WO2012065062A1 - Nouveaux composés antiviraux - Google Patents

Nouveaux composés antiviraux Download PDF

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Publication number
WO2012065062A1
WO2012065062A1 PCT/US2011/060370 US2011060370W WO2012065062A1 WO 2012065062 A1 WO2012065062 A1 WO 2012065062A1 US 2011060370 W US2011060370 W US 2011060370W WO 2012065062 A1 WO2012065062 A1 WO 2012065062A1
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alkyl
cycloalkyl
substituted
compound
phenyl
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PCT/US2011/060370
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English (en)
Inventor
Ping Chen
Ding Zhou
David Pryde
Andrew Bell
Tao Li
Zhiliang He
Zhen-Wei Cai
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Pharmaresources(Shanghai)Co., Ltd.
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Publication of WO2012065062A1 publication Critical patent/WO2012065062A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to novel compounds as anti-viral agents, which can be useful in the treatment of viral infections such as HIV, HBV and HCV; to processes for their preparation; to pharmaceutical compositions comprising them; and to methods of using them.
  • RT transcriptase
  • PR protease
  • Virus assembly is a particularly attractive target for antiviral intervention because viral structures are formed by multiple, relatively weak non-covalent interactions.
  • few assembly inhibitors have been identified to date in any viral systems, mainly due to insufficient information regarding particle structure and inter-subunit interactions and the lack of suitable assays.
  • HIV is released from the infected cells as an immature, non-infectious particle containing a spherical protein shell of approximately 5,000 Gag molecules underneath the viral membrane.
  • MA matrix
  • CA capsid
  • NC nucleocapsid
  • the last but critical proteolytic cleavage step of CA-SPl generates a mature p24 CA protein, which is capable of forming the higher-order complexes that comprise the mature viral core. In the absence of this maturation, viral particles remain to be non-infectious.
  • the present invention provides a compound of formula I,
  • W is optionally substituted 8-10 membered bicyclic carbocycle or heterocycle; each of Ri and R 2 is independently H, (Ci-C 4 )alkyl, hydroxyl, fluoro, or NR b R c , or Ri and R 2 together form (C 3 -C 5 )cycloalkyl, or substituted (C 3 -C 5 )cycloalkyl;
  • R 3 is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl
  • R 4 is H, (Ci-C 4 )alkyl, substituted (Ci-C 4 )alkyl, (C 3 -Cy)cycloalkyl, or substituted
  • R 5 is (CR 8 Rc)) q -cycloalkyl, cycloalkyl, (CR 8 Rc)) q -aryl, (CR 8 Rc)) q - substituted aryl, heterocycle; each of Rg and R9 is independently H, (Ci-C 4 )alkyl, hydroxyl, fluoro, or NRbRc, or Ri and R 2 together form (C 3 -C 5 )cycloalkyl, or substituted (C 3 -C 5 )cycloalkyl; each of Rb and R c is independently hydrogen, alkyl or substituted alkyl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle; each q is independently 0, 1, 2, 3, or 4; and n is 1 or 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound as described herein and a pharmaceutically-acceptable carrier.
  • the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.
  • the present invention provides a method for treating or preventing HIV infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound as described herein.
  • alkyl and “alk” refer to a straight or branched chain alkane
  • hydrocarbon radical containing from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • (Ci-C 4 )alkyl refers to a straight or branched chain alkane (hydrocarbon) radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl.
  • “Substituted alkyl” refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g.
  • each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , Rc and Rj is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond.
  • C 2 -C 6 alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but- 2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2- enyl, (E)-pent-l-enyl, (Z)-hex-l-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)- hex-l-enyl, (E)-hex-l-enyl, (E)-hex-l-enyl, (E)-hex
  • Substituted alkenyl refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g.
  • each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, R c and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Rg is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • the exemplary substitutents is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon to carbon triple bond.
  • C 2 -C 6 alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-l-ynyl, prop-2-ynyl, but-l-ynyl, but-2-ynyl, pent-l-ynyl, pent-2-ynyl, hex-l-ynyl, hex-2-ynyl, hex-3-ynyl.
  • Substituted alkynyl refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g.
  • each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and Rj is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • the exemplary substitutents can themselves be optionally substituted.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring.
  • C 3 -C 7 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • Substituted cycloalkyl refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and Rd is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of Rg is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • exemplary substitutents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substitutents can themselves be optionally substituted.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc.
  • Substituted cycloalkenyl refers to a cycloalkenyl group substituted with one more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g.
  • each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , Rc and Rj is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and Rc together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R e is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • exemplary substitutents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cylic substituents, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl, phenanthrenyl and the like). "Substituted aryl” refers to an aryl group substituted by one or more substituents, preferably 1 to 3 substituents, at any available point of attachment.
  • each occurrence of R a is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle; and each occurrence of R s is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • exemplary substitutents can themselves be optionally substituted.
  • exemplary substituents also include fused cylic groups, especially fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • carrier refers to a fully saturated or partially saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring, or cyclic, aromatic hydrocarbon groups that have 1 to 5 aromatic rings, especially monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.
  • carrier encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined hereinabove.
  • substituted carbocycle refers to carbocycle or carbocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl and substituted aryl.
  • substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • heterocycle and “heterocyclic” refer to fully saturated, or partially or fully unsaturated, including aromatic (i.e., “heteroaryl”) cyclic groups (for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems) which have at least one heteroatom in at least one carbon atom-containing ring.
  • aromatic i.e., "heteroaryl”
  • cyclic groups for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 8 to 16 membered tricyclic ring systems
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4
  • heteroaryl refers to a heterocycle containing at least one aromatic ring (e.g., pyridyl or benzo[d][l,3]dioxolyl).
  • heteroarylium refers to a heteroaryl group bearing a quaternary nitrogen atom and thus a positive charge.
  • the heterocyclic group may be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system.
  • Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridy
  • Substituted heterocycle and “substituted heterocyclic” (such as “substituted heteroaryl”) refer to heterocycle or heterocyclic groups substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.
  • substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g.
  • Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl
  • each occurrence of R b , R c and R d is independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle
  • each occurrence of R s is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl.
  • exemplary substitutents can themselves be optionally substituted.
  • exemplary substituents also include spiro-attached or fused cyclic substituents at any available point or points of attachment, especially spiro-attached cycloalkyl, spiro-attached cycloalkenyl, spiro-attached heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the aforementioned cycloalkyl, cycloalkenyl, heterocycle and aryl substituents can themselves be optionally substituted.
  • alkylamino refers to a group having the structure -NHR', wherein R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cyclolakyl, as defined herein.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, n- propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.
  • dialkylamino refers to a group having the structure -NRR', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cyclolalkenyl, aryl or substituted aryl, heterocylyl or susbstituted heterocyclyl, as defined herein. R and R' may be the same or different in an dialkyamino moiety.
  • dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso- propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino,
  • R and R' are linked to form a cyclic structure.
  • the resulting cyclic structure may be aromatic or non-aromatic.
  • Examples of cyclic diaminoalkyl groups include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.
  • halogen or halo refer to chlorine, bromine, fluorine or iodine.
  • any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
  • the compounds of the present invention may form salts which are also within the scope of this invention.
  • Reference to a compound of the present invention is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)" denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
  • zwitterions inner salts
  • inner salts may be formed and are included within the term “salt(s)" as used herein.
  • Salts of the compounds of the present invention may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • the compounds of the present invention which contain a basic moiety may form salts with a variety of organic and inorganic acids.
  • Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides,
  • methanesulfonates methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
  • naphthalenesulfonates e.g., 2-naphthalenesulfonates
  • nicotinates e.g., nitrates, oxalates
  • pectinates persulfates
  • the compounds of the present invention which contain an acidic moiety may form salts with a variety of organic and inorganic bases.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D- glucamines, N-methyl-D-glycamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • the term "prodrug” as employed herein denotes a compound that, upon
  • Solvates of the compounds of the present invention include, for example, hydrates.
  • All stereoisomers of the present compounds are contemplated within the scope of this invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected,
  • the chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974
  • racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates by any suitable method, including without limitation, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 90%, for example, equal to greater than 95%, equal to or greater than 99% of the compounds ("substantially pure” compounds), which is then used or formulated as described herein. Such “substantially pure” compounds of the present invention are also contemplated herein as part of the present invention.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans -isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90: 10, 95:5, 96:4, 97:3, 98:2, 99: 1, or 100:0 isomer ratios are all contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.
  • the present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, U C, 14 C, 15 N, 18 0, 17 0, 31 P,
  • isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl,
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the compounds, as described herein, may be substituted with any number of substituents or functional moieties.
  • substituted whether preceded by the term “optionally” or not, and substituents contained in formulas of this invention, refer to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • the substituent may be either the same or different at every position.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment, for example, of infectious diseases or proliferative disorders.
  • stable as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • the present invention provides a compound of the formula (I):
  • W is optionally substituted 8-10 membered bicyclic carbocycle or heterocycle
  • each of Ri and R 2 is independently H, (Ci-C 4 )alkyl, hydroxyl, fluoro, or NR b R c , or Ri and R 2 together form (C3-C 5 )cycloalkyl, or substituted (C3-C 5 )cycloalkyl;
  • R 3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl
  • R 4 is H, (Ci-C 4 )alkyl, substituted (Ci-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, or substituted (C 3 - C 7 )cycloalkyl;
  • R 5 is (CRgRs q -cycloalkyl, cycloalkyl, (CRgRc>) q -aryl, (CRgRc>) q - substituted aryl, (CRgRc)) q -heterocycle, or (CRgRgVsubstituted heterocycle; each of Rg and R9 is independently H, (Ci-C4)alkyl, hydroxyl, fluoro, or NR b R c , or Ri and R 2 together form (C 3 -C 5 )cycloalkyl, or substituted (C 3 -C 5 )cycloalkyl;
  • each of R b and R c is independently hydrogen, alkyl or substituted alkyl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle;
  • each q is independently 0, 1, 2, 3, or 4;
  • n 1 or 2.
  • W is selected from:
  • each of Z l s Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , and Z 9 is independently carbon or nitrogen, provided that at least one of Z 5 , Z 6 , Z 7 and Zg is carbon;
  • each of Xi, X 2 , X 3 , X 4 , X 5 , X 6 , X7, and Xg is independently carbon or nitrogen, provided that at least one of Xi, X 2 , X 3 , and X 4 is carbon, and at least one of X 5 , X 6 , X 7 , and Xg is carbon;
  • J is nitrogen or carbon
  • L is nitrogen or oxygen
  • Q is nitrogen or oxygen
  • each of Ri and R 2 is independently H or (Ci-C4)alkyl
  • R 3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl
  • R 4 is H, (Ci-C 4 )alkyl, substituted (Ci-C 4 )alkyl, (C 3 -Cv)cycloalkyl, or substituted (C 3 - C 7 )cycloalkyl;
  • R 5 is (CRgR q -cycloalkyl, (CR 8 R 9 ) q -substituted cycloalkyl, (CR 8 R 9 ) q -aryl, (CR 8 R 9 ) q - substituted aryl, (CR 8 R 9 ) q -heteroaryl, or (CR 8 R 9 ) q -substituted heteroaryl;
  • each of R 8 and R9 is independently H or (Ci-C4)alkyl
  • each occurrence of R a , R b , and R c is independently hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, or said R b and Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle;
  • n and q are each independently 0, 1, 2, 3, or 4;
  • n 1 or 2;
  • the compound of Formula (I) has the structure of Formula (II):
  • the compound of Formula (I) has the structure of Formula (III):
  • Z b Z 2 , Z , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , R ls R 2 , R 3 , R4, R5, R ⁇ ;, R7, m and p are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (IV):
  • Z h Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Ri, R 2 , R 3 , R 4 , R5, Re, R7, and p are defined as hereinabove, and m is 0, 1, 2, or 3.
  • the compound of Formula (I) has the structure of Formula (V):
  • the compound of Formula (I) has the structure of Formula (VI):
  • R R 2 , R 3 , R4, R 5 , R6, R7 and p are defined as hereinabove, and m is 1 , 2, or 3.
  • the compound of Formula (I) has having the structure of Formula (Via):
  • R l s R 2 , R 3 , R 4 , R 5 , R6, and R 7 are defined as hereinabove; and m is 1 , 2, or 3.
  • the compound of Formula (I) has the structure of Formula (VII):
  • Z h Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 9 , Ri, R 2 , R3, RA, R5, Re, R7, m and p are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (VIII):
  • Z 2 , Z 3 , Z 5 , Z 6 , Z 7 , Z 8 , Ri, R 2 , R 3 , R 4 , R5, Re, R7, and m are defined as hereinabove, and p is 1 or 2.
  • the compound of Formula (I) has the structure of Formula (IX):
  • Z 5 , Z 6 , Z 7 , Z 8 , Ri, R 2 , R 3 , R4, R5, Rs, R7, and m are defined as hereinabove, and p is 1 or 2.
  • the compound of Formula (I) has the structure of Formula (X):
  • R ls R 2 , R 3 , R4, R5, R5, R7, and m are defined as hereinabove, and p is 1 or 2.
  • the compound of Formula (I) has the structure of Formula (Xa):
  • R ls R 2 , R 3 , R4, R5, R5, R7, and m are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (XI):
  • Z 5 , Z 6 , Z 7 , Zg, Ri, R 2 , R 3 , Rt, R5, R5, R7, and m are defined as hereinabove, and p is 1 or 2.
  • the compound of Formula (I) has the structure of Formula (XII):
  • R R 2 , R 3 , R 4 , R 5 , R6, R7, and m are defined as hereinabove, and p is 1 or 2.
  • the compound of Formula (I) has the structure of Formula (XIII):
  • R l5 R 2 , R 3 , R 4 , R5, R6, R 7 , and m are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (XIV):
  • Z 5 , Z 6 , Z 7 , Z 8 , Ri, R 2 , R 3 , R4, R5, R6, R7, and m are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (XV):
  • R ls R 2 , R 3 , R 4 , R5, R6, R7, and m are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (XVI):
  • the compound of Formula (I) has the structure of Formula (XVII):
  • R l s R 2 , R3, R4, R5, R5, R7, and m are defined as hereinabove.
  • the compound of Formula (I) has the structure of Formula (XVIII):
  • R l s R 2 , R3, R4, R5, Re, R7, and m are defined as hereinabove.
  • each of Ri and R 2 is independently H. In certain other embodiments, each of Ri and R 2 is independently (Ci-C 4 )alkyl. In yet other embodiments, each of Ri and R 2 is independently hydroxyl or fluoro. In yet other embodiments, each of Ri and R 2 is independently NRbRc, in which each of Rb and R c is independently hydrogen, alkyl or substituted alkyl, or said Rb and Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle. In yet other embodiments, Ri and R 2 together form (C 3 -C 5 )cycloalkyl, or substituted (C 3 -C 5 )cycloalkyl. In yet other embodiments, Ri and R 2 together form cyclopropyl.
  • R 3 is phenyl. In certain other embodiments, R 3 is substituted phenyl. In yet other embodiments, R 3 is heteroaryl. In yet other embodiments, R 3 is substituted heteroaryl. In yet other embodiments, R 3 is pyridyl. In yet other embodiments, substituted pyridyl.
  • R 3 is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl) substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (Ci-C4)alkyl, (C 3 -Cv)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH 2 ) q -OH, (CH 2 ) q -0-(Ci-C 4 )alkyl, (CH 2 ) q -NR b R c , (CH 2 ) q -(C 3 -C 7 )cycloalkyl, (CH 2 ) q - substituted (C 3 -C 7 )cycloalkyl, (CH 2 ) q -phenyl, (CH 2 )
  • R4 is H. In certain other embodiments, R 4 is (Ci- C 4 )alkyl. In yet other embodiments, R 4 is methyl. In yet other embodiments, R 4 is ethyl.
  • R 5 is (CH 2 ) q -cycloalkyl, (CH 2 ) q -substituted cycloalkyl, (CH 2 ) q -aryl, (CH 2 ) q -substituted aryl, (CH 2 ) q -heteroaryl, or (CH 2 ) q -substituted heteroaryl, in which q is 0 or 1.
  • R 5 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
  • R 5 is phenyl or substituted phenyl.
  • R 5 is pyridyl or substituted pyridyl.
  • R 5 is phenyl or pyridyl substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (Ci-C 4 )alkyl, (C 3 - C 7 )cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH 2 ) q -OH, (CH 2 ) q -0-(Ci-C 4 )alkyl, (CH 2 ) q -NR b R c , (CH 2 ) q -(C 3 -C 7 )cycloalkyl, (CH 2 ) q -phenyl, and (CH 2 ) q -heteroaryl; each occurrence of R b , and R c is independently hydrogen, (Ci-C 4 )alkyl, and R c is independently hydrogen
  • R 5 is phenyl or heteroaryl selected from thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, l,2,4-oxadiazol-5-yl,
  • each R 6 is independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (Ci-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH 2 ) q -OH, (CH 2 ) q -0-(Ci-C 4 )alkyl, (CH 2 ) q -NR b R c , (CH 2 ) q -(C 3 -C 7 )cycloalkyl, (CH 2 ) q -phenyl, or (CH 2 ) q -heteroaryl; each occurrence of R b , and R c is independently hydrogen, (Ci-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, 3-10 member
  • each R 7 is independently hydrogen, halogen, cyano, nitro, azide, CF 3 , (Ci-C4)alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl, 3-10 membered
  • heterocycle independently hydrogen, (Ci-C 4 )alkyl, (C 3 -C 7 )cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, or aryl, or said Rb and R c together with the N to which they are bonded optionally form a heterocycle, in which said heterocycle is a 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S; and each q is independently 0, 1, 2, 3, or 4.
  • each R 7 is independently (Ci-C 4 )alkyl.
  • each of Rg and R9 is independently H.
  • each of R b , and R c is independently hydrogen or (Ci- C 4 )alkyl, or said R b and R c together with the N to which they are bonded optionally form a 3-
  • substitutents selected from (Ci-C 4 )alkyl, OH, (Ci-C 4 alkyl)-OH, and -0-(Ci-C 4 )alkyl.
  • the present invention provides a compound of Formula (IXX),
  • R 3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF 3 , OCF 3 , (Ci-C 4 )alkyl, or (Ci-C 4 )alkoxy;
  • R4 is H or (Ci-C 4 )alkyl
  • R 5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (Ci-C 4 )alkyl, (C 3 - C 7 )cycloalkyl, (Ci-C 4 )alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH 2 ) q -OH, (CH 2 ) q -0- (Ci-C 4 )alkyl, (CH 2 ) q -NR b Rc, (CH 2 ) q -(C 3 -C 7 )cycloalkyl, (CH 2 ) q -phenyl, and (CH 2 ) q - heteroaryl; each R 6 is independently hydrogen, halogen, cyano, nitro, CF 3 , O
  • R 7a is hydrogen, or (Ci-C4)alkyl
  • R 7 b is hydrogen, or (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl, NR b R c ,
  • the compound of Formula (I) has the structure of Formula (Xb):
  • R 3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF 3 , OCF 3 , (Ci-C 4 )alkyl, or (d-C 4 )alkoxy;
  • R4 is H or (Ci-C 4 )alkyl
  • R 5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (Ci-C4)alkyl, (C 3 - C 7 )cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH 2 ) q -OH, (CH 2 ) q -0- (Ci-C 4 )alkyl, (CH 2 ) q -NR b Rc, (CH 2 ) q -(C 3 -C 7 )cycloalkyl, (CH 2 ) q -phenyl, and (CH 2 ) q - heteroaryl; each R 6 is independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 ,
  • R 7a is hydrogen, or (Ci-C 4 )alkyl
  • R 7b is hydrogen, or (Ci-C 4 )alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C 4 )alkoxy, (C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl, NR b R c ,
  • each occurrence of R a , R b , and R c is independently hydrogen, (Ci-C 4 )alkyl, (C 3 - C 7 )cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, or aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle, in which said heterocycle is a 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S; and m and q are each independently 0, 1, 2, 3, or 4.
  • the compound of Formula (I) has the structure of Formula (Xllla):
  • R 3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF 3 , OCF 3 , (Ci-C 4 )alkyl, or (Ci-C 4 )alkoxy;
  • R 4 is H or (Ci-C 4 )alkyl
  • R 5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF 3 , OCF 3 , (Ci-C 4 )alkyl, (C 3 - Cy)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH 2 ) q -OH, (CH 2 ) q -0- (Ci-C 4 )alkyl, (CH 2 ) q -NR b R c , (CH 2 ) q -(C 3 -C 7 )cycloalkyl, (CH 2 ) q -phenyl, and (CH 2 ) q - heteroaryl; each R 6 is independently hydrogen, halogen, cyano, nitro, CF 3 , OCF 3
  • R 7a is hydrogen, or (Ci-C 4 )alkyl
  • R 7b is hydrogen, or (Ci-C 4 )alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C 4 )alkoxy, (C 2 -C 6 )alkenyl, (C 3 -C 7 )cycloalkyl, NR b R c ,
  • each occurrence of R a , R b , and R c is independently hydrogen, (Ci-C 4 )alkyl, (C 3 - C 7 )cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, or aryl, or said R b and R c together with the N to which they are bonded optionally form a heterocycle, in which said heterocycle is a 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S; and m and q are each independently 0, 1, 2, 3, or 4.
  • R5 is phenyl or heteroaryl selected from thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, l,2,4-oxadiazol-5-yl,
  • Re is hydrogen, halogen or (Ci-C 4 )alkyl.
  • each occurrence of Rb, and R c is independently hydrogen or (Ci-C 4 )alkyl, or said Rb and R c together with the N to which they are bonded optionally form a 3-8 membered heterocycle containing at least one heteroatom selected from N, O and S.
  • the present invention provides a compound selected from Examples 1 through 248 as described herein.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound described herein and a pharmaceutically-acceptable carrier or diluent.
  • the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound described herein.
  • the viral infection is HIV infection.
  • the viral infection is HBV infection.
  • the viral infection is HCV infection.
  • the viral infection is influenza A virus infection, severe acute respiratory syndrome coronavirus infection or vaccinia virus infection.
  • the present invention provides a method for treating or preventing HIV infection in a mammalian species in need thereof, the method comprising administering to the mammalian species a therapeutically effective amount of at least one compound described herein.
  • R 2 group of VI' was halogen, such as CI, Br
  • reaction of VI' with reductive reagent, such as lithium aluminum hydride, hydrogenation catalyzed by palladium on carbon could reduce the halogen to hydrogen
  • R4 such as ester could be converted to R4' such as alcohol, affords mono-substituted indole VIII'.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as butylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically-acceptable salts.
  • pharmaceutically-acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate napthylate
  • mesylate mesylate
  • glucoheptonate lactobionate
  • laurylsulphonate salts and the like See, for example, Berg
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, butionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine,
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polybutylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient, which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10%> to about 30%.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol;
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid
  • binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia
  • humectants such as glycerol
  • disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and sodium starch glycolate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymer; absorbents, such as kaolin and bentonite clay;
  • compositions such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents.
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxybutylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be, made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxybutylmethyl cellulose in varying butortions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if apbutriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isobutyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, butylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • cyclodextrins e.g., hydroxybutyl-.beta
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar— agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar— agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active pharmaceutical agents of the invention.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active pharmaceutical agents of the invention.
  • administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be apbutriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or butellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary butellants, such as chlorofluorohydrocarbons and volatile unsubstituted
  • hydrocarbons such as butane and butane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving, or dispersing the pharmaceutical agents in the buter medium.
  • Absorption enhancers can also be used to increase the flux of the pharmaceutical agents of the invention across the skin. The rate of such flux can be controlled, by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • One strategy for depot injections includes the use of polyethylene oxide-polybutylene oxide copolymers wherein the vehicle is fluid at room temperature and solidifies at body temperature.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissue.
  • compositions containing, for example, 0.1% to 99.5% (more preferably, 0.5%> to 90%>) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of the present invention may be administered concurrently with another anti-HCV agent), or they may achieve different effects (e.g., control of any adverse effects).
  • the compounds of the invention may be administered intravenously,
  • the compounds may be used to treat arthritic conditions in mammals (i.e., humans, livestock, and domestic animals), birds, lizards, and any other organism, which can tolerate the compounds.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of
  • Example 123F (5V2-(2-(3-ethyl-2,4-dimethyl- lH-indol- 1 -yr)acetamidoVN-(6- methoxypyridin-3 -yl)-N-methyl-3 -phenylpropanamide
  • Example 129C Preparation of 2-(4-chloro-2-methyl-lH-indol-3-yl)ethanol [0338] n-BuLi (21.9 g, 343 mmol, 6.0 eq) was added to a solution of 2-(7-bromo-4- chloro-2-methyl-lH-indol-3-yl)ethanol (16.5 g, 57.1 mmol, 1.0 eq) in anhydrous THF (200 mL) at -70°C. The mixture was then stirred at that temperature for 30 minutes and at room temperature for 30 minutes. The mixture was cooled to 0°C, followed by addition of a.q NH 4 CI to quench the reaction. The mixture was then extracted with EA. The organic layers were combined, dried and concentrated to afford the procuct (11.5 g, 54.7 mmol, yield: 96.0%).
  • Example 150 1H NMR (400 MHz, CDC1 3 ) ⁇ 8.54-8.49 (m, 1H), 7.67-7.61 (m, 1H), 7.22-7.04 (m, 8H), 6.89-6.82 (m, 1H), 6.20-6.18 (m, 1H), 5.31-5.11 (m, 1H), 4.75-4.44 (m, 4H), 3.93-3.88 (m, 2H), 3.46 (s, 3H), 3.34-3.30 (m, 1H), 3.15-3.08 (m, 1H), 2.90 (s, 3H), 2.28 (s, 3H).
  • Example 161A Preparation of (6 -2-(l-(2-(l-(benzo[(i [l,3]dioxol-5-yl(methyl)amino)-l- oxo-3-phenylpropan-2-yl-amino)-2-oxoethyl)-4-chloro-2-methyl-lH-indol-3-yl)ethyl4- methylbenzenesulfonate
  • Example 161B Preparation of (6 -2-(2-(3-(2-azidoethyl)-4-chloro-2-methyl-lH-indol-l- yl)acetamido)-N-(benzo[ ⁇ i1- [l,31dioxol-5-yl)-N-methyl-3-phenylpropanamide
  • Example 161C Preparation of (6 -2-(2-(3-(2-aminoethyl)-4-chloro-2-methyl-lH-indol-l- yl)acetamido)-N-(benzor ⁇ i1 ⁇ 1 ,31dioxol-5-yl)-N-methyl-3-phenylpropanamide
  • Example 162A Preparation of (6 -N-(benzo[(i [l ,31dioxol-5-yl)-2-(2-(4-chloro-2-methyl-3- (2-oxo- ethyl)- lH-indol- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
  • Example 162B Preparation of (S)-N-(3 ⁇ 4eDzor /iri.31dioxol-5-ylV2-(2-(4-chlon)-3-(2.2- difluoro- ethyl)-2-methyl- lH-indol- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
  • Example 1641 Preparation of ( ⁇ - ⁇ - ⁇ 6 ⁇ .31 ⁇ 1-5- ⁇ -2-(2-(3-(2- 6 ⁇ 1 ⁇ ⁇ - methylsilyloxy)ethyl)-2-((tert-butyldimethylsilyloxy)methyl)-4-chloro- lH-indol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide
  • Example 164J Preparation of (6 -N-(benzor(iiri,31dioxol-5-yl)-2-(2-(4-chloro-3-(2-hvdroxy- ethyl)-2-(methoxymethyl)-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide
  • Example 166B Preparation of (6 -2-(2-(4-chloro-2-(difluoromethyl)-lH-indol-l- yl)acetamido)-N-(2,2-difluorobenzo ⁇ d] [ 1 ,3 ] dioxol-5 -yl)-N-methyl-3 -phenylpropanamide
  • Example 167F Preparation of (6 -N-(ri,31dioxolor4,5-&1pyridin-5-yl)-2-(2-(4-chloro-3-(2- hvdroxyethyl)-2-methyl-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide
  • Example 168C Preparation of(6 -N-(benzor(iiri,31dioxol-5-yl)-2-(2-(3-(2-hvdroxyethyl)- 2,4,7-trimethyl- lH-indol- 1 -yl)acetamido)-N-methyl-3-(pyridin-4-yl)propanamide
  • Example 171E Preparation of (6 -N-(ri,31dioxolor4,5-&1pyridin-5-yl)-2-(2-(4-chloro-3-(2- hydroxyethyl)-2-methyl-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide
  • reaction mixture was quenched by the addition of methanol (5 mL), then evaporated to give a residue which was added H 2 0 2 (3 mL, 30%) and aqueous NaOH (2 mL,50%>). The reaction mixture was stirred at room temperature for 5 hours, and then extracted with EtOAc (10 mL).
  • Example 175G Preparation of ( ⁇ -N-(benzor6nri.31dioxol-5-vn-N-methyl-2-(2-(2-methyl-3- vinyl- lH-pyrrolor2,3-&1pyridin- 1 -yl)acetamido)-3-phenylpropanamide
  • reaction mixture was quenched by the addition of methanol (5 mL), then evaporated to give a residue which was treated with H 2 0 2 (3 mL,30%>) and aqueous NaOH (2 mL,50%).
  • the resulting reaction mixture was stirred at room temperature for 5 hours, and then extracted with EtOAc (10 mL).

Abstract

La présente invention concerne un composé de formule I : ou un sel pharmaceutiquement acceptable de celui-ci, où les symboles sont tels que définis dans la description ; une composition pharmaceutique comprenant celui-ci, une méthode de traitement ou de prévention d'une infection virale telle que par le VIH à l'aide de ceux-ci.
PCT/US2011/060370 2010-11-12 2011-11-11 Nouveaux composés antiviraux WO2012065062A1 (fr)

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Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014016358A1 (fr) * 2012-07-24 2014-01-30 Medical Research Council Inhibition d'infection par le vih-1 grâce à l'inhibition de la liaison du cpsf à la capside virale
WO2015130964A1 (fr) * 2014-02-28 2015-09-03 Gilead Sciences, Inc. Composés thérapeutiques
WO2015130966A1 (fr) * 2014-02-28 2015-09-03 Gilead Sciences, Inc. Agents antiviraux
WO2017136395A1 (fr) 2016-02-01 2017-08-10 Biocryst Pharmaceuticals, Inc. Composés benzopyrazole et analogues de ceux-ci
US9951043B2 (en) 2013-03-01 2018-04-24 Gilead Sciences, Inc. Therapeutic compounds
US10071985B2 (en) 2016-08-19 2018-09-11 Gilead Sciences, Inc. Therapeutic compounds
WO2018203235A1 (fr) 2017-05-02 2018-11-08 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
US10370358B2 (en) 2011-07-06 2019-08-06 Gilead Sciences, Inc. Compounds for the treatment of HIV
WO2019198024A1 (fr) 2018-04-11 2019-10-17 VIIV Healthcare UK (No.5) Limited Composés de 4-oxo-3,4-dihydroquinazoline utilisés en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2019246545A1 (fr) * 2018-06-21 2019-12-26 Drexel University Inhibiteurs de protéine capsidique du vih-1 à petites molécules et leurs procédés d'utilisation
WO2020031112A1 (fr) 2018-08-09 2020-02-13 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020053811A1 (fr) 2018-09-14 2020-03-19 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020058844A1 (fr) 2018-09-20 2020-03-26 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020084492A1 (fr) 2018-10-24 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020084480A1 (fr) 2018-10-25 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020084491A1 (fr) 2018-10-24 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020089778A1 (fr) 2018-10-29 2020-05-07 VIIV Healthcare UK (No.5) Limited Dérivés de quinazolinyle-indazole et leur utilisation en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020095177A1 (fr) 2018-11-05 2020-05-14 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020095176A1 (fr) 2018-11-05 2020-05-14 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
US10696657B2 (en) 2018-02-16 2020-06-30 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
WO2020157692A1 (fr) 2019-02-01 2020-08-06 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020222108A1 (fr) 2019-04-30 2020-11-05 VIIV Healthcare UK (No.5) Limited Inhibiteurs de réplication du virus de l'immunodéficience humaine
US10836746B2 (en) 2018-02-15 2020-11-17 Gilead Sciences, Inc. Therapeutic compounds
US10849892B2 (en) 2017-08-17 2020-12-01 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
WO2020254985A1 (fr) 2019-06-19 2020-12-24 VIIV Healthcare UK (No.5) Limited Dérivés de pyrido [2,3-d] pyrimidine en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021064571A1 (fr) 2019-10-01 2021-04-08 VIIV Healthcare UK (No.5) Limited Dérivés de-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yle n-substitués utilisés comme inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021064570A1 (fr) 2019-10-01 2021-04-08 VIIV Healthcare UK (No.5) Limited Dérivés de 6-oxo-1,6-dihydropyrimidine-2-yl n-substitués utilisés en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021064677A1 (fr) 2019-10-04 2021-04-08 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021070054A1 (fr) 2019-10-08 2021-04-15 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021107066A1 (fr) 2019-11-28 2021-06-03 塩野義製薬株式会社 Agent pharmaceutique prophylactique et thérapeutique pour maladies infectieuses à vih, caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'intégrase et d'un agent anti-vih
WO2021176366A1 (fr) 2020-03-06 2021-09-10 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021176367A1 (fr) 2020-03-06 2021-09-10 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021209900A1 (fr) 2020-04-15 2021-10-21 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
US11267799B2 (en) 2017-08-17 2022-03-08 Gilead Sciences, Inc. Solid forms of an HIV capsid inhibitor
WO2022114808A1 (fr) 2020-11-26 2022-06-02 에스앤케이테라퓨틱스 Nouveau composé à petites molécules pour lutter contre un récepteur de type toll endosomal et agent thérapeutique pour maladies auto-immunes l'utilisant
US11680064B2 (en) 2020-06-25 2023-06-20 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV
US11787825B2 (en) 2021-12-03 2023-10-17 Gilead Sciences, Inc. Therapeutic compounds for HIV virus infection
US11807625B2 (en) 2019-11-26 2023-11-07 Gilead Sciences, Inc. Capsid inhibitors for the prevention of HIV
US11944611B2 (en) 2018-07-16 2024-04-02 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103788020B (zh) * 2014-01-22 2015-11-04 苏州明锐医药科技有限公司 沃替西汀的制备方法
CN110128422B (zh) * 2019-01-04 2022-03-18 金凯(辽宁)生命科技股份有限公司 5-甲氧基-7-氮杂吲哚的合成方法
CN113912544B (zh) * 2021-11-29 2023-03-17 沧州普瑞东方科技有限公司 一种5-溴-1-甲基吲唑的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0030303D0 (en) * 2000-12-13 2001-01-24 Lilly Co Eli Compounds
WO2010065799A2 (fr) * 2008-12-04 2010-06-10 Palatin Technologies, Inc. Composés spécifiques du récepteur de mélanocortine piperidine substitué amine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PORNILLOS ET AL.: "X-Ray Structures of the Hexameric Building Block of the HIV Capsid.", CELL, vol. 137, 2009, pages 1282 - 1292 *
SHI ET AL.: "Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization.", JOURNAL OF VIROLOGY, vol. 85, 20 October 2010 (2010-10-20), pages 542 - 549 *

Cited By (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034668B2 (en) 2011-07-06 2021-06-15 Gilead Sciences, Inc. Compounds for the treatment of HIV
US10370358B2 (en) 2011-07-06 2019-08-06 Gilead Sciences, Inc. Compounds for the treatment of HIV
WO2014016358A1 (fr) * 2012-07-24 2014-01-30 Medical Research Council Inhibition d'infection par le vih-1 grâce à l'inhibition de la liaison du cpsf à la capside virale
US9951043B2 (en) 2013-03-01 2018-04-24 Gilead Sciences, Inc. Therapeutic compounds
US10202353B2 (en) 2014-02-28 2019-02-12 Gilead Sciences, Inc. Therapeutic compounds
WO2015130966A1 (fr) * 2014-02-28 2015-09-03 Gilead Sciences, Inc. Agents antiviraux
WO2015130964A1 (fr) * 2014-02-28 2015-09-03 Gilead Sciences, Inc. Composés thérapeutiques
EP3411411A4 (fr) * 2016-02-01 2019-08-28 Biocryst Pharmaceuticals, Inc. Composés benzopyrazole et analogues de ceux-ci
JP2019507130A (ja) * 2016-02-01 2019-03-14 バイオクリスト ファーマスーティカルズ，インコーポレイテッドＢｉｏｃｒｙｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． ベンゾピラゾール化合物及びその類似体
WO2017136395A1 (fr) 2016-02-01 2017-08-10 Biocryst Pharmaceuticals, Inc. Composés benzopyrazole et analogues de ceux-ci
AU2017213768B2 (en) * 2016-02-01 2023-12-14 Biocryst Pharmaceuticals, Inc. Benzopyrazole compounds and analogues thereof
US11559515B2 (en) 2016-02-01 2023-01-24 Biocryst Pharmaceuticals, Inc. Indole compounds and analogues thereof
CN109121414A (zh) * 2016-02-01 2019-01-01 拜奥克里斯特制药公司 苯并吡唑化合物和其类似物
TWI747873B (zh) * 2016-02-01 2021-12-01 美商百歐克斯製藥公司 苯并吡唑化合物及其類似物
US10849883B2 (en) 2016-02-01 2020-12-01 Biocryst Pharmaceuticals, Inc. Benzopyrazole compounds and analogues thereof
US10654827B2 (en) 2016-08-19 2020-05-19 Gilead Sciences, Inc. Therapeutic compounds
US10071985B2 (en) 2016-08-19 2018-09-11 Gilead Sciences, Inc. Therapeutic compounds
WO2018203235A1 (fr) 2017-05-02 2018-11-08 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
US11267799B2 (en) 2017-08-17 2022-03-08 Gilead Sciences, Inc. Solid forms of an HIV capsid inhibitor
US11845739B2 (en) 2017-08-17 2023-12-19 Gilead Sciences, Inc. Solid forms of an HIV capsid inhibitor
US11833143B2 (en) 2017-08-17 2023-12-05 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
US11266638B2 (en) 2017-08-17 2022-03-08 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
US10849892B2 (en) 2017-08-17 2020-12-01 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
US11753399B2 (en) 2018-02-15 2023-09-12 Gilead Sciences, Inc. Therapeutic compounds
US10836746B2 (en) 2018-02-15 2020-11-17 Gilead Sciences, Inc. Therapeutic compounds
US11267801B2 (en) 2018-02-15 2022-03-08 Gilead Sciences, Inc. Therapeutic compounds
US11117886B2 (en) 2018-02-16 2021-09-14 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
US11760746B2 (en) 2018-02-16 2023-09-19 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
US10696657B2 (en) 2018-02-16 2020-06-30 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
WO2019198024A1 (fr) 2018-04-11 2019-10-17 VIIV Healthcare UK (No.5) Limited Composés de 4-oxo-3,4-dihydroquinazoline utilisés en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2019246545A1 (fr) * 2018-06-21 2019-12-26 Drexel University Inhibiteurs de protéine capsidique du vih-1 à petites molécules et leurs procédés d'utilisation
US11944611B2 (en) 2018-07-16 2024-04-02 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV
WO2020031112A1 (fr) 2018-08-09 2020-02-13 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020053811A1 (fr) 2018-09-14 2020-03-19 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020058844A1 (fr) 2018-09-20 2020-03-26 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020084491A1 (fr) 2018-10-24 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020084492A1 (fr) 2018-10-24 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020084480A1 (fr) 2018-10-25 2020-04-30 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020089778A1 (fr) 2018-10-29 2020-05-07 VIIV Healthcare UK (No.5) Limited Dérivés de quinazolinyle-indazole et leur utilisation en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020095177A1 (fr) 2018-11-05 2020-05-14 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020095176A1 (fr) 2018-11-05 2020-05-14 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020157692A1 (fr) 2019-02-01 2020-08-06 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2020222108A1 (fr) 2019-04-30 2020-11-05 VIIV Healthcare UK (No.5) Limited Inhibiteurs de réplication du virus de l'immunodéficience humaine
WO2020254985A1 (fr) 2019-06-19 2020-12-24 VIIV Healthcare UK (No.5) Limited Dérivés de pyrido [2,3-d] pyrimidine en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021064571A1 (fr) 2019-10-01 2021-04-08 VIIV Healthcare UK (No.5) Limited Dérivés de-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yle n-substitués utilisés comme inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021064570A1 (fr) 2019-10-01 2021-04-08 VIIV Healthcare UK (No.5) Limited Dérivés de 6-oxo-1,6-dihydropyrimidine-2-yl n-substitués utilisés en tant qu'inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021064677A1 (fr) 2019-10-04 2021-04-08 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021070054A1 (fr) 2019-10-08 2021-04-15 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
US11807625B2 (en) 2019-11-26 2023-11-07 Gilead Sciences, Inc. Capsid inhibitors for the prevention of HIV
WO2021107066A1 (fr) 2019-11-28 2021-06-03 塩野義製薬株式会社 Agent pharmaceutique prophylactique et thérapeutique pour maladies infectieuses à vih, caractérisé en ce qu'il comprend une combinaison d'un inhibiteur d'intégrase et d'un agent anti-vih
WO2021176367A1 (fr) 2020-03-06 2021-09-10 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021176366A1 (fr) 2020-03-06 2021-09-10 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
WO2021209900A1 (fr) 2020-04-15 2021-10-21 VIIV Healthcare UK (No.5) Limited Inhibiteurs de la réplication du virus de l'immunodéficience humaine
US11680064B2 (en) 2020-06-25 2023-06-20 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV
WO2022114808A1 (fr) 2020-11-26 2022-06-02 에스앤케이테라퓨틱스 Nouveau composé à petites molécules pour lutter contre un récepteur de type toll endosomal et agent thérapeutique pour maladies auto-immunes l'utilisant
US11787825B2 (en) 2021-12-03 2023-10-17 Gilead Sciences, Inc. Therapeutic compounds for HIV virus infection

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