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WO2003057677A1 - Derives de 5,6-bisubstitue acyclopyrimidine nucleoside a activite antiretrovirale - Google Patents

Derives de 5,6-bisubstitue acyclopyrimidine nucleoside a activite antiretrovirale Download PDF

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Publication number
WO2003057677A1
WO2003057677A1 PCT/DK2003/000014 DK0300014W WO03057677A1 WO 2003057677 A1 WO2003057677 A1 WO 2003057677A1 DK 0300014 W DK0300014 W DK 0300014W WO 03057677 A1 WO03057677 A1 WO 03057677A1
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Prior art keywords
amino
alkyl
aryl
alkoxy
cyano
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PCT/DK2003/000014
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English (en)
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Erik Bjerregaard Pedersen
Per Trolle JØRGENSEN
Berit Dahan
Nasser R. El-Brollosy
Claus Nielsen
Anne Marie Boel
Bent Faber Vestergaard
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Syddansk Universitet
Statens Serum Institut
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Priority to AU2003205536A priority Critical patent/AU2003205536A1/en
Publication of WO2003057677A1 publication Critical patent/WO2003057677A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms

Definitions

  • the present invention relates to novel pyrimidine derivatives and pharmaceutically acceptable salts thereof specified by the presence of a (substituted) allyloxymethyl group at the 1-position of the pyrimidine ring and an ethyl group or an isopropyl group at the 5- position of the pyrimidine ring and the presence of a (substituted) benzyl group at the 6- position of the pyrimidine ring.
  • the pyrimidine nucleoside derivatives and pharmaceutically acceptable salts thereof show high anti-retroviral activity against wild-type and mutant HIV-1 and relatively low toxicity against the host cells and therefore are useful as antiviral agents.
  • the present invention also relates to the preparation of the novel pyrimidine nucleoside derivatives and pharmaceutically acceptable salts thereof and compositions which can be used in therapy for therapheutic and prophylactic treatment of the acquired immunodeficiency syndrome (AIDS) and infections caused by viruses requiring reverse transcriptase (RT) for replication, such as human immunodeficiency viruses (HIV, causes AIDS), human T-cell leukemia viruses (HTLV-1 and HTLV-2, cause human T-cell lymphomas and produces neurological disease), bovine leukemia virus (BIN, causes B-cell lymphoma), and hepatitis B (HBV, causes chronic hepatitis and liver tumours), and against enzymes requiring reverse transcriptase in their natural cycle of replication, such as the telomerase enzyme (playing a key role in human tumors).
  • HIV human immunodeficiency viruses
  • HTLV-1 and HTLV-2 human T-cell leukemia viruses
  • BIN bovine leukemia virus
  • HBV hepatitis
  • the compounds according to the present invention can be used in therapy for therapheutic and prophylactic treatment of other clinical conditions associated with retroviral infection, for example, Kaposi's sarcoma, Kawasaki diseases, psoriasis, thrombocytopenic purpura, AIDS-related complex as well as chronic neurological conditions such as multiple sclerosis or tropical spastic paraparesis.
  • retroviral infection for example, Kaposi's sarcoma, Kawasaki diseases, psoriasis, thrombocytopenic purpura, AIDS-related complex as well as chronic neurological conditions such as multiple sclerosis or tropical spastic paraparesis.
  • reverse transcriptase a vital enzyme that is responsible for the reverse transcription of retroviral R ⁇ A to proviral D ⁇ A.
  • This enzyme can be inhibited by two general classes of drugs defined by their structure as well as their mechanism of action.
  • nucleoside analogue reverse transcriptase inhibitors such as 3'-azido-3'-deoxythymidine (AZT, Zidovudine), 2',3'-dideoxyinosine (ddl, Didanosine), 2',3'-dideoxycytidine (ddC, Zalcitabine) and 3'- deoxy-2',3'-didehydrothymidine (d4T), bear a strong chemical resemblance to the natural bulding blocks (nucleosides) of DNA and interfere with the function of the enzyme by displacing the natural nucleosides used by the enzyme.
  • AZT Zidovudine
  • ddl 2',3'-dideoxyinosine
  • ddC didanosine
  • dC 2',3'-dideoxycytidine
  • d4T 3'- deoxy-2',3'-didehydrothymidine
  • the second general class, non-nucleoside reverse transcriptase inhibitors such as MKC- 442 (6-benzyl-l-(ethoxymethyl)-5-isopropyluracil), nevirapine (Viramune ® ), delavirdine (Rescriptor ® ), and efavirenz (Sustiva'”), is composed of an diverse group of chemicals that act by binding to the enzyme and modifying it so it functions less efficiently.
  • MKC- 442 6-benzyl-l-(ethoxymethyl)-5-isopropyluracil
  • nevirapine Virtualamune ®
  • Rescriptor ® delavirdine
  • efavirenz efavirenz
  • MKC-442 2,4-pyrimidinedione derivatives having 1-alkoxymethyl substituents, such as MKC-442 (J. Nled. Chem. 35, 4713, 1992). Although MKC-442 exhibit improved activity against HIV, there exists a need to develope non-toxic compounds having even higher potency against both wild-type and especially mutant HIV.
  • 6-substituted acyclopyrimidine nucleoside derivatives having a (substituted) allyloxymethyl group at the 1-position of the pyrimidine ring and having an ethyl group or isopropyl group at the 5-position of the pyrimidine ring and having a (substituted) benzyl group at the 6-position of the pyrimidine ring showed markedly excellent anti-retroviral activities against wild-type (drug-sensitive) and the clinically important Y181C, K103N and Y181C + K103N mutant strains of HIV known to be resistant to established non-nucleosides RT inhibitors.
  • the compounds of the invention have a superior anti-viral activity which greatly increases their potential as drug candidates.
  • the effective dose ED50 for compounds of the invention against wild-type HIV-1 replication is as low as 0.00002 ⁇ M which is superior to the known compounds.
  • an object of the present invention is to provide novel 6-substituted acyclopyrimidine nucleoside derivatives of the following formula (I): 2 ) n - R 3
  • R 1 represents a halogen atom or a group selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, polyaryl, heteroaryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylthio, arylthio, heteroarylthio, aralkyl, or heteroaralkyl, these groups optionally being substituted, e.g.
  • R 2 represents an cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, polyaryl, heteroaryl, or heteropolyaryl group, these groups optionally being substituted, e.g. by one or more of substituents selected from a halogen atom, alkyl, halogenated alkyl, alkoxy, hydroxyl, nitro, amino, cyano and acyl groups,
  • R 3 represents a benzocycloalkyl, naphtocycloalkyl, polyarylenecycloalkyl, polyaryl, heteroaryl, heteropolyaryl, benzocycloalkyl, naphtocycloalkyl, polyarylenecycloalkyl, heteroarylenecycloalkyl, heteropolyarylenecycloalkyl, benzocycloalkenyl, naphtocycloalkenyl, polyarylenecycloalkenyl, heteroarylenecycloalkenyl, heteropolyarylenecycloalkenyl, cyano, alkoxycarbonyl, carbamoyl alkoxy, hydroxyl, mercapto, nitro, amino, substituted amino, disubstituted amino, alkylsulfonamido, arylsulfonamido and acyl groups; or R 3 represents a benzocycloalkyl, naphtocycloalkyl, polyarylenecycloalkyl, polyarylenecycloalky
  • A represents O, S or Se, B represents O, S or Se, or a pharmaceutically acceptable salt thereof.
  • the invention also relates to esters, amides, prodrugs and solvates of the compounds of formula (I).
  • R 1 represents a halogen atom
  • C x to C 10 alkyl optionally substituted, e.g. by one or more substituents selected from a halogen atom, to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, Cj to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 3 to C 10 cycloalkyl optionally substituted, e.g.
  • substituents selected from a halogen atom, C to C 5 alkyl, C to C 5 halogenated alkyl, C 6 to C 1 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, C t to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 2 to C 5 alkenyl optionally substituted, e.g.
  • substituents selected from a halogen atom, to C 5 alkyl, C x to C 5 halogenated alkyl, C 6 to C 1 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 3 to C ⁇ 0 cycloalkenyl optionally substituted, e.g.
  • substituents selected from a halogen atom, to C 5 alkyl, to C 5 halogenated alkyl, C 6 to C i4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 2 to C 5 alkynyl optionally substituted, e.g.
  • substituents selected from a halogen atom, Cx to C 5 alkyl, Ci to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, C x to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 6 to C 12 aryl optionally substituted, e.g.
  • substituents selected from a halogen atom, C t to C 5 alkyl, Ci to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, C ⁇ to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 10 to C 22 polyaryl optionally substituted, e.g.
  • substituents selected from a halogen atom, C t to C 5 alkyl, C x to C 5 halogenated alkyl, C 6 to C 1 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, C t to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 4 to C u heteroaryl optionally substituted, e.g.
  • substituents selected from a halogen atom, Cj to C 5 alkyl, Cj to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C ⁇ 5 aryloxycarbonyl, carbamoyl, to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 2 to C 5 alkylcarbonyl optionally substituted, e.g.
  • substituents selected from a halogen atom, Cj to C 5 alkyl, d to C 5 halogenated alkyl, C 5 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 7 to C 13 arylcarbonyl optionally substituted, e.g.
  • halogen atom selected from a halogen atom, Ci to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, C ⁇ to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 4 to Cu heteroarylcarbonyl optionally substituted, e.g. by one or more substituents selected from a halogen atom, Cj .
  • C 5 alkyl C ⁇ to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C ⁇ 5 aryloxycarbonyl, carbamoyl, t to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 8 to C 14 arylcarbonylalkyl optionally substituted, e.g.
  • substituents selected from a halogen atom, C to C 5 alkyl, Ci to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, C x to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 4 to Cu heteroarylcarbonylalkyl optionally substituted, e.g.
  • substituents selected from a halogen atom, Q to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C x to C 5 alkylthio optionally substituted, e.g.
  • substituents selected from a halogen atom, C x to C 5 alkyl, C ⁇ to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 5 alkoxycarbonyl, C 7 to C ⁇ 5 aryloxycarbonyl, carbamoyl, to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 6 to C i2 arylthio optionally substituted, e.g.
  • substituents selected from a halogen atom, Ci to C 5 alkyl, Q to C s halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 4 to C lt heteroarylthio optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C i4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C 15 aryloxycarbonyl, carbamoyl, to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 7 to C 17 aralkyl group optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, C ⁇ to C 5 halogenated alkyl, C 6 to C 1 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C ⁇ 5 aryloxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; or C 4 to Cu heteroaralkyl optionally substituted, e.g.
  • R 2 represents halogen atom; C 3 to C 10 cycloalkyl optionally substituted, e.g.
  • substituents selected from a halogen atom, to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 2 to C 5 alkenyl optionally substituted, e.g.
  • substituents selected from a halogen atom, to C 5 alkyl, Ci to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 3 to C i0 cycloalkenyl optionally substituted, e.g.
  • substituents selected from a halogen atom, Ci to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 1 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 2 to C 5 alkynyl optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 6 to C 12 aryl optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to Ci 4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 10 to C 22 polyaryl optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; C 4 to Cu heteroaryl group optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, nitro, amino and C 2 to C 7 acyl groups; or C 8 to C 22 heteropolyaryl optionally substituted, e.g.
  • halogen atom d to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C 14 aryl, do to C 22 polyaryl, C 4 to Cu heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C 10 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C 16 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, C x to C 5 alk
  • halogen atom selected from a halogen atom, C x to C 5 alkyl, Ci to C 5 halogenated alkyl, C 6 to C 1 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C 10 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C 16 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, to C 5 alkoxy, hydroxy
  • halogen atom Ci to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C 14 aryl, do to C 22 polyaryl, C 4 to di heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C 10 benzocycloalkyl, C ⁇ 2 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C 12 to C i4 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl,
  • halogen atom d to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C 14 aryl, C i0 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C 10 benzocycloalkyl, C 12 to d naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C 16 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl,
  • a halogen atom selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C i4 aryl, Cio to C 22 polyaryl, C 4 to C tl heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to do benzocycloalkyl, C i2 to C 1 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to do benzocycloalkenyl, C i2 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C 14 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C ⁇ 2 to C i4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C 16 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl, carbam
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C i4 aryl, Cjo to C 2 polyaryl, C 4 to C heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C i2 to Ci 4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C i6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to do benzocycloalkenyl, C i2 to C J4 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C i6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxy
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C M aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C i2 to C ⁇ 4 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C i6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C i0 benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C i5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2
  • a halogen atom Ci to C s alkyl, C x to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C i4 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C i0 benzocycloalkyl, C i2 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C ⁇ 2 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2
  • a halogen atom selected from a halogen atom, C x to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C i4 aryl, C ⁇ 0 to C 22 polyaryl, C to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C ⁇ 2 to C i naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, d 2 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2
  • halogen atom selected from a halogen atom, d to C 5 halogenated alkyl, C 3 to C i0 cycloalkyl, C 6 to C i4 aryl, C ⁇ 0 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C i5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C ⁇ 2 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbon
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C i4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbon
  • a halogen atom selected from a halogen atom, d to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C J4 aryl, C 10 to C 22 polyaryl, C to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C 12 to C i4 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C s to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C ⁇ 4 aryl, Cio to C 22 polyaryl, C 4 to C heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C 10 benzocycloalkyl, C i2 to C i4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C i2 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C 14 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C ⁇ 4 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C i6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C ⁇ 2 to C 14 naphtocycloalkenyl, C i5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alk
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C ⁇ 4 aryl, C 10 to C 22 polyaryl, C 4 to C 1% heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C i2 to C M naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, d 2 to C i4 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C i6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C ⁇ 4 aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to do benzocycloalkyl, C i2 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to Ci 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, C i5 to C 22 polyarylenecycloalkenyl, C 7 to Ci6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl
  • halogen atom selected from a halogen atom, C ⁇ to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C i4 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C J2 to C i4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 5 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C 12 to C 1 naphtocycloalkenyl, C i5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, d 2 to C J4 naphtocycloalkyl, C i5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C J2 to C M naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C
  • a halogen atom Ci to C 5 alkyl, C x to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C 10 benzocycloalkyl, C i2 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, Cj 2 to C i4 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C
  • a halogen atom selected from a halogen atom, C t to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C M aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C 12 to d naphtocycloalkyl, Ci 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C 12 to C i4 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 5 alkoxycarbon
  • a halogen atom selected from a halogen atom, d to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C 14 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C x2 to C 14 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C i6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C 12 to C i4 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C i6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, C ⁇ 0 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C i2 to C 14 naphtocycloalkenyl, C i5 to C 22 polyarylenecycloalkenyl, C 7 to C i6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano,
  • a halogen atom Ci to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, C ⁇ 0 to C 22 polyaryl, C to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to do benzocycloalkyl, C i2 to C i naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to Ci 6 heteroarylenecycloalkyl, C 5 to C 22 heteropolyarylenecycloalkyl, C 8 to C i0 benzocycloalkenyl, C i2 to C i4 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to Ci 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to
  • halogen atom d to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C i4 aryl, C ⁇ 0 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C i2 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C i6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cj 0 benzocycloalkenyl, C ⁇ 2 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C ⁇ 2 to C 14 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to Ci 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C i2 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to Cie heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbonyl,
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C 14 aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 5 to C 22 heteropolyarylenecycloalkyl, C 8 to C i0 benzocycloalkenyl, C 12 to C 14 naphtocycloalkenyl, Ci 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbon
  • a halogen atom selected from a halogen atom, C t to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C 14 aryl, Cio to C 22 polyaryl, C 4 to C ⁇ heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C 7 to C i6 heteroarylenecycloalkyl, C 5 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C i2 to C i4 naphtocycloalkenyl, d 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C ⁇ 4 aryl, C 10 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C 14 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to Cio benzocycloalkenyl, C i2 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C 6 alkoxycarbon
  • a halogen atom selected from a halogen atom, d to C s alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to Cio benzocycloalkyl, C 12 to C1 4 naphtocycloalkyl, C i5 to C 22 polyarylenecycloalkyl, C 7 to C 16 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C i2 to C 14 naphtocycloalkenyl, C 15 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C
  • a halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, C ⁇ 0 to C 22 polyaryl, C to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C ⁇ 2 to C i4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C 16 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C 10 benzocycloalkenyl, C ⁇ 2 to C i naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C 16 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C 2 to C
  • a halogen atom Ci to C 5 alkyl, Ci to C s halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, Cio to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C i0 benzocycloalkyl, C J2 to C ⁇ 4 naphtocycloalkyl, C 15 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C i2 to C ⁇ 4 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano
  • halogen atom selected from a halogen atom, C to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 5 to C 14 aryl, C ⁇ 0 to C 22 polyaryl, C 4 to Cn heteroaryl, C 8 to C 22 heteropolyaryl, C 8 to C ⁇ 0 benzocycloalkyl, C 12 to C i4 naphtocycloalkyl, Ci 5 to C 22 polyarylenecycloalkyl, C 7 to C ⁇ 6 heteroarylenecycloalkyl, C 6 to C 22 - heteropolyarylenecycloalkyl, C 8 to C ⁇ 0 benzocycloalkenyl, C J2 to C 14 naphtocycloalkenyl, C ⁇ 5 to C 22 polyarylenecycloalkenyl, C 7 to C ⁇ 6 heteroarylenecycloalkenyl, C 6 to C 22 heteropolyarylenecycloalkenyl, cyano, C
  • halogen atom Ci to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, Ci to C ⁇ 0 substituted amino, C 2 to C 20 disubstituted amino, Cj to C 5 alkylsulfonamido, C 6 to C 14 arylsulfonamido, and C 2 to C 7 acyl groups; C 12 to C 14 naphtocycloalkyl group optionally substituted, e.g.
  • halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to C 10 cycloalkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, d to C ⁇ 0 substituted amino, C 2 to C 20 disubstituted amino, C x to C 5 alkylsulfonamido, C 6 to C 1 arylsulfonamido, and C 2 to C 7 acyl groups; C 15 to C 22 polyarylenecycloalkyl group optionally substituted, e.g.
  • halogen atom selected from a halogen atom, Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C i4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, Ci to C ⁇ 0 substituted amino, C 2 to C 20 disubstituted amino, Ci to C 5 alkylsulfonamido, C 6 to d 4 arylsulfonamido, and C 2 to C 7 acyl groups; C 7 to C 16 heteroarylenecycloalkyl group optionally substituted, e.g.
  • halogen atom selected from a halogen atom, Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to d 4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, d to Cio substituted amino, C 2 to C 20 disubstituted amino, Ci to C 5 alkylsulfonamido, C 6 to C 14 arylsulfonamido, and C 2 to C 7 acyl groups; C 6 to C 22 heteropolyarylenecycloalkyl group optionally substituted, e.g.
  • a halogen atom Ci to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C i4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, Ci to Cio substituted amino, C 2 to C 20 disubstituted amino, Ci to C 5 alkylsulfonamido, C 6 to C ⁇ 4 arylsulfonamido, and C 2 to C 7 acyl groups; C 7 to C 16 benzocycloalkenyl group optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, C x to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, Ci to Cio substituted amino, C 2 to C 20 disubstituted amino, Ci to C 5 alkylsulfonamido, C 6 to C 14 arylsulfonamido, and C 2 to C 7 acyl groups; C 12 to C 14 naphtocycloalkenyl group optionally substituted, e.g.
  • substituents selected from a halogen atom, d to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to C ⁇ 0 cycloalkyl, C 6 to d aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, C x to C i0 substituted amino, C 2 to C 20 disubstituted amino, Ci to C 5 alkylsulfonamido, C 6 to C 14 arylsulfonamido, and C 2 to C 7 acyl groups; C 15 to C 22 polyarylenecycloalkenyl group optionally substituted, e.g.
  • halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to d 4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, d to C i0 substituted amino, C 2 to C 20 disubstituted amino, d to C 5 alkylsulfonamido, C 6 to C 14 arylsulfonamido, and C 2 to C 7 acyl groups; C 7 to C 16 heteroarylenecycloalkenyl group optionally substituted, e.g.
  • substituents selected from a halogen atom, C 2 to C 5 alkyl, d to C 5 halogenated alkyl, C 3 to Cio cycloalkyl, C 6 to C 14 aryl, cyano, C 2 to C 6 alkoxycarbonyl, carbamoyl, d to C 5 alkoxy, hydroxyl, mercapto, nitro, amino, C x to Cio substituted amino, C 2 to C 20 disubstituted amino, Ci to C 5 alkylsulfonamido, C 6 to C 14 arylsulfonamido, and C 2 to C 7 acyl groups; C 6 to C 22 heteropolyarylenecycloalkenyl group optionally substituted, e.g.
  • R 3 represents a C 8 to C i0 benzocycloalkyl, C ⁇ 2 to C i4 naphtocycloalkyl, C ⁇ 5 to C 22 polyarylenecycloalkyl, C ⁇ 5 to C 22 heteroarylenecycloalkyl, C 6 to C 22 heteropolyarylenecycloalkyl, C 8 to C
  • halogen atom Ci to C 5 alkyl, Ci to C 5 halogenated alkyl, C 6 to C i4 aryl, cyano, C 2 to C 6 alkoxycarbonyl, C 7 to C ⁇ 5 aryloxycarbonyl, carbamoyl, Ci to C 5 alkoxy, hydroxyl, nitro, amino, and C 2 to C 7 acyl groups
  • R 1 represents C ⁇ -C 6 alkyl
  • R 2 represents phenyl, optional substituted by one or more C ⁇ -C 6 alkyl groups
  • R 3 represents C ⁇ -C 6 alken-1-yl
  • A, B and X all represent O
  • Z represents -(CH 2 ) m -, m represents an integer of 1 to 5
  • n represents an integer of 1 to 2.
  • R 1 represents an ethyl group or an isopropyl group
  • R 2 represents a phenyl group or a 3,5-dimethylphenyl group
  • R 3 represent a vinyl group or a ethynyl group or a 1- methylvinyl group or a 2,2-dimethyIviny! group or an indan-1-yl group or an indan-2-yl group
  • Z represents a methylene group or a carbonyl group
  • n represents 0 or integer of 1.
  • the invention relates to an antiviral agent which contains as an active ingredient a 6-substituted acyclopyrimidine nucleoside derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention relates to a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, preferably in combination with a pharmaceutical vehicle.
  • the pharmaceutical composition has an effective antiviral activity, particularly anti-retroviral activity.
  • the antiviral agents of the general formula (I) can be administered through various administration routes, for example, oral, enteral, parenteral or topical route.
  • the clinical dose of the antiviral agents varies depending on age, weight, conditions or the like of patient to be treated.
  • Appropriate daily dosage of the compound of the formula (I) to adult is generally about 0.1-100 mg/kg weight, preferably about l-50mg/kg weight, which may be administered once, or in two to several divisions at appropriate intervals.
  • the invention relates to the use of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof in a process for the production of a pharmaceutical composition for the treatment or prevention of diseases caused by viral, particularly retroviral infection, especially in human beings.
  • the invention relates to a process for the preparation of a compound represented by formula (I), which comprises reacting a compound represented by the following general formula (II)
  • the invention relates to a process for the preparation of a compound represented by the general formula (I), wherein R 1 , R 2 , R 3 , A, B, X, Z, and n have the same meanings as defined above, which comprises reacting a compound represented the general formula (II), wherein R4 R 2 , A, B, and 72.
  • silylation with a silylating agent for example 1,1,1,3,3,3- hexamethyldisilazane or /V / 0-bis-(trimethylsilyl)acetamide
  • a compound represented with the general formula (III) or (IV) wherein R 3 , X, and n has the same meaning as defined above, in the presence of a Lewis acid catalyst, for example trimethylsilyl triflouromethanesulfonat.
  • the preparation of a compound by the formula (I) can be illustrated by a process which comprises reacting a compound represented by the following general formula (II) in Scheme 1, wherein R 1 , R 2 , A, B, and Z have the same meanings as defined in Table 1, with a compound by the following general formula (III) in Scheme 1, wherein R 3 , X and n have the same meaning as defined in Table 1.
  • the compound represented by the general formula (II) as a starting material was prepared according to the method of ours; Danel et al. (Synthesis, p. 934, (1995) and Synthesis, p. 1021, (1997)).
  • Compound (II) was generally prepared via ethyl 2-alkyl-4- aryl-3-oxo esters using the method of Hannich and Kishi (J. Org. Chem., 48, p. 3833, (1983)) by reaction of the corresponding aryl acetonitriles with zinc and ethyl 2- bromoalkanoates.
  • the compound represented by the general formula (III) as a starting material was prepared according to the method of Nazaretyan et al. (3. Appl. Chem., USSR, p. 2396, (1985)) by refluxing the corresponding allylalcohol, dibromomethane and tetrabutylammonium bromide in benzene to afford the diallyloxymethane (III) after destilation under reduced pressure.
  • the substituents have the same meanings as in IUPAC Compendium of Chemical Terminology unless otherwise defined.
  • the substituent definition comprises a range (e.g. ; C 6 to C 22 or Ci to C ⁇ o,) .
  • the range is understood to comprise all integers in that range, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 etc.
  • substituted means that one or more (such as 1, 2, 3, 4, 5, or 6) hydrogen atoms are substituted with substituents independently selected from groups such as: halogen atoms, nitro groups, hydroxyl, mercapto, cyano, carbamoyl, optionally substituted amino, optionally substituted alkyl (e.g.
  • perhalogenalk ⁇ l optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalk(en/yn)yl, optionally substituted aryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted (hetero)aryl, optionally substituted (hetero)aryloxy or acyl groups.
  • halogen represents fluoro, chloro, bromo, or iodo.
  • heteroatom includes atoms such as O, S, or N.
  • alkyl includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Preferably, the alkyl group have 1-10 carbon atoms, and most preferred 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl groups may be interrupted by one or more heteroatoms, and may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t- butyl.
  • cycloalkyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings of preferably 3, 4, 5, 6, or 7 ring members, which can be fused or isolated.
  • the rings may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or alkyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • alkenyl includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g. 2, 3, 4, 5, 6 or 10 carbon atoms) with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms.
  • the chain hydrogens may be substituted, e.g. with groups as defined above, such as halogen.
  • Preferred straight or branched alkenyl groups include vinyl, allyl, 1-butenyl, l-methyl-2- propenyl and 4-pentenyl.
  • alkynyl includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g. 2, 3, 4, 5, 6 or 10 carbon atoms) with at least one carbon-carbon triple bond, the chain being optionally interrupted by one or more heteroatoms.
  • the chain hydrogens may be substituted, e.g with groups as defined above, such as halogen.
  • Preferred straight or branched alkynyl groups include ethynyl, propynyl, 1-butynyl, 1- methyl-2-propynyl and 4-pentynyl.
  • cycloalkenyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings of preferably 3, 4, 5, 6, or 7 ring members containing a carbon-carbon double bond, which can be fused or isolated.
  • the rings may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, alkoxy, or alkyl.
  • Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
  • aryl refers to carbon-based rings which are aromatic.
  • the rings may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be substituted, e.g. with groups as defined above, such as alkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.
  • Preferred aryl groups include phenyl, 3- (trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
  • heteroaryl refers to aromatic hydrocarbon rings (having such as 3, 4, 5, 6, or 7 ring members) which contain at least one (e.g. 1, 2, 3, 4, or 5) heteroatom(s) in the ring. Heteroaryl rings may be isolated, preferably with 5 to 6 ring atoms, or fused, preferably with 8, 9 or 10 ring atoms.
  • the heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted, e.g. with groups as defined above, such as alkyl or halogen.
  • heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
  • acyl groups are formyl, C ⁇ -6 alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-d- 6 alk(en/yn)ylcarbonyl, cycloalkylcarbonyl, or cycloalkyl-C ⁇ -6 alk(en/yn)ylcarbonyl group.
  • polyaryl refers to molecules having 3 or more (e.g. 3, 4, 5 or 6) fused aromatic hydrocarbon rings.
  • One or more og the ring hydrogens may be substituted, e.g. with groups as defined above, such as alkyl, halogen, etc.
  • Preferred polyaryl groups include anthryl, pheranthryl, and pyrenyl.
  • the polyaryl group is optionally substituted.
  • arylene- means a divalent group derived from an arene by removing two ring hydrogens (or by removing one hydrogen from an aryl group, cf. above).
  • arene refers to carbon-based rings which are aromatic. The rings may be isolated, such as benzene, or fused, such as naphthylene. The arylene group is optionally substituted.
  • heteroarylene- have the same meaning as defined above for arylene but contain at least one (e.g. 1, 2, 3, 4, or 5) heteroatom(s) in the aromatic ring structure, cf. the above definition for heteroaryl.
  • the heteroarylene group is optionally substituted.
  • polyaryiene- means a divalent group derived from a polyarene by removing two ring hydrogens.
  • polyarene refers to three or more fused aromatic hydrocarbon ring.
  • the polyaryiene group is optionally substituted.
  • heteropolyarylene- have the same meaning as defined above for polyaryiene but contain at least one (e.g. 1, 2, 3, 4, or 5) heteroatom(s) in the ring.
  • the heteropolyarylene group is optionally substituted.
  • salts examples include the iodide, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2- benzoate, bromide, isobutyrate, phenylbutyrate, g-hydroxybutyrate, b-hydroxybutyrate, butyne-l,4-dioate, hexyne-l,4-dioate, hexyne-l,6-dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nic
  • solvate represents an aggregate that comprises one or more molecules of the compound of the invention, with one or more molecules of solvent.
  • Solvents may be, by way of example, water, ethanol, or acetic acid.
  • Example 1 except that bis(2-methyl-2-propenyloxy)methane was used instead of bis(3- methyl-2-butenyloxy)methane.
  • the melting point of the obtained compound was determined to be 1421144 °C (EtOH!H z O).
  • Example 11 5 Preparation of l-(3-cyclohexen-l-ylmethoxymethyl)-5-ethyl-6-(3,5-dimethylbenzyl)uracil (compound no. 11 in Table 1).
  • the title compound, having the melting point of 149-150 °C, was obtained in 72 % (285 mg) yield by repeating Example 7 except that 5-isopropyl-6-(3,5- dimethylphenyl)methyluracil was used instead of 5-ethyl-6-(3,5- dimethylphenyl)methyluracil, and bis(3-cyclohexen-l-ylmethoxy)methane was used 25 instead of b ⁇ s(2-cyclohexen-l-yloxy)methane.
  • Example 13 35 Preparation of 6-benzyl-l-(3-cyclohexen-l-ylmethoxymethyl)-5-isopropyluracil (compound no. 13 in Table 1).
  • the title compound, having the melting point of 130-131 °C, was obtained in 79 % (290 mg) yield by repeating Example 7 except that 6-benzyl-5-isopropyluracil was used instead of 5-ethyl-6-(3,5-dimethylphenyl)methyluracil, and bis(3-cyclohexen-l- ylmethoxy)methane was used instead of bis(2-cyclohexen-l-yloxy)methane.
  • the title compound, having the melting point of 104-105 °C, was obtained in 72 % (245 mg) yield by repeating Example 7 except that 5-isopropyl-6-(3,5- dimethylphenyl)methyluracil was used instead of 5-ethyl-6-(3,5- dimethylphenyl)methyluracil, and bis(allyloxymethyl)methane was used instead of bis(2- cyclohexen-l-yloxy)methane.
  • the title compound was obtained in 60 % yield (250 mg) as a clear colorless oil, by repeating Example 7 except that 5-isopropyl-6-(3,5-dimethylphenyl)methyluracil was used instead of 5-ethyl-6-(3,5-dimethylphenyl)methyluracil, and bis(trans- cinnamyloxy)methane was used instead of bis(2-cyclohexen-l-yloxy)methane.
  • the title compound was obtained in 57 % yield (230 mg) as a clear colorless oil, by repeating Example 7 except that 6-benzyl-5-isopropyluracil was used instead of 5-ethyl-6- (3,5-dimethylphenyl)methyluracil, and bis(2-methyI-3-phenylallyloxy)methane was used instead of bis(2-cyclohexen-l-yloxy)methane.
  • Example 30 by repeating Example 7 except that 5-isopropyl-6-(3,5-dimethylphenyl)methyluracil was used instead of 5-ethyl-6-(3,5-dimethylphenyl)methyluracil, and bis(2-methyl-3- phenylallyloxy)methane was used instead of bis(2-cyclohexen-l-yloxy)methane.
  • Example 21 5 Preparation of 6-benzyl-l-(indan-2-yl-oxymethyl)-5-isopropyluracil (compound no. 21 in Table 1).
  • Example 22 20 Preparation of 5-ethyl-6-(3,5-dimethylbenzyl)-l-(indan-2-yl-oxymethyl)uracil (compound no. 22 in Table 1).
  • the title compound was obtained in 56 % yield (220 mg) as an white foam, by repeating Example 7 except that 6-benzyl-5-isopropyluracil was used instead of 5-ethyl-6-(3,5- dimethylphenyl)methyluracil, and bis(indan-l-yloxy)methane was used instead of bis(2- cyclohexen-l-yloxy)methane.
  • Example 7 except that bis(indan-l-yloxy)methane was used instead of bis(2-cyclohexen-l- yloxy)methane.
  • the title compound was obtained in 51 % yield (215 mg) as an white foam, by repeating Example 7 except that 5-isopropyl-6-(3,5-dimethylphenyl)methyluracil was used instead of 5-ethyl-6-(3,5-dimethylphenyl)methyluracil, and bis(indan-l-yloxy)methane was used instead of bis(2-cyclohexen-l-yloxy)methane.
  • the title compound, having the melting point of 119-123 °C, was obtained in 72 % yield (253 mg), by repeating Example 7 except that 5-ethyl-6-(l-naphthyl)methyluracil was used instead of 5-ethyl-6-(3,5-dimethylphenyl)methyluracil, and bis(allyloxymethyl)methane was used instead of bis(2-cyclohexen-l-yloxy)methane.
  • the inhibitory activity against HIV-1 infection was evaluated using MT-4 cells (S. Harada et al., Science, 229, p. 563, (1985)) as target cells and the HIV-1 strain HTLV-IIIB (M. 5 Popovic et al., Science, 224, p. 497, (1984)) as infectious virus.
  • the virus was propagated in H9 cells (S. Harada et al., Science, 229, p. 563, (1985)) at 37 °C, 5 % C0 2 using RPMI 1640 with 10 % heat-inactivated Fetal Calf Serum (FCS) and antibiotics (growth medium).
  • MKC-442 (6-benzyl-l-ethoxymethyl-5-isopropyluracil), Nevirapine (Viramune ® ), Delavirdine (Rescriptor ® ), and Efavirenz (Sustiva TM ) was employed as a comparative compound.
  • Antiviral activities of the inventive compounds were determined against Y181C, K103N, and Y181C + K103N which is representative HIV-1 mutant having high resistance against anti-HIV-1 non-nucleosides, e.g., Nevirapine, by the MTT method.
  • MKC-442, Nevirapine (Viramune ® ), Delavirdine (Rescriptor ® ), and Efavirenz (Sustiva TM ) was employed as a comparative compound.
  • the novel antiviral 2,4-pyrimidinedione derivatives of the present invention possess high antiviral activity against HIV-1, both wild-type and mutant HIV-1, and at the same time show high selectivity indices, i.e., low toxicity.
  • the inventive compounds can therefore be used as a drug for treating AIDS. While the invention has been described with respect to the specific embodiments, it should be recognized that various modifications and changes may be made by those skilled in the art to the invention which also fall within the scope of the invention as defined by the appended claims.

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Abstract

La présente invention concerne de nouveaux dérivés de pyrimidine nucléoside représentés par la formule (I) HN I R2 CH (CH2)n 2,X 1∩ D3 , dans laquelle R1 représente par exemple un groupe alkyle; R2 représente par exemple un groupe phényle ou un groupe 3,5-diméthylphényle; et R3 représente par exemple un groupe vinyle ou un groupe éthynyle; A, B et X représentent par exemple des atomes d'oxygène; Z représente par exemple un groupe méthylène ou un groupe carbonyle; n représente, par exemple, 1. On a remarqué que ces composés sont très actifs contre le VIH-1 de type sauvage et de type mutant. Formule (I)
PCT/DK2003/000014 2002-01-11 2003-01-10 Derives de 5,6-bisubstitue acyclopyrimidine nucleoside a activite antiretrovirale WO2003057677A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106064B2 (en) 2006-07-24 2012-01-31 Korea Research Institute Of Chemical Technology Pyrimidine-2,4-dione HIV reverse transcriptase inhibitors
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
CN102816184A (zh) * 2012-09-07 2012-12-12 山东大学 (2-(2-氧基-4-硫代嘧啶)乙氧基)甲基膦酸酯类衍生物及其制备与应用
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones

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EP0829476A2 (fr) * 1989-09-29 1998-03-18 Mitsubishi Chemical Corporation Dérivés de nucléoside acylopyrimidine 6-substitués et agent antiviral les contenant comme ingrédient actif

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EP0829476A2 (fr) * 1989-09-29 1998-03-18 Mitsubishi Chemical Corporation Dérivés de nucléoside acylopyrimidine 6-substitués et agent antiviral les contenant comme ingrédient actif

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BAI-CHUAN PAN,ZHI-HAO CHEN: "SYNTHESIS A. ANTI-HIV-1 ACTIVITIES OF 6-ARYLTHIO A. 6-ARYLSELENOACYCLONUCLEOSIDES.", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 31, no. 1, January 1994 (1994-01-01), HETEROCORPORATION. PROVO., US, pages 177 - 185, XP002209278, ISSN: 0022-152X *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106064B2 (en) 2006-07-24 2012-01-31 Korea Research Institute Of Chemical Technology Pyrimidine-2,4-dione HIV reverse transcriptase inhibitors
US8334295B2 (en) 2007-06-29 2012-12-18 Korea Research Institute Of Chemical Technology Pyrimidine derivatives as HIV reverse transcriptase inhibitors
US8354421B2 (en) 2007-06-29 2013-01-15 Korea Research Insitute Of Chemical Technology HIV reverse transcriptase inhibitors
US8119800B2 (en) 2007-12-21 2012-02-21 Korea Research Institute Of Chemical Technology Processes for preparing HIV reverse transcriptase inhibitors
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US8841314B2 (en) 2011-11-11 2014-09-23 Pfizer Inc. 2-Thiopyrimidinones
US9399626B2 (en) 2011-11-11 2016-07-26 Pfizer Inc. 2-thiopyrimidinones
US9873673B2 (en) 2011-11-11 2018-01-23 Pfizer Inc. 2-thiopyrimidinones
CN102816184A (zh) * 2012-09-07 2012-12-12 山东大学 (2-(2-氧基-4-硫代嘧啶)乙氧基)甲基膦酸酯类衍生物及其制备与应用
CN102816184B (zh) * 2012-09-07 2015-11-18 山东大学 (2-(2-氧基-4-硫代嘧啶)乙氧基)甲基膦酸酯类衍生物及其制备与应用
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones

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