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WO2018181892A1 - Composé de quinolinone et médicament anti-virus à arn - Google Patents

Composé de quinolinone et médicament anti-virus à arn Download PDF

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Publication number
WO2018181892A1
WO2018181892A1 PCT/JP2018/013592 JP2018013592W WO2018181892A1 WO 2018181892 A1 WO2018181892 A1 WO 2018181892A1 JP 2018013592 W JP2018013592 W JP 2018013592W WO 2018181892 A1 WO2018181892 A1 WO 2018181892A1
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group
compound
methyl
hydrogen atom
optionally substituted
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Japanese (ja)
Inventor
賢志 水田
健 渡邊
教行 西田
剛 濱田
岳志 石川
田中　義正
大樹 大滝
二朗 安田
秀造 浦田
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Nagasaki University NUC
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Nagasaki University NUC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • C07D215/60—N-oxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a compound having excellent anti-RNA virus activity and useful as an anti-RNA virus drug, particularly as an anti-influenza virus drug.
  • Symmetrel (registered trademark) (generic name: amantadine)
  • Symmetrel targets the membrane protein M2 and inhibits the ion channel activity of M2, which is essential for virus uncoating.
  • Tamiflu registered trademark
  • Relenza registered trademark
  • NA glycoprotein neuraminidase
  • zanamivir has relatively few reports of resistant viruses compared to Tamiflu, it is poorly absorbed from the intestinal tract and needs to be inhaled with a special inhaler rather than a tablet that can be taken orally. Compared to certain Tamiflu, medication in children is more difficult. Inavir is a similar inhalant.
  • Abigan registered trademark
  • favipiravir the newest anti-influenza virus drug.
  • Avigan is approved for drugs that target viral RNA polymerase, but it is not manufactured to prepare for future pandemic virus outbreaks and is not currently used to treat influenza. Further, as anti-influenza virus drugs under development, International Publication No.
  • Patent Document 1 International Publication No. 2013/019828
  • Patent Document 3 Japanese Patent Application Laid-Open No. 2012-77058
  • Patent Document 4 Japanese Unexamined Patent Publication No. 2016-172749
  • the compound described in Patent Document 1 is under development as a compound that inhibits the recognition of the cap structure of PB2, but has not yet been clinically used as an anti-influenza virus drug.
  • the first desired condition for a newly invented substance is that the first has a mechanism of action different from that of conventional anti-influenza virus drugs, and the second is that the substance is easily industrially produced.
  • the third is that it has the effect of suppressing the growth of influenza virus.
  • An object of the present invention is to provide a compound useful as an anti-RNA virus drug, particularly as an anti-influenza virus drug.
  • the gene of influenza virus is encoded in 8 segmented genomes, and 10 major proteins are made from the genome.
  • the HA protein is a protein present on the particle surface and is involved in binding to the cell surface, so it has already been targeted for vaccine development and is excluded from development.
  • Drugs that target M2 and NA proteins have already been approved, and resistant viruses have emerged.
  • M1, NP, NS1, NS2 proteins have no enzyme activity. Therefore, drug development is difficult and is excluded from the development target.
  • the remaining three proteins PA, PB1, and PB2 constitute viral RNA polymerase.
  • the enzyme activity of viral RNA polymerase is essential for influenza virus growth (Non-patent Document 3), and is excellent as a development target for anti-influenza virus drugs.
  • PA-49 represented by the following formula has high anti-influenza virus activity.
  • R 10 is a hydrogen atom or a C 1-6 alkyl group
  • R 11 is a hydrogen atom or a halogen atom
  • R 1 is an optionally substituted C 6-10 aryl group or an optionally substituted aromatic heterocyclic group
  • R 3 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with a hydroxy group
  • R 2 is (1) an optionally substituted C 6-10 aryl group, (2) an aromatic heterocyclic group which may be substituted, (3) a C 3-6 cycloalkyl group, or (4) a C 1-6 alkyl group optionally substituted with a hydroxy group
  • R 4 is a hydrogen atom or a C 1-6 alkyl group that may be substituted with a hydroxy group
  • R 2 and R 4 together with the carbon atom to which they are attached are optionally substituted C May form
  • R 1 and R 2 are each independently an optionally substituted C 6-10 aryl group or an optionally substituted aromatic heterocyclic group; The compound or a salt thereof according to [1], wherein R 3 and R 4 are each independently a hydrogen atom or a C 1-6 alkyl group.
  • R 3 and R 4 are each independently a hydrogen atom or a C 1-6 alkyl group.
  • R 5 is a hydrogen atom
  • R 6 is (1) a hydrogen atom
  • R 21 and R 22 are each independently a C 1-6 alkyl group
  • R 21 and R 22 are each independently a C 1-6 alkyl group
  • R 21 and R 22 are each independently a C 1-6 alkyl group
  • (4) a C 1-6 alkyl group (5) a C 1-6 haloalkyl group, (6) a C 2-6 alkynyl group, or (7) a triazolyl group optionally substituted with a C 3-6 cycloalkyl group, or R 5 and R 6 together with the carbon atom to which they are attached
  • R 1 and R 2 are each independently (A) a halogen atom, (B) a C 1-6 alkyl group, (C) a C 1-6 haloalkyl group, (D) substituted with a substituent selected from the group consisting of (i) a C 1-6 alkoxy group, (ii) a C 1-6 alkoxy-carbonyl group, (iii) a carboxy group, and (iv) a hydroxy group An optionally substituted C 1-6 alkoxy group, (E) a C 6-10 aryl group, (F) a hydroxy group, (G) a carbamoyl group, (H) a C 1-6 haloalkoxy group, (I) a C 1-6 alkylthio group, (J) a di (C 1-6 alkyl) amino group, (K) a C 1-6 haloalkylthio group, and (l) a C 6-10 aryl group or an aromatic heterocycle, each of which
  • R 1 and R 2 are each independently (A) a halogen atom, (B) a C 1-6 alkyl group, (C) a C 1-6 haloalkyl group, and (d) a C 6-10 aryl group, each optionally substituted with one or two substituents selected from the group consisting of C 1-6 alkoxy groups, or The compound or a salt thereof according to any one of [1] to [6], which is an aromatic heterocyclic group.
  • R 1 and R 2 are each independently a phenyl group which may be substituted with one or two substituents selected from the group consisting of a halogen atom and a C 1-6 alkyl group, A naphthyl group; R 3 and R 4 are each independently a hydrogen atom or a methyl group; R 5 , R 6 and R 7 are hydrogen atoms; R 8 and R 9 are each independently a hydrogen atom or a C 1-6 alkyl group; The compound or a salt thereof according to [3], wherein R 10 is a hydrogen atom. [10] A medicament comprising the compound or salt thereof according to any one of [1] to [9]. [11] The medicament according to [10], which is an anti-RNA virus drug.
  • a method for preventing or treating an RNA virus infection in a mammal comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [9] to a mammal.
  • R 10 is a hydrogen atom or a C 1-6 alkyl group
  • R 11 is a hydrogen atom or a halogen atom
  • R 1 is an optionally substituted C 6-10 aryl group or an optionally substituted aromatic heterocyclic group
  • R 3 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with a hydroxy group
  • R 2 is (1) an optionally substituted C 6-10 aryl group, (2) an aromatic heterocyclic group which may be substituted, (3) a C 3-6 cycloalkyl group, or (4) a C 1-6 alkyl group optionally substituted with a hydroxy group
  • R 4 is a hydrogen atom or a C 1-6 alkyl group that may be substituted with a hydroxy group
  • R 2 and R 4 together with the carbon atom to which they are attached are optionally substituted C May form
  • a method for preventing or treating an RNA virus infection in a mammal comprising administering an effective amount of a compound represented by the formula (I ′) according to [16] or a salt thereof to a mammal.
  • the compound represented by the formula (I) or (I ′) of the present invention or a salt thereof does not target neuraminidase, it is resistant to Tamiflu. It is also effective for stocks. In addition, it does not directly target the enzymatic activity of the polymerase, and exhibits a very high specific action by a completely new mechanism of action "inhibiting protein-protein interaction necessary for expression of enzyme activity". Furthermore, the amino acid sequence of viral RNA polymerase is highly conserved even in highly pathogenic avian influenza and viruses that have been pandemic in the past, and an effect on unknown viruses can be expected. In the unlikely event of a pandemic of a new influenza virus, a stable supply in large quantities is indispensable. However, in the production of the compound of the present invention, it is also a great advantage that a complicated synthesis method is not required.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1 -Ethylpropyl, 1,1-dimethylpropyl, 2-methylbutyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • examples of the “C 1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • C 1-6 haloalkyl group means 1 to 7 (preferably 1 to 5, more preferably 1 to 3) halogen atoms (eg, fluorine atom, A C 1-6 alkyl group which may be substituted with a chlorine atom or a bromine atom).
  • Suitable examples of the C 1-6 haloalkyl group include trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, chloromethyl, trichloromethyl, 2-bromoethyl, tetrafluoroethyl, pentafluoroethyl, 3, 3,3-trifluoropropyl and the like can be mentioned.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, -Pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-methylbutyloxy, Examples include pentyloxy and hexyloxy.
  • examples of the “C 1-4 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, Examples thereof include tert-butoxycarbonyl, 2-methylbutyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • the “C 1-6 haloalkoxy group” is 1 to 7 (preferably 1 to 5, more preferably 1 to 3) halogen atoms (eg, fluorine atom) , A chlorine atom, a bromine atom) and a C 1-6 alkoxy group which may be substituted.
  • Suitable examples of the C 1-6 haloalkoxy group include trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, chloromethoxy, trichloromethoxy, 2-bromoethoxy, tetrafluoroethoxy, pentafluoroethoxy, 3,3,3-trifluoropropoxy and the like.
  • examples of the “C 1-6 alkylthio group” include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio , Neopentylthio, 1-ethylpropylthio, 1,1-dimethylpropylthio, 2-methylbutylthio, hexylthio, isohexylthio, 1,1-dimethylbutylthio, 2,2-dimethylbutylthio, 3,3 -Dimethylbutylthio, 2-ethylbutylthio and the like.
  • C 1-6 haloalkylthio group means 1 to 7 (preferably 1 to 5, more preferably 1 to 3) halogen atoms (eg, fluorine atom) , A chlorine atom, a bromine atom) and a C 1-6 alkylthio group which may be substituted.
  • C 1-6 haloalkylthio group examples include trifluoromethylthio, 2,2,2-trifluoroethylthio, difluoromethylthio, chloromethylthio, trichloromethylthio, 2-bromoethylthio, tetrafluoroethylthio, penta Fluoroethylthio, 3,3,3-trifluoropropylthio and the like can be mentioned.
  • the “di (C 1-6 alkyl) amino group” means an amino group substituted by two C 1-6 alkyl groups. Each C 1-6 alkyl group may be the same or different. Examples include dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-methyl-N-butylamino and the like.
  • examples of the “C 3-6 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • examples of the “C 6-10 aryl group” include phenyl and naphthyl.
  • aromatic heterocyclic group includes, for example, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom And 5- to 10-membered aromatic heterocyclic group.
  • aromatic heterocyclic group examples include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 2- Pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4 -
  • examples of the “6-membered aromatic heterocyclic group” include 6-membered aromatic heterocyclic groups containing 1 to 3 nitrogen atoms in addition to carbon atoms as ring-constituting atoms. .
  • 6-membered aromatic heterocyclic group examples include pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl ( Examples, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), triazinyl (eg, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1, 2,4-triazin-6-yl) and the like.
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl
  • pyridazinyl Examples, 3-pyridazinyl, 4-
  • examples of the “C 3-6 cycloalkane ring” include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.
  • R 10 is preferably N (R 10 ) —C ( ⁇ O).
  • the “C 1-6 alkyl group” represented by R 10 is preferably a “C 1-4 alkyl group”, and examples thereof include methyl, ethyl and the like.
  • Examples of the “halogen atom” represented by R 11 include a chlorine atom.
  • R 10 is preferably a hydrogen atom.
  • R 11 is preferably a hydrogen atom.
  • R 1 is an optionally substituted C 6-10 aryl group or an optionally substituted aromatic heterocyclic group
  • R 3 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with a hydroxy group
  • R 2 is (1) an optionally substituted C 6-10 aryl group, (2) an aromatic heterocyclic group which may be substituted, (3) a C 3-6 cycloalkyl group, or (4) a C 1-6 alkyl group optionally substituted with a hydroxy group
  • R 4 is a hydrogen atom or a C 1-6 alkyl group optionally substituted with a hydroxy group
  • R 2 and R 4 are optionally substituted C together with the carbon atom to which they are attached.
  • a 3-6 cycloalkane ring or an optionally substituted tetrahydronaphthalene ring may be formed.
  • R 1 and R 2 are preferably each independently an optionally substituted C 6-10 aryl group or an optionally substituted aromatic heterocyclic group.
  • the “ring group” may have 1 to 3 (preferably 1 or 2) substituents at any substitutable position.
  • substituents include: (1) halogen atom (eg, fluorine atom, chlorine atom), (2) C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl), (3) a C 1-6 haloalkyl group (eg, trifluoromethyl), (4) (i) C 1-6 alkoxy group (eg, methoxy), (ii) C 1-6 alkoxy-carbonyl group (eg, tert-butoxycarbonyl), (iii) carboxy group, and (iv) hydroxy group A C 1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy) optionally substituted with a substituent selected from the group consisting of: (5) C 1-6 haloalkoxy group (eg, trifluoromethoxy, difluoromethoxy), (6) a C 2-6 alkenyl group, (7) a C 2-6 alkynyl group
  • Examples of the “C 6-10 aryl group” of the “optionally substituted C 6-10 aryl group” represented by R 1 or R 2 include a phenyl group and a naphthyl group, preferably a phenyl group.
  • the “aromatic heterocyclic group” of the “optionally substituted aromatic heterocyclic group” represented by R 1 or R 2 is a 6-membered aromatic heterocyclic group (eg, pyridyl group, pyrimidinyl group, pyridazinyl group). , Pyrazinyl group), and is preferably a pyridyl group.
  • Examples of the “C 3-6 cycloalkyl group” represented by R 2 include cyclohexyl.
  • the “C 1-6 alkyl group optionally substituted with a hydroxy group” represented by R 2 is substituted with 1 to 3 (preferably 1 or 2, more preferably 1) hydroxy groups. Examples thereof include C 1-6 alkyl groups, and examples thereof include 2-hydroxyethyl and the like.
  • R 1 and R 2 are preferably each independently (A) a halogen atom, (B) a C 1-6 alkyl group, (C) a C 1-6 haloalkyl group, (D) substituted with a substituent selected from the group consisting of (i) a C 1-6 alkoxy group, (ii) a C 1-6 alkoxy-carbonyl group, (iii) a carboxy group, and (iv) a hydroxy group An optionally substituted C 1-6 alkoxy group, (E) a C 6-10 aryl group, (F) a hydroxy group, (G) a carbamoyl group, (H) a C 1-6 haloalkoxy group, (I) a C 1-6 alkylthio group, (J) a di (C 1-6 alkyl) amino group, (K) a C 1-6 haloalkylthio group, and (l) a C 6-10 aryl group or an aromatic heterocycle, each of which
  • R 1 and R 2 are more preferably each independently (A) a halogen atom (eg, fluorine atom, chlorine atom), (B) a C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl), (C) each substituted with 1 or 2 substituents selected from the group consisting of a C 1-6 haloalkyl group (eg, trifluoromethyl) and (d) a C 1-6 alkoxy group (eg, methoxy). And optionally a C 6-10 aryl group (eg, phenyl, naphthyl) or an aromatic heterocyclic group (eg, pyridyl).
  • a halogen atom eg, fluorine atom, chlorine atom
  • B a C 1-6 alkyl group
  • C each substituted with 1 or 2 substituents selected from the group consisting of a C 1-6 haloalkyl group (eg, triflu
  • R 1 and R 2 are even more preferably each independently (A) a halogen atom (eg, fluorine atom, chlorine atom), (B) a C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl), (C) a C 1-6 haloalkyl group (eg, trifluoromethyl), and (d) a C 1-6 alkoxy group (eg, methoxy).
  • R 3 and R 4 are each independently a hydrogen atom or a C 1-6 alkyl group which may be substituted with a hydroxy group.
  • the “C 1-6 alkyl group optionally substituted with hydroxy group” represented by R 3 or R 4 is 1 to 3 (preferably 1 or 2, more preferably 1) hydroxy groups. Examples thereof include an optionally substituted C 1-6 alkyl group, and examples thereof include hydroxymethyl and the like.
  • R 3 and R 4 are preferably each independently a hydrogen atom or a C 1-6 alkyl group.
  • the “C 1-6 alkyl group” represented by R 3 or R 4 is preferably a “C 1-4 alkyl group”, and examples thereof include methyl, ethyl and the like.
  • R 3 and R 4 are preferably each independently a hydrogen atom or a methyl group.
  • R 2 and R 4 together with the carbon atom to which they are attached may form an optionally substituted C 3-6 cycloalkane ring, or an optionally substituted tetrahydronaphthalene ring.
  • C 3-6 of “optionally substituted C 3-6 cycloalkane ring” and “optionally substituted tetrahydronaphthalene ring” formed by R 2 and R 4 together with the carbon atom to which they are bonded.
  • the “cycloalkane ring” and the “tetrahydronaphthalene ring” may have 1 to 3 (preferably 1 or 2, more preferably 1) substituents at any substitutable position.
  • substituents examples include “C 6-10 aryl group which may be substituted” represented by R 1 or R 2 and “C 6-10 of“ aromatic heterocyclic group which may be substituted ”. Examples thereof include the same substituents as the substituents that the “aryl group” and the “aromatic heterocyclic group” may have. Preferably, it is a C 1-6 alkoxy group (eg, methoxy).
  • C 3-6 cycloalkane ring” of the “optionally substituted C 3-6 cycloalkane ring” formed by R 2 and R 4 together with the carbon atom to which they are bonded includes, for example, a cyclopentane ring Etc.
  • R 5 is a hydrogen atom
  • R 6 is (1) a hydrogen atom, (2) a cyano group, (3) —P ( ⁇ O) (OR 21 ) (OR 22 ) (wherein R 21 and R 22 are each independently a C 1-6 alkyl group), (4) a C 1-6 alkyl group, (5) a C 1-6 haloalkyl group, (6) a C 2-6 alkynyl group, (7) a triazolyl group optionally substituted with a C 3-6 cycloalkyl group, or (8) a tetrazolyl group substituted with a C 1-4 alkyl group, or R 5 and R 6 are A carbonyl group is formed together with the carbon atom to be bonded.
  • the “C 1-6 alkyl group” represented by R 21 or R 22 is preferably a “C 1-4 alkyl group”, and examples thereof include methyl, ethyl and the like.
  • Examples of the “C 1-6 alkyl group” represented by R 6 include methyl, butyl and the like.
  • Examples of the “C 1-6 haloalkyl group” represented by R 6 include trifluoromethyl and the like.
  • Examples of the “C 2-6 alkynyl group” represented by R 6 include ethynyl and the like.
  • Examples of the “triazolyl group optionally substituted with a C 3-6 cycloalkyl group” represented by R 6 include, for example, a triazolyl group optionally substituted with a cyclohexyl group (eg, 1H-1,2,3- Triazol-4-yl) and the like.
  • Examples of the “tetrazolyl group substituted with a C 1-4 alkyl group” represented by R 6 include a tetrazolyl group substituted with a tert-butyl group (eg, 1H-tetrazol-5-yl).
  • R 5 is a hydrogen atom
  • R 6 is (1) a hydrogen atom, (2) a cyano group, (3) —P ( ⁇ O) (OR 21 ) (OR 22 ) (wherein R 21 and R 22 are each independently a C 1-6 alkyl group), (4) a C 1-6 alkyl group, (5) a C 1-6 haloalkyl group, (6) a C 2-6 alkynyl group, or (7) a triazolyl group optionally substituted with a C 3-6 cycloalkyl group, or R 5 and R 6 together with the carbon atom to which they are attached, A carbonyl group is formed.
  • R 5 and R 6 are hydrogen atoms.
  • R 5A is a hydrogen atom
  • R 6A is (1) a hydrogen atom, (2) a cyano group, (3) —P ( ⁇ O) (OR 21 ) (OR 22 ) (wherein R 21 and R 22 are each independently a C 1-6 alkyl group), (4) a C 1-6 alkyl group, (5) a C 1-6 haloalkyl group, (6) a C 2-6 alkynyl group, (7) a triazolyl group optionally substituted with a C 3-6 cycloalkyl group, or (8) a tetrazolyl group substituted with a C 1-6 alkyl group or a C 3-6 cycloalkyl group, or R 5A and R 6A together with the carbon atom to which they are attached form a carbonyl group.
  • the “C 1-6 alkyl group” represented by R 21 or R 22 is preferably a “C 1-4 alkyl group”, and examples thereof include methyl, ethyl and the like.
  • Examples of the “C 1-6 alkyl group” represented by R 6A include methyl, butyl and the like.
  • Examples of the “C 1-6 haloalkyl group” represented by R 6A include trifluoromethyl and the like.
  • Examples of the “C 2-6 alkynyl group” represented by R 6A include ethynyl and the like.
  • Examples of the “triazolyl group optionally substituted with a C 3-6 cycloalkyl group” represented by R 6A include a triazolyl group optionally substituted with a cyclohexyl group.
  • Examples of the “tetrazolyl group substituted with a C 1-6 alkyl group or a C 3-6 cycloalkyl group” represented by R 6A include, for example, a 1,1-dimethylpropyl group, a tert-butyl group, a cyclopentyl group, or a cyclohexyl group. And a tetrazolyl group substituted with.
  • R 5A is a hydrogen atom
  • R 6A is (1) a hydrogen atom, (2) a cyano group, (3) —P ( ⁇ O) (OR 21 ) (OR 22 ) (wherein R 21 and R 22 are each independently a C 1-6 alkyl group), (4) a C 1-6 alkyl group, (5) a C 1-6 haloalkyl group, (6) a C 2-6 alkynyl group, or (7) a triazolyl group optionally substituted with a C 3-6 cycloalkyl group, or R 5A and R 6A together with the carbon atom to which they are attached, A carbonyl group is formed.
  • R 5A and R 6A are hydrogen atoms.
  • R 7 is a hydrogen atom or a hydroxy group.
  • R 7 is preferably a hydrogen atom.
  • R 8 and R 9 are each independently a hydrogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group.
  • the “C 1-6 alkyl group” represented by R 8 or R 9 is preferably a “C 1-4 alkyl group”, and examples thereof include methyl, ethyl, propyl, isopropyl and the like.
  • the “C 1-6 alkoxy group” represented by R 8 or R 9 is preferably a “C 1-4 alkoxy group”, and examples thereof include methoxy, ethoxy and the like.
  • Preferred examples of compound (I) include the following compounds.
  • R 1 is (A) a halogen atom, (B) a C 1-6 alkyl group, (C) a C 1-6 haloalkyl group, (D) substituted with a substituent selected from the group consisting of (i) a C 1-6 alkoxy group, (ii) a C 1-6 alkoxy-carbonyl group, (iii) a carboxy group, and (iv) a hydroxy group An optionally substituted C 1-6 alkoxy group, (E) a C 6-10 aryl group, (F) a hydroxy group, (G) a carbamoyl group, (H) a C 1-6 haloalkoxy group, (I) a C 1-6 alkylthio group, (J) a di (C 1-6 alkyl) amino group, (K) a C 1-6 haloalkylthio group, and (l) a C 6-10 aryl group (eg, phenyl), each
  • R 1 and R 2 are each independently (A) a halogen atom (eg, fluorine atom, chlorine atom), (B) a C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl), (C) a C 1-6 haloalkyl group (eg, trifluoromethyl), and (d) a C 1-6 alkoxy group (eg, methoxy).
  • a halogen atom eg, fluorine atom, chlorine atom
  • B a C 1-6 alkyl group
  • C a C 1-6 haloalkyl group
  • C a C 1-6 alkoxy group eg, methoxy
  • a C 6-10 aryl group eg, phenyl, naphthyl or an aromatic heterocyclic group (eg, pyridyl), each of which may be substituted with 1 or 2 substituents selected from the group consisting of:
  • R 5 is a hydrogen atom
  • R 6 is (1) a hydrogen atom
  • (3) —P ( ⁇ O) (OR 21 ) (OR 22 ) (wherein R 21 and R 22 are each independently a C 1-6 alkyl group), (4) C 1-6 alkyl group (eg, methyl, butyl), (5) C 1-6 haloalkyl group (eg, trifluoromethyl), (6) a C 2-6 alkynyl group (eg, ethynyl), or (7) a triazolyl group (eg, 1H-1,2,3) optionally substituted by a C 3-6 cycloalkyl group (eg, cyclohexyl) -Triazol-4
  • R 1 and R 2 are each independently (A) a halogen atom (eg, fluorine atom, chlorine atom), (B) a C 1-6 alkyl group (eg, methyl, ethyl, isopropyl, tert-butyl), (C) a C 1-6 haloalkyl group (eg, trifluoromethyl), and (d) a C 1-6 alkoxy group (eg, methoxy).
  • a halogen atom eg, fluorine atom, chlorine atom
  • B a C 1-6 alkyl group
  • C a C 1-6 haloalkyl group
  • C a C 1-6 alkoxy group eg, methoxy
  • a C 6-10 aryl group eg, phenyl, naphthyl
  • an aromatic heterocyclic group eg, pyridyl
  • R 3 and R 4 are each independently a hydrogen atom or a methyl group
  • Compound (I) wherein R 5 and R 6 are a hydrogen atom.
  • Preferred examples of compound (I) include compound numbers PAS-1 to PAS-10, PAS-12 to PAS-15, PAS-17 to PAS-53, and PAS-56 to PAS-69 or salts thereof described below. Is mentioned.
  • Examples of the salt of compound (I) or compound (I ′) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Is mentioned.
  • Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • pharmaceutically acceptable salts are preferred.
  • the compound (I) or the compound (I ′) and a salt thereof are collectively referred to as a compound of the present invention.
  • any one of the isomers and a mixture are also included in the compound of the present invention.
  • an optical isomer exists in the compound of the present invention
  • an optical isomer resolved from a racemate is also included in the compound of the present invention.
  • isomers are known per se synthesis methods, separation methods (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (eg, fractional recrystallization method, chiral column method, diastereomer method, etc.) ) Etc., each can be obtained as a single item.
  • the compound of the present invention may be a crystal, and the compound of the present invention includes a single crystal form or a mixture of crystal forms.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • the compound of the present invention may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • the compound of the present invention may be a solvate (eg, hydrate etc.) or a non-solvate (eg, non-hydrate etc.), and both are included in the compound of the present invention.
  • Compounds labeled with isotopes eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I, etc.
  • deuterium converters are also encompassed in the compounds of the present invention.
  • a prodrug of the compound of the present invention is a compound that is converted into the compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidizes, reduces, hydrolyzes, etc.
  • a compound in which the amino group of the compound of the present invention is acylated, alkylated or phosphorylated eg, the amino group of the compound of the present invention is eicosanoylated, alanylated, pentylaminocarbonylated, (5 -Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.); compounds of the present invention Compounds in which the hydroxy group is acylated, alkylated, phosphorylated, borated (eg, the hydroxy group of the compound of the present invention is acety
  • the prodrug of the compound of the present invention changes to the compound of the present invention under physiological conditions as described in Drug Development, Volume 7 (Molecular Design), pp. 163-198 (Hirokawa Shoten). May be.
  • Viruses are broadly divided into two types: DNA viruses and RNA viruses, and all viruses belong to one of them.
  • DNA viruses include the Poxviridae, Herpesviridae, Adenoviridae, Papovaviridae, Hepadnaviridae, Parvoviridae and the like.
  • RNA viruses share common characteristics during the growth process. For example, RNA synthesis by RNA-dependent RNA polymerase can be mentioned. Therefore, a drug showing inhibition of the growth of a typical RNA virus (for example, influenza virus of Orthomyxoviridae) can be expected to have a common effect as an anti-RNA virus drug.
  • viruses to be used as anti-RNA virus drugs in the present invention include orthomyxoviridae influenza virus, arenaviridae Lassa virus, lymphocytic choriomeningitis virus (LCMV), caliciviridae norovirus, Sapovirus, Coronaviridae SARS Coronavirus, Togaviridae rubella virus, Nodaviridae viral neuronecrosis virus, Paramyxoviridae mumps virus, Measles virus, RS virus, Picornaviridae poliovirus, Coxsackie virus, Echovirus, Marburg virus of Filoviridae, Ebola virus, Crimea-Congo hemorrhagic fever virus of Bunyaviridae, Severe febrile thrombocytopenia virus (SFTSV), Hazara virus, Flaviviridae Fever virus, Dengue virus, Hepatitis C virus (HCV), Hepatitis G virus (HGV), Rhabdoviridae rabies virus, Ve
  • RNA viruses for example, influenza virus of Orthomyxoviridae, severe fever thrombocytopenia syndrome virus (SFTSV), Hazara virus of Bunyaviridae
  • mammals eg, Mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.
  • anti-RNA virus drug for example, anti-influenza virus drug.
  • Anti-RNA virus drug means a preventive or therapeutic drug for RNA virus infection.
  • Anti-influenza virus drug means a preventive or therapeutic drug for influenza infection.
  • RNA infection examples include the infections of the RNA viruses exemplified above, and in particular, influenza virus infections.
  • the compound of the present invention or a prodrug thereof has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.), and stability and pharmacokinetics ( Since it is excellent in absorption, distribution, metabolism, excretion, etc., it is useful as a pharmaceutical product.
  • the medicament containing the compound of the present invention or a prodrug thereof is prepared by the compound of the present invention or the method according to a method known per se (eg, the method described in the Japanese Pharmacopoeia, etc.)
  • the prodrug alone or mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders , Granules, capsules (including soft capsules and microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release preparations) Microcapsule), aerosol, film (eg, orally disintegrating film, oral mucosal film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), point Preparations, transdermal preparations
  • a pharmacologically acceptable carrier for example
  • Oral or parenteral eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, lesion, etc.
  • the content of the compound of the present invention or a prodrug thereof in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament.
  • the dose of the pharmaceutical of the present invention varies depending on the administration subject, administration route, disease, symptom, etc.
  • the compound of the present invention or The prodrug when orally administered to an adult patient for the purpose of prevention or treatment of influenza virus infection, is about 0.001 to about 100 mg / kg body weight, preferably about 0.005 to about 50 mg / kg body weight, more preferably about 0.01 to about 2 mg / kg body weight. Depending on the dose, it is desirable to administer about 1 to 3 times a day.
  • the pharmacologically acceptable carrier examples include various organic or inorganic carrier substances that are conventionally used as pharmaceutical materials.
  • excipients examples include excipients, lubricants, binders and disintegrants in solid preparations, or solvents in liquid preparations. , Solubilizing agents, suspending agents, tonicity agents, buffers, soothing agents and the like.
  • additives such as usual preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples thereof include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compound of the present invention or a prodrug thereof When the compound of the present invention or a prodrug thereof is applied to each of the above-mentioned diseases, it can be appropriately used in combination with a drug or a therapeutic method usually used for those diseases.
  • the combination agent of the present invention the combined use of the compound of the present invention or a prodrug thereof and a concomitant drug is referred to as “the combination agent of the present invention”.
  • the concomitant drug include other anti-RNA virus drugs, other anti-influenza virus drugs (eg, oseltamivir, zanamivir, laninamivir octanoate, peramivir, favipiravir) and the like.
  • the compound of the present invention or a prodrug thereof By combining the compound of the present invention or a prodrug thereof and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or a prodrug thereof, or a concomitant drug is administered alone. (2) A concomitant drug can be selected according to the patient's symptoms (mild, severe, etc.) (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention or a prodrug thereof, the therapeutic effect can be sustained. (5) By using the compound of the present invention or a prodrug thereof together with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or a prodrug thereof, or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier in accordance with a method known per se.
  • a pharmacologically acceptable carrier for example, tablets (including sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules, solutions, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.) It can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.) as a patch, orally disintegrating tablet, orally disintegrating film and the like.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials.
  • excipients and lubricants in solid preparations Binders and disintegrants, solvents in liquid preparations, solubilizers, suspending agents, tonicity agents, buffers and soothing agents.
  • additives such as usual preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • the timing of administration of the compound of the present invention or a prodrug thereof and a concomitant drug is not limited, and the compound of the present invention or a prodrug thereof or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof May be administered to the administration subject at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention or a prodrug thereof and a concomitant drug, and (2) use in combination with the compound of the present invention or a prodrug thereof.
  • the compounding ratio of the compound of the present invention or a prodrug thereof and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention or a prodrug thereof in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. The same content may be used when the compound of the present invention or a prodrug thereof and a concomitant drug are formulated separately.
  • the compound (I) of the present invention can be produced by the production method described below.
  • the compound in each following scheme includes the case where the salt is formed, As such a salt, the thing similar to the salt of compound (I) etc. are mentioned, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by means of separation such as recrystallization, distillation, chromatography, etc. Can be easily purified.
  • a commercially available product can be used as it is.
  • the raw material compound or the production intermediate has a functional group such as an amino group, a carboxy group, or a hydroxyl group
  • these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Introduction or removal of these protecting groups a method known per se, for example, Wiley-Interscience, Inc. 1999 annual “Protective Groups in Organic Synthesis, 3 rd Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to And so on.
  • X 1 represents a leaving group, and other symbols are as defined above
  • Examples of the “leaving group” represented by X 1 include a halogen atom (eg, chlorine atom, bromine atom, iodine atom) and the like, and preferably a chlorine atom.
  • Compound (I) can be produced by reacting compound (1) and compound (2) in the presence of a base in a solvent that does not adversely influence the reaction.
  • the base include potassium carbonate, sodium carbonate, cesium carbonate and the like, preferably potassium carbonate.
  • Examples of the solvent that does not adversely influence the reaction include N, N-dimethylformamide.
  • the amount of the base to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (1).
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Compound (I) -1 can be produced by reacting compound (3), compound (2) and cyanotrimethylsilane in a solvent that does not adversely influence the reaction.
  • solvent that does not adversely influence the reaction include trifluoroethanol.
  • the amount of compound (2) and cyanotrimethylsilane to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (3).
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Dialkyl phosphite represented by compound (3), compound (2) and HP ( ⁇ O) (OR 21 ) (OR 22 ) (wherein R 21 and R 22 are C 1-6 alkyl groups) Can be reacted in a solvent that does not adversely influence the reaction to produce compound (I) -2.
  • the solvent that does not adversely influence the reaction include trifluoroethanol.
  • the amount of dialkyl phosphite to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (3).
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 8 hours.
  • Compound (3) -1 in which is NH—C ( ⁇ O) and R 7 is a hydrogen atom can be produced by the method described in the following scheme.
  • Step (a) Compound (5) can be produced by reacting compound (4) and phosphoryl chloride in a solvent that does not adversely influence the reaction.
  • the solvent that does not adversely influence the reaction include N, N-dimethylformamide.
  • the amount of phosphoryl chloride to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (4).
  • the reaction temperature is usually from room temperature to 250 ° C, preferably from room temperature to 150 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Step (b) Compound (3) -1 can be produced by reacting compound (5) and acetic acid in a solvent that does not adversely influence the reaction.
  • a solvent that does not adversely influence the reaction include water.
  • the amount of acetic acid to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (5).
  • the reaction temperature is usually from room temperature to 250 ° C, preferably from room temperature to 150 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • compound (I) -3 in which R 5 is a hydrogen atom and R 6 is an ethynyl group can be produced by the method described in the following scheme.
  • Compound (I) -3 can be produced by reacting compound (6), compound (2) and copper (I) iodide in the presence of a base in a solvent that does not adversely influence the reaction.
  • a base examples include diisopropylethylamine and triethylamine, and diisopropylethylamine is preferable.
  • the amount of the base to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (1).
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Compound (I) -4 can be produced by reacting compound (I) -3, copper (I) iodide and trimethylsilyl azide in a solvent that does not adversely influence the reaction.
  • a solvent that does not adversely influence the reaction include N, N-dimethylformamide, methanol, or a mixture thereof.
  • the amount of copper (I) iodide and trimethylsilyl azide to be used is generally 0.5 to 20 molar equivalents, preferably 0.8 to 5 molar equivalents, relative to compound (I) -3.
  • the reaction temperature is usually from room temperature to 250 ° C, preferably from room temperature to 150 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Compound (I) -5 can be produced by reacting compound (I) -3, azide compound (7), copper (II) sulfate and sodium L-ascorbate in a solvent that does not adversely influence the reaction. it can.
  • the solvent that does not adversely influence the reaction include tetrahydrofuran, water, or a mixture thereof.
  • the amount of copper (II) sulfate and sodium L-ascorbate to be used is generally 0.5 to 20 molar equivalents, preferably 0.8 to 5 molar equivalents, relative to compound (I) -3. .
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Compound (I) -7 in which is N ( ⁇ O) ⁇ C (R 11 ) can be produced by the method described in the following scheme.
  • Compound (I) -7 can be produced by reacting compound (I) -6 with an oxidizing agent in a solvent that does not adversely influence the reaction.
  • the solvent that does not adversely influence the reaction include dichloromethane, chloroform, carbon tetrachloride, etc., preferably dichloromethane.
  • the oxidizing agent include peracids such as m-chloroperbenzoic acid.
  • the amount of the oxidizing agent to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (I) -6.
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • compound (I) -8 in which R 5 is a hydrogen atom can be produced by the method described in the following scheme.
  • Step (a) Compound (10) can be produced by reacting compound (3) with Grignard reagent (8) or organolithium reagent (9) in a solvent that does not adversely influence the reaction.
  • the solvent that does not adversely influence the reaction include ethers such as diethyl ether and tetrahydrofuran.
  • the amount of Grignard reagent (8) or organolithium reagent (9) to be used is generally 0.5 mol equivalent to 1.5 mol equivalent, preferably 0.8 mol equivalent to 1.2 mol, relative to compound (3). Is equivalent.
  • the reaction temperature is generally ⁇ 78 ° C. to 150 ° C., preferably ⁇ 20 ° C. to 120 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Step (b) Compound (11) can be produced by reacting compound (10) with a halogenating agent in a solvent that does not adversely influence the reaction.
  • the halogenating agent include thionyl chloride and phosphoryl chloride.
  • the solvent that does not adversely influence the reaction include dichloromethane, chloroform, carbon tetrachloride, etc., preferably dichloromethane.
  • the amount of the halogenating agent to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (10).
  • the reaction temperature is usually from room temperature to 250 ° C, preferably from room temperature to 150 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Step (c) Compound (I) -8 can be produced by reacting compound (11) and compound (2) in the presence of a base in a solvent that does not adversely influence the reaction.
  • a base include potassium carbonate, sodium carbonate, cesium carbonate and the like, preferably potassium carbonate.
  • the solvent that does not adversely influence the reaction include N, N-dimethylformamide.
  • the amount of the base to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (11).
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Step (a) Compound (12) can be produced by reacting compound (4) with a reducing agent in a solvent that does not adversely influence the reaction.
  • a solvent that does not adversely influence the reaction include methanol, ethanol and the like.
  • the reducing agent include sodium borohydride.
  • the amount of the reducing agent to be used is generally 0.5 molar equivalent to 20 molar equivalents, preferably 0.8 molar equivalent to 5 molar equivalents, relative to compound (4).
  • the reaction temperature is usually room temperature to 150 ° C, preferably room temperature to 80 ° C.
  • the reaction time is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • Step (b) Compound (13) can be produced by reacting compound (12) with a halogenating agent in a solvent that does not adversely influence the reaction. This reaction can be carried out in the same manner as in step (b) of production method 8.
  • Step (c) Compound (I) -9 can be produced by reacting compound (13) and compound (2) in the presence of a base in a solvent that does not adversely influence the reaction. This reaction can be carried out in the same manner as in step (c) of production method 8.
  • Example 2 2- (Benzyl (4-fluorobenzyl) amino) -2- (2-oxo-1,2-dihydroquinolin-3-yl) acetonitrile (Compound No. PAS-2)
  • Example 1 using 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (55 mg), N-benzyl-1- (4-fluorophenyl) methanamine (69 mg) and cyanotrimethylsilane (40 ⁇ L) To give the title compound of interest (67 mg, 53% yield).
  • Example 3 2- (Dibenzylamino) -2- (8-methyl-2-oxo-1,2-dihydroquinolin-3-yl) acetonitrile (Compound No. PAS-3) As described in Example 1 using 8-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N, N-dibenzylamine (63 mg) and cyanotrimethylsilane (40 ⁇ L). The title compound (47 mg, 37% yield) was obtained by a reaction treatment according to the above method.
  • Example 8 Dimethyl ((benzyl (4-fluorobenzyl) amino) (8-methyl-2-oxo-1,2-dihydroquinolin-3-yl) methyl) phosphonate (Compound No. PAS-8) Using 8-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N-benzyl-1- (4-fluorophenyl) methanamine (69 mg) and trimethyl phosphite (40 mg) The reaction was carried out according to the method described in Example 1 to obtain the title compound of interest (20 mg, 13% yield).
  • Example 9 2- (Benzyl (4-isopropylbenzyl) amino) -2- (8-methyl-2-oxo-1,2-dihydroquinolin-3-yl) acetonitrile (Compound No. PAS-9) Using 8-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (77 mg) and cyanotrimethylsilane (40 ⁇ L) The reaction was carried out according to the method described in Example 1 to obtain the title object compound (84 mg, yield 60%).
  • Example 10 2- (Benzyl (4-fluorobenzyl) amino) -2- (7-methyl-2-oxo-1,2-dihydroquinolin-3-yl) acetonitrile (Compound No. PAS-10) Using 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N-benzyl-1- (4-fluorophenyl) methanamine (69 mg) and cyanotrimethylsilane (40 ⁇ L). The reaction was carried out according to the method described in Example 1 to obtain the title compound of interest (70 mg, 53% yield).
  • Example 12 Dimethyl ((benzyl (4-fluorobenzyl) amino) (7-methyl-2-oxo-1,2-dihydroquinolin-3-yl) methyl) phosphonate (Compound No. PAS-12) Using 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N-benzyl-1- (4-fluorophenyl) methanamine (69 mg) and trimethyl phosphite (40 mg) The reaction was carried out according to the method described in Example 1 to obtain the title compound of interest (15 mg, 9% yield).
  • Example 13 2- (Benzyl (4-isopropylbenzyl) amino) -2- (7-methyl-2-oxo-1,2-dihydroquinolin-3-yl) acetonitrile (Compound No. PAS-13) Using 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (77 mg) and cyanotrimethylsilane (40 ⁇ L). The reaction was carried out according to the method described in Example 1 to obtain the title compound of interest (71 mg, yield 51%).
  • Example 17 Dimethyl ((benzyl (4-isopropylbenzyl) amino) (7-methyl-2-oxo-1,2-dihydroquinolin-3-yl) methyl) phosphonate (Compound No. PAS-17) Using 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (77 mg) and trimethyl phosphite (40 mg) The reaction was carried out according to the method described in Example 1 to obtain the title target compound (16 mg, yield 10%).
  • Example 18 2-((4-Isopropylbenzyl) (4-methoxybenzyl) amino) -2- (7-methyl-2-oxo-1,2-dihydroquinolin-3-yl) acetonitrile (Compound No. PAS-18) 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (60 mg), N- (4-fluorobenzyl) -1- (4-isopropylphenyl) methanamine (83 mg) and cyanotrimethylsilane (40 ⁇ L) The title compound (93 mg, 64% yield) was obtained by reaction according to the method described in Example 1.
  • reaction solution was diluted with a saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate.
  • the extract was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • Example 20 N-benzyl-N- (4-isopropylbenzyl) -1- (quinolin-3-yl) -2-propyn-1-amine (Compound No. PAS-20) 1- (Quinolin-3-yl) -2-propyn-1-yl acetate (225 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (239 mg), copper (I) iodide (20 mg) and diisopropyl Reaction was carried out using ethylamine (350 ⁇ L) according to the method described in Example 14 to obtain the title compound of interest (131 mg, yield 32%).
  • Example 25 2- (Benzyl (4-isopropylbenzyl) amino) -2- (7-methylquinolin-3-yl) acetonitrile (Compound No. PAS-25) Reaction according to the method described in Example 1 using 7-methylquinoline-3-carbaldehyde (83 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (115 mg) and cyanotrimethylsilane (72 ⁇ L). Treatment gave the title compound (147 mg, 73% yield).
  • Example 26 1-((1-cyclohexyl-1H-1,2,3-triazol-4-yl) ((4-fluorobenzyl) (4-isopropylbenzyl) amino) methyl) quinoline 1-oxide (Compound No. PAS-26) 1- (1-cyclohexyl-1H-1,2,3-triazol-4-yl) -N- (4-fluorobenzyl) -N- (4-isopropylbenzyl) -1- (quinolin-3-yl)- The reaction was performed according to the method described in Example 21 using 1-methanamine (50 mg) and m-CPBA (70%, 17 mg) to give the title object compound (10 mg, yield 20%).
  • PAS-52) 7-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (80 mg) was dissolved in methanol (2.5 mL), and N- (4-tert-butylbenzyl) -1- (4-fluoro Phenyl) methanamine (108 mg), tert-butyl isocyanate (54 ⁇ L) and trimethylsilyl azide (80 ⁇ L) were added, and the mixture was stirred at 60 ° C. for 24 hours.
  • the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • Example 27 2- (Benzyl (4-isopropylbenzyl) amino) -2- (2-chloro-7-methylquinolin-3-yl) acetonitrile (Compound No. PAS-27) As described in Example 1 using 2-chloro-7-methylquinoline-3-carbaldehyde (66 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (77 mg) and cyanotrimethylsilane (40 ⁇ L). The title compound (86 mg, yield 59%) was obtained by a reaction treatment according to the above method.
  • Example 28 N-benzyl-N- (4-isopropylbenzyl) -1- (7-methylquinolin-3-yl) -2-propyn-1-amine (Compound No. PAS-28) 1- (7-Methylquinolin-3-yl) -2-propyn-1-yl acetate (148 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (148 mg), copper (I) iodide (12 mg ) And diisopropylethylamine (220 ⁇ L) according to the method described in Example 14 to give the title compound (55 mg, 21% yield).
  • Example 30 2- (Benzyl (4-isopropylbenzyl) amino) -2- (7-methylquinolin-3-yl) acetonitrile (Compound No. PAS-30) Reaction according to the method described in Example 1 using 7-methylquinoline-3-carbaldehyde (83 mg), N-benzyl-1- (4-isopropylphenyl) methanamine (115 mg) and cyanotrimethylsilane (72 ⁇ L). Treatment gave the title compound (147 mg, 73% yield).
  • Example 33 3- (1-((4-Fluorobenzyl) (4-isopropylbenzyl) amino) ethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-33) 3- (1-Chloroethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (57 mg) was dissolved in N, N-dimethylformamide (3 mL), and N- (4-fluorobenzyl) -1- (4-Isopropylphenyl) methanamine (67 mg) and potassium carbonate (72 mg) were added, and the mixture was stirred at 80 ° C. for 16 hours.
  • reaction solution was diluted with distilled water (10 mL) and extracted with ethyl acetate.
  • the extract was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • the extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was suspended in dichloromethane (5 mL), thionyl chloride (500 ⁇ L) was added dropwise, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off from the reaction solution under reduced pressure, followed by drying under reduced pressure to obtain the title object compound (23 mg, yield 17%).
  • Example 35 3- (1-((4-Fluorobenzyl) (4-isopropylbenzyl) amino) pentyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-35) 3- (1-Chloropentyl) -7-methyl-2-oxo-1,2-dihydroquinoline (23 mg) was dissolved in N, N-dimethylformamide (3 mL), and N- (4-fluorobenzyl) -1 -(4-Isopropylphenyl) methanamine (25 mg) and potassium carbonate (28 mg) were added, and the mixture was stirred at 80 ° C. for 16 hours.
  • reaction solution was diluted with distilled water (10 mL) and extracted with ethyl acetate.
  • the extract was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • Example 37 N- (4-Fluorobenzyl) -4-hydroxy-N- (4-isopropylbenzyl) -2-oxo-1,2-dihydroquinoline-3-carboxamide (Compound No. PAS-37) Using methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (108 mg) and N- (4-isopropylbenzyl) -1- (4-fluorophenyl) methanamine (137 mg) The reaction was conducted according to the method described in Example 36 to obtain the title object compound (162 mg, yield 72%).
  • reaction solution was diluted with distilled water (10 mL) and extracted with ethyl acetate.
  • the extract was washed successively with water and saturated brine, and dried over magnesium sulfate.
  • Example 40 3-((((4-chlorobenzyl) (4-isopropylbenzyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-40) 3- (chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-chlorobenzyl) -1- (4-isopropylphenyl) methanamine (97 mg) and potassium carbonate ( 108 mg) was used according to the method described in Example 32 to give the title compound (79 mg, 46% yield).
  • Example 42 3-(((2-Fluorobenzyl) (4-isopropylbenzyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-42) 3- (chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (2-fluorobenzyl) -1- (4-isopropylphenyl) methanamine (91 mg) and potassium carbonate ( 108 mg) was used according to the method described in Example 32 to give the title compound of interest (94 mg, 48% yield).
  • Example 43 3-((((3-Fluorobenzyl) (4-isopropylbenzyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-43) 3- (chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (3-fluorobenzyl) -1- (4-isopropylphenyl) methanamine (91 mg) and potassium carbonate ( 108 mg) to give the title compound of interest (88 mg, 53% yield) according to the procedure described in Example 32.
  • Example 45 3-((((4-Ethylbenzyl) (4-fluorobenzyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-45) 3- (Chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-ethylbenzyl) -1- (4-fluorophenyl) methanamine (95 mg) and potassium carbonate ( 108 mg) and the reaction was carried out according to the method described in Example 32 to give the title compound of interest (112 mg, 69% yield).
  • Example 46 3-(((4-Fluorobenzyl) (4-trifluoromethylbenzyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-46) 3- (Chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-fluorobenzyl) -1- (4-trifluoromethylphenyl) methanamine (97 mg) and carbonic acid Reaction was carried out using potassium (108 mg) according to the method described in Example 32 to obtain the title compound of interest (64 mg, yield 36%).
  • Example 47 3-((((4-tert-butylbenzyl) (3,4-difluorobenzyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-47) 3- (Chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-tert-butylbenzyl) -1- (3,4-difluorophenyl) methanamine (104 mg) And potassium carbonate (108 mg) according to the method described in Example 32 to give the title compound (72 mg, 40% yield).
  • Example 48 3-((((4-tert-butylbenzyl) (4-fluorobenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-48) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) methanamine (96 mg) and carbonic acid The reaction was carried out using potassium (108 mg) according to the method described in Example 32 to obtain the title compound of interest (40 mg, 23% yield).
  • Example 49 3-((((4-tert-butylbenzyl) (4-fluorobenzyl) amino) methyl) -8-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-49) 3- (Chloromethyl) -8-methyl-2-oxo-1,2-dihydroquinoline (70 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) methanamine (85 mg) and carbonic acid The reaction was performed using potassium (87 mg) according to the method described in Example 32 to give the title object compound (28 mg, 18% yield).
  • Example 50 3-((((4-tert-butylbenzyl) (4-fluorobenzyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-50) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) methanamine (89 mg) and carbonic acid Reaction was carried out using potassium (91 mg) according to the method described in Example 32 to obtain the title compound of interest (130 mg, yield 79%).
  • Example 51 3-((((4-tert-butylbenzyl) (1- (4-fluorophenyl) ethyl) amino) methyl) -7-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-51) 3- (Chloromethyl) -7-methyl-2-oxo-1,2-dihydroquinoline (50 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) ethan-1-amine ( 63 mg) and potassium carbonate (61 mg) according to the method described in Example 32 to give the title compound (38 mg, 35% yield).
  • Example 53 3-((((4-tert-butylbenzyl) (1- (4-fluorophenyl) ethyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-53) 3- (chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (30 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) ethan-1-amine ( 41 mg) and potassium carbonate (61 mg) according to the method described in Example 32 to give the title compound (16 mg, 25% yield).
  • Example 56 3-(((4-tert-butylbenzyl) (4-fluorobenzyl) amino) methyl) -6-isopropyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-56) 3- (Chloromethyl) -6-isopropyl-2-oxo-1,2-dihydroquinoline (83 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) methanamine (85 mg) and carbonic acid Reaction was carried out using potassium (87 mg) according to the method described in Example 32 to obtain the title compound of interest (66 mg, 40% yield).
  • Example 57 3-((((4-tert-butylbenzyl) (4-fluorobenzyl) amino) methyl) -6-propyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-57) 3- (Chloromethyl) -6-propyl-2-oxo-1,2-dihydroquinoline (80 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) methanamine (89 mg) and carbonic acid Reaction was carried out using potassium (91 mg) according to the method described in Example 32 to obtain the title compound of interest (69 mg, 42% yield).
  • Example 58 3-((((4-tert-butylbenzyl) (1- (4-fluorophenyl) ethyl) amino) methyl) -6-isopropyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-58) 3- (Chloromethyl) -6-isopropyl-2-oxo-1,2-dihydroquinoline (83 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) ethan-1-amine ( 91 mg) and potassium carbonate (87 mg) according to the method described in Example 32 to give the title compound (52 mg, 31% yield).
  • Example 59 3-((((4-tert-butylbenzyl) (1- (4-fluorophenyl) ethyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-59) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (78 mg), N- (4-tert-butylbenzyl) -1- (4-fluorophenyl) ethan-1-amine ( 91 mg) and potassium carbonate (87 mg) according to the method described in Example 32 to give the title compound (44 mg, 26% yield).
  • Example 60 3-((((4-tert-butylbenzyl) (3,4-difluorobenzyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-60) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (78 mg), N- (4-tert-butylbenzyl) -1- (3,4-difluorophenyl) methanamine (93 mg) And potassium carbonate (87 mg) according to the method described in Example 32 to give the title compound (27 mg, 16% yield).
  • Example 61 3-(((1- (4-Fluorophenyl) ethyl) (naphthalen-2-ylmethyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-61) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (44 mg), 1- (4-fluorophenyl) -N- (naphthalen-2-ylmethyl) ethan-1-amine (56 mg ) And potassium carbonate (55 mg) according to the method described in Example 32 to give the title compound of interest (12 mg, 12% yield).
  • Example 62 3-(((1- (4-Fluorophenyl) ethyl) (naphthalen-2-ylmethyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-62) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (48 mg), N- (4-fluorobenzyl) -1- (naphthalen-2-yl) methanamine (53 mg) and potassium carbonate (55 mg) was used to react according to the method described in Example 32 to give the title compound of interest (23 mg, 23% yield).
  • Example 63 3-(((1- (3-Fluorophenyl) ethyl) (naphthalen-2-ylmethyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-63) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (3-fluorobenzyl) -1- (naphthalen-2-yl) methanamine (56 mg) and potassium carbonate (55 mg) was used to react according to the method described in Example 32 to give the title object compound (57 mg, 59% yield).
  • Example 64 3-(((((1- (3-fluorophenyl) ethyl) (naphthalen-2-ylmethyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-64) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (48 mg), N- (3-fluorobenzyl) -1- (naphthalen-2-yl) methanamine (56 mg) and potassium carbonate (55 mg) was used to react according to the method described in Example 32 to give the title object compound (57 mg, 83% yield).
  • Example 65 3-((Benzyl (4-tert-butylbenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-65) Using 3- (chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4-tert-butylbenzyl) benzylamine (50 mg) and potassium carbonate (55 mg) The product was treated according to the method described in Example 32 to obtain the title target compound (59 mg, yield 69%).
  • Example 73 3-(((([[[1,1′-biphenyl] -4-ylmethyl) (4-fluorobenzyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-73 ) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (48 mg), 1- [1,1′-biphenyl] -4-yl) -N- (4-fluorobenzyl) methanamine (58 mg) and potassium carbonate (55 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (49 mg, 51% yield).
  • Example 74 3-(((1- (4-Fluorophenyl) ethyl) (naphthalen-1-ylmethyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-74) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4-fluorobenzyl) -1- (naphthalen-1-yl) methanamine (53 mg) and potassium carbonate (55 mg) was used to react according to the method described in Example 32 to give the title compound of interest (37 mg, 42% yield).
  • Example 75 3-(((1- (4-Fluorophenyl) ethyl) (naphthalen-1-ylmethyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-75) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (48 mg), N- (4-fluorobenzyl) -1- (naphthalen-1-yl) methanamine (53 mg) and potassium carbonate (55 mg) was used to react according to the method described in Example 32 to give the title object compound (30 mg, 34% yield).
  • Example 76 3-((((4- (tert-butyl) benzyl) (cyclopentyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-76) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4- (tert-butyl) benzyl) (cyclopentyl) amine hydrochloride (54 mg) and potassium carbonate ( The title compound (42 mg, 53% yield) was obtained by reaction according to the method described in Example 32.
  • Example 77 3-((((4- (tert-butyl) benzyl) (cyclopentyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-77) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (48 mg), N- (4- (tert-butyl) benzyl) (cyclopentyl) amine hydrochloride (54 mg) and potassium carbonate ( The title compound (42 mg, 53% yield) was obtained by reaction according to the method described in Example 32.
  • Example 78 3-((((4- (tert-butyl) benzyl) (3-hydroxypropyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-78) 3- (chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4- (tert-butyl) benzyl) (3-hydroxypropyl) amine hydrochloride (44 mg) and The reaction was performed according to the method described in Example 32 using potassium carbonate (83 mg) to obtain the title compound of interest (21 mg, yield 27%).
  • Example 79 3-((((4- (tert-butyl) benzyl) (3-hydroxypropyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-79) 3- (chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (48 mg), N- (4- (tert-butyl) benzyl) (3-hydroxypropyl) amine hydrochloride (44 mg) and The reaction was performed according to the method described in Example 32 using potassium carbonate (83 mg) to obtain the title compound of interest (23 mg, yield 28%).
  • Example 80 3-((((4- (tert-butyl) benzyl) (4- (methoxymethoxy) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-80) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (62 mg), N- (4- (tert-butyl) benzyl) -1- (4- (methoxymethoxy) phenyl) methanamine (93 mg) and potassium carbonate (83 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (44 mg, 30% yield).
  • Example 81 3-((((4- (tert-butyl) benzyl) (4-hydroxybenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-81) 3-((((4- (tert-butyl) benzyl) (4- (methoxymethoxy) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (35 mg) was added to methanol (1. 5 mL), 2 concentrations of concentrated hydrochloric acid were added, and the mixture was stirred at 50 ° C. for 1 hour.
  • Example 82 3-((((4- (tert-butyl) benzyl) (4- (methoxymethoxy) benzyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-82) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (75 mg), N- (4- (tert-butyl) benzyl) -1- (4- (methoxymethoxy) phenyl) methanamine (93 mg) and potassium carbonate (83 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (106 mg, yield 87%).
  • reaction solution was diluted with a saturated aqueous sodium hydrogen carbonate solution (15 mL) and extracted with dichloromethane. The extract was washed successively with water and saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the title compound (43 mg, yield 63%) was obtained as a white solid.
  • Example 88 3-((((4- (tert-butyl) benzyl) (4-methoxybenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-88) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4-methoxyphenyl) methanamine hydrochloride ( 64 mg) and potassium carbonate (88 mg) according to the method described in Example 32 to give the title compound (42 mg, 46% yield).
  • Example 89 3-((((4- (tert-butyl) benzyl) (4-ethoxybenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-89) 3- (chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4-ethoxyphenyl) methanamine hydrochloride ( 67 mg) and potassium carbonate (88 mg) according to the method described in Example 32 to give the title compound (38 mg, 41% yield).
  • Example 90 3-((((4- (tert-butyl) benzyl) (cyclohexylmethyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-90) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1-cyclohexylmethanamine hydrochloride (60 mg) and carbonic acid Reaction was carried out using potassium (88 mg) according to the method described in Example 32 to obtain the title compound of interest (16 mg, yield 19%).
  • Example 91 3-((((4- (tert-butyl) benzyl) (4-isopropoxybenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-91) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4-isopropoxyphenyl) methanamine hydrochloride (70 mg) and potassium carbonate (88 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (31 mg, yield 32%).
  • Example 92 3-((((4- (tert-butyl) benzyl) (4-propoxybenzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-92) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4-propoxyphenyl) methanamine hydrochloride ( 70 mg) and potassium carbonate (88 mg) according to the method described in Example 32 to give the title compound (62 mg, 64% yield).
  • Example 93 4-((((4- (tert-butyl) benzyl) ((6-methyl-2-oxo-1,2-dihydroquinolin-3-yl) amino) methyl) benzamide (Compound No. PAS-93) 3- (chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), 4-((((4- (tert-butyl) benzyl) amino) methyl) benzamide hydrochloride (64 mg) and The reaction was performed according to the method described in Example 32 using potassium carbonate (88 mg) to obtain the title compound of interest (62 mg, yield 32%).
  • Example 94 3-((((4- (tert-butyl) benzyl) (4- (2-hydroxyethoxy) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-94) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), 2- (4-((tert-butyl) benzyl) amino) methyl) phenoxy) ethanol hydrochloride (69 mg) And potassium carbonate (88 mg) according to the method described in Example 32 to give the title object compound (10 mg, 10% yield).
  • Example 95 3-((((4- (tert-butyl) benzyl) (4- (trifluoromethoxy) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-95) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4-((tert-butyl) benzyl) 1- (4- (trifluoromethoxy) phenyl) The reaction was performed according to the method described in Example 32 using methanamine hydrochloride (74 mg) and potassium carbonate (88 mg) to obtain the title object compound (56 mg, yield 55%).
  • Example 96 3-((((4- (tert-butyl) benzyl) (4- (difluoromethoxy) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-96) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4-((tert-butyl) benzyl) 1- (4- (difluoromethoxy) phenyl) methanamine (70 mg) and potassium carbonate (55 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (34 mg, 35% yield).
  • Example 97 3-((((4- (tert-butyl) benzyl) (4- (methylthio) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-97) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4-((tert-butyl) benzyl) 1- (4- (methylthio) phenyl) methanamine ( 60 mg) and potassium carbonate (55 mg) according to the method described in Example 32 to give the title compound (76 mg, 81% yield).
  • Example 98 3-((((4-Butoxybenzyl) (4- (tert-butyl) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-98) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4-butoxybenzyl) -1- (4-((tert-butyl) phenyl) methanamine (72 mg ) And potassium carbonate (55 mg) according to the method described in Example 32 to give the title compound (60 mg, 60% yield).
  • Example 99 3-((((4- (tert-butyl) benzyl) 1- (4-methoxyphenyl) ethyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-99) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4-methoxyphenyl) ethane-1- The reaction was performed according to the method described in Example 32 using amine (60 mg) and potassium carbonate (55 mg) to give the title object compound (42 mg, yield 45%).
  • Example 100 3-((((4- (tert-butyl) benzyl) (4- (dimethylamino) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-100) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), 4 (((4- (tert-butyl) benzyl) amino) methyl) -N, N-dimethylaniline ( 60 mg) and potassium carbonate (55 mg) according to the method described in Example 32 to give the title compound (56 mg, 54% yield).
  • Example 101 3-((((4- (tert-butyl) benzyl) (4- (trifluoromethyl) thio) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS- 101) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4-trifluoromethyl) thio) phenyl ) Methanamine (71 mg) and potassium carbonate (55 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (59 mg, 56% yield).
  • Example 102 3-((((4- (tert-butyl) benzyl) (1-4- (methoxyphenyl) ethyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-102 ) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4- (tert-butyl) benzyl) -1- (4-methoxyphenyl) ethane-1- The reaction was performed according to the method described in Example 32 using amine (60 mg) and potassium carbonate (55 mg) to obtain the title object compound (36 mg, yield 37%).
  • Example 103 3-((((4- (tert-butyl) benzyl) (4- (difluoromethoxy) benzyl) amino) methyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS-103) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4- (tert-butyl) benzyl) -1- (4- (difluoromethoxy) phenyl) methanamine
  • the reaction was performed according to the method described in Example 32 using hydrochloride (71 mg) and potassium carbonate (88 mg) to obtain the title object compound (56 mg, yield 55%).
  • Example 104 4-((((4- (tert-butyl) benzyl) ((6-methyl-2-oxo-1,2-dihydroquinolin-3-yl) methyl) amino) methyl) benzonitrile (Compound No. PAS-104) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), 4-(((4- (tert-butyl) benzyl) amino) methyl) benzonitrile (56 mg) and carbonic acid Reaction was carried out using potassium (55 mg) according to the method described in Example 32 to obtain the title compound of interest (32 mg, 36% yield).
  • PAS-107) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -6-methoxy-1,2,3,4 Reaction was carried out using tetrahydronaphthalen-1-amine (64 mg) and potassium carbonate (55 mg) according to the method described in Example 32 to obtain the title compound of interest (45 mg, 46% yield).
  • 1 HNMR 500 MHz, d-DMSO
  • 1.44-1.55 (m, 1H)
  • PAS -108) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1- (4- (difluoromethoxy) phenyl) ethane
  • the reaction was conducted according to the method described in Example 32 using 1-amine (67 mg) and potassium carbonate (55 mg) to give the title object compound (19 mg, yield 19%).
  • PAS-109) 3- (Chloromethyl) -6-ethyl-2-oxo-1,2-dihydroquinoline (44 mg), N- (4- (tert-butyl) benzyl) -1- (4- (difluoromethoxy) phenyl) ethane
  • the reaction was conducted according to the method described in Example 32 using 1-amine (67 mg) and potassium carbonate (55 mg) to give the title object compound (36 mg, yield 35%).
  • Example 110 3-((((4- (tert-butyl) benzyl) (4-((difluoromethyl) thio) benzyl) amino) methyl) -6-methyl-2-oxo-1,2-dihydroquinoline (Compound No. PAS- 110) 3- (Chloromethyl) -6-methyl-2-oxo-1,2-dihydroquinoline (42 mg), N- (4- (tert-butyl) benzyl) -1-((difluoromethyl) thio) phenyl) methanamine (67 mg) and potassium carbonate (55 mg) were used for the reaction according to the method described in Example 32 to obtain the title compound of interest (42 mg, 41% yield).
  • Antiviral activity was quantified by crystal violet assay (CV assay). Influenza virus grows in about 12-16 hours when it infects cells. As the virus grows, the cells die and change shape (cytopathic effect, CPE). In a typical example, cultured cells attached to a plate float round due to CPE. If the compound has anti-influenza virus activity, the cells will not float because CPE is suppressed. Cells that do not float can be quantitatively evaluated because they remain on the plate after fixation with a crystal violet dye. Use this principle.
  • the crystal violet assay is as follows. All operations were performed aseptically in a clean bench.
  • Canine kidney-derived cells (MDCK cells) seeded at 4 ⁇ 3 ⁇ 10 4 cells per well in a 96-well plate were used.
  • a compound dissolved in 100% DMSO is serially diluted in advance with a MEM + vitamin solution.
  • the medium of the plate on which the cells were seeded was removed with an aspirator, and 100 ⁇ L of MEM + vitamin solution was added for washing.
  • the medium was once again removed with an aspirator, and the diluted sample solution was added to the corresponding well at a concentration of 100 ⁇ L / well from the lower concentration.
  • MEM + vitamin was added at 100 ⁇ L / well to the wells of uninfected cells, and influenza virus solution diluted to 1000 TCID 50 / mL was added at 100 ⁇ L / well to the wells of infected cells.
  • influenza virus solution diluted to 1000 TCID 50 / mL was added at 100 ⁇ L / well to the wells of infected cells.
  • the 96-well plate was cultured at 37 ° C. in a 5% CO 2 incubator for 2 days. Thereafter, 150 ⁇ L of the culture supernatant was collected from the 96-well plate immediately before fixed staining and separately used for quantifying the amount of virus in the culture supernatant.
  • fixation staining remove the medium from the 96-well plate with an aspirator, add 200 ⁇ L of 70% EtOH, fix the cells at room temperature for 5 minutes, add 100 ⁇ L of 0.5% crystal violet staining solution, and stain at room temperature for 5 minutes. . After dyeing, washing with water, drying, and photography were performed. The intensity of antiviral activity was determined at the lowest concentration at which cells stained purple (black in black and white photography). In the case of the cytotoxicity test, MEM + vitamin containing no virus was used instead of the virus solution in the above procedure.
  • MIC Indicates the minimum inhibitory concentration of each compound in the antiviral activity test. The lowest density at which 96 wells were visually stained by 50% or more. Toxicity: In this case, the cells are peeled off and not stained in the cytotoxicity test. Antiviral activity test and cytotoxicity test were also conducted on PA-49 (commercial compound) and Tamiflu represented by the following formula. The results are shown in Table 2.
  • the compounds of the invention have anti-influenza virus activity.
  • Compound number PAS-48, PAS-59, PAS-66, PAS-80, PAS-88, PAS-89, PAS-95, PAS-96, PAS-99, PAS-100, PAS-102 to PAS-106, PAS-108 to PAS-110 were found to have anti-influenza virus activity equivalent to or better than PA-49 and Tamiflu.
  • Test Example 2 Determination of the amount of virus in the culture supernatant by HA assay
  • the culture supernatant was collected immediately before fixation staining (48 hours after virus infection), and a 2-fold serial dilution series in another round-bottom 96-well plate Create Red blood cells are added thereto, mixed and allowed to stand, and the presence or absence of an agglutination reaction is observed. If virus is present, erythrocytes will aggregate without sinking, and the entire well will appear uniform. A dark circle at the center of the well indicates that red blood cells have settled at the center of the round bottom, that is, they have not aggregated.
  • the amount of virus in the culture supernatant was quantified by utilizing the property of influenza virus binding to sialic acid on the surface of erythrocytes (hemagglutination reaction).
  • hemagglutination reaction By adding serially diluted virus solution to a certain number (concentration) of red blood cells, red blood cells can be completely agglomerated where the virus solution is concentrated, but red blood cells can aggregate red blood cells. Can not be.
  • the hemagglutination reaction was performed by the following method. Add 2 mL of chicken erythrocyte suspension (Nihon Biotest) to 38 mL of phosphate buffer (PBS), mix well, centrifuge the erythrocytes, suck out the supernatant, and make up to 40 mL with PBS.
  • 5% erythrocyte fluid was used.
  • 50 ⁇ L of PBS was dispensed, and 50 ⁇ L of a virus measuring solution was added to the first row and mixed with PBS.
  • 50 ⁇ L of the mixed solution was transferred to the second row, mixed with PBS as in the first row, and transferred to the third row. This 2-fold dilution operation was performed up to the 11th row.
  • 50 ⁇ L of 5% red blood cell solution was added in order from the 12th row to the 1st row, mixed, and allowed to stand at room temperature. After 1 hour, the presence or absence of erythrocyte aggregation was visually determined.
  • the amount of virus is indicated by the HA value (HAU, HA unit).
  • HAU HA unit
  • the specific calculation method is as follows. Calculate how many times the virus stock solution was diluted with PBS in the thinnest dilution series where erythrocyte aggregation was observed. For example, if red blood cells have aggregated from the first row to the fifth row, the first row is diluted 2-fold with PBS, the second row is 4-fold diluted, the third row is 8-fold, the fourth row is 16-fold, the fifth row 32 times. Since the amount of virus solution is 50 ⁇ ⁇ ⁇ ⁇ L, 32 HAU (HA unit) per 50 ⁇ L.
  • FIG. 1 shows the virus titer in the presence of the target compound, assuming that the HA titer of the culture supernatant in which only the virus infection was performed without adding the compound was 100%.
  • Fig. 1 Relationship between relative cell viability and relative viral load in culture supernatant Antiviral activity test for PAS-48, PAS-59, PA-49, Tamiflu (registered trademark) (generic name: oseltamivir) ( ⁇ ) and viral load quantification by HA assay ( ⁇ ) are summarized in one graph.
  • the horizontal axis is the sample concentration
  • the vertical axis (left) is the relative OD value (Relative OD) (%) obtained from the antiviral activity test
  • the vertical axis (right) is the relative viral load (Relative) obtained by the HA assay. titer) (%).
  • the concentration increases, the relative OD value increases, the relative viral load decreases, and it is found that the concentration is higher than the detection limit at concentrations higher than 1 ⁇ M.
  • a commercially available product (GeneTex GTX118991) was used.
  • Bovine serum albumin (BSA) as a stabilizer was removed in advance by purification of protein A-bound beads, and dialyzed at 4 ° C. using PBS buffer. The buffer was exchanged twice, and the antibody after dialysis was stored at 4 ° C.
  • the PA antibody was immobilized by an amine coupling method on a sensor chip (CM5) dedicated to a surface plasmon resonance measurement device (GE Healthcare Biacore T200). Subsequently, the PA protein was captured by an antibody and used as a ligand.
  • CM5 sensor chip
  • GE Healthcare Biacore T200 surface plasmon resonance measurement device
  • PAS-48 concentration on the horizontal axis and reaction (RU) on the vertical axis from the sensorgram of each concentration of PAS-48, and dissociation constant (KD) of PAS-48 from the fitting curve (typical example, Fig. 2) was calculated.
  • the dissociation constant was calculated to be 6.1 ⁇ 0.8 ⁇ M from three independent experiments.
  • Fig. 2 Analysis of PA protein-PAS-48 interaction using Biacore.
  • the horizontal axis shows the PAS-48 concentration, and the vertical axis shows the relative production amount (Response) of the PA protein-PAS-48 complex.
  • Complex formation occurs in a concentration-dependent manner, and it can be seen that complex formation reaches a plateau at high concentrations. From this, the dissociation binding constant was calculated.
  • SFTSV anti SFTS virus
  • the culture supernatant containing the virus diluted 10-fold serially was added to Vero76 cells from which the culture supernatant was removed, and the culture was continued for 20 hours. Thereafter, the culture supernatant was removed, 4% paraformaldehyde was added at 50 ⁇ L / well, and the infected cells were fixed by allowing to stand at room temperature for 30 minutes or longer. Thereafter, the whole plate was inactivated by immersing the whole plate in 4% paraformaldehyde for 30 minutes or more.
  • SW13 cells were seeded on a 24-well plate at 1.5 ⁇ 10 5 / well, and the culture supernatant containing the virus diluted 10-fold on the day after seeding was infected with SW13 cells excluding the culture supernatant. After 1 minute, remove the culture supernatant containing virus, wash once with PBS (-), completely dissolve in a microwave oven, then warm to 50 ° C in a water bath (1 g agarose (1 g agarose (Seakem ME ) Was dissolved in 100 mL MilliQ water and autoclaved) and mixed 1: 1 with 2 x MEM (2% glutamine, 2% penicillin / streptomycin, 1.4% FBS) warmed to 37 ° C.
  • PBS PBS
  • PFU Plaque forming unit
  • the compound of the present invention has excellent anti-RNA virus activity and is useful as an anti-RNA virus drug, particularly as an anti-influenza virus drug.

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Abstract

La présente invention concerne un composé qui possède une activité anti-virus à ARN et qui est destiné à être utilisé en tant que médicament anti-virus à ARN, en particulier un médicament contre le virus de la grippe. La présente invention concerne également un composé représenté par la formule (I) (chaque symbole étant tel que défini dans la description) ou un sel de celui-ci.
PCT/JP2018/013592 2017-03-31 2018-03-30 Composé de quinolinone et médicament anti-virus à arn Ceased WO2018181892A1 (fr)

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