WO2009125808A1 - Dérivé d’aminocyclohexyle - Google Patents

Dérivé d’aminocyclohexyle Download PDF

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Publication number
WO2009125808A1
WO2009125808A1 PCT/JP2009/057244 JP2009057244W WO2009125808A1 WO 2009125808 A1 WO2009125808 A1 WO 2009125808A1 JP 2009057244 W JP2009057244 W JP 2009057244W WO 2009125808 A1 WO2009125808 A1 WO 2009125808A1
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group
carboxy
optionally substituted
amino
atom
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PCT/JP2009/057244
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English (en)
Japanese (ja)
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裕章 稲垣
哲則 藤沢
雅夫 伊藤
美穂 早川
敏史 津田
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a novel compound having excellent antibacterial activity against gram positive bacteria and gram negative bacteria, or a salt thereof, and an antibacterial agent containing them.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant enterococci
  • PRSP penicillin-resistant pneumococci
  • Patent Document 1 discloses a quinolone compound that is effective against resistant Gram-positive bacteria.
  • compounds described in Patent Documents 2 to 6 are known as compounds having a mechanism of action different from that of existing drugs.
  • the present inventors have found that the compound represented by the following formula (I) or a salt thereof has a broad and powerful antibacterial activity against Gram-positive bacteria and Gram-negative bacteria.
  • the present invention was completed by finding that it has activity and has high safety as an antibacterial agent and a preventive / therapeutic agent for infectious diseases.
  • the present invention provides a compound represented by the following formula (I), a salt thereof, or a hydrate thereof. That is, the present invention (1) A compound represented by formula (I), or a pharmacologically acceptable salt thereof,
  • X 1 and X 2 each independently represent a nitrogen atom or a carbon atom to which one hydrogen atom is bonded;
  • X 3 represents a nitrogen atom or a general formula CR 1a (Wherein, substituent R 1a represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, or a group selected from substituent group ⁇ )
  • X 4 represents a nitrogen atom or a general formula CR 1b (Wherein, substituent R 1b represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, or a group selected from substituent group ⁇ ) Represents
  • a 1 is a general formula CR 2 (Wherein the substituent R 2 is A bond that forms a double bond together with the bond of an atom on the adjacent L 1 or a bond of the adjacent A 2 ; Halogen atoms, A cyano group, or Represents a group selected from the substituent group ⁇ ), Or represents a nitrogen atom,
  • a 2 represents a general formula CR 3 R 4 (Wherein the substituents R 3 and R 4 are each independently When A 1 is of the general formula CR 2, it is integrated with the bond of A 1 or double bond with the bond of A 3 (A 4 when A 3 itself is a bond).
  • a 3 has the general formula CR 6 R 7 (wherein the substituents R 6 and R 7 are each independently A bond that forms a double bond with the adjacent A 2 or A 4 bond; Halogen atoms, A cyano group, or A group selected from the substituent group ⁇ , or R 6 and R 7 together form an oxo group or an optionally substituted hydroxyimino group), NR 8 (wherein the substituent R 8 is A bond that forms a double bond together with an adjacent A 2 or A 4 bond, or Represents a group selected from the substituent group ⁇ ), Oxygen atom, Represents a sulfur atom which may be oxidized, or a bond,
  • a 4 represents a general formula CR 9 R 10
  • the substituents R 9 and R 10 are each independently A bond that forms a double bond together with the adjacent A 3 (A 2 if A 3 itself is a bond); Halogen atoms, A cyano group, or A group selected from the substituent group ⁇ , or R 9 and R 10 together form an oxo group or an optionally substituted hydroxyimino group), NR 11 (wherein the substituent R 11 is An adjacent A 3 (which represents a bond selected from the substituent group ⁇ , or a bond that forms a double bond together with the bond of A 2 when A 3 itself is a bond), Represents an oxygen atom or an optionally oxidized sulfur atom; L 1 represents a carbon atom that is bonded to A 1 and may be substituted with a group selected from substituent group ⁇ ;
  • Q 1 is a structure between L 1 and L 2 represented by the following formula (II) (* indicates a bond),
  • Z 1 and Z 4 each independently represent a general formula CR 20 (wherein the substituent R 20 represents a halogen atom, a cyano group, or a group selected from the substituent group ⁇ ), or a nitrogen atom. Represent,
  • Z 2 , Z 3 , Z 5 and Z 6 are each independently General formula CR 21 R 22 (wherein the substituents R 21 and R 22 are each independently Halogen atoms, A cyano group, or A group selected from the substituent group ⁇ , or R 21 and R 22 together form an oxo group or an optionally substituted hydroxyimino group)
  • Z 7 represents a nitrogen atom which may be substituted with a group selected from the substituent group ⁇ , an oxygen atom, a sulfur atom which may be oxidized, or a bond,
  • L 2 is an atom bonded to Z 7 on Q 1 , and is substituted by an oxo group and a group selected from substituent group ⁇ , with the general formula —Y 3 —Y 4 —Y 5 — (Y 3 Carbon atoms, or Represents a sulfur atom which may be oxidized,
  • Y 4 is a bond, Represents a carbon atom which may be substituted by a group selected from the substituent group ⁇ and may form multiple bonds with adjacent carbon atoms;
  • Y 5 is a bond, A carbon atom that may be substituted by a group selected from the substituent group ⁇ and may form multiple bonds with adjacent carbon atoms; A nitrogen atom optionally substituted with a group selected from substituent group ⁇ , An oxygen atom, or Represents an optionally oxidized sulfur atom),
  • Q 2 is a condensed bicyclic “6-membered ring / 6-membered ring” or “6-membered ring / 5-membered ring” heterocyclic structure represented by the following formula (III), or a group having 5 to 7 atoms: Is a monocyclic structure (* represents a bond to L 2 ),
  • Z 8 , Z 9 , Z 10 , Z 15 , Z 16 , and Z 17 are each independently A carbon group that may be substituted by a group selected from the substituent group ⁇ and an optionally substituted lower alkoxy group, or Represents a nitrogen atom,
  • Z 11 , Z 14 , Z 18 , and Z 20 are each independently A nitrogen atom optionally substituted by a group selected from substituent group ⁇ , an oxygen atom, or Represents a sulfur atom which may be oxidized, Furthermore, they may form a double bond with adjacent Z 12 , Z 13 or Z 19 ,
  • Z 12 , Z 13 , and Z 19 are each independently A substituent group ⁇ , and a carbon atom optionally substituted by a group selected from an oxo group, A nitrogen atom optionally substituted by a group selected from the substituent group ⁇ , An oxygen atom, or Represents a sulfur atom which may be oxidized, In addition, they may form double bonds with adjacent atoms,
  • Z 21 , Z 22 , Z 23 , Z 24 , Z 25 , Z 26 , Z 27 , Z 28 , Z 29 , Z 30 , Z 31 , Z 32 , Z 33 , Z 34 , Z 35 , Z 36 , Z 37 , and Z 38 are each independently A carbon atom optionally substituted by a group selected from the substituent group ⁇ , A nitrogen atom optionally substituted by a group selected from the substituent group ⁇ , An oxygen atom, or Represents a sulfur atom which may be oxidized, Furthermore, they may form double bonds with adjacent atoms.
  • Substituent group ⁇ hydrogen atom, optionally substituted lower alkyl group, optionally substituted lower alkenyl group, optionally substituted monocyclic hydrocarbon ring group or heterocyclic group, protected or Optionally substituted hydroxy group, optionally substituted lower alkoxy group, protected or optionally substituted amino group, azide group, optionally substituted amidino group, optionally protected carboxy group , An optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkylsulfinyl group, and an optionally substituted aminosulfonyl group.
  • Substituent group ⁇ hydrogen atom, halogen atom, cyano group, hydroxy group which may be protected or substituted, amino group which may be protected or substituted, carboxy group which may be protected, substituted An optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted aminosulfonyl group, an oxo group, and an optionally substituted hydroxyimino group;
  • Substituent group ⁇ hydrogen atom, optionally substituted lower alkyl group, optionally substituted lower alkanoyl group, optionally protected carboxy group, optionally substituted aminocarbonyl group, substituted An optionally substituted lower alkylsulfonyl group, and an optionally substituted aminosulfonyl group.
  • Substituent group ⁇ a hydrogen atom, a halogen atom, a hydroxy group that may be protected or substituted, a lower alkoxy group that may be substituted, an oxo group, and a hydroxyimino group that may be substituted.
  • [Substituent group ⁇ ] a hydrogen atom, a halogen atom, and an optionally substituted lower alkyl group.
  • Substituent group ⁇ hydrogen atom, halogen atom, optionally substituted lower alkyl group, optionally substituted lower alkenyl group, protected or optionally substituted hydroxy group, optionally substituted Lower alkoxy group, cyano group, oxo group which may be protected, hydroxyimino group which may be substituted, carboxy group which may be protected, aminocarbonyl group which may be substituted, and protected or substituted An amino group that may be present.
  • Substituent group ⁇ hydrogen atom, optionally substituted lower alkyl group, protected or optionally substituted hydroxy group, optionally substituted lower alkanoyl group, optionally substituted lower alkoxycarbonyl A group, an optionally substituted aminocarbonyl group, an optionally substituted aminosulfonyl group, and an optionally substituted lower alkylsulfonyl group.
  • Q 1 is between L 1 and L 2 represented by the following formula (IV) (wherein R 23 and R 24 are each independently a hydrogen atom, a hydroxymethyl group, (2-amino- 1,2-dioxoethyl) aminomethyl group, (aminosulfonyl) aminomethyl group, 1,2,3-triazol-1-yl group, hydroxy group, aminocarbonyloxy group, amino group, acetylamino group, methylamino group, Any one of (1) to (8) above, wherein dimethylamino group, azido group, carboxy group, aminocarbonyl group, oxo group, or O-methylhydroxyimino group. Or a pharmacologically acceptable salt thereof,
  • Q 2 is a 2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl group, a 2,3-dihydro [1,4] dioxino [2,3-c] Pyridin-7-yl group, 2,3-dihydrobenzo [1,4] dioxin-6-yl group, 8-methoxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine-6 -Yl group, 8-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 5-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 2-methyl-3-oxo-3 , 4-Dihydro-2
  • a medicament comprising the compound according to any one of (1) to (11) above, or a pharmacologically acceptable salt thereof,
  • An antibacterial agent comprising the compound according to any one of (1) to (11) above, or a pharmacologically acceptable salt thereof, and,
  • An infectious disease therapeutic agent comprising the compound according to any one of (1) to (11) above, or a pharmacologically acceptable salt thereof, I will provide a.
  • the compound of the general formula (I) or a salt thereof has a strong antibacterial activity and is useful as an antibacterial agent. Further, the compound of the general formula (I) or a salt thereof is useful as an antibacterial agent because it has a strong antibacterial effect against resistant bacteria such as MRSA and is excellent in tissue migration.
  • Halogen atom means fluorine atom, chlorine atom, bromine atom, iodine atom
  • “Lower alkyl group” means a group having 1 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc. 6 straight-chain or branched alkyl groups are represented.
  • the “lower alkenyl group” represents a linear or branched alkenyl group having 1 to 6 carbon atoms such as a methylidene group, a vinyl group, a 1-propenyl group, or a 2-propenyl group.
  • “Lower alkoxy group” means a methoxy group, ethoxy group, n-propyloxy group, n-butyloxy group, n-pentyloxy group, isopropyloxy group, isobutyloxy group, trt-butyloxy group, etc. Represents a linear or branched alkyloxy group.
  • “Lower alkanoyl group” refers to a linear or branched alkanoyl group having 1 to 6 carbon atoms such as acetyl group, n-propanoyl group, n-butanoyl group, isobutanoyl group, pivaloyl group and the like.
  • the “lower alkylsulfinyl group” represents a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms such as a methylsulfinyl group, an ethylsulfinyl group, an n-propylsulfinyl group, and an isopropylsulfinyl group.
  • the “lower alkylsulfonyl group” represents a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group and the like.
  • “Lower alkoxycarbonyl group” means a straight or branched chain having 2 to 7 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, tert-butyloxycarbonyl group, etc. Represents an alkyloxycarbonyl group.
  • the “optionally substituted lower alkyl group” includes an unsubstituted lower alkyl group, for example, a lower alkyl substituted with a hydroxy group, an alkoxy group, an amino group, a carboxy group, a carbamoyl group, a halogen atom, or the like.
  • Groups such as hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, carboxymethyl group, carbamoylmethyl group, 2-fluoroethyl group, 1- Examples include a fluoroethyl group, a 2,2,2-trifluoroethyl group, a 1,1-difluoroethyl group, and the like.
  • the “optionally substituted lower alkenyl group” includes an unsubstituted lower alkenyl group, for example, a lower alkenyl group substituted by a hydroxy group, an alkoxy group, an amino group, a carboxy group, a carbamoyl group, a halogen atom, or the like. Examples thereof include a methylidene group, a difluoromethylidene group, a vinyl group, a 1-fluorovinyl group, a 2-carboxyvinyl group, a 3-hydroxy-1-propenyl group, and a 3-amino-1-propenyl group. .
  • the “optionally substituted lower alkoxy group” includes an unsubstituted lower alkoxy group, such as 2-hydroxyethyloxy, which is a lower alkoxy group substituted by a hydroxy group, an alkoxy group, a halogen atom, or the like.
  • 2-methoxyethyloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethyloxy group, 1-fluoroethyloxy group, 1,1-difluoroethyloxy group, 2,2,2 -A trifluoroethyloxy group etc. can be illustrated.
  • the “optionally substituted lower alkanoyl group” includes an unsubstituted lower alkanoyl group such as a hydroxyacetyl group, a methoxy group which is a lower alkanoyl group substituted by a hydroxy group, an alkoxy group, a halogen atom, or the like. Examples thereof include an acetyl group, a trifluoroacetyl group, and a 2-fluoro-2-methylpropanoyl group.
  • the “optionally substituted lower alkylsulfinyl group” includes an unsubstituted lower alkylsulfinyl group, for example, a lower alkylsulfinyl group substituted by a hydroxy group, an alkoxy group, a halogen atom, etc., 2- Hydroxyethylsulfinyl group, 2-methoxyethylsulfinyl group, fluoromethylsulfinyl group, difluoromethylsulfinyl group, trifluoromethylsulfinyl group, 2-fluoroethylsulfinyl group, 1,1-difluoroethylsulfinyl group, 2,2,2- A trifluoroethylsulfinyl group etc. can be illustrated.
  • the “optionally substituted lower alkylsulfonyl group” includes an unsubstituted lower alkylsulfonyl group, for example, a lower alkylsulfonyl group substituted by a hydroxy group, an alkoxy group, a halogen atom, or the like.
  • Hydroxyethylsulfonyl group 2-methoxyethylsulfonyl group, fluoromethylsulfonyl group, difluoromethylsulfonyl group, trifluoromethylsulfonyl group, 2-fluoroethylsulfonyl group, 1,1-difluoroethylsulfonyl group, 2,2,2- A trifluoroethylsulfonyl group etc. can be illustrated.
  • the “optionally substituted aminocarbonyl group” includes an unsubstituted aminocarbonyl group, such as a methyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-fluoroethyl group, acetyl group, etc.
  • N-methylaminocarbonyl group N, N-dimethylaminocarbonyl group, N- (2-hydroxyethyl) aminocarbonyl group, N- (2-methoxyethyl) aminocarbonyl group, which are aminocarbonyl groups substituted by Examples thereof include N- (2-fluoroethyl) aminocarbonyl group, N- (acetyl) aminocarbonyl group, N- (methanesulfonyl) aminocarbonyl group and the like.
  • the “optionally substituted aminosulfonyl group” includes an unsubstituted aminosulfonyl group, such as a methyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-fluoroethyl group, acetyl group, etc.
  • Optionally protected hydroxy groups include, in addition to unprotected hydroxy groups, hydroxy groups substituted by any group that can be used as a normal hydroxy protecting group, for example, Green Protective Groups in Organic Synthesis, 4th edition, 16-366, 2006, John Wiley & Sons, Wuts et al. Inc.). Specifically, for example, formyl group, acetyl group, pivaloyl group, tert-butyl group, benzyl group, methoxymethyl group, benzyloxymethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, tert-butyldimethyl A silyl group etc.
  • a protective group can be mentioned as a protective group.
  • the “optionally substituted hydroxy group” include, for example, a hydroxy group substituted by a phenyl group, a pyridyl group, an aminocarbonyl group, an aminosulfonyl group, etc., in addition to an unsubstituted hydroxy group. Can do.
  • the “optionally protected amino group” includes all groups that can be used as ordinary amino protecting groups in addition to unprotected amino groups, such as Green, Wuts et al. Protective Group in Organic Synthesis, 4th edition, pages 696-926, 2006, published in John Wiley & Sons, Inc. An example can be given.
  • formyl group, acetyl group, trifluoroacetyl group, trichloroacetyl group, pivaloyl group, benzoyl group, phthaloyl group, trityl group, allyl group, benzyl group, p-methoxybenzyl group, methoxycarbonyl group, benzyloxy Carbonyl group, (9-fluorenyl) methoxycarbonyl group, allyloxycarbonyl group, methanesulfonyl group, p-toluenesulfonyl group, benzylidene group, diphenylmethylene group, diphenylphosphoryl group, tert-butylsulfinyl group, trimethylsilyl group, tert-butyl A dimethylsilyl group etc. can be mentioned.
  • the “optionally substituted amino group” means, for example, a methyl group, an isopropyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-fluoroethyl group, a phenyl group, in addition to an unsubstituted amino group.
  • Examples thereof include an amino group substituted by a group, a pyridyl group, an aminocarbonyl group, an aminosulfonyl group, and the like.
  • the “optionally protected carboxy group” includes all groups that can be used as a normal carboxy protecting group in addition to the unprotected carboxy group, such as Green, Wuts et al. Protective Group in Organic Synthesis 4th Edition, 533-646, 2006, John Wiley & Sons, Inc. An example can be given. Specifically, for example, methyl group, ethyl group, tert-butyl group, (9-fluorenyl) methyl group, allyl group, benzyl group, diphenylmethyl group, trityl group, trimethylsilyl group, tert-butyldimethylsilyl group, etc. Can be mentioned.
  • the “optionally substituted hydroxyimino group” means, for example, a methyl group, a difluoromethyl group, a 2-hydroxyethyl group, a 2-methoxyethyl group, a 2-fluoroethyl in addition to an unsubstituted hydroxyimino group.
  • examples thereof include a hydroxyimino group in which an oxygen atom is substituted by a group, (hydroxycarbonyl) methyl group, difluoro (hydroxycarbonyl) methyl group, benzyl group, acyl group, aminocarbonyl group, aminosulfonyl group, and the like.
  • Optionally protected oxo group includes all groups that can be used as conventional carbonyl protecting groups in addition to unprotected oxo groups, such as Green, Wuts et al. Protective Group in Organic Synthesis, 4th edition, pp. 435-527, 2006, John Wiley & Sons, Inc. An example can be given. Specific examples include dimethyl ketal group, 1,3-dioxane group, 1,3-dioxolane group and the like.
  • the “optionally substituted lower alkoxycarbonyl group” is substituted with, for example, a halogen atom, a hydroxy group, an alkoxy group, an optionally substituted amino group, etc. in addition to an unsubstituted lower alkoxycarbonyl group.
  • a halogen atom for example, 2-hydroxyethyloxycarbonyl group, 2-methoxyethyloxycarbonyl group, fluoromethoxycarbonyl group, difluoromethoxycarbonyl group, trifluoromethoxycarbonyl group and the like, which are lower alkoxycarbonyl groups.
  • the “optionally substituted amidino group” includes, for example, an amidoxime group and an O-methylamidoxime group in addition to the unsubstituted amidino group.
  • the “optionally substituted monocyclic hydrocarbon ring group or heterocyclic group” is a saturated or unsaturated group having 3 to 7 ring atoms which may contain carbon, nitrogen, oxygen, or sulfur atoms in the ring atoms.
  • Represents a saturated cyclic substituent for example, phenyl group, pyridyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, thiazolyl group, thiophenyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrahydrofuran
  • monocyclic substituents substituted with oxo group, carboxyl group, carbamoyl group, etc. be able to.
  • Examples of the “optionally oxidized sulfur atom” include —S (O 2 ) —, —S (O) —, —S— and the like.
  • X 1 and X 2 each independently represent a nitrogen atom or a carbon atom to which one hydrogen atom is bonded.
  • X 1 is a nitrogen atom
  • X 2 has one hydrogen atom bonded thereto. It is a carbon atom or a nitrogen atom, and particularly preferably, X 1 is a nitrogen atom, and X 2 is a carbon atom to which one hydrogen atom is bonded.
  • X 3 represents a nitrogen atom or a general formula CR 1a (wherein R 1a represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, or a group selected from a substituent group ⁇ )
  • R 1a represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, or a group selected from a substituent group ⁇
  • R 1a represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, an optionally substituted lower alkyl group, or an optionally substituted group.
  • Monocyclic hydrocarbon ring group or heterocyclic group hydroxy group which may be protected or substituted, lower alkoxy group which may be substituted, amino group which may be protected or substituted, azide group, substituted An amidino group, an optionally protected carboxy group, an optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, a substituted Which may be a lower alkyl sulfinyl group, and a substituted aminosulfonyl group.
  • R 1a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, acetyl group, n-propanoyl group, n-butanoyl group, isobutanoyl group, pivaloyl group, hydroxyacetyl group, methoxyacetyl Group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, 2-fluoro-2-methylpropanoyl group, 2,2-difluoropropanoyl group, methyl Group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxymethyl group, methoxy
  • R 1a include fluorine atom, chlorine atom, bromine atom, cyano group, acetyl group, n-propanoyl group, n-butanoyl group, isobutanoyl group, pivaloyl group, hydroxyacetyl group, methoxyacetyl group, trifluoroacetyl group 2-fluoro-2-methylpropanoyl group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxy Methyl group, methoxymethyl group, 1-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2,2-trifluoroethyl group, 1, 1-d
  • R 1a More preferred examples of R 1a include fluorine atom, chlorine atom, bromine atom, cyano group, acetyl group, n-propanoyl group, trifluoroacetyl group, methyl group, ethyl group, isopropyl group, hydroxymethyl group, 1-hydroxyethyl.
  • X 4 represents a nitrogen atom, or a general formula CR 1b (wherein R 1b represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, or a group selected from a substituent group ⁇ )
  • R 1b represents a halogen atom, a cyano group, an optionally substituted lower alkanoyl group, or a group selected from a substituent group ⁇
  • the substituent R 1b is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, or a substituted group.
  • Monocyclic hydrocarbon ring group or heterocyclic group which may be substituted, hydroxy group which may be protected or substituted, lower alkoxy group which may be substituted, amino group which may be protected or substituted, azide Group, an optionally substituted amidino group, an optionally protected carboxy group, an optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl Group, optionally substituted lower alkylsulfinyl group, and an optionally substituted aminosulfonyl group.
  • R 1b examples include hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, acetyl group, n-propanoyl group, n-butanoyl group, isobutanoyl group, pivaloyl group, hydroxyacetyl group, methoxyacetyl Group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, 2-fluoro-2-methylpropanoyl group, 2,2-difluoropropanoyl group, methyl Group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxymethyl group, methoxymethyl group
  • R 1b examples include hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec -Butyl group, tert-butyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, 1-aminoethyl group 2-aminoethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydroxyethyl group, 1-amino- 2-hydroxyethyl, 2-amino-1-hydroxyethyl, 1,2-di
  • R 1b More preferable examples of R 1b include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, an aminomethyl group, 1 -Aminoethyl group, 2-aminoethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxy Methyl group, 1-carboxy-1-hydroxymethyl group, 2-carboxyethyl group, 2-carboxy-1-hydroxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-carboxy-1,2-dihydroxyethyl group 2-amino-1,2-dihydroxyethyl group 2-amino
  • R 1b are hydrogen atom, cyano group, methyl group, 2-carboxy-1,2-dihydroxyethyl group, 2-carboxyvinyl group, 5-carboxythiophenyl group, amidino group, amidoxime group, O -Methylamidoxime group and O-acetylamidoxime group.
  • a 1 is a general formula CR 2 [wherein R 2 is a double bond (integral with a bond of an adjacent atom on L 1 or an integral bond of an adjacent A 2 ). Represents a group selected from a halogen atom, a cyano group, or a substituent group ⁇ ], or represents a nitrogen atom, preferably a nitrogen atom, but with a general formula CR 2 In some cases, the substituent R 2 may be bonded to a bond (integral with the bond of an atom on the adjacent L 1 or combined with the bond of the adjacent A 2 to form a double bond.
  • a hydrogen atom, a halogen atom, a cyano group, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, an optionally substituted monocyclic hydrocarbon ring group or a heterocyclic group A hydroxy group which may be protected or substituted, Lower alkoxy group which may be substituted, amino group which may be protected or substituted, azide group, amidino group which may be substituted, carboxy group which may be protected, aminocarbonyl which may be substituted Selected from a group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkylsulfinyl group, and an optionally substituted aminosulfonyl group.
  • R 2 a bond (integrally with an adjacent bond of an atom on L 1 or an integral with an adjacent bond of A 2 forms a double bond), Hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl Group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1- Aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoromethyl group, 1-fluoro
  • R 2 include a bond (integral with the bond of an atom on the adjacent L 1 or a bond with the bond of the adjacent A 2 to form a double bond), a hydrogen atom, Fluorine atom, cyano group, methyl group, ethyl group, n-propyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, amino Methyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxy
  • a bond (integrated with an adjacent bond of an atom on L 1 or an adjacent A 2 bond to form a double bond), a hydrogen atom, a fluorine atom, Cyano group, methyl group, ethyl group, hydroxymethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, 2-fluoroethyl group, 1,2 -Dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy-1-hydroxymethyl group, 2 -Carboxyethyl group, 2-carboxy-1-hydroxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-carboxy-1,2- Hydroxyethyl group, 2-amino-1,2-diox
  • a 2 represents a general formula CR 3 R 4 , NR 5 , an oxygen atom, or an optionally oxidized sulfur atom, as described above, and is preferably a general formula CR 3 R 4 .
  • R 3 and R 4 are each independently a bond (integral with the bond of A 1 when A 1 is a carbon atom, or A 3 (when A 3 itself is a bond, it forms a double bond together with the bond of A 4 ), a hydrogen atom, a halogen atom, a cyano group, an optionally substituted lower alkyl group, Optionally substituted lower alkenyl group, optionally substituted monocyclic hydrocarbon ring group or heterocyclic group, protected or optionally substituted hydroxy group, optionally substituted lower alkoxy group, protected Or an optionally substituted amino group, an azide group, an optionally substituted amidino group, an optionally protected carboxy group, an optionally substituted aminocarbonyl group, an optionally substituted lower alkyl group; A phonyl group, an optionally substituted lower alkylsulfinyl group, an optionally substituted aminosulfonyl group, an oxo group formed by
  • R 3 and R 4 each independently represents a bond (integrated with a bond of A 1 when A 1 is a carbon atom, or A 3 (A 3 itself is a bond). In this case, a double bond is formed integrally with the bond of A 4 )), hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, n-propyl group, n-butyl Group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1 -Methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl
  • R 3 and R 4 are independently a bond (when A 1 is a carbon atom, it is integrated with a bond of A 1 or A 3 (when A 3 itself is a bond) A 4 ) forms a double bond integrally with the bond of)), hydrogen atom, fluorine atom, cyano group, methyl group, ethyl group, n-propyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxy Ethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group Difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoroe Group, 1,2-di
  • R 3 and R 4 are each independently a bond (when A 1 is a carbon atom, it is integrated with the bond of A 1 or A 3 (A 3 itself is a bond) Are combined with the bond of A 4 ) to form a double bond), hydrogen atom, methyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, aminomethyl group, Methylaminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group 1,2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy-1-hydroxymethyl group, 2-carboxyethyl group, 2-carbo Si-1-hydroxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-carboxy-1,2-dihydroxy
  • a bond (A 1, together with the bond of A 1 when a carbon atom, or in the case of A 3 (A 3 itself bond together with bond A 4) Forming a double bond), a hydrogen atom, a methyl group, and an oxo group.
  • the substituent R 5 is bonded to a bond (when A 1 is a carbon atom, it is integrated with the bond of A 1 or A 3 (A 3 itself is a bond). In this case, a double bond is formed integrally with the bond of A 4 )), a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, or an optionally substituted group.
  • a bond of a bond (integrated with a bond of A 1 when A 1 is a carbon atom, or A 3 (A 4 when A 3 itself is a bond)) Unite with a hand to form a double bond), hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert -Butyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group
  • a 2 is a sulfur atom which may be oxidized, for example, —S (O 2 ) —, —S (O) —, —S— and the like can be exemplified.
  • a 3 represents a general formula CR 6 R 7 , a general formula NR 8 , an oxygen atom, an optionally oxidized sulfur atom, or a bond, but the general formula CR 6 R 7 , the general formula NR 8 , an oxygen atom and a bond are preferable.
  • R 6 and R 7 independently, a bond (integrally formed with a bond of adjacent A 2 or A 4 to form a double bond), a hydrogen atom, a fluorine atom, Chlorine, bromine, cyano, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, Methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2- Aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2, -Trifluor
  • R 6 and R 7 are each independently a bond (integrally formed with the adjacent A 2 or A 4 bond to form a double bond), a hydrogen atom, a fluorine atom, a cyano group, Methyl group, ethyl group, n-propyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, methylaminomethyl Group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2,2- Trifluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group,
  • R 6 and R 7 are independently a bond (when A 1 is a carbon atom, it is integrated with the bond of A 1 or A 3 (when A 3 itself is a bond) A 4 ) form a double bond integrally with the bond of)), hydrogen atom, methyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, aminomethyl group, methyl Aminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy-1-hydroxymethyl group, 2-carboxyethyl group, 2-carboxy 1-hydroxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-carboxy-1,2-dihydroxyethyl group, 1-
  • the substituent R 8 is substituted with a bond (integrated with an adjacent A 2 or A 4 bond to form a double bond), a hydrogen atom, Optionally substituted lower alkyl group, optionally substituted lower alkanoyl group, optionally substituted monocyclic hydrocarbon ring group or heterocyclic group, protected or optionally substituted hydroxy group, substituted Lower alkoxy group which may be protected, amino group which may be protected or substituted, azide group, amidino group which may be substituted, carboxy group which may be protected, aminocarbonyl group which may be substituted, substituted A lower alkylsulfonyl group which may be substituted, a lower alkylsulfinyl group which may be substituted, or an aminosulfonyl group which may be substituted.
  • R 8 a bond (forming a double bond integrally with the adjacent A 2 or A 4 bond), a hydrogen atom, a methyl group, an ethyl group, an n-propyl group N-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxy Ethyl, 1-methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 1-aminoethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2- Fluoroethyl group, 1-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydro
  • R 8 include a bond (forming a double bond together with the adjacent A 2 or A 4 bond), a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, 2 -Hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy- 2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, 2-hydroxy-1-oxoethyl group, 2-amino-1 -Oxoethyl group, 2- (methylamino) -1-oxoethyl group, 2- (dimethylamino) -1-oxyl group, 2-
  • R 8 a bond (forming a double bond together with the adjacent A 2 or A 4 bond), a hydrogen atom, a methyl group, a 1-carboxymethyl group, 2- Carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, 2-hydroxy-1- Oxoethyl group, 2-amino-1-oxoethyl group, 2- (methylamino) -1-oxoethyl group, 2- (dimethylamino) -1-oxoethyl group, 2,3-dihydroxypropyl group, 2-amino-3- Hydroxypropyl group, 3-amino-2-hydroxypropyl group, 2,3-diaminopropyl group, hydroxy group, methoxy group, ethoxy group, meth
  • R 8 are a bond, a hydrogen atom, and a hydroxy group.
  • a 3 is an optionally oxidized sulfur atom, for example, —S (O 2 ) —, —S (O) —, —S— and the like can be exemplified.
  • a 4 represents a general formula CR 9 R 10 , a general formula NR 11 , an oxygen atom, or an optionally oxidized sulfur atom as described above, and the general formula CR 9 R 10 , the general formula NR 11 , An oxygen atom is preferable.
  • R 9 and R 10 are each independently a bond of the bond (adjacent A 3 (or A 2 when A 3 itself is a bond)) Together form a double bond), hydrogen atom, halogen atom, cyano group, optionally substituted lower alkyl group, optionally substituted lower alkanoyl group, optionally substituted monocyclic Hydrocarbon ring group or heterocyclic group, hydroxy group which may be protected or substituted, lower alkoxy group which may be substituted, amino group which may be protected or substituted, azide group, which may be substituted An amidino group, an optionally protected carboxy group, an optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkylsulfur group; Group, optionally substituted aminosulfonyl group, and, R 9, R 10 is an oxo group or an optionally substituted hydroxyimino group, formed together.
  • R 9 and R 10 each independently forms a double bond integrally with a bond of a bond (adjacent A 3 (A 2 when A 3 itself is a bond)).
  • R 9 and R 10 are each independently a bond (integrated with a bond of an adjacent A 3 (or A 2 when A 3 itself is a bond) to form a double bond) , Hydrogen atom, fluorine atom, cyano group, methyl group, ethyl group, n-propyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxy Ethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1- Fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydroxyethyl group, 1-amino
  • R 9 and R 10 each independently forms a double bond integrally with the bond of the bond (adjacent A 3 (A 2 when A 3 itself is a bond)).
  • a 4 has the general formula NR 11
  • the substituent R 11 in the formula is bonded to the bond of the bond (adjacent A 3 (or A 2 when A 3 itself is a bond)).
  • Forming a heavy bond a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, an optionally substituted monocyclic hydrocarbon ring group or heterocyclic group, protected or Optionally substituted hydroxy group, optionally substituted lower alkoxy group, protected or optionally substituted amino group, azide group, optionally substituted amidino group, optionally protected carboxy group
  • An optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkylsulfinyl group, or an optionally substituted amino group Is a Ruhoniru group.
  • R 11 a bond (forming a double bond integrally with a bond of an adjacent A 3 (or A 2 when A 3 itself is a bond)), a hydrogen atom, methyl Group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 1-methoxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl Group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2,2,2-trifluoroethyl group
  • R 11 include a hydrogen atom, methyl group, ethyl group, n-propyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2-fluoroethyl group, 2,2, 2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 1-amino-1-carboxymethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, 2-hydroxy-1-oxoethyl group, 2-amino-1-oxoethyl group, 2- (methylamino) -1-oxoethyl group, 2 -(Dimethylamino) -1-oxoethyl group, 2,3-dihydroxypropyl group
  • R 11 More preferred specific examples of R 11 include a hydrogen atom, a methyl group, an ethyl group, a 2-hydroxyethyl group, a 2-aminoethyl group, a 2-fluoroethyl group, a 1-carboxymethyl group, a 2-carboxyethyl group, 2- Carboxy-2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 1-amino-1-carboxymethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, 2- Hydroxy-1-oxoethyl group, 2-amino-1-oxoethyl group, 2- (methylamino) -1-oxoethyl group, 2- (dimethylamino) -1-oxoethyl group, 2,3-dihydroxypropyl group, 2- Amino-3-hydroxypropyl group, methoxy group
  • Particularly preferred is a hydrogen atom.
  • a 4 is an optionally oxidized sulfur atom, for example, —S (O 2 ) —, —S (O) —, —S— and the like can be exemplified.
  • preferred examples of the general formula (Ia) include the following structures (* represents a bond with L 1.
  • X 2 , R 1a , R 1b , R 5 , R 8 , And R 11 is the same as the definition of the substituent in formula (I).
  • L 1 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group which may be protected or substituted, an amino group which may be protected or substituted, a carboxy group which may be protected, or an optionally substituted group.
  • a carbon atom substituted by a group selected from an aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted aminosulfonyl group, an oxo group, and an optionally substituted hydroxyimino group is there.
  • specific examples of the group substituted with L 1 include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a hydroxy group, an aminocarbonyloxy group, a methoxymethyloxy group, a benzyloxymethyloxy group, a tetrahydropyrani group.
  • Ruoxy trimethylsilyloxy, triethylsilyloxy, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyloxy, acetoxy, trifluoroacetoxy, trichloroacetoxy, pivaloyloxy, benzyloxy, p- Methoxybenzyloxy group, p-nitrobenzyloxy group, benzhydryloxy group, trityloxy group, amino group, formylamino group, acetylamino group, trifluoroacetylamino group, trichloroacetylamino group, pivaloyl Amino group, benzoylamino group, phthaloylamino group, tritylamino group, allylamino group, benzylamino group, p-methoxybenzylamino group, methoxycarbonylamino group, benzyloxycarbonylamino group, (9
  • Preferred examples of the group substituted for L 1 include a hydrogen atom, a cyano group, a hydroxy group, an aminocarbonyloxy group, an amino group, a formylamino group, an acetylamino group, a methoxycarbonylamino group, a methanesulfonylamino group, a methylamino group, Dimethylamino group, 2-hydroxyethylamino group, 2-fluoroethylamino group, aminocarbonylamino group, aminosulfonylamino group, carboxy group, aminocarbonyl group, N-methylaminocarbonyl group, N, N-dimethylaminocarbonyl group N- (2-hydroxyethyl) aminocarbonyl group, N- (acetyl) aminocarbonyl group, N- (methanesulfonyl) aminocarbonyl group, methylsulfonyl group, 2-hydroxyethylsulfonyl group,
  • More preferred specific examples of the group substituted for L 1 include a hydrogen atom, a cyano group, a hydroxy group, an aminocarbonyloxy group, an amino group, a methoxycarbonylamino group, a methanesulfonylamino group, a methylamino group, a dimethylamino group, and an aminocarbonyl.
  • L 1 is a carbon atom substituted by a hydrogen atom or an oxo group.
  • Q 1 represents a structure represented by the following formula (II), which is represented by the following formula (II), and has a 6-membered ring between L 1 and L 2 and one atom extending in the L 2 direction therefrom,
  • Z 1 and Z 4 each independently represent the general formula CR 20 or a nitrogen atom, with the general formula CR 20 being preferred,
  • the substituent R 20 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, A monocyclic hydrocarbon ring group or heterocyclic group which may be substituted, a hydroxy group which may be protected or substituted, a lower alkoxy group which may be substituted, an amino group which may be protected or substituted, An azido group, an optionally substituted amidino group, an optionally protected carboxy group, an optionally substituted aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkyl A sulfinyl group and an optionally substituted aminosulfonyl group.
  • R 20 examples include hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl.
  • R 20 include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, an n-propyl group, a hydroxymethyl group, a methoxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, and aminomethyl.
  • R 20 More preferred specific examples of R 20 include a hydrogen atom, a cyano group, a methyl group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 1 , 2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy-1-hydroxymethyl group 1-amino-1-carboxymethyl group, hydroxy group, aminocarbonyloxy group, methoxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, carboxymethyloxy group, amino group, acetylamino group, methanesulfonylamino Group, methylamino group, dimethylamino group, 2-hydroxye
  • Z 2 , Z 3 , Z 5 and Z 6 each independently represent the general formula CR 21 R 22 , and each of the substituents R 21 and R 22 independently represents a hydrogen atom, a halogen atom, A cyano group, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, an optionally substituted monocyclic hydrocarbon ring group or a heterocyclic group, protected or optionally substituted hydroxy Group, optionally substituted lower alkoxy group, protected or optionally substituted amino group, azide group, optionally substituted amidino group, optionally protected carboxy group, optionally substituted An aminocarbonyl group, an optionally substituted lower alkylsulfonyl group, an optionally substituted lower alkylsulfinyl group, and an optionally substituted Nosuruhoniru group or, R 21, R 22 means an oxo group or an optionally substituted hydroxyimino group, formed together.
  • R 21 and R 22 include hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group.
  • R 21 and R 22 include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, an n-propyl group, a hydroxymethyl group, a methoxymethyl group, a 1-hydroxyethyl group, and a 2-hydroxyethyl group.
  • Aminomethyl group methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,2-dihydroxyethyl group, 1- Amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy-1-hydroxymethyl group, 2-carboxyethyl group, 2- Carboxy-1-hydroxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-carbo Ci-1,2-dihydroxyethyl group, 2-amino-1,2-dioxoethyl group, 1-amino-1-carboxymethyl group, 1-amino-2-carboxyethyl group, 2-amino-2-carboxyethyl group 2-carboxy-1-oxoethyl group
  • R 21 and R 22 include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, a fluoromethyl group, a difluoromethyl group, Fluoromethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy- 1-hydroxymethyl group, 1-amino-1-carboxymethyl group, 2-carboxy-1-oxoethyl group, (2-amino-1,2-dioxoethyl) aminomethyl group, (aminosulfonyl) aminomethyl group, 2- Thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 1-pyrrolyl group, 2-pyrrolyl group
  • R 21 and R 22 include a hydrogen atom, a hydroxymethyl group, (2-amino-1,2-dioxoethyl) aminomethyl group, (aminosulfonyl) aminomethyl group, 1,2,3-triazole-1 -Yl group, hydroxy group, aminocarbonyloxy group, amino group, acetylamino group, methylamino group, dimethylamino group, azido group, carboxy group, aminocarbonyl group, oxo group, and O-methylhydroxyimino group. ,
  • Z 7 represents a nitrogen atom that may be substituted, an oxygen atom, a sulfur atom that may be oxidized, or a bond, as described above, and is preferably a nitrogen atom that may be substituted.
  • the group substituted on the nitrogen atom is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, an optionally protected carboxy group, An aminocarbonyl group which may be substituted, a lower alkylsulfonyl group which may be substituted, and an aminosulfonyl group which may be substituted.
  • specific examples of the group that substitutes for the nitrogen atom include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopropyl group, an isobutyl group, a sec-butyl group, tert-butyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2,3-dihydroxypropyl group, 2-amino-3-hydroxypropyl group, 3-amino-2-hydroxypropyl group 2,3-diaminopropyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2- Amino-1,2-dioxoethyl group, 2-amino-2-carboxyeth
  • Preferred examples include hydrogen atom, acetyl group, hydroxyacetyl group, methoxyacetyl group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, methyl group, ethyl group, 2-hydroxyethyl group, 2-methoxyethyl group.
  • 2-aminoethyl group 2,3-dihydroxypropyl group, 2-amino-3-hydroxypropyl group, 3-amino-2-hydroxypropyl group, 2,3-diaminopropyl group, 2-fluoroethyl group, 2 2,2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 2-amino-2-carboxy group Ethyl group, 2-carboxy-1-oxoethyl group, methoxycarbonyl group, ethoxycal Nyl group, aminocarbonyl group, N-methylaminocarbonyl group, N, N-dimethylaminocarbonyl group, N- (acetyl) aminocarbonyl group, N- (methanesulfonyl) aminocarbonyl group, methylsulfonyl group, 2-hydroxye
  • hydrogen atom acetyl group, hydroxyacetyl group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, methyl group, 2-hydroxyethyl group, 2-aminoethyl group, 2,3-dihydroxy Propyl group, 2-amino-3-hydroxypropyl group, 3-amino-2-hydroxypropyl group, 2,3-diaminopropyl group, 2-fluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2 -Carboxy-2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, methoxycarbonyl group, aminocarbonyl group, N-methyl Aminocarbonyl group, N, N-dimethylaminocarbonyl group, N
  • Q 1 include structures between L 1 and L 2 represented by the following formula.
  • L 2 has the general formula —Y 3 —Y 4 —Y 5 —structure as described above,
  • the constituent Y 3 represents an optionally substituted carbon atom and an optionally oxidized sulfur atom, and is preferably an optionally substituted carbon atom.
  • the group that may be substituted on the carbon atom includes a hydrogen atom, an oxo group, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, an optionally protected carboxy group, and a substituted group.
  • specific examples of the group that may be substituted on the carbon atom include a hydrogen atom, an oxo group, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an isopropyl group, and isobutyl.
  • Preferred examples of the group which may be substituted on the carbon atom include a hydrogen atom, acetyl group, n-propanoyl group, hydroxyacetyl group, methoxyacetyl group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, fluoro Acetyl group, 2-fluoro-2-methylpropanoyl group, 2,2-difluoropropanoyl group, methyl group, ethyl group, n-propyl group, hydroxymethyl group, methoxymethyl group, 2-hydroxyethyl group, 2- Methoxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-tri Fluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydroxy
  • More preferable examples of the group which may be substituted on the carbon atom include a hydrogen atom, an acetyl group, a hydroxyacetyl group, an aminoacetyl group, a methylaminoacetyl group, a dimethylaminoacetyl group, a fluoroacetyl group, a methyl group, and hydroxymethyl.
  • Y 3 is an optionally oxidized sulfur atom
  • specific examples include —S (O 2 ) —, —S (O) —, —S—, and the like.
  • Y 4 as a constituent element of L 2 means a bond (forms a multiple bond with the carbon atom of adjacent Y 5 ) or an optionally substituted carbon atom as described above. It ’s a bond.
  • the group substituted on the carbon atom is a hydrogen atom, a halogen atom, a hydroxy group that may be protected or substituted, a lower alkoxy group that may be substituted, an oxo group, or a substituent. It may be a hydroxyimino group.
  • specific examples of the group substituted on the carbon atom include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, an aminocarbonyloxy group, a methoxymethyloxy group, a benzyloxymethyloxy group, and a tetrahydropyranyloxy group.
  • Preferred examples of the group substituted on the carbon atom include a hydrogen atom, a fluorine atom, a hydroxy group, an aminocarbonyloxy group, a methoxy group, an ethoxy group, a 2-hydroxyethyloxy group, a 2-methoxyethyloxy group, a fluoromethoxy group, Difluoromethoxy group, trifluoromethoxy group, 2-fluoroethyloxy group, 1,1-difluoroethyloxy group, 2,2,2-trifluoroethyloxy group, carboxymethyloxy group, 2-aminoethyloxy group, oxo Group, hydroxyimino group, O-methylhydroxyimino group, O- (fluoromethyl) hydroxyimino group, O- (difluoromethyl) hydroxyimino group, O- (trifluoromethyl) hydroxyimino group, O- (carboxymethyl) Hydroxyimino group, O- (difluor
  • More preferred examples of the group substituted on the carbon atom include a hydrogen atom, a fluorine atom, a hydroxy group, an aminocarbonyloxy group, a methoxy group, a carboxymethyloxy group, a 2-aminoethyloxy group, an oxo group, a hydroxyimino group, an O -Methylhydroxyimino group, O- (fluoromethyl) hydroxyimino group, O- (carboxymethyl) hydroxyimino group, etc., particularly preferably a hydrogen atom.
  • Y 5 which is a component of L 2 is a bond (forms a multiple bond with the carbon atom of adjacent Y 4 ), an optionally substituted carbon atom, or an optionally substituted nitrogen.
  • the group which may be substituted on the carbon atom is hydrogen atom, fluorine atom, chlorine atom, bromine atom, hydroxy group, aminocarbonyloxy group, methoxymethyloxy group, benzyloxymethyloxy group, tetrahydropyranyl.
  • Oxy group trimethylsilyloxy group, triethylsilyloxy group, tert-butyldimethylsilyloxy group, tert-butyldiphenylsilyloxy group, acetoxy group, trifluoroacetoxy group, trichloroacetoxy group, pivaloyloxy group, benzyloxy group, p-methoxy Benzyloxy group, p-nitrobenzyloxy group, benzhydryloxy group, trityloxy group, methoxy group, ethoxy group, n-propyloxy group, n-butyloxy group, n-pentyloxy group, isopropyloxy group, isobuty Oxy group, tert-butyloxy group, 2-hydroxyethyloxy group, 2-methoxyethyloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethyloxy group, 1-
  • Preferred examples of the group that may be substituted on the carbon atom include a bond (forms a multiple bond with the carbon atom of adjacent Y 5 ), a hydrogen atom, a fluorine atom, a hydroxy group, an aminocarbonyloxy group, and a methoxy group.
  • Ethoxy group 2-hydroxyethyloxy group, 2-methoxyethyloxy group, fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethyloxy group, 1,1-difluoroethyloxy group, 2,2 , 2-trifluoroethyloxy group, carboxymethyloxy group, 2-aminoethyloxy group, oxo group, hydroxyimino group, O-methylhydroxyimino group, O- (fluoromethyl) hydroxyimino group, O- (difluoromethyl) ) Hydroxyimino group, O- (trifluoromethyl) hydroxyimino group, O- And (ruboxymethyl) hydroxyimino group, O- (difluorocarboxymethyl) hydroxyimino group, O- (2-carboxyisopropyl) hydroxyimino group and the like.
  • More preferred examples of the group that may be substituted on the carbon atom include a bond (forms a multiple bond with the adjacent Y 5 carbon atom), hydrogen atom, fluorine atom, hydroxy group, aminocarbonyloxy group, methoxy group.
  • a particularly preferred example is a hydrogen atom.
  • specific examples of the group that may be substituted on the nitrogen atom include a hydrogen atom, an acetyl group, an n-propanoyl group, an n-butanoyl group, an isobutanoyl group, a pivaloyl group, a hydroxyacetyl group, a methoxyacetyl group, an aminoacetyl group.
  • methylaminoacetyl group dimethylaminoacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, 2-fluoro-2-methylpropanoyl group, 2,2-difluoropropanoyl group, methyl group, ethyl group N-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2,3-dihydroxypropyl group, 2-amino-3-hydroxypropyl group, 3- Mino-2-hydroxypropyl group, 2,3-diaminopropyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxye
  • Preferred examples of the group that may be substituted with the nitrogen atom include a hydrogen atom, acetyl group, hydroxyacetyl group, methoxyacetyl group, aminoacetyl group, methylaminoacetyl group, dimethylaminoacetyl group, methyl group, ethyl group, 2 -Hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2,3-dihydroxypropyl group, 2-amino-3-hydroxypropyl group, 3-amino-2-hydroxypropyl group, 2,3-diamino Propyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-amino-1,2- Dioxoethyl group, 2-amino-2-carboxyethyl group,
  • More preferred examples of the group that may be substituted with the nitrogen atom include a hydrogen atom, an acetyl group, a hydroxyacetyl group, an aminoacetyl group, a methylaminoacetyl group, a dimethylaminoacetyl group, a methyl group, a 2-hydroxyethyl group, 2 -Aminoethyl group, 2,3-dihydroxypropyl group, 2-amino-3-hydroxypropyl group, 3-amino-2-hydroxypropyl group, 2,3-diaminopropyl group, 2-fluoroethyl group, 1-carboxy Methyl group, 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, methoxy Carbonyl group, aminocarbonyl
  • L 2 preferred examples include —CH 2 — and —CH 2 —CH 2 —.
  • Q 2 is, as described above, a condensed bicyclic “6-membered ring / 6-membered ring” or “6-membered ring / 5-membered ring” heterocyclic structure represented by the following formula (III), or an atom A monocyclic structure of Formula 5-7 is shown, and a condensed bicyclic “6-membered ring / 6-membered ring” or “6-membered ring / 5-membered ring” heterocyclic structure is preferable.
  • Z 8 , Z 9 , Z 10 , Z 15 , Z 16 and Z 17 are each independently a nitrogen atom or an optionally substituted carbon atom as described above.
  • the group that may be substituted on the carbon atom is a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group.
  • Preferred examples are hydrogen atom, fluorine atom, chlorine atom, methyl group, hydroxymethyl group, methoxymethyl group, 2-hydroxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 2-aminoethyl group, Fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,1-difluoroethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1 , 2-diaminoethyl group, 1-carboxymethyl group, 1-carboxy-1-hydroxymethyl group, 2-carboxyethyl group, 2-carboxy-1-hydroxyethyl group, 2-carboxy-2-hydroxyethyl group, 2 -Carboxy-1,2-dihydroxyethyl group, 2-amino-1,2-dioxoethyl 1-amino-1-carboxymethyl
  • More preferred examples are hydrogen atom, fluorine atom, chlorine atom, methyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 1,2-dihydroxyethyl.
  • Z 11 , Z 14 , Z 18 , and Z 20 each independently represent a nitrogen atom that may be substituted, an oxygen atom, or a sulfur atom that may be oxidized, and adjacent Z 12 , Z 13 , or Z 19 may form a double bond, but preferably, Z 11 and Z 18 are oxygen atoms or sulfur atoms, and Z 14 and Z 20 are substituted. It may be a nitrogen atom or an oxygen atom.
  • the group that may be substituted on the nitrogen atom is a hydrogen atom, an optionally substituted lower alkyl group, an optionally protected hydroxy group, and an optionally substituted lower alkoxy group.
  • a hydrogen atom methyl group, ethyl group, 2-hydroxyethyl group, 2-aminoethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2,3-dihydroxypropyl group, 2 -Amino-3-hydroxypropyl group, 3-amino-2-hydroxypropyl group, 2,3-diaminopropyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy-2-hydroxyethyl group, 2 -Amino-1,2-dioxoethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, hydroxy group, methoxymethyloxy group, methoxy group, 2-hydroxyethyloxy group, 2-methoxy
  • Examples include an ethyloxy group, a carboxymethyloxy group, and a 2-aminoethyloxy group.
  • a hydrogen atom methyl group, 2-hydroxyethyl group, 2-aminoethyl group, 2-fluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-amino-1,2-dioxoethyl group 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, hydroxy group, methoxy group, 2-hydroxyethyloxy group, carboxymethyloxy group, 2-aminoethyloxy group, etc.
  • Particularly preferred is a hydrogen atom.
  • Z 11 , Z 14 , Z 18 , and Z 20 are sulfur atoms that may be oxidized, specifically, —S—, —S (O) —, —S (O 2 ) —, etc. It can be illustrated.
  • Z 12 , Z 13 and Z 19 are each independently an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom, or an optionally oxidized sulfur atom. And may form a double bond with adjacent atoms, but is preferably an optionally substituted carbon atom.
  • the group that may be substituted on the carbon atom is a hydrogen atom, a halogen atom, an oxo group, or an optionally substituted lower alkyl group.
  • Preferred examples include a hydrogen atom, fluorine atom, chlorine atom, methyl group, hydroxymethyl group, methoxymethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1-difluoroethyl group, 1,2-dihydroxyethyl Group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group, 2-amino-1,2-dioxoethyl group, 2-carboxy A 1-oxoethyl group, an oxo group, and the like.
  • More preferred examples include a hydrogen atom, a fluorine atom, a methyl group, a hydroxymethyl group, an aminomethyl group, a methylaminomethyl group, a dimethylaminomethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and 1,2-dihydroxy.
  • Ethyl group 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 2-amino-1,2-dioxoethyl group, 2-carboxy-1-oxoethyl group
  • an oxo group particularly preferably a hydrogen atom, an oxo group, a fluorine atom, and a methyl group.
  • the group that may be substituted on the nitrogen atom is a hydrogen atom, an optionally substituted lower alkyl group, an optionally protected hydroxy group, and an optionally substituted lower alkoxy group.
  • Preferred examples are hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group, 2-methoxyethyl group, 2-aminoethyl group, 2,3-dihydroxypropyl group, 2-amino-3-hydroxypropyl group, 3 -Amino-2-hydroxypropyl group, 2,3-diaminopropyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 1-carboxymethyl group, 2-carboxyethyl group, 2-carboxy- 2-hydroxyethyl group, 2-amino-1,2-dioxoethyl group, 2-amino-2-carboxyethyl group, 2-carboxy-1-oxoethyl group, hydroxy group, methoxy group, ethoxy group, 2-hydroxyethyloxy Group, 2-methoxyethyloxy group, carboxymethyloxy group, 2-aminoethyloxy group, etc. Kill.
  • More preferred examples include a hydrogen atom, a methyl group, a 2-hydroxyethyl group, a 2-aminoethyl group, a 2,3-dihydroxypropyl group, a 2-amino-3-hydroxypropyl group, and a 3-amino-2-hydroxypropyl group.
  • 2,3-diaminopropyl group, 2-fluoroethyl group, 2-amino-1,2-dioxoethyl group, 2-carboxy-1-oxoethyl group, hydroxy group, methoxy group, 2-hydroxyethyloxy group, 2- An aminoethyloxy group etc. can be mentioned.
  • Z 12 , Z 13 and Z 19 are sulfur atoms which may be oxidized, specific examples include —S—, —S (O) —, —S (O 2 ) — and the like. it can.
  • Z 21, Z 22, Z 23 , Z 24, Z 25, Z 26, Z 27, Z 28, Z 29, Z 30, Z 31, Z 32, Z 33, Z 34, Z 35, Z 36, Z 37 , And Z 38 each independently represents an optionally substituted carbon atom, an optionally substituted nitrogen atom, an oxygen atom, or an optionally oxidized sulfur atom, adjacent to each other. May form a double bond with the atom
  • the group that may be substituted on the carbon atom includes a hydrogen atom, a halogen atom, a cyano group, an optionally substituted lower alkyl group, an optionally substituted lower alkanoyl group, and an optionally protected hydroxy group.
  • specific examples of the group that may be substituted on the carbon atom include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, n-pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, hydroxymethyl, methoxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-methoxyethyl, 1-methoxy Ethyl group, aminomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 1- Fluoroethyl group, 2,2,2-trifluoroethyl group, 1,1
  • Preferred examples of the group that may be substituted on the carbon atom include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, an ethyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, and a 2-methoxyethyl group.
  • Aminomethyl group methylaminomethyl group, dimethylaminomethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group 1,1-difluoroethyl group, 1,2-dihydroxyethyl group, 1-amino-2-hydroxyethyl group, 2-amino-1-hydroxyethyl group, 1,2-diaminoethyl group, 1-carboxymethyl group 1-carboxy-1-hydroxymethyl group, 2-carboxyethyl group, 2-carboxy-1-hydroxyethyl group 2-carboxy-2-hydroxyethyl group, 2-carboxy-1,2-dihydroxyethyl group, 2-amino-1,2-dihydroxyethyl group, 2-amino-1,2-dioxoethyl group, 1-amino-1-carboxymethyl group, 1-amino
  • More preferred examples of the group that may be substituted on the carbon atom include a hydrogen atom, a fluorine atom, a cyano group, a methyl group, a hydroxymethyl group, a 2-hydroxyethyl group, an aminomethyl group, a methylaminomethyl group, and dimethylamino.
  • Particularly preferred examples include a hydrogen atom, a fluorine atom, and a cyano group. And methylidene group, hydroxy group, methoxy group, methanesulfonylamino group, oxo group, 1,3-dioxolan-2-yl group, hydroxyimino group, O-methylhydroxyimino group and the like.
  • the group which may be substituted on the nitrogen atom is a hydrogen atom, an optionally substituted lower alkanoyl group, an optionally substituted lower alkyl group, an optionally protected hydroxy group, or an optionally substituted group.
  • specific examples of the group which may be substituted on the nitrogen atom include a hydrogen atom, an acetyl group, an n-propanoyl group, an n-butanoyl group, an isobutanoyl group, a pivaloyl group, a hydroxyacetyl group, a methoxyacetyl group, an amino group.
  • Acetyl group methylaminoacetyl group, dimethylaminoacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, 2-fluoro-2-methylpropanoyl group, 2,2-difluoropropanoyl group, methyl group, ethyl Group, n-propyl group, n-butyl group, n-pentyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, hydroxymethyl group, methoxymethyl group, 1-hydroxyethyl group, 2-hydroxy Ethyl group, 2-methoxyethyl group, 1-methoxyethyl group, a Nomethyl group, methylaminomethyl group, dimethylaminomethyl group, 1-aminoethyl group, 2-aminoethyl group, fluoromethyl group, difluoromethyl group, triflu
  • Preferred examples of the group that may be substituted with the nitrogen atom include a hydrogen atom, an acetyl group, a hydroxyacetyl group, a methoxyacetyl group, an aminoacetyl group, a methylaminoacetyl group, a dimethylaminoacetyl group, a fluoroacetyl group, and a methyl group.
  • More preferred examples of the group that may be substituted on the nitrogen atom include a hydrogen atom, an acetyl group, a hydroxyacetyl group, an aminoacetyl group, a methylaminoacetyl group, a dimethylaminoacetyl group, a fluoroacetyl group, a methyl group, and an ethyl group.
  • Z 38 is an optionally oxidized sulfur atom
  • specific examples include —S—, —S (O) —, —S (O 2 ) — and the like.
  • Z 38 is an optionally oxidized sulfur atom
  • specific examples include —S—, —S (O) —, —S (O 2 ) — and the like.
  • Q 2 include [1,2,3] thiadiazolo [5,4-b] pyridin-6-yl group, 1H-pyrrolo [2,3-b] pyridin-2-yl group, 2,3- Dihydro [1,4] dioxino [2,3-b] pyridin-6-yl group, 2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl group, 2,3- Dihydro [1,4] dioxino [2,3-c] pyridin-7-yl group, 2,3-dihydrobenzo [1,4] dioxin-6-yl group, 2-oxo-2,3-dihydro-1H -Pyrid [2,3-b] [1,4] oxazin-7-yl group, 2-oxo-2,3-dihydro-1H-pyrido [2,3-b] [1,4] thiazine-7- Yl group, 3,4-dihydro
  • Preferred examples include 2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl group, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine-7.
  • -Yl group 2,3-dihydrobenzo [1,4] dioxin-6-yl group, 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 8-methoxy -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 5-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 6-yl group, 7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 2-methyl-3-oxo-3,4-dihydro-2H-benzo [
  • More preferred examples include 2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl group, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine- 7-yl group, 2,3-dihydrobenzo [1,4] dioxin-6-yl group, 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 8- Methoxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 8-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine -6-yl group, 5-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,
  • Particularly preferred examples include 2,3-dihydro [1,4] dioxino [2,3-b] pyridin-7-yl group, 2,3-dihydro [1,4] dioxino [2,3-c] pyridine- 7-yl group, 2,3-dihydrobenzo [1,4] dioxin-6-yl group, 8-methoxy-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl 8-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 5-methyl-3-oxo-3,4-dihydro-2H-benzo [1 , 4] oxazin-6-yl group, 7-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl group, 2-methyl-3-oxo-3,4 A dihydro-2H-benzo [
  • the compound of the present invention represented by the general formula (I) can be produced by various methods.
  • the compound (I) of the present invention can be produced by the following method.
  • LG 1 in the general formula (3a) is a leaving group substituted by a reactive atom in the L 1 structure which is bonded to A 1 later, and remains in the compound of the general formula (4) after the reaction. May or may not be. Further, LG 1 may not be present when the reactivity of the reactive atom is sufficiently high. Examples of LG 1 include chlorine, bromine, iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group, and the like.
  • PG 1 in the general formulas (3a), (3b), and (4) is a protecting group substituted with a reactive atom in the Q 1 structure that is bonded to L 2 later, and the reactivity of the reactive atom is It may be absent if it does not affect the production of the compound of the general formula (4).
  • L 11 in the general formula (3b) is a structure shorter by one methylene chain in the L 1 structure.
  • the general formula (3b) may be not only the aldehyde shown, but also a carbonyl compound (3c) such as a ketone.
  • LG 2 in the general formula (6a) is a leaving group that is substituted with a reactive atom in the L 2 structure that is bonded to Q 1 later. Good or not. LG 2 may not be present when the reactivity of the reactive atom is sufficiently high. Examples of LG 2 include chlorine, bromine, iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group, and the like.
  • the general formula (6b) may be not only the aldehyde shown, but also a carbonyl compound (6c) such as a ketone.
  • L 21 in the general formula (6b) is a structure shorter by one methylene chain in the L 2 structure.
  • the compound of the general formula (4) can be produced, for example, by reacting the amine derivative of the general formula (2) with the compound of the general formula (3a) in the presence of a base and optionally an iodide. .
  • This reaction was described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), 499-500, 513-515, 2001, John Wiley & Sons, Inc. It can be performed by a method according to it.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • Halogen hydrocarbons such as methylene, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ketones such as acetone, 2-butanone and tert-butyl methyl ketone, diethyl ether, diisopropyl ether Tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, and other ethers, dimethyl
  • sulfoxides such as sulfoxide
  • esters such as ethyl acetate and tert-butyl acetate
  • amides such as N, N-dimethylformamide, N
  • Examples of the base used in this reaction include triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8- Diazabicyclo [5,4,0] undec-7-ene, 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a] pyrimidine, 2-tert-butylimino-2-diethylamino- Organic bases such as 1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, lithium diisopropylamide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide , Sodium bicarbonate, sodium carbonate, potassium carbonate Cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydrox
  • phase transfer catalyst may be allowed to coexist if necessary, and examples of the phase transfer catalyst include tetra n-butylammonium chloride, triethylbenzylammonium chloride, 18-crown-6, and the like.
  • the amount of the base used may be 1 to 10 times mol of the general formula (2), and the iodide may be 0.01 to 10 times mol.
  • the phase transfer catalyst may be 0.01 to 10 times mol.
  • the reaction temperature is ⁇ 100 to 250 ° C., preferably ⁇ 80 to 150 ° C., and the reaction time may be 10 minutes to 24 hours.
  • the amine derivative of the general formula (2) and the compound of the general formula (3a) are reacted in the presence of a base or a Lewis acid, if desired.
  • a base or a Lewis acid if desired.
  • the general formula (3a) is a Michael acceptor
  • the amine derivative of the general formula (2) and the compound of the general formula (3a) are optionally reacted in the presence of a base or a Lewis acid.
  • the compound of the general formula (4) can be produced.
  • This reaction is a method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), pages 1022-1024, 2001, John Wiley & Sons, Inc. be able to.
  • an amine derivative of the general formula (2) and a compound of the general formula (3a) are optionally added.
  • the compound of the general formula (4) can be produced.
  • the general formula (3) is a carboxylic acid or the like
  • the amine derivative of the general formula (2) and the compound of the general formula (3a) are reacted with a condensing agent in the presence of a base, if desired.
  • the compound of (4) can be produced.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • Halogen hydrocarbons such as methylene, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ketones such as acetone, 2-butanone and tert-butyl methyl ketone
  • diether diisopropyl ether Tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, and other ethers, dimethyl
  • examples include sulfoxides such as sulfoxide, esters such as ethyl acetate and tert-butyl
  • acid halides examples include acid halides such as acid chloride, acid bromide, and acid fluoride, carboxylic acid and ethyl chlorocarbonate, isobutyl chlorocarbonate, or pivaloyl chloride in the presence of an organic base.
  • acid halides such as acid chloride, acid bromide, and acid fluoride, carboxylic acid and ethyl chlorocarbonate, isobutyl chlorocarbonate, or pivaloyl chloride in the presence of an organic base.
  • Examples of the base used in this reaction include triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine, 1,8-diazabicyclo [5,4,0] undec-7-ene, 1,3,3.
  • condensing agent used in this reaction examples include carbodiimides such as N, N-dicyclohexylcarbodiimide and N-ethyl-N ′-(3-dimethylamino) carbodiimide, diisopropylcarbodiimide, carbonyls such as carbonyldiimidazole, and diphenyl.
  • carbodiimides such as N, N-dicyclohexylcarbodiimide and N-ethyl-N ′-(3-dimethylamino) carbodiimide
  • diisopropylcarbodiimide examples include carbonyls such as carbonyldiimidazole, and diphenyl.
  • Acid azides such as phosphoryl azide, acid cyanides such as diethyl phosphoryl cyanide, 1- [bis (dimethylamino) methylene] -1H-benzotriazonium hexafluorophosphate 3-oxide, 1- [bis (dimethylamino) ) Methylene] -1H-benzotriazolium tetrafluoroborate 3-oxide, 1- [bis (dimethylamino) methylene] -5-chloro-1H-benzotriazolium hexafluorophosphate 3-oxide, 1- [ Screw( Methylamino) methylene] -5-chloro-1H-benzotriazolium tetrafluoroborate, guanidinium salts such as 3-oxide, O- (7-azabenzotriazol-1-yl) -1,1,3,3- Tetramethyluronium hexafluorophosphate, bromotris (pyrrolidino) phosphonium he
  • the amount of the base and condensing agent used in this reaction may be 0.01 to 50 times mol, preferably 1 to 5 times mol for the general formula (2).
  • the reaction temperature is ⁇ 80 to 150 ° C., preferably ⁇ 20 to 120 ° C., and the reaction time is 1 minute to 48 hours.
  • the compound of General formula (4) can be manufactured by making the amine derivative of General formula (2) react with carbonyl compounds, such as General formula (3b), in presence of a reducing agent.
  • This reaction is described in WO2007 / 081597, WO2007 / 071936 or Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), 1187-1189, 2001, John Wiley & c. Can be carried out by the method described in 1) or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • Halogen hydrocarbons such as methylene, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether
  • ethylene Ethers such as glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether
  • sulfoxides such as dimethyl sulfoxide, ethyl acetate, tert-butyl acetate
  • Esters such as esters, N, N-dimethylformamide, N, N- dimethyl
  • Examples of the reducing agent used in this reaction include lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and other hydrogenated complex compounds such as borane, sodium and sodium amalgam. Can be mentioned. Further, catalytic reduction using Raney nickel, platinum oxide or palladium black, reduction using zinc and an acid, and the like can also be used.
  • the reducing agent may be used in an amount of 1 to 20 times mol, preferably 1 to 5 times mol, of the compound of the general formula (2).
  • the reaction temperature is ⁇ 50 to 200 ° C., preferably ⁇ 10 to 100 ° C., and the reaction time is 10 minutes to 72 hours.
  • the compound of the general formula (2) and the general formula Production by reacting the compound of general formula (5) with the compound of general formula (6a) in the same manner as in the case of obtaining the compound of general formula (4) by reacting the compound of 3a) Can do. Further, in the same manner as in the case of obtaining the compound of the general formula (4) by reacting the compound of the general formula (2) and the compound of the general formula (3b), the compound of the general formula (5) and the general formula ( It can be produced by reacting the compound of 6b).
  • the substituent and functional group of the compound may be appropriately protected with a protecting group, or may be deprotected at an appropriate stage.
  • the compound of the general formula (I) can also be produced from the compound of the general formula (2) according to Scheme 2.
  • the compound of the general formula (2) is obtained in the same manner as in the case of obtaining the compound of the general formula (4) by reacting the compound of the general formula (2) with the compound of the general formula (3a) or (3b). And a compound of the general formula (7a) or (7b) can be produced.
  • the general formula (7b) may be not only the illustrated aldehyde but also a carbonyl compound (7c) such as a ketone.
  • the compound of the general formula (2) can be produced, for example, according to Scheme 3.
  • LG 3 and LG 4 in the general formulas (8), (10) and (11) are leaving groups, and LG 4 remains in the compound of the general formula (10) or (2) after the reaction. May or may not be.
  • LG 3 and LG 4 may be converted from appropriate precursor functional groups to LG 3 and LG 4 at appropriate stages of the following production methods, respectively, when the reactivity of the A 2 atom is sufficiently high. LG 4 may not be present.
  • Examples of LG 3 and LG 4 include chlorine, bromine, iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group, and the like.
  • PG 2 and PG 3 in the general formulas (9), (10), and (11) are an amino protecting group or hydrogen, and in the case of an amino protecting group, for example, protection by Green, Wuts et al. • Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2006, described in John Wiley & Sons, Inc. An example is given.
  • One or both of PG 2 and PG 3 may be hydrogen as long as the reaction is not hindered.
  • the compound of the general formula (2) can be produced from the compound of the general formula (8) via the compound of the general formula (10).
  • the compound of the general formula (8) is converted to the compound of the general formula (9) by the same method as that for producing the compound of the general formula (4) from the compound of the general formula (2) and the compound of the general formula (3a).
  • the compound of general formula (10) can be manufactured by making it react.
  • the compound of the general formula (9) may be replaced with a metal azide.
  • the azide group is reduced to an amine after the reaction (in the compound of the general formula (10), both PG 2 and PG 3 Can be used in subsequent reactions.
  • nucleophilic substitution reaction with an azide ion used in this case is carried out in the presence of iodide, if desired.
  • Advanced Organic Chemistry 5th edition by Michael B. Smith and Jerry March), pp. 515-516, 2001 , John Wiley & Sons, Inc., etc.
  • the solvent used in the azidation reaction may be any solvent that does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • Halogen hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ketones such as acetone, 2-butanone and tert-butyl methyl ketone
  • diethyl ether diisopropyl Ethers such as ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether
  • examples include sulfoxides such as methyl sulfoxide, esters such as ethyl acetate and
  • Examples of the iodide used include potassium iodide and sodium iodide.
  • Examples of azide ions used include sodium azide and trimethylsilyl azide.
  • the amount of iodide used may be 0.1 to 10 times mol of the general formula (8), and the azide ion may be 1 to 10 times mol of the compound of the general formula (8).
  • the reaction temperature is 0 to 200 ° C., preferably 20 to 120 ° C., and the reaction time may be 5 minutes to 48 hours.
  • hydride-based reducing reagents such as lithium aluminum hydride, sodium borohydride, thiol, triphenylphosphine, trihydrophenylsilane, polymethylhydrosiloxane And a catalytic amount of hexabutylstanohexane.
  • the solvent used in the reduction reaction may be any solvent that does not adversely affect the reaction.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • chloride Halogen hydrocarbons such as methylene, chloroform and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, ketones such as acetone, 2-butanone and tert-butyl methyl ketone, diethyl ether, diisopropyl ether Ethers such as tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether and ethylene glycol monomethyl ether; Sulfoxides such as sulfoxide, esters such as ethyl acetate and tert-butyl acetate,
  • the reducing agent may be used in an amount of 1 to 10 times the mol of the azide compound.
  • the reaction temperature is 0 to 200 ° C., preferably 0 to 120 ° C., and the reaction time may be 5 minutes to 48 hours.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • Halogen hydrocarbons such as methylene, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ketones such as acetone, 2-butanone and tert-butyl methyl ketone, diethyl ether, diisopropyl ether Tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, and other ethers, dimethyl
  • sulfoxides such as sulfoxide
  • esters such as ethyl acetate and tert-butyl acetate
  • amides such as N, N-dimethylformamide, N
  • Examples of the base used in this reaction include triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8- Diazabicyclo [5,4,0] undec-7-ene, 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a] pyrimidine, 2-tert-butylimino-2-diethylamino- Organic bases such as 1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, lithium diisopropylamide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide , Sodium bicarbonate, sodium carbonate, potassium carbonate , Cesium carbonate, potassium phosphate, sodium hydroxide, potassium
  • examples of the iodide used include potassium iodide, sodium iodide, lithium iodide and the like.
  • Examples of the catalyst used include palladium (II) acetate, palladium carbon catalyst, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (acetonitrile) palladium (II).
  • Et al. Metal-Catalyzed Cross-Coupling Reactions, Volume 2, Second Edition (edited by Armin de meijer et al.), Page 705, 2004, WILEY-VCH Verlag GmbH & Co.
  • phase transfer catalyst can be allowed to coexist if necessary, and examples of the phase transfer catalyst include tetra n-butylammonium chloride, triethylbenzylammonium chloride, 18-crown-6 and the like.
  • the amount of the base used may be 1 to 10 times mol of the compound of the general formula (10), and the iodide may be 0.01 to 10 times mol.
  • the amount of the catalyst used may be 0.005 to 10 times the molar amount of the general formula (10).
  • the phase transfer catalyst may be 0.01 to 10 times mol.
  • the reaction temperature is ⁇ 100 to 250 ° C., preferably 20 to 150 ° C., and the reaction time may be 1 minute to 72 hours.
  • the compound of the general formula (2) can also be produced from the compound of the general formula (8) via the compound of the general formula (11).
  • the same method as that for producing the compound of the general formula (2) from the compound of the general formula (10) is applied to the intermolecular reaction to react the compound of the general formula (2) with the compound of the general formula (9).
  • the compound of the general formula (11) can be produced.
  • the compound of the general formula (9) may be replaced with a metal azide.
  • the azide group is reduced to an amine after the reaction (in the compound of the general formula (11), PG 2 , PG 3 Both are hydrogen) and can be used in subsequent reactions.
  • the compound of the general formula (11) is either after deprotection of one or both, or when one or both of PG 2 or PG 3 is hydrogen.
  • the compound of the general formula (2) is produced from the compound of the general formula (2) and the compound of the general formula (3a) by the same method as that for producing the compound of the general formula (4). Can lead.
  • the compound of the general formula (2) can also be prepared directly from a compound of a compound of general formula (8) and general formula (9). That is, the compound of the general formula (2) is converted from the compound of the general formula (8) by the same method as that for producing the compound of the general formula (11) from the compound of the general formula (8) and the compound of the general formula (9). Can lead directly to.
  • the compound of the general formula (4) can also be produced by the scheme 4 from the compound of the general formula (8).
  • the general formula (8) is produced by the same method as that for producing the compound of the general formula (10) from the compound of the general formula (8) and the compound of the general formula (9).
  • the compound of general formula (13) was synthesized from the compound of general formula (12), and then PG 2 was deprotected to produce the compound of general formula (2) from the compound of general formula (10).
  • the compound of the general formula (4) can be produced by the same method.
  • the compound of the general formula (8) and the compound of the general formula (12) are produced by the same method as that for producing the compound of the general formula (11) from the compound of the general formula (8) and the compound of the general formula (9).
  • the compound of the general formula (14) is synthesized, and then PG 2 is deprotected, and the compound of the general formula (2) is produced from the compound of the general formula (11) by the same method as that for producing the compound of the general formula (4). ) Can be produced.
  • the compound of the general formula (8) is produced by the same method as that for producing the compound of the general formula (2) directly from the compound of the general formula (8) and the compound of the general formula (9).
  • the compound of the general formula (4) can be produced by reacting the compound with the compound of the general formula (12).
  • the compound of General formula (4) can also be manufactured from the compound of General formula (8) through the compound of General formula (10) or General formula (11).
  • the compound of the general formula (13) is produced by the same method as that for producing the compound of the general formula (4) from the compound of the general formula (2) and the compound of the general formula (3a) or (3b).
  • PG 2 is deprotected, and the compound of the general formula (4) can be produced by the same method as that for producing the compound of the general formula (2) from the compound of the general formula (10).
  • the compound of the general formula (11) is after deprotection of one or both of them, or when one or both of PG 2 and PG 3 is hydrogen,
  • the compound of the general formula (14) is produced by the same method as that for producing the compound of the general formula (4) from the compound of the general formula (2) and the compound of the general formula (3a) or (3b).
  • PG 2 is deprotected, and the compound of the general formula (4) can be produced by the same method as that for producing the compound of the general formula (2) from the compound of the general formula (11).
  • a more specific example of the above production method is shown in Scheme 5.
  • Compound (8a) is produced from compound (15) and compound (16) by the method described in Journal of Medicinal Chemistry, Vol. 33, 527-533, 1990, etc.
  • Compound (2a) can be produced by heating compound (8a) and a suitable solvent saturated with ammonia gas (9a) in a sealed tube.
  • Compound (17) can be produced by heating compound (8a) and 2,4-dimethoxyanisidine (9b) in the presence of a palladium catalyst and a base, and then the 2,4-dimethoxybenzyl group is removed.
  • the compound (2a) can also be produced by protecting.
  • compound (10b) can also be manufactured by reacting compound (8a) with sodium azide to synthesize compound (10c), and subsequently reducing the azide group using triphenylphosphine / water. .
  • the compound (2a) obtained above can be reacted with the iodide 3aa in the presence of a base to give the compound (4a) according to scheme 6, for example, and the Boc group is deprotected to obtain the compound (5a). Thereafter, for example, reductive amination reaction with aldehyde 6ba can be carried out to produce target compound (I) -a.
  • compound (8a) is reacted with, for example, compound (12a) in the presence of a base, or compound (10b) is reacted with, for example, 3ab in the presence of a base to give compound (13a).
  • the compound (4b) can be produced by heating in the presence of a base or heating in the presence of a palladium catalyst and a base.
  • Compound (4b) can also be produced directly by heating compound (8a) and compound (12a) in the presence of a base or in the presence of a palladium catalyst and a base.
  • Compound (4b) can be converted to the compound of general formula (I) by the methods described so far.
  • Compound (19) was synthesized by allowing phosphorus oxychloride to act on compound (18) described in Chemical Pharmaceutical Bulletin, Vol. 55, Item 821-824, 2007, etc.
  • Compound (20) can be produced by reacting aminoethanol. By allowing bromine in acetic acid to act on the obtained compound (20), a compound (21) having a bromine atom introduced regioselectively can be produced.
  • the compound (2b) can be produced by heating this in the presence of a base or by heating in the presence of a copper catalyst and a base.
  • the compound of general formula (I) can be produced from compound (2b) by the same method as described above.
  • LG 5 is a leaving group and may or may not remain in the compound of the general formula (8) or the general formula (13) after the reaction. LG 5 may not be present, for example, when the reactivity of the A 3 atom is sufficiently high.
  • LG 5 includes, for example, chlorine, bromine, iodine atom, methanesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like.
  • General formulas (23b) and (24b) are not limited to the aldehydes shown, but may be carbonyl compounds such as ketones and ⁇ -ketoesters such as 3c and 6c.
  • the compound of the general formula (22) and the compound of the general formula (23a) or (23b) are converted into the compound of the general formula (2) and the general formula (3a) or
  • the compound of the general formula (8) can be produced by reacting the compound of the general formula (4) from the compound of the (3b) by the same method. Thereafter, the compound of the general formula (I) can be produced by the method already described.
  • the compound of the general formula (13) can be produced from the compound of the general formula (22) and the compound of the general formula (24a) or (24b). From the compound of the general formula (13), the general formula The compound (I) can be produced.
  • the compound of general formula (22) and the compound of general formula (23a) are produced, and the compound of general formula (4) is produced from the compound of general formula (2) and the compound of general formula (3a).
  • the compound of General formula (8) can be manufactured by making it react by the method similar to having performed. For example, the method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), pp. 477-488, 2001, John Wiley & Sons, Inc., etc. it can. Thereafter, the compound of the general formula (I) can be produced by the method already described.
  • the compound of the general formula (13) can be produced from the compound of the general formula (22) and the compound of the general formula (24a). From the compound of the general formula (13), Compounds can be produced.
  • compound (25) described in Journal of Medicinal Chemistry, Vol. 36, Item 1669-1673, 1993, etc. is hydrolyzed, and the resulting carboxylic acid compound (26) is tert-butyl.
  • Compound (27) can be produced by reacting and heating diphenyl phosphate azide together with alcohol. After deprotecting the Boc protecting group of compound (27) to give compound (28), compound (8b) can be produced by reacting with chloroacetic acid chloride. Subsequently, the compound (8b) and the compound (12b) are heated together with a base to obtain the compound (13b), and the compound (4c) can be produced by further heating.
  • Compound (4c) can be converted to the compound of general formula (I) by the methods described so far.
  • R A11 represents L 1 -Q 1 -L 2 -Q 2 itself, or a substituent into which L 1 -Q 1 -L 2 -Q 2 can be introduced later, or L 1 -Q 1 -L 2
  • R A12 is a substituent that can be converted to —Q 2
  • R A12 is a substituent itself that is substituted with carbon A 1 or a functional group that can be subsequently converted to a substituent.
  • R A11 and R A12 are electron-withdrawing substituents, and therefore the methylene between R A11 and R A12 of the compound (22) can be deprotonated in the presence of a base.
  • the electron-withdrawing substituent include a ketone group, an ester group, a nitrile group, a nitro group, a carboxy group, a sulfoxide, a sulfone, and a sulfonic acid ester.
  • the compound of the general formula (30) can be first produced.
  • This reaction is, for example, a method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), pages 548 to 556, 2001, published by John Wiley & Sons, Inc., etc. It can be carried out.
  • the compound of the general formula (31) can be produced by reacting the compound of the general formula (30) in the presence of a base and a catalyst, if desired.
  • This reaction is, for example, Advanced Organic Chemistry, 5th edition (by Michael B. Smith and Jerry March), pages 869-870, 2001, John Wiley & Sons, Inc., Revol. 26, Chem106. -It can be carried out by the method described in page 2710, 2006, etc. or a method analogous thereto.
  • the solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction.
  • alcohols such as methanol, ethanol, 2-propanol, n-butanol, and 2-methyl-2-propanol
  • Halogen hydrocarbons such as methylene, chloroform and 1,2-dichloroethane
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ketones such as acetone, 2-butanone and tert-butyl methyl ketone
  • diethyl ether diisopropyl ether Tert-butyl methyl ether, dioxane, tetrahydrofuran, anisole, diphenyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, and other ethers, dimethyl
  • examples include sulfoxides such as sulfoxide, esters such as ethyl acetate and tert
  • Examples of the base used in this reaction include triethylamine, diisopropylethylamine, imidazole, pyridine, dimethylaminopyridine, hexamethylguanidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8- Diazabicyclo [5,4,0] undec-7-ene, 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a] pyrimidine, 2-tert-butylimino-2-diethylamino- Organic bases such as 1,3-dimethyl-perhydro-1,3,2-diazaphosphorine, lithium diisopropylamide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide , Sodium bicarbonate, sodium carbonate, potassium carbonate , Cesium carbonate, potassium phosphate, sodium hydroxide, potassium
  • Examples of the catalyst used in this reaction include palladium (II) acetate, palladium carbon catalyst, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (acetonitrile) palladium. (II), etc., and catalysts prepared in advance from ligands described in BINAP, Tol-BINAP, etc., Chemical Reviews, 106, 2658-2659, 2006, etc.
  • the resulting catalyst Metal-Catalyzed Cross-Coupling Reactions, Volume 2, Second Edition (edited by Armin de meijer et al.), Page 707, 2004, WILEY-VCH Verlag GmbH & Co. Examples include catalysts described in KGaA publication. Is mentioned.
  • the amount of the base used may be 0.1 to 10 times mol of the compound of the general formula (30), and the catalyst may be 0.001 to 10 times mol.
  • the reaction temperature is 0 to 200 ° C., preferably 0 to 120 ° C., and the reaction time may be 5 minutes to 72 hours.
  • the compound of the general formula (31) may be the compound of the general formula (I) itself, or any one or both of R A11 and R A12 may be appropriately chemically converted to convert the compound of the general formula (I) It can also be manufactured.
  • R A12 of the compound of the general formula (31) is an ester group, a carboxy group or the like
  • the compound of the general formula (32) can be produced by deesterification or decarboxylation by an appropriate method.
  • the compound of the general formula (32) may be the compound of the general formula (I) itself, or R A11 may be appropriately chemically converted to produce the compound of the general formula (I).
  • ester group of the compound of the general formula (31a) can be selectively hydrolyzed using an alkali and water to produce the compound of the general formula (33a).
  • This reaction is, for example, a method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), pages 469-474, 2001, John Wiley & Sons, Inc. It can be carried out.
  • the compound of the general formula (32a) can be produced by optionally heating the compound of the general formula (33a) in the presence of an acid, a base or a salt.
  • This reaction is described in, for example, the method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), pages 808-813, 2001, John Wiley & Sons, Inc., etc. Can be done by the method.
  • the compound of the general formula (32a) can be directly produced from the compound of the general formula (31a).
  • a Krapcho dealkoxycarbonylation reaction in which the compound of the general formula (31a) is heated in a hydrous aprotic polar solvent in the presence of a salt can be used.
  • This reaction is described in Strategic Applications of Name Reactions in Organic Synthesis (edited by Laszlo Kurti et al.), Pages 252-253, 2005, Elsevier Inc. Publication or Synthesis, pages 805 to 822, 1982, etc., or a method analogous thereto.
  • the compound of the general formula (33a) can be reduced to a compound of the general formula (34a) by reducing the carboxy group with a reducing agent or by converting the carboxy group into an acid halide or acid anhydride. it can.
  • This reaction is a method described in, for example, Comprehensive Organic Transformations, 2nd edition (by Richard C. Larock), 1114-1116, 1121, 1999, John Wiley & Sons, Inc. It can be carried out.
  • Examples of the reducing agent used in this reaction include borane / tetrahydrofuran complex, borane / dimethyl sulfide complex, sodium borohydride, and the like.
  • the compound of the general formula (34a) can also be produced by treating the compound of the general formula (31a) with an appropriate reducing agent. This reaction can be carried out by the method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), page 533, 2001, John Wiley & Sons, Inc. it can.
  • Examples of the reducing agent used in this reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium aluminum hydride, sodium (2-methoxyethoxy) aluminum and the like.
  • the compound of the general formula (34a) can be oxidized to produce the compound of the general formula (35a).
  • This reaction is performed, for example, by the method described in Comprehensive Organic Transformations, 2nd edition (by Richard C. Larock), pages 1234-1249, 1999, John Wiley & Sons, Inc., or the like. be able to.
  • oxidizing agent used in this reaction examples include dimethyl sulfoxide activated by sulfur trioxide, pyridine, oxalyl chloride, Dess-Martin periodinane, chromium trioxide, dichromic acid, dichromate, pyridinium chloro. And chromate, pyridinium dichromate, and tetra-n-propylammonium pearlate.
  • a catalytic amount of an oxidant and a stoichiometric amount or more of a co-oxidant can be used together.
  • the compound of the general formula (35a) can also be produced by treating the compound of the general formula (31a) with an appropriate reducing agent. This reaction is carried out by a method described in Advanced Organic Chemistry 5th edition (by Michael B. Smith and Jerry March), page 533, 2001, John Wiley & Sons, Inc. it can.
  • Examples of the reducing agent used in this reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium aluminum hydride, sodium (2-methoxyethoxy) aluminum and the like.
  • the compound of the general formula (35a) and the compound of the general formula (36) are the same as the compound of the general formula (4) produced from the compound of the general formula (2) and the compound of the general formula (3b).
  • the compound of the general formula (37a) can be produced by reacting by a method.
  • the compound of the general formula (37a) can be led to the compound of the general formula (I) by the method described so far.
  • the compound of the general formula (32a) is obtained by converting the compound of the general formula (31a) via the compounds of the general formulas (33a), (34a), (35a), and (37a).
  • the compound of the general formula (I) it can be led to the compound of the general formula (I) via the compounds of the general formulas (38a), (39a), (40a), (41a). it can.
  • compound (30b) can be produced by heating a mixture of compound (8a) and diethyl malonate in the presence of potassium carbonate, and the resulting 30b can be prepared in the presence of a palladium catalyst and a base.
  • the cyclized compound (31b) can be produced by heating.
  • the deesterified compound (32b) can be prepared by heating the compound (31b) in hydrous N, N-dimethylformamide in the presence of lithium chloride, followed by reduction with Red-Al to obtain the aldehyde compound (40b).
  • Compound (41b) can be produced by allowing sodium triacetoxyborohydride to act on a mixture of compound (40b) and amine compound (36a), and from the obtained 41b, the general formula (I ) Can be produced.
  • Y 1 is hydrogen or an electron-withdrawing substituent that facilitates an aromatic nucleophilic substitution reaction, and examples thereof include a carboxy group, an ester group, a cyano group, and a nitro group.
  • Y 2 is a substituent that can be converted from Y 1 and later converted into a cyclic structure containing —A 1 -A 2 -A 3 -A 4 — together with Y 3 and the like.
  • Y 3 is substituted into A 1 arrangement the primary atom, later -A 1 -A 2 -A 3 -A 4 with Y 2 and the like - is a substituent that can be converted into cyclic structure containing a.
  • Y 4 and Y 5 may be hydrogen and are substituents that can be converted to R A11 and R A12 later.
  • EWG 1 facilitates deprotonation of the adjacent methylene or methine group, and performs aromatic nucleophilic substitution reaction and cross-coupling reaction between the compound of general formula (42) and the compound of general formula (48). It is an electron-withdrawing substituent that facilitates the occurrence.
  • the compound of the general formula (42) and the compound of the general formula (9) are reacted in the same manner as in the production of the compound of the general formula (2) from the compound of the general formula (10).
  • the compound of (43) can be produced.
  • the compound of the general formula (43) is appropriately subjected to operations of converting Y 1 to Y 2 and introducing Y 3 after deprotecting the protecting group PG 2, thereby giving the general formula (44). ) Can be produced.
  • the compound of the general formula (44) can be subjected to a suitable cyclization reaction to produce the compound of the general formula (45).
  • the compound of the general formula (45 is the same as described above).
  • the compound of the general formula (2) can be led to the compound of the general formula (I) Appropriate cyclization reaction leading to the compound of the general formula (44) to the compound of the general formula (45)
  • the compound of the general formula (42) and the compound of the general formula (12) From the compound of the general formula (43), the compound of the general formula (44), the compound of the general formula (45), the compound of the general formula (2)
  • the compound of general formula (46) is converted to the compound of general formula (47) and the compound of general formula (4).
  • the compound of (I) can be manufactured.
  • the compound of the general formula (42) is synthesized in the same manner as in the production of the compound of the general formula (31) from the compound of the general formula (30).
  • the compound of the general formula (49) can be produced from the compound of the general formula (48).
  • the compound of the general formula (49), the compound of the general formula (50) the compound of the general formula (31) by the same method as that for producing the compound of the general formula (I) via the compound of the formula (2)
  • the compound of general formula (I) can be produced via the compound.
  • the compound of the general formula (I) of the present invention is reacted with an acid when it has a basic group such as an amino group, or with a base when it has an acidic group such as a carboxy group.
  • a salt can be obtained.
  • Salts based on basic groups include, for example, hydrohalides such as hydrochloride, hydrobromide and hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate ; Lower alkane sulfonate such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, aryl sulfonate such as benzene sulfonate, p-toluene sulfonate, acetate, malate , Organic acid salts such as fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; or glycine, lysine, arginine, ornithine, glutamate, It is an amino acid salt such as aspartate.
  • hydrohalides such as hydrochloride, hydrobromide and hydroiodide
  • inorganic acid salts such as
  • salts based on acidic groups include, for example, alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt; Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, Organics such as dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts
  • stereoisomers which are R-coordinate and S-coordinate. Any ratio of compounds is encompassed by the present invention.
  • compound (I) is synthesized using an optically resolved starting material compound, or the synthesized compound (I) is optically resolved using an ordinary optical resolution or separation method as desired. be able to.
  • the compound of the general formula (I) of the present invention or a salt thereof has optical isomers, and any of the respective optical isomers and a mixture of these optical isomers are included in the present invention.
  • the compound of the general formula (I) or a salt thereof of the present invention may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or recrystallized. Such water-containing compounds and salts are also encompassed by the present invention.
  • the compound (I) of the present invention Since the compound (I) of the present invention has strong antibacterial activity and high safety, it can be used as a medicine for humans, animals, fish and the like, or as a preservative for agricultural chemicals and foods.
  • the dosage varies depending on the age, sex, symptoms, etc. of the patient, but is 50 mg to 1 g per day for adults, more preferably 100 mg to 800 mg.
  • the dose for animals varies depending on the purpose of administration, the size of the animal to be treated, the type of infected pathogen, and the degree, but is generally 1 mg to 200 mg per kg of animal body weight as a daily dose. 5 mg to 100 mg is more preferable. This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above amount as necessary.
  • the medicament of the present invention comprises the compound (I) of the present invention, a salt thereof or a hydrate thereof as an active ingredient, and this dosage form is not particularly limited and can be appropriately selected.
  • tablets, powders, granules Oral solid and liquid preparations such as pills, capsules, solutions, syrups, elixirs, oily or aqueous suspensions; parenteral preparations such as injections and suppositories; finely divided powders and liquids Any of inhalants such as aerosols; external preparations, eye drops, patches and the like may be used.
  • These dosage forms can be prepared by blending a pharmaceutically acceptable carrier and preparing various preparations commonly used.
  • the solid preparation may contain a pharmaceutically acceptable carrier together with the compound (I).
  • the carrier include fillers, extenders, binders, disintegrants, and solution accelerators. , Wetting agents, lubricants and the like.
  • liquid preparations include solutions, suspensions, and emulsions, but suspending agents, emulsifiers, and the like may be included as additives.
  • As injections, stabilizers, preservatives, solution adjuvants, etc. may be used in the preparation. After storing a solution that may contain these adjuvants in a container, it is used as a solid preparation by lyophilization or the like. It may be a preparation prepared at the time. One dose may be stored in a container, and multiple doses may be stored in the same container.
  • the preparation for external use examples include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like.
  • the pharmaceutical composition of the present invention comprises other clinically useful antibacterial agents (for example, macrolides, quinolones, ⁇ -lactams, or aminoglucosides), and And / or may contain or be co-administered with one or more known drugs selected from other anti-infective agents (eg, antifungal triazole or amphotericin) Good.
  • Said known drugs include carbapenem, such as meropenem or imipenem, which can broaden the therapeutic efficacy.
  • the compounds of the present invention may also comprise a bactericidal permeabilized protein (BPI) product or an efflux pump inhibitor to improve activity against gram negative bacteria and bacterial resistance to antibacterial agents, Or you may co-administer with them.
  • BPI bactericidal permeabilized protein
  • the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 1 6-[( ⁇ trans-4-[(9-methoxy-3,4-dihydrobenzo [h] [1,6] naphthyridin-1 (2H) -yl) methyl] cyclohexyl ⁇ amino) methyl ] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ⁇ Trans-4-[(9-methoxy-3,4-dihydro-2H-benzo [h] [1,6] naphthyridin-1-yl) methyl] cyclohexyl ⁇ carbamic acid benzyl ester obtained in Reference Example 5 128 mg, 0.279 mmol) was dissolved in methanol (5 mL) and 1N hydrochloric acid (0.56 mL), and 10% palladium carbon catalyst (M, about 50% water content, 60 mg) was added thereto, and catalytic hydrogenation was performed at room temperature for 1 hour.
  • M palladium carbon catalyst
  • Example 2 6-[( ⁇ trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ Amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one Trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexaneamine obtained in Reference Example 10 (46 .8 mg, 0.143 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (described in International Publication No.
  • Example 9 6-[( ⁇ trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ Amino) methyl] -2-methyl-2H-1,4-benzoxazine-3 (4H) -one Trans-4-[(9-Methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexaneamine (0 .050 g, 0.15 mmol) in dichloromethane (5 mL) and 2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (WO 2001/081324) Description, 0.040 g, 0.18 mmol) and sodium triacetoxyborohydride (0.065 g, 0.31 mmol) were added
  • Example 11 6-[( ⁇ trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ Amino) methyl] -8-methyl-2H-1,4-benzoxazine-3 (4H) -one Trans-4-[(9-Methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexaneamine (0 (.050 g, 0.15 mmol) in dichloromethane (5 mL) was added 8-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (WO 2004/052373).
  • Example 12 8-Methoxy-6-[( ⁇ trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl ) Methyl] cyclohexyl ⁇ amino) methyl] -2H-1,4-benzoxazine-3 (4H) -one Trans-4-[(9-Methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexaneamine (0 To a solution of .050 g, 0.15 mmol) in dichloromethane (5 mL) and methanol (2 mL), 8-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (International Publication) No.
  • the reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate.
  • the obtained extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Reference Example 28 6-Hydroxymethyl-7-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine 7-Methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid 2-ethoxy-2-oxoethyl ester obtained in Reference Example 27 (241 mg, 0.822 mmol) To a dichloromethane (4 mL) solution was added a diisobutylaluminum hydride / toluene solution (0.99 M, 4.15 mL, 4.11 mmol) at ⁇ 78 ° C., and the mixture was stirred at the same temperature for 1.5 hours.
  • Example 14 6-[( ⁇ trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ Amino) methyl] -5-methyl-2H-1,4-benzoxazine-3 (4H) -one Trans-4-[(9-Methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexaneamine (0 (.040 g, 0.12 mmol) in dichloromethane (5 mL) was added 5-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (Reference Example 34).
  • Example 15 1- ⁇ [1- (2-Cyclohexylethyl) piperidin-4-yl] methyl ⁇ -9-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine 4-[(9-methoxy-3,4-dihydrobenzo [h] [1,6] naphthyridin-1 (2H) -yl) methyl] piperidine-1-carboxylate tert-butyl obtained in Reference Example 36
  • the ester (84 mg, 0.20 mmol) was dissolved in dichloromethane (1.6 mL), trifluoroacetic acid (0.8 mL) was added, and the mixture was stirred at room temperature for 50 minutes.
  • the solvent was distilled off under reduced pressure, and the mixture was made alkaline by adding a saturated aqueous sodium hydrogencarbonate solution under ice cooling. After extraction with chloroform and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 485 mg (quantitative) of the title compound as a light brown oil.
  • Example 19 6-[( ⁇ 1-[(2-Methoxy-7,8,9,10-tetrahydrophenanthridin-10-yl) methyl] piperidin-4-yl ⁇ amino) methyl] -2H- 1,4-Benzoxazine-3 (4H) -one 1-[(2-Methoxy-7,8,9,10-tetrahydrophenanthridin-10-yl) methyl] piperidin-4-ylamine (67.0 mg, 0.206 mmol) dichloromethane obtained in Reference Example 45 -To a solution of tetrahydrofuran (4 mL-2 mL) was added 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbaldehyde (37 mg, 0.206 mmol) and sodium triacetoxyborohydride (69 mg, 0.309 mmol) was added and stirred for 12 hours.
  • Example 20 6-[( ⁇ trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ Amino) methyl] -2H-pyrido [3,2-b] [1,4] thiazin-3 (4H) -one Trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexaneamine (65) obtained in Reference Example 10 .5 mg, 0.200 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carbaldehyde (described in WO 2006/032466, etc.) , 42.7 mg, 0.220 mmol) is suspended in a mixed solvent of methanol: dich
  • Acetic acid (1 mL) was added and stirred for 23 hours.
  • Example 26 9-Methoxy-1-[(trans-4- ⁇ [(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) Methyl] amino ⁇ cyclohexyl) methyl] -2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-7-carbonitrile 1-[(trans-4-aminocyclohexyl) methyl] -9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-7- obtained in Reference Example 67 Carbonitrile (224 mg, 0.636 mmol), 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carbaldehyde (WO 2006/032466, etc.) , 125 mg, 0.700 mmol) is
  • Chloroform was added, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 190.2 mg (87%) of the title compound as a brown oil.
  • reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate.
  • the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure.
  • reaction mixture was cooled to 0 ° C., methanol (5 mL) was added, and 1N hydrochloric acid (5 mL) was added little by little while being careful of foaming.
  • 1N hydrochloric acid 5 mL was added little by little while being careful of foaming.
  • the reaction solution was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure.
  • Example 33 6-[( ⁇ (1SR, 2SR, 4SR) -2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c ] Quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one Under an argon atmosphere, (1SR, 2SR, 5SR) -2-amino-5-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-] obtained in Reference Example 84 was obtained.
  • Example 34 6-[( ⁇ (1SR, 2SR, 4SR) -2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c ] Quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] thiazin-3 (4H) -one Under a nitrogen atmosphere, (1SR, 2SR, 5SR) -2-amino-5-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-] obtained in Reference Example 84 was obtained.
  • reaction solution was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Example 35 6-[( ⁇ (1SR, 2RS, 4SR) -2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c ] Quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one Under a nitrogen atmosphere, (1SR, 2RS, 5SR) -2-amino-5-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3- c] quinolin-1-yl) methyl] cyclohexanol (200 mg, 0.582 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine-6-carba Hydrogenation of aldehyde (described in WO 2006/03
  • Example 36 6-[( ⁇ (1SR, 2RS, 4SR) -2-hydroxy-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c ] Quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] thiazin-3 (4H) -one Under a nitrogen atmosphere, (1SR, 2RS, 5SR) -2-amino-5-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3- c] quinolin-1-yl) methyl] cyclohexanol (100 mg, 0.291 mmol) and 3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] thiazine-6-carba Hydrogenation of aldehyde (described in WO 2006/032466
  • Methanesulfonyl chloride (0.351 mL, 4.53 mmol) was added dropwise. After stirring at the same temperature for 19 hours, triethylamine (0.23 mL, 1.65 mmol) and methanesulfonyl chloride (0.064 mL, 0.824 mmol) were added, and the mixture was further stirred for 24 hours. The reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Example 38 6-[( ⁇ (1SR, 2SR, 4SR) -2-azido-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c ] Quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ⁇ (1SR, 2SR, 4SR) -2-azido-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3] obtained in Reference Example 94 under nitrogen atmosphere To a solution of -c] quinolin-1-yl) methyl] cyclohexyl ⁇ carbamic acid tert-butyl ester (300 mg, 0.640 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (2.0 mL) at room
  • Example 39 6-[( ⁇ (1SR, 2RS, 4SR) -2-azido-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c ] Quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ⁇ (1SR, 2RS, 4SR) -2-azido-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3] obtained in Reference Example 96 under nitrogen atmosphere To a solution of -c] quinolin-1-yl) methyl] cyclohexyl ⁇ carbamic acid tert-butyl ester (120 mg, 0.256 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL) at room
  • Example 42 6-[( ⁇ (1SR, 2SR, 4SR) -2- (dimethylamino) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2, 3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one Reference Example 99 under nitrogen atmosphere] ⁇ (1SR, 2SR, 4SR) -2- (dimethylamino) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3 -C] Quinolin-1-yl) methyl] cyclohexyl ⁇ carbamic acid tert-butyl ester (84.8 mg, 0.180 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (1.0 mL
  • Example 43 6-[( ⁇ (1SR, 2SR, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-1 -Yl) methyl] -2-([1,2,3] triazol-1-yl) cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) -on ⁇ (1SR, 2SR, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline obtained in Reference Example 100 under nitrogen atmosphere -1-yl) methyl] -2-([1,2,3] triazol-1-yl) cyclohexyl ⁇ carbamic acid tert-butyl ester (43.9 mg, 0.0888 mmol) in dichloromethane (4.0 mL
  • Example 44 6-[( ⁇ (1SR, 2RS, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-1 -Yl) methyl] -2-([1,2,3] triazol-1-yl) cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazine-3 (4H) -on ⁇ (1SR, 2RS, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline obtained in Reference Example 101 under nitrogen atmosphere -1-yl) methyl] -2-([1,2,3] triazol-1-yl) cyclohexyl ⁇ carbamic acid tert-butyl ester (43.2 mg, 0.0873 mmol) in dichloromethane (5.0 mL
  • Example 45 6-[( ⁇ (1SR, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl ) Methyl] -2-((E) -methoxyimino) cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ⁇ (1SR, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-1 obtained in Reference Example 103 under nitrogen atmosphere -Il) methyl] -2-((E) -methoxyimino) cyclohexyl ⁇ carbamic acid tert-butyl ester (107 mg, 0.223 mmol) in dichloromethane (8.0 mL) at room temperature in tri
  • Example 46 6-[( ⁇ (1SR, 2SR, 4SR) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-1 -Yl) methyl] -2- (methylamino) cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one, 6-[( ⁇ (1SR , 2SR, 4SR) -2-amino-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ amino ) Methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ⁇ (1SR, 2SR, 4SR) -2-azido-4-[(9
  • the obtained residue was purified by silica gel column chromatography (NH silica gel, dichloromethane: methanol 49: 1 ⁇ 19: 1 ⁇ 9: 1) to obtain 63 mg of a mixture of amine derivatives.
  • the obtained mixture was dissolved in dichloromethane (5.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at the same temperature for 17 hours, and then the reaction mixture was concentrated under reduced pressure.
  • reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 16.35 g of a crude product of (1RS, 3SR, 4SR) -4- ⁇ [(triphenylmethyl) oxy] methyl ⁇ -3-vinylcyclohexyl mesylate.
  • the reaction mixture was concentrated under reduced pressure to about 20 mL, acidified with 0.5N hydrochloric acid, and washed with diethyl ether.
  • the aqueous layer after washing was made alkaline with 4N aqueous sodium hydroxide solution, 1,4-dioxane (60 mL) and di (tertiary butyl) dicarbonate (9.88 g, 45.3 mmol) were added at room temperature. Stir for 20 hours.
  • the reaction mixture was concentrated under reduced pressure to about half volume, ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Example 51 1-[(trans-4- ⁇ [(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl) methyl] amino ⁇ Cyclohexyl) methyl] -2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinoline-9-carbonitrile ⁇ Trans-4-[(9-cyano-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ carbamine obtained in Reference Example 120 To a solution of acid tertiary butyl ester (53 mg, 0.126 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 40 minutes.
  • lithium aluminum hydride (661 mg, 17.42 mmol) was further added at the same temperature over 5 minutes, and then stirred at room temperature for 5 hours.
  • the reaction mixture was ice-cooled again, diluted with tetrahydrofuran (160 mL), water (1.26 mL), 3N aqueous sodium hydroxide solution (1.26 mL), and water (3.78 mL) were carefully added successively, and then room temperature. For 4 hours.
  • Chloroform: methanol 9: 1 mixed solvent was added to the reaction solution, then anhydrous sodium sulfate was added and stirred for a while, followed by filtration through celite, and the filtrate was concentrated under reduced pressure.
  • reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 52 9-methoxy-1-[(trans-4- ⁇ [(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) Methyl] amino ⁇ cyclohexyl) methyl] -1H- [1,4] oxazino [2,3-c] quinolin-2 (3H) -one ⁇ Trans-4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ carbamine obtained in Reference Example 126 Trifluoroacetic acid (1 mL) was added to a solution of tertiary butyl acid (53 mg, 0.120 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for 30 minutes.
  • Example 53 8-Methoxy-1-[(trans-4- ⁇ [(3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-6-yl ) Methyl] amino ⁇ cyclohexyl) methyl] [1,3] oxazolo [5,4-c] quinolin-2 (1H) -one
  • Trifluoroacetic acid (2 mL) was added to a solution of crude tertiary butyl product (134 mg, 0.296 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 30 minutes.
  • reaction solution was ice-cooled, and the ⁇ (1RS, 2SR, 4RS) -4- (iodomethyl) -2-[(methoxymethoxy) methyl] cyclohexyl ⁇ carbamic acid tertiary butyl ester (16 .27 g, 39.4 mmol) in N, N-dimethylacetamide (60 mL) was added over 5 minutes.
  • the reaction mixture was stirred at room temperature for 8 hours, poured into ice water, and extracted with ethyl acetate. The extracts were combined, dried over anhydrous sodium sulfate and filtered.
  • Example 54 6-[( ⁇ (1RS, 2SR, 4RS) -2- (hydroxymethyl) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2, 3-c] quinolin-1-yl) methyl] cyclohexyl ⁇ amino) methyl] -2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one ⁇ (1RS, 2SR, 4RS) -4-[(9-methoxy-2,3-dihydro-1H- [1,4] oxazino [2,3-c] quinolin-1-yl obtained in Reference Example 133 ) Methyl] -2-[(methoxymethoxy) methyl] cyclohexyl ⁇ carbamic acid tert-butyl ester (262 mg, 0.523 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) and
  • the obtained product was dissolved in 7N hydrochloric acid (8 mL) at room temperature and stirred at the same temperature for 1 hour.
  • the extracts were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water and saturated brine. After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure. Trifluoroacetic acid (20 mL) was added to a dichloromethane (40 mL) solution of the obtained residue at room temperature, and the mixture was stirred at the same temperature for 40 minutes. The reaction solution was concentrated under reduced pressure and azeotroped with toluene and isopropyl alcohol.

Abstract

L’invention concerne une substance qui présente une activité antibactérienne puissante et de spectre large contre les bactéries à gram positif, les bactéries à gram négatif et leurs bactéries résistantes, et qui présente une grande sûreté. Des études approfondies ont été réalisées et ont permis de découvrir qu’un composé représenté par la formule (I) ou un de ses sels présente une activité antibactérienne puissante et de spectre large contre les bactéries à gram positif et les bactéries à gram négatif, ainsi qu’une grande sûreté à un niveau approprié pour une utilisation en tant qu’agent antibactérien ou agent prophylactique ou thérapeutique pour maladies infectieuses. L’invention concerne par conséquent un composé représenté par la formule (I), un de ses sels pharmacologiquement acceptables, ou un hydrate du composé ou du sel.
PCT/JP2009/057244 2008-04-11 2009-04-09 Dérivé d’aminocyclohexyle WO2009125808A1 (fr)

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WO2012171860A1 (fr) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Antibiotiques tricycliques
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9533954B2 (en) 2010-12-22 2017-01-03 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
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US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
WO2023109909A1 (fr) * 2021-12-15 2023-06-22 上海翊石医药科技有限公司 Composés hétérocycliques aromatiques, leur procédé de préparation et leurs utilisations
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
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