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WO2005121132A1 - Composé hétérocyclique fondu ayant un effet anti-vhc - Google Patents

Composé hétérocyclique fondu ayant un effet anti-vhc Download PDF

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Publication number
WO2005121132A1
WO2005121132A1 PCT/JP2005/010548 JP2005010548W WO2005121132A1 WO 2005121132 A1 WO2005121132 A1 WO 2005121132A1 JP 2005010548 W JP2005010548 W JP 2005010548W WO 2005121132 A1 WO2005121132 A1 WO 2005121132A1
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WIPO (PCT)
Prior art keywords
optionally substituted
substituted
alkyl
hydrogen
pharmaceutically acceptable
Prior art date
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PCT/JP2005/010548
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English (en)
Japanese (ja)
Inventor
Toshio Fujishita
Kenji Abe
Akira Naito
Itsuo Makino
Hiroshi Matsumoto
Naohiro Onodera
Takeshi Endoh
Minako Iwata
Original Assignee
Shionogi & Co., Ltd.
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Publication of WO2005121132A1 publication Critical patent/WO2005121132A1/fr

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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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 fused heterocyclic compound having an anti-hepatitis C virus (hereinafter, also referred to as HCV) activity.
  • This compound is an anti-HCV drug, specifically a replication inhibitor, and is useful as a therapeutic agent for hepatitis C and the like.
  • RNA-dependent RNA synthases As enzymes that are targets of anti-HCV drugs, proteases, RNA helicases, RNA-dependent RNA synthases, and the like are known, and inhibitors for these are being studied.
  • various benzimidazole derivatives are known as compounds having an RNA-dependent RNA synthase inhibitory activity (see: Patent Documents:! To 3).
  • the substituent at the 2-position on the imidazole ring of the benzimidazole derivative described in Patent Document 3 is limited to a substituted phenyl group.
  • some heterocyclic groups eg, tetrazolyl and oxo-substituted heterocyclic groups
  • Het in the compound of the present invention is It's listed, nare ,.
  • Patent Document 1 W ⁇ 2001/47883
  • Patent Document 2 W ⁇ 2002/4425
  • Patent Document 3 W ⁇ 03/26587
  • Patent Document 4 W ⁇ 2002/50062
  • Patent Document 5 JP-A-11-352623
  • Patent Document 6 USP 3, 336, 192
  • Patent Document 7 FR 1450560
  • Patent Document 8 W ⁇ 03/40112
  • Non-patent document l Khimiya Geterotsiklicheskikh Soedinenii 1967, (2), 209-14
  • the present inventors have conducted various studies on condensed heterocyclic compounds such as benzimidazole derivatives and indole derivatives by changing substituents on the ring, and as a result, have completed the invention described below.
  • A is N or CH
  • R ° is hydrogen, halogen, alkyl which may be substituted, alkyl which may be substituted, alkyl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted , heteroaralkyl to optionally substituted, _C_ ⁇ _O R a (R a is hydrogen or ester residue), or - C_ ⁇ _NR b R e (R b and each independent hydrogen or amide residue, Group);
  • R is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, a substituted Heteroaralkyl, —CO ⁇ R a (R a is hydrogen or an ester residue), or —CONR b R e (R b and are each independently hydrogen or an amide residue);
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, substituted Heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycle, optionally substituted arylcarbonyl, optionally substituted heterocarbonyl Arylcarbonyl, optionally substituted aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl or NR d R e (R d and R e are each independently hydrogen or an amino residue);
  • R 2 is hydrogen, alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, Optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycle, optionally substituted araryl carbonyl, optionally substituted heteroarylcarbonyl, substituted which may be Ariruokishi, optionally substituted Ariruchio, optionally substituted Ariru sulfonyl, NR d R e (R d and R e are hydrogen or Amino acid residues independently), hydro alkoxy, alkylthio or alkyl Sulfonyl; provided that when R 2 is hydrogen, Het is (a) or (c);
  • R 3 is each independently an optionally substituted alkyl, alkenyl, halogen, nitro, alkoxy or substituted or unsubstituted amino.
  • p is an integer from 0 to 3;
  • Het is a group represented by (a), R. Is hydrogen, R is alkyl, R 1 is alkyl, and R 2 is substituted and is heteroaralkyl,
  • A is N, the compound according to the above 1, a pharmaceutically acceptable salt thereof, or a salt thereof. Solvate.
  • R ° is hydrogen, alkyl, aryl which may be substituted, or —C ⁇ OR a (R a is hydrogen or alkyl), the compound according to the above 1, or a pharmaceutically acceptable salt thereof; Or their solvates.
  • R is an optionally substituted aryl, an optionally substituted heteroaryl, a substituted aryl, an aryl, or a substituted aryl, a heteroaryl, a heteroarylalkyl Or the pharmaceutically acceptable salt thereof or the solvate thereof.
  • R is substituted, substituted, aryl, or substituted, substituted, aralkyl, and the substituent is 1-3 halogens, alkyl halides, or lower alkoxy. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R is an optionally substituted phenyl, an optionally substituted benzyl or an optionally substituted phenethyl, wherein the substituent is halogen, alkyl halide, Or the lower alkoxy, the pharmaceutically acceptable salt thereof, or the solvate thereof.
  • (16) 1 ⁇ is an optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aralkyl, the compound according to the above 1, or a pharmaceutically acceptable salt thereof, Or their solvates.
  • R 2 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, a substituted
  • R 2 is an optionally substituted cycloalkyl, an optionally substituted aryl, a substituted aryl, a heteroaryl, or a substituted aryl, a heteroaryl, or a heterocycle. Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • A is N; Het is a or b; R ° is hydrogen; R is substituted or diaryl; R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aralkyl; R 2 is an optionally substituted aralkyl; 2.
  • the compound according to the above which is a good cycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heterocycle, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • A is N; Het is a or b; R ° is hydrogen; R is substituted, substituted or unsubstituted aralkyl (substituent ::! ⁇ R 1 is cycloalkyl, or aralkyl; R 2 is cycloalkyl, optionally substituted heteroaryl, or optionally substituted; 3 halogens, halogenated alkyl, or lower alkoxy); 2.
  • A is N; Het is a or b; R ° is hydrogen; R is substituted, substituted or unsubstituted aralkyl (substituent ::! ⁇ R 1 is C 3 -C 10 cycloalkyl; R 2 is cyclohexyl, furyl, monorefolino, tetrahydroviranyl, or pyridyl; 3 halogens, halogenated alkyl, or lower alkoxy); Or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • A is CH; Het is a or b; R ° is hydrogen; R is substituted, substituted, aryl, or optionally substituted aralkyl; R 1 is substituted An optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aralkyl; R 2 is an optionally substituted cycloalkyl, an optionally substituted heteroaryl, or an optionally substituted 2.
  • the compound according to the above which is an optionally substituted heterocycle, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R ° is hydrogen, halogen, alkyl which may be substituted, alkyl which may be substituted, alkyl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted , heteroaralkyl to optionally substituted, _C_ ⁇ _O R a (R a is hydrogen or ester residue), or _C_ ⁇ _NR b R e (R b and each independent hydrogen or amide residue, );
  • R 1 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted Optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycle, optionally substituted araryl carbonyl, optionally substituted heteroarylcarbonyl, substituted which may be Ariruokishi, optionally substituted Ariruchio, optionally substituted Ariru sulfonyl or NR d R e (R d and R e are hydrogen or Amino acid residues independently);
  • R 2 is hydrogen, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted, heteroaralkyl which may be substituted; An optionally substituted heterocycle, hydroxy, alkylthio or alkylsulfonyl;
  • R 3 is each independently an optionally substituted alkyl, alkenyl, halogen, nitro, alkoxy or substituted or unsubstituted amino.
  • R 4 is each independently hydroxy, carboxy, halogen, alkyl halide, anorecynole, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, and may be substituted Ami , Azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, optionally substituted carbamoyl, optionally substituted sulfamoyl, isyl, forminoleoxy, halohonorenominole, Oxiza mouth, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, snorefino, sulfo, sno
  • p is an integer from 0 to 3;
  • q is an integer from 0 to 5.
  • R 1 is hydrogen, alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, Optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycle, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, substituted You can I Ariruokishi, optionally substituted Ariruchio, optionally substituted Ari Noresuruhoniru or NR d R e (R d and represents a hydrogen or Amino acid residues independently)
  • R 2 is hydrogen, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted, heteroaralkyl which may be substituted; An optionally substituted heterocycle, hydroxy, alkylthio or alkylsulfonyl;
  • R 3 is each independently an optionally substituted alkyl, alkenyl, halogen, nitro, alkoxy or substituted or unsubstituted amino.
  • R 4 is each independently hydroxy, carboxy, halogen, alkyl halide, anorecynole, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, and may be substituted Amino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, optionally substituted sorbamoyl, optionally substituted sulfamoyl, acil, forminoleoxy, halohonoremyl , Oxoza, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, snolequino, sulfo, sulfoamin
  • p is an integer from 0 to 3;
  • q is an integer from 0 to 5.
  • the compound has an antiviral effect.
  • viruses include, for example, flaviviruses of the Flapivirus family (eg, yellow fever virus, dengue virus, West Nile virus), hepaciviruses (eg, hepatitis C virus (HCV)), and pestiviruses (eg, (Civiral diarrhea virus, swine fever virus).
  • HCV hepatitis C virus
  • pestiviruses eg, (Civiral diarrhea virus, swine fever virus).
  • the compound has a strong replication inhibitory effect on viruses.
  • it may have a direct inhibitory effect on the various target enzymes of Winores.
  • the preferred conjugates are further excellent in metabolic stability, CYP inhibition, solubility and the like. Therefore, it is useful as a drug, particularly an anti-hepatitis C virus agent, a therapeutic agent for hepatitis C, and the like.
  • Alkyl means a linear or branched alkyl group having 1 to 10 carbon atoms, for example, methynole, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butynole, n-pentynole, isopentynole, neopentynole, tert-pentynole, n_hexynole, isohexyl, n-heptyl, n-octyl, n-noel, n_decyl and the like.
  • it is a lower alkyl, more preferably an alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methinole, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butylene, tert. -Butynole, n-pentinole, isopentinole, neopentinole, tert-pentinole, n_hexyl, isohexyl.
  • Alkenyl means a straight-chain or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds in the above “alkyl”, for example, butyl, 1-probenyl , 2-propenyl, 1-butul, 2-butul, 3-butul, 1,3-butagenyl, 3-methyl-2-butenyl and the like.
  • Cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes, for example, cyclopropynole-cyclobutynole, cyclopentynole, cyclohexynole-cycloheptinole, cycloalkyl Octyl and the like. Preferably, it is a cycloalkyl having 3 to 8 carbon atoms, more preferably 5 to 8 carbon atoms, and examples thereof include cyclobutyl, cyclopentyl and cyclohexyl.
  • Aryl refers to monocyclic aromatic hydrocarbon groups (eg, phenyl) and polycyclic aromatic hydrocarbon groups (eg, 1-naphthyl, 2-naphthyl, 1_anthryl, 2-anthryl, 9-anthryl, 1- _ Means phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.).
  • phenyl or naphthyl (1-naphthyl, 2-naphthyl) is used.
  • Heteroaryl means a monocyclic aromatic heterocyclic group and a fused aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is an optional substitutable group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen atoms, sulfur atoms, and Z or nitrogen atoms in the ring. Means a group having a bond at the position.
  • a fused aromatic heterocyclic group may contain an oxygen atom, a sulfur atom, and / or a nitrogen atom in the ring:! Means a group that has a bond at any substitutable position that is fused to an 8-membered aromatic carbon ring or another 5- to 8-membered aromatic heterocycle. .
  • Heteroaryl includes, for example, furyl (eg, 2-furyl, 3-furyl), phenyl (eg, 2-phenyl, 3-phenyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , Imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-birazolinole, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg, 1,2,4-triazole-1-) 1,2,4-triazolyl_3_yl, 1,2,4-triazol-4-yl), tetrazolyl (eg, 1-tetrazolinole, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 2-
  • 6-phthalagel isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg, 2-pteridinyl, 4 -Pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, ataridinyl (eg, 1-ataridinyl, 2-atalidinyl, 3-atalidinyl, 4-atalidinyl, 9-ataridinyl), indolyl (eg, 1-indolyl, 2-Indolyl, 3-Indolino, 4-Indolyl, 5-Indolyl, 6-Indolyl, 7-Indolyl), Isoindolyl, Fanadinyl (eg 1-Phenadiny
  • Alkyl means the above “alkyl” substituted with! To 3 "aryl”, such as benzyl, diphenylmethyl, triphenylmethyl, phenyl, 1-naphthylmethyl, 2_naphthylmethyl, etc. Is mentioned. Preferably, it is benzyl.
  • Heteroaralkyl means the following “alkyl” substituted by 3 to 3 "heteroaryls”, with preference given to heteroaralkyls having 1 to 4 carbon atoms in the alkyl portion. In particular, heteroaralkyl having 1 or 2 carbon atoms in the alkyl moiety is preferred.
  • the "heterocycle” may include an oxygen atom, a sulfur atom, and / or a nitrogen atom in the ring:! To 4, and may have a bond at any substitutable position. Or a non-aromatic heterocyclic group. It may be saturated or unsaturated. It is preferably a 5- to 8-membered ring.
  • ester residue examples include alkyl (eg, methinole, ethyl), aralkyl (eg, benzyl, Phenyl), aryl (eg, phenyl, naphthyl), alkoxyalkyl (eg, methoxymethyl, ethoxyxetyl), aryloxyalkyl (eg, phenoxethyl), and heterocyclic alkyl (eg, pyridylmethyl).
  • alkyl eg, methinole, ethyl
  • aralkyl eg, benzyl, Phenyl
  • aryl eg, phenyl, naphthyl
  • alkoxyalkyl eg, methoxymethyl, ethoxyxetyl
  • aryloxyalkyl eg, phenoxethyl
  • heterocyclic alkyl eg, pyridylmethyl
  • it is alky
  • Examples of the amino or amide residue include: 1) substituted, alkyl, and alkyl (eg, methynole, ethyl, butyl); examples of the substituent: hydroxy, alkoxy (eg, methoxy); May be substituted, heteroaryl (eg, imidazolyl), substituted, substituted, aryl (eg, 4 _ C1 _Ph)), 2) optionally substituted heterocycle (eg, 2-oxo) Pyrrolidinyl), 3) a force S exemplified by optionally substituted aryl (eg 4_Cl_Ph), preferably alkyl.
  • alkyl eg, methynole, ethyl, butyl
  • substituent hydroxy, alkoxy (eg, methoxy); May be substituted, heteroaryl (eg, imidazolyl), substituted, substituted, aryl (eg, 4 _ C1 _Ph)), 2) optionally substitute
  • Halogen means F, Cl, Br, or I.
  • Alkoxy means a hydroxy group substituted by the above “alkyl”. For example, methoxy, ethoxy, n-propoxy, tripropoxy and the like can be mentioned.
  • Halogenated alkyl means the above “alkyl” substituted by 1 to 3 above “halogens”.
  • Cycloalkenyl means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms and having one or more double bonds in the above “cycloalkyl”.
  • substituent in “may be substituted” examples include hydroxy, carboxy, halogen (eg, F, Cl, Br, 1), alkyl halide (eg, CF, CH CF, CH CC1), A
  • benzyl Xia input Isoshiano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (e.g. methylthio), alkylsulfonyl (e.g.
  • methanesulfonic two Nore, ethanesulfonyl optionally substituted rubamoyl (eg, alkyl rubamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl)), optionally substituted sulfamoyl, acyl (eg, formyl) , Alkylcarbonyl (eg, acetyl)), forminoleoxy, haloformyl, oxaza mouth, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfino, sulfo, snorephoamino, hydrazino, azide, ureido, which may be substituted Amididine-containing guanidino, phthalimide, oxo, optionally substituted heteroaryl, optionally substituted hetero
  • alkyloxycarbonyl, alkylsulfonyl, alkyl, optionally substituted rubamoyl for example, carbamoyl, N-alkyl rubamoyl
  • alkylcarbonyl forminole
  • rubamoylcarbonyl e.g, N-alkyl rubamoylcarbonyl, NN dialkyl rubamoylcarboninole
  • amidino sulfamoyl, alkyloxyalkylcarbonyl, optionally substituted rubamoylalkyl (E.g., N-alkynolecarbonylaminoalkyl), alkylsulfonyl halide, alkyloxycarbonylcarbonyl, optionally substituted aminoalkylcarbonyl (e.g., NN dialkylalkylaminoalkylcarbonyl), Bo alkoxycarbonyl include Ararukiru.
  • the substituent on the nitrogen of the amino group is combined with an adjacent nitrogen atom to form a 5- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated carbocyclic or heterocyclic ring. Is also good.
  • the ring may be interposed with an oxygen atom (_ ⁇ _), a nitrogen atom (_S—), or a nitrogen atom (_NH_), and may be substituted with oxo, alkyl, or the like.
  • substituted or unsubstituted or substituted rubamoyl substituted or unsubstituted or substituted sulfamoyl, alkyl, hydroxyalkyl, alkylsulfonyl, alkylo Xycarbonylalkyl.
  • substituent on the nitrogen of the carbamoyl group is combined with an adjacent nitrogen atom to form a 5- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated carbocyclic or heterocyclic ring.
  • the ring may be intervened with an oxygen atom (-O), a nitrogen atom (_S-), or a nitrogen atom (_NH_), and may be substituted with oxo, alkyl, or the like.
  • A is N or CH, preferably N.
  • Het is a group selected from the group consisting of optionally substituted, heteroaryl and heterocycle.
  • Het is a group selected from the groups (a) to (g). It is preferably the group (a), (b) or (c), more preferably the group (a) or (b), and particularly preferably the group (a).
  • R ° and R are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted Optionally substituted aralkyl, optionally substituted heteroalkyl, —C ⁇ OR a (R a is hydrogen or an ester residue), and C ⁇ NR b R e (R b and are each independently hydrogen, Or an amide residue).
  • R ° is preferably hydrogen, alkyl optionally substituted, optionally substituted ⁇ Li Lumpur or a CO_ ⁇ _R a, (R a is hydrogen or ester residue), more preferably hydrogen , Alkyl, optionally substituted aryl (examples of the substituents are: a, gen, alkyl, alkoxy, alkyl halide, hydroxy, amino, arylkyamino, alkoxycarbonyl, carboxy, carboxy, preferably halogen), or one CO ⁇ R a ( Ra is hydrogen or an ester residue (eg, alkyl)). More preferably, it is hydrogen, C1-C4 alkyl (eg, methyl), phenyl optionally substituted with halogen (eg, pF-Ph), COOH, or COOEt, and particularly preferably hydrogen.
  • R ° is preferably bonded to the adjacent position of the N atom in the group represented by (a) or (b).
  • R is preferably an optionally substituted alkyl, an optionally substituted cycloalkylene, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, Optionally substituted arylcarbonyl, _C ⁇ R a (R a is hydrogen or an ester residue), or — C ⁇ NR b R e (R b and are each independently Hydrogen or an amide residue).
  • the substituent of the optionally substituted alkyl or the optionally substituted cycloalkyl is preferably alkoxy (eg, methoxy), dirubamoyl, alkyl dirubamoyl (eg, methylcarbamoyl), aryloxy (eg, pheno).
  • arylamino (example: phenylamino), hydroxy, carboxy, alkoxycarbonyl (example: methoxycarbonyl), halogen, aryloxy (example: phenyloxy), amino, anolequinoleamino, arylamino (example: phenylamino), substituted Heteroital (eg, 1,5-dioxopyrrolidinyl) which may be used.
  • substituted aryl group substituted aryl group, heteroaryl group, substituted aryl group, substituted aryl group, aralkyl group, preferably a halogen, alkyl halide (eg, CF) , Alkoxy (eg, meth
  • Xy hydroxy, alkoxycarbonylamino (eg, methoxycarbonylamino, t-butoxycarbonylamino), alkylamino (eg, methylamino, dimethylamino), carbamoyl, alkylcarbamoyl (eg, methylcarbamoyl, Dimethylcarbamoyl),
  • alkoxycarbonylamino eg, methoxycarbonylamino, t-butoxycarbonylamino
  • alkylamino eg, methylamino, dimethylamino
  • carbamoyl alkylcarbamoyl (eg, methylcarbamoyl, Dimethylcarbamoyl)
  • Examples include CN, an optionally substituted heterocycle (eg, 2-oxopyrrolidinyl), and alkylsulfonylamino (eg, methylsulfonylamino).
  • the heteroaryl is preferably an optionally substituted monocyclic aromatic heterocyclic group, for example, phenyl and pyridyl.
  • R is more preferably an optionally substituted aryl, an optionally substituted aralkyl, and more preferably an optionally substituted phenyl, an optionally substituted benzene, or an optionally substituted phenyl. May be phenethyl.
  • the substituent is preferably a halogen, an alkyl halide (eg, CF 3), or an alkoxy (eg, methoxy). Particularly preferred
  • R is preferably bonded to the position shown by (a) or (b) adjacent to the O or S atom.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted, alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl An optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, an optionally substituted heterocycle, Substituted, substituted, arylcarbonyl, substituted, substituted, heteroarylcarbonyl, optionally substituted aryloxy, optionally substituted arylthio, substituted Optionally selected from the group consisting of arylsulfonyl and NR3 ⁇ 4 e (R d and are each independently hydrogen or an amino residue).
  • R 1 is preferably hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted An aralkyl, an optionally substituted heteroaralkyl, or a substituted or unsubstituted heterocycle.
  • substituent for the substituted or unsubstituted alkyl, or the optionally substituted cycloalkyl preferred are alkoxy (eg, methoxy), carboxy, alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl), Examples include cycloalkyl (eg, cyclohexyl), hydroxy, halogen, and amino. Preferred is alkoxy.
  • substituted, substituted, aryl, substituted, substituted, heteroaryl, substituted, substituted, aralkyl, substituted substituted, modified, heteroaralkyl Or a substituted or unsubstituted heterocycle substituent is preferably hydroxy, alkyl (eg, methyl), oxo, alkylcarbonyl (eg, acetyl), carboxy, alkoxycarbonyl (eg, methoxycarbonyl) , Halogens, alkyl halides (eg, CF), and alkoxy (eg,
  • the heteroaryl is preferably a substituted or unsubstituted, monocyclic aromatic heterocyclic group, and is fujinore, cedinore, pididinole, or imidazodinole.
  • the heterocycle is preferably a substituted or unsubstituted 5- to 7-membered ring, for example, monorefolino, tetrahydrovinylinole, or piperidino.
  • R 1 is more preferably hydrogen, alkyl optionally substituted (e.g., methyl, Echiru, flop port pills, butyl, alkoxyalkyl (e.g. 2-Metokishechiru, 3-methoxypropyl), alkoxycarbonyl Alkyl (eg, 3-ethoxycarbonylpropyl), cycloalkynolealkyl (eg, cyclohexylmethyl), substituted or unsubstituted, cycloalkyl (eg, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctynole) ), Optionally substituted aryl (eg phenyl, naphthyl, preferably phenyl), substituted Aralkyl (eg, benzyl, phenethyl, adamantyl, preferably benzyl). R 1 is more preferably cycloalkyl
  • R 2 is preferably an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, Optionally substituted aralkyl, optionally substituted heterocycle, optionally substituted arylcarbonyl, optionally substituted aryloxy, optionally substituted arylthio, or NR d R e it is (R d and R e Waso respectively independently hydrogen or Amino acid residues).
  • R 2 is more preferably an optionally substituted alkyl (eg, methyl, butyl, alkoxyalkyl (eg, 3-methoxypropyl)), substituted or unsubstituted, alkenyl (eg, 1-propyl Alkenyl optionally substituted with phenyl or aryl (eg, 2-phenylvinyl), cycloalkyl optionally substituted with (eg, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl) ), Optionally substituted aryl (eg, phenyl, carboxyphenyl), optionally substituted heteroaryl (eg, furyl, pyridyl, phenyl, imidazolyl), optionally substituted aralkyl (eg, Phenyl, naphthyl, substituted with rhogen, benzyl or naphthyl), substituted with hetero, hetero
  • R 2 is more preferably substituted or unsubstituted, cycloalkyl (especially cyclohexyl), optionally substituted heteroaryl (especially furyl or pyridyl), optionally substituted Heterocycline (especially morpholino, tetrahydroviranyl).
  • the substituent is preferably aryl (eg, phenyl), carboxy, hydroxy, lower alkyl (eg, methyl), lower alkoxy, lower alkanol (eg, acetyl), lower alkoxycarbonyl (eg, acetyl). Examples: methoxycarbonyl), alkynaminoamino, rubamoyl, alkyl rubamoyl, halogen, lower alkyl halide and the like.
  • aryl eg, phenyl
  • carboxy hydroxy, lower alkyl (eg, methyl), lower alkoxy, lower alkanol (eg, acetyl), lower alkoxycarbonyl (eg, acetyl).
  • methoxycarbonyl alkynaminoamino, rubamoyl, alkyl rubamoyl, halogen, lower alkyl halide and the like.
  • Het is a or b; R ° is hydrogen; R is optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroaryl; R 1 is substituted An optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aralkyl; R 2 is an optionally substituted cycloalkyl, an optionally substituted heteroaryl, or Compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an optionally substituted heterocycle.
  • R is bonded to the adjacent carbon of ⁇ or S (hereinafter the same).
  • Het is a or b group; R ° is hydrogen; R is substituted or unsubstituted, aryl or optionally substituted aralkyl (substituent::! To 3 halogens, R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aralkyl; R 2 is an optionally substituted cycloalkyl A compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an optionally substituted heteroaryl or an optionally substituted heteroaryl.
  • Het is an a or b group; R ° is hydrogen; R is a substituted or unsubstituted aryl, or an optionally substituted aralkyl (substituent::! To 3 halogens, R 1 is cycloalkyl or aralkyl; R 2 is cycloalkyl, heteroaryl or heterocycle, compound (1), a pharmaceutically acceptable salt thereof, or Their solvates.
  • Het is a or b; R ° is hydrogen; R is substituted, substituted, phenyl or substituted R 1 is cycloalkyl (preferably having 5 to 8 carbon atoms) or benzyl or phenethyl (substituent: 1 to 3 halogen, alkyl halide, lower alkoxy); R 2 is cycloalkyl (preferably having 5 to 7 carbon atoms), heteroaryl (preferably, a 5- to 7-membered aromatic heterocyclic group containing at least an O atom and / or an N atom); Compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a cycle (preferably a 5- to 7-membered ring group containing at least an O atom and / or an N atom).
  • Het is c to f, any group; R ° is hydrogen; R is substituted, substituted, aryl, or optionally substituted aralkyl; R 1 is substituted Optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted aralkyl; R 2 is optionally substituted cycloalkyl, optionally substituted heteroaryl, or substituted Compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an optionally substituted heterocycle.
  • Het is c to f or any group;
  • R ° is hydrogen;
  • R is substituted, substituted or aryl, substituted or substituted, substituted aralkyl (substituent R 1 is an optionally substituted alkyl, an optionally substituted cycloalkylene, or an optionally substituted aralkyl;
  • R 2 is an optionally substituted alkyl; (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an optionally substituted cycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heterocycle.
  • Het is c to f, any group; R ° is hydrogen; R is substituted, substituted, aryl, or substituted, substituted, aryl, substituted R 1 is cycloalkyl or aralkyl; R 2 is cycloalkyl, heteroaryl or heterocycle, compound (1), a pharmaceutical thereof. Above acceptable salts, or solvates thereof.
  • Het is c to f, any group; R ° is hydrogen; R is substituted, substituted, substituted, substituted, substituted, substituted, benzyl, or phenethyl (Substituent: 1 to 3 halogen or alkyl halide); R 1 is cycloalkyl (preferably having 5 to 8 carbon atoms) R 2 is cycloalkyl (preferably having 5 to 7 carbon atoms), heteroaryl (preferably a 5 to 7-membered aromatic heterocyclic group containing at least O atom and / or N atom), or heteroaryl.
  • Het is a or b; R ° is hydrogen; R is substituted, substituted, aryl, or optionally substituted aralkyl; R 1 is optionally substituted alkyl; Or an optionally substituted cycloalkyl or an optionally substituted aralkyl; R 2 may be an optionally substituted cycloalkyl, an optionally substituted heteroaryl, or an optionally substituted Compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a heterocycle.
  • Het is a or b; R ° is hydrogen; R is substituted, substituted, aryl, or substituted, substituted, aralkyl (substituent: 1-3 R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, or an optionally substituted aralkyl; R 2 is an optionally substituted cycloalkyl Compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is an alkyl, substituted, substituted, heteroaryl, or substituted, substituted, heterocycle. object.
  • Het is a or b; R ° is hydrogen; R is substituted, substituted, aryl, substituted or substituted, aralkyl (substituent: 1-3 Halogen or alkyl halide)
  • R 1 is cycloalkyl or aralkyl
  • R 2 is cycloalkyl, heteroaryl or heterocycle
  • compound (1) a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Het is a or b; R ° is hydrogen; R is substituted, optionally, phenyl or substituted, optionally, benzyl or phenethyl (substituents: 1 to R 1 is cycloalkyl (preferably having 5 to 8 carbon atoms) or benzyl; R 2 is cycloalkyl (preferably having 5 to 7 carbon atoms), heteroaryl (preferably 5 halogen atoms or halogenated alkyl).
  • a 5- to 7-membered aromatic heterocyclic group containing at least an O atom and a Z or N atom), or a heterocycle (preferably a 5- to 7-membered aromatic group containing at least an O atom and a Z or N atom) ring A compound (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Het is a group from c to f; Is hydrogen; R is substituted, substituted, aryl, or optionally substituted aralkyl; R 1 is optionally substituted alkyl, optionally substituted cycloalkyl, or substituted An optionally substituted aralkyl; R 2 is an optionally substituted cycloalkyl, an optionally substituted heteroaryl, or an optionally substituted heterocycle, a compound (1), Pharmaceutically acceptable salts, or solvates thereof.
  • R ° is hydrogen; R is substituted, substituted, aryl, or substituted, substituted, aralkyl (substituted)
  • R 1 is an optionally substituted alkyl, an optionally substituted cycloalkylene, or an optionally substituted aralkyl;
  • R 2 is an optionally substituted aralkyl;
  • Het is c to f, any group; R ° is hydrogen; R is substituted, aryl, aryl or substituted aryl, arylalkyl (substituent R 1 is cycloalkyl or aralkyl; R 2 is cycloalkyl, heteroaryl or heterocycle, compound (1), which is pharmaceutically acceptable. Acceptable salts, or solvates thereof.
  • Het is c to f, any group; R ° is hydrogen; R is substituted, substituted, substituted, substituted, substituted, substituted, benzyl, or phenethyl (Substituent: 1 to 3 halogen or alkyl halide); R 1 is cycloalkyl (preferably 5 to 8 carbon atoms) or benzyl; R 2 is cycloalkyl (preferably 5 to 5 carbon atoms) 7), heteroaryl (preferably, a 5- to 7-membered aromatic heterocyclic group containing at least O atom and / or N atom), or heterocycle (preferably containing at least O atom and / or N atom) Compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the case of the above P-1 or 2 more preferably the case of P-1.
  • the present invention includes the following cases as another embodiment.
  • P— 5 A is N
  • Het is a to g, preferably a or b group; R ° is hydrogen; R is optionally substituted aryl or optionally substituted aralkyl; R 1 is cycloalkyl R 2 is cycloalkyl, heteroaryl, or heterocycle, compound (I)
  • Het is a group of a to g, preferably a or b groups; is R, Ararukiru may be good I Ariru or substituted optionally substituted;; R ° is hydrogen R 1 is cycloalkyl Or an aralkyl; R 2 is an aromatic or non-aromatic heterocyclic group containing 5 to 7 membered 0, S and / or N atoms:! To 3; compound (1); Or a salt thereof, or a solvate thereof.
  • Het is an ag group, preferably an a or b group; R ° is hydrogen; R is an optionally substituted aryl or an optionally substituted aralkyl; R 1 is a cycloalkyl Or compound (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R 2 is furyl or morpholino.
  • Het is an ag group, preferably an a or b group; is hydrogen; R is an optionally substituted aryl or an optionally substituted aralkyl; R 1 is cycloalkyl, preferably Is cyclohexyl; R 2 is cycloalkyl, heteroaryl, or heterocycle, each of which may be substituted; compound (1), a pharmaceutically acceptable salt thereof, or a solvent thereof.
  • Japanese food is an ag group, preferably an a or b group; is hydrogen; R is an optionally substituted aryl or an optionally substituted aralkyl; R 1 is cycloalkyl, preferably Is cyclohexyl; R 2 is cycloalkyl, heteroaryl, or heterocycle, each of which may be substituted; compound (1), a pharmaceutically acceptable salt thereof, or a solvent thereof.
  • R ° represents hydrogen, alkyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted, heteroaralkyl also to be optionally, _C_ ⁇ _OR a (R a is hydrogen or ester residue), or _CONR b R e (R b and R e are each independently hydrogen or amide residue,);
  • R 1 is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted, heteroaralkyl or substituted Te, te, het, heterocycle;
  • R 2 is hydrogen, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted, heteroaralkyl which may be substituted; An optionally substituted heterocycle, hydroxy, alkylthio or alkylsulfonyl;
  • R 3 is each independently hydrogen, alkyl, alkenyl, halogen, nitro, alkoxy or substituted or substituted, amino;
  • R 4 is each independently hydrogen, hydroxy, carboxy, halogen, halogenated alkyl, anolequinole, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, substituted Resamino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, optionally substituted sorbamoyl, optionally substituted sulfamoyl, asyl, forminoleoxy, haloformyl , Okiza mouth, thioformyl, thiocarboxy, dithiocarboxy, chioka Rubamoyl, Snorrefino, Sulfo, Snorefoamino, Hydrazino
  • R 1 is hydrogen, alkyl which may be substituted, alkenyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, Optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycle, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, substituted Aryloxy, optionally substituted arylthio, optionally substituted arylsulfonyl or NR d R e (R d and R e are each independently hydrogen or an amino residue)
  • R 2 is hydrogen, cycloalkyl which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, aralkyl which may be substituted, heteroaralkyl which may be substituted; An optionally substituted heterocycle, hydroxy, anoalkylthio or alkylsulfonyl;
  • R 3 is each independently an optionally substituted alkyl, alkenyl, halogen, nitro, alkoxy or substituted or unsubstituted amino.
  • R 4 is each independently hydroxy, carboxy, halogen, alkyl halide, anorecynole, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkoxycarbonyl, nitro, nitroso, and may be substituted Amino, azide, aryl, aralkyl, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio, alkylsulfonyl, optionally substituted sorbamoyl, optionally substituted sulfamoyl, acil, forminoleoxy, halohonoremyl , Oxoza, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, snolequino, sulfo, sulfoamin
  • p is an integer from 0 to 3;
  • q is an integer from 0 to 5.
  • the compound of the present invention is useful as an active ingredient of the pharmaceutical composition of the present invention, and is also useful as an intermediate for synthesizing those active ingredients.
  • sodium Alkali metal salts such as salts and potassium salts
  • alkaline earth metal salts such as calcium salts and magnesium salts
  • ammonium salts trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine Salts, brocaine salts, megnoremine salts, aliphatic ethanol salts such as diethanolamine salts or ethylenediamine salts; aralkylamine salts such as N, N-dibenzylethylenediamine, veneamine salts; pyridine salts, picoline salts, quinoline salts, isoquinoline salts, etc.
  • the acidic salt examples include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, and perchlorate; acetate, propionate, lactate, maleate, and the like.
  • Organic salts such as fumarate, tartrate, malate, citrate, and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and P-toluenesulfonate;
  • acids such as aspartate and gnoretamate.
  • the solvate means a solvate of compound (I) or a pharmaceutically acceptable salt thereof, and includes, for example, alcohol (eg, ethanol) solvate and hydrate.
  • alcohol eg, ethanol
  • hydrate examples include a monohydrate and a dihydrate.
  • the amine derivative (5) is obtained. Then, (5) is reduced to obtain diamine (6).
  • the compound of the present invention (7) can be synthesized by reacting (6) with various aldehydes (R 2 CH ⁇ ) in the presence of an oxidizing agent. Alternatively, (7) can be synthesized by condensing (6) with various carboxylic acids or carboxylic acid chlorides, via the amide derivative (8), and then heating in a solvent using an acid catalyst. Examples of the agent include pyridine when acid chloride is reacted.
  • HOBt (1-hydroxybenztriazole I EDC (1_ (3_dimethylaminopropyl-3-ethylcarboimide hydrochloride I triethylamine, etc.) in DMF can be used.
  • EDC (1_dimethylaminopropyl-3-ethylcarboimide hydrochloride I triethylamine, etc.
  • H / Pd—C etc.
  • the oxidizing agent is OXON
  • Examples of the intermediate 4 include IntA in Reference Example 1 described later.
  • Compound 19a is a known compound described in WO01Z47883, or can be synthesized according to the method described therein.
  • the (19a) or (19b) compound obtained by the synthetic route C leads to the rubamoyl compound (30), and then the thioamide (31) is obtained.
  • the compound (32) can be synthesized by reacting (31) with various haloketones (32) in ethanol.
  • Inventive compound (37) can be synthesized by reacting (35) with various amines, alcohols or thiols in the presence of a base, if desired.
  • the obtained compound of the present invention may be further chemically modified to induce another compound of the present invention.
  • Examples of the solvent include acetonitrile, THF, DMF and the like.
  • the base examples include an alkylamine (eg, trimethylamine, triethylamine).
  • the reaction temperature is usually from room temperature to 150 ° C. or reflux temperature.
  • Compound (IV) can be obtained by reducing (III) by a conventional method, for example, with H 2 / Pd—C or the like.
  • Compound (V) can be obtained by condensing (IV) with various carboxylic acids or carboxylic acid chlorides as described above.
  • compounds (I) having various heterocyclic groups (Het) are synthesized.
  • Indole derivatives can be obtained, for example, by further chemically modifying a known indole derivative as shown in Example 162 and the like.
  • the compound used in the present invention can be administered orally or parenterally.
  • the compound used in the present invention may be prepared by a conventional preparation, for example, a solid preparation such as tablets, powders, granules and capsules; a liquid preparation; an oily suspension; or a syrup or an elixir. Can be used as any dosage form of the liquid preparation.
  • the compound used in the present invention can be used as an aqueous or oily suspension for injection or nasal drops.
  • Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent.
  • the formulations of the compounds used in the present invention are prepared by known methods using well-known, readily available ingredients.
  • the dose of the compound used in the present invention varies depending on the method of administration, the age, weight, condition and disease type of the patient.In general, when administered orally, about 0.05 mg to 3000 mg per adult per day is used. Preferably, about 0.1 mg to:! OOOmg, if necessary, dividedly for administration. In the case of parenteral administration, about 0.05 Olmg to: 1000 mg, preferably about 0.05 mg to 500 mg per adult per day is administered.
  • the pharmaceutical composition of the present invention may contain other therapeutic agents for hepatitis C (eg, interferon, ribavirin, protease inhibitor, nucleic acid synthetase inhibitor, immunostimulant, etc.).
  • other therapeutic agents for hepatitis C eg, interferon, ribavirin, protease inhibitor, nucleic acid synthetase inhibitor, immunostimulant, etc.
  • a drug having an action mechanism different from that of the drug of the present invention eg, a protease inhibitor
  • a synergistic effect with the compound of the present invention is preferred.
  • the present invention provides a method for treating hepatitis C, which comprises administering a therapeutic agent for hepatitis C containing the compound of the present invention, and the use of the compound of the present invention for producing a therapeutic agent for hepatitis C. Is also included.
  • NBS N-bromosuccinimide
  • CDI 1,1'-carbonyldiimidazole
  • reaction mixture was returned to room temperature, stirred for 1 hour, and partitioned between ethyl acetate-water.
  • the ethyl acetate layer was washed with an aqueous solution of sodium bicarbonate, water and saturated saline, and dried. After evaporating the solvent, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate.
  • Example 71 (1) is based on the method of Example 79.

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Est exposé ici un composé représenté par la formule (I) ci-dessous, un de ses sels acceptable d'un point de vue pharmaceutique, ou un de leur solvate. (I) (Dans la formule, A représente N ou CH, Het représente n'importe lequel des groupes suivants : (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), R0 et R représentent respectivement un hydrogène, un alkyle optionnellement substitué, un cycloalkyle optionnellement substitué, un aryl optionnellement substitué ou des produits similaires ; R1 et R2 représentent respectivement un hydrogène, un alkyle optionnellement substitué, un alkenyle optionnellement substitué, un cycloalkyle optionnellement substitué, un aryl optionnellement substitué, un hétéroaryl optionnellement substitué ou des produits similaires ; p est un entier compris entre 0-3 ; et R3 représente un alkyl optionnellement substitué ou un produit similaire.)
PCT/JP2005/010548 2004-06-11 2005-06-09 Composé hétérocyclique fondu ayant un effet anti-vhc WO2005121132A1 (fr)

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WO2010044404A1 (fr) 2008-10-15 2010-04-22 キッセイ薬品工業株式会社 Derive heterocyclique fusionne et son utilisation a des fins medicales
DE102009004061A1 (de) 2009-01-08 2010-07-15 Merck Patent Gmbh Pyridazinonderivate
WO2010080874A1 (fr) 2009-01-07 2010-07-15 Scynexis, Inc. Dérivé de cyclosporine convenant au traitement de l'infection par vhc et vih
US7816348B2 (en) 2006-02-03 2010-10-19 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7879850B2 (en) 2007-09-28 2011-02-01 Novartis Ag Organic compounds
US7897622B2 (en) 2006-08-17 2011-03-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
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US8030334B2 (en) 2008-06-27 2011-10-04 Novartis Ag Organic compounds
US8242140B2 (en) 2007-08-03 2012-08-14 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8394969B2 (en) 2008-09-26 2013-03-12 Merck Sharp & Dohme Corp. Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8410284B2 (en) 2008-10-22 2013-04-02 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8563746B2 (en) 2008-10-29 2013-10-22 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8835451B2 (en) 2006-03-31 2014-09-16 Novartis Ag Compounds
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JP2016523259A (ja) * 2013-06-21 2016-08-08 ゼニス・エピジェネティクス・コーポレイションＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｃｏｒｐ． 新規の二環式ブロモドメイン阻害剤
JP2016530283A (ja) * 2013-08-27 2016-09-29 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｉｄｏ阻害剤
WO2016198322A1 (fr) 2015-06-08 2016-12-15 Bayer Pharma Aktiengesellschaft N-menthylbenzimidazoles à titre d'inhibiteurs de midh1
WO2017009325A1 (fr) 2015-07-16 2017-01-19 Bayer Pharma Aktiengesellschaft 5-hydroxyalkylbenzimidazoles en tant qu'inhibiteurs de midh1
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US9951027B2 (en) 2014-02-11 2018-04-24 Bayer Pharma Aktiengesellschaft Benzimidazol-2-amines as MIDH1 inhibitors
US9957235B2 (en) 2014-02-11 2018-05-01 Bayer Pharma Aktiengesellschaft Benzimidazol-2-amines as mIDH1 inhibitors
US10138226B2 (en) 2014-10-23 2018-11-27 Bayer Pharma Aktiengesellschaft Benzimidazol-2-amines as MIDH1 inhibitors
US10166215B2 (en) 2013-06-21 2019-01-01 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
US10231953B2 (en) 2014-12-17 2019-03-19 Zenith Epigenetics Ltd. Inhibitors of bromodomains
US10292968B2 (en) 2014-12-11 2019-05-21 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
US10500209B2 (en) 2013-07-31 2019-12-10 Zenith Epigenetics Ltd. Quinazolinones as bromodomain inhibitors
US10710992B2 (en) 2014-12-01 2020-07-14 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
WO2021057915A1 (fr) * 2019-09-27 2021-04-01 成都海创药业有限公司 Inhibiteur de ep300/cbp
CN113286777A (zh) * 2018-11-27 2021-08-20 纽约市哥伦比亚大学理事会 用于调节铁死亡和治疗兴奋性神经毒性障碍的化合物、组合物和方法
WO2022095989A1 (fr) * 2020-11-06 2022-05-12 贝达药业股份有限公司 Inhibiteurs de p300 et leur utilisation en médecine

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