  • Ethers such as getyl ether, tetrahydrofuran, and dioxane; alcohols, such as methanol, ethanol, and isopropanol; amides, such as dimethylformamide, dimethylacetamide, and hexamethinole triamide; dichloromethane, and methyl chloride Halogenated hydrocarbons such as form, 1,2-dichloroethane; or a mixture thereof, preferably in the absence of a solvent when using atarilonitrile; When using acid esters, use dimethylformamide. To.
  • the base used is, for example, an organic base such as 1,4-diazabicyclo [2.2.2] octane, potassium tert-butoxide; or an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate. It can be a base, preferably 1,4-diazavic octane [2.2.2] octane or potassium carbonate.
  • the amount of acrylonitrile or acrylate used is usually 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (2).
  • the reaction temperature varies depending on the type of the starting compound, the reaction reagent and the solvent, but is usually in the range of from room temperature to heating, preferably from room temperature to the reflux temperature of the solvent.
  • the reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 50 hours.
  • This step is a step of hydrolyzing a compound represented by the formula (3) in a solvent in the presence of an acid or a base to produce a compound represented by the formula (4).
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • hydrocarbons such as benzene, toluene, xylene, hexane and heptane; getyl ether, Ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; Amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chlorophonolem, and 1,2-dichloroethane; or a mixture thereof; Preferably, it is dioxane.
  • the acid used can be, for example, hydrochloric acid or sulfuric acid.
  • the base used can be, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, and is preferably sodium hydroxide.
  • the reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range from cooling to heating, preferably from 0 ° C to the reflux temperature of the solvent.
  • the reaction time varies depending on the starting compound, the reaction reagent, the type of solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane. Athenoles such as getinoleether, tetrahydrofuran, and dioxane; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; dimethylformamide, dimethylacetamide, hexamethylphosphoric acid Amides, such as triamides; or mixtures thereof, also preferably in the absence of a solvent, preferably tetrahydrofuran or dimethylformamide.
  • the halogenating agent used may be, for example, a chlorinating agent such as oxalchloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride; or a brominating agent such as phosphorus tribromide.
  • a chlorinating agent such as oxalchloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride
  • a brominating agent such as phosphorus tribromide.
  • the catalyst used can be, for example, dimethylformamide.
  • the reaction temperature varies depending on the type of the starting compound, the reaction reagent, and the solvent.
  • the temperature ranges from rejection to heating, and is preferably from 0 ° C to the reflux temperature of the solvent. .
  • the reaction time varies depending on the starting compound, the reaction reagent, the type of solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.
  • a compound represented by the formula (5) is reacted with an amine compound represented by the formula RrNH in the presence or absence of a solvent in the presence of a base to obtain a compound represented by the formula (1- This is a process for producing the target compound represented by 1).
  • the solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • examples include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane.
  • Ethers such as getyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; amides such as dimethylformamide, dimethylacetamide, and hexamethyl phosphate triamide.
  • Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; or mixtures thereof, preferably tetrahydrofuran or dimethylacetamide, but without solvent. The following reaction is also preferred.
  • the base used can be, for example, an organic base such as triethylamine, pyridine; or an inorganic base such as sodium hydroxide, hydroxylated sodium hydroxide, sodium carbonate, preferably pyridine or triethylamine. is there.
  • the amount of the amine compound to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to compound (5).
  • the reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C to the reflux temperature of the solvent.
  • the reaction time varies depending on the starting compound, the reaction reagent, the type of solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.
  • the amine compound used in this step may be a commercially available one or a conventional method (for example, (1) replacing aryl halide with a corresponding amine, (2) R 1 is not a hydrogen atom. In such a case, a method of converting the corresponding arylamine into R 1 and a method of (3) reductive amination are exemplified.) (Step 6)
  • This step is a step of directly obtaining the compound (I-11) of the present invention from the compound (4).
  • the compound represented by the formula (4) is This is achieved by reacting an amine compound represented by the formula R r NH.
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • hydrocarbons such as benzene, toluene, xylene, hexane and heptane; getyl ether, Ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, and isopropanol; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; dichloromethane, chloroform, Halogenated hydrocarbons such as 2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as formate and ethyl acetate; or mixtures thereof, preferably tetrahydrofuran or It is dichloromethane.
  • the base used can be, for example, organic bases such as triethylamine, pyridine.
  • the condensing agent used can be, for example, getyl cyanophosphonate, N-ethyl-N,-(3-dimethylaminopropyl) carbodiimide or dicyclohexyl carbyl imide.
  • the amount of the amine compound to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to compound (4).
  • the reaction temperature varies depending on the types of the starting compound, the reaction reagent, and the solvent.
  • the reaction temperature is usually in a range from cooling to heating, and is preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the type of the starting compound, the reaction reagent, the solvent and the reaction temperature, but is usually from 0.5 hours to several days, preferably from 1 hour to 10 hours.
  • amine compound used in this step a commercially available one may be used, or a conventional method may be used (for example, (1) a method in which aryl halide is replaced with the corresponding amine, (2) 1 ⁇ is a hydrogen atom If not, there may be mentioned a method of converting the corresponding arylamine into R 1 and a method of (3) reductive amination, etc.).
  • Method B is a method for producing the chromene compound (1-2) of the present invention.
  • RR 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Ar and X have the same meanings as described above. '
  • the solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent.
  • hydrocarbons such as benzene, toluene, xylene, hexane and heptane; getyl ether, Ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, and isopropanol; amides such as dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; dichloromethane, chlorophonolem, and 1,2-dichloroethane Or a mixture thereof.
  • the base used may be, for example, an inorganic base such as sodium hydroxide, hydroxylated sodium, sodium hydride; or an organic base such as pyrrolidine, piperazine, potassium 1: 1-butoxide, piperidine. And preferably pyrrolidine or piperazine It is.
  • an inorganic base such as sodium hydroxide, hydroxylated sodium, sodium hydride
  • an organic base such as pyrrolidine, piperazine, potassium 1: 1-butoxide, piperidine.
  • the reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, and is usually in a range from cooling to heating, preferably from 0 ° C to 50 ° C.
  • the reaction time varies depending on the starting compound, the reaction reagent, the type of solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.
  • This step is a reaction generally known as the Vilsmeier-Haak reaction, and the compound represented by the formula (8) is produced by formylating the compound represented by the formula (7) in a solvent. It is a process.
  • This step can be performed, for example, according to the method described in Organic Synthesis, Collective Volume 4, 539 (1963).

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Abstract

L'invention concerne un composé représenté par la formule (I): dans laquelle R1 représente un hydrogène, un groupe C¿1-6? alkyle, C6-10aryle ou C1-12acyle éventuellement substitué, R?2, R3, R4, et R5¿ sont identiques ou différents et représentent chacun notamment un hydrogène, un halogéno, un groupe C¿1-6? alkyle ou C3-6cycloalkyle, R?6¿ représente un hydrogène, un halogéno, un groupe C¿1-6?alkyle, C2-6alcényle ou C 2-6 alkynyle éventuellement substitué, R?7 et R8¿ sont identiques ou différents et représentent chacun un hydrogène, un halogéno, un groupe C¿1-6? alkyle, C3-6cycloalkyle, C6-10aryle éventuellement substitué ou un groupe hétérocyclique de cinq à dix membres éventuellement substitué, ....... représente une liaison double ou simple, et Ar représente un groupe C6-10aryle éventuellement substitué ou un groupe hétérocyclique de cinq à dix membres éventuellement substitué. L'invention concerne aussi un sel de ce composé, acceptable sur le plan pharmaceutique, ainsi qu'un médicament contenant ce composé ou un de ses sels en tant que principe actif.
PCT/JP2002/001501 2001-02-21 2002-02-20 Derives de chromene WO2002066454A1 (fr)

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WO2005004859A1 (fr) * 2003-06-30 2005-01-20 Bausch & Lomb Incorporated Derives de la coumarine destines au traitement de troubles ophtalmiques
US7855289B2 (en) 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7893086B2 (en) 2007-06-20 2011-02-22 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8034811B2 (en) 2003-12-03 2011-10-11 Leo Pharma A/S Hydroxamic acid esters and pharmaceutical use thereof
US8088928B2 (en) 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8093401B2 (en) 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
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US8343997B2 (en) 2008-12-19 2013-01-01 Sirtris Pharmaceuticals, Inc. Thiazolopyridine sirtuin modulating compounds
CN105153188A (zh) * 2009-10-22 2015-12-16 法博太科制药有限公司 抗纤维化剂的稠环类似物
CN105636943A (zh) * 2013-10-18 2016-06-01 阿塔克斯生物制药有限公司 作为TCR-Nck相互作用的抑制剂的色烯衍生物
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005004859A1 (fr) * 2003-06-30 2005-01-20 Bausch & Lomb Incorporated Derives de la coumarine destines au traitement de troubles ophtalmiques
US8034811B2 (en) 2003-12-03 2011-10-11 Leo Pharma A/S Hydroxamic acid esters and pharmaceutical use thereof
US8178536B2 (en) 2005-08-04 2012-05-15 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7855289B2 (en) 2005-08-04 2010-12-21 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8088928B2 (en) 2005-08-04 2012-01-03 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8093401B2 (en) 2005-08-04 2012-01-10 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8163908B2 (en) 2005-08-04 2012-04-24 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8268862B2 (en) 2007-06-20 2012-09-18 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US7893086B2 (en) 2007-06-20 2011-02-22 Sirtris Pharmaceuticals, Inc. Sirtuin modulating compounds
US8343997B2 (en) 2008-12-19 2013-01-01 Sirtris Pharmaceuticals, Inc. Thiazolopyridine sirtuin modulating compounds
US8492401B2 (en) 2008-12-19 2013-07-23 Glaxosmithkline Llc Thiazolopyridine sirtuin modulating compounds
CN105153188A (zh) * 2009-10-22 2015-12-16 法博太科制药有限公司 抗纤维化剂的稠环类似物
US9951087B2 (en) 2009-10-22 2018-04-24 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
CN105636943A (zh) * 2013-10-18 2016-06-01 阿塔克斯生物制药有限公司 作为TCR-Nck相互作用的抑制剂的色烯衍生物
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
US11603349B2 (en) 2017-02-03 2023-03-14 Certa Therapeutics Pty Ltd Anti-fibrotic compounds

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