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WO2013002357A1 - Inhibiteur de réplication du vih - Google Patents

Inhibiteur de réplication du vih Download PDF

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Publication number
WO2013002357A1
WO2013002357A1 PCT/JP2012/066642 JP2012066642W WO2013002357A1 WO 2013002357 A1 WO2013002357 A1 WO 2013002357A1 JP 2012066642 W JP2012066642 W JP 2012066642W WO 2013002357 A1 WO2013002357 A1 WO 2013002357A1
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Prior art keywords
substituted
unsubstituted
compound
aromatic heterocyclic
aromatic
Prior art date
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English (en)
Japanese (ja)
Inventor
一成 服部
奈緒子 栗原
努 岩耒
崇嗣 井上
俊行 秋山
靖 長谷川
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • Dialkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Preferred embodiments of “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl part is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic carbocyclic amino” means a group in which “aromatic carbocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, phenylamino, naphthylamino and the like can be mentioned.
  • “Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • Non-aromatic heterocyclic amino means a group in which “non-aromatic heterocyclic” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • N is preferably 1 or 2, particularly preferably 1.
  • R 5 has a substituent
  • preferred substituents are halogen, hydroxy, amino, cyano, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyl, monoalkylamino, Dialkylamino, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic group alkyl, Non-aromatic carbocyclic group alkyl, aromatic heterocyclic group alkyl or non-aromatic heterocyclic group alkyl, more preferred substituents are halogen, oxo, alkyl, aromatic carbocyclic group, non-aromatic Carbocyclic group, aromatic heterocyclic group, non-aromatic heterocycl
  • R 5 ′ and R 6 may form a ring A together with adjacent atoms.
  • substituents are halogen, hydroxy, amino, cyano, oxo, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyl, monoalkylamino, Dialkylamino, alkylsulfanyl, alkenylsulfanyl, or alkynylsulfanyl, more preferred substituents are halogen, alkyl, alkenyl, or alkyloxy, and more preferred substituents are fluoro, chloro, bromo, methyl, ethyl, or Methyloxy and particularly preferred substituents are chloro or methyl.
  • R 5 is also particularly preferably a group shown below.
  • Y is preferably a single bond, alkylene, alkenylene or alkynylene (provided that when R 5 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, Y is a single bond. More preferably a single bond, alkenylene, or alkynylene, still more preferably a single bond, ethenylene, or ethynylene, and particularly preferably a single bond.
  • Ring A is preferably an aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle, more preferably an aromatic carbocycle or non-aromatic heterocycle, and still more preferably Is a 5- to 8-membered aromatic carbocycle or a 3- to 8-membered non-aromatic heterocycle, particularly preferably benzene or dihydropyridine, and most preferably benzene.
  • R 4 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocycle And a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, particularly preferably a hydrogen atom.
  • R 1 is substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyloxy
  • n is 1
  • R 3 is a substituted or unsubstituted non-aromatic carbocyclic group
  • R 4 is a hydrogen atom
  • R 5 is a substituted or unsubstituted non-aromatic carbocyclic carbonylamino
  • Y is a single bond
  • R 6 is a substituted or unsubstituted alkyl.
  • R 1 is substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyloxy
  • n is 1
  • R 3 is a substituted or unsubstituted non-aromatic carbocyclic group
  • R 4 is a hydrogen atom
  • R 5 is —NR 51 R 52 (R 51 is a substituted or unsubstituted alkylcarbonyl; R 52 is a substituted or unsubstituted aromatic carbocyclic group)
  • Y is a single atom A compound wherein R 6 is substituted or unsubstituted alkyl.
  • R 1 is substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyloxy
  • n is 1
  • R 3 is a substituted or unsubstituted non-aromatic heterocyclic group
  • R 4 is a hydrogen atom
  • R 5 is a substituted or unsubstituted monoalkylcarbamoyl
  • Y is a single bond
  • R 6 is a substituted or unsubstituted alkyl.
  • R 1 is substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyloxy
  • n is 1
  • R 3 is substituted or unsubstituted non-aromatic heterocyclic group
  • R 4 is a hydrogen atom
  • R 5 is a substituted or unsubstituted aromatic carbocyclic group
  • Y is a single bond
  • R 6 is a substituted or unsubstituted alkyl.
  • R 1 is substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyloxy
  • n is 1
  • R 3 is substituted or unsubstituted non-aromatic A compound which is a heterocyclic group and R 4 is a hydrogen atom.
  • m is 1, R A is halogen, R 1 is substituted or unsubstituted alkyl, R 2 is substituted or unsubstituted alkyloxy, n is 1, and R 3 is substituted Alternatively, a compound which is an unsubstituted aromatic carbocyclic group and R 4 is a hydrogen atom.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions.
  • a prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • a5 is mixed with a phosphine such as tritert-butylphosphine, tricyclohexylphosphine, triphenylphosphine and the like, dibenzylideneacetone palladium, palladium acetate in a solvent such as DMF, DMA, THF, dioxane or the like. Further, a catalyst such as dichlorobistriphenylphosphine palladium and silyl enol ether (a6) prepared separately from zinc fluoride are added, and the temperature is 30 to 130 ° C., preferably 50 to 150 ° C. for 0.1 to 6 hours, preferably Can be reacted for 0.5 to 1 hour to give compound a7.
  • a catalyst such as dichlorobistriphenylphosphine palladium and silyl enol ether (a6) prepared separately from zinc fluoride are added, and the temperature is 30 to 130 ° C., preferably 50 to 150 ° C. for
  • Step 9 Compound A-1 is added with a base such as aqueous sodium hydroxide, aqueous potassium hydroxide or aqueous lithium hydroxide in a solvent such as methanol, THF, dioxane or the like, or a mixture thereof.
  • Compound A-2 can be obtained by reacting at 100 ° C., preferably 10 ° C. to 70 ° C., for 0.1 hour to 5 hours, preferably 0.5 hour to 1 hour.
  • Triazole and the like, condensing agents such as dicyclohexylcarbodiimide and diisopropylcarbodiimide, and a base such as triethylamine, diisopropylethylamine and N-methylmorpholine are added, and 0 ° C to 100 ° C, preferably 20 ° C to 50 ° C, preferably 1 hour to 48 hours, preferably Can be reacted for 2 to 24 hours to give compound a35.
  • Seventh Step From compound a35 compound A-9 can be obtained in the same manner as in the eighth step in "1) Synthesis of compounds A-1 and A-2" described above.
  • Eighth Step From compound A-9, compound A-10 can be obtained in the same manner as in the ninth step in "1) Synthesis of compounds A-1 and A-2" described above.
  • the compound c8 is obtained by adding a palladium catalyst and reacting in a nitrogen atmosphere at 20 ° C. to 150 ° C., preferably 70 ° C. to 120 ° C., for 0.1 hour to 24 hours, preferably 0.5 to 5 hours. be able to.
  • Step 8 Compound c8 is added with a brominating agent such as bromine or NBS in a solvent such as dichloromethane, chloroform, dichloroethane or the like, or a mixed solvent thereof, and is ⁇ 50 ° C. to 50 ° C., preferably ⁇ 30 ° C. to 30 ° C.
  • the compound c9 can be obtained by reacting for 0.1 to 4 hours, preferably 0.5 to 1 hour.
  • Compound C-1 can be obtained by reacting for ⁇ 3 hours.
  • Step 15 Compound C-1 is added to a base such as aqueous sodium hydroxide, aqueous potassium hydroxide or aqueous lithium hydroxide in a solvent such as methanol, THF, dioxane or the like, or a mixed solvent thereof.
  • Compound C-2 can be obtained by reacting at 100 ° C., preferably 10 ° C. to 70 ° C., for 0.1 hour to 5 hours, preferably 0.5 hour to 1 hour.
  • Ninth Step A brominating agent such as bromine or NBS is added to compound c39 in a solvent such as dichloromethane, chloroform, dichloroethane, or a mixed solvent thereof, at ⁇ 50 ° C. to 50 ° C., preferably at ⁇ 30 ° C. to 30 ° C.
  • the compound c40 can be obtained by reacting for 0.1 to 4 hours, preferably 0.5 to 1 hour.
  • Step 11 MnO 2 and an oxidizing reagent such as 2-iodoxybenzoic acid and Dess-Martin reagent are added to compound c43 in a solvent such as methylene chloride, dichloroethane, tetrahydrofuran, etc., and -100 ° C to 50 ° C, preferably -60 ° C to 30 ° C.
  • Compound c44 can be obtained by reacting at 0.5 ° C. for 10 hours, preferably 1 hour to 3 hours.
  • Compound d11 can be obtained by reacting for a period of time, preferably 1 to 6 hours.
  • Step 12 Compound d12 is obtained by condensing compound a11 with an enantiopure chiral auxiliary compound such as R-(+)-4-benzyl-2-oxazolidinone (compound (A)) to form a diastereomeric mixture, It can synthesize
  • a solvent such as anhydrous dichloromethane, anhydrous chloroform, anhydrous THF, etc.
  • Second Step From compound e16 compound e17 was prepared in the same manner as in the first step in "(6) Synthesis of compounds F-1 to F-4-2) Synthesis method of compounds F-3 and F-4" described later. Can be obtained.
  • Third Step From compound e17 compound e18 was prepared in the same manner as in the second step of “(6) Synthesis of compounds F-1 to F-4-2) Synthesis method of compounds F-3 and F-4” described later. Can be obtained.
  • Fourth Step From compound e18 compound E18 was prepared in the same manner as in the fourth step in "(6) Synthesis of compounds F-1 to F-4-2) Synthesis method of compounds F-3 and F-4" described later. -3 can be obtained.
  • Fifth Step From compound E-3 in the same manner as in the eighth step in “(6) Synthesis of compounds F-1 to F-4-2) Synthesis method of compounds F-3 and F-4” described later, Compound E-4 can be obtained.
  • compound f11 can be obtained in the same manner as in the seventh step in “1) Synthesis of Compounds F-1 and F-2” described above.
  • Fourth Step In a solvent such as THF, diethyl ether, toluene, etc., compound f11 is mixed with a base such as lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and R 2 ⁇ .
  • a base such as lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and R 2 ⁇ .
  • I, R 2 —Br, R 2 —Cl and the like are added and reacted at ⁇ 70 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • the compound of the present invention was quantified using HPLC by an absolute calibration curve method.

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Abstract

Cette invention concerne : un nouveau composé représenté par la formule (I), qui a une activité antivirale ; et une composition pharmaceutique le contenant. (Dans la formule, la ligne en pointillés indique la présence ou l'absence d'une liaison ; chacun des X1, X2 et X3 représente indépendamment un atome de carbone ou un atome d'azote, et au moins un des X1, X2 et X3 représente un atome d'azote ; R1 représente un groupe alkyle substitué ou non, ou autre ; R2 représente un groupe alkyloxy substitué ou non, ou autre ; n représente 1 ou 2 ; R3 représente un groupe cyclique substitué ou non ; R4 représente un atome d'hydrogène ou autre ; R5' représente un groupe cyclique substitué ou non, ou autre ; et R6 représente un groupe alkyle substitué ou non, ou autre).
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Cited By (16)

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WO2013157622A1 (fr) * 2012-04-19 2013-10-24 塩野義製薬株式会社 Inhibiteur de la réplication du vih
WO2014119636A1 (fr) 2013-01-31 2014-08-07 塩野義製薬株式会社 Inhibiteur de la réplication du vih
EP2821082A1 (fr) 2013-07-05 2015-01-07 Laboratoire Biodim Procédé de production d'un lentivirus inactivé, notamment le VIH, vaccin, kit et procédé d'utilisation
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
WO2015179448A1 (fr) * 2014-05-21 2015-11-26 Gilead Sciences, Inc. Composés thérapeutiques
WO2016012913A1 (fr) * 2014-07-21 2016-01-28 Viiv Healthcare Uk Limited Pyridinones substitués par phényle et acide tertbutylacétique à effet anti-vih
US9284323B2 (en) 2012-01-04 2016-03-15 Gilead Sciences, Inc. Naphthalene acetic acid derivatives against HIV infection
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
US10494380B2 (en) 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
WO2023050007A1 (fr) * 2021-09-29 2023-04-06 Repare Therapeutics Inc. Composés n-([(l,3,4-thiadiazolyle) ou (thiazolyle)]-5-substitués)carboxamide (substitué) et leur utilisation pour inhiber la polymérase thêta humaine
CN118702662A (zh) * 2024-06-06 2024-09-27 无锡小荷智化科技有限公司 一种4-甲基-2h-吡喃-2,6(3h)-二酮合成的绿色工艺
WO2024197401A1 (fr) * 2023-03-30 2024-10-03 Repare Therapeutics Inc. Composés 1,3,4-thiadiazol-2-yl carboxamide et 1,3-thiazol-2-yl carboxamide et leurs utilisations en tant qu'inhibiteurs de la polymérase thêta humaine

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US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
US9284323B2 (en) 2012-01-04 2016-03-15 Gilead Sciences, Inc. Naphthalene acetic acid derivatives against HIV infection
WO2013157622A1 (fr) * 2012-04-19 2013-10-24 塩野義製薬株式会社 Inhibiteur de la réplication du vih
US9096586B2 (en) 2012-04-20 2015-08-04 Gilead Sciences, Inc. Therapeutic compounds
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
WO2014119636A1 (fr) 2013-01-31 2014-08-07 塩野義製薬株式会社 Inhibiteur de la réplication du vih
EP2821082A1 (fr) 2013-07-05 2015-01-07 Laboratoire Biodim Procédé de production d'un lentivirus inactivé, notamment le VIH, vaccin, kit et procédé d'utilisation
US9975906B2 (en) 2014-05-16 2018-05-22 Shionogi & Co., Ltd. Tricyclic heterocycle derivatives having HIV replication inhibitory effect
WO2015179448A1 (fr) * 2014-05-21 2015-11-26 Gilead Sciences, Inc. Composés thérapeutiques
WO2016012913A1 (fr) * 2014-07-21 2016-01-28 Viiv Healthcare Uk Limited Pyridinones substitués par phényle et acide tertbutylacétique à effet anti-vih
CN106536482A (zh) * 2014-07-21 2017-03-22 Viiv保健英国有限公司 具有抗hiv作用的苯基和叔丁基乙酸取代的吡啶酮
JP2017521455A (ja) * 2014-07-21 2017-08-03 ヴィーブ ヘルスケア ユーケー リミテッド 抗ＨＩＶ作用を有するフェニル及びｔｅｒｔ−ブチル酢酸置換ピリジノン
AU2015293578B2 (en) * 2014-07-21 2017-10-05 Viiv Healthcare Uk Limited Phenyl and tertbutylacetic acid substituted pyridinones having anti-HIV effects
US9802898B2 (en) 2014-07-21 2017-10-31 Viiv Healthcare Uk Limited Phenyl and tertbutylacetic acid substituted pyridinones having anti-HIV effects
US10494380B2 (en) 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
US10870661B2 (en) 2015-05-29 2020-12-22 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
WO2023050007A1 (fr) * 2021-09-29 2023-04-06 Repare Therapeutics Inc. Composés n-([(l,3,4-thiadiazolyle) ou (thiazolyle)]-5-substitués)carboxamide (substitué) et leur utilisation pour inhiber la polymérase thêta humaine
WO2024197401A1 (fr) * 2023-03-30 2024-10-03 Repare Therapeutics Inc. Composés 1,3,4-thiadiazol-2-yl carboxamide et 1,3-thiazol-2-yl carboxamide et leurs utilisations en tant qu'inhibiteurs de la polymérase thêta humaine
CN118702662A (zh) * 2024-06-06 2024-09-27 无锡小荷智化科技有限公司 一种4-甲基-2h-吡喃-2,6(3h)-二酮合成的绿色工艺

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