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WO2012065062A1 - Novel antiviral compounds - Google Patents

Novel antiviral compounds 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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Prior art keywords
alkyl
cycloalkyl
substituted
compound
phenyl
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PCT/US2011/060370
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French (fr)
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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PHARMARESOURCES(SHANGHAI)CO Ltd
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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).

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Abstract

The present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein the symbols are as defined in the specification; a pharmaceutical composition comprising the same, a method for treating or preventing a viral infection such as HIV using the same.

Description

NOVEL ANTIVIRAL COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of Chinese Application No. 201010541329.0, filed November 12, 2010, and U.S. Provisional Patent Application No. 61/431,195, filed January 10, 2011, the entire contents of which are hereby incorporated by reference herein.
FIELD OF THE INVENTION
[0002] 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.
BACKGROUND OF THE INVENTION
[0003] Despite the significant success of blockade of AIDS progression in HIV infected patients by the development of various anti-retroviral drugs targeting the envelope protein, reverse transcriptase (RT), integrase (IN) and protease (PR), there is a continuing and urgent need for novel therapy due to the emergence of acquired drug resistance and the serious side- effects or intolerance of the existing drugs. Among the 20+ drugs currently on the market for treatment of HIV- 1 infection, 19 of them target one of two viral enzymes, reverse
transcriptase (RT) or protease (PR). Viral isolates resistant to the approved drugs eventually emerge, which reduce the choice and effectiveness of treatment options. As such, there is a major unmet need for new classes of drugs with unique mode(s) of action with activity against HIV strains resistant to currently approved therapies.
[0004] The discovery of new class of drugs aiming at inhibition of HIV replication cycle via new mechanism(s) offers the best hope to patients carrying resistant HIV variants as the new drug class will not confer cross-resistance to the existing classes of drug, and therefore will provide value to the novel combination therapies. In addition, since the current standard of care requires lifetime therapy for HIV-infected patients, novel drugs with improved activity/toxicity/ safety profile (improved therapeutic window) will provide added benefits to the AIDS patients regardless of carrying wide -type or mutant/resistant viral strains.
[0005] Virus assembly is a particularly attractive target for antiviral intervention because viral structures are formed by multiple, relatively weak non-covalent interactions. However, 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.
[0006] 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. Concomitant with the release, sequential proteolytic processing of Gag polyprotein by the viral protease leads to the formation of a mature infectious virus with a conical capsid containing individual structural proteins including matrix (MA), capsid (CA), nucleocapsid (NC), and the p6 protein in addition to two spacer peptides SP1 and SP2.
Importantly, 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.
[0007] Several antiviral drugs of novel mechanism targeting virion maturation are currently under clinic evaluation.1"6 Inhibitors that target HIV-1 capsid have been reported to include a helical peptide inhibitor (CAI),7"9 two small molecule inhibitors CAP-1 and CAP- 210 and several thiaurea-based inhibitors.11 In addition, compounds that act on capsid have been disclosed in patent applications.12"16
SUMMARY OF THE INVENTION
[0008] In one aspect, the present invention provides a compound of formula I,
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is optionally substituted 8-10 membered bicyclic carbocycle or heterocycle; each of Ri and R2 is independently H, (Ci-C4)alkyl, hydroxyl, fluoro, or NRbRc, or Ri and R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl;
R3 is phenyl, substituted phenyl, heteroaryl, or substituted heteroaryl;
R4 is H, (Ci-C4)alkyl, substituted (Ci-C4)alkyl, (C3-Cy)cycloalkyl, or substituted
(C3-Cy)cycloalkyl;
R5 is (CR8Rc))q-cycloalkyl,
Figure imgf000003_0002
cycloalkyl, (CR8Rc))q-aryl, (CR8Rc))q- substituted aryl,
Figure imgf000003_0003
heterocycle; each of Rg and R9 is independently H, (Ci-C4)alkyl, hydroxyl, fluoro, or NRbRc, or Ri and R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl; each of Rb and Rc 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.
[0009] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound as described herein and a pharmaceutically-acceptable carrier.
[0010] In yet another aspect, 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.
[0011] In a further aspect, 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.
FURTHER DESCRIPTION OF THE INVENTION
Definitions
[0012] The following are definitions of terms used in the present specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.
[0013] The terms "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. Exemplary "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. The term "(Ci-C4)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. , a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re, S(=0)2Re,
Figure imgf000005_0001
NRbRc, NRbS(=0)2Re,
Figure imgf000005_0002
C(=0)ORd, C(=0)Ra,
C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc,
NRdS(=0)2NRbRc,
Figure imgf000005_0003
NRbC(=0)Ra, or wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc 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 Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the aforementioned exemplary substitutents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted.
[0014] The term "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.
Exemplary such groups include ethenyl or allyl. The term "C2-C6 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, , (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-l ,3-dienyl.
"Substituted alkenyl" refers to an alkenyl 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. , a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Rs, S(=0)2Rs,
Figure imgf000005_0004
P(=0)2NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc,
NRbC(=0)ORe, NRdC(=0)NRbRc, NRdS(=0)2NRbRc, NRdP(=0)2NRbRc, NRbC(=0)Ra, or NRbP(=0)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd 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 Rg is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted.
[0015] The term "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.
Exemplary such groups include ethynyl. The term "C2-C6 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. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g. , a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re,
Figure imgf000006_0001
S(=0)2ORe, P(=0)2ORe, NRbRc,
Figure imgf000006_0002
P(=0)2NRbRc, C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc,
NRdS(=0)2NRbRc, NRdP(=0)2NRbRc, NRbC(=0)Ra, or
Figure imgf000006_0003
wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc 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 Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substitutents can themselves be optionally substituted.
[0016] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 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. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e. , =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re,
Figure imgf000007_0001
S(=0)2ORe, P(=0)2ORe, NRbRe,
Figure imgf000007_0002
C(=0)ORd, C(=0)Ra,
Figure imgf000007_0003
NRdC(=0)NRbRc,
Figure imgf000007_0004
NRdP(=0)2NRbRc, NRbC(=0)Ra, or NRbP(=0)2Re, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd 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 Rg is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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. [0017] The term "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. , a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SR,, S(=0)2ORe, P(=0)2ORe, NRbRe, NRbS(=0)2Re, NRbP(=0)2Re,
Figure imgf000007_0005
C(=0)ORd, C(=0)Ra, C(=0)NRbRc, OC( NRbC(=0)O
NRdS(=0)2NRbRc,
Figure imgf000007_0006
bC(=0)Ra, or n each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc 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 Re is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.
[0018] The term "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.
Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re, S(=0)2Re, P(=0)2Re, S(=0)2ORe, P(=0)2ORe, NRbRe, NRbS(=0)2Re,
NRbP(=0)2Re,
Figure imgf000008_0001
C(=0)ORd, C(=0)Ra, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORe, NRdC(=0)NRbRc,
Figure imgf000008_0002
NRbC(=0)Ra, or NRbP(=0)2Rs, wherein each occurrence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd 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 Rs is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.
[0019] The term "carbocycle" 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. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined hereinabove. The term
"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. Exemplary substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl and substituted aryl.
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.
[0020] The terms "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. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4
heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The term "heteroaryl" refers to a heterocycle containing at least one aromatic ring (e.g., pyridyl or benzo[d][l,3]dioxolyl). (The term "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, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1- dioxothienyl, and the like. Exemplary bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl,
benzo[d][l,3]dioxolyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, quinuclidinyl, quinolinyl, quinoxalinyl, quinazolinyl, [l,2,4]triazolo[l,5-a]pyridinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, phthalazinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl) or furo[2,3- b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo- quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl,
phenanthridinyl, xanthenyl and the like.
[0021] "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. Exemplary substituents include but are not limited to one or more of the following groups: hydrogen, halogen (e.g. , a single halogen substituent or multiple halo substitutents forming, in the latter case, groups such as CF3 or an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, ORa, SRa, S(=0)Re,
S(=0)2Re,
Figure imgf000010_0001
S(=0)2NRbRc, C(=0)ORd, C(=0)Ra
OC(=0)NRbRc
Figure imgf000010_0002
, NRbC(=0)ORe, NRdC(=0)NRbRc,
NRbC(=0)Ra, or NRbP(=0)2Rs, wherein each occurence of Ra is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; each occurrence of Rb, Rc and Rd 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 Rs is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The 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.
[0022] The term "alkylamino" refers to a group having the structure -NHR', wherein R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cyclolakyl, as defined herein. Examples of 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.
[0023] The term "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. Examples of 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,
di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, 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.
[0024] The terms "halogen" or "halo" refer to chlorine, bromine, fluorine or iodine.
[0025] Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
[0026] 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)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a compound of the present invention contains both a basic moiety, such as but not limited to a pyridine or imidazole, and an acidic moiety such as but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. 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.
[0027] The compounds of the present invention which contain a basic moiety, such as but not limited to an amine or a pyridine or imidazole ring, 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, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactates, maleates,
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.
[0028] The compounds of the present invention which contain an acidic moiety, such but not limited to a carboxylic acid, 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.
[0029] Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term "prodrug" as employed herein denotes a compound that, upon
administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the present invention, or a salt and/or solvate thereof.
Solvates of the compounds of the present invention include, for example, hydrates.
[0030] Compounds of the present invention, and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
[0031] All stereoisomers of the present compounds (for example, those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, 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,
stereoisomers. 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
Recommendations. The 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.
[0032] 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.
[0033] All configurational isomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds of the present invention embraces both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.
[0034] Throughout the specifications, groups and substituents thereof may be chosen to provide stable moieties and compounds.
[0035] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.
[0036] 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.
[0037] 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.
[0038] 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. Examples of 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 2H, 3H, 13C, UC, 14C, 15N, 180, 170, 31P,
32 35 18 36
P, S, F, and CI, respectively. Compounds of the present invention, or a
pharmaceutically acceptable salt thereof, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. 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.
[0039] If, for instance, a particular enantiomer of a compound of the present invention is desired, it 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. Alternatively, where 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.
[0040] It will be appreciated that the compounds, as described herein, may be substituted with any number of substituents or functional moieties. In general, the term "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. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For purposes of this invention, 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. Furthermore, 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. The term "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.
Compounds
[0041] In one aspect, the present invention provides a compound of the formula (I):
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is optionally substituted 8-10 membered bicyclic carbocycle or heterocycle;
each of Ri and R2 is independently H, (Ci-C4)alkyl, hydroxyl, fluoro, or NRbRc, or Ri and R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl;
R3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
R4 is H, (Ci-C4)alkyl, substituted (Ci-C4)alkyl, (C3-C7)cycloalkyl, or substituted (C3- C7)cycloalkyl;
R5 is (CRgRs q-cycloalkyl,
Figure imgf000015_0002
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 NRbRc, or Ri and R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl;
each of Rb and Rc 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.
[0042 In certain embodiments, W is selected from:
Figure imgf000016_0001
wherein: , z, ^ z2
II II /
zi in Formula (la) and (lb) denotes ¾ or zi ;
= in Formula (Id) denotes a double bond or single bond;
each of Zl s Z2, Z3, Z4, Z5, Z6, Z7, Z8, and Z9 is independently carbon or nitrogen, provided that at least one of Z5, Z6, Z7 and Zg is carbon;
each of Xi, X2, X3, X4, X5, X6, X7, and Xg is independently carbon or nitrogen, provided that at least one of Xi, X2, X3, and X4 is carbon, and at least one of X5, X6, X7, and Xg is carbon;
J is nitrogen or carbon;
L is nitrogen or oxygen; Q is nitrogen or oxygen;
each of Ri and R2 is independently H or (Ci-C4)alkyl;
R3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
R4 is H, (Ci-C4)alkyl, substituted (Ci-C4)alkyl, (C3-Cv)cycloalkyl, or substituted (C3- C7)cycloalkyl;
R5 is (CRgR q-cycloalkyl, (CR8R9)q-substituted cycloalkyl, (CR8R9)q-aryl, (CR8R9)q- substituted aryl, (CR8R9)q-heteroaryl, or (CR8R9)q-substituted heteroaryl;
each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclyl or substituted heterocyclyl, aryl or substituted aryl, ORa, SRa, S(=0)Ra, S(=0)2Ra, S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra, C(=0)NRbRe, OC(=0)Ra, OC(=0)NRbRe, NRbC(=0)ORa, NRaC(=0)NRbRc, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q- cycloalkyl or (CR8R9)q-substituted cycloalkyl, (CR8R9)q-phenyl or (CR8R9)q-substituted phenyl, or (CR8R9)q-heteroaryl or (CR8R9)q-substituted heteroaryl;
each R7 is independently hydrogen, halogen, cyano, nitro, azide, CF3, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclyl or substituted heterocyclyl, aryl or substituted aryl, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc,
Figure imgf000017_0001
(CR8R9)q-NRbC(=0)Ra, (CH2)q-cycloalkyl or (CR8R9)q-substituted cycloalkyl, (CR8R9)q-phenyl or (CR8R9)q-substituted phenyl, or (CR8R9)q-heteroaryl or (CR8R9)q-substituted heteroaryl;
each of R8 and R9 is independently H or (Ci-C4)alkyl;
each occurrence of Ra, Rb, and Rc 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 Rb and Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle;
m and q are each independently 0, 1, 2, 3, or 4;
n is 1 or 2; and
p is 0, 1, 2 or 3. [0043] In certain other embodiments, the compound of Formula (I) has the structure of Formula (II):
Figure imgf000018_0001
wherein W, Ri, R2, R3, R4, and R5 are defined as hereinabove.
[0044] In yet other embodiments, the compound of Formula (I) has the structure of Formula (III):
Figure imgf000018_0002
wherein Zb Z2, Z , Z4, Z5, Z6, Z7, Z8, Z9, Rls R2, R3, R4, R5, R<;, R7, m and p are defined as hereinabove.
[0045] In yet other embodiments, the compound of Formula (I) has the structure of Formula (IV):
Figure imgf000018_0003
wherein Zh Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Ri, R2, R3, R4, R5, Re, R7, and p are defined as hereinabove, and m is 0, 1, 2, or 3.
[0046] In yet other embodiments, the compound of Formula (I) has the structure of Formula (V):
Figure imgf000018_0004
wherein Zi, Z2, Z3, Rls R2, R3, R4, R5, R6, R7, and p are defined as hereinabove, and m is 0, 1, 2, or 3.
[0047] In yet other embodiments, the compound of Formula (I) has the structure of Formula (VI):
Figure imgf000019_0001
wherein R R2, R3, R4, R5, R6, R7 and p are defined as hereinabove, and m is 1 , 2, or 3.
[0048] In yet other embodiments, the compound of Formula (I) has having the structure of Formula (Via):
Figure imgf000019_0002
wherein Rl s R2, R3, R4, R5, R6, and R7 are defined as hereinabove; and m is 1 , 2, or 3.
[0049] In yet other embodiments, the compound of Formula (I) has the structure of Formula (VII):
Figure imgf000019_0003
wherein Zh Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Ri, R2, R3, RA, R5, Re, R7, m and p are defined as hereinabove.
[0050] In yet other embodiments, the compound of Formula (I) has the structure of Formula (VIII):
Figure imgf000019_0004
wherein Z2, Z3, Z5, Z6, Z7, Z8, Ri, R2, R3, R4, R5, Re, R7, and m are defined as hereinabove, and p is 1 or 2.
[0051] In yet other embodiments, the compound of Formula (I) has the structure of Formula (IX):
Figure imgf000020_0001
wherein Z5, Z6, Z7, Z8, Ri, R2, R3, R4, R5, Rs, R7, and m are defined as hereinabove, and p is 1 or 2.
[0052] In yet other embodiments, the compound of Formula (I) has the structure of Formula (X):
Figure imgf000020_0002
wherein Rls R2, R3, R4, R5, R5, R7, and m are defined as hereinabove, and p is 1 or 2.
[0053] In yet other embodiments, the compound of Formula (I) has the structure of Formula (Xa):
Figure imgf000020_0003
wherein Rls R2, R3, R4, R5, R5, R7, and m are defined as hereinabove.
[0054] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XI):
Figure imgf000020_0004
wherein Z5, Z6, Z7, Zg, Ri, R2, R3, Rt, R5, R5, R7, and m are defined as hereinabove, and p is 1 or 2.
[0055] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XII):
Figure imgf000021_0001
wherein R R2, R3, R4, R5, R6, R7, and m are defined as hereinabove, and p is 1 or 2.
[0056] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XIII):
Figure imgf000021_0002
wherein Rl5 R2, R3, R4, R5, R6, R7, and m are defined as hereinabove.
[0057] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XIV):
Figure imgf000021_0003
wherein Z5, Z6, Z7, Z8, Ri, R2, R3, R4, R5, R6, R7, and m are defined as hereinabove.
[0058] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XV):
Figure imgf000021_0004
wherein Rls R2, R3, R4, R5, R6, R7, and m are defined as hereinabove.
[0059] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XVI):
Figure imgf000021_0005
wherein Z5, Z6, Z7, Z8, Ri, R2, R3, R4, R5, Re, R7, and m are defined as hereinabove.
[0060] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XVII):
Figure imgf000022_0001
wherein Rl s R2, R3, R4, R5, R5, R7, and m are defined as hereinabove.
[0061] In yet other embodiments, the compound of Formula (I) has the structure of Formula (XVIII):
Figure imgf000022_0002
wherein Rl s R2, R3, R4, R5, Re, R7, and m are defined as hereinabove.
[0062] In certain embodiments, W is a 8-10 membered bicyclic carbocycle or heterocycle substituted with one to six substitutents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, ORa, SRa, S(=0)Ra, S(=0)2Ra, S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra,
Figure imgf000022_0003
OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORa, NRaC(=0)NRbRc, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(C1-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-cycloalkyl, (CR8Rc))q-phenyl, and (CR8R9)q-heteroaryl; each of R8 and R9 is independently H or (Ci-C4)alkyl; each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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.
[0063] In certain embodiments, each of Ri and R2 is independently H. In certain other embodiments, each of Ri and R2 is independently (Ci-C4)alkyl. In yet other embodiments, each of Ri and R2 is independently hydroxyl or fluoro. In yet other embodiments, each of Ri and R2 is independently NRbRc, in which each of Rb and Rc 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 R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl. In yet other embodiments, Ri and R2 together form cyclopropyl.
[0064] In certain embodiments, R3 is phenyl. In certain other embodiments, R3 is substituted phenyl. In yet other embodiments, R3 is heteroaryl. In yet other embodiments, R3 is substituted heteroaryl. In yet other embodiments, R3 is pyridyl. In yet other embodiments, substituted pyridyl. In certain embodiments, R3 is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl) substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3-Cv)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q- substituted (C3-C7)cycloalkyl, (CH2)q-phenyl, (CH2)q-substituted phenyl, (CH2)q-heteroaryl, and (CH2)q-substituted heteroaryl, in which q is 0, 1, 2, 3, or 4; and each occurrence of Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle.
[0065] In certain embodiments, R4 is H. In certain other embodiments, R4 is (Ci- C4)alkyl. In yet other embodiments, R4 is methyl. In yet other embodiments, R4 is ethyl.
[0066] In certain embodiments, R5 is (CH2)q-cycloalkyl, (CH2)q-substituted cycloalkyl, (CH2)q-aryl, (CH2)q-substituted aryl, (CH2)q-heteroaryl, or (CH2)q-substituted heteroaryl, in which q is 0 or 1. In certain other embodiments, R5 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In yet other embodiments, R5 is phenyl or substituted phenyl. In yet other embodiments, R5 is pyridyl or substituted pyridyl.
[0067] In yet other embodiments, R5 is aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl) substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, ORa, SRa, S(=0)Ra, S(=0)2Ra, S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra, OC(=0)NRbRc, NRbC(=0)ORa, NRaC(=0)NRbRc, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(C1-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-cycloalkyl, (CRgRgVphenyl, and (CRgRc))q-heteroaryl; each of Rg and R9 is independently H or (Ci-C4)alkyl; each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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.
[0068] In yet other embodiments, R5 is phenyl or pyridyl substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q-heteroaryl; each occurrence of Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
[0069] In certain embodiments, R5 is phenyl or heteroaryl selected from thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, l,2,4-oxadiazol-5-yl,
benzo[d][l,3]dioxolyl, benzoimidazolyl, quinolinyl, quinoxalinyl, quinazolinyl,
[l,2,4]triazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridin-7-yl, benzo[<i]oxazol-5-yl, imidazo[l,2-¾]pyridazin-6-yl, imidazo[l,2-a]pyridin-3-yl, phthalazinyl, and cinnolinyl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q-heteroaryl; each occurrence of Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
[0070] In certain embodiments, each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3- Cy)cycloalkenyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, ORa, SRa, S(=0)Ra, S(=0)2Ra,
S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra,
Figure imgf000025_0001
NRbC(=0)ORa, NRaC(=0)NRbRe, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-cycloalkyl, (CR8R9)q-phenyl, or (CR8R9)q-heteroaryl; each of R8 and R9 is independently H or (Ci-C4)alkyl; each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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.
[0071] In certain other embodiments, each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3-C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl; each occurrence of Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
[0072] In certain other embodiments, each R7 is independently halogen, cyano, nitro, azide, CF3, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-NRbC(=0)Ra, (CH2)q-cycloalkyl,
(CR8R9)q-phenyl, or (CR8R9)q-heteroaryl, wherein said alkyl is optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3- C7)cycloalkyl, NRbRc, C(=0)NRbRc, C(=0)Ra, C(=0)ORa, and OH; each of R8 and R9 is independently H or (Ci-C4)alkyl; each occurrence of Ra, Rb, and Rc is independently hydrogen, (C C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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. [0073] In certain other embodiments, each R7 is independently hydrogen, halogen, cyano, nitro, azide, CF3, (Ci-C4)alkyl, (C2-C6)alkenyl, (C3-C7)cycloalkyl, 3-10 membered
monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, or aryl, (CH2)q-OH, (C C4)alkyl substituted by one or two OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-NRbC(=0)Ra, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q- heteroaryl, wherein said (Ci-C4)alkyl is optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc, C(=0)NRbRc, C(=0)Ra, C(=0)ORa, and OH; each occurrence of Ra, Rb, and Rc is
independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
[0074] In certain other embodiments, each R7 is independently halogen, cyano, nitro, azide, CF3, (Ci-C4)alkyl, (C3-C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, or aryl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-NRbC(=0)Ra, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl; each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
[0075] In yet other embodiments, each R7 is independently (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2- C6)alkenyl, (C3-C7)cycloalkyl, NRbRc, C(=0)NRbRc, C(=0)Ra, C(=0)ORa, and OH; each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
[0076] In yet other embodiments, each R7 is independently (Ci-C4)alkyl. In yet other embodiments, each R7 is independently (CR8R9)2-NRbC(=0)Ra; each of R8 and R9 is independently H or (Ci-C4)alkyl; and each occurrence of Ra, and Rb is independently hydrogen, (Ci-C4)alkyl, (C3-Cy)cycloalkyl, aryl, or 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S. In certain embodiments, each of Rg and R9 is independently H.
[0077] In certain embodiments, each of Rb, and Rc is independently hydrogen or (Ci- C4)alkyl, or said Rb and Rc together with the N to which they are bonded optionally form a 3-
Figure imgf000027_0001
substitutents selected from (Ci-C4)alkyl, OH, (Ci-C4alkyl)-OH, and -0-(Ci-C4)alkyl.
[0079] In a further aspect, the present invention provides a compound of Formula (IXX),
Figure imgf000027_0002
wherein wherein R3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF3, OCF3, (Ci-C4)alkyl, or (Ci-C4)alkoxy;
R4 is H or (Ci-C4)alkyl;
R5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0- (Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q- heteroaryl; each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- Cy)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl;
R7a is hydrogen, or (Ci-C4)alkyl;
R7b is hydrogen, or (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc,
C(=0)NRbRc, C(=0)Ra, C(=0)ORa, OH, or 3-10-membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S (e.g., pyridyl); each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3- C7)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 Rc 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.
[0080] In certain embodiments, the compound of Formula (I) has the structure of Formula (Xb):
Figure imgf000028_0001
wherein R3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF3, OCF3, (Ci-C4)alkyl, or (d-C4)alkoxy;
R4 is H or (Ci-C4)alkyl;
R5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0- (Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q- heteroaryl; each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl;
R7a is hydrogen, or (Ci-C4)alkyl;
R7b is hydrogen, or (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc,
C(=0)NRbRc, C(=0)Ra, C(=0)ORa, OH, or 3-10-membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S (e.g., pyridyl); each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3- C7)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 Rc 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.
[0081] In certain embodiments, the compound of Formula (I) has the structure of Formula (Xllla):
Figure imgf000029_0001
(Xllla) wherein R3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF3, OCF3, (Ci-C4)alkyl, or (Ci-C4)alkoxy;
R4 is H or (Ci-C4)alkyl;
R5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- 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, (CH2)q-OH, (CH2)q-0- (Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q- heteroaryl; each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRe, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl;
R7a is hydrogen, or (Ci-C4)alkyl;
R7b is hydrogen, or (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc,
C(=0)NRbRc, C(=0)Ra, C(=0)ORa, OH, or 3-10-membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S (e.g., pyridyl); each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3- C7)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 Rc 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.
[0082] In certain embodiments, R5 is phenyl or heteroaryl selected from thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, l,2,4-oxadiazol-5-yl,
benzo[d][l,3]dioxolyl, benzoimidazolyl, quinolinyl, quinoxalinyl, quinazolinyl,
[l,2,4]triazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridin-7-yl, benzo[<i]oxazol-5-yl, imidazo[l,2-¾]pyridazin-6-yl, imidazo[l,2-a]pyridin-3-yl, phthalazinyl, and cinnolinyl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(C C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q-heteroaryl. [0083] In certain embodiments, Re is hydrogen, halogen or (Ci-C4)alkyl. In certain other embodiments, each occurrence of Rb, and Rc is independently hydrogen or (Ci-C4)alkyl, or said Rb and Rc 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.
[0084] In one aspect, the present invention provides a compound selected from Examples 1 through 248 as described herein.
[0085] In another aspect, the present invention provides a pharmaceutical composition comprising at least one compound described herein and a pharmaceutically-acceptable carrier or diluent.
[0086] In a further aspect, 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. In certain embodiments, the viral infection is HIV infection. In certain other embodiments, the viral infection is HBV infection. In yet other embodiments, the viral infection is HCV infection. In yet other embodiments, the viral infection is influenza A virus infection, severe acute respiratory syndrome coronavirus infection or vaccinia virus infection.
[0087] In another aspect, 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.
Abbreviations
ACN Acetonitrile
EA Ethyl acetate
DMF Dimethyl formamide
PE Petroleum ether
DCM Dichloromethane
THF Tetrahydrofuran
HOBT 1 -Hydroxybenzotriazole
EDCI 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide
HBTU 2-( 1 H-Benzotriazole- 1 -y 1)- 1 , 1 ,3 ,3 -tetramethyluronium
hexafluorophosphate
HATU N-[(dimethylamino)(3H-l,2,3-triazolelo(4,4-b)pyridin-3- yloxy)methylene]-N-methylmethaneaminium hexafluorophosphate PyBOP 1 H-Benzotriazol- 1 -yloxytripyrrolidinophosphoniumhexafluorophosphate
BOPC1 Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
BOP Benzotriazol- 1 -yloxytris(diethylamino)phosphonium hexafluorophospahte
TEA Triethylamine
DIPEA Diisopropylethylamine
DMAP 4-Dimethylaminopyridine
PCC Pyridinium chlorochromate
PDC Pyridinium dichromate
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NIS N-iodosuccinimide
9-BBN 9-Borabicyclo[3.3.1 Jnonane
TsOH p-Toluenesulfonic acid
TFA Trifluoroacetamide
CDI Carbonyldiimidazole
Methods of Preparation
[0088] Following are general synthetic schemes for manufacturing compounds of the present invention. These schemes are illustrative and are not meant to limit the possible techniques one skilled in the art any use to manufacture compounds disclosed herein.
Different methods will be evident to those skilled in the art. Additionally, the various steps in the synthesis may be performed in an alternate sequence or order to give the desired compound(s). All documents cited herein are incorporated herein by reference in their entirety. For example, the following reactions are illustrations but not limitations of the preparation of some of the starting materials and examples used herein.
[0089] Schemes 1-10 describe various methods for the synthesis of intermediates that may be used to prepare compounds of the present invention. Various modifications to these methods may be envisioned by those skilled in the art to achieve similar results to that of the inventors given below.
[0090] Intermediate indole acid V may be prepared as shown in Scheme 1. Scheme 1
Figure imgf000033_0001
Step 1
[0091] Reaction of substituted nitro compounds I' with Ranney nickel and hydrazine in the alcohol, such as methanol, ethanol, affords substituted aniline II'.
Step 2
[0092] Reaction of substituted aniline II' with sodium nitrite in the presence of an acid, such as hydrogen chloride, followed by treatment with tin (II) chloride in the presence of an acid, such as hydrogen chloride, affords substituted phenylhydrazine II'.
Step 3
[0093] Reaction of phenylhydrazine III' with 4-oxopentanoate in the presence of a base, such as sodium hydrogen carbonate, followed by treatment with Lewis acid, such as zinc (II) chloride, acetic acid, affords substituted indole IV.
Step 4
[0094] Treatment of intermediate IV with halide, such as iodomethane, bromoethane and so on, in the presence of a base, such as sodium hydride, potassium carbonate, followed by adding another base, such as with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords indole acid V.
[0095] Intermediate indole acid VIII' may be prepared as shown in Scheme 2.
Scheme 2
Figure imgf000033_0002
Step 1
[0096] Reaction of II' with a ketoester, such as ethyl 4-oxopentanoate in the presence of a base, such as sodium hydrogen carbonate, followed by treatment with Lewis acid, such as zinc (II) chloride, acetic acid, affords substituted indole VI'.
Step 2
[0097] Reaction of indole VI' with a haloacetate, such as ethyl bromoacetate in the presence of a base, such as sodium hydride, or sodium hydroxide, followed by treatment with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords intermediate VII'.
Step 3
[0098] If R2 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'.
[0099] Intermediate indazole acid XIV may be prepared as shown in Scheme 3.
Scheme 3
Figure imgf000034_0001
XIII' xiv' O
Step 1
[0100] Reaction of aldehyde X' with Grignard reagent, such as methylmagnesium bromide, ethylmagnesium bromide, in non-protonic solvent, such as THF, Et20, dioxane, affords the alcochol XI'.
Step 2
[0101] Reaction of alcohol XI' with oxidant reagent, such as PCC, PDC, Jones reagent, in acetone, DCM or DMF, affords the ketone intermediates XII'. Step 3
[0102] Reaction of the ketone intermediates XII' with hydrazine hydrate, in the solvent such as DME, THF or dichloroethane, affords the indazole intermediates XIII'.
Step 4
[0103] Reaction of indazle XIII' with a haloacetate, such as ethyl bromoacetate in the presence of a base, such as sodium hydride, or sodium hydroxide, followed by treatment with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords intermediate XIV.
[0104] Intermediate indazole acid XX' may be prepared as shown in Scheme 4.
Scheme 4
Figure imgf000035_0001
Step 1
[0105] Reaction of the aldehyde X' with hydrazine hydrate, in the solvent such as DME, THF or dichloroethane, affords the indazole intermediates XV.
Step 2
[0106] Reaction of indazole intermediate XV with halogenation reagents, such as NBS, NCS, NIS, I2 or Br2, in DMF or THF, affords the halide XVI'.
Step 3
[0107] Reaction of the halide XVI' with acetic acid chloride or acetic anhydride, in the present of a base, such as DIPEA, TEA and so on, affords the intermediate XVII'.
Step 4
[0108] Reaction of the intermediate XVII' with the vinly coupling reagents, such as boric acid, organotin reagents, Grignard reagents or organozinc reagents, in the present of catalyst, such as palladium reagents, in the solvent such as THF, DMF or DME, affords the coupling product XVIII'. Step 5
[0109] Reaction of the intermediate XVIII' with boronic reagents, such as borane or 9- BBN, in the solvent such as THF, DME, followed by treatment with hydrogen peroxide in the presence of a base, such as sodium hydroxide, or potassium hydroxide, affords the product XIX'.
Step 6
[0110] Reaction of indazle XIX' with a haloacetate, such as ethyl bromoacetate in the presence of a base, such as sodium hydride, or sodium hydroxide, followed by treatment with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords intermediate XX'.
[0111] Intermediate azaindole acid XXV may be prepared as shown in Scheme 5.
Scheme 5
Figure imgf000036_0001
xxr xxir xxiir
Figure imgf000036_0002
(where A', B', C, D' = CH or N independently)
Step 1
[0112] Reaction of starting materials XXI' in non-protonic solvent, such as THF, Et20 or dioxane with strong base, such as n-BuLi, s-BuLi, t-BuLi, and then followed by addition of another reagent such as DMF, DMA or EtOAc, affords azaindole intermediate XXII'.
Step 2
[0113] Reaction of azaindole intermediate XXII' with halogenation reagents, such as NBS, NCS, NIS, I2 or Br2, in DMF or THF, affords the intermediate XXIII'.
Step 3
[0114] Reaction of the intermediate XXIII' with the coupling reagents, such as boric acid, organotin reagents, Grignard reagents or organozinc reagents, in the present of catalyst, such as palladium reagents, in the solvent such as THF, DMF or DME, affords the coupling product XXIV. Step 4
[0115] Reaction of indazle XXIV with a haloacetate, such as ethyl bromoacetate in the presence of a base, such as sodium hydride, or sodium hydroxide, followed by treatment with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords intermediate XXV.
[0116] Intermediate azaindole acid XXIX' may be prepared as shown in Scheme 6.
Scheme 6
Figure imgf000037_0001
Step 1
[0117] Reaction of azaindole XXII' with halide, such as bromoethane, iodomethane or isopropanyl bromide, in the present of a base, such as sodium hydride, or sodium hydroxide, affords the intermediate XXVI'.
Step 2
[0118] Reaction of intermediate XXII' with oxalic chloride in the present of base, such as TEA, DIPEA and so on, followed by quenching with alcohol, such as methanol or ethanol, affords the intermediate XXVII'.
Step 3
[0119] Reaction of intermediate XXII' with hydrogen in the present of catalyst, such as palladium on carbon, affords the intermediate XXVIII'.
Step 4
[0120] Hydrolysis the intermediate XXVIII' with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords azaindole acid XXIX'.
[0121] Intermediate benzoimidazole acid XXXIV may be prepared as shown in Scheme
7. Scheme 7
Figure imgf000038_0001
XXX' XXXI' XXXII'
Figure imgf000038_0002
(Where X = H or O)
Step 1
[0122] The nitrobenzene or aniline XXX' was treated by mixed acid such as concentrated sulfuric acid and concentrated nitric acid, affords the dinitro intermediates XXXI'.
Step 2
[0123] Reaction of substituted dinitro compounds XXXI' with Ranney nickel and hydrazine, or hydrogen and Pd/C in the alcohol, such as methanol, ethanol, affords substituted aniline XXXII'.
Step 3
[0124] Treatment of aniline XXXII' with carboxyl acid such as formic acid, acetic acid, or trifluoroacetic acid, affords the benzoimidazole intermediates XXXIII'.
Step 4
[0125] Reaction of the benzoimidazole XXXIII' with haloacetate, such as ethyl bromoacetate in the presence of a base, such as sodium hydride, or sodium hydroxide, followed by treatment with a base, such as lithium hydroxide, or sodium hydroxide, or potassium hydroxide, affords the benzoimidazole acid XXXIV.
[0126] Intermediate benzoimidazole acid XXXVIII' may be prepared as shown in
Scheme 8. Scheme 8
Figure imgf000039_0001
XXXII' XXXVI'
Figure imgf000039_0002
Step 1
[0127] Treatment of aniline XXXII' with CDI or triphosgene in the solvent such as THF, DME or DMF, affords the benzoimidazole intermediates XXXV'.
Step 2
[0128] Treatment of benzoimidazole intermediates XXXV' with chlorinated reagents such as POCl3 PCI5 or SOCl2, affords the intermediates XXXVI'.
Step 3
[0129] Reaction of the benzoimidazole XXXIII' with an haloacetate, such as ethyl bromoacetate in the presence of a base, such as sodium hydride, or sodium hydroxide, followed by treatment with diluted acid, such as diluted HCl, diluted H2S04, affords the benzoimidazole acid XXXIV.
Step 4
[0130] Reaction of benzoimidazole acid XXXIV with halide, such as bromoethane, iodomethane or isopropanyl bromide, in the present of a base, such as sodium hydride, or sodium hydroxide, affords the intermediate XXXVIII'.
[0131] Intermediate amine XLII' may be prepared as shown in Scheme 9.
Scheme 9
Figure imgf000039_0003
(where X, Y, Z = CH, CF or N independently) Step 1
[0132] Reaction of primary amine XXXIX' with aldehyde, such as paraformaldehyde, acetaldehyde and so on in the solvent of alcohol, followed by treatment with reductive reagents, such as NaBH4, NaBH3CN or NaBH3OAc, affords the secondary amine XL'.
Step 2
[0133] Reaction of the amine XL' and N-Boc-Phenylalanine analogs in the present of condensating agent, such as HOBT/EDCI, HATU, HBTU, PyBOP, BOPCl, BOP reagent and so on, and base such as TEA, DIPEA or DMAP, in the solvent such as DCM, DMF, THF and so on, affords the amide compounds XLI'.
Step 3
[0134] Treatment of the intermediates XLI' with HC1 solution such as HC1 in MeOH,
HC1 in THF and so on, affords the amine intermediates XLII'.
[0135] The compounds XLIV may be prepared as shown in Scheme 10.
Scheme 10
Figure imgf000040_0001
(where A', B', C, D', E', F', G', = CH or N independently)
Step 1
[0136] Reaction of the acid XLIII' and the amine XLII' in the present of coupling agent, such as HOBT/EDCI, HATU, HBTU, PyBOP, BOPCl, BOP and so on, and base such as TEA, DIPEA or DMAP, with the solvent such as DCM, DMF or THF, affords the amide compounds XLIV.
[0137] In addition, other compounds of formula I may be prepared by the procedures generally known to those skilled in the art. In particular, the following examples provide additional methods for preparing compounds of this invention.
[0138] The invention will now be further described by the working examples as below, which are preferred embodiments of the invention. These examples are illustrated rather than limiting, and it is to be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the claims appended hereto. Pharmaceutical Compositions
[0139] This invention also provides a pharmaceutical composition comprising at least one of the compounds as described herein or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable carrier.
[0140] The phrase "pharmaceutically-acceptable carrier" as used herein 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. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of 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; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
[0141] As set out above, certain embodiments of the present pharmaceutical agents may be provided in the form of pharmaceutically-acceptable salts. The term "pharmaceutically- acceptable salt", in this respect, 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. (See, for example, Berge et ah, (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19.) [0142] 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. For example, 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.
[0143] In other cases, 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. The term "pharmaceutically-acceptable salts" in these instances 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. 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,
diethanolamine, piperazine and the like. (See, for example, Berge et ah, supra.)
[0144] 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.
[0145] 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%.
[0146] 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. In general, 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.
[0147] 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.
[0148] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), 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;
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;
lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, 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.
[0149] 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.
[0150] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, 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. They 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. Examples of 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.
[0151] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, 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. Additionally, cyclodextrins, e.g., hydroxybutyl-.beta.-cyclodextrin, may be used to solubilize compounds.
[0152] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
[0153] 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.
[0154] 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.
[0155] Formulations of the present invention which are suitable for vaginal
administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be apbutriate.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such 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.
[0160] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. [0161] Pharmaceutical 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.
[0162] In some cases, 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.
[0163] 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.
[0164] When the compounds of the present invention are administered as
pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5%> to 90%>) of active ingredient in combination with a pharmaceutically acceptable carrier.
[0165] 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).
[0166] The compounds of the invention may be administered intravenously,
intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by other acceptable means. 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.
[0167] 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. 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
pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
Equivalents
[0168] The representative examples which follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art. The following examples contain important additional information, exemplification and guidance which can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
EXAMPLES
Example 1
[0169] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2,4,7-trimethyl-lH-indol-3- yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000047_0001
Example 1A. Preparation of 2,5-dimethylaniline
Figure imgf000048_0001
[0170] To a solution of 2,5-dimethyl nitrobenzene (5.0 g, 33.1 mmol, 1.0 eq) in methanol (50 mL), Ranney nickel (1.0 mL, suspension in water) was added, and the resulting mixture was cooled to 0 °C. Then hydrazine hydrate (2.0 mL, 53.1 mmol, 1.8 eq, 85% aqueous solution) was added dropwise, and the mixture was stirred at 0 °C for 2 hours until TLC indicated the SM had disappeared. Then the solid was filtrated off and the filtrate was concentrated, the residue was dissolved in ethyl acetate and washed with water, and brine, dried with anhydrous Na2S04 and evaporated the solvent to give the desired product 2,5- dimethylaniline (3.81 g, 31.5 mmol, yield: 95%). LC/MS: m/z M++l = 122.
Example IB. Preparation of 1 -(2, 5-dimethylphenyl)hydrazine
Figure imgf000048_0002
[0171] 2,5-Dimethylbenzenamine (20.0 g, 165 mmol, 1.0 eq) was dissolved in 50%> aqueous HC1 (180 mL) and cooled into 0 °C. The aqueous solution of NaN02 (1 1.4 g, 165 mmol, l .Oeq, 88 mL) was added dropwise. The temperature was closely monitored during the addition and was not allowed to exceed 5 °C. After addition, the bright orange solution was stirred at the same temperature for an additional 1 hour. Then the mixture of SnCl2 (46.8 g, 248 mmol, 1.5 eq) in concentrated HC1 (120 mL) was added to the reaction mixture at 0 °C over a period of 40 min. The mixture was then warmed to room temperature and stirred overnight. The solid was filtered, washed with water (150 mL). The filtrate was basified by NaOH solution at 0 °C and extracted by EtOAc (3 x 200 mL). The organic layer combined, concentrated to obtain the product (14 g, purity: 90%, yield: 64%). LC/MS: m/z M++l = 137. Example 1C. Preparation of ethyl 2-(2,4,7-trimethyl-lH-indol-3-yl)acetate
Figure imgf000048_0003
[0172] To a solution of l-(2,5-dimethylphenyl)hydrazine (2.0 g, 11.6 mmol, 1.0 eq) in DCM (11 mL), was added the saturated aq NaHC03 (11 mL) under vigorous stirring, then followed by addition of ethyl 4-oxopentanoate (1.68 g, 11.6 mmol, 1.Oeq). The mixture was stirred at room temperature for 3 hours until TLC (PE:EA=5: 1) was indicated the SM was disappeared. Then water was added, and the mixture was extracted by DCM (10 mL), washed with water several times. The organic extract was dried over anhydrous MgS04, concentrated to give a pale yellow oil. The residue was added to freshly dried ZnCl2 and heated to 140 °C overnight. Then water and MeOH (10 mL) were added, and the mixture was then extracted by DCM. After normal work-up, the crude product was purified by silica gel chromatography (PE: EA=15: 1) to give the solid (560mg, yield: 21.5%). LC/MS: m/z M++l = 246.
Example ID. Preparation of 2-(l-ethyl-2,4,7-trimethyl-lH-indol-3-yl)acetic acid
Figure imgf000049_0001
[0173] Ethyl 2-(2,4,7-trimethyl-lH-indol-3-yl)acetate (300 mg, 1.22 mmol, 1.0 eq) was dissolved in DMF (3 mL), then NaH (122 mg, 3.05 mmol, 2.5 eq) was added at room temperature. After 10 minutes, bromoethane (0.18 mL, 2.44 mmol, 2.0 eq) was added. The mixture was stirred at room temperature for 30 minutes until the SM had disappeared. H20 and aq NaOH (2M, 3 mL) solution were added at 0 °C subsequently. The mixture was stirred at 50 °C for 4 hours, and then HC1 was added to adjust to pH to 5. The precipitate was filtered, the solid was collected to give the product (210 mg, yield: 70%). LC/MS: m/z M++l = 246.
Example IE. Preparation of N-methylbenzor(iiri,31dioxol-5-amine
Figure imgf000049_0002
[0174] To a solution of Benzo[ ][l,3]dioxol-5-amine (2.1 g, 15.3 mmol, 1.0 eq) in THF (17 mL), BuLi (7.65 mL, 15.3 mmol) was added dropwise under nitrogen atmosphere over 20 minutes at 0 °C. After 10 minutes, Mel (0.95 mL,15.3 mmol, l .Oeq) was added slowly over 20 minutes at 0 °C. The reaction monitored by TLC (PE:EA=6: 1) until the SM had disappeared, then water was added to quench the reaction. The organic solvent was removed in vacuo. The product was extracted by EA(2x30 mL), washed with brine (3x40 mL) and purified by silica gel chromatography to give the product (950 mg, yield: 41.3%), LC/MS: m/z M++l = 152.
Example IF. Preparation of (6 -tert-butyll-(benzo[(i [l,31dioxol-5-yl(methyl)amino)-l-oxo- phenylpropan-2-ylcarbamate
Figure imgf000050_0001
[0175] To a mixture of (5)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (2.17 g, 8.18 mmol, 1.3 eq) and N-methylbenzo[d][l,3]dioxol-5-amine (950 mg, 6.29 mmol, 1.0 eq) in DMF (20 mL), were added EDCI (1.8 g, 9.43 mmol, 1.5eq), HOBt (1.7 g, 12.6 mmol, 2.0 eq) and DIPEA (1.62 g, 12.6 mmol, 2.0 eq). The resulting mixture was stirred at room temperature overnight. Water was added and the mixture was extracted by EA (2x25 mL), washed with LiCl aqueous solution (3x40 mL), and the organic layer was dried and concentrated. The residue was purified by silica gel chromatography column with PE and EA to give the product (2.2 g, yield: 88%), LC/MS: m/z M++l = 399.
Example 1G. Preparation of (6 -2-amino-N-(benzor(iiri,31dioxol-5-yl)-N-methyl-3- phenylpropanamide hydrochloride
Figure imgf000050_0002
[0176] (5)-tert-butyll -(benzo[<i] [ 1 ,3]dioxol-5-yl(methyl)amino)- 1 -oxo-3-phenylpropan- 2-ylcarbamate (2.2 g, 5.52 mmol, 1.0 eq) was dissolved in MeOH/HCl (1M, 6 mL), the mixture was stirred at room temperature for 1 hour until the TLC indicated the SM had disappeared. The solvent was removed under reduced pressure to give the product (2.2 g, yield: 98%), LC/MS: m/z M++l = 299. Example 1H. Preparation of (6 -N-(benzo[(i [l,31dioxol-5-yl)-2-(2-(l-ethyl-2,4,7-trimethyl- lH-indol-3-yl)acetamido)-N-methyl-3-phenylpropanamide
[0177] To a solution of (5)-2-amino-N-(benzo[ ] [ 1 ,3]dioxol-5-yl)-N-methyl-3- phenylpropanamide hydrochloride (73 mg, 0.245 mmol, 1.2 eq) in DCM (1.5 mL), were added 2-(l-ethyl-2,4,7-trimethyl-lH-indol-3-yl)acetic acid (50 mg, 0.2 mmol. 1.0 eq), EDCI (97 mg, 0.5 mmol, 2.5 eq), HOBt (55 mg, 0.4 lmg, 2.0 eq), and DMAP(5 mg). The mixture was stirred at room temperature overnight. The resulting solution was washed with water, NaHC03 and HCl solution subsequently, then the oil layer was concentrated under vacuum, the mixture was purified by prep-HPLC with MeOH and H20 to give the product (40 mg, yield: 50%). LC/MS: m/z M++l = 526, HPLC retention time = 3.43 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0178] 1H NMR (400 MHz, DMSO) δ 7.88 (d, J= 8.1 Hz, 1H), 7.21 - 7.12 (m, 3H), 6.92 (d, J= 8.3 Hz, 1H), 6.86 - 6.81 (m, 2H), 6.79 (s, 1H), 6.72 (d, J= 8.2 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 6.51 (d, J= 7.3 Hz, 1H), 6.06 (d, J= 4.5 Hz, 2H), 4.46 (s, 1H), 4.25 (q, J= 7.2 Hz, 2H), 3.59 (s, 2H), 3.08 (s, 3H), 2.84 (dd, J= 13.4, 4.5 Hz, 1H), 2.70 - 2.57 (m, 4H), 2.38 (s, 3H), 2.17 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H).
[0179] Compounds 2-76 were prepared using a method analogous to that of Example 1 utilizing corresponding acids and amines.
Examples 2 to 76
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
(S)-N-(6-methoxypyridin-3 - yl)-N-methyl-3-phenyl-2-(2-
54 (2,4,7-trimethyl- 1 -propyl- 527 3.45 lH-indol-3- yl)acetamido)propanamide
(S)-2-(2-(7-chloro- 1 -ethyl- 2,4-dimethyl- lH-indol-3- yl)acetamido)-N-(6-
55 533 3.49 methoxypyridin-3 -yl)-N- methyl-3- phenylpropanamide
(S)-2-(2-(7-chloro- 1 -ethyls- methyl- lH-indol-3- yl)acetamido)-N-(6-
56 519 3.38 methoxypyridin-3 -yl)-N- methyl-3- phenylpropanamide
(5)-N-(benzo[ ][l ,3]dioxol- 5-yl)-2-(2-(7-chl 1 -ethyl-
57 y :> oro- 2-methyl- lH-indol-3- 532 3.44 yl)acetamido)-N-methyl-3 - phenylpropanamide
(S)-2-(2-(l-isobutyl-2,4,7- trimethyl- lH-indol-3 - yl)acetamido)-N-(6-
58 541 2.56 methoxypyridin-3 -yl)-N- methyl-3- phenylpropanamide
(S)-2-(2-(7-chloro- 1 - ethyls- methyl- lH-indol-3-
59 yl)acetamido)-N-methyl-N- 503 3.85
Figure imgf000058_0001
(6-methylpyridin-3 -yl)-3 - phenylpropanamide
(S)-2-(2-(7-chloro- 1 -ethyl-2- methyl- lH-indol-3-
60 488 4.10 yl)acetamido)-N-methyl- N,3-diphenylpropanamide
(5)-N-(benzo[ ][l ,3]dioxol- 5-yl)-2-(2-(7-chloro- 1 -ethyl-
61 2,4-dimethyl- lH-indol-3- 546 3.57 yl)acetamido)-N-methyl-3 - phenylpropanamide
(S)-2-(2-(7-chloro - 1 -ethyl- 2,4-dimethyl- lH-indol-3-
62 502 3.63 yl)acetamido)-N-methyl- N,3-diphenylpropanamide
(R)-2-(2-(l-ethyl-2,7- dimethyl- lH-indol-3-
63 483 3.60 yl)acetamido)-N-methyl-N- (6-methylpyridin-3 -yl)-3 -
Figure imgf000059_0001
Figure imgf000060_0001
[0180] (Example 2): 1H NMR (400 MHz, DMSO) δ 8.46 (d, J= 7.9 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J= 8.9 Hz, 1H), 7.26 (ddd, J= 18.0, 14.8, 7.1 Hz, 7H), 7.18 - 7.08 (m, 3H), 6.99 (t, J= 7.7 Hz, 1H), 6.88 (t, J= 7.5 Hz, 3H), 6.81 (d, J= 8.7 Hz, 1H), 4.26 (s, 1H), 4.07 (t, J= 7.4 Hz, 2H), 3.83 (s, 3H), 3.44 (d, J= 20.4 Hz, 2H), 3.10 (s, 3H), 2.94 - 2.83 (m, 1H), 2.75 - 2.60 (m, 3H), 2.23 (s, 3H), 1.98 - 1.85 (m, 2H).
[0181] (Example 3): 1H NMR (400 MHz, DMSO) δ 8.49 (d, J= 7.7 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.32 (dd, J= 10.6, 8.1 Hz, 2H), 7.24 - 7.06 (m, 3H), 7.01 (t, J = 7.3 Hz, 1H), 6.96 - 6.55 (m, 4H), 4.25 (dd, J= 13.0, 9.0 Hz, 1H), 4.10 (q, J= 7.0 Hz, 2H), 3.84 (s, 3H), 3.62 - 3.39 (m, 2H), 3.11 (s, 3H), 2.88 (dd, J= 13.4, 4.7 Hz, 1H), 2.72 (dd, J = 13.5, 9.5 Hz, 1H), 2.27 (s, 3H), 1.18 (t, J= 7.1 Hz, 3H). [0182] (Example 4): 1H NMR (400 MHz, DMSO) δ 8.50 (d, J= 7.6 Hz, 1H), 8.05 (s, 1H), 7.49 (d, J= 9.0 Hz, 1H), 7.36 (d, J= 7.7 Hz, 1H), 7.34 - 7.22 (m, 4H), 7.21 - 7.08 (m, 3H), 6.94 (dt, J= 13.6, 8.8 Hz, 6H), 6.82 (d, J= 8.8 Hz, 1H), 5.35 (s, 2H), 4.29 (s, 1H), 3.84 (s, 3H), 3.58 - 3.43 (m, 2H), 3.11 (s, 3H), 2.95 - 2.85 (m, 1H), 2.71 (dd, J= 13.5, 9.7 Hz, 1H), 2.23 (s, 3H).
[0183] (Example 5): 1H NMR (400 MHz, DMSO) δ 8.51 (dd, J= 12.0, 6.3 Hz, 2H), 8.04 (s, 1H), 7.67 (dd, J= 9.4, 7.7 Hz, 1H), 7.49 (d, J= 7.0 Hz, 1H), 7.38 - 7.23 (m, 3H), 7.23 - 7.03 (m, 3H), 6.94 (dt, J= 29.9, 6.1 Hz, 4H), 6.79 (dd, J= 21.5, 8.4 Hz, 2H), 5.41 (s, 2H), 4.28 (d, J= 4.3 Hz, 1H), 3.84 (s, 3H), 3.49 (d, J= 20.7 Hz, 2H), 3.11 (s, 3H), 2.88 (dd, J = 13.4, 4.7 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.27 (s, 3H).
[0184] (Example 6): 1H NMR (400 MHz, CDC13) δ 8.44 (d, J= 5.6 Hz, 2H), 8.39 (d, J = 8.1 Hz, 1H), 7.46 - 7.33 (m, 4H), 7.27 (t, J= 8.0 Hz, 3H), 7.08 (d, J= 6.6 Hz, 3H), 6.99 (t, J = 7.4 Hz, 1H), 6.90 (dd, J= 17.2, 6.6 Hz, 3H), 6.78 (d, J= 5.6 Hz, 2H), 5.41 (s, 2H), 4.41 (s, 1H), 3.52 (s, 2H), 3.16 (s, 3H), 2.83 (d, J= 9.8 Hz, 1H), 2.73 - 2.62 (m, 1H), 2.19 (s, 3H).
[0185] (Example 7): 1H NMR (400 MHz, CDC13) δ 8.42 (d, J= 10.7 Hz, 2H), 8.31 (s, 1H), 7.40 (t, J= 8.9 Hz, 3H), 7.34 (d, J= 8.4 Hz, 2H), 7.28 (s, 4H), 7.09 (d, J= 6.9 Hz, 3H), 7.00 (t, J= 7.6 Hz, 1H), 6.90 (t, J= 7.4 Hz, 1H), 6.77 (d, J= 6.1 Hz, 2H), 5.41 (s, 2H), 4.40 (s, 1H), 3.54 (s, 2H), 3.16 (s, 3H), 2.82 (d, J= 9.1 Hz, 1H), 2.72 - 2.61 (m, 1H), 2.24 (s, 3H).
[0186] (Example 8): 1H NMR (400 MHz, CDC13) δ 8.52 (d, J= 4.7 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 7.66 (d, J= 7.7 Hz, 1H), 7.42 (d, J= 7.5 Hz, 3H), 7.29 (dt, J= 28.2, 9.8 Hz, 5H), 7.09 (d, J= 6.6 Hz, 3H), 6.98 (t, J= 7.6 Hz, 1H), 6.89 (t, J= 7.3 Hz, 1H), 6.77 (t, J = 7.0 Hz, 3H), 5.40 (s, 2H), 4.40 (s, 1H), 3.54 (s, 2H), 3.15 (s, 3H), 2.83 (d, J= 13.3 Hz, 1H), 2.67 (s, 1H), 2.25 (s, 3H).
[0187] (Example 9): 1H NMR (400 MHz, DMSO) δ 7.94 (d, J= 7.4 Hz, 1H), 7.43 (d, J = 7.3 Hz, 3H), 7.29 (d, J= 7.0 Hz, 2H), 7.13 (s, 3H), 6.72 (s, 2H), 6.62 (d, J= 7.0 Hz, 1H), 6.50 (d, J= 6.9 Hz, 1H), 4.44 (s, 1H), 4.25 (d, J= 7.0 Hz, 2H), 3.58 (s, 2H), 3.15 (s, 3H), 2.77 (s, 1H), 2.61 (s, 4H), 2.37 (s, 3H), 2.17 (s, 3H), 1.16 (t, J= 7.0 Hz, 3H).
[0188] (Example 10): 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.41 (d, J= 8.2 Hz, 3H), 7.28 (s, 4H), 7.13 (s, 3H), 6.99 (s, 1H), 6.87 (s, 1H), 6.79 (s, 2H), 4.38 (s, 1H), 4.22 (s, 2H), 3.53 (s, 2H), 3.46 (s, 2H), 3.17 (d, J= 11.5 Hz, 6H), 2.81 (s, 1H), 2.68 (s, 1H), 2.26 (s, 3H).
[0189] (Example 11): 1H NMR (400 MHz, DMSO) δ 8.35 (d, J= 7.7 Hz, 1H), 7.41 (d, J = 7.4 Hz, 3H), 7.34 - 7.25 (m, 5H), 7.22 (s, 4H), 7.09 (s, 3H), 6.98 (d, J= 7.9 Hz, 1H), 6.87 (d, J= 7.3 Hz, 1H), 6.76 (s, 2H), 4.37 (s, 1H), 4.06 (s, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.80 (s, 1H), 2.64 (d, J= 7.9 Hz, 3H), 2.21 (s, 3H), 1.89 (s, 2H).
[0190] (Example 12): 1H NMR (400 MHz, DMSO) δ 8.39 (d, J= 7.4 Hz, 1H), 7.40 (t, J = 9.1 Hz, 3H), 7.37 - 7.24 (m, 6H), 7.22 (d, J= 7.1 Hz, 1H), 7.09 (d, J= 6.5 Hz, 3H), 6.98 (t, J= 8.6 Hz, 3H), 6.90 (d, J= 7.7 Hz, 1H), 6.77 (d, J= 6.6 Hz, 2H), 5.35 (s, 2H), 4.40 (s, 1H), 3.51 (s, 2H), 3.15 (s, 3H), 2.83 (d, J= 13.6 Hz, 1H), 2.73 - 2.61 (m, 1H), 2.22 (s, 3H).
[0191] (Example 13): 1H NMR (400 MHz, DMSO) δ 8.39 (d, J= 7.6 Hz, 1H), 8.22 (s, 1H), 7.41 (d, J= 7.5 Hz, 3H), 7.29 (t, J= 8.0 Hz, 3H), 7.12 (s, 3H), 6.99 (d, J= 7.8 Hz, 1H), 6.88 (d, J= 7.5 Hz, 1H), 6.79 (s, 2H), 4.38 (s, 1H), 4.09 (d, J= 7.8 Hz, 2H), 3.50 (s, 2H), 3.15 (s, 3H), 2.81 (s, 1H), 2.67 (s, 1H), 2.26 (s, 3H), 1.04 (d, J= 6.5 Hz, 3H).
[0192] (Example 14): 1H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 7.41 (d, J= 7.7 Hz, 3H), 7.29 (d, J= 7.9 Hz, 3H), 7.12 (s, 3H), 7.01 (s, 1H), 6.87 (s, 1H), 6.79 (s, 2H), 4.37 (s, 1H), 3.60 (s, 3H), 3.45 (d, J= 16.8 Hz, 2H), 3.15 (s, 3H), 2.80 (s, 1H), 2.67 (s, 1H), 2.25 (s, 3H).
[0193] (Example 15): 1H NMR (400 MHz, DMSO) δ 7.93 (d, J= 8.1 Hz, 1H), 7.36 (dd, J= 59.7, 7.6 Hz, 5H), 7.14 (s, 3H), 6.73 (s, 2H), 6.59 (d, J= 6.9 Hz, 1H), 6.47 (d, J= 7.2 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.84 (s, 3H), 3.57 (s, 2H), 3.15 (s, 3H), 2.85 - 2.75 (m, 1H), 2.66 (s, 4H), 2.35 (s, 3H), 2.15 (s, 3H).
[0194] (Example 16): 1H NMR (400 MHz, DMSO) δ 8.47 (d, J= 7.5 Hz, 1H), 8.03 (s, 1H), 7.45 (s, 1H), 7.31 (dd, J= 14.6, 8.1 Hz, 2H), 7.16 (d, J = 3.5 Hz, 2H), 7.02 (t, J= 7.6 Hz, 1H), 6.87 (dd, J= 21.6, 13.6 Hz, 4H), 4.25 (s, 1H), 3.84 (s, 3H), 3.60 (s, 3H), 3.49 (d, J = 15.0 Hz, 2H), 3.10 (s, 3H), 2.90 (s, 1H), 2.73 (d, J= 7.7 Hz, 1H), 2.26 (s, 3H).
[0195] (Example 17): 1H NMR (400 MHz, DMSO) δ 8.10 - 7.95 (m, 2H), 7.46 (s, 1H), 7.25 - 7.11 (m, 3H), 6.84 (d, J= 8.8 Hz, 3H), 6.59 (d, J= 7.3 Hz, 1H), 6.48 (d, J= 7.1 Hz, 1H), 4.30 (s, 1H), 3.85 (d, J= 2.6 Hz, 6H), 3.58 (s, 2H), 3.10 (s, 3H), 2.91 - 2.79 (m, 1H), 2.68 (d, J= 20.4 Hz, 4H), 2.38 (s, 3H), 2.16 (s, 3H).
[0196] (Example 18): 1H NMR (400 MHz, DMSO) δ 8.49 (d, J= 7.7 Hz, 1H), 8.03 (s, 1H), 7.47 (d, J= 8.3 Hz, 1H), 7.31 (t, J= 7.4 Hz, 2H), 7.26 - 7.09 (m, 3H), 7.00 (t, J= 8.0 Hz, 1H), 6.89 (dd, J= 14.3, 6.5 Hz, 3H), 6.81 (d, J= 8.8 Hz, 1H), 4.23 (t, J= 5.5 Hz, 3H), 3.84 (s, 3H), 3.52 (dd, J= 19.8, 14.3 Hz, 4H), 3.19 (s, 3H), 3.11 (s, 3H), 2.88 (dd, J= 13.4, 5.0 Hz, 1H), 2.71 (dd, J= 13.8, 9.4 Hz, 1H), 2.27 (s, 3H).
[0197] (Example 19): 1H NMR (400 MHz, DMSO) δ 8.16 - 7.87 (m, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.24 - 7.09 (m, 3H), 6.85 (t, J= 6.3 Hz, 3H), 6.62 (d, J= 7.3 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 4.43 - 4.19 (m, 3H), 3.85 (s, 3H), 3.59 (s, 2H), 3.10 (s, 3H), 2.85 (dd, J = 13.6, 4.9 Hz, 1H), 2.77 - 2.56 (m, 4H), 2.42 (d, J= 23.9 Hz, 3H), 2.18 (s, 3H), 1.17 (t, J= 7.1 Hz, 3H).
[0198] (Example 20): 1H NMR (400 MHz, DMSO) δ 8.51 (d, J= 7.8 Hz, 1H), 8.48 - 8.39 (m, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.49 (d, J= 8.9 Hz, 1H), 7.42 - 7.31 (m, 2H), 7.28 (s, 2H), 7.14 (dd, J= 5.0, 1.9 Hz, 3H), 7.01 (t, J= 7.5 Hz, 1H), 6.91 (dd, J= 12.9, 7.6 Hz, 3H), 6.82 (d, J= 8.8 Hz, 1H), 5.42 (s, 2H), 4.41 - 4.21 (m, 1H), 3.84 (s, 3H), 3.49 (d, J = 21.1 Hz, 2H), 3.11 (s, 3H), 2.88 (dd, J= 13.4, 4.9 Hz, 1H), 2.71 (dd, J= 13.7, 9.7 Hz, 1H),
2.25 (s, 3H).
[0199] (Example 21): 1H NMR (400 MHz, DMSO) δ 8.50 (d, J= 7.8 Hz, 1H), 8.45 (d, J = 5.9 Hz, 2H), 8.05 (s, 1H), 7.50 (d, J= 7.0 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.27 (d, J= 8.0 Hz, 1H), 7.21 - 7.07 (m, 3H), 7.00 (t, J= 7.5 Hz, 1H), 6.96 - 6.77 (m, 6H), 5.42 (s, 2H), 4.39 - 4.20 (m, 1H), 3.85 (s, 3H), 3.53 (s, 2H), 3.11 (s, 3H), 2.88 (dd, J= 13.5, 4.6 Hz, 1H), 2.72 (dd, J= 13.3, 9.5 Hz, 1H), 2.20 (s, 3H).
[0200] (Example 22): 1H NMR (400 MHz, DMSO) δ 8.05 (s, 2H), 7.49 (d, J= 7.9 Hz, 1H), 7.27 (ddd, J= 22.9, 15.4, 7.3 Hz, 5H), 7.16 (dd, J= 11.5, 8.2 Hz, 3H), 7.01 - 6.67 (m, 3H), 6.59 (d, J= 7.3 Hz, 1H), 6.49 (d, J= 7.3 Hz, 1H), 4.31 (dd, J= 13.4, 8.9 Hz, 1H), 4.26 - 4.12 (m, 2H), 3.84 (s, 3H), 3.58 (s, 2H), 3.09 (s, 3H), 2.84 (dd, J= 13.8, 4.9 Hz, 1H), 2.73 - 2.61 (m, 3H), 2.46 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H), 1.80 (s, 2H).
[0201] (Example 23): 1H NMR (400 MHz, DMSO) δ 8.06 (d, J= 10.1 Hz, 2H), 7.48 (d, J= 7.3 Hz, 1H), 7.19 (t, J= 10.8 Hz, 3H), 6.84 (d, J= 8.7 Hz, 3H), 6.62 (d, J= 7.1 Hz, 1H), 6.51 (d, J= 7.2 Hz, 1H), 4.48 - 4.10 (m, 3H), 3.85 (s, 3H), 3.59 (s, 2H), 3.33 - 3.30 (m, 2H),
3.26 (s, 3H), 3.10 (s, 3H), 2.85 (dd, J= 13.5, 5.0 Hz, 1H), 2.74 - 2.64 (m, 1H), 2.60 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 1.75 (s, 2H).
[0202] (Example 24): 1H NMR (400 MHz, DMSO) δ 8.05 (d, J= 7.9 Hz, 2H), 7.48 (d, J = 7.4 Hz, 1H), 7.25 - 7.07 (m, 3H), 6.84 (dd, J= 9.1, 3.1 Hz, 3H), 6.62 (d, J= 7.3 Hz, 1H), 6.51 (d, J= 7.4 Hz, 1H), 4.41 (t, J= 6.0 Hz, 2H), 4.32 (dd, J= 12.9, 9.0 Hz, 1H), 3.85 (s, 3H), 3.59 (s, 2H), 3.50 (t, J= 6.0 Hz, 2H), 3.20 (s, 3H), 3.10 (s, 3H), 2.85 (dd, J= 13.7, 4.9 Hz, 1H), 2.67 (dd, J= 13.4, 9.2 Hz, 1H), 2.59 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H).
[0203] (Example 25): 1H NMR (400 MHz, DMSO) δ 8.46 (d, J= 5.6 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H), 7.49 (d, 1H), 7.14 (s, 3H), 6.82 (dd, J= 33.1, 7.1 Hz, 5H), 6.58 (dd, J= 15.0, 7.2 Hz, 2H), 5.58 (s, 2H), 4.45 - 4.29 (m, 1H), 3.86 (s, 3H), 3.67 (s, 2H), 3.11 (s, 3H), 2.93 - 2.79 (m, J= 9.0 Hz, 1H), 2.72 - 2.63 (m, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.10 (s, 3H).
[0204] (Example 26): 1H NMR (400 MHz, DMSO) δ 8.44 (d, J= 4.5 Hz, 1H), 8.09 (t, J = 13.6 Hz, 3H), 7.48 (s, 1H), 7.30 (dd, J= 7.9, 4.6 Hz, 1H), 7.26 - 7.11 (m, 3H), 7.06 (d, J = 8.1 Hz, IH), 6.86 (d, J= 8.7 Hz, 3H), 6.58 (dd, J= 17.3, 7.3 Hz, 2H), 5.60 (s, 2H), 4.36 (d, J = 4.1 Hz, IH), 3.86 (s, 3H), 3.66 (s, 2H), 3.1 1 (s, 3H), 2.86 (dd, J = 13.2, 5.2 Hz, IH), 2.69 (dd, J= 13.7, 9.1 Hz, IH), 2.55 (s, 3H), 2.43 (s, 3H), 2.39 (s, 3H), 2.12 (s, 3H).
[0205] (Example 27): 1H NMR (400 MHz, DMSO) δ 7.92 (d, J= 7.7 Hz, IH), 7.53 - 7.34 (m, 3H), 7.28 (d, J= 7.1 Hz, 2H), 7.13 (d, J= 6.2 Hz, 3H), 6.71 (d, J= 5.1 Hz, 2H), 6.62 (d, J= 7.3 Hz, IH), 6.51 (d, J= 7.2 Hz, 1H), 4.41 (t, J= 6.0 Hz, 3H), 3.58 (s, 2H), 3.50 (t, J = 6.0 Hz, 2H), 3.23 - 3.10 (m, 6H), 2.79 (d, J= 9.4 Hz, IH), 2.59 (s, 3H), 2.37 (s, 3H), 2.19 (s, 3H).
[0206] (Example 28): 1H NMR (400 MHz, DMSO) δ 7.91 (d, J= 7.9 Hz, IH), 7.41 (dd, J= 13.3, 7.1 Hz, 3H), 7.35 - 7.15 (m, 7H), 7.10 (s, 3H), 6.69 (s, 2H), 6.59 (d, J= 7.3 Hz, IH), 6.49 (d, J= 7.1 Hz, IH), 4.44 (s, IH), 4.26 - 4.08 (m, 2H), 3.57 (s, 2H), 3.14 (s, 3H),
2.77 (d, J= 9.4 Hz, IH), 2.64 (dt, J= 22.6, 10.4 Hz, 3H), 2.46 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.80 (s, 2H).
[0207] (Example 29): 1H NMR (400 MHz, DMSO) δ 7.92 (s, IH), 7.43 (d, J = 6.6 Hz, 2H), 7.29 (s, 2H), 7.13 (s, 3H), 6.72 (s, 2H), 6.60 (s, IH), 6.51 (s, IH), 4.43 (s, IH), 4.26 (s, 2H), 3.58 (s, 2H), 3.32 - 3.30 (m, 2H), 3.25 (s, 3H), 3.14 (s, 3H), 2.76 (s, IH), 2.60 (s, 4H), 2.36 (s, 3H), 2.16 (s, 3H), 1.73 (s, 2H).
[0208] (Example 30): 1H NMR (400 MHz, DMSO) δ 8.45 (d, J= 4.5 Hz, 2H), 7.93 (d, J = 7.6 Hz, IH), 7.43 (dd, J= 14.5, 7.2 Hz, 3H), 7.29 (d, J= 7.5 Hz, 2H), 7.09 (s, 3H), 6.90 - 6.66 (m, 4H), 6.58 (dd, J= 16.5, 7.4 Hz, 2H), 5.58 (s, 2H), 4.50 (s, IH), 3.66 (s, 2H), 3.15 (s, 3H), 2.79 (d, J= 8.8 Hz, IH), 2.70 - 2.60 (m, IH), 2.39 (d, J= 27.3 Hz, 6H), 2.09 (s, 3H).
[0209] (Example 31): 1H NMR (400 MHz, DMSO) δ 8.44 (s, IH), 8.10 (s, IH), 7.97 (d, J= 7.8 Hz, IH), 7.49 - 7.35 (m, 3H), 7.28 (d, J = 7.6 Hz, 3H), 7.08 (d, J= 14.6 Hz, 4H), 6.72 (s, 2H), 6.57 (dd, J= 18.6, 7.3 Hz, 2H), 5.59 (s, 2H), 4.47 (s, IH), 3.64 (s, 2H), 3.15 (s, 3H),
2.78 (s, IH), 2.64 (d, J= 9.9 Hz, IH), 2.39 (d, J= 7.4 Hz, 6H), 2.11 (s, 3H).
[0210] (Example 32): 1H NMR (400 MHz, DMSO) δ 8.55 (d, J= 4.8 Hz, IH), 7.90 (d, J = 7.6 Hz, IH), 7.65 (s, IH), 7.43 (dd, J = 14.5, 7.4 Hz, 3H), 7.29 (d, J = 7.2 Hz, 3H), 7.10 (s, 3H), 6.72 (s, 2H), 6.56 (dd, J= 16.7, 7.4 Hz, 2H), 6.41 (d, J= 7.8 Hz, IH), 5.60 (s, 2H), 4.49 (s, IH), 3.65 (s, 2H), 3.15 (s, 3H), 2.78 (s, IH), 2.64 (d, J= 8.9 Hz, IH), 2.39 (d, J= 16.0 Hz, 6H), 2.12 (s, 3H).
[0211] (Example 33): 1H NMR (400 MHz, DMSO) δ 8.55 (d, J= 4.4 Hz, IH), 8.05 (d, J = 7.5 Hz, 2H), 7.66 (t, J= 6.8 Hz, IH), 7.49 (d, J= 7.5 Hz, IH), 7.28 - 7.13 (m, 4H), 6.86 (d, J = 8.7 Hz, 3H), 6.56 (dd, J = 15.2, 7.2 Hz, 2H), 6.41 (d, J = 7.8 Hz, IH), 5.60 (s, 2H), 4.36 (d, J= 5.2 Hz, 1H), 3.86 (s, 3H), 3.66 (s, 2H), 3.10 (s, 3H), 2.85 (dd, J= 13.4, 4.7 Hz, 1H), 2.68 (dd, J= 13.2, 9.4 Hz, 1H), 2.43 (s, 3H), 2.37 (s, 3H), 2.13 (s, 3H).
[0212] (Example 34): 1H NMR (400 MHz, DMSO) δ 8.52 (d, J= 8.0 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 8.5 Hz, 2H), 7.21 - 7.12 (m, 3H), 7.00 (t, J= 7.7 Hz, 1H), 6.88 (dd, J= 14.4, 6.7 Hz, 3H), 6.81 (d, J= 8.8 Hz, 1H), 4.30 - 4.20 (m, 1H), 3.98 (d, J= 6.7 Hz, 2H), 3.84 (s, 3H), 3.53 - 3.41 (m, 2H), 3.11 (s, 3H), 2.88 (dd, J= 13.2, 4.8 Hz, 1H), 2.77 - 2.66 (m, 1H), 2.29 (s, 3H), 1.10 (dt, J= 12.2, 6.2 Hz, 1H), 0.47 - 0.39 (m, 2H), 0.37 - 0.30 (m, 2H).
[0213] (Example 35): 1H NMR (400 MHz, DMSO) δ 8.49 (d, J= 7.7 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J= 8.1 Hz, 1H), 7.31 (dd, J= 14.5, 8.0 Hz, 2H), 7.20 - 7.13 (m, 3H), 7.02 (t, J = 7.7 Hz, 1H), 6.89 (t, J= 7.3 Hz, 3H), 6.81 (d, J= 8.7 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.18 - 4.12 (m, 2H), 3.84 (s, 3H), 3.58 (s, 3H), 3.45 (dd, J= 34.7, 14.8 Hz, 5H), 3.11 (s, 3H), 2.88 (dd, J= 13.8, 5.0 Hz, 1H), 2.71 (dd, J= 13.6, 9.5 Hz, 1H), 2.47 (d, J= 7.1 Hz, 2H), 2.28 (s, 3H), 2.26 (s, 6H).
[0214] (Example 36): 1H NMR (400 MHz, DMSO) δ 8.47 (d, J= 7.8 Hz, 1H), 8.04 (s, 1H), 7.47 (d, J= 6.2 Hz, 1H), 7.32 (t, J= 8.4 Hz, 2H), 7.16 (s, 3H), 7.01 (t, J= 7.4 Hz, 1H), 6.88 (dd, J= 13.0, 5.3 Hz, 3H), 6.81 (d, J= 8.6 Hz, 1H), 4.26 (dd, J= 13.8, 7.3 Hz, 1H), 4.07 (t, J= 7.0 Hz, 2H), 3.84 (s, 3H), 3.52 - 3.42 (m, 3H), 3.10 (s, 3H), 2.88 (dd, J= 13.5, 4.9 Hz, 1H), 2.71 (dd, J= 13.5, 10.3 Hz, 1H), 2.28 (s, 3H), 2.20 (t, J= 6.4 Hz, 2H), 2.14 (s, 6H), 1.77 - 1.68 (m, 2H).
[0215] (Example 37): 1H NMR (400 MHz, DMSO) δ 8.47 (d, J= 7.9 Hz, 1H), 8.04 (s, 1H), 7.48 (d, J= 6.4 Hz, 1H), 7.31 (dd, J= 10.7, 8.2 Hz, 2H), 7.19 - 7.12 (m, 3H), 7.00 (t, J = 7.5 Hz, 1H), 6.89 (t, J= 6.3 Hz, 3H), 6.81 (d, J= 8.7 Hz, 1H), 4.26 (td, J= 9.2, 6.0 Hz, 1H), 4.06 (t, J= 7.1 Hz, 2H), 3.84 (s, 3H), 3.53 - 3.42 (m, 2H), 3.31 (t, J = 6.2 Hz, 2H), 3.20 (s, 3H), 3.11 (s, 3H), 2.88 (dd, J= 13.5, 4.9 Hz, 1H), 2.71 (dd, J= 13.3, 9.8 Hz, 1H), 2.26 (s, 3H), 1.66 - 1.58 (m, 2H), 1.50 (dt, J= 14.3, 7.0 Hz, 2H).
[0216] (Example 38): 1H NMR (400 MHz, DMSO) δ 8.46 (d, J= 5.7 Hz, 2H), 8.41 (d, J = 4.7 Hz, 1H), 8.04 (s, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.48 (dd, J= 9.2, 1.9 Hz, 1H), 7.34 - 7.26 (m, 3H), 7.15 - 7.10 (m, 3H), 7.00 (t, J= 7.5 Hz, 1H), 6.89 (t, J= 6.5 Hz, 3H), 6.81 (d, J = 8.8 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.11 - 4.06 (m, 2H), 3.83 (s, 3H), 3.52 - 3.41 (m, 9H), 3.10 (s, 3H), 2.87 (dd, J= 13.4, 4.7 Hz, 1H), 2.74 - 2.64 (m, 3H), 2.24 (s, 3H), 1.95 - 1.87 (m, 2H).
[0217] (Example 39): 1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 8.11 - 8.04 (m, 1H), 7.48 (d, J= 8.5 Hz, 1H), 7.21 - 7.14 (m, 3H), 6.84 (d, J= 8.8 Hz, 3H), 6.63 (d, J= 7.3 Hz, 1H), 6.52 (d, J= 7.1 Hz, 1H), 4.39 - 4.29 (m, 3H), 3.85 (s, 3H), 3.59 (s, 4H), 3.10 (s, 3H), 2.85 (dd, J= 13.7, 5.1 Hz, 1H), 2.72 - 2.66 (m, 1H), 2.63 (s, 3H), 2.39 (s, 3H), 2.33 (s, 6H),
2.21 (s, 3H).
[0218] (Example 40): 1H NMR (400 MHz, DMSO) δ 8.46 (d, J= 7.6 Hz, 1H), 8.04 (s, 1H), 7.47 (d, J= 7.8 Hz, 1H), 7.31 (dd, J= 11.8, 7.9 Hz, 2H), 7.19 - 7.13 (m, 3H), 7.00 (t, J = 7.4 Hz, 1H), 6.89 (dd, J= 14.0, 6.8 Hz, 3H), 6.81 (d, J= 8.8 Hz, 1H), 4.88 (s, 1H), 4.29 -
4.22 (m, 1H), 4.11 (t, J = 5.9 Hz, 2H), 3.84 (s, 3H), 3.60 (s, 2H), 3.51 - 3.42 (m, 2H), 3.10 (s, 3H), 2.88 (dd, J= 13.5, 4.8 Hz, 1H), 2.72 (dd, J= 13.6, 9.5 Hz, 1H), 2.28 (s, 3H).
[0219] (Example 41): 1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 8.10 (d, J= 7.7 Hz, 1H), 7.48 (d, J= 8.6 Hz, 1H), 7.19 - 7.17 (m, 3H), 6.85 (dd, J= 11.4, 7.6 Hz, 4H), 6.63 (d, J = 7.1 Hz, 1H), 6.52 (d, J= 7.1 Hz, 1H), 4.35 - 4.30 (m, 1H), 4.25 - 4.20 (m, 2H), 3.85 (s, 3H), 3.60 (s, 2H), 3.10 (s, 3H), 2.88 - 2.83 (m, 1H), 2.71 - 2.60 (m, 6H), 2.40 (d, J= 13.2 Hz, 9H), 2.20 (s, 3H), 1.79 - 1.73 (m, 2H).
[0220] (Example 42): 1H NMR (400 MHz, CDC13) δ 8.11 - 7.96 (m, 2H), 7.48 (s, 1H), 7.18 (s, 3H), 6.84 (d, J= 8.4 Hz, 3H), 6.61 (d, J= 7.1 Hz, 1H), 6.51 (d, J= 6.9 Hz, 1H), 4.97 (s, 1H), 4.30 (s, 3H), 3.85 (s, 3H), 3.63 - 3.50 (m, 4H), 3.10 (s, 3H), 2.84 (d, J= 9.1 Hz, 1H), 2.73 - 2.63 (m, 1H), 2.61 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H).
[0221] (Example 43): 1H NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 8.43 (d, J= 4.9 Hz, 1H), 8.08 - 8.00 (m, 2H), 7.69 (d, J= 7.8 Hz, 1H), 7.48 (d, J= 5.2 Hz, 1H), 7.33 (dd, J= 7.6, 4.8 Hz, 1H), 7.20 - 7.11 (m, 3H), 6.84 (d, J= 8.8 Hz, 3H), 6.60 (d, J= 7.4 Hz, 1H), 6.50 (d, J = 7.2 Hz, 1H), 4.31 (dt, J= 12.5, 6.8 Hz, 1H), 4.20 (dd, J= 9.2, 7.1 Hz, 2H), 3.84 (s, 3H), 3.58 (s, 2H), 3.09 (s, 3H), 2.83 (dd, J= 12.8, 4.1 Hz, 1H), 2.68 (dd, J= 19.3, 12.4 Hz, 3H), 2.47 (s, 3H), 2.38 (s, 3H), 2.13 (s, 3H), 1.87 - 1.77 (m, 2H).
[0222] (Example 44): 1H NMR (400 MHz, DMSO) δ 8.41 (d, J= 7.6 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.30 (dd, J= 16.6, 8.0 Hz, 4H), 7.12 (d, J= 3.5 Hz, 3H), 6.99 (t, J= 7.3 Hz, 1H), 6.86 (t, J= 7.2 Hz, 1H), 6.81 - 6.74 (m, 2H), 4.40 - 4.34 (m, 1H), 3.97 (d, J= 6.9 Hz, 2H), 3.55 - 3.47 (m, 4H), 3.15 (s, 3H), 2.82 (dd, J= 14.8, 3.9 Hz, 1H), 2.68 (dd, J= 7.0, 5.0 Hz, 1H), 2.28 (s, 3H), 1.13 - 1.05 (m, 1H), 0.47 - 0.40 (m, 2H), 0.36 - 0.31 (m, 2H).
[0223] (Example 45): 1H NMR (400 MHz, CDC13) δ 7.94 (d, J= 7.8 Hz, 1H), 7.48 - 7.37 (m, 3H), 7.29 (d, J= 7.5 Hz, 2H), 7.12 (d, J= 5.2 Hz, 3H), 6.71 (d, J= 7.2 Hz, 2H), 6.63 (d, J= 7.0 Hz, 1H), 6.51 (d, J= 7.1 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.22 (dd, J= 10.1, 4.2 Hz, 2H), 3.59 (s, 2H), 3.15 (s, 3H), 2.79 (dd, J= 8.6, 7.7 Hz, 1H), 2.65 (s, 3H), 2.59 (dd, J= 9.4, 2.0 Hz, lH), 2.37 (s, 3H), 2.17 (s, 3H), 1.05 - 0.95 (m, 1H), 0.41 (d, J= 8.3 Hz, 2H), 0.20 (d, J= 3.9 Hz, 2H). [0224] (Example 46): 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.41 (d, J= 4.1 Hz, 1H), 8.34 (d, J= 7.7 Hz, 1H), 7.64 (d, J= 7.7 Hz, 1H), 7.45 - 7.34 (m, 3H), 7.29 (dt, J = 13.4, 6.1 Hz, 5H), 7.12 - 7.04 (m, 3H), 7.00 (t, J= 7.9 Hz, 1H), 6.87 (t, J= 7.5 Hz, 1H), 6.79 - 6.73 (m, 2H), 4.41 - 4.33 (m, 1H), 4.08 (t, J= 7.1 Hz, 2H), 3.60 (s, 2H), 3.15 (s, 3H), 2.81 (dd, J= 13.6, 4.6 Hz, 1H), 2.66 (dd, J= 14.7, 7.1 Hz, 3H), 2.23 (s, 3H), 1.95 - 1.85 (m, 2H).
[0225] (Example 47): 1H NMR (400 MHz, DMSO) δ 8.39 (d, J= 8.1 Hz, 1H), 7.45 -
7.34 (m, 3H), 7.29 (t, J= 8.3 Hz, 4H), 7.12 (dd, J= 4.9, 1.5 Hz, 3H), 7.01 (t, J= 7.5 Hz, 1H), 6.87 (t, J= 7.4 Hz, 1H), 6.80 - 6.73 (m, 2H), 4.41 - 4.33 (m, 1H), 4.13 (t, J= 7.2 Hz, 2H), 3.56 (s, 2H), 3.15 (s, 3H), 2.82 (dd, J= 13.5, 3.8 Hz, 1H), 2.70 - 2.63 (m, 1H), 2.44 (t, J = 7.1 Hz, 2H), 2.27 (s, 3H), 2.22 (s, 6H).
[0226] (Example 48): 1H NMR (400 MHz, DMSO) δ 7.95 (d, J = 8.1 Hz, 1H), 7.48 - 7.37 (m, 3H), 7.29 (d, J= 7.5 Hz, 2H), 7.13 (d, J= 4.8 Hz, 3H), 6.75 - 6.68 (m, 2H), 6.62 (d, J= 7.3 Hz, 1H), 6.51 (d, J= 7.6 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.31 (dd, J = 9.4, 6.5 Hz, 2H), 3.58 (s, 2H), 3.15 (s, 3H), 2.79 (dd, J= 13.8, 4.6 Hz, 1H), 2.62 (s, 4H), 2.37 (s, 5H), 2.24 (s, 6H), 2.18 (s, 3H).
[0227] (Example 49): 1H NMR (400 MHz, DMSO) δ 8.37 (d, J= 7.7 Hz, 1H), 7.44 -
7.35 (m, 3H), 7.29 (t, J= 8.1 Hz, 4H), 7.11 (d, J= 3.5 Hz, 3H), 7.00 (t, J= 7.5 Hz, 1H), 6.86 (t, J= 7.6 Hz, 1H), 6.80 - 6.75 (m, 2H), 4.41 - 4.34 (m, 1H), 4.06 (t, J= 7.1 Hz, 2H), 3.50 - 3.42 (m, 2H), 3.30 (t, J= 6.3 Hz, 3H), 3.20 (s, 3H), 3.15 (s, 3H), 2.82 (dd, J= 15.3, 6.0 Hz, 1H), 2.71 - 2.62 (m, 1H), 2.25 (s, 3H), 1.66 - 1.56 (m, 2H), 1.54 - 1.45 (m, 2H).
[0228] (Example 50): 1H NMR (400 MHz, DMSO) δ 7.89 (d, J= 7.9 Hz, 1H), 7.48 - 7.37 (m, 3H), 7.30 (d, J= 7.0 Hz, 2H), 7.12 (d, J= 5.5 Hz, 3H), 6.74 - 6.66 (m, 2H), 6.61 (d, J= 7.4 Hz, 1H), 6.50 (d, J= 7.1 Hz, 1H), 4.96 (t, J= 5.4 Hz, 1H), 4.49 - 4.38 (m, 1H), 4.29 (dd, J= 7.4, 5.2 Hz, 2H), 3.63 - 3.47 (m, 4H), 3.15 (s, 3H), 2.78 (dd, J= 12.8, 4.4 Hz, 1H), 2.60 (s, 4H), 2.37 (s, 3H), 2.18 (s, 3H).
[0229] (Example 51): 1H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 8.43 (d, J= 3.7 Hz, 1H), 7.92 (d, J= 7.7 Hz, 1H), 7.69 (d, J= 7.8 Hz, 1H), 7.48 - 7.36 (m, 3H), 7.36 - 7.24 (m, 3H), 7.13 - 7.03 (m, 3H), 6.70 (dd, J= 6.8, 3.4 Hz, 2H), 6.60 (d, J= 7.4 Hz, 1H), 6.49 (d, J = 7.4 Hz, 1H), 4.43 (ddd, J= 11.6, 7.4, 3.9 Hz, 1H), 4.24 - 4.16 (m, 2H), 3.57 (s, 2H), 3.14 (s, 3H), 2.81 - 2.73 (m, 1H), 2.69 (t, J= 7.4 Hz, 2H), 2.65 - 2.56 (m, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 2.12 (s, 3H), 1.87 - 1.77 (m, 2H).
[0230] (Example 52): 1H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.06 (d, J= 7.7 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J= 8.5 Hz, 1H), 7.18 (s, 3H), 6.83 (s, 2H), 6.63 (d, J= 7.2 Hz, 1H), 6.52 (d, J= 7.2 Hz, 1H), 4.35 - 4.19 (m, 3H), 3.60 (s, 2H), 3.12 (s, 3H), 2.84 (d, J= 8.5 Hz, IH), 2.68 (s, IH), 2.62 (s, 3H), 2.48 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 1.18 (t, J= 7.0 Hz, 3H).
[0231] (Example 53): 1H NMR (400 MHz, DMSO) δ 8.06 (d, J= 7.4 Hz, 2H), 7.48 (s, IH), 7.22 - 7.15 (m, 3H), 6.85 (d, J= 8.5 Hz, 3H), 6.62 (d, J= 7.5 Hz, IH), 6.51 (d, J= 7.0 Hz, IH), 4.32 (s, IH), 4.26 - 4.12 (m, 2H), 3.86 (s, 3H), 3.60 (s, 2H), 3.11 (s, 3H), 2.85 (d, J = 8.3 Hz, 1H), 2.68 (t, J= 11.4 Hz, IH), 2.60 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 1.51 (s, 2H), 1.35 (dd, J= 14.8, 7.3 Hz, 2H), 0.93 (t, J= 7.2 Hz, 3H).
[0232] (Example 54): 1H NMR (400 MHz, DMSO) δ 8.06 (d, J= 7.6 Hz, 2H), 7.49 (d, J = 8.0 Hz, IH), 7.22 - 7.14 (m, 3H), 6.85 (d, J= 8.5 Hz, 3H), 6.62 (d, J= 7.4 Hz, IH), 6.51 (d, J= 7.3 Hz, IH), 4.33 (dd, J= 13.7, 8.7 Hz, IH), 4.19 - 4.07 (m, 2H), 3.86 (s, 3H), 3.60 (s, 2H), 3.11 (s, 3H), 2.85 (dd, J= 13.5, 5.0 Hz, IH), 2.68 (dd, J= 13.6, 9.2 Hz, IH), 2.60 (s, 3H), 2.39 (s, 3H), 2.19 (s, 3H), 1.55 (dd, J= 15.6, 7.8 Hz, 2H), 0.90 (t, J= 7.3 Hz, 3H).
[0233] (Example 55): 1H NMR (400 MHz, CDC13) δ 8.27 (d, J= 7.6 Hz, IH), 8.06 (s, IH), 7.50 (d, J= 7.2 Hz, IH), 7.23 - 7.14 (m, 3H), 6.95 - 6.81 (m, 4H), 6.63 (d, J= 7.9 Hz, IH), 4.45 (q, J= 7.3 Hz, 2H), 4.33 (dd, J= 13.0, 9.0 Hz, IH), 3.86 (s, 3H), 3.69 - 3.55 (m, 2H), 3.12 (s, 3H), 2.88 (dd, J= 13.6, 4.9 Hz, IH), 2.71 (dd, J= 13.4, 9.3 Hz, IH), 2.43 (s, 3H), 2.22 (s, 3H), 1.24 (t, J= 7.0 Hz, 3H).
[0234] (Example 56): 1H NMR (400 MHz, DMSO) δ 8.55 (d, J= 7.8 Hz, IH), 8.05 (d, J = 2.0 Hz, IH), 7.49 (d, J= 8.7 Hz, IH), 7.30 (d, J= 7.6 Hz, IH), 7.20 - 7.12 (m, 3H), 7.02 (d, J= 7.4 Hz, IH), 6.87 (ddd, J= 20.7, 9.9, 6.2 Hz, 4H), 4.42 (q, J= 6.9 Hz, 2H), 4.26 (td, J = 9.3, 4.7 Hz, IH), 3.84 (s, 3H), 3.46 (dd, J= 31.1, 15.1 Hz, 2H), 3.11 (s, 3H), 2.96 - 2.83 (m, IH), 2.71 (dd, J= 13.5, 9.6 Hz, IH), 2.28 (s, 3H), 1.24 (t, J= 7.0 Hz, 3H).
[0235] (Example 57): 1H NMR (400 MHz, DMSO) δ 8.49 (d, J= 7.8 Hz, IH), 7.33 (d, J = 7.2 Hz, IH), 7.25 - 7.16 (m, 3H), 7.06 (d, J= 6.9 Hz, IH), 6.92 (ddd, J= 17.4, 13.6, 7.9 Hz, 4H), 6.84 (s, IH), 6.81 - 6.73 (m, IH), 6.09 (d, J= 7.2 Hz, 2H), 4.55 - 4.34 (m, 3H), 3.53 (t, J= 10.3 Hz, IH), 3.13 (s, 3H), 2.92 (dd, J= 13.5, 4.2 Hz, IH), 2.73 (dd, J= 13.4, 10.0 Hz, 1H), 2.31 (s, 3H), 1.28 (t, J= 7.0 Hz, 3H).
[0236] (Example 58): 1H NMR (400 MHz, DMSO) δ 8.03 (s, IH), 7.97 (d, J= 7.5 Hz, IH), 7.47 (s, IH), 7.22 - 7.14 (m, 3H), 6.85 (d, J= 8.8 Hz, 3H), 6.63 (d, J= 7.6 Hz, IH), 6.53 (d, J= 7.2 Hz, IH), 4.34 (s, IH), 4.05 (s, 2H), 3.86 (s, 3H), 3.61 (s, 2H), 3.10 (s, 3H), 2.90 - 2.79 (m, IH), 2.70 - 2.61 (m, 2H), 2.57 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H), 1.85 (s, IH), 0.78 (t, J = 6.3 Hz, 6H).
[0237] (Example 59): 1H NMR (400 MHz, CDC13) δ 7.87 (s, IH), 7.27 (d, J= 7.1 Hz, IH), 7.23 - 7.07 (m, 6H), 6.97 (t, J= 7.7 Hz, IH), 6.73 (d, J= 7.1 Hz, 2H), 6.07 (d, J= 8.2 Hz, 1H), 4.66 - 4.44 (m, 3H), 3.65 - 3.50 (m, 2H), 3.13 (s, 3H), 2.72 (dd, J= 13.2, 7.9 Hz, 1H), 2.63 - 2.48 (m, 4H), 2.30 (s, 3H), 1.38 (t, J= 7.1 Hz, 3H).
[0238] (Example 60): 1H NMR (400 MHz, CDC13) δ 7.36 (q, J = 6.1 Hz, 3H), 7.24 (s, 1H), 7.13 (d, J= 7.7 Hz, 2H), 7.05 (t, J= 7.4 Hz, 2H), 6.96 (t, J= 7.7 Hz, 3H), 6.62 (d, J = 7.3 Hz, 2H), 6.07 (d, J= 8.5 Hz, 1H), 4.76 (dd, J= 15.1, 7.2 Hz, 1H), 4.60 - 4.45 (m, 2H), 3.57 (q, J= 17.3 Hz, 2H), 3.18 (s, 3H), 2.71 (dd, J= 13.4, 6.7 Hz, 1H), 2.50 (dd, J= 13.3, 7.3 Hz, 1H), 2.28 (s, 3H), 1.37 (t, J= 7.1 Hz, 3H).
[0239] (Example 61): 1H NMR (400 MHz, CDC13) δ 8.10 (d, J= 7.3 Hz, 1H), 7.17 (s, 3H), 6.96 - 6.88 (m, 2H), 6.85 (d, J= 7.3 Hz, 2H), 6.80 (s, 1H), 6.73 (d, J= 7.5 Hz, 1H), 6.62 (d, J= 7.8 Hz, 1H), 6.06 (d, J= 4.6 Hz, 2H), 4.44 (d, J= 7.1 Hz, 3H), 3.61 (s, 2H), 3.09 (s, 3H), 2.86 (d, J= 13.6 Hz, 1H), 2.67 (t, J= 11.7 Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H), 1.23 (t, J= 7.0 Hz, 3H).
[0240] (Example 62): 1H NMR (400 MHz, CDC13) δ 8.11 (d, J= 7.8 Hz, 1H), 7.42 (dd, J = 13.4, 7.5 Hz, 3H), 7.29 (d, J= 7.1 Hz, 2H), 7.13 (s, 3H), 6.90 (d, J= 7.7 Hz, 1H), 6.73 (d, J = 3.6 Hz, 2H), 6.62 (d, J= 7.6 Hz, 1H), 4.44 (d, J= 7.0 Hz, 3H), 3.61 (s, 2H), 3.15 (s, 3H), 2.81 (d, J= 13.7 Hz, 1H), 2.71 - 2.57 (m, 1H), 2.39 (s, 3H), 2.20 (s, 3H), 1.23 (t, J= 7.0 Hz, 3H).
[0241] (Example 63): 1H NMR (400 MHz, DMSO) δ 8.39 (d, J= 7.8 Hz, 1H), 8.26 (s, 1H), 7.44 (d, J= 8.1 Hz, 1H), 7.29 - 7.12 (m, 5H), 6.87 (d, J= 3.2 Hz, 2H), 6.80 - 6.72 (m, 2H), 4.24 (t, J= 6.5 Hz, 3H), 3.52 - 3.39 (m, 2H), 3.12 (s, 3H), 2.87 (dd, J= 13.5, 4.8 Hz, 1H), 2.75 - 2.66 (m, 1H), 2.64 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 1.19 (t, J= 7.1 Hz, 3H).
[0242] (Example 64): 1H NMR (400 MHz, DMSO) δ 8.41 (d, J= 7.4 Hz, 1H), 8.03 (s, 1H), 7.47 (d, J= 7.4 Hz, 1H), 7.17 (s, 4H), 6.91 (s, 2H), 6.85 - 6.69 (m, 3H), 4.25 (d, J= 7.0 Hz, 3H), 3.84 (s, 3H), 3.51 - 3.39 (m, 2H), 3.10 (s, 3H), 2.93 - 2.82 (m, 1H), 2.72 (d, J= 9.5 Hz, 1H), 2.64 (s, 3H), 2.25 (s, 3H), 1.19 (t, J= 6.9 Hz, 3H).
[0243] (Example 65): 1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 4.7 Hz, 4H), 6.90 (d, J= 7.1 Hz, 3H), 6.84 - 6.67 (m, 4H), 6.05 (d, J= 8.7 Hz, 2H), 4.37 (s, 1H), 4.25 (d, J= 7.2 Hz, 2H), 3.52 - 3.39 (m, 2H), 3.09 (s, 3H), 2.87 (d, J= 9.0 Hz, 1H), 2.70 (d, J= 10.1 Hz, 1H), 2.64 (s, 3H), 2.24 (s, 3H), 1.19 (t, J= 7.0 Hz, 3H).
[0244] (Example 66): 1H NMR (400 MHz, DMSO) δ 8.40 (d, J= 7.8 Hz, 1H), 7.32 (dd, J= 8.7, 4.6 Hz, 1H), 7.21 (dd, J= 10.2, 2.3 Hz, 1H), 7.13 (d, J= 3.5 Hz, 3H), 6.94 - 6.86 (m, 3H), 6.83 (dd, J= 8.9, 1.8 Hz, 1H), 6.78 (s, 1H), 6.71 (d, J= 8.4 Hz, 1H), 6.05 (d, J= 7.9 Hz, 2H), 4.37 (s, 1H), 4.10 (d, J= 7.0 Hz, 2H), 3.47 (d, J= 14.8 Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J = 14.5, 5.5 Hz, 1H), 2.69 (dd, J= 13.2, 9.6 Hz, 1H), 2.27 (s, J= 67.4 Hz, 3H), 1.18 (t, J= 7.0 Hz, 3H).
[0245] (Example 67): 1H NMR (400 MHz, DMSO) δ 8.38 (d, J= 7.9 Hz, 1H), 7.30 (dd, J= 8.7, 4.5 Hz, 1H), 7.19 (dd, J= 10.2, 2.6 Hz, 1H), 7.17 - 7.10 (m, 3H), 6.90 (dd, J= 7.7, 3.4 Hz, 3H), 6.86 - 6.80 (m, 1H), 6.77 (s, 1H), 6.71 (d, J= 8.3 Hz, 1H), 6.05 (d, J= 7.4 Hz, 2H), 4.87 (t, J= 5.4 Hz, 1H), 4.37 (s, 1H), 4.11 (t, J= 5.7 Hz, 2H), 3.63 - 3.56 (m, 2H), 3.46 (d, J= 14.7 Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J= 13.3, 4.4 Hz, 1H), 2.68 (dd, J= 13.5, 12.1 Hz, 1H), 2.27 (s, 3H).
[0246] (Example 68): 1H NMR (400 MHz, DMSO) δ 8.27 (dd, J= 13.7, 7.4 Hz, 1H), 7.16 (d, J= 3.8 Hz, 4H), 6.93 - 6.86 (m, 3H), 6.80 - 6.65 (m, 4H), 6.05 (d, J= 8.2 Hz, 2H), 4.38 (dd, J= 10.4, 4.3 Hz, 2H), 4.29 (t, J= 5.1 Hz, 1H), 3.63 - 3.54 (m, 2H), 3.45 (d, J= 1.7 Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J= 14.9, 6.6 Hz, 1H), 2.69 (dd, J= 8.2, 6.4 Hz, 1H), 2.63 (d, J = 1.7 Hz, 3H), 2.26 (d, J = 4.2 Hz, 3H).
[0247] (Example 69): 1H NMR (400 MHz, CDC13) δ 7.41 (d, J= 7.8 Hz, 1H), 7.25 (s, 1H), 7.21 - 7.13 (m, 2H), 7.10 (t, J= 7.2 Hz, 3H), 6.74 (dd, J= 14.9, 7.6 Hz, 3H), 6.16 (d, J = 8.2 Hz, 1H), 6.01 (s, 2H), 5.94 (tdd, J= 14.9, 10.2, 4.6 Hz, 1H), 5.12 (dd, J= 10.3, 1.1 Hz, 1H), 4.83 - 4.67 (m, 4H), 3.71 - 3.56 (m, 2H), 3.09 (s, 3H), 2.74 (dd, J= 13.2, 7.5 Hz, 1H), 2.58 (dd, J= 13.2, 6.7 Hz, 1H), 2.28 (s, 3H).
[0248] (Example 70): 1H NMR (400 MHz, CDC13) δ 7.35 (d, J= 7.1 Hz, 1H), 7.25 - 7.16 (m, 3H), 7.17 - 7.12 (m, 2H), 7.10 (d, J= 3.6 Hz, 1H), 7.07 (d, J= 7.7 Hz, 1H), 6.81 - 6.74 (m, 3H), 6.23 (d, J= 8.6 Hz, 1H), 6.04 (s, 2H), 5.60 (d, J= 26.2 Hz, 2H), 5.19 (s, 2H), 4.82 (dd, J= 14.7, 6.9 Hz, 1H), 3.61 (d, J= 9.9 Hz, 2H), 3.10 (s, J= 6.1 Hz, 3H), 2.78 (dd, J = 13.5, 7.0 Hz, 1H), 2.63 (dd, J= 13.4, 6.6 Hz, 1H), 2.28 (s, 3H).
[0249] (Example 71): 1H NMR (400 MHz, DMSO) δ 7.47 - 7.39 (m, 1H), 7.37 - 7.30 (m, 1H), 7.24 - 7.07 (m, 5H), 6.87 - 6.77 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.51 - 6.29 (m, 2H), 6.02 (t, J= 4.2 Hz, 2H), 4.81 (dt, J= 13.9, 7.0 Hz, 1H), 4.24 - 4.11 (m, 2H), 4.07 - 3.89 (m, 1H), 3.67 - 3.60 (m, 2H), 3.60 - 3.28 (m, 2H), 3.07 (d, J= 3.8 Hz, 3H), 2.83 - 2.57 (m, 2H), 2.32 (d, J= 3.3 Hz, 3H).
[0250] (Example 72): 1H NMR (400 MHz, CDC13) δ 7.33 (dd, J= 7.8, 1.0 Hz, 1H), 7.23 - 7.10 (m, 4H), 7.04 (t, J= 7.7 Hz, 1H), 6.84 - 6.78 (m, 2H), 6.73 (d, J= 8.2 Hz, 1H), 6.22 (d, J= 8.5 Hz, 1H), 6.03 (s, 2H), 4.86 - 4.56 (m, 3H), 3.97 (t, J= 5.0 Hz, 2H), 3.59 (d, J = 17.6 Hz, 2H), 3.06 (s, 3H), 2.73 (dd, J= 13.3, 7.7 Hz, 1H), 2.62 (dd, J= 13.2, 6.2 Hz, 1H), 2.40 (s, 3H). [0251] (Example 73): 1H NMR (400 MHz, CDC13) δ 7.35 (d, J= 7.7 Hz, 1H), 7.10 (ddd, J= 21.4, 20.1, 7.6 Hz, 5H), 6.76 (d, J= 6.8 Hz, 3H), 6.16 (d, J= 8.2 Hz, 1H), 6.04 (s, 2H), 4.89 (d, J= 14.6 Hz, 1H), 4.79 (d, J= 7.7 Hz, 1H), 4.21 (s, 1H), 4.06 (d, J= 14.6 Hz, 1H), 3.62 (dd, J= 35.0, 17.5 Hz, 2H), 3.10 (d, J= 11.9 Hz, 3H), 2.62 (ddd, J= 19.6, 13.3, 7.0 Hz, 2H), 2.46 - 2.34 (m, 3H), 1.33 (d, J= 6.2 Hz, 3H).
[0252] (Example 74): 1H NMR (400 MHz, CDC13) δ 7.35 (dd, J= 7.8, 0.9 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.21 - 7.08 (m, 3H), 7.07 - 6.94 (m, 2H), 6.89 - 6.79 (m, 2H), 6.69 - 6.38 (m, 1H), 6.18 (t, J= 13.0 Hz, 1H), 4.73 - 4.61 (m, 2H), 4.00 - 3.76 (m, 2H), 3.75 - 3.50 (m, 4H), 3.13 - 3.02 (m, 3H), 2.79 - 2.58 (m, 2H), 2.46 - 2.36 (m, 3H).
[0253] (Example 75): 1H NMR (400 MHz, CDC13) δ7.33 (d, J= 7.7 Hz, 1H), 7.29 - 7.23 (m, 2H), 7.19 (t, J = 7.3 Hz, 2H), 7.05 (t, J= 7.5 Hz, 1H), 6.97 (dd, J= 15.0, 5.9 Hz, 2H), 6.86 (t, J= 6.0 Hz, 2H), 6.30 (d, J= 8.5 Hz, 1H), 4.66 (td, J= 8.8, 5.9 Hz, 1H), 4.50 (t, J = 5.1 Hz, 2H), 3.90 - 3.82 (m, 2H), 3.65 (dd, J= 5.5, 2.5 Hz, 2H), 3.02 (s, 3H), 2.71 (s, 3H), 2.70 - 2.63 (m, 2H), 2.40 (s, 3H).
[0254] (Example 76): 1H NMR (400 MHz, CDC13) δ 8.90 (s, 2H), 8.12 (d, J= 8.9 Hz, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.20 (t, J= 7.4 Hz, 1H), 7.04 (d, J= 13.1 Hz, 2H), 6.81 (d, J = 7.3 Hz, 1H), 6.72 (d, J= 7.3 Hz, 1H), 6.65 (d, J= 6.2 Hz, 2H), 6.17 (d, J= 2.8 Hz, 1H), 4.84 (d, J= 4.6 Hz, 1H), 4.45 - 4.28 (m, 2H), 4.15 (q, J= 7.1 Hz, 1H), 3.81 (s, 2H), 3.28 (s, 3H), 2.74 (d, J= 12.4 Hz, 4H), 2.59 (s, 1H), 2.50 (s, 3H), 2.31 (s, 3H), 1.33 (t, J= 7.1 Hz, 3H). Example 77
(5)-2-(2-(4-chloro-2,7-dimethyl-lH-indol-3-yl)acetamido)-N-methyl-N,3-
Figure imgf000071_0001
Example 77A. Preparation of 2-(4-chloro-2,7-dimethyl-lH-indol-3-yl)acetic acid
Figure imgf000071_0002
[0256] To a methanol solution of 2-(4-chloro-2,7-dimethyl-lH-indol-3-yl)acetic acid (327 mg, 1.26 mmol, 1.0 eq) which was synthesized by a method analogous to that of 1 A, IB and 1C, was added NaOH aqueous solution (2N, 3 mL). The mixture was stirred at 50 °C for 4 hours, then aqueous HCl solution was added to adjust pH to 5. The resulting precipitate was filtered, the solid was collected to give the product (210 mg, yield: 70%), LC/MS: m/z M++l = 238.
Example 77B. (^-2-(2-(4-chloro-2,7-dimethyl-lH-indol-3-vnacetamido -N-methyl-N.3- diphenylpropanamide
[0257] The procedure was similar to 1H utilizing the corresponding acid and amine to obtain the product, LC/MS: m/z M++l = 474, HPLC retention time = 3.10 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0258] 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.40 (d, J = 7.6 Hz, 3H), 7.21 (d, J= 7.0 Hz, 2H), 7.12 (d, J = 6.3 Hz, 3H), 6.76 (q, J= 7.7 Hz, 4H), 4.48 (d, J= 4.7 Hz, 1H), 3.67 (s, 2H), 3.13 (s, 3H), 2.78 (dd, J= 13.1, 4.4 Hz, 1H), 2.70 - 2.57 (m, 1H), 2.39 (s, 3H), 2.20 (s, 3H).
[0259] Compounds 78-96 were prepared using a method analogous to that of Example 77 utilizing corresponding acids and amines.
Examples 78 to 96
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
p eny propanam e
[0260] (Example 78): 1H NMR (400 MHz, CDC13) δ 10.99 (s, 1H), 8.04 - 7.91 (m, 2H), 7.42 (s, 1H), 7.22 - 7.14 (m, 3H), 6.89 (d, J= 3.5 Hz, 2H), 6.85 - 6.69 (m, 3H), 4.36 (d, J = 5.7 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 2H), 3.09 (s, 3H), 2.84 (dd, J= 13.1, 5.5 Hz, 1H), 2.69 (dd, J= 13 , 8.2 Hz, 1H), 2.39 (s, 3H), 2.21 (s, 3H).
[0261] (Example 79): 1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.41 (dd, J= 12.3, 7.2 Hz, 3H), 7.26 (d, J= 7.0 Hz, 2H), 7.12 (d, J= 6.3 Hz, 3H), 6.71 (d, J= 5.7 Hz, 2H), 6.62 (d, J= 7.2 Hz, 1H), 6.50 (d, J= 7.2 Hz, 1H), 4.46 (s, 1H), 3.54 (s, 2H), 3.14 (s, 3H), 2.77 (d, J= 9.3 Hz, 1H), 2.64 - 2.56 (m, 1H), 2.35 (s, 6H), 2.20 (s, 3H). [0262] (Example 80): 1H NMR (400 MHz, CDC13) δ 10.58 (s, IH), 8.07 - 7.96 (m, 2H), 7.48 (d, J= 10.5 Hz, IH), 7.18 (s, 3H), 6.84 (d, J= 8.5 Hz, 3H), 6.61 (d, J= 7.3 Hz, IH), 6.50 (d, J= 7.0 Hz, IH), 4.32 (dd, J= 13.4, 8.4 Hz, IH), 3.85 (s, 3H), 3.54 (s, 2H), 3.10 (s, 3H), 2.84 (d, J= 9.0 Hz, IH), 2.73 - 2.61 (m, IH), 2.36 (d, J= 10.6 Hz, 6H), 2.21 (s, 3H).
[0263] (Example 81): 1H NMR (400 MHz, CDC13) δ 10.58 (s, IH), 7.94 (d, J= 7.7 Hz, 2H), 7.41 - 7.28 (m, IH), 7.19 (d, J= 2.5 Hz, 3H), 6.94 - 6.77 (m, 3H), 6.62 (d, J= 7.0 Hz, IH), 6.50 (d, J= 6.9 Hz, IH), 4.25 (d, IH), 3.85 (s, 3H), 3.55 (s, 4H), 2.89 - 2.83 (m, IH), 2.70 - 2.66 (m, IH), 2.36 (d, J= 10.7 Hz, 6H), 2.21 (s, 3H), 0.95 (t, J= 7.1 Hz, 3H).
[0264] (Example 82): 1H NMR (400 MHz, CDC13) δ 10.57 (s, IH), 8.26 (s, IH), 7.96 (d, J= 8.8 Hz, IH), 7.45 (d, J= 9.7 Hz, IH), 7.28 (d, J= 8.6 Hz, IH), 7.17 (s, 3H), 6.82 (s, 2H), 6.62 (d, J= 7.3 Hz, IH), 6.50 (d, J= 7.1 Hz, 1H), 4.31 (s, IH), 3.54 (s, 2H), 3.11 (s, 3H), 2.85 - 2.83 (m, IH), 2.68 (s, IH), 2.48 (s, 3H), 2.35 (t, J= 6.8 Hz, 6H), 2.21 (s, 3H).
[0265] (Example 83): 1H NMR (400 MHz, CDC13) δ 10.57 (s, IH), 7.84 (d, J= 7.7 Hz, IH), 7.22 - 7.13 (m, 3H), 6.93 (d, J= 8.2 Hz, IH), 6.82 (dd, J= 12.4, 9.1 Hz, 3H), 6.55 (dd, J= 49.2, 7.2 Hz, 2H), 6.07 (d, J= 4.7 Hz, 2H), 4.45 (s, IH), 3.54 (s, 2H), 3.08 (s, 3H), 2.83 (dd, J= 13.6, 4.6 Hz, IH), 2.64 (dd, J= 13.5, 9.4 Hz, IH), 2.36 (d, J= 6.5 Hz, 6H), 2.20 (s, 3H).
[0266] (Example 84): 1H NMR (400 MHz, CDC13) δ 10.65 (s, IH), 8.22 (d, J= 7.5 Hz, IH), 7.36 (t, J= 8.5 Hz, 3H), 7.23 (t, J= 8.0 Hz, 3H), 7.18 - 7.01 (m, 4H), 6.90 (t, J= 7.4 Hz, IH), 6.79 (dd, J= 17.1, 9.7 Hz, 3H), 4.54 - 4.15 (m, IH), 3.11 (s, 3H), 2.78 (d, J= 9.8 Hz, IH), 2.73 - 2.57 (m, IH), 2.20 (s, 3H).
[0267] (Example 85): 1H NMR (400 MHz, CDC13) δ 10.58 (s, IH), 7.77 (d, J= 7.9 Hz, IH), 7.15 (d, J= 2.6 Hz, 3H), 6.94 (d, J= 8.6 Hz, IH), 6.86 (s, IH), 6.79 (s, 3H), 6.62 (d, J = 7.1 Hz, IH), 6.50 (d, J= 7.5 Hz, IH), 4.52 (s, IH), 3.76 (s, 3H), 3.66 (s, 3H), 3.54 (s, 2H), 3.11 (s, 3H), 2.83 (d, J= 13.1 Hz, IH), 2.64 (d, J= 9.8 Hz, IH), 2.36 (d, J= 9.0 Hz, 6H), 2.21 (s, 3H).
[0268] (Example 86): 1H NMR (400 MHz, DMSO) δ 11.00 (s, IH), 8.27 (s, IH), 8.16 (d, J= 7.7 Hz, IH), 7.44 (s, IH), 7.28 (d, J= 8.3 Hz, IH), 7.18 (s, 3H), 6.89 (d, J= 7.7 Hz, IH), 6.83 (s, 2H), 6.61 (d, J= 7.7 Hz, IH), 4.30 (s, IH), 3.55 (s, 2H), 3.11 (s, 3H), 2.84 (dd, J = 15.7, 5.4 Hz, IH), 2.69 (dd, J= 13.3, 8.3 Hz, 2H), 2.48 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H).
[0269] (Example 87): 1H NMR (400 MHz, CDC13) δ 10.99 (s, IH), 8.20 (s, IH), 7.98 (d, J= 7.7 Hz, IH), 7.39 (d, J= 6.7 Hz, IH), 7.26 (d, J= 8.2 Hz, IH), 7.18 (s, 3H), 6.86 (d, J = 3.7 Hz, 2H), 6.78 - 6.71 (m, 2H), 4.34 (d, J= 6.0 Hz, IH), 3.66 (s, 2H), 3.10 (s, 3H), 2.83 (dd, J= 13.5, 5.4 Hz, IH), 2.68 (d, J= 1.8 Hz, IH), 2.47 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H). [0270] (Example 88): 1H NMR (400 MHz, DMSO) δ 11.49 - 11.43 (m, 1H), 8.22 - 7.38 (m, 7H), 7.26 (d, J= 8.5 Hz, 1H), 7.22 - 7.12 (m, 3H), 7.03 (d, J= 8.3 Hz, 1H), 6.94 - 6.80 (m, 3H), 4.32 (s, J= 12.5 Hz, 1H), 3.66 (s, 2H), 3.11 (s, 3H), 2.85 (dd, J= 13.2, 5.9 Hz, 1H), 2.70 (dd, J= 10.4, 3.6 Hz, 1H), 2.47 (s, 3H), 2.23 (s, 3H).
[0271] (Example 89): 1H NMR (400 MHz, DMSO) δ 11.44 (s, 1H), 8.12 (d, J= 7.8 Hz, 1H), 7.98 (s, 1H), 7.41 (d, J= 7.5 Hz, 1H), 7.26 - 7.15 (m, 3H), 7.02 (d, J= 8.1 Hz, 1H), 6.89 (d, J= 8.1 Hz, 3H), 6.81 (d, J= 8.7 Hz, 1H), 4.41 - 4.32 (m, 1H), 3.85 (s, 3H), 3.67 (s, 2H), 3.09 (s, 3H), 2.92 - 2.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.23 (s, 3H).
[0272] (Example 90): 1H NMR (400 MHz, CDC13) δ 11.44 (s, 1H), 8.02 (d, J= 7.9 Hz, 1H), 7.40 (t, J= 8.7 Hz, 3H), 7.23 (d, J= 7.3 Hz, 2H), 7.13 (s, 3H), 7.02 (d, J= 8.1 Hz, 1H), 6.89 (d, J= 8.1 Hz, 1H), 6.78 (s, 1H), 4.47 (s, 1H), 3.66 (s, 2H), 3.14 (s, 3H), 2.80 (d, J= 8.6 Hz, 1H), 2.71 - 2.60 (m, 1H), 2.22 (s, 3H).
[0273] (Example 91): 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.07 (d, J= 7.4 Hz, 1H), 7.50 - 7.35 (m, 3H), 7.29 (d, J= 6.7 Hz, 2H), 7.13 (s, 3H), 6.88 (d, J= 7.6 Hz, 1H), 6.73 (s, 2H), 6.60 (d, J= 7.9 Hz, 1H), 4.44 (s, 1H), 3.55 (s, 2H), 3.15 (s, 3H), 2.80 (d, J= 9.8 Hz, 1H), 2.66 (d, J= 10.2 Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H).
[0274] (Example 92): 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.19 (d, J= 7.7 Hz, 1H), 8.04 (s, 1H), 7.47 (s, 1H), 7.22 - 7.14 (m, 3H), 6.86 (dd, J= 17.8, 8.2 Hz, 4H), 6.60 (d, J = 7.9 Hz, 1H), 4.32 (d, J= 4.3 Hz, 1H), 3.85 (s, 3H), 3.55 (s, 2H), 3.10 (s, 3H), 2.86 (dd, J = 13.3, 4.7 Hz, 1H), 2.69 (dd, J= 13.6, 9.1 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H).
[0275] (Example 93): 1H NMR (400 MHz, DMSO) δ 10.61 (s, 1H), 10.02 (s, 1H), 7.66 (d, J= 8.3 Hz, 1H), 7.27 - 7.07 (m, 6H), 6.89 (dt, J= 23.3, 5.2 Hz, 2H), 6.63 (d, J= 7.3 Hz, 1H), 6.51 (d, J= 7.4 Hz, 1H), 5.98 (d, J= 1.4 Hz, 2H), 4.65 (td, J= 8.5, 5.2 Hz, 1H), 3.60 (s, 2H), 2.98 (dd, J= 13.6, 5.0 Hz, 1H), 2.86 (dd, J= 13.6, 9.1 Hz, 1H), 2.37 (d, J= 5.1 Hz, 6H), 2.22 (s, 3H).
[0276] (Example 94): 1H NMR (400 MHz, CDC13) δ 8.34 (s, 1H), 7.40 - 7.12 (m, 4H),
7.04 (dd, J= 21.6, 7.4 Hz, 2H), 6.82 (d, J= 7.1 Hz, 2H), 6.73 (d, J= 8.0 Hz, 1H), 6.31 (d, J = 8.3 Hz, 1H), 5.98 (t, J= 15.0 Hz, 2H), 4.83 (dd, J= 14.7, 7.2 Hz, 1H), 3.62 (s, 2H), 3.12 (s, 3H), 2.82 (dt, J= 14.2, 7.6 Hz, 3H), 2.65 (dd, J= 13.2, 6.5 Hz, 1H), 2.30 (s, 3H), 1.38 (t, J = 7.6 Hz, 3H).
[0277] (Example 95): 1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 8.25 (d, J= 7.7 Hz, 1H), 7.22 - 7.06 (m, 4H), 6.89 (dd, J= 7.5, 3.4 Hz, 3H), 6.81 - 6.59 (m, 4H), 6.05 (d, J= 7.5 Hz, 2H), 4.38 (td, J= 8.9, 4.6 Hz, 1H), 3.52 - 3.37 (m, 2H), 3.08 (s, 3H), 2.86 (dd, J= 13.5,
4.5 Hz, 1H), 2.78 - 2.59 (m, 3H), 2.25 (s, 3H), 1.72 - 1.55 (m, 2H), 0.93 (t, J= 7.3 Hz, 3H). [0278] (Example 96): 1H NMR (400 MHz, CDC13) δ 10.81 (s, 1H), 8.34 (d, J= 7.8 Hz, 1H), 7.22 - 7.08 (m, 5H), 6.95 - 6.84 (m, 3H), 6.77 (td, J= 9.4, 2.6 Hz, 2H), 6.70 (d, J= 7.8 Hz, 1H), 6.11 - 5.98 (m, 2H), 4.38 (s, 1H), 3.43 (d, J= 14.8 Hz, 2H), 3.09 (s, 3H), 2.87 (dd, J = 13.5, 4.5 Hz, 1H), 2.68 (dd, J= 13.4, 9.6 Hz, 1H), 2.24 (s, 3H).
Example 97
[0279] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-N-methyl-2-(2-(2-methyl-7-vinyl-lH-indol-3- yl)acetamido)-3-phenylpropanamide
Figure imgf000077_0001
Example 97A. Preparation of ethyl 2-(7-bromo-2 -methyl- lH-indol-3-yl)acetate
Figure imgf000077_0002
[0280] The procedure of synthesis of 97A was similar to 1C with (2- bromophenyl)hydrazine as starting materials, LC/MS: m/z M++l = 296.
Example 97B. Preparation of ethyl 2-(l-acetyl-7-bromo-2-methyl-lH-indol-3-yl)acetate
Figure imgf000077_0003
[0281] To a solution of ethyl 2-(7-bromo-2-methyl-lH-indol-3-yl)acetate (3.0 g, 10.1 mmol, 1.0 eq) in DCM (25 mL), was added triethylamine (4.2 mL, 17.2 mmol, 3.0 eq) and followed by acetyl chloride (1.57 g, 11.6 mmol, 2.0 eq). The mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of water (10 mL) and extracted with DCM (2x15 mL), and the organic extracts were evaporated to give a residue which was purified on silica gel chromatography (PE : EA=10: 1) to give ethyl 2-(l- acetyl-7-bromo-2-methyl-lH-indol-3-yl)acetate (2.89 g, 8.6 mmol, yield: 85% ), LC/MS: m/z M++l = 338.
Example 97C. Preparation of ethyl 2-(2-methyl-7-vinyl-lH-indol-3-yl)acetate
Figure imgf000078_0001
[0282] To a solution of ethyl 2-(l-acetyl-7-bromo-2-methyl-lH-indol-3-yl)acetate (540 mg, 1.6mmol, 1.0 eq) in DMF (10 mL), were added tributyl(vinyl)tin (1.9 g, 6.4 mmol, 4.0 eq) and Pd(PPh3)4 (0.05 g, 0.1 eq). The mixture was refluxed for overnight under nitrogen atmosphere until TLC (petroleum ether/EtOAc = 3: 1) indicated the reaction was completed. The resulting mixture was quenched by water (10 mL), cooled to room temperature, and extracted with EtOAc(2x20 mL), the organic extracts were evaporated and the residue was purified by silica gel chromatography (PE:EA=5: 1) to give ethyl 2-(2-methyl-7-vinyl-lH- indol-3-yl)acetate (291 mg, 1.2 mmol, yield: 75%), LC/MS: m/z M++l = 244.
Example 97D. Preparation of 2-(2-methyl-7-vinyl-lH-indol-3-yl)acetic acid
Figure imgf000078_0002
[0283] The procedure was similar to 74A utilizing 2-(2-methyl-7-vinyl-lH-indol-3- yl)acetate as starting materials, LC/MS: m/z M++l = 216.
Example 97E. Preparation of (6 -N-(benzor(iiri,31dioxol-5-yl)-2-(2-(7-(2-hvdroxyethyl)-2- methyl-lH-indol-3-yl)acetamido)-N-methyl-3-phenylpropanamide
[0284] The procedure was similar to 1H utilizing the corresponding acid and amine to obtain the product, LC/MS: m/z M++l = 496, HPLC retention time = 3.07 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0285] 1H NMR (400 MHz, DMSO) δ 10.77 (s, 1H), 8.27 (d, J= 7.7 Hz, 1H), 7.25 - 7.12 (m, 6H), 6.91 - 6.83 (m, 4H), 6.77 (s, 1H), 6.70 (d, J= 7.7 Hz, 1H), 6.05 (d, J= 7.5 Hz, 2H), 5.86 (d, J= 17.6 Hz, 1H), 5.32 (d, J= 11.3 Hz, 1H), 4.39 (td, J= 8.1, 4.3 Hz, 1H), 3.46 (d, J = 15.1 Hz, 2H), 3.08 (s, 3H), 2.86 (dd, J= 13.5, 4.6 Hz, 1H), 2.68 (dd, J= 13.3, 9.8 Hz, 1H), 2.27 (s, 3H).
Example 98.
[0286] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(7-(2-hydroxyethyl)-2-methyl-lH-indol-3- yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000079_0001
Example 98A. Preparation of 2-(7-(2-hydroxyethyl)-2-methyl-lH-indol-3-yl)acetic acid
Figure imgf000079_0002
[0287] To a solution of 9-Borabicyclo[3.3.1]nonane (0.5 M, 5 mL) in THF, was added (2- (2-methyl-7-vinyl-lH-indol-3-yl)acetic acid (200 mg, 0.93 mmol, 1.0 eq). The mixture was stirred at room temperature for 2 hours until TLC (PE:EA=2: 1) indicated the SM had disappeared. The reaction mixture was quenched by methanol (5 mL). The solvent was evaporated to give the residue. To this, H202 (3 mL, 30%) and aqueous NaOH (2 mL, 50%>) were added subsequently. The resulting mixture was stirred at room temperature for 5 hours, and then extracted with EtOAc (10 mL). The organic extract was evaporated to give a residue which was purified by prep-HPLC to give the product 2-(7-(2-hydroxyethyl)-2- methyl-lH-indol-3-yl)acetic acid (91 mg, 0.39 mmol, isolated yield: 42%), LC/MS: m/z M++l = 234.
Example 98B. Preparation of (^-Λ^-^6ηζοΓ^1Π.31άίοχο1-5-νη-2-(2-(7-(2^νάΓθχν6&νη-2- methyl-lH-indol-3-yl)acetamido)-N-methyl-3-phenylpropanamide
[0288] The procedure was similar to 1H utilizing the corresponding acids and amines to afford the product, LC/MS: m/z M++l = 514, HPLC retention time = 3.23 minutes (10-90% MeCN and water solution, contained 0.1% TFA). [0289] 1H NMR (400 MHz, CDC13) δ 8.91 (s, 1H), 7.30 (s, 1H), 7.17 (dt, J= 14.1, 6.8 Hz, 3H), 7.06 (t, J= 7.5 Hz, 1H), 6.97 (d, J= 7.1 Hz, 1H), 6.83 (d, J= 6.9 Hz, 2H), 6.73 (d, J = 8.2 Hz, 1H), 6.27 (d, J= 8.2 Hz, 1H), 6.02 (s, 2H), 4.82 (dd, J= 15.0, 7.4 Hz, 1H), 4.15 (q, J= 7.2 Hz, 1H), 4.02 (t, J= 5.7 Hz, 2H), 3.60 (d, J= 1.5 Hz, 2H), 3.09 (d, J= 8.3 Hz, 5H), 2.79 (dd, J= 13.1, 7.6 Hz, 1H), 2.64 (dd, J= 13.2, 6.5 Hz, 1H), 2.34 (s, 3H).
Example 99
[0290] (5)-2-(2-(7-chloro- 1 -ethyl-2-methyl- lH-indol-3 -yl)acetamido)-N,3- diphenylpropanamide
Figure imgf000080_0001
[0291] The procedure was similar to Example 1 utilizing the corresponding acid and amine to obtain the product, LC/MS: m/z M++l = 474, HPLC retention time = 3.50 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0292] 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 8.33 (d, J= 8.2 Hz, 1H), 7.56 (d, J =
7.6 Hz, 2H), 7.26 (tdd, J= 11.1, 8.0, 5.8 Hz, 8H), 7.05 (dd, J= 12.3, 7.4 Hz, 2H), 6.87 (t, J =
7.7 Hz, lH), 4.64 (td, J= 9.3, 4.6 Hz, 1H), 4.43 (dd, J= 8.2, 6.4 Hz, 2H), 3.52 (d, J= 5.1 Hz, 2H), 3.02 (d, J= 4.7 Hz, 1H), 2.89 (dd, J= 13.4, 9.8 Hz, 1H), 2.27 (s, 3H), 1.25 (t, J= 7.0 Hz, 3H).
[0293] Compounds 100-106 were prepared using a method analogous to that of Example 99 utilizing the corresponding acids and amines.
Examples 100 to 106
Figure imgf000080_0002
phenylpropanamide
0S)-N-(benzo[d][l,3]dioxol- 5-yl)-2-(2-(l-ethyl-2,4,7-
101 trimethyl- lH-indol-3 - 512 3.39
yl)acetamido)-3- phenylpropanamide
(5)-N-(benzo[ ][l,3]dioxol- 5-yl)-2-(2-(7-chloro-l-
102 ethyl-2-methyl- lH-indol-3 - 532 3.32
yl)acetamido)-3-
Figure imgf000081_0001
phenylpropanamide
(5)-N-(benzo[ ][l,3]dioxol- ci 5-yl)-2-(2-(7-chloro-l-
103 ethyl-2,4-dimethyl- 1H- 532 3.54
indol-3-yl)acetamido)-3- phenylpropanamide
(5)-2-(2-(7-chloro- 1 -ethyl- ci 2,4-dimethyl- lH-indol-3-
104 488 3.62
yl)acetamido)-N,3- diphenylpropanamide
(S)-2-(2-(7-chloro - 1 -ethyl- ci 2,4-dimethyl- lH-indol-3-
105 yl)acetamido)-N-(6- 519 3.45
N OMe methoxypyridin-3 -yl)-3 - phenylpropanamide
(S)-2-(2-(7-chloro - 1 -ethyl- 2-methyl- lH-indol-3-
106 yl)acetamido)-N-(6- 519 3.60
N OMe methoxypyridin-3 -yl)-3 -
Figure imgf000081_0002
phenylpropanamide
[0294] (Example 100): 1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.29 (d, J= 2.6 Hz, 1H), 7.84 (dd, J= 8.9, 2.7 Hz, 1H), 7.80 (d, J= 8.1 Hz, 1H), 7.29 - 7.13 (m, 5H), 6.80 (d, J = 8.8 Hz, 1H), 6.63 (d, J= 7.3 Hz, 1H), 6.52 (d, J= 7.4 Hz, 1H), 4.72 - 4.60 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.65 (s, 2H), 3.02 (dd, J= 13.6, 5.0 Hz, 1H), 2.88 (dd, J= 13.7, 9.2 Hz, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 1.17 (t, J= 7.1 Hz, 3H).
[0295] (Example 101): 1H NMR (400 MHz, CDC13) δ 10.01 (s, 1H), 7.70 (d, J= 8.2 Hz, 1H), 7.30 - 7.08 (m, 6H), 6.92 (dd, J= 8.4, 2.0 Hz, 1H), 6.85 (d, J= 8.4 Hz, 1H), 6.64 (d, J = 7.2 Hz, 1H), 6.52 (d, J= 7.2 Hz, 1H), 6.03 - 5.92 (m, 2H), 4.69 - 4.56 (m, 1H), 4.27 (q, J = 7.0 Hz, 2H), 3.65 (s, 2H), 2.99 (dd, J= 13.6, 5.0 Hz, 1H), 2.86 (dd, J= 13.6, 9.1 Hz, 1H), 2.62 (s, 3H), 2.39 (s, 3H), 2.18 (d, J= 10.0 Hz, 3H), 1.17 (t, J= 7.0 Hz, 3H).
[0296] (Example 102): 1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.32 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 7.8 Hz, 1H), 7.29 - 7.14 (m, 6H), 7.04 (d, J= 7.5 Hz, 1H), 6.93 (dd, J= 8.4, 1.9 Hz, 1H), 6.91 - 6.81 (m, 2H), 6.04 - 5.92 (m, 2H), 4.59 (dd, J= 13.3, 8.8 Hz, 1H), 4.44 (d, J= 7.1 Hz, 2H), 3.52 (d, J= 4.3 Hz, 2H), 3.02 (dd, J= 13.6, 4.8 Hz, 1H), 2.87 (dd, J = 13.7, 9.8 Hz, 1H), 2.28 (s, 3H), 1.25 - 1.19 (m, 3H).
[0297] (Example 103): 1H NMR (400 MHz, CDC13) δ 10.02 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.26 - 7.19 (m, 5H), 6.98 - 6.88 (m, 2H), 6.85 (d, J= 8.4 Hz, 1H), 6.63 (d, J= 8.3 Hz, 1H), 5.98 (d, J= 1.2 Hz, 2H), 4.69 - 4.59 (m, 1H), 4.46 (q, J= 7.1 Hz, 2H), 3.67 (s, 2H), 3.01 (dd, J= 13.5, 4.9 Hz, 1H), 2.87 (dd, J= 13.5, 9.6 Hz, 1H), 2.41 (s, 3H), 2.22 (s, 3H), 1.24 (t, J= 7.0 Hz, 3H).
[0298] (Example 104): 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.56 (d, J= 7.6 Hz, 2H), 7.31 (t, J= 7.9 Hz, 2H), 7.26 - 7.15 (m, 5H), 7.06 (t, J= 7.4 Hz, 1H), 6.91 (d, J= 7.7 Hz, 1H), 6.63 (d, J= 7.7 Hz, 1H), 4.73 - 4.64 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 3.67 (s, 2H), 3.04 (dd, J= 13.7, 4.9 Hz, 1H), 2.88 (dd, J= 13.8, 9.4 Hz, 1H), 2.41 (s, 3H), 2.21 (s, 3H), 1.24 (t, J= 7.0 Hz, 3H).
[0299] (Example 105): 1H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.31 (s, 1H), 8.00 (d, J= 7.6 Hz, 1H), 7.85 (d, J= 7.9 Hz, 1H), 7.22 (s, 5H), 6.92 (d, J= 7.7 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.63 (d, J= 7.6 Hz, 1H), 4.68 (s, 1H), 4.46 (d, J= 6.7 Hz, 2H), 3.82 (s, 3H), 3.68 (s, 2H), 3.05 (d, J= 9.5 Hz, 1H), 2.96 - 2.85 (m, 1H), 2.42 (s, 3H), 2.22 (s, 3H), 1.24 (s, 3H).
[0300] (Example 106): 1H NMR (400 MHz, DMSO) δ 10.14 (s, 1H), 8.36 (d, J= 8.2 Hz, 1H), 8.31 (d, J= 2.6 Hz, 1H), 7.85 (dd, J= 8.9, 2.6 Hz, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.29 - 7.14 (m, 5H), 7.04 (d, J= 7.6 Hz, 1H), 6.87 (t, J= 7.7 Hz, 1H), 6.80 (d, J= 8.9 Hz, 1H), 4.62 (dd, J= 13.6, 9.1 Hz, 1H), 4.44 (d, J= 7.0 Hz, 2H), 3.82 (s, 3H), 3.52 (d, J= 4.4 Hz, 2H), 3.04 (dd, J= 13.5, 4.9 Hz, 1H), 2.89 (dd, J= 13.4, 9.7 Hz, 1H), 2.28 (s, 3H), 1.25 (t, J= 6.9 Hz, 3H).
Example 107
[0301] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2,4,7-trimethyl-lH-indol-3- yl)acetamido)-N-methyl-3-(pyridin-4-yl)propanamide
Figure imgf000082_0001
Example 107A. Preparation of (6 -2-amino-N-(benzo[(i [l,31dioxol-5-yl)-N-methyl-3- (pyridin-4-yl)propanamide
BocHN
Figure imgf000083_0001
[0302] To a mixture of (5)-2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanoic acid (500 mg, 3.0 mmol, 1.0 eq) and N-methylbenzo[d][ 1,3] dioxol-5 -amine (549 mg, 3.6 mmol, 1.2 eq) in DCM (lOmL), were added EDCI (864 mg, 4.5 mmol, 1.5 eq), HOBt (810 mg, 6.0 mmol, 2.0 eq) and DIPEA (1.0 mL, 6.0 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated, the residue was purified by chromatography to give the product (S)- tert-butyl( 1 -(benzo [d] [ 1 ,3 ] dioxol-5 -yl(methyl)amino)- 1 -oxo-3 -(pyridin-4-yl)propan-2- yl)carbamate (450 mg, 1.13 mmol, isolated yield:37.7%), LC/MS: m/z M++l = 400.
Example 107B. Preparation of (6 -2-amino-N-(benzor(iiri,31dioxol-5-yl)-N-methyl-3- (pyridin-4-yl)propanamide
Figure imgf000083_0002
[0303] To a solution of (5)-tert-butyl(l -(benzo[<i] [ 1 ,3] dioxol-5 -yl(methyl)amino)- 1 -oxo- 3-(pyridin-4-yl)propan-2-yl)carbamate (450 mg, 1.13 mmol, 1.0 eq) in MeOH, was added a solution of acetyl chloride (3 mL) in MeOH at 0 °C. The mixture was stirred at at room temperature for 2 hours. The solvent was removed in vacuo to give the crude product (330 mg, 1.10 mmol, yield: 97.3%), LC/MS: m/z M++l = 300. Example 107C. Preparation of (S -N-(benzor /iri 1dioxol-5-yl)-2-(2-(l-ethyl-2.4.7- trimethyl-lH-indol-3-yl)acetamido)-N-methyl-3-(pyridin-4-yl)propanamide
[0304] The procedure was similar to 1H utilizing the corresponding acid and amine to obtain the product, LC/MS: m/z M++l = 527, HPLC retention time = 3.60 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0305] 1H NMR (400 MHz, DMSO) δ 8.34 (d, J= 5.7 Hz, 2H), 7.94 (d, J= 8.0 Hz, 1H), 6.93 (dd, J= 17.4, 5.0 Hz, 2H), 6.87 - 6.76 (m, 3H), 6.62 (d, J= 7.3 Hz, 1H), 6.50 (d, J= 7.2 Hz, 1H), 6.07 (d, J= 2.5 Hz, 2H), 4.52 (s, 1H), 4.25 (q, J= 7.0 Hz, 2H), 3.58 (s, 2H), 3.10 (s, 3H), 2.86 (dd, J= 13.6, 3.9 Hz, 1H), 2.75 - 2.64 (m, 1H), 2.61 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H), 1.16 (t, J = 6.9 Hz, 3H).
[0306] Compounds 108-110 were prepared using a method analogous to that of Example 107 utilizing the corresponding acids and amines.
Examples 108 to 110
Figure imgf000084_0001
[0307] (Example 108): 1H NMR (400 MHz, DMSO) δ 6.81 (dd, J= 7.6, 4.7 Hz, 2H), 6.73 (dd, J= 10.0, 7.5 Hz, 3H), 6.61 (dd, J= 8.6, 5.4 Hz, 2H), 6.51 (s, 1H), 6.09 (d, J= 8.5 Hz, 1H), 6.05 (dd, J= 2.9, 1.3 Hz, 2H), 4.81 (dd, J= 15.1, 7.1 Hz, 1H), 4.46 - 4.28 (m, 2H),
3.77 (q, J= 18.1 Hz, 2H), 3.14 (s, 3H), 2.75 (s, 3H), 2.70 (dd, J= 13.5, 6.8 Hz, 1H), 2.53 (dd, J= 13.6, 7.1 Hz, 1H), 2.45 (s, 3H), 2.30 (s, 3H), 1.31 (t, J= 7.1 Hz, 3H).
[0308] (Example 109): 1H NMR (400 MHz, CDC13) δ 8.05 (d, J= 4.1 Hz, 1H), 7.30 (s, 2H), 7.03 - 6.96 (m, 1H), 6.81 (dd, J= 13.4, 7.7 Hz, 2H), 6.67 (d, J= 7.2 Hz, 1H), 6.61 (t, J = 7.8 Hz, 2H), 6.05 (d, J= 1.7 Hz, 2H), 4.89 (dd, J= 13.8, 7.6 Hz, 1H), 4.42 - 4.34 (m, 2H),
3.78 (q, J= 18.0 Hz, 2H), 3.17 (s, 3H), 2.89 (dd, J= 13.2, 5.5 Hz, 1H), 2.81 - 2.68 (m, 4H), 2.45 (s, 3H), 2.33 (s, 4H), 1.31 (t, J = 7.2 Hz, 10H).
[0309] (Example 110): 1H NMR (400 MHz, DMSO) δ 8.42 (s, 1H), 8.05 (d, J= 10.3 Hz, 1H), 6.95 (t, J= 3.2 Hz, 2H), 6.81 (dd, J= 7.7, 5.1 Hz, 2H), 6.72 (d, J= 7.4 Hz, 1H), 6.18 (d, J= 8.4 Hz, 1H), 6.06 (s, 2H), 4.87 (dd, J= 15.2, 7.2 Hz, 1H), 4.43 - 4.32 (m, 2H), 3.84 - 3.72 (m, 2H), 3.14 (s, 3H), 2.78 (d, J= 6.6 Hz, 1H), 2.74 (d, J= 4.8 Hz, 3H), 2.57 (dd, J = 13.7, 7.2 Hz, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 1.32 (t, J= 7.1 Hz, 4H).
Example 111
[0310] (5)-2-(2-(3-ethyl-2-methyl-lH-indol-l-yl)acetamido)-N-methyl-N,3- diphenylpropanamide
Figure imgf000085_0001
Example 111 A. Preparation of phenylhvdrazine
Figure imgf000085_0002
[0311] To a stirred solution of aniline (10.0 g, 53.8 mmol, 1.0 eq) in HC1 (6M, 180 mL), was added aqueous NaN02 (4.5 g, 64.5 mmol, 1.2 eq) at -5 °C until the mixture became clear. A solution of SnCl2 (16.9 g, 75.3 mmol, 1.4eq) in HC1 (6N, 90 mL) was added while keeping the reaction temperature at -5 °C to 5 °C. The resulting mixture was stirred for 10 minutes and then filtered. The filtrate was basified with saturated NaOH solution to pH>l 1. The mixture was extracted with EA, washed with water and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give crude phenylhydrazine (2.0 g, 18.5 mmol, yield: 34.5%), LC/MS: m/z M++l = 109.
Example 11 IB. Preparation of 3-ethyl-2-methyl-lH-indole
Figure imgf000086_0001
[0312] To a mixture of phenylhydrazine (2.0 g, 18.5 mmol, 1.0 eq) and pentan-2-one (2.4 g, 27.3 mmol, 1.5 eq) in DCM, was added saturated NaHC03 solution (1 : 1). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with DCM, and the organic extract was washed with water, dried over anhydrous Na2S04 and concentrated under reduced pressure to dryness to give intermediate. Then the intermediate and anhydrous ZnCl2 (3.0 g, 22.2 mmol) was heated tol40 °C overnight. The solution of the crude product in MeOH was filtered and concentrated under reduced pressure to dryness to give crude product which was purified by column chromatography on silica gel (PE:EA=5: 1) to give 3-ethyl-2-methyl-lH-indole (500 mg, 3.1 mmol. yield: 17.0%), LC/MS: m/z M++l = 160.
Example 111C. Preparation of 2-(3-ethyl-2-methyl-lH-indol-l-yl)acetic acid
Figure imgf000086_0002
[0313] To a THF solution of 3-ethyl-2-methyl-lH-indole (500 mg, 3.1 mmol, 1.0 eq), was added slowly NaH (310 mg, 7.8 mmol, 2.5 eq). After 20 minutes, ethyl 2-bromoacetate (617.9 mg, 3.7 mmol, 1.2 eq) was added dropwise for a period of 30 minutes, and the resulting mixture was stirred at 0 °C for 30 minutes until TLC (DCM : MeOH = 10: 1) indicated the SM had disappeared. Water (15mL) was added to quench the reaction and followed addition of NaOH (1.2 g, 31 mmol, 10 eq). The mixture was stirred at room temperature for another 30 minutes, then HC1 (2M) was added to adjust pH to 4. The resulting precipitate was collected by filtration, washed and dried at 50 °C to give the product 2-(3-ethyl-2-methyl-lH-indol-l-yl)acetic acid (400 mg, 58.7%), LC/MS: m/z M++l = 218. Example 11 ID. Preparation of (6 -2-(2-(3-ethyl-2-methyl-lH-indol-l-yl)acetamido)-N- methyl-N,3 -diphenylpropanamide
[0314] To a mixture of 2-(3-ethyl-2 -methyl- lH-indol-l-yl)acetic acid (50 mg, 0.2 mmol,1.0 eq), (5)-2-amino-N-methyl-N,3-diphenylpropanamide (76.2 mg, 0.3 mmol, 1.5 eq) in DCM (2.0 mL), was added EDCI(57.3 mg, 0.3 mmol, 1.5 eq), HOBt (54 mg, 0.4 mmol, 2.0 eq) and DIPEA (51.6 mg, 0.4 mmol, 2.0 eq). The mixture was stirred at room
temperature overnight under N2 atmosphere. The resulting solution was washed with water 3 times, dried and concentrated. The residue was purified by prep-HPLC to give the desired product (5)-2-(2-(3-ethyl-2-methyl-lH-indol-l-yl)acetamido)-N-methyl-N,3- diphenylpropanamide (25 mg, 0.06 mmol, isolated yield: 24%). LC/MS: m/z M++1 = 454, HPLC retention time = 3.48 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0315] 1H NMR (400 MHz, CDC13) δ 8.68 (d, J= 8.2 Hz, 1H), 7.48 - 7.33 (m, 4H), 7.26 (d, J= 7.4 Hz, 2H), 7.15 (d, J= 2.4 Hz, 3H), 7.10 (d, J= 7.0 Hz, 1H), 7.00 - 6.87 (m, 2H), 6.79 (s, 2H), 4.68 (q, J= 16.6 Hz, 2H), 4.45 (s, 1H), 3.16 (s, 3H), 2.93 - 2.79 (m, 1H), 2.69 (d, J= 10.4 Hz, 1H), 2.62 (dd, J= 14.8, 7.3 Hz, 2H), 2.13 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H).
[0316] Compounds 112-122 were prepared using a method analogous to that of Example 111 utilizing the corresponding acids and amines.
Examples 112 to 122
Figure imgf000087_0001
Figure imgf000088_0001
p enypropanam e
[0317] (Example 112): 1H NMR (400 MHz, CDC13) δ 10.21 (s, 1H), 8.63 (d, J= 8.4 Hz, 1H), 8.31 (d,J=2.5 Hz, 1H), 7.86 (dd, J= 8.8, 2.7 Hz, 1H), 7.40 (d,J=7.1 Hz, 1H), 7.28 (d, J= 4.3 Hz, 4H), 7.22 (dd, J= 8.9, 4.3 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.81 (d, J= 8.8 Hz, 1H), 4.84 - 4.62 (m, 3H), 3.82 (s, 3H), 3.09 (dd, J= 13.8, 5.0 Hz, 1H), 2.90 (dd, J= 13.6, 9.5 Hz, 1H), 2.63 (q, J= 7.4 Hz, 2H), 2.13 (d, J= 12.6 Hz, 3H), 1.11 (t, J = 7.5 Hz, 3H).
[0318] (Example 113): 1H NMR (400 MHz, DMSO) δ 8.78 (d, J= 7.9 Hz, 1H), 8.02 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.39 (d, J= 7.2 Hz, 1H), 7.21 (s, 3H), 7.12 (d, J= 7.6 Hz, 1H),
7.02 - 6.89 (m, 4H), 6.82 (d, J= 8.7 Hz, 1H), 4.69 (q, J= 16.8 Hz, 2H), 4.42 - 4.24 (m, 1H), 3.84 (s, 3H), 3.12 (s, 3H), 2.93 (dd, J= 13.3, 4.6 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.63 (q, J = 7.5 Hz, 2H), 2.15 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H).
[0319] (Example 114): 1H NMR (400 MHz, CDC13) δ 8.67 (d, J= 7.7 Hz, 1H), 7.39 (d, J = 7.0 Hz, 1H), 7.19 (t, J= 6.6 Hz, 3H), 7.11 (d, J= 7.0 Hz, 1H), 6.93 (dt, J= 17.1, 4.9 Hz, 5H), 6.77 (s, 1H), 6.71 (d, J= 8.0 Hz, 1H), 6.05 (d, J= 5.3 Hz, 2H), 4.76 - 4.59 (m, 2H), 4.46 (s, 1H), 3.09 (s, 3H), 2.92 (dd, J= 13.5, 4.4 Hz, 1H), 2.70 (dd, J= 13.5, 9.8 Hz, 1H), 2.62 (q, J= 7.6 Hz, 2H), 2.14 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H).
[0320] (Example 115): 1H NMR (400 MHz, CDC13) δ 8.76 (d, J= 7.8 Hz, 1H), 8.24 (s, 1H), 7.48 - 7.35 (m, 2H), 7.26 (d, J= 8.2 Hz, 1H), 7.20 (d, J= 3.6 Hz, 3H), 7.12 (d, J= 7.5 Hz, 1H), 6.96 (dd, J= 14.0, 7.1 Hz, 2H), 6.92 - 6.82 (m, 2H), 4.68 (q, J= 16.8 Hz, 2H), 4.32 (dd, J= 13.4, 8.2 Hz, 1H), 3.12 (s, 3H), 2.92 (dd, J= 13.4, 5.0 Hz, 1H), 2.72 (dd, J= 13.3,
9.3 Hz, 1H), 2.62 (q, J= 7.4 Hz, 2H), 2.46 (s, 3H), 2.14 (s, 3H), 1.11 (t, J= 7.5 Hz, 3H).
[0321] (Example 116): 1H NMR (400 MHz, DMSO) δ 8.75 (d, J= 7.9 Hz, 1H), 7.95 (d, J= 8.4 Hz, 2H), 7.80 (d, J= 7.2 Ηζ,ΙΗ), 7.63 (s, 1H), 7.56 (dd, J= 17.5, 13.6 Hz, 2H), 7.35 (dd, J= 17.1, 7.8 Hz, 2H), 7.14 (dd, J= 18.6, 7.6 Hz, 4H), 6.96 (dt, J= 14.8, 7.3 Hz, 2H), 6.80 (d, J= 7.1 Hz, 2H), 6.14 (s, 1H), 4.73 (q, J= 16.9 Hz, 2H), 4.49 (dd, J= 13.1, 8.5 Hz, 1H), 3.24 (s, 3H), 2.99 (dd, J= 12.9, 5.3 Hz, 1H), 2.85 - 2.66 (m, 1H), 2.22 (s, 3H).
[0322] (Example 117): 1H NMR (400 MHz, DMSO) δ 7.60 - 7.56 (m, 2H), 7.48 - 7.41 (m, 2H), 7.39 - 7.31 (m, 1H), 7.21 - 6.97 (m, 15H), 6.86 (td, J = 7.6, 1.2 Hz, 1H), 6.69 (d, J = 6.9 Hz, 2H), 6.53 (dd, J = 7.7, 1.6 Hz, 1H), 6.38 (dd, J = 15.1, 10.5 Hz, 4H), 5.94 (dd, J = 125.8, 8.7 Hz, 2H), 4.79 - 4.55 (m, 6H), 3.82 (d, J = 37.6 Hz, 6H), 3.15 (d, J = 37.6 Hz, 6H), 2.79 - 2.49 (m, 3H), 2.32 (dd, J = 30.7, 0.7 Hz, 6H).
[0323] (Example 118): 1H NMR (400 MHz, CDC13) δ 7.59 (dd, J = 5.2, 2.5 Hz, 4H),
7.38 - 7.33 (m, 8H), 7.20 - 7.01 (m, 26H), 6.66 (d, J = 7.7 Hz, 3H), 6.55 (d, J = 7.2 Hz, 5H),
6.39 (dd, J = 16.0, 6.3 Hz, 6H), 5.78 (dd, J = 62.4, 8.3 Hz, 4H), 4.68 - 4.53 (m, 8H), 4.47 (td, J = 8.5, 5.7 Hz, 3H), 3.17 (d, J = 7.8 Hz, 11H), 2.84 - 2.60 (m, 4H), 2.52 - 2.34 (m, 4H), 2.30 (d, J = 5.0 Hz, 12H), 2.28 (d, J = 9.8 Hz, 11H).
[0324] (Example 119): 1H NMR (400 MHz, CDC13) δ 8.99 (d, J= 2.8 Hz, 1H), 8.12 (t, J = 8.3 Hz, 2H), 7.58 (dt, J= 16.0, 8.1 Hz, 1H), 7.48 (dd, J= 8.3, 4.3 Hz, 1H), 7.42 - 7.29 (m, 2H), 7.23 - 7.11 (m, 4H), 7.07 (t, J= 7.6 Hz, 2H), 6.57 (d, J= 7.3 Hz, 2H), 6.37 (d, J= 9.9 Hz, 1H), 5.87 (d, J= 7.8 Hz, 1H), 4.83 - 4.58 (m, 3H), 3.28 (s, 3H), 2.74 (dd, J= 13.2, 7.3 Hz, 1H), 2.49 (dd, J= 13.3, 7.5 Hz, 1H), 2.36 (s, 3H).
[0325] (Example 120): 1H NMR (400 MHz, CDC13) δ 8.86 (dd, J = 72.8, 2.7 Hz, 1H), 8.23 (dd, J = 38.5, 7.6 Hz, 1H), 7.92 (dd, J = 22.0, 7.8 Hz, 1H), 7.83 - 7.63 (m, 9H), 7.56 (d, J = 5.8 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.34 (dd, J = 14.9, 7.4 Hz, 1H), 7.23 - 7.08 (m, 3H), 7.06 - 6.94 (m, 1H), 6.84 (dd, J = 19.6, 7.4 Hz, 2H), 6.34 (d, J = 15.7 Hz, 1H), 6.25 (d, J =
6.4 Hz, 0.5H), 6.10 (d, J = 6.9 Hz, 1H), 5.79 (d, J = 7.8 Hz, 0.5H), 4.76 - 4.44 (m, 3H), 3.53 - 3.18 (m, 3H), 2.83 - 2.52 (m, 2H), 2.32 (d, J = 52.6 Hz, 3H).
[0326] (Example 121): 1H NMR (400 MHz, DMSO) δ 7.49 - 6.86 (m, 9H), 6.18 (s, 1H),
5.05 - 4.86 (m, 1H), 4.75 (s, 2H), 3.52 (s, 1H), 3.05 - 2.80 (m, 2H), 2.67 (s, 3H), 2.27 (s, 3H), 1.40 (ddd, J = 101.4, 87.8, 50.7 Hz, 10H).
[0327] (Example 122): 1H NMR (400 MHz, CDC13) δ 7.58 (d, J= 7.3 Hz, 1H), 7.24 - 7.11 (m, 5H), 7.00 - 6.94 (m, 1H), 6.93 - 6.86 (m, 1H), 6.37 (d, J= 4.9 Hz, 1H), 6.27 (s, 1H), 5.16 (ddd, J= 68.6, 15.1, 7.2 Hz, 1H), 4.68 (t, J= 9.0 Hz, 2H), 4.89 - 4.05 (m, 1H), 2.83 (dtd, J= 34.8, 13.6, 6.9 Hz, 2H), 2.65 (d, J= 55.1 Hz, 3H), 2.36 (d, J= 6.1 Hz, 3H), 1.74 - 1.50 (m, 8H).
Example 123
[0328] (S)-2-(2-(3-ethyl-2,4-dimethyl- lH-indol- 1 -yl)acetamido)-N-(6-methoxypyridin-3- yl)-N-methyl-3-phenylpropanamide
Figure imgf000090_0001
Example 123A. Preparation of 2-bromo-5-methylbenzenamine
Figure imgf000090_0002
[0329] To a solution of bromo-4-methyl-2-nitrobenzene (5 g, 23.3 mmol, 1.0 eq) in MeOH, was added Ranney Nickel (2 mL). The mixture was stirred for 15 minutes, and hydrazine hydrate (2.33 g, 46.6 mmol, 2 eq) was added dropwise. The resulting mixture was stirred for 2 hours at room temperature Then the reaction mixture was filtered, the filtrate was concentrated under vacuum. The residue was washed with H20 (2x30 mL), extracted with EtOAc (2x20 mL). The combined organic extracts were evaporated to afford 2-bromo- 5-methylbenzenamine (4.2 g, 22.7 mmol, yield: 97.4%), LC/MS: m/z M++l = 186.
Example 123B. Preparation of 1 -(2 -bromo-5-methylphenyl)hydrazine
Figure imgf000091_0001
[0330] To a stirred solution of 2-bromo-5-methylbenzenamine (4.2 g, 22.7 mmol, 1.0 eq) in HC1 (6M, 80 mL), was added aqueous NaN02 (1.9 g, 27.2 mmol, 1.2eq) at -5 °C until the mixture became clear. A solution of SnCl2 (7.2 g, 31.8 mmol, 1.4 eq) in 50mL HC1 (6M) was added while keeping the reaction temperature at -5 °C to 5 °C. The resulting mixture was stirred for 10 minutes and then filtered. The filtrate was basified with saturated NaOH solution to pH>l 1. The mixture was extracted with EA, washed with water and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give desired phenylhydrazine (3.0 g, 15.0 mmol, yield: 66.1%), LC/MS: m/z M++l = 201.
Example 123C. Preparation of 7-bromo-3-ethyl-2,4-dimethyl-lH-indole
Figure imgf000091_0002
[0331] To a mixture of l-(2-bromo-5-methylphenyl)hydrazine (3.0 g, 15.0 mmol, 1.0 eq) and pentan-2-one (1.94 g, 22.5 mmol, 1.5 eq) in DCM, was added saturated NaHC03 solution (1 : 1). The resulting mixture was stirred at room temperature for 3 hours. The mixture reaction was extracted with DCM, and the combined organic layers were washed with water and dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to dryness to give intermediate. Then the intermediate and anhydrous ZnCl2 (2.4 g, 18.0 mmol, 1.2 eq) were heat to 140 °C overnight. The solution of the crude product in MeOH was filtered and concentrated under reduced pressure to dryness to give crude product which was purified by chromatography on silica gel (PE:EA=5: 1) to give 7-bromo-3-ethyl-2,4-dimethyl- lH-indole (800 mg, 3.2 mmol. yield: 21.3%), LC/MS: m/z M++l = 252. Example 123D. Preparation of 3-ethyl-2,4-dimethyl-lH-indole
Figure imgf000092_0001
[0332] To a stirred solution of Lithium aluminium hydride (384.0 mg, 9.6 mmol, 3.0 eq) in anhydrous THF (8 mL). The mixture was stirred at room temperature for 20 minutes, then a solution of 7-bromo-3-ethyl-2,4-dimethyl-lH-indole (800 mg, 3.2 mmol, 1.0 eq) was added dropwise. The reaction mixture was stirred overnight. The reaction mixture was quenched by ice water, and then the mixture was filtered. The filtrate was dried in vacuum. The mixture was extracted with EtOAc (2x50 mL), then the organic extracts were evaporated to afford the product 3-ethyl-2,4-dimethyl-lH-indole (300 mg, 1.73 mmol, yield: 54.1%)
Example 123E. Preparation of 2-(3-ethyl-2,4-dimethyl-lH-indol-l-yl)acetic acid
[0333] To a DMF solution of 3-ethyl-2,4-dimethyl-lH-indole (300 mg, 1.73 mmol, 1.0 eq), was added slowly NaH (124.6 mg, 5.2 mmol, 3 eq). After 20 minutes, ethyl 2- bromoacetate (346.5 mg, 2.1 mmol, 1.2 eq) was added dropwise for a period of 30 minutes. The mixture was then stirred at at 0 °C for 60 minutes until TLC (DCM:MeOH=10: l) indicated the SM had disappeared. Water (15mL) was added to quench the reaction and NaOH (700 mg, 17.3 mmol, 10 eq) was added. The mixture was stirred at room temperature for another 30 minutes, then HCl (2M) was added to adjust pH to 4, precipitate formed and the solid was collected by filtration, washed and dried at 50 °C to give the product 2-(3-ethyl- 2,4-dimethyl-lH-indol-l-yl)acetic acid (250 mg, 1.1 mmol, yield: 63.6%), LC/MS: m/z M++l = 232.
Example 123F. (5V2-(2-(3-ethyl-2,4-dimethyl- lH-indol- 1 -yr)acetamidoVN-(6- methoxypyridin-3 -yl)-N-methyl-3 -phenylpropanamide
[0334] To a mixture of 2-(3-ethyl-2,4-dimethyl- lH-indol- 1 -yl)acetic acid (80 mg, 0.35 mmol, 1.0 eq) and (5)-2-amino-N-(6-methoxypyridin-3-yl)-N-methyl-3 -phenylpropanamide
(125.2 mg, 0.42 mmol, 1.2 eq) in DCM (3.0 mL), were added EDCI (101.2 mg, 0.53 mmol, 1.5 eq), HOBt (94.5 mg, 0.7 mmol, 2.0 eq) and DIPEA (90.3 mg, 0.7 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated, the residue was purified by prep-HPLC to give the final product (5)-2-(2-(3-ethyl-2,4-dimethyl-lH-indol-l-yl)acetamido)-N-(6- methoxypyridin-3-yl)-N-methyl-3-phenylpropanamide (23.6 mg, 0.05 mmol, isolated yield: 14.3%). LC/MS: m/z M++l = 499, HPLC retention time = 3.48 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0335] 1H NMR (400 MHz, DMSO) δ 8.73 (d, J= 7.6 Hz, 1H), 8.01 (s, 1H), 7.46 (d, J = 9.6 Hz, 1H), 7.21 (d, J= 5.9 Hz, 3H), 6.93 (t, J= 7.5 Hz, 3H), 6.88 - 6.78 (m, 2H), 6.67 (d, J = 6.9 Hz, 1H), 4.67 (q, J= 16.9 Hz, 2H), 4.35 (dd, J= 13.5, 8.3 Hz, 1H), 3.84 (s, 3H), 3.11 (s, 3H), 2.92 (dd, J= 13.7, 4.8 Hz, 1H), 2.73 (t, J= 10.3 Hz, 3H), 2.58 (s, 3H), 2.14 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H).
Example 129A. Preparation of utyl 2-(7-bromo-4-chloro-2-methyl-lH-indol-3-yl)acetate
Figure imgf000093_0001
[0336] Concentrated H2SO4 (30 mL) was added to a solution of (2-bromo-5- chlorophenyl)-hydrazine (78 g, 0.23 mol, 1.0 eq) and 4-oxopentanoic acid (27 g, 0.23 mol, 1.0 eq) in n-butanol (450 mL) at room temperature then the mixture was stirred at 130°C overnight. The solvent was moved and the residue was washed with water, and extracted with EA. The organic layers were combined, dried and concentrated, purified by column chromatography on silica gel to give product (34 g, 95 mmol, yield : 31.4%).
Example 129B. Preparation of 2-(7-bromo-4-chloro-2-methyl-lH-indol-3-yl)ethanol
Figure imgf000093_0002
[0337] Ice-water (9 mL) and 10% NaOH a.q. (9 mL) were added dropwise to the mixture. The mixture was filtered and the filtrate was extracted with EA. The organic layers were combined, dried and concentrated to afford product (16.5g, 57.5 mmol, yield : 85.6%).
Example 129C. Preparation of 2-(4-chloro-2-methyl-lH-indol-3-yl)ethanol
Figure imgf000093_0003
[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 NH4CI 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 129D. Preparation of Ethyl 2-(4-chloro-3-(2 -hvdroxyethvD-2 -methyl- lH-indol-1- yDacetate
Figure imgf000094_0001
[0339] Ethyl 2-bromoacetate (18.3 g, 109.4 mmol, 2.0 eq) was added to a solution of 2- (4-chloro-2-methyl-lH-indol-3-yl)ethanol (11.5 g, 54.7 mmol, 1.0 eq) and K2C03 (22.6 g, 164.1 mmol, 3.0 eq) in DMF. The solution was stirred at room temperature overnight. The reaction was quenched by addition of water and then extracted with EA. The organic layers were combined, dried and concentrated. The residue was purified by column
chromatography on silica gel to give the product (11.0 g, 37.2 mmol, yield: 68.0%).
Example 129E. Preparation of 2-(4-chloro-3 -(2 -hydroxy ethyl)-2-methyl-lH-indol-l-yl)acetic acid
Figure imgf000094_0002
[0340] IN solution of NaOH (800 mg, 20.4 mmol, 2.0 eq) was added to a solution of ethyl 2-(4-chloro-3-(2-hydroxyethyl)-2-methyl-lH-indol-l-yl)acetate (3 g, 10.2 mmol, 1.0 eq) in THF and stirred at room temperature for 1 hour. HC1 a.q was added to adjust pH to 4. The mixture was then extracted with EA. The organic layers were combined, dried and concentrated, concentrated to afford product (2.3 g, 8.58 mmol, yield : 84.1%).
[0341] Compounds 124-159 were prepared using a method analogous to that of example 123 utilizing the corresponding acids and amines. Examples 124 to 159
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
5H), 6.94 (d,J=8.2 Hz, 1H), 6.89 (d,J=7.1 Hz, 1H), 6.79 (d,J=8.5Hz, 1H), 6.66 (d,J = 7.2 Hz, 2H), 6.05 (s, 2H), 5.80 (d, J= 8.0 Hz, 1H), 4.74 (d, J= 6.4 Hz, 1H), 4.61 (q, J= 18.0 Hz, 2H), 3.15 (s, 3H), 2.89 (q, J= 7.6 Hz, 2H), 2.80 - 2.69 (m, 4H), 2.49 (dd, J= 13.5, 7.7 Hz, 1H), 2.24 (s, 3H), 1.23 (t, J= 7.5 Hz, 3H).
[0343] (Example 125): 1H NMR (400 MHz, CDC13) δ 8.01 (s, 1H), 7.27 - 7.10 (m, 5H), 7.08-7.01 (m, 1H), 6.95 (d,J=8.1 Hz, 1H), 6.89 (d,J=7.0Hz, 1H), 6.66 (d,J=7.5Hz, 2H), 5.79 (d, J= 7.8 Hz, 1H), 4.72 - 4.53 (m, 3H), 3.17 (d, J= 7.0 Hz, 3H), 2.89 (q, J= 7.5 Hz, 2H), 2.75 (s, 3H), 2.73 - 2.66 (m, 1H), 2.61 (s, 3H), 2.51 (dd, J= 13.4, 7.6 Hz, 1H), 2.25 (s, 3H), 1.24 (t, J = 7.5 Hz, 3H).
[0344] (Example 126): 1H NMR (400 MHz, DMSO) δ 8.73 (d, J= 8.0 Hz, 1H), 7.21 (q, J= 6.3 Hz, 3H), 7.10 (dd, J= 6.8, 2.2 Hz, 1H), 6.98 - 6.87 (m, 5H), 6.77 (s, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.06 (d, J= 4.3 Hz, 2H), 4.72 (q, J= 16.8 Hz, 2H), 4.48 (s, 1H), 3.10 (s, 3H), 2.93 (dd, J= 13.4, 4.3 Hz, 1H), 2.82 (q, J= 7.4 Hz, 2H), 2.70 (dd, J= 13.3, 9.7 Hz, 1H), 2.15 (s, 3H), 1.12 (t, J= 7.4 Hz, 3H).
[0345] (Example 127): 1H NMR (400 MHz, DMSO) δ 8.72 (d, J= 7.5 Hz, 2H), 8.24 (s, 2H), 7.43 (d, J= 7.8 Hz, 2H), 7.30 - 7.16 (m, 9H), 6.98 - 6.79 (m, 8H), 6.67 (d, J= 6.5 Hz, 2H), 4.67 (d, J= 7.9 Hz, 6H), 4.33 (s, 2H), 3.45 (s, 4H), 3.13 (s, 6H), 2.91 (s, 6H), 2.71 (d, J = 13.2 Hz, 3H), 2.59 (s, 6H), 2.47 (s, 6H), 2.14 (s, 6H).
[0346] (Example 128): 1H NMR (400 MHz, CDC13) δ 8.62 (d, J= 8.0 Hz, 1H), 7.21 (q, J = 5.7 Hz, 3H), 6.92 (t, J= 10.0 Hz, 4H), 6.82 (t, J= 7.6 Hz, 1H), 6.76 (s, 1H), 6.68 (dd, J = 13.8, 7.6 Hz, 2H), 6.06 (d, J= 4.7 Hz, 2H), 4.66 (d, J= 6.4 Hz, 3H), 4.47 (s, 1H), 3.46 (d, J = 7.5 Hz, 2H), 3.10 (s, 3H), 2.91 (dd, J= 14.9, 7.7 Hz, 3H), 2.73 (s, 1H), 2.58 (s, 3H), 2.14 (s, 3H).
[0347] (Example 129): 1H NMR (400 MHz, DMSO) δ 8.71 (d, J= 7.9 Hz, 1H), 7.20 (t, J = 6.6 Hz, 3H), 7.11 (dd, J= 7.0, 2.0 Hz, 1H), 6.93 (dd, J= 13.1, 7.0 Hz, 5H), 6.77 (s, 1H), 6.71 (d, J= 8.2 Hz, 1H), 6.06 (d, J= 4.1 Hz, 2H), 4.72 (q, J= 16.8 Hz, 2H), 4.59 (s, 1H), 4.48 (s, 1H), 3.51 (s, 2H), 3.10 (s, 3H), 3.04 - 2.87 (m, 3H), 2.70 (dd, J= 13.4, 9.5 Hz, 1H), 2.15 (s, 3H).
[0348] (Example 130): 1H NMR (400 MHz, CDC13) δ 7.19 - 7.09 (m, 3H), 6.97 (dd, J = 8.4, 3.9 Hz, 1H), 6.74 (ddd, J= 11.3, 10.3, 5.0 Hz, 4H), 6.36 (s, 2H), 6.01 (s, 2H), 5.68 (s, 1H), 4.97 (d, J = 17.8 Hz, 1H), 4.77 (dd, J= 20.7, 13.2 Hz, 2H), 3.94 - 3.86 (m, 2H), 3.30 (dt, J= 14.5, 5.3 Hz, 1H), 3.14 - 3.05 (m, 4H), 2.71 (dd, J= 13.4, 7.0 Hz, 1H), 2.56 (dd, J = 13.4, 6.6 Hz, 1H), 2.28 (s, 3H).
[0349] (Example 131): 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 8 Hz, 1H), 7.2- 7.18 (m, 3H), 6.95-6.65 (m, 8H), 6.05 (d, J= 8.8 Hz, 2H), 4.71-4.61 (m, 3H), 4.48-4.44 (m, 1H), 3.48-3.42 (m, 2H), 3.09 (s, 1H), 2.94-2.88 (m, 3H), 2.72-2.66 (m, 1H), 2.51 (s, 3H), 2.13 (s, 3H).
[0350] (Example 132): 1H NMR (400 MHz, DMSO-d6) δ8.75 (d, J =1.6 Hz, 1H), 7.18 - 7.24 (m, 3H), 6.89 - 7.10 (m, 6H), 6.66 - 6.72 (m, 2H), 6.26 (s, 1H), 6.04 (d, J = 4.0 Hz, 2H), 4.74 - 4.85 (m, 3H), 4.46-4.47 (m, 1H), 3.68-3.72 (m, 2H), 3.09 (s, 3H), 2.91-2.95 (m, 1H), 2.68-2.79 (m, 3H)
[0351] (Example 133): 1H NMR (400 MHz, CDC13) δ 7.30 - 7.21 (m, 2H), 7.21 - 7.11 (m, 3H), 7.10 - 7.01 (m, 2H), 6.76 - 6.53 (m, 3H), 5.68 (d, J= 8.2 Hz, 1H), 4.78 - 4.57 (m, 3H), 3.98 - 3.83 (m, 2H), 3.33 (dt, J= 14.3, 5.5 Hz, 1H), 3.23 - 3.14 (m, 1H), 3.13 - 3.02 (m, 3H), 2.71 - 2.62 (m, 1H), 2.54 (dd, J= 13.2, 6.5 Hz, 1H), 2.32 (d, J= 9.6 Hz, 3H).
[0352] (Example 134): 1H NMR (400 MHz, CDC13) δ 9.01 (dd, J= 19.4, 3.5 Hz, 1H), 8.22 (dd, J= 21.1, 8.6 Hz, 1H), 7.86 (ddd, J= 69.4, 68.3, 32.3 Hz, 2H), 7.62 - 7.29 (m, 2H), 7.28 - 6.78 (m, 6H), 6.53 (d, J= 7.3 Hz, 1H), 6.26 (d, J= 7.9 Hz, 1H), 5.44 (d, J= 7.9 Hz, 1H), 4.60 (dd, J= 35.1, 1 1.0 Hz, 2H), 4.04 (dd, J= 58.2, 6.3 Hz, 3H), 3.52 - 2.98 (m, 5H), 2.74 (dd, J= 13.4, 6.8 Hz, 1H), 2.61 - 2.46 (m, 1H), 2.32 (d, J = 4.4 Hz, 3H).
[0353] (Example 135): 1H NMR (400 MHz, CDC13) δ 8.92 (s, 2H), 8.12 (d, J= 8.9 Hz, 1H), 7.68 (s, 1H), 7.28 - 7.02 (m, 7H), 6.59 (d, J= 7.5 Hz, 2H), 5.69 (d, J= 7.8 Hz, 1H),
4.86 - 4.65 (m, 3H), 3.95 (s, 2H), 3.35 (d, J= 14.2 Hz, 1H), 3.28 (d, J= 2.4 Hz, 3H), 3.19 (dd, J= 14.0, 6.9 Hz, 1H), 2.71 - 2.48 (m, 2H), 2.35 (s, 3H).
[0354] (Example 136): 1H NMR (400 MHz, CDC13) δ 9.00 (d, J= 2.8 Hz, 1H), 8.19 - 8.02 (m, 2H), 7.49 (dd, J= 8.2, 4.3 Hz, 1H), 7.28 - 6.95 (m, 8H), 6.59 (d, J= 7.3 Hz, 2H),
5.64 (d, J = 8.3 Hz, 1H), 4.82 - 4.61 (m, 3H), 3.96 (t, J= 5.4 Hz, 2H), 3.48 - 3.10 (m, 5H),
2.65 (dd, J= 13.5, 7.5 Hz, 1H), 2.52 (s, 1H), 2.35 (s, 3H).
[0355] (Example 137): 1H NMR (400 MHz, CDC13) δ 8.39 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.88 - 7.73 (m, 2H), 7.70 - 7.42 (m, 2H), 7.26 (d, J= 7.5 Hz, 1H), 7.23 - 6.95 (m, 5H), 6.67 (t, J = 8.6 Hz, 2H), 5.66 (d, J= 8.1 Hz, 1H), 4.83 - 4.59 (m, 3H), 3.97 (t, J= 6.0 Hz, 2H), 3.42 - 3.07 (m, 5H), 2.67 (dd, J= 13.1, 8.1 Hz, 1H), 2.55 (dd, J = 13.3, 6.4 Hz, 1H), 2.36 (s, 3H).
[0356] (Example 138): 1H NMR (400 MHz, CDC13) δ 7.82 (d, J= 2.0 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.16 - 7.10 (m, 3H), 7.09 (s, 1H), 7.08 - 7.03 (m, 1H), 7.02 - 6.88 (m, 1H), 6.65 (d, J= 7.4 Hz, 2H), 6.32 (d, J= 8.6 Hz, 1H), 5.66 (d, J= 8.3 Hz, 1H), 4.74 (dt, J= 11.6, 5.8 Hz, 1H), 4.66 (d, J= 4.6 Hz, 2H), 3.98 - 3.89 (m, 2H), 3.53 - 3.44 (m, 4H), 3.35 (dt, J = 14.2, 5.2 Hz, 1H), 3.16 (dd, J= 7.5, 6.0 Hz, 1H), 3.12 (s, 3H), 2.69 (dd, J= 13.6, 6.3 Hz, 1H), 2.53 (dd, J= 13.6, 7.0 Hz, 1H), 2.30 (s, 3H), 2.09 - 2.02 (m, 4H).
[0357] (Example 139): 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.68 (d, J= 8.3 Hz, 1H), 7.30 - 7.26 (m, 4H), 7.25 - 7.20 (m, 1H), 7.17 - 7.10 (m, 1H), 7.00 - 6.90 (m, 3H),
6.87 (d, J= 8.4 Hz, 1H), 6.00 (s, 2H), 4.79 (q, J= 16.9 Hz, 2H), 4.71 - 4.64 (m, 1H), 4.61 (t, J= 4.9 Hz, 1H), 3.55 - 3.47 (m, 2H), 3.06 (dd, J= 13.3, 4.7 Hz, 1H), 2.99 (t, J = 7.5 Hz, 2H), 2.92 - 2.86 (m, 1H), 2.14 (d, J= 9.7 Hz, 3H).
[0358] (Example 140): 1H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.86 (m, 2H), 7.81 - 7.74 (m, 1H), 7.60 - 7.54 (m, 2H), 7.27 - 7.04 (m, 8H), 6.56 (d, J = 7.2 Hz, 2H), 5.63 (d, J = 8.5 Hz, 1H), 4.84 - 4.77 (m, 1H), 4.69 (d, J = 0.9 Hz, 2H), 3.98 - 3.91 (m, 2H), 3.51 (s, 1H), 3.40 - 3.33 (m, 1H), 3.25 (s, 3H), 3.20 - 3.12 (m, 1H), 2.68 - 2.62 (m, 1H), 2.52 - 2.45 (m, 1H), 2.34 (s, 3H).
[0359] (Example 141): 1H NMR (400 MHz, CDC13) δ 8.41 (s, 1H), 7.70 (d, J= 8.9 Hz, 1H), 7.32 (t, J= 7.5 Hz, 1H), 7.28 - 6.95 (m, 7H), 6.76 (d, J = 7.5 Hz, 2H), 5.67 (d, J= 7.6 Hz, 1H), 4.72 (s, 2H), 4.59 (dd, J= 14.6, 8.5 Hz, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.39 - 3.12 (m, 5H), 2.75 - 2.54 (m, 2H), 2.37 (s, 3H).
[0360] (Example 142): 1H NMR (400 MHz, CDC13) δ 9.35 (d, J= 40.0 Hz, 2H), 8.05 (d, J= 8.7 Hz, 1H), 7.40 (s, 1H), 7.28 - 6.99 (m, 7H), 6.67 (d, J= 7.5 Hz, 2H), 5.72 (d, J= 8.0 Hz, 1H), 4.84 - 4.58 (m, 3H), 3.97 (s, 2H), 3.40 - 3.12 (m, 5H), 2.65 (d, J= 8.8 Hz, 2H), 2.37 (s, 3H).
[0361] (Example 143): 1H NMR (400 MHz, DMSO-d6) δ 12.61 (d, J= 9.2 Hz, 1H), 8.72 (dd, J= 18.2, 7.9 Hz, 1H), 8.28 (d, J= 8.4 Hz, 1H), 7.59 - 7.49 (m, 1H), 7.17 - 7.03 (m, 5H),
6.95 - 6.89 (m, 2H), 6.80 - 6.70 (m, 2H), 4.72 (qd, J= 16.9, 5.1 Hz, 2H), 4.62 - 4.56 (m, 1H), 4.50 - 4.39 (m, 1H), 3.56 - 3.41 (m, 3H), 3.20 (s, 3H), 3.02 - 2.89 (m, 3H), 2.75 - 2.63 (m, lH), 2.13 (s, 3H).
[0362] (Example 144): 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J= 7.2 Hz, 1H), 8.40 (s, 1H), 7.28 - 6.98 (m, 7H), 6.70 (s, 3H), 5.70 (s, 1H), 4.72 (s, 3H), 3.94 (s, 2H), 3.42 - 3.10 (m, 5H), 2.68 (s, 2H), 2.36 (s, 3H).
[0363] (Example 145): 1H NMR (400 MHz, CDC13) δ 9.39 (d, J = 22.2 Hz, 2H), 7.94 (d, J= 8.6 Hz, 1H), 7.55 (s, 1H), 7.25 - 6.96 (m, 7H), 6.57 (s, 2H), 5.70 (s, 1H), 4.75 (d, J= 44.0 Hz, 3H), 3.92 (s, 2H), 3.35 - 3.14 (m, 5H), 2.64 (s, 2H), 2.33 (s, 3H).
[0364] (Example 146): 1H NMR (400 MHz, CDC13) δ 9.35 (d, J = 5.8 Hz, 1H), 8.51 (d, J = 9.0 Hz, 1H), 7.76 (d, J= 5.8 Hz, 1H), 7.27 (s, 1H), 7.25 - 7.05 (m, 7H), 6.62 (s, 2H), 5.74 (s, 1H), 4.73 (d, J= 18.5 Hz, 3H), 3.93 (d, J= 5.6 Hz, 2H), 3.35 - 3.14 (m, 5H), 2.64 (s, 2H), 2.35 (s, 3H).
[0365] (Example 147): 1H NMR (400 MHz, CDC13) δ 9.55 (s, 1H), 9.40 (s, 1H), 7.92 -
7.96 (d, J= 16.0 Hz, 1H), 7.5 l(m, 1H), 7.06-7.29 (m, 6H), 6.67 (m, 2H), 5.76 (m, 1H), 4.62- 4.70 (m, 3H), 3.96 (m, 2H), 3.17-3.35 (m, 5H), 2.64-2.68 (m,2H), 2.37 (s, 3H). [0366] (Example 148): 1H NMR (400 MHz, CDC13) δ 7.79 (s, 2H), 7.25 - 7.21 (m, 1H), 7.17 - 7.06 (m, 5H), 6.73 (d, J= 7.1 Hz, 2H), 5.64 (d, J = 8.2 Hz, 1H), 4.69 (d, J= 3.7 Hz, 2H), 3.97 - 3.91 (m, 2H), 3.84 (d, J= 3.6 Hz, 4H), 3.82 - 3.75 (m, 5H), 3.39 - 3.29 (m, 1H), 3.23 - 3.14 (m, 1H), 3.09 (s, 3H), 2.68 (dd, J= 13.4, 7.4 Hz, 1H), 2.57 (dd, J= 13.3, 6.6 Hz, 1H), 2.32 (s, 3H).
[0367] (Example 149): 1H NMR (400 MHz, CDC13) δ 7.19 (dd, J= 8.4, 6.2 Hz, 1H), 7.16 - 7.03 (m, 5H), 6.78 (d, J= 8.2 Hz, 1H), 6.65 (d, J= 7.0 Hz, 2H), 6.41 (t, J= 29.1 Hz, 2H), 6.04 (s, 2H), 5.68 (d, J= 8.4 Hz, 1H), 4.79 - 4.60 (m, 3H), 3.93 (td, J= 5.4, 2.3 Hz, 2H), 3.34 (dt, J= 14.4, 5.4 Hz, 1H), 3.23 - 3.11 (m, 1H), 2.69 (dd, J= 13.5, 6.6 Hz, 1H), 2.51 (dd, J= 13.5, 7.2 Hz, 1H), 2.31 (s, 3H).
[0368] (Example 150): 1H NMR (400 MHz, CDC13) δ 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).
[0369] (Example 151): 1H NMR (400 MHz, CDC13) δ 8.55-8.43 (m, 2H), 7.29-6.88 (m, 10H), 6.19 (d, J= 8 Hz, 1H), 5.31-5.11 (m, 1H), 4.78-4.68 (m, 2H), 4.49-4.29 (m, 2H), 3.96- 3.90 (m, 2H), 3.39 (s, 2H), 3.33-3.29 (m, 1H), 3.18-3.13 (m, 1H), 2.80 (s, 3H), 2.29 (s, 3H).
[0370] (Example 152): 1H NMR (400 MHz, CDC13) δ 7.19-7.01 (m, 7H), 6.87-6.74 (m, 2H), 5.96 (d, J= 8 Hz, 1H), 4.99-4.94 (m, 1H), 4.75-4.62 (m, 2H), 4.20 (s, 2H), 3.95-3.88 (m, 2H), 3.76 (s, 3H), 3.35-3.30 (m, 1H), 3.13-3.08 (m, 1H), 2.76-2.71 (m, 2H), 2.66 (s, 3H), 2.27 (s, 3H), 2.06 (s, 3H).
[0371] (Example 153): 1H NMR (400 MHz, CDC13) δ 7.28-7.24 (m, 2H), 7.18-7.13 (m, 3H), 7.08-7.03 (m, 3H), 6.88-6.86 (m, 2H), 6.51-6.50 (m, 1H), 5.01-4.99 (m, 1H), 4.84 (m, 4H), 4.71-4.61 (m, 2H), 3.88-3.86 (m, 2H), 3.44-3.38 (m, 3H), 3.30-3.23 (m, 1H), 3.10-3.05 (m, 1H), 3.23 (s, 3H).
[0372] (Example 154): 1H NMR (400 MHz, CDC13) δ 8.05-8.03 (m, 2H), 7.50-7.44 (m, 3H), 7.16-7.02 (m, 6H), 6.88-6.86 (m, 2H), 5.94 (d, J= 8 Hz, 1H), 5.29-5.14 (m, 1H), 4.75- 4.62 (m, 1H), 4.49-4.45 (m, 1H), 3.87-3.82 (m, 2H), 3.34-3.26 (m, 1H), 3.10-2.99 (m, 4H), 2.89-2.80 (m, 2H), 2.36 (s, 3H).
[0373] (Example 155): 1H NMR (400 MHz, CDC13) δ7.30 - 7.26 (m, 1H), 7.24 - 6.92 (m, 9H), 6.80 (dd, J= 42.6, 6.8 Hz, 2H), 5.93 (d, J= 8.1 Hz, 1H), 5.04 (dd, J= 14.8, 6.6 Hz, 1H), 4.78 - 4.50 (m, 3H), 4.36 (d, J= 14.3 Hz, 1H), 3.91 (dd, J= 11.0, 5.6 Hz, 2H), 3.35 (dt, J= 14.4, 4.7 Hz, 1H), 3.16 - 3.05 (m, 1H), 2.74 (d, J= 7.0 Hz, 5H), 2.28 (d, J= 4.9 Hz, 3H). [0374] (Example 156): 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J= 7.8 Hz, 1H), 7.28 - 7.15 (m, 3H), 7.12 (d, J= 6.8 Hz, 1H), 6.98 - 6.87 (m, 5H), 6.75 - 6.60 (m, 1H), 6.07 (d, J = 4.5 Hz, 2H), 4.74 (q, J= 16.9 Hz, 2H), 4.62 (t, J= 4.4 Hz, 1H), 4.54 (t, J= 4.8 Hz, 1H), 4.43 (dd, J= 12.1, 7.3 Hz, 2H), 3.99 - 3.75 (m, 2H), 3.55 - 3.45 (m, 2H), 3.03 - 2.92 (m, 3H), 2.72 (dd, J= 13.3, 9.8 Hz, 1H), 2.15 (s, 3H).
[0375] (Example 157): 1H NMR (400 MHz, DMSO) δ 8.71 (d, J = 7.9 Hz, 1H), 7.20 (t, J = 6.6 Hz, 3H), 7.11 (dd, J = 7.0, 2.0 Hz, 1H), 6.93 (dd, J = 13.1, 7.0 Hz, 5H), 6.77 (s, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.06 (d, J = 4.1 Hz, 2H), 4.59 (s, 1H), 4.48 (s, 1H), 3.51 (s, 2H), 3.10 (s, 3H), 3.04 - 2.87 (m, 3H), 2.70 (dd, J = 13.4, 9.5 Hz, 1H), 2.15 (s, 3H).
[0376] (Example 158): 1H NMR (400 MHz, CDC13) δ 8.41 (s, 1H), 7.70 (d, J= 8.9 Hz, 1H), 7.32 (t, J= 7.5 Hz, 1H), 7.28 - 6.95 (m, 7H), 6.76 (d, J = 7.5 Hz, 2H), 5.67 (d, J= 7.6 Hz, 1H), 4.72 (s, 2H), 4.59 (dd, J= 14.6, 8.5 Hz, 1H), 3.96 (t, J = 6.0 Hz, 2H), 3.39 - 3.12 (m, 5H), 2.75 - 2.54 (m, 2H), 2.37 (s, 3H).
[0377] (Example 159): (400 MHz, DMSO-d6) δ 8.55 (d, J= 7.2 Hz, 1H), 8.40 (s, 1H), 7.28 - 6.98 (m, 7H), 6.70 (s, 3H), 5.70 (s, 1H), 4.72 (s, 3H), 3.94 (s, 2H), 3.42 - 3.10 (m, 5H), 2.68 (s, 2H), 2.36 (s, 3H).
Example 160
[0378] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2-fluoroethyl)-2-methyl-lH- indol- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000105_0001
[0379] To a mixture of (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2- hydroxyethyl)-2-methyl- lH-indol- 1 -yl)acetamido)-N-methyl-3 -phenylpropanamide (40 mg) in dry DCM (5 mL) at 0°C was added DAST (1.5 eq). The mixture was then stirred at 0°C for 3 hours. The reaction mixture was washed with water, dried over Na2S04 and
concentrated. The residue was purified by flash chromatography to give a white solid (15 mg). LC/MS: m/z M++l = 550.
[0380] 1H NMR (400 MHz, CDC13) 57.19 - 7.07 (m, 5H), 7.03 (t, J= 7.8 Hz, 1H), 6.97 (dd, J= 8.9, 1.7 Hz, 1H), 6.78 (d, J= 8.3 Hz, 1H), 6.62 (d, J= 6.7 Hz, 2H), 6.51 (dd, J = 14.2, 5.0 Hz, 1H), 6.02 (s, 2H), 5.72 (d, J= 7.3 Hz, 1H), 4.73 (dd, J= 10.4, 7.1 Hz, 2H), 4.62 - 4.58 (m, 2H), 3.39 (dt, J= 13.7, 6.3 Hz, 2H), 3.15 (s, 3H), 2.75 (dd, J= 13.2, 6.0 Hz, 1H), 2.49 (dd, J= 12.8, 7.3 Hz, 1H), 2.25 (s, 3H).
Example 161
[0381] (5)-2-(2-(3-(2-aminoethyl)-4-chloro-2-methyl-lH-indol-l-yl)acetamido)-N- (benzo [d] [1,3] dioxol-5 -yl)-N-methyl-3 -phenylpropanamide
Figure imgf000106_0001
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
Tosl
Figure imgf000106_0002
[0382] To a solution of (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2- hydroxyethyl)-2-methyl- lH-indol- 1 -yl)acetamido)-N-methyl-3 -phenylpropanamide (100 mg, 0.18 mmole, 1.0 eq) in dry DCM (10 mL) were added DIPEA (0.1 mL, 0.45 mmol, 2.5 eq) and DMAP (56 mg, 0.27 mmol, 2.5 eq). After the mixture was cooled down to 0°C, a solution of TsCl (52 mg, 0.27 mmol, 1.5 eq) in DCM (1 mL) was added dropwise over 10 minutes. After the addition, the mixture was stirred at 0-5°C for 1 hour and then quenched with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2x10 mL). The combined organic layers were washed with sat. NaHC03 (20 mL), dried over Na2S04 and concentrated in vacuo to give crude product (180 m g, 0.26 mmol, yield: 140%) as a yellow solid without purification for the next step.
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
Figure imgf000106_0003
[0383] To a solution of crude (5)-2-(l-(2-(l-(benzo[<i][l,3]dioxol-5-yl(methyl)amino)-l- oxo-3-phenylpropan-2-ylamino)-2-oxoethyl)-4-chloro-2-methyl-lH-indol-3-yl)ethyl 4- methylbenzenesulfonate (180 mg, 0.26 mmole, 1.0 eq) in DMF (4 mL) was added sodium azide (169 mg, 2.6 mmol, 10.0 eq). The resulting mixture was stirred at 40°C for 18 hours. After cooling to room temperature, the reaction mixture was treated with DCM (20 mL) and H20 (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2x10 mL). The combined organic layes were washed with aq. LiCl (15 mL), dried over Na2S04 and concentrated in vacuo, the residue was purified by preparative TLC to give product (40 mg, 0.069 mmol, 27%) as a colorless oil.
Example 161C. Preparation of (6 -2-(2-(3-(2-aminoethyl)-4-chloro-2-methyl-lH-indol-l- yl)acetamido)-N-(benzor<i1 Γ 1 ,31dioxol-5-yl)-N-methyl-3-phenylpropanamide
[0384] To a solution of (5)-2-(2-(3-(2-azidoethyl)-4-chloro-2-methyl- lH-indol- 1 -yl)- acetamido)-N-(benzo[(i][l,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide (40 mg, 0.069 mmole, 1.0 eq) in THF (10 mL) were added Ph3P (50 mg, 0.19 mmol, 2.7 eq) and water (0.2 mL). The resulting mixture was refluxed for 18 hoursand then concentrated. The residue was purified by preparative HPLC to give the desired product (15 mg, 0.027 mmol, 39.5%) as a white solid. LC/MS: m/z M++l = 547.
[0385] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J =7.6 Hz, 1H), 8.42 (s, 1H), 7.13 - 7.24 (m, 5H), 6.90 - 6.99 (m, 4H), 6.69 - 6.77 (m, 2H), 6.05 (d, J= 4.4 Hz, 2H), 4.73 - 4.79 (m, 2H), 4.47-4.48 (m, 1H), 3.04-3.22 (m, 6H), 2.83-2.95 (m, 4H), 2.67-2.73(m, 2H), 2.16 (s, 3H)
Example 162
[0386] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2,2-difiuoroethyl)-2-methyl- lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000107_0001
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
Figure imgf000108_0001
[0387] To a solution of (5)-N-(benzo[ ][l ,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2- hydroxyethyl)-2-methyl-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide (270 mg, 0.493 mmol) in dichloromethane (5 mL) at 0 °C was added Dess-Martin reagent (250.7 mg, 0.591 mmol) portionwise. After addition, the mixture was stirred at 0 °C for 1 hour and another 1 hour at room temperature. The mixture was then concentrated to give the crude, which was purified by column chromatography to give the desired product (210 mg, yield 77.8%) as a white solid.
Example 162B. Preparation of (S)-N-(¾eDzor /iri.31dioxol-5-ylV2-(2-(4-chlon)-3-(2.2- difluoro- ethyl)-2-methyl- lH-indol- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
[0388] To a solution of (5)-N-(benzo[ ][l ,3]dioxol-5-yl)-2-(2-(4-chloro-2-methyl-3-(2- oxoethyl)-lH-indol-l -yl)acetamido)-N-methyl-3-phenylpropanamide (210 mg, 0.385 mmol) in dichloromethane (6 mL) at 0 °C was added DAST (186 mg, 1.15 mmol) dropwise. After addition, the mixture was stirred at 0 °C for 1 hour. Water (10 mL) was added to quench the reaction and the resulting mixture was extracted with dichloromethane (3x15 mL). The combined organic layers were dried over Na2S04 and concentrated to give the crude product, which was purified via column chromatography to give (5)-N-(benzo[<i][l ,3]dioxol-5-yl)-2- (2-(4-chloro-3-(2,2-difluoro- ethyl)-2-methyl-lH-indol-l-yl)acetamido)-N-methyl-3- phenylpropanamide (120 mg, yield 54.87%) as a white solid. LC/MS: m/z M++l = 568.
[0389] 1H NMR (400 MHz, CDC13) δ 6.97-7.18 (m, 6H), 6.76-6.78 (d, J= 8.0 Hz, 1H), 6.63-6.65 (d, J = 7.2 Hz, 2H), 6.36-6.49(m, 1H), 5.74-6.10 (m, 1H), 6.02 (s, 2H), 4.73-4.75 (m, 1H), 4.55-4.63 (q, 4H), 3.51-3.59 (m, 2H), 3.14 (s, 3H), 2.74-2.79 (m, 2H), 2.47-2.51 (m, 1H), 2.24 (s, 3H).
Example 163
[0390] (S)-2-(l -(2-(l -(benzo[<i] [ 1 ,3]dioxol-5-yl(methyl)amino)- 1 -oxo-3-phenylpropan-2- ylamino)-2-oxoethyl)-4-chloro-2-methyl-lH-indol-3-yl)acetic acid
Figure imgf000109_0001
[0391] To a mixture of (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-2-methyl-3-(2- oxo- ethyl)- lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide (90 mg) and MgS04 (29.7 mg) in acetone (4.5 mL) at 0 °C was added a solution of KMn04 (28.9 mg) in acetone (2.7 mL). The mixture was stirred at 0 °C for 1 hour, quenched by addition of 10% aq.
Na2S203 and then concentrated. The residue was acidified by 2Naq. HCl solution to pH 2-3. The mixture was then extracted with EtOAc (3x10 mL). The combined organic layers dried over Na2S04 and concentrated. The residue was purified by prep-HPLC to give a white solid (7.8 mg). LC/MS: m/z M++l = 568.
[0392] 1H NMR (400 MHz, CDC13) δ 7.17-7.03 (m, 5H), 6.90-6.60 (m, 6H), 5.99 (s, 2H), 4.70-4.67 (m, 1H), 4.33 (m, 2H), 4.01-3.99 (m, 2H), 3.12 (s, 3H), 2.79-2.75 (m, 1H), 2.58- 2.53 (m, lH), 2.12 (s, 3H).
Example 164
[0393] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2-hydroxy ethyl)-2- (methoxymeth- yl)-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000109_0002
Example 164A. Preparation of 4-chloro-l-tosyl-lH-indole
Figure imgf000109_0003
[0394] To a solution of 4-Cl-indole (3 g, 19.86 mmol) and Bu4NHS04 (674 mg, 1.98 mmol) in 50 mL of anhydrous DCM was added NaOH aq. (11 mL, con. 50%). The mixture was stirred for 15 minutes and TsCl (5.68 g, 29.8 mmol) was added thereto. The reaction was vigorously stirred at room temperature for 3 hours and then poured into water. The resulting mixture was extracted with DCM (30 mL><3). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired product 4-chloro-l- tosyl-lH-indole (5.0 g, 83%).
Example 164B. Preparation of 4-chloro-l-tosyl-lH-indole-2-carbaldehvde
Figure imgf000110_0001
[0395] To a solution of 4-chloro-l-tosyl-lH-indole (12 g, 39.3 mmol) in 120 mL of anhydrous THF at -70°C was added 2.5 Nn-BuLi (22 mL, 51 mmol) in THF. After addition, the mixture was warmed to 0°C and stirred for 1 hour. After the reaction was cooled down to -70°C, dry DMF (3.77g, 51 mmol) was added thereto. The resulting mixture was vigorously stirred at room temperature for 1 hour and then quenched with sat.NH4Cl. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired product 4-chloro-l-tosyl-lH- indole-2-carbaldehyde (4.5 g, 35%).
Example 164C. Preparation of (4-chloro-l-tosyl-lH-indol-2-yl)methanol
Figure imgf000110_0002
[0396] To a solution of 4-chloro-l-tosyl-lH-indole-2-carbaldehyde (4.4 g, 13.2 mmol) in 50 mL of MeOH at 0°C was added NaBH4 (0.6 g, 15.8 mmol). After addition, the mixture was stirred at room temperature for 1 hour, quenched with water (60 mL). After stirring for 30 minutes, the resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo to give the desired product (4-chloro-l-tosyl-lH-indol-2-yl)methanol (4.3 g, 97%).
Example 164D. Preparation of (4-chloro-lH-indol-2-yl)methanol
Figure imgf000110_0003
[0397] To a suspension of (4-chloro-l-tosyl-lH-indol-2-yl)methanol (3.2 g, 9.55 mmol) in 6 mL of anhydrous THF and 60 mL of EtOH was added KOH (2.67 g, 47.7 mmol). The mixture was refluxed for 2 hours. Aftert the reaction mixture was cooled down to room temperature and water was added to quench the reaction. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo to give the desired product (4- chloro-lH-indol-2-yl)methanol (1.7 g, 95%).
Example 164E. Preparation of 2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-lH-indole
Figure imgf000111_0001
[0398] To a solution of (4-chloro-lH-indol-2-yl)methanol (1.7 g, 9.4 mmol) in 20 mL of anhydrous DMF was added imidazole (1.3 g, 18.8 mmol) and TBDPSC1 (3.87 g, 14 mmol). The mixture was stirred at room temperature for 2 hours and then poured into water. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired product 2-((tert- butyldiphenylsilyloxy)methyl)-4-chloro-lH-indole (3.2 g, 82%).
Example 164F. Preparation of ethyl 2-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-lH- indol-3-yl)-2-oxoacetate
Figure imgf000111_0002
[0399] To a solution of 2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-lH-indole (1 g, 2.38 mmol) in 5 mL of anhydrous THF was added ethyl 2-chloro-2-oxoacetate (1.63 g, 11.9 mmol) and pyridine (0.94 g, 11.9 mmol). The mixture was refluxed for 2 hours and then ethyl 2-chloro-2-oxoacetate (2.6 g, 19 mmol) and pyridine (1.5 g, 19 mmol) was added. After the reaction was refluxed overnight and cooled down to room temperature, sa. NaHCOs solution was added thereto, and the resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired product ethyl 2-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-lH-indol-3- yl)-2-oxoacetate (460 mg, 37%). Example 164G. Preparation of 2-(4-chloro-2-(hydroxymethyl)-lH-indol-3-yl)ethanol
Figure imgf000112_0001
[0400] To a suspension of L1AIH4 (439 mg, 11.5 mmol) in 20 mL of anhydrous THF was added ethyl 2-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro- lH-indol-3-yl)-2-oxoacetate (1.2 g, 2.31 mmol) and the reaction mixture was refluxed for 2 hours. After the reaction was cooled down to room temperature, water was added to quench the reaction. The solid was filtered off and the filtrate was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo to give the desired product 2-(4-chloro-2-(hydroxymethyl)-lH-indol-3-yl)ethanol (378 mg, 72%).
Example 164H. Preparation of 3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((tert- butyldimethylsilyl -oxy)methyl)-4-chloro- lH-indole
Figure imgf000112_0002
[0401] To a solution of 2-(4-chloro-2-(hydroxymethyl)-lH-indol-3-yl)ethanol (378 mg, 1.68 mmol) in 10 mL of anhydrous DMF was added imidazole (343 mg, 5.03 mmol) and TBSC1 (760 mg, 5.03 mmol). The mixture was stirred at room temperature for 2 hours and then poured into water. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired product 3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((tert- butyldimethylsilyloxy)methyl)-4-chloro-lH-indole (550 mg, 72%).
Example 1641. Preparation of (^-Λ^-^6ηζοΓάΠΠ.31άίοχο1-5-νη-2-(2-(3-(2- 6ΐ1^η άί- methylsilyloxy)ethyl)-2-((tert-butyldimethylsilyloxy)methyl)-4-chloro- lH-indol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000112_0003
[0402] The mixture of 3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((tert-butyldimethylsilyl- oxy)methyl)-4-chloro-lH-indole (150 mg, 0.33 mmol), (S)-N-(benzo[d][l,3]dioxol-5-yl)-2- (2-bromoacetamido)-N-methyl-3-phenylpropanamide (207 mg, 1.496 mmol) and CS2CO3 (162 mg, 0.496 mmol) in 10 mL of anhydrous DMF was stirred at 80 °C for 2 hours and then poured into water. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired product (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-(2-(tert- butyldimethylsilyloxy)ethyl)-2-((tert-butyldimethylsilyloxy)methyl)-4-chloro- lH-indol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide (180 mg, 69%).
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
[0403] To a solution of (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-(2-(tert- butyldimethylsilyl-oxy)ethyl)-2-((tert-butyldimethylsilyloxy)methyl)-4-chloro- lH-indol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide (300 mg, 0.38 mmol) in 6 mL of DCM at 0°C was added a solution of p-TSA (130 mg, 0.76 mmol) in 2 mL of MeOH. The mixture was stirred at room temperature for 2 hours, and then poured into 1% K3PO4 solution (2mL) at 0°C. The solution was then extracted with DCM (3x10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by silica gel chromatography to give the desired title product (60 mg, 28%). LC-MS: m/z M++l = 578.
[0404] 1H NMR (400 MHz, CDC13) δ 7.14-7.05 (m, 6H), 6.75-6.65 (m, 3H), 6.36-6.32 (m, 2H), 6.03 (s, 2H), 4.83-4.69 (m, 3H), 4.56 (s, 2H), 4.15-4.13 (m, 1H), 3.91 (brs, 2H), 3.46 (s, 3H), 3.43-3.35 (m, 1H), 3.28-3.25 (m, 1H), 3.10 (s, 3H), 2.73-2.68 (m, 1H), 2.55-2.50 (m, 1H).
Example 165
[0405] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2-hydroxyethyl)-2-(hydroxyl- methyl)-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000113_0001
[0406] To a solution of (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-(2-(tert- butyldimethylsilyl-oxy)ethyl)-2-((tert-butyldimethylsilyloxy)methyl)-4-chloro- lH-indol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide (150 mg, 0.19 mmol) in 3 mL of THF at 0°C was added 1 NTBAF in THF solution (0.57 mL, 0.57 mmol). The mixture was stirred at room temperature for 2 hours, and then poured into water. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine and dried over anhydrous Na2S04. Solvent was removed in vacuo, and the residue was purified by HPLC to give the desired product (55 mg, 52%). LC-MS: m/z M++l = 564.
[0407] 1H NMR (400 MHz, DMSO-d6) δ 7.21-7.20 (m, 1H), 7.18-6.89 (m, 6H), 6.74- 6.67 (m, 3H), 6.05-6.04 (m, 2H), 5.11 (d, J= 6.8Hz, 2H), 5.11-5.09 (m, 1H), 4.91-4.80 (m, 2H), 4.73-4.71 (m, 1H), 4.50-4.45 (m, 3H), 3.57-3.51 (m, 2H), 3.09-3.05 (m, 5H), 2.93-2.89 (m, 1H), 2.71-2.66 (m, 1H).
Example 166
[0408] (5)-N-(benzo[ d][ 1 ,3]dioxol-5-yl)-2-(2-(4-chloro-2-(difluoromethyl)- lH-indol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000114_0001
Example 166A. Preparation of 4-chloro-2-(difluoromethyl)-l-tosyl-lH-indole
Figure imgf000114_0002
[0409] DAST (0.12 mL, 0.9 mmol, 3.0 eq) was added to a solution of 4-chloro-l-tosyl- lH-indole-2-carbaldehyde (100 mg, 0.3 mmol, 1.0 eq) in anhydrous DCM (2 mL) at 0 °C and the reaction mixture was stirred at 20 °C for 1 hour. After concentrated, the mixture was purified by prep-TLC to afford the product (100 mg, 0.28 mmol, yield: 93.6%) as a white solid.
Example 166B. Preparation of 4-chloro-2-(difluoromethyl)-lH-indole
Figure imgf000114_0003
[0410] TBAF (0.42 mL, 0.42 mmol, 3.0 eq) was added to a solution of 4-chloro-2- (difluoro- methyl)- 1-tosyl-lH-indole (50 mg, 0.14 mmol, 1.0 eq) in anhydrous THF (2 mL) under nitrogen atmosphere. The mixture was stirred at 75 °C for 2 hours. Upon cooling, the mixture was partitioned between EtOAc and 0.2 NHC1. The organic phase was separated, dried over anhydrous Na2S04 and concentrated. The residue was purified by pre-TLC to afford the product (20 mg, 0.10 mmol, yield: 71.4%) as a yellow liquid.
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
Figure imgf000115_0001
[0411] CS2CO3 (59 mg, 0.18 mmol, 2.0 eq) was added to a solution of 4-chloro-2- (difiuoro- methyl)- lH-indole (18 mg, 0.09 mmol, 1.0 eq) and (25)-N-(benzo [d] [1,3] dioxol-5 - yl)-2-(2-bromopropanamido)-N-methyl-3-phenylpropanamide (45 mg, 0.11 mmol, 1.2 eq) in anhydrous MeCN (1 mL) at nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours and quenched by addition of sa. NaHC03. The resulting mixture was extracted with EtOAc (3x15 mL). The combined organic layers was dried over anhydrous Na2S04 and concentrated. The residue was purified by prep-TLC to afford the product (23 mg, 0.04 mmol, yield : 44.4%) as white solid. LC-MS: m/z M++l = 540.
[0412] 1H NMR (400 MHz, CDC13) δ 7.27 - 7.12 (m, 6H), 6.98 (s, 1H), 6.81 - 6.73 (m, 3H), 6.36 (s, 1H), 6.03 (s, 3H), 4.94 - 4.77 (m, 3H), 3.13 (s, 3H), 2.81 (dd, J= 13.2, 7.4 Hz, 1H), 2.63 (dd, J= 13.3, 6.9 Hz, 1H), 1.60 (s, 3H).
Example 167
[0413] (5)-N-([l,3]dioxolo[4,5-b]pyridin-5-yl)-2-(2-(4-chloro-3-(2-hydroxyethyl)-2- methyl- lH-indol- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000115_0002
Example 167A. Preparation of [l,31dioxolo[4,5-&lpyridine
Figure imgf000116_0001
[0414] To a solution of 2,3-dihyroxylpyridine (5.0 g, 45.0 mmol, 1.0 eq) in NMP (50 mL), was added CH2Br2 (7.83 g, 45.0 mmol, 1.0 eq). The mixture was heated to 120 °C for 48 hours. The excess NMP was evaporated in vacuum and the residue was dissolved in EtOAc and washed with water and brine, dried and concentrated to give the product
[l,3]dioxolo[4,5-b]pyridine (1.0 g, 8.1 mmol, yield: 18.0%), LC/MS: m/z M++l = 124. Example 167B. Preparation of 5-nitro-[l,31dioxolo[4,5-&lpyridine
Figure imgf000116_0002
[0415] To a mixture of concentrated sulfuric acid (5 mL) and the concentrated nitric acid (4 mL), was added dropwise a solution of [l,3]dioxolo[4,5-£]pyridine (200 mg, 1.62 mmol, 1.0 eq) in concentrated H2S04 (1 mL), and the temperature was maintained between 35 °C and 40 °C. The mixture was stirred at this temperature for 2 hours until TLC indicated the SM had disappeared. The mixture was poured onto ice and basified to pH 10, and then extracted with EtOAc (3x10 mL). The combined organic extracts were washed with water and brine, dried and concentrated to give the product 5-nitro-[l,3]dioxolo[4,5-£]pyridine (120 mg, 0.71 mmol, yield: 44.1%), LC/MS: m/z M++l = 169.
Example 167C. Preparation of [l,3]dioxolo[4,5-¾lpyridin-5-amine
Figure imgf000116_0003
[0416] To a solution of 5-nitro-[l,3]dioxolo[4,5-£]pyridinein (1.0 g, 5.95 mmol, 1.0 eq) in methanol (20 mL), Ranney nickel (0.5 mL, suspending in water) was added and the mixture was cooled to 0 °C. Then hydrazine hydrate (0.5 mL, 26.6 mmol, 4.5 eq, 85% aq solution) was added dropwise, and the mixture was stirred at 0 °C for 2 hours until TLC indicated the SM had disappeared. Then the solid was filtrated off and the filtrate was concentrated, the residue was dissolved in ethyl acetate and washed with water, and brine. The organic extract was dried over anhydrous Na2S04. After filtration and concentration, the desired crude product was obtained. [l,3]dioxolo[4,5-b]pyridin-5-amine (756 mg, 5.48 mmol, yield: 92%). LC/MS: m/z M++l = 139. Example 167D. Preparation of N-methyl-[l,31dioxolo[4,5-¾lpyridin-5-amine
Figure imgf000117_0001
[0417] To a solution of sodium methoxide (1.48 g, 27.4 mmol, 5.0 eq) in MeOH (20 mL), were added paraformaldehyde (1.64 g, 54.8 mmol, 10.0 eq) and [l,3]dioxolo[4,5-£]pyridin-5- amine (756 mg, 5.48 mmol, 1.0 eq). The mixture was stirred at room temperature for 24 hours until TLC indicated the SM was disappeared. Then sodium borohydride (625 mg, 16.5 mmol, 3.0 eq) was added portionwise, and the mixture was stirred at 40 °C for additional 3 hours. The resulting mixture was concentrated and dissolved in EtOAc, washed with water and brine, dried with anhydrous Na2SC>4. After filtration and concentration, the residue was purified by silica gel column chromatography to give the desired product N-methyl- [l,3]dioxolo[4,5- yridin-5-amine (816 mg, 5.37 mmol, yield: 98%). LC/MS: m/z M++l = 153.
Example 167E. Preparation of (6 -N-([l,31dioxolo[4,5-¾lpyridin-5-yl)-2-amino-N-methyl-3- phenylpropanamide
Figure imgf000117_0002
[0418] The procedure was similar to 102 A and 102B utilizing the N-methyl- [l,3]dioxolo[4,5-¾]pyridin-5-amine as starting material to obtain the product, LC/MS: m/z M++l = 300.
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
[0419] To a mixture of 2-(4-chloro-3-ethyl-2-dimethyl-lH-indol-l-yl)acetic acid (80 mg, 0.35 mmol, 1.0 eq) and (5)-2-amino-N-methyl-N,3-diphenylpropanamide (125.2 mg, 0.42 mmol, 1.2 eq) in DCM (3.0 mL), were added EDCI (101.2 mg, 0.53 mmol, 1.5eq), HOBt (94.5 mg, 0.7 mmol, 2.0 eq) and DIPEA (90.3 mg, 0.7 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times. The organic extract was dried and concentrated. The residue was purified by prep-HPLC to give the final product (5)-N-([l,3]dioxolo[4,5-b]pyridin-5-yl)-2-(2-(3-ethyl- 2,4-dimethyl-lH-indol-l-yl)acetamido)-N-methyl-3-phenylpropanamide (23.6 mg, 0.05 mmol, isolated yield: 14.3%), LC/MS: m/z M++l = 549, HPLC retention time = 2.79 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0420] 1H NMR (400 MHz, DMSO) (400 MHz, CDC13) δ 7.22 - 6.99 (m, 6H), 6.66 (d, J = 6.7 Hz, 2H), 6.58 (d, J = 8.0 Hz, 1H), 6.17 (s, 2H), 5.79 (s, 1H), 4.94 (s, 1H), 4.75 - 4.57 (m, 2H), 3.90 (t, J = 10.6 Hz, 2H), 3.43 - 3.28 (m, 1H), 3.18 (d, J = 15.2 Hz, 3H), 3.17 - 3.05 (m, 1H), 2.82 (d, J = 8.9 Hz, 1H), 2.55 (s, 1H), 2.29 (s, 3H).
Example 168
[0421] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-(2-hydroxyethyl)-2,4,7-trimethyl-lH- indol- 1 -yl)acetamido)-N-meth l-3-(pyridin-4-yl)propanamide
Figure imgf000118_0001
Example 168A. Preparation of (6 -2-amino-N-(benzo[dl[l,31dioxol-5-yl)-N-methyl-3- (pyridin-4-yl)propanamide
Figure imgf000118_0002
[0422] To a mixture of (5)-2-((tert-butoxycarbonyl)amino)-3-(pyridin-4-yl)propanoic acid (500 mg, 3.0 mmol, 1.0 eq) and N-methylbenzo[d][l,3]dioxol-5-amine (549 mg, 3.6 mmol, 1.2 eq) in DCM (10 mL), were added EDCI (864 mg, 4.5 mmol, 1.5 eq), HOBt (810 mg, 6.0 mmol, 2.0 eq) and DIPEA (1 mL, 6.0 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2 atmosphere. The resulting solution was washed with water 3 times, dried and concentrated, and the residue was purified by column
chromatography to give the product (5)-tert-butyl(l-(benzo[<i][l,3]dioxol-5- yl(methyl)amino)-l-oxo-3-(pyridin-4-yl)propan-2-yl)carbamate (450 mg, 1.13 mmol, isolated yield: 37.7%), LC/MS: m/z M++l = 400. Example 168B. Preparation of (6 -2-amino-N-(benzo[(i [l,31dioxol-5-yl)-N-methyl-3- (pyridin-4-yl)propanamide
Figure imgf000119_0001
[0423] To a solution of (5)-tert-butyl(l -(benzo[<i] [ 1 ,3]dioxol-5-yl(methyl)amino)- 1 -oxo- 3-(pyridin-4-yl)propan-2-yl)carbamate(450 mg, 1.13 mmol, 1.0 eq) in MeOH , was added a solution of acetyl chloride (3 mL) in MeOH at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give the crude product (330 mg, 1.10 mmol, yield: 97.3%), LC/MS: m/z M++l = 300.
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
[0424] The procedure was similar to 1H utilizing the corresponding acid and amine to obtain the product, LC/MS: m/z M++l = 543, HPLC retention time = 2.47 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0425] 1H NMR (400 MHz, MeOD) δ 8.49 (t, J= 3.2 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.19 - 7.09 (m, 2H), 6.94 (d, J= 8.7 Hz, 1H), 6.76 (dt, J= 16.2, 8.0 Hz, 3H), 6.02 (s, 2H), 4.81 (dd, J= 15.7, 7.4 Hz, 1H), 3.88 (dd, J= 44.5, 15.4 Hz, 2H), 3.78 - 3.69 (m, 1H), 3.62 (dd, J= 15.9, 7.0 Hz, 1H), 3.27 - 3.07 (m, 5H), 2.74 (dd, J= 13.5, 7.7 Hz, 1H), 2.67 (s, 3H), 2.48 (s, 3H), 2.45 (dd, J= 13.5, 7.7 Hz, 1H), 2.43 (s, 1H).
[0426] Compounds 169-170 were prepared using a method analogous to that of Example 168 utilizing the corresponding acids and amines.
Examples 169 to 170
Figure imgf000119_0002
trimethyl-lH-indol-3- yl)acetamido)-N-methyl-3 - (pyridin-2-yl)propanamide
(S)-N-(benzo[d][l,3]dioxol-5- yl)-2-(2-(l-ethyl-2,4,7-
170 trimethyl-lH-indol-3- 543 2.42
yl)acetamido)-N-methyl-3 - (pyridin-3 -yl)propanamide
[0427] (Example 169): 1H NMR (400 MHz, CDC13) δ 8.50 (s, 1H), 8.01 (s, 1H), 7.55 (s, 1H), 7.50 - 7.09 (m, 4H), 6.89 (d, J= 7.2 Hz, 1H), 6.77 (d, J= 11.7 Hz, 3H), 6.02 (s, 2H), 4.96 (d, J= 6.7 Hz, 1H), 3.89 (dd, J= 34.3, 15.3 Hz, 2H), 3.77 - 3.57 (m, 2H), 3.19 (s, 3H), 3.00 (s, 1H), 2.80 (s, 1H), 2.66 (s, 3H), 2.47 (s, 3H), 2.42 (s, 3H).
[0428] (Example 170): 1H NMR (400 MHz, CDC13) δ 8.41 (d, J= 5.1 Hz, 2H), 8.21 (d, J = 9.4 Hz, 1H), 6.90 (d, J= 8.9 Hz, 1H), 6.77 (dt, J= 11.8, 6.0 Hz, 5H), 6.35 (s, 1H), 6.03 (s, 2H), 4.86 (dd, J= 15.8, 7.5 Hz, 1H), 3.93 (d, J= 15.6 Hz, 1H), 3.76 (dd, J= 15.1, 7.5 Hz, 2H), 3.63 - 3.53 (m, 1H), 3.51 (s, 2H), 3.18 (s, 3H), 3.27 - 3.07 (m, 2H), 2.73 (dd, J= 13.3, 7.0 Hz, 1H), 2.66 (s, 3H), 2.45 (s, 3H), 2.41 - 2.36 (m, 1H).
Example 171
[0429] (5)-2-(2-(4-chloro-3-ethyl-lH-indazol-l-yl)acetamido)-N-(6-methoxypyridin-3- yl)-N-methyl-3-phenylpropanamide
Figure imgf000120_0001
Example 171 A. Preparation of l-(2-chloro-6-fluorophenyl)propan-l-ol
Figure imgf000120_0002
[0430] To a solution of 2-chloro-6-fluorobenzaldehyde (5.0 g, 31.6 mmol, 1.0 eq) in THF at 0 °C under N2 atmosphere, was added dropwise ethylmagnesium bromide 1M solution in THF (63 mL, 63.0 mmol, 2.0 eq). The mixture was stirred room temperature for 2 hours. The reaction mixture was quenched by saturated aqueous NH4C1 solution and extracted with EA, and the organic phase was evaporated. The residue was purified by chromatography on silica gel (PE:EA=10: 1) to give l-(2-chloro-6-fluorophenyl)propan-l-ol (2.5 g, 13.3 mmol .yield: 43% ) , LC/MS: m/z M++l = 189.
Example 17 IB. Preparation of l-(2-chloro-6-fluorophenyl)propan-l-one
Figure imgf000121_0001
[0431] To an acetone solution of l-(2-chloro-6-fluorophenyl)propan-l-ol (2.5 g,13.3 mmol, 1.0 eq), was added dropwise Jones reagent until TLC (PE:EA=5:1) indicated the SM had disappeared. Isopropanol was added to quench the reaction, and then followed by addition of H20. The mixture was extracted with EA. The organic phase was evaporated to give the residue which was purified by chromatography on silica gel (PE:EA=10: 1) to give 1 (2-chloro-6-fluorophenyl)propan-l-one (2.2 g, 11.8 mmol, yield: 89%), LC/MS: m/z M++l = 187.
Example 171C. Preparation of 4-chloro-3 -ethyl- lH-indazole
Figure imgf000121_0002
[0432] Hydrazine hydrate (85%>,20 mL) was added over a period of 10 minutes to a solution of l-(2-chloro-6-fluorophenyl)propan-l-one (2.2 g, 11.8 mmol, l .Oeq) in DME (20 mL). The reaction mixture was refluxed overnight and concentrated in vacuum to approximately 20 mL. Water (20 mL) was added to the mixture. The resulting precipitate was collected by filtration and dried to give 4-chloro-3-ethyl-lH-indazole (1.8 g, 10 mmol, yield: 85% ) , LC/MS: m/z M++l = 181.
Example 171D. Preparation of 2-(4-chloro-3-ethyl-lH-indazol-l-yl)acetic acid
Figure imgf000121_0003
[0433] To a DMF solution of 4-chloro-3-ethyl-lH-indazole (800 mg, 4.4 mmol, 1.0 eq), was added slowly NaH (264 mg, 6.6 mmol, 1.5 eq). After 30 minutes, ethyl 2-bromoacetate (0.76 mL, 6.6 mmol, 1.5 eq) was added dropwise. The mixture was stirred at 0 °C for 30 minutes until TLC (PE:EA=10: 1) indicated the SM had disappeared. Water (10 mL) was added to quench the reaction and followed by addition of NaOH (176 mg, 4.4 mmol, 1.0 eq). The mixture was stirred at room temperature for additional 30 minutes, and then extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04 and concentrated to give 2-(4-chloro-3-ethyl-lH-indazol-l-yl)acetic acid (380 mg, 1.3 mmol, yield: 36%), LC/MS: m/z M++l = 239.
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
[0434] The procedure was similar to 1H utilizing the corresponding acid and amine to obtain the product, LC/MS: m/z M++l = 506, HPLC retention time = 3.28 minutes (10-90% MeCN and water solution, contained 0.1% TFA).
[0435] Compounds 172-173 were prepared using a method analogous to that of Example 1772utilizing the corresponding acids and amines.
Examples 172 to 173
Figure imgf000122_0001
Figure imgf000122_0002
[0436] (Example 172): 1H NMR (400 MHz, DMSO) δ 7.86 (s, 1H), 7.27 - 7.09 (m, 7H), 6.81 (d, J= 7.0 Hz, 2H), 6.72 (d, J= 8.0 Hz, 1H), 4.92 (q, J= 17.1 Hz, 2H), 4.65 (dd, J = 14.7, 8.0 Hz, 1H), 3.25 (q, J= 7.5 Hz, 2H), 3.16 (s, 3H), 2.83 (dd, J= 13.1, 8.1 Hz, 1H), 2.68 (dd, J= 13.1, 6.5 Hz, 1H), 2.59 (s, 3H), 1.45 (t, J= 7.5 Hz, 3H). [0437] (Example 173): 1H NMR (400 MHz, DMSO) δ 7.32 - 7.24 (m, 2H), 7.23 - 7.07 (m, 5H), 6.82 (d, J= 7.0 Hz, 2H), 6.73 (d, J= 8.2 Hz, 1H), 6.65 (d, J= 8.2 Hz, 1H), 6.03 (s, 2H), 4.91 (q, J= 17.1 Hz, 2H), 4.80 (dd, J= 14.9, 7.5 Hz, 1H), 3.24 (q, J= 7.5 Hz, 2H), 3.14 (s, 3H), 2.84 (dd, J= 13.2, 7.5 Hz, 1H), 2.67 (dd, J= 13.3, 6.7 Hz, 1H), 1.44 (t, J = 7.5 Hz, 3H).
Example 174
[0438] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2-hydroxyethyl)-lH-indazol- 1 -yl)acetamido)-N-methyl-3 -phenylpropanamide
Figure imgf000123_0001
Example 174A. Preparation of 4-chloro-lH-indazole
Figure imgf000123_0002
[0439] Hydrazine hydrate (85%, 50 mL) was added over a period of 10 minutes to a solution of 2-chloro-6-fluorobenzaldehyde (5.0 g, 31.6 mmol, 1.0 eq) in DME (50 mL). The reaction mixture was re fluxed overnight and concentrated in vacuum to approximately 50 mL. Water (50 mL) was added to the mixture. The resulting solid precipitate was collected by filtration and dried to give 4-chloro-lH-indazole (2.5 g, 16.4 mmol, yield: 52%), LC/MS: m/z M++l = 153.
Example 174B. Preparation of 4-chloro-3-iodo-lH-indazole
Figure imgf000123_0003
[0440] To a solution of 4-chloro-lH-indazole (1.7 g, 11.2 mmol, 1.0 eq) in DMF (20 mL), was added KOH (1.25 g, 22.4 mmol, 2.0eq). The mixture was stirred at room temperature for 30 minutes. To the resulting mixture, was added I2 (5.64 g, 22.4 mmol, 2.0 eq) in portions at 0 °C, and the mixture was stirred at room temperature overnight. LC-MS analysis showed the reaction was completed. The reaction mixture was poured into ice water and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with saturated aqueous Na2S03 (20 mL x 2), brine (20 mL x 2), dried over Na2S04 and concentrated to give 4-chloro-3-iodo-lH-indazole (2.7 g, 9.7 mmol , yield: 87%), LC/MS: m/z M++l = 279. Example 174C. Preparation of l-(4-chloro-3-iodo-lH-indazol-l-yl)ethanone
Figure imgf000124_0001
[0441] To a solution of 4-chloro-3-iodo-lH-indazole (1.6 g, 5.8 mmol, 1.0 eq) in DCM (15 mL), was added triethylamine (2.4 mL, 17.2 mmol, 3 eq) and followed by acetyl chloride (0.9 g, 11.6 mmol, 2.0 eq). The mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of water (10 mL), extracted with DCM (15 mL x 2), and the organic phase was evaporated to give the residue which was purified by chromatography on silica gel (PE:EA=10: 1) to give l-(4-chloro-3-iodo-lH-indazol-l- yl)ethanone (1.4 g, 4.3 mmol, yield: 76%), LC/MS: m/z M++l = 321.
Example 174D. Preparation of 4-chloro-3-vinyl-lH-indazole
Figure imgf000124_0002
[0442] To a solution of l-(4-chloro-3-iodo-lH-indazol-l-yl)ethanone (500 mg, 1.6 mmol, 1.0 eq) in DMF (10 mL), were added tributyl(vinyl)tin (1.9 g, 6.4 mmol, 4.0 eq) and
Pd(PPh3)4 (0.05 g, 0.1 eq). The resulting mixture was refluxed overnight under N2 atmosphere. TLC (petroleum ether/EtOAc 3: 1) indicated the reaction was completed. The reaction mixture was quenched by the addition of water (10 mL),then the mixture was cooled to room temperature and extracted with EtOAc (2x20 mL). The organic phase was evaporated to give a residue which was purified by column chromatography on silica gel (PE:EA=5: 1) to give 4-chloro-3-vinyl-lH-indazole (210 mg, 1.2 mmol, yield: 75%), LC/MS: m/z M++l = 179. Example 174E. Preparation of 2-(4-chloro-3-vinyl-lH-indazol-l-yl)acetic acid
Figure imgf000125_0001
[0443] To a stirred mixture of 4-chloro-3-vinyl-lH-indazole (210 mg, 1.2 mmol, 1.0 eq) and potassium carbonate (662 mg, 4.8 mmol, 4.0 eq)in DMF (5 mL), was added dropwise ethyl 2-bromoacetate (0.26 mL, 2.4 mmol, 2.0 eq). The mixture was stirred at room temperature for 50 minutes until TLC (PE:EtOAc=l : 1) indicated the SM was disappeared. Water (10 mL) was added to quench the reaction, and then NaOH (48 mg, 1.2 mmol, 1.0 eq) was added. The mixture was stirred at room temperature for another 30 minutes, and then extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (2x10 mL), dried over Na2S04 and concentrated to give 2-(4-chloro-3-vinyl-lH-indazol-l- yl)acetic acid (200 mg, 0.85 mmol, yield: 72%) , LC/MS: m/z M++l = 237.
Example 174F. (S)-JV-(benzor< l Γ 1.31dioxol-5-yl)-2-(2-(4-chloro-3-vinyl- lH-indazol-1 - yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000125_0002
[0444] To a mixture of 2-(4-chloro-3-vinyl-lH-indazol-l-yl)acetic acid (80 mg, 0.34 mmol, 1.0 eq) and (5)-2-amino-N-(benzo[<i][l,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide (101 mg, 0.34 mmol, 1.0 eq) in DCM (3 mL), were added EDCI (129 mg, 0.68 mmol, 2.0 eq), HOBt (91 mg, 0.68 mmol, 2.0 eq) and DIPEA (0.45 mL, 1.3 mmol, 4.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water (3mL x 2), dried and concentrated, and the residue was purified by prep-HPLC to give (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-vinyl-lH-indazol-l-yl)acetamido)-N- methyl-3-phenylpropanamide (130 mg, 0.25 mmol, yield: 28%), LC/MS: m/z M++l = 517. Example 174G. (S)-N-(benzo\d]\\ .31dioxol-5-yl)-2-(2-(4-chloro-3-vinyl- lH-indazol- 1 - yl)acetamido)-N-methyl-3-phenylpropanamide
[0445] To a solution of 9-borabicyclo[3.3.1]nonane in THF (0.5M, 5 mL), was added (5)- N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-vinyl-lH-indazol-l-yl)acetamido)-N-methyl- 3-phenylpropanamide (13 Omg, 0.25 mmol, 1.0 eq). The mixture was stirred at room temperature for 2 hours until TLC (PE:EA=2: 1) indicated the SM had disappeared. The reaction mixture was quenched by the addition of methanol (5 mL), then evaporated to give a residue which was added H202 (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). The organic extract was evaporated to give a residue which was purified by prep-HPLC to give the final product (5)-N-(benzo[<i][l,3]dioxol-5-yl)-2-(2-(4-chloro-3-(2-hydroxyethyl)- lH-indazol-l-yl)acetamido)-N-methyl-3-phenylpropanamide(50 mg, 0.09 mmol, isolated yield: 37%). LC/MS: m/z M++1 = 535, HPLC retention time = 2.82 minutes (10-90% MeCN and water solution, contained 0.1% TFA).
[0446] 1H NMR (400 MHz, DMSO) δ 8.71 (d, J= 7.9 Hz, 1H), 7.30 - 7.19 (m, 5H), 7.13 (dd, J= 5.1, 3.0 Hz, 1H), 7.00 - 6.80 (m, 3H), 6.66 (d, J= 19.5 Hz, 2H), 6.05 (d, J= 3.3 Hz, 2H), 5.00 (q, J= 16.6 Hz, 2H), 4.74 (t, J= 5.5 Hz, 1H), 4.47 (dd, J= 13.5, 8.4 Hz, 1H), 3.75 (dd, J= 12.8, 7.4 Hz, 2H), 3.21 (t, J= 7.5 Hz, 2H), 3.09 (s, 3H), 2.93 (dd, J= 13.4, 5.0 Hz, 1H), 2.71 (dd, J= 13.4, 9.1 Hz, 1H).
Example 175
[0447] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-ethyl-2-methyl-lH-pyrrolo[2,3- b]pyridin- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
Figure imgf000126_0001
Example 175 A. Preparation of tert-butyl (3-methylpyridin-2-yl)carbamate
Figure imgf000126_0002
[0448] To a solution of 3-methylpyridin-2-amine (15 g, 0.14 mol, 1.0 eq) in EtOAc (30 mL) and petroleum ether (120 mL), was added Boc20 (48.5 g, 0.55 mol, 1.6 eq). The reaction mixture was stirred at room temperature for 4 hours. TLC (petroleum ether/EtOAc 3: 1) showed the reaction was completed. The reaction mixture concentrated in vacuum to give the crude product, which was purified by column chromatography on silica gel to give tert-butyl (3-methylpyridin-2-yl)carbamate (20 g, 0.096 mmol, yield: 68.6%), LC/MS: m/z M++l = 209.
Example 175B. Preparation of 2-methyl-lH-pyrrolo[2,3-&lpyridine
Figure imgf000127_0001
[0449] ft-BuLi (2.5M, 19.4 mL, 50.4 mmol, 7 eq) was added dropwise to a solution of tert-butyl (3-methylpyridin-2-yl)carbamate (1.5 g, 7.2 mmol, leq) in dry THF (50 mL) at -78 °C, and the resulting solution was stirred at -78 °C for 2 hours. Then DMA (3 g, 36 mmol, 5 eq) was added dropwise. The mixture was stirred at -78°C for another 2 hours. TLC (100%) EtOAc) indicated the reaction was completed. H20 (10 mL) were added to the reaction mixture to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2S04 and concentrated in vacuum. The residue was dissolved in concentrated HC1 (15 mL) and then re fluxed for 12 hours. The mixture was then cooled to room temperature, washed with EtOAc, the aqueous layer was concentrated in vacuum to give 2-methyl-lH-pyrrolo[2,3-b]pyridine (0.3 g, 2.27 mmol, yield: 31.5%), LC/MS: m/z M++l = 133.
Example 175C. Preparation of 3-iodo-2-methyl-lH-pyrrolo[2,3-¾lpyridine
[0450] To a solution of 2-methyl-lH-pyrrolo[2,3-£]pyridine (1.0 g, 7.58 mmol, 1 eq) in DMF (20 mL), was added KOH (0.42 g, 7.58 mmol, 1 eq) at 0 °C. The mixture was stirred at room temperature for 30 minutes. To this resulting mixture, was added I2 (3.85 g, 15.16 mmol, 2 eq) in portions at 0 °C, and the mixture was stirred at room temperature overnight. TLC (petroleum ether/EtOAc 1 : 1) showed the reaction was completed. The reaction mixture was poured into ice water and extracted with EtOAc (80 mL x 2). The combined organic extracts were washed with saturated aqueous Na2S03 (10 mL x 2), brine (10 mL x 2), dried over Na2S04 and concentrated to give 3-iodo-2-methyl-lH-pyrrolo[2,3-b]pyridine (1.0 g,
3.86 mmol , yield: 51.5%), LC/MS: m/z M++l = 259. Example 175D. Preparation of tert-butyl 2-(3-iodo-2-methyl-lH-pyrrolo[2,3-blpyridin-l- yDacetate
Figure imgf000128_0001
[0451] To a DMF solution of 3-iodo-2-methyl-lH-pyrrolo[2,3-£]pyridine (0.3 g, 1.16 mmol, 1 eq), NaH (70 mg, 1.74 mmol, 1.5 eq) was added slowly. After 20 minutes, tert- butyl 2-bromoacetate (0.23 g, 1.16 mmol, leq) was added dropwise. The mixture was stirred at 0 °C for 30 minutes until TLC (petroleum ether/EtOAc 1 : 1) indicated the SM had disappeared. Water (15 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (10 mL x 2), dried over Na2S04 and concentrated to give tert-butyl 2-(3-iodo-2-methyl-lH-pyrrolo[2,3- b]pyridin-l-yl)acetate (0.20 g, 0.53 mmol, yield: 46%), LC/MS: m/z M++l = 373.
Example 175E. Preparation of tert-butyl 2-(2-methyl-3-vinyl-lH-pyrrolor2,3-¾1pyridin-l- vDacetate
Figure imgf000128_0002
[0452] To a solution of tert-butyl 2-(3-iodo-2 -methyl- lH-pyrrolo[2,3-¾]pyridin-l- yl)acetate (0.3 g, 0.8 mmol, 1 eq) and tributyl(vinyl)tin (1 g, 3.2 mmol, 4 eq) in DMF (10 mL), was added Pd(PPh3)4 (0.03 g) under N2. The resulting mixture was refluxed overnight. TLC (petroleum ether/EtOAc 1 : 1) indicated the reaction was completed. The reaction mixture was cooled to room temperature and then filtered. Wet cake was washed with EtOAc (20 mL). The filtrate was concentrated in vacuum to give residue, which was purified by column chromatography on silica gel to give tert-butyl 2-(2-methyl-3-vinyl-lH- pyrrolo[2,3-b]pyridin-l-yl)acetate (0.15 g, 0.55 mmol, yield: 69%), LC/MS: m/z M++l = 273. Example 175F. Preparation of 2-(2-methyl-3-vinyl-lH-pyrrolo[2,3-¾lpyridin-l-yl)acetic acid
Figure imgf000129_0001
[0453] A mixture of 2-(2-methyl-3-vinyl-lH-pyrrolo[2,3-¾]pyridin-l-yl)acetic acid (0.3 g, 1.1 mmol, 1 eq), and NaOH (88 mg, 2.2 mmol, 2 eq) in MeOH (10 mL) and H20(15 mL) was stirred at room temperature for 3 hours. TLC (petroleum ether/EtOAc 1 : 1) showed the reaction was completed. The reaction mixture was concentrated to remove MeOH, and the residue was acidified to pH 6-7 and extracted with EtOAc (20 mL x 2) and THF (10 mL x 2). The combined organic extracts were washed with brine (10 mL), dried over Na2S04 and concentrated to give 2-(2-methyl-3-vinyl-lH-pyrrolo[2,3-¾]pyridin-l-yl)acetic acid (0.2 g, 3.86 mmol , yield: 84%), LC/MS: m/z M++l = 217.
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
Figure imgf000129_0002
[0454] To a mixture of 2-(2-methyl-3-vinyl-lH-pyrrolo[2,3-¾]pyridin-l-yl)acetic acid (lOOmg, 0.46mmol, leq), (5)-2-amino-N-(benzo[ ][l,3]dioxol-5-yl)-N-methyl-3- phenylpropanamide (137 mg, 0.46 mmol, 1.0 eq) in DCM (5 mL), were added EDCI (132 mg, 0.69 mmol, 1.5 eq), HOBt (124 mg, 0.92 mmol, 2.0eq) and DIPEA (118 mg, 0.92 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated, and the residue was purified by prep-HPLC to give the product ((5)-N-(benzo[ ][l,3]dioxol-5-yl)-N-methyl-2-(2-(2- methyl-3-vinyl-lH-pyrrolo[2,3-¾]pyridin-l-yl)acetamido)-3-phenylpropanamide (40 mg, 80 mmol , yield: 17%), LC/MS: m/z M++l = 497. Example 175H. Preparation οΐ (S)-N-(b zo\d]\l^dioxol-5 )-2-(2-(3-Qthyl-2- Qthyl-lH- pyrrolo [2,3 -^lpyridin- 1 -yl)acetamido)-N-methyl-3 -phenylpropanamide
[0455] To a mixture of ((5)-N-(benzo[ ][l,3]dioxol-5-yl)-N-methyl-2-(2-(2-methyl-3- vinyl-lH-pyrrolo[2,3-¾]pyridin-l-yl)acetamido)-3-phenylpropanamide (40 mg, 0.08 mmol, 1 eq) in MeOH (20 mL), was added Pt/C (10 mg). The suspension was degassed under vacuum and purged with H2 for 3 times. The mixture was stirred under H2 (55 psi) at room
temperature for 12 hours. TLC (petroleum ether/EtOAc = 1 : 1) showed the reaction was completed. The mixture was filtered and the filtrate was concentrated in vacuo to give the residue, which was purified by prep-HPLC to give the final product (5)-N- (benzo[<i][l,3]dioxol-5-yl)-2-(2-(3-ethyl-2-methyl-lH-pyrrolo[2,3-b]pyridin-l-yl)acetamido)- N-methyl-3 -phenylpropanamide (16 mg, 0.026 mmol, yield: 33.4%). LC/MS: m/z M++l = 499, HPLC retention time = 3.13 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0456] 1H NMR (400 MHz, CDC13) δ 8.24 (dd, J= 4.8, 1.4 Hz, 1H), 7.87 (dd, J= 7.8, 1.4 Hz, 1H), 7.28 (s, 1H), 7.12 (ddd, J= 12.6, 10.9, 6.0 Hz, 4H), 6.75 (dd, J= 16.5, 7.5 Hz, 3H), 6.66 (d, J= 7.3 Hz, 1H),6.02 (s, 2H), 5.32 (s, 1H), 4.97 - 4.80 (m, 2H), 4.76 (q, J= 7.4 Hz, 1H), 3.17 - 3.10 (m, 3H), 2.83 (dd, J= 13.2, 7.3 Hz, 1H), 2.74 (q, J= 7.6 Hz, 2H), 2.63 (dd, J= 13.3, 7.2 Hz, 1H), 2.29 (d, J= 4.6 Hz, 3H), 1.25 (t, J= 7.6 Hz, 3H).
Example 176
[0457] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-(2-hydroxyethyl)-2-methyl-lH- pyrrolo [2,3 -¾]pyridin- 1 -yl)acetami -N-methyl-3 -phenylpropanamide
Figure imgf000130_0001
To a solution of ((5)-N-(benzo[ ][l,3]dioxol-5-yl)-N-methyl-2-(2-(2-methyl-3-vinyl-lH- pyrrolo[2,3-¾]pyridin-l-yl)acetamido)-3-phenylpropanamide (130 mg, 0.25 mmol, 1.0 eq), was added a solution of 9-Borabicyclo[3.3.1]nonane in THF (0.5 M, 5 mL). The mixture was stirred at room temperature for 2 hours until TLC(PE:EA=2:1) indicated the SM had disappeared. The reaction mixture was quenched by the addition of methanol (5 mL), then evaporated to give a residue which was treated with H202 (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). The organic extract was evaporated to give a residue which was purified by prep-HPLC to give the final product(S)-N-(benzo[d][l,3]dioxol-5-yl)- 2-(2-(3-(2-hydroxyethyl)-2-methyl- lH-pyrrolo[2,3-b]pyridin- 1 -yl)acetamido)-N-methyl-3- phenylpropanamide (50 mg, 0.09 mmol, isolated yield: 37%). LC/MS: m/z M++1 = 515, HPLC retention time = 2.52 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0458] 1H NMR(400 MHz, CDC13) δ 8.28 (d, J= 4.8 Hz, 1H), 7.86 (d, J= 7.8 Hz, 1H), 7.47 (d, J= 7.4 Hz, 1H), 7.34 (d, J= 7.2 Hz, 2H), 7.22 - 7.04 (m, 4H), 6.75 (dd, J= 14.0, 7.6 Hz, 3H), 6.29 (d, J= 8.0 Hz, 1H), 6.02 (s, 2H), 5.01 (d, J= 16.9 Hz, 1H), 4.92 - 4.75 (m, 2H), 3.93 - 3.80 (m, 2H), 3.10 (s, 3H), 2.98 (t, J= 5.9 Hz, 2H), 2.77 - 2.71 (m, 1H), 2.61 (dd, J= 13.3, 6.6 Hz, 1H), 2.33 (s, 3H).
Example 177
[0459] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2-methyl-lH-pyrrolo[2,3- c]pyridin-3 -yl)acetamido)-N-methyl-3 -phenylpropanamide
Figure imgf000131_0001
Example 177A. Preparation of 2-methyl-lH-pyrrolo[2,3-clpyridine
Figure imgf000131_0002
[0460] Sec-BuLi (1.3 M, 50 mL, 65 mmol, 2.4 eq) was added dropwise to a solution of 4- methylpyridin-3 -amine (3.0 g, 27 mmol, 1.0 eq) in dry THF (50 mL) at -78 °C, and the resulting solution was stirred at -78 °C for 2 h. Then EtOAc (9.75 g, 108 mmol, 4 eq) was added dropwise and the resulting mixture was stirred at -78 °C for another 3 h. TLC
(petroleum ether/EtOAc 0: 1) indicated the reaction was completed. H20 (15 mL) were added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (500 mL), dried over Na2S04 and concentrated in vacuo. The residue was dissolved in cone. HCl (15 mL) and then refluxed for 12 hours. The mixture was then cooled to room temperature, washed with EtOAc, the aqueous layer was concentrated in vacuo. The residue was neutralized to pH 7, purified by column chromatography on silica gel to give 2 -methyl- 1H- pyrrolo[2,3-c]pyridine (1.2 g, 10 mmol, yield: 33.6%), LC/MS: m/z M++l = 133.
Example 177B. Preparation of l-ethyl-2-methyl-lH-pyrrolor2,3-c1pyridine
Figure imgf000132_0001
[0461] To a DMF solution of 2-methyl-lH-pyrrolo[2,3-c]pyridine (0.2 g, 1.51 mmol, leq), was added slowly NaH (90 mg, 2.26 mmol, 1.5 eq). After 20 minutes, bromoethane (0.16 g, 1.51 mmol, 1 eq) was added dropwise, and the mixture was stirred at at room temperature for 30 minutes. TLC (petroleum ether/EtOAc 0: 1) indicated the SM
disappeared. Water (15 mL) was added to quench the reaction and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04 and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel to give l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridine (0.15 g, 0.9 mmol, yield: 62.5%), LC/MS: m/z M++l = 161.
Example 177C. Preparation of methyl 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-clpyridin-3-yl)-2- oxoacetate
Figure imgf000132_0002
[0462] To a THF solution of l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridine (0.1 g, 0.625 mmol, 1 eq), was added oxalyl chloride (0.078 g, 0.625 mmol, 1 eq) dropwise. The mixture was stirred at at 0 °C for 30 minutes until TLC (petroleum ether/EtOAc 1 : 1) indicated the SM had disappeared. MeOH (15 mL) was added to the reaction and stirred for another 30 minutes and concentrated to give a residue, which was purified by column chromatography on silica gel to give methyl 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (0.1 g, 0.4 mmol, yield: 65%), LC/MS: m/z M++l = 247.
Example 177D. Preparation of methyl 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-clpyridin-3- vDacetate
^-OMe [0463] To a solution of methyl 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)-2- oxoacetate (0.1 g, 0.4 mmol, 1 eq) and TFA (0.5 mL) in THF (10 mL) was added
triethylsilane (0.09 g, 0.8 mmol, 2 eq) dropwise. The resulting mixture was stirred at 55 °C for 3 hours. TLC (petroleum ether/EtOAc 3: 1) indicated the reaction was completed. The reaction mixture was cooled to room temperature and concentrated to a residue, which was purified by column chromatography on silica gel to give methyl 2-(l-ethyl-2-methyl-lH- pyrrolo[2,3-c]pyridin-3-yl)acetate (0.08 g, 0.34 mmol, yield: 86%), LC/MS: m/z M++l = 233. Example 177E. Preparation of 2-(l-ethyl-2-methyl-lH-pyrrolor2,3-c1pyridin-3-yl)acetic acid
Figure imgf000133_0001
[0464] A solution of 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)acetate (0.08 g, 0.34 mmol, 1 eq) and NaOH (27 mg, 0.68 mmol, 2 eq) in MeOH (10 mL) and H20 (15 mL) was stirred at room temperature for 3 hours. TLC (petroleum ether/EtOAc 1 : 1) showed the reaction was completed. The reaction mixture was concentrated to remove MeOH, the residue was acidified to pH 6-7 and extracted with EtOAc (20 mL x 2) and THF (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2S04 and concentrated to give 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)acetic acid (0.01 g, 0.045 mmol , yield: 13.5%), LC/MS: m/z M++l = 219.
Example 177F. Preparation of (^-Λ^-^6ηζοΓ^1Π.31άίοχο1-5-νη-2-(2-(1-6&ν1-2^6&ν1-1^ pyrrolo [2,3 -clpyridin-3 -yl)acetamido)-N-methyl-3 -phenylpropanamide
[0465] To a mixture of 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)acetic acid (10 mg, 0.045 mmol, leq) and (5)-2-amino-N-(benzo[<i][l,3]dioxol-5-yl)-N-methyl-3- phenylpropanamide (13.4 mg, 0.045 mmol, 1.0 eq) in DMF (5 mL), were added EDCI (66.24 mg, 0.35 mmol, 1.5 eq), HOBt (62 mg, 0.46 mmol, 2.0 eq), and DIPEA (59 mg, 0.46 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated, the residue was purified by prep-HPLC to give the product (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2-methyl-lH- pyrrolo[2,3-c]pyridin-3-yl)acetamido)-N-methyl-3-phenylpropanamide (2 mg, 0.004 mmol , yield: 8.9%). LC/MS: m/z M++l = 499, HPLC retention time = 3.32 minutes (10-90% MeCN in water, containing 0.1% TFA). [0466] 1H NMR (400 MHz, CDC13) δ 8.82 (s, 1H), 8.23 (d, J= 5.7 Hz, 1H), 7.48 (s, 1H), 7.34 (d, J= 8.3 Hz, 2H), 7.15 (dt, J= 14.6, 7.2 Hz, 3H), 6.76 (dd, J= 12.6, 7.7 Hz, 3H), 6.11 (d, J= 7.7 Hz, 1H), 6.03 (s, 2H), 4.81 (d, J= 7.9 Hz, 1H), 4.24 (q, J= 7.0 Hz, 2H), 3.58 (s, 2H), 3.15 (s, 3H), 2.81 (dd, J= 13.4, 7.1 Hz, 1H), 2.64 (d, J= 7.0 Hz, 1H), 2.37 (s, 3H), 1.41 (d, J= 7.2 Hz, 3H).
Example 178
[0467] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2-methyl-lH-pyrrolo[2,3- ¾]pyridin-3 -yl)acetamido)-N-methyl-3 -phenylpropanamide
Figure imgf000134_0001
The procedure was similar to Example 177 utilizing the SM which was synthesized by 175B to afford the product, LC/MS: m/z M++l = 506, HPLC retention time = 3.28 minutes (10- 90% MeCN in water, containing 0.1% TFA).
[0468] 1H NMR (400 MHz, DMSO) δ 7.67 (s, 1H), 7.27 (s, 1H), 7.23 - 7.11 (m, 5H), 6.82 (d, J= 7.0 Hz, 2H), 6.66 (t, J= 8.2 Hz, 2H), 4.92 (q, J= 17.1 Hz, 2H), 4.69 (dd, J = 14.7, 7.9 Hz, 1H), 3.96 (s, 3H), 3.27 (d, J= 7.5 Hz, 2H), 3.14 (s, 3H), 2.83 (dd, J= 13.2, 8.0 Hz, 1H), 2.67 (dd, J= 13.2, 6.6 Hz, 1H), 1.45 (t, J= 7.5 Hz, 3H).
Example 179
[0469] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-lH-indol-3-yl)-2-oxoacetamido)- N-methyl-3 -phenylpropanamide
Figure imgf000134_0002
Example 179A. Preparation of methyl 2-(2 -methyl- lH-indol-3-yl)-2-oxoacetate
Figure imgf000135_0001
[0470] To a THF solution of 2-methylindole (2.0 g, 15.2 mmol, 1.0 eq), was added oxalyl chloride (1.94 g, 15.2 mmol, 1.0 q) dropwise. The mixture was stirred at 0 °C for 30 minutes until TLC (petroleum ether/EtOAc 1 : 1) indicated the SM was disappeared. MeOH (15 mL) was added to the reaction. After being stirred for another 30 minutes, the mixture was concentrated to give a residue, which was purified by column chromatography on silica gel to give methyl 2-(l-ethyl-2-methyl-lH-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (2.42 g, 11.1 mmol, yield: 73%), LC/MS: m/z M++l = 218.
Example 179B. Preparation of 2-(l-ethyl-2 -methyl- lH-indol-3-yl)-2-oxoacetic acid
Figure imgf000135_0002
[0471] To a DMF solution of methyl 2-(2-methyl-lH-indol-3-yl)-2-oxoacetate (400 mg, 1.84 mmol, 1.0 eq), was added slowly NaH (110 mg, 2.76 mmol, 1.5 eq) at 0 °C. After 20 minutes, bromoethane (0.20 mL, 2.76 mmol, 1.5 eq) was added dropwise. The mixture was stirred at 0 °C for 2 hours. Ice water (5 mL) was added to quench the reaction, and HC1 was used to adjust pH to 4. The mixture was extracted with EA and the desired product was precipitated by PE to give the product 2-(l-ethyl-2-methyl-lH-indol-3-yl)-2-oxoacetic acid (245 mg, 1.13 mmol, yield: 61.4%), LC/MS: m/z M++l = 232.
Example 179C. Preparation of (^-Λ^-^6ηζοΓ^1Π.31άίοχο1-5-νη-2-(2-(1-6&ν1-2^6&ν1-1^ indol-3 -yl)-2-oxoacetamido)-N-methyl-3 -phenylpropanamide
[0472] To a mixture of 2-(l-ethyl-2 -methyl- lH-indol-3-yl)-2-oxoacetic acid (150 mg, 0.69 mmol, 1.0 eq) and (5)-2-amino-N-(benzo[ ][l,3]dioxol-5-yl)-N-methyl-3- phenylpropanamide (247 mg, 0.83 mmol, 1.2 eq) in DCM (5 mL), were added EDCI (198.7 mg, 1.04 mmol, 1.5 eq), HOBt (186.3 mg, 1.38 mmol, 2.0 eq), and DIPEA (178 mg, 1.38 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated, the residue was purified by prep-HPLC to give the product (5)-N-(benzo[<i][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2- methyl-lH-indol-3-yl)-2-oxoacetamido)-N-methyl-3-phenylpropanamide (110 mg, 0.22 mmol, isolated yield: 32%). LC/MS: m/z M++l = 512, HPLC retention time = 3.10 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0473] 1H NMR (400 MHz, CDC13) δ 9.13 (d, J= 7.8 Hz, 1H), 7.76 (d, J= 7.9 Hz, 1H), 7.55 (d, J= 8.2 Hz, 1H), 7.39 (dd, J= 16.3, 8.0 Hz, 1H), 7.29 - 7.15 (m, 4H), 7.10 (t, J= 7.5 Hz, 1H), 7.07 - 6.90 (m, 4H), 6.12 (d, J= 5.6 Hz, 2H), 4.67 (dd, J= 12.7, 8.9 Hz, 1H), 4.23 (q, J= 7.3 Hz, 2H), 4.15 (q, J = 7.2 Hz, 1H), 3.16 (d, J= 5.7 Hz, 3H), 3.00 (dd, J= 13.6, 4.9 Hz, 1H), 2.81 (dd, J= 13.5, 9.6 Hz, 1H), 2.31 (s, 3H), 1.24 (t, J= 7.1 Hz, 4H).
[0474] Compounds 180-181 were prepared using a method analogous to that of Example 179 utilizing the corresponding acids and amines.
Examples 180 to 181
Figure imgf000136_0001
[0475] (Example 180): 1H NMR (400 MHz, DMSO) δ 12.06 (s, 1H), 9.23 (d, J= 7.7 Hz, 1H), 8.07 (s, 1H), 7.82 (d, J= 7.7 Hz, 1H), 7.52 (s, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.28 - 7.20 (m, 3H), 7.16 (dd, J= 11.0, 4.1 Hz, 1H), 7.10 (t, J= 7.1 Hz, 1H), 6.95 (dd, J= 12.0, 6.3 Hz, 3H), 4.54 (dd, J= 13.3, 8.8 Hz, 1H), 3.92 (s, 3H), 3.18 (s, 3H), 3.00 (dd, J= 13.6, 5.3 Hz, 1H), 2.83 (dd, J= 13.5, 9.3 Hz, 1H), 2.21 (s, 3H).
[0476] (Example 181): 1H NMR (400 MHz, CDC13) δ 7.94 (dd, J= 6.1, 2.8 Hz, 1H), 7.63 (s, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.31 (dd, J= 4.0, 2.4 Hz, 5H), 7.27 - 7.21 (m, 2H), 7.15 - 7.08 (m, 2H), 6.68 (d, J= 8.6 Hz, 1H), 4.88 (td, J= 8.5, 6.5 Hz, 1H), 4.20 (q, J= 7.3 Hz, 2H), 3.97 (s, 3H), 3.20 (s, 3H), 3.10 (dd, J= 17.5, 8.9 Hz, 1H), 2.97 (dd, J= 13.0, 6.4 Hz, 1H), 2.65 (s, 3H), 1.40 (t, J= 7.2 Hz, 3H). Example 182
[0477] Preparation of (25)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2-methyl-lH- indol-3 -yl)-2-hydroxyacetamido)- -methyl-3 -phenylpropanamide
Figure imgf000137_0001
To a MeOH solution of (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(l-ethyl-2-methyl-lH-indol-3- yl)-2-oxoacetamido)-N-methyl-3-phenylpropanamide (50 mg, 0.10 mmol, 1.0 eq), was added slowly NaBH4 (6 mg, 0.15 mmol, 1.5 eq) at 0 °C. The mixture was stirred at at room temperature for 2 hours. MeOH was removed in vacuo and the residue was extracted with EA, then purified by prep-HPLC to give the product (38 mg,0.08 mmol, yield: 80%).
LC/MS: m/z M++l = 514, HPLC retention time = 3.00 minutes (10-90% MeCN in water, containing 0.1% TF A).
[0478] 1H NMR (400 MHz, DMSO) 5 8.01 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.41 (d, J= 8.2 Hz, 1H), 7.26 (dd, J= 5.1, 1.8 Hz, 3H), 7.10 (t, J= 7.1 Hz, 1H), 7.04 - 6.96 (m, 3H), 6.89 (d, J= 8.2 Hz, 1H), 6.54 (s, 2H), 6.10 (d, J= 1.2 Hz, 2H), 5.88 (d, J= 3.9 Hz, 1H), 5.18 (d, J= 3.9 Hz, 1H), 4.61 (d, J= 6.8 Hz, 1H), 4.19 (t, J= 6.2 Hz, 2H), 3.16 (s, 3H), 2.97 (dd, J= 13.4, 6.2 Hz, 1H), 2.86 (dd, J= 13.5, 8.0 Hz, 1H), 2.41 (s, 3H), 1.30 (t, J= 8.4 Hz, 3H).
Example 183
[0479] (5)-2-(2-(4,7-dimethyl-lH-benzo[ ]imidazol-l-yl)acetamido)-N-methyl-N-(6- methylpyridin-3 -yl)-3 -phenylpropanamide
Figure imgf000137_0002
Example 183 A. Preparation of l,4-dimethyl-2,3-dinitrobenzene
Figure imgf000137_0003
[0480] 1 ,4-Dimethyl-2 -nitrobenzene (9.0 g, 59.0 mmol, 1.0 eq) was dissolved in concentrated HNO3 at 0 °C. To this, concentrated H2SO4 was added dropwise at this temperature. The mixture was stirred at 0 °C for 2 h until TLC indicated the SM had disappeared. Then the mixture was poured onto ice slowly, stirred at 0 °C for 30 minutes, and the solid was collected by filtration, washed with water and dried under vacuum to give l,4-dimethyl-2,3-dinitrobenzene (10.0 g, crude, 51.3 mmol, yield: 86.9%), LC/MS: m/z M++l = 197.
Example 183B. Preparation of 3, 6-dimethylbenzene-l,2-diamine
Figure imgf000138_0001
[0481] To a mixture of l,4-dimethyl-2,3-dinitrobenzene (10.0 g, crude, 51.3 mmol, 1.0 eq) in MeOH (30 mL), was added slowly Pd/C (1.5g, 15%) under N2. The mixture was stirred at 40 °C overnight under H2 atmosphere. Then Pd/C was filtered off, and the filtrate was concentrated to give the product 3,6-dimethylbenzene-l,2-diamine (6.0 g crude, 44.1 mmol, yield: 86.5%), LC/MS: m/z M++l = 137.
Example 183C. Preparation of 4 -dimethyl-lH-benzor 1imidazole
Figure imgf000138_0002
[0482] A mixture of 3,6-dimethylbenzene-l,2-diamine (3.0 g, 22.1 mmol, 1.0 eq) was dissolved in acetic acid (6 mL) was heated at reflux overnight. Then NaOH aqueous solution (3M) was added to adjust pH to 8, the precipitate was collected by filtration, and dried to give the product 4,7-dimethyl-lH-benzo[ ]imidazole (3.0 g, 20.7 mmol, yield: 94%), LC/MS: m/z M++l = 147.
Example 183D. Preparation of 2-(4,7-dimethyl-lH-benzo[(i imidazol-l-yl)acetic acid
Figure imgf000138_0003
[0483] To a THF solution of 4,7-dimethyl-lH-benzo[d]imidazole (1.0 g, 6.8 mmol, 1.0 eq), was added slowly NaH (408 mg,10.2 mmol, 1.5 eq). After 20 minutes, ethyl 2- bromoacetate (0.9 mL, 8.2 mmol, 1.2 eq) was added dropwise over a period of 30 minutes. The resulting mixture was stirred at at 0 °C for 30 minutes until TLC (DCM:MeOH=10: l) indicated the SM had disappeared. Water (15 mL) was added to quench the reaction and foolowed by addition of NaOH (100 mg, 2.5 mmol, 0.37 eq). The mixture was stirred at room temperature for another 30 minutes, then HC1 (2N) was added to adjust pH to 4, precipitate appeared and the solid was collected by filtration, washed and dried at 75 °C to give the product 2-(4,7-dimethyl-lH-benzo[<i]imidazol-l-yl)acetic acid (600 mg, 3.1 mmol, yield: 46%), LC/MS: m/z M++l = 205.0.
Example 183E. Preparation of (6 -2-(2-(4,7-lH-benzor(i1imidazol-l-yl)acetamido)-N-methyl- N-(6-methylpyridin-3 -vD-3 -phenylpropanamide
[0484] To a mixture of (i?)-2-amino-N-methyl-N-(6-methylpyridin-3-yl)-3- phenylpropanamide hydrochloride (64.5 mg, 0.24 mmol, 1.2 eq) and 2-(4,7-dimethyl-lH- benzo[d]imidazol-l-yl)acetic acid (40 mg, 0.2 mmol, 1.0 eq) in DCM (1.5 mL), were added EDCI (57.3 mg, 0.3 mmol, 1.5 eq), HOBt (54 mg, 0.4 mmol, 2.0 eq), and DIPEA (51.6 mg, 0.4 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated. The residue was purified by prep-HPLC to give the final product (S)-2-(2-(4,7-lH-benzo[i ]imidazol-l- yl)acetamido)-N-methyl-N-(6-methylpyridin-3-yl)-3 -phenylpropanamide (30 mg, 0.07 mmol, isolated yield:33%). LC/MS: m/z M++l = 456, HPLC retention time = 2.15 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0485] 1H NMR (400 MHz, DMSO) δ 8.93 (d, J= 7.6 Hz, 3H), 8.22 (d, J= 14.7 Hz, 5H), 7.97 (s, 3H), 7.40 (d, J= 7.4 Hz, 3H), 7.35 - 7.17 (m, 13H), 6.99 - 6.69 (m, 12H), 5.03 (dd, J = 35.9, 17.2 Hz, 7H), 4.34 (dd, J= 13.7, 8.8 Hz, 4H), 3.12 (s, 10H), 2.94 (d, J= 8.1 Hz, 4H), 2.74 (dd, J= 13.8, 9.7 Hz, 3H), 2.46 (s, 20H), 2.24 (s, 9H).
[0486] Compounds 184-211 were prepared using a method analogous to that of Example 183 utilizing the corresponding acids and amines.
Examples 184 to 211
Figure imgf000139_0001
Figure imgf000140_0001
phenylpropanamide
(5)-2-(2-(4-chloro-7-methyl- lH-benzo[d]imidazol- 1 -
194 yl)acetamido)-N-(6- 492 2.57 methoxypyridin-3 -yl)-N- methyl-3 -phenylpropanamide
(5)-2-(2-(7-chloro-4-methyl- lH-benzo[d]imidazol- 1 -
195 yl)acetamido)-N-(6- 492 2.57 methoxypyridin-3 -yl)-N-
CI methyl-3 -phenylpropanamide
0S)-2-(2-(5,6-dimethyl-2- (trifluoromethyl)- 1 H-
196 benzo [ Jimidazol- 1 - 509 2.99 yl)acetamido)-N-methyl-N,3- diphenylpropanamide
0S)-2-(2-(5,6-dimethyl-2- (trifluoromethyl)- 1 H- benzo [ Jimidazol- 1 -
197 540 2.86 yl)acetamido)-N-(6- methoxypyridin-3 -yl)-N- methyl-3 -phenylpropanamide
(S)-2-(2-(4,7-dimethyl-2- (trifluoromethyl)- 1 H-
198 benzo [ Jimidazol- 1 - 509 2.13 yl)acetamido)-N-methyl-N,3- diphenylpropanamide
(S)-2-(2-(4,7-dimethyl-2- (trifluoromethyl)- 1 H- benzo [ Jimidazol- 1 -
199 540 2.92 yl)acetamido)-N-(6- methoxypyridin-3 -yl)-N- methyl-3 -phenylpropanamide
(5)-2-(2-(4-chloro-7-methyl- lH-benzo[d]imidazol- 1 -
200 X) yl)acetamido)-N-methyl-N,3- 461 2.71 diphenylpropanamide
0S)-2-(2-(7-chloro-4-methyl- lH-benzo[d]imidazol- 1 -
201 X) yl)acetamido)-N-methyl-N,3- 461 2.71 diphenylpropanamide
CI
0S)-N-(benzo[d][l ,3]dioxol-5- yl)-2-(2-(5,6-dimethyl-2- (trifluoromethyl)- 1 H-
202 553 2.92 benzo [ Jimidazol- 1 - yl)acetamido)-N-methyl-3 - phenylpropanamide
Figure imgf000142_0001
p enypropanam e
[0487] (Example 184): 1H NMR (400 MHz, CDC13) δ 8.92 (d, J= 8.3 Hz, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.41 (d, J= 7.7 Hz, 3H), 7.27 - 7.04 (m, 5H), 6.81 (s, 2H), 4.93 (q, J= 16.2 Hz, 2H), 4.48 (s, 1H), 3.17 (s, 3H), 2.90 (d, J= 9.0 Hz, 1H), 2.73 - 2.61 (m, 1H).
[0488] (Example 185): 1H NMR (400 MHz, DMSO) δ 8.85 (d, J= 7.9 Hz, 1H), 7.97 (s, 1H), 7.49 - 7.34 (m, 3H), 7.27 - 7.14 (m, 5H), 6.85 - 6.70 (m, 4H), 5.02 (dd, J= 40.7, 17.3 Hz, 2H), 4.46 (s, 1H), 3.15 (s, 3H), 2.90 (d, J= 14.1 Hz, 1H), 2.68 (d, J= 13.3 Hz, 1H), 2.45 (s, 3H), 2.21 (s, 3H).
[0489] (Example 186): 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.97 (s, 2H), 7.42 (s, 1H), 7.22 (s, 3H), 6.99 - 6.69 (m, 5H), 5.13 - 4.90 (m, 2H), 4.37 (s, 1H), 3.84 (s, 3H), 3.11 (s, 3H), 2.95 (d, J= 13.7 Hz, 1H), 2.74 (t, J= 15.1 Hz, 1H), 2.46 (s, 3H), 2.24 (s, 3H).
[0490] (Example 187): 1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.22 (d, J= 6.4 Hz, 3H), 6.90 (d, J= 7.9 Hz, 3H), 6.83 (d, J= 7.3 Hz, 1H), 6.76 - 6.63 (m, 3H), 6.05 (s, 2H), 5.02 (q, J= 17.4 Hz, 2H), 4.48 (s, 1H), 3.09 (s, 4H), 2.94 (d, J= 9.4 Hz, 1H), 2.75 - 2.67 (m, 1H), 2.45 (s, 3H), 2.22 (s, 3H).
[0491] (Example 188): 1H NMR (400 MHz, DMSO) δ 8.98 (d, J= 8.1 Hz, 1H), 8.20 (s, 1H), 7.94 (d, J= 7.3 Hz, 2H), 7.62 (s, 1H), 7.41 (s, 1H), 7.20 (d, J= 4.1 Hz, 3H), 6.92 (d, J = 4.3 Hz, 2H), 6.81 (d, J= 8.7 Hz, 1H), 4.93 (q, J= 16.6 Hz, 2H), 4.38 (d, J= 5.6 Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.94 (d, J= 8.4 Hz, 1H), 2.76 - 2.65 (m, 1H).
[0492] (Example 189): 1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 8.2 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.19 (s, 3H), 6.93 (d, J= 8.5 Hz, 1H), 6.84 (dd, J= 13.2, 7.8 Hz, 4H), 6.74 (d, J= 7.3 Hz, 1H), 5.02 (dd, J= 38.2, 17.3 Hz, 2H), 4.55 (s, 1H), 3.75 (s, 6H), 3.13 (s, 3H), 2.95 (d, J= 13.5 Hz, 1H), 2.76 - 2.65 (m, 1H), 2.45 (s, 3H), 2.24 (s, 3H).
[0493] (Example 190): 1H NMR (400 MHz, DMSO) δ 8.97 (d, J= 8.0 Hz, 1H), 7.94 (d, J= 15.2 Hz, 2H), 7.39 (s, 2H), 7.22 (d, J= 5.7 Hz, 3H), 7.01 - 6.90 (m, 3H), 6.81 (d, J= 8.6 Hz, 1H), 4.83 (dd, J= 37.9, 16.4 Hz, 2H), 4.37 (dd, J= 13.8, 8.3 Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.95 (dd, J= 13.5, 5.4 Hz, 1H), 2.75 (dd, J= 13.5, 9.2 Hz, 1H), 2.28 (s, 6H).
[0494] (Example 191): 1H NMR (400 MHz, DMSO) δ 8.90 (d, J= 7.9 Hz, 1H), 7.92 (s, 1H), 7.49 - 7.31 (m, 4H), 7.19 (dd, J= 13.2, 5.2 Hz, 5H), 6.96 (s, 1H), 6.83 (s, 2H), 4.82 (dd, J= 40.9, 16.4 Hz, 2H), 4.47 (s, 1H), 3.16 (s, 3H), 2.96 - 2.85 (m, 1H), 2.76 - 2.63 (m, 1H), 2.28 (d, J= 3.2 Hz, 6H).
[0495] (Example 192): 1H NMR (400 MHz, DMSO) δ 9.02 (d, J= 7.7 Hz, 1H), 8.20 (d, J= 12.9 Hz, 2H), 7.45 - 7.35 (m, 2H), 7.23 (dd, J= 13.4, 6.1 Hz, 4H), 7.04 (s, 1H), 6.91 (d, J = 4.1 Hz, 2H), 4.89 (dd, J= 35.9, 16.4 Hz, 2H), 4.34 (d, J= 5.3 Hz, 1H), 3.12 (s, 3H), 2.94 (dd, J= 13.5, 5.2 Hz, 1H), 2.79 - 2.70 (m, 1H), 2.45 (s, 3H), 2.30 (d, J= 2.8 Hz, 6H). [0496] (Example 193): 1H NMR (400 MHz, DMSO) δ 8.97 (d, J= 8.4 Hz, 1H), 8.27 - 8.11 (m, 2H), 7.92 (s, 1H), 7.61 (s, 1H), 7.38 (d, J= 7.8 Hz, 1H), 7.22 (dd, J = 23.7, 5.8 Hz, 4H), 6.89 (d, J= 4.0 Hz, 2H), 4.93 (q, J= 16.5 Hz, 2H), 4.36 (d, J= 5.4 Hz, 1H), 3.13 (s, 3H), 2.93 (dd, J= 13.5, 5.6 Hz, 1H), 2.77 - 2.65 (m, 1H), 2.46 (s, 3H).
[0497] (Example 194): 1H NMR (400 MHz, CDC13) δ 8.95 (d, J= 7.8 Hz, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.43 (d, J= 8.7 Hz, 1H), 7.22 (dd, J= 4.8, 1.7 Hz, 3H), 7.12 (d, J= 7.8 Hz, 1H), 6.93 - 6.86 (m, 3H), 6.83 (d, J= 8.7 Hz, 1H), 5.07 (dd, J= 36.1, 17.5 Hz, 2H), 4.42 - 4.34 (m, 1H), 3.84 (s, 3H), 3.11 (s, 3H), 2.95 (dd, J= 13.5, 5.1 Hz, 1H), 2.74 (dd, J= 13.5, 9.3 Hz, 1H), 2.25 (s, 3H).
[0498] (Example 195): 1H NMR (400 MHz, CDC13) δ 8.89 (d, J= 8.1 Hz, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.38 (s, 1H), 7.22 (dd, J= 4.7, 1.4 Hz, 3H), 7.04 (d, J= 7.8 Hz, 1H), 7.00 - 6.92 (m, 3H), 6.80 (d, J= 9.0 Hz, 1H), 5.12 (s, 2H), 4.38 (dd, J= 14.4, 9.2 Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.94 (dd, J= 8.0, 7.1 Hz, 1H), 2.76 - 2.72 (m, 1H), 2.49 (s, 3H).
[0499] (Example 196): 1H NMR (400 MHz, DMSO) δ 8.95 (d, J= 7.9 Hz, 1H), 7.55 (s, 1H), 7.39 (d, J= 7.7 Hz, 3H), 7.30 (s, 1H), 7.17 (dd, J= 9.8, 5.1 Hz, 5H), 6.82 (s, 2H), 4.99 (dd, J= 37.0, 18.0 Hz, 2H), 4.47 (s, 1H), 3.16 (s, 3H), 2.90 (dd, J= 14.2, 5.2 Hz, 1H), 2.72 - 2.66 (m, 1H), 2.34 (s, 3H), 2.33 (s, 3H).
[0500] (Example 197): 1H NMR (400 MHz, DMSO) δ 9.01 (d, J= 8.1 Hz, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 7.31 (s, 1H), 7.26 - 7.19 (m, 3H), 6.97 - 6.89 (m, 2H), 6.79 (d, J= 8.7 Hz, 1H), 4.99 (q, J= 17.5 Hz, 2H), 4.45 - 4.31 (m, 1H), 3.82 (s, 3H), 3.11 (s, 3H), 2.95 (dd, J= 13.3, 5.5 Hz, 1H), 2.73 (dd, J= 13.4, 8.7 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 3H).
[0501] (Example 198): 1H NMR (400 MHz, DMSO) δ 8.95 (d, J= 8.2 Hz, 1H), 7.46 - 7.34 (m, 3H), 7.24 - 7.12 (m, 5H), 7.01 (q, J= 7.2 Hz, 2H), 6.78 (dd, J= 6.5, 2.2 Hz, 22H), 5.10 (d, J= 42.7 Hz, 2H), 4.50 (s, 1H), 3.16 (s, 3H), 2.90 (dd, J= 13.5, 4.5 Hz, 1H), 2.70 - 2.66 (m, 1H), 2.33 (d, J= 1.9 Hz, 6H).
[0502] (Example 199): 1H NMR (400 MHz, CDC13) δ 8.98 (d, J= 7.7 Hz, 1H), 7.91 (s, 1H), 7.35 (d, J= 7.6 Hz, 1H), 7.22 (dd, J= 5.0, 1.7 Hz, 3H), 7.01 (q, J= 7.3 Hz, 2H), 6.91 (dd, J= 6.7, 2.5 Hz, 2H), 6.81 (d, J= 8.8 Hz, 1H), 5.10 (dd, J= 42.6, 9.2 Hz, 2H), 4.42 (dd, J = 16.0, 8.1 Hz, 1H), 3.83 (s, 3H), 3.11 (s, 3H), 2.94 (dd, J= 13.5, 5.6 Hz, 1H), 2.72 (dd, J = 15.8, 6.7 Hz, 1H), 2.36 (s, 3H).
[0503] (Example 200): 1H NMR (400 MHz, DMSO) δ 8.91 (d, J= 8.1 Hz, 1H), 8.12 (s, 1H), 7.46 - 7.34 (m, 3H), 7.24 (d, J= 6.9 Hz, 2H), 7.21 - 7.14 (m, 3H), 7.11 (d, J= 7.8 Hz, 1H), 6.86 (d, J= 7.6 Hz, 1H), 6.81 - 6.75 (m, 2H), 5.06 (dd, J= 42.3, 17.6 Hz, 2H), 4.47 (s, 1H), 3.16 (s, 3H), 2.90 (dd, J= 13.9, 4.3 Hz, 1H), 2.70 (dd, J= 13.6, 3.7 Hz, 1H), 2.22 (s, 3H).
[0504] (Example 201): 1H NMR (400 MHz, DMSO) δ 8.84 (d, J = 7.9 Hz, 1H), 8.13 (s, 1H), 7.43 - 7.36 (m, 3H), 7.22 - 7.14 (m, 5H), 7.02 (d, J= 7.9 Hz, 1H), 6.96 (d, J= 8.1 Hz, 1H), 6.86 - 6.78 (m, 2H), 5.16 - 5.05 (m, 2H), 4.47 (s, 1H), 3.15 (s, 3H), 2.89 (dd, J= 13.7, 4.1 Hz, 1H), 2.68 (dd, J= 6.2, 3.0 Hz, 1H), 2.48 (s, 3H).
[0505] (Example 202): 1H NMR (400 MHz, DMSO) δ 8.91 (d, J= 8.1 Hz, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 7.24 - 7.17 (m, 3H), 6.91 (dd, J= 7.7, 1.5 Hz, 2H), 6.86 (d, J= 8.3 Hz, 1H), 6.61 (d, J= 16.4 Hz, 2H), 6.02 (d, J= 4.6 Hz, 2H), 4.96 (q, J= 17.6 Hz, 2H), 4.51 - 4.43 (m, 1H), 3.07 (s, 3H), 2.92 (dd, J= 13.6, 5.0 Hz, 1H), 2.68 (dd, J= 13.6, 9.2 Hz, 1H), 2.32 (s, 3H), 2.31 (s, 3H).
[0506] (Example 203): 1H NMR (400 MHz, DMSO) δ 9.00 (d, J = 8.2 Hz, 1H), 8.11 (s, 1H), 7.54 (s, 1H), 7.29 (t, J= 5.2 Hz, 3H), 7.23 - 7.17 (m, 3H), 6.93 - 6.84 (m, 2H), 4.98 (q, J= 18.0 Hz, 2H), 4.39 - 4.30 (m, 1H), 3.10 (s, 3H), 2.92 (dd, J= 13.5, 6.9 Hz, 1H), 2.71 (dd, J= 14.2, 9.2 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H).
[0507] (Example 204): 1H NMR (400 MHz, CDC13) δ 8.30 (s, 1H), 7.89 (d, J= 8.5 Hz, 2H), 7.74 (t, J= 12.2 Hz, 2H), 7.59 - 7.51 (m, 2H), 7.32 - 7.28 (m, 2H), 7.27 - 7.08 (m, 5H), 6.67 (d, J= 7.5 Hz, 38H), 4.88 (q, J= 7.7 Hz, 1H), 4.68 (d, J= 3.3 Hz, 2H), 3.32 (s, 3H), 2.90 (dd, J= 13.6, 6.7 Hz, 1H), 2.64 (dd, J= 13.4, 7.9 Hz, 1H), 3.52 (s, 3H).
[0508] (Example 205): 1H NMR (400 MHz, CDC13) δ 8.26 (s, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.49 - 7.29 (m, 3H), 7.27 - 7.02 (m, 7H), 6.97 - 6.78 (m, 3H), 6.55 (ddd, J = 16.2, 15.0, 7.6 Hz, 2H), 4.90 - 4.58 (m, 4H), 3.75 (d, J = 106.0 Hz, 4H), 3.20 (d, J = 28.6 Hz, 4H), 2.95 - 2.63 (m, 2H), 2.47 (dd, J = 24.7, 13.7 Hz, 4H).
[0509] (Example 206): 1H NMR (400 MHz, CDC13) δ 7.88 (dd, J= 20.6, 13.5 Hz, 2H), 7.45 (t, J= 8.0 Hz, 1H), 7.40 - 7.29 (m, 3H), 7.27 - 7.02 (m, 5H), 6.98 - 6.79 (m, 2H), 6.55 (dd, J= 43.5, 7.6 Hz, 2H), 4.94 - 4.64 (m, 3H), 3.75 (d, J= 102.4 Hz, 3H), 3.19 (d, J= 32.7 Hz, 3H), 2.83 (ddd, J= 18.1, 13.5, 5.5 Hz, 1H), 2.57 (ddd, J = 22.9, 13.6, 7.7 Hz, 1H).
[0510] (Example 207): 1H NMR (400 MHz, CDC13) δ 8.24 (s, 1H), 7.77 (s, 1H), 7.43 - 7.30 (m, 4H), 7.27 - 7.03 (m, 6H), 6.69 (dd, J= 19.6, 7.4 Hz, 2H), 4.74 - 4.49 (m, 3H), 3.21 (d, J= 3.6 Hz, 3H), 2.93 (dd, J= 13.7, 5.6 Hz, 1H), 2.65 (ddd, J= 22.4, 13.7, 6.4 Hz, 1H), 2.47 (s, 3H), 2.22 (d, J= 13.4 Hz, 3H).
[0511] (Example 208): 1H NMR (400 MHz, CDC13) δ 7.98 (s, 1H), 7.87 (d, J = 8.2 Hz, 3H), 7.74 (d, J = 5.7 Hz, 1H), 7.59 - 7.50 (m, 2H), 7.34 (dd, J = 13.2, 6.4 Hz, 3H), 7.27 - 7.16 (m, 3H), 7.13 (t, J = 7.4 Hz, 3H), 6.72 (d, J = 7.5 Hz, 2H), 4.88 (dt, J = 14.3, 7.0 Hz, 1H), 4.79 (d, J = 6.8 Hz, 2H), 3.30 (s, 3H), 2.90 (dd, J = 13.2, 7.3 Hz, 1H), 2.68 (dd, J = 13.1, 7.3 Hz, 1H).
[0512] (Example 209): 1H NMR (400 MHz, CDC13) δ 8.31 (d, J= 40.9 Hz, 2H), 8.13 (d, J= 8.5 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.70 (d, J= 8.1 Hz, 1H), 7.60 (t, J= 7.5 Hz, 1H), 7.48 - 7.30 (m, 5H), 7.20 (t, J= 7.5 Hz, 2H), 6.82 (d, J= 7.2 Hz, 2H), 4.94 (s, 2H), 4.71 (dd, J = 14.6, 7.9 Hz, 1H), 3.27 (s, 3H), 2.93 (dd, J= 12.7, 9.2 Hz, 1H), 2.78 - 2.74 (m, 1H).
[0513] (Example 210): 1H NMR (400 MHz, CDC13) δ 7.79 - 7.71 (m, 1H), 7.28 - 7.26 (m, 1H), 7.26 - 7.22 (m, 3H), 7.22 - 7.18 (m, 1H), 7.12 - 7.04 (m, 2H), 7.00 - 6.90 (m, 1H), 5.18 (ddd, J = 34.4, 14.6, 7.4 Hz, 1H), 4.73 (d, J = 3.0 Hz, 2H), 4.42 - 4.19 (m, 1H), 3.49 - 3.35 (m, 2H), 3.04 - 2.86 (m, 2H), 2.70 (d, J = 64.0 Hz, 3H), 2.56 (s, 3H), 1.78 - 1.04 (m, 10H).
[0514] (Example 211): 1H NMR(400 MHz, CDC13) δ 7.93 (d, J = 40.9 Hz, 2H), 7.40 - 7.29 (m, 3H), 7.28 - 7.19 (m, 3H), 7.14 - 6.99 (m, 2H), 6.87 (s, 1H), 5.16 (dt, J = 22.2, 7.2 Hz, 1H), 4.82 (t, J = 3.2 Hz, 2H), 3.74 (q, J = 7.0 Hz, 1H), 3.04 - 2.85 (m, 2H), 2.67 (d, J = 76.7 Hz, 3H), 1.47 - 0.95 (m, 10H).
Example 212
[0515] (5)-2-(2-(4,7-dimethyl-lH-benzo[ ]imidazol-l-yl)acetamido)-N-ethyl-N-(6- methoxypyridin-3 -yl)-3 -phenylpropanamide
Figure imgf000146_0001
This compound was prepared by an analogous method to (5)-2-(2-(4,7-dimethyl-lH- benzo [djimidazol- 1 -yl)acetamido)-N-methyl-N-(6-methylpyridin-3 -yl)-3 - phenylpropanamide, to give the title compound as a solid (yield: 30%). LC/MS: m/z M++l = 468, HPLC retention time = 2.54 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0516] 1H NMR (400 MHz, DMSO) δ 8.89 (d, J= 7.8 Hz, 1H), 7.97 (s, 1H), 7.91 - 7.76 (m, 1H), 7.32 - 7.19 (m, 3H), 7.04 - 6.62 (m, 5H), 5.03 (dd, J= 34.7, 17.3 Hz, 2H), 4.27 (dd, J= 12.2, 7.3 Hz, 1H), 3.83 (s, 3H), 2.95 (dd, J= 13.7, 5.9 Hz, 1H), 2.77 - 2.64 (m, 1H), 2.45 (s, 3H), 2.23 (s, 3H), 1.24 (s, 1H), 0.98 (dd, J= 32.4, 25.4 Hz, 3H). Example 213
[0517] (5)-N-(benzo[ ][l,3]dioxol-5-yl)-2-(2-(3-ethyl-4,7-dimethyl-2-oxo-2,3- dihydrobenzo [ Jimidazol- 1 -y ropanamide
Figure imgf000147_0001
Example 213A. Preparation of 4,7-dimethyl-lH-benzo[dlimidazol-2(3H)-one
Figure imgf000147_0002
[0518] A mixture of 3,6-dimethylbenzene-l ,2-diamine (1.0 g, 7.35 mmol, 1.0 eq) and CDI (1.1 eq) in THF (10 mL) was stirred at room temperature overnight. Then excess of solvent was removed. To the residue, water was added, and the resulting mixture was extracted with EA and recrystallized with PE to afford the product 4,7-dimethyl-lH- benzo[ ]imidazol-2(3H)-one (760 mg, 4.69 mmol, yield: 63.9%), LC/MS: m/z M++l = 163. Example 213B. Preparation of 2-chloro-4,7-dimethyl-lH-benzord1imidazole
Figure imgf000147_0003
[0519] A mixture of 4,7-dimethyl-lH-benzo[<i]imidazol-2(3H)-one (400 mg, 2.47 mmol, 1.0 eq) in POCI3 was heated at reflux. The mixture was poured onto ice-water, then NaOH was added to adjust pH to 8, extracted with EA and purified by chromatography to give the product 2-chloro-4,7-dimethyl-lH-benzo[(i]imidazole (170 mg, 0.94 mmol, yield: 38.2%), LC/MS: m/z M++l = 181.
Example 213C. Preparation of 2-(2-chloro-4,7-dimethyl-lH-benzor(i1imidazol-l-yl)acetic acid
Figure imgf000147_0004
[0520] To a DMF solution of 2-chloro-4,7-dimethyl-lH-benzo[d]imidazole (170 g, 0.94 mmol, 1.0 eq) at 0 °C, was added slowly NaH ( 56.4 mg, 1.41 mmol, 1.5 eq). After 20 minutes, ethyl 2-bromoacetate (0.16 mL, 1.41 mmol, 1.5 eq) was added dropwise. The mixture was stirred at 0 °C for 50 minutes until TLC (PE: EA=5: 1) indicated the SM had disappeared. Ice water (5 mL) was added to quench the reaction and HCl was added to adjust pH to 2. After normal work-up, a crude product 2-(4,7-dimethyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)acetic acid (180 mg, 0.81 mmol, yield: 87.0%) was obtained, LC/MS: m/z M++l = 221.
Example 213D. Preparation of 2-(3-ethyl-4,7-dimethyl-2-oxo-2,3-dihydro- 1H- benzo[ imidazol-l-yl)acetic acid
Figure imgf000148_0001
[0521] To a DMF solution of 2-(4,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[<i]imidazol-
1- yl)acetic (100 mg, 0.45 mmol, 1.0 eq) at 0°C, was added slowly NaH ( 27.3 mg, 0.68 mmol, 1.5 eq). After 20 minutes, bromoethane (0.05 mL, 0.68 mmol, 1.5 eq) was added dropwise. The mixture was stirred at 0 °C for 2 hours. Ice water (5 mL) was added to quench the reaction, and then HCl was added to adjust pH to 4. The mixture was extracted with EA and concentrated to give the crude product 2-(3-ethyl-4,7-dimethyl-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l-yl)acetic acid (60 mg, 0.24 mmol, yield: 53.8%), LC/MS: m/z M++l = 249.
Figure imgf000148_0002
2- oxo-2,3-dihydro- lH-benzo[ imidazol- 1 -yl)acetamido)-N-methyl-3-phenylpropanamide
[0522] To a mixture of 2-(3-ethyl-4,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[<i]imidazol- l-yl)acetic acid (60 mg, 0.24 mmol, l .Oeq) and (5)-2-amino-N-(benzo[<i][l,3]dioxol-5-yl)-N- methyl-3-phenylpropanamide (86 mg, 0.29 mmol, 1.2 eq) in DCM (5 mL), was added EDCI (68.7 mg, 0.36 mmol, 1.5 eq), HOBt (65 mg, 0.48 mmol, 2.0 eq), and DIPEA (62 mg, 0.48 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated, and the residue was purified by prep-HPLC to give the final product (5)-N-(benzo[<i][l,3]dioxol-5-yl)-2-(2- (3-ethyl-4,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[(i]imidazol-l-yl)acetamido)-N-methyl-3- phenylpropanamide (30 mg, 0.06 mmol, isolate yield: 25%). LC/MS: m/z M++l = 529, HPLC retention time = 3.05 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0523] 1H NMR (400 MHz, DMSO) δ 8.69 (d, J= 7.8 Hz, 1H), 7.20 (t, J= 5.8 Hz, 3H), 6.91 (t, J= 8.1 Hz, 3H), 6.73 (s, 1H), 6.68 (d, J= 7.8 Hz, 2H), 6.58 (d, J= 7.9 Hz, 1H), 6.06 (d, J= 1.0 Hz, 2H), 4.58 (dd, J= 51.6, 17.6 Hz, 2H), 4.49 (m, 1H),4.01 (q, J= 7.1 Hz, 2H), 3.10 (s, 3H), 2.93 (dd, J= 13.3, 4.6 Hz, 1H), 2.69 (dd, J= 13.7, 9.6 Hz, 1H), 2.49 (s, 3H), 2.05 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H).
[0524] Compounds 214-215 were prepared using a method analogous to that of Example 213 utilizing the corresponding acids and amines.
Examples 214 to 215
Figure imgf000149_0001
[0525] (Example 214): 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.84 (d, J= 7.8 Hz, 1H), 7.94 (d, J= 42.7 Hz, 1H), 7.44 (s, 1H), 7.22 (d, J= 3.8 Hz, 3H), 6.91 (d, J= 3.8 Hz, 2H), 6.84 (d, J= 8.7 Hz, 1H), 6.65 (d, J= 7.7 Hz, 1H), 6.55 (d, J= 8.0 Hz, 1H), 4.53 (dd, J = 47.7, 17.6 Hz, 2H), 4.42 - 4.28 (m, 1H), 3.86 (s, 3H), 3.12 (s, 3H), 2.92 (dd, J= 13.3, 4.8 Hz, 1H), 2.81 - 2.67 (m, 1H), 2.22 (s, 3H), 2.05 (s, 3H).
[0526] (Example 215): 1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.67 (d, J= 7.9 Hz, 1H), 7.21 (d, J= 6.7 Hz, 3H), 6.91 (t, J= 7.1 Hz, 3H), 6.76 - 6.61 (m, 3H), 6.54 (d, J= 7.8 Hz, 1H), 6.07 (s, 2H), 4.57 (d, J= 17.6 Hz, 1H), 4.45 (d, J= 17.5 Hz, 2H), 3.10 (s, 3H), 2.92 (dd, J= 13.2, 4.8 Hz, 1H), 2.75 - 2.63 (m, 1H), 2.21 (s, 3H), 2.03 (s, 3H). Example 216
[0527] (5)-N-(benzo[ ][l ,3]dioxol-5-yl)-N-methyl-2-(2-(l-methyl-lH-indol-4- yl)acetamido)-3-phenylpropanamide
Figure imgf000150_0001
Example 216A. Preparation of 1 -methyl-6,7-dihydro- lH-indol-4(5H)-one
Figure imgf000150_0002
[0528] To a solution of cyclohexane-l ,3-dione (10 g, 89 mmol, 1 eq) in toluene (150 mL), were added 2,2-dimethoxy-N-methylethanamine (16 g, 134 mmol, 1.5 eq) and TsOH (0.8 g, 4.65 mmol, 0.05 eq). The mixture was heated at reflux for 12 hours. TLC (petroleum ether/EtOAc 0: 1) analysis showed the reaction was completed. The reaction mixture was concentrated in vacuo to give residue, which was purified by column chromatography on silica gel to give l-methyl-6,7-dihydro-lH-indol-4(5H)-one (3 g, 20.1 mmol, yield: 22.47%), LC/MS: m/z M++l = 150.
Example 216B. Preparation of (E)-2-(l-methyl-6,7-dihydro-lH-indol-4(5H)- ylidene)acetonitrile
Figure imgf000150_0003
[0529] To a THF solution of l-methyl-6,7-dihydro-lH-indol-4(5H)-one (2.7 g, 18.1 mmol, leq), was added slowly NaH (2.1 g, 54.3 mmol, 3eq). After 40 minutes, dimethyl (cyanomethyl)phosphonate (2.1 g, 54.3 mmol, 3 eq) was added dropwise. The mixture was heated at reflux overnight. TLC (petroleum ether/EtOAc 1 : 1) indicated the SM had disappeared. Water (30 mL) was added to quench the reaction. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2S04 and concentrated to give (E)-2-(l-methyl-6,7-dihydro-lH-indol-4(5H)- ylidene)acetonitrile (2 g, 1 1.6 mmol , yield: 64.2%), LC/MS: m/z M++l = 173. Example 216C. Preparation of 2-(l -methyl- lH-indol-4-yl)acetonitrile
Figure imgf000151_0001
[0530] A solution of (E)-2-( 1 -methyl-6,7-dihydro- lH-indol-4(5H)-ylidene)acetonitrile (1.0 g, 5.81 mmol, leq) , Pd/C (0.5 g ) in 1 ,2-diethoxyethane (3 mL) was stirred at 200 °C for 3 hours. TLC (petroleum ether/EtOAc 3 : 1) showed the reaction was completed. The reaction mixture was cooled to room temperature and then filtered. Wet cake was washed with DCM (30 mL). The filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography on silica gel to give 2-(l-methyl-lH-indol-4- yl)acetonitrile (0.6 g, 3.53 mmoL, yield: 60%), LC/MS: m/z M++l = 171.
Example 216D. Preparation of 2-(l -methyl- lH-indol-4-yl)acetic acid
Figure imgf000151_0002
[0531] A solution of 2-(l -methyl- lH-indol-4-yl)acetonitrile (0.3 g, 1.76 mmol, 1 eq) in cone. HCl (10 mL) was heated at reflux for 12 hours. TLC (petroleum ether/EtOAc 1 : 1) showed the reaction was completed. The reaction mixture was concentrated to remove HCl, and the residue was basified to pH=10 by aq.NaOH, and then washed with Et20 (2x20 mL). The aqueous layers were then acidified to pH=4 and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and
concentrated to give 2-(l -methyl- lH-indol-4-yl)acetic acid (0.2 g, 1 mmoL, yield: 60%), LC/MS: m/z M++l = 190.
Example 216E. Preparation of (6 -N-(benzor(iiri,31dioxol-5-yl)-N-methyl-2-(2-(l-methyl- lH-indol-4-yl)acetamido)-3-phenylpropanamide
[0532] To a mixture of 2-(l -methyl- lH-indol-4-yl)acetic acid (30 mg, 0.16 mmol, 1.0 eq) and (5)-2-amino-N-(benzo[(i][l ,3]dioxol-5-yl)-N-methyl-3-phenylpropanamide (48 mg, 0.16 mmol, 1.0 eq) in DMF (5mL), were added EDCI (46 mg, 0.24 mmol, 1.5 eq), HOBt (43 mg, 0.32 mmol, 2.0 eq), and DIPEA (41.3 mg, 0.32 mmol, 2.0 eq). The mixture was stirred at room temperature overnight under N2. The resulting solution was washed with water 3 times, dried and concentrated. The residue was purified by prep-HPLC to give the product (5)-N- (benzo[ ][l ,3]dioxol-5-yl)-N-methyl-2-(2-(l-methyl-lH-indol-4-yl)acetamido)-3- phenylpropanamide (33 mg, 0.07 mmoL , yield: 44%). LC/MS: m/z M++l = 470, HPLC retention time = 2.94 minutes (10-90% MeCN in water, containing 0.1% TFA). [0533] 1H NMR (400 MHz, CDC13) δ 7.28 (s, 2H), 7.26 - 7.11 (m, 4H), 7.08 (d, J = 3.1 Hz, 1H), 6.96 (d, J = 7.0 Hz, 1H), 6.80 (d, J = 7.1 Hz, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.46 (d, J = 3.1 Hz, 1H), 6.12 (d, J = 8.6 Hz, 1H), 6.02 (s, 2H), 4.79 (dd, J = 14.7, 7.8 Hz, 1H), 3.83 (d, J = 8.5 Hz, 5H), 3.09 (s, 3H), 2.75 (dd, J = 13.2, 7.9 Hz, 1H), 2.62 (dd, J = 13.1, 6.3 Hz, 1H).
[0534] Compounds 217-220 were prepared using a method analogous to that of Example 216 utilizing the corresponding acids and amines.
Examples 217 to 220
Figure imgf000152_0001
Figure imgf000152_0002
[0535] (Example 217): 1H NMR (400 MHz, CDC13) δ 7.92 - 7.80 (m, 2H), 7.70 (s, 1H), 7.61 - 7.50 (m, 2H), 7.32 - 7.29 (m, 3H), 7.27 - 7.18 (m, 2H), 7.10 (dd, J= 14.8, 5.4 Hz, 3H), 6.98 (d, J= 6.7 Hz, 1H), 6.73 (d, J= 7.6 Hz, 2H), 6.47 (d, J= 3.0 Hz, 1H), 6.12 (d, J = 8.3 Hz, 1H), 4.83 (dd, J= 14.5, 8.1 Hz, 1H), 3.89 - 3.78 (m, 5H), 3.23 (s, 3H), 2.75 (dd, J = 13.2, 8.1 Hz, 1H), 2.59 (dd, J= 13.0, 6.1 Hz, 1H).
[0536] (Example 218): 1H NMR (400 MHz, CDC13) δ 7.45 - 7.30 (m, 2H), 7.25 - 6.96 (m, 6H), 6.94 - 6.71 (m, 3H), 6.57 (d, J= 7.4 Hz, 1H), 6.45 (dd, J= 31.6, 3.0 Hz, 1H), 6.35 - 6.04 (m, 2H), 4.73 (dd, J= 79.5, 5.3 Hz, 1H), 3.81 (dd, J= 20.9, 6.0 Hz, 6H), 3.59 (d, J = 63.8 Hz, 2H), 3.11 (d, J= 45.4 Hz, 3H), 2.71 - 2.63 (m, 1H), 2.38 (dd, J= 14.0, 7.8 Hz, 1H).
[0537] (Example 219): 1H NMR (400 MHz, CDC13) δ 8.22 (s, 1H), 8.13 (d, J= 8.3 Hz, 1H), 7.76 (dd, J= 16.8, 8.4 Hz, 2H), 7.60 (t, J= 7.4 Hz, 1H), 7.34 - 7.28 (m, 4H), 7.21 (dt, J = 19.2, 7.3 Hz, 3H), 7.10 (d, J= 3.2 Hz, 1H), 7.00 (d, J= 7.0 Hz, 1H), 6.81 (d, J= 7.7 Hz, 1H), 6.49 (d, J= 3.2 Hz, 1H), 6.10 (d, J= 8.6 Hz, 1H), 4.70 (dd, J= 14.9, 8.5 Hz, 1H), 3.85 (d, J= 4.9 Hz, 5H), 3.22 (s, 3H), 2.83 - 2.69 (m, 1H), 2.62 (dd, J= 12.9, 5.8 Hz, 1H).
[0538] (Example 220): 1H NMR (400 MHz, CDC13) δ 7.26 - 7.11 (m, 5H), 7.07 (d, J = 2.8 Hz, 1H), 7.03 - 6.79 (m, 3H), 6.55 - 6.46 (m, 1H), 6.42 (d, J = 8.2 Hz, 1H), 5.12 (ddd, J = 38.1, 13.7, 8.0 Hz, 1H), 3.83 (s, 1H), 3.81 (s, 3H), 3.50 (d, J = 105.4 Hz, 1H), 2.94 - 2.76 (m, 2H), 2.58 (d, J = 76.9 Hz, 3H), 1.81 - 1.64 (m, 2H), 1.62 - 0.76 (m, 10H).
Example 221
[0539] (5)-2-(2-(5,8-dimethyl-l-oxoisoquinolin-2(lH)-yl)acetamido)-N-methyl-N,3- diphenylpropanamide
Figure imgf000153_0001
The experimental procedure for preparation of Example 181 was similar to 1H utilizing the corresponding acids and amines to afford the product, LC/MS: m/z M++l = 468, HPLC retention time = 3.71 minutes (10-90% MeCN in water, containing 0.1% TFA).
[0540] 1H NMR (400 MHz, CDC13) δ 8.68 (d, J= 7.7 Hz, 1H), 7.37 (dd, J= 12.3, 7.4 Hz, 4H), 7.27 (d, J= 7.6 Hz, 1H), 7.23 - 7.09 (m, 6H), 6.87 (d, J= 3.8 Hz, 2H), 6.52 (d, J= 7.5 Hz, 1H), 4.54 (dd, J= 39.0, 15.9 Hz, 2H), 4.44 (d, J= 5.7 Hz, 1H), 3.14 (s, 3H), 2.88 (dd, J = 13.3, 5.1 Hz, 1H), 2.74 - 2.64 (m, 4H), 2.42 (s, 3H).
[0541] Compounds 222-224 were prepared using a method analogous to that of Example 221 utilizing the corresponding acids and amines.
Examples 222 to 224
HPLC
Ex.
Structure Name [M+H] Rt
No.
(min)
Figure imgf000154_0001
[0542] (Example 222): 1H NMR (400 MHz, CDC13) δ 8.68 (d, J= 7.5 Hz, 1H), 7.92 (s, 1H), 7.38 (dd, J= 15.4, 8.0 Hz, 4H), 7.23 - 7.10 (m, 6H), 6.89 - 6.78 (m, 2H), 6.45 (d, J = 7.3 Hz, 1H), 4.56 (dd, J= 60.1, 16.0 Hz, 2H), 4.46 - 4.38 (m, 1H), 3.14 (s, 3H), 2.87 (dd, J = 13.5, 5.4 Hz, 1H), 2.68 (dd, J= 13.2, 9.3 Hz, 1H), 2.35 (d, J= 1.8 Hz, 6H).
[0543] (Example 223): 1H NMR (400 MHz, DMSO) δ 8.75 (d, J= 7.6 Hz, 1H), 7.93 (s, 1H), 7.88 (s, 1H), 7.41 (s, 1H), 7.31 - 7.19 (m, 4H), 7.16 (d, J= 7.3 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.76 (d, J= 8.8 Hz, 1H), 6.46 (d, J= 7.3 Hz, 1H), 4.62 (d, J= 16.0 Hz, 1H), 4.51 (d, J = 16.0 Hz, 1H), 4.34 (dd, J= 14.3, 7.5 Hz, 1H), 3.82 (s, 3H), 3.08 (s, 3H), 2.92 (dd, J= 13.3, 6.2 Hz, 1H), 2.73 (dd, J= 13.1, 7.9 Hz, 1H), 2.36 (s, 6H).
[0544] (Example 224): 1H NMR (400 MHz, DMSO) δ 8.65 (d, J= 7.8 Hz, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 7.28 - 7.18 (m, 3H), 7.14 (d, J= 7.3 Hz, 1H), 6.95 (d, J= 7.7 Hz, 2H), 6.87 (d, J= 8.2 Hz, 1H), 6.60 (s, 2H), 6.45 (d, J= 7.4 Hz, 1H), 6.04 (d, J= 4.9 Hz, 2H), 4.62 (d, J= 15.9 Hz, 1H), 4.48 (dd, J= 17.5, 10.9 Hz, 2H), 3.07 (s, 3H), 2.91 (dd, J= 13.1, 5.5 Hz, 1H), 2.71 (dd, J= 13.3, 8.7 Hz, 1H), 2.36 (s, 6H).
[0545] The following Examples 225-258 can be prepared using a method analogous to that of the examples described hereinabove. The corresponding biological data are obtained using a method described hereinbelow in biological assays.
Ex. Structure ECso (nM) Cytotox
No. CCso (nM)
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Biological Assays
[0546] MT2rep assay: MT2 cells are pelleted by centrifugation and re-suspended with appropriate volume of RPMI 1640 (10% FBS) to give a cell density about 1.34x l05/mL. Appropriate volume HIV-l(NL4-3) stock is added to the above MT2 cells to give a MOI about μΐ, of MT2 cells/HIV- 1 mixture 0.01 TCID50 per cell. MT2 cells90 μΐ,) are added to 384-well antiviral assay plates containing compounds and 45(1.34>< 105/ml, without virus addition) is added to 384-well cytotoxicity assay plates containing compounds. The assay plates are incubated in a 5% C02 incubator at 37 °C for 3 days. Three days post MT2 infection, ΙΟμΙ^ per well of supernatant from 384-well antiviral assay plates is transferred to a new 384-well plate and 40 μΐ, of JC53BL cells (0.4xl06 cells/mL) is added to this plate. 24 hours later β-Gal activity is measured as following. Add 30 of the FluorAce solution to each well of the assay plate. Incubate the plates in 5% (v/v) C02 incubator at 37 °C for 2 hours. Add 10 μΐ, stop solution to each well and read plates with PE Victor 3 under the umbelliferone channel. The compound cytotoxicity is measured three days post MT2 seeding by Celltiter Glo kit with conditions recommended by Promega except that 10 μΐ^ per well of reagent is added. The following data were obtained using the method described hereinabove. [0547] The following are biological data obtained for compounds of Examples 1-224 using the biological assays described hereinabove. A compound with the value "++++" had an IC50 value less than or equal to 100 nM; a compound with the value "+++" had an IC50 value between 100 nM and 1,000 nM; a compound with the value "++" had an IC50 value greater than or equal to 1,000 nM but less than 10,000 nM; a compound with the value "+" had an IC50 value greater than or equal to 10,000 nM.
Figure imgf000159_0001
37 ++ >20,000
38 +++ >20,000
39 ++ >20,000
40 ++++ >20,000
41 ++ >20,000
42 ++++ >20,000
43 +++ >20,000
44 +++ >20,000
45 +++ >20,000
46 ++ >20,000
47 ++ >20,000
48 ++ >20,000
49 ++ >20,000
50 ++++ >20,000
51 ++ >20,000
52 ++++ >20,000
53 ++ >20,000
54 +++ >20,000
55 ++++ >20,000
56 ++++ >20,000
57 ++++ 7,300
58 ++ >20,000
59 ++++ >20,000
60 +++ >20,000
61 +++ >20,000
62 +++ >20,000
63 ++++ >20,000
64 ++++ >20,000
65 ++++ >20,000
66 +++ >20,000
67 ++++ >20,000
68 ++++ >20,000
69 +++ >20,000
70 +++ >20,000
71 ++ >20,000
72 ++++ >20,000
73 +++ >20,000
74 +++ >20,000
75 +++ >20,000
76 ++++ >20,000
77 +++ >20,000
78 +++ >20,000
79 +++ >20,000
80 ++++ >20,000
81 +++ >20,000
82 ++++ >20,000
83 +++ >20,000
84 +++ >20,000 85 +++ >20,000
86 ++++ >20,000
87 +++ >20,000
88 +++ >20,000
89 +++ >20,000
90 +++ >20,000
91 +++ >20,000
92 ++++ >20,000
93 + >20,000
94 +++ >20,000
95 +++ >20,000
96 ++++ >20,000
97 +++ >20,000
98 +++ >20,000
99 + >20,000
100 + >20,000
101 + >20,000
102 + >20,000
103 + >20,000
104 + >20,000
105 + >20,000
106 + >20,000
107 +++ >20,000
108 +++ >20,000
109 ++ >20,000
110 +++ >20,000
111 +++ >20,000
112 + >20,000
113 +++ >20,000
114 +++ >20,000
115 +++ >20,000
116 +++ >20,000
117 ++ >20,000
118 +++ >20,000
119 +++ >20,000
120 +++ >20,000
121 ++ >20,000
122 + >20,000
123 ++++ >20,000
124 ++++ >20,000
125 ++++ >20,000
126 +++ >20,000
127 ++++ >20,000
128 ++++ >20,000
129 ++++ >20,000
130 +++ >20,000
131 +++ >20,000
132 +++ >20,000 133 +++ >20,000
134 ++++ >20,000
135 ++++ >20,000
136 ++++ >20,000
137 ++++ >20,000
138 +++ >20,000
139 + >20,000
140 ++++ >20,000
141 +++ >20,000
142 ++++ >20,000
143 +++ >20,000
144 +++ >20,000
145 +++ >20,000
146 +++ >20,000
147 +++ >20,000
148 +++ >20,000
149 ++++ >20,000
150 +++ >20,000
151 ++ >20,000
152 ++ >20,000
153 ++ >20,000
154 +++ >20,000
155 ++ >20,000
156 +++ >20,000
157 ++++ >20,000
158 +++ >20,000
159 ++ >20,000
160 +++ >20,000
161 ++ >20,000
162 ++ >20,000
163 + >20,000
164 ++++ >20,000
165 ++++ >20,000
166 + >20,000
167 ++++ >20,000
168 + >20,000
169 + >20,000
170 + >20,000
171 +++ >20,000
172 +++ >20,000
173 +++ >20,000
174 +++ >20,000
175 +++ >20,000
176 +++ >20,000
177 +++ >20,000
178 ++ >20,000
179 ++ >20,000
180 ++ >20,000 181 ++ >20,000
182 +++ >20,000
183 ++++ >20,000
184 ++ >20,000
185 +++ >20,000
186 +++ >20,000
187 +++ >20,000
188 ++ >20,000
189 +++ >20,000
190 +++ >20,000
191 +++ >20,000
192 +++ >20,000
193 ++ >20,000
194 +++ >20,000
195 +++ >20,000
196 +++ >20,000
197 +++ >20,000
198 ++ >20,000
199 +++ >20,000
200 +++ >20,000
201 +++ >20,000
202 +++ >20,000
203 +++ >20,000
204 +++ >20,000
205 ++ >20,000
206 ++ >20,000
207 +++ >20,000
208 +++ >20,000
209 ++ >20,000
210 ++ >20,000
211 + >20,000
212 + >20,000
213 +++ >20,000
214 ++ >20,000
215 +++ >20,000
216 +++ >20,000
217 +++ >20,000
218 ++ >20,000
219 +++ >20,000
220 + >20,000
221 ++ >20,000
222 + >20,000
223 + >20,000
224 ++ >20,000 References:
1) Salzwedel, K., D. E. Matin, and M. Sakalian, "Maturation inhibitors: a new
therapeutic class targets the virus structure", 2007, AIDS Rev. 9, 162-172;
2) Smith, P. E., A. Ogundele, A. Forrest, J. Wilton, K. Salzwedel, J. Doto, G. P.
Allaway, and D. E. Martin, "Phase I and II study of the safety, virologic effect, and pharmacokinetics/pharmacodynamics of single-dose 3-0-(3,3'-dimethylsuccinyl) betulinic acid (bevirimat) against human immunodeficiency virus infection", Antimacrob. Agents Chemother. 2007, 51, 3574-3581;
3) Baichwal, V., H. Austin, B. Brown, R. McKinnon, K. Yager, V. Kumar, D. Gerrish, M. Anderson, and R. Carlson, "Anti-viral characterization in vitro of anovel maturation inhibitor, MPC-9055," 2009, Poster 561, 16th Conf. Retrovir. Opport. Infect., Montreal, Canada;
4) Beelen, A., J. Otto, M. Fidler, E. Sanguinetti, P. Smiley, A. Balch, M. Medlock, M.
Jackson, and E. Swabb, "Phase- 1 single ascending oral dose study of the safety, tolerability, and pharmacokinetics of a novel HIV-1 maturation inhibitor in HIV negative, healthy volunteers", 2009, Poster 570, 16th Conf. Retrovir. Opport. Infect., Montreal, Canada;
5) Li, F., R. Goila-Gaur, K. Salzwedel, N. R. Kilgore, M. Reddick, C. Matallana, A.
Castillo, D. Zoumplis, D. E. Martin, J. M. Orenstein, G. P. Allaway, E. O. Freed, and C. T. Wild, "PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing", 2003, Proc. Natl. Acad. Sci., USA 100, 13555-13560;
6) Martin, D., J. Jacobson, D. Schurmann, E. Osswald, J. Doto, C. Wild, and G. P.
Allaway, "PA-457: the first-in-class maturation inhibitor, exhibits antiviral activity ollowing a single oral dose in HIV-1 infected patients", 2005, Oral presentation 159, 12th Conf. Retrovir. Opport. Infect., Boston, MA, USA;
7) Ganser-Pornillos, B. K., Cheng, A., Yeager, M., Cell 2007, 131, 70;
8) Sundquist, W. I., Hill, P.C., Cell 2007, 131, 17;
9) Ternois, F.; Sticht, J., Duquerroy, S., Krausslich, H. G.; Rey, F. A., Nat. Struct. Mol.
Biol. 2005, 12, 678;
10) Tang, C, Loeliger, E., Kinde, I., Kyere, S., Mayo, K., Barklis, E., Sun, Y., Huang, M., Summers, M. F. J. Mol, Biol, 2003, 327, 1013;
11) Li, J., Tan, Z., Tang, S., Hewlett, I., Pang, R., He, M., He, S., Tian, B. Chen, K., Yang, M. Bioorg. Med. Chem. 2009, 17, 3177-3188;
12) Prevelige, P. Jr., "Small molecule inhibitors of HIV-1 capsid assembly", PCT Int.
Appl. 2007, WO2007048042A2; ) Yang, M., He, S., Yuan, D., "Preparation of phenylthiourea derivatives as capsid protein inhibitors for treatment of HIV", Faming Zhuanli Shenqing Gongkai Shuomingshu, 2006, CN1793120A;
) Summers, M. F., Agarwal, A., Chen, X., Deshpande, M. F. "Preparation of thiazole derevatives as inhibitors of HIV-1 capsid formation", U.S. Pat. Appl. Publ. 2006, US2006100232A1;
) Salzwedel, K., Li, F., Wild, C. T., AUaway, G. P., Freed, E. O., "Inhibition of HIV-1 replication by disruption of the processing of the viral capsid-spacer peptide 1 protein", PCT Int. Appl. 2005, WO2005113059 A2;
) Summers, M. F., Tang, C, Huang, M., "Antiviral inhibitions of capsid proteins", PCT Int. Appl. 2003, Wo2003089615A2;

Claims

We Claim:
1. A compound of formula I:
Figure imgf000166_0001
or a pharmaceutically acceptable salt thereof, wherein:
W is optionally substituted 8-10 membered bicyclic carbocycle or heterocycle;
each of Ri and R2 is independently H, (Ci-C4)alkyl, hydroxyl, fluoro, or NRbRc, or Ri and R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl;
R3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
R4 is H, (Ci-C4)alkyl, substituted (Ci-C4)alkyl, (C3-Cv)cycloalkyl, or substituted
(C3-C7)cycloalkyl;
R5 is (CR8R9)q-cycloalkyl, (CR8R9)q-substituted cycloalkyl, (CRgR9)q-aryl, (CRgRg substituted aryl, (CR8R9)q-heterocycle, or (CRgR9)q-substituted heterocycle;
each of Rg and R9 is independently H, (Ci-C4)alkyl, hydroxyl, fluoro, or NRbRc, or Ri and R2 together form (C3-C5)cycloalkyl, or substituted (C3-C5)cycloalkyl; each of Rb and Rc 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.
2. The compound of claim 1, wherein W is selected from:
Figure imgf000166_0002
Figure imgf000167_0001
wherein:
II II I
zi in Formula (la) and (lb) denotes ¾ or zi ;
= in Formula (Id) denotes a double bond or single bond;
each of Zl s Z2, Z3, Z4, Z5, Z6, Z7, Z8, and Z9 is independently carbon or nitrogen, provided that at least one of Z5, Z6, Z7 and Zg is carbon;
each of Xi, X2, X3, X4, X5, X6, X7, and X8 is independently carbon or nitrogen, provided that at least one of Xi, X2, X3, and X4 is carbon, and at least one of X5, X6, X7, and Xg is carbon;
J is nitrogen or carbon;
L is nitrogen or oxygen;
Q is sulfur or oxygen;
each of Ri and R2 is independently H or (Ci-C4)alkyl;
R3 is phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
R4 is H, (Ci-C4)alkyl, substituted (Ci-C4)alkyl, (C3-C7)cycloalkyl, or substituted
(C3-C7)cycloalkyl;
R5 is (CRgR9)q-cycloalkyl, (CRgR9)q-substituted cycloalkyl, (CRgRg)q-aryl, (CRgRg)q- substituted aryl, (CRgR9)q-heteroaryl, or (CRgRc))q-substituted heteroaryl;
each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclyl or substituted heterocyclyl, aryl or substituted aryl, ORa, SRa, S(=0)Ra, S(=0)2Ra, S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra,
Figure imgf000167_0002
NRbC(=0)ORa, NRaC(=0)NRbRc, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q- cycloalkyl or (CR8R9)q-substituted cycloalkyl, (CR8R9)q-phenyl or (CR8R9)q-substituted phenyl, or (CR8R9)q-heteroaryl or (CR8R9)q-substituted heteroaryl;
each R7 is independently hydrogen, halogen, cyano, nitro, azide, CF3, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclyl or substituted heterocyclyl, aryl or substituted aryl, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc,
(CR8R9)q-C(=0)NRbRe, (CR8R9)q-NRbC(=0)Ra, (CR8R9)q-S02NRbRc, (CR8R9)q-S02Ra, (CH2)q-cycloalkyl or (CR8R9)q-substituted cycloalkyl, (CR8R9)q-phenyl or (CR8R9)q- substituted phenyl, or (CR8R9)q-heteroaryl or (CR8R9)q-substituted heteroaryl;
each of R8 and R9 is independently H or (Ci-C4)alkyl;
each occurrence of Ra, Rb, and Rc 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 Rb and Rc together with the N to which they are bonded optionally form a heterocycle or substituted heterocycle;
m and q are each independently 0, 1, 2, 3, or 4;
n is 1 or 2; and
p is 0, 1, 2 or 3.
3. The compound of claim 1 or 2, having the structure of Formula (II):
Figure imgf000168_0001
wherein W, Ri, R2, R3, R4, and R5 are as defined in claim 1 or 2.
4. The compound of claim 2, having the structure of Formula (III):
Figure imgf000168_0002
wherein Zls Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Rls R2, R3, R4, R5, Re, R7, m and p are as defined in claim 2.
5. The compound of claim 2, having the structure of Formula (IV):
Figure imgf000169_0001
wherein Zls Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Rls R2, R3, R4, R5, Re, R7, and p are as defined in claim 2, and m is 0, 1, 2, or 3.
6. The compound of claim 2, having the structure of Formula (V):
Figure imgf000169_0002
wherein Zls Z2, Z3, Ri, R2, R3, R4, R5, R6, R7, and p are as defined in claim 2, and m is 0, 1, 2, or 3.
7. The compound of claim 2, having the structure of Formula (VI):
Figure imgf000169_0003
wherein Rls R2, R3, R4, R5, R6, R7 and p are as defined in claim 2, and m is 1, 2, or 3.
8. The compound of claim 2, having the structure of Formula (Via):
Figure imgf000169_0004
wherein Rls R2, R3, R4, R5, R6, and R7 are as defined in claim 2; and m is 1, 2, or 3.
9. The compound of claim 2, having the structure of Formula (VII):
Figure imgf000170_0001
wherein Zls Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Rls R2, R3, R4, R5, R6, R7, m and p are as defined in claim 2.
10. The compound of claim 2, having the structure of Formula (VIII):
Figure imgf000170_0002
wherein Z2, Z3, Z5, Z6, Z7, Z8, Rls R2, R3, R4, R5, R6, R7, and m are as defined in claim 2, and p is 1 or 2.
11. The compound of claim 2, having the structure of Formula (IX):
Figure imgf000170_0003
wherein Z5, Z6, Z7, Z8, Rls R2, R3, R4, R5, R6, R7, and m are as defined in claim 2, and p is 1 or 2.
12. The compound of claim 2, having the structure of Formula (X):
Figure imgf000170_0004
wherein Rls R2, R3, R4, R5, 5, R7, and m are as defined in claim 2, and p is 1 or 2.
13. The compound of claim 2, having the structure of Formula (Xa):
Figure imgf000171_0001
wherein Rl s R2, R3, R4, R5, R5, R7, and m are as defined in claim 2.
14. The compound of claim 2, having the structure of Formula (XI):
Figure imgf000171_0002
wherein Z5, Z6, Z7, Zg, Ri, R2, R3, R4, R5, R5, R7, and m are as defined in claim 2, and p is 1 or 2.
15. The compound of claim 2, having the structure of Formula (XII):
Figure imgf000171_0003
wherein Rl s R2, R3, R4, R5, R5, R7, and m are as defined in claim 2, and p is 1 or 2.
16. The compound of claim 2, having the structure of Formula (XIII):
Figure imgf000171_0004
(xiii), wherein Ri, R2, R3, R4, R5, R;, R7, and m are as defined in claim 2.
17. The compound of claim 2, having the structure of Formula (XIV):
Figure imgf000172_0001
wherein Z5, Z6, Z7, Z8, Ri, R2, R3, R4, R5, Re, R7, and m are as defined in claim 2. 18. The compound of claim 2, having the structure of Formula (XV):
Figure imgf000172_0002
wherein Rls R2, R3, R4, R5, Re, R7, and m are as defined in claim 2.
19. The compound of claim 2, having the structure of Formula (XVI):
Figure imgf000172_0003
wherein Z5, Z6, Z7, Z8, Rls R2, R3, R4, R5, R6, R7, and m are as defined in claim 2. 20. The compound of claim 2, having the structure of Formula (XVII):
Figure imgf000172_0004
wherein Rls R2, R3, R4, R5, Re, R7, and m are as defined in claim 2.
21. The compound of claim 2, having the structure of Formula (XVIII):
Figure imgf000172_0005
(XVIII), wherein Rls R2, R3, R4, R5, Re, R7, and m are as defined in claim 2.
22. The compound of any one of claims 1-21, wherein each of Ri and R2 is independently H.
23. The compound of any one of claims 1-22, wherein R3 is phenyl.
24. The compound of any one of claims 1-22, wherein R3 is substituted phenyl.
25. The compound of any one of claims 1-22, wherein R3 is heteroaryl.
26. The compound of any one of claims 1-22, wherein R3 is substituted heteroaryl.
27. The compound of any one of claims 1-22, wherein R3 is pyridyl.
28. The compound of any one of claims 1-22, wherein R3 is substituted pyridyl.
29. The compound of any one of claims 1-28, wherein R4 is H.
30. The compound of any one of claims 1-28, wherein R4 is (Ci-C4)alkyl.
31. The compound of any one of claims 1-28, wherein R4 is methyl.
32. The compound of any one of claims 1-31, wherein R5 is (CH2)q-cycloalkyl, (CH2)q- substituted cycloalkyl, (CH2)q-aryl, (CH2)q-substituted aryl, (CH2)q-heteroaryl, or (CH2)q- substituted heteroaryl, in which q is 0 or 1.
33. The compound of any one of claims 1-32, wherein R5 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
34. The compound of any one of claims 1-33, wherein R5 is phenyl or substituted phenyl.
35. The compound of any one of claims 1-33, wherein R5 is pyridyl or substituted pyridyl.
36. The compound of any one of claims 1-32, wherein:
R5 is aryl or heteroaryl optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cy)cycloalkyl, (C3-Cy)cycloalkenyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, ORa, SRa, S(=0)Ra, S(=0)2Ra, S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra,
C(=0)NRbRc, OC(=0)Ra,
Figure imgf000173_0001
NRbC(=0)ORa, NRaC(=0)NRbRc, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-cycloalkyl, (CR8R9)q- phenyl, and (CR8R9)q-heteroaryl;
each of R8 and R9 is independently H or (Ci-C4)alkyl;
each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-Cy)cycloalkyl, (C3-Cy)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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.
37. The compound of any one of claims 1-32, wherein:
R5 is phenyl or heteroaryl selected from thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, l,2,4-oxadiazol-5-yl, benzo[d][l,3]dioxolyl, benzoimidazolyl, quinolinyl, quinoxalinyl, quinazolinyl, [1 ,2,4]triazolo[l ,5-a]pyridinyl, [1 ,2,4]triazolo[4,3-a]pyridin-7-yl, benzo[<i]oxazol-5-yl, imidazo[l,2-¾]pyridazin-6-yl, imidazo[l,2-a]pyridin-3-yl, phthalazinyl, and cinnolinyl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3-C7)cycloalkyl, (Ci- C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q-heteroaryl;
each occurrence of Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
38. The compound of any one of claims 2-37, wherein: each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, ORa, SRa, S(=0)Ra, S(=0)2Ra, S(=0)2ORa, NRbRc, C(=0)ORa, C(=0)Ra, C(=0)NRbRc, OC(=0)Ra,
Figure imgf000175_0001
NRbC(=0)ORa, NRaC(=0)NRbRc, NRbC(=0)Ra, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-cycloalkyl, (CR8R9)q- phenyl, or (CR8R9)q-heteroaryl;
each of R8 and R9 is independently H or (Ci-C4)alkyl;
each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (C3-Cy)cycloalkyl, (C3-Cy)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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.
39. The compound of any one of claims 2-37, wherein: each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- Cy)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl;
each occurrence of Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3-C7)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 Rc 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.
40. The compound of any one of claims 2-39, wherein: each R7 is independently halogen, cyano, nitro, azide, CF3, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, (CR8R9)q-OH, (CR8R9)q-0-(Ci-C4)alkyl, (CR8R9)q-NRbRc, (CR8R9)q-NRbC(=0)Ra, (CH2)q-cycloalkyl, (CR8R9)q-phenyl, or (CR8R9)q- heteroaryl, wherein said alkyl is optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc,
C(=0)NRbRc, C(=0)Ra, C(=0)ORa, and OH; each of R8 and R9 is independently H or (Ci-C4)alkyl; each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (C3-Cy)cycloalkyl, (C3-Cy)cycloalkenyl, heterocycle, or aryl, or said Rb and Rc 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.
41. The compound of any one of claims 2-39, wherein: each R7 is independently hydrogen, halogen, cyano, nitro, azide, CF3, (Ci-C4)alkyl, (C2- C6)alkenyl, (C3-Cy)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, or aryl, (CH2)q-OH, (Ci-C4)alkyl substituted by one or two OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-NRbC(=0)Ra, (CH2)q-(C3-Cy)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl, wherein said (Ci-C4)alkyl is optionally substituted with one to two substituents selected from phenyl, halogen, (Ci- C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc, C(=0)NRbRc, C(=0)Ra, C(=0)ORa, and OH;
each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3- Cy)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 Rc 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.
42. The compound of any one of claims 2-39, wherein each Ry is independently (Ci- C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc, C(=0)NRbRc, C(=0)Ra,
C(=0)ORa, and OH.
43. The compound of any one of claims 2-39, wherein each Ry is independently
(CR8R9)2-NRbC(=0)Ra, in which each of R8 and R9 is independently H or (Ci-C4)alkyl; and each occurrence of Ra and Rb is independently hydrogen, (Ci-C4)alkyl, (C3-Cy)cycloalkyl, aryl, or 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S. The compound of claim 1 , having the structure of formula (Xb)
Figure imgf000177_0001
wherein R3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF3, OCF3, (Ci-C4)alkyl, or (C C4)alkoxy;
R4 is H or (Ci-C4)alkyl;
R5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- 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, (CH2)q-OH, (CH2)q-0- (Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q- heteroaryl; each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl;
R7a is hydrogen, or (Ci-C4)alkyl;
R7b is hydrogen, or (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc,
C(=0)NRbRc, C(=0)Ra, C(=0)ORa, OH, or 3-10-membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S (e.g., pyridyl); each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3- C7)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 Rc 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.
45. The compound of claim 1, having the structure of formula (Xllla):
Figure imgf000178_0001
(Xllla) wherein R3 is phenyl or pyridyl optionally substituted by halogen, cyano, nitro, azide, CF3, OCF3, (Ci-C4)alkyl, or (Ci-C4)alkoxy;
R4 is H or (Ci-C4)alkyl;
R5 is phenyl or heteroaryl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0- (Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, and (CH2)q- heteroaryl; each R6 is independently hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3- C7)cycloalkyl, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-C7)cycloalkyl, (CH2)q-phenyl, or (CH2)q-heteroaryl;
R7a is hydrogen, or (Ci-C4)alkyl;
R7b is hydrogen, or (Ci-C4)alkyl optionally substituted with one to two substituents selected from phenyl, halogen, (Ci-C4)alkoxy, (C2-C6)alkenyl, (C3-C7)cycloalkyl, NRbRc,
C(=0)NRbRc, C(=0)Ra, C(=0)ORa, OH, or 3-10-membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S (e.g., pyridyl); each occurrence of Ra, Rb, and Rc is independently hydrogen, (Ci-C4)alkyl, (C3- Cy)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 Rc 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.
46. The compound of claim 44 or 45, wherein R5 is phenyl or heteroaryl selected from thiophenyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, l,2,4-oxadiazol-5-yl, benzo[d][l,3]dioxolyl, benzoimidazolyl, quinolinyl, quinoxalinyl, quinazolinyl,
[l,2,4]triazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridin-7-yl, benzo[<i]oxazol-5-yl, imidazo[l,2-¾]pyridazin-6-yl, imidazo[l,2-a]pyridin-3-yl, phthalazinyl, and cinnolinyl, each of which is optionally substituted with one to four substituents selected from hydrogen, halogen, cyano, nitro, CF3, OCF3, (Ci-C4)alkyl, (C3-Cv)cycloalkyl, (Ci-C4)alkoxy, 3-10 membered monocyclic or bicyclic heterocycle containing at least one heteroatom selected from N, O and S, phenyl, naphthyl, (CH2)q-OH, (CH2)q-0-(Ci-C4)alkyl, (CH2)q-NRbRc, (CH2)q-(C3-Cy)cycloalkyl, (CH2)q-phenyl, and (CH2)q-heteroaryl.
47. The compound of any one of claims 2-46, wherein R6 is hydrogen, halogen or (Ci- C4)alkyl.
48. The compound of any one of claims 2-47, wherein: each occurrence of Rb, and Rc is independently hydrogen or (Ci-C4)alkyl, or said Rb and Rc 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.
49. A compound selected from Examples 1 through 258.
50. A pharmaceutical composition comprising at least one compound according to any one of claims 1-49 and a pharmaceutically-acceptable carrier or diluent.
51. 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 according to any one of claims 1-49.
52. 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 according to any one of claims 1-49.
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